peediatria1

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contents

NeoReviews™ Articles

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NeoReviews™ Editorial Board Disclosures The American Academy of Pediatrics (AAP) Policy on Disclosure of Financial Relationships and Resolution of Conflicts of Interest for AAP CME Activities is designed to ensure quality, objective, balanced, and scientifically rigorous AAP CME activities by identifying and resolving all potential conflicts of interest before the confirmation of service of those in a position to influence and/or control CME content.

Educational Perspectives: The Individualized Learning Plan: Supporting the Self-Directed Learning Process Rachel L. Chapman

Neonatal Seizures Donald M. Olson

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Agenesis of Corpus Callosum and Associated Malformations: From Aicardi to Zellweger Syndromes Jin S. Hahn, Jane MacLean, Kristen Yeom

NeoReviews™ (ISSN 1526-9906) is owned and controlled by the American Academy of Pediatrics. It is published monthly by the American Academy of Pediatrics, 141 Northwest Point Blvd., Elk Grove Village, IL 60007-1098.

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Vol.13 No.4 April 2012

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Hydranencephaly: Transillumination May Not Illuminate Diagnosis Jeffrey M. Chinsky

Core Concepts: Development of the Blood-Brain Barrier Shadi N. Malaeb, Susan S. Cohen, Daniela Virgintino, Barbara S. Stonestreet

e251 e254 e263

Index of Suspicion in the Nursery Fetal Intracerebral Mass With Major Perinatal Implications Meredith Giffin, Barbara Brennan, Bosco A. Paes

Strip of the Month: April 2012 Maurice L. Druzin, Nancy Peterson

Visual Diagnosis: Right-side Chest Wall Prominence Rebecca Perry, Alice Abrahamian, Victoria Niklas

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•

Ivan Hand, MD, FAAP, disclosed that he participates in the Abbott Nutrition and MedImmune speaker bureaus.

Josef Neu, MD, FAAP, disclosed that he serves as a consultant to Abbott Nutrition, Life Sciences Research Offices, Environs and Nestlé; and that he has a research grant, serves as a consultant and on the advisory board of Mead Johnson.

William Truog, MD, FAAP, disclosed that he participates in a pilot clinical research study for ONY Inc; and participates in the Trial of Late Surfactant (to Prevent BPD) of the National Heart, Blood and Lung Institute.

Answer Key for March Issue: Intrahepatic Cholestasis of Pregnancy: 1. E; 2. D; 3. E; 4. E; 5. E G6PD Deficiency: 1. D; 2. C; 3. D; 4. E; 5. A

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The AAP designates this journal-based CME activity for a maximum of 24 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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The Individualized Learning Plan: Supporting the Self-Directed Learning Process Rachel L. Chapman Neoreviews 2012;13;e207 DOI: 10.1542/neo.13-4-e207

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://neoreviews.aappublications.org/content/13/4/e207

Neoreviews is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since . Neoreviews is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright Š 2012 by the American Academy of Pediatrics. All rights reserved. Print ISSN: .

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educational perspectives

The Individualized Learning Plan: Supporting the Self-Directed Learning Process Rachel L. Chapman, MD*

Abstract The ability of physicians to identify strengths and weaknesses, formulate learning goals, and track progress is relevant throughout training and practice. The importance of these skills has been recently explicitly incorporated into requirements for resident and subspecialty training and for maintenance of board certification. The individualized learning plan is a tool that can be utilized both in training and in practice to support and document the lifelong learning process.

Objectives The reader is encouraged to write possible diagnoses for each case before turning to the discussion.

We invite readers to contribute case presentations and discussions.

Please inquire first by contacting Dr. Philip at aphilip@stanford.edu.

Author Disclosure Dr Chapman has disclosed no financial relationships relevant to this article.

This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.

After completing this article, readers should be able to:

1. Define self-directed learning in the context of medical education.

2. Identify the key components of an individualized learning plan.

3. Identify the role of the individualized learning plan in graduate medical education.

4. Identify supportive strategies for progress toward self-identified learning goals.

5. Identify the role of self-assessment and self-directed learning in the maintenance of board certification.

Introduction In their “Professionalism in Pediatrics: Statement of Principles” published in 2007, the American Academy of Pediatrics Committee on Bioethics specifically included as a core principle: “Self-improvement—involves a commitment to life-long learning and education.”(p. 896, 1) The concept of self-directed learning is not new and has been identified as a crucial component of “being a physician” as early as the beginning of the 20th century by Sir William Osler in a discussion on the education of the physician: “The hardest conviction to get into the mind of a beginner is that

Abbreviations ILP: individualized learning plan MOC: maintenance of certification

*Department of Pediatrics, Division of NeonatalPerinatal Medicine, University of Michigan School of Medicine, C.S. Mott Children’s Hospital, Ann Arbor, MI.

the education upon which he is engaged is not a college course, not a medical course, but a life course, for which the work of a few years under teachers is but a preparation.”(2) The concepts of self-directed learning/lifelong learning (used interchangeably in this article) are founded in adult learning theory and are relevant to all phases of physician development. Documentation of participation in educational experiences after residency has been a major, long-standing component of continuing medical education requirements for medical licensure and hospital privileges. More recently, board certification bodies also have begun to require documentation of participation in continuing medical education, and the ability to self-assess and direct one’s own learning has been identified more specifically as NeoReviews Vol.13 No.4 April 2012 e207

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a competency to be learned and demonstrated throughout one’s career.

Having first introduced competencybased medical education in 1999, the Accreditation Council for Graduate Medical Education has required its full adoption by all accredited residency and fellowship programs since 2006. Six core competencies have been identified: patient care, medical knowledge and skills, interpersonal communication and skills, professionalism, system-based practice, and practice-based learning and improvement. (3) The practice-based learning and improvement competency, further defined in Table 1, specifically addresses the ability of trainees to selfassess, set learning goals, and monitor performance. (4) Concurrently, the American Board of Medical Specialties formally established the Maintenance of Certification (MOC) program, which includes four

major components: professional standing (including maintenance of medical licensure), documentation of lifelong learning and self-assessment, demonstration of cognitive expertise, and practice performance assessment. (5) These four components have been incorporated into the American Board of Pediatrics’ MOC program, with the documentation of lifelong learning and self-assessment identified as part 2 of the MOC program. (6) The use of an individualized learning plan (ILP) as a tool for supporting and documenting lifelong learning is potentially applicable to all phases of a physician’s career. The typical components of an ILP are: identification of learning needs; generation of learning goals; identification of learning strategies appropriate for each goal; and assessment of progress. In the remaining text, the concepts of lifelong learning, self-assessment, and

Practice-Based Learning and Improvement Core Competency Table 1.

Residents must demonstrate the ability to investigate and evaluate their care of patients, to appraise and assimilate scientific evidence, and to continuously improve patient care based on constant self-evaluation and lifelong learning.

Residents are expected to develop skills and habits to be able to meet the following goals: 1. Identify strengths, deficiencies, and limits in one’s knowledge and expertise; 2. Set learning and improvement goals; 3. Identify and perform appropriate learning activities; 4. Systematically analyze practice using quality improvement methods and implement changes with the goal of practice improvement (review committees should define expectations regarding quality improvement within specialtyspecific program requirements); 5. Incorporate formative evaluation feedback into daily practice; 6. Locate, appraise, and assimilate evidence from scientific studies related to their patients’ health problems; 7. Use information technology to optimize learning; and 8. Participate in the education of patients, families, students, residents, and other health professionals.

Reprinted with permission from the Accreditation Council for Graduate Medical Education.

Common program requirements, effective July 1, 2011. Available at: http://www.acgme.org/ acWebsite/dutyHours/dh_dutyhoursCommonPR07012007.pdf. Please check the Web site for updates and changes.

goal setting are reviewed, followed by a review of the literature related to the use of ILPs, and concluding with suggestions and resources regarding utilization of the ILP as a tool to support and document lifelong learning.

Theoretical Background Although multiple definitions of selfdirected learning exist, the conceptual definition proposed by Hojat et al is particularly appealing, defining lifelong learning as “a concept that involves a set of self-initiated activities (behavioral aspect), and information seeking skills (capabilities) that are activated in individuals with a sustained motivation to learn and ability to recognize their own learning needs (cognition).”(7) In this definition, ability to self-assess has been identified as a core component of the self-directed learning process.

As highlighted in the changing requirements for graduate medical education and for MOC, it is clear that physicians are increasingly expected to identify their own learning needs.

Although the need to self-assess makes sense intuitively, the literature to date regarding the accuracy and value of physician self-assessment has been disappointing. Based on several reviews of the current literature, much of which consists of small studies involving limited educational domains, there is little evidence that selfassessment accurately identifies learner needs, that it influences choice of or participation in learning activities, or that it has an impact on performance. (8)(9)(10) Overall, the accuracy of self-assessment of physicians and physicians-in-training appears to be limited, and it is quite worrisome that “a number of studies found the worst accuracy in self-assessment among physicians who were the least skilled and those who were the most confident.”(9)

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Based on these reviews, however, some themes have emerged that inform the role of self-assessment in the self-directed learning process. In their systematic review of the literature, Colthart et al did find evidence that accuracy of self-assessment can be enhanced by feedback. (8) Davis et al also noted the potential role of feedback and facilitation as modulators of self-assessment in their literature review. (9) Concerns about the accuracy of physician self-assessment support the value of including faculty facilitators and review of external assessments (such as standardized examinations, direct observation, and multisource feedback) in the process of identifying “self-directed” learning goals, a consideration in the development of a learning plan to support this process. These findings emphasize the potential impact of the increasing emphasis on learning to self-assess in residency and fellowship training, while in an environment conducive to the provision of regular feedback and mentorship on the physician’s later ability to self-identify strengths and weaknesses throughout his or her career.

In thinking about ILPs as a tool for linking self-assessments and, potentially, external assessments to the development of goals for improvement, it is helpful to examine the theoretical basis of goal setting. Locke and Latham summarized the psychology literature pertaining to theory development behind goal setting and task motivation in 2002. (11) The authors specifically identified core aspects of a goal, mechanisms for attainment, moderators of attainment, and how these relate to performance, satisfaction, and willingness to commit to new goals (Fig 1). In the literature reviewed, there is clear evidence that the most difficult or “high-level” goals produce the most effort and performance, and that specific, difficult goals

yield more progress than general directives, such as “do your best.”(12) The identification of properties of a goal (ie, specificity, difficulty, relationship to daily tasks), and moderators of success are likely critical to the success of the self-directed learning process and have been refined further within the medical education literature.

ILPs in Medical Education Although ILPs currently are required by residency and fellowship programs, the literature describing the optimal use of ILPs in graduate medical education is sparse. Small, single-institution studies have identified significant challenges in the use of ILPs in resident education, particularly regarding the ability of residents to identify strengths and weaknesses, the ability to write meaningful and achievable goals, and in the abilities of faculty to effectively mentor the process. (13)(14)(15)

A large, multicenter survey of pediatric and medicine/pediatric residents and residency program directors from across the United States has led to further understanding of important factors in the development and monitoring of the ILP process, barriers to and modulators of successful identification and fulfillment of learning goals, and the development of a conceptual model of lifelong learning utilizing the concept of personalized learning plans. (16)(17)(18)(19) Specifically, the quantitative and qualitative analysis of these data has led to identification of important factors in the development and monitoring of the ILP process, including the identification of barriers to and modulators of successful formulation and fulfillment of learning goals. A qualitative analysis of the survey results identified strategies associated with the achievement of learning goals, specifically that the goals were I-SMART: important to the learner, specific, associated with

Figure 1. Essential elements of goal-setting theory and the high-performance cycle.

(Reprinted with permission from Locke EA, Latham GP. Building a practically useful theory of goal setting and task motivation: A 35-year odyssey. Am Psychol. 2002;57 [9]:714.)

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a measurable outcome and an accountability strategy (a tracking system and the development of an external accountability system through faculty or peer mentorship), realistic and achievable, and linked to time limitations and/or a strategy for incorporating into a time-crunched schedule. (16) Of note, the development of a tracking system to assist with internal accountability as well as an external accountability system was identified as the most significant element associated with greater progress toward goal attainment, independent of the type of learning goal. (17) A conceptual model of lifelong learning through the development of a learning plan was developed by Li et al based on this national sample (Fig 2). (16) This model identifies the essential components of the process as individual reflection and self-assessment, incorporating external evaluation and mentorship, generation of

goals, development of a plan, and assessment of progress. Importantly, Li et al describe this model as an iterative process. The authors also identified strategies associated with the achievement of learning goals. These strategies align well with goal-setting theory and also emphasize the role of feedback and mentorship in setting and achieving learning goals.

ILPs in Fellowship Training and in MOC In a companion document outlining guidelines for pediatric subspecialty program information documentation, the Accreditation Council for Graduate Medical Education specifically requires the development of an “individualized learning plan (documenting a minimum of three personal learning objectives to address identified areas of needed improvement and strategies to achieve these objectives). This

Figure 2. A conceptual model of a lifelong learning process in medical education in which goals and plans are based on I-SMART strategies. I-SMART, Important: choose goals relevant to learner, prioritize achievement of learning goals. Specific: break broader goals into incremental steps, plan how to accomplish incremental steps.

Measurable: set a measurable outcome. Accountable: use a reminder and tracking system, build in external accountability, establish internal accountability. Realistic: create achievable goals, seek out and use available opportunities, self-adjust. Timeline: develop timeline for achieving goals, incorporate goals into daily routine. (Reprinted with permission from Li ST, Paterniti DA, Co JPT, West DC. Successful self-directed lifelong learning in medicine: a conceptual model derived from qualitative analysis of a national survey of pediatric residents. Acad Med. 2010;85[7]:1236.)

plan should be updated at least annually with the final plan focusing on transition to the next phase of one’s career and a plan for life-long learning.” (19) Similarly, the American Board of Pediatrics has identified mechanisms for fulfilling part 2 of MOC (documentation of lifelong learning and self-assessment).

