Clinical Review for the USMLE Step 1
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Clinical Review for the USMLE Step 1 EDITORS Sapan S. Desai, M.D., Ph.D. Assistant Professor Department of Surgery Duke University Medical Center Durham, North Carolina
Danny O. Jacobs, M.D., M.P.H. Professor and Chair Department of Surgery Duke University Medical Center Durham, North Carolina
Clinical Review for the USMLE Step 1 Edited by Sapan S. Desai, MD, PhD and Danny O. Jacobs, MD, MPH Copyright ÂŠ 2012 Surgisphere Corporation, All Rights Reserved. www.ClinicalReview.com | www.CatalystPublishers.com | www.Surgisphere.com Prepared in the United States of America
This title is published by Catalyst Publishers in association with the Surgisphere Corporation, 4706 Carmen Lane, Durham, NC 27707. No part of this book may be reproduced in any form or by any means, mechanical or electronic, including photocopying, recording, electronic storage, virtual or actual without written permission from the Surgisphere Corporation. You may not alter or remove any notice of copyright or ownership from this content. Surgisphere and the Surgisphere logo are trademarks of the Surgisphere Corporation. The Catalyst Publishers logo is a trademark of Catalyst Publishers. Various images within this text are used under various versions of the Creative Commons license. Credit is provided in all instances the original author can be identified. Images contained are used with permission; if a particular image is not referenced or used appropriately, please contact us so that the appropriate arrangements can be made. While every precaution has been taken in the preparation of this textbook, the authors, editors, Catalyst Publishers, and the Surgisphere Corporation assume no responsibility for errors, omissions, or damages arising from the use of the information contained herein.
Clinical Review for the USMLE Step 1
1. Medicine 2. Exam Preparation
I. Surgisphere Corporation
01 / 10 9 8 7 6 5 4 3 2
II. Clinical Review for the USMLE Step 1
For Eashan Desai
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There is a single light of science, and to brighten it anywhere is to brighten it everywhere. Isaac Asimov
he United States Medical Licensing Examination is taken throughout the year by medical students and residents around the country. It is used by residency programs as one measure of the caliber of potential candidates and is required to become a physician eligible to practice medicine.1 Poor performance on the USMLE is likely to adversely affect your application for residency, may limit the opportunities available for you in career selection, and jeopardizes your medical career.
This textbook and its accompanying online course were created to improve the quality of medical education and thereby help to improve the quality of care our patients receive. While there can be no substitute for studying the reference textbooks in the field, there are numerous moments during medical school and residency to quickly review and understand high-yield topics. The focus of this program is to provide a high-yield review of topics commonly tested on the USMLE. This material is derived from the major medical reference textbooks and covers topics that have appeared on recent USMLE examinations. The overall organization of this textbook reflects the content outline produced by the FSMB and NBME to ensure that every subject area is given due consideration. Students and residents who have used this program in recent years have reported scores in the top 1% across the world. The online program available last year was used by medical students from nearly every medical school around the world, and residents from nearly every residency program across the nation.2 Based on their feedback and our proven approach to education, this is our solution for preparing for the USMLE.
Sapan S. Desai, MD, PhD
Assistant Professor of Surgery Duke University Medical Center Executive Editor Journal of Surgical Radiology Chief Executive Officer Surgisphere Corporation
Residency programs use the USMLE score as one element in selecting residents during the match. Poor scores mitigate the opportunity for competitive specialties and for joining top-tier residency programs. Poor performance may even prevent the ability to become a certified medical practitioner. Students around the world and residents around the United States used this review program from 20062011 to prepare for the USMLE.
Copyright MedicalRf.com. Used with permission. I will pass over the other arts in silence and direct my words for a while to that which is responsible for the health of mankind; certainly of all the arts that human genius has discovered, this is by far the most useful, indispensible, difficult, and laborious. Andreas Vesalius De Humani Corporus Fabrica, 1543
Foreword..................................................................... vi Contents..................................................................... viii Contributors................................................................ xx Introduction.............................................................. xxiv 1. Overview of Topics.............................................................................. 1 2. Organization of Text............................................................................ 1 3. Study Plan.......................................................................................... 1 4. Feedback........................................................................................... 2
General Principles........................................................... 4 1. Introduction......................................................................................... 5 2. Biochemistry and Molecular Biology....................................................... 5 2.1.
Gene Expression..................................................................... 5
Protein and Enzyme Structure and Function............................... 13
Energy Metabolism................................................................ 15
2.4. Biochemical Disorders............................................................ 20
3. Biology of Cells................................................................................. 24 3.1.
Adaptive Cell Responses and Cellular Homeostasis.................... 24
Mechanisms of Injury and Necrosis.......................................... 25
3.3. Apoptosis............................................................................. 26 3.4.
Mechanisms of Dysregulation.................................................. 26
Cell Structure and Function..................................................... 31
Growth Factors..................................................................... 37
4. Human Development and Genetics.......................................................38 4.1.
Pedigree Analysis.................................................................. 38
Population Genetics............................................................... 39
Gene Therapy....................................................................... 40
4.4. Genetic Testing and Counseling............................................... 40
5. Inflammation and Repair......................................................................42 5.1. Fever................................................................................... 42 5.2.
Systemic Inflammatory Response Syndrome............................... 43
5.3. Sepsis.................................................................................. 44 ix
Clinical Review for the USMLE Step 1 5.4. Shock.................................................................................. 45 5.5. Wound Healing.................................................................... 46
6. Psychology........................................................................................47 6.1.
Life Cycle............................................................................. 47
Theories of Development........................................................ 50
Coping Mechanisms.............................................................. 53
6.4. Conditioning and Patient Adherence........................................ 57 6.5.
Patient Interviewing and Challenging Situations.......................... 59
6.6. Medical Ethics...................................................................... 61
7. Fluid, Electrolytes, Nutrition, and Acid-Base........................................... 66 7.1.
Electrolyte Disturbances.......................................................... 66
7.2. Nutrition............................................................................... 70 7.3. Acid-Base............................................................................. 75 7.4. Fluids................................................................................... 77 7.5.
Metabolic Disorders............................................................... 78
8. Pharmacology................................................................................... 80 8.1. Pharmacokinetics................................................................... 80 8.2. Pharmacodynamics................................................................ 81 8.3.
Efficacy and Potency.............................................................. 82
8.4. Drug Development................................................................. 82
9. Microbiology.....................................................................................82 9.1. Bacteria............................................................................... 82 9.2. Organisms............................................................................ 86 9.3. Antimicrobials....................................................................... 90 9.4. Fungus................................................................................. 94 9.5. Virus.................................................................................... 96 9.6. Parasites............................................................................... 99 9.7.
Common Infections.............................................................. 100
10. Biostatistics.....................................................................................102 10.1. Introduction........................................................................ 102 10.2. Descriptive Statistics............................................................. 102 10.3. Measures of Central Tendency: Mean, Median, and Mode....... 103 10.4. Measures of Spread: Range, variance and Standard Deviation.. 103 10.5. Normal Distributions............................................................ 104 x
10.6. Skewed Distributions............................................................ 104 10.7. Estimation and Bias.............................................................. 105 10.8. Hypothesis Testing............................................................... 107 10.9. Tests of Significance............................................................. 109 10.10. Study Designs and Measures of Association............................. 111 10.11. Measures of Associations Between Two Binary Variables ..........112 10.12. Diagnostic Tests....................................................................114
Hematology. ..............................................................116 1. Basic Science................................................................................... 117 1.1. Embryology.........................................................................117 1.2.
Developmental Structure and Function.....................................117
1.3. Erythrocytes.........................................................................117 1.4. Platelets............................................................................. 120 1.5. Coagulation....................................................................... 120 1.6.
Overview of Hemostasis ...................................................... 124
2. Hematologic Disorders...................................................................... 126 2.1.
Preoperative Assessment....................................................... 126
Approach to The Bleeding Patient.......................................... 126
Acquired Bleeding Disorders................................................. 127
2.4. Dilutional Coagulopathy .......................................................131 2.5.
Venous Thromboembolism..................................................... 132
2.7. Anemias............................................................................. 133 2.8.
Transfusion Reactions........................................................... 139
Other Red Blood Cell Conditions........................................... 140
2.10. Platelets and Coagulation......................................................141
3. Pharmacology and Treatment.............................................................143 3.1.
Anticoagulants and Hemostatic Agents................................... 143
Blood Products.................................................................... 143
Jehovah’s Witnesses............................................................ 146
CNS & PNS............................................................. 148 1. Introduction......................................................................................149 xi
Clinical Review for the USMLE Step 1 2. Embryology.....................................................................................149 2.1. Embryogenesis.................................................................... 149 2.2.
Embryologic Tissue Derivatives.............................................. 150
Branchial Apparatus............................................................ 150
2.4. Twins................................................................................. 152 2.5.
Neural Plate and Neural Tube............................................... 152
Development of the Inner Ear................................................ 154
Development of the Eye........................................................ 155
3. Anatomy.........................................................................................155 3.1.
Vascular Supply to the Head and Neck.................................. 155
Vascular Supply to the Upper Extremity.................................. 158
Vascular Supply to the Abdomen and Pelvis............................ 160
Vascular Supply to the Lower Extremity....................................161
3.5. Cranial Nerves................................................................... 163 3.6.
Brain Nuclei....................................................................... 169
Triangles of the Neck........................................................... 177
3.8. Innervation......................................................................... 179
4. Physiology.......................................................................................184 4.1. Neurons............................................................................. 184 4.2.
Supporting Cells.................................................................. 186
Brain Death........................................................................ 186
4.4. Peripheral Vascular Resistance............................................... 186 4.5. Autoregulation.................................................................... 187 4.6.
Venous Hemodynamics........................................................ 187
Respiratory Flow Variation.................................................... 187
4.8. Vasoactive Mediators........................................................... 188 4.9.
Cerebral Perfusion Pressure................................................... 188
5. CNS and PNS Pathology...................................................................189 5.1.
Spinal Cord Pathology......................................................... 189
Sensory Disturbances........................................................... 199
Infectious Diseases............................................................... 201
Neurodegenerative Disorders................................................ 203
Sleep Disorders................................................................... 207
5.7. Epilepsy............................................................................. 208 5.8. Cancer.............................................................................. 209 xii
Salivary Gland Tumors..........................................................210
6. Psychopathology.............................................................................. 211 6.1.
6.4. Cognitive Disorders...............................................................217 6.5.
Somatoform Disorders.......................................................... 220
Malingering and Factitious Disorders...................................... 221
Personality Disorders............................................................ 221
Substance Abuse Disorders................................................... 224
7. Pharmacology..................................................................................230 7.1.
Cholinergic Agents.............................................................. 230
Adrenergic Agents............................................................... 231
Serotoninergic Agents.......................................................... 233
7.4. Toxicology.......................................................................... 233 7.5. Anticonvulsants................................................................... 236 7.6.
Cognitive Agents................................................................. 236
7.7. Anesthetics......................................................................... 237 7.8. Analgesics.......................................................................... 238 7.9. Antipsychotics..................................................................... 239 7.10. Antidepressants................................................................... 242 7.11. Mood Stabilizers................................................................. 246 7.12. Anxiolytics.......................................................................... 249 7.13. Other Medications............................................................... 251 7.14. Major Adverse Drug Effects.................................................. 251
Skin & Soft Tissue...................................................... 254 1. Introduction......................................................................................255 2. Basic Science...................................................................................255 2.1. Anatomy............................................................................ 255 2.2. Embryology........................................................................ 256 2.3.
Repair and Regeneration...................................................... 256
2.4. Scar Formation.................................................................... 258
3. Pathology........................................................................................258 xiii
Clinical Review for the USMLE Step 1 3.1.
Infectious and Inflammatory Disorders.................................... 258
3.2. Trauma.............................................................................. 270 3.3. Cancer.............................................................................. 275 3.4.
Soft Tissue Tumors............................................................... 278
Musculoskeletal. ........................................................ 280 1. Basic Science................................................................................... 281 1.1.
Embryology and Histology.................................................... 281
1.2. Physiology.......................................................................... 281
2. Pathology........................................................................................284 2.1.
Anatomic Disorders............................................................. 284
Metabolic Bone Diseases...................................................... 290
Inflammatory and Infectious Disorders.................................... 292
2.4. Cancer.............................................................................. 300
Respiratory. ............................................................... 304 1. Basic Science...................................................................................305 1.1. Anatomy............................................................................ 305 1.2. Physiology.......................................................................... 305
2. Pathology........................................................................................307 2.1.
Congenital and Structural..................................................... 307
Inflammatory and Infectious...................................................319
2.3. Vascular............................................................................. 326 2.4. Trauma.............................................................................. 327 2.5. Cancer.............................................................................. 329
3. Pharmacology..................................................................................334 3.1.
Endotracheal Intubation........................................................ 335
Cardiovascular.......................................................... 340 1. Introduction......................................................................................341 2. Epidemiology...................................................................................341 2.1.
Causes of Death.................................................................. 341
2.2. Preventive Medicine............................................................. 341 2.3. xiv
Use of Tests........................................................................ 342
2.4. Routine Screening................................................................ 342 2.5.
Cancer Screening................................................................ 342
3. Basic Science.................................................................................. 344 3.1. Embryology........................................................................ 344 3.2. Anatomy............................................................................ 344 3.3. Physiology.......................................................................... 346 3.4.
Vasoactive Mediators........................................................... 350
4. Pathology........................................................................................351 4.1.
Basic Topics........................................................................ 351
Congenital Heart Defects...................................................... 353
Coronary Heart Disease....................................................... 354
4.4. Valvular Heart Disease......................................................... 365 4.5. Cardiomyopathy................................................................. 371 4.6. Pericardial Disease...............................................................374 4.7. Arrhythmia......................................................................... 378 4.8.
Aortic Diseases................................................................... 382
Vascular Disorders............................................................... 385
5. Pharmacology..................................................................................389 5.1. Nitrates.............................................................................. 389 5.2.
Adrenergic Agents and Antihypertensives............................... 389
5.3. ACE-Inhibitors..................................................................... 392 5.4. Aspirin............................................................................... 392 5.5. Heparin............................................................................. 392 5.6.
Streptokinase and Alteplase.................................................. 393
5.7. Digoxin.............................................................................. 393 5.8. Antihyperlipidemics.............................................................. 393 5.9. Antiarrhythmics................................................................... 395 5.10. Pressors and Inotropes......................................................... 396 5.11. Studies and Procedures........................................................ 397
Gastrointestinal......................................................... 400 1. Basic Science...................................................................................401 1.1. Embryology........................................................................ 401 1.2. Anatomy............................................................................ 401 1.3. Physiology...........................................................................412 xv
Clinical Review for the USMLE Step 1 2. Pathology........................................................................................ 421 2.1. Esophagus.......................................................................... 421 2.2. Stomach............................................................................. 430 2.3.
Small Intestine..................................................................... 437
2.4. Large Intestine..................................................................... 447 2.5.
Rectum and Anus................................................................. 466
Abdominal Wall.................................................................. 470
2.7. Liver.................................................................................. 475 2.8.
Biliary Disease.................................................................... 485
Pancreatic Disorders............................................................ 490
2.10. Spleen............................................................................... 495
Genitourinary............................................................ 500 1. Basic Science...................................................................................501 1.1. Embryology........................................................................ 501 1.2. Anatomy............................................................................ 502 1.3. Histology............................................................................ 502 1.4. Physiology.......................................................................... 502
2. Pathology........................................................................................507 2.1.
Renal Failure....................................................................... 507
Structural and Metabolic Disorders......................................... 508
2.4. Inflammatory and Metabolic Disorders....................................515 2.5.
Glomerular and Nephrotic Disease.........................................516
Infectious Diseases............................................................... 520
Sexually-Transmitted Diseases................................................ 523
2.8. Trauma.............................................................................. 528 2.9. Cancer.............................................................................. 528
Reproductive.............................................................. 534 1. Basic Science...................................................................................535 1.1. Embryology........................................................................ 535 1.2. Gametogenesis................................................................... 535 1.3. Anatomy............................................................................ 536 xvi
1.4. Physiology.......................................................................... 537
2. Fetal / Neonatal Pathology................................................................553 2.1.
General Concepts............................................................... 553
Genetic Disorders................................................................ 554
Disorders of the Chest.......................................................... 557
2.4. Disorders of the Abdomen.................................................... 561 2.5.
Hepatobiliary Disease.......................................................... 565
Pediatric Tumors.................................................................. 566
3. Breast Pathology...............................................................................567 3.1.
Diagnostic Imaging.............................................................. 567
Benign Breast Disease.......................................................... 569
Malignant Breast Disease..................................................... 570
4. Gynecology.....................................................................................573 4.1.
Ovarian Disease................................................................. 573
Cervical, Uterine, and Vaginal Disease................................... 577
5. Pharmacology..................................................................................582 5.1.
Steroid Hormones................................................................ 582
Endocrine................................................................. 584 1. Basic Science...................................................................................585 1.1. Anatomy............................................................................ 585 1.2. Physiology.......................................................................... 588 1.3.
Diagnostic Studies............................................................... 590
2. Pathology........................................................................................ 591 2.1.
Hypothalamus and Pituitary.................................................. 591
2.2. Thyroid.............................................................................. 593 2.3. Parathyroid......................................................................... 598 2.4. Adrenal Gland.................................................................... 601 2.5. Pancreas............................................................................ 606 2.6.
Multiple Endocrine Neoplasia................................................612
3. Pharmacology.................................................................................. 613 3.1. Diabetes.............................................................................613 3.2.
Hormonal Agents and Corticosteroids.....................................614
Clinical Review for the USMLE Step 1
Immune System............................................................616 1. Basic Science................................................................................... 617 1.1. Immunization.......................................................................617 1.2.
General Concepts in Immunology...........................................618
Immune-Mediated Pathology................................................. 631
2. Oncology........................................................................................637 2.1. Pathology........................................................................... 637 2.2. Pharmacology..................................................................... 645
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Surgisphere is grateful for the contributions of more than 40 authors to the Clinical Review Series over the past several years. Adaptations of their contributions are used in this textbook.
Gowthami Arepally, MD, PhD
William Eward, DVM, MD
Associate Professor of Hematology Department of Medicine Duke University Medical Center
Resident Department of Surgery Duke University Medical Center
Ali Azizzadeh, MD
Jackie Garonzik, MD
Associate Professor Department of Surgery University of Texas at Houston
Resident Department of Surgery Johns Hopkins University
Tara Brennan, MD
Prateek K. Gupta, MD
Resident Department of Ophthalmology University of Illinois
Resident Department of Surgery Creighton University
Johnny T. Chang, MD
John W. Hallett, MD
Resident Department of Surgery Brown University
Professor Department of Surgery University of South Carolina
Mani Daneshmand, MD
Joseph P. Hart, MD
Resident Department of Surgery Duke University Medical Center
Assistant Professor Department of Surgery University of South Carolina
Melissa Danko, MD
Jeff Hoehner, MD, PhD
Resident Department of Surgery Duke University Medical Center
Associate Professor Department of Surgery Duke University Medical Center
Niketa Desai, PharmD
G. Chad Hughes, MD
Pharmacist Department of Pharmacology Long Island University
Associate Professor Department of Surgery Duke University Medical Center
Sapan S. Desai, MD, PhD
Danny O. Jacobs, MD, MPH
Assistant Professor Department of Surgery Duke University Medical Center
Professor and Chair Department of Surgery Duke University Medical Center
Amahuaro Edebiri, MD
Issam Koleilat, MD
Professor and Chair Department of Obstetrics & Gynecology Bayero University
Resident Department of Surgery Albany Medical College
Clinical Review for the USMLE Step 1
Michael Lidsky, MD
Leontine Narcisse, MD, PhD
Resident Department of Surgery Duke University Medical Center
Fellow Department of Surgery Westchester Medical Center
Keri E. Lunsford, MD, PhD
Theodore Pappas, MD
Resident Department of Surgery Duke University Medical Center
Professor Department of Surgery Duke University Medical Center
Alice D. Ma, MD
Luigi Pascarella, MD
Associate Professor of Hematology Department of Medicine Duke University Medical Center
Resident Department of Surgery Duke University Medical Center
Jerimiah Mason, MD
David A. Peterson, MD
Resident Department of Surgery Baptist Medical Center
Fellow Department of Surgery Duke University Medical Center
Stephanie Mayer, MD
Scott K. Pruitt, MD, PhD
Resident Department of Surgery Duke University Medical Center
Associate Professor Department of Surgery Duke University Medical Center
Richard L. McCann, MD
Elaheh Rahbar, PhD
Professor Department of Surgery Duke University Medical Center
Professor Department of Surgery University of Texas at Houston
Eric Mowatt-Larssen, MD
Mohammad Hossein Rahbar, PhD
Assistant Professor Department of Surgery Duke University Medical Center
Professor and Director Dept of Epidemiology & Biostatistics University of Texas at Houston
Daniel Murariu, MD
Randall Scheri, MD
Resident Department of Surgery University of Hawaii
Assistant Professor Department of Surgery Duke University Medical Center
Charles Murphy, MD
Mark Shapiro, MD
Assistant Professor Department of Surgery Duke University Medical Center
Associate Professor Department of Surgery Duke University Medical Center
Tamarah Westmoreland, MD, PhD
Professor Department of Surgery Duke University Medical Center
Resident Department of Surgery Duke University Medical Center
Suzanne Stewart, MD
Judson Williams, MD
Resident Department of Surgery Duke University Medical Center
Resident Department of Surgery Duke University Medical Center
Elisabeth Tracy, MD
Mark D. Williams, MD
Resident Department of Surgery Duke University Medical Center
Professor Department of Surgery St. Elizabeth Medical Center
Immanuel Turner, MD
Jocelyn Wittstein, MD
Resident Department of Surgery Duke University Medical Center
Resident Department of Surgery Duke University Medical Center
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Cynthia Shortell, MD
Copyright MedicalRf.com. Used with permission. The matter is already quite difficult enough, and I have no wish to make it even more obscure. Andreas Vesalius De Humani Corporus Fabrica, 1543
The United States Medical Licensing Examination Step 1 must be successfully passed in order to complete medical school and be eligible for a residency program. This examination tests your ability to apply basic medical and clinical topics to the practice of medicine. It covers a broad variety of topics from every major field of medicine with an emphasis on concepts that pertain to the practice of medicine. The Step 1 examination seeks to measure your basic science and clinical acumen, and ability to identify key principles regarding common medical diseases.
This textbook and the Comprehensive Review Course faithfully follow the content outline for the USMLE Step 1 Examination. This course covers essential topics in the clinical sciences that you are expected to master. High-yield topics are covered with an emphasis on understanding the key information. Every attempt is made to highlight material that is particularly important for the practice of medicine, and therefore more likely to appear on the boards. A subject-based approach is used in this textbook, with the first half of the book focused on basic science principles and the latter half focused on clinical principles. Appropriate emphasis is placed on basic science topics and clinical medicine topics, and this series is formulated specifically for the basic science and clinical topics that you are expected to master for the Step 1. Following most sections are pertinent questions to help you further your knowledge in additional areas while practicing what you have learned.
3. Study Plan How you study for the USMLE depends on how much time you have available. Motivated students and residents who prepare in advance will benefit the most from the online review program and the enormous body of information available on the website. Regardless of how much time you have available, this entire review program is designed to be done piecemeal using the short periods of time you have available on call nights and down time. Each topic is designed to be covered in just a few minutes, and many students report making good progress on the question bank by doing a few questions over lunch each day. Based on student feedback, our recommendation is to keep this book with you at all times. It is a handy book to go through whenever a few minutes are available. While each individual study plan will be different, there are a few trends that we have noticed with high scorers: 1.
Use this book in conjunction with the online questions and your existing reference books
Do questions and read through several topics every night starting at least a month in advance
Review the high-yield PowerPoint presentations at least a week in advance of your exam
Take note of your strengths and weaknesses and focus on them accordingly
Complete the entire Comprehensive Review Course
We recommend going through this resource in its entirety. Topics that have appeared on recent exams or more than once are marked by a star. In addition, topics that the reviewers have deemed to be particularly worthwhile are also highlighted. It is important to reiterate that the purpose of this book is to 1
Clinical Review for the USMLE Step 1 help you become a better doctor â€“ your score on this exam should reflect your mastery of basic science and clinical medicine. Students that are more pressed for time may want to take advantage of the High-Yield Topic section at the back of the textbook. This section highlights the most frequently tested material and is a good review of key facts. Organizing your study around this is a good way to start, but no comprehensive study plan is complete without a thorough review of practice questions and a chance to reinforce what you have learned. Take advantage of our Comprehensive Review Course to maximize your score and truly get closer to your potential. Use this textbook in conjunction with the Comprehensive Review Course at www.ClinicalReview.com. This will permit you to practice nearly 10,000 questions, review explanations, go through a detailed high-yield PowerPoint slide presentation, watch audio/video lectures, and access all of our textbooks online.
4. Feedback We are always searching for ways to improve our products. If you have any comments or suggestions, we would love to hear from you. Contact us at Support@ClinicalReview.com any time.
Sapan S. Desai, MD, PhD Assistant Professor of Surgery Duke University Medical Center Executive Editor Journal of Surgical Radiology Chief Executive Officer Surgisphere Corporation
Copyright MedicalRF.com. Used with permission.
Section Editors Sapan S. Desai, MD, PhD
Danny O. Jacobs, MD, MPH
Assistant Professor Department of Surgery Duke University Medical Center
Professor and Chair Department of Surgery Duke University Medical Center
Contributors Mohammad Hossein Rahbar, PhD
Elaheh Rahbar, PhD
Professor and Director Dept of Epidemiology & Biostatistics University of Texas at Houston
Professor Department of Surgery University of Texas at Houston
Eric Mowatt-Larssen, MD Assistant Professor Department of Surgery Duke University Medical Center Biostatistics (adapted from the Clinical Review of Phlebology and Venous Ultrasound)
Sapan S. Desai, MD, PhD
Mark D. Williams, MD
Assistant Professor Professor Department of Surgery Department of Surgery Duke University Medical Center St. Elizabeth Medical Center Surgical Critical Care (adapted from the Clinical Review of Surgery)
Scott K. Pruitt, MD, PhD
Tara Brennan, MD
Associate Professor Resident Department of Surgery Department of Ophthalmology Duke University Medical Center University of Illinois
Leontine Narcisse, MD, PhD
Jerimiah Mason, MD
Fellow Resident Department of Surgery Department of Surgery Westchester Medical Center Baptist Medical Center
Niketa Desai, PharmD Pharmacist Department of Pharmacology Long Island University Surgical Principles (adapted from the Clinical Review of Surgery)
1. Introduction The content outline produced by the National Board of Medical Examiners and Federation of State Medical Boards includes a hodgepodge of 10 topics under General Principles. Some of the topics are straightforward, such as the Biology of Cells and the Biology of Tissue Response to Disease. Others are more complex topics typically covered over a full year course in medical school, such as Biochemistry and Molecular Biology, Pharmacology, and Microbiology. The content outline serves as a rough basis for what the board deems is a topic that may appear on the USMLE. It is impossible for any review course to cover every topic that could appear on the exam - that is the purpose for reading the large textbooks and going to medical school. What we will focus on in this section are the high-yield topics loosely organized according to the USMLE content outline.
2.1. Gene Expression 2.1.1
As you have had repeatedly instilled within you since high school, DNA is a double helix composed of nucleotides. These four nucleotide bases are divided into purines (adenine and guanine) and pyrimidines (cytosine and thymine). Hydrogen bonds connect A to T and C to G - base pairs that are anchored along a 2-deoxyribose pentose sugar backbone that relies on phosphodiester bonds. DNA is transcribed into RNA (discussed below). If the sequence on the DNA strand is the same as the resulting mRNA copy that is created, that strand is called the â€œsenseâ€? strand. The other strand then becomes the antisense strand. Sequences along a long strand of DNA that can be used to transcribe RNA are known as genes. There are more than 3 billion DNA base pairs in the human genome. Extensive supercoiling occurs to help condense these strands of DNA into a more manageable structure - these are known as chromosomes when they become hypercondensed. There are 23 pairs of chromosomes and approximately 23,000 protein-coding genes in the human genome, with only about 1.5% of the total genome used to code for proteins.
DNA replication begins at specific protein complexes that facilitate separating the DNA into Figure 1. Copyright Madeleine Price Ball. Used with two strands and create a replication fork. A permission. 5
Clinical Review for the USMLE Step 1 protein complex forms at the fork and RNA primers attach to the leading strand and lagging strand. The leading strand typically receives a single RNA primer as it will be created in one piece from start to finish (3’ to 5’). The lagging strand receives several RNA primers as it will be created in short sequences known as Okazaki fragments (5’ to 3’). The RNA primers will eventually be removed by RNase and replaced with DNA-appropriate nucleotides. As the replication fork causes the DNA strands to separate and unwind, DNA gyrase helps to create negative rotations in the DNA to reduce the rotational tension that would otherwise occur. There are also a variety of DNA polymerases that assist with DNA replication. Polymerase alpha helps to synthesize RNA primer and initiate polymerization. Polymerase beta plays a role in DNA repair. Polymerase gamma is used for mitochondrial DNA replication and also has proofreading capability. Polymerase delta helps to fill gaps following RNA primer excision and also plays major role in polymerization; it also has proofreading capability. Finally, polymerase epsilon plays a role in proofreading as well and helps to assist polymerase delta. Proofreading on the completed strand occurs in a 3’ to 5’ direction.
DNA exchange takes the form of genetic recombination, of which there are several different types. Recombination can occur between similar molecules of DNA, known as homologous recombination; it can also occur among dissimilar DNA molecules and is Figure 2. Copyright Madeleine Price Ball. Used termed non-homologous recombination. Recombinawith permission. tion plays an important role in two scenarios: first, it is an important method of DNA repair; second, recombination is an important part of chromosomal crossover in meiosis and is responsible for the genetic variation we see in our offspring. Additional genetic recombination occurs in B cells as part of antibody production. Homologous recombination occurs when the damaged portion of a DNA strand is resected and the remaining strand attached to its complimentary strand on its sister chromosome. In the case of damaged DNA, crossover does not occur and there is no genetic rearrangement. In meiosis, crossover does occur with reassortment of genes. Homologous recombination occurs in the S and G2 phases of the cell cycle due to the availability of sister chromatids. Non-homologous recombination, more precisely termed non-homologous end joining, is used when there is a double-strand break in DNA. When a break typically occurs, there is some overlap in the complimentary strands that can be processed by various repair proteins to facilitate accurate ligation. Defects in non-homologous end joining can occur if there is insufficient overlap or the ligation does not 6
Biochemistry and Molecular Biology occur correctly; in the worst case, this can lead to truncation of a protein product and the creation of a tumorgenic focus. Over 3 billion exposed nucleotides, at least 100,000 mutations occur pay day secondary to endogenous factors such as free radicals and exogenous factors like UV radiation and toxins. Disorders in DNA repair are well known and lead to a variety of syndromes. Ataxia-telangiectasia is characterized by radiation and chemical sensitivity leading to early aging. Bloom syndrome is sensitivity to UV radiation leading to leukemia and other cancers. Cockayne syndrome is sensitivity to UV radiation and chemicals leading to carcinogenesis and mental retardation. Fanconi anemia is a defect in DNA repair leading to pancytopenia. Trichothiodystrophy is characterized by sensitive nails, hair, and skin leading to their early destruction. Werner syndrome leads to early senescence and growth retardation. Xeroderma pigmentosum is UV radiation sensitivity that leads to early senescence and skin cancer. Breast cancer and colon cancer are also related to defects in DNA repair. A variety of other mutations can also occur. Among the most common are point mutations, in which a Figure 3. Copyright Wikimedia. Used with permalfunction of DNA repair or direct toxic damage mission. leads to one nucleotide being exchanged for another. Point mutations may have one of three effects. A silent mutation occurs when the same amino acid is coded due to tRNA wobble and degeneracy of the DNA code. A missense mutation occurs when a different amino acid is coded. Phenotypic effects may or may not be present depending on changes to protein folding and post-translational modification. Finally, nonsense mutations occur when a truncated protein product is formed due to early stop sequence. Deletions occur when a nucleotide is excised from the DNA. This may lead to the same effects as insertion. Deletions are most commonly due to the effect of transposable elements. Insertions occur when an additional nucleotide is added to the DNA code. If one or two nucleotides are added, a frameshift mutation occurs in which the reading frame is shifted and the protein that is created is different. This most often results in a nonsense mutation. Transitions occur when an adenine to guanine or cytosine to thymine shift occurs. Transversions occur when adenine is changed to thymine or guanine changed to cytosine. Interstitial deletions occur when distant genes on the same chromosome are juxtaposed due to loss of genetic material in between. Interstitial deletions may lead to linkage disequilibrium, in which nonmendelian inheritance occurs because two genes are very close to each other and thus prone to be inherited together due to a lower chance of reassortment independent of each other. All of these mutations can lead to one of two phenotypically-significant effects. A gain of function mutation occurs when a new protein product is formed that has new and typically abnormal function. Gain of function mutations commonly have dominant effects. Loss of function mutations occur with the 7
Clinical Review for the USMLE Step 1 formation of a gene product with no function. Loss of function mutations are also known as amorphic mutation and commonly have recessive effects, unless there is a dominant negative mutation. Dominant negative mutation lead to an altered gene product that inhibits normal protein production by the intact allele leading to a partially-dominant phenotype. This is seen in osteogenesis imperfecta. Additional genetic effects also occur. Anticipation occurs when the severity of inherited disorder worsens with successive generations due to the accumulation of trinucleotide repeat sequences, as seen in Huntingtonâ€™s disease, myotonic dystrophy, and fragile X. Imprinting is when genetic reprogramming occurs based on whether gene is inherited from father or mother. Imprinting leads to changes in clonal DNA and is seen in Prader-Willi and Angelman syndrome (chromosome 15). In Prader-Willi syndrome, 2 chromosomes are inherited from the mother and it presents with hyperphagia, mental retardation, and large, offset ears. Angelman syndrome occurs when 2 chromosomes are inherited from the father. Angelman syndrome presents with memory defects, poor feeding, absent speech, and seizures. Loss of heterozygosity occurs when one unique allele is lost, leading to only one functional allele. Mosaicism, as seen in calico cats, occurs when a gene is penetrant in different tissues. Mosaicism may be due to alterations in methylation of DNA, leading to staggered inactivation and incomplete penetrance. Penetrance relates to the expression of genes that occurs if the gene Figure 4. Copyright Yassine Mrabet. Used with per- is present (highly penetrant) or one that is reliant on environmental effects and other genes mission. (low penetrance). Variable expression of genes is seen when the expression of genes in a similar inheritance leads to different phenotypes from one person to another. A gene may also be completely penetrant and fully expressed in certain people. Finally, pleiotropy is seen when one gene that functions on several targets leads to several distinct phenotypic traits. This is seen in phenylketonurea.
Epigenetics is the study of modifications to gene expression or the phenotype that occur from non-DNArelated causes. For example, methylation of the DNA may lead to inactivation of certain transcription pathways and plays a role in inactivation of one of the paired X chromosomes in women. Modification 8
Figure 5. Copyright Mikael Haggstrom. Used with permission.
Biochemistry and Molecular Biology
Clinical Review for the USMLE Step 1
Figure 7. DNA replication. Copyright Mariana Ruiz. Used with permission. of DNA histones via acetylation, methylation, ubiquination, or other methods can also lead to changes in activity. In 2011, epigenetics was demonstrated to play a role in RNA activity.
DNA transcription creates a messenger RNA sequence based off a DNA sequence. The chief difference between the DNA and RNA sequences is that the thymine found in DNA is replaced with a uracil nucleotide in RNA. Transcription proceeds with unwinding of the DNA similar to what occurs in DNA replication; this action is facilitated by RNA polymerase. The RNA nucleotides then pair with their complimentary DNA nucleotides (A with T, U with A, C with G, and G with C). An anchoring platform forms for the RNA nucleotides in the form of a sugar backbone, and the RNA strand is separated from its complimentary DNA strand. The RNA undergoes modification by the addition of a 3’ poly-adenylation tail and a 5’ methyl cap. The 5’ methyl cap permits binding of the mRNA to ribosomes, while the 3’ poly-A tail increases stability and prevents early breakdown by exonucleases. The poly-A tail also facilitates transport out of the nucleus and into the rough endoplasmic reticulum (rER), where translation into proteins will occur. Prior to this transport, additional modification to the mRNA will occur where non-coding introns are excised, leaving only the coding exons. Alternative splicing can also occur on the mature transcript to generate different protein products. The mRNA will eventually be degraded by RNases.
Figure 6. DNA transcription with RNA polymerase. Copyright Forluvoft. Used with permission. 10
Biochemistry and Molecular Biology A variety of proteins and domains are involved in DNA transcription. The promoter enables gene transcription after being recognized by RNA polymerase. The TATA box, located near transcriptional site, binds to transcription factors and helps to position them for transcription. Enhancers are protein-binding regions within DNA that help to increase the efficiency and speed of transcription; they are not necessarily located near transcriptional site. Repressors decrease the transcription rate by preventing the formation of mRNA. There are three major RNA polymerases. RNA polymerase I forms rRNA and does not need a TATA box to function. RNA polymerase I uses upstream binding factors and various transcription factors to bind to the upstream control sequence. RNA polymerase II forms mRNA and snRNA. RNA polymerase II requires a TATA box. RNA polymerase III forms tRNA and 5S rRNA and also uses a TATA box. Of the three major products created, rRNA is the most common, mRNA is the largest, and tRNA is the smallest. The function of these RNA fragments will be discussed in â€œ2.1.6 DNA Translation and Protein Synthesisâ€? on page 12. Reverse transcription is found with certain virus such as HIV, where an RNA product can be converted into DNA using an enzyme called reverse transcriptase. Ribonuclease H then generates a complimentary DNA strand and forms a double helix. Integrase can then be used to integrate this DNA sequence into the primary genome. Thereafter, further transcription will generate the RNA products and eventually the protein machinery for the virus. This technology has been used to develop protein products that can replace defective hormones, such as insulin in type I diabetics.
Figure 8. RNA translation. Copyright Mariana Ruiz. Used with permission. 11
Clinical Review for the USMLE Step 1 2.1.6
DNA Translation and Protein Synthesis
Translation uses the mRNA template to construct proteins in the cytoplasm after nuclear modification of the mRNA sequence is complete. Protein formation occurs over four phases, starting with activation. Activation relies on the appropriate amino acid binding to transfer RNA (tRNA), a process that relies on ATP. tRNA transfers the amino acid to the growing polypeptide chain at the ribosome to help produce proteins translated from the mRNA sequence. The anticodon region recognizes codon sequence in the reading frame on mRNA. The mRNA codon specifies only one amino acid, and so is unambiguous. However, other codons may also specify that amino acid (degeneracy). There is no pause between reading frames â€“ they are all continuous (commaless). The sequences that specify amino acids are used by other species; the only exceptions are mitochondria and certain primitive species (universal). tRNA is approximately 90 nucleotides in length and is able to permit one amino acid to bind to more than one codon sequence due to wobble. Wobble requires recognition of the first two nucleotides. In certain circumstances, the third nucleotide may vary and the same amino acid will still bind. This contributes to degeneracy. Initiation, the second step in the process, occurs when the ribosomal RNA (rRNA) binds to the 5â€™ side of the mRNA to promote elongation of the polypeptide sequence. Methionine, the start codon, binds first. Elongation, the third step in the process, occurs when additional amino acids are added by tRNAs that recognize the codon sequence on the mRNA. After binding the tRNA and translocating to the next amino acid in the polypeptide, the growing sequence is done. After creation of the polypeptide, the final step in the process is termination at a UAA, UAG, or UGA codon. These three sequences do not code for amino acids and halt further development of the polypeptide. Ribosomal RNA is composed of four separate molecules, including a 5S (large subunit), 5.8S (large subunit), 18S (small subunit), and 28S (large subunit) subunits. rRNA is generally made in the nucleolus. The counterparts to rRNA in the mitochondria are the 16S and 23S subunits. Small RNA Proteins, or snRNPs, are used for RNA splicing, transcription factor regulation, maintaining telomeres, and to serve as RNA polymerase II. When complexed with small nuclear ribonucleoproteins, these proteins excise introns to develop the mature mRNA transcript. Small nucleolar RNAs are also used to methylate RNA. Other small RNA proteins are used to modify the transcript and increase RNA functionality. Protein synthesis can also take other forms. The process of translation can be time-consuming and an inefficient way to deliver proteins that are needed urgently by the cell. In this instance, precursors can be generated via translation and made available to the cell. Post-translational modification or enzymatic cleavage can lead to the generation of the active form of the protein.
Post-Translational Processing and Protein Modifications
Post-translational processing and modification of proteins occurs in rER and Golgi complex. This process involves numerous modifications individualized to the protein. A variety of modifications can occur, including acetylation of the N-terminus, biotinylation on lysine residues, glutamylation on glutamic acid residues, glycylation on the C-terminal, glycosylation on asparagine, hydroxylysine, serine, or threonine, phosphorylation on serine, tyrosine, threonine, or histidine groups, sulfur groups added to tyrosine, disulfide bridges added to cysteine groups, and ubiquitin added if proteins need to be marked for proteolysis. These processes are disrupted in Angelman syndrome and Von Hippel-Lindau syndrome, leading to defects in protein function. Antibodies to ubiquitin are present as neurofibrillary tangles in Alzheimer disease, Lewy bodies in Parkinson disease, Pick bodies in Pick disease, Mallory bodies in 12
Biochemistry and Molecular Biology alcoholic hepatitis, and Rosenthal fibers in astrocytes, leading to accumulation of malfunctioning protein products. The Golgi apparatus (“Golgi Apparatus” on page 32), rough endoplasmic reticulum (“Rough Endoplasmic Reticulum” on page 31), and smooth endoplasmic reticulum each play a unique role in posttranslational processing of proteins.
Following creation of a protein product, it must be appropriately guided to the organelle or extracellular destination. This is often done by embedding a targeting signal in the polypeptide chain. Post-translational modification such as glycosylation also helps to guide proteins to their final destination. Two additional forms of protein translocation exist - cotranslational translocation occurs while the protein is still being manufactured. A signal recognition particle initiates translocation of the protein molecule via a receptor on the rER and eventually transported to the Golgi apparatus. Posttranslational translocation occurs after all of the protein processing by the rER and Golgi apparatus are completed. This occurs in proteins intended for the mitochondria and nucleus.
Proteolysis can lead to additional modification of proteins, or even lead to their complete breakdown into their constituent amino acids. Examples of modification via proteolysis include removal of methionine residues after translation and deletion of signaling sequences that help navigate proteins throughout and out of the cell. Total degradation can occur with digested proteins using enzymes such as trypsin, chymotrypsin, and others created by the pancreas. A form of proteolysis occurs when the pro-form of the digestive enzymes are cleaved to generate their active form.
2.2. Protein and Enzyme Structure and Function 2.2.1
Protein structure comes in one of four forms. Primary structure is based off the amino acid sequence only and has no fold- Figure 9. Copyright Mariana Ruiz. Used with permission. ing or three dimensional changes. Second13
Clinical Review for the USMLE Step 1 ary structure has alpha helices and beta-pleated sheets. Tertiary structure coalesces the molecule into a three-dimensional manifold that can have complex interactions with other proteins and molecules. Finally, quaternary structure creates complex protein superstructures through interaction of various subunits and other proteins.
Enzyme regulation typically occurs in one of three forms. Competitive inhibitors bind to active sites and prevent the activator of the enzyme from binding. This leads to a dose-dependent effect which can be overcome by adding more activator. Allosteric inhibitors bind to the ectopic portion of enzymes to cause a conformational change in the binding site. This leads to non-competitive inhibition.
Figure 10. Hexose monophosphate shunt. Copyright Mike Jones. Used with permission. 14
Biochemistry and Molecular Biology Irreversible inhibitors bind covalently to the active site of the enzyme and lead to its inactivation. This leads to non-competitive inhibition and is a common mode of function for various poisons. Enzyme function is dependent on the kinetics of its activity, which is measured by Km and Vmax. Km is a measure of affinity and refers to the affinity of substrate to enzyme at Â˝ Vmax. Low numbers indicate increased affinity. Vmax is the maximum velocity at which reaction can proceed. Competitive inhibitors increase Km and do not change Vmax, while non-competitive inhibitors decrease Vmax but do not change Km. A third type of inhibitor, uncompetitive inhibitors, decrease Km and increase Vmax.
2.3. Energy Metabolism 2.3.1
Hexose Monophosphate Shunt
Nucleotides are generated by the hexose monophosphate (HMP) shunt, an anabolic pathway that uses glucose to form 5 carbon sugars. The HMP shunt generates NADPH for reduction reactions and forms ribose-5-phosphate for use in nucleotide synthesis. The HMP shunt plays a major role especially in the liver, lipocytes, adrenal cortex, testis, and mammary gland where high production of proteins and a high level of translation occurs. The HMP shunt operates in the cytoplasm. The key enzymes include transketolase, which rearranges 2-carbon groups and requires thiamine; transaldolase, which rearranges 3-carbon groups; glucose6-phosphate dehydrogenase (G6PD) which is required in NADPH formation and regeneration of glutathione. Deficiency of G6PD provides immunity against malaria.
Overview The majority of ATP is made through aerobic metabolism, yielding between 36-38 ATP molecules per glucose. Anaerobic metabolism yields 2 ATP per glucose, and if glucose is formed to produce ATP, there is a net loss of 2 ATP. Glycolysis will produce pyruvate, yielding 4 NADH and 2 ATP. Pyruvate Figure 11. ATP molecule. will generate acetyl CoA and 2 NADH. The citric acid cycle will use the Copyright Ben Mills. Used acetyl CoA and generate 6 NADH, 2 FADH 2, and 2 GTP. with permission.
Glycolysis Glycolysis can be distilled into approximately 11 major steps with a variety of reversible and irreversible components. The exam tests your knowledge of both (see Figure 12 on page 16). 1.
Glucose is converted to glucose-6-phosphate by hexokinase (most tissues) or glucokinase (liver). This is irreversible.
G-6-P is converted to fructose-6-phosphate by phosphoglucose isomerase.
F-6-P is converted to fructose-1,6-bisphosphate by phosphofructokinase-1 (irreversible).
F-1,6-BP is converted to dihydroxyacetone phosphate by aldolase. 15
Clinical Review for the USMLE Step 1
Figure 12. Glycolysis. Copyright Yassine Mrabet. Used with permission.
Biochemistry and Molecular Biology 5.
DHAP is converted to glyceraldehyde-3-phosphate by triose phosphate isomerase.
G-3-P is converted to 1,3-bisphosphoglycerate by glyceraldehyde 3-phosphate dehydrogenase.
1,3-BP is converted to 3-phosphoglycerate by phosphoglycerate kinase.
3-PG is converted to 2-phosphoglycerate by phosphoglyceromutase.
2-PG is converted to phosphoenolpyruvate by enolase.
10. PEP is converted to pyruvate by pyruvate kinase (irreversible). 11. Pyruvate is converted to acetyl-CoA by pyruvate dehydrogenase (irreversible). The net production of glycolysis is 4 NADH, 2 ATP, and pyruvate. The essential cofactors include pyruvate dehydrogenase, vitamin B1 (thiamine), B2 (riboflavin), B3 (niacin), B5 (pantothenate), and lipoic acid. A deficiency in pyruvate dehydrogenase can be treated with a high fat diet to increase content of ketogenic nutrients. Enzymatic control during glycolysis occurs at four key places. Hexokinase is inhibited by G6P; glucokinase is not inhibited by G6P. PFK-1 is inhibited by ATP and citrate and stimulated by AMP and
Figure 13. Citric acid cycle. Copyright Yassine Mrabet. Used with permission. 17
Clinical Review for the USMLE Step 1 F-2,6-BP. Pyruvate kinase is inhibited by ATP and alanine; it is stimulated by F-1,6-BP. Finally, pyruvate dehydrogenase is inhibited by ATP, NADH, acetyl-CoA.
Citric Acid Cycle The citric acid cycle can also be condensed into a number of steps. The key reaction starts with citrate, which is converted to succinyl-CoA, then alpha-ketoglutarate, followed by citrate, oxaloacetate, malate, fumarate, and succinate. 1.
Citrate is converted to cis-aconitate, then isocitrate by aconitase
Isocitrate is converted to oxalosuccinate then alpha-ketoglutarate by isocitrate dehydrogenase
Alpha-ketoglutarate is converted to succinyl-CoA by alpha-ketoglutarate dehydrogenase
Succinyl-CoA is converted to succinate by succinyl-CoA synthetase
Succinate is converted to fumarate by succinate dehydrogenase
Fumarate is converted to L-malate by fumarase
Malate is converted to oxaloacetate by malate dehydrogenase
Oxaloacetate is used to reform citrate with citrate synthase
From citrate to succinyl-CoA, a total of 2 NADH and 2 CO足2 are produced by molecule of acetyl-CoA. From succinylCoA to oxaloacetate a total of 1 NADH, 1 FADH 2, 1 GTP, and 1 CoA are produced per molecule of acetyl-CoA. A net of 12 ATP per acetyl-CoA are produced with these byproducts (24 per glucose). In summary: Acetyl-CoA + 3 NAD+ + FAD + GDP + Pi + 3 H2O --> CoASH + 3 NADH + H+ + FADH 2 + GTP + 2 CO2 + 3 H+ The end result is 2 ATP, 6 NADH, and 2 FADH 2.
Electron Transport Chain The electron transport chain is a series of redox reactions Figure 14. Electron transport chain. Copyright Tim Vickers. Used with that occurs in the inner mem- permission. brane of mitochondria to gen18
Biochemistry and Molecular Biology erate a proton-gradient used to produce ATP. It uses four complexes which generally use NADH and a proton pump to generate the necessary gradient. Complex I is NADH dehydrogenase (proton pump), which can be inhibited by amytal and rotenone. Complex II is succinate dehydrogenase. Complex III is cytochrome bc1 (proton pump) and is inhibited by antimycin A. Complex IV is cytochrome c (proton pump) and is inhibited by cyanide, carbon monoxide, and azide. The electron transport chain culminates in a proton pump which mitochondrial F-ATPase uses to generate ATP; this ATPase can be inhibited by oligomycin. Uncoupling agents such as 2,4-dinitrophenol increase membrane permeability to lead to malignant hyperpyrexia through futile proton gradient activity.
NADH and NADPH Generation
Figure 15. Copyright with permission.
NADH is the reduced form of NAD, and NAD+ is the oxidized form of NAD. NADH is generated in glycolysis and citric acid cycle to help form ATP. NADPH is generated by adding a phosphate group to NAD followed by reduction. NADPH plays a role in anabolic reactions to generate fat and nucleic acids. NADPH also plays a vital role in the oxygen-dependent respiratory burst and is used with NADPH oxidase to form oxygen free radicals. These free radicals are used to generate hydrogen peroxide with superoxide dismutase. H 2O2 is converted to bleach (HOCl) by myeloperoxidase. Excess H 2O2 is deactivated along with oxygen free radicals by catalase, which forms water. NADPH is reconstituted by this reaction. Glutathione reductase plays a vital role in this reaction, and is regenerated through the action of glucose6-phosphate dehydrogenase (which forms more G6P, used in this reaction).
Amino Acid Pathways Amino acids can be divided into essential and nonessential. Typically, the essential amino acids are precursors for other amino acids or cannot otherwise be manufactured de novo by the body. Examples
Figure 16. The Cori cycle. Copyright Eyal Bairey. Used with permission. 19
Clinical Review for the USMLE Step 1 include phenylalanine, tryptophan, histidine, glycine, and arginine. Phenylalanine is converted to tyrosine, which is converted to L-dopa; L-dopa is converted to dopamine, which is converted to norepinephrine by the adrenal gland. Norepinephrine is used to manufacture epinephrine. Tyrosine is used to manufacture thyroxine. Dopamine is used to produce melanin. Tryptophan is an important precursor to niacin, serotonin, and melatonin. Histidine helps to form histamine. Glycine is used to produce porphyrin, which is a component of heme. Arginine is used to produce creatine, urea, and nitric oxide.
Cori Cycle The Cori cycle, also known as the lactic acid cycle, is a mechanism through which lactate production by the muscle is converted to glucose in the liver. This is a direct consequence of the inability of muscles to produce glucose through their lack of glucose-6-phosphatase. The Cori cycle prevents lactic acidosis within the muscle during anaerobic conditions while maintaining the ability to produce ATP.
Irreversible Enzymes We had a brief discussion of irreversible enzymes above in â€œGlycolysisâ€? on page 15. However, the following is a list of the major enzymes by organelle; this is provided in a single place for your reference and also to highlight their relative importance on the USMLE. 1.
Pyruvate carboxylase converts pyruvate to oxaloacetate; this reaction occurs in the mitochondria.
PEP carboxykinase converts oxaloacetate to PEP; this reaction occurs in the cytosol.
Fructose 1,6-bisphosphatase converts F-1,6-BP to F-6-P; this reaction also occurs in the cytosol.
Glucose-6-phosphatase converts G-6-P to glucose in the cytosol. This enzyme is found in the liver, kidney, and intestines, but not in the muscle. Defect in any of these enzymes will lead to hypoglycemia.
2.4. Biochemical Disorders There are a variety of high-yield disorders covered in this section. All of these are exam-worthy in that they test important biochemical pathways. Knowledge of their enzymatic defect, presentation, and management is important.
Iron Pathway Defects
Acute Intermittent Porphyria Acute intermittent porphyria is a deficiency in uroporphyrinogen I synthase leading to deltaALA accumulation. It leads to excess porphobilinogen in urine and CNS changes.
Figure 17. Heme synthesis. Copyright Piemmea. Used Lead poisoning leads to inhibition of ferroche- with permission. latase and ALA dehydratase, leading to excess ALA and coproporphyrin in urine. It presents with anemia, stippled RBCs, and lead lines in bone. 20
Biochemistry and Molecular Biology Porphyria Cutanea Tarda Porphyria cutanea tarda is a deficiency in uroporphyrinogen decarboxylase that leads to uroporphyrin in urine. It is one of the most common enzyme defects and is treated with hemin to inhibit ALA synthase.
Amino Acid Diseases
Phenylketonuria PKU is caused by a lack of phenylalanine hydroxylase, lack of tetrahydrobiopterin cofactor, and a defect in dihydropterine reductase. It leads to the build up of phenylalanine, making tyrosine an essential amino acid in these patients. PKU presents with progressive mental retardation, fair skin with eczema, and a particular body odor.
Alkaptonuria Alkaptonuria is a defect in homogentisic acid oxidase that leads to an inability to degrade tyrosine. Alkaptonuria presents with dark urine and arthralgias. It is typically a benign disorder.
Albinism Albinism is due a defect in tyrosinase that leads to the inability to make melanin from tyrosine. This results in the lack of neural crest migration to skin and subsequent lack of melanin. This increases the risk of skin cancer.
Homocystinuria Homocystinuria should not be confused with homocysteinemia. Homocystinuria is due to a defect in cystathionine synthase and methionine synthase leading to the inability to reabsorb homocysteine. Cysteine becomes an essential amino acid with this disorder. Homocystinuria presents with a Marfanoid habitus, lens dislocation, mental retardation, and osteoporosis. Treatment is with having a low protein diet, particularly in methionine.
Cystinuria Cystinuria is a defect in tubular amino acid transporter leading to a defect in the transportation of cystine, ornithine, lysine, and arginine in the kidneys. It presents with cystine kidney stones and can be treated with acetazolamide.
Maple Syrup Urine Disease Maple syrup urine disease is a defect in alpha-ketoacid dehydrogenase that leads to the inability to degrade branched amino acids, including isoleucine, leucine, and valine. It presents with mental retardation and leads to death.
Purine and Pyrimidine Salvage Diseases
Adenosine Deaminase Deficiency Adenosine deaminase deficiency leads to excess ATP and dATP with the inability to make ribonucleo21
Clinical Review for the USMLE Step 1 tide reductase, leading to a defect in DNA synthesis and a decrease in lymphocyte count. It presents with severe combined immunodeficiency syndrome.
Lesch-Nyhan Disease Lesch-Nyhan disease is an X-linked recessive disorder due to a defect in HGPRTase leading to a defect in purine salvage pathway. Patients have an inability to convert hypoxanthine to inosine monophosphate and an inability to convert guanine to guanosine monophosphate. Lesch-Nyhan disease presents with excess uric acid production with deposition throughout brain, leading to self-mutilation, significant aggression, hyperuricemia, and gout. Renal failure occurs in the 20â€™s.
Lysosomal Storage Diseases
Fabry Disease Fabry disease is an X-linked recessive sphingolipidosis that leads to a defect in alpha-glactosidase A and subsequent accumulation of ceramide trihexoside. Fabry disease presents with renal failure, neuropathy, corneal opacity, nodules, angiokeratomas, and hypertension.
Krabbe Disease Krabbe disease is an autosomal recessive sphingolipidosis that leads to a defect in glactosylceramide beta-glactosidase and the accumulation of galactocerebroside. It presents with neural degeneration, optic atrophy, spasticity, and death by age 2.
Gaucher Disease Gaucher disease is a sphingolipidosis that has a defect in beta-glucocerebrosidase, leading to the accumulation of glucocerebroside. It causes damage to CNS, hepatomegaly, splenomegaly, and bone marrow atrophy but has a normal lifespan. Macrophages have a fibrillary appearance in this autosomal recessive disorder.
Niemann-Pick Disease Niemann-Pick disease is a sphingolipidosis with a defect in sphingomyelinase, leading to the build up of sphingomyelin. It causes failure to thrive, deafness, blindness, hepatosplenomegaly, and has a characteristic red spot on fundoscopy. Patients die by age 3 in this autosomal recessive disease.
Tay-Sachs Disease Tay-Sachs is a sphingolipidosis that has a lack of hexosaminidase A, leading to the accumulation of GM2 ganglioside. It presents with progressive blindness, deafness, seizures, and death by age 3. TaySachs also has a cherry red spot on fundoscopy. This is an autosomal recessive disease that primarily affects the Ashkenazi Jewish population.
Metachromatic Leukodystrophy Metachromatic leukodystrophy is a sphingolipidosis that has a deficiency of arylsulfatase A, leading to the accumulation of sulfatide in brain. This causes abnormalities within myelin, presenting with mental retardation, neuropathy, and metachromasia. This is an autosomal recessive disorder. 22
Biochemistry and Molecular Biology Hurler Syndrome Hurler syndrome is a mucopolysaccharidosis that has a defect in alpha-L-iduronidase. It presents with corneal clouding and mental retardation. It is an autosomal recessive disease.
Hunter Syndrome Hunter syndrome is a mucopolysaccharidosis with a defect in L-iduronosulfate sulfatase, leading to the accumulation of heparan sulfate and dermatan sulfate. It is a milder form of Hurlerâ€™s syndrome and lacks corneal clouding with only mild mental retardation. It is an X-linked recessive disorder.
Glycogen Storage Diseases
Von Gierke Disease Von Gierke disease is a glycogen storage disease that has a defect in glucose-6-phosphatase. It leads to the inability to remove phosphate, keeping glucose trapped in liver. Glycogen structure is normal, but the disease is characterized by severe hypoglycemia, lactic acidosis, hepatomegaly, hyperlipidemia, hyperuricemia, short stature, increase in VLDLs, and xanthomas.
Pompe Disease Pompe disease is a glycogen storage disease with a defect in alpha 1,4-glucosidase in the lysosome. It leads to glycogen accumulation in inclusion bodies, presenting with cardiomegaly, muscle weakness, and death by age 2.
Cori Disease Cori disease is a glycogen storage disease with a defect in glycogen debranching enzyme. The glycogen in this disease is characterized by short outer branches and single glucose residues at outer branches due to a lack of alpha 1,6 branch breakdown. It presents with mild hypoglycemia and hepatomegaly.
Anderson Disease Anderson disease is a glycogen storage disease with amylopectinosis, a defect in a branching enzyme, and a subsequent paucity of branches in glycogen edges. It presents with hypotonia, cirrhosis, and death by age 2.
McArdle Disease McArdle disease is a glycogen storage disease with a defect in muscle glycogen phosphorylase. It leads to the accumulation of glycogen, a decrease in glucose, and an increase in lactic acid formation. It presents with muscle cramps and weakness on exercise. McArdle disease is diagnosed via muscle biopsy and a normal glycogen structure.
Hers Disease Hers disease is a glycogen storage disease with a defect in hepatic glycogen phosphorylase. It leads to a mild fasting hypoglycemia with hepatomegaly and cirrhosis. Glycogen structure is normal.
Clinical Review for the USMLE Step 1
3.1. Adaptive Cell Responses 3.1.1
The cell cycle begins with interphase. The first growth phase occurs during interphase and is when the cell prepares nucleoside kinases for DNA transcription. The cell is currently 2N. S phase starts when DNA synthesis begins. The genetic material is now 4N. S phase is also a part of interphase. Failure of DNA repair in this stage may lead to G0 and cessation of cell duplication. The second growth phase is the final part of interphase and is the final opportunity for the cell to ensure that all enzymes and proteins necessary to complete mitosis are prepared and available. G0 phase is a stop phase that occurs due to several reasons. The inability to progress through cell division is often due to missing enzymes or insufficient nutrients / minerals. G0 is a quiescent state for neuronal population, and a resting state for most cells in the body until a growth factor signal is received Figure 18. Copyright Richard Wheeler. Used with indicating cell duplication. permission. Mitosis is composed of prophase, prometaphase, metaphase, anaphase, telophase, and cytokinesis. Prophase has heterochromatin and is marked by the start of mitotic spindle. Prometaphase has dissolution of the nuclear envelope. Metaphase occurs when the kinetochores move to opposite sides of the cell. Anaphase has separation of sister chromatids. Telophase has separation of genetic material to opposite poles of the cell. Finally, cytokinesis is marked by a cleavage furrow and cell separation.
Figure 19. Adapted from the NIH. Used with permission.
Biology of Cells
3.2. Mechanisms Necrosis 3.2.1
Cell necrosis is unprogrammed cell death, and it occurs due to direct injury to cells leading to disordered destruction. There is no organized pattern of chromatin condensation, karyorrhexis, or signaling to phagocytes. With cell necrosis, there is damage to nearby cells due to release of toxic byproducts, such as lysosomal enzymes. Figure 20. Coagulative necrosis in the heart followMorphologic features of necrosis can be catego- ing myocardial infarction. Copyright Wikimedia. rized as coagulative necrosis, liquefactive necro- Used with permission. sis, caseous necrosis, fatty necrosis, and fibrinoid necrosis.
Coagulative necrosis is a cellular necrosis that maintains outlines of the cells. It leads to a homogenous, eosinophilic mass due to protein coagulation, and is typically the result of ischemic infarcts. Coagulative necrosis is commonly found in myocardial infarcts, but may occur in most tissues that suffer from ischemic infarction.
Figure 21. Liquefactive necrosis in the brain following a CVA. Copyright Wikimedia. Used with perLiquefactive necrosis occurs due to significant mission. cellular destruction mediated by the immune system. It is often found with significant pus production due to neutrophil phagocytosis and later destruction. Liquefactive necrosis occurs in pneumonia and with severe pancreatitis due to the action of pancreatic enzymes.
Caseous necrosis is the combination of coagulation of proteins and liquefactive cellular destruction leading to a cheese-like appearance. It is most prominent in tuberculosis.
Figure 22. Caseous necrosis in the lung in a patient with tuberculosis. Copyright Wikimedia. Used with Fatty necrosis leads to the destruction of lipo- permission. cytes due to the action of various enzymes. It 25
Clinical Review for the USMLE Step 1 is commonly the result of pancreatitis leading to pancreatic enzyme-mediated lipocyte destruction. It also occurs following breast surgery due to inflammation.
Fibrinoid necrosis is the result of vascular damage leading to fibrin deposition within arterial walls leading to thickening. It is an immune-mediated disease.
Figure 23. Fat necrosis following trauma. Copyright Wikimedia. Used with permission.
Apoptosis is programmed cell death and occurs as part of normal development. It is a normal response to cell damage, infection, stress, or DNA damage and is a necessary part of normal tissue turnover. The morphologic features include rounding of the cell, condensation and degradation of chromatin, karyorrhexis, blebbing of plasma membrane, and the formation of apoptotic bodies with subsequent phagocytosis. Mediators of apoptosis include PARP-1 (poly-ADP ribose polymerase-1), a number of caspases, and Fas-associated death do- Figure 24. Fibrinoid necrosis of an artery. Copymains (FADD). right Wikimedia. Used with permission.
3.4. Mechanisms of Dysregulation 3.4.1
Aplasia, Hypoplasia, Atrophy, and Atresia
Aplasia is the failure of organ development and is an original defect, not an acquired defect. One exception to this rule is aplastic anemia, which is a misnomer as this is an acquired defect. Hypoplasia refers to an organ that does not grow to its intended size, while atrophy refers to a decrease in cellular size and is reversible (vs. apoptosis, which is irreversible). Atresia is the failure of luminal development, whether inherited or acquired. This occurs with biliary atresia.
Stenosis is the narrowing of a lumen, which is seen in coronary artery stenosis in unstable angina. It should not be confused with occlusion, which is total elimination of the lumen of a vessel.
