Clinical research case studies of successes and failures 1st edition john g. brock-utne (auth.) - Do
Visit to download the full and correct content document: https://textbookfull.com/product/clinical-research-case-studies-of-successes-and-failur es-1st-edition-john-g-brock-utne-auth/
More products digital (pdf, epub, mobi) instant download maybe you interests ...
Successes and Failures of Knowledge Management 1st
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made.
Printed on acid-free paper
Springer Science+Business Media LLC New York is part of Springer Science+Business Media (www.springer.com)
For the next generation:
Matthew B. Brock-Utne
Tobias J. Brock-Utne
Anders C. Brock-Utne
Jasper L. Brock-Utne
Stefan S. Brock-Utne
Charlotte E. Brock-Utne
Preface
The intention of this book is to highlight the many pitfalls that can occur when contemplating doing clinical research. This is based on my over 45 years of involvement in clinical research in four continents. Even though some of my mishaps have occurred over 40 years ago, I can assure you that these mistakes occur even to this day with monotonous regularity. Hence the book.
After each case history a question is posed. These are questions you may be faced with as a clinical researcher. The solutions suggested may be controversial and as such may form the basis for discussions on how best to proceed in your special circumstance.
The object of these many stories is to alert the clinical researcher and especially the El Toro researcher that there are many potential disasters waiting to happen when you embark on clinical research. But most of all the reader will hopefully understand that meticulous planning is essential for being successful in this field. Always remember that the object is to achieve one’s research goals quickly with a minimal risk of wasting time and resources.
To quote Marks (1) and to paraphrase Hippocrates of Kos (2):
(1. “The success of research project depends on how well thought out a project is and how potential problems have been identified and resolved before date collection begins” (Marks RG. Designing a research project. The basics of biomedical research methodology. Belmont: Lifetime Learning Publications: A division of Wadsworth 1982).
2. The Art is long Life is short Experiments perilous Decisions difficult.)
Stanford, CA, USA
John G. Brock-Utne
Acknowledgment
To the following, who started me on my clinical research venture. They are presented in the order in which I met them:
1971, Dr. Jon Gjessing, Professor of Anesthesia, Rikshospitalet, University of Oslo, Norway
1973, Dr. John W. Downing, Professor of Anesthesia, University of Natal, Durban, South Africa
1977, Dr. Jay B. Brodsky, Professor of Anesthesia, Anesthesiology, Perioperative and Pain Medicine, Director of the Operating Room at Stanford University School of Medicine, Stanford, CA 94305, USA
A person who must not go unmentioned is my friend Dr. Steve Shafer, Professor of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine Stanford, CA 94305, USA, and Editor in Chief of Anesthesia & Analgesia His many excellent Editorials and comments about clinical research have been invaluable to me. This is especially true about plagiarism and fraud in clinical research.
To my wife, Sue (48 years married), for her constant encouragement and help with proofreading.
To Shelley Reinhardt (Springer) and Joanna Perey (Springer) for all their help and support
I am also indebted to my research colleagues around the world with whom I have published. I thank them for their hard work, camaraderie, and commitment in our quest to find answers to the questions posed or the clinical observations made. The list is shown below. It may be that I have unintentionally left a few out for which I sincerely apologize.
Barry Adam, Miriam Adhikari, Scott Ahlbrand, Neetu Ahluwalia, John Atchison, Craig T. Albanese, DM Alexander, Karim Ali, Russell Allen, Eric Amador, Gabriel Amir, Nick Anast, Wayne Anderson, Andrew Andrews, Trevor Andrews, Tim Angelotti, Martin Angst, John Archer, Kayvan Ariani, Christopher Arkind, Dave Armstrong, Dan Azar, Nasima Badsha, Brian Baker, Andy J. Barclay, John
J. Barry, John Bean, Peter Bean, David Benaron, Melissa Berhow, Orr Bernstein, Tess Bhatia, Kevin Blaine, Gordon Blake, Paul Blignaut, Patrick Bolton, Gail Boltz, Jerry Bortz, Adrian Bosenberg, Erin Botha, Gregory Botz, Robin Boulle, Jonathan Bradley, Ioana Brisc, Arne J. Brock-Utne, Jay B. Brodsky, Helen M. Bronte-Stewart, Michael Brook, Christopher Brouckaert, Colin Brown, Douglas Brown, Davie Browne, Susan Browne, Carlos Brun, John Bryer, Robert Buley, Ross Bullock, Erin Bushell, Sharon Bux, Jorge Caballero, Pat Callander, Walter Cannon, Alice Cantwell, Brian Cantwell, Carol Canup, Barbara Carr, Brendan Carvalho, Jane Ceranski, Anant Chandel, Peter Chang, Steven D. Chang, Paul Chard, Michael Charles, Robert Cheetham, Marianne Chen, Samuel Chen, Alan Cheng, Rena Chhokra, Alexander Chiu, John Chow, Anne Chowet, Larry F. Chu, Sam Chun, Christopher Church, Rebecca Claure, Michael Coady, Michael Cochran, Sheila Cohen, Anthony Coleman, Jeremy S. Collins, Joe Conradie, Russell Cooper, Jerry Coovadia, Eric Cornidez, John Cosnett, Doug Crockett, Chris Cuerden, John Cummings, Miram Curet, Charles Debattista, Carol A. Diachun, Friederike Dietz, Michael Dillingham, George Dimopoulos, Tom Dow, Laura Downey, John W. Downing, David Drover, Johan DuPreez, Barry Dyck, Paul Eckinger, Henry Edwards, Joshua Edwards, Talmage Egan, Mark Eggen, Christoph Egger-Halbeis, Arne Martin Eide, Inga Elson, Matthew Eng, Herbert Engelbrecht, Michael Ennis, Roy Esaki, Paul Fairbrother, Gary Fanton, Marie Farstad, Bill Feaster, Larry Feld, Vladimir Firago, Steve Fischer, Jason Fleming, Linda Foppiano, Seth Friedland, Maika Fujiki, Louise Furukawa, David M. Gaba, Ray Gaeta, Stephen L. Gaffin, Kingsuk Ganguly, Premjith Gathiram, Monica Gerstner, Rona Giffard, Jon Gjessing, Mark Gjolaj, Christopher Good, Steven Goodman, Stuart Goodman, Neal Goodwin, Dennis Grahn, Lorentz Gran, Mike Greenberg, Ronald Green-Thompson, Mike Gregory, Steve Griffin, Cosmin Guta, Ali Habibi, Alvin Hackel, Gordon Haddow, Ariff Ahmed Haffejee, Jennifer Hah, Christopher Hamilton, David Hamilton, William A. Hampton, Frank L. Hanley, Leland Hanowell, Edmund John Harris, Kyle Harrison, Natalya Hasan, James Healzer, Craig Heller, Jaimie Henderson, Cathy Heninger, Erin K. Hennessey, Erin Hepworth, Jerome Hester, John Hicks, Jesse Hill, Laureen Hill, Gillian Hilton, Lerner B. Hinshaw, Asher Hirshberg, Shawn Hodge, Robert Holbrook, Allan Hold, Jeffrey P. Holden, Allison Holloway, Jung Hong, Susan Hoopes, Peter Houlton, Steve Howard, William Huizinga, David Humphrey, Paul Husby, Jerry Ingrande, Richard A. Jaffe, Mike James, Mark Jamieson, David Jarvis, Stephanie Jeffrey, Chrystina Jette, Derek G. Jordaan, John Jordaan, Bassam Kadry, Ahmed (Mahmood) Kadwa, Hassan Kadwa, Soromini Kallichurum, Sunder Roopsun Kambaran, Komal Kamra, Norman Kaplan, Jadwiga Katolik, Ralph Katzwinkel, Robert Kaye, Michael Keating, Steve Kelleher, Mary Khaing, Muhammad Fazl-Ur Rahman Khan, Andrew Kim, Tae-Wu Edward Kim, Harry Kingston, Yvonne Koen, Marie Koller, Jiang-T Kong, Ted Kreitzman, R Kremer, Vivek Kulkarni, Joseph Kumm, Erin Lachman, Cathy Lammers, Gary Lau, Kenneth Lau, Nigel Lavies, George Lederhaas, Eugene S. Lee, Jennifer Lee, Phoebe Leith, Harry Lemmens, Jody Leng, Theodore Leng, David C. Levi, Robert Levitan, Geoffrey Lighthall, Per Gustav Lilleaasen, Yuan-Chi Lin, Steven Lipman,