(6) Those most relevant to neonatalperinatal medicine physicians are identified in Table 2; these options specifically include the development of an ILP (through the PediaLink program) as an approved method of fulfilling this requirement. More details about the American Board of Pediatrics MOC program are available at www.abp.org.

Although the basic elements of an ILP can be supported on paper or electronically, the ability to easily modify and track progress toward goals and to efficiently share goals to facilitate feedback and motivational support makes an electronic format potentially quite attractive.

An option for a prepackaged electronic format is offered by the American Academy of Pediatrics through the PediaLink program. (20) This program includes a self-assessment of strengths and weaknesses, identification of career aspirations, and space for recording goals, strategies for achievement, and progress toward attainment. In addition, an option exists to link medical knowledge self-assessments performed through the NeoReviewsPlus program to the development of an ILP through the PediaLink platform.

PediaLink provides separate formats for residents, fellows, and pediatricians in practice. PediaLink also supports the provision of feedback by a mentor for trainees and a link to other PediaLink members for feedback and motivational purposes for practicing physicians.

Review of the medical education and psychology literature provides

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Selected Resources for Self-Assessment and Self-Directed Learning Applicable to Neonatal-Perinatal Providers and Approved for American Board of Pediatrics MOC, Part 2 Credit

Table 2.

Sponsoring Organization

SelfAssessment

Primary Domains Assessed

American Academy of Pediatrics

PediaLink in Practice: ILP

Practiced-based learning (core competencies and personal attributes)

NeoReviewsPlus

Medical knowledge (general neonatology) Systems-based practice (patient safety)

American Board of Medical Specialties (ABMS)

ABMS Patient Safety Foundations

Mayo Clinic

Mayo Self Assessment Program in Quality Improvement (SAP QI) Breastfeeding selfassessment

University of Virginia

insight into self-directed learning plans, with the identification of strategies for improving self-assessment and for formulating goals in a way that is most likely to facilitate progress toward goal attainment (I-SMART strategies). Potential resources supporting the self-directed process were reviewed, and it is likely that additional resources will be identified in the coming years given the increasing attention to lifelong learning in medical education. Areas for future research include identification of resources to improve the self-assessment process in medical education, the role of self-assessments versus external assessments in driving individual continuing medical education efforts in both graduate and postgraduate medical education, and ultimately, the generation of evidence supporting a link between self-directed learning and improvement in patient care, which

Web Site for Information

Fee (Yes/No) No (with American Academy of Pediatrics membership) Yes Yes

Medical knowledge/practicebased learning/systemsbased practice (quality improvement)

Yes

Medical knowledge/practicebased learning (breastfeeding medicine)

No

remains the ultimate goal of medical education efforts.

American Board of Pediatrics Neonatal-Perinatal Medicine Content Specifications • Understand the basic principles of adult learning theory (ie, adult learners are selfdirected, goaloriented, and practical; they need to feel respected and build on life experiences; and they learn best when learning is based on an existing framework).

• Understand the importance of "reflective practice" in teaching and learning.

• Identify strategies that motivate learners.

• Understand the role of needs assessment in educational planning.

www.pedialink.org

http://neoplus.aap.org/ (or free trial) http://www.abms.org/ Products_and_ Publications/pdf/ ABMS_PS_Foundations. pdf http://www.mayo.edu/cme/ quality-2011r738

http://www.breastfeedingpi. org/Login.aspx?Igt[1

References 1. Fallat ME, Glover J; American Academy of Pediatrics, Committee on Bioethics. Professionalism in pediatrics: statement of principles. Pediatrics. 2007;120(4):895–897 2. Osler SW. Aequanimitas and Other Addresses to Medical Students, Nurses, and Practitioners of Medicine. 2nd ed. Philadelphia, PA: Blakiston; 1906 3. Accreditation Council for Graduate Medical Education. Common program requirements, effective July 1, 2011. Available at: http:// www.acgme.org/acWebsite/dutyHours/ dh_dutyhoursCommonPR07012007.pdf.

Accessed December 1, 2011 4. Accreditation Council for Graduate Medical Education. Common program requirements, effective July 1, 2011. Available at: http:// www.acgme.org/acWebsite/dutyHours/dh_ dutyhoursCommonPR7012007.pdf. Accessed December 1, 2011 5. Miller SH. American Board of Medical Specialties and repositioning for excellence in lifelong learning: maintenance of certification. J Contin Educ Health Prof. 2005;25 (3):151–156 6. American Board of Pediatrics. Maintenance of certification (MOC) four part NeoReviews Vol.13 No.4 April 2012 e211

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structure. Available at: https://www.abp. org/abpwebsite/moc/aboutmoc/maintenance ofcertification(moc)four-partstructure.htm.

Accessed December 1, 2011 7. Hojat M, Veloski J, Nasca TJ, Erdmann JB, Gonnella JS. Assessing physicians' orientation toward lifelong learning. J Gen Intern Med. 2006;21:931–936 8. Colthart I, Bagnall G, Evans A, et al.

The effectiveness of self-assessment on the identification of learner needs, learner activity, and impact on clinical practice: BEME guide no. 10. Med Teach. 2008;30 (2):124–145 9. Davis DA, Mazmanian PE, Fordis M, Van Harrison R, Thorpe KE, Perrier L. Accuracy of physician self-assessment compared with observed measures of competence: a systematic review. JAMA. 2006;296 (9):1094–1102 10. Eva KW, Regehr G. Self-assessment in the health professions: a reformulation and research agenda. Acad Med. 2005;80(suppl 10):S46–S54

11. Locke EA, Latham GP. Building a practically useful theory of goal setting and task motivation: a 35-year odyssey. Am Psychol.

2002;57(9):705–717 12. Latham GP, Winters D, Lock E. Cognitive and motivational effects of participation: a mediator study. J Organ Behav.

1994;15:49–63 13. Li ST, Favreau MA, West DC. Pediatric resident and faculty attitudes toward selfassessment and self-directed learning: a crosssectional study. BMC Med Educ. 2009;9:16 14. Stuart E, Sectish TC, Huffman LC. Are residents ready for self-directed learning? A pilot program of individualized learning plans in continuity clinic. Ambul Pediatr.

2005;5(5):298–301 15. Caverzagie KJ, Shea JA, Kogan JR. Resident identification of learning objectives after performing self-assessment based upon the ACGME core competencies. J Gen Intern Med. 2008;23(7):1024–1027 16. Li ST, Paterniti DA, Co JPT, West DC. Successful self-directed lifelong learning in

medicine: a conceptual model derived from qualitative analysis of a national survey of pediatric residents. Acad Med. 2010;85(7): 1229–1236 17. Li ST, Paterniti DA, Tancredi DJ, Co JPT, West DC. Is residents’ progress on individualized learning plans related to the type of learning goal set? Acad Med. 2011; 86(10):1293–1299 18. Li ST, Tancredi DJ, Co JPT, West DC. Factors associated with successful self-directed learning using individualized learning plans during pediatric residency. Acad Pediatr. 2010; 10(2):124–130 19. Accreditation Council for Graduate Medical Education. Companion document: guidelines for subspecialty PIF documentation. Available at: http://www.acgme.org/ acWebsite/downloads/RRC_progReq/320_ pediatrics_subs_companion.pdf. Accessed December 1, 2011 20. PedialinkÒ Online Center for Lifelong Learning. Available at: www.pedialink.org.

Accessed December 1, 2011

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The Individualized Learning Plan: Supporting the Self-Directed Learning Process Rachel L. Chapman Neoreviews 2012;13;e207 DOI: 10.1542/neo.13-4-e207

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References

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Neonatal Seizures Donald M. Olson Neoreviews 2012;13;e213 DOI: 10.1542/neo.13-4-e213

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://neoreviews.aappublications.org/content/13/4/e213

Data Supplement (unedited) at: http://neoreviews.aappublications.org/content/suppl/2012/03/27/13.4.e213.DC3.html http://neoreviews.aappublications.org/content/suppl/2012/03/27/13.4.e213.DC4.html http://neoreviews.aappublications.org/content/suppl/2012/03/27/13.4.e213.DC2.html http://neoreviews.aappublications.org/content/suppl/2012/03/26/13.4.e213.DC1.html

Neoreviews is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since . Neoreviews is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright Š 2012 by the American Academy of Pediatrics. All rights reserved. Print ISSN: .

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Article

neurology

Neonatal Seizures Educational Gaps

Donald M. Olson, MD*

Author Disclosure Dr Olson has disclosed

1. Physiological differences contribute to different appearances and drug responses in neonates as compared with older children.

2. Nonepileptic behaviors can be mistaken for neonatal seizures.

no financial relationships relevant

Abstract

to this article. This

Neonatal seizures are a common problem encountered or suspected by those caring for neonates. The estimated incidence of newborns affected is between 0.1% to 0.5%.

Because several causes of seizures in newborns require rapid recognition and treatment to prevent further injury, early recognition is important. Seizures in newborns frequently have more subtle clinical manifestations than in older children. Electroencephalographic seizures without clinical signs present additional diagnostic and therapeutic challenges. This article reviews the various seizure types, etiologies, diagnostic modalities, and treatment options for neonates with seizures and seizure-like episodes.

commentary does contain a discussion of an unapproved/ investigative use of a commercial product/ device.

Objectives

After completing this article, readers should be able to:

1. Be familiar with the different categories of neonatal seizures.

2. Know the common causes of neonatal seizures and recognize them as risk factors for seizure occurrence.

3. Understand the contribution of various electroencephalographic techniques to identification of neonatal seizures.

Introduction Neonatal seizures are a common problem encountered by doctors and nurses caring for sick newborns. To recognize the often subtle clinical manifestations and treat the seizures and their underlying causes promptly, it is important to recognize the risk factors and potential causes of seizures in infants.

Epidemiology Neonatal seizures are a relatively common occurrence. (1)(2) They are estimated to occur in w0.1% to 0.5% of newborns. In underdeveloped countries, the estimates are even higher. Seizures are more common in the ďŹ rst week of life than at any other time. (3) Several factors account for this high incidence: the neonatal brain is more seizure-prone because of maturational factors, late gestational and birth-related injuries can provoke seizures, and congenital malformations, genetic disorders, and acute metabolic derangements are often manifest in the neonate. (4)(5)(6)(7)

Abbreviations EEG: EIEE: EME: GABA:

Pathophysiology

electroencephalographic early infantile epileptic encephalopathy early myoclonic encephalopathy g-aminobutyric acid

Seizures are caused by excessive, hypersynchronous neuronal activity, typically thought of as excessive excitatory or deďŹ cient inhibitory neuronal function. The newborn brain is more prone to deďŹ cient inhibition because g-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in

*Stanford University School of Medicine, Stanford, CA.

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the more mature brain, has a net excitatory effect in infants.

(8) The GABA receptor modulates chloride and potassium flux. Typically, there is a net influx of chloride which results in a decreased cellular membrane resting potential, countering the excitatory effect of depolarizing stimuli that initially cause an influx of positive sodium and calcium ions into the neuron via predominantly glutamate-modulated stimuli. In the immature brain, there is a relatively higher concentration of chloride in the neuron, so the overall inhibitory effect of GABA is muted and sometimes has a net excitatory effect, (9) which may explain the often incomplete response of neonatal seizures to commonly used seizure medications that act via GABAergic mechanisms (ie, phenobarbital and benzodiazepines). Phenobarbital acts by way of a more prolonged opening of the chloride channel, whereas benzodiazepines act via more frequent opening of the chloride channel.

Generally seizures are regarded as arising in the cerebral cortex. Stereotyped, paroxysmal seizure-like behavior that arises from subcortical structures such as the brainstem are characterized as “brainstem-release phenomena” or primitive reflexes “released” owing to a depressed cortex providing diminished inhibition on “downstream” neuronal structures. (10) The immature GABAergic function matures in a caudalto-rostral fashion. For this reason, GABAergic drugs can inhibit the motor “throughput” at a brainstem level, suppressing the motor manifestations of seizures while the cortex, with a persistent net excitatory GABA effect, continues to seize. (11) (See discussion of clinical and electroencephalographic [EEG] manifestation of seizures in the following sections.)

Clinical Manifestation Neonatal seizures are typically more subtle than seizures in more mature children. At the time of birth, the brain does not have the capacity to manifest generalized tonic clonic seizures. There is incomplete myelination and less capacity for seizures to secondarily generalize from a single focus or for seizures from multiple foci to coalesce into a generalized seizure. (12) Neonatal seizures are most commonly classified within one of five basic categories: focal (or multifocal) clonic, focal tonic, generalized tonic, myoclonic, and subtle. (10) Focal clonic seizures are the most easily recognized as “epileptic.” They manifest as slow rhythmic jerking of an extremity or rhythmic twitching of the face. The rate is usually between 0.5 and 2.0 jerks per second. There is good correlation between the clinical seizure and the rate of the rhythmic epileptiform discharges on the EEG

result (Fig 1). When clonic seizures in neonates look generalized, careful observation and analysis of the coincident EEG findings will show that there are independent bilateral seizures occurring with differing rates and different evolution (Fig 2). The main nonepileptic phenomena that may be mistaken for clonic seizures are jittery movements, limb clonus, and benign sleep myoclonus (Supplemental Video 1). (13) Jittery movements often appear in infants who are recovering from an acute perinatal hypoxic insult or in those who are withdrawing from sedative and opiate medications (including maternal drug exposure). Jittery movements are usually very rapid, short-duration tremulous movements that are typically not isolated in one extremity from episode to episode. They occur when the infant is aroused and subside with sleep or sedation.

During an episode they often abate when a limb is repositioned, unlike focal clonic seizures that persist despite limb repositioning.