Malformation, Deformation, and Hamartoma
Congenital deformity in a structure are known as malformations. Acquired defects in a structure are known as deformations. Hamartomas are disarrangements of normal organ components.
Biology of Cells 3.4.4
Fistulas are abnormal connection between two regions, which can be seen in Crohn’s disease. In Crohn’s, fistulas form between the GI tract and other organs due to transluminal inflammation.
Hypertrophy and Hyperplasia
Hypertrophy is an increase in the size of a cell. This occurs in muscles (hypertrophic cardiomyopathy). Hyperplasia is an increase in the number of cells and can be seen in the prostate with benign prostatic hyperplasia.
Metaplasia, Dysplasia, and Anaplasia
Metaplasia is the replacement of one cell type by another as part of an adaptive response. This is a reversible process and is not cancerous. Metaplasia occurs in Barrett’s esophagus in GERD. Dysplasia is the loss of cell polarity with hyperplastic changes leading to carcinoma in-situ. This is a pre-cancerous change. It is marked by changes in cellular size from one to another. There are dark-staining nucleus with increased nucleus to cytoplasm (N:C) ratio, and numerous mitotic spindles. Dysplasia is due to underlying accumulated genetic mutations.
Figure 25. Various signal transduction pathways used in apoptosis, including the FADD pathway. Copyright Boghog2. Used with permission. 27
Clinical Review for the USMLE Step 1 Anaplasia is characterized by the loss of apical/basolateral cell polarity with cells able to survive without being anchored to a basement membrane. There is significant variability in cell size, regression to immature-looking cells, and a significantly increased N:C ratio. There are also multiple, odd-looking mitotic spindles, multiple genetic abnormalities and mutations.
Tumor Suppressor Genes Tumor suppressor genes include p53 and RB (retinoblastoma gene). Tumor suppressor genes serve to modulate differentiation of cells and play a role in limiting cellular proliferation. Defects in tumor suppressor genes eliminates this inhibitory effect and permits cells to differentiate and proliferate at will. This is known as a loss of function mutation.
Oncogenes Oncogenes also regulate cell growth and proliferation, but there are strict controls on their function. Mutations in oncogenes lead to amplification and over-expression of the gene, eliminating the effect of their controls. A fusion gene or other alterations of the gene can lead to the production of oncogene proteins that no longer respond to their traditional controls. Examples of oncogenes include the ras and myc family of proto-oncogenes. Oncogenes can be classified into growth factors (discussed further in section “3.6. Growth Factors” on page 37), receptor tyrosine kinases, cytoplasmic tyrosine kinases, serine/threonine kinases, GTP proteins, and transcription factors (discussed below in section “3.5.4 Cell Receptors” on page 36).
Hereditary Tumors There are a variety of hereditary tumors that have a basis in genetics. Often, the defect can be isolated to a particular part of the chromosome. However, it is important to note that cancer occurs as a result of multiple mutations in a variety of tumor suppressor genes and oncogenes. Table 1. Hereditary tumors. Type
Cell cycle regulation, apoptosis.
Brain tumor, sarcoma, leukemia, breast cancer.
Cell cycle regulation.
Retinoblastoma, osteogenic sarcoma.
Pediatric kidney CA.
RAS inactivation promoter.
Neurofibromas, sarcomas, gliomas.
Cell membrane to cytoskeleton linker.
Vestibulocochlear schwannomas, meningiomas, astrocytomas, Ependymomas.
Familial adenomatous polyposis
Adhesion molecule signaling.
Tuberous sclerosis 1
Facial angiofibromas + tubers
Tuberous sclerosis 2
Hamartomas throughout, rhabdomyosarcomas.
Deleted in pancreatic carcinoma
DPC4 / SMAD4 TSR
TGF-B/BMP signal transduction regulator.
Pancreatic CA, colon CA.
Biology of Cells Deleted in colorectal carcinoma
Transmembrane receptor for axonal guidance.
Familial breast CA 1
Double strand breakage repair w/ Rad51.
Breast and ovarian CA; more common in women.
Familial breast CA 2
Double strand breakage repair.
Breast and ovarian CA; more common in men â€“ also causes pancreatic CA and prostate CA.
STK11 TSR (STK)
Hyperpigmentation, hamartoma polyps, colorectal CA, breast CA, ovarian CA.
DNA mismatch repair enzyme.
Hereditary nonpolyposis colorectal CA type 1
Hereditary nonpolyposis colorectal CA type 2
DNA mismatch repair enzyme.
Von Hippel-Lindau syndrome
Transcription elongation regulator.
Renal CA, Hemangioblastoma, pheochromocytoma.
Melanoma, pancreatic CA.
Basal cell carcinoma
Hedgehog signal regulator.
Basal cell CA.
Parathyroid, pituitary, islet cell, carcinoid
TK for GDNF.
Medullary thyroid, pheochromocytoma, mucosal hamartomas.
Cell cycle regulator.
Wilms tumor, adrenocortical CA, hepatoblastoma.
Multiple, ATM gene
Failure to halt cell cycle after damage to DNA.
Lymphoma, ataxia, immunodeficiency.
Solid tumors, immunodeficiency.
Table 2. Carcinogens. Type
Esophageal CA and stomach CA
Mesothelioma, bronchogenic CA
Centrilobular necrosis of liver
Bladder CA (TCC)
Adult T-cell leukemia
Burkittâ€™s lymphoma, nasopharyngeal CA
HPV 16, 18, 31, 33
Kaposi sarcoma, B cell lymphoma
Clinical Review for the USMLE Step 1 Table 3. Tumors markers. Type
Hepatocellular CA, embryonal cell tumors of the Follow after Dx. testes, yolk sac tumors, mixed germ cell tumors.
Multiple myeloma, CLL, lymphomas.
Germ cell tumors, choriocarcinoma, mediastinal tumors.
Bladder tumor antigen
Bladder CA, used w/ NMP22.
Recurrence of tumor indicator.
CA 15 -3
Elevated in advanced disease.
Ovarian CA; positive in fibroids, endometriosis, lung CA.
Possible screening test, but would miss many early CA (hence why many are not used as screening tests).
Ovarian CA, stomach CA.
CA 19 -9
Pancreatic CA +/- colorectal CA.
CEA better for colorectal CA; highly sensitive for pancreatic CA.
Medullary thyroid CA (parafollicular C cells).
Early detection of CA.
Colorectal CA; also elevated in lung CA and breast CA.
Carcinoid, neuroblastoma, SCLC.
Estrogen receptors / progesterone receptors
Tamoxifen (raloxifene for osteoporosis).
HER-2/neu / c-erbB-2
Positive in 1 in 3 patients; prognostic indicator â€“ use trastuzumab in patients w/ positive result.
SCLC, neuroblastoma, carcinoid.
Prostate CA, BPH.
NOT for use as a screening test; prognostic; not 100%.
Prostate acid phosphatase
PSA is more sensitive.
Melanoma, Histiocytosis X.
Metastasis and Cancer Staging
Metastasis Metastasis occurs when cancer spreads from one part of the body to another. Metastasis can occur hematogenously, via lymphatics, via body cavities (such as peritoneal carcinomatosis), and iatrogenically during cancer operations. Metastatic cancer has mutated sufficiently for it to no longer require basic signalling molecules to control its proliferation and spread. Cells no longer respond to signals from the basement membrane and are free to grow in any direction. Signals that control apoptosis, proliferation, and control differentiation no longer affect the mutated cells.
Cancer Staging Each type of cancer is divided into four stages, I through IV. The specific characteristics of each stage de30
Biology of Cells pend on the particular type of tumor. Generally, stage I cancers are highly amenable to surgical or medical management and can be treated successfully with the appropriate therapy. Most patients with stage I cancer will have a five year survival between 75 and 100%. Stage II cancers tend to be larger and may have involvement of lymph nodes. They are also generally amenable to surgical management, although some types of cancers may also be treated with chemotherapy. Five year survival varies by cancer, but generally ranges between 50-75%. Stage III cancers typically have lymph node involvement and may even involve proximal structures through direct growth. Due to their large size and extensive involvement, they are often pre-treated with chemotherapeutic agents, followed by surgery in selected individuals. Many patients will often have chemotherapy following surgical resection. Five year survival typically ranges between 25-50%. Stage IV cancers are commonly metastatic to distant sites, involve lymph nodes, and are large in size. Their metastatic nature implies Figure 26. Rough endoplasmic reticulum photomicrothat they no longer respond to common sig- graph. Copyright Louisa Howard. Used with permisnalling mechanisms. Treatment is difficult sion. and often simply palliative. Chemotherapy is often the mainstay of management, although selected patients may benefit from surgery to relieve pain. Exceptions to this rule exist for certain cancers; colon cancer metastatic to the liver may be treated with liver resection and colectomy in conjunction with chemotherapy. Survival in this particular case may be as high as 40% over several years. However, most stage IV cancers tend to have dismal survival, ranging from a few months for pancreatic cancer to a couple of years for melanomas. Due to the toxic effects of the chemotherapy, the rapid proliferation of the cancer, and the cachectic effects of the cancer, survival more than a few years is uncommon.
3.5. Cell Structure 3.5.1
Rough Endoplasmic Reticulum The rough endoplasmic reticulum (rER) plays a role in protein synthesis, sequesters calcium and thereby serves as an intracellular store, produces steroids, helps to synthesize and store glycogen, and helps to create membrane proteins. The rER is studded with ribosomes and is directly connected to the outer nuclear membrane. It permits proteins to be targeted for the cell membrane or secreted from the cell and has the ability to add N-linked oligosaccharides to proteins to as- Figure 27. Photomicrograph of the Golgi apparatus. sist with signaling. The rER is found in large Copyright Louisa Howard. Used with permission. 31
Clinical Review for the USMLE Step 1 amounts in tissues that synthesize numerous secretory proteins, including neurons (Nissl substance), the small intestine (Goblet cells), plasma cells (antibody production), and endocrine glands (hormone production).
Smooth Endoplasmic Reticulum The smooth endoplasmic reticulum (sER) plays a role in lipophilic substance generation, forms steroid hormones, and detoxifies many substances. It plays a major role in drug and toxin detoxification. The sER is found in large amounts in areas that synthesize lipophilic substances or break down toxins or drugs, including the liver (P-450 system for drug conversion and detoxification), adrenal cortex (steroid hormones), testes and ovaries (steroid hormones), and thyroid (steroid hormones). The steroid hormones include progesterone, estrogen, testosterone, cortisol, aldosterone, and thyroid hormone.
Golgi Apparatus The Golgi apparatus has three distinct tiers of function. The first tier serves as an extension of the rER and receives proteins from the rER to start early processing of proteins. The second tier is the modification complex and modifies the N-oligosaccharide group on asparagine that was added in rER. It also adds an O-oligosaccharide group on serine and threonine. Glycosylation permits proper protein folding and increases protein stability. It also prevents early protein degradation. This part of the Golgi apparatus also adds disulfide bonds on glycoproteins and tyrosine groups, O-N-acetylglucosamine groups to serine and threonine to prevent activation by phosphorylation, and a GPI anchor to keep proteins anchored to the membrane. This anchor permits controlled release of proteins from the cell when the anchor is cleaved. Failure of these processes may play a role in oncogenesis and diabetes. Tier three of the Golgi functions as the export complex. It sends proteins to the rER, lysosomes, cytosol, cell membrane, or secretes them from the cell. Proteins destined for the lysosome have a mannose6-phosphate group added here. A defect in this protein is involved in I-cell disease and leads to the inability to target lysosomal enzymes properly, leading to their secretion from cell.
Nucleolus The nucleolus is created by chromosomes and is composed of ribosomal RNA segments that are being formed. It is separated into the pars fibrosa (newly transcribed rRNA) and pars granulosa (large and small ribosomal subunits / ribonucleoproteins).
Mitochondria The mitochondria are composed of an outer membrane and inner membrane. The inner membrane contains cardiolipin, which permits only proteins with an NH 2 sequence to enter. The inner membrane requires the action of hsp70 to promote protein unfolding prior to entry. The oxidation reactions of the electron transport chain and ATP synthesis takes place within the inner membrane. The matrix is the innermost part of the mitochondrion and permits pyruvate and fatty acid oxidation. This is where the citric acid cycle takes place. Other roles of the mitochondria include heme synthesis, steroid synthesis, and heat production. Mitochondria undergo clonal replication. They are inherited as a haplotype from the mother and generally unchanged across generations. Mitochondria provides history of human derivation but only in terms of females.
Biology of Cells Lysosomes Lysosomes contain acid hydrolases to digest large molecules, along with lipase, carbohydrases, proteases, and nucleases. Their internal pH is 4.8. Lysosomes play an important role in the initiation of apoptosis. A side effect of ischemia and cell damage is that rupturing lysosomes will contribute to damage in the penumbra region following local ischemia to some cells, such as what occurs after a myocardial infarction or stroke. Lysosomes are involved in a variety of diseases, including mucopolysaccharidoses, gangliosidoses, lipid storage diseases, glycoproteinoses, mucolipidoses, and leukodystrophies (see ““2.4.4 Lysosomal Storage Diseases” on page 22).
3.5.2 Cytoskeleton, Plasma Membrane, and Extracellular Matrix
Figure 28. Microtubules stained in green and actin filaments in red. Copyright Wikimedia. Used with permission.
Cilia and Microtubules The cytoskeleton is composed of microtubules arranged as nine pairs of doublets (9+2). The axoneme, or core of the cilium, is anchored to a basal body, also known as a microtubule organizing center (MTOC). The basal body is made from the centriole, which has a 9+0 organization (no central doublet). Microtubules within the cell are used to transport substances. Kinesin provides the energy for anterograde transport, while dynein provides the energy for retrograde transport. Dynein also provides energy for ciliary motion. Kinesin and dynein are both ATPases. Cilia are commonly found in the trachea, oviducts, and inner ear. Microtubular transport is essential in neurons for the transport of neurotransmitters from the Nissl substance to the axon terminal.
Stereocilia Stereocilia are cilia are found in the form of a large kinocilium that imparts polarity to the mechanosensory hair cells of the vestibular and Figure 29. Cell junctions. Copyright Mariana Ruiz. auditory system. Stereocilia do not contain mi- Used with permission. crotubules (“false cilia”). They are composed of actin, myosin, and cadherins. Stereocilia bear a similarity to microvilli. 33
Clinical Review for the USMLE Step 1
Figure 30. Stereocilia found in type I and type II hair cells of the vestibular system. The single large structure in the center is a kinocilium. Copyright Sapan Desai. Used with permission.
Plasma Membrane The plasma membrane is a fluid membrane anchored to a cytoskeleton to provide apical and basolateral polarity to a cell as the cell is anchored on its basement membrane. Its semipermeable nature permits small carbohydrates and water to penetrate readily. Ion channels permit selective transport of electro34
Biology of Cells lytes, which generates an electric potential to the cell. Signal transduction molecules permit activation of cell processes via binding of protein hormones. Steroid hormones readily pass through the cell membrane and directly affect nuclear messengers and DNA transcription.
Channels, Transporters, and Gap Junctions
Membrane Ports Membrane ports function via a variety of transport mechanisms. With active transport, ATP mediates the transport of solutes across the plasma membrane, typically against the concentration gradient. In facilitated transport, an ion that moves along its concentration gradient is used to drive passage of another ion against its concentration gradient. The ion flowing along its concentration gradient was previously transported against its concentration gradient by active transport. Facilitated transport indirectly uses ATP. Passive transport provides a passageway for an ion or solute to move across a plasma membrane and does not directly or indirectly use ATP. Symports permit two ions to move across the membrane together, while antiports permit two ions to move in opposite directions across the membrane.
Active Transporters The Na-K ATPase (P-type ATPase) is the primary mediator of cell potential and is found on all cells. It pumps sodium out of the cell and potassium into the cell in a 3:2 ratio (3 sodium, 2 potassium). The Na-K ATPase relies on ATP to phosphorylate the pump to permit release of sodium once the ions travel to the outside surface of the cell. The H-K ATPase (P-type ATPase) is found in parietal cells of the stomach to acidify gastric contents. V-type ATPases are found on many intracellular organelles and are used to modulate hydrogen concentration; sometimes paired with calcium or other ions. F-type ATPases are found in bacteria and mitochondrial inner membranes to drive ATP synthesis.
Ion Channels Voltage-gated ion channels are commonly Na, K, Cl, or Ca channels that open or close depending on the membrane potential of the cell to permit s elective transport of ions down their concentration gradients. Ligand-gated channels provide selective transport of various ions following binding of a ligand to the ion channel. A common example is the nicotininc acetylcholine receptor.
Figure 31. Nicotinic acetylcholine receptor with labeled subStretch receptors are potassium units. Copyright Sapan Desai. Used with permission. channels found in the tip links of 35
Clinical Review for the USMLE Step 1 the stereocilia and kinocilium of the hair cells in the vestibular and auditory system. G-protein-gated open in response to binding of G-proteins. Inward-rectifier K channels are found in the pacemaker cells of the heart, beta cells in pancreas. Funny currents are spontaneously depolarizing sodium channels found in the pacemaker cells of the heart. Various toxins can bind to these channels and inhibit their action. Tetrodotoxin binds to sodium channels and prevents their function. Lidocaine also binds to sodium channels. Dendrotoxin binds to potassium channels. Various rare genetic conditions can lead to malfunction of these channels, including episodic ataxia, generalized epilepsy with febrile seizures, paramyotonia congenital, potassium-aggravated myotonias, and hyperkalemic periodic paralysis. Mutations are also found in various types of ion channels.
G-Proteins G-proteins are embedded within the plasma membrane and play a role in activating cell signaling pathways. G-proteins are made up of alpha, beta, and gamma subunits. Proteins bind to G-proteins in order to modulate their activity, such as ras. G-protein activation influences pathways in many cells with the end result leading to modulation of DNA synthesis and other cell activity. Gs proteins stimulate cAMP and PKA formation, Gi proteins inhibit cAMP and PKA formation, and Gq proteins stimulate IP3 and DAG formation to increase Ca and PKC, respectively. Gs proteins are activated by B1, B2, D1, D5, H2, and V2 receptors. Gi proteins are activated by A2, M2, M4, D2, D4 receptors. Gq proteins are activated by A1, M1, M3, M5, D3, H1, and V1 receptors.
Receptor Subtypes Table 4. List of receptors, their signaling pathway, and their general function in the body. Receptor
→ IP3, DAG
Decrease SNS activity
Increase SNS activity
→ IP3, DAG
Cortex and hippocampus (memory)
→ IP3, DAG
Substantia nigra (Parkinson’s disease)
Renal vasodilation, psychosis
Caudate, putamen, nucleus accumbens, olfactory tubercle, septum, hypothalamus, and cortex; also plays a role in psychosis
Limbic structures (cognitive and emotional traits), psychosis
→ IP3, DAG
Limbic structures (cognitive and emotional traits), psychosis
Hippocampus, hypothalamus (pain and affect)
→ cAMP → IP3, DAG
Decrease heart rate (increase PNS) Increase exocrine gland and GI activity Neostriatum
Biology of Cells Receptor
→ IP3, DAG
Bronchoconstriction, mucus production in respiratory tract, and pruritus
Increase GI activity
→ IP3, DAG
Vasoconstriction (via ADH)
Increase water absorption by the kidney (via ADH)
3.6. Growth Factors 3.6.1
Platelet-derived growth factor (PDGF) comes from multiple sources, including platelets, macrophages, and neurons. It serves to regulate cell growth, cell migration, angiogenesis, and embryonic signaling. Pathology related to PDGF leads to atherosclerosis, fibrosis, and malignancy. PDGF functions via the tyrosine kinase receptor.
Epidermal growth factor (EGF) is derived from macrophages, neurons, and the skin. It leads to elevations in calcium, glycolysis, and protein synthesis leading to cell proliferation. Defects lead to tumorigenesis. EGF works via the tyrosine kinase receptor.
Transforming growth factor alpha (TGF-α) is derived from macrophages, neurons, and skin. It serves a role in epithelial development, neuronal proliferation, and stem cell development. Defects lead to cancer. TGF-α works via the tyrosine kinase receptor.
TGF-β has numerous sources. It plays a role in inflammation modulation, tissue regeneration, differentiation, and embryonal signaling. Pathological conditions with this growth factor lead to renal fibrosis following damage and diabetes (treated by ACE-inhibitors). It functions via the serine, threonine kinase receptor.
Neuronal growth factor is derived from neurons and helps to maintain neuronal survival through feedback activation. It plays a role in some degenerative conditions, such as Alzheimer disease. It functions on neurons via TrkA receptors.
Erythropoiein is derived from mesangial cells of the kidney. It is essential for the development of erythrocytes in bone marrow. Defects in EPO can lead to polycythemia vera, primary and secondary erythropoiesis. It functions via EpoR receptors in RBC precursors.
Clinical Review for the USMLE Step 1 3.6.7
Insulin growth factor 1 (IGF-1) is derived from the liver and is released in significant amounts after stimulation by growth hormone. IGF-1, also known as somatomedin C, stimulates cell growth, differentiation, and development via a system-wide response. Pathology associated with IGF-1 leads to acromegaly, tumorigenesis, hypoglycemia, lipohypertrophy, and tonsillar hypertrophy. IGF-1 works via the tyrosine kinase receptor. It can play a therapeutic role in patients with IGF / GH deficiency and ALS.
IGF-2 is derived from the brain, kidney, pancreas, muscle. IGF-2 has more specific sources and targets compared to IGF-1. It is important in fetal development, development of brain, kidney, and liver. Defects lead to hypoglycemia. It leads to activation of the IGF-1 receptor; the IGF-2 receptor is not paired with a cell-signaling pathway.
4. Human Development
4.1. Pedigree Analysis 4.1.1
Inheritance Patterns and Risk Determination
Pedigrees are diagrams that delineate genetic relationships between related people. Pedigrees can be used to determine inheritance patterns, such as autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive, and mitochondrial. Several conventions are used for pedigrees: squares are used to represent males, while circles represent females. A couple that has mated is shown at the same level and are connected by horizontal lines. Children are represented by vertical lines emanating from their parents. Shaded squares and circles represent individuals with a particular trait.
Autosomal Dominant Figure 32. Example of an autosomal Autosomal dominant conditions are phenotypically-evident if dominant condition. Copyright Wikithe individual has at least one allele for the condition. Passing media. Used with permission. on the allele to their children occurs 50% of the time. Rarely, individuals may be â€œdouble positiveâ€? and have both alleles for an autosomal dominant condition; for most diseases, this leads to severe problems that are incompatible with life. Examples include Huntington disease and polycystic kidney disease.
Autosomal Recessive Autosomal recessive traits, such as albinism, are passed on only if two affected individuals each pass on the allele that codes for the disease. These individuals do not need to have the phenotype for the disease, as the trait is recessive by definiFigure 33. Example of an autosomal tion. For example, in the figure to the right, the father is a carrecessive trait. Copyright Wikimedia. rier for the trait while the mother has both alleles for the trait. Used with permission. Roughly 50% of her children will also have the trait. Their son 38
Human Development and Genetics on the far right marries a woman who also has both alleles for the trait; given that at least one of their children then has the phenotype, that son must be a carrier for the trait. Were this inheritance pattern autosomal dominant, all children would have been positive. Had it been X-linked recessive, all of her male children would have been positive. Finally, had this pattern been mitochondrial, all of her children would again had the trait. Other examples of autosomal recessive diseases include sickle cell disease, Tay-Sachs disease, and cystic fibro- Figure 34. X-linked dominant trait. sis. It is common to skip generations with autosomal recessive Copyright Wikimedia. Used with permission. disorders.
X-Linked Dominant X-linked dominant traits are passed on to all females of affected fathers as they will donate their only X chromosome to their daughters. Their sons will all be negative as their X chromosome will come from the mother. For affected mothers, their children have a 50% chance of inheriting the disease depending on which of the two alleles they receive. Figure 35. X-linked recessive trait shown skipping generations. CopyX-linked recessive traits are evident in the sons of phenotypi- right Wikimedia. Used with permiscally-affected mothers given that the mother has two positive sion. alleles and that the son will receive one of these X chromosomes. Daughters have a 50% chance of becoming a carrier. It is common to skip generations with X-linked recessive disorders. Examples include color blindness, hemophila A and B, and various muscular dystrophies.
Mitochondrial Inheritance Mitochondrial inheritance affects all children of the mother, and her daughters continue to pass along the trait. Sons will not pass the trait along to their children unless they marry a Figure 36. Example of a mitochondrial woman who is afflicted. Examples include diseases related to inheritance pedigree. The motherâ€™s son exercise intolerance and dysfunction of the muscles. does not pass it on to his children on the far right of the diagram. Copyright Wikimedia. Used with permission. 4.2. Population Genetics
Clinical Review for the USMLE Step 1 seen with the Ashkenazi Jew population. Small population sizes lead to increased predisposition toward genetic disease. Genetic drift has a greater chance for deleterious mutations leading to negative effects due to random mutations. Genetic diversity minimizes the effects of negative mutations. Population bottlenecks lead to a dramatic reduction in population and increased genetic drift and founder-effect type effects. Selection occurs when adaptive traits impart Figure 37. Illustration of gene therapy. Copyright Terese Winslow / advantage and thus are transmitted more readily through NIH. Used with permission. the population.
4.3. Gene Therapy Gene therapy offers the potential to use adenovirus vectors to insert beneficial sequences into the hostâ€™s DNA, thereby leading to a change in a phenotype. For example, patients with loss of function mutations can have a gene inserted that produces the relevant protein product. If the sperm or egg cells are affected, the changes will be passed along to their progeny. A second method for transmitting beneficial sequences is to use stem cells. These totipotent cells can be implanted into the brain or marrow and allowed to proliferate and replace abnormally functioning cells. Long term studies using these two techniques are pending in the form of clinical trials at major institutions.
4.4. Genetic Testing 4.4.1
DNA sequencing involves determining the entire nucleotide structure of a particular gene. Various methods exist to determine the precise nucleotide sequence of DNA. The negative aspect is that it is difficult to tell the differences between introns and exons. Sequencing is important to identify where various genes are located in chromosomes and to better understand the human genetic code. The human genome project completed a map of the entire human genome at the nucleotide level and used this map to identify the location of approximately 25,000-30,000 human genes. Approximately 3 billion nucleotides were sequenced and used to provide genetic testing to identify the presence of potentially deleterious genes.
Human Development and Genetics 4.4.2
Polymerase chain reaction (PCR) permits amplification of a particular DNA sequence for additional testing or analysis. It uses a DNA template that binds to the target and isolates it for amplification. Primers bind to the target and begin transcription, which is performed by heat-stable taq polymerase. A series of deoxynucleotides provides the nucleic acids for transcription. Exponential amplification occurs so as few as 20 cycles can yield over a million copies
Restriction fragment length polymorphisms (RFLPs) are used on purified DNA that has been amplified using PCR. The DNA is cut into restriction fragments by endonucleases and separated on an agarose gel through electrophoresis. The separated fragments provide a unique DNA fingerprint for an individual due to differences in where the enzymes cut. This is the result of random mutations. The fragments can be used to positively identify an individual or make judgments regarding relationships between individuals (paternity testing).
DNA chips contain thousands of organized probes in a known configuration. The microarray can be used to quickly identify whether a person has a particular gene for a disease using tissue collected from that person. Microarrays lead to the issue of information analysis given the sheer amount of data they generate. Careful statistical analysis is necessary to avoid issues with confounding and incidental findings.
Figure 38. Western blot. Copyright Ernst Hempelmann. Used Southern blots use DNA probes to identify specific DNA sequencwith permission. es. They can be used to verify that a particular DNA sequence exists.
Northern blots use a DNA probe to bind to an RNA sequence. A reverse procedure can be used to bind DNA on a gel with probes made from cell RNA. This permits gene expression profiling on an ongoing basis for various cells.
Western blots are used to detect protein within a homogenous tissue extract. Western blots initially separate proteins denatured proteins by gel electrophoresis. Proteins are probed using antibodies to determine whether the protein is present. Western blots can be used as a confirmatory test due to its high specificity; examples include HIV, bovine spongiform encephalopathy, and lyme disease. 41
Clinical Review for the USMLE Step 1 4.4.8
Immunohistochemistry uses antibodies to precisely locate various proteins on intact tissue mounted to slides. Direct immunofluorescence has an antibody bind to tissue that also fluoresces upon binding. Indirect immunofluorescence works by having an antibody bind to tissue, which is then bound to a secondary antibody. A color reaction occurs upon application of an enzyme.
Enzyme-linked immunosorbent assay (ELISA) is used to detect an antibody in a sample. Generating quantitative information is possible, a benefit difficult to realize with other techniques. ELISA may be used to ascertain competitive binding of various proteins.
Genetic counseling relies on completing a targeted analysis of a patientâ€™s DNA to determine if they have risk factors for a particular disease. For example, the presence of BRCA 1 in a woman with a strong family history of breast cancer is likely to develop breast cancer at a young age. An appropriate analysis of both genetic and environmental risk factors can help patientâ€™s make decisions for future care. For example, a young woman with BRCA 1 may elect to undergo prophylactic bilateral mastectomy to minimize the risk of breast cancer.
5.1. Fever 5.1.1
Fever can be generated from endogenous, exogenous, and toxic causes. Endogenous mediators include IL-1, IL-6, and TNF-alpha. Exogenous causes include endotoxin. Toxic injury from products like 2,4DNP can also lead to fever. Fever is never normal and is not compensation for hypothermia. Fever following surgery is a common occurrence; the cause can often be narrowed down by postoperative day and the presentation of the patient.
Postoperative Days 1 and 2
Fevers that occur by postoperative day two are typically due to atelectasis. Atelectasis can be minimized with the use of an incentive spirometer and facilitating deep breathing and cough. This is particular important in patients who undergo open chest procedures or those with multiple rib fractures; an epidural to manage postoperative chest pain may be particularly beneficial.
Postoperative Days 3 Through 5
The most common cause of postoperative fever between postoperative days three and five is due to urinary tract infection. Prophylactic measures can be taken in patients who are more susceptible than normal for developing UTIs. This population includes patients who have indwelling Foley catheters, and who have a historical predilection for developing UTI.
Inflammation and Repair 5.1.4
Postoperative Days 4 Through 6
Deep vein thrombosis is the most common cause of postoperative fever on days four through six. DVT is a serious issue than can lead to sudden death due to a massive pulmonary embolism, and astute surgeons and health care providers take steps to minimize this potentially disastrous outcome. Low-dose heparin given subcutaneously and the use of sequential compressed devices (SCD) have been shown to reduce the incidence of DVT. The best way to reduce the chances of DVT occurring is to have the patient ambulate as soon as possible following surgery. Patients most at risk for DVT/PE are trauma patients, and those who have undergone pelvic procedures, orthopedic surgery, or a general surgery procedure.
Postoperative Days 5 Through 7
Infections of the surgical wound are most common postoperative days five through seven. Prophylactic antibiotics dosed during surgery and continued for 24 hours are an important part of any surgical procedure, even in some clean cases. Finally, fevers that occur after postoperative day seven are often iatrogenic, often from medications.
5.2. Systemic Inflammatory Response Syndrome Systemic inflammatory response syndrome (SIRS) is the presence of two or more of the following: •
Fever / Chills: > 38°C or < 36°C
Tachycardia: > 90 bpm
Tachypnea: > 20 breaths per minute or a PaCO2 < 32 mmHg
Leukocytosis: > 12,000/µL or < 4,000/µL or > 10% bands
SIRS can be due to bacteremia (sepsis) and can progress to end-organ damage (severe sepsis). SIRS should be thought of as a global inflammatory state with a pronounced cytokine cascade activation leading to multiple organ dysfunction syndrome (MODS). The proinflammatory state includes numerous acute phase reactants and release of vasoactive cytokines. The more end organs affected, the higher the risk of mortality. With lactic acidosis, change in mental status, decreased urine production, or other signs of organ dysfunction, MODS develops with SIRS. If the etiology is bacteremia, the sepsis becomes severe sepsis. The addition of hypotension to sepsis (SIRS due to bacteremia) is septic shock. Systolic BP < 90 mmHg or a need for vasopressors is septic shock. SIRS is treated with admission to the ICU, antibiotics if infection is suspected, and supportive therapy. Fluid sequestration and third space fluid losses can be large; thus fluid resuscitation is necessary. A pulmonary artery catheter (PAC) can be used to monitor cardiac function, however their use for monitoring resuscitation is becoming rare as there is little clinical data showing that their use leads to a better clinical outcome. There are newer technologies now becoming available that can monitor cardiac function noninvasively. Activated protein C (Xigris) leads to fibrinolysis and reduces inflammation but can lead to bleeding. Aggressive fluid resuscitation with correction of central venous PO2, serum lactate, base excess, urine output, and blood pressure must be done. Intravenous steroids are often used not only in patients with adrenal dysfunction but also in septic shock patients who are not responding. Patients in septic shock 43
Clinical Review for the USMLE Step 1 who otherwise do not have adrenal dysfunction cannot mount the massive adrenal response necessary and steroids need to be added. Tight glucose control has been shown to be beneficial. If the etiology of SIRS (usually infection) is not discovered and treated, the patient will progress to severe sepsis, MODS, and septic shock.
5.3. Sepsis Sepsis is SIRS with bacteremia. The most common cause of sepsis is from gram negative bacteremia. The most common source is genitourinary, followed by respiratory and abdomen. Diversion of blood flow from the central circulation to the peripheral vessels occurs due to increased heat production from hypermetabolism. Without fluid repletion, ischemia of central tissues occurs. Further, there is a diffuse increase in microvascular permeability secondary to the inflammatory response taking place. Left uncontrolled, the end result is decreased urine output from renal hypoperfusion, hypotension from diversion of intravascular volume, and warming of the extremities from decreased systemic vascular resistance (SVR). Cardiac output increases to compensate for the hypotension. Sepsis causes decreased oxygen consumption and exerts its effects on the mitochondria of cells. In sepsis with a pronounced inflammatory response and cytokine activation, no matter how much oxygen is delivered to the cells, they do not use it well. Sepsis also causes microthrombosis at the capillary level which produces shunting of oxygenated blood from the pre-capillary arterioles to post-capillary venules without the oxygen being used by the tissue. APC works by preventing this microthrombosis. This decreased oxygen consumption produces an increase in mixed venous oxygen content. Proof that infection is the etiology of the SIRS can be elusive, but sepsis has a source of infection. If organ dysfunction is evident, the sepsis is severe sepsis. Numerous general symptoms are often present. Fever and mental status changes are common. The source of infection must be diligently sought. IV lines should be immediately tested and changed, especially central lines. A complete physical exam should be done to identify any source of infection. If tachypnea is one of the features of the SIRS, respiratory alkalosis is often present. Virtually any uncontrolled infection or significant disease process can lead to SIRS. Almost anything can cause SIRS: an amusement part thrill ride often makes people tachycardic and tachypneic. Many disease processes can cause SIRS and organ dysfunction yet that is not sepsis unless an infection is involved. For instance, sterile fulminant pancreatitis can cause SIRS, MODS and even death without sepsis. Glucocorticoid release in shock leads to insulin resistance. The resulting hyperglycemia is the earliest sign of impending sepsis and may occur up to 24 hours preceding hypotension, low SVR, high CO, and warm extremities. Respiratory alkalosis, hyperventilation, and altered mental status are other early signs of sepsis. Sepsis is associated with an increase in IL 6. Late sepsis will progress with worsening hypotension, a decrease in cardiac output from poor filling pressures (low CVP and BV), increased PVR, cold extremities, conversion to lactic acidosis with metabolic acidosis, and hypoventilation. Supportive therapy and maintaining organ perfusion are essential to decrease morbidity and mortality. Infection by IV lines may be treated with imipenem, meropenem, cefoperazone, cefepime, or vancomycin. APC (Xigris) used in the treatment of sepsis leads to fibrinolysis, but has strict criteria for use.
Inflammation and Repair
5.4. Shock 5.4.1
Septic shock is sepsis with shock and causes hypoperfusion of end organs. Tachypnea and abnormalities in the WBC are typically present. Distributive shock is the early stage of septic shock and results with uneven fluid distribution (third space fluid sequestration and diversion of blood from central organs to the periphery) throughout the body. This is secondary to release of acute phase reactants and a gross systemic inflammatory reaction. This inflammation is commonly secondary to infection by gram negative organisms and subsequent production of endotoxins. Unopposed activation of TNF commonly occurs as the initiator of this inflammatory cascade. With continued hypoperfusion, the period of warm septic shock with shunting of blood to the periphery is replaced with late shock and leads to a state of global hypoperfusion and imminent cardiovascular collapse. Treatment for septic shock requires correction of the underlying septic source, fluid resuscitation, and the use of pressors. End organ dysfunction must be corrected as quickly as possible to avoid long term damage. Steroids may have some role to help mitigate the immune response. Septic patients with end organ failure who meet APACHE II criteria may be candidates for APC (Xigris).
Severe hypovolemia can overwhelm the bodyâ€™s ability to generate sufficient vasoconstriction and cardiac output. Hypovolemic shock is the most common type of shock and can occur secondary to hemorrhage, burns, dehydration, abuse of diuretics, vomiting, and diarrhea. The initial response is increased peripheral vasoconstriction and cardiac contractility, tachycardia and cool extremities. The renin-angiotensinaldosterone axis is stimulated, ANP release by the heart is inhibited to decrease diuresis, and the desire to drink fluid is stimulated. Hypovolemia requires replacement of the intravascular volume. Typically, lactated ringers is given as a bolus. In the adult when hemorrhage is thought to be the etiology of the shock, if two liters of ringers lactact does not correct the shock or if the hemorrhage continues, packed red blood cells should be infused. Correction of the inciting events leading to the hypovolemia (stop the hemorrhage!) is the first priority. Admission to an ICU and use of invasive pressure monitoring may be required.
Cardiogenic shock is due to compromised function of the heart, such as with heart failure following a myocardial infarction, arrhythmia, cardiomyopathy, or high-grade congestive heart failure. Sustained hypotension leading to hypoperfusion is the result even with satisfactory filling pressure of the left ventricle. Cardiogenic shock therefore presents with prerenal failure, mental status changes, and cool extremities. Jugular venous distention and pulmonary edema are other findings. Pericardial tamponade, saddle pulmonary embolus, and tension pneumothorax must be ruled out as they can produce symptoms similar to cardiogenic shock. Following diagnosis, most practitioners will consider the use of a pulmonary artery catheter to help guide resuscitation and tailor therapy according to the available cardiac function. Inotropic agents such as dobutamine are often necessary to augment cardiac function. If the left heart failure is poignant, an intra-aortic balloon pump may be necessary to reduce afterload and augment cardiac function. Failing this, a left ventricular assist device or heart transplantation may be required. 45
Clinical Review for the USMLE Step 1 5.4.4
Widespread vasodilation in response to excess histamine release leads to anaphylactic shock. It is secondary to a severe type I hypersensitivity reaction. Systemic vasodilation occurs and overwhelms the ability of the heart to generate sufficient output. There are a variety of causes, including bee stings and allergic reaction to various medications. Anaphylactic shock is induced by IgE. Severe swelling of the face and throat can occur and lead to obstruction of the airway. Anaphylactic shock requires immediate supportive therapy due to the risk of respiratory arrest. Epinephrine is used to forestall the collapse of the airway and stimulate the cardiovascular system.
Neurogenic shock occurs secondary to acute disruption of central nervous system pathways, typically at the level of the spinal cord from acute trauma. Loss of background sympathetic activity leads to hypotension, bradycardia, and peripheral vasodilation. Treatment of neurogenic shock requires supportive therapy and stabilization of any fractures leading to compromise of the spinal cord. A significant amount of fluid resuscitation may be necessary. Atropine may be used for symptomatic bradycardia. Pressors may be required. If the neurogenic shock is due to trauma, hemorrhagic shock must first be ruled out (stop the bleeding!) as the source of the shock.
Endocrine shock may occur secondary to profound hypothyroidism, thyrotoxicosis, or adrenal insufficiency. A combination of hypovolemic and cardiogenic shock may occur. Treatment is to support the endocrine function. Endocrine shock may contribute to septic shock as an inadequate adrenal response to septic shock has been recognized and steroid supplementation may be needed.
5.5. Wound Healing 5.5.1
Phases of Wound Healing
Wound healing consists of three phases: the inflammatory phase, the proliferative phase, and the maturation or remodeling phase. The inflammatory phase lasts approximately 5 days and is marked by the hemostatic and cellular responses. The proliferative phase begins at day 4 and lasts approximately 3 weeks and sees the creation of a disorganized framework of extracellular matrix and blood vessels. The remodeling phase can last up to a year and consists of the gradual reorganization of matrix and vascular structures into a more functional and stronger form. The inflammatory phase of healing (days 1 through 5) begins immediately after injury with the appearance of platelets, which participate in coagulation and hemostasis. Platelets release cytokines and growth factors that promote chemotaxis and migration of important inflammatory mediators into the injury site. Neutrophils arrive within the first two days and play a minor role in wound healing through phagocytosis of local debris. Macrophages become the dominant cell type by day 3 and orchestrate the wound healing process by releasing crucial cytokines and growth factors such as IL-1 and TGF-Î˛ that direct the migration and work of other cells. In addition, epithelialization begins during the inflammatory phase with cell migration and mitosis, signaled by the loss of contact inhibition between cells and regulated by various growth factors such as EGF. In a primarily closed surgical wound, epithelialization is complete within the first 48 hours, sealing the wound against external contamination. 46
Psychology By the end of the first week, the proliferative phase has begun (days 5 through 21). Fibroblasts become the dominant cell type and rapidly synthesize collagen as well as matrix material such as GAGs (glycosaminoglycans). Although wound tensile strength begins to increase as a result, the collagen is predominantly type III, whereas in normal skin there is a 4:1 ratio between type I and type III collagen. Wound contraction occurs with the appearance of myofibroblasts, specialized fibroblasts with contractile cytoplasmic microfilaments. Angiogenesis begins during the proliferative phase under the influence of factors such as VEGF (vascular endothelial growth factor) secreted by platelets and other cells. The maturation or remodeling phase (week 4 up to 1 year) begins as the rate of collagen breakdown mediated by metalloproteases increases to match the rate of collagen synthesis. Type III collagen is replaced by type I, reestablishing the normal 4:1 ratio. The collagen also becomes more organized and better cross linked, and the tissue becomes less cellular. The wound reaches its peak strength, about 80% of baseline, after about 60 days. Type I collagen is the predominant collagen in mature scars. Type II collagen is the primary constituent of cartilage. Type III collagen is found in embryonic tissue, vasculature, uterus, and gastrointestinal tract; it is the predominant collagen in immature scars. Type IV collagen is found in basement membrane. Wound healing may be negatively affected by increasing age, systemic disease, immunosuppression, steroids (which can be reversed by vitamin A), malnutrition, smoking, infection, foreign bodies, radiation, and scar formation. Abnormal scarring may occur in the form of widened, hypertrophic, or keloid scars. Widened scars are marked by normal quantities of collagen spread over a larger area, whereas the histology of hypertrophic and keloid scars are similar and involve excessive collagen deposition. Keloid scars differ from hypertrophic in that keloids grow beyond the normal wound borders. Widened and hypertrophic scars both result largely from excessive tension on the wound, whereas the etiology of keloids is unclear but may be influenced by autoimmune and endocrine factors. Keloids also differ from widened and hypertrophic scars in that the latter generally respond well to treatment (primarily excision and closure), but keloids often worsen and require combination therapy with multiple modalities. In addition, keloids show a much higher correlation with genetic, familial, and racial factors.
6. Psychology 6.1. Life Cycle 6.1.1
The neonate is born with excellent sensory skills, including the ability to distinguish between various tastes, mimick a parentâ€™s expressions, respond to loud noises, follow an object with his eyes, and being comforted by a voice or being picked up. Basic reflexes present at birth include the palmar grasp reflex (the child automatically holds onto an object placed in his palm), the rooting reflex, (the child turns in the direction of stroking of his cheek), the stepping reflex (the child moves as if he is walking when held upright), the Moro reflex (the neonate extends his limbs when startled), and the Babinski reflex (the child moves his great toe upwards and fans his toes outward when the plantar surface is stroked). The palmar grasp reflex remains until 2 months of age, the rooting reflex remains until 3 months of age, and the stepping reflex, Moro reflex, and Babinski reflex remain for about 1 year. Continuation of these reflexes several months after they should have rescinded may indicate an underlying pathology.
Clinical Review for the USMLE Step 1 6.1.2
During infancy (from birth to 18 months) the baby begins to spontaneously smile. Spontaneous smiling begins at approximately 1 week and disappears by 3 months. The infant begins to develop a social smile (smiling at a face) by 2 months. At three months, the infant begins to use facial expressions to show underlying emotions. Laughing begins at four months. The infant begins to exhibit stranger anxiety at 7 months and is oriented to the voice of his mother and father. Stranger anxiety typically resolves in a few months. At 15 months of age, the infant develops separation anxiety when kept from his mother and this separation may cause great distress. These ranges are inexact and vary child to child. Motor development progresses to the point where the infant is able to roll over at 3 months. Around 6 months, the infant begins to crawl, and at 7 months, the infant is able to sit unsupported. At one year of age, the infant is able to stand without support, can walk if given assistance, and says his first word. By 15 months, the child is able to walk independently. Language development begins at 3 months with babbling. The first words are usually echoes of what is spoken to the infant (echolalia). It is no wonder that the first words are typically something repeatedly said to the infant, such as mama or papa. During visits to the physician, guidance to the parents should center on childproofing the house, because the infant begins to move from place to place and is now at risk of numerous environmental dangers.
From 18 months to 3 years is the toddler period. During this time, the toddler is going through the anal period (Freud), autonomy versus shame and doubt (Erikson), and the perioperational phase (Piaget). Autonomy is manifest during this time by the child saying “no” to simple parental requests, even when the child would ordinarily say “yes.” Language continues to develop with simple two-word sentences at age 2, three-word sentences at age 3, four-word sentences at age 4, and five-word sentences at age 5. Vocabulary extends to several hundred words at age 2, even though only several dozen words make up the spoken vocabulary. Some stuttering may occur at this early age, as the motor pathways continue to develop. Control over bowel movements is typically completed by age 3, and control over micturition is controlled by age 4. Toilet training should typically not be attempted until cues are given by the child, including curiosity about the bathroom, squatting to expel feces, and displeasure after urination or defecation. At 1 year of age, the child is able to stack three blocks, throw a ball, scribble on paper, run, and climb stairs using one foot at a time. The child moves to and fro from his mother, which is known as rapprochement. At age 2, the child can stack six blocks, kick a ball, undress himself, and use utensils. The child plays alongside other children (parallel play), and can name body parts. This is also the time that autonomy becomes most noticeable with frequent use of the word “No.” Counseling by the physician during this time should include management of tantrums. Techniques that the parents should be educated on include ignoring the toddler’s outburst completely, shifting the child’s attention to something else, and using “time out” periods to teach the child that tantrums are unacceptable. The most significant task during the second year of life is resolving separation anxiety and alleviating the distress in the child caused by removing him from his mother. In children who are hospitalized at this age, their most significant concern is separation from their parents, which supersedes even their fear of bodily harm or pain. The child’s height at age 2 should be noted, as this is typically half their height as an adult.
Development by Age 3 Preschool aged children (ages 3-6) have significantly larger vocabularies, numbering in the thousands of words. Pronouns, age, gender, and name are articulated by age 3, prepositions are complete by age 4, and an understanding of the concept of time is complete by age 5, including the use of the future tense. At age 3, the child can stack 9 blocks, can ride a tricycle, use scissors, partially dress himself, and can climb stairs using alternate feet. At this point, the child is typically able to spend a portion of the day away from his mother, and can also identify colors. At this time there is no evidence that daily separation from his mother has long-term sequelae, and a good day care setting may be recommended by the physician.
Development by Age 4 At age 4, the child is able to create simple drawings of people, button her clothes, and brush her teeth. She can hop on one foot and copy a cross. Social development continues at this age with interest in sexual identity, having nightmares, developing imaginary companions, and being overly concerned about disease and injury. Preschool-aged children typically can play cooperatively with other children, and have good self-expression.
Development by Age 5 At age 5, the preschooler can draw a person in detail, play hopscotch, and copy a square. Freudâ€™s Oedipal stage reaches its climax at this age, as the child begins to have a rivalry with the same-sex parent, and the child is unable to understand the meaning of death. The loss of friends, relatives, or pets is typically not understood to be permanent and the child may expect them to return at any given moment.
As school-aged children (ages 6-12), they become more mature and cooperative and tend to start becoming more involved with people other than their parents. As they begin to develop role models, these children tend to identify with the same sex parent, and psychosocial issues tend to be dormant at this age. Children at this age have well-developed motor skills and a strong moral sense. They are able to tie shoelaces, ride a bicycle, copy a triangle, print letters, and learns to read. By age 6, the child understands that the death of others is permanent. Due to a well-developing superego, this is often considered the best time for elective surgery. With regard to the ability to draw shapes, a three year old can draw a circle, a four year old can draw a cross and a rectangle, a five year old can draw a square, a six year old can draw a triangle, and a seven year old can draw a diamond. Note that one way to remember this progression is to note that circle, cross, rectangle, square, and triangle are in alphabetical order.
Puberty begins in these years and is hallmarked by the onset of menarche in females (between ages 9-12) and ejaculation in males (between the ages of 10-13). Physical development at this age, in addition to side effects such as acne, lead to a number of psychosocial issues for this age group. These issues often include a preoccupation with body image and gender roles. They now begin to deeply explore their sexuality and solidify their sense of identity. 49
Clinical Review for the USMLE Step 1 Homosexual experiences may occur at this age as role confusion develops. Some element of risk-taking behavior is typically present. This hazardous behavior may be minimized by using short-term consequences. Both the parents and physician should serve as mentors and role models as teenagers experiment with their sexuality. In their counseling role, birth control and education regarding sexually transmitted diseases should be discussed. The first age of sexual intercourse is typically around 16, but less than 1/3 of teenagers regularly use birth control. This has led to a serious problem with teenage pregnancy, leading to over one million United States pregnancies in this age group yearly. Of that number of pregnancies, nearly 400,000 end in abortion, and often require parental consent depending on state law. Risk factors for teenage pregnancy include divorced parents, lack of planning for the future, psychosocial issues leading to depression, and poor performance in school.
With early adulthood spanning the ages of 20 to 40, typical concerns include marriage and having children. Nearly 75% of Americans have been married and with children by age 30, but only 25% of families have two parents living in the home. It is also at this age that a reappraisal of one’s life starts and the adult’s role in society is more clearly defined.
Middle adulthood, from 40 to 65, leads to more concern over power and authority. Failures in this stage often lead to a change in profession, a change in lifestyle, divorce or infidelity, use of illicit drugs, and depression. This is what is often termed as a “midlife crisis,” and it is widely believed to be caused by one’s increased awareness of their mortality. This is typically punctuated by menopause in women and diminished strength, stamina, and sexual performance in both genders. However, it is important to note that hormone levels stay the same and there is no evidence of decreased “sexual drive.”
The average life expectancy in the United States is 76 years, and the fastest growing age group in the population is adults over age 85. African American men have the lowest life expectancy at 66 years of age, followed by white men and black women at 74, and white women at 80. Physical changes at this age make independent living more difficult due to decreased vision and hearing, incontinence, diminished immune responses, a general decrease in body system functioning and reserve, diminished strength, and decreased bone mass. Decreased cerebral blood flow and age-related mental function changes lead to some memory lapses, but any change in intelligence should be considered pathological. There are also changes in sleep patterns leading to a loss of sleep and decreased quality.
6.2. Theories 6.2.1
Child development covers the maturation of a child from birth through the teenage years. There are three major theories that attempt to describe the various stages a child goes through. Sigmund Freud breaks down the developmental process as falling into the oral period, anal period, oedipal period, latency, and intensification of sexual activity. Erik Erikson breaks the stages down into a time of basic trust versus mistrust, autonomy versus shame and doubt, initiative versus guilt, industry versus inferiority, and identity versus role confusion. Finally, Jean Piaget breaks down these stages into a period of 50
Psychology sensorimotor development, perioperational development, preoperational development, concrete operations, and formal operations. Table 5. Theories of development. Theories of Development Sigmund Freud
Basic trust versus mistrust
Autonomy versus shame and doubt
Initiative versus guilt
Industry versus inferiority
Intensification of sexual activity
Identity versus role confusion
Freud’s stages are centered on the erotogenic zones. He believes that the first period is the oral phase, as this is the stage in which the child derives pleasure from suckling. If the child is able to successfully meet his needs through suckling, Freud says he will later be able to meet the needs of other stages. The oral stage begins at birth and continues until about 18 months of age. The anal period is when the child is able to exert readiness and self control through activities such as toilet training. During this period of time, the conflicts in the child’s life center on self-control versus parental demands. With too much control by the parents during this time, Freud believes that the child will become stubborn and compulsive as an adult. This period spans the time from 18 months to 3 years. The Oedipal period is when the child develops feelings for the opposite-sex parent. The child is fearful of retaliation by the opposite sex parent at this time, and resolves this conflict by identifying with the same-sex parent. This occurs during the preschool years, from 3 years to 6 years of age. The latent period is next. During this stage the child is able to translate his sexual drive into schoolwork and play. This stage occurs during the early schooling years, from 6 to 12 years of age. Finally, Freud believes that the last period occurs during the teenage years and is a time of increased sexuality. Table 6. Freud’s stages. Freud’s Stages Birth to 18 months
18 months to 3 years
3 years to 6 years
6 years to 12 years
12 years to adulthood
Intensification of sexual activity
Erikson’s stages are similar in concept to Freud’s, without the focus on human sexuality. The first period is the development of basic trust versus mistrust, and occurs from birth to 18 months. It is during this time that the child learns to rely upon his parents, especially his mother as he forms a bond through suckling and intimate care. From 18 months to 3 years, the child begins to focus on autonomy versus 51
Clinical Review for the USMLE Step 1 shame and doubt, learning to take care of tasks on his own and continuing to take on additional responsibilities. Initiative versus guilt follows in the preschool years, from age 3 to 6. This is the time that the child begins to communicate more with the outside world; positive feedback at this stage is important as the child develops language abilities. From 6 years of age to 12, the child begins to take pride in his education and takes part in various hobbies and sports. This is the development of industry versus inferiority. The teenage years hallmark the development of identity versus role confusion as the child learns who he is and how he fits into the world. Various social, physical, and emotional strengths and weaknesses are explored during these years. From age 12 to 20, teenagers undergo identity versus role confusion. They explore their sexuality more and try to understand their role as they experiment with various relationships. Experimentation with the same sex at this point is not uncommon. For young adults from age 20 to 40, intimacy versus isolation becomes the predominant phase. Relationships with their life partner and children begin to form at this point. In middle aged adults (age 40-65), additional maturation, creativity, and productivity takes place in the generativity versus stagnation period. In the elderly, Erikson’s ego integrity versus despair stage is dominant. Pride over one’s accomplishments at this age typically prevents depression, anxiety, and worsening of any underlying abuse of alcohol or drugs. The combination of continued physical and occupational activity, in addition to higher education, a strong social support system, and a beneficial family history are all contributors to increased longevity. Table 7. Erikson’s stages. Erikson’s Stages Birth to 18 months
Basic trust versus mistrust
18 months to 3 years
Autonomy versus shame and doubt
3 years to 6 years
Initiative versus guilt
6 years to 12 years
Industry versus inferiority
12 years to 20 years
Identity versus role confusion
20 years to 40 years
Intimacy versus isolation
40 years to 65 years
Generativity versus stagnation
65 years +
Ego integrity versus despair
Piaget hallmarks the period from birth to 18 months as the sensorimotor period, during which the child learns basic interactions with the outside world. This includes both sensory and motor stimulation, as the child initially learns through direct interactions with the environment, followed by out of sight, then out of mind, and finally learning object permanence. The next phase, spanning 18 months to 3 years, is the perioperational phase. The child’s intuition is the main source of decision-making, not logic, during this phase. From 3 years to 6 years, the preoperational phase appears and the child believes that moving objects are alive and have feelings (animism); the child is egocentric and so believes that the world exists for only them, and assigns meaning to events around themselves that do not have a foundation in reality (artificialism). 52
Psychology In the school age years, from 6 to 12, the child develops concrete operations and learns about conservatism and reversibility. The child begins to realize that water poured from a large, thin glass into a short, wide glass is still the same amount of water. Reversibility occurs when the child learns that taking 3 blocks from 10 yields 7 blocks, and adding 3 blocks to 7 gives 10 blocks. During the teenage years, formal operations are developed where the adolescent learns abstract reasoning and post conventional morality. During this stage, the teen becomes aware that exceptions to rules exist and should be exercised when ethically permissible. Table 8. Piagetâ€™s stages. Piagetâ€™s Stages Birth to 18 months
18 months to 3 years
3 years to 6 years
6 years to 12 years
12 years to adulthood
Abstract reasoning and post conventional morality
Progression of Stages
It is important to realize that subsequent stages cannot proceed until the stage before it is completed successfully. For example, it is difficult to develop abstract reasoning when basic logic skills are not in place. Circumstances that prevent maturation into the next stage can include brain injury, prolonged neglect, prolonged hospitalization, and a variety of developmental disorders. There are also a number of influences on child development, including genetic factors, prenatal care, socioeconomic status, gender, temperament, parental attachment, and the quality of the parental relationships. If development proceeds without significant delay or interference, the child begins to develop basic skills by a certain age. Failure to develop these abilities leads to developmental retardation with sequelae that can continue all the way through adulthood.
6.3. Coping Mechanisms 6.3.1
Ego defenses are techniques that people use to cope with stresses presented to them by their environment. These defenses are unconscious reactions to this stress. Over time, a personâ€™s ego defenses typically mature as a function of age and experience. There are four mature ego defenses, including altruism, humor, sublimation, and suppression; these are adaptive behavioral responses to external stressors and illness. There are a number of immature ego defenses, including acting out, blocking, denial, displacement, dissociation, fixation, identification, isolation of affect, passive-aggressive behavior, projection, rationalization, reaction formation, regression, repression, somatization, splitting, and undoing; generally, these are maladaptive responses to stress and illness.
Clinical Review for the USMLE Step 1 Table 9. Ego defenses. Mature Ego Defenses
Immature Ego Defenses
Isolation of affect
Mature Ego Defenses
Altruism Altruism is a mature ego defense in which the person gives to others without expecting anything in return. Altruistic behavior is typically preformed to alleviate guilty feelings. Large donations during the holidays by anonymous individuals may be done to reduce guilty feelings regarding the amount of wealth they have (“share the wealth”).
Humor Humor is a mature ego defense that individuals use to reduce anxiety in a difficult situation. Making jokes helps to alleviate tension in an otherwise intractable situation; for example, humor is especially common in anatomy labs where it is sometimes the only way to deal with the macabre nature of what medical students have to confront.
Sublimation Sublimation is the replacement of thoughts or actions that are unacceptable with a more desirable action. The new action is consistent with the person’s ethics and morals, whereas the previous action was more impulsive and less responsible. Art and literature are prime examples of sublimation, where one artist’s feelings may be transformed into an attractive painting.
Suppression Suppression is a voluntary ego mechanism and so is different from the other mature ego defenses in that it is not automatic. Suppression involves temporarily removing a thought from the consciousness in order to continue to cope with the outside world. A mature application of this is to temporarily stop thinking about various appointments that one must go to until the day after your wedding (“take it one step at a time”). Suppression should be differentiated from repression in that removing a thought from the consciousness is temporary in suppression; in repression, the thought is removed from memory and the person forgets that the thought was removed. Repression is an immature ego defense.
Immature Ego Defenses
Acting Out Immature ego defenses deal with the outside world in ways that only forestall dealing with a difficult situation. They typically do not lead to resolution of events. Acting out is an example of an immature ego defense in which a person will express undesirable feelings with equally undesirable actions. An example of acting out is throwing a temper tantrum. In this behavior a child’s frustration with a parent may lead to an immature emotional outburst. Acting out covers the real emotion (the child’s frustration) and so is different than displacement.
Blocking Blocking is an immature defense mechanism in which a person will transiently stop thinking about a particular thought. It is different than suppression in that the conflict is never resolved, and the person continues to stop thinking about the thought whenever it occurs. For example, a homosexual male embarrassed about being attracted to other men may block his libidinous thoughts instead of coming to terms with his sexual orientation.
Denial Denial is an immature ego defense in which the person contradicts a fact to avoid pain. Denial is typically the first stage in dealing with death in which a person will believe that the results of accurate medical tests are false. Denial can best be treated by explaining the situation in terms that the patient can comprehend and helping them become aware that there may be a more responsible or mature method of dealing with the situation at hand (“you can’t argue with the facts”).
Displacement Displacement is an immature way to transfer unacceptable feelings towards one person onto another person. A person who has a bad day at work and yells at his wife when he comes home is displacing his negative feelings towards his boss onto his wife. There is no change in the unacceptable feelings – fear in one situation is expressed as fear in another situation; anger with anger. Dealing with displacement may be helping the person to realize where the underlying feelings are coming from and helping them to deal with the adverse situation in a more constructive manner (“face the truth”).
Dissociation Dissociation is a method of changing one’s identity to avoid a stressful situation. In its more extreme presentation, a stressful situation may lead to dissociative identity disorder or multiple personality disorder. A person may deal with a stressful situation by packing up his things and creating an entirely different life elsewhere. More common presentations involve changing aspects of one’s personality, actions, memory, or consciousness.
Fixation Fixation is having a preoccupation with a certain event. An obsession with the sports channel or with cooking shows on television may be an egosyntonic method (albeit immature way) of avoiding other obligations. Dealing with fixation may be done by empowering a person with other methods of dealing with their stressful obligations. 55
Clinical Review for the USMLE Step 1 Identification Identification is an immature ego defense of believing that the averse actions one person has experienced makes it acceptable for the patient to employ those same actions on another. This is common in abused children who later become the abusers. Assisting a person involves helping them realize where their negative tendencies originated from, and transforming those tendencies into more positive actions that do not harm others (also known as sublimation).
Isolation of Affect Isolation of affect results in separating one’s feelings from an idea or event. Separating one’s feelings prevents a person from being hurt while dealing with an otherwise stressful event. This may be common in cold-blooded murders, in which the person does not demonstrate remorse when conducting a distressing and despicable action. If the process is more cognitive, isolation of affect is termed intellectualization. This is common in patients with obsessive-compulsive disorder in which the patient ruminates about actions that they cannot help conducting. Schizophrenics sometimes demonstrate isolation of affect.
Passive-Aggressive Passive-aggressive ego defenses are an immature method of being unconsciously hostile towards others in order to relieve negative feelings toward them. A person may demonstrate passive-aggressive behavior towards his boss by not alerting him that his vehicle is parked in a tow-away zone. Passive-aggressive behavior is common in patients with borderline personality disorder and in children. A person behaving badly towards another is an intentional act, and is by definition not a manifestation of passiveaggressiveness.
Projection Projection is attributing an unacceptable thought or impulse as being due to another source. For example, a person who is angry with another person may believe that others are angry towards him. Another example is where a man who hates dogs believes that dogs hate him when they urinate on his property. Projection is especially common in patients with paranoid delusions (“everyone is against me”). The belief that the world exists for the individual, for example, the sports fan that believes that the event is being held for her benefit, is known as introjection. Projection is often tested on the USMLE.
Rationalization Rationalization is a method to relieve guilt and shame by creating a faulty logical reasoning for why the action is somehow beneficial. For example, spending money on toys instead of spending it to provide food and shelter can be rationalized by believing that one needs the toys for her survival. Rationalization is the method that obsessive-compulsives use to alleviate their remorse over their actions and thoughts.
Reaction Formation Reaction formation is an immature method of taking a negative impulse and doing the opposite action. A person who wants to destroy another person’s career but instead takes steps to help them gain a promotion is engaging in reaction formation. It is an immature ego defense since the underlying negative impulse is never resolved. Reaction formation may underlie the behavior of long-time hostages when they illogically take steps to protect their abuser. 56
Psychology Regression Regression is common in stressed children, such as those hospitalized or confronted with the birth of a new sibling. Regression is returning to a previous level of functioning, such as suddenly becoming incontinent after years of successful toilet training. Regression also occurs in severely ill adults, who suddenly require all of their needs to be taken care of when they are capable of being somewhat independent.
Repression Repression, as discussed above, is an immature ego defense whereby the person takes an untenable idea, forgets it, and then forgets that they forgot it. Repressed memories are common in sexually abused patients who attempt to move on with their lives by forgetting all details of the event. Repression is an immature mechanism because stimuli later in life may lead to a sudden and dramatic recall of events leading to sudden collapse of the ego. One way to deal with repression is to gradually bring memories to the forefront in an egosyntonic method, best resolved by creating a permissible and egosyntonic atmosphere.
Somatization Somatization is an immature method of having physical symptoms to escape an otherwise stressful event. For example, developing a headache to avoid a disturbing conversation is an immature ego defense. Somatization is common in somatoform disorder.
Splitting Splitting is the belief that things are either one way or the opposite way. There is no middle ground. For example, the belief that all things are either good or evil is splitting (“black of white, no shades of gray”). Splitting is especially common in borderline personality disorder and in people with prejudices and stereotypes.