Sanford Littwin, N Lopes, Jaime R. Lopez, Andrew Love, Tom Lund, Joe Luther, Alex Macario, Robin MacGillvray, Bruce MacIver, Rob MacKenzie, Sean Mackey, TA MacPherson, Rajend Maharaj, Nisha Malhotra, Ann Marie Mallat, Kevin Mallott, Emmanuel (“Mannie”) Mankowitz, Steve Manos, Steve Mantin, Ed Mariano, Masizane Marivate, Jim B.D. Mark, James Mark, Maurice Mars, Aileen Marszalek, William Mathers, Amitabh Mathur, Parag Mathur, Nasim Mayat, Robin McAravey, Larry McFadden, Ashley Micks, Fred Mihm, Samuel A. Mireles, Jon Miser, Lyle L. Moldawer, Vanessa Moll, Jack Moodley, Linesh Moodley, David Morrell, John Morton, Mike Moshal, Ali Mossa, Ryan Mountjoy, Robert Moynihan, Khobi Msimang, Radha Muthukumarasamy, Rai Naidu, Clint Naiker, Sim Naicker, Robert Negrin, Andy Neice, Vladimir Nekhendzy, Camran Nezhat, John Nguyen, Birgit Niestroj, James Nixon, Andy Norbury, Robert Norman Steve O’Keefe, Eli Ohayon, Christopher Olcott, Matthew Oldroyd, Megan Olejniczak, Brent Oskarssen, Einar Ottestad, Ilian Parachikov, David Parris, Andrew Patterson, David Patterson, Nirupa Paulraj, Tim Pavy, Ronald Pearl, Bridget Phillip, Cindy Pillay, Fausto Pinto, John Pollard, Diane Pond, John Propst, Dennis Pudifin, Alex Quick, Deshandra Raidoo, Chandra Ramamoorthy, RJ Ramamurthi, George Ramjee, SA Ramzi, Emily Ratner, Andrew Rauch, Mahmood Razavi, Vadiyala M. Reddy, Catherine Reid, Ed Riley, Sherman Ripley, Archie Ritchie, Peter Ritchie, Frain Rivera, John Robbs, Joe Roberson, George Roberts, Joseph Robertson, Berklee Robins, RM Robins-Browne, Marnie Robinson, Beaver Robles, Tony Rocke, Ed Ronningen, JL Rosen, Jeanne L. Rosner, Chris Rout, Joe Rubin, Cathy Russo, Tom Ruttman, John Ryu, Lawrence Saidman, Robert Salisbury, Stanley Samuels, Rorbert Sanborn, Frank H. Sarnquist, Sunita Sastry, Amit Saxena, Carolyn Schifftner, Cliff Schmiesing, Ingela Schnittger, HS Schoeman, David Schurman, Robert Schuster, Inga Schwegmann, Soraya Seedat, Lars Segadal, David Seidman, Lori Sheehan, Paul Shuttleworth, Lawrence Siegel, Ruwan Amila Silva, Larry Silver, Vanila Singh, Mark Singleton, Jan Sliwa, David Smith, Roy Soetikno, Ezra Sohar, Hugh Brent Solvason, Ted Sommerville, Shaina Sonobe, Eldar Soreide, David Spain, Jean Marie Spitaels, Gary Steinberg, David Stemple, David Stevenson, Robin Stiebel, Marie Strassburg, Paul Strube, Naiyi Sun, David Sze, John Talavera, James Tan, Chris Tataru, Vivianne Tawfik, Renae Tays, Natacha Telusca, Stephen Ternlund, P Tew, J Thai, Kyu Thin, Shaun Mark Thompson, Sandie R. Thomson, Peter John Tomlin, Rodney Torralva, HS Townsend, James R. Trudell, Kendall Truelsen, Brian Tunink, Scott Tweten, Ankeet D. Udani, James Van Dellen, Johan Van den Ende, Pieter Van der Starre, Jason Varner, William Vaughan, G. Hoosen M. Vawda, Mark Vierra, Terry Vitez, Tracey Vogel, Lindsey Vokach-Brodsky, BJ Vorster, Hendrik J. Vreman, David Walker, Brant Walton, Michael Wang, Rachel Wang, David Waterpaugh, Michelle Wells, Steve Welman, Nigel Welsh, Brian Wessels, Mike Wiggins, Frank Wilkins, Deborah Williams, Ron Williamson, Gail Wilmot, Tim Winning, Russell Kong-Yen, Bernhard Wranne, Troy Wu, Imad Yamout, Steve Yu, Amadeo Zanotti, Karl Zheng, Gail Zisook, Andy Zumaran, Gary Zupfer, and Stephan Zweig.
Basic Premise
A. Why Is Clinical Research Necessary?
Everything we do as physicians carries a potential hazard. It could be the technique and equipment which we use, or it could be the medication which we give. We use these techniques, etc., to treat our patients, hoping that the benefits will outweigh the potential harm. Our clinical decisions are based on what we are mostly taught by our peers, tradition, and some human and many animal studies. Our experience is limited, so where do we get the knowledge to help us make the best decisions to help each patient? The answer is a properly conducted clinical research.
From the early days of medicine, doctors knew that certain treatments were dangerous. Hippocrates of Kos (born 460 BC and died 370 BC) stated: “Primum non nocere” (First, do no harm) and he also said “Desperate diseases require desperate remedies.” I remember as a little boy that my father, a doctor, said: “Vondt skal vondt fordrive,” which in Norwegian means: “Pain will get rid of pain.” He told me this as he lanced an abscess from my finger, without using local anesthesia. (He did not have any.)
Before 1950, there were no government regulations regarding how clinical research should be performed. Most techniques or treatments were brought to the marketplace with minimal or no clinical studies to prove that they were beneficial or, more importantly, safe.
In September/October 1937, a congressional inquiry led to the beginning of the Food and Drug Administration (FDA) after the 73 deaths in the USA from a drug called “Elixir of Sulfanilame.” This Elixir contained a solvent, diethylene glycol, which is toxic.
In France, an organic preparation called Stalinon (1956–1957) contained diethyltin diiodide (15 mg) and linoleic acid (100 mg) per capsule. The adult dose was six capsules a day which was a toxic dose. Two hundred and seventeen persons were severely poisoned by Stalinon, and of those, over 100 died.
Even though each country had an FDA of some sort, it was highly ineffective in controlling what was sold to the public. But all this changed with the Thalidomide
(Contergan) tragedy in 1961. The drug, when used by pregnant patients suffering from heartburn, led to the birth of deformed babies. The public all over the world was outraged. Governments decided that the pharmaceutical industry needed to be tightly regulated. As a result, governments decided that they would in the future:
1. Make sure that adequate clinical pharmacological studies would be done on new drugs prior to their release for general use. These studies should include safety testing (in both animals and humans) and clinical trials.