Limb clonus typically is seen in infants who have emerging hyperreflexia after a previous brain insult such as hypoxia. The jerking of clonus usually is restricted to one joint (commonly the ankle), and it is rapid and of short duration. Repositioning the limb by reducing the stretch on the affected tendon (eg, plantar flexing the foot and knee) often causes the jerking to stop (Supplemental Video 2).

Benign sleep myoclonus usually involves one to five rapid jerks of a limb over a few seconds. The jerks involve the whole limb, the trunk, or the face. The quick jerks involve one limb, then another in a seemingly random fashion. Arousing the infant causes the jerks to remit.

Focal tonic seizures appear as slowly evolving stiffening and posturing of a limb. The movements from seizure to seizure are stereotyped. They cannot be interrupted consistently by repositioning, but of course may stop coincidentally with arousal or stimulation. Other clues as to the epileptic nature of the spells can include tonic eye deviation and head turning. As with focal clonic seizures, there is usually good correlation with an epileptiform rhythmic discharge on the EEG result (Supplemental Video 3).

Generalized tonic seizures are whole-body stiffening with limb extension or flexion and trunk stiffening. Tonic seizures usually occur in infants with a history of significant brain injury. The EEG reading may not reveal an ictal rhythmic discharge, suggesting that these events are not originating in the cerebral cortex and are more likely a brainstem-release phenomenon.

Myoclonic seizures are quick, single jerks of a limb or limbs and trunk. When repetitive, they are not rhythmic like clonic seizures. Myoclonic seizures may occur in the

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Figure 1. Evolving rhythmic ictal discharge maximum in EEG lead C3 (arrows). This EEG sample of a 3-day-old term infant with

sepsis, hypocalcemia, and hypomagnesemia includes channels showing eye movement, chin electromyogram (EMG), respiration, and electrocardiogram (ECG).

setting of a recognized brain insult, but they also may be a first sign of an underlying metabolic or genetic condition. They are more persistent than benign sleep myoclonus and typically occur in wakefulness, not only in sleep. Jittery movements are usually more sustained for several seconds, whereas myoclonic seizures occur singly.

There is often no coincident EEG ictal correlate (Fig 3, Supplemental Video 4).

Subtle seizures are the hardest seizures to differentiate from normal behavior and nonepileptic pathological behaviors. Subtle seizures are sometimes divided into subtle motor seizures and subtle autonomic seizures. Motor behaviors may be stereotyped spells of eye deviation and nystagmus, abnormal chewing movements, rhythmic tongue thrusting, swimming movements of the arms, or bicycling movements of the legs. Autonomic signs include tachycardia (more than bradycardia), apnea, and changes in blood pressure (typically sudden increases). Subtle seizures usually occur in infants with recognized encephalopathic conditions. The EEG reading sometimes shows an ictal correlate and sometimes does not.

Etiology When infants present with seizures, the underlying cause must be investigated carefully. The first step is to look for correctable metabolic derangements that, if untreated, may lead to additional brain injury. Hypoglycemia in particular must be recognized and treated quickly to avoid further brain injury. Although infants born to mothers with diabetes are recognized easily as being at risk for hypoglycemia, other etiologies may be less readily suspected, such as hyperinsulinism. Other metabolic derangements that should be sought at the outset of seizure evaluation and treatment include hypocalcemia, hypomagnesemia, and hyponatremia.

The most common cause of neonatal seizures is perinatal asphyxia and other hypoxic conditions such as those caused by cardiac disorders. (14) In this setting, seizures usually manifest themselves in the first hours to the first day. (15) Depending on the degree of encephalopathy and the severity of the insult, the seizures may range from focal clonic seizures to subtle seizures.

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Figure 2. Independent rhythmic ictal discharges from the left temporal region, T3 (top arrow, w2 Hz), and the right temporal region, T4 (bottom arrow, w4 Hz). This sample is for a 1-day-old term infant with perinatal asphyxia.

may result in some superficial, subarachnoid hemorrhage with seizures occurring transiently. In more severe cases with signs of trauma such as bruising, seizures may be more persistent. Sinovenous thrombosis also can result in superficial and intraparenchymal bleeding that is symptomatic with seizures. (16) Acute and chronic strokes may present with seizures as well, even if there is no hemorrhagic component. (17) In the setting of stroke or unexplained intracranial bleeding, it may be advisable to look for inherited hemorrhagic or prothrombotic disorders. Encephalitis and meningitis may present with seizures. Both bacterial meningitis (eg, group B b-hemolytic streptococcus) and viral encephalitis (eg, herpes simplex virus) can be causes of seizures. (18)(19) Congenital brain malformations may manifest with seizures in the neonatal period, although in many cases, particularly with small focal dysplasias and heterotopia, seizures may begin at several months or years of age.

Some of the more severe malformations that may manifest with seizures in the neonate are lissencephaly, holoprosencephaly, and varying degrees of hydranencephaly.

The malformations often contain neurons that have persistent immature GABAergic function. (20) There are numerous genetic disorders that can present with seizures. Most often the seizures start days (or weeks) after the infant starts to feed and is no longer regulated by the mother’s normal metabolism. Abnormal metabolic intermediates start to accumulate. The usual initial manifestations of these disorders are unexplained encephalopathy and seizures. A detailed review of these disorders is beyond the scope of this review, but consideration of specific causes treatable with dietary restriction or supplementation warrants discussion. Some of the amino acidopathies and organic acidopathies may be amenable to dietary restrictions (ie, restricting branch chain amino acids in maple syrup urine disease). Seizures caused by biotinidase deficiency will respond to biotin supplementation. (21) The classic but rare cause of unexpected and often early seizures (an exception to the rule of seizures starting a few days after feeding) is pyridoxine dependency and folinic acid–responsive seizures. Seizures often are present

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Figure 3. Muscle artifact on EEG, but with no ictal discharge during a myoclonic seizure in a 3-day-old term infant with severe neonatal encephalopathy.

early and occur unexpectedly in infants not known to be at risk. The seizures are usually medically refractory, and the EEG findings are very disorganized. In this setting, an empirical trial of pyridoxine possibly followed by folinic acid may be diagnostic and therapeutic. (22)(23)(24) There are two well-characterized benign neonatal seizure syndromes: benign familial neonatal convulsions and benign neonatal seizures. The seizures are usually focal clonic seizures that respond easily to antiseizure medication. With benign familial neonatal convulsions, as the name implies, there is a family history of neonatal seizures. The seizures usually remit spontaneously after a few days or weeks. With benign neonatal seizures (so-called Fifth Day Fits because they manifest themselves between 4–6 days of life), there is not a positive family history.

The diagnosis is suspected because of the lack of seizure risk factors, an otherwise benign examination, a normal background EEG reading, and a benign clinical course.

(25)(26) In both cases, medication can be withdrawn after a few weeks or months.

Early infantile epileptic encephalopathy (EIEE, Otahara syndrome) and early myoclonic encephalopathy (EME) are two very concerning neonatal seizure syndromes. Infants

with EIEE usually present with tonic spasms. In EME, as the name implies, myoclonic seizures are a major feature. EEG findings in both usually show a burstsuppression pattern or other very abnormal background. For both syndromes, the prognosis for a normal outcome is poor. EME is most often a manifestation of an underlying genetic-metabolic disorder. (27) EIEE is more often a manifestation of a serious cerebral malformation. (28)

Diagnostic Studies EEG Readings EEG study is used primarily to determine the risk of seizures in a given patient and whether seizures are occurring during the EEG reading. Unlike in older children and adults, “sharp waves” or “spikes” occurring in isolation in the EEG study of a neonate are not indicative of significantly increased risk of seizures. Instead, an excess of sharp waves is considered a nonspecific indicator of encephalopathy. Bursts of repetitive or short, stereotyped evolving rhythmic bursts of sharp waves (brief electroencephalography rhythmic discharges) are more supportive of an increased seizure risk (Fig 4). (29) NeoReviews Vol.13 No.4 April 2012 e217

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Figure 4. Brief electroencephalogram rhythmic discharges (BERDs) in the right central region (C4, boxes) of a 2-day-old term infant

with moderate to severe neonatal encephalopathy. Later in the recording, a focal clonic seizure occurred with left leg rhythmic movements.

Evolving rhythmic discharges longer than 10 seconds typically are identified as seizures and not brief electroencephalography rhythmic discharges. Neonates often have electrographic seizures without corresponding ictal behavior. (30) Seizures on EEG, but without obvious clinical signs, are sometimes colloquially referred to as “subclinical” seizures, although “electrographic seizures” is a more accurate designation. A fairly common scenario is for clinically apparent seizures to be controlled after administration of seizure medication, only to find that the EEG reading shows frequent (or sometimes continuous) electrographic seizures. (11)

Long-term EEG readings (>1 hour) often are used to monitor for seizures in infants who have unusual paroxysmal behavior suggestive of seizures but not sufficiently clear from a bedside observation perspective to warrant loading with an antiseizure medication. In such cases, long-term EEG monitoring with simultaneous video recording usually provides an answer as to the epileptic versus nonepileptic nature of such behaviors, assuming they occur often enough to be recorded.

The other scenario in which continuous EEG monitoring can be useful is when infants are very sick or pharmacologically paralyzed, such that there is concern their

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condition will mask frequently occurring seizures. (31) (32) In these cases, otherwise unexplained variations in blood pressure, heart rate, and oxygen saturation may raise the question of subtle seizures. The mere presence of some brief, self-limited seizures is of uncertain clinical significance, but most practitioners treat very frequent or continuous electrographic seizures even in the absence of clinical signs.

Amplitude-integrated EEG monitoring is a technique used to follow the EEG state of the infant and to provide a means of early recognition of changes in cerebral function. It consists of a graphic display of EEG frequency and amplitude information from a limited number of scalp electrodes (usually two to four). Certain changes in the tracing can suggest the occurrence of seizures, but it is important to correlate such changes with routine EEG tracings. (33)

MRI (Ultrasonography and Computed Tomography) Neuroimaging is a valuable tool for defining structural abnormalities that may be etiologies of seizures such as cerebral malformations and strokes. Hemorrhage and signs of asphyxial injury may be apparent. (34)(35)(36) MRI is the most sensitive modality and often reveals subtle cortical malformations not evident on cranial ultrasound or computed tomography (CT). Ultrasonography is very accessible and much less invasive for infants in the NICU but is insensitive for more subtle cortical malformations. CT and MRI scanning usually involve transportation out of the NICU to obtain the imaging study, but acquisition times are faster with computed tomography than MRI, decreasing the need for sedation and speeding the sick infant’s return to the intensive care suite.

Treatment Most of the data for treatment of neonates with seizures come from studies and reports in term or near-term infants. Much less is known about any differences in efficacy and adverse effects in very premature infants. Differences in renal function and hepatic function in very low birth weight infants should prompt conservative antiseizure medication dosing, and when available, following of drug serum concentrations.

ACUTE TREATMENT OF METABOLIC DERANGEMENTS. The first priority when beginning to treat the neonate with seizures is to ensure that there is adequate oxygenation and cardiac function. Once these basic things are addressed, there needs to be rapid assurance that the

infant is not hypoglycemic, hypocalcemic, hypomagnesemic, or hyponatremic. Correction of these metabolic derangements will either control the seizures or “allow” the seizure medications to be effective.

PHENOBARBITAL. Phenobarbital has long been a mainstay of seizure treatment in the neonate. Administration intravenously can be accomplished quickly once intravenous access is obtained, serum concentrations can be determined rapidly, and further doses can be administered to achieve a desired value. The enteral formulation is well absorbed, so transition from parenteral to oral solution is typically simple to achieve. Phenobarbital typically is given as a loading dose of 15 to 20 mg/kg. In cases of an acute, transient seizure-provoking insult, maintenance treatment may not be needed. If, however, seizures recur after loading, or if there is a perceived chronic seizure-provoking etiology, maintenance dosing is initially 3 to 4 mg/kg per day divided into two daily doses. Phenobarbital is metabolized in the liver, so maintenance dosing often needs to be increased to the range of 5 to 8 mg/kg per day because infants mature and recover from acute liver dysfunction after asphyxia. (37) Hypothermia also decreases phenobarbital metabolism.

PHENYTOIN/FOSPHENYTOIN. Phenytoin is as effective for initial seizure control as phenobarbital. (38) Because the transition to enteral administration is often challenging owing to difficulty sustaining therapeutic serum concentrations, many infants are treated initially with phenobarbital. Another disadvantage of phenytoin compared with phenobarbital is the much higher protein binding. There may be drug-drug interactions with other highly protein-bound medications. On the other hand, a loading dose of phenytoin is less likely than phenobarbital to cause sedation. Phenytoin typically is given as a loading dose of 15 to 20 mg/kg followed by maintenance doses ranging from 5 to 8 mg/kg per day divided into two daily doses. Phenytoin is poorly soluble at neutral pH, and it precipitates in solution with dextrose, so it must be given in dextrose-free intravenous solutions. The vehicle is also very irritating and can cause soft tissue injury when it extravasates. Fosphenytoin is more soluble at neutral pH, is less irritating to soft tissue, and can be administered faster than phenytoin without as great a risk of bradycardia. (39)(40) The loading dose for fosphenytoin is essentially the same as for phenytoin because it is dosed in “mgPE” for “phenytoin equivalents.” Phenytoin’s antiepileptic mechanism is sodium channel blockade: it reduces repetitive neuronal firing.

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When adding a second antiseizure medication to a child’s treatment regimen, it is reasonable to use a drug with a different mechanism of action than that of the initial drug. For this reason, phenobarbital and phenytoin, with their respective inhibition-enhancing and excitationsuppressing mechanisms, have long been used in combination when neonatal seizures prove refractory to initial monotherapy.