Undoing and Transference Undoing is an attempt to prevent an unacceptable impulse or event from occurring without taking any concrete and logical actions. An example of this is knocking on wood after saying that one has never been in a car accident in an attempt to magically avoid future car accidents. Transference is projection of one’s feelings, due to ideas or events in their life, onto another person. Patients often transfer their anger with a disease onto the physician. In this case, the physician may also be guilty of countertransference. In this situation the physician’s resentment of the patient being angry with him and causes him to become angry with his patient.
6.4. Conditioning 6.4.1
Conditioning is a topic that is worth a careful but brief review for the USMLE. The topics are easily tested and it is important not to confuse the various types of conditioning. Reinforcement schedules are confusing to remember, but it is important to have a clear understanding of this so you can successfully answer a simple recall-type question on the boards. Knowing the basic information and being comfortable in applying it to the exam and in clinical practice is vital. These mechanisms also serve to help 57
Clinical Review for the USMLE Step 1 motivate patients to make lifestyle changes and improve their health.
Conditioning pairs a stimulus with a response. The unconditioned response is the automatic response we make to a certain stimulus. For example, we salivate when presented with a tasty meal. Salivating is the unconditioned response to the meal, which acts as the stimulus. Since we are biologically programmed to respond to food, food is the unconditioned stimulus – unconditioned because it does not require any learning on our part. Pavlov conducted these experiments in dogs, where he realized that if he paired ringing the bell with providing the dogs food that they would begin to associate the ringing of the bell with the unconditioned response, salivation. Eventually, he was able to simply ring the bell and cause the dogs to salivate. The ringing of the bell became the conditioned stimulus – conditioned because it required the development of a learned behavior in the dogs, and the salivation the conditioned response – because the bell now caused the salivation (which is not a normal response) Table 10. Classical conditioning. Classical Conditioning Unconditioned response
Automatic response to a particular stimulus
An item that produces an automatic response
An action that replaces the unconditioned stimulus to produce the conditioned response
Automatic response to a conditioned stimulus
Operant conditioning is eliciting a particular response in order for the experimental subject to receive a reward. For example, giving a dog a treat when she responds to an oral command is an example of operant conditioning – operant because the reward is operating to create a particular response. Operant conditioning is different from classical conditioning because it does not involve innate responses to innate stimuli in order to cause a change.
Operant conditioning is broken into positive and negative reinforcement, and positive and negative punishment. Positive reinforcement is giving a reward once a desired action is performed. In the example above, giving the dog a treat once it obeys a command is an example of positive reinforcement – positive because something is given, reinforcement because it strengthens the chance of a particular behavior occurring. Negative reinforcement is removing something negative if a desired behavior occurs. Read this example carefully – an example of negative reinforcement is taking away the leash of a dog that obeys a command to sit (assuming the leash serves as something the dog dislikes). The dog learns to sit (reinforcement of an action), and learns that if it obeys that command, the leash will be removed (a negative stimulus). Negative reinforcement is often confused with punishment. Negative reinforcement is taking something negative away. Positive punishment is taking a negative action to suppress an undesired behavior. For example, spanking a child when they throw a tantrum is positive punishment – positive because an action is taken (spanking), and punishment because something negative is done to avoid a behavior. Negative punishment is taking away something positive in order to stop a particular behavior. An ex58
Psychology ample of negative punishment is taking away a child’s favorite toy when they are misbehaving. Negative punishment is different than negative reinforcement in that negative reinforcement involves taking away something negative (the leash), while negative punishment involves taking away something positive (the toy). Punishment is typically ineffective in removing a negative behavior as the unwanted behavior quickly returns once the punishment stops. Long lasting changes tend to occur only with reinforcement.
Reinforcement schedules also influence the speed at which a wanted behavior is learned or an unwanted behavior extinguished. Continuous reinforcement, or providing a reward every time a particular action is desired, leads to rapid extinction of the desired action once the reward is stopped. One way to think about this is that the person learns to associate the desired action with the reward, and that there is no reason to continue the desired action once there is no reward coming. Variable ratio reinforcement has the slowest extinction once the reward is stopped; the next most successful reinforcement schedule is fixed ratio reinforcement. Slot machines demonstrate variable ratio reinforcement due to their payoff at seemingly random times. Vending machines demonstrate continuous reinforcement since they reward the user every time money is spent. These disparate reinforcement schedules explain why people get angry when vending machines malfunction, but do not get angry when they do not win in a casino on their first attempt. To complete this section, it should be noted that money is an example of a tool that provides secondary reinforcement as accumulation of wealth through hard work assists in obtaining additional rewards. Finally, studies have demonstrated that an increase in GABA is necessary to prevent learned helplessness. For example, mice may simply accept that they will be shocked if they do not pull a lever to prevent the negative stimulus. Table 11. Reinforcement schedules. Reinforcement Schedules Variable ratio reinforcement
Giving a reward at variable times that a desired action is completed
Fixed ratio reinforcement
Giving a reward at a predetermined interval that a desired action is completed
Providing a reward every time a desired action is done
6.5. Patient Interviewing 6.5.1
There are a number of disorders that take place primarily in children. These psychiatric illnesses are traditionally placed along axis II disorders and may be present from birth or develop spontaneously during the formative years. A majority of these disorders are present throughout the lifespan, and can often lead to severe psychosocial dysfunction. It should also be noted that the majority of illnesses that occur in adults can also present in children, and the astute clinician should be wary of these developments.
Structuring interviews with children requires investigators to be more concrete with their questions. For example, the questions posed to children should be both precise and accurate – “Do you hit your younger brother when you get mad?” is preferable to “How do you react when you get angry?” It is also important to observe children in their interactions with others and to be cognizant that this younger age group often presents with comorbid mental illnesses. 59
Clinical Review for the USMLE Step 1 6.5.3
Child psychiatry often makes use of various psychological tests. The most common tests of general intelligence are the Stanford- Binet Intelligence Scale and the revised Wechsler Intelligence Scale for Children (WISC-R). The latter is the most commonly used test in children who attend school. The WISC-R yields a comprehensive performance score including verbal and performance scores that can be used to gauge a childâ€™s intelligence quotient (IQ). A number of other tests also exist to measure personality traits, behavior, motor skills, perceptual skills, etc.
Definition Mental retardation is defined as having an intelligence quotient of less than 70. According to the WISCR examination, IQ can be quantified as the mental age (defined by the test) divided by the chronologic age of the child, multiplied by 100. For example, if a five-year old child scores a 10 on the WISC-R, the childâ€™s IQ is 200. A mentally retarded child would score an IQ of less than 70. A diagnosis of mild mental retardation is made if the IQ of the child is between 50 and 70 (85% of the mentally-retarded population); moderate mental retardation has an IQ between 35 and 50 (10%); severe mental retardation has an IQ between 20 and 35, and profound mental retardation has an IQ less than 20.
Epidemiology Mental retardation affects approximately 2% of the population, and is more common in males. Mental retardation has positive predictors, including low socioeconomic status (SES), which can lead to mild mental retardation (but is most likely a side effect of the poorer education and poor nutrition and therefore poorer performance on intelligence tests). More severe forms of mental retardation are independent of socioeconomic status.
Etiology The most common causes of mental retardation are Down syndrome (Trisomy 21), fragile X syndrome (the most common cause of heritable mental retardation), inborn errors of metabolism, maternal diabetes, substance abuse, rubella, and perinatal or early childhood injuries. Approximately one-third of all patients do not have a clear cause of the retardation.
Presentation Mental retardation typically manifests with physical malformations, such as the moon faces of Down syndrome. Infants are eventually identified by their inability to meet developmental milestones including delayed speech, inability to care for self, and poor social skills.
Diagnosis In order for mental retardation to be diagnosed, symptoms must be present prior to age 18, and the childâ€™s IQ must be less than 70 with congruent deficits in functioning. Mental retardation has a long differential diagnosis, but some of the more common etiologies include attention deficit hyperactivity disorder (ADHD), learning disorders, depression, and schizophrenia. Tests to rule out some of these etiologies include EEGs for seizure disorder, an MRI or CT of the brain to rule out organic brain diseases, IQ testing, and a thorough medical, neurologic, and psychiatric work-up. 60
Psychology Prognosis The majority of children with mental retardation progress through the normal developmental milestones, but at a slower pace. These children often require supplemental resources at school and occasionally a more structured environment to help them manage their resources and stay focused on task. Children with mild mental retardation can be educated so that they can read, write, and perform basic mathematical tasks. Many of these children can live with their parents and become productive citizens in society by holding a job. Children with moderate mental retardation typically can only be trained to perform basic tasks and to perform basic self-care, thereby enabling them to live in a structured group home. Children with profound mental retardation invariably require institutionalized care starting in early life. Many of these children often have a severe inborn error of metabolism such as Tay-Sachs disease, leading to progressive decline and early death.
6.6. Medical Ethics 6.6.1
A number of concepts dealing with medical ethics are tested. You can expect up to a dozen questions asking you to use your clinical decision making capability to arrive at the best course of action available to the physician in response to a particular case scenario. Concepts on autonomy, informed consent, and advanced directives are virtually guaranteed to be tested, as these are encountered on a regular basis in clinical practice. The physician’s response to a particular ethical situation is also common on the exam. This section on medical ethics will start with a definition of common terms, followed by discussions of informed consent, advanced directives, confidentiality, and malpractice. The last section delineates the appropriate response of a physician to various hypothetical patient case presentations.
Autonomy Autonomy is defined as the recognition that patients are individuals with their own preferences, and that the physician should make efforts to honor the patient’s right to request or refuse medical care whenever possible. Autonomy is tested on the USMLE by testing the limits of when it is appropriate to listen to a patient and follow their requests or when ancillary measures must be taken, such as receiving parental permission or a court order in order to take action. For example, minors (those less than eighteen years of age) have autonomy in treatment for sexually transmitted diseases. No parental consent is required, and minors have the right to refuse care for their illness. Minors also have autonomy in treatment for substance abuse, birth control, and prenatal care. However, parental permission must be obtained before conducting an abortion. Discussing illnesses with children should always be done after a thorough discussion with the parent. The physician must first understand what the parent has told the child, and inform the child in accordance with the parent’s wishes.
Nonmaleficence Nonmaleficence is more colloquially known as “do no harm.” This is a relative consideration, as certain therapies for cancer may cause a number of dangerous treatment-related side effects, but the therapy should proceed as scheduled as not treating the patient at all is almost certainly going to lead to death.
Clinical Review for the USMLE Step 1 Beneficence Beneficence is a related concept in which physicians are required to act in the patient’s best interest when no contradictory decision otherwise exists. This is the default action a physician should always take in the absence of other information. In this manner, the physician is acting as a fiduciary for the patient. Patient autonomy supersedes beneficence in almost every situation and it is very difficult ethically and legally to institute positive treatment for a patient against her will. The few exceptions to this are when the patient is a danger to themselves or to others.
Overview The USMLE may present you with a number of situations where you are required to use your clinical judgment to decide what the appropriate response would be. The question writers follow very specific guidelines regarding the appropriate ethical and moral conduct of a physician. Keeping the concepts of autonomy, informed consent, decision-making capacity, nonmaleficence, beneficence, confidentiality, and malpractice in mind should clarify what the appropriate decision should be in a particular case.
Noncompliance In situations where the patient is noncompliant with his medical care, such as not taking a necessary prescription, the best course of action is to identify the basic issue that prevents compliance. In response to most case-scenarios, the best way to proceed is to work to improve the trust in the physician-patient relationship. In situations where the patient is attempting to be compliant but has difficulty with maintaining the proper schedule, written directions should be provided to the patient. If appropriate, and within the patient’s wishes, additional help may be solicited with family members and other health caretakers.
Demanding Patients Patients may occasionally make uncomfortable demands on the physician. Patients who request unnecessary procedures that are not medically indicated, or refuse to undertake a necessary procedure deserve to have an honest discussion with the physician. Understanding the patient’s thinking is the key to resolving these types of problems. A common course of action with patient’s requiring unnecessary cosmetic surgery is to alleviate the underlying psychological insecurity issues. Unnecessary procedures should not be performed in the interest of nonmaleficence. Physician-assisted suicide (euthanasia) is not medically acceptable. However, in the interest of beneficence, the physician may provide strong pain relieving medications when medically indicated, even though their administration will coincidentally lead to a decreased life span.
Angry Patients Patients also get angry for a number of reasons in a health care setting. Anger over the amount of time spent waiting to see the doctor should be handled by apologizing to the patient for the wait. The physician is not obligated (and should not) attempt to explain the reasons for the delay. A patient upset with another physician or the level of care she has received elsewhere should be handled carefully. It is not professionally appropriate to discuss this situation with the patient; instead, the patient should be encouraged to speak directly with the individual that caused his grievance. In cases where the patient is upset with a member of your staff, the patient should be told that you will personally speak with that 62
Psychology individual and address the patientâ€™s concerns.
Patient-Physician Relationships Finally, patients may state that they find you attractive and that they are interested in a romantic relationship with you. While standards on this vary from place to place (and are often left to the discretion of the physician but never advisable from a legal standpoint), for the purposes of the USMLE, romantic relationships are never appropriate between a physician and patient. In this situation, direct, closeended questions should be used and the presence of a chaperone may be indicated. Another situation in which a chaperone is indicated is when a male physician does a breast or pelvic exam on a female.
Impaired Physicians It is not uncommon to encounter questions related to impaired physicians on the USMLE. If a colleague is under the influence of alcohol or drugs, has impaired judgment from sleep deprivation, or can no longer adequately function due to age-related issues, it is the responsibility of the physician to relieve themselves of duty. If this is not done in a responsibile manner, colleagues should ensure that a high level of patient care continues to be provided and take steps to have the impaired physician removed from duty. This can initially take the form of having a frank discussion with the physician, then escalating it to the administrative level with appropriate documentation.
Communicating Bad News Discussing complications or untimely death can be a difficult situation for most physicians. Adverse events are best handled in an open and honest manner. It may also be advisable to alert the hospitalâ€™s risk management team so that they can also assist with any medicolegal aspects of the adverse event. Discussing these complex issues is best done in the presence of the responsible members of the family. Accept responsibility where it is appropriate, apologize where it is relevant, and assist the family in any manner you can as they navigate the challenges they have ahead.
Medicolegal Definition Informed consent is the practice of obtaining permission in order to perform an invasive procedure. Informed consent is traditionally in the written form and can serve as a legal document. Most procedures require informed consent except when the procedure must be performed on an emergency basis and consent cannot be acquired or is impractical (treat the latter situation carefully). In order for informed consent to be successfully obtained, the patient must be educated in a clear and simple manner regarding the benefits of the procedure, the risks of the procedure, alternatives to the procedure, and the consequences of not having any procedure performed. The legal standards are further met by obtaining this consent with a discussion of the pertinent information, establishing written consent stating the patientâ€™s agreement to the procedure offered, and gaining this consent in a manner free from coercion.
Exceptions to Informed Consent Informed consent is not practically obtained in a number of circumstances, and familiarity with the exceptions to this rule are likely to be tested. Informed consent does not need to be obtained in cases where emergency treatment is required to alleviate a life-threatening condition and there is no time to discuss the benefits and alternatives; in cases where therapeutic privilege is instituted, in which information must be withheld from the patient to prevent even greater harm than would occur with the 63
Clinical Review for the USMLE Step 1 therapy (but make this decision very carefully, as therapeutic privilege is often successfully challenged in a court); when the patient lacks the cognitive or physical ability to competently make an informed decision; and in cases where the patient signs a waiver to obtaining informed consent. It is important to note that family members cannot require that a physician not inform the patient regarding their illness. In this case, the appropriate course of action is to discuss the situation in a private room with the family members first, determine whether informing the patient would create even greater harm, and if it does not, then moving forward to inform the patient regarding their illness.
Competency A patientâ€™s competence is established through their sound decision-making capability. Elements of a good decision-making ability include informing the patient regarding the intervention, the patientâ€™s decision does not repeatedly change over time, the decision appears to be consistent with other choices the patient would make, the patient does not have any psychosocial issues that complicate their ability to make an informed decision, and if the patient communicates a clear choice to the physician.
Oral Advanced Directives Advanced directives are a guide to providing treatment to a patient when she is otherwise unable to make a choice due to an intervening medical illness. In this case, a patientâ€™s prior oral directives take precedence, especially if the patient was able to make an informed, clear choice and communicate this lucidly to the physician ahead of time. The decision is considered valid if it is repeated over time.
Written Advanced Directives Written advanced directives are used in cases where an oral directive was not established. There are two major types of written advanced directives, including living wills and durable power of attorney. Living wills direct the physician to employ only certain life-saving measures and dictate if and when they can be withheld or withdrawn. Living wills take precedence only when there is no prior oral directive. Living wills are not flexible and are being replaced with durable power of attorney, in many cases.
Durable Power of Attorney Durable power of attorney is the designation of a surrogate, usually a spouse or other family member, who makes the judgment on behalf of the patient regarding medical decisions. The legality of durable power of attorney is predicated on the designated person making a decision similar to what the patient would choose if she were competent. A durable power of attorney incorporates elements of a living will in that the patient can designate that certain measures be taken in various clinical situations. Written advanced directives can be revoked at any time by the patient.
HIPPA Guidelines As discussed previously, information flow between patients, family members, and health care team members should follow HIPPA guidelines. The health care issues involved with a patient should not be discussed with anybody except health care personnel immediately involved with care of that patient. With permission from the patient, information can be provided to family members. According to HIP64
Psychology PA guidelines, this discussion should take place in a private place that protects the privacy of the information; hence, discussions regarding specific patients should be undertaken only if their privacy can be protected. Identifying information should be avoided, and discussion in public places should be limited.
HIPPA Provisions Confidentiality is an important cornerstone to providing medical care in a secure environment while protecting the privacy of patients. Recent regulations instituted via the Health Information Privacy Protection Act (HIPPA) dictate when and how confidentiality should operate. Generally, disclosing information about the patient to anybody except members of the health care team directly involved with the patient is disallowed. Information can be disclosed only on a need to know basis, although family members can be informed regarding the patientâ€™s condition if it is compatible with what the physician believes the patient would desire. Waivers to confidentiality can be signed by the patient.
Exceptions to Confidentiality Confidentiality also has its own exceptions. Informing others regarding a patientâ€™s condition is allowed in situations where the potential harm to others is serious, as can occur if the patient is a danger to society. Confidentiality is also waived in situations where the patient is a danger to himself and the physician may make decisions to protect the patient from himself or others as deemed medically necessary. Physicians are required by law to inform people who may be harmed by the patient, thus breaching confidentiality. Other exceptions to confidentiality include informing health officials and people at risk for infectious diseases, situations involving abuse of children or elders, patients who are at risk of harming others due to inability to operate a motor vehicle or operate in a safe manner in their vocation, and in patients prone to suicide or homicide.
HMO Health maintenance organizations (HMOs) force patients to see providers within the network and do not cover outside provider expenses. With an HMO, providers contract with outside organization to receive more patients, which they serve at a discount. Patients must see their primary care physician before any specialists can be consulted; this physician plays a gatekeeper role to the more expensive specialists. HMOs have an utilization review that seeks to ensure that the proper amount of care is being delivered without ordering too many or too few lab tests and studies.
PPO Patient provider organizations (PPOs) allow patients to see any provider within or out of the network. There is decreased reimbursement for out of network expenses, leading to greater personal expense for the patient if they go out of network to see another doctor. Older insurance plans incorporated capitation into their plans, where they gave a single lump payment for the total number of patients under a physicianâ€™s care. This has fallen out of favor as physicians were less likely to order needed studies or laboratory tests as this led to decreased net profit.
Medicare Medicare is a federal program to provide assistance to the elderly and certain disabled persons. It has three major components, or parts. Part A covers hospital expenses, part B covers physician expenses, and part D covers certain medicine expenses. Medicare traditionally covers ambulance, dialysis, speech 65
Clinical Review for the USMLE Step 1 and occupational therapy costs, but does not cover the cost of a physical exam or nursing home care after a certain amount of time.
Medicaid Medicaid is a federal and state assistance program to those unable to pay for their own health care. It offers basic access to healthcare and is similar to public aid programs.
7. Fluid, Electrolytes, Nutrition,
7.1. Electrolyte Disturbances 7.1.1 Hyponatremia Hyponatremia = serum Na+ < 135 mEq/L Hypotonic Hypovolemic • Diuretics, salt wasting syndromes, vomiting, diarrhea, burns • Third-space losses (pancreatitis, peritonitis) Isovolemic • Renal failure, SIADH, glucocorticoid deficiency, hypothyroidism, various medications Hypervolemic • Cirrhosis, CHF, nephrotic syndrome Isotonic • Excessive isotonic infusions with glucose or mannitol, pseudohyponatremia Hypertonic • Hyperglycemia 100 mL/dL > normal causes Na+ decrease of 1.6 mEq/L • Hypertonic infusions of glucose or mannitol
Figure 39. The three major types of hyponatremia. Copyright Surgisphere Corporation. Used with permission. The severity of symptoms depends for a large part on how quickly the sodium level drops. Minor hyponatremia is typically asymptomatic. Moderate hyponatremia can lead to confusion, lethargy, anorexia, and myalgia. Severe hyponatremia can lead to coma or seizures. The diagnosis is made by examining the osmolarity, carefully assessing the patient for objective signs and symptoms (i.e. tachycardia, dehydration), and measuring serum glucose. Pseudohyponatremia is diagnosed with normal or elevated osmolarity that does not match the calculated osmolarity; common causes include multiple myeloma and hypertriglyceridemia that increase the protein or lipid fraction in the plasma. The sodium deficit can be calculated because 60% of body weigh is fluid and 140 mEq/L is the normal Na+ concentration: 0.6 x (weight in kg) x (desired sodium - actual sodium) The treatment for hyponatremia is to slowly correct the serum sodium with half corrected in the first 24 hours. A rate no faster than 1 mEq/hr should be used to avoid central pontine myelinolysis (CPM), 66
Fluid, Electrolytes, Nutrition, and Acid-Base seizure, and increased intracranial pressure (ICP). Hypovolemic hyponatremia is corrected with 0.9% normal saline (NS); hypervolemic hyponatremia is corrected with sodium and water restriction and ACE-inhibitors may be beneficial. CPM tends to occur in severe hyponatremia and presents with stupor, confusion, lethargy, and quadriparesis. Some patients recover from CPM over a period of weeks. Conservation of sodium is done through an ADH-independent reabsorption.
Hypernatremia Hypernatremia, Na+ > 145 mEq/L Hypovolemic • Water loss from diuretics, GI, respiratory, and skin Isovolemic • Decreased TBW with decreased ECF, DI, skin losses, central defects in osmolarity Hypervolemic • Increased TBW with increased Na+, hypertonic fluid, excess salt intake, Conn or Cushing syndrome
Figure 40. Hypernatremia is divided into hypovolemic, isovolemic, and hypervolemic. Copyright Surgisphere Corporation. Used with permission. Just as in hyponatremia, the severity of symptoms is due largely to how quickly the hypernatremia develops. Hypernatremia presents with fatigue, confusion, and lethargy that can progress to seizures and coma. Hypovolemic hypernatremia is treated with NS given at 2 mOsm/kg/hr. Isovolemic hypernatremia is treated with 0.45% NaCl (½ NS) with half the water deficit corrected over the first day. No more than 1 mEq/L/hr should be given in an acute setting. DI is treated with vasopressin. Hypervolemic hypernatremia is treated with ½ NS and loop diuretics.
Hypochloremic alkalosis should be treated with potassium. Vomiting will lead to hypochloremic metabolic alkalosis.
Hypokalemia is K+ < 3.5 mEq/L Decreased intake • Especially in the elderly or in those receiving total parenteral nutrition Increased losses • Diuretics, mineralocorticoids, hyperaldosteronism, osmotic diuresis, excess urine flow, and gastrointestinal losses from diarrhea) • Vomiting: loss of volume and gastric acid causes extracellular Na+ shift (volume) in exchange for K+ plus renal reabsorption of Na+ with loss of K+ Intracellular shift • Acute insulin therapy for hyperglycemia • B12, ß-blockers, digibind, and alkalosis (each 0.1 pH increase leads to a shift of 0.5 mEq/L of K+).
Figure 41. Various causes of hypokalemia. Copyright Surgisphere Corporation. Used with permission. 67
Clinical Review for the USMLE Step 1 Hypokalemia presents with hypertension if the underlying cause is primary hyperaldosteronism or licorice ingestion, while hypotension may suggest laxative abuse, Bartter syndrome, or bulimia. Hypokalemia may also present with flaccidity, muscle weakness, and loss of deep tendon reflexes (DTRs). Arrhythmia can also occur. Prevent further potassium loss and replenish the stores to treat hypokalemia. Most K+ is intracellular so serum K+ may underestimate the replenishment needed. No more than 10 mEq/hr can be infused via peripheral lines due to venous irritation. A maximum of 40 mEq/hr can be infused through central lines in emergent situations.
Hyperkalemia is the result of increased intake of potassium, impaired excretion of potassium, or a shift from the intracellular to extracellular space. Decreased excretion is commonly due to potassiumsparing diuretics, ACE-inhibitors, NSAIDs, type IV RTA, and renal failure. Hyperkalemia is common in hospitalized patients, rhabdomyolysis, and diabetes. The adrenocortical syndromes pertaining to 21-hydroxylase deficiency and 11-beta hydroxylase deficiency are other causes. Mortality occurs with the development of fatal arrhythmias in very high potassium titers. Identifying the etiology of hyperkalemia is done by renal function tests to identify renal insufficiency. Obtain: urine K+ urine osmolality, serum K+, serum osmolality, and EKG. Hyperkalemia causes EKG changes including peaked T waves, PR interval prolongation, QRS widening, disappearance of the P wave, and sinus arrest. Bradycardia may also be present. Treatment involves correcting toxicity caused by the hyperkalemia, removing excess sources of potassium, and shifting potassium intracellularly with glucose and insulin administration. Bicarbonate and Ă&#x;-blockers can be used to correct the metabolic acidosis and to decrease extracellular potassium. Potassium excretion can be facilitated with fluorohydrocortisone and stopping potassium-sparing diuretics and ACE-inhibitors. GI excretion can be increased with potassium-binding resins such as Kayexalate. Dialysis is an option in emergency situations.
Hypocalcemia occurs with serum calcium level less than 8.5 mg/dL. Loss of calcium regulation by vitamin D, parathyroid hormone (PTH), calcitonin, hypomagnesemia, and hyperphosphatemia account for the majority of hypocalcemic presentations. Other causes include pancreatitis, sepsis, rhabdomyolysis, and exposure to toxins such as fluoride, ethanol, phenytoin, citrate, and cimetidine. Since 50% of the calcium is bound to albumin, hypoalbuminemia produces a low serum calcium but the ionized calcium concentration (the physiologically active form) remains normal. Symptomatic hypocalcemia may lead to circumoral paresthesia, Chvostek sign (facial spasm after tapping on the facial nerve anterior to the tragus), and Trousseau sign (spasm of the wrist after stopping forearm blood flow with a blood pressure cuff). Diagnosis is made by electrolyte panels and EKG findings positive for a prolonged QT interval. Albumin levels should be checked and the Ca2+ value corrected: Corrected Ca2+ = Ca2+ â€“ albumin + 4. The ionized Ca2+ can be measured instead. Treatment of hypocalcemia includes identifying PTH deficits, giving vitamin D or calcitriol along with thiazide diuretics to prevent excess Ca2+ excretion, correcting hypomagnesemia, restricting phosphate, oral Ca2+ supplementation, and infusion in emergent situations. Calcium carbonate is useful as an oral 68
Fluid, Electrolytes, Nutrition, and Acid-Base supplement. Calcium chloride infusion requires a central line, while calcium gluconate can be given via a peripheral line.
Hypercalcemia is diagnosed with a serum Ca2+ level more than 10.5 mg/dL. Half of the Ca2+ is bound to albumin, which must be measured in order to determine the amount of free ionized calcium, unless the lab can provide free ionized Ca2+ concentrations. Hypercalcemia primarily affects the kidneys and CNS and leads to fatigue, depression, personality changes, confusion, somnolence, and even coma and death. Nephrolithiasis, positive inotropy, arrhythmia, constipation, and anorexia are other manifestations. The vast majority of cases are due to hyperparathyroidism or malignancy from metastatic cancer to the bone or parathyroid hormone related peptide (PTHrP) secretion by lung cancer. Other conditions include vitamin A or D excess and renal failure. Dehydration is common in hypercalcemia, and metastatic calcifications in other tissues are common in more severe cases (termed calciphylaxis), particularly if phosphorus is also high. PTH levels should be measured and a search for malignancy should be undertaken. A shortened QT interval may be present on EKG. Always check albumin levels. Treatment involves volume repletion, mobilization, reducing GI Ca2+ absorption with prednisone and oral phosphate, preventing bone resorption with biphosphonates such as pamidronate, etidronate, risedronate, and alendronate, and administering calcitonin. Dialysis may also be used in more serious cases. A surgical option includes a partial parathyroidectomy. Hypercalcemia with diarrhea should begin a search for MEN syndrome; gastrin levels should be measured as the diarrhea may be a sign of a gastrinoma.
Phosphate levels less than 2.5 mg/dL qualify as hypophosphatemia. Causes for hypophosphatemia include poor intake, increased excretion, or a shift from the extracellular to intracellular space. Alcoholics, patients with eating disorders, Crohn disease, vitamin D deficiency, RTA, antacids that bind to phosphate, hyperparathyroidism, hypokalemia, hypomagnesemia, volume expansion, respiratory alkalosis, and acetazolamide are other causes for hypophosphatemia. Hypophosphatemia presents with rhabdomyolysis, seizures, coma, hemolytic anemia, and platelet dysfunction. The urine phosphate content is measured. Deficits less than 100 mg/d imply gastrointestinal loss or redistribution of phosphate; greater deficits are due to Fanconi syndrome. High Ca2+ with hypophosphatemia implies primary hyperparathyroidism or malignancy as the chief cause. Low Ca2+ with hypophosphatemia indicates 2o hyperparathyroidism, rickets, renal failure, and familial causes. Hypophosphatemia leads to decreased cardiac output, increased RBC destruction, depletion of 2,3 DPG, and left shift in the oxygen-hemoglobin curve. There is also increased difficulty weaning from a ventilator. Treatment for hypophosphatemia includes oral repletion in minor cases or IV administration if severe. Vitamin D supplementation is given. Primary or secondary hyperparathyroidism may require a parathyroidectomy. Hypophosphatemia following refeeding presents as respiratory failure and prolonged dependence on a mechanical ventilator. Refeeding syndrome is due to phosphorylation of glucose intermediaries and leads to decreased phosphate available for ATP generation. Failure of ATP production occurs. The most appropriate therapy is to replete phosphate. 69
Clinical Review for the USMLE Step 1 7.1.9
Hyperphosphatemia is defined as phosphate greater than 5 mg/dL in the serum. Excess intake can occur with vitamin D intoxication. Decreased clearance can occur with hypoparathyroidism or renal failure. A shift from the intracellular to extracellular space occurs in rhabdomyolysis and tumor lysis syndrome. Hyperphosphatemia presents with hypocalcemia and calciphylaxis. Most patients are asymptomatic, but muscle cramps, perioral paresthesia, uremic symptoms, and general malaise can occur. Hyperphosphatemia is treated by temporizing renal failure, dietary restriction of phosphate, binders such as calcium carbonate, insulin and glucose infusion as a temporary measure, and dialysis in more serious cases.
Hypomagnesemia is magnesium less than 1.8 mg/dL. It is commonly due to malabsorption, poor dietary intake, excess excretion, or redistribution within the body. Causes of excess excretion include diarrhea, diuretic abuse, ATN, hypokalemia, hypercalciuria, or endocrine disturbances. Redistribution in the body can occur with hypoalbuminemia, pancreatitis, glucose and insulin administration. Hypomagnesemia presents with weakness, hyperreflexia, seizures, hypokalemia, and hypocalcemia. EKG changes include prolonged QT and PR, flattened T waves, atrial fibrillation, and torsade de pointes. Treatment of hypomagnesemia is by oral magnesium oxide supplements or IV magnesium sulfate. Cardiac dysfunction must be addressed.
Hypermagnesemia is magnesium greater than 2.5 mg/dL. It is due to renal failure with decreased excretion, abuse of antacids, tumor lysis syndrome, rhabdomyolysis, DKA, pheochromocytoma, and toxicity from lithium. Hypermagnesemia presents with decreased DTR, hypotension, paresthesia, coma, and specific EKG changes. EKG changes are opposite of those found with hypomagnesemia. Reverse EKG changes in hypermagnesemia with IV calcium. If necessary, dialysis may be used to regain normal magnesium homeostasis.
7.2. Nutrition 7.2.1
Familiarity with nutritional requirements and energy content of various sources of intake are an important component of providing appropriate nutritional care to the surgical patient. The major source of protein turnover is skeletal muscle, which becomes especially significant in prolonged starvation and acute injury. Table 12. Energy content for carbohydrates, proteins, and lipids. Carbohydrate Protein Lipid 70
3.4 kcal / g 4 kcal / g 9 kcal / g
Fluid, Electrolytes, Nutrition, and Acid-Base The Harris-Benedict equation is used to determine basal energy expenditure. Various modifications are used to determine the estimated caloric needs for patients. The equation varies for men and women. The average caloric need for a 70 kg male is about 1700 kcal/day. The average caloric need for a 70 kg female is slightly less. The metabolic cart can also be used to calculate overall nutritional status and the respiratory quotient. Indirect calorimetry works by calculating CO2 production. The respiratory quotient is calculated as the ratio between CO2 produced to O2 consumed. The respiratory quotient is a unitless number calculated as the ratio between the amount of carbon dioxide produced and the amount of oxygen consumed. This value typically correlates to the caloric value for each liter of carbon dioxide produced. Table 13. Respiratory quotient for various metabolic processes. Carbohydrate oxidation Fat oxidation Protein breakdown Lipogenesis Normal
1 0.7 0.8 > 1.0 0.8
Enteral and Parenteral Nutrition
Enteral Nutrition Enteral feeding provides the advantage of a decreased risk of sepsis through line infection, induction of the immune system through small intestine production of IgA, and maintenance of the gastrointestinal tract. This leads to increased integrity of the GI tract with decreased spontaneous bacterial translocation across the cell wall. Gastrin induction increases insulin release and anabolism. Enteral nutrition, however, has a decreased rate of absorption in the immediate postoperative period. Tube feeding does not improve longevity or quality of life in nursing home residents. Nonocclusive bowel necrosis may occur within two weeks of starting enteral feeds and present with pneumatosis and necrosis. Treatment is reversion to TPN.
Parenteral Nutrition Parenteral nutrition has specific indications due to the significant morbidity and mortality associated with TPN. TPN has a proven benefit with enterocutaneous fistulae and improves their closure rate, decreases the incidence of renal failure in ARF, improves morbidity with short gut syndrome and severe burn patients when enteral feeding would be insufficient, and may induce remission of Crohn disease. TPN has also been used to mitigate symptomatic pneumatosis intestinalis when surgery is not indicated. The essential minerals that should be included with long term TPN include acetate, gluconate, calcium, chloride, chromium, copper, iodine, magnesium, manganese, phosphorus, potassium, selenium, sodium, and zinc.
Essential Amino Acids
Arginine is an essential amino acid that augments the immune system. Glutamine is the amino acid most abundant in circulation. Glutamine levels following intestinal surgery are decreased due to an increase in utilization by the intestinal cells. 71
Clinical Review for the USMLE Step 1 7.2.4
Malnutrition and Obesity
Obesity Obesity is an epidemic in the United States, affecting over a quarter of the population. It is especially common in American Indians, Hawaiians, Hispanics, and African Americans. Obesity is defined as having a body mass index (BMI) over the 85th percentile or more than 30 kg/m2, calculated as weight (kg) divided by height (m2). Obesity has a genetic inheritance, but changes in society, poor diet, and lack of exercise all contribute. Complications of obesity include obstructive sleep apnea (OSA), pseudotumor cerebri, liver dysfunction, cardiovascular disease, hypertension, hypertriglyceridemia, arthritis, diabetes, and cancer. Other factors that can contribute to obesity include Prader-Willi syndrome, Down syndrome, Turner syndrome, growth hormone deficiencies, pseudohypoparathyroidism, hypothyroidism, polycystic ovarian syndrome, and medications such as antidepressants and oral contraceptives. Treatment of obesity requires major lifestyle changes; thus treatment is multifaceted and must include reducing other risk factors (such as smoking or alcohol abuse), and treating any concomitant disorders such as DM, HTN, CVA, and heart disease. The last resort is surgical intervention in the form of bariatric surgery â€“ this is typically used in patients with a BMI exceeding 40. Expanded criteria for surgery are used at centers of excellence due to experience.
Malnutrition Malnutrition may present as kwashiorkor with protein starvation and edema, and marasmus with both protein and caloric starvation leading to cachexia. Deficiencies in multiple vitamins and significantly poor diet are commonly implicated for malnutrition. There are systemic effects with significant cognitive and physical retardation, and diminished immune activity. Severe malnutrition is rare in the United States; nearly 150 million children worldwide are affected by malnutrition. Malnutrition presents with weight loss, trailing off the normal growth curves, and behavioral/cognitive changes. Physical exam detects anasarca with kwashiorkor. Cheilosis, angular stomatitis, fatty hepatomegaly, and skin hyperpigmentation with peeling are present. Thin and brittle hair is commonly found. Iron deficiency presents with constitutional symptoms, anemia, decreased cognition, headache, glossitis, and koilonychia. Iodine deficiency presents with goiter and physical and mental retardation. Albumin is not recommended for acute monitoring due to its long half-life; pre-albumin and transferrin are better markers for nutrition due to their shorter half-lives.
Vitamin A Deficiency Retinol deficiency is primarily due to poor diet and excessive rice consumption, and secondarily due to malabsorption syndromes and malnutrition syndromes. Vitamin A deficiency presents with growth retardation, night blindness, xerophthalmia, hair changes, keratomalacia, follicular hyperkeratosis, and Bitot spots with foamy patches in the conjunctiva.
Fluid, Electrolytes, Nutrition, and Acid-Base Vitamin C Deficiency Vitamin C deficiency is due to poor diet, pregnancy, thyrotoxicosis, inflammatory disease, after surgery, burns, and diarrhea. Scurvy presents with splinter hemorrhages in the nail bed, swollen and friable gums, loss of teeth, breakdown of old scars, poor healing, spontaneous hemorrhage, petechiae, and hyperkeratotic hair follicles. A dietary deficiency as the etiology of scurvy amongst their sailors was proven by a surgeon in the British Navy. The British are referred to as ‘limeys’ as they carried and consumed limes (a good source of vitamin C) on their long sea voyages by sail and prevented their sailors from becoming ‘scurvy dogs.’
Vitamin D Deficiency Vitamin D deficiency is primarily due to poor sunlight exposure or poor intake of calcium or phosphorus. Secondary causes include hypoparathyroidism, hereditary diseases, and poor absorption. The effect of vitamin D deficiency is rickets in children and osteomalacia in adults. Treatment is adequate intake of calcium, phosphorus, and vitamin D supplements.
Vitamin E Deficiency Tocopherol deficiency is a natural state in infants but may present later in life with poor intake, malabsorption syndromes, or genetic causes. Vitamin E deficiency presents with hemolytic anemia, reticulocytosis, hyperbilirubinemia, abetalipoproteinemia, neuropathy such as spinocerebellar ataxia and loss of DTRs, and retinopathy.
Vitamin K Deficiency Vitamin K is a lipid soluble vitamin essential for the formation of clotting factors. It is produced by colonic bacteria. Terminal ileum disease or resection prevents normal vitamin K production and absorption as there is an enterohepatic circulaton of vitamin K from intestine, ileal absorption, portal venous system, liver, bile back to intestine. Deficiency may occur from cirrhosis, malabsorption syndromes, biliary disease, various medications (coumadin, INH, rifampin, barbiturates, and others), lupus, DIC, polycythemia vera, cystic fibrosis, and leukemia. Vitamin K helps to form coagulation factor II (prothrombin), factor VII (proconvertin), factor IX (Christmas factor), and factor X (Stuart factor). Protein C, protein S, Protein Z, and several bone matrix proteins reliant on glutamic acid residue conversion by vitamin K are also modified by vitamin K. Coumadin is used as a therapeutic anticoagulant because it interferes with vitamin K metabolism which causes a deficiency in the vitamin K dependent clotting factors Vitamin K deficiency presents as hemorrhagic disease of newborns (HDN) or as a bleeding diathesis in adults. Vitamin K deficiency, if severe enough, presents as complaints of significant hemorrhage following mild trauma. Ecchymoses, petechiae, hematomas, and oozing of blood are common. GI bleeds, hematuria, menorrhagia, epistaxis, and mucosal bleeds occur frequently. PT and aPTT are elevated. Des-gamma-carboxy prothrombin is present in the absence of vitamin K. Treatment for vitamin K deficiency involves correcting the cause of the underlying deficit and providing vitamin K supplements. FFP is necessary in severe disease to prevent hemorrhage. Subcutaneous injections of phylloquinone (vitamin K1) can be given; menadione (vitamin K3) can be given orally in malabsorption syndromes. Phytonadione can also be directly injected in severe disease. Green leafy vegetables and oils provide a good source of vitamin K. 73
Clinical Review for the USMLE Step 1 Vitamin B1 Deficiency Primary thiamine deficiency is due to decreased intake especially in a high-rice diet. Secondary deficiency is due to hyperthyroidism, pregnancy, fever, malabsorption syndromes, diarrhea, and liver disease. Alcoholism impairs utilization. Thiamine deficiency presents as dry beriberi with peripheral neurologic symptoms including distal extremity paresthesias, cramps, and pain, CNS symptoms including Wernicke-Korsakoff syndrome, and cardiovascular symptoms including high output cardiac failure with tachycardia, diaphoresis, warm skin, and lactic acidosis. Korsakoff syndrome presents first with confusion and confabulations, Wernicke encephalopathy happens last and consists of nystagmus, ophthalmoplegia, and coma. Shock can occur and death ensues rapidly if treatment is not started in time. Magnesium sulfate is given with thiamine to reduce peripheral resistance to thiamine. Electrolyte replacement is also be necessary.
Vitamin B2 Deficiency Riboflavin deficiency is due to decreased intake of milk and animal products; secondary deficiency is due to malabsorption syndromes, diarrhea, liver disease, and alcoholism. Riboflavin deficiency presents with pallor, mucosal ulceration such as angular stomatitis and cheilosis, and linear fissures in the skin commonly infected by Candida. A red tongue is present, and cutaneous lesions leading to erythema and acanthosis may occur. Keratitis may lead to lacrimation and photophobia.
Nicotinic Acid Deficiency Niacin, vitamin B3, deficiency is due to excessive maize consumption, amino acid imbalances, malabsorption syndromes, cirrhosis, and alcoholism. Pellagra may occur and present with a photosensitive rash, red stomatitis, glossitis, bloody diarrhea, and CNS changes. Desquamation, keratosis, edema of the tongue and other mucous membranes, GI discomfort, confabulations, cogwheel rigidity, and psychiatric changes occur in severe cases. Tryptophan deficiency may present in a similar manner. Deficiency is treated with niacinamide along with replenishment of other lacking vitamins.
Vitamin B6 Deficiency Pyridoxine deficiency is rarely a primary deficiency; secondary causes include oral contraceptive use, use of hydralazine, cycloserine, or penicillamine, and increased metabolic activity. Seborrheic dermatosis, cheilosis, glossitis, peripheral neuropathy, lymphopenia, seizures, and anemia develop with worsening deficiency.
Biotin Deficiency Biotin deficiency occurs in raw egg consumption or long term total parenteral nutrition (TPN). Biotin deficiency presents with alopecia, keratoconjunctivitis, immunologic deficiencies, and retardation of development.
Mineral Deficiency Chromium deficiency leads to hyperglycemia after prolonged TPN. Selenium deficiency leads to myalgia and cardiomyopathy. Like most mineral nutrients, iron from digested food or supplements is almost entirely absorbed in the duodenum. Iron deficiency may occur following a pancreaticoduodenectomy.
Fluid, Electrolytes, Nutrition, and Acid-Base 7.2.6
Vitamin A Toxicity Excessive vitamin A causes thickening of hair and increased hair loss throughout the body. As the toxicity worsens, pseudotumor cerebri, headache, and weakness may develop. Hepatosplenomegaly is also seen.
Vitamin D Toxicity Vitamin D toxicity leads to anorexia, nausea, vomiting, polyuria, polydipsia, pruritus, azotemia, proteinuria, metastatic calcifications from hypercalcemia, and anxiety. Acidifying the urine and administering corticosteroids are treatment options.
Vitamin E Toxicity Tocopherol toxicity can decrease the effectiveness of vitamin K, which may lead to spontaneous hemorrhage in patients on warfarin.
Vitamin K Toxicity Vitamin K toxicity is rare, but very high doses of its precursor, menadione, may lead to hemolytic anemia and kernicterus.
Vitamin B6 Toxicity Excessive vitamin B6 consumption may lead to sensory ataxia and decreased lower extremity proprioception.
7.3. Acid -Base 7.3.1
Arterial Blood Gas
The ABG is used to measure oxygenation of the blood and to determine the nature of hypoxia. ABG measures five values: pH, PaCO2, PaO2, HCO3 –, and O2 saturation, while the base excess is automatically calculated. Acidosis or alkalosis is determined by the pH. Hypoxemia is determined by the PaO2. Compensation for any potential metabolic acidosis or alkalosis is measured by PaCO2 and HCO3 –. The change is pH due to a change in the PCO2 (hyper or hypoventilation) can be calculated: Corrected HCO3 – = measured HCO3 – + (anion gap – 12) Anion gap = (Na+ + K+) - (Cl– + HCO3 –) Expected PaCO2 = (1.5 x HCO3 –) + (8±2) Acute respiratory acidosis: pH = 0.08 x [(PaCO2 – 40) / 10] Chronic respiratory acidosis: pH = 0.03 x [(PaCO2 – 40) / 10] Acute respiratory alkalosis: pH = 0.08 x [(40 – PaCO2) / 10] Chronic respiratory alkalosis: pH = 0.03 x [(40 – PaCO2) / 10] 75
Clinical Review for the USMLE Step 1 A corrected HCO3– is calculated to determine whether there is also a metabolic acidosis or alkalosis. Because the measured bicarbonate may be normal due to a changed anion gap. This correction is relatively straightforward: The normal corrected HCO3 – should be approximately 24. Significant variation indicates a complex metabolic disturbance – HCO3 – more than 24 indicates a coexisting metabolic alkalosis, while an HCO3– less than 24 indicates a coexisting non-anion gap metabolic acidosis. The expected respiratory compensation for a metabolic acidosis can be calculated with Winter’s formula. This is due to a linear relationship between changes in HCO3 - and compensation by the lung to change in PaCO2. Metabolic acidosis causes hyperventilation and a drop in PaCO2 as respiratory compensation. Variation outside of the range specified by Winter’s formula indicates a concurrent respiratory disturbance and not just compensation for a metabolic acidosis. Winter’s formula can only be used for metabolic acidosis; it does not predict the respiratory compensation in response to a metabolic alkalosis. With metabolic alkalosis, the respiratory response is hypoventilation and a PaCO2 above 40 but less than 50, and alkalotic pH above 7.42.
Anion Gap Metabolic Acidosis An anion gap metabolic acidosis means that the metabolic acidosis is due to hydrogen ions not measured by the laboratory standard chem 7. It is commonly due to lactic acidosis (commnly from hypoperfusion of end organs, shock) ketoacidosis (but not ketone bodies), uremia in chronic renal failure, and ingestion of toxins such as aspirin, ethylene glycol, methanol, and paraldehyde. Anion gap metabolic acidosis is diagnosed by the presence of ketoacids (as in alcoholic ketoacidosis, diabetic ketoacidosis, paraldehyde poisoning, starvation, high-fat diet, and isopropyl alcohol poisoning) or ketoacids being absent (as in renal failure, lactic acidosis, methanol poisoning, ethylene glycol poisoning, and aspirin poisoning). The indications for dialysis include acidosis, hyperkalemia, symptomatic uremia, drug filtration, and fluid overload.
Non-Anion Gap Metabolic Acidosis A non-anion gap metabolic acidosis means that the metabolic acidosis is due to hydrogen ions measured by the chem 7. It is a disturbance common in renal tubular acidosis (RTA), diarrhea, GI tract fistulas, pancreatic disease, use of carbonic anhydrase inhibitors, acid ingestion, dilution of alkali, ileostomy, and various medications (beta-blockers, spironolactone). Treatment is to correct the underlying etiology but to avoid hypernatremia, fluid overload, and excessive bicarbonate infusion.
Renal Tubular Acidosis RTA type I is known as distal RTA, and occurs with medications such as amphotericin, lithium, and NSAIDs, and in diseases such as nephrolithiasis, sickle cell anemia, infection, and autoimmune disorders. RTA type I presents with inability to acidify urine with secondary hyperaldosteronism, hypokalemia, nephrolithiasis, and nephrocalcinosis. RTA type II is known as proximal RTA, and occurs with Wilson disease, Fanconi syndrome, amyloidosis, vitamin D deficiency, hypocalcemia, hepatitis, and autoimmune diseases. RTA type II leads to basic urine in the early stage until the bicarbonate is lost, then subsequent urine acidification. RTA type II 76
Fluid, Electrolytes, Nutrition, and Acid-Base also leads to hypokalemia, osteomalacia and rickets. RTA type IV is known as hypoaldosteronism RTA, and occurs from a decrease in aldosterone or insensitivity to angiotensin II, diabetes, Addison disease, sickle cell disease, and renal insufficiency. RTA type IV presents with hyperkalemia and hyperchloremic non-anion gap metabolic acidosis. RTA type I is treated with oral bicarbonate and potassium replacement. RTA type II is treated with potassium replacement and volume depletion to enhance bicarbonate reabsorption. Thiazide diuretics are also useful. RTA type IV is treated with fludrocortisone, a mineralocorticoid.
Metabolic alkalosis is an increase in pH, increased bicarbonate, and compensatory hypoventilation with an increase in PaCO2 (the opposite of metabolic acidosis). Chloride-responsive metabolic alkalosis has a urine chloride of less than 15, and is commonly due to vomiting, pyloric stenosis, laxative abuse, diuretics, and hypercapnia. Chloride-resistant forms have a urine chloride more than 15, and are commonly a result of severe potassium or magnesium deficiency (as in diuretic abuse), increased mineralocorticoids, Bartterâ€™s syndrome, chewing tobacco, and licorice consumption. Neuromuscular excitability, hypokalemia, and hypovolemia are commonly found on exam, and treatment involves correcting the underlying disorder. KCl is sometimes given to correct significant electrolyte abnormalities. Potassium must be corrected first in chloride-resistant metabolic alkalosis.
Respiratory acidosis is due to hypoventilation and produces a compensatory increased bicarbonate. Causes of respiratory suppression include COPD, airway obstruction, pneumothorax, myasthenia gravis, muscular dystrophy, nervous system disorders (such as Guillain-BarrĂŠ syndrome), botulism, tetanus, organophosphate poisoning, and central depression of the respiratory system (as in narcotic abuse or general endotracheal anesthesia). Presenting signs include confusion leading to stupor and coma, and encephalopathy. Respiratory acidosis is managed by treating the underlying cause, and using artificial ventilation to decrease CO2 retention. Oxygenation of COPD patients who are chronically hypoxic and depend on hypoxia for respiratory stimulation, may lead to depression of the respiratory drive, so only the minimum amount of oxygen via nasal cannula should be provided to maintain oxygenation of the blood.
Respiratory alkalosis is elevated pH, because of hyperventilation (decrease PCO2), and a compensatory decrease in bicarbonate. It is commonly a result of anxiety causing hyperventilation but may also be a consequence of shock, pulmonary disease, pregnancy, cirrhosis, hyperthyroidism, and aspirin poisoning. Presentation is with rapid, deep breathing, anxiety, chest pain, and circumoral paresthesia. Treat respiratory alkalosis by minimizing anxiety in the patient, breathing into a paper bag to increase PCO2, and decreasing minute volume if the patient is artificially ventilated.
7.4. Fluids The SAFE study and Australian ICU study, two of the best studies of the plethora of research over 77
Clinical Review for the USMLE Step 1 decades that have compared crystalloid to colloid, have indicated that crystalloid administration for hypotensive patients is as effective as colloids or blood unless the patient is anemic and has a specific indication for transfusion.
7.5. Metabolic Disorders A variety of metabolic disorders were discussed in “2.4.1 Iron Pathway Defects” on page 20, “2.4.2 Amino Acid Diseases” on page 21, “2.4.3 Purine and Pyrimidine Salvage Diseases” on page 21, “2.4.4 Lysosomal Storage Diseases” on page 22, and “2.4.5 Glycogen Storage Diseases” on page 23.
7.5.1 Cholesterol Cholesterol is formed from acetyl-CoA through the HMG-CoA reductase pathway. About ¼ of all production occurs in liver, but there is significant production by intestines, adrenal glands, testes, and ovaries as well. Approximately 50% of all intestinal cholesterol content is reabFigure 42. Cholesterol synthesis pathway. Copyright Ku- sorbed; levels are regulated by existing cholesterol concentrations. This pathway pirijo. Used with permission. is mediated by the sterol regulatory element binding protein and others, which transcribes genes for the LDL receptor and HMG-CoA reductase (rate-limiting step). Cholesterol is excreted via bile. Chylomicrons are made by intestinal epithelial cells, and transport triglycerides to tissues. They also transport cholesterol to the liver, and may lead to pancreatitis if in excess. VLDLs transport triglycerides from the liver to tissues and are made by the liver. If they are in excess, VLDLs may contribute to acute pancreatitis. LDLs transport cholesterol from the liver to tissues and are made by VLDL conversion. They are regulated by receptor-mediated endocytosis uptake; excess leads to atherosclerosis, xanthomas, xanthelesmas. Most circulating cholesterol is bound to LDL. HDL transports cholesterol from tissues back to liver for processing and excretion. HDLs are made by the liver and intestines. HDLs use scavenger receptors to enter hepatocytes, ovaries, testes, and adrenal glands. HDLs carry significant amounts of cholesterol. There are four major apolipoproteins for USMLE purposes. A-1 activates lecithin-cholesterol acyltrans-
Fluid, Electrolytes, Nutrition, and Acid-Base ferase, and high levels decrease the risk of coronary artery disease. A-1 is known as lecithin in liver and transfers fatty acids from lecithin to cholesterol and traps it in HDL. A-1 prevents plaque formation. B-100 binds to the LDL receptor and is upregulated in hypercholesterolemia. C-II is a cofactor to lipoprotein lipase, which mediates fatty acid uptake into cells from chylomicrons and VLDLs. Finally, apolipoprotein E mediates the uptake of remnants.
Type I hypercholesterolemia is an autosomal recessive disorder that leads to increased chylomicrons and elevated triglycerides. It is due to a lipoprotein lipase deficiency and subsequent failure of ApoC-II to function. Type IIa hypercholesterolemia is an autosomal dominant disorder that leads to increased LDL and cholesterol. It is due to a decrease in LDL receptors.
Figure 43. Cholesterol pathways. Copyright Jag123 and Wikimedia. Used with permission.
Clinical Review for the USMLE Step 1 Type IIb is a combined hyperlipidemia with increased LDL and VLDL leading to increased triglycerides and cholesterol. It is due to increased liver synthesis of VLDLs. Type III hypercholesterolemia is a dysbetalipoproteinemia hallmarked by an increased IDL, VLDL, and chylomicron remnants. It causes elevated triglycerides and cholesterol and is due to altered ApoE function. Type IV is a hypertriglyceridemia leading to increased VLDLs and triglycerides. It is due to overproduction of VLDL by the liver. Type V hypercholesterolemia is a mixed hypertriglyceridemia that leads to increased VLDL and chylomicrons, with subsequently increased triglycerides and cholesterol. There is increased production of VLDL and decreased clearance of VLDLs and chylomicrons.
8. Pharmacology 8.1. Pharmacokinetics The Michaelis-Menten reaction is used to model enzyme behavior. A free enzyme binds to a free substrate to form an enzyme-substrate complex. The enzyme-substrate complex is catalyzed to reform the enzyme and generate a product. Steady state is reached when the addition of new substrate equals formation of new product. The enzyme is always conserved in reactions. The velocity of product formation is directly dependent on the maximum velocity of the reaction and inversely dependent on the affinity of the enzyme and amount of substrate. The volume of distribution (V D) quantifies the amount of drug Figure 44. Saturation curve showing rate vs. concentration. found in the body. High lipid solubil- Copyright Wikimedia. Used with permission. ity means high volume of distribution. This is similar with drugs that have a low plasma protein binding and high tissue binding affinities. V D = total drug in body / drug concentration in blood Clearance refers to the rate of elimination of a drug from the body as compared to its plasma concentration. CL = drug elimination / plasma drug concentration Half-life is the time it takes to clear the body of half of the current amount of drug. Approximately 4 tÂ˝ are required to achieve 95% clearance. t1/2 = (0.7 x V D) / CL = 0. / k 80
Pharmacology Zero-order elimination proceeds linearly with a fixed amount of drug eliminated per unit time. It is typically due to saturation of the elimination enzymes. First-order elimination proceeds as exponential decay with fixed ratio of drug eliminated per unit time. Enzymes are functioning below saturation levels. The loading dose is the amount of drug that may be given initially to reach a target plasma concentration more quickly. LD = Cp x (V D/F) LD = Loading Dose
Figure 45. Effect of a partial agonist. Copyright Wikimedia. Used with permission.
Cp = Plasma Concentration V D = Volume of Distribution F = Bioavailability The maintenance dose is the amount of drug that is given to achieve a steady-state concentration between drug plasma concentration and drug elimination. Figure 46. Dose response curve showing efficacy and potency. MD = Cp x (CL/F) Copyright Wikimedia. Used with permission. MD = Maintenance Dose
8.2. Pharmacodynamics Competitive antagonist lead to a rightward shift in the amount of enzyme needed to achieve the same level of activity. Such a shift also occurs when a patient has become tolerant to the effects of a particular drug, such as where increasing amounts of narcotic are needed to maintain a low pain level. Partial agonists decrease the efficacy of a particular medication, as seen in the figure. Even with increasing drug concentrations, the overall response remains lower than the baseline. Noncompetitive antagonists are similar to the partial agonist in the graph to the right. At ED50 (effective dose) for the drug, Figure 47. Drug development process. Produced by the FDA half of all patients will respond. As the / public domain. dose is increased, more and more pa81
Clinical Review for the USMLE Step 1 tients will enter the range of the lethal dose and risk succumbing to the lethal side effects of the drug.
Efficacy is when two drugs that reach the same maximum desired effect have similar clinical outcomes. Heroin and morphine have approximately the same efficacy in that both can lead to 100% analgesia. Codeine is less efficacious than either of these drugs. Potency refers to the minimum dose needed to achieve a desirable therapeutic effect. Heroin is more potent than morphine in that a lower dose is needed to achieve 100% analgesia.
8.4. Drug Development Drug development involves hundreds of millions of dollars in capital with dozens of potential drug candidates. After extensive testing, a few prototypic drugs are chosen for further analysis. Based on early trials in patients, the number of potential drugs is narrowed. Approval is submitted for the best drugs, a process that takes nearly 10 years.
9. Microbiology 9.1. Bacteria 9.1.1
Clinical Review for the USMLE Step 1
Microbiology 9.1.2 Anatomy
The peptidoglycan capsule is an osmotic pressure protection mechanism and provides protection from phagocytosis. The cell wall is found in gram positives and is a significant antigen; it also contains teichoic acid in gram positive bacteria. The outer and inner membranes have an endotoxin component from lipopolysaccharide layer in gram negative bacteria. The fimbria play a role in sexual reproduction, plasmid transmission, and adherence to cell surface. Plasmids have a resistance mechanism that can be transferred between bacteria. Figure 48. Bacterial anatomy. Copyright Mariana Ruiz. Used with permission. Gram positive bugs have teichoic acid, which play a role in adherence and virulence. They are characterized by a large cell wall with a peptidoglycan layer. Gram negative bugs have endotoxin within a lipopolysaccharide layer.
Exotoxins are found in both gram-positive and gram-negative bugs. Examples include C. diphtheriae, C. tetani, C. botulinum, C. perfringens, B. anthracis, S. aureus, S. pyogenes, E. coli, V. cholerae, and B. pertussis. Exotoxins are preformed, secreted, and highly toxic. They are also heat-labile. Endotoxins are found in all gram-negative bugs with a lipopolysaccharide layer. It is a component of the bacterial membrane. There is a low lethal index but induces significant acute phase reaction with fever. Endotoxins are heat-stable.
Prokaryotic DNA replication relies on primase, which forms the RNA primer; DNA ligase, which seals nicks; and DNA topoisom85
Clinical Review for the USMLE Step 1 erase I, which creates a single nick to relieve supercoils. DNA topoisomerase II and DNA gyrase nick both strands to relieve supercoils. DNA polymerase I excises RNA primer, DNA repair, 3’ à 5’ 3’ nick translation à proofreading, 5’. DNA polymerase II is involved in damaged DNA replication with 5’ à 3’ and 5’ activity à 3’. DNA polymerase III is involved in 3’ à 5’ exonuclease proofreading. DNA polymerase IV functions as a DNA polymerase. DNA polymerase V bypasses damaged DNA. Bacteria have a circular plasmid genome with multiple start sites and alternative protein formation with offset reading frames (not commaless). Prokaryotic RNA translation uses a single RNA polymerase.
Bacteria have a variety of pigments. Blue-green is found with Pseudomonas, yellow with S. aureus, and red with S. marcescens. Agars can be used to separate various bacteria. Blood agar is used to separate GAS, GBS, and GDS based on hemolysis. Alpha-hemolytic bacteria will undergo partial hemolysis (green); examples include S. pneumonia and S. viridans. Beta-hemolytic bacteria undergo complete hemolysis (clear); examples include S. pyogenes and S. agalactiae. Gamma-hemolytic bacteria undergo no hemolysis (red); examples include E. fecalis and S. bovis. Chocolate agar can be used to grow N. meningitidis, N. gonorrhea, H. influenza, and H. ducreyi. Thayer-Martin agar can be used to grow N. gonorrhea. Bile esculin agar (BEA) grows Group D streptococci (S. bovis, E. fecalis) and enterococci. Hektoen enteric agar (HEA) isolates the Enterobacteriaceae group (especially shigella and salmonella). MacConkey agar (MAC) inhibits gram positive bacteria. Mannitol salt agar (MSA) permits mannitol fermentation. Phenylethyl alcohol agar (PEA) grows Staphylococcus spp.. Trypticase soy agar (TSA) grows Brucella spp., Corynebacterium spp., Listeria spp., Neisseria spp., and Vibrio spp. Xylose-lysin-deoxycholate agar (XLD) grows gram-negative bacteria from stool. Sabouraud agar grows fungus. Hay infusion agar grows mold.
9.2. Organisms 9.2.1
Gram Positive Cocci
Staphylococcus Staphylococcus spp. form a biofilm that protects bacteria from antibiotics. Table 14. Gram Positive Cocci: Staphylococcus Etiology
Pathophysiology Superantigen with IL-1/IL-2 synthesis.
Toxic shock syndrome from TSS toxin-1 that leads to cytokine release. Scaled skin syndrome from exfoliative toxin release – exotoxins ET-A and ET-B that breakdown tight junctions. Preformed toxin.
Presentation Toxic shock syndrome – fever, hypotension, hyperemia. Scalded skin syndrome Acute bacterial endocarditis. Osteomyelitis
Treatment Methicillin Vancomycin Clindamycin TMP-SMX Linezolid
Streptococcus IgA protease permits organisms to colonize mucosal surfaces and cause infection. Encapsulated bugs that cause infection following splenectomy: S. pneumoniae, N. meningitidis, H. influenzae B., and K. pneumoniae. 86
Microbiology Table 15. Gram Positive Cocci: Streptococcus Etiology
IgA protease. Encapsulated.
#1 cause of meningitis in children and elderly, otitis media, and pneumonia.
Meningitis Neonatal conjunctivitis. Otitis media, Pneumonia
Treatment Penicillin Ampicillin
Pharyngitis Erythrogenic toxin (superantigen) and streptolysin O (ASO titers; hemolysin). M protein antibody.
GAS Streptococcus pyogenes
Bacitracin sensitive. Exotoxin
Gas production in necrotizing fasciitis (other causes include C. perfringens and Vibrio). Superantigen SSA expression may lead to systemic symptoms.
Cellulitis / Necrotizing fasciitis Impetigo / Erysipelas Scarlet fever â€“ erythema, fever, strawberry tongue, desquamation Toxic shock syndrome Rheumatic fever â€“ erythema marginatum, mitral valve damage
Clindamycin and vancomycin for necrotizing fasciitis
Acute glomerulonephritis (PSGN)
Gram Negative Cocci
Neisseria Table 16. Gram Negative Cocci: Neisseria Etiology
Features IgA protease.
Maltose and glucose fermenter. Encapsulated.
Pathophysiology Common cause of meningitis.
Presentation Meningitis Waterhouse-Friderichsen syndrome.
Treatment Vaccination available. Ceftriaxone
Gram Positive Rods
Non-Spore Formers Table 17. Gram Positive Rods: Non-Spore Formers Etiology
Features Obligate anaerobe.