2. Recognize and publish any adverse effects that may arise after the release of a new drug [1].
Hence, clinical research is necessary to answer the questions:
1. How good are our medicines, techniques, and equipment?
2. How bad are our medicines, techniques, and equipment?
B. Why Do Physicians Do Clinical Research?
Physicians start doing clinical research for various reasons. Many do it because they have passion for a certain technique, drug treatment, and/or a device. They want to show that their idea is better than everyone else’s. These researchers often get “bitten by the bug” and make clinical research their life’s work.
Others do research purely to get promoted in the university system. The wellknown phrase “Publish or Die” is alive and well in academia. An academician’s quality and quantity of research output is an easy way to measure his/her academic achievements.
Some people do research to get acknowledged by their peers and to see their name in “golden lights.”
Some people do clinical research because of their clinical expertise. Outside agencies recognize this and pay the researcher to conduct research in their field. This financial support can be large and may even pay for part or whole of their annual salary. In addition to the salary, the outside supporters pay the university for using its facilities (usually 35 % of the grand total). In addition, they also pay for research assistants, laboratory fees, etc. In the USA, the financial support to do a 20-patient study can amount to about $300,000.
The individual reasons for doing clinical research vary tremendously and can be one or a combination of any of the above factors. But most importantly, clinical research can be fascinating, rewarding, and fun.
So has the interest in clinical research increased, decreased, or stayed constant in the last 70 years? Take anesthesia, for example. Feneck et al. [2] have indicated that there appears to be a decline in published anesthetic articles. However, Green and Kumar [3] point out that Feneck et al. only reviewed seven journals. It is interesting to note that the first anesthetic journal, Anesthesia & Analgesia, came out in 1921.
By 2005, there were 262 anesthetic specialty journals across the world [4]. In the 10 years from 1995 to 2005, there were 56 new journals [4]. Hence, it is more likely that the actual amount of original manuscripts produced in the field of anesthesia has increased tremendously.
C. What Are the Various Experimental Designs?
1. Case report or case series. Simple and mainly descriptive.
2. Random controlled trials. These are considered the “gold standard.”
3. Group comparisons. Here, for example, the groups are selected based on the presence or absence of disease.
4. Cohort studies: These can be prospective or retrospective. The groups are selected based on the presence or absence of exposure to treatment, health risks, etc.
There are several sampling methods like random selection, random allocation, or sequential allocation. The method used must include inclusion and exclusion criteria. Statistical analysis must be appropriate and the results summarized clearly. Graphs must be labeled and easy to comprehend.
D. Ethical Issues on Informed Consent and Recruitment for Clinical Trials
It is imperative to obtain informed consent from any patient/volunteer who you want to study. There are obvious moral, sociologic, and legal reasons [5, 6].
My personal success rate in obtaining informed consent is about 50 %. You may think this is low, but I feel that if the patient is unsure about participating, I immediately tell them not to worry and withdraw my proposal. You should never try to pressure people to participate. Patient autonomy must always be respected. If you sense that they are feeling guilty or fearful by not agreeing to participate in your clinical trial, then it is your job to allay their anxiety.
From time to time, I have had patients who have consented to a clinical trial and asked if they can be placed in a specific study group. I have always denied this request as each person is randomly placed in either group. Most clinical researchers will agree with this action. If the requests were agreed to, the groups would no longer be randomized.
There are authors who recommend pre-randomization [7, 8]. This means that patients are randomized to a treatment group before the patient gives consent. Myles et al. [9] found that there was no recruitment improvement when using a prerandomization protocol. Since they found no benefit and given the ethical concerns raised [9], they recommend that pre-randomization should no longer be used.
References
1. Becker C. Drug pullout. Massive recall of Vioxx poses logistical problems. Mod Health. 2004;34(42):17.
2. Feneck RO, Natarajan N, Sebastian R, Naughton C. Decline in research publications from the United Kingdom in anesthesia journals from 1997–2006. Anaesthesia. 2008;63:270–5.
3. Green J, Kumar S. Apparent decline in published anaesthetic articles. Anaesthesia. 2008;63:1148.
4. Green J, Kumar S. Apparent decline in published anaesthetic articles. Anaesthesia. 2008;63(10):1148–9. http://www.hcuge.ch/anesthesie/anglais/evidence/journals.htm#list
5. Beecher HK. Ethics and clinical research. NEJM. 1966;274:1354–60.
6. Zelen M. A new design for randomized clinical trials. NEJM. 1979;300:1242–5.
7. Myles PS, Buckland MR, Cannon GB, Bujor M, Langley M, Breaden A, Salamonsen RF, Davis BB. Comparison of patient-controlled analgesia and conventional analgesia after cardiac surgery. Anaesth Intensive Care. 1994;22:672–8.
8. O’Rourke PP, Crone RK, Vacanti JP, Ware JH, Lillehei CW, Parad RB, Epstein M. Extracorporeal membrane oxygenation and conventional medical therapy in neonates with persistent pulmonary hypertension of newborn: a prospective randomized study. Pediatrics. 1989;84:957–63.
9. Myles PS, Fletcher HE, Cairo S, McRae R, Cooper J, Devonshire D, Hunt JO, Richardson J, Machlin H, Morgan EB, Moloney J, Downey G. Randomized trial of informed consent and recruitment of clinical trials in the immediate perioperative period. Anesthesiology. 1999;91:969–78.
Chapter 1 Case 1: A “Good” Question
Before you start doing clinical research, you must have a question that you want to solve. The question should be of great interest to you and you must have a strong passion to solve it.
Equally important as finding the right question is to be very critical of your own idea. You must consider all the various aspects that can possibly prevent you from completing the study, for example, not having enough time, not having enough patients, etc. If you are unsuccessful in finding any reason why you should not attempt to do the study, then you must pursue it steadfastly.
One of the best areas to pick for your research is the one that relates to your everyday practice in the hope to improve patient care. The improvement in patient care has always been my primary motivation for doing clinical research. You can study patients in a primary care setting, a ward, a specialized treatment (dialysis) or investigational unit (endoscopic suites), an ICU, or operating room. Any idea that can benefit patient care is worthy of investigating. But before you embark on your quest, you must prepare well. This will take much longer than you think. Remember the study must be well designed and executed so that it will be accepted for publication. Broadcasting your results is the final and important sequence of the clinical research process.
Prior to the start of the study, you must check that you have everything you need (enough potential patients, equipment, etc.) to be able to answer the question that you will be posing. If you are planning a randomized controlled trial, it is important that the control arm of the study should reflect present clinical practice. Otherwise, how can you interpret the results of the treatment arm? Also consider which peerreviewed journal will be interested in your study, because you will want, as I say, to get the results published.
The question should be something like: How good or how bad are our medicines, techniques, or equipment?
Other studies that are acceptable can elucidate mechanism of action in, for example, pharmacology.
Having found your question, remember to keep it simple and specific. Also never change the question halfway through the study; this may compromise the ability of the data analysis to reach the correct/useful conclusions. By changing the question halfway, you will most likely have changed or modified your end point. Hence, it is imperative to have the correct question to solve from the very beginning and to stick to it. Here is an example of a good clinical question that we concluded a few years ago [1]: Does nitrous oxide (N2O) cause bowel distention in morbidly obese patients during general anesthesia?
There is controversy in the literature if nitrous oxide (N20) can cause bowel distention or not. This information is important to surgeons as should the bowel be distended, it may be difficult to close the abdomen.
Besides this reason, why do you think this was a good study (at least 8 reasons)?