BENZODIAZEPINES. The three commonly used parenteral benzodiazepines are midazolam, diazepam, and lorazepam. (41)(42)(43) All are effective antiseizure medications, although controlled trials in neonates are lacking. Lorazepam has the longest duration of action among these three medications. Midazolam and diazepam have a slightly faster onset of action because of greater lipid solubility, but they redistribute out of the brain more quickly than lorazepam. In the acute seizure setting, when the need for maintenance antiseizure medication therapy is uncertain, stopping the seizure with a benzodiazepine then assessing the situation may be the best balance between efficacy, safety, and prevention of longer-duration, drug-induced sedation. In older children, rectal administration of diazepam and nasal administration of midazolam are often effective in the absence of intravenous access. Again, data for neonates are sparse. For lorazepam, the usual dose for acute treatment of seizures is 0.05 mg/kg, repeated once in 15 to 20 minutes if the initial dose is not efficacious.

OTHER MEDICATIONS. Many other seizure medications often prescribed for older children have been reported as being used in neonates, typically in small case series. (44) Among all these medications, levetiracetam has been adopted with some enthusiasm, despite the lack of controlled trials in neonates. (45)(46)(47) It has no drug-drug interactions, and it is not metabolized in the liver. It is also available as an oral solution, making conversion from parenteral to oral/enteral maintenance dosing fairly easy. Its exact mechanism of action remains uncertain, but it does not act via direct modulation of inhibitory or excitatory neurotransmission.

Numerous case series indicate its efficacy and absence of serious side effects. There is no standard dosing regimen for neonates, but described approaches range from an initial loading dose between 10 and 50 mg/ kg and daily maintenance doses in a similar range (divided into twice-daily dosing). (46)(47)(48) Because it is excreted in the urine, infants with renal dysfunction need lower doses.

WITHDRAWAL OF TREATMENT. In many cases, neonatal seizures occur over a fairly brief period. Particularly in the setting of an acute insult such as mild trauma or mild to moderate asphyxia, the seizures may remit in a few days or weeks. In such cases, an initial single loading dose of an antiseizure medication followed by observation may be reasonable. In other cases, maintenance therapy with antiseizure medications may be discontinued in a few days. Even with more significant initial injuries, infants whose seizures have been well controlled may be tried off medication a few weeks or a few months after discharge.

Prognosis Seizures are a marker of increased risk for an abnormal neurologic outcome. Estimates for morbidity vary greatly among published series but generally range between 35% and 60%. There is an increased risk of cerebral palsy, abnormal cognitive outcome, and epilepsy. (49)(50)(51) Neonatal seizures are regarded largely as a marker of brain injury. It has proven very difficult to define whether the seizure burden alone, independent of the underlying etiology and severity of the brain injury, contributes significantly to the functional outcome. For this reason, the degree of aggressiveness of intervention for brief, selflimited, and infrequent electrographic seizures without clinical signs remains uncertain. It is generally accepted that adding a second medication (eg, adding phenytoin to phenobarbital) to try to achieve better control of electrographic seizures is associated with a relatively low risk.

But once one adds additional medications (eg, benzodiazepines), the risk of hypotension and the attendant risk of decreased cerebral perfusion must be weighed carefully.

American Board of Pediatrics–Perinatal Medicine Content Specifications • Understand the spectrum of clinical seizures in the newborn infant.

• Understand the differential diagnoses and evaluation of neonatal seizures.

• Understand the management and prognosis of neonatal seizures.

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48. Khan O, Chang E, Cipriani C, Wright C, Crisp E, Kirmani B. Use of intravenous levetiracetam for management of acute seizures in neonates. Pediatr Neurol. 2011;44(4):265–269 49. Davis AS, Hintz SR, Van Meurs KP, et al. Seizures in extremely low birth weight infants are associated with adverse outcome.

J Pediatr. 2010;157(5):720–725.e1–2 50. Ronen GM, Buckley D, Penney S, Streiner DL. Long-term prognosis in children with neonatal seizures: a population-based study. Neurology. 2007;69(19):1816–1822 51. Dlugos D, Sirven JI. Prognosis of neonatal seizures: “It’s the etiology, Stupid”—or is it? Neurology. 2007;69(19):1812– 1813

NeoReviews Quiz New minimum performance level requirements Per the 2010 revision of the American Medical Association (AMA) Physician’s Recognition Award (PRA) and credit system, a minimum performance level must be established on enduring material and journal-based CME activities that are certified for AMA PRA Category 1 CreditTM. In order to successfully complete 2012 NeoReviews articles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance level of 60% or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity.

Starting with 2012 NeoReviews, AMA PRA Category 1 CreditTM can be claimed only if 60% or more of the questions are answered correctly. If you score less than 60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved.

1. A 12-hour-old infant born at 26 weeks’ gestation has a hypoglycemic-induced seizure. In contrast, a 1month-old infant with the same degree of hypoglycemia does not have a seizure. Of the following, the most likely reason for a premature infant to be more prone to seizure activity than an older infant is a(n): A. decrease in the excitatory effect of g-aminobutyric acid (GABA) B. enhanced neuronal secretion of calcium C. greater concentration of chloride in the neuron D. higher amount of intracellular neuronal ATP E. increased amount of GABA inhibitors 2. A nurse in the newborn nursery is concerned that a 2-hour-old infant might have seizure activity. The infant’s prenatal course was benign and he was born by emergent cesarean delivery following a late fetal heart rate deceleration. After birth, the infant had a short period of apnea that required positive-pressure ventilation for a few minutes. Upon arrival to the newborn nursery, the nurse observed rapid jerking of his right ankle for 5 seconds while he was crying. After plantar flexing his right foot, the movements resolved.

Of the following, the most likely cause of this infant’s jerky movements is: A. benign sleep monoclonus B. focal clonic seizure C. jittery movement D. limb clonus E. subtle motor seizure 3. A 12-hour-old full-term infant has episodic stiffening and posturing of the left leg that does not resolve with repositioning of the leg. These movements are sometimes associated with eye deviation and head turning and correlate with epileptiform rhythmic discharges on an electroencephalogram. Of the following, this neonatal seizure is most likely classified as a: A. focal clonic seizure B. focal tonic seizure e222 NeoReviews Vol.13 No.4 April 2012

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C. generalized tonic seizure D. myoclonic seizure E. subtle seizure 4. A full-term female infant presents at age 5 days with a focal-clonic seizure. Her antepartum and postnatal courses are benign. The infant’s physical examination is normal, and her vital signs remain stable during the seizure. There is no family history of neonatal seizures. The infant’s electroencephalogram shows epileptiform activity during the seizure period but has a normal background pattern. She receives phenobarbital for 4 months, and the seizure activity does not recur. Of the following, this infant’s most likely diagnosis is: A. benign neonatal seizure B. biotinidase deficiency C. Ohtahara syndrome D. pyridoxine deficiency E. subtle autonomic seizure 5. A term male infant is receiving therapeutic hypothermia after severe perinatal depression. He has a generalized tonic seizure at age 16 hours. The neonatology fellow is teaching the pediatric resident about the risks and benefits of phenobarbital and phenytoin. Of the following, the most likely rationale for initially treating this infant with phenobarbital instead of phenytoin is: A. B. C. D. E.

A loading dose of phenobarbital is less likely to cause sedation.

Phenobarbital has lower protein-binding and fewer interactions with other medications.

Phenobarbital is more effective for initial seizure control.

Phenobarbital is not metabolized by the liver.

Therapeutic hypothermia has no effect on phenobarbital metabolism.

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Neonatal Seizures Donald M. Olson Neoreviews 2012;13;e213 DOI: 10.1542/neo.13-4-e213

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Agenesis of Corpus Callosum and Associated Malformations : From Aicardi to Zellweger Syndromes Jin S. Hahn, Jane MacLean and Kristen Yeom Neoreviews 2012;13;e224 DOI: 10.1542/neo.13-4-e224

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://neoreviews.aappublications.org/content/13/4/e224

Neoreviews is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since . Neoreviews is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright Š 2012 by the American Academy of Pediatrics. All rights reserved. Print ISSN: .

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Article

neurology

Agenesis of Corpus Callosum and Associated Malformations: From Aicardi to Zellweger Syndromes Educational Gaps

Jin S. Hahn, MD,*,† Jane MacLean, MD,*,† and Kristen Yeom, MD†,‡

Author Disclosure

1. Agenesis of the corpus callosum (ACC) is much more common than generally appreciated.

2. Improved diagnostic techniques, including prenatal assessments (such as fetal MRI) are now available to better evaluate ACC.

Drs Hahn, MacLean, and Yeom have

Abstract

disclosed no financial

Agenesis of the corpus callosum (ACC) is one of the more common brain malformations encountered by neonatologists and pediatricians. It may occur in isolation but more often is associated with other brain malformations. ACC also is a feature in >100 genetic syndromes. Fetal neuroimaging advances have allowed prenatal detection of callosal agenesis and associated anomalies in the brain and other organs.

The outcome in ACC is varied and depends largely on the related anomalies and underlying etiology. This review discusses the etiologies and diagnosis of ACC and provides strategies for a more specific prenatal diagnosis, such as Aicardi and Zellweger syndromes.

relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device.

Objectives

After completing this article, readers should be able to:

1. Understand that agenesis of corpus callosum (ACC) is a common neurologic disorder.

2. Recognize that ACC is a component of numerous syndromes.

3. Discuss neuroimaging modalities that are used to diagnose ACC prenatally and postnatally.

4. Discuss how to evaluate and manage a newborn who presents with ACC.

Introduction Agenesis of the corpus callosum (ACC) is one of the more common brain malformations.

It may occur in isolation, but often is associated with other brain malformations or genetic syndromes. This review article discusses the etiologies, diagnosis, and management of ACC. Tremendous advances in neuroimaging with MRI have significantly improved our ability to diagnose brain malformations such as ACC. In conjunction, rapid advances in neurobiology have led to a better understanding of how the brain develops and how disruptions of development lead to malformation. Application of MRI techniques to the fetus has enabled prenatal identification of ACC and other brain malformations in utero and improved the ability to provide prognosis and management counseling.

Abbreviations ACC: AS: CNS: DTI: GA: ZS:

agenesis of the corpus callosum Aicardi syndrome central nervous system diffusion tensor imaging gestational age Zellweger syndrome

Definitions Development of the Corpus Callosum The corpus callosum is a fiber tract bridge that connects neurons between the two hemispheres from opposing homotopic regions. Its function is to coordinate communication

*Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA. † Lucile Packard Children’s Hospital, Palo Alto, CA. ‡ Department of Diagnostic Radiology, Stanford University School of Medicine, Stanford, CA.

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of information between the left and right cerebral hemispheres (Fig 1). The corpus callosum begins to develop dorsal to the connections between the anterior hippocampi between 6 and 8 weeks of gestation. The corpus callosum forms between the 8th and 14th weeks of fetal development. The last of nearly 200 million axons (commissural fibers) cross at 18 to 20 weeks. (1)

Callosal Defect ACC occurs when there is a defect in the development of the crossing fiber tract. Agenesis may be complete or partial. When partial, the defect is usually in the posterior portion of the corpus callosum. When agenesis is

complete, the cingulate gyrus fails to form and a radial orientation of the mesial gyri is seen on sagittal MRI (Fig 2A). The fibers that were destined to connect the two hemispheres often traverse in anterior-posterior direction (and vice versa), forming the Probst bundle (Fig 2 B and C). The enlargement of the occipital horns of the lateral ventricles associated with ACC is known as colpocephaly (Fig 2D). Although the lateral ventricles in colpocephaly appear to be enlarged (ventriculomegaly), they should not be mistaken for hydrocephalus.

“True” callosal agenesis should be distinguished from secondary agenesis that is associated with major brain malformation of the embryonic forebrain, such as holoprosencephaly. (2)

Epidemiology A California birth defect study showed that ACC is found in 1:4000 live births. (3) However, because many cases are detected after birth, the true incidence is estimated to be 1:3000. In the developmentally disabled population, prevalence is 2.3%. (1) It is the second most common brain malformation after spina bifida. (3)

Etiology

Figure 1. Diffusion tensor MRI of a healthy young adult. A. Midsagittal 3D image with callosal fibers are highlighted in red (indicating that the fibers are crossing between the hemispheres, in right-left orientation). B. Coronal diffusion tensor imaging (DTI) color map with superimposed tractography of callosal fiber indicates crossing fibers in the callosal body (red, indicating right-left orientation) radiating to the cortex (blue, indicating a superior-inferior orientation). C. Axial DTI color map with superimposed tractography at the level of the frontal horns reveals prominent crossing fibers in the genu and splenium of the corpus callosum (red) that continue into the white matter of the frontal and occipital lobes (green indicating anterior-posterior orientation). D. Axial DTI color map with superimposed tractography higher up shows prominent crossing fibers in the body of the corpus callosum (red). DTI, diffusion tensor imaging.

ACC can result from many causes, including infections, inherited errors of metabolism, and genetic syndromes. There are >100 congenital syndromes associated with ACC. (4)(5) Some of the syndromes in which ACC is found are listed in Table 1. ACC may also be associated with specific chromosomal abnormalities, such as Trisomy 8 and 18. There is an increasing recognition that subtle copy number variants may play a critical role in the etiology. (6)(7) Isolated ACC may be inherited, but no single gene defect has yet been identified.

Neuroimaging Studies and Diagnosis Direct visualization of ACC on fetal ultrasound examination is difficult. ACC can be inferred if there NeoReviews Vol.13 No.4 April 2012 e225

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cases had associated anomalies in the CNS, including cortical malformations, cysts, and posterior fossa findings. (1)(8) The most common coexisting malformations include Dandy-Walker malformation, interhemispheric cysts, hydrocephalus, midline lipoma of the corpus callosum, and Chiari II malformation. Cortical anomalies associated with ACC include diffuse or focal cortical malformations, heterotopias, polymicrogyria, and pachygyria (broad, wide gyri), and delayed sulcal development. (8) In one study, delayed sulcal development was a common finding (seen in 20 of 29 cases), (8) but often resolved in the third trimester or after birth.

Many cases of ACC are also associated with birth defects in other organ systems, including the eyes, heart, and kidneys. These extracerebral findings may provide clues toward a syndromic diagnosis.