Draining sulfur granules (yellow flecks).
Presentation Oral / facial abscess. IUD infection.
Treatment Penicillin (SNAP)
Clinical Review for the USMLE Step 1 Spore Formers Table 18. Gram Positive Rods: Spore Formers Etiology
Caused by clindamycin, neomycin, and broad-spectrum antibiotics.
Exotoxin Obligate anaerobe.
Lecithinase with gas production.
Pseudomembranous colitis â€“ diarrhea, fever, sepsis. Myonecrosis â€“ gas gangrene with severe infection. Food poisoning from reheated meat.
Surgical debridement and IV antibiotics
Serious exotoxin production occurs with Clostridial spp., which can lead to the development of necrotizing fasciitis as soon as six hours following an operation. The clostridial group functions as gram positive rods, and is obligate anaerobes. C. perfringens in particular produces several toxins, including a necrotizing, hemolytic Lecithinase (alpha toxin), a hemolysin (theta toxin), a collagenase (kappa toxin), a hyaluronidase (mu toxin), and a deoxyribonuclease (nu toxin). An endotoxin is also produced by this potent bacterium. Rapid spread requiring surgical intervention and serial debridement may be required in the worst cases, and may lead to death even with aggressive therapy. C. difficile produces a potent exotoxin that leads to pseudomembranous colitis leading to diarrhea. Metronidazole or vancomycin is orally given with infection. Cholestyramine can be given to bind toxin. C. tetani produces a neurotoxin that leads to rigidity and muscular spasms, culminating in asphyxiation and death. Treatment is wound debridement and penicillin. C. botulinum produces a neurotoxin leading to GI symptoms, diplopia, and finally paralysis.
Gram Negative Rods
Aerobes Table 19. Gram Negative Rods: Aerobes Etiology Pseudomonas aeruginosa
Features Blue-green pigment. Lactose nonfermenter. Oxidase positive. Encapsulated
Burn infections, pneumonia in CF, sepsis, otitis externa, and UTI
Ampicillin and gentamicin
Eschar formation in burn patients with secondary infection.
Facultative Anaerobes Table 20. Gram Negative Rods: Facultative Anaerobes Etiology Helicobacter pylori
Pathophysiology Uses urease to breakdown mucus layer and lead to ulcer formation in stomach and duodenum
Presentation Gastritis, duodenal ulcer, gastric ulcer
Treatment Bismuth, metronidazole, amoxicillin, clarithromycin, omeprazole.
Primary antigen is a polysaccharide of endotoxin. The K antigen is a capsular antigen (virulence factor); the H antigen is found in motile varieties. Enterobacteriaceae are glucose fermenters. Table 21. Gram Negative Rods: Enterobacteriaceae Etiology
Bacteremia, lower respiratory tract infecImipenem, cilastatin, Meropetion. Most common cause of liver abscess in nem, Cefepime, Ciprofloxacin. a patient with diverticulitis
Enterobacter Heat-labile toxin with adenylate cyclase production through ADP ribosylation of Gs protein; heat-stable works on guanylate cyclase.
Klebsiella pneumoniae Ammonium magnesium phosphate stones.
10,000 required for disease.
Food poisoning from undercooked meat; watery diarrhea (ETEC). Bloody diarrhea (EIEC, EHEC, EHEC O157:H7). Meningitis in elderly. Bacteremia in biliary tract (most common)
Ampicillin and gentamicin Meropenem Ciprofloxacin
Pneumonia with currant jelly sputum. Cholecystitis (uncommon).
Cefotaxime, Ceftriaxone, Gentamicin, Amikacin, Piperacillin / tazobactam.
Struvite stones in UTI.
Ceftriaxone, Gentamicin, Imipenem / cilastatin. Surgical stone removal.
Food poisoning from poultry, meat, eggs with bloody diarrhea
Permit natural course as antibiotics will worsen disease. Consider TMP-SMX for systemic disease.
Obligate anaerobes lack catalase and are foul smelling gas formers. B. fragilis is the most common bacterium within the intestine. Table 22. Gram Negative Rods: Anaerobes Etiology
Presentation Normal bowel flora
Treatment Neomycin, Clindamycin.
Table 23. Atypical Bacteria Etiology
Found in the apex of the lung due to the highest PO2.
Tuberculosis â€“ night sweats, fever, anorexia, hemoptysis. Primary: Ghon complex in lower nodes with fibrotic healing and caseating granulomas, progressive disease, bacteremia, or allergic reaction. Secondary: Fibrocaseous cavitation with secondary spread in body.
Rifampin, Isoniazid, Streptomycin, Pyrazinamide, Ethambutol, Cycloserine
Clinical Review for the USMLE Step 1
9.3. Antimicrobials 9.3.1
Resistance to penicillins comes from beta-lactamases that cleave the penicillins to make them impotent. Penicillins bind to PBPs with subsequent inhibition of the transpeptidase step leading to cell lysis. It will not affect organisms that do not have a cell wall. Penicillins are cleared by the kidneys, which can be slowed with the administration of probenecid. Table 24. Antimicrobials: Penicillin Drug
Mechanism of Action
GPC (Streptococcus, meningococcus, enterococcus), GPR
Inhibits cross-linking of cell wall leading to bacterial lysis Ă bactericidal
GPC, GPR, GNR, E. coli, H. influenzae, L. monocytogenes
Extended spectrum. Pseudomonas and GNR.
Hypersensitivity (anaphylaxis), hemolytic anemia
Do not use in bacteria with beta-lactamases or w/ known hypersensitivity (common rxn is skin rash)
Effective against Neisseria spp., C. perfringens, Fusobacteria, and Treponema
Inhibits cross-linking of cell wall leading to bacterial lysis
As above plus pseudomembranous colitis. Seizures at high doses.
Do not use if hypersensitivity to penicillins.
Use with clavulanic acid or sulbactam to block beta-lactamases. Wide spectrum. Oral.
Inhibits cross-linking of cell wall leading to bacterial lysis
Hypersensitivity, Do not use if hypersensitivity to penicillins. Sodium hemolytic anemia, platelet dysfunction. loading.
Cephalosporins â€“ First Generation
Resistance to cephalosporins comes from beta-lactamases that cleave the penicillins to make them impotent. Cephalosporins have a hexagonal ring with two functional groups. Penicillins have a pentagonal ring with one functional group. Both are susceptible to beta-lactamases. Table 25. Antimicrobials: First Generation Cephalosporins Drug
Mechanism of Action
E. coli K. pneumoniae P. mirabilis
Inhibit cell wall synthesis by preventing cross-linking. Bactericidal.
10% penicillin cross hypersensitivity
Alcohol (disulfiram reaction)
Less susceptible to beta-lactamases.
Cephalosporins â€“ Second Generation
Table 26. Antimicrobials: Second Generation Cephalosporins Drug
Mechanism of Action
Avoid with aminoglycosides (nephrotoxicity).
Less susceptible to beta-lactamases.
Avoid with alcohol (disulfiram reaction)
Broader range compared to first generation.
GPC, E. coli Enterobacter
Inhibit cell wall synthesis by preventing crosslinking.
H. influenzae Cefoxitin
K. pneumoniae Neisseria spp.
P. mirabilis Serratia spp.
Cephalosporins â€“ Third Generation
Table 27. Antimicrobials: Third Generation Cephalosporins Drug
Mechanism of Action
Inhibit cell wall synthesis by preventing crosslinking.
Meningitis Resistant organisms Ceftriaxone
Broad range. Low activity against gram positives.
Avoid with aminoglycosides (nephrotoxicity). Hypersensitivity (rash). Avoid with alcohol (disulfiram reaction)
Notes Cross blood-brain barrier.
Ceftazidime is especially good against Pseudomonas.
Monobactams / Carbapenems
Table 28. Antimicrobials: Monobactams and Carbapenems Drug
Mechanism of Action
GNR, Klebsiella spp., Pseudomonas spp., Serratia spp.
Prevents synthesis of cell wall. Bactericidal.
GPC, GNR Imipenem
Improved activity with aminoglycosides Beta-lactamase resistant cell wall synthesis inhibitor. Bactericidal.
GI Sx. Rash. CNS toxicity leading to seizures at high doses. Nephrotoxic. Eosinophilia.
No effect against anaerobes or grampositive bacteria.
No cross-sensitivity with penicillins. Especially recommended in renal disease.
Imipenem is always given with cilastatin to avoid inactivation in kidney. Synthetic.
Clinical Review for the USMLE Step 1 9.3.6
R-factor resistance leads to drug inactivation and decreased uptake. May also be modified through acetylation, adenylation, or phosphorylation of the compound. Excreted unchanged by kidney. Table 29. Antimicrobials: Aminoglycosides Drug
Indications Severe gramnegative infections. Aerobes only. Pseudomonas.
Mechanism of Action
Do not use with cephalosporins.
Cause mRNA misreading by preventing formation of initiation complex à bactericidal.
Cause NMJ blockade after surgery.
Do not use with loop diuretics.
Renal clearance – avoid in renal disease.
Notes Require O2 for use – no effect against anaerobes.
R-factor resistance leads to drug inactivation and decreased uptake. Also has increased removal from cell. Avoid dairy foods, iron-containing preparations, and antacids with use of tetracyclines. Table 30. Antimicrobials: Tetracyclines Drug
Tooth discoloration and stunted growth in children.
Mechanism of Action
30S inhibitor prevents tRNA attachment.
Avoid in renal patients. Avoid in children.
Do not use in CNS infections.
Resistance by rRNA methylation leading to prevention of binding to 50S unit. Table 31. Antimicrobials: Macrolides
Pneumonia and URTI., GPC, Mycoplasma, Legionella, Chlamydia, Neisseria
Mechanism of Action 50S inhibitor prevents translocation and inhibits protein synthesis. Bacteriostatic.
GI Sx (common). Hepatitis. Eosinophilia. Skin rashes.
Avoid in hepatic patients. Macrolides are excreted in bile.
Resistance by change in DNA gyrase. Drug penetration may also change. No plasmid-resistance. Table 32. Antimicrobials: Fluoroquinolones Drug
GNR, Pseudomonas, Neisseria spp., Gram-positives (MRSA), UTI, TB
Mechanism of Action Prevents action of topoisomerase II. Bactericidal.
Complications GI Sx. Tendon rupture. Theophylline levels increase in plasma.
Contraindications Avoid in pregnancy and children due to cartilage damage. Avoid in renal patients.
Notes Very potent drugs. Broad spectrum except against anaerobes and some GPC. Renal secretion.
Sulfonamides / Trimethoprims
Resistance by modification of DHP synthase, increased synthesis of PABA, or decreased uptake of drug. Table 33. Antimicrobials: Sulfonamides and Trimethoprims Drug
Gram-positives, gram-negatives, Nocardia, Chlamydia, recurrent otitis media, UTI
UTI, prostatitis, Shigella, Salmonella, P. carinii, Nocardiosis, and HIB
Mechanism of Action Inhibits DHP synthase by PABA metabolites. Bacteriostatic.
Prevents the use of DHFR in bacteria. Bacteriostatic. Additive with SMX.
Complications Allergic reactions. Nephrotoxicity, kernicterus, changes volume of other medications. Rash, anemia, crystalluria.
Megaloblastic anemia, pancytopenia. BMS.
Contraindications G6PD deficiency, avoid in infants, use with care with other drugs. Avoid in pregnancy.
Notes Combined with TMP. Resembles PABA. Penetrate CNS. Give with folate to avoid anemia. Used for recurrent UTIs. TMP-SMX used for P. carinii pneumonia.
Resistance to vancomycin comes from mutation of D-ala D-ala to D-ala D-lac. Plasmid-mediated. Rfactor resistance for chloramphenicol leads to drug inactivation by acetyltransferase inactivation and decreased uptake.
Clinical Review for the USMLE Step 1 Table 34. Antimicrobials: Other Drugs Drug
Mechanism of Action
50S inhibitor to decrease tRNA binding to A site. Bacteriostatic.
Protozoa. G. vaginalis. Anaerobes. Bacteroides. Clostridium spp.
Formation of toxic products. Bactericidal.
Avoid with alcohol due to disulfiram reaction.
Used for numerous STDs.
Resistant GPRs, S. aureus / MRSA / PRSP, C. difficile
Prevents cell wall formation through D-ala D-ala binding and sequestration.
Nephrotoxic. Ototoxic (deafness). DVTs. Red man syndrome.
Renal disease. Renally cleared agent.
Avoid red man syndrome with antihistamines and gradual administration.
Anaerobic infections. B. fragilis. C. perfringens.
50S inhibitor. Bacteriostatic.
Renal and hepatic clearance.
PO. Treat pseudomembranous colitis with flagyl. A lincosamide.
9.4. Fungus 9.4.1
Aplastic anemia, gray baby syndrome.
Avoid in pregnancy and infants (low UDPglucuronyl transferase).
Fungi are single or multicellular heterotrophs. Multicellular fungi have hyphae that aggregate to form a mycelium. Fungi can reproduce asexually via budding. Yeast are a unicellular fungus that use asexual reproduction or ascospores. Dimorphism permits switching between a yeast-like form to multicellular filamentous form (as in Candida).
Sabouraud agar is used to grow fungus. Hay infusion agar grows mold.
Topical Infections Table 35. Cutaneous Fungal Infections Etiology Candida albicans
Budding yeast with pseudohyphae and germ tube formation. Water soluble toxin leads to pain.
Oral thrush. Infectious Nystatin topical therapy. Fluconesophagitis. Diaper rash. azole or amphotericin B for sysVaginal infection. temic infection or vaginal infection.
Systemic Infections Table 36. Systemic Fungal Infections Etiology
Lung cavitary lesions with fungus balls followed by disseminated cutaneous infection. Papules, ulcers, eschars.
Primary â€“ flu-like illness and erythema nodosum common in kids and travelers. Systemic â€“ African Americans and other groups with an HLA predisposition leading to skin, tissue, bone, and meningeal infection.
Systemic: amphotericin B
Meningitis or acute pulmonary infection in IC.
Diffuse pneumonia in IC.
Pentamidine, TMP-SMX, Dapsone
Amphotericin B Local: fluconazole
Mold form outside body. Yeast form, in warmer temperatures, inside body.
Clinical Review for the USMLE Step 1 9.4.5
Table 37. Antifungals Drug
Mechanism of Action
Meningitis Cryptococcus Amphotericin B
Aspergillus Histoplasma Candida
Sequesters ergosterol and has detergentlike effect on cell wall. Fungicidal at high doses.
F/C. Hypotension. Nephrotoxicity.
Avoid in renal disease.
Does not cross BBB. Must be given intrathecally for meningitis. Given slowly via IV.
Sequesters ergosterol, disrupts cell wall.
Oral candidiasis. Topical only.
Systemic infections. Fluconazole
Block formation of ergosterol by lanosterol. Fungistatic.
9.5. Virus 9.5.1
Gynecomastia, hepatitis, F/C.
Avoid in hepatic disease.
Good absorption and CNS penetration.
Clinical Review for the USMLE Step 1
Viruses use either DNA or RNA for transcription. A capsid serves as an enclosure for nucleic acid that serves to protect nucleic acid from digestion, permits binding to host cells, and permits penetration into host cell. The envelope is a lipid bilayer that surrounds capsid, typically obtained from the cell membrane itself. Used to attach to the host cell and to evade host defenses. dsDNA viral nucleic acids are infectious, along with positive strand ssRNA nucleic acids. Negative strand virus nucleic acids by themselves are not infectious. Only retroviruses are diploid. Of the DNA viruses, only poxvirus replicates in the cytoplasm, and of the RNA viruses, only influenza virus and retroviruses replicate in the nucleus. Reassortment involves rearrangement of segments that may occur in orthomyxoviruses, bunyaviruses, arenaviruses, and reoviruses. Oncogenic viruses include the papillomavirus family, herpesvirus family, hepadnavirus family, flaviviruses, adenoviruses, poxviruses, and retroviruses. HPV 6 and 11 typically form genital warts, but may progress to form epidermodysplasia verruciformis. HPV 16, 18, 31, 33, and 45 can lead to cervical, penile, and vulvar cancer. Herpesviruses that can lead to cancer include EBV, which typically causes infectious mononucleosis, but may also cause Burkittâ€™s lymphoma, nasopharyngeal carcinoma, and contribute to Hodgkin disease. Hepadnavirus that can lead to cancer include HBV, which typically causes infectious hepatitis, but may progress to hepatocellular carcinoma. Flaviviridae such as HCV may lead to hepatocellular carcinoma through p53 effects.
Microbiology Adenoviridae typically causes the common cold, but may lead to adenocarcinoma of the upper respiratory tract. Poxviridae typically causes small pox, but may contribute to various malignancies. Retroviridae such as HTLV cause adult T-cell leukemia and contribute to lymphoma.
Phosphorylation by the virus of DNA polymerase permits DNA polymerase binding and subsequent inhibition of DNA synthesis. Table 38. Antivirals Drug
CMV in IC EBV in IC
Mechanism of Action
Inhibits viral DNA polymerase, guanine analog.
Avoid in renal patients.
Also treated with vidarabine (adenosine analog)
Inhibits viral DNA polymerase.
Pancytopenia, especially with WBCs.
Use with care due to BMS.
9.6. Parasites 9.6.1
Clinical Review for the USMLE Step 1 9.6.2
Table 39. Antiparasitics Drug Metronidazole
Indications Giardia, Entaboeba histolytica, Gardnerella vaginalis, Trichomonas
Mechanism of Action Targets DNA.
Complications Disulfiram-like reaction.
Notes Does not eliminate cysts.
9.7. Common Infections 9.7.1
Toxic Shock Syndrome
Toxic shock syndrome (TSS) is erythema leading to systemic manifestations of shock due to S. aureus. Superantigen known as TSS toxin-1 (TSST-1) leading to cytokine release throughout the body leads to the diffuse injury and systemic symptoms. TSS presents with symptoms include fever, hypotension, organ involvement, and distal extremity desquamation. Erythema is present with a scarlatiniform eruption. The tongue is cherry red, and hyperemia of mucous membranes is common. Several organs may be involved leading to serious systemwide damage and complications. Diagnosis is made by culture. Supportive therapy is used with TSS, including IVF, pressors, antibiotics, and draining the affected regions. Silver sulfadiazine cream is contraindicated; mupirocin ointment is used instead. Standard antistaphylococcus antibiotics are used as previously discussed.
Toxic Epidermal Necrolysis / Stevens Johnson Syndrome
Causes of toxic epidermal necrolysis include dilantin and bactrim. Biopsy of the skin will indicate nondisjunction of the dermal and epidermal interface. Treatment includes steroid therapy and stopping the offending agent.
Following a human bite, an incision and drainage should be done. Augmentin should be given to the patient. Tetanus vaccination should also be verified and IgG should be considered. Human bites lead to infection with S. aureus and Eikenella corrodens. Wounds are typically left open following irrigation and debridement. Bites from animals are treated in a similar fashion. Cat bites are more likely to be infected than dog bites due to the presence of Pasteurella multocida. Bites from most animals (and humans) can be safely treated with Augmentin or Bactrim. A bite from a brown recluse spider can be treated with dapsone.
Tetanus is caused by neurotoxin release by C. tetani, leading to a 30% mortality rate if not treated early. Tetanus infection must be especially considered in the presence of dirty wounds contaminated by soil or feces, puncture wounds, burns, and frostbite. For clean, minor wounds, children under 7 should be treated with a DPT (Diphtheriae, Pertussis, and Tetanus) vaccination as prophylaxis. Children over 7 100
Microbiology can be treated with the Td (tetanus toxoid) vaccination for similar wounds. Adults should receive a Td if the most recent vaccination is over 10 years ago. All dirty or major wounds receive a Td unless the full immunization schedule has been followed and the most recent vaccination is less than 5 years ago.
Sexually Transmitted Diseases
Urethritis, cervicitis, and prostatitis due to N. gonorrhea or Chlamydia are treated with ceftriaxone, ciprofloxacin with doxycycline, or ciprofloxacin with azithromycin. Disseminated gonococcal infection is treated with ceftriaxone followed by ciprofloxacin. PID is treated with ceftriaxone with doxycycline or cefotetan with doxycycline. HSV receives ACV or VCV. Haemophilus ducreyi leading to chancroid is treated with ceftriaxone, erythromycin, or azithromycin. LGV due to Chlamydia is treated with doxycycline. Syphilis due to Treponema pallidum is treated with benzathine penicillin or penicillin G if neurosyphilis is present. Table 40. STDs STD
Urethritis, cervicitis, and prostatitis due to N. gonorrhea or Chlamydia
Ceftriaxone, ciprofloxacin with doxycycline, or ciprofloxacin with azithromycin
Disseminated gonococcal infection
Ceftriaxone followed by Cipro.
Ceftriaxone with doxycycline or cefotetan with doxycycline.
ACV or VCV.
Ceftriaxone, erythromycin, or azithromycin.
LGV due to Chlamydia
Diseases that may lead to outbreaks or signify an underlying quality control defect must be reported to the state department of public health. These include AIDS (but not necessarily HIV), measles, mumps, rubella, pertussis, chickenpox, smallpox, shigella, salmonella, hepatitis A-E, syphilis, rabies, tuberculosis, gonorrhea, chlamydia, lyme disease, and Legionaireâ€™s.
9.8. Prions Prions are misfolded proteins that catalyze changes in other proteins to cause structural and physiological malformations. This process infects other cells and leads to aggregations of proteins that cannot be broken down by the body. Such aggregations accumulate until they lead to cell death, then become a nexus for infecting other nearby cells. Normal proteins serve as the basis for a prion-based infection. These are known as PrPC (common); the prion form is known as PrPSc (scrapie). Infectious prion proteins reproduce by one of two methods. In the het- Figure 49. The fibril model for prion replicaerodimer model, one prion protein binds to a normal tion. Copyright Wikimedia. Used with permisprotein and causes a structural shift. This catalyzes sion. 101
Clinical Review for the USMLE Step 1 structural changes in other proteins and propagates the prion. In the heterodimer model, there is exponential growth in the rate of infection. In the fibril model, expanding linear chains of proteins occur, with prion-based structural changes occurring only at the tips of the fibrils. Unless the fibrils break off, growth is linear. There are several prion diseases that affect humans, including Creutzfeldt-Jakob disease, fatal familial insomnia, and kuru. Creutzfeldt-Jakob disease is a fatal, degenerative neurological disorder that leads to progressive breakdown of the brain. Fatal familial insomnia is an autosomal dominant prion disorder that leads to progressive insomnia and eventually death, with initial presentation in middle-aged adults. Figure 50. The heterodimer model of prion replication. Finally, kuru is a disease once spread via Copyright Wikimedia. Used with permission. cannabalism that presents with progressive neurological degeneration and seizures. Infection is typically via ingestion of the prion protein such as consuming a meat product. However, spread via feces (fecal-oral spread) and airborne methods can also occur. As in the case of fatal familial insomnia, genetic spread is also possible. Sterilization is difficult as typical denaturization processes via heat, acids, radiation, and proteases are not 100% effective.
10. Biostatistics 10.1. Introduction Biostatistics is a branch of statistics that applies statistical methods to medical and biological problems. It is of essential importance in the successful conduct of clinical and translational studies. An understanding of biostatistics enables the critical analysis of scholarly articles and their proper assimilation into oneâ€™s own practice. In recent years, as a result of extraordinary advancement in computational capabilities, there have been significant improvements in statistical techniques and research design methodologies, including adaptive designs, randomization and Bayesian methods in clinical trials. However, clinical and translational investigators are often unaware of these new statistical methods. The lack of awareness is compounded by the tendency for individual clinical and translational studies to have either too few study subjects (Levin & Danesh-Meyer, 2010), too much random noise in the study data (Baggerly, Morris, Edmonson, & Coombes, 2005), or too much potential for bias (Ransohoff & Gourlay, 2010; Ioannidis, 2005). In this section, we provide an introduction to biostatistics and cover the essentials of descriptive and inferential statistics including estimation and hypothesis testing. In addition, we discuss major types of study designs and the importance of sensitivity and specificity, measures of absolute and relative risk, common errors and sources of bias in scientific studies.
Biostatistics Before we can discuss the steps in developing a good clinical study and the appropriate statistical testing methods, we must go over the basics of descriptive statistics. The basic statistical problem is that we are trying to infer the properties of the underlying population from a limited number of measurements from the population. In order to successfully do this, we must understand how to describe the sample data and define the relationships between the sample and population.
Central Tendency: Mean, Median,
The mean, median, and mode are statistics used to describe a distribution. The mean is the average of all measurements. It is important to distinguish the difference between the mean of a measurement in a population vs. the mean of a measurement in a sample; the population mean is often denoted by µ and the sample mean is denoted by . The sample mean is simply a point estimate for the population mean. This will be further discussed in the following section. The median is the middle measurement when all of the measurements are sorted in an ascending or descending order, which can be a better measure of central tendency in skewed distributions. In normal (bell-shaped) distributions the average and median values are the same. The mode is the measurement with the highest frequency. Based on these three measures of central tendency one can understand the shape of the distribution. Furthermore, depending on the type of measurements and shape of the distribution one may choose one or more of these measures of central tendency to describe their data set.
Measures of Spread: Range, variance and Standard Deviation
Sample range is the difference between the highest and the lowest measurements. Therefore, it is a very sensitive measure of variability because of the extreme observations. For situations in which there are extreme observations, some researchers use the inter-quartile range (IQR) which represents the difference between the 25th percentile and 75% percentile. Sample variance (s2) is another important measure of variability, which is calculated by the following formula, where xi are the individual measurements and n is the sample size:
∑ ( xi − x ) n
Since the unit of variance is squared of the original unit of measure, the sample standard deviation (s) is often used as another measure of spread, which is simply the square root of the sample variance.
∑ ( xi − x ) n
s= s =
It is important to distinguish the difference between population and sample measures of spread. For example, population standard deviation (s) is a measure of spread over the entire population of size N with a mean of µ; similarly, population variance is denoted by s2. The reason for using “n-1” in calculating sample variance (s2) and standard deviation (s) is to ensure that the estimates for variability remain 103
Clinical Review for the USMLE Step 1 unbiased. This concept is discussed in standard statistical textbooks and we refer the reader to “Fundamentals of Biostatistics” by Bernard Rosner for additional information.
∑ (xi − µ ) N
In practice, many measurements including weight and height, have a bell-shaped distribution. Mathematically these distributions can be characterized by a normal (guassian) distribution with mean µ and standard deviation s. The normal distribution is symmetrical and has the property that about 68% of the observations lie within one standard deviation from the mean, 95% within 2 standard deviations and 99.7% within 3 standard deviations.
Figure 1. A normal distribution of the population with mean µ and standard deviation s.
Not all distributions are normal in nature. In fact, skewed distributions are common in clinical data. In a negatively skewed distribution (i.e. skewed towards the left), the mean is less than the median. In a positively skewed distribution (i.e. skewed towards the right), the median is less than the mean. In a bimodal distribution, there are two modes, one mean, and one median. For irregular distributions, one may be interested in describing the data in terms of the median and interquartile range.
Figure 2. A negatively skewed curve has a mode that is greater than the median, which is greater than the mean (left-skewed). A positively skewed curve has the opposite finding (right-skewed).
As stated earlier, one of the objectives of statistics is to infer the properties of the underlying population from a sample (i.e. subset of the population). Statistical inference can be subdivided into two main areas: estimation and hypothesis testing. Estimation is concerned with estimating the values of specific population parameters. It is therefore, very important to understand the relationships between the sample characteristics and population parameters.
Point and Interval Estimators for the Population Mean
A natural estimator for µ is the sample mean , which is referred to as a point estimate. Suppose we want to determine the appropriate sample size for estimating the mean of a population (µ) which is unknown. We can start by taking a random sample to determine the sample mean and sample variance. However, the sample mean values can change from sample to sample. Therefore, it is necessary for us to determine the variation in the point estimate (e.g., sample mean). Assuming that the sample size is large (n>30), we can determine an interval estimate (e.g. 95% confidence interval) for the population parameters. For example if the population parameter is µ, a 95% confidence interval can be calculated by the following formula. The value 1.96 is the exact value determined from the normal distribution, which is based on the fact that 95% of the measurements are within 1.96 (approximately 2) standard deviations of the mean.
x ± 1.96
The quantity to the right of the mean is known as the margin of error or the bound on the error of estimation (b). In general, as sample size increases b decreases. However, this inverse relationship is not linear. In order to decrease b by half, one must increase the sample size by a factor of 4. This relationship between margin of error, b, and sample size allow researchers to calculate the appropriate sample size to achieve the desired bound on the error with 95% confidence and will be further elaborated in the sample size determination section.
Clinical Review for the USMLE Step 1 10.7.2
Standard Error of the Mean
The standard error of the mean (SEM) or standard error (SE) is the standard deviation of sample mean. There is a mathematical relationship between the standard deviation of the measurements in the population and the SEM. This mathematical relationship helps to calculated SEM based on one random sample of size “n”. SEM is equal to the standard deviation divided by the square root of the sample size “n”. The SEM is affected by the sample size; as the sample size increases, the SEM decreases.
Point and Interval Estimators for the Population Proportion
In clinical studies, one is often interested in assessing the prevalence of a certain characteristic of the population. In this case, it is important to determine the point and interval estimators for the population proportion (p). The point estimator for the population proportion is defined as the proportion of the observed characteristic of interest in the sample.
ˆ = p
For large samples, such that npˆ (1− pˆ ) ≥ 5 , a 95% confidence interval for the population proportion p is calculated as follows:
pˆ ± 1.96
pˆ (1 − pˆ ) n
The quantity to the right of the sample proportion ( pˆ ) is known as the margin of error or the bound on the error of estimation (b). As shown before in the case of point estimates for the population mean, this relationship can be used to estimate the appropriate sample size, which will be explained later.
Generally, bias is defined as ‘a partiality that prevents objective consideration of an issue’. In statistics, bias means ‘a tendency of an estimate to deviate in one direction from a true value’. In terms of the population means and proportion estimates described in the previous sections, bias can be defined as:
Bias = ( x − µ ) Bias = ( pˆ − p ) 106
Biostatistics From a statistical perspective, an estimator is considered unbiased if the average bias based on repeated sampling is zero. For example, is an unbiased estimator of µ and pˆ is an unbiased estimator for p. However, there are multiple sources of bias inherent in any study that may occur during the course of the study, from allocation of participants, delivery of interventions, to measurement of outcomes. Bias can also occur before the study begins or after the study during analysis. Late look bias occurs with reexamination and re-interpretation of the collected data after the study has been un-blinded. Lead-time bias occurs when earlier examination of patients with a particular disease lead to earlier diagnosis, giving the false impression that the patient will live longer. Measurement bias occurs when an investigator familiar with the study does the measurement and makes a series of errors towards the conclusion they expect. Recall bias occurs when patients informed about their disease are more likely to recall risk factors than uninformed patients. Sampling bias occurs when the sample used in the study is not representative of the population and so conclusions may not be generalizable to the whole population. Finally, selection bias occurs when the lack of randomization leads to patient’s choosing their experimental group which could introduce confounding.
Developing a Hypothesis
A research question can be formulated into null and alternative hypotheses for statistical testing. The null hypothesis states that there is no difference between the parameter of interest and the hypothesized value of the parameter. Whereas the alternative hypothesis is that there is some kind of difference. The alternative hypothesis cannot be tested directly; it is accepted by default if the test of statistical significance rejects the null hypothesis. In the case of comparing two population parameters, the null hypothesis is that there is no difference between groups (A or B) on the measured outcome. Whereas the alternative hypothesis is that there is a difference between the measured outcome and the group (A or B). Alternatively, the null hypothesis can be written as no association between group (A or B) and measured outcome vs. alternative hypothesis that there is an association between group (A or B) and the measured outcome. In later sections, you will see that some researchers prefer to write the hypotheses in terms of ratio of the two population parameters [e.g., Relative Risk (RR) or Odds Ratio (OR)]. In this case the null hypothesis can be written as RR=1 (OR=1) vs RR≠1 (OR≠1).
Other Elements of Testing Hypothesis
In addition to the null and alternative hypotheses, we must have a test statistic, a rejection region, and p-value to conduct a formal testing hypothesis. A test statistic calculates the difference between the observed data and the hypothesized values of the parameters assuming the null hypothesis is true. For example, for comparing means of two normal distributions we can use a test statistic, which has a tdistribution under the null hypothesis. Rejection region is the range of values of the distribution of the test statistic for which the null hypothesis is rejected, in favor of the alternative hypothesis. Traditionally, for each testing hypothesis one must determine a cut off value for the rejection region, based on a probability of type I error (α = 0.05).
Types of Error
Type I error occurs when the null hypothesis is rejected despite being true. The probability of type I error (α) is usually considered acceptable at 5%. P-value is the probability of observing more extreme values than what has been already observed in the sample assuming the null hypothesis is true. If pvalue < α, then the null hypothesis can be rejected. On the other hand, type II error occurs when the null hypothesis is not rejected when it should be. The probability of type II error (β) is more difficult 107
Clinical Review for the USMLE Step 1 to calculate because we usually do not know the true value of the parameter of interest under the alternative hypothesis. Additionally, it is important to note that as alpha increases, beta decreases and the power of the study increases.
The power of a test is the probability of rejecting the null hypothesis when it is false. Mathematically, power is defined as 1-β. The power of a test is directly related to its sample size; increasing sample size results in a higher power. However, the power is also directly dependent upon the variance of the measurement. Using more sensitive and specific instruments that can measure a finer gradient (such as reliably estimating HDL to 3 decimal places) can also improve the power of a study. An insufficiently powered study can lead to false acceptance of the null hypothesis and thereby lead to a type II error. In other words, a study may incorrectly conclude that there is no difference between two groups (e.g., two treatments) when one really existed. To avoid these errors, the power of a study must be determined by the need to estimate expected differences between two groups.
Sample Size Determination
The sample size (n) is the total number of patients enrolled in a particular study. This number plays a critical role in the statistical power and relevance of the findings from the study. The sample size can be determined through two inferential techniques. First, for determining the minimum sample size required to estimate a certain parameter of interest within a certain margin of error we need the variance of the measurement, level of confidence and the margin of error. Referring back to the definition of margin of error, we can calculate the sample size for estimating the difference between two means (µ1-µ 2) based on two independent samples equal size with the following formula:
1.96 2 2 n1 = n2 ≥ ⋅ (σ 1 + σ 2 ) B For estimating the mean of one population, the sample size formula is slightly different and we refer the reader to Rosner’s textbook “Fundamentals of Biostatistics”. Secondly, for the testing hypothesis, sample size is determined from variance of the measurement, level of confidence and effect size. For comparing two population means, the effect size is defined as the absolute difference between the mean of the two populations divided by the standard deviation of the measurement of the control group. Together, the formula for sample size for a two population study with an α=0.05 and β=0.2 (i.e. 80% power) is as follows:
n1 = n2 ≥
+ 0.84 ) σ 12 + σ 22 ∆2 2
where s12 and s22 are the variances of each population and D = |m1 – m2|. This method is only appropriate when the sample size between the two groups is the equal. For unequal groups we refer you to Rosner’s textbook. 108
Biostatistics To determine the sample size for estimating a population proportion (p) within a certain margin of error (B) with 95% confidence, we need to have an initial estimate for the population proportion of interest. If no such estimate is available the most conservative sample size can be determined by replacing p=0.5 in the following formula:
1.96 n≥ ( p)(1 − p ) B Furthermore, to determine the required sample size for comparing two population proportions assuming an absolute difference of delta (p1-p2) and equal sample sizes in both groups, we will use the following formula. This formula is specifically for having at least 80% power (β=0.2) with α=0.05, where D = |p1 – p2|.
n1 = n2
)2 [ p1 (1 − p1 ) + p2 (1 − p2 )] ∆2
Similar to before, if p1 and p2 are unknown the most conservative estimate of n1 and n2 can be obtained by assuming a value of 0.5 for p1 and p2 in the above formula. This method is only appropriate when the sample size between the two groups is the equal. For unequal groups we refer you to Rosner’s textbook “Fundamentals of Biostatistics”.
The Student’s t-test was developed in 1908 by William S Gosset using the penname Student. He created this statistical test as a method of monitoring the quality of Guinness stout, comparing one batch to another and ensuring that production was of consistent quality. The t-test assumes that the groups being compared come from a normally distributed population. There are three different types of t-tests: one sample t-test, two sample t-test and paired-sample t-tests. The one sample t-test compares the mean of a population to a specified (hypothesized) value. In the two-sample t-test, two independent samples are compared for differences between the population means. However, if the two samples being compared are dependent or matched, a paired t-test must be used. The limitation of the t-test is that it can only compare two groups at any given time. For comparing more than two group means we will introduce one-way analysis of variance (ANOVA) in the next section.
The analysis of variance (ANOVA) is a statistical procedure based on the F-test that can be used to simultaneously compare means from more than two groups. Similar to the t-test, ANOVA assumes that the populations being compared have normal distributions. It is particularly useful when comparing dose response curves of a medication given at differing doses to a group of patients. ANOVA helps to avoid inflation of type I error potentially caused by conducting multiple t-tests between groups when 109
Clinical Review for the USMLE Step 1 there are more than 2 groups.
Chi-Square Test of Indepdendence
The Chi-square test of independence allows testing for association or lack of it between two categorical variables. For example, in testing associations between disease status (D+/D-) and ethnicity (Caucasian, African American, Hispanic, Other) we can form a contingency table that provides the count for the frequency of observations in each combination of the rows and columns. The Chi-square test of independence has (r-1)(c-1) degrees of freedom where r is the number of rows and c is the number of columns in the contingency table. The rejection region for the chi-square test will be on the right tail of the Chi-square distribution. For computation of test statistics and p-values one can use standard statistical software.
Regressions and Correlations
Up to this point we have discussed hypothesis and statistical testing methods; the next step is to evaluate if there are any correlations between the outcome variable and group (class) variables. Linear-regression methods allow one to study how an outcome variable (y) is related to one or more predictor variables (x1,x 2,….xk).
Simple Linear Regression
Simple linear regressions are often fitted to the data using the Least Squares method where the best-fit line is determined by minimizing the sum of squared distances of the data points from the regression line. The simple linear regression equation often takes the form, where a is the y-intercept and b is the slope of the regression line in the population (Equation 13). y = a + bx The slope of the regression line (b coefficient) represents the estimated average increase in y per one unit increases in x. It is used to make predictions between the two variables, x and y. However, predictions are not always easy to make with clinical data and often we are interested in describing the relationship between x and y. In this case, the sample correlation coefficient (r) is a useful tool for quantifying the relationship between variables and is better suited than the estimated regression coefficient. The population correlation coefficient is denoted by ρ. In other words, r is a natural point estimator for ρ.
Correlation coefficients help to describe linear relationships between two variables. It is of vital importance to understand that correlation does not imply causation. In correlation analysis, it is important to look at the scatter plot which is a graphical presentation of pairs of (X, Y) coordinates plotted on the X-Y axis. The X is the independent variable and the Y is the dependent variable. The correlation coefficient must lie between -1 and 1. A correlation coefficient of 0 means that there is no linear relationship between the two variables (or X and Y are uncorrelated). However, the two variables might still be otherwise related (e.g., U shaped-relationship). A correlation coefficient between 0 and 1 means a positive correlation exists, as X goes up, the Y variable generally goes up. A negative correlation implies an inverse relationship, as X increases the Y variable generally decreases. Thus, the correlation coefficient provides a quantitative measure of dependence between the two variables. Please note that dependence of Y on X does not imply that there us a causal relationship between X and Y. 110
As mentioned in the previous section, it is important to determine correlations and associations between the dependent and independent variables. In this section we discuss the concepts of associations in relation to the study designs implemented.
10.10.1 Study Design It is important to design a study that will answer the proposed research question in a non-biased and efficient manner. As stated earlier, it is important to clearly define the “disease” and “treatment” variables so that one can effectively assess a disease-treatment relationship. Randomization, blinding, minimizing bias, using placebos, internal controls, and a sufficient sample size should be used whenever possible. However, not all scientific questions are practically answered by high quality, multi-institutional, randomized controlled trials. As a result, a variety of study designs are available for various types of epidemiologic, clinical and translational research.
10.10.2 Case Study Case studies examine the outcome of a single patient with a disease who received a particular treatment. Case studies are useful to note interesting or odd effects of treatment, or to note an off-label use of a medication, and they may spur more rigorous clinical investigations.
10.10.3 Case-Control Study Case-control studies are retrospective studies that identify two groups of patients; one group with the known disease (cases) and another group without the disease (controls). The goal is to compare the proportion of a certain exposure between case and control groups. These studies are often susceptible to recall bias as patients with knowledge of their disease are likely to recall being subjected to a particular exposure (e.g., high tension power lines). However, case-control studies are very useful for identifying risk factors of a rare disease. Additionally, confounding factors (i.e. factors that are associated with both the disease and exposure) may also introduce bias. In this case, matched case-control studies are used to minimize confounding. For example, when attempting to identify risk factors for type II diabetes through a case-control study it is important to control for age because age is associated with both type II diabetes and various exposures.
10.10.4 Cohort Study Cohort studies are prospective studies that follow a predetermined disease-free group of patients over a period of time. As the study progresses, some individuals develop the disease and others do not. The development of the disease is then related to the exposure variables observed over the time period of the study. These studies sometimes require a long span of time, during which loss of patients is likely to occur. Cohort studies are useful when examining the effect of various risk factors on the development of disease.
10.10.5 Cross-Sectional Study In cross-sectional studies, the patient population is asked about their current disease status and current and/or past exposure status to various risk factors. Cross-sectional studies compare the prevalence of disease at one point in time between exposed and unexposed individuals. This is different than the prospective (cohort study) where the incidence of disease rather than prevalence of disease is investigated. 111
Clinical Review for the USMLE Step 1 10.10.6 Clinical Trial Clinical trials are distinguished by several traits that help make their findings more valid and reliable. Good clinical trials are randomized, which helps to minimize selection bias. They are double-blinded, which minimizes measurement bias by reducing confounding by investigators and patients who may be aware of the therapy they are giving or receiving. Multi-centered trials eliminate confounding due to local or regional differences and limited sample sizes. Placebo controls help to ensure that the trial is double-blind and helps to reduce measurement bias. A crossover design ensures that a patient receives a therapy for at least half of the trial and a placebo for the remainder â€“ it helps to serve as an internal control and reduces measurement bias. The best clinical trials incorporate as many of these traits as possible. They are designed in such a way that their outcomes can typically be trusted if all tenets of the study design are faithfully followed. The major determent to clinical trials is their high cost. One note regarding clinical trials: in order for a randomized study to be properly evaluated, the sample size must be carefully predetermined.
Associations Between Two Binary Variables
Depending on the study design, different measures of association can be used to display relationships between variables. As mentioned earlier, the Chi-square test of independence can be used to test the null hypothesis that the exposure and disease are not associated with each other against the alternative that there is an association. However, there are several methods to measure associations between two binary variables including odds ratio and relative risk. In a case control study, where a group of patients who have the disease are compared to a group of patients who do not have the disease with respect to their exposure, the data can be organized in the form of a 2 x 2 contingency table. Disease
Figure 3. Illustration of the 4 possible scenarios from a â€œdisease-exposureâ€? relationship.
The odds ratio is a descriptive statistic that can be thought of as determining the strength of an association between two binary variables. The odds ratio is defined as the ratio of odds of exposure among patients who have the disease relative to the odds of exposure among patients who do not have the disease. The odds of an event refers to the probability of the event occurring over the probability of the event not occurring. Simply, the odds ratio is calculated by the formula below. It is often used in retrospective, case-control and cross-sectional studies to evaluate the particular effect of a risk factor on disease.
Odds Ratio =
Standard statistical packages provide 95% confidence intervals for odds ratios. If the 95% confidence intervals for odds ratios do not include 1, then one can conclude that there is an association between 112
Biostatistics the disease and exposure. Also there is a formula for calculating the 95% confidence intervals for odds ratios based on the information in the contingency table. For additional information we refer the reader to Rosner’s textbook “Fundamentals of Biostatistics”.
10.11.2 Relative Risk Relative risk is used to compare the chance of a particular disease between the exposed and non-exposed groups. For example, in a cohort study, the risk of a smoker developing lung cancer would be compared to the group of non-smokers and the result given in terms of the relative risk of lung cancer. Relative risk is calculated as follows:
Relative Risk =
a (a + b ) c (c + d )
Standard statistical packages also provide 95% confidence intervals for relative risk. If the 95% confidence intervals for relative risks do not include 1, then one can conclude that there is an association between the disease and exposure. The formula for calculating the 95% confidence intervals for relative risks can be found in Rosner’s textbook “Fundamentals of Biostatistics”. The relative risk must be used with care as minor differences in risks between the two groups can result in a large ratio. In these cases, you must also report the absolute risk for the disease, which is simply the probability of the disease.
10.11.3 Attributable Risk To compare risks of disease between exposed and non-exposed groups in a cohort study, one can calculate the attributable risk. It is calculated as the difference between the incidence of disease in exposed group and incidence of disease in non-exposed group. Therefore, it represents the additional incidence of disease related to exposures and often called the risk difference.
Attributable Risk =
a c − a+b c+d
10.11.4 Associations Versus Causal Relationships It is important to note that associations do not imply causal relationships. In fact, in clinical research it is very difficult to establish causal relationships. Depending on the study design, one can build evidence for or against a causal relationship. For example, in randomized control trials it is easier to establish causal relationships than in retrospective studies. Randomized controlled trials with adequate sample size and blinding are usually the best evidence for a cause and effect relationship. When investigating whether an exposure has a causal relationship with a disease, it is important to evaluate if the association is an artifact of measurement bias or random variation (chance). If the association is not due to bias and seems unlikely, then one must consider if the association is occurring indirectly, potentially through confounding factors. If one does not find confounding and the study is well designed a causal relationship is likely. For more detailed discussion on causality, we refer the reader to Fletcher’s book “Clinical Epidemiology” and Rothman’s book “Modern Epidemiology”. 113
Clinical Review for the USMLE Step 1
So far the focus of this chapter has been on the use of statistics in the development of various clinical studies to investigate the associations between exposures and disease. However, clinicians are also interested in assessing the predictive power of diagnostic tests. In order to assess the accuracy of a diagnostic test result, one must know the personâ€™s true status of the disease. Results from a diagnostic test can be classified as true positives, true negatives, false positives, and false negatives. A true positive occurs when a test designed to determine the presence of a disease reports a correct answer. A true negative occurs when a test correctly reports that a disease is not present. False positives can be psychologically detrimental to a patient, such as when a test reports positive HIV status when the patient actually does not have this disease. They can also result in increased cost of care for unnecessary treatments since the patient has been falsely identified as diseased. False negatives can prevent a patient from receiving therapy when a test incorrectly reports that a patient does not have a disease.
TP + FN
FP + TN
Total TP + FP
FN + TN
Table 41. The four results that can be obtained from a test for a particular disease, along with the calculations for sensitivity, specificity, positive predictive value, and negative predictive value.
10.12.1 Sensitivity Sensitivity is a measure of the proportion of true positives, calculated as the number of people tested positive among all who have the disease. A highly sensitive test will have a low rate of false negatives. Further, if the sensitivity is high enough, and the test results negative, one can trust that the patient does not have a disease. Sensitive tests are often valuable as screening tests for a population.
10.12.2 Specificity Specificity is a measure of the proportion of true negatives, calculated as the number of people tested negative among all who do not have the disease. Specific tests have very low rates of false positives, so 114
Biostatistics a true positive result is considered to be trustworthy. If a patient obtains a positive result on a specific test, they are effectively ruled in for a particular disease.
10.12.3 Positive Predictive Value Positive predictive values are used to determine the chance of having a disease given a positive test result. It is calculated as the number of true positives divided by the total of positive test results. The positive predictive value is used in conjunction with the pretest probability to determine the chance the patient truly has a disease. For example, doing a test for the Ebola virus is unlikely to be meaningful, even with a positive result, on a healthy American in Nebraska who has never traveled to Africa.
10.12.4 Negative Predictive Value The negative predictive value determines the chance of not having a particular disease given a negative test result. It is calculated as the number of true negatives divided by the total number of negative test results. The negative predictive value is also used in conjunction with pretest probability and clinical suspicion to determine whether a patient is likely to have a particular disease.
Section Editors Sapan S. Desai, MD, PhD
Danny O. Jacobs, MD, MPH
Assistant Professor Department of Surgery Duke University Medical Center
Professor and Chair Department of Surgery Duke University Medical Center
Contributors Gowthami Arepally, MD, PhD
Alice D. Ma, MD
Associate Professor of Hematology Department of Medicine Duke University Medical Center
Associate Professor of Hematology Department of Medicine Duke University Medical Center
Hematology (adapted from the Clinical Review of Vascular Surgery)
Sapan S. Desai, MD, PhD
Eric Mowatt-Larssen, MD
Assistant Professor Department of Surgery Duke University Medical Center
Assistant Professor Department of Surgery Duke University Medical Center
Ali Azizzadeh, MD Associate Professor Department of Surgery University of Texas at Houston Pathophysiology of Thrombosis and Obstruction (adapted from the Clinical Review of Phlebology and Venous Ultrasound)
Scott K. Pruitt, MD, PhD
Tara Brennan, MD
Associate Professor Resident Department of Surgery Department of Ophthalmology Duke University Medical Center University of Illinois
Leontine Narcisse, MD, PhD
Jerimiah Mason, MD
Fellow Resident Department of Surgery Department of Surgery Westchester Medical Center Baptist Medical Center
Niketa Desai, PharmD Pharmacist Department of Pharmacology Long Island University Surgical Principles (adapted from the Clinical Review of Surgery)
1. Basic Science 1.1. Embryology There are three main lineages for all blood cells: erythrocytes, lymphocytes, and myelocytes. This chapter will discuss red blood cells and all of their associated disorders. The last section of this textbook will discuss white blood cells, immunology, and their related disorders.
1.2. Developmental Structure
During development, hematopoiesis begins in the yolk sac, where it remains until about 3 months. Starting at about 1 month and continuing until birth, the liver begins to serve as the primary site for hematopoiesis. The spleen and lymph nodes augment the function of the liver; after birth, both of these locations serve a secondary function to permit the maturation of lymphocytes. Hematopoiesis in the bone marrow begins at about 4 months and continues throughout life. Hematopoiesis occurs in different locations during development, eventually occurring primarily in bone marrow in the adult. In children, this is primarily in the femur and tibia; in adults, hematopoiesis generally occurs in the pelvis, vertebrae, and sternum.
Figure 1. Hematopoiesis from the fetus to adult. Copyright M. Komorniczak. Used with permission.
1.3. Erythrocytes 1.3.1
Multipotential hematopoietic stem cells differentiate into common myeloid and common lymphoid progenitor cells. The common lymphoid progenitor cell is discussed further in the immunology section. The common myeloid progenitor cell differentiates into the megakaryoblast, proerythroblast, myeloblast, and mast cells. Proerythroblasts differentiate into basophilic erythroblasts, then polychromatic erythroblasts, followed by normoblasts. At this point, these cells lose their nuclei and become reticulocytes. Reticulocytes mature into erythrocytes, also known as red blood cells (RBCs). 117
Clinical Review for the USMLE Step 1
Figure 2. Hematopoiesis. Copyright A. Rad. Used with permission.
RBCs have a highly deformable membrane skeleton, which permits travel through tiny capillaries that are half of the RBCs normal diameter. The most important of these structural proteins are the ankyrin complex that links the skeleton to the plasma membrane, and the protein 4.1R complex that helps to anchor various transporters and also plays a role in expressing glycoproteins. The ankyrin complex also contains a protein known as band 3, which helps to transport carbon dioxide and helps to regulate RBC physiology. A variety of transporters play a role in RBCs. In addition to the standard Na+/K+ ATPase found on most cells, there are also water transporters and a number of ion symports and antiports. Interaction of the RBC with other cells is mediated by the ICAM-4 complex and BCAM glycoprotein complex.
RBCs carry hemoglobin, which binds to oxygen ironcontaining heme groups. This Figure 3. RBC plasma membrane and cytoskeleton components. oxygen is carried to tissues, Copyright Tim Vickers. Used with permission. 118
Figure 4. Cytokines and growth factors that play a role in hematopoiesis. Copyright Mikael Haggstrom. Used with permission. which is then exchanged for carbon dioxide. The carbon dioxide is carried by RBCs back to the lungs, where it is exchanged with oxygen. Approximately 20 trillion RBCs travel throughout the body at any given time, corresponding to about 5 million erythrocytes per microliter. Hemoglobin binds to oxygen in a sigmoid-shaped fashion. This is the result of cooperative binding, in which additional molecules of oxygen bind easily after at least two are bound, for a maximum of four molecules of oxygen per heme molecule. This binding can be modified by several factors: increase in altitude leads to higher levels of 2,3 bisphosphoglycerate (2,3-BPG), leading to a right-shift of the dissociation curve seen in the figure below. Fetal hemoglobin has a higher affinity for oxygen than adult hemoglobin, thereby ensuring that the fetus will receive an ample supply of oxygen; this leads to a leftshift of the curve. Decreasing pH and increasing temperature both lead to a right-shift.
Clinical Review for the USMLE Step 1
1.4. Platelets The megakaryoblast, discussed above, differentiates into promegakaryocytes, which becomes megakaryocytes and buds off platelets. Platelets have a variety of cytokines and growth factors that help lead to hemostasis. This is discussed in more detail in the following section.
1.5. Coagulation An exploration of the coagulation cascade and its attendant contributors is important to understand the various pathologies that contribute to DVT. A breakdown in one of several critical steps is all that is necessary to initiate a hypercoagulable state. Normal coagulation relies on three main contributors, including the exposed endothe- Figure 5. Oxygen-hemoglobin dissociation lium, platelets, and circulating proteins in the plasma. curve. Copyright Aaron Sharpe. Used with Just as important as these three main contributors, fi- permission. brinolytic enzymes are also required to help reform the clot and restore vascular patency. This last component is critical for normal wound healing. Normal coagulation typically begins with trauma to the vessel wall, exposing thrombogenic proteins under the endothelium such as von Willebrand Factor (vWF). vWF binds to a variety of circulating clotting factors, including collagen and factor VIII. This creates a matrix upon which platelets bind using glycoprotein Ia/IIa and Ib/IX/V receptors. Platelet activation then leads to release of alpha and dense granules. Release of thrombogenic proteins and growth factors occurs, leading to platelet clumping and the formation of fibrinogen cross-links using glycoprotein IIb/IIIa receptors. This process is known as primary hemostasis. Disruption of primary hemostasis, such as in disseminated intravascular coagulopathy (DIC), druginduced reactions with quinidine, quinine, vancomycin, or gold salts, bone marrow suppressed states, cardiopulmonary bypass, and alcohol toxicity, leads to the inability to form an enduring clot and presents as mucocutaneous bleeding. Defects in primary hemostasis can be diagnosed with platelet aggregation assays, von Willebrand Factor functional assays, and a platelet function analyzer (PFA). After formation of the platelet plug, secondary hemostasis is initiated with the coagulation cascade to form a stable fibrin plug. Both an intrinsic and extrinsic pathway are available to initiate secondary hemostasis; this dual pathway ensures that even patients with defects in primary hemostasis eventually develop some form of enduring clot over time. The most important pathway in secondary hemostasis is the extrinsic pathway, which relies upon the transmembrane receptor tissue factor (TF). Tissue factor is found within vascular endothelium, adventitia, brain, lung, heart, and placenta. While deficiencies in factors VIII and IX (hemophilia A and B, respectively) have been identified, the absence of tissue factor is typically incompatible with life.63 Constitutively low production of tissue factor is associated with spontaneous hemorrhage in the heart, lung, and placenta. Tissue factor is normally unmasked from the vascular wall following trauma. However, this factor is expressed by monocytes and possibly neutrophils, and may initiate thrombosis in patients with disseminated intravascular coagulation. Tissue factor expression upon neutrophils has been implicated 120
Basic Science as one of the causes of autoimmunity-based hypercoagulable disorders such as antiphospholipid antibody syndrome.
Trauma initiates a process whereby tissue factor interacts with factor VII, forming an activated complex and beginning the cycle of thrombosis. This activated complex leads to the activation of factor X and the beginning of the final common pathway that both the extrinsic and intrinsic pathways share, discussed below. The extrinsic pathway has a number of strict controls to prevent runaway thrombosis. This is necessary as factor VII is one of the most common factors in circulation and the lack of strict regulation would lead to rapid propagation of clot. The tissue factor â€“ factor VIIa complex is inhibited by tissue factor pathway inhibitor (TFPI), a single chain polypeptide that also inhibits factors Xa and IIa (thrombin).
I n t r in s i c
Figure 6. Platelets and the two types of granules they contain. Alpha granules contain insulin-like growth factor 1 (IGF-1), platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-B), platelet factor 4 (PF4), von Willebrand Factor (vWF), thrombospondin, and fibronectin. Dense granules contain ADP, ATP, calcium, and serotonin. Both types of granules are necessary for the coagulation cascade to function correctly. Copyright Surgisphere Corporation. Used with permission.
While the extrinsic pathway seems critical for thrombosis, defects in the intrinsic pathway are associated with delayed clot formation with arterial injury. The primary importance of the intrinsic pathway therefore appears to be with arterial thrombosis; clot formation throughout the veins and much of the rest of the body appears to be controlled by the extrinsic pathway.54,60-62 Indeed, elevated levels of factor XI has been found to be associated with increased risk of myocardial infarction and an independent risk factor for stroke. Contact activation initiates the intrinsic pathway when factor XII binds to an appropriately charged sur121
Clinical Review for the USMLE Step 1
Figure 7. The intrinsic and extrinsic pathway of coagulation with the interplay between the various types of factors demonstrated. Illustration by Joe Dunckley. Used in accordance with the GNU Free Documentation License Version 1.2. face, typically the site of some sort of injury. This initiates a cascade reaction where a series of trypsinlike enzymes amplify the reaction and promote thrombosis. Factor XII is activated, leading in turn to the activation of factor XI. These factors work together to activate factor IX; a deficiency of this factor leads to hemophilia B (discussed below). Factor IXa binds to activated factor VIII to initiate the activation of factor X and the beginning of the final common pathway; defects in factor VIII lead to hemophilia A. Of note, independent activation of factor XI can also occur, as seen in patients with defects in factor XII (Hageman factor deficiency).
Final Common Pathway
The final common pathway begins with factor Xa and is regulated by factor V. The activation of factor V is inhibited by protein C; the activation of protein C is modulated by protein S. Therefore, protein C and S serve as inhibitory mediators for coagulation and their deficiency leads to a hypercoagulable state; this is seen in warfarin administration without prior anticoagulation with heparin. Protein C and S are vitamin K dependent factors with short half-lives, and are down-regulated within the first 24-48 hours of warfarin administration. This leads to a transient hypercoagulable state while the other factors are still being down-regulated to sufficient levels. 122
Basic Science Activated factors X and V lead to the conversion of prothrombin (factor II) to thrombin (factor IIa). Thrombin leads to feedback regulation by stimulating the production of protein C and thrombomodulin. Thrombin serves to convert fibrinogen to fibrin, leading to the deposition of the hemostatic plug. Cross-linking of the fibrin clot occurs with the action of factor XIII, the production of which is also upregulated by thrombin. Organization of this blood clot occurs via plasmin-mediated fibrinolysis. Proper functioning of the coagulation cascade requires the factors discussed above, along with adequate concentrations of calcium and vitamin K. Calcium is a cofactor that is required for the activation of various factors; its deficiency is associated with coagulopathy. Vitamin K is required for the synthesis of factors II, VII, IX, X, and proteins C and S. A third protein, protein Z, is also regulated by vitamin K; this protein appears to play a role in degradation of factor Xa and XI. Defects in protein Z have been associated with hypercoagulable disorders.
Regulation of the coagulation cascade relies on a variety of mediators. Protein C and S inhibit the production of factor Va, leading to cessation of further thrombin production. Protein C and S production are up-regulated by thrombin, leading to a feedback inhibition reaction at the level of the final common pathway. Tissue factor pathway inhibitor inhibits tissue factor, temporizing clot formation at the extrinsic pathway level. Prostacyclin (PGI2) leads to the production of adenylyl cyclase and cAMP production by platelets, leading to sequestration of calcium and general inhibition of coagulation.
Two other complex systems help to control coagulation: the first is the thrombolytic system, which involves plasmin and tissue plasminogen activator (tPA), and the second involves a group of inhibitors of the coagulation factors, including antithrombin III, protein C, and protein S. The thrombolytic system dissolves fibrin clots using the serine protease plasmin. Plasmin is formed from its inactive precursor plasminogen. Interestingly, plasmin is also activated by thrombin, which thereby limits its own clot-forming ability. The second anticoagulant system is made up of antithrombin III and proteins C and S. Antithrombin breaks down factors IXa, Xa, Xia, XIIa, and thrombin, leading to inhibition of coagulation at both the intrinsic and final common pathways, and its activity is enhanced up to 2000-fold by heparin.
There are several general tests of clotting factors commonly used to measure overall function of the coagulation cascade. The activated partial thromboplastin time test (PTT) measures the intrinsic pathway, and will be increased in deficiencies of factors VII, IX, XI, XII, von Willebrand fibrinogen. PTT testing is used to monitor heparin efficacy in patients on heparin drips. The prothrombin time test (PT) measures the extrinsic pathway and will be abnormal in deficiencies of factors II, V, VII, X and fibrinogen. Because of variations in PT level reporting, the international normalized ratio (INR) was developed to allow comparison of levels across laboratories. PT/INR testing is used to monitor vitamin K and warfarin efficacy. The coagulation cascade is a complex interplay between dozens of proteins and cells. Its seamless function is required to avoid coagulopathies and hypercoagulable states. The division into an intrinsic and extrinsic pathway play unique roles in coagulation, and offer scientists numerous targets to deal with 123
Clinical Review for the USMLE Step 1 disorders in coagulation.
Hemostasis is the process whereby cells and circulating proteins interact to form an intravascular blood clot in response to vessel injury. This is a critical protective mechanism to occlude blood vessels and prevent life-threatening hemorrhage. This physiological process is generally referred to as â€˜hemostasis.â€™ Thrombosis, by contrast, occurs when the coagulation system is activated by pathologic conditions such as atherosclerosis, infection or inflammation, leading to the formation of intravascular thromboses that obstruct blood flow and/or embolize to a distant site. Effective clotting requires the integrated action of three distinct components: 1) plate- Figure 8. Fibrinolysis. Copyright J.F. Wolff. Used with lets, which mediate primary hemostasis, 2) permission. circulating clotting factors, which mediate secondary hemostasis, and, 3) fibrinolytic enzymes, which dissolve clots to restore vascular patency and promote wound healing. Defects or activation in one of these components can lead to bleeding or clotting complications.
Primary hemostasis refers to the initial and rapid interaction of platelets with the injured vessel wall. Primary hemostasis is initiated by exposure of subendothelial proteins, such as collagen and von Willebrand Factor (vWF) and subsequent adhesion of platelets. Platelet adhesion is rapidly accompanied by platelet activation and aggregation to form a platelet plug at the injured site. Defects in primary hemostasis manifest as mucocutaneous bleeding within minutes to hours of injury and are primarily caused by quantitative or qualitative disorders of platelet function. Vessel wall dysfunction (inherited or acquired) can also lead to mucocutaneous bleeding, but is less commonly encountered in clinical practice. Testing for primary hemostasis involves measuring platelet counts and assessing platelet function using the platelet function analyzer (PFA), platelet aggregation studies and measurement of von Willebrand factor levels and activity.
Basic Science Table 1. Common conditions associated with derangements in bleeding or clotting. Associated with bleeding •
Non-heparin drugs (GP IIb/IIIa inhibitors, quinidine, quinine, vancomycin, gold salts and others)
Marrow suppression (chemotherapy, radiation)
Sequestration due to cirrhosis and/or shock liver
Alcohol toxicity and/or withdrawal
Associated with clotting •
Heparin-Induced Thrombocytopenia (HIT)
Thrombotic-thrombocytopenic purpura (TTP; drug induced)
No bleeding or clotting complications
Secondary hemostasis is the process leading to the formation of a stable fibrin plug through a sequential activation of clotting enzymes. The coagulation system is activated through exposure of plasma proteins to subendothelial tissue factor (TF). TF binds to Factor VIIa and activate Factors X to Xa (FXa) and Factor IX or IXa (FIXa). Once activated, FXa localizes to a phospholipid membrane (typically platelet derived) and with its cofactor, FVa, cleaves prothrombin (FII) to thrombin (FIIa). Thrombin, one of the most potent activators of primary (platelet mediated) and secondary (clotting factor mediated) hemostasis, potentiates further clotting through: 1) cleavage of fibrinogen, thus enabling polymerization of fibrin, 2) activation of platelet receptors, 3) activation of endothelium, 4) conversion of Factors V, VIII and XI to their activated forms (thus promoting further thrombin generation), 5) activation of FXIII leading to cross-linking of fibrinogen, and 6) activation of the enzyme, thrombin-activated fibrinolytic inhibitor (TAFI) which prevents premature fibrinolytic degradation of fibrin. Naturally occurring anticoagulants, such as protein C, S and antithrombin serve to regulate thrombin generation at sites distant from vascular injury. Defects in secondary hemostasis typically manifest as delayed bleeding within hours to days of initial injury. Disorders of secondary hemostasis are caused by acquired or congenital causes. Tests for secondary hemostasis include global tests of coagulation, the prothrombin time (PT), activated partial thromboplastin time (aPTT) and assessing the functional activity of individual clotting factors.