Answer/Solution
It was a good study since:
1. It was a simple study.
2. One end point. Was the bowel distended or not?
3. Surgeon was “blinded” to N2O being used or not.
4. We had a lot of morbidly obese cases per week.
5. We had interested and supportive surgeons.
6. It was very easy to get consent from the subjects, as there were minimal risks to the patients.
7. It was easy to get IRB approval.
8. There was controversy in the literature (see Chap. 29).
Discussion
That this turned out to be a good question can be seen from the following facts that are summarized below:
1. July 2004. Defined the question, invited the surgeon to participate as “a blinded observer” to N2O being used or not, wrote out the proposal, and submitted it to the IRB.
2. September 2004. IRB approval.
3. September 2004. Study started. Fifty patients were enrolled.
4. November 2004. Study finished, stats done, and paper written up and submitted. For your information, a simple t-test, Fisher’s exact test, or chi-squared tests were used for intergroup comparisons.
5. December 2004. Four weeks after submission, the paper was accepted for publication.
The question was answered: Surgeons could not differentiate if N2O was used or not. Therefore, the use of N2O in these cases is an acceptable practice.
Lesson
To do research, you must have a question. This must be simple and when the study is finished, it should preferably give you a “yes” or a “no” answer.
Many years ago, while working as an anesthesiologist and critical care registrar (resident) in King Edward VIII Hospital, University of KwaZulu-Natal, Durban, South Africa, I got interested in the following question: Does chest physiotherapy (CPT) have a role in the prevention of postoperative respiratory failure after upper abdominal surgery?
I was young and I thought the question could easily be answered, since some surgeons used CPT postoperatively and some did not prescribe to it. Hence, I had two groups. The IRB was easily obtained and so was the consent. I also knew that there would be no lack of patients because upper abdominal knife wounds were very common at our hospital at that time.
After 30 cases, I reviewed the data sheets with my research nurse. On the basis of these findings, we stopped the study. We had not taken into account the many clinical variables that can affect a result. What variables do you think they were (at least 8)?
2 Case 2: A “Bad” Question
Answer/Solution
The study was stopped as it had not taken into account the following (in no particular order):
1. Associated injuries/diseases.
2. Length of surgery, due to the surgical problems and surgeon’s skills.
3. Smoking history.
4. Frequency and duration of CPT.
5. Different types of CPT by different physiotherapists.
6. Antibiotics. Some surgeons used them and some did not.
7. If the antibiotics were used, the timing and dosing of the antibiotics varied tremendously.
8. Mucolytics/bronchodilators. Some physiotherapists used one or the other or both and some did not use any.
Lesson
Always consider the multiple causes that can change a clinical outcome.
Chapter 3
Case 3: Why Were 116 Patients Excluded?
In Case 2, you learned to always consider the multiple causes that can change a clinical outcome. In the end in Case 2, there were no results to write about. So what would you do when faced with this dilemma? Give up or start again?
We redesigned the study and took into account all the points mentioned in solution made in Case 2. After many months, we reviewed the findings. Two hundred and twelve patients had been enrolled successfully. But we had to exclude a total of 116 patients.
Why were these 116 cases excluded?
Answer/Solution
The 116 cases were excluded mainly because the surgeons had used different antibiotics from the ones we had agreed to. Furthermore, we found that the antibiotics were not given preoperatively as prescribed.
Other causes of exclusion included the differences in physiotherapy techniques and the duration of the therapy. The physiotherapists had been instructed how to do the therapy and had agreed to do it using a mucolytic. However, when reviewing the data sheet and later when questioning the physiotherapists, some had not adhered to the instructions.
We gave up the study. But I learned many lessons from this disaster. I mention them here for your benefit:
1. Always be aware of the multitude of changes that can alter a clinical result.
2. If you rely on other health-care providers in the treatment, make sure that you invite them to be authors, should the results be publishable. This makes them more accountable.
3. Always routinely check the status of trials by regularly reviewing the data sheet, observe how the physiotherapy is done, make sure the antibiotic is given at the prescribed time, etc.
4. Never let clinical trials go over one year. People involved with the study will get bored, lose focus, cut corners, etc.
The best thing to do in a proposed study that involves many different departments and researchers is to do a trial run. You will not regret it.
Lesson
Make sure you have a simple question. Minimize most/all the clinical changes that can affect your results and conclusion.
Chapter 4
Case 4: Sometimes a Good Question Evolves from a Bad One
Case 2 told you about a “bad” question and what happened. Should this happen to you, then always reflect on the bad outcome.
We decided that the biggest “killer” of this study was that the timing of the antibiotics was not adhered to. At the time, there was very little literature on the pharmacokinetics of the potential importance of giving prophylactic antibiotics prior to a surgical incision. There were recommendations that preoperative antibiotics should be given prophylactically prior to abdominal surgery, but there was no scientific proof that this would be beneficial.
What study would you now propose to try and address the lack of pharmacokinetics data?
Another random document with no related content on Scribd:
11 “Nephritis et Arthrites saturnines: coincidence de ces Affections paralleles avec la Nephrite et l'Arthrite goutteuse,” Arch. gén. de méd., Decembre, 1881.
4. Lead Palsy; Lead Paralysis; Paralysie Saturnine; Bleilähmung.—
This condition is fourth among the affections due to chronic leadpoisoning, both in frequency and in the order of succession. Nevertheless, like each of the others, it may be the first in the order of appearance after disturbances of nutrition which are in some rare cases of very slight degree. As a rule, however, the paralysis has been preceded by colic or by joint affection, or by both. Tanquerel12 found that in 88 cases of lead palsy 25 had been preceded by an attack of colic, 15 by two attacks, 3 by ten attacks, 1 by fifteen attacks, and that in single cases as many as twenty, and even thirty, attacks of lead colic had occurred before the appearance of paralysis.
12 Loc. cit.
The length of time over which habitual exposure to lead without the development of palsy may extend was found by the same observer to vary from eight days to ten, twenty, or even twenty-five years. One individual first suffered from paralysis after fifty-two years of exposure.
Without dwelling upon the sources of error in statistics of this kind, it must be conceded that they establish in a general way the extraordinary differences in the susceptibility of individuals. There are persons who every time they are attacked with colic, of whatever degree of severity, suffer also from paralysis. Others, on the contrary, suffer from repeated attacks of violent colic without the development of paralysis.
Lead palsy is an affection of adult life. Of 102 cases, 2 only occurred in individuals below twenty years of age.
Like the other specific lead affections except the encephalopathy, palsy is more common in the summer than at any other season.
Those who have once suffered are very liable to successive attacks. Tanquerel and Maréchal have observed many returns of paralysis, presenting the characters of the original attack, many years after the patient had withdrawn from exposure to lead.
Perverted sensations of the parts about to be affected, such as coldness, numbness, and hyperæsthenia, may precede the attack. Impairment of motor-power, manifested by feebleness, stiffness, or awkwardness and tremor, also appears in the prodromic period. This trembling consists in slight agitation of the muscles, rather than in well-marked rhythmical contractions. These precursors may indeed constitute the attack, which occasionally, and especially under treatment, terminates at this point. The prodromic symptoms are less severe during the day, while the patient is at work; at night they are aggravated. After some days they end in the characteristic paralysis. Colic is a common precursor. After the attack some stiffness of the muscles is experienced, which terminates by rapid loss of power or abruptly in actual palsy. Occasionally encephalopathy precedes the paralysis. It is rare that prodromes are wholly absent.