Figure 2. MRI of a 13-month-old boy with agenesis of corpus callosum and basal meningocele. A. Sagittal T1-weighted image shows complete absence of the corpus callosum and cingulate gyrus. There is a radial orientation of the mesial gyri (arrowheads).

B. Coronal T2-weighted image shows absence of crossing callosal fibers of the corpus callosum (arrow). The slightly dilated third ventricle communicates with the interhemispheric fissure superiorly. Medial to the bodies of the lateral ventricles, darker myelinated fibers are present and represent Probst bundles (arrowheads). C. Axial T2-weighted image near the vertex shows lateral ventricles that are parallel in orientation.

Medial to the lateral ventricles darker fibers are the Probst bundles that run in anteriorposterior direction. D. Axial T2-weighted image more caudally shows colopocephaly, a dilated and round appearance of the posterior horns of the lateral ventricles (asterisks).

is failure to visualize the “cavum septum pellucidum,” on an ultrasound study performed between 18 and 20 weeks’ gestational age (GA). MRI is the neuroimaging technique of choice, because the brain can be imaged in three orthogonal planes. MRI provides a better assessment of the extent of corpus callosal hypogenesis than computed tomography. With fetal MRI, direct visualization of the corpus callosum is possible by 20 weeks’ GA (or postmenstrual age). Fetal MRI is optimally obtained at 21 to 23 weeks and can confirm the ACC and identify any associated central nervous system (CNS) anomalies (Fig 3).

ACC often is associated with several other CNS malformations. Studies indicate that w50% to 70% of ACC

Outcome

There is a great diversity of clinical outcomes in ACC. The underlying etiology has a large impact on the outcome. Children with isolated ACC may appear and function normally in early years. However, as they grow older, an increasingly greater proportion show cognitive deficits. In a series of 17 children (11 complete and 6 partial ACC), the percentage of children scoring below normal fullscale IQ was 19% at 2 years, 33.5% at 4 years, and 43% at 6 years. (9) Many individuals with isolated ACC have deficits in social and behavioral domains, which may place them in the autism spectrum. With testing, difficulties in higher cortical function, language, perception, behavior, and integration of hemispheric functions may be demonstrated.

When there are other CNS malformations associated with ACC, the outcomes are often less favorable in comparison with the isolated type. These patients may have intellectual disabilities, cerebral palsy, and epilepsy. In some children with chromosomal, metabolic, and single-gene

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Syndromes Associated With Agenesis of Corpus Callosum

Table 1.

Acrocallosal syndrome (AR) Aicardi syndrome (X-linked dominant) Andermann syndrome (AR) Cerebrooculofacio-skeletal (COFS) syndrome (AR) Cutis laxa, type IIIB (AR) Dandy-Walker syndrome Dellman syndrome (oculocerebrocutaneous syndrome) Fryns syndrome (AR) Holoprosencephaly Marden-Walker syndrome (AR) Meckel-Gruber syndrome (AR) Micro-ophthalmia-linear skin defects syndrome (X-linked dominant) Miller-Dieker lissencephaly syndrome (AD) Neu-Laxova syndrome (AR) Sakoda complex (ACC with sphenoethmoidal encephalomeningocele) Septo-optic dysplasia sequence Soto syndrome Walker-Warburg syndrome or Fukuyama congenital muscular dystrophy (AR) Wolf-Hirschhorn (4p microdeletion) syndrome Zellweger syndrome (AR) AD=autosomal dominant; AR=autosomal recessive.

causes, the outcome can be quite severe with a significantly shortened life expectancy.

Fetal Brain MRI Findings Suggestive of Aicardi Syndrome

Table 2.

Required Agenesis of corpus callosum Supportive Absent septum pellucidum Interhemispheric cyst Other cysts (eg, posterior fossa) Ocular abnormalities (eg, coloboma) Cortical malformations Periventricular heterotopias Asymmetric lateral ventricles and cerebral hemispheres Cerebellar anomalies (eg, hemisphere asymmetry, vermian hypoplasia)

with ACC are so variable. Given the myriad of disorders associated with ACC, it would be ideal to prenatally make a specific diagnosis of a syndrome, so that a more accurate prognosis can be provided. Amniocentesis is often performed for high-resolution karyotyping to detect chromosomal abnormalities. However, ACCs due to chromosomal defects constitute a small minority of the cases. Prenatal diagnosis of certain syndromic ACCs may be possible, and we discuss two of them, namely Aicardi and Zellweger syndromes.

Aicardi Syndrome

Prenatal Diagnosis of Associated Syndromes

Aicardi syndrome (AS) is a congenital disorder characterProviding prognostic information prenatally can be quite ized by the triad of ACC, infantile spasms, and choriochallenging in ACC, because the outcomes for patients retinal lacunae. (10) The estimated incidence is 1 in 100 000 live births. (11) Since the original description on this classic triad in 1965, numerous other CNS anomalies have been found to be associated with AS on neuroimaging and pathology studies (Table 2).

(12)(13) Although the natural history of AS varies between patients, the overall prognosis is poor, with most patients having severe to profound developmental delay, intractable epilepsy, and spasticity. It is an X-linked dominant disorder that affects females and is lethal Figure 3. Fetal MRI at 23 weeks with isolated ACC in three planes: A. sagittal, B. axial, in males with only a single X chroand C. coronal. All images are T2-weighted by using a single shot fast spin echo mosome. Because the triad involves sequence. not only a neuroimaging finding, NeoReviews Vol.13 No.4 April 2012 e227

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CASE REPORT. The mother of the patient was referred for fetal MRI after a fetal ultrasound showed absent septum pellucidum. She underwent a fetal MRI at 31 weeks’ gestation. MRI findings included ACC, absent septum pellucidum, asymmetric lateral ventricles, interhemispheric cyst (and multiple other cerebral cysts), cortical malformations, asymmetry of the globes, and ocular coloboma (Fig 4). The infant was delivered at term. Postnatally, she met criteria for AS based on MRI findings and the presence of bilateral chorioretinal lacunae and optic nerve colobomas (Fig 5). She developed infantile spasms at 2 months of age. At 24 months she continues to have intractable seizures and has global developmental delay. She is able to roll over and make consonant sounds. Her vision is limited to light perception.

In this patient, AS was highly suspected because of the associated cerebral anomalies in addition to ACC, such as cortical polymicrogyFigure 4. MRI of a 31-weeks’ GA female fetus with Aicardi syndrome. All images are ria, periventricular heterotopias, T2-weighted by using a single shot fast spin echo sequence. A. Sagittal image demonstrates and neuroependymal cysts in the inabsence of corpus callosum. Neuroependymal cysts are noted posteriorly (asterisks).

B. Coronal image shows absence of crossing callosal fibers (arrow) and dilated third terhemispheric region. She also had ventricle, which is continuous with the interhemispheric fissure. C. Axial image shows asymmetric hemispheres and lateral asymmetric frontal lobes with polymicrogyria (arrowheads) on one side and periventricular ventricles, a feature that is almost inheterotopia arrow) on the other. D. Axial image more caudally demonstrates a retro- variant, according to Aicardi. (10) orbital mass representing an optic nerve coloboma (arrow) and a parapontine cyst Cysts in AS can be found not only (asterisks). in the interhemispheric region, but also in the posterior fossa, choroid plexus, and pineal regions. The presence of optic nerve coloboma, as in our case, makes but also clinical findings, prenatal diagnosis is challenging. Nevertheless, recognition of this complex on fethe diagnosis more certain. However, because the optic tal MRI is sometimes possible because of the associated nerve is small and difficult to image with fetal MRI, it has been our experience that it is difficult to definitively brain and eye malformations. Prenatal diagnosis of determine absence or presence of colobomas. ChorioreAS is important because it carries a much more severe tinal lacunae, the pathognomonic findings of AS, are retprognosis than that of isolated ACC. Evidence of AS inal defects that cannot be diagnosed by using current prenatally may prove useful when informing parents refetal MRI techniques. garding prognosis, and perhaps it may even have treatFemale infants who have ACC on fetal MRI are at inment implications.

To illustrate these points, we describe a patient who creased risk of having AS. Therefore, their imaging studwas highly suspected of having AS based on fetal MRI ies should be carefully evaluated for cerebral cysts, optic nerve colobomas, and cortical malformations, which findings and was found to meet clinical criteria for AS would suggest a diagnosis of AS. postnatally. e228 NeoReviews Vol.13 No.4 April 2012

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ZS illustrates an inborn error of metabolism that can lead to brain malformations. There are many other inborn errors of metabolism that have been associated with cerebral malformation such as ACC. (17) It also highlights the importance of fetal imaging of other organs for associated anomalies, which may help provide the diagnosis and possibly guide the management.

AS and ZS represent just two of the syndromes associated with ACC. Prenatal diagnosis of other syndromes such as Sakoda complex (ACC with sphenoethmoidal encephalomeningocele) may be possible. However, in most cases of ACC detected on fetal MRI the associated CNS findings are more subtle or nonspecific in nature, and thus no specific diagnosis is possible. In cases of ACC, prenatal counseling should be carried out by a neurologist, a geneticist, and a neonatologist who have expertise in CNS developmental anomalies.

Postnatal Management Figure 5. Fundoscopic image of right eye in a newborn girl with Aicardi syndrome (same patient as in Fig 4) demonstrates a large and prominent optic nerve coloboma (arrow) and scattered adjacent chorioretinal lacunae with central depigmentation (arrowheads).

Zellweger Syndrome Zellweger syndrome (ZS) is an autosomal recessive disorder that affects w1/50,000 births. (14) It is the most severe form of the peroxisome biogenesis disorders, and is usually fatal during infancy. ZS is associated with facial dysmorphisms, ophthalmologic defects, neurologic impairment, hepatic dysfunction, renal cysts, and punctate calcifications of the patella. (15) MRI abnormalities in ZS include cortical malformations of the perisylvian and perirolandic regions (polymicrogyria and pachygyria), hypomyelination (periventricular dysmyelination), and subependymal germinolytic cysts. Identification of this triad on fetal MRI would be highly suggestive of ZS. ACC is seen in some variants of ZS, (16) but is not a prerequisite as it is in AS. The additional extraCNS finding of ZS, such as renal microcysts, hepatomegaly, and heterogeneous signal hypointensities of the liver, can be detected on fetal MRI. (15) Therefore, when the constellation of these CNS and extra-CNS findings is found on fetal MRI, a prenatal diagnosis of ZS may be possible. Early diagnosis is important for counseling and management, because ZS has a devastating prognosis, with death usually by 6 months of age.

There are limitations to the resolution of fetal MRI. Although it is relatively easy to detect overt anomalies, such as severe hydrocephalus and ACC, it is challenging at times to detect subtle lesions such as microdysgenesis, heterotopias, and gyral malformations. This is particularly true because, in the United States, MRIs are often done between 20 and 23 weeks’ GA. During this period the immature fetal brain is small, has poor gray-white matter signal contrast, and often has smooth-appearing cortical surfaces (see Fig 3 for example). Therefore, fetal MRIs performed at 21 to 23 weeks’ GA may not detect subtle migrational abnormalities and myelination abnormalities.

To better detect these types of abnormalities an MRI should be performed ideally between 28 and 34 weeks’ GA. The need for neuroimaging studies after birth depends on the extent of prenatal imaging studies. If there are abnormalities detected in the CNS on fetal ultrasound or MRI, then another MRI after birth may be indicated. This is not always the case. For example, a neonate who had isolated ACC diagnosed prenatally with fetal MRI and who is clinically doing well does not need a postnatal MRI in the newborn period. If the child develops neurologic symptoms and signs, such as seizures, another MRI would be indicated because more subtle lesions will be easier to detect on a postnatal scan. MRI is favored over computed tomography because of its higher resolution, as well as its ability to scan in three orthogonal planes. Newer MRI techniques also enable mapping of the white matter fiber tracts that go awry in ACC (Fig 6).

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development. A careful evaluation of the placenta and cord may also provide clues to in utero encephaloclastic lesions.

If a newborn is found to have ACC for the first time on a postnatal ultrasound examination, an MRI is recommended as part of the evaluation. MRI will provide a more detailed imaging of the agenesis and associated CNS anomalies. Other studies as noted previously may contribute in providing the diagnosis and prognosis.

Summary

Figure 6. Combined diffusion tensor imaging (DTI) and volumetric MRI in a healthy young

adult (A and B) and in a 13-month-old boy with ACC (C and D, same patient as in Fig 2).

Color directions for the DTI maps are the same as those in Fig 1. In ACC, the Probst bundles that have an anterior-posterior orientation are indicated by the green fiber tracts near the lateral ventricles (C and D).

After birth, it is important to determine if the child has a genetic syndrome associated with ACC. Careful investigation for extracerebral malformations should be undertaken as well as a genetic evaluation. Consultation with neurologists, geneticists, ophthalmologists, and other specialists should be considered. If amniocentesis has not been performed, high-resolution chromosomes or a microarray study is often done after birth. The clinical examinations, postnatal MRI, and other testing may enable clinicians to provide a specific diagnosis and precise prognosis.

Some cases of ACC, especially secondary ACC, may be due to environmental causes. Thus, it is important to ascertain a careful history of any complications during the pregnancy (eg, drug exposure, infections, trauma, bleeding) and try to correlate the timing of those events to the stage of embryonic/fetal brain

ACC is a common brain malformation that easily can be detected prenatally. ACC can be inferred on prenatal ultrasound at 18 to 20 weeks. Fetal MRI can confirm ACC as early as 20 weeks and provide detailed imaging of the brain and other organs. Because ACC can occur in isolation or in conjunction with >100 genetic syndromes, the prognosis and outcome is quite varied. Providing a specific diagnosis, either prenatally or postnatally, has obvious important implications for prognosis

American Board of Pediatrics Neonatal–Perinatal Medicine Content Specifications • Recognize clinical features associated with autosomal recessive disorders.