Fibrinolysis is the physiologic process by which clots are dissolved to restore vascular patency. The 125
Clinical Review for the USMLE Step 1 enzyme, plasmin, is the principal mediator of fibrinolysis. Plasmin is converted from its precursor, plasminogen, by endogenous plasminogen activators present in the intravascular (tissue plasminogen activator, tPA) or extravascular compartments (urokinase plasminogen activator, uPA). The principal regulators of fibrinolysis are 2-anti-plasmin, which inhibits plasmin, and plasminogen activator inhibitors (PAIs), which bind and inhibit circulating tPA. Defects in fibrinolysis result in significant bleeding with injury and/or delayed bleeding due to clot instability. Assessment of fibrinolytic pathways is performed through measurement of fibrinolytic proteins (fibrinogen, plasminogen, 2-anti-plasmin, Factor XIII), and fibrin degradation products (fibrin split products, D-dimer).
2. Hematologic Disorders 2.1. Preoperative Assessment A medical history is the most vital tool for assessing surgical risk of bleeding. Relevant medical history includes information regarding spontaneous or traumatic bleeding, menstrual bleeding history (in females), severity of bleeding with minor and/or major procedures, comorbidities, especially hepatic disease, and family history of bleeding disorders. Medications should be reviewed for drugs that interfere with clotting function (aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), clopidogrel, warfarin, and/or low-molecular weight heparins). If the bleeding history is negative, current guidelines do not advise further coagulation testing. If the clinical history is positive for bleeding, then further clinical evaluation by a hematology consultant is advised.1
The Bleeding Patient
Clinical evaluation of any symptomatic bleeding requires immediate bedside assessment. Initial evaluation should include assessment of hemodynamic stability, rate of blood loss, and source of blood loss. Hemodynamic instability should be rapidly addressed with appropriate interventions to restore blood pressure and/or cardiopulmonary function. Major blood loss is usually defined as 50% loss of blood volume (~3.8-5.3 L) over a three hour period or 150 mL/min. In cases of major blood loss, it is paramount to determine type of bleeding (surgical vs. coagulopathic bleeding) and direct interventions to arrest bleeding (including volume support, blood products and/or surgery). Distinguishing surgical from coagulopathic bleeding may be challenging, particularly in patients who have had intraoperative or immediate postoperative complications, such as hypotension and/or prolonged periods of tissue ischemia. As well, previously undiagnosed acquired or inherited coagulopathies may manifest for the first time after surgical trauma. In general, surgical bleeding tends to be localized to the site of surgery, with excessive bleeding occurring at the surgical site or surrounding tissue planes. Coagulopathic bleeding can manifest either locally at site of surgical trauma, with a disproportionate amount of blood loss for a given procedure, or can be generalized and diffuse with bleeding from other sites of minor trauma (including venipuncture and catheter sites) and/or spontaneous bleeding. Laboratory abnormalities (PT/aPTT or fibrinogen) may be seen with coagulopathic bleeding, whereas surgical bleeding, if not severe or life-threatening, is generally associated with normal laboratories. Coagulopathic bleeding can be caused by a variety of congenital or acquired bleeding disorders. For patients without known history of bleeding and/or congenital bleeding disorders, the temporal relationship of bleeding to surgery may offer clues to type of hemostatic defect. Bleeding from mucocutaneous sites within minutes to hours of surgery, including bleeding at the surgical incision, implies defects 126
Hematologic Disorders in primary hemostasis. Assessment should be directed at platelet and/or vessel wall function, recent anti-platelet therapies, and/or acquired qualitative or quantitative platelet defects (see below). Delayed bleeding (hours to days after surgery) occurs from defects in secondary hemostasis, most often due to complications arising from anticoagulant therapies, medical comorbidities, and/or surgery (sepsis, dilutional coagulopathy). Severe derangements of fibrinolysis can manifest as intraoperative or immediate post-operative bleeding, depending on the etiology of fibrinolytic defect.
2.3. Acquired Bleeding Disorders The following sections review the diagnostic and therapeutic considerations for patients with commonly acquired bleeding disorders in the surgical setting. Bleeding complications arising from congenital disorders are beyond the scope of this discussion and are reviewed elsewhere.2
Bleeding From Platelet Defects
Bleeding from platelet dysfunction manifests as mucocutaneous bleeding and occurs within minutes of injury. Bleeding can be caused by quantitative or qualitative platelet defects.
Thrombocytopenias Acquired thrombocytopenias in surgical patients can be caused by consumption, immune destruction and/or marrow suppression (from drugs or infection). Assessment of acquired thrombocytopenia should include review of patients preoperative baseline platelet counts (if available), thorough evaluation of medication history, in particular, heparin use, and examination of the peripheral blood film to rule out platelet clumping or pseudo-thrombocytopenia. Thrombocytopenia is a common manifestation of bacteremia and/or sepsis and often occurs in the absence of disseminated intravascular coagulation. Depending on the etiology, acquired thrombocytopenias may be associated with bleeding or clotting complications. For non-surgical patients with non-immune mediated platelet destruction, bleeding risk is increased with platelet counts <10,000/ÂľL. Prospective data are lacking on threshold platelet counts necessary for maintaining hemostasis during surgical procedures. For post-operative patients, prophylactic platelet transfusions to keep platelet counts above 50,000/ÂľL are advised within 24 hours of major surgery and/ or with active bleeding. Table 2. Minimum platelet levels prior to completing surgery. Type of Surgery
Threshold Platelet Count /Âľ L
Ocular surgery or neurosurgery
Major Surgery with risk factors for bleeding
Major Surgery, non-critical sites
Minor procedures (lumbar puncture, epidural anesthesia, endoscopy, central line, liver biopsy, etc.)
Heparin-Induced Thrombocytopenia Heparin-Induced Thrombocytopenia (HIT) is a recognized immune complication of heparin therapy. HIT is caused by antibodies directed to complexes containing heparin, and a platelet protein, Platelet 127
Clinical Review for the USMLE Step 1 Factor 4 (PF4). The spectrum of illness associated with PF4/heparin antibodies ranges from asymptomatic antibodies (in most individuals) to isolated thrombocytopenia in 1-5% of patients and/or lifethreatening thrombosis in a smaller subset of patients (0.5-1%). Clinical HIT is diagnosed by the presence of absolute (platelet count <150,000/µL) or relative thrombocytopenia (decrease from baseline platelet counts of 30-50%) within 5-7 days of heparin therapy, and/or development of new thrombosis, which develops in 20-50% of patients with thrombocytopenia. Mortality from thrombotic complications remains high (6-27%). Diagnosis of HIT is made using clinical criteria: 1) drop in platelet count or thrombosis within 4-14 days of heparin therapy (in previously unexposed patients or within 24 hours in previously exposed patients) 2) exclusion of other causes and demonstration of PF4/heparin antibodies by serologic or platelet activation assays. Treatment is directed at avoiding heparin therapy and using alternative anticoagulants, such as the direct thrombin inhibitors (argatroban, lepirudin or bivalirudin).
Bleeding From Qualitative Platelet Defects Bleeding from acquired platelet dysfunction in hospitalized patients is most frequently caused by drugs and/or medical comorbidities. Platelet function can be inhibited by drugs targeting platelet function (aspirin, aspirin derivatives, clopidogrel and GPIIb/IIIa inhibitors) or drugs with off-target effects (selective serotonin reuptake inhibitors, antibiotics, etc). Medical conditions associated with acquired platelet dysfunction include renal or liver disease, paraproteinemia or marrow disorders (leukemia, myelodysplasia and/or myeloproliferative diseases).
Bleeding from ASA/Clopidogrel The effects of aspirin and clopidogrel on platelet function are permanent for the 7-10 day life-span of the platelet. Recovery of platelet function is dependent on synthesis and release of new platelets by megakaryocytes. Generalized bleeding is not increased with aspirin or clopidogrel therapy (bruising or epistaxis <2-4%), unless the patient has a coexisting defect in hemostasis. Surgical bleeding is increased with clopidogrel and drug should be discontinued 7-10 days prior to surgery. It is never appropriate to transfuse platelets for elective procedures in patients who have consumed aspirin or clopidogrel. These patients should discontinue drug and have their procedures rescheduled.
Bleeding From GPIIb/IIIa Inhibitors GPIIb/IIIa inhibitors [abciximab, eptifibatide (a cyclic heptapeptide), and tirofiban (a nonpeptide)] lead to nearly complete inhibition of platelet aggregation due to occupancy of platelet GPIIb/IIIa, the platelet fibrinogen receptor. Antiplatelet effects wane rapidly, depending on drug half-life (4‑36 hours). Bleeding rates with GPIIb/IIIa inhibitors is comparable to heparin therapy. For severe or life-threatening bleeding secondary to GPIIb/IIIa inhibitors, reversal of therapy can achieved with discontinuation of drug, followed by platelet transfusion. Timing of platelet transfusion must take into account the clearance of drug from plasma (10-30 minutes for abciximab, and approximately 2 hours for eptifibatide and tirofiban), to keep fresh platelets from being inactivated by circulating drug.
Bleeding From Platelet Dysfunction Platelet dysfunction caused by medical disorders or other drugs is most effectively addressed by treating the underlying medical condition and/or drug discontinuation. In the event of severe or life-threatening bleeding, platelet transfusions are recommended to maintain platelet counts >50,000 / µL. Other therapeutic options include use of desmopressin (1-deamino-8 D-arginine vasopressin or DDAVP).
Hematologic Disorders 2.3.2
Bleeding From Hemostatic Defects
As stated previously, it is often difficult to discern bleeding from surgical and non-surgical causes. This section covers bleeding from hemostatic derangements caused by drugs, medical comorbidities or coagulopathy arising from surgical complications.
Bleeding From Anticoagulants
Anticoagulant agents exert their inhibitory effects on clot formation through direct inhibition of clot formation (thrombin inhibitors) or through augmentation of inhibitory pathways (antithrombin III or proteins C & S). Hemorrhagic episodes occur predictably when full dose anticoagulation (UFH or LMWH) is given within 12-24 hours of surgery. Excessive post-operative bleeding is not seen with thromboprophylactic doses of unfractionated heparin (UFH) or low-molecular weight heparin (LMWH). In general, hemorrhagic complications correlate with the intensity of anticoagulation (therapeutic > prophylactic), concomitant use of GPIIb/IIIa inhibitors or thrombolytic therapy, gender (F > M), patient comorbid conditions (including renal and/or liver disease) and coexisting hemostatic defects (congenital or acquired platelet or clotting factor deficiency).
Bleeding from Warfarin For elective procedures or surgery, it is recommended that warfarin be discontinued 4-5 days prior to the planned procedure. LMWH can be started when the INR falls below 2 and discontinued 12 hours before surgery. Prophylactic infusion of FFP may be required of the INR is greater than 1.6, but is not required when the INR is below this value. In emergency cases or when bleeding is noted due to warfarin, following the guidelines of the American College of Chest Physicians for warfarin reversal is recommended.3 Depending on the degree of the INR elevation and the severity of bleeding, patients may require vitamin K, FFP, or consideration of infusion of a prothrombin complex concentrate such as Bebulin of Profilnine or recombinant activated factor VII (NovoSeven).
Bleeding From UFH For elective procedures or surgery, discontinuing therapeutic doses of UFH 4 hours prior to the procedure and measuring an aPTT is all that is needed, as normal hemostasis is restored in this time frame in most cases. If the aPTT remains elevated, then hourly measurements are advised until the aPTT returns to baseline. In cases where hemorrhage is brisk or life-threatening, the anticoagulant effects of UFH can be reversed with protamine sulfate, a positively charged protein extracted from fish sperm, at a ratio of 1 mg of IV protamine for 100 units of UFH. For patients who are on continuous infusion of heparin, the dose of heparin administered within 2-2.5 hours should be calculated to arrive at an approximate protamine dose. If the dose of heparin is unknown, the maximal tolerated protamine dose of 50 mg can be administered slowly over 10 minutes followed by serial measurements of the aPTT. Side effects of protamine include hypersensitivity reactions, including anaphylaxis, hypotension and pulmonary hypertension. Allergic responses to protamine are more common in patients who have been previously exposed to the drug for heparin neutralization or through protamine containing insulin [Neutral Protamine Hagedorn (NPH) insulin].
Clinical Review for the USMLE Step 1 Bleeding From LMWH and Fondaparinux For patients receiving therapeutic doses of LMWH who require elective procedures or regional anesthesia, a delay of 24 hours after the last dose of LMWH is recommended. Therapeutic dose LMWH should not be restarted for 24 hours after a major procedure or neuraxial anesthesia. Prophylactic doses of LMWH, however, can be safely administered within 12-24 hours of most procedures. Protamine is only partially effective in reversing the anti-Xa effects of LMWHs, with maximum neutralization of 6075% to be expected. For suspected overdose, or life threatening hemorrhage, manufacturers of LMWHs recommend IV protamine at a dose of 1Â mg per 100 mg anti-Xa IU of LMWH, followed by a second 0.5 mg per 100 anti-Xa IU if the aPTT is prolonged. Recombinant VIIa has been used for life-threatening bleeding from LMWHs or fondaparinux.
Bleeding from Direct Thrombin Inhibitors The hirudin analogs, lepirudin and bivalirudin, and argatroban are three currently approved agents which directly inactivate circulating and clot bound thrombin. Presently, there are no antidotes for reversing the hemorrhagic effects of these agents. Both lepirudin and bivalirudin can be removed from circulation through hemodialysis. There is no mechanism for removing argatroban from the circulation.
Bleeding From Medical Comorbidities
Coexisting renal and/or liver disease is associated with higher rates of intraoperative and post-operative bleeding. Vitamin K deficiency may arise from decreased oral intake, especially when coupled with the use of parenteral antibiotics. Surgical bleeding may also be the first manifestation of an underlying congenital or acquired bleeding disorder (such as von Willebrand disease or hemophilia). Laboratory abnormalities will often direct identification of the hemostatic defect. Therapy for bleeding secondary to medical conditions should be individualized and proceed in consultation with a hematologist.
Acquired Factor V Inhibitors
Acquired clotting factor inhibitors occur rarely, but are associated with significant morbidity and mortality. In vascular surgery, acquired Factor V is the most commonly encountered due to contamination of topical thrombin with small amounts of bovine Factor V, which cross-reacts with human factor V. This immunologic cross-reactivity in some cases triggers development of an inhibitory antibody to human Factor V. Factor V inhibitors typically manifest 5-10 days after surgery with profound bleeding and are typically associated with a prolonged PT and aPTT Diagnosis of Factor V inhibitors is made through plasma mixing studies, by mixing patient plasma with normal plasma at a 1:1 ratio. The mixing study distinguishes a Factor V deficiency (correction of PT/aPTT with mixing) from acquired Factor V inhibitors (which do not correct the PT/aPTT after mixing) Patients who are bleeding may respond to transfusions of platelets, which carry their own store of Factor V which is less accessible to inhibition. Plasma exchange and IVIG have also been reported to be effective.
Bleeding From Surgical Complications
Excessive bleeding after surgery may result from the surgical procedure itself (from vessel injury) or complications resulting from surgery including dilutional coagulopathy, use of colloid plasma expanders (dextran or starch), and consumption of clotting factors with or without disseminated intravascular coagulation (DIC). Hypothermia and acidosis also inhibit the function of coagulation factors and contribute to the coagulopathy.
2.4. Dilutional Coagulopathy Dilutional coagulopathy results from excessive transfusion of red cell concentrates without replacement of plasma and/or platelets. Replacement of 1.5 blood volumes with packed red cells can lead to prolongation of the PT/aPTT and decreases in platelet counts and fibrinogen. Laboratory tests (CBC, PT/aPTT and fibrinogen) should be monitored in patients receiving >10-15 units PRBCs and appropriate blood products (fresh frozen plasma, FFP; cryoglobulin or platelets) should be transfused to correct the coagulopathy.
Disseminated Intravascular Coagulation
Consumption of clotting factors and/or platelets occurs with major surgery, and can be exacerbated by prolonged hypotension, acidosis, hypothermia or tissue ischemia. In severe cases, consumption of clotting factors may initiate DIC and profound hemostatic derangements. Evaluation for DIC in the postoperative setting is difficult. In non-surgical patients, laboratory abnormalities (decreased fibrinogen and platelet counts (with or without microangiopathic hemolysis), elevated D-dimers and prolonged PT/aPTT) can be used to support a diagnosis of DIC in the appropriate clinical context (sepsis, obstetric catastrophe, massive trauma, cancer). However, in the surgical patient, tissue injury resulting from surgery as well as elevation of acute phase reactants leading to elevations in D-dimer and fibrinogen may mask signs of DIC. A recommended strategy for DIC in the post-surgical patient includes laboratory assessment of CBC, PT/aPTT, fibrinogen and peripheral blood film. Treatment is generally supportive and includes transfusion of blood products and correction of the underlying cause, if one can be identified.
Colloid Plasma Expanders
Colloid plasma expanders used in surgery (hydroxyethylstarch or gelatin solutions) can impair hemostasis beyond dilutional effects on coagulation. The exact mechanisms for starch induced coagulopathy is not known, but changes in activity of Factor VIII, von Willebrand factor (vWF), diminished platelet activation and defects in fibrin polymerization have been described. Changes in coagulation parameters are correlated with molecular weight of the polymer (hetastarch, MW 450kDa > pentastarch MW=200Â kDa) and are dose dependent (>20 mL/kg/d). Starch solutions are primarily excreted by the kidney and can remain in circulation for 2-4 days after administration. Coagulopathy can be corrected with appropriate replacement, if abnormalities in vWF or FVIII can be identified. Cryoprecipitate has been used successfully in some patients but not others.
2.5. Hypercoagulable States Although thrombosis can affect any vascular bed, the pathogenesis of arterial and venous thrombosis is often distinct and only rarely overlaps. Arterial thrombosis is principally caused by acute or chronic endothelial injury resulting from atherosclerosis. Atherosclerotic rupture exposes subendothelial matrix, rich in tissue factor, collagen and other proteins, and enable rapid platelet adhesion and activation. Arterial occlusions are characterized by platelet rich thrombi, as adherent platelets, stabilized by vWF and fibrinogen, are able to withstand the higher shear forces and flow rates found in the arterial bed. Atraumatic acute arterial thrombi in the limbs can occur from plaque rupture from advanced atherosclerosis or from cardiac or noncardiac sources of emboli. Cardiac emboli can arise from complications of atrial fibrillation, intraventricular mural thrombi, or valvular disease. Noncardiac emboli may arise from arterial aneurysms, remote atherosclerotic plaque rupture, paradoxical venous thrombi or recent procedures. 131
Clinical Review for the USMLE Step 1 Venous thrombi occur in vascular beds with lower flow rates and are composed of red cells organized in a fibrin mesh. The elements of Virchowâ€™s triad first conceptualized over 150 years ago by the German pathologist, Rudolf Virchow, remain essential to our current view of the pathogenesis of venous thrombosis, which involves changes in: 1) blood flow 2) clotting factors and 3) endothelial injury. Thrombotic risk factors are characterized as inherited or acquired, although acquired risk factors are most often the trigger for thrombosis in patients with and without inherited thrombophilic tendencies. The majority of antithrombotic agents in clinical use (antiplatelet agents and anticoagulants) affects thrombus initiation or extension, and can therefore be considered prophylactic agents. Antithrombotic therapy used for the prevention of thrombus initiation is considered primary prophylaxis, whereas preventive therapy directed at clot extension is considered secondary prophylaxis. Fibrinolytic agents, in contrast, lead to dissolution of clots, and are used in the management of active thrombosis. In general, antiplatelet agents appear to be more effective in arterial thrombo-occlusive disease, and anticoagulants more useful in the treatment of venous thromboembolic disease, although clinical overlap of these agents occur in a variety of disease settings.
2.6. Venous Thromboembolism 2.6.1
Thromboprophylaxis in Surgery
Asymptomatic DVT occurs in 15-25% of patients undergoing surgery not receiving thromboprophylaxis and symptomatic venous thromboembolism (VTE) occurs in ~2% of patients undergoing vascular surgery. Higher rates of VTE have been reported in patients undergoing aortic aneurysm repair and aortofemoral bypass. Thromboprophylaxis should be considered for most surgical procedures.7
Postsurgical Acute Venous Thromboembolism
When patients present with acute VTE in the postsurgical setting, treatment is complicated by a higher bleeding risk. Full-intensity anticoagulation should be avoided for 5-7 days or longer after major (open) intraabdominal surgery or surgery involving a vital organ. Use of an inferior vena cava (IVC) filter may be considered in this setting. For patients undergoing minor procedures or at low risk of bleeding, anticoagulation with UFH is recommended, as this agent can be reversed with protamine in the event of bleeding. A hematology consultation is advised to assist in determining the optimal perioperative management of patient with acute VTE.
Patients on long-term anticoagulation may require anticoagulation in the perioperative or postoperative setting. Risk stratification for perioperative anticoagulation must be individualized due to the number of variables affecting both thrombotic and bleeding risk. Variables to consider include: 1)Â indication for anticoagulation therapy, 2) remoteness of thrombotic event, 3) type of surgery and attendant hypercoagulable and bleeding risk, and 4) age and comorbid illness. If patients have had recent arterial or venous thrombosis (<3 months), elective surgery should be deferred due to the high hypercoagulable risk posed by surgery. For those patients with recent thrombosis and an urgent surgical indication, consultation with a hematologist or internist is advised to determine need for pre/post-operative anticoagulation and/or adjunctive therapies (inferior vena caval filters or IVCs). For those with more remote clotting histories, indications for post-operative anticoagulation must be individualized due to the heterogeneity of disease conditions and types of procedures. 132
2.7. Anemias 2.7.1
Iron-Deficiency Anemia Iron-deficiency anemia is due to decreased iron stores following poor intake, excess loss, or poor absorption. Iron-deficiency anemia is the most commonly encountered anemia in general practice. It is most common in the reproductive years of women and in pregnant women. The most common cause in men is the result of an occult GI bleed. Other causes include alveolar hemorrhage, nosocomial loss, CRF treated with hemodialysis, following surgery, and various types of hemolysis. Iron-deficiency anemia presents with constitutional symptoms, exertional dyspnea, anorexia, melena, hematochezia, and / or hemoptysis, depending on the particular cause of blood loss. Objective signs include glossitis, angular stomatitis, koilonychias, pallor; iron-deficiency anemia can also be entirely subclinical. Anisocytosis and increased RDW are early signs of this disorder, and MCV indicates a hypochromic microcytic anemia. These results, combined with low ferritin, are diagnostic for irondeficiency anemia. Treatment involves replacing iron stores and correcting any underlying etiology. Ferrous sulfate is the agent of choice to replenish iron stores in the body.
Sickle Cell Anemia (SCA) Sickle cell anemia (SCA) is a commonly inherited disease that is associated with significant morbidity and decreased lifespan. An autosomal recessive defect in the beta chain of the adult hemoglobin (HbA) leads to the sickle cell hemoglobin (HbS). Due to defects in RBC deformability, obstruction of blood vessels leads to sickle cell pain crises and organ damage, in addition to anemia. SCA presents with constitutional symptoms and anemia. Painful crises occur intermittently due to vessel blockade (and possibly hand-foot syndrome) cause swelling and pain in the distal upper and lower extremities. Stroke is common, along with TIAs and RIND. Priapism may also occur with SCA. Acute presentations can include acute chest syndrome (ACS), which may present with severe chest pain due to blockade within the pulmonary vasculature. Chronic SCA can present with growth retardation, hepatomegaly, splenomegaly, pallor, jaundice, cardiomegaly with an SEM, skin ulceration, and cholelithiasis. A proliferative retinopathy is often present as well. Serious complications may also occur similar to an infection. Diagnosis of SCA is made by hemoglobin studies. SCA is definitively cured only by bone marrow transplantation. In most individuals, treatment centers on avoiding pain crises, giving prophylaxis for infection, and reducing the symptoms and damage from SCA. Fluid repletion is commonly the first step in any acute presentation. NSAIDs are the first line of treatment for pain management followed by hydroxyurea (by some clinicians). Penicillin is often given to avoid pneumonia, which is common in SCA, and folic acid supplements.
Alpha-Thalassemia Alpha-thalassemia is the result of a hereditary defect in hemoglobin synthesis leading to an excess of beta-globins and the formation of hemoglobin H tetramers. Alpha-thalassemia affects Africans, Asians, Mediterraneanâ€™s, and Europeans. A cis deletion is one in which two alpha genes are lost on the same chromosome; cis loss has a greater potential to lead to more serious disease in offspring. Deletion of 133
Clinical Review for the USMLE Step 1 just one gene is asymptomatic and clinically insignificant. A cis deletion or trans deletion leads to alphathalassemia. Loss of three alpha hemoglobin genes leads to chronic hemolytic anemia. Loss of all four alpha hemoglobin genes leads to death in utero due to hydrops fetalis. Alpha-thalassemia has variable penetrance and can lead to a hemolytic anemia. Multiple blood transfusions are necessary in some individuals, leading to hemochromatosis and widespread organ damage. Pallor is evident with significant anemia. Jaundice and hepatosplenomegaly are also typically present, along with folic acid deficiency. Ulceration and a predisposition to infection are common. A hypochromic, microcytic hemolytic anemia is typically present. Pigment gallstones from the hemolytic anemia may also develop. Hemoglobin electrophoresis demonstrates HbH. Treatment for alpha-thalassemia involves supportive therapy, rapid resolution of infections, transfusion, if symptomatic severe anemia hemoglobin titers occur below 7 g / dL, treatment of hemochromatosis, and in severe cases, a bone marrow transplantation â€“ the only definitive cure. Hemoglobin H disease, also known as Bartâ€™s hemoglobin, requires blood transfusions for survival. Alpha-thalassemia minor leads to subclinical disease.
Beta-Thalassemia Beta-thalassemia presents with an excess of alpha-globins leading to alpha-globin tetramers. Deletions and substitutions within the genetic framework account for most cases of beta-thalassemia and spontaneous disease is possible. Beta-thalassemia deals with a maternal and paternal allele; as a result, damage to one allele leads to reduced formation of the beta-globin. Damage to both alleles leads to formation of only alpha chains. Beta-thalassemia is especially common in Italians, Greeks, and Southeast Asians. Beta-thalassemia presents as a congenital condition that leads to severe jaundice and anemia early in life. Constitutional symptoms, symptoms of anemia, and hypersplenism are common. Gallstones may also be present. Diagnostic workup proceeds in the same fashion as alpha-thalassemia. Beta-thalassemia major leads to early splenomegaly and symptoms of anemia, and typically requires transfusions to maintain hemoglobin above 3-5 g / dL. Thalassemia intermedia leads to a hemoglobin titer between 6 and 9 g / dL. Thalassemia minor leads to clinically insignificant disease. Treatment for beta-thalassemia includes transfusion for symptomatic, severe anemia and supportive therapy is a must. Like alpha-thalassemia, splenectomy may be necessary to decrease the number of required transfusions. Early treatment for infections is required. Bone marrow transplantation is curative.
Megaloblastic Anemia Megaloblastic anemia is the presence of immature erythroblasts with an increase in MCV. Megaloblastic anemia is commonly found in vitamin B12 deficiency or folate deficiency. The former may be due to an autoimmune defect leading to pernicious anemia, poor intake, or malabsorption due to ileal disease. The latter may be due to alcoholism, poor intake, chronic hemolytic anemia, or various malabsorption syndromes. Various chemotherapy drugs may also lead to megaloblastic anemia. Megaloblastic anemia is more common with increasing age. African American women and the elderly are most at risk.
Folate Deficiency Folate deficiency may be the result of poor dietary intake, increased demand, as in pregnancy, or increased demand, as in chronic hemolytic anemias. Any number of hemolytic anemias may lead to an in134
Hematologic Disorders creased requirement in folate levels. Malabsorption syndromes such as Crohn disease or other enteropathies can lead to failure to properly absorb folate. Antagonists to folate such as methotrexate, or those agents that affect metabolism such as alcohol, sulfasalazine, triamterene, TMP-SMX, barbiturates, and nitric oxide can impede the use of folate by RBCs. Exposure to heavy metals or toxins such as arsenic or chlordane can also lead to retardation of folate utilization. Folate-deficiency megaloblastic anemia presents with pallor and glossitis. There are no neurologic deficits.
Vitamin B12 Deficiency Vitamin B12 deficiency may be a result of many of the causes that lead to folate deficiency. In addition, pernicious anemia due to antibodies against parietal cells may lead to diminished amounts of intrinsic factor required for binding and absorption of vitamin B12. Lack of animal protein in strict vegetarian diets can also lead to deficiencies in vitamin B12. Diverticulosis and bacterial overgrowth, or infection by D. latum also lead to decreased vitamin B12 available for absorption. Vitamin B12-deficiency megaloblastic anemia presents with pallor, glossitis, and a peripheral sensory neuropathy that advances to a loss of deep tendon reflexes (DTR). Confusion and memory loss may be present. Delirium and dementia may occur in later stages. Diagnosis of megaloblastic anemia is made by increases in MCV, identified decrease in folate and / or vitamin B12, and the presence of an anemia. Hypersegmented neutrophils may be present in pernicious anemia. A Schilling test may be done to test the ability to absorb vitamin B12. Methylmalonic acid is normal in folate-deficiency megaloblastic anemia but positive in vitamin B12-deficiency megaloblastic anemia. Antibodies to intrinsic factor can be demonstrated for pernicious anemia. Treatment for megaloblastic anemia is to replace the vitamin deficiency. Care should be taken in reversing a vitamin B12 deficiency by folate. Folate, however, will not prevent further progression of the neurologic symptoms from a vitamin B12 deficiency. Transfusion is occasionally undertaken in severe anemia, but pulmonary edema may develop. Vitamin replacement is the standard of care.
Anemia of Chronic Disease The most common cause of a normocytic anemia is anemia of chronic disease (ACD); ACD is also the second most common type of anemia. While ACD tends to be a normocytic normochromic anemia, some presentations may have a microcytic anemia. ACD is due to decreased bone marrow production of erythrocytes after longstanding chronic disease, itself the result of a combination of erythropoietin resistance, decreased production, and decreased RBC half-life. ACD may also be due to chronic inflammation, cancer, and systemic diseases. ACD tends to develop with a moderate- or low-grade anemia and is typically subclinical in presentation. More severe cases may present with symptoms of anemia. Treatment of the primary disease is the only way to resolve ACD. Blood transfusions are rarely required.
Sideroblastic Anemia Sideroblastic anemia presents with ring sideroblasts in the bone marrow, decreased heme synthesis, and a normocytic anemia. The general cause is a disruption in the normal metabolism of mitochondria leading to decreased ATP available for consumption by the RBC. This injury may be the result of numerous etiologies, including hereditary mechanisms such as a congenital X-linked disorder, an autosomal 135
Clinical Review for the USMLE Step 1 dominant disorder, an autosomal recessive disorder, and inherited mitochondrial cytopathy; acquired etiologies include myelodysplastic syndrome (MDS), certain drugs such as alcohol, INH, chloramphenicol, and cycloserine, toxins such as lead and zinc, and nutritional deficiencies such as lack of copper or pyridoxine. MDS is a dysfunction in hematopoietic stem cell function that affects all three cell lines (myeloid precursors, erythroid precursors, and megakaryocytes) leading to ineffective erythropoiesis, marrow dysfunction, and eventually, the development of acute leukemia. Various drugs lead to sideroblastic anemia through blockade of the heme biosynthetic pathway; INH in particular has been implicated in numerous cases of sideroblastic anemia. Sideroblastic anemia presents with moderate or severe anemia with the typical symptoms of anemia â€“ including constitutional symptoms such as fatigue, dizziness, and decreased exercise tolerance. A history identifying a particular etiology may also be present, such as alcoholism or toxin exposure. Basophilic stippling is evident on examination of a peripheral blood smear; hypochromia and microcytosis may be present in some cases instead of the typical normocytic anemia. Treatment of sideroblastic anemia involves reversing those etiologies that are amenable to treatment. Blood transfusions are often required in other cases. Pyridoxine is sometimes effective. Monitoring iron load and using deferoxamine to avoid hemochromatosis is the standard of care in any situation involving chronic transfusions.
Aplastic Anemia Aplastic anemia is the development of pancytopenia as a result of an acquired or familial syndrome that leads to bone marrow failure. Acquired disease may be the result of exposure to viral infections such as EBV, HIV, HBV, or dengue fever, mycobacterial infection, autoimmune disease, toxic chemical exposure including benzene, chemotherapeutic agents, arsenic, and estrogens, and exposure to ionizing radiation. Many other medications can also lead to aplastic anemia, but they are a rare complication. Insecticides and gold compounds in particular can lead to serious illness. Aplastic anemia affects fewer than 1 patient in 100,000, and generally peaks in the elderly. Transient causes include vitamin B12 or folate deficiency and infection by agents such as parvovirus B19. Aplastic anemia presents with abnormalities in bleeding, epistaxis, fever, pharyngitis, easy bruising, and various constitutional symptoms. Signs of anemia are present, along with oral ulcerations and retinal hemorrhage. Severe aplastic anemia has anemia with reticulocytopenia, thrombocytopenia, neutropenia, and a hypocellular bone marrow. Pancytopenia is found on CBC, and bone marrow biopsy confirms the diagnosis. A dry bone marrow tap is more typical of an infiltrative marrow disease, not aplastic anemia. Therapy for aplastic anemia revolves around correcting any reversible causes of the anemia and consideration of a bone marrow transplantation. Immunosuppressive therapy may be needed in patients who cannot receive a transplantation; cyclosporine and antithymocyte globulin are used in this case. Infection prophylaxis is important for good care.
Fanconi Anemia Fanconi anemia is an inherited failure of the bone marrow leading to pancytopenia and aplastic anemia. This autosomal recessive disease occurs due to mutations in several different genes that code for proteins responsible for DNA repair; the outcome is a series of birth defects, bone marrow dysfunction, and carcinogenesis. About 1 in 300 persons are carriers, but only about 1 in over 300,000 persons is 136
Hematologic Disorders affected. Ashkenazi Jews are more affected by Fanconi anemia. Morbidity in this disorder is due to bone marrow failure, the development of leukemia, and carcinogenesis. Fanconi anemia presents with growth retardation, anatomic defects in the genitourinary system, and radial ray anomalies. CafĂŠ au lait spots are present, along with petechiae and numerous constitutional symptoms. Symptoms of thrombocytopenia and pancytopenia are predominant over time. Short stature is nearly universal, along with profound defects of the head, face, and remaining skeleton. Conductive deafness and congenital cardiac defects are typically present. Diagnosis is made by chromosomal analysis and the presence of marrow failure. Imaging studies confirm the skeletal defects. Symptomatic and supportive therapies are the standard of care for patients with Fanconi anemia. Stem cell transplantation may prevent aplastic anemia, MDS, and leukemia. Surgical intervention is often necessary to repair limb defects.
Hemolytic Anemia Hemolytic anemia leads to early destruction of RBCs and presents with anemia when the bone marrow cannot compensate for the loss of RBCs. Numerous causes exist, but major ones include G6PD deficiency, hereditary spherocytosis, sickle cell anemia, DIC, HUS, TTP, prosthetic valves, and PNH. It is present in about 1 in 20 anemias and leads to symptoms only with severe anemia. Hemolytic anemia presents with symptoms of anemia. Tachycardia, dyspnea, and weakness are typically present in severe cases. Bilirubin pigmented stones may lead to cholelithiasis. Repeated transfusions may lead to hemochromatosis. A history of use of certain medications, such as penicillin, quinine, or L-dopa may be responsible for an immune reaction leading to hemolytic anemia. Favism is especially common in the Mediterranean type of G6PD. Pallor, jaundice, splenomegaly, leg ulcers, and other symptoms of anemia may be present on physical exam. Diagnosis is made by peripheral blood smear and standard tests for anemia. Treatment for hemolytic anemia is similar to that for any other type of anemia â€“ transfusions with symptomatic, severe anemia, avoiding triggers that worsen the anemia, and treating reversible causes.
Cold Hemolytic Anemia Cold agglutinin hemolytic anemia occurs due to IgM antibodies that induce a complement-mediated lysis of RBCs. The IgM antibodies may be due to a clonal expansion of B cells, or following infection by Mycoplasma pneumoniae, EBV, influenza, and HIV. Agglutination of the IgM antibodies and subsequent hemolysis occurs especially in colder temperatures, hence the name of this disease. Low titers of IgM are found in otherwise healthy persons; elevations may occur with infection, autoimmune disease, or periods of significant stress. Only 1 in 300,000 persons are affected. Cold agglutinin hemolytic anemia presents with Raynaudâ€™s phenomenon with significant symptoms during cold weather. Constitutional symptoms are typically present, along with symptoms from any concurrent infection. Dark urine may also be present with cold weather due to significant peripheral hemolysis. Pallor is typically present, but splenomegaly and jaundice are absent in this disease. It is differentiated from warm hemolytic anemia (discussed above) because this disorder is present only with cold temperatures. Diagnosis is made in a manner similar to that of other hemolytic anemias and with cold agglutination studies. Treatment is to avoid the cold and to properly protect the patient against cold weather. Otherwise, standard therapy for anemia is undertaken but rarely necessary as this anemia is typically mild in nature. 137
Clinical Review for the USMLE Step 1 Plasmapheresis may be intermittently necessary to remove excess IgM.
Paroxysmal Hemolytic Anemia (PHA) Paroxysmal hemolytic anemia (PHA) is also known as autoimmune hemolytic anemia (AIHA), a type of hemoglobinuria that occurs due to an autoimmune disorder leading to significant intravascular hemolysis and anemia. It is typically present during periods of significant stress such as infection. PHA is distinct from other hemolytic anemias in that it is highly symptomatic and also has a proteinuria with a Bence Jones-type of polypeptide. PHA is due to low temperatures leading to binding of a polyclonal IgG to RBCs inducing intravascular hemolysis. Postviral infections may induce the formation of this antibody and subsequent disease. PHA presents with significant symptoms of anemia that develop insidiously after cold exposure. Significant lower extremity pain and severe constitutional symptoms are acutely present. Renal failure can occur due to the significant level of hemolysis taking place. A concurrent viral infection may be present. Diagnosis is made by clinical history and confirmation through an anemia workup. LDH and unconjugated bilirubin are high, and free hemoglobin may be found in the plasma â€“ a testament to the rapid intravascular hemolysis taking place. A positive D-L antibody test also indicates cold temperaturemediated lysis of RBCs after the temperature rises. Treatment is similar to that of cold agglutinin hemolytic anemia. Rapid treatment of infections is necessary. Hydration is necessary to avoid renal failure and damage. Folic acid supplements are recommended, as they are in virtually all anemias.
Paroxysmal Nocturnal Hemoglobinuria Paroxysmal nocturnal hemoglobinuria (PNH) is the formation of dark urine due to hemolysis that occurs over time. Hemolytic anemia is present due to lack of deformability in the RBC membrane. Thrombosis of large vessels may occur in this disorder. Hemopoietic deficiencies may also be present and lead to pancytopenia or aplastic anemia. This triad distinguishes PNH from other hemolytic anemias. The underlying defect is due to inability to manufacture glycosyl-phosphatidylinositol (GPI), an anchor that latches proteins onto the cell membrane. The defect is in the phosphatidylinositol glycan class A (PIGA) gene, among defects found on other genes. PNH presents with dark urine early in the morning, but hemolysis continues throughout the day. Venous thrombosis may present with abdominal pain, hepatomegaly, ascites (as in Budd-Chiari syndrome), and symptoms of aplastic anemia. Painful skin nodules may be present, and severe headaches may occur as a result of the venous thrombosis. A predisposition to infection may also occur. Diagnosis is made by identifying the genetic defects and demonstrating the pathophysiology of PNH. Acidified serum lysis and the Ham test are diagnostic, along with a complement lysis sensitivity test. Stem cell transplantation is curative, but rarely an option. Glucocorticoids are sometimes used to alleviate the symptoms of PNH. Other standard principles of anemia therapy are used with PNH. As in other cases of bone marrow failure and aplastic anemia, antithymocyte globulin (ATG) has been used with success.
Hereditary Spherocytosis (HS) Hereditary spherocytosis (HS) is a familial disorder that can lead to severe hemolytic anemia. Loss of the RBC membrane leads to decreased integrity and an increased risk of hemolysis. These spherical RBCs are sequestered by the spleen, leading to marked splenomegaly in severe cases. HS may be due to 138
Hematologic Disorders defects in spectrin, ankyrin, band 3, and protein 4.2. Northern Europeans are affected the most by this usually autosomal trait. Morbidity and mortality are determined by the severity of the anemia. HS presents with anemia, jaundice, and splenomegaly. The nature of the anemia varies by individual, but it can be very severe and lead to significant mortality. Reticulocytosis and increased mean corpuscular hemoglobin concentration (MCHC) are common. Peripheral blood smears identify spherocytes, and hyperbilirubinemia may be detected. The osmotic fragility test may also be used to identify RBCs susceptible to hemolysis â€“ a sensitive but not specific test of acquired deficiencies in the RBC skeleton. Treatment of HS involves antibiotic and vaccination prophylaxis to avoid infections prior to splenectomy. Cholecystectomy may be required with severe cholelithiasis. Splenectomy is curative, but care should be taken to avoid infection by encapsulated organisms such as S. pneumoniae, H. influenzae, and Neisseria spp.
Glucose-6-Phosphatase Dehydrogenase Deficiency (G6PD) Glucose-6-phosphatase dehydrogenase (G6PD) deficiency is an X-linked disorder that affects nearly half a billion people around the world. Its protection against malaria is the likely reason G6PD deficiency is so prevalent. Defects in the ability to oxidize certain reactions lead to excess glutathione, which in turn leads to free radical formation and premature damage to RBCs. G6PD presents with neonatal jaundice and acute hemolytic anemia. Drug-induced hemolysis or consumption of fava beans leading to hemolytic anemia is common. Jaundice and splenomegaly is found on physical exam. Most patients are entirely asymptomatic. Diagnosis is confirmed by measuring the activity of G6PD enzyme. Alleviating symptoms by discontinuing the offending agent is the only treatment necessary, in addition to avoiding fava beans and giving supportive therapy in acute exacerbations.
2.8. Transfusion Reactions Transfusion reactions occur due to immune reactions against donated blood that does not match that of the recipient. Serious reactions can lead to death, and rapid identification and reversal are necessary. Acute reactions may be due to immunemediated reactions with various antibodies; those antibodies against the major blood groups (AB) can lead to death through notable intravascular hemolysis. Non-ABO antibodies result in extravascular reactions and are milder. Nonimmune Figure 9. Pentose phosphate pathway. Copyright reactions occur with damage to the donated RBCs G.D. Besten. Used with permission. leading to hemoglobinuria and hemoglobinemia. 139
Clinical Review for the USMLE Step 1 The presence of various cytokines in the donated blood can precipitate additional APRs and lead to constitutional symptoms. Immune reactions can present as severe anaphylaxis and lead to shock and death. Fatal reactions affect 4 persons in a million; nonfatal immune reactions affect 1 in 10,000 persons. Allergic reactions occur in 1 in 300 persons, and anaphylaxis may occur in 1 in 50,000 persons. Multiparous women are more likely to have symptoms than other groups. Transfusion reactions present with the aforementioned symptoms. Early signs include fever, dropping BP, flushing, anxiety, and wheezing. Later signs include DIC. In nonhemolytic reactions, only fever is present along with mild constitutional symptoms and hypotension. Allergic reactions may present with a maculopapular rash and pruritus. Anaphylactic reactions may present with dyspnea, wheezing, anxiety, bronchospasm, and hypotension. In transfusion-related acute lung injury (TRALI), SOB, hypoxia, and orthopnea with cardiac decompensation may be present. Diagnosis is made by workups for anemia and a direct Coombs test. Transfusion reactions are treated by stopping the transfusion and careful observation. Prophylaxis against renal failure and DIC are necessary. Diuresis may be necessary. Acetaminophen is used for fever, diphenhydramine for mild allergic reactions, and epinephrine for anaphylactic reactions. Severe symptoms may require admission to ICU and supportive therapy. A workup for sepsis may be necessary.
2.9. Other Red Blood Cell Conditions 2.9.1
Polycythemia Vera (PV)
Polycythemia vera (PV) is the development of a neoplastic marrow that leads to uncontrolled erythrocytosis, myelocytosis, and megakaryocytosis. The end result is thrombosis and bleeding diatheses. PV is rare. PV begins with symptoms of hyperviscosity in the vessels leading to thrombosis, headache, tinnitus, visual defects, angina, and claudication. Bleeding diatheses occur, and marked splenomegaly is present. Excess degranulation of mast cells and basophils can lead to pruritus. A red complexion is common, along with HTN. All hematopoietic cells are increased in number. Over half a million platelets are typically found in a CBC, along with elevated WBCs. PV is treated by therapeutic phlebotomy to reduce hematocrit (Hct) to 40%. Hydroxyurea may be necessary for myelosuppression. Platelet aggregation can be inhibited with anagrelide. Splenectomy is helpful.
Porphyria refers to six distinct disorders that are defects in metabolic enzymes leading to neuropsychiatric manifestations, abdominal pain, and accumulation of porphyrins in tissues. Porphyria is categorized as porphyria cutanea tarda, acute intermittent porphyria, erythropoietic protoporphyria, variegate porphyria, hereditary coproporphyria, and congenital erythropoietic porphyria. Specific enzyme defects lead to each of these specific porphyrias. Porphyria cutanea tarda may be acquired through HCV, exposure to hydrocarbons, alcohol abuse, and use of estrogens. Risk of developing porphyria is tied to liver disease and factors that affect the function of the liver. Porphyria cutanea tarda is the most common porphyria, and affects 1 in 10,000 persons. The others are significantly rarer. Congenital porphyrias present early in life, while porphyria cutanea tarda and acute intermittent porphyria present in young adults. Caucasians are affected more than other groups. Acute intermittent porphyria may present with constitutional symptoms, dysuria, incontinence, fever, 140
Hematologic Disorders extremity pain or pain in the torso, loss of the sensorium, seizures, disorientation, depression, hallucinations, and paranoia. Delta-aminolevulinic acid dehydratase deficiency porphyria presents similar to acute intermittent porphyria. Porphyria cutanea tarda presents with photosensitivity, bullous vesicles followed by crusting, blistering of the skin, red urine on standing, hypertrichosis, pigmentation changes on the skin, acanthosis, and onycholysis. Erythropoietic protoporphyria presents with early onset of photosensitivity even with room lights, gallstones, hepatic disease, and acanthosis. Variegate porphyria presents similar to acute intermittent porphyria but with photosensitivity and lesions like porphyria cutanea tarda. Hereditary coproporphyria presents like variegate porphyria. Congenital erythropoietic porphyria is similar to erythropoietic porphyria except with a much earlier presentation. Alopecia and ocular abnormalities may be seen in this version. Acute intermittent porphyria is associated with HTN, CRF, hepatocellular carcinoma, and depression. Porphyria cutanea tarda is associated with a more infectious etiology, including HIV, HCV, hemochromatosis, and hepatocellular carcinoma. Diagnosis is made by examining metabolites in the urine, examining the venous blood by a total porphyrin test, and quantitative tests for porphyrins. Treating the porphyrias requires avoiding precipitating factors such as alcohol, estrogen, various medications such as NSAIDs and sulfonylureas, and iron supplements. Phlebotomy may be required to avoid hemochromatosis. Chloroquine may be necessary. Protection against the sun is necessary, and antioxidant therapy may be useful. Glucose is administered with neuropsychiatric manifestations, gabapentin for seizures, and hematin with severe symptoms. SSRIs are administered for depression. Avoiding the precipitating factors is the key for long term control.
2.10. Platelets 2.10.1
Immune Thrombocytopenic Purpura (ITP)
Also known as idiopathic thrombocytopenic purpura (ITP), this bleeding diathesis presents with thrombocytopenia, purpura, and petechiae along with a predisposition towards hemorrhage. The presence of autoantibodies against platelets leads to decreased platelet longevity due to macrophage phagocytosis in the spleen. The antibody appears to be against a GPI anchor. ITP is a relatively rare disorder due to its subclinical nature in most patients. Concurrent SLE, AML, CML, or MDS may be present; the disorder may also follow infection by EBV, VZV, CMV, rubella virus, HAV, HBV, HCV, HIV, or a generic URI. Medications that can lead to sensitization include quinine, cephalothins, rifampicin, gold salts, NSAIDs, HTN medications, diuretics, and abciximab. Heparin-induced thrombocytopenia (HIT) may also lead to ITP. ITP may lead to morbidity through intracranial hemorrhage or bleeding in other parts of the body. Petechiae and ecchymoses are typically present. Neurologic exam may be positive for findings, and a hemopericardium may be identified in some individuals. Diagnosis is confirmed by CBC and large platelets found in peripheral blood smears. Antiplatelet antibodies may also be present. A positive Coombs test is common. Marrow biopsy is normal. ITP is treated with corticosteroids, IVIG or Rho immune globulin (RhIG), and platelet transfusions, if severe bleeding is present. Splenectomy results in remission.
Von Willebrand Disease
Von Willebrand disease (vWD) is a bleeding diathesis that prevents hemostasis in response to vascular damage. Adhesion to platelets is impaired and stabilization of various coagulation factors never occurs. vWD is rather rare and morbidity varies. vWD is an inherited autosomal condition with onset at a young age; females especially present at onset of menarche.
Clinical Review for the USMLE Step 1 vWD presents with bleeding diatheses leading to epistaxis, easy bruising, and hematoma formation. Significant menstrual bleeding is possible. GI bleeds do not occur as frequently. A deficiency in von Willebrand factor (vWF) is diagnostic. This activity of vWF can be measured using a ristocetin activity test, while the presence of vWF can be determined with an antigen test. A PTT is increased in vWD, while PT is normal. The most severe vWF disease occurs in type III disease. Treatment of type I vWD involves DDAVP which leads to a rise in vWF due to release from storage vesicles. Type II vWD is treated with DDAVP as well, but concentrates with factor VIII and vWF may be necessary prior to surgery. Treatment of type III vWD involves vWF-containing factor VIII concentrates. Platelet transfusions are also therapeutic.
Hemophilia A is an X-linked recessive disorder with factor VIII leading to a bleeding diathesis through disruption of the normal coagulation cascade. Spontaneous bleeding can occur, and significant bleeding with trauma is possible. Incidence is 1 in 5,000 persons but the lifespan is normal if no blood-borne illnesses are transmitted through transfusion. Males are significantly more affected; females tend to be carriers. Hemorrhage occurs frequently with hemarthrosis, CNS complaints, GI bleeds, genitourinary bleeds such as hematuria, epistaxis, hemoptysis, compartment syndromes from hematomas, and contusions. Physical exam elicits signs of hemorrhage including tachycardia, tachypnea, hypotension, and orthostatic hypotension. Lab studies indicate a normal PT, elevated aPTT, normal platelet count, and deficits in factor VIII levels. Hemophilia A is treated with factor VIII infusions (recombinant factor VIII is preferred). Oral hemorrhage may be treated with a combination of factor VIII and epsilon aminocaproic acid to reduce fibrinolysis. DDAVP may increase levels of factor VIII.
Hemophilia B is an X-linked recessive disorder that leads to defects in factor IX and subsequent hemorrhage. 1 in 5,000 persons are affected and lifespan is normal in the absence of blood-borne illness from transfusion. Hemophilia B presents like hemophilia A. Hemoglobin, PT, and platelets are normal. aPTT is increased. Factor IX is decreased significantly. Hemophilia B is treated with recombinant factor IX infusion; epsilon aminocaproic acid is used with oral bleeds to prevent fibrinolysis.
Vitamin K Deficiency
Vitamin K is a lipid soluble vitamin that is essential for the formation of clotting factors. It is produced by colonic bacteria. Terminal ileum disease prevents normal vitamin K production and absorption. It presents as hemorrhagic disease of newborns (HDN) in infants; in adults, it presents as a bleeding diathesis. Other causes include parenchymal liver disease such as cirrhosis, in which case vitamin K supplements have little effect (fresh frozen plasma [FFP] is required), malabsorption syndromes, biliary disease, cholestyramine, coumadin, and various other medications (INH, rifampin, barbiturates, and others), lupus anticoagulant, DIC, polycythemia vera, cystic fibrosis, and leukemia. Vitamin K deficiency, if severe enough, presents as complaints of significant hemorrhage following mild trauma. Ecchymoses, petechiae, hematomas, and oozing of blood are common. GI bleeds, hematuria, menorrhagia, epistaxis, and mucosal bleeds occur frequently. PT and aPTT are elevated. Des-gamma142
Pharmacology and Treatment carboxy prothrombin (DCP) is present in the absence of vitamin K. Treatment for vitamin K deficiency involves correcting the cause of the underlying deficit and providing vitamin K supplements. FFP is necessary in severe disease. Subcutaneous injections of phylloquinone (vitamin K 1) can be given; menadione (vitamin K 3) can be given orally in malabsorption syndromes. Phytonadione can also be directly injected in severe disease. Green leafy vegetables and oils provide a good source of vitamin K.
Malaria is the result of infection by Plasmodium protozoa carried by the Anopheles mosquito leading to potentially serious illness. Plasmodium species that can cause infection include P. falciparum, P. vivax, P. ovale, and P. malariae. P. falciparum can be fatal. P. falciparum and P. vivax are commonly responsible for new infections. Infection begins after a mosquito transmits the infection to a human host. The liver phase begins first with transmission to hepatocytes. Blood borne illness occurs a few weeks later with merozoites developing into trophozoites then schizonts inside RBCs. The erythrocyte phase begins, and merozoites are released a short time later when the RBC undergoes lysis. Fever occurs, and additional RBCs are infected. The immune system now steps in to control the infection, but death can occur with P. falciparum before a sufficient host reaction develops. Gametocytes can form during this process and lead to repeated infections. Nearly 3 million deaths occur annually throughout the world due to malaria; malaria is not endemic to the United States. Constitutional symptoms can be quite severe with malaria and a flu-like illness may develop. P. falciparum in particular can induce coma due to cerebral infection leading to seizure. Severe anemia is also possible, along with renal failure due to blockade of vessels supplying the renal cortex. Pulmonary edema is also present in some cases. P. falciparum and, more rarely, the other causes of malaria can also cause death due to splenic rupture. Diagnosis is made by blood smears and identification of the parasites. A rapid dipstick test for P. falciparum exists. Treatment for malaria includes adequate prophylaxis to avoid infection. Atovaquone / proguanil are commonly prescribed for prophylaxis, but it is not for use by pregnant women or children. Doxycycline is also often used, but the same contraindications apply. Mefloquine is safe for use by pregnant women; contraindications include patients with depression or other psychiatric illnesses, a history of seizures, and those with cardiac conduction abnormalities. Primaquine is used in certain situations, but G6PD deficiency is an absolute contraindication, along with pregnant women. Chloroquine, hydroxychloroquine, insect repellants (such as N,N-diethyl-m-toluamide [DEET]) are also used.
3. Pharmacology 3.1. Anticoagulants
Common anticoagulants and hemostatic agents are discussed in the two tables on the prior page.
3.2. Blood Products Whole blood can be divided into packed red blood cells (PRBCs), fresh frozen plasma (FFP), platelets, and cryoprecipitate. Whole blood is rarely used as a resuscitative product due to its immunogenicity and the greater effectiveness of partial blood products. In patients with acute hemorrhage, resuscitation with PRBCs is the initial blood product of choice. However, due to the lack of coagulation factors and 143
Clinical Review for the USMLE Step 1
Anticoagulant 60-90 min (dose-dependent)
Protamine sulfate 60-75% effective
Antithrombinmediated antiIIa, Xa, XIa
HIT (<1%), cross-reactive with HIT antibodies
Unfractionated heparin (UFH)
HIT (1-5%), osteoporosis, hypersensitivity, hypoaldosteronism (rare)
Antithrombinmediated antiXa > anti-IIa
Low molecular weight heparin (LMWH)
None; can be hemodialyzed
Antithrombinmediated antiXa only
Non-neutralizing antibodies (50%)
2.5 mg SC (prophylactic); 5-10 mg SC for therapeutic dosing
None; can be hemodialyzed
Renal and proteolytic cleavage
0.15 mg/ kg/hr IV
Non-neutralizing antibodies (<1%)
Direct thrombin inhibitor
Direct thrombin inhibitor
2 mg/ kg/min IV continuous infusion
Direct thrombin inhibitor
Vitamin K, fresh frozen plasma PT/INR
Hepatic cytochrome p450 Coumadin
1 mg/kg IV bolus up to 2.5 mg/kg/ hour IV over 4 hours
Skin necrosis, hypersensitivity, purple toe syndrome Vitamin K antagonist
Table 28. Common anticoagulants and their Mechanism of Action.
IV or SC: 0.3 mg/kg
Aminocaproic acid (Amicar)
Peak drug levels seen at 2 hours, but clinical effects may take days
None (shortened PT and high factor VIIa levels seen due to in vitro effects on assay)
Platelet function analyzer (PFA), factor VIII activity, or vWF levels
30-60 minutes after IV infusion; 6090 minutes after SC or nasal administration
Table 29. Common hemostatic agents and their Mechanism of Action.
IV dosing: 4-5 g IV over 1 hour followed by 1 g/ hour (maximum dose is 30 mg/ day) 2 hours
Interferes with fibrinogen binding sites on plasminogen
Recombinant factor VIIa (Novo7)
Variable PO dosing
IV dosing (bolus or continuous in2.3 hours fusion) depending on indication
Enhancement of thrombin generation on the surface of activated platelets
Transiently increases Nasal: 1.5 mg/ factor VIII and mL solution with vWF one spray per nare
Consists of human fibrinogen and thrombin; may include additives such as human factor XIII or aprotinin
Surgical bleeding, hyperfibrinolysis, and sealing of suture lines and anastomoses
Prophylaxis or treatment for patients with congenital hemophilia with inhibitors, congenital bleeding disorders, or acquired hemophilia
Skin grafts and sealing of suture lines / anastomoses
Low surgical risk (mild hemophilia A, vWD type I), patients with congenital or acquired platelet dysfunction
Thrombosis in patients without congenital bleeding problems
Hypersensitivity to human blood products or aprotinin
Thrombogenic potential with risk of myocardial infarction
Pharmacology and Treatment
Clinical Review for the USMLE Step 1 platelets, administration of more than 2 units of PRBCs should be accompanied with FFP and platelets. In patient with hemophilia or severe bleeding, administration of cryoprecipitate is also of benefit as it contains factor VIII, factor XIII, vWF, and fibrinogen - all of which are in either low concentration or missing from FFP.
3.3. Jehovah’s Witnesses Jehovah’s Witnesses typically refuse blood transfusion as it constitutes a transplant of a foreign substance into their body. Some members will accept blood plasma fractions, and others will accept autologous transfusions. When a Jehovah’s Witness patient may require blood as a result of major surgery, it is best to ask about their religious beliefs and restrictions ahead of time.
Chee, Y.L., et al., Guidelines on the assessment of bleeding risk prior to surgery or invasive procedures. British Committee for Standards in Haematology. British Journal of Haematology, 2008. 140(5): p. 496-504.
Ragni, M.V., C.M. Kessler, and J.N. Lozier, Clinical aspects and therapy for hemophilia. In Hematology: Basic Principles and Practice, R. Hoffman, et al., Editors. 2009, Churchill Livingstone Elsevier, Philadelphia, PA.
Ansell, J., et al., Pharmacology and Management of the Vitamin K Antagonists. Chest, 2008. 133(6 suppl): p. 160S-198S.
Douketis, J.D., et al., The Perioperative Management of Antithrombotic Therapy. Chest, 2008. 133(6 suppl): p. 299S-339S.
Kearon, C., et al., Antithrombotic Therapy for Venous Thromboembolic Disease. Chest, 2008. 133(6 suppl): p. 454S-545S.
Sobel, M. and R. Verhaeghe, Antithrombotic Therapy for Peripheral Artery Occlusive Disease. Chest, 2008. 133(6 suppl): p. 815S-843S.
Geerts, W.H., et al., Prevention of Venous Thromboembolism. Chest, 2008. 133(6 suppl): p. 381S-453S.
Section Editors Sapan S. Desai, MD, PhD
Danny O. Jacobs, MD, MPH
Assistant Professor Department of Surgery Duke University Medical Center
Professor and Chair Department of Surgery Duke University Medical Center
CNS & PNS
Niketa Desai, PharmD
Daniel Murariu, MD
Pharmacist Resident Department of Pharmacology Department of Surgery Long Island University University of Hawaii Head and Neck Surgery (adapted from the Clinical Review of Surgery)
Stephanie Mayer, MD
William Eward, DVM, MD
Resident Resident Department of Surgery Department of Surgery Duke University Medical Center Duke University Medical Center
Jocelyn Wittstein, MD Resident Department of Surgery Duke University Medical Center Orthopedic Surgery (adapted from the Clinical Review of Surgery)
Judson Williams, MD
Mark Shapiro, MD
Resident Associate Professor Department of Surgery Department of Surgery Duke University Medical Center Duke University Medical Center Vascular Trauma (adapted from the Clinical Review of Vascular Surgery)
Sapan Desai, MD, PhD
Michael Lidsky, MD
Assistant Professor Resident Department of Surgery Department of Surgery Duke University Medical Center Duke University Medical Center
Luigi Pascarella, MD
Cynthia Shortell, MD
Resident Professor Department of Surgery Department of Surgery Duke University Medical Center Duke University Medical Center Surgical Principles (adapted from the Clinical Review of Vascular Surgery)
1. Introduction The USMLE outline combines a discussion of central nervous system and peripheral nervous system topics with psychopathology in this section. What follows is a discussion of the basic embryology, anatomy, and physiology of the CNS and PNS, followed by a series of topics on pathology and therapy. Psychopathology is handled separately.
2. Embryology 2.1. Embryogenesis
Figure 1. Embryology. Copyright Wikimedia. Used with permission. The zygote is formed on day 0 with the fertilization of the ovum with a single sperm in the fallopian tube. This prompts the ovum to complete metaphase II and embryogenesis begins. Over the first week, the blastocyst forms, having undergone cleavage, compaction, differentiation, and cavitation. Implantation then occurs in the uterus on about day 7. Over the following week, the bilaminar disk is formed within the blastocyst. The mesoderm begins to form and spread; during this time, the syncytiotrophoblast and cytotrophoblast form. The syncytiotrophoblast secretes B-hCG. 149
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Figure 2. The three layers created during embryogenesis. Copyright Wikimedia. Used with permission. During the third week of embryogenesis, gastrulation occurs. Three germ layers are formed, incluing the ectoderm, mesoderm, and endoderm. The cranial-caudal axis is formed, along wiht the optic and otic placodes. The upper limb buds appear and the rostral neuropore closes. In the fourth week, the caudal neuropore is closed (this is folate-dependent). The lower limb buds develop at this time. During week five, retinal pigment develops; this is followed by digital rays in week six, midgut herniation in week seven, and growth in body length weeks eight through eleven. The fetus continues to mature over the next two months, and lanugo hairs develop starting at about 20 weeks. The pupillary light reflex is intact starting around week 31. The fetus grows to term over the next two months.
2.2. Embryologic Tissue Derivatives The embryologic tissue derivatives include the ectoderm, mesoderm, and endoderm. The ectoderm is divided into the surface ectoderm and neuroectoderm. The surface ectoderm consists of the epidermis, dermis, anterior pituitary, and lens of the eye. The neuroectoderm includes the central nervous system (including the posterior pituitary, pineal), neural crest, and peripheral nervous system (including the adrenal medulla, APUD cells, melanocytes, and thyroid C cells). The ondontoblasts and pia also come from the PNS. The mesoderm gives rise to the cardiovascular system, Figure 3. Gastrulation. Copyright Pidalka. hematopoietic system, spleen, kidney, adrenal cortex, Used with permission. muscle, bone, and dura. The endoderm gives rise to the lungs, liver, thyroid, parathyroid, thymus, and pancreas. The notochord and nucleus pulposus of intervertebral disk also come from this layer.
2.3. Branchial Apparatus 2.3.1
Branchial Apparatus 1
The branchial apparatus can be divided into six major sections, but not all of them are present at the time of birth. The first apparatus gives rise to a branchial cleft, branchial arch, and branchial pouch. The first branchial cleft is derived from the ectoderm and becomes external auditory meatus. The first branchial arch is derived from the mesoderm and becomes the malleus and incus (dorsal portion), and a mandibular portion (Meckelâ€™s cartilage) that gives rise to the facial bones. All of the facial bones form through endochondral bone formation except the mandible. The mandibular portion also forms muscles of mastication (temporalis, masseter, medial pterygoid, lateral pterygoid) along with two accessory muscles (anterior belly of digastric and mylohyoid), gives rise to the tensor veli palatini and tensor 150
Embryology tympani, the maxillary artery, and is innervated by the mandibular division of the trigeminal nerve (V3). Treacher Collins syndrome can develop due to a defect in this arch and presents with an abnormal external ear, mandibular hypoplasia, and a lower eyelid defect. The Pierre Robin sequence can present with mandibular hypoplasia, cleft palate, eye and ear defects. Two other more common defects also occur: cleft palate which is due to failure of the palatine processes to fuse with the nasal septum, and cleft lip from failure of the maxillary and nasal processes to fuse. First branchial pouch is derived from the endoderm and becomes the middle ear cavity.