In the great majority of the cases the upper extremities and the extensor muscles are first attacked. If the paralysis be slight other muscles may escape. The characteristic form of lead paralysis consists in loss of power in the extensors of the hands and fingers, especially of the extensor communis, without implication of the supinator longus. The muscles affected are in the region of distribution of the musculo-spinal nerve. The deformity is known as wrist-drop. Next in order, the triceps and deltoid are most frequently attacked. The lower extremities commonly escape for a considerable time. When attacked, the extensor muscles of the feet and toes are the first to suffer.
Paralysis of the dorsal muscles occurs in rare instances. It gives rise to a peculiar stooping, uncertain, and tottering gait. Paralysis of the intercostal and laryngeal muscles was observed by Tanquerel. Paralysis of the muscles of the face or of those of the eye has never been observed in consequence of lead-poisoning. The loss of power
never corresponds strictly to the distribution of the branches of a single nerve-track.
The paralysis, as a rule, affects both sides, and frequently the corresponding muscles of the two extremities. Sometimes, however, the affected muscles of the two sides are not the same, and it occasionally happens that the affection is limited to one side. In very rare cases, the arm and leg on the same side being paralyzed, the affection resembles hemiplegia.
Local paralysis may be limited to the extensor muscle of a single finger or may involve all the muscles of a limb. There may be slight impairment of power in the flexor muscles. The enfeeblement of certain flexor muscles, especially of those of the fingers, may, Naunyn suggests, be only apparent, the position of the hands being in pure extensor paralysis unfavorable to the exercise of the flexors and limiting their function.
Sensation is not, as a rule, affected in lead paralysis. Pains in the paralyzed muscles, in neighboring muscular masses, and in the structures about the joints often precede the attack of paralysis. Anæsthesia of the skin is rare. When present, it is usually of slight degree, and corresponds to the region of the paralysis. Deep anæsthesia has also been observed.
Atrophy of the paralyzed muscles is constant and rapid. It frequently reaches a high degree, causing characteristic deformities, which are rendered more marked by the fact that the adjacent non-paralyzed muscles preserve to a great extent their original state of nutrition. As the neuro-muscular lesion progresses other deformities arise, in consequence of derangements of the balance of force between opposing muscles and from other causes. Among these deformities are partial or complete dislocations of the more movable joints, as the shoulder and phalanges, with the formation of tumors, which, when they occupy the dorsum of the hand, might be carelessly mistaken for the nodosities of gout. It is to be noted that the latter are occasionally present as complications.
There is rapid diminution, and finally complete loss, of the reaction to the faradic current. With the galvanic current the reaction of degeneration is usually well marked. The reaction of degeneration may be demonstrated in the extensors of the limbs in lead-poisoning before wrist-drop has occurred.
The course of lead palsy is very variable. In a few cases it is progressive. When local emaciation or atrophy arrives at the last degree of marasmus, the skin seems glued to the bones, to such an extent are the paralyzed parts wasted; the muscles especially are so thinned that the contour of the bones is easily distinguished. If the paralysis attack the whole of the limb, then this organ, abandoned to its own weight, stretches the ligaments and permits the head of the bone to leave its cavity. In other rare instances the paralysis remains stationary for long periods of time, only to grow worse after each new attack of lead disease. Much more frequently lead paralysis disappears spontaneously or under treatment in the course of some days or weeks. The convalescence is gradual, and usually rapid, when the gravity of the lesion is considered; occasionally it is complete in the lapse of a few days.
The prognosis depends upon the degree of lead cachexia present, the possibility of withdrawing the patient from the exposure, and finally upon the degree and extent of the paralysis and of the atrophy. It is rendered unfavorable by the necessity of the prolonged exposure of the patient to lead, by a high degree of disturbance of the general nutrition of the patient; and by the fact of his having presented for a considerable period the evidences of lead disease, with occasional attacks of colic or arthralgia; by the complete loss of power and electrical reactions in the affected muscles; and, finally, by absolute wasting of the muscular masses. The prognosis is less favorable in relapses than in the primary attack.
Progressive muscular atrophy has been frequently observed in patients suffering from lead disease (Naunyn).
5. The Encephalopathy; Encephalopathia Saturnina.—This term was suggested by Tanquerel to designate collectively the various morbid
cerebral phenomena produced by chronic lead-poisoning. It embraces, therefore, those affections due to the action of lead upon the central nervous system, and occasionally described as lead insanity, delirium, convulsions, epilepsy, coma, etc. It is, of all the disorders produced by lead, the most rare. Tanquerel met with seventy cases only. It occurs only in those individuals who are exposed to large quantities of lead, and in such a manner as to favor the absorption of the metal and its compounds by the digestive and respiratory tract. Hence house-painters and the workers in leadfactories supply the greater number of cases. The time of exposure elapsing before the manifestations of the special morbid action of the poison upon the nervous system show themselves varies from a few days to many years. In a large proportion of the cases the time has been less than one year.
Women are much less liable than men—a fact clearly due to the nature of their occupations even when involving exposure to lead.
The majority of the cases have occurred between the ages of twenty and fifty. Alcoholic habits, insufficient and unwholesome diet, privations, exposure, and an irregular life especially predispose those working in lead to the affection. Lead encephalopathy has developed with nearly equal frequency in warm and in cold weather. Relapses are frequent.
Among the prodromes are headache, vertigo, agitated and interrupted sleep marred by distressing dreams, and troublesome insomnia; derangements of the special senses, dimness of vision, alterations of the pupils, tinnitus aurium; dysphagia and a sense of constriction of the pharynx have also preceded the attack of cerebral disorder. It is usually preceded likewise, and often by a considerable lapse of time, by the other lead affections above described—namely, colic, arthralgia, and palsy. Psychical derangements—stupor, apathy, or excitement—also precede the attack. In a small number of cases lead encephalopathy has occurred abruptly without prodromes.
The symptomatology is exceedingly variable and irregular. Three forms, the delirious, the comatose, and the convulsive, have been
described. These conditions may succeed each other in the same attack. The delirium is variable in kind. It is apt to be at first tranquil; after some time it becomes paroxysmal and furious. It is broken by intervals of somnolence. At length true sleep supervenes, and the patient awakes restored almost completely to his reason.
Coma may develop suddenly, even instantaneously. In a very few cases the comatose form has developed itself alone during the course of chronic lead-poisoning. As a rule, however, it is preceded by delirium or convulsions.
The convulsive form is the most common. The convulsions may be partial, involving the face or the one side of it, a single limb, or one side of the body. They may be general, without loss of consciousness. These incomplete attacks are apt to be followed, after a period of dulness or unconsciousness, by acute eclampsia. Epileptiform attacks may now follow each other in rapid succession, ending in more or less profound coma. The attacks are sometimes separated by intervals of uneasiness, restlessness, or delirium. These attacks continue several days. If they are very violent and frequent death may rapidly supervene. In favorable cases consciousness is gradually restored, or the patient may awaken suddenly from his drowsiness after some hours or a day.
These attacks are not preceded by an aura.
Amaurosis is among the more important of the symptoms produced by the action of lead upon the nervous system. It is usually accompanied by dilatation of the pupils. The amaurosis gradually disappears as the other symptoms subside, and with the improvement in sight the pupils contract. Recovery is frequently complete. Occasionally vision does not return with the improved general condition. Norris13 saw, in two cases of lead-poisoning due to the use of white lead as a cosmetic, marked choking of the discs in connection with severe cerebral symptoms. The terminal condition, when recovery does not take place, is that of nerveatrophy.
13 See this System of Medicine, Vol. IV
Albuminuria is common in this as in other lead affections. It may be of moderate amount and due to the rapid breaking-down of the blood-corpuscles which marks the exacerbation of the general condition. Albuminuria may be a direct consequence of the eclampsia. Finally, it may be due to coexisting nephritis.
The prognosis is in a high degree unfavorable.