• Recognize the clinical features associated with X-linked disorders.

• Know the etiology, clinical manifestations, laboratory features, and management of infants with lysosomal, peroxisomal, and mitochondrial disorders.

• Know the indications for and limitations of various neuroimaging studies and be able to recognize normal and abnormal structures and changes during development and growth.

• Know the normal developmental course of neuronal proliferation, migration, and myelination and the factors affecting these.

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7. O’Driscoll MC, Black GC, Clayton-Smith J, Sherr EH, Dobyns WB. • Know the consequences of abnormalities of neuronal proliferation, migration, and myelination (eg, holoprosencephaly, agenesis of the corpus collosum, lissencephaly, and schizencephaly).

and management of the fetus or child with ACC. ACKNOWLEDGMENTS. The authors thank Drs Douglas Frederick and Debbie Alcorn for assistance with the retinal photograph.

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AJNR Am J Neuroradiol. 2006;27(2):333–336 16. al-Essa M, Dhaunsi GS, Rashed M, Ozand PT, Rahbeeni Z. Zellweger syndrome in Saudi Arabia and its distinct features. Clin Pediatr (Phila). 1999;38(2):77–86 17. Prasad AN, Bunzeluk K, Prasad C, Chodirker BN, Magnus KG, Greenberg CR. Agenesis of the corpus callosum and cerebral anomalies in inborn errors of metabolism. Congenit Anom (Kyoto).

2007;47(4):125–135

NeoReviews Quiz New minimum performance level requirements Per the 2010 revision of the American Medical Association (AMA) Physician’s Recognition Award (PRA) and credit system, a minimum performance level must be established on enduring material and journal-based CME activities that are certified for AMA PRA Category 1 CreditTM. In order to successfully complete 2012 NeoReviews articles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance level of 60% or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity.

Starting with 2012 NeoReviews, AMA PRA Category 1 CreditTM can be claimed only if 60% or more of the questions are answered correctly. If you score less than 60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved.

1. A fetus is diagnosed with an isolated complete agenesis of the corpus callosum. Of the following, the finding that is most likely found in this infant is: A. colpocephaly B. craniosynostosis C. dolichocephaly D. holoprosencephaly E. hydrocephalus

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neurology development of nervous system

2. Fetal ultrasonography at 19 weeks’ gestation reveals an absent corpus callosum. Fetal magnetic resonance imaging at 22 weeks’ gestation identifies additional abnormalities of the brain. Of the following, the brain abnormality that is least likely to be associated with agenesis of the corpus callosum is: A. Arnold-Chiari malformation type II B. cortical malformations C. Dandy-Walker malformation D. interhemispheric cysts E. Vein of Galen malformation 3. A female infant has a prenatal diagnosis of an isolated absent corpus callosum. The infant develops infantile spasms at age 6 months and the diagnosis of Aicardi syndrome is confirmed. Of the following, the most likely additional finding in this infant with Aicardi syndrome is (are): A. chorioretinal lacunae B. dysmorphic facial features C. hepatomegaly D. renal cysts E. structural cardiac defect 4. A newborn is found to have an absent corpus callosum and subependymal germinolytic cysts. The neonatologist speaks with the family about the possibility of Zellweger syndrome. Of the following, the most likely additional finding in an infant with Zellweger syndrome is (are): A. absent septum pellucidum B. coloboma C. infantile spasms D. renal cysts E. splenomegaly 5. Fetal magnetic resonance imaging (MRI) at 20 weeks’ gestation reveals an agenesis of corpus callosum. The parents have decided to continue with the pregnancy, but are concerned about additional abnormalities. The neurologist suggests waiting until 28 to 34 weeks’ gestation to obtain another MRI of the brain. Of the following, the most likely reason for repeating the fetal MRI is: A. B. C. D. E.

enhanced gray-white matter signal contrast greater cerebrospinal fluid production improved symmetry of the lateral ventricles increased smoothness of the cortical surface possible delay in formation of the corpus callosum

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Agenesis of Corpus Callosum and Associated Malformations : From Aicardi to Zellweger Syndromes Jin S. Hahn, Jane MacLean and Kristen Yeom Neoreviews 2012;13;e224 DOI: 10.1542/neo.13-4-e224

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Hydranencephaly : Transillumination May Not Illuminate Diagnosis Jeffrey M. Chinsky Neoreviews 2012;13;e233 DOI: 10.1542/neo.13-4-e233

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://neoreviews.aappublications.org/content/13/4/e233

Neoreviews is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since . Neoreviews is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright Š 2012 by the American Academy of Pediatrics. All rights reserved. Print ISSN: .

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Article

genetics/dysmorphism

Hydranencephaly: Transillumination May Not Illuminate Diagnosis Jeffrey M. Chinsky, MD,

Abstract

PhD*

Author Disclosure Dr Chinsky has disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device.

Hydranencephaly describes the condition of extensive absence of cerebral tissue that is replaced by a saclike accumulation of fluid. It first may be suspected by neonatal bedside transillumination, which is a screening tool but is not diagnostic. When noted at birth, it is imperative to rapidly distinguish this condition from extensive hydrocephalus, holoprosencephaly, large porencephalic cyst, and other conditions so that those conditions with indications for prompt treatment are identified. An illustrative case of hydranencephaly is presented with discussion of imaging techniques to distinguish between the diagnostic possibilities. Etiologies of the neuropathology of hydranencephaly are discussed. The importance of distinguishing this condition, with an associated poor prognosis, from extensive hydrocephalus, with potential for improved prognosis with early shunting procedures, is emphasized.

Objectives

After completing this article, readers should be able to:

1. Describe the utility and limitations of bedside neonatal skull transillumination in screening for hydranencephaly and other cerebral anomalies with extensive absence of cerebral tissue.

2. Describe the differences between hydranencephaly, extensive hydrocephalus, and holoprosencephaly on brain imaging.

3. Explain the likely diverse etiologies for the neuropathology associated with hydranencephaly.

4. Discuss the difference in therapeutic approaches toward hydranencephaly versus extensive hydrocephalus.

Introduction Hydranencephaly is a rare congenital anomaly of the brain that often presents difficulties in initial diagnosis and treatment strategies. It is one of several conditions to be considered when newborn transillumination reveals marked absence of cerebral tissue. The following case example illustrates typical difficulties that may be encountered.

A 25-year-old gravida 3 para 2002 woman presented to the emergency department of a community hospital with abdominal pain and no history of prenatal care. She was determined to be in active labor with likely spontaneous rupture of membranes about 28 hours before delivery. Bedside ultrasound demonstrated probable term intrauterine pregnancy in vertex presentation. Because of reported previous history, cesarean delivery was performed but required vacuum assistance to deliver the head. Routine stimulation and bulb suctioning resulted in a good cry, leading to pink color and spontaneous movement of all four extremities. Apgar scores were 9 and 9 at 1 and 5 minutes, respectively. An overtly large head with widely splayed sutures was noted and the infant was transferred to the NICU for further evaluation. The infant weighed 3215 g and her length was 49 cm, both at the 50th %tile for an estimated 38 weeks average for gestational age (AGA) infant. However, her head circumference was 38.5 cm, >99th %tile. The sutures were markedly split: metopic at least 2 cm, coronal at least 1 cm, and the lambdoid sutures at least 3 cm split. Transillumination of the infant’s head (see Fig 1) demonstrated extensive illumination throughout all areas of the skull.

The findings of the funduscopic examination were normal. The findings of the physical examination otherwise were normal, with the exception of mild dysmorphic features including *Department of Pediatrics and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

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minimally hyperteloric upslanting palpebral fissures, low-set but normal ears, right hand transverse crease, and bilateral mild fifth finger clinodactyly. The neurologic examination findings were normal, including all normal neonatal automatisms.

All maternal serologies were normal. Infant cord venous blood pH was 7.23, and cord arterial blood pH was 7.18. Subsequent arterial blood values were pH 7.30, pO2 81 mm Hg, pCO2 52 mm Hg, but these normalized within 24 hours.

Complete blood cell count and se- Figure 1. Transillumination of neonate with macrocephaly and split sutures. Extensive rum chemistries were normal. Bed- illumination to both the frontal and occipital prominences was noted. side head ultrasound findings were bottle-feeding attained, but most feedings required the reported as a large fluid-filled cranium, consistent with hyuse of a nasogastric tube. The infant was discharged from drocephalus with no visualization of normal cerebral hemithe hospital at 25 days of age with a weight at the 50th % spheres. A midline septum suggestive of falx cerebri and tile, and a length at the 38th %tile. The head circumference midline echogenic soft tissue suggesting intact thalami was 43.5 cm (>99th %tile for age) with noted gain of 5 cm and brainstem tissues were noted. Consultation with in 3.5 weeks. The patient developed overt seizures by 6 both Pediatric Genetics and Neurology services sugweeks of age associated with an additional 3- to 4-cm gested a differential diagnosis of severe hydrocephalus, holincrease in head circumference. She was started on oprosencephaly, and hydranencephaly. Follow-up brain MRI results (see Fig 2) did not clearly differentiate hydranencephaly versus extremely severe hydrocephalus. Only single vessels could be identified on brain MRI which were considered to be the basilar artery with no additional vessels of the circle of Willis. Subsequent brain computed tomography (CT) (see Fig 3) confirmed the most likely diagnosis as hydranencephaly. Karyotype, comparative genomic hybridization microarray analysis, and 7-dehydrocholesterol levels were normal. The therapeutic plan focused on comfort care and plans for home hospice. Over the next few days, the infant progressively developed exaggerated move- Figure 2. Brain MRI of described neonate suggesting hydranencephaly. A. Saggital T1 brain MRI sections demonstrated the absence of the majority of cerebral hemispheric ments of the upper and lower tissues, but preservation of cerebellar and midbrain tissues. Within the cerebral areas, extremities and overall increased stranded signals (white curvilinear signals in sea of grey) could not be interpreted as jitteriness. Intermittent vocaliza- either remnants of cerebral tissues or some type of septated tissue. B. Representative tions and infant cries were odd, brain T2 axial MRI image. Axial sections were difficult to interpret with very hyperintense and occasional “sun setting” of eyes signal intensities, but suggested that majority, if not all of cerebral tissue space, was filled was noted. Feeding advancement with fluid rather than tissue. It was suggested that the fluid was more proteinaceous than was slow, with a small amount of usual, accounting for the heterogeneous hyperintense T2 signal (white) distribution. e234 NeoReviews Vol.13 No.4 April 2012

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hydranencephaly. The infant survives during her second year after birth in home hospice care.

Case in Context

Figure 3. Axial head CT imaging of neonate with extensive

transillumination. A–D. Series of axial head CT images demonstrated the absence of supratentorial brain tissue within either hemisphere, replaced by a large fluid-filled cavity. The falx was visualized (see panels A and B) most notably posteriorly with some indications of being evident in the anterior and inferior regions (not shown). Infratentorial region (see panels C and D) demonstrated the cerebellum with prominent CSF space posterior to the cerebellum. These findings are most compatible with hydranencephaly.

anticonvulsants (Keppra), but the overall seizure pattern worsened. She underwent ventriculoperitoneal shunt placement at 8 weeks of age, when the head circumference was 50 cm (total 12-cm increase over 8 weeks, more than twice the normal rate for head circumference growth). She was noted to have panhypopituitarism including diabetes insipidus following ventriculoperitoneal shunt placement and was placed on hormonal replacement therapy. At this time, it was noted that she had developed multiple small (1–5 mm in size) skin hemangiomas (>15) over her scalp, arms, legs, hands, abdomen, external genitalia, and foot. A variant of the recently described PHACE syndrome, encompassing the association of posterior fossa malformations, hemangiomas, arterial anomalies, cardiac defects, eye abnormalities, sternal cleft and/or supraumbilical raphe (previously referred to as PHACES syndrome), was suggested as a possible etiology for the multiple hemangiomas with

This case typifies the complexity of treatment issues associated with newborns with hydranencephaly, knowing that the majority of patients will die within the first 2 years after birth, but occasionally longer survivals are reported even into the third decade. (1)(2) It is a diagnosis that may first be suspected by macrocephalic appearance, but many hydranencephalic neonates do not exhibit overt macrocephaly or split sutures. Neonatal skull transillumination is a simple bedside tool that uses any high-intensity light source applied directly over the open fontanelles or sutures. Complete skull transillumination, sometimes even with red retinal “reverse” reflex, may be noted with hydranencephaly, but other conditions need consideration. (3)(4) The suggestion of some cerebral tissue limiting such complete transillumination may confuse the diagnosis. Additional neuroimaging is mandated to differentiate hydranencephaly, which may be considered an untreatable condition with respect to outcome, and extreme hydrocephalus, which is usually approached as a treatable condition with potential for benefit from intervention (see Figs 4 and 5). (5)(6)(7) Lack of cerebral tissue may also reflect a form of holoprosencephaly, which is usually defined as alobar, semilobar, or lobar holoprosencephaly depending on the presence, type, and amount of residual cerebral hemispheric brain tissue and the extent of absence of interhemispheric fissure and other abnormalities (see Fig 6). Often, holoprosencephaly is associated with an identifiable systemic etiology, such as a chromosomal anomaly (common in trisomy 13), or defined genetic syndrome, such as the Smith-Lemli-Opitz spectrum. Therefore, the patient was screened for these anomalies, despite not having any of the associated syndromic features of either.