2.3.2 Branchial Apparatus 2 Figure 4. Neural crest and neural The second branchial apparatus also includes a cleft, arch, and plate. Copyright Vojtech Dostal. pouch. The second branchial cleft degenerates but may remain as a cervical sinus cyst of the neck if second arch does not completely Used with permission. fuse with epicardial ridge; this leads to fistula formation and is typically treated with excision. Branchial cleft cysts are treated with the Sistrunk procedure and require excision of a portion of the branchial arch derivative, the middle portion of the hyoid bone. The second branchial arch forms the stapes, styloid process, and part of hyoid bone. It also is responsible for the muscles of facial expression, stapedius, stylohyoid, and posterior belly of digastric. It is supplied by the facial nerve (VII). This arch also gives rise to the stapedial artery and hyoid artery. The second branchial pouch gives rise to the palatine tonsil.
Branchial Apparatus 3
The third branchial apparatus forms the third branchial cleft, which may remain as a cervical sinus cyst of the neck, the third branchial arch which forms the greater horn of the hyoid, stylopharyngeus muscle, common carotid artery, and is innervated by the glossopharyngeal nerve (IX), and the third branchial pouch, which forms the inferior parathyroid glands, thymus, and may lead to thymic cysts embedded within the thyroid.
Branchial Apparatus 4
The fourth branchial cleft may remain as cervical sinus cyst of the neck. The fourth branchial arch forms the thyroid, cricoid, and arytenoid cartilage of larynx, cricothyroid, levator veli palatini, and pharyngeal constrictor muscles, the aortic arch and right subclavian artery, and is innervated by the superior laryngeal nerve, a branch of the vagus (X). The fourth branchial pouch forms the superior parathyroid glands and ultimobranchial body (and eventually forms the parafollicular C cells of thyroid). DiGeorge syndrome may arise due to defects in the third and fourth branchial arches. This is due to a defect in chromosome 22, and is also referred to as velocardiofacial syndrome or CATCH 22 syndrome. It leads to Tetralogy of Fallot, cleft palate, learning disorders, hypocalcemia, T-cell immune deficiency, feeding problems, renal defects, hearing loss, seizures, and skeletal defects. It affects approximately 1:1500 babies.
Clinical Review for the USMLE Step 1 2.3.5
Branchial Apparatus 5
The fifth branchial apparatus is completely resorbed during development.
Branchial Apparatus 6
The sixth branchial arch forms the intrinsic muscles of the larynx except the cricothyroid, gives rise to the pulmonary trunk and ductus arteriosus, and is innervated by the recurrent laFigure 5. Monozygotic and dizygotic ryngeal nerve, a branch of the vagus nerve (X). twins. Copyright Wikimedia. Used with permission. 2.4. Twins Monozygotic twins are derived from one zygote that separates. They may be monoamniotic or diamniotic, and monochorionic or dichorionic. One amnion or one chorion means monozygotic. Dizygotic twins are derived from two separate zygotes with independent fertilization and requires two separate amnions, chorions, and placentae. Conjoined twins are monozygotic twins with incomplete separation.
2.5. Neural Plate Tube 2.5.1
Figure 6. Neural plate and growth signals. Copyright Wikimedia. Used with permission.
The neural plate and neural tube are induced by the notochord. It induces the neural groove to involute and form a closed neural tube and is composed of ectoderm. The neural tube eventually gives rise to the CNS. The neural crest cells remain in the dorsal portion and extend to become the PNS.
Neural Tube Defects
Anencephaly occurs from failure of the rostral neuropore to close. It leads to failure to develop the cerebrum with exposed CNS structures at birth and is generally incompat- Figure 7. Embryologic derivatives of the brain. Copyible with life. Encephalocele is due to pro- right Wikimedia. Used with permission. trusion of encephalic membranes through a 152
Embryology skull fissure. This condition is often fatal or presents with severe mental retardation. Spina bifida presents in several forms. Spina bifida occulta is due to failure of the outer portion of vertebral column to close and presents with only a tuft of hair at the site. There is no protrusion of the spinal cord. This is the mildest version of spina bifida and presents with incontinence, slight ataxia, and minor loss of sensation to lower extremities. Meningocele presents with damaged meninges protruding through a vertebral column defect. There is little loss of function. Meningomyelocele has protrusion of meninges and CNS matter through a vertebral column defect with visible cyst formation. It contains nerves and membranes and leads to paralysis and loss of sensation distal to site of damage. There is often hy- Figure 8. Components of the vestibular sysdrocephalus. There is increased risk of spina bifida in tem. Copyright Sapan Desai. Used with perpregnant women taking medications for epilepsy and mission. poor folic acid intake.
Parts of the CNS
The hindbrain, or rhombencephalon, gives rise to the myelencephalon and metencephalon. The myelencephalon gives rise to the medulla, 4th ventricle, and CN VIII, IX, X, XI, XII. The metencephalon gives rise to the pons, cerebellum, 4th ventricle, and CN V, VI, VII, VIII. The mesencephalon is composed of the midbrain, which is the least differentiated part of the mature brain. The mesencephalon includes the tectum, superior colliculus, inferior colliculus, cerebral peduncle, midbrain tegmentum, crus cerebri, substantia nigra, and pretectum. It is also involved with the substantia nigra, basal ganglia. The prosencephalon includes the diencephalon and telencephalon. The diencephalon includes the epithalamus, thalamus, hypothalamus, and subthalamus. It primarily plays a role in sensory and motor information relay between various parts of the Figure 9. Development of the inner ear. Copyright Sapan brain. The telencephalon gives rise to the Desai. Used with permission. cerebrum and also contains limbic system, part of the basal ganglia, corpus striatum, and olfactory bulb. 153
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Figure 10. Stem cells and hair cells of the inner ear. Copyright Sapan Desai. Used with permission.
2.6. Development 2.6.1
of the Inner
There are three distinct germ lines that lead to the development of the inner ear. The ectoderm forms the external auditory meatus (cleft 1); the mesoderm forms the malleus and incus from arch 1, stapes from arch 2, tensor tympani from arch 1, and stapedius muscle from arch 2. The endoderm creates the middle ear cavity, Eustachian tube, and mastoid air cells from pouch 1.
Stem Cells of the Inner Ear
The supporting cells of the inner ear may regress to become precursor stem cells, which in turn can undergo mitosis and differentiation to form hair cells and more supporting cells
The inner ear is composed of six sensory organs on each side: the utricular macula, saccular macula, cristae ampullares (3X), and cochlea. The first five are involved with the vestibular system and are responsible for horizontal, vertical, and angular acceleration. The cochlea is involved with the auditory system and is responsible for hearing. A variety of mechanosensory hair cells convert ion currents into 154
Anatomy nerve impulses; their location on these sensory organs is interpreted by the brain into positional and auditory information.
2.7. Development 2.7.1
The optic placode forms from the neural ectoderm that later gives rise to the diencephalon. The optic stalk and optic sulcus forms from the optic placode, the optic vesicles form from the sulcus, and the optic neural crest cells begin to form which will give rise to CN II. The optic cup forms which will later become the retina; the rim will become the iris. The lens placode develops from surface ectoderm. Maturity occurs over the next few weeks with completion of innervation and terminal differFigure 11. Anatomy of the eye. Copyright R.H. Castilentiation of structures. hos. Used with permission.
The major structures of the eye include the lens, cornea, iris, retina, and macula. Light converges onto retina, through the cornea. The iris is the colored ring that controls size of pupil. The retina is the sensory neuroepithelium with rods and cones; the highest concentration of cones is the macula.
3. Anatomy 3.1. Vascular Supply 3.1.1
The aorta arises from the left ventricle, gives off the right and left coronary arteries, and travels 5 cm to the sternum, where it becomes the arch of the aorta. At the apex, it gives rise to the brachiocephalic, left common carotid, and left subclavian arteries before continuing as the descending aorta. The brachiocephalic artery, occasionally referred to as the innominate artery, gives rise to the right subclavian and right common carotid arteries. At the distal portion of the arch is the ligamentum arteriosum, which shunts blood from the pulmonary artery to the aorta during ontogeny. Crossing anterior to the arch is the left vagus nerve, which sends the left recurrent laryngeal nerve around the arch and back up to the neck. The right recurrent laryngeal nerve hooks around the right subclavian artery as it comes off the brachiocephalic trunk.
Common Carotid Artery
The left common carotid artery arises as a direct branch of the aortic arch, while the right common carotid artery is a branch of the brachiocephalic artery as it gives rise to the right subclavian. The left 155
Clinical Review for the USMLE Step 1 common carotid artery is closely associated with the recurrent laryngeal nerve and thoracic duct, and eventually travels with the vagus and phrenic nerves as it goes more superior. The right common carotid artery has a similar relationship with these two nerves in the neck. Within the neck, the common carotid artery is enclosed by the carotid sheath, an extension of the deep cervical fascia. The sheath also includes the internal jugular vein and vagus nerve, and may occasionally include the descending branch of the hypoglossal nerve. The common carotid artery divides into the external and internal carotid arteries at the upper border of the thyroid cartilage, Figure 12. Aorta and other major vessels from the heart. Copy- at the level of the fourth cervical verright Mikael Haggstrom. Used with permission. tebra. The common carotid artery rarely has other branches, but they may occasionally include the thyroid arteries (superior and inferior), pharyngeal artery, and vertebral artery.
External Carotid Artery
The external carotid artery bifurcates to form the maxillary artery and superficial temporal artery within the parotid gland. It is anterior and medial to the internal carotid artery. Careful dissection is required as it is crossed by the hypoglossal nerve near its superior extent. The glossopharyngeal nerve is located posterior to this artery. The external carotid artery gives off the superior thyroid artery, facial artery, occipital artery, posterior auricular artery, and the two terminal branches discussed above.
Internal Carotid Artery
The Bouthillier classification is used primarily by neurosurgeons to divide the internal carotid artery into seven distinct segments. The internal carotid artery at its take off contains the carotid bulb. The carotid nerve plexus is intimately associated with the internal carotid and emanates from the superior cervical ganglion. The internal carotid artery is the chief supply to the circle of Willis anastomosis Figure 13. Carotid artery. Adapted from Grayâ€™s that supplies blood to the brain. Anatomy. Used with permission. 156
The carotid bifurcation is an important neurovascular structure. Within the bifurcation near the internal carotid artery, the carotid bulb contains mechanoreceptors and baroreceptors. Stimulation leads to bradycardia and vasodilatation via a parasympathetic reaction. The carotid sinus contains chemoreceptors which serve as detectors for CO2 and acidosis. Stimulation here leads to a sympathetic response.
The vertebral artery is the first branch of the subclavian artery and provides extensive collateral blood flow to the brain via the circle of Willis. The vertebral artery travels posterior to the transverse process of C6, then enters the transverse foramina until it reaches C1. It then travels posterior to the arch of the atlas and penetrates the skull through the foramen magnum. Anterior to the vertebral arteries at their takeoff are the internal jugular veins and inferior thyroid artery. The inferior cervical sympathetic ganglion is in close proximity to the artery when it is located proximal to the transverse processes. A portion of the vertebral artery may be uncovered within the suboccipital triangle, bound by the superior oblique, inferior oblique, and rectus capitis posterior major muscle. The suboccipital nerve is in close proximity to the vertebral artery at this point. The left vertebral artery tends to be somewhat larger and have higher flows compared to the right.
Circle of Willis
The circle of Willis provides a redundant blood supply to the entire brain via two paired arteries derived from branches of the aorta. The major blood supply comes from the paired internal carotid arteries and is supported by the paired vertebral arteries. Despite this rich anastomosis, the branches emanating from the circle of Willis tend to be end arteries. Hence, even brief disruptions in blood supply to these targets, such as via emboli or severe Figure 14. Circle of Willis. Copyright R.H. Castilhypotension, can lead to ischemia and stroke. hos. Used with permission.
3.1.8 the Brain
Blood Supply Targets in
The anterior choroidal artery supplies the optic tract, amygdala, LGN, hippocampus, internal capsule, and thalamus. The anterior cerebral artery supplies the frontal lobes, medial aspect of parietal and temporal lobes. The middle cerebral artery is among the most common pathways for stroke, and supplies the frontoparietal somatosensory cortex. The posterior cerebral artery distributes blood to the occipital 157
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Figure 15. Divisions of the brain. Copyright Sapan Desai. Used with permission. and inferior temporal lobes, and the hippocampus. The posterior communicating artery is one of the few anastomotic branches in the brain. The anterior spinal artery supplies the ventral portion of spinal cord, while the posterior spinal artery supplies the dorsal portion of spinal cord. The vertebral artery goes to the medulla. The anterior inferior cerebellar artery goes to the anterior inferior cerebellum and caudal pons. The posterior inferior cerebellar artery goes to the inferior cerebellum. The superior portion of the cerebellum is supplied by the superior cerebellar artery. The inner ear is supplied by the internal auditory artery.
The venous drainage of the brain begins with the cerebral veins, which empty into the dural venous sinuses, which ultimately empty into internal jugular veins. Another means of emptying is via the emissary veins. The basilar venous plexus communicates with the vertebral venous plexus. The cerebral venous system is composed of a valveless system with numerous anastomoses.
3.2. Vascular Supply 3.2.1
The blood supply to the upper extremity begins as the subclavian artery, a direct branch off the aorta to the left extremity and a branch of the brachiocephalic trunk for the right extremity. The first part of the 158
Anatomy subclavian artery travels to the medial border of the anterior scalene muscle, and is located anterior to the vagus and phrenic nerves. The artery is posterior to the sternohyoid and sternocleidomastoid muscles, and gives rise to the vertebral artery, internal thoracic artery, and thyrocervical artery. The second part of the subclavian artery travels posterior to the anterior scalene muscle and gives rise to the costocervical trunk. At this location proximal to the clavicle, the subclavian vein is located inferior and anterior to the subclavian artery. The third part of the subclavian artery commences at the lateral border of the anterior scalene muscle and becomes the axillary artery at the lateral Figure 16. Subclavian and axillary artery. Adapted from border of the first rib; this part gives Grayâ€™s Anatomy. Used with permission. rise to the dorsal scapular artery.
The axillary artery is divided into three parts based on its relationship to the pectoralis minor muscle. The first part of the axillary artery is proximal, the second part posterior, and the third part lateral to the pectoralis minor. The second part of the axillary artery is intimately associated with the brachial plexus cords. The superior thoracic artery arises from the first part, thoracoacromial and lateral thoracic arteries from the second part, and the subscapular and two circumflex arteries to the head of the humerus from the third part. Due to an anastomosis between the suprascapular artery and dorsal scapular artery, the axillary artery may be clamped proximal to the subscapular artery. The axillary artery supplies the upper arm and becomes the brachial artery at the border of the teres major.
The brachial artery divides into the radial and ulnar arteries at the cubital fossa. The brachial artery travels with the median nerve for much of its course. Several important collateral vessels are given off from the brachial artery, including the deep brachial, and superior and inferior ulnar collateral arteries. The deep brachial artery has branches that anastomose with recurrent branches emanating from the radial artery along with the inferior ulnar collateral artery. Due to its close proximity to the humerus, a fracture of this bone can compromise the brachial artery.
The radial artery is located in the anterior and lateral compartment of the forearm. It ends as the deep palmar arch after passing between the dorsal interosseus muscle and through the anatomic snuff box. The Allen test is done prior to using the radial artery for access as part of an arteriovenous fistula or insertion of an arterial line. This test is done by elevating the hand and making a fist, occluding the radial and ulnar arteries, opening the hand and confirming that it has pallor, then releasing the ulnar artery pressure to verify satisfactory collateral flow to the hand. The ulnar artery is typically the dominant artery to the hand; if the Allen test is abnormal, it implies that the radial artery is the dominant supply 159
Clinical Review for the USMLE Step 1 and should not be used to avoid vascular compromise to the hand.
The ulnar artery travels along the medial forearm and terminates as the superficial and deep palmar arch near the pisiform bone. The artery is proximal to the median nerve at its take off.
The veins of the upper extremity are divided into a superficial and deep distribution. The superficial distribution starts as the dorsal plexus of the hand and eventually gives rise to two major veins, the cephalic and basilic. The cephalic vein is lateral, while the basilic is medial. The major vein in the deep distribution is the brachial vein, which travels with the brachial artery. The brachial vein eventually joins the basilic at the lateral border of the teres minor; together they join the cephalic vein to form the axillary vein.
3.3. Vascular Supply to the Abdomen and Pelvis 3.3.1
The abdominal aorta gives rise to the major visceral arteries and eventually supplies blood to the lower extremity via the terminal common iliac artery branches. It begins at the diaphragm at T12 to give off the celiac trunk at T12, superior mesenteric and suprarenal arteries at L1, renal and Figure 17. Major arteries of the arm. gonadal arteries at L2, inferior mesenteric artery at L3, and Adapted from Grayâ€™s Anatomy. Used the common iliac bifurcation at L4. Various lumbar arteries with permission. also arise between L1 and L4. Collaterals around the aorta include the internal thoracic artery, which becomes the superior epigastric artery after it gives off the musculophrenic artery at the diaphragm; the superior epigastric anastomosis with the inferior epigastric artery, a branch of the external iliac artery. There are also collaterals between the inferior mesenteric artery and internal pudendal artery, and occasionally collaterals between the lumbar arteries and the internal iliac artery.
The celiac artery supplies the stomach, liver, duodenum, pancreas, and spleen. Its branches include the left gastric artery, splenic artery, and common hepatic artery. The splenic artery gives rise to six short gastric arteries, left gastroepiploic artery, and continues on to supply the spleen. The common hepatic artery gives rise to the gastroduodenal artery, then becomes the proper hepatic artery. The gastroduodenal artery becomes the anterior superior and posterior superior pancreaticoduodenal arteries and the right gastroepiploic artery. The proper hepatic artery gives off the cystic artery before dividing into the 160
Anatomy right and left hepatic arteries. In a quarter of all individuals, the left hepatic artery arises as a branch off the left gastric artery. In one in ten people, either a branch of or the entire common hepatic artery arises directly from the SMA. A small percentage of patients may have the hepatic artery arise directly from the aorta. The right hepatic artery may be replaced and arise entirely from the SMA; alternatively, an accessory right hepatic artery may arise from the SMA or aorta and complement flow from the natural right hepatic artery arising from the proper hepatic trunk.
3.3.3 Superior Mesenteric Artery The superior mesenteric artery gives rise to the anterior inferior and posterior inferior pancreaticoduodenal arteries, the jejunal and ileal branches, Figure 18. Abdominal aorta. Adapted from Grayâ€™s Anatomy. the ileocolic artery, and the right and Used with permission. middle colic arteries. The ileocolic artery also supplies the cecum.
Inferior Mesenteric Artery
The inferior mesenteric artery gives rise to the left colic artery, sigmoid arteries, and superior rectal artery. Loss of this artery may occur as part of a graft placement to treat an abdominal aortic aneurysm; sufficient collateral flow must be confirmed to avoid a potential compromise of the sigmoid colon.
3.4. Vascular Supply 3.4.1
to the Lower
The common iliac artery arises at L4 at the bifurcation of the aorta, and travels about 4 cm to the pelvic brim, where it divides into the internal and external iliac arteries. The internal iliac artery, frequently referred to as the hypogastric artery, gives rise to a plethora of branches that supply the pelvis, gonads, rectum, and anus. During open and endovascular repair of abdominal aortic aneurysms, preservation of one hypogastric artery is sufficient to preserve pelvic perfusion due to extensive collateralization. This includes anastomosis between the superior and middle rectal arteries, lumbar and iliolumbar arteries, and the medial and lateral sacral arteries. The external iliac artery gives rise to the inferior epigastric artery (discussed above), deep circumflex artery, and continues as the femoral artery at the inguinal ligament. 161
Clinical Review for the USMLE Step 1 3.4.2
The common femoral artery gives rise to the deep femoral artery superiorly within the thigh and continues as the femoral artery. The deep femoral artery forms a cruciate anastomosis around the femoral bone and provides collateral flow via anastomosis with recurrent branches below the popliteal fossa.
Figure 19. Major arteries of the leg. Copyright M.C. Strother. Used with permission.
The popliteal artery is the continuation of the femoral artery after it passes through the adductor canal and hiatus (also known as Hunterâ€™s canal). After forming a collateral supply around the knee, the popliteal artery bifurcates into the anterior tibial artery and the tibial-peroneal trunk. This trunk then quickly divides into the peroneal artery and posterior tibial artery. Congenital deformity of the muscle or tendon insertions into the popliteal fossa can lead to compression of this artery, causing popliteal artery entrapment syndrome (discussed below). 162
Tibial Artery and Lower Branches
The anterior tibial artery supplies the anterior compartment of the leg and dorsum of the foot as the dorsalis pedis. A number of recurrent branches are given off, which help provide a small collateral flow with branches of the deep femoral artery. The dorsalis pedis artery is anterior to the ankle and lateral to the extensor hallucis longus tendon. It may be naturally absent in up to 2% of patients. The posterior tibial artery supplies the posterior compartment of the leg and travels posterior and inferior to the medial malleolus. The peroneal artery supplies the lateral compartment and anastomosis with the anterior tibial artery.
The venous drainage of the lower extremity is much more extensive than that of the upper extremity, and also more susceptible to venous disorders due to its dependent position. Like the upper extremity, the venous system of the leg is divided into a superficial and deep system. The superficial veins of the leg start with the dorsal venous arches on the feet, which form the great and small saphenous veins. Various perforator branches and a posterior arch vein join the saphenous veins in the distal lower extremity. As they travel superiorly, the veins of Giaccomini and the anterolateral veins of the thigh join the great saphenous vein. A significant junction is present in the groin, where the circumflex iliac vein, inferior epigastric vein, external pudendal vein, and great saphenous vein come together at the saphenofemoral junction. This eventually forms the femoral vein. The great saphenous vein is more anterior and medial, while the small saphenous is posterior and somewhat lateral. The deep veins of the leg include the soleal sinusoids, which join the peroneal, and anterior and posterior tibial veins to form the popliteal vein. The popliteal vein joins the deep femoral vein to form the common femoral vein. After receiving inflow from the superficial system, the common femoral vein continues as the external iliac vein, then common iliac vein (after joining the internal iliac vein), and inferior vena cava.
3.5. Cranial Nerves 3.5.1
CN I - Olfactory Nerve
The olfactory nerve is cranial nerve one. It is a sensory nerve that originates from the telencephalon with its nucleus located in the anterior olfactory nucleus. Its function is to transmit smell from the olfactory foramina found in the cribriform plate, which is located in the ethmoid.
CN II - Optic Nerve
The optic nerve is cranial nerve two and is also a pure sensory nerve. Its nuclei are located in the ganglion cells of the retina, but it originates from the diencephalon. Its function is to transmit visual information via the optic canal. There are a variety of disorders that affect the optic nerve. Patients with trauma or mass effect upon the optic nerve have a presentation that depends upon the site of injury. Damage to the fibers proximal to the optic chiasm causes total loss of vision on the ipsilateral side to the damage, as the fibers have not yet crossed. 163
Clinical Review for the USMLE Step 1 Damage to the optic nerve at the optic chiasm leads to bitemporal hemianopsia - that is, loss of vision on the lateral side of both eyes. The optic chiasm is located near the pituitary gland and pituitary hyperplasia or tumors can have a mass effect here. Damage to the optic nerve fibers distal to the chiasm (that is, after they have crossed at the chiasm) leads to contralateral vision loss in one visual field only. The specific loss depends on exactly which fibers are damaged.
CN III - Oculomotor Nerve
The oculomotor nerve is a motor nerve that originates in the anterior midbrain. Its nuclei are located in the oculomotor nucleus and Edinger-Westphal nucleus. It supplies all major muscles of the eye except the superior oblique and lateral rectus. It also innervates the pupillary sphincter muscle and ciliary body muscles. The nerve travels to the Figure 20. Cranial nerves and their origination brain via the superior orbital fissure. points. Copyright D.W. Stultz. Used with permisThe Edinger-Westphal nucleus supplies the iris sion. constriction muscles and is a parasympathetic nucleus. Inability to constrict a pupil occurs with certain diseases such as syphilis and may be traced back to destruction of this nucleus. Multiple sclerosis and trauma can also lead to paralysis of the oculomotor nerve. The swinging flashlight test can be used to sequentially shine a bright light in both eyes. Both eyes should accomodate to the light no matter which eye has the light in it. However, damage to one part of the tract (such as demyelination secondary to multiple sclerosis) will lead to only one eye to react to the bright light.
CN IV - Trochlear Nerve
The trochlear nerve is the fourth cranial nerve and is a motor nerve. It supplies the superior oblique muscle of the eye and is responsible for its lateral rotation. It originates from the midbrain Figure 21. Optic nerve and chiand its nucleus is the trochlear nucleus. asm. Adapted from Grayâ€™s Anatomy. Used with permission.
CN V - Trigeminal Nerve
The trigeminal nerve is a three part cranial nerve that has both motor and sensory components. It originates from the pons and has several nuclei, including a sensory trigeminal nucleus, spinal trigeminal nucleus, mesencephalic trigeminal nucleus, and trigeminal motor nucleus. Its motor component inner164
Figure 22. Major cranial nerves and their ganglia. Sympathetic and parasympathetic fibers labeled. Copyright NetterImages. Used with permission. vates the muscles of mastication. Its sensory components supply the face via three branches: V1 is the ophthalmic branch and goes to the upper face via the superior orbital fissure; V2 is the maxillary branch and innervates the middle of the face via the foramen rotundum; finally, V3 is the mandibular branch and innervates the lower face via the foramen ovale. 165
Clinical Review for the USMLE Step 1 A stroke to the medulla can lead to a condition known as Wallenberg syndrome. In this case, pain and temperature sensory loss can occur on one side of the face, but affect the contralateral side of the body. This is because the sensory fibers that come from the face via the trigeminal nerve and go to the ascending spinothalamic tract do not cross, while those from the body have already decussated. The touch and positional information from the face is sent to the ventral posteromedial nucleus (VPM) of the thalamus, while similar information from the rest of the body is sent to the ventral posterolateral nucleus (VPL). This information is then further processed by the sensory cortex located in the postcentral gyrus in the parietal lobe. This sensory map can be portrayed in the form of a homunculus, which has an exaggerated face and hands. Pain and temperature is also sent to the same nu- Figure 23. Homunculus. Copyright Wikimedia. clei as touch and positional information. However, Used with permission. as this information may lead to automatic responses, it is also distributed to the various other nuclei for automatic processing.
CN VI - Abducens Nerve
The abducens nerve is cranial nerve six and controls the lateral rectus muscle to abduct the eye. This nerve originates from the pons and is controlled by the abducens nucleus; it travels to the lateral rectus muscle via the superior orbital fissure. The abducens nerve is the most commonly affected cranial nerve in patients with tuberculosis; this can lead to difficulty with conjugate gaze, internuclear ophthalmoplegia (INO) and generation of saccades. Normally, conjugate gaze is mediated by the medial longitudinal fasciculus (MLF), which coordinates the actions of CN III, IV, and VI.
CN VII - Facial Nerve
The facial nerve is the seventh cranial nerve and is a combination of a motor and sensory nerve. It is derived from the pons at the cerebellopontine angle, with nuclei located in the facial nucleus, solitary nucleus, and superior salivary nucleus. The facial nerve innervates the facial muscles and also the posterior belly of the digastric and stapedius muscles. The sensory portion includes taste from the anterior 2/3s of the tongue via the chorda tympani; the ganglia for these nerves are found in the geniculate ganglion. Parasympathetic fibers via the greater petrosal nerve innervate all of the salivary glands except the parotid gland; the parotid gland is supplied by the glossopharyngeal nerve. The facial nerve travels through the stylomastoid foramen after traveling through the internal acoustic canal. Viral infection can lead to Bellâ€™s palsy, which presents as partial paralysis of the facial nerve. Bellâ€™s palsy can also be secondary to Lyme disease. Viral infections can be treated with a prednisone taper, while Lyme disease should be treated with doxycycline. 166
CN VIII - Vestibulocochlear Nerve
The vestibulocochlear nerve is the eighth cranial nerve. It is divided into the vestibular portion and the auditory portion. The vestibular nerve innervates five sensory organs responsible for balance, including the utricular macula, saccular macula, and three cristae ampullares. The two maculae are responsible for linear acceleration, while the three cristae ampullares sense angular acceleration. The auditory division of the nerve innervates the cochlea and is responsible for sensing sound. As discussed previously, these end organs conduct mechanosensory information into electrical signals through the action of potassium currents. The precise location of the sensory hair cells that convert this information is coded into positional or frequency information that tells the brain where the body is moving in three dimensions (for the vestibular Figure 24. Facial nerve. Adapted from Grayâ€™s Anatosystem) or what frequency of sound is being my. Used with permission. heard (for the auditory system). The vestibulocochlear nerve emanates lateral to the facial nerve at the cerebellopontine angle. Its nuclei are located in the vestibular nuclei and cochlear nuclei. It travels in the internal acoustic canal with the facial nerve.
3.5.9 CN IX Glossophar yngeal Nerve The glossopharyngeal nerve is the ninth cranial nerve and has both sensory and motor components. It comes from the medulla with nuclei located in the nucleus ambiguus, inferior salivary nucleus, and solitary nucleus. It is responsible for taste from the posterior 1/3 of the Figure 25. Vestibulocochlear nerve. Copyright Sapan Desai. Used with tongue, salivary innervation permission. 167
Clinical Review for the USMLE Step 1 to the parotid gland, and motor innervation to the stylopharyngeus. It travels via the jugular foramen.
CN X - Vagus Nerve
The vagus nerve is the tenth cranial nerve and has both motor and sensory functions. It emanates from the medulla and has nuclei in the nucleus ambiguus, dorsal motor nucleus of the vagus, and solitary nucleus. The vagus nerve is motor to the laryngeal and pharyngeal muscles. It also supplies all major organs via parasympathetic fibers. All of the muscles of the larynx are supplied by the recurrent laryngeal nerve except the cricothyroid muscle; this is supplied by the external laryngeal branch of the vagus nerve. Damage to the recurrent laryngeal nerve can occur during thyroid surgery and lead to changes in voice; in more serious cases, it can lead to paralysis of the vocal folds and difficulty swallowing. Bilateral damage can lead to inability to protect the airway. The parasympathetic function of the vagus nerve upon the heart leads to lowerFigure 26. Depolarization of hair cells and ion curing of the heart rate. This occurs via the release of acetylcholine. A feedback loop rents. Copyright Sapan Desai. Used with permission. located near the carotid bifurcation works via the carotid sinus to regulate the heart rate. A baroreceptor here reacts to increased blood pressure by activating the vagus nerve to lower the heart rate; as a result, massage of the carotid sinus can lead to syncope in susceptible individuals.
CN XI - Spinal Accessory
The spinal accessory nerve is a motor nerve that innervates the trapezius and sternocleidomastoid muscles. Its nuclei are located in the nucleus ambiguus and spinal accessory nucleus. It travels via the jugular foramen.
CN XII - Hypoglossal Nerve
Figure 27. Major distal cranial nerves and their The hypoglossal nerve is a motor nerve that inner- ganglia. Adapted from Grayâ€™s Anatomy. Used vates all of the muscles of the tongue except the pala- with permission. 168
Anatomy toglossus (which is innervated by the vagus nerve). It emanates from the medulla and has its nucleus in the hypoglossal nucleus. It travels via the hypoglossal canal. Damage to this nerve can occur with carotid artery surgery and can lead to difficulty with swallowing and speech.
3.6. Brain Nuclei 3.6.1
The medulla is responsible for the autonomic outflow to the heart and lungs, autonomic outflow to the spinal cord, sound localization, sneezing, coughing, swallowing, and suckling. Through this autonomic outflow, it controls involuntary functions including the heart rate, blood pressure, and respiration. Motor fibers cross at the pyramidal decussation of the medulla. Sensory information including proprioception, pain, deep touch, and vibration from the middle and lower portion of the body travel to the fasciculus gracilis. Similar information from the upper body travels to the cuneate fasciculus. The inferior olivary nucleus helps to coordinate Figure 28. Cross section of the brain through the medulla. Adapted from Grayâ€™s Anatomy. Used with permission. movement.
The pons regulates autonomic outflow throughout body. It also serves as a sensory relay between the cerebellum and cerebrum. It generates the impulses that convert inspiration to expiration; at night, it is responsible for dreaming. It contains nuclei for the trigeminal sensory nucleus, and nuclei for cranial nerves VI through VIII. Central pontine myelinolysis can occur when correcting hyponatremia too quickly. Administration of hypertonic saline in this condition can lead to rapid swelling of the brain, necrosis of neurons, and cerebral hemorrhage. With the colocation of nuclei that help control eye movements, motor function, and the vestibular nuclei, the pons works to coordinate movement with motion of the eyes and remainder of the body. It also serves as a nexus for hearing, taste, and sensorimotor for the face. Destruction of the pons can lead to locked-in syndrome where higher order consciousness remains fully intact, but the ability to communicate with the outside world is destroyed with the exception of some eye movements controlled by the oculomotor nerve.
The cerebellum plays a major role in coordinating motor functions by contributing to precise and ac169
Clinical Review for the USMLE Step 1 curate movements. Defects in the cerebellum can lead to dysfunction in fine motor control and motor learning. The cerebellum is linked with multiple brain nuclei via a series of tracts, including the motor cortex and spinocerebellar tract. The cerebellum contains two major types of neurons, known as granule cells and Purkinje cells; the cerebellum has more cells than the rest of the brain combined. These cells are distributed among several major regions of the cerebellum. The flocculonodular lobe connects with the vestibular nuclei to coordinate balance and proprioception. The spinocerebellum helps to coordinate fine motor function via the spinocerebellar tract. The cerebrocerebellum helps to plan future movements and ensure that transitions from one movement to another are smooth. Two additional zones help to synchronize movement: the intermediate zone compares intended motor activity with actual motor activity, while the lateral zone plays a role in body posture information integration. The cerebellum contributes to the cerebral peduncles along with the cortex and spinal cord. The cerebral peduncle contains the corticospinal tract and corticobulbar tract and helps to relay motor fibers to various thalamic nuclei. It includes the midbrain, crus cerebri, substantia nigra, and pretectum.
The epithalamus is a portion of the diencephalon and connects the limbic system to the thalamus and other parts of the brain. It includes the pineal gland, which is responsible for the secretion of melatonin and helps to create a sense of day and night through diurnal variation. Melatonin also functions as an antioxidant, activates the immune system, and regulates hunger and thirst.
The thalamus is also a part of the diencephalon and serves as a relay system to transmit sensory information to the cortex. It modulates signals going to and from the cortex. The functions of the thalamus
Figure 29. The origination of the vestibulocochlear nerve and major nuclei of the brain related to the eighth cranial nerve. Copyright Sapan Desai. Used with permission. 170
Anatomy can be divided into a series of nuclei that control various functions: •
Anterior – memory formation
Dorsomedial – emotional behavior
Centromedian – basal ganglia modulation
Ventral anterior – motor relay facilitates movement
Ventral lateral – motor relay facilitates movement
Ventral posterolateral – somatosensory relay from body from ALS and DC/ ML system
Ventral posteromedial – somatosensory relay from face via trigeminothalamic tract; also includes taste
Lateral dorsal – sensory and emotional integration
Lateral geniculate nucleus – visual relay
Medial geniculate nucleus Figure 30. Nuclei of the thalamus. Copyright Madhero88. Used – auditory relay with permission.
Pulvinar – sensory integration
Reticular – arousal, sleep, reticular activation
The hypothalamus is a neuroendocrine organ that helps to convert neuronal signals into endocrine modulators that control the pituitary gland. It is also a part of the diencephalon and controls body homeostasis, maintains temperature, hormone levels, osmolarity, coordinates autonomic nervous system activity, and maintains proper sympathetic and parasympathetic outflow. Like the thalamus, the hypothalamus can also be divided into a series of nuclei that serve discrete functions. The medial preoptic nucleus controls the parasympathetic nervous system and releases GnRH. The supraoptic nucleus releases oxytocin and vasopressin. Damage to this nucleus can lead to diabetes insipidus. The suprachiasmatic nucleus also helps to release vasopressin, and projects to the pineal gland to help control circadian rhythms. The paraventricular nucleus releases oxytocin, vasopressin, and cortcotropin-releasing hormone (CRH). The anterior nucleus is larger in male heterosexuals and is thought to control sexual preference. It also controls temperature regulation. 171
Clinical Review for the USMLE Step 1 The dorsomedial nucleus inhibits eating and drinking and also regulates the blood pressure and heart rate. Damage leads to hyperphagia. The ventromedial nucleus plays a role in satiety. The arcuate nucleus is responsible for dopamine release to control prolactin secretion; it is also involved in appetite. The lateral nucleus plays a role in thirst and hunger. The posterior nucleus regulates the response to cold and controls sympathetic outflow. The mammillary bodies are part of the limbic system and are involved in memory formation and retrieving memory.
The subthalamus is a portion of the diencephalon responsible for efferent outflow to the striatum. It receives flow from the substantia nigra and striatum.
Overview The basal ganglia are a group of nuclei that connect the thalamus to the forebrain. The primary function of this group of nuclei is to coordinate complex executive tasks while inhibiting other impulses. Diseases that affect the basal ganglia therefore lead to disinhibition and problems with motor coordination; examples include Parkinson’s disease, Huntington’s disease, and Tourette’s syndrome. The basal ganglia use a variety of neurotransmitters.
Striatum The largest part of the basal ganglia is the striatum, composed of the caudate and putamen, and separated by the internal capsule. The majority of the neurons within the striatum are inhibitory (and therefore use GABA as their primary neurotransmitter). The striatum links to the cortex and helps to coordinate the sensorimotor aspects of decision-making. Destruction of the dopaminergic innervation to here and the substantia nigra occurs in Parkinson’s disease. Atrophy occurs in the striatum in Huntington’s disease.
Globus Pallidus The globus pallidus is divided into an internal segment and external segment. Like the striatum, these neurons are also typically inhibitory and use GABA as their primary neurotransmitter. The external segment receives motor information from the striatum, then forwards impulses to the subthalamic nucleus where excitatory impulses are produced. The internal segment also receives information from the striatum, but functions via both a direct and an indirect pathway.
Subthalamic Nucleus In contrast to the remainder of the basal ganglia, the subthalamic nucleus has primarily excitatory neurons that work via glutamate. The subtahalmic nucleus works with the indirect pathway to generate stimulatory impulses to the substantia nigra.
Direct and Indirect Pathway Figure 31. Facing page. The basal ganglia and their interconnections with other parts of the brain. Neurotransmitters are also noted. Copyright Mikael Haggstrom. Used with permission. 172
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Figure 32. Illustration of the interconnections of the basal ganglia. Copyright Wikimedia. Used with permission. The direct pathway has connections to the internal segment of the globus pallidus directly from the striatum. The indirect pathway functions via the external segment of the globus pallidus, which sends impulses to the internal segment via the substantia nigra. The direct pathway sends stimulatory impulses from the cortex to the striatum. The striatum sends inhibitory impulses to inhibitory neurons in the substantia nigra; this leads to disinhibition of the thalamus, which feeds back to the cortex and sends stimulatory information. The result is a hyperkinetic state in the motor system. With the direct pathway, there is net disinhibition of the thalamus. The indirect pathway starts with stimulatory information from the Figure 33. Copyright Wikimecortex, which activates inhibitory neurons in the striatum. This leads dia. Used with permission. to disinhibition of the external segment of the globus pallidus, which leads to stimulation of the subthalamic nucleus and inhibition of the substantia nigra. The thalamus is inhibited, which feeds back to the cortex and leads to inhibition of the motor system. With the indirect pathway, there is net inhibition of the thalamus due to more GABAergic pathways in the system. 174
The substantia nigra is a portion of the midbrain that is involved in attention and movement, and in reward pathways. It is abnormal in Parkinsonâ€™s disease. The pars reticulata contains inhibitory neurons similar in function to the internal segment of the globus pallidus. The pars compacta plays an important role in motor control and is the primary area of dysfunction in Parkinsonâ€™s disease.
The amygdala is a sexually-dimorphic nucleus that shrinks upon castration. It plays a key role in emotion-based memory, anxiety, phobias, fear conditioning, drug addiction, autism, and depression.
The hippocampus is a series of neurons that are a part of the limbic system. It is found in the temporal lobe and is involved in memory and navigation. It is commonly damaged in Alzheimer disease. The hippocampus plays an important role in new memory formation, especially episodic memory and declarative memory. Damage leads to anterograde and retrograde amnesia. Anterograde amnesia is the inability to form new memories following an insult or trauma. It occurs in Wernicke-Korsakoff syndrome and direct damage to brain nuclei. Retrograde amnesia is the inability to recall old memories prior to insult or trauma, and temporarily occurs following ECT for depression. It occurs in direct damage to brain nuclei.
Figure 34. Cross section of the midbrain showing key nuclei and pathways. Copyright Wikimedia. Used with permission. 175
Clinical Review for the USMLE Step 1 3.6.12
Ventral Tegmental Area
The ventral tegmental area plays a major role in connecting mesolimbic pathway to the nucleus accumbens. It uses a series of dopaminergic pathways and creates a pleasure pathway with incentive-based motivation. It modulates the mesocortical pathway, which connects the ventral tegmental area to the frontal lobe. Defects in the ventral tegmental area are tied to schizophrenia. The ventral tegmental area is directly targeted by cocaine and plays a role in addiction.
The frontal lobe plays a major role in impulse control, judgement, language, memory, motor function, problem-solving, sexual behavior, socialization, spontaneity, planning and coordination of behavior, cognitive maturity, and speech. Our personality is controlled by the frontal lobe. Speech production is controlled by Broca’s area. The precentral gyrus, located on the posterior portion of the frontal lobe, serves as the primary motor cortex.
The parietal lobe integrates sensory information and helps manipulate objects in three dimensions. It is responsible for visuospatial processing. The somatosensory gyrus is located on the anterior portion of the parietal lobe.
The temporal lobe serves as an auditory relay from the cochlea and has an auditory association area. It helps with the comprehension of speech through Wernicke’s area. The arcuate fasciculus connects Wernicke’s with Broca’s. The temporal lobe also has a facial and visual recognition system, is responsible for episodic and declarative memory, and is also the location for the hippocampus and amygdala.
The occipital lobe is the visual association cortex and has the reading and writing centers located within.
Spinal Cord Organization
Dorsal Column-Medial Lemniscus The dorsal column-medial lemniscus pathway is a sensory pathway responsible for fine touch. It goes from the skin to thalamus, then to the cortex. It uses Meissner’s corpuscles in the dermis for sensation. This tract crosses in the brainstem.
Spinothalamic Tract The spinothalamic tract is responsible for pain, temperature, itch, and crude touch. It is a part of the anterolateral system and crosses in the spinal cord.
Corticospinal Tract The corticospinal tract is the motor outflow from the brain. The lateral corticospinal tract crosses in the pyramids, while the medial corticospinal tract crosses at the spinal cord root level. 176
Figure 35. Major tracts of the spinal cord. Copyright Mikael Haggstrom. Used with permission.
Vestibulospinal Tract The medial vestibulospinal tract has a bilateral projection to the cervical cord and is responsible for head adjustments in response to vestibular stimuli. The lateral vestibulospinal tract is an uncrossed projection through the ipsilateral spinal cord and helps to maintain balance and posture.
Spinal Reflex The primary spinal reflex is the deep tendon reflex. The most common example of this is the â€œkneejerkâ€? reflex that tests the stretch receptors. A spinal cord arc occurs with motor neurons leading to a closed loop reaction that does not involve the brain at all.
3.7. Triangles 3.7.1
Anterior Cervical Triangle
Overview The anterior cervical triangle is bound by the sternocleidomastoid muscle laterally, the inferior border of the mandible superiorly, and the anterior midline of the neck medially. The anterior cervical triangle may be subdivided into four smaller triangles: the submandibular, submental, carotid, and muscular.
Submandibular Triangle The submandibular triangle is delimited by the inferior border of the mandible, and the anterior and posterior belly of the digastric muscle. The submandibular gland is the largest structure within this triangle. Other structures within this triangle are the anterior and posterior facial veins, facial artery, submental branch of the facial artery, the superficial and deep layer of the submaxillary fascia, and hypoglossal nerve. The facial artery is a branch of the external carotid artery and enters the submandibular triangle under the posterior belly of the digastric, the stylohyoid muscle, and the submandibular gland. It then becomes superficial and lies under the platysma when it encounters the mandible.
Clinical Review for the USMLE Step 1
Figure 36. The anterior cervical triangle. Copyright Olek Remesz. Used with permission.
Submental Triangle The submental triangle is bound by the anterior belly of the digastric muscle laterally, the hyoid bone medially, the mylohyoid muscle posteriorly, the midline medially, and the skin and superficial fascia anteriorly. Lymph nodes draining from the chin, lower lip, floor of the mouth, and tip of the tongue are found in this triangle.
Carotid Triangle The carotid triangle is bound by the sternocleidomastoid muscle posteriorly, the anterior belly of the omohyoid anteriorly, and the posterior belly of the digastric superiorly. The hyoglossus muscle, inferior and middle constrictors of the pharynx, and thyrohyoid are noted medially. The common carotid artery, its bifurcation as the external and internal branches, vagus nerve, spinal accessory muscle, hypoglossal nerve, ansa hypoglossi, and cervical sympathetic nerves are within the carotid triangle. The jugular lymph nodes drain in the supraclavicular lymph nodes.
Muscular Triangle The muscular triangle is bound by the anterior belly of the omohyoid superiorly, sternocleidomastoid muscle inferiorly, midline of the neck medially, prevertebral fascia and muscle posteriorly, and the deep layer of the deep cervical fascia, sternohyoid muscle, and cricothyroid muscle anteriorly. The thyroid and parathyroid glands, trachea, esophagus, and sympathetic trunk are found within the muscular triangle.
Figure 37. The posterior cervical triangle. Copyright Olek Remesz. Used with permission.
Posterior Cervical Triangle
Occipital Triangle The occipital triangle is bound by the sternocleidomastoid, trapezius, and omohyoid muscles. The spinal accessory nerve crosses the occipital triangle as it travels to the trapezius. A variety of lymph nodes and the external jugular vein also cross this space.
Subclavian Triangle The subclavian triangle is bound by the clavicle, omohyoid, and sternocleidomastoid. The third portion of the subclavian artery runs through this space. The brachial plexus can also be accessed through this triangle.
3.8. Innervation 3.8.1
Nerves of the Upper Extremity
Overview The brachial plexus forms the backbone of the network of nerves that supplies the entire upper extremity and emanates from spinal nerves C5, C6, C7, C8, and T1. Although these roots, trunks, divisions, cords, and branches anastomose to various degrees, a simplified model of the function of each of these roots is illustrated in the following table:
Clinical Review for the USMLE Step 1 Table 3. Major function of various nerve roots. C5
Shoulder abduction, extension, and external rotation; some elbow flexion
Elbow flexion, forearm pronation and supination, some wrist extension
Diffuse loss of function in the extremity without complete paralysis of a specific muscle group, consistently supplies the latissimus dorsi Finger extensors, finger flexors, wrist flexors, hand intrinsics
The ulnar nerve is responsible for innervations to the intrinsic muscles of the hand. Transection of this nerve is not repaired primarily.
Long Thoracic Nerve The long thoracic nerve (C5, C6, C7) supplies the serratus anterior muscle, and is commonly tested in the context of a modified radical mastectomy with axillary dissection. Damage to this nerve during that operation can lead to â€œwinged scapula,â€? which is evident when the patient pushes against a wall with an outstretched arm. The long thoracic nerve descends along the lateral border of the pectoralis minor and medial border of the teres major.
Thoracodorsal Nerve The thoracodorsal nerve (C6, C7, C8) travels with the subscapular artery, crosses the axilla, and innervates the latissimus dorsi. Variations in its course may take the crossing somewhat more inferiorly. Care must be taken to avoid transaction of this nerve during an axillary dissection as part of a mastectomy.
Pectoral Nerves The lateral pectoral nerve (C5, C6, C7) passes through the coracoclavicular fascia to supply the pectoralis major. The medial pectoral nerve (C8, T1) supplies the pectoralis minor and major muscles.
Musculocutaneous Nerve The musculocutaneous nerve (C5, C6, C7) is the chief nerve supply to the coracobrachialis, biceps brachii, and brachialis. This nerve travels along the lateral aspect of the arm between the biceps and brachialis. Direct damage to this nerve is therefore rare given the extensive muscular protection.
Median Nerve The median nerve (C5, C6, C7, C8, T1) is a major nerve from the brachial plexus and travels along the medial aspect of the arm just lateral to the brachial artery. It crosses the brachial artery at its bifurcation within the cubital fossa and travels medially. The median nerve primarily supplies the flexors and pronators of the distal upper extremity. Branches also supply the hand. The median nerve travels deep to the flexor retinaculum and may be affected in carpal tunnel syndrome.
Axillary Nerve The axillary nerve (C5, C6) supplies the teres minor and deltoid muscles. Damage to this nerve may occur with anterior dislocation of the shoulder or fracture of the head of the humerus. Erb-Duchenne palsy occurs following damage to the superior roots of the brachial plexus (C5, C6), 180
Figure 38. The brachial plexus. Adapted from Grayâ€™s Anatomy. Used with permission. leading to paralysis of the deltoid, biceps, brachialis, coracobrachialis, brachioradialis, supraspinatus, infraspinatus, teres minor, and subscapularis. The upper limb is adducted at shoulder, medially rotated, and extended at the elbow. Erb-Duchenne palsy is the result of excess traction on the neck as can occur during delivery or from falls.
Radial Nerve The radial nerve (C5, C6, C7, C8, T1) supplies the triceps brachii and the extensor compartment of the arm. This nerve initially travels in the posterior compartment of the upper arm, and then crosses through the lateral intermuscular septum to travel in the anterior compartment. In the upper arm, it is located along the radial groove of the humerus and is therefore susceptible to damage in a midshaft fracture. The nerve is also located in close proximity to the lateral epicondyle. The superficial branch of the radial nerve travels deep to the brachioradialis. The radial nerve also supplies muscles of the hand. Saturday night palsy is due to injury to the radial nerve as a result of a mid-shaft humerus fracture. It leads to wrist drop. The deep branch of the radial nerve can be injured by deep puncture wounds to the forearm, leading to extension of the thumb and the metacarpophalangeal joints. Superficial damage leaves a coin-shaped area distal to the bases of the 1st and 2nd metacarpals without sensation.
Clinical Review for the USMLE Step 1
Figure 39. The brachial plexus. Copyright Marshall Strother. Used with permission.
Ulnar Nerve The ulnar nerve (C8, T1) is a mostly unprotected nerve that supplies several flexors and muscles of the hand. It is most likely to be injured at the medial epicondyle of the humerus. The ulnar nerve travels along the posterior and medial aspect of the humerus, then travels with the ulnar artery in the forearm. This nerve passes superior to the flexor retinaculum. Klumpke palsy is due to lower brachial plexus injury. It occurs when a person grabs something to break a fall. The dorsal and ventral roots of the spinal nerves that form the inferior trunk of the brachial plexus (C8 and T1) may be avulsed. As a result, the short muscles of the hand are affected. It presents as claw hand.
Nerves of the Lower Extremity
Overview There are three major plexuses that provide innervation to the pelvis and lower extremities. The lumbar plexus includes a variety of cutaneous and motor nerves to the inguinal region and proximal lower extremity. The sacral plexus predominantly supplies the distal lower extremity, while the coccygeal plexus supplies structures of the perineum and anus.
Lumbar Plexus The chief nerves of the lumbar plexus are the iliohypogastric, ilioinguinal, genitofemoral, lateral femoral cutaneous, obturator, and femoral nerves. The lateral femoral cutaneous nerve provides sensory innervation to the lateral thigh. The obturator nerve (L2, L3, L4) passes through the psoas major, deep to the common iliac artery, and through the obturator canal. It provides sensory innervation to the medial thigh and motor to the adductor muscles. The femoral nerve (L2, L3, L4) travels with the femoral vessels deep the inguinal ligament and provides sensory innervation to the majority of the lower leg and motor to the quadriceps (i.e. the rectus femoris, vastus lateralis, vastus medialis, and vastus intermedius). The major sensory branch is the saphenous nerve, which travels with the great saphenous vein deep to the sartorius.
Anatomy Sacral Plexus The common fibular, tibial, and sural nerves are major branches of the sciatic nerve, itself a major derivative of the sacral plexus. The superior and inferior gluteal nerves and cutaneous nerves to the thigh also emanate from the sacral plexus. In conjunction with the cutaneous nerves from the lumbar plexus, branches of the sural nerve provide sensory innervation to the entire leg. The sacral plexus includes nerve roots from L4, L5, S1, S2, S3, and S4.
Figure 40. Lumbar plexus. Adapted from Gray’s Anatomy. Used with permisThe coccygeal sion. plexus is formed by roots S4 and the coccygeal nerve. It gives rise to the pudendal nerve, a somatic nerve that regulates the function of the bulbospongiosus and ischiocavernosus muscles, external anal sphincter (via the inferior rectal branch), scrotum (via the superficial perineal nerve), and genitalia (via the dorsal nerve of the penis or clitoris).
These nerves also play a role in several important reflexes. Testing these reflexes is especially important as part of a trauma workup, as a specific dysfunction may be an indicator of spinal cord injury. Table 4. Major reflexes of the upper and lower extremities. Biceps Reflex
C5, C6 – Musculocutaneous nerve
C6, C7 – Radial nerve
L3, L4 – Femoral and common peroneal nerves
L5, S1 – Tibial nerve
Clinical Review for the USMLE Step 1 3.8.4
Autonomic Nervous System
Parasympathetic Nervous System The autonomic nervous system is divided into the parasympathetic and sympathetic nervous systems. The parasympathetic nervous system has its cell bodies in the brainstem (CN III, VII, IX, X) or sacral spinal cord (S2-S4). These preganglionic neurons synapse with their postganglionic neurons in either the parasympathetic ganglia of the head or near their target organ. The primary targets of the parasympathetic nervous system are visceral organs. They function to dilate blood vessels in the gastrointestinal tract prior to digestion, induce bradycardia, cause pupillary constriction, and induce erection and sexual arousal.
Sympathetic Nervous System The sympathetic nervous system has its cell bodies in the lateral horn of the spinal cord, within the intermediolateral cell column. These preganglionic, general visceral efferent neurons are located between T1 and L2, and synapse with their postganglionic neurons on the sympathetic chain, prevertebral ganglia such as the celiac or mesenteric ganglia, and chromaffin cells of the adrenal medulla. The sympathetic nervous system leads to tachycardia, diverts blood away from the gastrointestinal system, dilates the pupils, and stimulates orgasm. The primary neurotransmitter of the autonomic nervous system is acetylcholine. The effector organs such as the adrenal Figure 41. The autonomic nervous sysgland use epinephrine. tem. Adapted from Grayâ€™s Anatomy. Used with permission.
4. Physiology 4.1. Neurons 4.1.1
Neurons are specialized cells that respond to chemical signals, generate an electrical impulse, and release neurotransmitters. Synthesis of neurotransmitters and other proteins occurs in the soma. Input is received via dendrites, which make contact with axons from other neurons. Axons transmit electrical signals, up to 1.5 meters along the dorsal column. Axons transport neurotransmitters using microtubules. Kinesins and dyneins are ATP-linked proteins that can transport proteins along the microtubule chains. Neurons generate electrical impulses that travel along the axon through sodium, potassium, chloride, and calcium ions. The action potential transmits this charge rapidly down the axon. Myelinated fibers permit faster transmission as the charge will jump from one node of Ranvier to another down the 184
Physiology sheath. Once the action potential is started, it becomes an all-or-nothing phenomenon. The impulse is generated once the sum of the excitatory inputs and inhibitory inputs is calculated from the various dendrites. Peripheral nerve fibers can be divided into one of three groups. A fibers are typically motor or sensory. They are large diameter, myelinated, and carry impulses rapidly. B fibers are preganglionic fibers, myelinated, and small diameter. C fibers are unmyelinated, thin diameter fibers that typically carry pain, temperature, and pressure. Their lack of myelin is why touching a hot stove leads to a rapid reflex first, followed by the sensation of pain and heat.
Neurons use a variety of neurotransmitters to effect changes on target neurons (and other cells throughout the body). Acetylcholine is the predominant neurotransmitter and can activate ligand-gated ion channels, muscarinic receptors, and nicotinic receptors. GABA is the predominant inhibitory neurotransmitter of the nervous system and binds to anion channels that release chloride and hyperpolarize the target neuron, making it more difficult to activate them. Glutamate is an excitatory neurotransmitter that can bind to ligand-gated ion channels such as AMPA, NMDA, or metabotropic receptors. Excess stimulation can lead to damage via release of toxic amounts of calcium and sodium.
Figure 42. Components of a neuron and its axon terminals. Copyright Mariana Ruiz. Used with permission. 185
Clinical Review for the USMLE Step 1 Dopamine functions via a variety of G-protein linked receptors. D1 and D5 are excitatory, while D2-D4 are inhibitory G proteins. Serotonin functions via 5-HT receptors and is generated by tryptophan.
4.2. Supporting Cells Supporting cells of the nervous system include a variety of cells. Astrocytes modulate the internal environment of the brain and help control the flow of blood in the brain. As such, astrocytes are the primary constituent of the blood-brain barrier, a highly selective membrane that permits travel of vital minerals, electrolytes, fluids, and certain drugs while excluding larger proteins and cells (such as RBCs). Oligodendrocytes produce myelin. Ependymal cells produce cerebrospinal fluid (CSF), which circulates within the ventricles, brain, and spinal cord. The CSF is produced in the choroid plexus and travels from the lateral ventricle, through the foramen of Monro, into the third ventricle, through the Sylvian aqueduct, and into the fourth ventricle. From there, it travels into the subarachoid space and spinal cord via the foramen of Luschka and foramen of Magendie. The CSF helps to maintain the buoyancy of the brain and contains isotonic concentrations of sodium, potassium, and chloride. It is relatively poor in RBCs, WBCs, glucose, and protein. Ependymal cells are also thought to serve a stem cell-like function in that they can repopulate neurons and supporting cells of the CNS. Schwann cells function like oligodendrocytes in the peripheral nervous system. They produce myelin and also produce a template that peripheral nervous system neurons can use to help regrow their axons. This requires the Schwann cells to remain largely intact, and peripheral nerve regrowth is effective only over short distances and with minimal injury to surrounding structures. Microglia are macrophages located in the nervous system. Their primary role is immunologic.
4.3. Brain Death Brain death is distinct from a persistent vegetative state and coma. Brain death implies the total and permanent cessation of all brain activity and occurs due to neuronal cell death following anoxia. The specific legal definition varies between death of the brain stem and death of the entire brain, but the effect is generally the same. The only reflexes that may be present are the corneal reflex and the vestibuloocular reflex. There are no spontaneous respirations, no response to pain, and no cranial nerve reflexes. Brain death can be diagnosed only after excluding drug overdose (especially barbiturates and alcohol) and a vegetative state. There is no signal on EEG. A persistent vegetative state occurs following severe brain damage that leads to disruption of consciousness. Basic brain functions, including spontaneous respiration and cranial nerve reflexes, are maintained. However, there is no voluntary communication with the outside world. A persistent vegetative state is distinguished from locked-in syndrome, which occurs following trauma to the pons where consciousness is not disrupted but the ability to communicate with the outside world is severely restricted.
4.4. Peripheral Vascular Resistance Peripheral vascular resistance relies on the tone of the vasculature. Both intrinsic and extrinsic mediators regulate the overall tone within a vascular bed. Peripheral vessels are predominantly found in the skin as well as muscle beds. Sympathetic tone is primarily responsible for the peripheral vascular resistance in the skin and superficial tissue, and responds to body temperature. Activation of the sympathetic nervous system results in vasoconstriction peripherally, an attempt to conserve heat. On the other hand, when body temperature rises, a vasodilation reflex occurs as sympathetic tone is withdrawn. 186
Physiology The vasculature found within a muscle bed is innervated by not only a system that vasoconstricts, but also one that vasodilates. Postural changes elicit vasoconstriction of the arterial system in an attempt to maintain blood pressure. However, in times of stress (i.e. exercise), metabolites build up, and combined with ischemia of exercise, the vascular bed vasodilates in an attempt to increase peripheral blood flow. The balance of vasodilator and vasoconstrictive mediators is responsible for the overall peripheral vascular resistance.Â
4.5. Autoregulation Autoregulation is responsible for maintaining constant and consistent blood flow to a target region or organ as perfusion pressure increases and decreases. Conceptually, as blood pressure rises and falls, resistance vessels constrict or dilate, respectively, to ensure a constant level of flow through that vessel. This is particularly important in the cerebral vasculature, in that a rising blood pressure elicits a constrictive response to protect the brain from hypertension. Autoregulation, mediated by local and sympathetic mediators, preserves blood flow over a range of blood pressures.
4.6. Venous Hemodynamics Veins are thin, compressible, valve-containing structures that contain a significant percentage of the bodyâ€™s blood supply. Both the deep and superficial veins in the periphery are responsible for returning blood to the heart, and do so in a fluctuant manner. This rapidly changing flow through the venous system can be explained by the forces that act on blood within the system: dynamic pressure transmitted through the vasculature from the contractile force of the heart, hydrostatic pressure that is affected by gravity, and filling pressure that varies with venous elasticity. Given that the contractile forces of the heart are transmitted through the arteries and capillaries, it may be negligible at the venous level. Hydrostatic pressure, on the other hand, varies depending on where it is measured with regards to the heart, with the greatest hydrostatic pressure being found at the point most inferior to the heart in an upright individual. Lastly, in applying what we know about orthostatics, the venous system alone does not constrict in response to the increased blood volume (i.e.,Â when a patient is moved from supine to upright), which corresponds to a relatively innate filling pressure. The characteristic filling pressure is what is responsible for the great capacitance of the venous system that separates it from the arterial system. Understanding each entity is important, but it is the combination of these factors within the venous system that generates the overall venous pressure.
4.7. Respiratory Flow Variation Respiration has significant impact on flow through the venous system. Not only does venous return rely on the dynamic pressure transmitted through the arterial system from the heart as well as the pumping effect of the muscles, there is significant pull generated by changes in pressure within the thoracic and abdominal cavities. Inspiration involves descent of the diaphragm into the abdomen, which in turn increases the intraabdominal pressure. This increase in pressure impedes venous flow from the legs into the central venous system because the pressure gradient between the two systems is diminished. On the other hand, during expiration, the diaphragm ascends back into the chest, decreasing intraabdominal pressure, thereby allowing increased flow into the vena cava. This concept also applies to venous flow from the upper extremities and head, in that inspiration and the resultant descent of the diaphragm decreases the intrathoracic pressure, and venous blood is then drawn into the chest.
Clinical Review for the USMLE Step 1
4.8. Vasoactive Mediators 4.8.1
Proteases are enzymes involved in many bodily processes, including hemostasis, the inflammatory response, and the migration of inflammatory and remodeling cells. Proteases are involved in intimal hyperplasia as well. Plasmin, formed from plasminogen, is a potent activator of such proteases, including matrix metalloproteinases (MMPs). These MMPs, together with plasmin and other proteases, work to break down, rebuild, and remodel the extracellular matrix. There are three subclasses of MMPs. First are the interstitial collagenases, which act on type I and type III collagen. Next, gelatinases, alter gelatin, type IV and type V collagen, as well as elastin. Lastly, the stromelysins, function to degrade laminin, fibronectin, and proteoglycans. It is the lack of balance between activation and inhibition of these proteases that is thought to lead to atherosclerotic plaque formation as well as their instability that ultimately leads to plaque rupture. MMPs are also involved in the pathogenesis of aneurysmal disease, the intimal hyperplastic response of vein grafts, as well as vein wall remodeling that eventually leads to varicosities.
Nitric oxide, previously called endothelium-derived relaxing factor, acts as a potent vasodilator within the microcirculation. Nitric oxide is produced from arginine in a process catalyzed by nitric oxide synthase, an enzyme present within endothelial cells. As shear stress increases, the force acting on the endothelium also increases which activates nitric oxide synthase, and vasodilation is achieved. Nitric oxide is a lipophilic gas that acts on a receptor that functions as a guanylyl cyclase. Once activated, the guanylyl cyclase converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP-dependent protein kinases go on to phosphorylate myosin light chain kinase (MLCK) and SERCA. MLCK is inactivated by phosphorylation which leads to a decreased activation of myosin light chain (MLC), yielding less interaction between actin and myosin. In addition, phosphorylation activates SERCA, which removes calcium from the intracellular space, thus reducing calcium ions available for contraction. Therefore, nitric oxide leads to vasodilation be relaxing vascular smooth muscle cells within the vessel wall.