MORBID ANATOMY AND PATHOLOGY.—There are no well-characterized anatomical lesions in chronic lead-poisoning. Lead has been found in almost every organ and tissue in the body. It exists in combination with the albumen of the tissues. The changes in the nervous system that have thus far been described are neither constant nor characteristic. The same is true of the lesions of the intestines. The paralyzed muscles are found to have undergone atrophy, with loss of the striæ and increase of connective tissue. The nerve-trunks are also the seat of atrophic degeneration.
The mode of action of lead is not yet determined. The view of Henle, that lead acts chiefly upon the unstriped muscular fibre, was at one time generally accepted, and served to explain many of the characteristic phenomena of the disease. On the other hand, there is much in the clinical history to support the opinion of Heubel, that its primary action is upon the nervous system. Whether the peripheral degeneration by which the paralysis is to be explained is primary or secondary to central degeneration in the anterior cornua of the gray matter of the spinal cord, is yet in dispute. Some of the forms of encephalopathy are doubtless due to the nephritis which is found in many cases of chronic lead disease, and are, in fact, symptoms of uræmia. In the great majority of the cases this is not the case. The morbid condition must be explained by the direct toxic action of lead upon the central nervous system. No theory adequate to account for all the cerebral manifestations has yet been suggested. Naunyn has pointed out the resemblance between the nervous and psychical derangements in lead encephalopathy and those which characterize chronic alcoholism, and suggests that lead, like alcohol, produces
these effects not as a direct poison, but indirectly in consequence of abnormal nutrition of the whole system, brought about by the continued circulation of a foreign poisonous material in the blood.
Chronic Lead-Poisoning in Animals.—Animals exposed to lead under conditions favorable to the development of the lead affections in man suffer in like manner. Instances of this kind are of frequent occurrence in and about large lead-factories. The drinking of water containing lead also gives rise to these affections in animals. Horses, dogs, cats, and fowls have frequently suffered from lead colic. Horses used in lead-factories suffer from a form of laryngeal obstruction due to lead paralysis of the muscles of the larynx. Relief has followed tracheotomy and the introduction of a canula, and removal to an atmosphere free from lead has resulted in recovery. Cats who spend some time in red-lead workshops frequently are paralyzed. Even the rats in lead-factories become paralytic (Tanquerel).
DIAGNOSIS.—The diagnosis of the affections due to chronic leadpoisoning is, as a rule, unattended with difficulty. The malnutrition, anæmia, poor digestion, foul mouth, stubborn constipation, and the gingival line, considered in connection with the history of prolonged or habitual exposure to lead, would warrant the assumption that the relation between this poison and the symptoms is a causal one. When there is added colic, arthropathies, and paralysis, or the cerebral states having the characters above described, the assumption becomes a certainty. The absence of any one of the ordinary phenomena, such as the blue line or constipation, would still leave the clinical picture sufficiently full to justify the diagnosis. The reaction of degeneration, which is usually marked in saturnine wristdrop, with the escape of the supinators, distinguishes it from pressure paralysis of the musculo-spiral.
TREATMENT.—A. Prophylaxis.—Free ventilation and scrupulous cleanliness constitute, in general terms, the most efficient safeguards for those whose occupations involve prolonged exposure to lead. Workmen employed in lead-factories and those otherwise
exposed to lead should be compelled to wash their hands and change their outer clothing before eating; they should also bathe regularly every day on leaving work; under no circumstances should they be suffered to eat or sleep in or near the workshops. As all kinds of work in the manufacturing of lead preparations are not attended with equal risk, the workers should from time to time be transferred from one department to another or from in-door to outdoor work. In order to prevent the constant rising of dust, the floors are to be kept constantly sprinkled or covered with moist sawdust. It is unnecessary to go into further details in regard to the hygiene of the subject. It is probable that towels and sponges worn over the mouth, or other forms of respirators, because of the inconvenience which they occasion and the false sense of security which attends their use, are of less value than has been generally supposed.
It appears scarcely needful to here insist upon the avoidance of cosmetics and hair-dyes containing lead, or upon the exercise of reasonable prudence in the matter of the manufacture, sale, and use of articles of food or drink which are liable either by accident or design to become adulterated with lead compounds.
The use of sulphuric-acid lemonade is a measure of prophylaxis of less real value than was at one time supposed, seeing that the sulphate of lead is in itself capable of producing the disease. Occasional doses of magnesia sulphate are of use where a tendency to constipation exists. Workmen who begins to show signs of chronic lead-poisoning should without delay abandon their work and seek some occupation free from its peculiar dangers.
The precautions against the use of water contaminated with lead have been pointed out under the heading Etiology.
B. Curative Treatment.—When the disease shows itself, no matter in what form, the primary indication is the discontinuance of exposure to lead. Chronic cases of malnutrition, constipation, functional nervous disorder, will occasionally be found upon careful search to depend upon long exposure to lead in some unsuspected way. The cause being removed, such cases often promptly recover.
Measures aimed first at the separation of the lead from the tissues, and then at its elimination from the body, constitute a rational treatment. Sulphur baths and the internal administration of sulphur may be employed with a view of converting the lead eliminated by the skin and mucous membranes into an insoluble sulphide, and thus preventing its resorption. Repeated laxative doses of castor oil will remove unabsorbed lead from the intestinal canal. The plan of treatment at present in general favor consists in the combined use of potassium iodide and magnesium sulphate. From five to twenty grains of the iodide are to be given in not less than six or eight fluidounces of water three times daily, the stomach being empty: two hours after each dose one or two drachms of the magnesium sulphate are to be taken; after this dose an ordinary meal.
This treatment is designed to dissolve the lead deposited in the tissues, and cause its elimination by the mucus of the alimentary canal in part, and to a slight extent also by the urine. The magnesium sulphate tends to remove such lead as finds its way into the alimentary canal thence with all possible rapidity. These measures, together with the removal of the patient from further exposure, exert of themselves a favorable influence upon the malnutrition and anæmia. Quinine, strychnine, iron, cod-liver oil may be advantageously administered as the toxic effects of the lead pass away.
The colic demands the administration of opium or its derivatives to relieve the pain, which is commonly excruciating. For this purpose the hypodermic injection of morphia is our most efficient remedy. Alum in doses of twenty to thirty grains every four or six hours is useful in lead colic.
For the relief of the local paralytic affections local as well as general treatment is necessary. Massage is of great use, especially when combined with passive movements. Galvanism, one large electrode being applied to the cervical vertebræ, the other to the extensor surface of the affected limbs, is followed by excellent results. Labile currents of fifteen or twenty cells should be thus applied, the poles
being changed several times at each sitting. As the nutrition of the muscles improves faradic currents may be occasionally substituted. Persevering treatment is necessary to obtain the best results.
For the present relief of the arthralgia gentle frictions with or without anodyne liniments must be employed. The hypodermic use of morphine may become necessary in cases in which the pain is urgent. It is, however, here as elsewhere, to be if possible avoided. The tendency to recurrent joint-pains rapidly disappears as the poison is eliminated from the organism.
For the relief of the severe cerebral symptoms which are described under the term Encephalopathy special treatment is of little avail. All observers agree in recommending an expectant plan. The measures of treatment directed against the general condition, as above described, must be steadily continued. The influence of chronic leadpoisoning upon pregnancy is very deleterious. Constantine Paul14 and others have shown that the early death of the fœtus very constantly occurs. The prompt removal of women who have become pregnant, from all exposure to lead, and energetic medicinal treatment, are needed to obviate the danger of abortion.
14 Arch. gén. de Méd., vol. xv., 1860.
BY CHARLES K. MILLS, A.M., M.D.