The question of whether or not to immediately refer such neonates with extensive transillumination to a neurosurgical specialist for shunting therefore depends upon the definition of the specific brain anomaly. As in this case, many prefer brain MRI as the follow-up imaging of choice, because it provides more detail of the brain parenchyma than CT scan (or cephalic ultrasound). However, difficulty in the interpretation of some signals as remnants of cerebral tissue often mandates additional imaging with brain CT imaging, which may be very helpful in establishing comfort with the diagnosis of hydranencephaly. (8)(9)(10)(11)(12) More extensive CT angiography studies (felt superior to MR angiography to limit NeoReviews Vol.13 No.4 April 2012 e235

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demonstrate irritability, hyperreflexia, hypertonia, quadriparesis, and decerebrate posture. EEGs may be normal at first but with time, infantile spasms, seizures and disconjugate extraocular movements are usually evident. Brainstem auditory-evoked responses are preserved, but visualevoked responses are absent. (13) (14) Lengths of survival may be very variable, most not surviving past 2 years of age but surprisingly longer periods of survival have been reported. (1)(2)

Discussion Hydranencephaly is a rare congenital brain anomaly occurring approximately in one per 10,000 births.

Fetal autopsies may suggest slightly higher rates. It is defined by the absence of cerebral tissue that is replaced by a leptomeningeal saclike Figure 4. Axial brain CT imaging of two infants with minimal frontal cerebral tissue. A. structure, with preservation of the Axial brain CT (three scans) in infant with difficult-to-ascertain mixed hydranencephaly/ midbrain and cerebellar structures. extreme hydrocephalus characteristics on head CT. Patient did receive ventricular shunt The falx cerebri, partial or complete, placement. After follow-up over 1 year, subsequent CTs confirmed interpretation of is present, distinguishing it from most likely hydranencephaly with minimal frontal cerebral remnant. B. Axial brain CT forms of holoprosencephaly. In hyin infant with likely extreme hydrocephalus. Note symmetrical cerebral tissue remnant dranencephaly, partial remnants of distribution. cerebral tissue may be present at birth and they are often asymmetric. motion artifacts) to identify abnormal patterns of cerebral In contrast, marked hydrocephalus demonstrates symmetand brainstem vessels may be available at certain tertiary rical thin cortical remnants. In both hydranencephaly and care pediatric institutions as well. (10) If it is felt that the hydrocephalus, in contrast to holoprosencephaly, the falx imaging reveals extensive or extreme hydrocephalus, cerebri and unfused thalami should be evident. The overall most agree that early ventriculoperitoneal shunting is inimage of hydranencephaly should be distinguishable from dicated (see Fig 4), whereas hydranencephaly and holoa very large porencephalic cyst or other cystic structures, prosencephaly may not lead to that intervention with especially if both head MRI and CT imaging are used. (15) respect to consideration of beneficial outcomes. (5) The pathophysiology of development of hydranenceThe extensive counseling issues were evident in this phaly reflects an interruption by likely diverse mechacase, because the prognosis is grim and there are no clear nisms of the normal embryonic brain development, parameters for improving outcomes or predicting lengths affecting primarily the prosencephalon (forebrain) with of survival with or without ventriculoperitoneal shunting relative sparing of the mesencephalon and rhombencephintervention. For hydranencephaly, postnatal excessive alon derivatives, beginning anytime after the third to rate of head circumference growth is typical, as in this fourth gestational month. Animal models of occlusion case, and ventriculoperitoneal shunting may be offered of both internal carotid arteries produce subsequent fetal to limit eventual head size for comfort and easier care. brain anomalies similar to what is seen in human hydraClinical progression, however, is generally unaffected, nencephaly. Therefore, intrauterine insults affecting these manifesting neurologic abnormalities associated with vessels producing strokes is postulated as a mechanism for failure in the development of normal cerebrocortical some individuals. (16) A variety of etiologies, including inhibitory processes. Over time, the patients usually environmental factors and genetic mechanisms, have e236 NeoReviews Vol.13 No.4 April 2012

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which may include hydranencephaly; arterial cardiovascular anomalies; cardiac defects and/or aortic abnormalities; eye anomalies; and sternal defects and/or supraumbilical raphe. Now renamed PHACE syndrome, it may be associated with internal carotid artery agenesis or hypoplasia, predisposing to aneurysm and ischemia.

(16)(20) In PHACE syndrome and hydranencephaly, observed cerebral anomalies are likely secondary to poor development of the in utero carotid vessel brain distribution. (20) However, this infant did not fit the clinical criteria for PHACE syndrome, lacking the typical segmental locations for hemangiomas and associated anomalies other than hydranencephaly. NoneFigure 5. Extensive neonatal hydrocephalus. Neonate with arthrogryposis demonstrating theless, a PHACE-like vasculopathy marked macrocephaly for body habitus who had extensive skull transillumination (not syndrome producing hydranenceshown). Axial head CT series demonstrated prominent symmetric frontal cerebral phaly and hemangiomas certainly tissue and increasingly thin remnants progressively toward the posterior and caudal could explain the clinical findings. regions until a questionable absence of occipital tissue was noted. An interhemiThe varied anecdotal chromospheric falx was present and the thalami were not fused, ruling out holoprosencephaly. The pattern and amount of cortical rim tissue is most consistent with extreme somal anomalies associated with hydranencephaly are in a minority hydrocephaly. of overall cases, and it is unclear which genes or chromosomal regions may be associbeen anecdotally reported to support this mechanism. ated with this cerebral anomaly. Nonetheless, karyoAny mechanism for internal carotid artery occlusion or vasculopathy may be associated with hydranencephaly. type and comparative genomic hybridization assays Fowler syndrome is an autosomal recessively inherited (microarrays or similar) are indicated in the workup of patients with hydranencephaly. This not only allows condition consisting of “proliferative vasculopathy with better understanding of possible etiologies, but also hydranencephaly-hydrocephaly” but with other lesions a specific finding often allows better acceptance of also identified in the brain stem, basal ganglia, and spinal the patient’s condition by parents and caretakers. cord. (17)(18) Mutations in the FLVCR2 gene are the The structures observed to be preserved in hydranenbasis for this syndrome. Mutations in a separate gene, cephaly appear to be those supplied by the posterior cirARX, have also been associated with a pleiotropy of brain anomalies, including hydranencephaly. (19) Other likely culation (the vertebrobasilar system) and variable derived genetic influences on embryonic vascular development feeder vessels. Therefore, the posterior fossa structures, occipital lobes, and thalami are present and portions of affecting the internal carotid arterial distribution likely the occipital, temporal, and even small basilar portions play a role in the development of the prosencephalic of the frontal lobes, may be intact. Either circulation anomalies associated with human hydranencephaly. Many may supply the embryonic development of the basal ganof these may similarly produce individuals with a spectrum glia, and therefore its absence is a variable finding in hyof associated anomalies perhaps related to the vasculopdranencephaly. The brainstem is preserved but may be athy, such as the extensive number of hemangiomas noted in our described patient. atrophic at times. (13)(15) PHACES syndrome previously was defined by segOther mechanisms for hydranencephaly include intrauterine infections, including reports of associated mental hemangioma(s) plus at least one of the following: viruses (cytomegalovirus, rubella, herpes simplex virus, posterior fossa and/or other structural brain anomalies, NeoReviews Vol.13 No.4 April 2012 e237

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Figure 6. Neonatal semilobar holoprosencephaly. Axial head CT in infant with marked midface hypoplasia, hypotelorism, cleft lip and palate, ultimately diagnosed with trisomy 13. Head CT series suggested semilobar holoprosencephaly with fluid-filled spaces in regions with absent cerebral tissue development but identifiable midbrain tissues, including two thalamic lobes, partially fused.

Normal cerebral falx was not evident.

Epstein-Barr virus, adenovirus, parvovirus, respiratory syncytial virus), toxoplasmosis, and others, (11) or other intrauterine insults producing extensive fetal brain damage and subsequent resorption and replacement with cerebrospinal fluid (CSF). Toxic effects of drugs (for example, cocaine), diffuse hypoxic ischemic damage, and any cause of intrauterine strokes and/or emboli may produce sufficient cerebral tissue necrosis to result in ultimate appearance of hydranencephaly. The association of hydranencephaly with a deceased co-twin in utero is postulated to be an embolic product phenomenon. Similarly, severe genetic or environmentally influenced defects in cerebral embryogenesis may result in cortical agenesis or extreme dysgenesis and may play a role in the development of hydranencephaly in some cases.

Some have reported the possibility of extreme hydrocephalus that has progressed in utero to the extent of resembling hydranencephaly on imaging studies. (6) However, hydrocephalus is the end result of blockage of CSF flow and hydranencephaly is more likely

a disorder of embryonic brain tissue formation or/or extensive destruction and resorption. For this reason, when cortical remnants are observed in both, the patterns usually appear different (see Fig 4), and the apparent membrane structures surrounding the fluid are different in histology. The membranous sacs in hydranencephaly are usually composed of glial tissue covered by intact meninges. In hydrocephalus, thin cortical grey matter remnants should be observed. The fluid in hydranencephaly may be clear, cloudy, or blood stained, and it is usually more proteinaceous than typical CSF fluid, such as that observed in hydrocephalus. Postnatal processes leading to massive cerebral tissue destruction may also produce a hydranencephalic picture, such as infantile herpes simplex virus encephalitis. (21) Early prenatal imaging by ultrasound may demonstrate an ongoing destructive process that ultimately evolves into a classic hydranencephalic image, such as hypoxic ischemic damage, severe hemorrhage, or other diffusely damaging processes. (22) Hydrocephalus, hydranencephaly, and

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alobar holoprosencephaly may initially be difficult to distinguish early on in utero. (12)(22) In these cases, fetal MRI may help suggest the likely diagnosis. Again, the important distinguishing features include the absence of a cortical mantle (versus its presence in hydrocephalus), the presence of a falx cerebri and unfused thalami and cortical tissue, and the extent of remaining nonfused cerebral tissue. In holoprosencephaly, there should be no falx cerebri, and the thalami and cerebral tissue should at least appear partially, if not totally, fused. Postnatally, MRI signals suggesting rims of cortical tissue, membranous septae, or movement artifacts may be distinguished by follow-up CT scanning. Hydranencephaly should show absence of most supratentorial cerebral tissue, preservation of the falx, and unfused thalami, but may have varying amounts, especially of occipital tissue as well as basal ganglia, parietal, and even frontal tissues.

(5)(6)(8)(9)(22) Bedside transillumination of the skull, also known as skull diaphanoscopy, is a screening tool, not a diagnostic procedure. (3)(4) If the cortical rim segment is <1 cm in thickness, diffuse illumination will occur. Besides hydranencephaly, extensive hydrocephalus, and holoprosencephaly, extensive transillumination may suggest a large porencephalic cyst or a large subdural hematoma/effusion. Further imaging is required for definitive diagnosis, which will drive treatment plans. The current recommendations for ventriculoperitoneal shunting of even extreme hydrocephalus mandates resolution of the diagnosis as early as possible. In one study, 10 neonates with marked absence of visible cerebral cortex on CT were followed by subsequent CT and EEG studies for developmental and/or imaging progression following shunting procedures. (5) The five infants with minimal frontal cerebral mantle on CT and presence of electrical activity on EEG demonstrated improvement with time, including the appearance of considerable brain substance and neurologic development that was either normal or mildly delayed. In contrast, five infants with absent cortical activity on EEG and CT demonstrating minimal occipital brain parenchyma connected by thin bridge of tissue to intact basal ganglia showed no improvement with time, either neurologically or radiologically.

A pattern of diffusely absent cerebral tissue with only minimal occipital brain tissue and absent EEG activity defined true hydranencephaly with little effect of shunting interventions. In contrast, the presence of frontal cerebral mantle tissue on CT and the presence of electrical activity on EEG was felt to indicate more likely extreme hydrocephalus and indication for prompt shunting. (5) For that reason, it is extremely important to distinguish

hydranencephaly from extreme hydrocephalus. In unclear cases, ventriculoperitoneal shunting is indicated as early as possible, such as for the infants shown in Fig 4, one who did improve (hydrocephalus) and one who did not and ultimately was felt to have hydranencephaly with frontal lobe remnants. Transillumination may be demonstrated in a neonate, but it simply will not illuminate this very important distinction for not only diagnosis, but also approaches to treatment that might affect an otherwise very grave, nonilluminating, prognosis.

American Board of Pediatrics Neonatal-Perinatal Medicine Content Specifications • Know the indications for and limitations of various neuroimaging studies and be able to recognize normal and abnormal structures and changes during development and growth.

• Be able to differentiate the familial/ genetic features of neurologic disorders associated with increased head circumference.

• Know the etiology, familial/genetic features, and abnormalities associated with hydrocephalus.

• Know the management and outcome of such management in an infant with hydrocephalus.

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Hydranencephaly : Transillumination May Not Illuminate Diagnosis Jeffrey M. Chinsky Neoreviews 2012;13;e233 DOI: 10.1542/neo.13-4-e233

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including high resolution figures, can be found at: http://neoreviews.aappublications.org/content/13/4/e233

References

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Core Concepts : Development of the Blood-Brain Barrier Shadi N. Malaeb, Susan S. Cohen, Daniela Virgintino and Barbara S. Stonestreet Neoreviews 2012;13;e241 DOI: 10.1542/neo.13-4-e241

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Article

core concepts

Core Concepts: Development of the Blood-Brain Barrier Shadi N. Malaeb, MD,* Susan S. Cohen, MD,†

Abstract

Daniela Virgintino, MD,**

The blood-brain barrier maintains central nervous system homeostasis and limits the entry of blood-borne substances that could alter neuronal function and survival. The barrier exists predominantly at the endothelium of cerebral vascular microvessels. The cerebral vascular endothelium becomes highly specialized during the formation of the neurovascular unit early in embryonic development. The blood-brain barrier is present and functional early in fetal life. The tightness of the barrier gradually increases throughout gestation and in the newborn period. Alterations in the basolateral environment of the cerebral microvasculature can modify the blood-brain barrier properties by modulating the expression of the endothelial tight junctions and other biochemical properties of the cerebral vascular endothelium. Maturation of the blood-brain barrier late in gestation correlates with increases in endogenous corticosteroids and with exposure to exogenous corticosteroids. Several adverse fetal and neonatal conditions can alter the structure and function of the blood-brain barrier. Impairment of blood-brain barrier function in the perinatal period could increase the entry of bilirubin and other neurotoxic substances from the systemic circulation into the brain, thereby exacerbating and/or causing damage to the developing brain.