VEGF, EGF, and Angiogenesis
Vascular endothelial growth factor (VEGF) is an important growth factor that leads to the production of new endothelial cells. It has great impact not only in embryogenesis, but also in the formation of collateral circulation in the setting of ischemia. Epidermal growth factor (EGF) is another stimulant of endothelial cell proliferation and migration important in angiogenesis that works via tyrosine kinase pathways. Angiogenesis requires the formation of new capillary-like structures that bud from existing vessels. This process is promoted by antigenic factors such as VEGF. Hypoxia is thought to be a dominating stimulus that leads to the production of VEGF, ultimately leading to the production and sprouting of new vessels.
4.9. Cerebral Perfusion Pressure The cerebral perfusion pressure (CPP) is the pressure generated by blood flow to the brain. There are three constituents that modify the CPP, including the mean arterial pressure (MAP), intracranial pressure (ICP), and jugular venous pressure (JVP). Cerebral perfusion pressure is defined as the difference between the MAP and ICP. CPP divided by the cerebral vascular resistance (CVR) yields cerebral blood 188
CNS and PNS Pathology flow, a quantity that is difficult to measure directly. CPP = MAP â€“ ICP The major constituents that affect ICP include brain volume, cerebral spinal fluid (CSF), and blood. Changes in one or more of these variables can lead to a rise in intracranial pressure, which in turn can reduce cerebral perfusion pressure, decrease, blood flow to the brain, and cause cerebral ischemia with stroke. Normal MAP ranges between 60 and 150 mmHg and ICP is typically about 10 mmHg. Autoregulation within the brain modulates CPP to between 70 and 90 mmHg. Once the limits of autoregulation are exceeded, a drop in CPP below 70 mmHg leads to cerebral ischemia. In selected, stable patients, the tolerated range for CPP can vary between 50 and 150 mmHg, and a lower limit for children of 60 mmHg may be tolerated. Urgent correction of potential causes of CPP derangement is required. Rising ICP should be treated with a ventriculostomy drain. Rapid sequence intubation, sedation, mannitol, hypothermia, paralysis, and raising the head of the bed are all means of mitigating a rise in ICP. Pressors may be used to increase MAP to overcome a continuing rise in ICP. Hyperventilation to cause a PaCO2 of 35 mmHg may reduce cerebral vasospasm and improve circulation. Hypotonic saline can also be used to control ICP to some extent. Severe derangements in intracranial pressure may lead to uncal herniation and death. Early signs include papillary dilation with a sluggish reaction, suggesting compromise of the ipsilateral oculomotor nerve from overstretching. Table 5. Intracranial pressure Drug
Mechanism of Action
Reduce intracranial pressure
Hypertonic solution to increase water and salt excretion in distal tubule
Oliguric renal failure
Also opens BBB through shrinking the endothelial cells
Sweetener for diabetes
Notes Sometimes used as an adulterant for opioid abuse Also given for tropical fish poisoning
5.1. Spinal Cord Pathology 5.1.1
Spinal Cord Compression
Compression of the spinal cord is a neurologic emergency that requires prompt medical attention to avoid lifelong sequelae. Common causes include tumor spread to the back, disk herniation, abscess, and hematoma formation. The most common site of compression is the thoracic spinal cord. Cord compression presents as sudden onset of neurologic symptoms distal to the site of spinal cord compression, with symptoms including sudden weakness in lower extremities, incontinence, sexual dysfunction, and sensory changes. Pain is common in nearly all patients. Diagnosis is made by careful history and physical exam, including a full neurologic exam that identifies focal deficits. Plain films are typically diagnostic, but MRI and CT myelogram are all used for additional information.
Clinical Review for the USMLE Step 1 Cord compression is treated with immediate steroid therapy, including high doses of dexamethasone. The key to this treatment is to reduce any inflammation and prevent further injury. Cancer-induced compression should be treated with chemotherapy or radiation therapy, while surgical options are available for disk herniation, hematoma, and abscesses. Outcome depends on the promptness of medical therapy, but the majority of patients are able to regain their baseline function, if they had good function previously.
Syringomyelia is divided into a communicating cavitation or noncommunicating cavitation of the spinal cord. Communicating syringomyelia is associated with Arnold-Chiari malformation, and noncommunicating syringomyelia is typically secondary to spinal cord trauma. Neurologic symptoms include sensory deficits and some lower motor neuron defects. The cervical spinal cord is most commonly affected. Treatment involves surgery.
Subacute Combined Degeneration (SACD)
Subacute combined degeneration is due to vitamin B12 deficiency, itself commonly the result of intrinsic factor deficiency, decreased intake, terminal ileum disorders, Diphyllobothrium latum infection, or atrophic gastritis. In addition to the megaloblastic anemia that develops, vitamin B12 deficiency leads to weakness of the extremities with paresthesia. Ataxia is common. Plantar extension and hyperreflexia are found on physical exam, along with deficits in vibration sensation and proprioception. Treatment is to administer vitamin B12.
Anterior Spinal Artery Infarction
Anterior spinal artery infarction is rare and leads to flaccid paralysis followed by spastic paresis through ischemic damage to the spinal cord. Vibration and proprioception remain intact, but pain and temperature are lost.
Spinal Cord Trauma
Patients with trauma to the head and neck are also at risk for specific trauma to the spinal cord. Direct trauma to the vertebral column can also lead to herniation of discs, bony fragments, and direct injury to the spinal cord. Hematoma formation can lead to occlusion, while vascular disruption can lead to ischemia. All patients who are suspected of head, neck, or back trauma should be stabilized in a hard cervical collar (i.e. a Miami J) and backboard. Expeditious clearing of the cervical spine and removal of the backboard should be completed. Injuries to the spinal cord are most likely to occur at the cervical level (55%), followed by the thoracic (30%) and lumbar (15%) regions. Spinal shock may occur with injuries above T5, leading to loss of background excitability from loss of lower pathways, decreased reflex function for at least 1 week and perhaps permanently, and loss of vestibulospinal and reticulospinal pathways. This leads to bradycardia, vasodilation, and hypotension. Treat spinal shock with fluids and pressors. Nonpenetrating injuries of the spinal cord that occurred within 3 hours should be treated with 24 hours of methylprednisolone. Injuries that occurred within 8 hours should be treated with 48 hours of methylprednisolone. Injuries that occurred greater than 8 hour ago should not be treated with steroids. These findings are based off the somewhat controversial NASCIS trials.
CNS and PNS Pathology Clearance of the C-spine in an intubated and sedated patient without neurologic findings can be done with a CT scan through T1, but ligamentous injury cannot be excluded. If suspected, extension/flexion films and physical exam are key. An MRI is also a sensitive test for detecting ligamentous injury. Cord compression is commonly the result of tumor, disk herniation, abscess, or hematoma formation â€“ especially in the thoracic levels. Disturbances to the upper central cord lead to loss of sensory and motor function in the distal upper extremities with sparing of the lower extremities. Brown-Sequard syndrome occurs in the setting of severe trauma in which anatomic or functional hemisection of the spinal cord has occurred. It presents with hemiparesis with limb drift, hyperreflexia, spasticity, Babinski sign, and loss of contralateral pain and temperature. Damage above T1 leads to Horner syndrome, which presents with miosis, ptosis, and anhidrosis. This particular manifestation can occur with metastatic lung cancer. Complete spinal cord transection above T6 will lead to autonomic dysreflexia in about half of all patients and leads to cardiovascular instability, hypertension leading to hemorrhage and seizures, and vasoconstriction below the level of injury. Unopposed parasympathetic activation leads to diaphoresis, vasodilation, and headache. Autonomic dysreflexia often occurs in response to an uncomfortable stimulus below the level of injury.
5.2. Brain Pathology 5.2.1
There are two major CNS malformations that commonly appear on the exam. Arnold-Chiari malformation is a congenital disorder that presents with a small posterior fossa, cerebellum malformation, vermis herniation, and hydrocephalus. It can present with stridor, no gag reflex, dysphagia, spastic quadriparesis, nystagmus, syncope, progressive loss of function, pneumonia, and GERD. Dandy-Walker malformation is another congenital defect that presents with a large posterior fossa, no vermis, and CSF foramen atresia. It presents with ataxia, syringomyelia, microcephaly, spina bifida, and cardiac anomalies. Empty sella syndrome presents with a missing pituitary incidentally seen on CT; however, hormonal Figure 43. Spinal cord trauma. Copyright F.P. function remains normal. Jacquot. Used with permission. 191
Clinical Review for the USMLE Step 1 5.2.2
Epidemiology Cerebrovascular accidents (CVA) affect more than 400,000 patients a year with a rapid increase projected over the next 50 years. Stroke is the third leading cause of death; overall, it is the second leading cause of death worldwide. Men are at more risk than women, and up to Âź of all strokes affect individuals under the age of 65.
Etiology Cerebrovascular disease (CVD) and cerebrovascular accidents present with acute focal neurologic deficits commonly due to loss of circulation to a portion of the brain. Also known as a stroke, there are numerous types of CVAs. Broadly, CVA is categorized as either hemorrhagic or ischemic. Ischemic strokes are commonly secondary to embolism from elsewhere in the body or intracranial thrombosis. Disruption of the blood flow leads to neuronal death and infarction of the brain. Common sources of the embolism include valvular or mural thrombi, carotid circulation, and occasionally, the right heart in the presence of a right to left shunt. About 1/5 of all strokes lead to lacunar infarcts (which involve the subcortical cerebrum and brainstem). Lacunar infarcts are most common in patients with DM and HTN. Lacunar infarcts lead to either a pure sensory deficit, a pure motor deficit, or a hemiparetic stroke with ataxia. Sources of thrombus formation include the branch points within the circle of Willis and near the internal carotid artery (ICA). Stenosis, atherosclerosis, and platelet defects are common causes of arterial blockade; other causes are hypercoagulable states, polycythemia, and sickle cell anemia. Overall, other causes of stroke include vascular dissection, hypotension, and excessive hemorrhage. Risk factors that increase CVA include increasing age, HTN, smoking, CHD, LVH, atrial fibrillation, hypertriglyceridemia, oral contraceptive use, pregnancy, and hypercoagulable states. Thrombotic strokes are typically slower in onset, while embolic strokes are sudden in onset.
Pathophysiology of Ischemic Stroke The brain is highly sensitive to disruption in blood supply. An ischemic cascade begins almost immediately following loss of perfusion and eventually leads to irreversible infarction. The area of the brain that still receives some transient blood flow is a region of reversible ischemia; this region forms a sort of penumbra (think of the sun during a full eclipse) around the area of the stroke. The result of ischemia is a failure of membrane transport, large calcium influx, large quantities of neurotransmitter release with additional calcium influx, and local oxidative and ischemic injury. Large amounts of inflammatory mediators are created and free radical injury occurs. Degradation of the cell membrane occurs, and necrosis and apoptosis take place. The region that has infarcted has little chance of restoration. Current medical efforts attempt to save the region of the ischemic penumbra through limitation of toxic free radical formation, reducing the duration of ischemia, and protecting the neurons from additional insults. Reperfusion must take place within 3 hours to avoid permanent damage to the penumbra. Short of removing the arterial blockade, little can be done to reverse the changes in the region of apoptosis and necrosis.
Pathophysiology of Hemorrhagic Stroke Hemorrhagic stroke is categorized as either subarachnoid bleeds or intracerebral bleeds. Subarachnoid bleeds most commonly occur as the result of head trauma, AV malformations, and aneurysms. Intracerebral bleeds may occur in HTN, bleeding diatheses, and amyloidosis. Hypoperfusion may also lead to stroke and affect especially the parasagittal strips of the cortex (a region known as the watershed area 192
CNS and PNS Pathology where the end points of the circulation to the brain are located). Hemorrhagic stroke leads to direct injury to neurons by the toxic effects of blood. Compressive injury and electrolyte imbalances worsen the injury. Hemorrhagic strokes worsen with rising in the morning and evolve over a period of minutes. There are several types of CVA that may occur. The term “stroke” refers to the presence of infarcted tissue in the brain. A “stroke in evolution” is progressive, ongoing injury. A “completed stroke” has caused irreparable harm to a certain portion of the brain and has been stable in its course for a few days. There is a type of stroke that spontaneously resolves with no damage; this type is known as a “transient ischemic attack” (TIA) and typically resolves within 30 minutes to 24 hours. Repeated TIAs are referred to as “crescendo TIAs.”. A TIA that lasts more than 24 hours but less than 3 weeks and has progressive improvement is known as a reversible ischemic neurologic deficit (RIND). TIAs and RINDs are highly indicative of a future stroke potential.
Presentation CVAs present as an acute neurologic deficit or an altered state of consciousness. Numerous constitutional symptoms are typically present in addition to one or more of the following: abrupt onset of paresis, visual deficits, vestibular or hearing deficits, aphasia, dysarthria, and ataxia. Physical exam may uncover cardiac or vasculature abnormalities or evidence of trauma that can be used to pinpoint the cause of the stroke. A full neurologic exam is required and together with diagnostic testing, can be used to identify the precise site of neurologic injury. There are four major stroke syndromes that can occur depending on the anatomic location of the ischemic injury and the particular artery that is affected. Strokes from occlusion of the anterior cerebral artery (ACA) present with changes in mental status, impaired judgment, apraxia, and weakness of the contralateral lower extremities. Other symptoms commonly include incontinence and personality or behavioral changes. The region that is affected is mostly the frontal lobe. Middle cerebral artery (MCA) strokes lead to contralateral hemiparesis and hemiplegia with sensory loss. Ipsilateral hemianopsia presents with a gaze preference ipsilateral to the side of injury. Agnosia and aphasia may occur especially if the dominant hemisphere is affected. Upper extremity deficits are typically prominent. The posterior cerebral artery (PCA) may occlude and present as changes in vision via a homonymous hemianopsia or blindness, agnosia, defects in memory, and altered mental status. The PCA can also lead to Weber syndrome through cranial nerve (CN) III palsy (leading to contralateral hemiplegia, or contralateral ataxia [known as Benedikt syndrome]). Strokes of the vertebrobasilar artery present with a number of diverse deficits and are difficult to diagnose. Symptoms include vestibular effects (such as vertigo or nystagmus), visual effects (including diplopia or field deficits), motor defects (such as dysarthria or dysphagia), ataxia, syncope, and loss of pain and temperature sensations on the ipsilateral face and contralateral body. Other stroke syndromes typically present with ipsilateral symptoms. Occlusion of the paramedian branches can lead to lockedin-syndrome with only intact eye movements but complete quadriparesis. Blockage of the posterior inferior cerebellar artery (PICA) can lead to Wallenberg syndrome, presenting as ipsilateral loss of sensation to the face and contralateral paresthesias of the body. Horner syndrome occasionally accompanies PCA and PICA stroke. Horner syndrome includes hemianhidrosis, unilateral effects, ptosis, miosis, and enophthalmos. Occlusion of the cerebellar arteries presents with vertigo, nystagmus, nausea, and vomiting. Ataxia of 193
Clinical Review for the USMLE Step 1 an extremity is also common. Occlusion of the anterior inferior cerebellar artery (AICA) presents with gaze palsy, deafness, tinnitus, and weakness of the ipsilateral face. Infarctions affecting the lenticulostriate arteries branching from the MCA are most commonly affected in patients with HTN. A pure sensory stroke may occur with loss of sensory information in one half of the body. A pure motor stroke may occur with loss of motor ability in the face or one of the extremities. Ataxic hemiparesis may also result as a combined motor and sensory loss leading to ataxia. Dysarthria with retardation of normal motor and sensory transmission may occur leading to weakness and impediments in normal motion of one of the extremities or face. Table 6. Clinical Diagnosis of Stroke Anterior cerebral artery
Changes in mental status, impaired judgment, apraxia, and weakness of the contralateral lower extremities, incontinence & personality or behavioral changes.
Middle cerebral artery
Contralateral hemiparesis and hemiplegia with sensory loss. Ipsilateral hemianopsia. Agnosia and aphasia may occur, especially if the dominant hemisphere is affected. Upper extremity deficits are typically prominent.
Posterior cerebral artery
Changes in vision, agnosia, defects in memory, and altered mental status. Weber & Benedikt syndromes.
Vestibular effects, visual effects, motor defects, and loss of pain and temperature on the ipsilateral face and contralateral body.
Wallenberg syndrome, Horner syndrome.
Vertigo, nystagmus, nausea, and vomiting. Ataxia of an extremity, gaze palsy, deafness, tinnitus, and weakness of the ipsilateral face.
Sensory stroke may occur with loss of sensory information in half of the body. A pure motor stroke may occur with loss of motor ability in the face or one of the extremities. Ataxic hemiparesis may also result as a combined motor and sensory loss leading to ataxia. Dysarthria with retardation of normal motor and sensory transmission may occur leading to weakness and impediments in normal motion of one of the extremities or face.
Diagnosis Noncontrast CT is the initial preferred test and is mandatory for distinguishing the various types of stroke and identifying the particular location of injury. Patients with acute ischemic stroke may entirely bypass this diagnostic study and be taken for immediate therapy. CT has normal findings in the first 6 hours; however, edema over this time leads to changes in the form of a hypodense region. Lumbar puncture should be done in all patients suspected of having a subarachnoid hemorrhage, as CT changes are sometimes nonspecific in this particular etiology. Carotid duplex scanning is done in patients who may have stenosis of the carotid artery, leading to possible endarterectomy in some patients. Echocardiography and other diagnostic studies are also used if particular causes of stroke are suspected. MRI is useful in patients that have a cerebellar or lacunar defect. Angiography is the definitive study that precisely identifies even subtle occlusion.
Glasgow Coma Scale (GCS) The Glasgow coma scale is used for rapid neurologic assessment following acute head injury or stroke. It is closely tied to outcome and is often used to dictate therapy in certain instances. The GCS ranges between 3 and 15, with 3 being the worst. Three responses are gauged, including eye response, verbal response, and motor response. The eye responses range from 1-4, and include no eye opening (1 point), eye response to pain (2), eye response to verbal command (3), and spontaneous eye response (4). No verbal response gets 1 point, incomprehensive sounds (2), inappropriate words (3), confused (4), and 194
CNS and PNS Pathology oriented gets 5 points. Motor responses range from no response (1), extension to pain (2), flexion to pain (3), withdrawal from pain (4), localizing pain (5), and obeying commands (6). A range of 13 or more correlates with mild or nonexistent brain injury. Between 9 and 12 is considered a moderate injury, and less than 9 is a severe injury. Table 7. Glasgow Coma Scale (GCS) Eye response
No eye opening (1 point), eye response to pain (2), eye response to verbal command (3), and spontaneous eye response (4).
No verbal response gets 1 point, incomprehensive sounds (2), inappropriate words (3), confused (4), and oriented gets 5 points.
No response (1), extension to pain (2), flexion to pain (3), withdrawal from pain (4), localizing pain (5), and obeying commands (6).
>13 mild or nonexistent brain injury; 12-9 moderate injury; <9 is severe.
Treatment Treatment of stroke depends on the particular type and severity of stroke. Basic emergency management includes establishing airway, breathing, and circulation (ABCs), especially with a GCS of less than 9 or dropping GCS scores. Lidocaine, pancuronium, succinylcholine, and oral endotracheal intubation may be necessary with increased intracranial pressure (ICP). Hyperventilation is the key to decreasing ICP and cerebral blood flow. Hydration status should be assessed and overhydration prevented. Lowering BP is necessary with HTN, and commonly used agents include nitroprusside and labetalol. Antipyretics should be used with fever, and cerebral edema prevented. Use of calcium-channel blockers such as lubeluzole may be beneficial very early in the evolution of stroke to avoid calcium influx. Free-radical scavengers such as tirilazad and citicoline and stabilizers of neuronal membranes such as citicoline are useful later in the ischemic cascade. Antibodies against leukocyte adhesion molecules, such as enlimomab, may serve a neuroprotective role. Anticoagulation with heparin may have some protection in progressive stroke and especially with occlusion affecting the vertebrobasilar artery. However, anticoagulation for stroke has up to a 4% risk of hemorrhage. Contraindications for anticoagulation include concomitant HTN, bleeding diatheses, and intracranial hemorrhage. Tissue-plasminogen activators (t-PA) can be used to restore cerebral blood flow and help resolve an evolving neurologic defect. However, the use of tPAs such as streptokinase, urokinase, or alteplase can increase mortality in some groups through increased intracranial bleed (which can lead to death in up to half of all patients). Overall, 1 in 8 patients had full recovery with t-PA treatment, 1 in 17 had intracranial bleeds, and 1 in 40 died from complications of therapy. Of all the medications available for t-PA, only alteplase is recommended and approved for therapy; streptokinase is not recommended. t-PA therapy should be given within 3 hours in order to be effective. TIAs should be treated with antiplatelet agents including aspirin and clopidogrel. Anticoagulation may be necessary with heparin and warfarin. Carotid endarterectomy should be considered if the carotid artery is implicated as a causative agent.
Complications There are several complications to stroke. Several syndromes may develop. Anosognosia may occur with the inability to identify parts of the body as belonging to the individual. Aphasia may occur with defects in spoken or written language comprehension or expression. Broca aphasia may occur with inability to express speech or write. Wernicke aphasia may occur through impaired comprehension but copious 195
Clinical Review for the USMLE Step 1 amounts of nonsensical speech. Apraxia can occur with the inability to repeat learned motor motions. Dysarthria is the inability to speak, and dysphagia is difficulty with swallowing. As discussed above, numerous stroke syndromes can occur including Horner syndrome, Wallenberg syndrome, Weber syndrome, and Benedikt syndrome.
Trauma to the head consists of lacerations to the scalp, fractures of the skull, and intracranial damage. The closed space of the calvarium makes it especially susceptible to intracranial injury, as the resulting hematoma and cerebral edema can lead to a significant alteration in cerebral blood flow and potential herniation of the brain. The initial approach to a trauma patient with suspected intracranial injury is to complete the ATLS protocol. The airway, breathing, and circulation should all be secured. Attention should be paid to the patients neurologic examination. A concise but complete head to toe examination should be completed, and the entire examination carefully documented. Should the patient require urgent intubation, the neurologic examination prior to sedation and/or paralysis should be documented. Once the patient is stabilized and is a suitable candidate for imaging, a diagnostic CT of the head and neck should be completed. Plain films of the thoracic, lumbar, and sacral spine should be completed unless there is a specific focus of concern, in which case CT reformats of the entire spine should be completed. Due to the thin soft tissue overlying the bone, there is little potential for soft tissue to occlude bleeding and promote hemostasis. As a result, scalp lacerations tend to bleed profusely. Hemostasis is the first line of management and consists of applying stitches or staples to close the laceration once it has been thoroughly irrigated and debrided. More extensive injuries that disrupt all of the layers of the scalp may require a split thickness skin graft for closure. Severe injuries to the head may lead to skull fractures; these injuries are divided into displaced and nondisplaced. Non-displaced fractures can typically be managed conservatively, but a thorough workup for intracranial injury and potential hematoma formation should be completed. Displaced injuries require retrieval of the bony fragments and intraoperative irrigation, debridement, and repair. All open skull fractures should also be managed surgically. Basilar skull fractures can lead to drainage of CSF. Most cases will resolve spontaneously, but continuing drainage 7 days after the injury may require operative repair. Severe basilar skull fractures may lead to disruption of the vestibulocochlear complex and require urgent repair to minimize the risk of damage to this nerve. Intracranial injury is commonly secondary to severe acceleration or deceleration causing diffuse axonal injury from the excessive shearing forces. Intracranial injury can also lead to shearing forces on the bridging veins and intracranial arteries, causing hemorrhage and additional damage. Mild intracranial injury leads to a temporary loss of consciousness, referred to as a concussion. Supportive management and observation are typically all that is required for concussions. More severe injuries may lead to cerebral edema and hemorrhage with an increase in ICP and reduction in CBF. Aggressive surgical management may be necessary in severe cases to avoid neural compromise from hernation and ischemic injury.
Figure 44. Epidural hemorrhage. Copyright J.F. Wolff. Used with Following severe head trauma, spinal cord function may remain inpermission. tact with brisk deep tendon reflexes in patients who are brain dead. 196
CNS and PNS Pathology A patient with a closed head injury who has hypernatremia and a urine osmolarity greater than 300 should receive DDAVP for the treatment of diabetes insipidus. The Cushing response involves bradycardia, hypertension, and irregular respirations, and is a sign of a head injury. Hypotension in the setting of head trauma requires urgent fluid resuscitation. Most patients with head injury will receive 24 hours of seizure prophylaxis.
An epidural hemorrhage may occur secondary to trauma to the head that causes a temporal bone fracture. Hemorrhage occurs from rupture of the middle meningeal artery, a branch of the maxillary artery. Epidural hemorrhages typically have a lucid interval following the initial trauma. As the bleeding continues and causes a mass effect on the brain, rapid deterioration occurs. The diagnosis is typically made by head CT, which reveals a hemorrhagic mass that does not cross suture lines. Treatment typically involves surgery to control the bleeding and evacuate the clot.
Subdural hemorrhages can also occur following trauma, but they are far more likely to occur in susceptible individuals including the elderly and alcoholics. In these individuals, atrophy of the brain leads to increased distance of the brain from the surrounding dura and greater mobility. Following trauma, rupture of the bridging veins can occur leading to venous bleeding. Symptoms progress over time. Diagnosis is made by head CT and shows blood crossing suture lines. Treatment is supportive and may involve surgery if the patient continues to hemorrhage. decompensate. A subdural hematoma is associated with a high Figure 45. Subdural Copyright J.F. Wolff. Used with permortality rate due to the underlying brain contusion that likely mission. accompanies this presentation.
Subarachnoid hemorrhage may be the result of a ruptured berry aneurysm. It is more common in susceptible populations, such as those with adult polycystic kidney disease, EhlersDanlos syndrome, and Marfan syndrome. The most common location is at the anterior communicating artery. Patients commonly present with a severe headache, and diagnosis is made by head CT. Treatment is typically supportive, but surgery may be needed in some patients.
Introduction Headaches are a common complaint among many patients, Figure 46. Subarachnoid hemorbut the causes of headache are vast and of varying importance. rhage. Copyright J.F. Wolff. Used with Primary causes of headache include migraines, tension head- permission. 197
Clinical Review for the USMLE Step 1 aches, and cluster headaches. Secondary causes include intracranial hemorrhage, tumor, meningitis, temporal arteritis, and glaucoma. The top ten causes of headache include various headache syndromes such as migraine, cluster headaches, and tension headaches, subarachnoid hemorrhage, meningitis, HTN, masses, temporal arteritis, trigeminal neuralgia, brain abscess, pseudotumor cerebri, and subdural hematoma. Worrisome headaches occur when they are of new onset in a patient who has no prior history of headaches. Extremely severe headache may herald an intracranial hemorrhage and requires rapid diagnosis and treatment.
Migraine Headache Migraine headaches are thought to occur as a result of vasodilation following cerebral vasoconstriction. More than 1 in 10 persons are affected, women more than men. The majority of patients have a positive family history. Migraines may present with or without an aura that precedes the actual onset of the headache. Auras are focal neurologic findings that include photophobia, sonophobia, tinnitus, bright lights, ataxia, weakness, or any other focal, stereotyped, repeated occurrence that precedes the migraine. This type of migraine is known as a classic migraine. Migraines without auras, known as common migraines, present with photophobia and sonophobia along with symptoms of the headache. The headache itself leads to nausea and vomiting, and general constitutional symptoms. A prodrome that occurs before the onset of the migraine may occur several days prior to migraine and may include lethargy, depression, edema, or food cravings. Migraines are ongoing for several hours, are unilateral, and present as a severe, throbbing pain. Migraine headaches are treated by avoiding triggers, reducing stress, and resting in a dark, quiet environment. NSAIDs are commonly used, along with ergotamines. Sumatriptan, a 5-HT receptor agonist, is popular among patients with migraines; however, in sufficient doses, this class of drugs may cause vasospasm. Metoclopramide may be given as an antiemetic. Migraine prophylaxis includes calcium channel blockers, beta blockers, and SSRIs.
Tension Headache Tension headaches occur following significant stress, and typically present as head and neck stiffness. Tension headaches have no prodrome, no aura, and are bilateral. They worsen over the course of the day. Tension headaches are described as a band-like or vise-like pain that surrounds the head or neck region. Tension headaches are alleviated by NSAIDs. If severe, narcotics can be used. Amitriptyline, a tricyclic antidepressant, has been used as tension headache prophylaxis.
Cluster Headache Cluster headaches are severe, periorbital pains that significantly worsen immediately after onset. They tend to occur in clusters, and the unrelenting, severe facial pain that occurs is highly debilitating. Cluster headaches may last up to an hour and a half, occur several times a day, and last for up to a month or two. Associated symptoms include rhinorrhea, injected conjunctiva, lacrimation, ptosis, miosis, facial sweating, and nausea. There are no obvious triggers. Treatment for cluster headaches is to use high-flow oxygen, lidocaine, ergotamine, sumatriptan, and antiemetics for symptomatic control. Verapamil, methysergide, prednisone, and indomethacin are all effective in some patients for prophylaxis.
CNS and PNS Pathology 5.2.8
Giant Cell Arteritis (GCA)
Giant cell arteritis, also known as temporal arteritis, is an immune-mediated, idiopathic inflammation of the temporal artery. Giant multinucleated cells are found in the region, and the majority of patients suffer from polymyalgia rheumatica. GCA affects mostly women and patients over 60 years of age. GCA presents with a unilateral headache pain along the course of the temporal artery. Palpation of the arteries yields thickened, tender arteries. Claudication can occur leading to ischemic changes in the masseter, temporalis, and tongue. Ipsilateral loss of vision may also occur. A pulsatile flow may be apparent in the temporal artery. Diagnosis is made by an elevated ESR and CRP, and confirmed by biopsy of the temporal artery. Corticosteroids are used to control the inflammation and reduce symptoms of temporal arteritis. Corticosteroids also protect the vision. NSAIDs are used for pain control.
Normal Pressure Hydrocephalus (NPH)
Normal pressure hydrocephalus (NPH) is increased CSF but no increase in ICP. NPH is commonly the result of subarachnoid hemorrhage, meningitis, tumor, or trauma. NPH presents with a triad of gait disturbance, incontinence, and dementia. Treating the gait disturbance is often successful, but the dementia usually is refractory to medical management. Diagnosis of NPH is made by ruling out other etiologies by a normal LP, detecting ventricular hypertrophy on CT or MRI, and finding improvement in symptoms after a therapeutic LP. Treatment for NPH involves therapeutic CSF removal, placing a ventriculoperitoneal shunt to remove excess CSF, and possibly removing a portion of the choroid plexus.
5.3. Sensory Disturbances 5.3.1
There are a number of causes for sudden loss of vision. Although many of these are discussed in more detail in the Clinical Review of Ophthalmology, a brief discussion of some of these etiologies is pertinent here. Central retinal artery occlusion (CRAO) is a sudden, painless loss of vision due to ischemia to the retina. A red spot is present on the fovea. Treatment of CRAO is to remove the embolism to avoid permanent blindness. Retinal detachment is another potentially treatable cause of blindness, and commonly presents with flashes of light and floaters. Optic neuritis is a painful loss of vision on one side due to inflammation of the optic nerve leading to demyelination. Many of these patients experience this as their first manifestation of MS. Optic neuritis typically resolves with steroid therapy. Finally, vitreous hemorrhage is due to bleeding into the vitreous humor and leads to progressive blindness. Therapy is to coagulate the bleeding or perform a vitrectomy.
Conductive Hearing Loss Hearing loss may be due to either a problem with conduction or with the vestibulocochlear nerve (CN VIII). Loss of hearing due to conductive abnormalities are often attributed to impaction of excessive amounts of cerumen, external auditory canal swelling and blockade, perforation of the tympanic membrane (30 dB), fluid within the middle ear (40 dB), cholesteatoma, otosclerosis, and abnormalities within the malleus, incus, and stapes. Otosclerosis is proliferation of the temporal bone leading to impingement of the footplate of the stapes and thus the inability of the ossicular chain to transmit mechanical waves in the fluid of the inner ear. 199
Clinical Review for the USMLE Step 1 Stapedectomy is the preferred treatment for otosclerosis; a prosthesis is then placed to permit transmission of sound.
Sensorineural Hearing Loss Sudden loss of hearing can occur for a variety of poorly understood reasons. This condition presents an otolaryngology emergency that requires prompt treatment to help these patients regain their hearing. Sudden loss of hearing can be treated with high dose steroids that are tapered over a period of weeks. Antivirals have also been shown to have some positive effect. The combination of prednisone 60 mg over a three week taper in addition to famcyclovir 500 mg TID for 10 days has been shown to lead to recovery in 67% of all patients that experience this condition. Other types of sensorineural hearing loss may be due to damage to the hair cells of the cochlea responsible for transducing the mechanical sound vibrations into the electrical signal of the nervous system. Common causes include exposure to loud noises on a regular basis, unfavorable congenital or genetic traits, age-related changes (known as presbycusis), infection, inflammation, and tumor growth. Age-related changes tend to be symmetrical. Presbycusis may also lead to difficulties with speech discrimination. Asymmetric hearing losses may be due to acoustic neuromas of the vestibulocochlear nerve. In such patients, there is typically poor speech discrimination, tinnitus, disequilibrium, and other symptoms. Diagnosis of acoustic neuroma is preferably made through gadolinium MRI.
Vestibular disorders affect people of all ages. The incidence of vestibular dysfunction increases with age, and as many as one-third of those between 65-75 years of age report significant problems with dizziness and imbalance. Some of the more serious vestibular diseases, such as Ménière’s disease, affect 16 out of 100,000 people every year. More serious disorders can lead to imbalance, nausea, confusion and disorientation, headaches, and vertigo (which is not to be confused with dizziness). Vestibular disorders center on the sensations of vertigo, dizziness, lightheadedness, syncope, and ataxia. When dealing with patients with a chief complaint of dizziness, it is important to elucidate the precise nature of the complaint in more descriptive and precise terms. The more serious disorders can lead to imbalance, nausea, disorientation, headaches, acute and chronic vertigo, and even death. A more thorough account of vestibular disorders is presented in the Clinical Review of Otolaryngology. While spinning in a circle and attempting to walk around is relatively benign, dizziness becomes significantly more disruptive with age causing falls and, therefore, one of the leading causes of death in the elderly. This situation is likely exacerbated by various medications consumed by this population that have side effects that further disrupt normal vestibular function. Differentiating central vertigo from peripheral vertigo is important. Central vertigo is gradual in onset and occurs with defects in other sensory functions. A vertical nystagmus is often present. Causes of central vertigo can be from acoustic neuroma, hemorrhage, or ischemia. Multiple sclerosis may also present with central vertigo. Peripheral vertigo presents suddenly with hearing loss and tinnitus. There is typically a horizontal nystagmus. Causes of peripheral vertigo include benign paroxysmal positional vertigo (BPPV), Ménière’s disease, labyrinthitis, and antibiotic ototoxicity. Treatment of vestibular disorders should be tailored to the particular etiology. Ménière disease is typically treated with low-salt diet and diuretics, followed by labyrinthectomy, if the disorder is refractory to medical management. BPPV is treated with the Dix-Hallpike maneuver. Labyrinthitis is treated with meclizine and diazepam. 200
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5.4. Infectious Diseases 5.4.1
Rabies is the progressive and lethal infection that ravages the nervous system. Rabies is exceedingly rare, but common causes include bites from raccoons, skunks, feral dogs, foxes, and exposure to bats. Corneal transplants may also lead to rabies in rare instances. Replication of the rabies virus occurs in the region of the bite, followed by transmission to the CNS, peripheral nerves, and salivary glands. The prodromal phase in rabies infection leads to irritability, hydrophobia, GI symptoms, pain, and aerophobia. The excitation phase leads to hyperactivity with disorientation and seizures. Lethargy appears later with cardiac and respiratory decompensation, shortly followed by death. Diagnosis is confirmed by the presence of Negri bodies and positive antibody tests with polymerase chain reaction (PCR). Rabies is treated with rabies immunoglobulin and a human diploid cell rabies vaccine. Isolation is required and prophylactic vaccination is used with high-risk populations.
Bacterial meningitis is commonly the result of infection of the pia and arachnoid membranes by Streptococcus pneumoniae (over half of all cases), Neisseria meningitidis, Listeria monocytogenes, gram-negative rods, Haemophilus influenzae, and group B streptococcus (GBS). Young adults are likely to have meningitis from N. meningitidis; IC patients are more likely to suffer from L. monocytogenes; neonates are likely to acquire GBS perinatally. Infection may occur through the bloodstream, direct invasion, or from otitis or sinusitis. Meningitis presents with headache, neck stiffness, fever, and photophobia. Mental status changes leading to increasing Glasgow coma scale scores is common. Kernigâ€™s sign is typically positive with extension of the knee and thigh leading to pain in the back. Brudzinskiâ€™s sign is positive demonstrating neck flexion and leads to knee and hip flexion. CBC indicates a leukocytosis with PMNs. Blood cultures are positive in about half of all individuals. Lumbar puncture indicates increased neutrophils, increased protein, low glucose, and high opening pressure. CSF culture is more sensitive than blood culture. The presence of numerous monocytes indicates infection by L. monocytogenes. Treatment of bacterial meningitis is empirical and typically includes vancomycin plus cefotaxime or ceftriaxone. This is also the standard treatment for Streptococcus pneumoniae. If N. meningitidis is the identified cause, treatment can proceed with penicillin G or ceftriaxone. L. monocytogenes infection is treated with ampicillin and gentamicin.
Viral meningitis, also referred to as aseptic meningitis, is more common than bacterial meningitis. Viral meningitis is typically benign with signs and symptoms similar to that of bacterial meningitis. Lumbar puncture (LP) typically indicates high WBCs with mostly lymphocytes, normal protein and glucose, and a normal or high opening pressure. Treatment is primarily supportive.
Fungal meningitis presents with a high WBC count of mostly lymphocytes on LP. Protein is high, glucose is low, and opening pressure is high. Treatment of fungal meningitis is with appropriate antifungals. 201
Clinical Review for the USMLE Step 1 5.4.5
Viral encephalitis is typically more of an aseptic meningoencephalitis that generally occurs in teenagers and young adults. Viruses interact with various cell surface molecules to propagate their infection; for example, the rabies virus takes advantage of acetylcholine receptors. Infection may occur through retrograde neuronal infection or spread through the vasculature. Unlike viral meningitis, viral encephalitis may lead to significant destruction and neuronal cell death and even be fatal. Nearly 1 in 10,000 persons are affected annually. Causes include HSV, VZV, influenza virus, enterovirus, rabies virus, lymphocytic choriomeningitis virus (LCV), lassa fever, mumps, measles, nipah virus, eastern equine virus (EEV), western equine virus (WEV), St. Louis Encephalitis, West Nile virus, Dengue fever, Colorado tick fever, and a whole host of more rare causes. Viral encephalitis presents with acute fever, headache, neck stiffness, focal neurologic findings, seizures, stupor and coma. CNS changes are common. HSV is the most common infectious cause. Lymphocytes dominate the CBC. Viral cultures and antibody tests can be attempted by collecting the CSF or even a brain biopsy in some cases. Low density lesions may be found on CT scan with HSV infection, especially around the temporal lobe. More details about these infections can be found in the Clinical Review of Neurology. Treatment for viral encephalitis includes supportive management after protecting the airway. Reducing ICP and seizure prophylaxis is important. Ribavirin, ACV, and other antivirals are sometimes effective.
A brain abscess may develop insidiously or following trauma, surgery, or with spread from a nearby infection such as sinusitis or otitis media. The incidence has increased with AIDS, and mortality is very high if the abscess ruptures. Common causes are S. aureus, S. intermedius, Bacteroides, Prevotella, Fusobacterium, Enterobacteriaceae, Pseudomonas, and other infectious agents. Brain abscess is typically present for only a few weeks prior to diagnosis. Symptoms of neurologic impingement occur, including headache, neurologic changes and deficits, fever, seizures, nuchal rigidity, and papilledema. Rupture may lead to rapid decompensation. Abscess in the cerebellum may lead to defects in motor balance and subsequent ataxia and nystagmus. Abscess in the brainstem may lead to auditory and facial nerve defects. Frontal abscess may lead to mental status changes. Temporal lobe abscess may lead to visual defects. CT is the preferred test to determine the extent of disease. Surgical excision with long-term antibiotic use is the standard of care following precise planning of the surgical approach with the aid of CT. Penicillin is a good choice against streptococci and staphylococci. Metronidazole is used against gram-negative bacilli. Ceftazidime is used against Pseudomonas. A third generation cephalosporin with metronidazole is commonly used with otitis, mastoiditis, and sinusitis. Dental infections get penicillin and metronidazole. Vancomycin plus a cephalosporin is used following trauma or surgery.
Botulism occurs due to ingestion of toxins formed by Clostridium botulinum leading to flaccid paralysis. It commonly occurs from poor preparation and canning of foods, and contamination of open wounds. It presents after about one day and its effects are due to blockade of acetylcholine release in peripheral nerves. Symptoms include dry mouth, diplopia, dysphagia, dysarthria, weakness of the extremities, and weakness of respiratory muscles. Constitutional symptoms are typically present, including nausea and vomiting, diarrhea, and abdominal cramping. Diagnosis is by serology to detect the toxin. Honey carries botulinum spores and can lead to botulism in infants through replication in their relatively imma202
CNS and PNS Pathology ture GI tract (doubtful see recent literature). The toxin may be inactivated after ten minutes of boiling, but destroying the spores requires several hours of boiling. Botulism is treated by administering the antitoxin and decreasing absorption by inducing vomiting or diarrhea. Penicillin and antitoxin are given if the focus is a contaminated wound. Ventilator support may be necessary to avoid respiratory failure.
5.5. Neurodegenerative Disorders 5.5.1
Alzheimer Disease (AD)
Alzheimer disease results in dementia, cognitive deficits, and behavioral changes in more than 5 million people in the US. The elderly are the fastest growing population in the US, and the prevalence of AD is expected to increase significantly. The lifetime risk is on the order of 1 in 3 individuals, with increasing risk with age. AD is the leading cause of death after cancer and cerebrovascular disease, and the primary cause of death is intercurrent illness. AD increases with age and af- Figure 47. Alzheimerâ€™s disease. Copyright NIH. Used with permission. fects both men and women equally. AD is tied to the development of neurofibrillary tangles (NFTs), senile plaques (SPs), and cerebrocortical atrophy in the temporal lobe. NFTs and SPs occur in other neurodegenerative conditions and in normal aging, but AD is distinct in that the temporal lobe has a preponderance of these two anatomic defects with neuronal loss and synaptic degeneration. While NFTs and SPs are not pathognomonic for AD, their coexistence in sufficient numbers in the temporal lobe is diagnostic. Later stages of AD have NFTs and SPs in other regions of the brain. Causes include genetic risk factors such as APP on chromosome 21, presenilin I on chromosome 14, presenilin II on chromosome 1, Figure 48. Neurofibrillary tangles in Alzheimerâ€™s disand various other markers on chromosomes ease. Copyright KGH. Used with permission. 12 and 19; advancing age-related changes, 203
Clinical Review for the USMLE Step 1 and head injury. AD presents with progressive memory deficits, cognitive impairment, and personality changes leading to dementia and loss of higher order brain functions over time. Delirium is not present, which would signify an entirely separate etiology. A mini mental status examination (MMSE) and a language examination make up the repertoire of physical exam tools available to the clinician. CT and MRI are used to diagnose the cerebral atrophy and rule out other causes of brain damage. EEG has specific findings in AD. Treatment for AD is limited and there is no cure or therapy that slows its progression. Alleviating psychiatric and psychologic factors (such as anxiety) help somewhat, along with behavioral therapy and cognitive therapy. Managing any concurrent psychiatric ailments is important (see the Clinical Review of Psychiatry for a more thorough discussion of these agents). Anticonvulsants such as gabapentin in particular may be useful. Acetylcholinesterase (AChE) inhibitors such as donepezil, tacrine, and rivastigmine may assist in the treatment of AD by avoiding ACh depletion in the cerebral cortex and hippocampus. N-methyl-D-aspartate (NMDA) antagonists such as memantine may assist in various neurodegenerative conditions by preventing overstimulation of glutamate receptors. Depression is commonly found in AD, and the use of antidepressants is the key to alleviating some of the symptoms of AD. Free-radical scavengers are also occasionally used.
Parkinson Disease (PD)
Parkinson disease affects 1 out of 500 individuals. It is more common in men and PD increases with age, especially after the age of 60. PD is the result of loss of pigmented dopaminergic neurons from the substantia nigra (SN) especially in the ventral lateral SN. Lewy bodies (which are dense core bodies found within neurons throughout the cortex, nucleus basalis, locus ceruleus (LC), intermediolateral (IML) column, and the SN) are also found. Lewy bodies are non-specific findings in PD. Defects in the output of the basal ganglia-thalamocortical motor circuit as the transmissions pass through the SN lead to abnormalities in motor suppression. Failure to activate the direct pathway and inhibit the indirect pathway in the striatum leads to the pathognomonic features of PD, discussed below. Causes include genetic predisposition, exposure to certain pesticides or industrial toxins, and use of 1-methyl4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Oxidative damage leading to lipid peroxidation has also been implicated. PD is predominantly a clinical diagnosis made by the presence of an asymmetric resting tremor, bradykinesia, rigidity, gait abnormalities, and constitutional symptoms. Tremor and motor derangements progress with axial flexor, dysphagia, and autonomic dysfunction. The three most important signs in diagnosing PD include a resting tremor, rigidity, and bradykinesia. Postural instability arises later in the disease. The rigidity takes the form of either a lead-pipe rigidity or cogwheel rigidity. Loss of spontaneous movements and slowness of motion characterizes bradykinesia. Loss of righting reflexes leads to postural instability. Dementia occurs late in the disease and Figure 49. Lewy bodies in Parkinsonâ€™s disease. affects about 1/3 of patients. Imaging studies are Copyright Andreas Becker. Used with permission. used only to exclude other etiologies. Positron emission tomography (PET) and single photon 204
CNS and PNS Pathology emission CT (SPECT) are useful for diagnosis. Treatment of PD centers on supportive therapy to reduce symptoms and retain baseline functioning for as long as possible. Selegiline is used as a neuroprotective agent against MPTP toxicity. Tocopherol, or vitamin E, has also been used with some benefit and increases the time before levodopa is necessary. The use of levodopa becomes necessary in reducing the symptoms of Parkinsonism, but some studies suggest that long-acting dopamine agonists such as bromocriptine, pergolide, pramipexole, ropinirole, and cabergoline are preferred in certain situations. Stereotaxic surgery to stimulate portions of the thalamus has been found to be beneficial in some groups of patients. Pallidotomy can be done to reduce dyskinesia. Newer therapeutic options may offer transplantation of dopaminergic cells to the affected region.
Huntington Disease (HD)
Huntington disease (HD) is a progressive, autosomal dominant disorder that leads to neuron loss within the cortex and basal ganglia. Atrophy of the caudate and putamen nuclei occurs with atrophy of other related structures over time. The basic cause is a triplet CAG expansion in a protein product that leads to derangements in synaptic vesicles, microtubules, and mitochondria with concomitant mutant protein accumulation and the development of cellular inclusions. Disease occurs with neuronal cell death from excessive inclusion. Other causes of HD include increased excitotoxicity, oxidative stress, impaired neuronal energy metabolism, and apoptosis. HD affects 5 out of 100,000 people and is more common in certain European populations. It manifests itself in the 50s with death several decades later, primarily from pneumonia or cardiovascular disease. HD in younger patients reflects genetic inheritance with anticipation. HD presents with chorea, a movement disorder that begins with increased fidgeting followed by flailing of the extremities in a phenomenon known as hemiballism. Chorea progresses to dystonia, bradykinesia, rigidity, postural instability, and finally, an akinetic-rigid state. Clonus and spasticity are present later in disease. Ocular abnormalities and tic disorders are common Figure 50. Inclusion bodies seen in early on. Early onset of HD (known as the Westphal variant) Huntingtonâ€™s disease. Copyright Steleads to early dementia and the development of a seizure disor- ven Finkbeiner. Used with permission. der. Impairments in cognition proceed at variable rates, and depression is common. Changes in personality can occur. Imaging tests are used to rule out other disorders. Genetic testing is used to confirm the diagnosis by identifying multiple CAG repeats. Treatment involves reducing the chorea with agents such as tetrabenazine, various benzodiazepines, or anticonvulsants. Levodopa can be used to modify the bradykinesia and rigidity. Depression should be treated early with selective serotonin reuptake inhibitors (SSRIs). Antipsychotics may be used to modify psychotic symptoms and irritability. Personality changes should be addressed with medications as appropriate. Surgical ablation and cell transplant options are currently being studied.
Clinical Review for the USMLE Step 1 5.5.4
Multiple sclerosis (MS) is a progressive, inflammatory, demyelinating disorder of the CNS that leads to physical disability. Infiltration of lymphocytes and macrophages into nervous tissue cause inflammation and disruption of the nerve. Surgery and other external stressors may be a trigger for onset. The initial presenting sign may be acute blindness, followed by rapid resolution. After a waxing and waning course, neurodegeneration progresses rapidly. Weakness and fatigue are universal. Cognitive changes occur in some, ataxia in others, along with hemiparesis, depression, and psychomotor changes. Bilateral facial weakness and trigeminal neuralgia are strongly indicative of MS. CSF studies reveal oligoclonal banding, normal glucose, normal or high protein, and high WBC count with excess IgG. MRI is used to localize the regions of sclerosis. MS is treated with supportive care while miniFigure 51. MRI changes seen in MS. Copyright mizing the effects of intercurrent illness and psyBrookhaven National Labs. Used with permission. chomotor stressors. Amantadine or modafinil are beneficial for fatigue mitigation. Disease progression can be slowed with interferon beta-1a, interferon beta-1b, and glatiramer acetate. Acute exacerbations can be minimized with methylprednisone, and high-dose IV steroids may be beneficial in certain situations.
Myasthenia gravis is a rare autoimmune disorder that leads to weakness and fatigue as a result of antibody-mediated loss of the acetylcholine receptor (AChR) and neuromuscular junction (NMJ). MG is exacerbated by a number of drugs, including penicillamine. MG presents as variable weakness worsened on exertion and improved with rest. Extraocular muscles (EOM) are weak and ptosis may be present in many patients. CXR is used to rule out thymoma, which affects 25% of patients, and thymectomy may forestall symptoms for many years. Electromyography (EMG) is diagnostic, and the edrophonium test can be used when other studies are deemed inconclusive. MG has no clear treatment. Inhibitors of AChE have been used with some effect; medications include pyridostigmine and neostigmine. Immunomodulation with prednisone, azathioprine, and cyclosporine A (CsA) has some benefit. Plasmapheresis can remove antibodies emergently and prevent relapse.
Pseudobulbar palsy is bilateral dysfunction of cranial nerves IX through XII, leading to a dysfunction in speech, deglutination, and mastication. Failure of deglutination may lead to aspiration. The cause is an upper motor neuron lesion within the pyramidal tract. There are a variety of causes, including head trauma, MS, and bilateral hemisphere infarction. 206
CNS and PNS Pathology
5.6. Sleep Disorders 5.6.1
Normal Sleep Stages
Sleep is separated into four distinct stages and REM sleep. Stage 1 is typically only 5% of the sleep cycle, and is a period of light sleep. Stage 2 of sleep is about 45% of the time, and is a deeper sleep. The deepest sleep occurs in stages 3 and 4, during which one-quarter of the sleep cycle is spent. Stages 3 and 4 of sleep are the period during which night terrors, sleepwalking (somnambulism), and bed-wetting occurs. REM sleep consumes one-quarter of the sleep cycle, and is the period during which dreaming occurs. There is a loss of muscle tone during REM sleep, increased processing by the brain of the daily events, memory retention, erections, and elevated use of oxygen by the brain. REM sleep occurs every 90 minutes, increases in duration during the night, and decreases with age. The extraocular movements that occur in REM sleep are due to action potentials emanating from the paramedian pontine reticular formation, also known as the conjugate gaze center. Waveforms vary by the period of sleep or wakefulness. When a person is awake with their eyes open, beta waves, or high frequency, low amplitude waves, predominate. A person who is awake with their eyes closed has mostly alpha waves. Stage 1 of sleep is characterized by theta waves. Stage 2 of sleep has sleep spindles and K-complexes. Stages 3 and 4 of sleep have delta waves, which are the lowest frequency but highest amplitude waves found on an EEG. REM sleep has beta waves. The mnemonic BATS Drink Blood can be used to remember the waveforms seen in wakefulness and sleep. Table 8. Stages of sleep and their associated wave forms Stage 1, Light sleep
Stage 2, Deeper sleep
Sleep spindles and K complexes
Stage 3, Deepest sleep
Stage 4, Deepest sleep
REM, Rapid eye movement and dreaming
Sleep is initiated by the serotonergic raphe nuclei. Acetylcholine aids in initiating the onset of REM sleep. Elevated levels of norepinephrine reduce REM sleep. Night terrors and sleepwalking seen in stages 3 and 4 can be reduced through the use of benzodiazepines. Bed-wetting, known as enuresis, can be reduced with imipramine. Sleep disorders are separated into dyssomnias and parasomnias. Dyssomnias are primary sleep disorders that are characterized by a difficulty in initiating or maintaining sleep. This leads to difficulty in feeling rested after sleep, and can lead to excessive sleepiness. The five types of dyssomnias are insomnia, hypersomnia, narcolepsy, breathing-related sleep disorder, and circadian rhythm sleep disorder. Parasomnias are disorders that occur during sleep that can lead to arousal from sleep. Parasomnias include excessive nightmares, sleep terrors, and sleep walking. Secondary sleep disorders can also occur, and are attributable to other psychiatric illnesses, a general medical condition, or a substance-induced sleep disorder. Narcolepsy occurs when an individual suddenly falls asleep. Hallucinations may accompany narcolepsy 207
Clinical Review for the USMLE Step 1 â€“ if the hallucinations occur just as the person is falling asleep, they are known as hypnagogic hallucinations; those that occur just as the person is waking up are known as hypnapompic hallucinations. A person who experiences an episode of narcolepsy while standing, and then falls to the floor, experiences cataplexy. Narcolepsy is best treated with stimulants.
5.7. Epilepsy 5.7.1
Epilepsy is the presence of recurrent seizures, or abnormal bursts of CNS activity leading to abnormalities in motor behavior, autonomic activity, and changes in consciousness. There are two types of seizures, generalized and partial seizures. Generalized seizures are broken down into tonic-clonic, or grand mal seizures, absence or petit mal seizures, atonic seizures, and myoclonic seizures. Common causes of seizure include vascular defects, cerebral infection, penetrating trauma to the head, autoimmune disorders, metabolic derangements, neoplasm, psychiatric causes, and idiopathic causes.
Tonic-clonic seizures begin with a loss of consciousness (LOC) and loss of postural control, followed by the tonic phase. The tonic phase is characterized by muscle rigidity throughout the body. The clonic phase follows, with rhythmic contractions of the extremities. Incontinence is often a feature of tonicclonic seizures. EEG changes reflect the abnormal activity taking place.
Absence seizures are brief disruptions of consciousness leading to the individual appearing as if they are not paying attention or concentrating on the task at hand. There are occasionally some motor cues, including lip-smacking, chewing, or partial loss of motor tone. Bilaterally synchronous slow wave activity is seen on EEG.
Atonic seizures are brief losses of consciousness and postural tone, leading to a sudden fall to the floor in standing individuals. This type of seizure is similar to the cataplexy of narcolepsy.
Myoclonic seizures are muscle contractions without a superimposed loss of consciousness. Myoclonic seizures are more common in neurodegenerative disorders.
Partial seizures are broken down into simple and complex partial seizures. Simple partial seizures have a straightforward sensory, motor, or autonomic abnormality during the seizure. The nature of the defect is dependent on the particular part of the brain that has the epileptiform focus. Complex partial seizures meet the criteria for simple partial seizures, except there is a superimposed disturbance in cognition. This type of seizure activity is the most common type of seizure disorder found in adults. Dream-like sensations may be present during the seizure.
CNS and PNS Pathology 5.7.7
Status Epilepticus and Preictal Symptoms
Seizures can present with preictal symptoms such as auras or sensations. Postictal symptoms typically include delirium, amnesia, or focal paralysis (known as Todd paralysis). Status epilepticus presents with continuous seizures.
Diagnosis and Treatment
Diagnosis of seizure activity is made by electroencephalogram. Derangements in electrolytes and other causes of seizures must be identified and appropriately treated. CT scan or MRI is used to identify any anatomic defects. Seizure treatment includes securing the ABCs. Reversible causes should be treated immediately. The initial drugs of choice are benzodiazepines, including lorazepam or diazepam. If potentiating GABA function does not inhibit the epileptic focus, treatment with phenytoin or fosphenytoin is initiated to inhibit sodium-dependent action potentials. Phenobarbital, a barbiturate, is added. Finally, if seizures continue with this complex regimen, midazolam or propofol can be added to induce anesthesia. Firsttime seizures are treated only with a clear family history, abnormal EEG, or abnormal neurologic exam. Tonic-clonic seizures are primarily treated with valproic acid, followed by lamotrigine to increase GABA availability or decreasing glutamate release, respectively. Absence seizures are treated with ethosuximide or valproic acid. Myoclonic and atonic seizures are primarily treated with valproic acid. Partial seizures are all treated with carbamazepine, phenytoin, valproic acid, or lamotrigine. Side effects of seizure treatment are numerous. Phenytoin may lead to ataxia, dizziness, diplopia, hirsutism, and rash. Phenobarbital can lead to ataxia and rash. Valproic acid may cause ataxia, hepatotoxicity, thrombocytopenia, GI irritation, or hyponatremia. Lamotrigine is implicated in causing Stevens-Johnson syndrome, in addition to rash and ataxia.
5.8. Cancer Brain tumors kill over 13,000 patients a year, but metastatic tumors to the brain occur in more than 80,000 additional cases. Metastasis occurs most commonly from the breast, lung, and melanomas. Brain tumors are the most common solid tumor in children. The most common tumors include gliomas, meningiomas, and schwannomas. Brain tumors in adults are commonly the result of exposure to radiation or HIV infection. Genetic transmission also occurs, but most tumors tend to occur earlier in age. Brain tumors present with headache in most patients. The headache is present on awakening and disappears within an hour or so. Headaches with brain tumors can rouse a patient from sleep, and typically worsen when lying supine. A common cause of a new headache in older patients is a brain tumor. Nausea and vomiting are typically present, along with focal neurologic changes including vision loss, weakness, and seizures. Diagnosis is made by CT, MRI, and confirmed by biopsy. Treatment for brain tumors consists of decreased ICP with steroids, followed by surgical resection, chemotherapy, and radiation.
Clinical Review for the USMLE Step 1 Table 9. Brain and spinal cord cancers. Types
Palisading tumor cells with necrosis, hemorrhage, rapid growth, bilateral.
Elderly most affected; most common primary tumor; malignant, often fatal; found in cerebral hemispheres.
Psammoma bodies. May present as a cranial nerve palsy.
Women most affected especially at cerebral hemispheres; benign tumor outside of brain; treat with resection.
Palisading tumor cells; typically vestibulocochlear schwannoma; if bilateral, consider NF-2 (Chr 22).
Later in life or hereditary. May be spontaneous or secondary to neurofibromatosis 2.
Fried egg appearance, calcifications.
Slow growing, indolent.
Bitemporal hemianopsia, typically secretes prolactin (amenorrhea in women with gynecomastia).
Diffuse with Rosenthal fibers. High grade tumor.
Narrow and diffuse subtypes. Typically benign in children, but may herald a poor prognosis in adults.
Hydrocephalus, mass effects, rosettes.
Children most affected, especially at cerebellum; very malignant but radiosensitive.
Rosettes with rod-shaped inclusions.
Most common spinal cord tumor with metastasis to vertebral body; 4th ventricle. Excellent prognosis if found early.
Foam cells, vascularity, polycythemia from EPO production.
Cerebellar, VHL syndrome (WT-1 w/ aniridia).
Calcification in remnant of Rathkeâ€™s pouch â€“ no hormone production.
Unilateral or bilateral retinal tumor development.
Occurs in children, commonly in cerebral hemispheres. Related to defects in the N-myc oncogene. Very young children most affected; most common eye tumor of children. Related to Rb gene deletions.
May lead to headaches, visual defects, and personality changes.
Embryonal tumor found near the sacrum
Due to derangements in B cell function.
5.9. Salivary Gland Tumors Tumors of the salivary glands may affect the parotid, submandibular, sublingual, or minor salivary glands. The larger glands are more likely to have benign tumors, while the smaller glands are more likely to present with malignant masses. The most common site for a salivary tumor is the parotid gland. Malignant tumors typically present with an enlarging mass, paresthesia of cranial nerves (i.e. CN VII, IX), and discomfort. All masses should have a fine needle aspiration for pathologic evaluation, along with a CT or MRI for staging and surgical planning. Pleomorphic adenomas are the most common benign parotid gland tumors. This tumor may be superficial or deep. Superficial tumors are best treated with a facial nerve-sparing superficial parotidectomy. Deep tumors should be treated with careful resection of the parotid gland with sparing of the facial nerve. Papillary cystadenomas (Warthin tumor) may also occur in the tail of the parotid gland and are treated similar to pleomorphic adenomas. While 80% of parotid gland tumors are benign, 20% may be malignant and typically present as a mucoepidermoid or adenoid cystic tumor. Low grade malignant tumors of the parotid gland can be treated a nerve-sparing parotidectomy. However, high-grade, ag210
Psychopathology gressive tumors should elicit a total parotidectomy with modified radical neck dissection and adjuvant radiotherapy. Resection of the facial nerve with nerve interposition can be completed if there is any evidence of perineural invasion, which is especially common with the high-grade cancers.
6. Psychopathology 6.1. Psychotic Disorders 6.1.1
Psychosis is impairment in the ability to distinguish what is real from what is not. Examples of psychosis include hallucinations, delusions, illusions, ideas of reference, ideas or influence, and disorganization of thought. A primary psychosis is differentiated from a mood disorder that has psychotic features in that a mood disorder is fundamentally characterized by the affective disarrangement. Some components of psychosis can include ideas of influence, in which an individual believes that some outside force or entity is controlling them; ideas of reference, in which an individual believes that people on television or on the radio are speaking directly to the person; noesis, in which a person feels a revelation has been made to them and that they are a leader; and clang associations in which words are associated based on similar sounds (homonyms).
Schizophrenia is one of the most common psychoses, affecting nearly 1% of the population. Schizophrenia is defined as a psychotic disorder with psychosocial dysfunction lasting greater than six months. Schizophrenia tends to occur in young adults, earlier in men than in women with nearly one third of women having their first psychotic episode in their 30s. Schizophrenia is more likely to be diagnosed in the indigent, and although a number of theories have been postulated, they have yet to be scientifically proven. Several studies have also indicated that schizophrenia is more prevalent in individuals with lower socioeconomic status. One hypothesis is that patients with schizophrenia are less likely to maintain steady jobs and thus fall into a lower economic standing due to chronic joblessness. Schizophrenia has a strong genetic component, but does occur spontaneously. A neurobiological basis has been postulated, known as the dopamine hypothesis. According to this theory, schizophrenia is due to an increase in activity of the dopaminergic pathways. This is substantiated by the Mechanism of Action of antipsychotics, which serve to reduce dopamine levels in the brain. Further, postmortem studies have demonstrated elevated levels of dopamine receptors in certain subcortical nuclei of the brain. The dopamine hypothesis also explains why cocaine and other amphetamines lead to psychosis, as these drugs are known to work through a dopamine-mediated mechanism. Schizophrenia has both positive and negative symptoms. Positive symptoms include having: disorganized, unusual type of thinking; auditory or visual hallucinations; eccentric behavior. Negative symptoms are the absence of normal mentation and psychosocial functions. For example, amotivation, isolation, and poor hygiene are all negative symptoms. It appears that certain medications are better suited for treating positive symptoms of schizophrenia, while others are better for dealing with the negative symptoms. The formal diagnosis of schizophrenia requires the presence of two or more of the following criteria, including delusions, hallucinations, dysarthria (disorganized speech), disorganized or catatonic motor behavior, and the presence of negative symptoms. The negative symptoms can be characterized as flat211
Clinical Review for the USMLE Step 1 tened affect, alogia (lack of words), and asociality (isolation from others). Schizophrenia, as a clinical diagnosis, also requires significant alterations in oneâ€™s psychosocial or occupational function. Finally, these symptoms must be present for more than six months. Straightforward presentations of schizophrenia are primarily managed through medical intervention. For example, neuroleptics, also known as antipsychotic agents, are used to treat both acute presentations and for maintenance. In patients with schizophrenia that is refractory to simple medical management, a combination of agents is necessary to achieve satisfactory resolution of symptoms. These agents include psychosocial interventions, such as stable reality-oriented psychotherapy, family interventions, structured environments, and possibly electroconvulsive therapy (ECT).
Schizophreniform disorder meets the criteria for schizophrenia with the exception of time-constraint. Schizophreniform disorder is the name given for the psychosis with schizophrenia-type features, but with a time course less than six months but more than one month. Patients who develop schizophreniform disorder tend to go on to develop schizophrenia, although some develop a mood disorder with psychotic features instead. Schizophreniform disorder is additionally differentiated from schizophrenia in that social withdrawal is not required for this diagnosis.
Brief Psychotic Disorder
A brief psychotic disorder is characterized as a short-lived, acute derangement with features similar to schizophrenia without a triggering event. Psychotic symptoms last for at least one day, but must resolve within one month with a return to normal baseline functioning. If symptoms last for more than one month a diagnosis of schizophreniform disorder and eventually schizophrenia must be considered.