DEFINITION.—Progressive unilateral facial atrophy is a disease characterized by progressive wasting of the skin, connective tissue, fat, bone, and more rarely muscles of one side of the face.
SYNONYMS.—Progressive facial hemiatrophy, Neurotic atrophy of the face (Virchow), Facial trophoneurosis (Romberg), Prosopodismorphia (Bergson), Atrophy of the connective tissue of the face or Laminar aplasia (Lande).
HISTORY AND LITERATURE.—This disease has been known to the medical profession since 1825, when, according to Eulenburg, it was first described by Parry. The Index Catalogue contains references to thirty books and articles on the subject in various languages. Eulenburg gives a bibliography which contains thirteen references not given in the Index Catalogue. One personal case, which will be detailed later, has fallen under observation. In all, I have collected from fifty to sixty cases. The number of reported cases is slowly increasing; nevertheless, the disease must still be regarded as rare. Carswell,1 according to Lasègue,2 first arranged scientifically the various lesions which might arise in consequence of a retardation and arrest, or even inverted action, in nutrition, and at the same time that he assigned their causes pointed out the several forms of atrophy. Aran3 has written a contribution on the subject, furnishing valuable material for classifying atrophies. Romberg called general attention to the disease in his clinical researches, published in 1846. He described the disease under the name of a new form of atrophy of the face, and took the position that it was a primary trophoneurosis. Of contributions by American writers, a paper by Bannister4 is the most complete and valuable. This not only contains two fully and carefully reported cases, but also a thorough discussion of special symptoms and the pathology of the disease. The chapter
of Eulenburg5 contains an excellent sketch of the disease, and is especially valuable for the discussion of the various theories as to its nature.
1 Illustrations of the Elementary Forms of Disease, 1836.
2 Archives générales de Médecine, May, 1852, p. 71.
3 Ibid., Sept. and Oct., 1850.
4 Journal of Nervous and Mental Disease, vol. iii., No. 4, Oct., 1876, p. 539.
5 Ziemssen's Cyclopædia of the Practice of Medicine, vol. xiv., 1877.
ETIOLOGY.—The disease is of much more frequent occurrence among females than males. Out of 25 cases which I have been able to classify, 9 were in men and 16 in women. It is an affection of comparatively early life. The following were the ages of 25 patients: under ten years, 7; from ten to twenty years, 11; from twenty to thirty years, 6; over thirty years, 1.
Graefe6 reports a case due to syphilis, in which there was also paralysis of the left oculo-motor externus and trigeminus. In one of Bannister's cases the patient had suffered repeatedly from slight frost-bites. Among the causes which seem to be thoroughly established traumatism holds the first place. The affection could be traced to injury in a fair number of the published cases. A case is reported by Maragliano7 of a child who had a fall in which she struck the left half of her face, and in consequence of which a circumscribed swelling appeared near the external angle of the left eye and remained for a few days. Shortly after this the left half of the face began to grow smaller than the right. Schuchardt8 speaks of a fall on the head which left a cicatrix on the right parietal bone below the coronary suture, the injury being followed by facial atrophy. Panas9 reports a case in which the wasting of the face followed a fracture of the lower jaw. In one of two cases reported by Bannister,10 a man, aged forty-two, is stated to have been thrown from a stagecoach, falling on his head, and not losing consciousness, but
receiving a scalp wound over the coronal suture. Subsequent to this time he had cerebral symptoms, physical and mental, and unilateral facial atrophy developed.
6 Quoted by Rosenthal.
7 Note di Clinica Medica, Genoa, 1881, translated by Joseph Workman, M.D.— Alienist and Neurologist, vol. ii. No. 2, April, 1881, p. 146.
8 Quoted by Eulenburg.
9 Bull. Soc. de Chir. de Par., 1869, 1870, 2d S. ex., 198, and Gaz. des Hôpitaux, 1869.
10 Journ. Nerv. and Ment. Dis., Chicago, 1876, iii. pp. 539-560.
SYMPTOMATOLOGY.—Before discussing the symptomatology I will give brief notes of the following case, which has not been before reported, and which was observed by me while in charge of the Nervous Dispensary of the Hospital of the University of Pennsylvania several years since.
C——, aged seventeen, white, a mill-operative, had a good family history. Three years before coming under observation a white spot appeared in the skin over the right malar prominence, and since that time this side of the face had gradually atrophied. When this patient was first examined the skin had a mottled appearance. Close examination showed that the skin, connective tissue, and bone were decidedly wasted, and there seemed also to be some loss of substance in the muscles of the right side of the face. The mouth, however, could be closed properly, the lips showing no puckering or drawing to one side. The right half arches of the palate were atrophied. The uvula was drawn slightly but positively to the left. Careful examination of the membrane of the drum of the right ear showed it to be atrophied. An ophthalmoscopic examination of both eyes was made, but no changes were discovered. No changes were noted in the hair of the patient on the affected side. He was able to perform all movements with the facial muscles, but the creases and
contours of the face in repose and in motion were less marked on the right side than on the left. The skin of the right side of the face seemed to be bound closely to the bone. The muscles on the same side responded well to the faradic and galvanic current. The patient had at times a peculiar sensation of stinging in the atrophied half of the face. He was treated with electricity, local massage, and tonics, and did not improve, but did not get worse while under observation, a period of several months.
At the Hospital of the University of Pennsylvania I also observed one well-marked case of unilateral atrophy of the tongue without atrophy of the face, of which, unfortunately, I have not preserved the notes. The patient was a middle-aged man with a syphilitic history. The atrophy in the reported cases has occurred much more frequently upon the left than upon the right side of the face.
Changes in the skin are among the most constant and striking phenomena. By some dermatologists the disease is regarded as a form of morphœa, the keloid of Addison. Morphœa as described by Duhring11 occurs in the form of patches, rounded, ovoid, or irregular in outline, small or large, tough or leathery, smooth or shiny, and may also manifest itself in the form of atrophic pit-like depressions in the skin. The skin alterations differ somewhat in character; frequently one of the first signs of the disease is the appearance of a white spot on the cheek. This was the first noticeable phenomenon observed in the above case. After a time this spot or patch may change in color, becoming of a yellowish or brownish hue. A number of spots appearing and undergoing change, the skin after a time assumes a mottled appearance. In some of the reported cases a yellowish, or yellowish-gray, or brownish appearance is recorded as having been present. In these the observations were probably made after the affection had existed for some time, and in them the white spots or patches were probably at first present. In one of Romberg's cases, first recorded when the patient was nine and a half years of age, he noted the deposit of a yellowish-gray pigment which began at the median line and extended to the angle of the jaw across the lower half of the face and neck, divided here and there by portions of
healthy skin. Discoloration, varying in intensity, also existed in irregular patches on the upper part of the face and on the forehead. The discolored tissues were glossy and greasy-looking. The skin adhering to the bone often gives the patient an aged appearance. Pruritus has been several times observed.
11 Medical News, vol. xlv. No. 4, July 26, 1884, p. 85.
Changes take place in the hair. Sometimes it simply changes color; at other times it falls out or ceases to grow. The beard or hair of the head will thus be gray or white upon one side, or in one or two locations of one side and not of the other; or the hair may be absent or simply thinned out. Peculiar limitations in the extent to which the hair is affected are sometimes observed. In one of Romberg's cases, for example, complete absence of the eyelashes from the inner angle of the eye to the middle of the lids was noted; the hair was very thin, and in some parts altogether wanting, and the left eyebrow was almost entirely devoid of hair. The changes which take place in the color of the hair in some severe cases of chronic trigeminal neuralgia will be recalled in this connection. I have known of several instances in which a few locks of hair were turned gray or white on the neuralgic side. Anstie, author of the work on Neuralgia, was a sufferer from supraorbital neuralgia, and the eyebrow of the same side contained a white tuft. Facts of this kind serve to corroborate and emphasize the view that unilateral facial atrophy is a trophoneurosis.
Anidrosis, or absence of perspiration, on the atrophied side of the face is a nearly constant phenomenon. In one of Bannister's cases, a printer, attention was first called to the patient by the fact that in working a hand printing-press in the hot weather he perspired only on the right side of his face. The left side remained perfectly dry, no matter how warm the temperature or hard the labor. This hemidrosis, or unilateral sweating, was confined only to the right side of the forehead, the right cheek, side of the nose, and lip. On the chin it encroached a little on the left. Under the chin and in the throat there was a little excess of perspiration on the right side; on other portions
of the body no difference was noted. Nicati12 considers a combination of symptoms, several of which were present in a recorded case—namely, lowered temperature, stoppage of perspiration, and wasting of the side of the face—as indicating a paralysis of the sympathetic nerve in what he calls its second or more advanced stage. In true facial hemiatrophy, however, other phenomena of such paralysis are wanting. Brunner13 gives a case in which perspiration, tears, mucous secretions, and temperature were all diminished on the affected side, and in which were also present exophthalmos and dilatation of the pupil. The cervical sympathetic in this case was irritated by a tumor. I agree with Bannister, however, that while we cannot exclude the possibility of the participation of the sympathetic in hemiatrophy of the face, the evidence is not sufficiently positive. Mechanical interference with the sweat-glands by pressure or otherwise has been suggested. The true view to take would seem to be that the perspiratory disorder is due to the same central or peripheral neurotic affection which gives rise primarily to the atrophy. Eulenburg says that the secretion of the sebaceous follicles is in most cases diminished or stopped on the atrophied side, while the sweat-glands often act in a normal manner; but his experience does not seem to correspond with that of the majority of other observers.
12 Sur Paralysie du Nerf sympathetique-cervical, Lausanne, 1873, quoted by Bannister
13 St. Petersburger Med. Zeitschr , ii., 1871, quoted by Bannister
Seguin, Dreschfeld, and others have found no notable differences in surface temperature between the two sides of the face. In one of Bannister's cases the temperature was tested in both ears, and a difference of six-tenths of a degree Fahrenheit in favor of the ear of the unatrophied side was found, that of the left ear being 97.6°, and that of the right 98.2°. This examination was repeated on another occasion with nearly the same result.
Weakness of pulsation in the carotid of the affected side has been observed. Sometimes the power to blush is lost on the affected side,
but this may return. In one instance the cheek, having been reddened by electrical stimulation, so remained for an hour or more.
Paræsthesiæ, such as pain, numbness, and stinging sensations, are not uncommon. A diminution of the general tactile sensibility of the skin of the affected side has been observed by Tanturri14 and by Vulpian,15 and perhaps by others, but anæsthesia is not commonly present.
14 Il Morgagni, 1872, quoted by Bannister.
15 L'Appareil vaso-moteur, ii. p. 430.
Eulenburg and Guttmann found atrophy of the muscles supplied by the motor branch of the fifth nerve—namely, the masseter and temporal. The changes which take place in the muscles of the affected side are, so far as can be judged, not of the character of fatty degeneration. Probably a general and uniform shrinkage of calibre of muscular fibres and bundles occurs. Certainly, this would seem to be true of the muscles supplied by the portio dura. The muscles on the atrophied side respond to both the faradic and galvanic currents, reactions of degeneration not being present. The absence of the reactions of degeneration in the facial muscles shows that normal muscular fibres remain. In one reported case the facial muscles seemed at first to react more readily than in normal conditions. The muscles of the upper lip sometimes appear to have wasted, preventing full closure of the mouth on this side. Fibrillary twitchings have been observed only very rarely. Voluntary control over the muscles of the affected side is not impaired.
In one of Bannister's cases the first upper molar of the left side sometimes ached, and the gum and bone were so wasted as to expose its roots for a considerable distance. Falling out of the teeth has been observed in a few other cases.
Atrophy of the tongue is associated with the facial wasting in a certain percentage of cases, and the uvula and soft palate are also
sometimes wasted. On the other hand, atrophy of the tongue has been observed as an isolated phenomena.
Atrophy of the bones of the face is frequently present, and has been determined by careful measurements. It will show to a greater or lesser extent according to the age of the patient. When the disease arises after the bony development has been fully acquired, there will be little external evidence of osseous involvement; when it begins during the time of active growth of the bone, as it does not infrequently, the arrest in the skeleton will be very apparent. Thus in a number of cases beginning in early childhood bone atrophy has been a very marked feature.
Eulenburg says that the functions of taste, smell, hearing, and seeing are not interfered with in any of the reported cases; but Bannister reports impairment of the sense of taste in both of his cases. In one the whole left half of the tongue was involved, in the other only the left posterior third. In the first of these, in which the whole left half of the tongue was involved, both the glossopharyngeal and the chorda tympani nerves were affected. According to Bannister, the significance of this observation is that either the glosso-pharyngeal and fifth nerves are both involved, or that the taste-fibres for the base as well as tip of the tongue are derived from the last-named nerve. In this case, however, which was due to a severe injury, the headache, mental confusion, loss of hearing, etc. more probably indicated a widespread intracranial lesion, affecting to some degree the nucleus of the glosso-pharyngeal. In the other case, which was apparently a typical one of unilateral facial atrophy in its early stage, no history of traumatism was present, and the sense of taste, which was carefully tested several times, was seriously impaired over the left posterior third of the tongue.
Bannister discusses the probable cause of impairment of taste in each case, as follows: “The atrophy seemed to involve the region supplied by the second division of the fifth nerve as much as, or more than, the other divisions; and on this is situated the sphenopalatine ganglion which gives off the Vidian nerve, the upper division
of which, the superior superficial petrosal nerve, is supposed by Schiff to contain the taste-fibres, which return from the lingual nerve through the chorda tympani. The usual theory of this disease is that it depends upon an affection of the trophic fibres contained in the fifth nerve or one or more of its divisions. Accepting this theory, Baerwinkel,16 noticing a case of unilateral atrophy of the face affecting only the second division of the fifth, and, as he held, indicating trouble with the spheno-palatine ganglion, its trophic centre, mentions the fact that there was no impairment of taste in the anterior portions of the tongue as rather against the hypothesis of Schiff as to the course of the taste-fibres. At the same time he gives two other observations of lesions of the trifacial and the seventh nerve that favor it. In our patient I should have expected a priori to have found the taste affected in the anterior portion of the tongue, if anywhere, but the reverse was the fact. It is difficult to suppose an accidental lesion of the glosso-pharyngeal coexisting with the one of the trigeminus that produces the atrophy when there are no more signs of nervous disorder than there were in this case. On the other hand, the taste-fibres of the glosso-pharyngeal are not generally supposed to have such connections with the fifth nerve as to be involved in its disease, while those of the chorda tympani, of the connections of which with the trigeminus there is much more physiological evidence, escape. The observation is a contradictory one, and I cannot at present explain it.”
16 Deutsch. Archiv f. klin. Med., xvii. 1, 1875.
So far as I know, ophthalmoscopic changes have never been noted. In a few cases enophthalmos, or sinking in of the eye, doubtless due to the disappearance of orbital fat as the disease advances, has been recorded.
Defects of hearing, and even partial deafness, have been reported in a very limited number of cases, making it questionable whether this symptom is a coincidence or a complication. In the case reported by me careful examination of the membrane of the tympanum by W.