Schizoaffective disorder is the presence of schizophrenia-like features but with an overlying mood disturbance. In order for this diagnosis to be tenable, psychotic features must persist in the absence of any mood disturbance. For example, a patient must have schizophrenia-type symptoms only for a certain period of time, and then have symptoms of both a mood disorder and schizophrenia simultaneously during a different period of time. Treatment of schizoaffective disorder is centered on treating the psychosis and the mood disturbance. These patients require treatment with both an antipsychotic medication and a mood stabilizing medication. Antidepressants and electroconvulsive therapy are also used as needed in the management of schizoaffective disorder.
Delusional disorder is characterized by the presence of delusions without other psychotic features. These fixed, false beliefs are nonbizarre, and are characterized by things that could happen in real life such as being followed, being poisoned, etc. Paranoid personality disorder is often an overlying condition in delusional disorder. Delusions in this disorder must be present for at least one month. The patient cannot meet criteria for any other mood disorder, and no social maladjustment is necessary for diagnosis.
Psychopathology Management of delusional disorder involves psychotherapy. No attempt to support or refute the delusion should be made; rather, the therapy should focus on creating a strong alliance with the patient. With time, the alliance may aid the patient in coming to terms with his or her fixed, false beliefs. Antipsychotics have also been used in treatment, but with few positive results.
6.2. Mood Disorders 6.2.1
Mood and Affect
Mood is defined as oneâ€™s emotional state, and differs from affect in that the latter is the external manifestation of feelings. Affect is what others see, while mood is what the individual feels inside.
Mood disorders are separated into three separate categories: unipolar mood disorders including major depressive disorder (MDD) and dysthymic disorder; bipolar mood disorders including bipolar I, bipolar II, and cyclothymic disorder; and substance-induced mood disorders or mood disorders due to a general medical condition.
Major depressive disorder is characterized by patients who have had one or more major depressive episodes. There are profound emotional changes with a concomitant changes in sleep patterns, interest in other activities, energy, and appetite. The lifetime prevalence of depression ranges from 5 to 20%, and it is twice as common in females as compared to males. Major depression is a psychiatric disorder that is not tied to a particular socioeconomic class, which is in contrast to schizophrenia. Major depression disorder primarily affects adults between twenty and forty years of age. The rate of recurrence is 60% after one episode. Risk factors for depression vary, but the highest correlation is with the actual or perceived loss of a person close to the patient. Recent theories postulate that this loss leads to a sudden shift in oneâ€™s regular egosyntonic controls and positive feedback mechanisms for self-regard, leading to a cognitive distortion and subsequent negative misperception of the external environment. Depression has a strong genetic component, and has a strong concordance in monozygotic twins. A genetic defect appears to lead to a dysfunction in normal amine neurotransmitter levels, especially in the hypothalamic-pituitary-adrenal axis. Clinical manifestations of major depression vary, but disturbances in sleeping patterns are nearly universal complaints. Sleep studies in depressed individuals have noted a decrease in stage 3 and 4 of sleep (delta waves). There is an increased time spent in REM sleep (beta waves), with decreased latency of the rapid eye movement (hence, faster onset of REM sleep). Other changes in major depression include having a depressed mood for the majority of the day on a regular and consistent basis, difficulty sleeping or excessive sleeping, anhedonia (lack of pleasure), feelings of worthlessness and guilt, low energy with chronic fatigue, decreased ability to concentrate on tasks, change in appetite with a resultant change in weight, psychomotor retardation or agitation, change in libido, and suicidal tendencies. Depression is best treated with psychotherapy and medical intervention. Antidepressant medications are the mainstay of medical treatment, and the best prognosis is found in patients treated with these medications coupled with psychotherapy, especially if the depression is severe. A number of classes of 213
Clinical Review for the USMLE Step 1 antidepressants are available, and it appears that tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAOIs) work well. Atypical antidepressants include thyroid hormone, psychostimulants, and lithium carbonate. All of these have all been used with positive effect. In depression refractory to medical treatment, electroconvulsive therapy has been used with positive effect. Anxiolytics may also be used as indicated, while phototherapy presents itself as an option in patients with seasonal mood disorders. The symptoms of depression can be remembered with the mnemonic SIG E CAPS, or sleep changes (hypersomnia or insomnia), interest (loss thereof), guilty feelings and worthlessness, energy changes (decreased), concentration deficits, appetite changes (increased or decreased), psychomotor agitation or retardation, and suicidal ideations. Depression may present with psychotic features, such as nihilistic delusions in which there are strong feelings that one’s self or others have been destroyed. Severe such delusions are termed Cotard syndrome. Such patients may complain of many bizarre losses, including various organs within their body, status, strength, respect, possessions, and so forth. Nihilistic delusions may also involve the world becoming nothingness. Cenesthetic delusions are also possible, in which there are false beliefs that things are occurring within the body.
Bipolar I Disorder
Bipolar I disorder is the most serious variant of the three bipolar disorders (bipolar I, bipolar II, and cyclothymic disorder). Bipolar I disorder is diagnosed in patients following a single episode of mania. These patients have major depressive episodes during their lifetime. The prevalence of bipolar I is approximately 1%, with an equal preponderance in males and females. Bipolar I disorder has a strong relationship to genetic heritage. Triggers for bipolar I include the typical psychosocial stressors, and disturbances in the sleep / wake cycle. The formal diagnosis of this disorder also requires several of the following criteria to be met: pressured speech, flight of ideas and / or racing thoughts, distractibility, increase in goal-directed activity and / or impulsivity, excess of pleasurable activities including hypersexuality, spending excess amounts of money, decreased need for sleep with only a few hours of sleep every night, and delusions of grandeur / inflated ego. One of the key indicators for bipolar disorder is the attempt to treat a major depressive episode with antidepressants, leading to a rapid manic episode. In these patients, since a substance is responsible for causing the manic episode, the formal diagnosis is really substance-induced mood disorder. Other psychiatric illnesses presenting with some features of bipolar disorder include schizoaffective disorder, cluster B borderline personality disorder, and depression with agitation. Bipolar I disorder is best clinically managed by antipsychotics and with benzodiazepines when patients present acutely (discussed below). Other drugs commonly used with positive effect include lithium carbonate (the most commonly used mood stabilizer when renal impairment is not present), and valproic acid (also known as depakote; the intramuscular version is known as depakene). Should these first-line agents fail, carbamazepine, gabapentin, lamotrigine, and long-acting benzodiazepines can be added to the treatment regimen. Finally, bipolar I disorder refractory to medical intervention can be treated with electroconvulsive therapy. The successful treatment of bipolar I disorder requires the use of a mood stabilizer to prevent cycling from “highs” and “lows.” Since patients with this diagnosis are often resistant to treatment, the use of psychotherapy is key in increasing compliance with medications. The first line treatment is lithium, followed by valproate, carbamazepine, and lamotrigine.
Bipolar II Disorder
Bipolar II disorder is similar to bipolar I disorder except for the absence of significant mania. Patients 214
Psychopathology with bipolar II have a milder form of mania, known as hypomania. These patients may still experience profound major depressive episodes. The lifetime prevalence of bipolar II disorder is half that of bipolar I disorder, ranging at approximately 0.5%. Like bipolar I, bipolar II is a cyclic disorder that varies between “highs” and “lows.” A similar proportion of these patients commit suicide as in bipolar I disorder. The treatment of bipolar II disorder is similar to that of bipolar I.
6.3. Anxiety Disorders 6.3.1
Anxiety is the over-reactive response to an impending challenge or event that is not congruent with the actual stress level of challenge or event. Anxiety disorders are the most common type of psychiatric illness, affecting nearly 8 percent of all people.
There are various types of anxiety disorders, including panic disorder with or without agoraphobia, agoraphobia, social phobia, a specific phobia, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), acute stress disorder, posttraumatic stress disorder (PTSD), substance-induced anxiety disorder (SIAD), anxiety disorder due to a general medical condition, and anxiety disorder not otherwise specified (NOS).
Panic disorder has a lifetime prevalence of two to three percent, and is most common in women. It typically has an onset in young adults. Agoraphobia has a similar prevalence, demographic breakdown, and onset. Patients with only agoraphobia are less likely to seek treatment; hence, most patients with agoraphobia seen in a clinical setting are likely to also have a panic disorder. Panic disorder has many possible pathologic bases, including excessive sensitivity to carbon dioxide (CO2), dysfunction in the locus ceruleus (LC) (controls arousal), elevated catecholamine levels in the central nervous system (CNS), and dysfunction in the gamma-amino butyric acid (GABA) receptor. The latter has been thought to be a potential mechanism mediating panic attacks due to the ability of benzodiazepines, which act through a GABA pathway, to prevent future recurrence of panic disorders. The converse has also been demonstrated: some patients can be induced to have anxiety disorder with GABA antagonists. Panic disorder is characterized by recurrent, random, unexpected attacks of disabling anxiety. These patients may occasionally experience severe dread of open places, where escape from a potentially difficult situation may be difficult. Panic disorder may occur with or without agoraphobia, and agoraphobia may occur by itself. Panic disorder often has a trigger, and can include the presence of being in any stressful or fearful situation. Four or more of the following symptoms are required for the formal diagnosis of panic disorder and these symptoms must reach a peak within ten minutes of the stressor: palpitations or accelerated heart rate (with or without chest pain); accelerated respiratory rate, shortness of breath, or a feeling of being choked; trembling or shaking; diaphoresis; chills or hot flashes; nausea, vomiting or acute gastrointestinal distress; dizziness or lightheadedness; depersonalization (detachment from self) or derealization (feeling of artificiality); fear of losing control or going crazy; a sense of impending doom or fear of dying; and paresthesia. 215
Clinical Review for the USMLE Step 1 Episodes of panic disorder occur suddenly and without warning, peak within ten minutes, and last between five and thirty minutes. These patients must experience these episodes for at least one month with significant worry about impending attacks, brooding about the sequelae of these attacks, and manifest a change in behavior in an attempt to minimize the implications of having these episodes. When panic disorder significantly affects a personâ€™s lifestyle, it becomes a clinical disorder. Panic disorder is primarily treated with a combination of medical interventions and cognitive-behavioral therapy (CBT). Certain selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors, and benzodiazepines have been shown to have positive effect. Benzodiazepines are good for immediate relief, while SSRIs or TCAs are the drug of choice for maintenance. Cognitive-behavioral therapy uses a combination of relaxation techniques and desensitization to mitigate the onset and complications of panic disorder. Teaching a patient that the episodes of panic disorder are innocuous can often reduce the severity of this psychiatric condition. Finally, exposure therapy can be used to teach a patient fearful of open spaces (agoraphobia) that such situations do not pose a danger.
The irrational fear seen in specific phobia is out of proportion with the actual danger. Diagnosis is made when the anticipation of being in a particular situation or the presence of a particular object leads to an extreme anxiety reaction and distress and with an impairment of oneâ€™s lifestyle and interpersonal relationships. Symptoms must be present for at least six months, if the onset of this disorder is in individuals younger than eighteen. Specific phobias often remits spontaneously, if the onset is in childhood. Chronic specific phobias can be treated with exposure therapy, with systematic desensitization, or flooding. No medical intervention is necessary.
As in specific phobia, a social phobia may be diagnosed in patients younger than eighteen only when it has been present for greater than six months. A generalized social phobia may be diagnosed if the patient responds with an anxiety reaction to any situation, or a limited social phobia may exist if only particular triggers exist for the anxiety reaction. Social phobia is managed with cognitive-behavioral therapy, but medication may be required for proper social functioning. SSRIs, low-dose benzodiazepines, and beta-blockers are available. Flooding and systemic desensitization are two approaches used in cognitive-behavioral therapy with good outcomes. Individual and group psychotherapeutic approaches have also been used and a combination of all of these therapies has been shown to have the best outcome.
Generalized Anxiety Disorder
Generalized anxiety disorder is characterized by an irrational fear of virtually every aspect of common, everyday events. Generalized anxiety disorder is diagnosed only when patients are found to worry to an excessive level with high feelings of anxiety. These patients experience excessive anxiety about every facet of their life, including excessive worry about interpersonal relationships, occupational situations, personal health, and the environment around them. This level of incongruent anxiety must be present for at least six months, and the worrying must be difficult to control. The formal diagnosis of generalized anxiety disorder also requires the presence of restlessness from the anxiety, fatigue, irritability, 216
Psychopathology sleep disturbances, difficulty concentrating, and tension in the musculoskeletal system. The key to this diagnosis is that the worry has to do with everyday, normal events, not the worrying associated with experiencing another psychiatric disorder or its manifestations. Generalized anxiety disorder is best managed with a combination of cognitive-behavioral therapy with relaxation techniques, and medical intervention through the use of benzodiazepines, non-benzodiazepine anxiolytics such as buspirone, beta-blockers, and gabapentin. Benzodiazepines are effective medications, but are limited in their use due to their habit-forming nature. Benzodiazepines are recommended for the immediate relief, while SSRIs, venlafaxine, and buspirone are better for maintenance.
Posttraumatic Stress Disorder
Posttraumatic stress disorder is characterized as an anxiety disorder with the patient repeatedly experiencing the original traumatic event. The patient attempts to block the recollection of this traumatic event. S/he is also in a hyperaroused state. Posttraumatic stress disorder affects nearly one percent of the population, especially women, and can occur in any age group at any time after the traumatic event. Posttraumatic stress disorder has been neurologically characterized by an increase in volume of the hippocampus. Patients with posttraumatic stress disorder report experiencing or witnessing a horrific and /or potentially deadly event. These patients repeatedly experience this event through thought insertions and intrusive dreams, hallucinations, illusions, or flashbacks. Treatment of posttraumatic stress disorder centers on the use of psychotherapy and symptom-based psychoactive medications, including antidepressants as necessary. SSRIs, buspirone, and mood stabilizers have positive effect in the treatment of PTSD. Anxiolytics such as beta-blockers, benzodiazepines, and clonidine are recommended as necessary.
The obsessions of this disorder include intrusive, repeated ideas or thoughts that lead to episodes of anxiety. Compulsions of this disorder are stereotyped, purposeful mental or physical rituals that the patient does in order to neutralize the obsessive ideas he or she is experiencing. Hence, a long-standing obsession can lead to compulsions in an effort to decrease anxiety and mitigate the perceived threat of not doing the action. The management of obsessive-compulsive disorder is best done with clomipramine and selective serotonin reuptake inhibitors. Cognitive-behavioral therapy in the form of flooding, systematic desensitization, or response prevention has also been used in some patients with positive effect.
6.4. Cognitive Disorders 6.4.1
A clear definition of illusions, delusions, and hallucinations is important to have a good understanding of various psychiatric illnesses. An illusion is an inaccurate interpretation of an actual outside stimulus. For example, believing that a boat is sounding a foghorn to warn of an impending crash when one hears a semi truck horn is an example of an illusion.
Clinical Review for the USMLE Step 1 6.4.2
Delusions are fixed, false beliefs that exist despite evidence to the contrary. Delusions are not an appropriate term if those beliefs are consistent with the beliefs of a particular culture or society. For example, a religious person believing in God is not a delusion; however, the belief that aliens are invading Earth is a delusion. Delusions are a malformed thought where the content of the thought itself is incorrect. Delusions are different than loose associations because the thoughts are connected to each other in a disorganized way.
Hallucinations are sensory perceptions in the absence of any outside stimuli. Believing that werewolves are attacking one is an example of a hallucination. There are a number of types of hallucinations. Tactile hallucinations involve feeling something in the absence of touch stimuli; they are especially common in substance abuse disorders such as delirium tremens in alcohol withdrawal, in cocaine abusers, and in amphetamine psychosis (these hallucinations are known as formication). Visual and auditory hallucinations such as hearing voices are especially common in schizophrenia. Olfactory hallucinations may occur as part of the aura of migraines or epilepsy.
Delirium is characterized by changes in attention and cognition due to a particular medical condition or substance. The most common substance-induced causes of delirium include alcohol or benzodiazepine withdrawal and toxicity from anticholinergic drugs. Delirium predominantly affects hospitalized, postsurgical patients, especially those over 65 and in intensive care units (ICUs). Delirium is hallmarked by a disturbance of consciousness leading to deficits in attention and arousal, an alteration in cognition and memory, relatively rapid development over a period of hours, and a distinct medical condition or substance-related trigger. In delirium, the sleep-wake cycle is disturbed, and profound psychomotor agitation may be present. There may be difficulty separating delirium from dementia, especially since dementia is a positive predictor for the onset of delirium. The key differences are that delirium is reversible, develops relatively quickly, and the presence of an obvious, immediate precipitating factor. Delirium carries with it a 50% chance of mortality in one year. Treatment of delirium includes mostly supportive therapy while addressing the cause of the delirium. Haloperidol has been used as an antipsychotic to reduce agitation. Benzodiazepines can also be used as needed. Brightly lit rooms, plenty of cues to help orient the patient, and the presence of health care personnel and family can help reassure a delirious patient.
Overview Dementia is distinguished from delirium in that dementia presents over a period of weeks to years, and so is much more gradual in onset. Dementia is stable over the short term, versus the fluctuating nature of delirium. Dementia also tends to be progressive over time, while delirium tends to improve with supportive therapy. Dementia may or may not impair attention, while delirium causes severe impairments to attention. Both delirium and dementia cause cognitive impairments, but the deficits in dementia also affect executive function of the brain. Both delirium and dementia affect the sleep / wake cycle and cause a labile affect with mood disturbances. While a specific, temporally near precipitant is typically present with delirium; the precipitant for dementia tends to be more chronic and distant, if it can be 218
Psychopathology identified at all. Dementia is the presence of memory impairment with superimposed cognitive deficits. Dementia is due to progressive neural loss secondary to an organic brain disorder, trauma, infection, infarction, hypoxia, or other biological precursor. Dementia has a prevalence of 3% after age 65, and over 20% in patients over 85. There are multiple causes of dementia, but some of the more prominent include Alzheimer disease, cerebrovascular disease, HIV, trauma to the head, Parkinson disease, Huntington disease, Pick disease, and Creutzfeldt-Jakob disease.
HIV-Dementia HIV-dementia is due to viral encephalitis and myelitis. Nearly â…” of cases are insidious in onset, and â…“ are florid. HIV-dementia presents with decreased memory, loss of concentration, confusion, withdrawal and apathy, dysphoria, ataxia, and muscle weakness. HIV-dementia is often diagnosed as depression, but an accurate diagnosis is critical as death often occurs within four months of onset of symptoms. Recall that death related to HIV infection is common in young adults up to middle age, and so onset of HIV-dementia is typically much earlier than Alzheimer disease.
Vascular Dementia Vascular dementia is due to patchy loss of neurons leading to cognitive deficits. Vascular dementia may be due to intermittent vascular occlusion due to strokes or vasospasm. Onset is usually in the 60s and so occurs earlier than Alzheimer disease but later than HIV dementia. Hypertension is a common overlying pathology and is likely responsible for the widespread, diffuse vascular disease.
6.5. Amnestic Disorders 6.5.1
Amnestic disorders are deficits of only memory, and are likely the result of a general medical condition or substance use disorder. Damage is common to the mamillary bodies, fornix, and hippocampus â€“ allimportant components of memory formation. This can lead to the inability to recall old memories and / or to form new memories (retrograde and anterograde amnesia).
Dissociative disorders are the failure to integrate mental functions, leading to a loss of memory of personal identifying information, fragmentation of personality, and altered reality perception. In dissociative amnesia, a patient is unable to recall his or her identity and other personal information.
Various forms exist. Localized amnesia is characterized by the inability to recall personal information over a certain period of time, typically following head trauma. Selective amnesia is where particular types of information are lost. Generalized amnesia is where the information is lost for the remainder of the lifespan. In continuous amnesia, information from a particular point of time to the present cannot be recalled. Particular categories of information are lost in systematized amnesia.
Clinical Review for the USMLE Step 1 6.5.4
One particular type of dissociative disorder is known as Ganser syndrome, a psychiatric illness that primarily occurs in inmates. These patients are characterized by giving approximate answers to questions, having chronic disorientation, amnesia, and perceptual abnormalities.
Dissociative fugue occurs in people who suddenly travel to a new place, create an entirely new identity and life, and continue to live as if nothing has transpired. These patients have an amnesia about their past, and have their cognitive and intellectual abilities completely intact. Dissociative fugues often remit over time without treatment or intervention.
Dissociative Identity Disorder
Dissociative identity disorder, formerly known as multiple personality disorder, is the presence of several separate and distinct personalities that have autonomous control over a personâ€™s behavior. Patients with dissociative identity disorder often complain of losing time, as each personality is unaware of others. Surveys of patients with this disorder indicate seven distinct personalities on average. Many of these patients are highly suggestible. Many report severe physical or sexual abuse during childhood, while others report abuse in a cult. To complicate this issue, these memories may not necessarily be true, but the individual with the disorder perceives them as real.
Depersonalization disorder is a feeling of being detached from the world around the person, as if the person were an onlooker. It leads to a persistent feeling of being detached, but reality testing remains intact. There can be clinically significant stress.
6.6. Somatoform Disorders 6.6.1
Somatoform disorders are those where individuals present with physical symptoms of a particular ailment without an identifiable medical cause. Somatoform disorders are distinct in that the symptoms produced by the patient are not intentional.
Somatization disorder is one diagnosable somatoform disorder in which an individual has multiple medical complaints with no particular identifiable medical illness. Somatization disorder can only be diagnosed when the patient presents with symptoms in four different parts of the body or parts of the body with different functions. For example, the patient has two distinct gastrointestinal complaints, one sexual complaint, and one neurologic complaint. The last three criteria cannot include pain. Further, a portion of these symptoms must have started prior to age 30 and have been present for several years. Many of these symptoms are refractory to treatment, and occasionally, medical and surgical interventions may actually be iatrogenic causes of some of these complaints. Somatization disorder is more common in females, and there appears to be a genetic cause for it, especially in families with antisocial personality disorder and substance abuse disorder. 220
Other Somatoform Disorders
Other somatoform disorders include undifferentiated somatoform disorder, which is a less severe form of somatization disorder with fewer complaints and a shorter duration. Conversion disorder is hallmarked by complaints with sensory and motor function not due to a medical cause. Pain disorder involves an exaggerated pain response not congruent with any present medical illness. Hypochondriasis is the fixed, false belief that the individual has a medical illness, but this is most likely a misinterpretation of a normal bodily function. Body dysmorphic disorder is an exaggerated perceived belief that a particular body part has a defect. Pseudocyesis is the development of physical signs of pregnancy and the false belief that one is pregnant in the face of negative laboratory tests and studies.
6.7. Malingering 6.7.1
Malingering is a psychiatric illness in which a person invents a disorder in order to receive a specific benefit. Symptoms are intentionally produced with the motivation to receive a specific gain. For example, a person may create the symptoms of the flu in order to avoid going to school. This is known as secondary gain because having the symptom (the flu) leads to a specific reward for the patient (avoiding school). Primary gain is the benefit to the patientâ€™s ego by having the symptom. Tertiary gain is the benefit to the caretaker due to the patient having the symptom. An example of primary gain is the increase in selfesteem by having the flu; an example of tertiary gain is the satisfaction the physician gains by diagnosing a rare disorder. Primary gain is not seen in malingering by definition as the gain is sought out intentionally. Tertiary gain may or may not be present depending on the caretaker.
Factitious disorder differs from somatization disorder in that the individual with a factitious disorder consciously creates a sign or symptom of a medical illness to have a primary or secondary gain. Factitious disorders are also different from malingering, in which an individual creates an illness to obtain gains that are different from those obtained by being in a sick role (secondary gains). Repeated admission to the hospital and willingness to undergo invasive procedures is termed Munchausenâ€™s syndrome. Parents who create symptoms of an illness in a child is termed Munchausenâ€™s syndrome by proxy.
6.8. Personality Disorders 6.8.1
Classification of Personality Disorders
Personality disorders are axis II disorders in the five axis evaluation of psychiatric disorders. Personality disorders can be characterized by one of three major types. Cluster A personality disorders include paranoid, schizoid, and schizotypal personality disorders, and can best be characterized as odd or eccentric in nature. Cluster B personality disorders include antisocial, borderline, histrionic, and narcissistic personality disorders, and can be characterized as overly dramatic or emotional in nature. Finally, cluster C personality disorders include avoidant, dependent, and obsessive-compulsive personality disorders, and tend to be anxious or fearful in nature. The dysfunction of personality disorders can be recalled with the mnemonic MEDIC, or maladaptive, enduring, deviation from cultural norms, inflexible, and causing psychosocial impairment.
Clinical Review for the USMLE Step 1 6.8.2
Cluster A Personality Disorders
Paranoid Personality Disorder Table 10. Diagnosis of Paranoid Personality Disorder Diagnosis of Paranoid Personality Disorder —DSM 301.0 Inherently distrustful High level of suspicion Requires separation from paranoia associated with psychotic disorders
Schizoid Personality Disorder Table 11. Diagnosis of Schizoid Personality Disorder Diagnosis of Schizoid Personality Disorder –DSM 301.20 Tend to avoid other people, emotionally distant and withdrawn Tend to be related to others in the family with schizophrenia or schizotypal personality disorder Detachment from the world Must be differentiated from avoidant personality disorder, social phobia, and schizophrenia
Schizotypal Personality Disorder Table 12. Diagnosis of Schizotypal Personality Disorder Diagnosis of Schizotypal Personality Disorder –DSM 301.22 Especially tied to patients who have families with a history of schizophrenia Avoid others Characterized by eccentric thoughts, bizarre affects, odd perceptions, incongruent beliefs Distrustful to the point of paranoia
Cluster B Personality Disorders
Antisocial Personality Disorder Table 13. Diagnosis of Antisocial Personality Disorder Diagnosis of Antisocial Personality Disorder – DSM 301.7 Disregard rules, aggressive Lie, cheat and exploit others Impulsive No remorse for illegal or moral actions Must be differentiated from bipolar and substance abuse disorders
Psychopathology Borderline Personality Disorder Table 14. Diagnosis of Borderline Personality Disorder Diagnosis of Borderline Personality Disorder –DSM 301.83 High levels of fear, anger, and worry about being abandoned their spouse Shifting idealization and devaluation of others Unpredictable changes in interpersonal relationships Respond with anger and panic or depression to unexpected stressors Tend to be suicidal or feign suicide; risk-taking behavior
Histrionic Personality Disorder Table 15. Diagnosis of Histrionic Personality Disorder Diagnosis of Histrionic Personality Disorder – DSM 301.50 Sexually seductive and socially inappropriate with regard to their hypersexuality Exaggerated emotional outbursts; theatrical attention-seeking behavior Unpredictable changes in interpersonal relationships Must be differentiated from somatization disorder
Narcissistic Personality Disorder Table 16. Diagnosis of Narcissistic Personality Disorder Diagnosis of Narcissistic Personality Disorder – DSM 301.81 Highly egocentric and arrogant (reaction formation to protect them from a fragile ego and low self-esteem) Demand attention and special treatment Little concern for others Differentiate from bipolar disorder with grandiose features
Cluster C Personality Disorders
Avoidant Personality Disorder Table 17. Diagnosis of Avoidant Personality Disorder Diagnosis of Avoidant Personality Disorder – DSM 301.82 Hypersensitive to criticism Feelings of extreme inadequacy to the point where there is no interaction with others due to fear of being singled out Extreme fear of humiliation and rejection by others Differentiate between avoidant personality and generalized social phobia
Clinical Review for the USMLE Step 1 Dependent Personality Disorder Table 18. Diagnosis of Dependent Personality Disorder Diagnosis of Dependent Personality Disorder â€“ DSM 301.6 Unable to function without the assistance from another Strong desire to be taken care of by others Cling to people due to fear of separation Tend to be highly submissive Differentiate from borderline personality disorder
Obsessive-Compulsive Personality Disorder Table 19. Diagnosis of Obsessive-Compulsive Personality Disorder Diagnosis of Obsessive-Compulsive Personality Disorder -DSM 301.4 Adhere to rigid schedules Rigid in interpersonal relationships Quick to judge Devoted to their work Avoid intimate relationships
Personality disorders are difficult to treat and are listed as axis II as a result of their ingrained nature. They are often an essential part of a personâ€™s makeup and are resistant to simple medical intervention. Therapy therefore consists of a variety of modalities to help the person understand the destructive behavior and make changes. Successful management invovles one or more of the following: long term psychotherapy, cognitive behavioral therapy, changes in interpersonal relationships, and medications such as mood stabilizers, benzodiazepines, SSRIs, and antipsychotics.
6.9. Substance Abuse Disorders 6.9.1
Substance abuse is less severe than substance dependence (abuse before dependence). Substance abuse is defined as a malformed pattern of ingestion of a particular substance that leads to impairment in oneâ€™s psychosocial obligations. At least one of the following conditions must be fulfilled in order to meet the requirements of diagnosis, including a failure to meet obligations or expectations at school, work, or home; repeated use of a substance in dangerous situations; repeated infractions with the law; or repeated use despite worsening social or interpersonal problems due to the negative effects of the substance.
Substance dependence is defined with regard to its clinical impairment, and requires at least three of the following criteria within a one year period for diagnosis: tolerance, withdrawal, repeated use, failed 224
Psychopathology efforts to cut down on use, large amount of time spent trying to obtain the substance, decrease in important social or occupational activities, use despite awareness of psychosocial impairments, use despite physical impairments, and excessive or unintended use of the compound.
Overview Alcohol intoxication is characterized by uncoordinated motor activity, slurred speech, imbalance, nystagmus, defect in concentration or memory, stupor or coma, and maladaptive or inappropriate behavior or functioning. Alcohol intoxication is quantified by serum tests such as a blood alcohol level (BAL). Other lab tests in severe, chronic alcohol abuse include elevated high-density lipoprotein (HDL), decreased low-density lipoprotein (LDL), elevated mean red blood cell volume (MCV), and elevated liver enzymes. Alcohol intoxication presents with loss of inhibition over oneâ€™s better judgment. Abusers are more prone to emotional lability, lose the ability to enunciate during speech, have difficulty walking and maintaining balance, can lose consciousness with heavy abuse, and in severe cases, fall into a coma. Alcohol dependence is a clinical disorder characterized by tolerance and withdrawal symptoms. The lifetime prevalence of alcoholism (alcohol dependence) is nearly 14%, with males disproportionately affected compared to females. There appears to be a genetic basis for alcoholism, especially in males. Alcoholics also tend to have a family history of antisocial personality disorder and depression. Table 20. Diagnosis of Alcohol Dependence-DSM 303.90 Tolerance
Excessive or unintended use of substance
Use despite physical impairment
Failed efforts to cut down on use
Repeated infractions with the law
Large amount of time spent trying to obtain substance
Decrease in social or occupational activities
Use despite awareness of psychosocial impairment
Atrophy of testicles
Alcoholics tend to strongly deny their illness, and the importance of obtaining collateral information cannot be overstated. Physical symptoms sometimes indicate the presence of this disorder, including palmar erythema, painless hepatomegaly, and acne rosacea. Advanced alcoholism includes signs of cirrhosis of the liver, jaundice, ascites, atrophy of the testicles, gynecomastia, and Dupuytrenâ€™s contracture. Sequelae of each of these clinical symptoms are also present depending on the stage of the alcoholism. There is also an increased incidence of cancer, pneumonia, heart disease, and hypertension. Alcoholism can also be gauged by the CAGE questions, or asking whether the individual has felt a need to cut down on their drinking, whether they have ever been annoyed by the criticism of others regarding their drinking, whether they feel guilty about their drinking, and whether they require an eye-opener or early morning drink. More than one positive answer makes alcoholism likely. 225
Clinical Review for the USMLE Step 1 Wernicke-Korsakoff Syndrome Wernicke-Korsakoff syndrome may also develop in alcoholics due to the destruction of the mamillary bodies. This syndrome develops due to a deficiency in thiamine. The initial stage of this disorder, known as the Wernicke stage, is characterized by nystagmus, ataxia, and mental confusion. Wernicke’s encephalopathy may be reversed with prompt administration of thiamine. However, failure to do so leads to progression to Wernicke-Korsakoff syndrome with Korsakoff’s psychosis, presenting with anterograde amnesia and confabulations. Korsakoff’s psychosis is frequently irreversible, and can be complicated with hallucinations, dementia, neuropathy, depression, and a greater tendency towards suicide. Alcohol-dependent patients also tend to have signs of old rib fractures on X-ray.
Withdrawal The symptoms of alcohol withdrawal include the development of a fine tremor, increased heart rate, increased blood pressure, nausea and vomiting, seizures, anxiety, and in severe cases, hallucinations and delirium tremens. Tremors may peak at approximately one day after cessation of alcohol. Such withdrawal can last nearly a week if untreated, and may be accompanied by nausea and vomiting, headache, tachycardia, and high blood pressure. These withdrawal symptoms, if minor, can be treated with benzodiazepines including oxazepam and chlordiazepoxide. These medications should be titrated to match the withdrawal symptoms and tapered over several days. More severe symptoms of withdrawal include seizures that can begin about half a day after cessation. These seizures can precede delirium tremens, and should be treated with benzodiazepines and prophylactic phenytoin, in high-risk patients. Strong auditory hallucinations may also be present in alcoholic hallucinosis, with an onset within two days after cessation. A neuroleptic such as haloperidol may be administered to treat this etiology.
Delirium Tremens Delirium tremens is serious sequelae of alcohol withdrawal, and can be fatal in 15-20% of patients, if untreated. Delirium tremens is characterized by confusion, disorientation, agitation, perceptual disturbances such as hallucinations, hyperarousal of the autonomic nervous system (ANS), and a mild fever. It typically begins several days after cessation of alcohol, and can occur in one in twenty hospitalized patients with alcohol dependence. Treatment includes benzodiazepines and supportive therapy and may require admission to an intensive care unit (ICU), if there is instability in the blood pressures or other problems of the autonomic nervous system. The duration of delirium tremens is typically three days, but can last up to one month.
Rehabilitation Rehabilitation of alcoholism requires admission to a twelve-step program such as alcoholics’ anonymous, completion of the entire program, and continued avoidance of all alcohol. Side effects of chronic alcohol use include depression and anxiety, both of which should be treated if they continue two to four weeks after cessation of alcohol abuse. Disulfiram can be used in some patients to maintain avoidance of alcohol as this enzyme inhibits aldehyde dehydrogenase; this causes conditioned avoidance. Consumption of alcohol after blocking this enzyme leads to rapid accumulation of acetaldehyde in the bloodstream and subsequent nausea, vomiting, flushing, palpitations, and hypotension. Naltrexone is another medication that can be used to maintain avoidance. This opiate antagonist reduces alcohol intake and frequency of intake. Naltrexone can be taken even if the patient continues alcohol. The Mechanism of Action of Naltrexone may be mediated by reducing the positive reinforcement of alcohol. Overall, alcohol rehabilitation has a fifty percent failure rate. 226
Anxiolytic, Sedative, and Hypnotic Substance Abuse
Barbiturates and benzodiazepines are examples of drugs that fall into the anxiolytic, sedative, and hypnotic category. These drugs are cross-tolerant with alcohol, and can form a co-dependence. Abuse of these drugs can lead to symptoms similar to alcohol intoxication and withdrawal. It is distinguished from alcohol intoxication by the absence of alcohol in the serum or a urine toxicology screen. Withdrawal symptoms are similar to that of alcohol, and specifically include anxiety, apprehension, restlessness, tremors, nausea and vomiting, weakness and fatigue, hyperreflexia, diaphoresis, seizures, and orthostatic hypotension. Three or more of these symptoms must be present for the diagnosis of substance dependence disorder. Visual and somatic hallucinations, disorientation, and confusion can begin several days after cessation of the drug. Management involves detoxification, administration of benzodiazepines or barbiturates with a controlled taper to minimize withdrawal symptoms, and symptomatic management. Barbiturates tend to be more dangerous than benzodiazepines, and withdrawal can lead to dangerously high fevers (hyperpyrexia) and death. Diazepam or phenobarbital is often used in withdrawal management. In patients who abuse both alcohol and benzodiazepines or barbiturates, a pentobarbital challenge test is required to quantify the tolerance to these compounds and quantify the amount of medication required for a controlled taper. Patients should also be referred to a twelve step program for further rehabilitation.
Morphine, codeine, heroin, meperidine, and hydromorphone are examples of substances that fall under opioid abuse disorders. Heroin is the only one of these substances that is completely illegal in the United States. Lifetime prevalence of abuse is less than 1%, though this number is increasing. Opioids are often taken intravenously, leading to intense pleasure and a diffuse orgasm. After these symptoms occur, general well being follows then subsequent psychomotor retardation, impaired concentration, sleepiness, and fatigue. Upon use, the pupils constrict (miosis), there is respiratory depression, slurred speech, bradycardia, hypotension, and hypothermia. Nausea, vomiting, and constipation can all be present in opiate use. Use of opiates more than three times a day is typically a hallmark of dependent behavior. Similar to the diagnosis of other dependence disorders, opiate dependence also includes one or more of the following: failure to meet school, home, or work obligations, repeated use of substance in dangerous situations, repeated infractions with the law, repeated use despite worsening social or interpersonal problems due to negative effects of the substance. Withdrawal begins within half a day after cessation, and signs and symptoms include dysphoria, rhinorrhea, lacrimation, diaphoresis, mydriasis, piloerection, hypertension, tachycardia, fever, diarrhea, insomnia, and yawning. Severe symptoms include nausea and vomiting, seizure especially in meperidine withdrawal, muscle aches, abdominal cramps, hot and cold flashes, and severe anxiety. Comorbid psychiatric illnesses often exist in opioid abusers, including antisocial or borderline personality disorder, and mood disorders. These patients tend to commit crimes in order to finance their drug habits, and also have a high mortality rate due to the intercurrent intravenously-transmitted illnesses, accidental overdoses, and tendency towards suicide. Opioid abusers should be withdrawn by methadone administration, a mu opiate receptor partial agonist. Methadone causes few positive or negative effects, and so is an ideal substance to take the place of the powerful stimulatory and withdrawal effects of opiates. Clonidine can also be used to treat withdrawal through its alpha-two receptor agonist abilities. Clonidine is effective at treating the acute auto227
Clinical Review for the USMLE Step 1 nomic dysfunction of withdrawal, but has little effect on managing the cravings of the opioid addict. Additional medications include treating abdominal cramps with dicyclomine, nausea with promethazine, and muscle aches with quinine. The combination of medical intervention and rehabilitation programs such as a twelve-step program is necessary, along with long-term administration of methadone. Abuse of narcotic pain medications is particularly prevalent among patients with chronic pain. Management of chronic pain often involves cooperation between clinicians, pain clinics, and the patient. Contracts with the patient to limit the intake of narcotic pain medications and correction of destructive behavior can help make a difference.
Cocaine and other amphetamines are commonly abused drugs. These drugs cause stimulation of the central nervous system and tend to drive the sympathetic nervous system. Cocaine can be either snorted in the powder form, or smoked in the crack form. Cocaine has a rapid onset, a short half-life, and a number of side effects. Intoxication with cocaine or other amphetamines includes dysfunctional behavioral changes such as hypervigilance or euphoria, mydriasis, nausea and vomiting, weight loss, confusion, seizures, dyskinesia, coma, muscular weakness, respiratory depression, chest pain, cardiac dysrhythmias, sudden cardiac death, either tachycardia or bradycardia, either hypertension or hypotension, either diaphoresis or chills, and either psychomotor retardation or agitation. Cocaine is one of the few drugs that can cause a tactile hallucination on intoxication, such as a feeling that bugs are crawling all over a person. A transient psychosis with visual hallucinations and paranoia can also occur during intoxication. Withdrawal symptoms can be severe but nonfatal, and include fatigue, nightmares, depression, headache, diaphoresis, muscle cramps, and hunger. Withdrawal typically lasts several days. Amphetamines are available through prescription for the treatment of obesity, attention-deficit hyperactivity disorder, and narcolepsy. Management of amphetamine abuse is typically supportive therapy, as the withdrawal is self-limited and not hazardous. Antipsychotics can be used for extreme anxiety, as indicated. A twelve-step rehabilitation program is required for proper treatment.
The abuse of marijuana or hashish (cannabis) is common throughout the world. Intoxication causes euphoria, impaired judgment, poor concentration, and decreased memory. Side effects include permanent memory effects, permanent intellectual impairment, testicular degeneration, delirium, and psychosis. Marijuana is a commonly abused drug that leads to a number of side effects. Marijuana leads to a profound feeling of pleasure, but abuse can also lead to anxiety and delusions or hallucinations. One of the effects of abuse is the feeling that time has slowed. Marijuana leads to impaired judgment and withdrawal from society (â€œstonedâ€?). Appetite is increased and dry mouth with bronchitis are common physical symptoms. The effects of marijuana can best be summarized as follows: respiratory effects, amotivation, and increased risk of mental illnesses. Marijuana increases serotonin through the function of an inhibitory G protein. This is the mechanism by which a dreamlike state is created and gives the sensation that time has slowed. The vomiting that can occur with marijuana is best treated with dronabinol.
Nicotine abuse leads to symptoms similar to caffeine abuse, including restlessness, difficulty sleeping, anxiety, and in severe cases, cardiac arrhythmias. Withdrawal from nicotine is similar to caffeinewithdrawal, including headaches, anxiety, and weight gain. Nicotine withdrawal also leads to a strong craving and elevated heart rate. Treatment for nicotine abuse is with bupropion, an antidepressant that reduces the craving for nicotine.
Caffeine abuse is common. Smaller doses of caffeine lead to restlessness and insomnia. Increasing doses can lead to a diuresis and muscle twitching. In susceptible individuals, potentially fatal cardiac arrhythmias can develop. Caffeine leads to an increase in cAMP release in neurons. Caffeine withdrawal is a common cause of headaches seen in a clinical setting. Withdrawal from caffeine also leads to fatigue, depression, and weight gain.
PCP (phencyclidine) abuse has been on the decline for sometime due to psychotic effects it induces in many individuals. PCP is one of the few drugs that lead to aggressive and belligerent behavior culminating in homicide or suicide. Individuals intoxicated with PCP tend to be very impulsive and act like they are “drunk”. There is a severe psychomotor anxiety, psychosis, and delirium. The activity of the autonomic nervous system is increased with elevated heart rate. Central nervous system symptoms of PCP abuse include ataxia, vertical and horizontal nystagmus, and fever. PCP withdrawal is unique in that it can lead to a repeat of the symptoms seen in PCP abuse. This occurs because the drug may be reabsorbed by the GI tract. This reabsorption over time can lead to episodes of sudden homicidal violence. Abuse is on the decline as people who abuse these drugs are more interested in the sense of euphoria than going to jail due to homicide.
LSD is different than PCP in that LSD breeds a cross tolerance with ecstasy and MDMA, but PCP does not. LSD abuse is like PCP abuse in that it leads to significant anxiety and delusions. LSD also causes profound visual hallucinations and flashbacks. Mydriasis is common. LSD is a partial postsynaptic serotonin agonist, and it is through this mechanism that flashbacks and synesthesias may occur. LSD can also lead to convulsions. There are no significant withdrawal symptoms of LSD. LSD abuse is similar to the effects of ecstasy and MDMA, but the latter two substances can induce a panic psychosis. Abuse is best treated with diazepam. MDMA leads to increased impulsiveness through destroyed serotonin receptors and can lead to memory gaps.
Ecstasy is frequently abused in dance clubs, and has a stimulant and euphoric effect. Ecstasy, also known as MDMA, can enhance one’s desire for intimacy. Long-term effects include loss of serotonin axons in the brain. Methamphetamine is a powerful amphetamine that can lead to destruction of dopamine neurons.
Clinical Review for the USMLE Step 1 6.9.13
Gamma-hydroxybutyrate (GHB) is a steroid drug that promotes an increase in muscle mass; overdoses can cause highs, but can lead to death due to respiratory arrest. The abuse of anabolic steroids can lead to skin atrophy, acne, spontaneous bruising, hypokalemia, cardiomyopathy, osteoporosis, hypertension, diabetes, emotional lability and depression, gynecomastia, testicular atrophy, and alopecia. Abuse is especially common in body builders, and their negative effects occasionally make headlines due to sudden cardiac death in some athletes (not to be confused with idiopathic hypertrophic cardiomyopathy and Brugada syndrome, both of which belong on the differential diagnosis in this case).
Ketamine is a dissociative anesthetic that can cause hallucinations. Rohypnol is a benzodiazepine that can cause sedation and amnesia, and is frequently used by sexual predators.
7. Pharmacology 7.1. Cholinergic Agents 7.1.1 Cholinergics – Direct Agonists Table 21. Cholinergics – Direct Agonists Drug Bethanechol Pilocarpine
Indications Urinary retention Ileus Closed angle glaucoma
Mechanism of Action
Stimulates bladder and intestinal smooth muscle
Ciliary muscle contraction, opening of meshwork, increased aqueous humor outflow
Cholinergics – Indirect Agonists
Table 22. Cholinergics – Indirect Agonists Drug
Mechanism of Action
Diagnosis of myasthenia gravis
Ileus, urinary retention, myasthenia gravis, reverses NMJ blockade
Anticholinergics – Muscarinic Antagonists
Anticholinergics have been used for the treatment of iatrogenic Parkinsonism and iatrogenic dystonic reactions. Benztropine and trihexyphenidyl are the most commonly used anticholinergics. Diphenhydramine has also been used, although this particular drug is an antihistamine. Anticholinergics and diphenhydramine are muscarinic receptor antagonists. Side effects are generally excessive anticholinergic activity, such as urinary retention, constipation, blurry vision, sedation, and delirium in elderly.
Pharmacology Table 23. Anticholinergics – Muscarinic Antagonists Drug
Mechanism of Action
Pupillary dilation Decrease acid secretion in PUD Atropine
Decrease urinary urgency
Inhibits parasympathetic muscarinic receptor
Tachycardia, T, xerostomia, dry skin, mydriasis with cycloplegia, constipation
Inhibits vagally-mediated reflexes
Epistaxis, nasal irritation
Decrease GI motility Reduce airway secretions Ipratropium
Table 24. Anticholinergics – Nicotinic Antagonists Drug Succinylcholine
Indications Muscle paralysis Mechanical ventilation Muscle paralysis Mechanical ventilation
Mechanism of Action Rapid onset and short duration with decrease in excitatory potential below threshold. Initial stage with prolonged depolarization leading to fasciculations and muscle pain. Second stage with repolarization but blockade of receptors. Nicotinic receptor blockade. Nondepolarizing blockade can be reversed with neostigmine, edrophonium, and cholinesterase inhibitors.
7.2. Adrenergic Agents 7.2.1
Adrenergic Agonists – Catecholamines
Table 25. Adrenergic Agonists - Catecholamines Drug Dopamine Norepinephrine
Mechanism of Action
Shock with renal protection
α1, α2, β1, β2
Complications Nausea, HTN, arrhythmia.
Open angle glaucoma Epinephrine
α1, α2, β1, β2
Increases aqueous humor outflow
Increase local anesthetic duration Isoproterenol
Bronchodilator Cardiac stimulant
β1, β2, α1
Increase cardiac contractility
Flushing, angina, arrhythmia
Clinical Review for the USMLE Step 1 7.2.2
Adrenergic Agonists – Non-Catecholamines
Table 26. Adrenergic Agonists – Non-Catecholamines Drug
Mechanism of Action
Complications Sedation, hemolytic anemia, liver disorders
ADHD, Tourette syndrome, HTN Asthma Ephedrine
Urinary incontinence Bronchospasm
Alpha Adrenergic Antagonists
Table 27. Alpha Adrenergic Antagonists Drug
Pheochromocytoma Peripheral vascular disease
Mechanism of Action α1, α2
Blocks dopamine carrier
Complications Orthostatic hypotension Reflex tachycardia Orthostatic hypotension on first dose, dizziness, syncope, and HA
Beta Adrenergic Antagonists
Beta-blockers are used for the treatment of akathisia, performance anxiety, impulsivity, and lithiuminduced tremors. Beta-blockers alter catecholamine function by diminishing central nervous system arousal, tachycardia, tremor, diaphoresis, and hyperventilation. Side effects are excessive decrease in the sympathetic nervous system, and also masking of diabetes. Depression-like symptoms may also be present in overdose.
Pharmacology Table 28. Beta Adrenergic Antagonists Drug
Akathisia, HTN, angina, migraine, IHSS
HTN Angina pectoris
β1, β2 β1
Pheochromocytoma and malignant HTN
Mechanism of Action
Also used for social phobia, akathisia, impulsivity, and performance anxiety through PNS inhibition.
α1, β1, β2
7.3. Serotoninergic Agents Table 29. Serotoninergic Agents Drug Sumatriptan
Indications Migraines Cluster headaches Treatment of N/V in chemotherapy
Mechanism of Action
5-HT1D agonist leading to acute vasoconstriction.
Distal paresthesia, ACS
CAD, variant (Prinzemetal) angina
5-HT3 receptor antagonist to reduce vagus nerve activity and reduce serotonin receptor activity in CTZ
Dizziness, generally rare
Hepatic disease (P450)
7.4. Toxicology Table 30. Toxicology. Toxic Agent
Fulminant hepatic failure and renal failure.
Increased arousal and significant sympathomimetic effects. Mental status changes, dyskinesia, agitation, formication, chest pain, dry mouth, diarrhea, diaphoresis, HTN, and mydriasis .
Patient restraint and supportive therapy after protecting the airway. Activated charcoal and benzodiazepines can be used. Using neuroleptics to manage psychosis along with dantrolene to relax the skeletal muscles and avoid hyperthermia Phentolamine is used to reduce cardiac activity, and nitroglycerin is given to reduce pain.
Skin flushing, dry skin, mydriasis, and changes in mental status. Tachycardia, diminished bowel sounds, ileus, HTN, and myoclonus are also present. Both anticholinergics and certain antihistamines can exert these effects.
ACLS, naloxone, benzodiazepines, activated charcoal, IVF, and the antidote, and physostigmine salicylate are all given.
TCAs lead to progressive decreases in CNS orientation and eventually coma. Seizures, hypotension, cardiac conduction abnormalities, hypoventilation, and various anticholinergic effects occur.
Treatment is sodium bicarbonate followed by IVF. Vasopressors may be used with severe hypotension. Activated charcoal is also used, along with epinephrine and benzodiazepines for seizure management.
Bloody diarrhea, vomiting, dehydration, QT prolongation, and hepatorenal damage.
Stabilize the patient and use BAL, DMSA, and DMPS.
Clinical Review for the USMLE Step 1
Respiratory and cardiac depression and decreased CNS function. Mental status changes and psychiatric changes are common. Decreased bowel sounds are found on exam. Bullous lesions may also be present.
Treat with ABCs, IVF ,ET intubation, administer activated charcoal, and alkalinize the urine with sodium bicarbonate. As in many instances of toxic substance consumption, hemodialysis and exchange transfusions may be required in the most serious cases.
Similar to that of barbiturate poisoning and may be worsened with concomitant ETOH abuse. Confusion, drowsiness, blurred vision, hallucinations, ataxia, hypotonia, amnesia, respiratory depression, and coma.
ABCs, O2, glucose, naloxone, flumazenil to deactivate the benzodiazepine, and activated charcoal.
Arrhythmia, hypotension, bradycardia, renal failure, dilated cardiomyopathy, seizure, bronchospasm, and coma.
ABCs, IVF, gastric lavage, activated charcoal, hemodialysis, close cardiac management including pacing, and atropine, epinephrine, dopamine, and isoproterenol for hypotension are the standard of care. Glucagon, calcium chloride, magnesium sulfate, and insulin are also frequently used to maintain function.
Constitutional symptoms, lethargy, DOE, depression, incontinence, and changes in memory. Tachycardia, hyperthermia, tachypnea, cherry red skin, flame retinal hemorrhages with red retinal veins, and psychiatric manifestations are common on exam.
Nonrebreather masks with continuous 100% oxygen, intubation, and hyperbaric oxygen.
Strong acids or alkali leads to coagulation necrosis especially in the pharynx, esophagus, stomach, and SI. Presentation includes dyspnea, dysphagia, odynophagia, chest pain, abdominal pain, nausea and vomiting, airway obstruction, drooling, peritonitis, and hematemesis.
Diluting alkaline ingestions with water or milk is sometimes done. Emesis is contraindicated. Maintain the ABCs and attempt gastric lavage. Large volume liquid ingestion is often used. Do not use acids with base ingestions or vice versa to avoid heat production and additional damage. Antibiotics are necessary due to extensive tissue injury. Antihistamines are also administered to avoid esophageal damage from stomach acid.
Cardiac arrhythmia, MI, stroke, subarachnoid hemorrhage, malignant hyperthermia, and sudden death. Rhabdomyolysis can also occur. Numerous respiratory, cardiac, neurologic, gastrointestinal, and renal ailments may occur. Mesenteric ischemia is relatively common. CARO and psychiatric manifestations also occur, with significant constitutional symptoms in withdrawal. Systemwide depression is a sign of late stage intoxication.
ABCs, O2, IVF, naloxone, benzodiazepines for seizures, patient restraint, insulin and glucose, epinephrine with caution in cardiac arrest, beta-blockers, and pressor as necessary to avoid cardiovascular collapse. Polyethylene glycol and activated charcoal are also used. Give vitamin B1 before glucose.
A sense of impending doom, numerous constitutional symptoms, neurologic symptoms, SOB, nausea, vomiting, mydriasis, pulmonary edema, cardiac conduction changes, and coma are apparent. Carboxyhemoglobin is present along with methemoglobin.
ABCs, oxygen, sodium bicarbonate, antidotes to cyanide (sodium nitrite, sodium thiosulfate, and hydroxocobalamin), anticonvulsants, and vasopressors are used as indicated. Amyl nitrate is another antidote that is sometimes used.
Palpitations, syncope, dyspnea, CNS changes, yellow-green vision, photophobia, halos, scotomas, GI symptoms, and cardiac conduction changes are present. Toxicity may be the result of drug interactions (see text above).
Provide O2, IVF, and monitor for cardiac functioning. Activated charcoal and antibodies to digitalis are used. Repair any changes in electrolytes and use magnesium sulfate to maintain rhythm.
Kussmaul respirations due to the severe metabolic acidosis, altered mental status, and formation of oxalate crystals in the kidneys and throughout the body. Serum osmolal gap is present.
IVF, bicarbonate, pyridoxine, thiamine, and ethanol. 4-methylpyrazole (4-MP, also known as fomepizole) has also been used with benefit. Dialysis is also used
GHB, the date-rape drug, presents with CNS depression, seizure disorder, bradycardia, hypotension, and some hypothermia.
Supportive therapy and maintaining the airway. Gastric lavage is sometimes used. Atropine is used to treat the bradycardia.
Pharmacology Reassure the patient, sedate with benzodiazepines, and restraints are the initial steps. Haloperidol and benzodiazepines for psychosis, ventilatory assistance, and nitroglycerin for elevations in BP.
LSD, PCP, ketamine, mescaline, MDMA, and THC, among other psychoactive compounds, presents with hallucinations, psychosis, flashbacks, self-injurious behavior, agitation, abdominal symptoms, and diaphoresis.
Lead exposure leads to GI dysfunction, encephalopathy, seizures, and anemia. Arsenic toxicity presents similar to lead toxicity, but a syndrome similar to Guillain-BarrĂŠ syndrome may develop. Mercury toxicity presents with tremor, hematochezia, esophagitis, acrodynia, stomatitis, salivation, and gingivitis.
Lead toxicity is treated PEG, chelation therapy with edetate calcium disodium (EDTA), dimercaprol (BAL), and DMSA, and supportive therapy. Arsenic toxicity is treated with fluid rehydration, PEG, and chelation with BAL, DMSA, or penicillamine. Mercury toxicity is treated with activated charcoal and chelation therapy with BAL, DMSA, and penicillamine. Succimer is another chelating agent similar to BAL.
GI tract corrosion and subsequent diarrhea and hematemesis. Cell death also occurs and affects the heart, kidney, and lung. Metabolic acidosis and hyperglycemia is common. Coagulopathy can develop with sufficient toxicity along with hepatic dysfunction and hypoglycemia.
Iron toxicity is treated with IVF, O2, and chelation with deferoxamine.
Increased activity of the SNS leading to HTN, hyperthermia, and tachycardia. Serotonin syndrome may also develop leading to further breakdown in thermoregulation and rhabdomyolysis. DIC and hepatotoxicity may occur. Hyponatremia also occurs, leading to seizures. Long term psychiatric dysfunction also occurs.
Symptomatic and supportive management to avoid the lethal sequelae of toxicity. Thiamine and glucose are given as necessary. Benzodiazepines are used for seizure control and fluids given to minimize the effects of rhabdomyolysis. Icing the patient helps reduce the very high temperatures that can develop.
Abuse presents as depression of the CNS and respiratory centers, miosis, euphoria, and seizures. Cardiac dysfunction may occur along with orthostatic hypotension.
Naloxone and restraints. Methadone, atropine, and various fentanyl derivatives may be necessary for refractory intoxication. Activated charcoal is also useful.
Changes in respiration, S3 gallop, water retention with HTN, mental status changes, tremors, seizures, ulcers, hepatorenal failure, and general malaise.
Significant catabolism leading to metabolic acidosis, respiratory alkalosis, aciduria, delirium, respiratory arrest, aspiration pneumonitis, ototoxicity with tinnitus or deafness, hypotension, U waves and flat T waves with a QT prolongation, CNS depression, GI distress, renal failure, diaphoresis, and dehydration.
ABCs, activated charcoal, hemodialysis, and supportive therapy.
Treated in a manner similar to other types of poisoning. Urine alkalization may be done with sodium bicarbonate. Hemodialysis is the best method of reducing toxic levels of salicylates.
Clinical Review for the USMLE Step 1
7.5. Anticonvulsants Table 31. Anticonvulsants Drug
Mechanism of Action
Partial seizures Tonic-clonic seizures
Blocks post tetanic potentiation
Tonic-clonic seizures Partial seizures
Diplopia, aplastic anemia, hepatotoxicity, P-450 induction GI Sx, urticaria, SJS
Tonic-clonic seizures Partial seizures
Sedation, P-450 induction
Status seizures Partial seizures Phenytoin
Blocks sodium channels
Nystagmus, diplopia, ataxia, gingival hyperplasia, hirsutism, anemia, teratogenic, malignant hyperthermia
Status epilepticus Topiramate
Sedation, nephrolithiasis, weight loss
Partial seizures Valproate
GI Sx, hepatotoxicity, NTDs, alopecia, tremor, pancreatitis
7.6. Cognitive Agents Donepezil and tacrine have been used for memory loss in Alzheimer disease. These medications reversibly inhibit acetylcholinesterase (AChE) and supplement the loss of cholinergic neurons in Alzheimer disease. Side effects include gastrointestinal upset, bradycardia, and increased gastric acid secretion. Tacrine has been shown to increase liver function enzymes.
Table 32. Alzheimer Disease Drug
Mechanism of Action
Used to minimize memory loss
Used to minimize memory loss
Hypersensitivity, asthma, â†‘LFTs, GI disease, CV disease.
Table 33. Parkinson Disease Drug Amantidine Levodopa Carbidopa Selegiline
Mechanism of Action
PD PD PD
Enhances dopamine release
Inhibits dopamine decarboxylase in periphery
Decreases conversion of dopamine to norepinephrine
Enhances levodopa effects
7.7. Anesthetics 7.7.1 Anesthetics – Inhaled Table 34. Anesthetics - Inhaled Drug
Bradycardia, respiratory depression, increased ICP
Lowest potency, combined with other agents
Airway irritation, coughing, respiratory depression, increased ICP
Most rapid onset
Anesthetics – Intravenous
Table 35. Anesthetics - Intravenous Drug
Mechanism of Action
Respiratory depression, amnesia
Benzodiazepine; reverse w/ flumazenil
↑CV, hallucinations, ↑ICP
No cumulative effects, strict aseptic technique must be maintained.
Uncontrolled skeletal muscle activity
Clinical Review for the USMLE Step 1 7.7.3
Anesthetics – Local
Table 36. Anesthetics - Local Drug
CNS stimulation, CV stimulation, HTN
CNS stimulation, HTN
Notes Greater amounts needed in infected tissue (acidic tissue) Smaller fibers affected first, so pain is lost first, then T, touch, and finally P Give with epinephrine to increase local effects No allergic cross reactivity between esters & amides. Long duration.
7.8. Analgesics 7.8.1
Analgesics – Opioid
Table 37. Analgesics - Opioid Drug
Mechanism of Action
Mu opioid agonists
Net effect is change in neural activity along various pathways, especially pain pathways
Complications Substance abuse and dependence, respiratory depression, miosis, CNS depression, constipation
Analgesics – NSAIDS
Table 38. Analgesics - NSAIDs Drug
Reversible inhibition of COX-1 and COX-2
Nephrotoxicity, aplastic anemia, PUD
PUD. Renal patients
Reversible inhibition of COX-1 and COX-2
Nephrotoxicity, aplastic anemia, PUD
PUD. Renal patients
Reversible inhibition of COX in CNS
Hepatic necrosis in OD, glutathione depletion
Avoids PUD. Nephrotoxic. Possible stroke.
PUD. Renal patients.
Irreversible COX1 and COX-2 inhibition inhibits prostaglandin formation
PUD, Reye syndrome, tinnitus, reflex acidosis from reflex hypoventilation due to initial hyperventilation (late stage poisoning)
ETOH, do NOT use in children especially with VZV or influenza infection
Anti-inflammatory Antipyretic Analgesia
Antipyretic Anti-inflammatory Antiplatelet aggregation
Mechanism Locus ceruleus
Myocardial infarction, arrhythmia
Seizures, syncope, bradycardia
Leukopenia, hemolytic anemia
Respiratory depression, ataxia Erythema multiforme, seizures
7.9. Antipsychotics Table 39. Antipsychotic Medications Typical
7.9.1 Indications Antipsychotic medications have a number of uses in treating various types of psychiatric illness. Typical antipsychotics, also known as neuroleptics, and atypical antipsychotics are the two major classes of antipsychotics. Antipsychotics are the drugs of choice for the treatment of psychotic symptoms such as hallucinations, delusions, and bizarre behavior. These psychotic symptoms can belong to any category of psychiatric illness so long as they are positive symptoms. Antipsychotics are generally less effective in treating negative symptoms such as amotivation, akinesia, isolation, and blunting of affect with the exception of clozapine. Antipsychotics have also been used in the treatment of various types of behavioral dysregulation as that seen in Alzheimerâ€™s, mental retardation, Tourette syndrome, and in patients with personality disorders.
Mechanism of Action
Antipsychotics are thought to act via a dopaminergic pathway, as that explained previously with regard to the dopamine hypothesis of schizophrenia. According to this hypothesis, antipsychotics block the dopamine 2 (D2) receptor, leading to a decrease in dopamine-mediated positive symptoms of psychosis. This is consistent with the dopamine hypothesis of schizophrenia, which states that the positive symptoms of schizophrenia are due in part to an excessive number of dopamine receptors leading to heightened stimulation of dopamine pathways. This theory is supported by the induction of psychosis with dopamine agonists such as amphetamines. Blockade of the dopamine pathways occurs in the ventral tegmental area and substantia nigra, both of 239
Clinical Review for the USMLE Step 1 which project to the basal ganglia, frontal cortex, and limbic regions of the brain. Reduction of the psychotic symptoms is thought to occur by the blockade in the cortical and limbic regions. However, the notable side effect of extrapyramidal symptoms (EPS) is thought to occur to unintentional blockade of D2 receptors in the basal ganglia.
Antipsychotics have a number of side effects related to their additional, still incompletely characterized functions elsewhere in the brain. Other antipsychotics, especially the atypical antipsychotics, have been found to work through a mechanism in addition to the dopamine blockade. Newer medications have the additional effect of blockading serotonin 5-hydroxytryptamine-2 (5HT2) receptors. Atypical antipsychotics are categorized as such based on their fewer extrapyramidal side effects, and their putative function through 5HT2 blockade. It is thought that blockade of these serotinergic pathways has a protective effect against extrapyramidal symptoms and even contribute to their antipsychotic effects. Of the atypical antipsychotics, risperidone is an example of a medication that preferentially blocks the D2 receptors. Clozapine, on the other hand, is an example of an atypical antipsychotic that primarily blocks the D4 receptor.
Therapy and Drug Reactions
Typical Antipsychotics The typical antipsychotics are thioridazine, chlorpromazine, perphenazine, trifluoperazine, thiothixene, haloperidol, and fluphenazine. Haloperidol and fluphenazine are the most potent of the typical antipsychotics, while thioridazine and chlorpromazine are the least efficacious. Thioridazine and chlorpromazine are highly sedating, while haloperidol and thiothixene are the least sedating. Thioridazine and chlorpromazine cause orthostatic hypotension, while the other drugs have a lower incidence of this. Thioridazine is highly anticholinergic. EPS symptoms are least prevalent with thioridazine and chlorpromazine. Thioridazine also causes a retinopathy and fatal cardiac events, and so is used only for schizophrenia refractory to other medications. A prevalence of anticholinergic effects can be partially reversed with the peripherally acting cholinergic stimulant bethanechol. Table 40. Antipsychotics â€“ Typical Dr