Barbara S. Stonestreet, MD‡

Author Disclosure Drs Malaeb, Cohen, Virgintino, and Stonestreet have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device.

Objectives

After completing this article, readers should be able to:

1. Describe the structure and function of the blood-brain barrier.

2. Describe the maturation of the blood-brain barrier throughout gestation.

3. Understand the impact of development, perinatal morbidities, and treatments on the fetal and neonatal blood-brain barrier.

Elements of the Blood-Brain Barrier Blood flow into the brain disperses into a large vascular network of capillaries with an estimated surface area of 150 to 200 cm2 for each gram of brain tissue. (1) The interface between the intravascular compartment and brain parenchyma is a very restrictive barrier, and is referred to as the blood-brain barrier (BBB). The BBB limits bidirectional passive diffusion of large molecules such as dyes, (2)(3) and proteins, (4) as well as of small polar molecules. (5) These molecules cross the microvascular endothelium of capillaries in the peripheral circulation via a paracellular route through spaces between adjacent endothelial Abbreviations cells and via a transcellular route through abundant endoAIB: a-aminoisobutyric acid thelial fenestrations and vesicular transport mechanisms.

BBB: blood-brain barrier In contrast, paracellular diffusion of electrolytes and polar CNS: central nervous system molecules between adjacent endothelial cells of the BBB is JAM: junctional adhesion molecule very restricted. The transendothelial electrical resistance across rate constant for influx Ki: microvascular endothelium in peripheral capillaries is estimated TJ: tight junction to be as low as 2 to 20 ohm$cm 2, whereas it can be up to 1800 ZO: zonula occludens ohm$cm 2 across cerebral vascular endothelium. (6) Moreover,

*Division of Newborn Medicine, Department of Pediatrics, Floating Hospital for Children at Tufts Medical Center, Tufts University School of Medicine, Boston, MA. † Division of Neonatology, Children’s Research Institute and Medical College of Wisconsin, Milwaukee, WI. **Anatomy and Histology Unit, Department of Basic Medical Science, Bari University School of Medicine, Bari, Italy. ‡ Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Women and Infants Hospital of Rhode Island, The Warren Alpert Medical School of Brown University, Providence, RI.

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capillaries that line the BBB are not fenestrated and show no significant transcellular vesicular transport. (7) High electrical resistance and low permeability to small polar molecules and large molecules represent the main barrier properties of the BBB. The properties of the BBB maintain central nervous system homeostasis and limit the entry of substances that could alter neuronal function and survival.

The Tight Junction

of the capillaries. Adherens junctions located basal to the TJ strands form desmosomes that provide more solid structural support and join the cytoskeletons of two adjacent cells. Disruption of the adherens junctions can result in breakdown of the TJ seal. (12) Occludin is a 522-amino-acid phosphoprotein that is encoded in humans by the OCLN gene. (13) It is a 60kDa protein when nonphosphorylated and a 65-kDa protein when phosphorylated. Occludin is an integral plasma membrane protein that spans the plasma membrane four times, forming two extracellular loops with both NH2 and COOH terminal ends in the cytosol. Occludin has binding domains that couple it with the ZO proteins.

(14) Phosphorylation/dephosphorylation of the COOH terminus by corresponding kinases plays a major role in regulating occludin and coupling occludin with other proteins. Therefore, occludin plays an important role in the regulation of the TJs. The claudins are small 20- to 27-kDa transmembrane proteins that in humans are encoded for by a multigene family of 24 different members. (15)(16) Similar to

Classical electron microscopic studies in the late 1960s identified continuous strands of epithelial-like junctions in the interendothelial cleft. (8)(9) These junctions were impermeable to fluids and polar molecules and were referred to as tight junctions (TJs). TJs constitute the primary anatomic substrate of the BBB. (10) TJs are composed of heteropolymer protein complexes that span the plasma membrane of the cerebral vascular endothelial cells. (11) They connect to the cytoskeleton from one side and to corresponding TJ elements on the surface of an adjacent cell from the other side. The individual TJ protein complexes join together to form a long branching network of fibrillar strands that continue along points of focal contact between membranes of adjacent endothelial cells and serve to seal the cleft between the two adjacent cells. These fibrils compose a continuous circumferential belt that separates luminal and basolateral plasma membrane domains of endothelial cells. The transmembrane segment of the TJ complex is composed of a heteropolymer of a three major proteins that include occludin, claudin, and a junctional adhesion molecule (JAM) protein (Fig 1). The cytosolic segment of the TJ complex is a plaque of a number of adaptor proteins that bind the TJ proteins together and anchor them to the cytoskeleton.

These proteins include members of the zonula occludens (ZO) family of proteins, and other proteins such Figure 1. Schematic diagram of the TJ protein complex at the apical side of two adjacent as cingulin, symplekin, and others. cerebral vascular endothelial cells. Transmembrane proteins such as occludin, claudin, and TJs limit the paracellular flux of JAM come together to seal the intercellular gap and limit the diffusion of molecules blood-borne substances into the across the endothelium. ZO and other cytosolic TJ proteins join the TJ complex to the brain parenchyma. However, TJs cytoskeleton. Adherens junctions provide structural strength to hold endothelial cells provide minimal mechanical sup- together. (Adapted with permission from Fo¨rster C. TJs and the modulation of barrier port to the microvascular structure function in disease. Histochem Cell Biol. 2008;130:55–70.) e242 NeoReviews Vol.13 No.4 April 2012

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occludin, claudins span the plasma membrane four times forming two extracellular loops with both NH2 and COOH terminals in the cytosol. Claudins have binding domains that couple with the PDZ domains of ZO proteins. (17) Claudins, especially claudin-3 and claudin-5, are essential to the seal function that produces the high electrical resistance of the TJ at the BBB. (15) JAM proteins are large proteins encoded by genes in the immunoglobulin superfamily. (18) They play a role in cell–cell adhesion, particularly in bridging the TJ protein complexes of two adjacent endothelial cells. (19) They also act as adhesive ligands for immune cells, (20) and may play a role in immune cell trafficking across the BBB. The JAM cytosolic domain can bind to ZO proteins, and may help in localizing the TJ strands to luminal side of the endothelium. (21) ZO proteins are located at the cytoplasmic surface of endothelial cells and have several domains that bind various transmembrane TJ proteins and other domains that bind to actin, which is the primary cytoskeleton protein.

(22) A ring of actin microfilaments underlies the complex and has a role in regulating permeability and structural integrity of the TJ. (11) Dynamic changes of the cytoskeleton through contractions of calcium-binding proteins can result in opening of the TJ seal.

The Neurovascular Unit The development of the central nervous system (CNS) vasculature begins during early stages of embryogenesis, when angioblasts arise in the mesoderm of the head region and form a perineural vascular plexus. The vascular plexus covers the entire surface of the neural tube by approximately the eighth week of gestation in humans. Vascular sprouts from the perineural plexus then invade the proliferating neuroectoderm. Newly formed stem vessels then elongate and radially penetrate the neuroectodermal tissue and give rise to manifold branches that grow and anastomose with adjacent sprouts to form a plexus of undifferentiated capillaries in the subventricular zone of the developing brain. Pericytes play a critical role in initialing and maintaining the branching morphology of cerebral microvascular endothelium. (23) Neural progenitor cells are the major cell type in the neuroectoderm during this stage of development. The interaction between neural progenitor cells and the primitive cerebral vascular endothelial cells induces the differentiation of both cell lines into more mature phenotypes. (24) Progenitor cells lining the neural tube proliferate and give rise to a multitude of neuronal and nonneuronal cells that organize into the complex tissue that forms the CNS. Neurons and oligodendrocytes

connect closely to one another and assemble into an intricate meshwork that is intertwined within a supporting network of closely connected astrocytes and endothelial cells.

The architecture is highly organized such that, in any region of the mature brain, a neuronal cell body is within 11 mm of the nearest capillary segment (Joseph D. Fenstermacher, PhD, personal communication, 2011). During angiogenesis, endothelial cells become invested with astrocytic end-feet processes, and capillary-astrocyte complexes resembling mature cerebral microvessels begin to develop between the 10th and 12th week of gestation.

The maturing cerebral microvascular endothelium becomes closely associated on the basolateral side with pericytes, astrocytic end feet, and neuronal cell processes, all embedded in a thick extracellular matrix. A basement membrane starts to develop, and the vessel decreases in diameter as the basement membrane thickens. Vascular fenestrae disappear, transcellular vesicular transport decreases, and TJ protein expression becomes detectable.

Cerebral vascularization continues through midgestation and is characterized by vascular branching, increasing microvessel density, and advancing barrier differentiation demonstrated by the detection of TJ complexes, barrierspecific nutrient transporters, and efflux carriers. The neurovascular unit maintains CNS homeostasis by providing nutritional and metabolic support to the brain and removing waste products. Nutrients can cross the BBB by means of specific transporters on endothelial cells for glucose, amino acids, and other essential nutrients.

Other efflux transporters remove toxins and metabolic byproducts from the brain into the circulation. Various components of the neurovascular unit interact to modulate the expression of transporters and TJ proteins and to regulate blood flow and permeability of cerebral microvessels to match the metabolic demands of the CNS tissue that they supply. (25) Recent evidence from in vitro co-culture models indicates that factors influencing the condition of the basolateral environment of the cerebral microvasculature can modify the barrier properties of the membrane by modulating the expression and biochemical properties of the endothelial TJ. (26)

Ontogeny of the Blood-Brain Barrier Barrier Permeability in Early Gestation Electron microscopy studies with horseradish peroxidase infusions and optimal freeze-fracturing suggest that the BBBs to proteins and large molecules are tight from the earliest stages of development. (27) Other studies found that the diffusion of small polar molecules such as sucrose from blood into brain decreases at early gestational ages in NeoReviews Vol.13 No.4 April 2012 e243

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fetal sheep. (28) The majority of the decrease in sucrose accumulation in the brain occurred between 49 and 70 days of gestation, ie, before midgestation in this species (term gestation is 150 days). Permeability to sucrose continued to decrease after midgestation and early neonatal life, but at a smaller decrement.

compared with 60% of gestation, particularly in caudal brain regions, (29) and was significantly lower in the newborn and older sheep brain than in the fetal brain at 90% of gestation. Permeability studies in rats also suggested that the BBB was more permeable to potassium in late fetal brains than in newborn or adult brains. (30) Barrier Permeability During Gestation Inspection of the regional Ki values for AIB (Fig 2) BBB permeability to a small polar molecule was quantialso suggests that the cerebrum exhibits the smallest diffied with the rate constant for influx (Ki) across the BBB ferences in the Ki between the fetuses at 60% of gestation with a radiolabeled low-molecular-weight (103 Da) synand the adult sheep, whereas the more caudal brain rethetic inert hydrophilic amino acid, a-aminoisobutyric gions, including the cerebellum, medulla, and spinal acid (AIB), in nonanesthetized chronically instrumented cord, exhibit relatively larger developmental decreases fetal sheep at 60% and 90% of gestation, in newborn and in permeability between the fetuses at 60% of gestation older lambs, and in adult sheep (Fig 2). (29) The BBB and adult sheep. These findings suggest that the cerebral was relatively impermeable to AIB in all age groups cortex represents a relatively privileged site because of its and brain regions studied. The relatively low permeability unique neuronal composition and function. These measto AIB at 60% of gestation in sheep suggests that a funcures of barrier function early in the sheep gestation are tionally tight barrier has already developed early in gestaconsistent with results suggesting very precocious barrier tion, consistent with the findings of the other studies differentiation in the human fetal cerebral cortex as dedescribed above. Permeability to AIB was lower at 90% scribed below.

These studies taken together demonstrate that tightening of the BBB occurs early in gestation during development of the cerebral microvascular endothelium. However, the tightness of the BBB continues to increase gradually throughout development.

The primary vessels of the telencephalon exhibit evidence in immunohistochemical studies for the presence of occludin and claudin-5 expression in the cytoplasm of primitive endothelial cells as early as the 12th week of gestation in humans.

(31) The immunoreactivity then shifts from the cytoplasm to the endothelial borders and concentrates in linear, discontinuous tracts that correspond to simple, incomplete networks of TJ strands (Fig 3). Subsequently, more extended and complex strands appear, and a near-continuous Figure 2. BBB permeability to an inert small amino acid molecule presented as regional staining pattern resembling that obblood-to-brain transfer constant for influx (Ki) to radiolabeled AIB at 60% and 90% of served in mature TJs becomes degestational age in fetal sheep, and in newborn and older lambs and adult sheep. Note that the magnitude of the changes from 60% of gestation to maturity was not large. The low tectable by 18 weeks of gestation. permeability to AIB at 60% of gestation suggests the presence of a functionally tight BBB However, in contrast, another study from very early in gestation (Modified with permission from Stonestreet BS, Patlak CS, showed that quantitative analysis Pettigrew KD, et al. Ontogeny of BBB function in ovine fetuses, lambs, and adults. Am J of occludin, claudin-5, and JAM-1 proteins on Western immunoblots Physiol. 1996;271:R1594–R1601.) e244 NeoReviews Vol.13 No.4 April 2012

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gestation or in newborn lambs.

(37)(38) Maternal treatment with corticosteroids also increased expression of occludin, claudin-1, and claudin-5 in select regions of the fetal brain. (34)(39) Increases in claudin-1 and claudin5 expression were associated with decreases in permeability in the fetal cerebral cortex. (39) Corticosteroids also have been shown to decrease permeability to sucrose, increase transendothelial electrical resistance across endothelial cell monolayers, and increase Figure 3. Human fetal telencephalon at 12 (A), 14 (B), and 18 (C) weeks of gestation. At 12 ZO-1 and occludin expression weeks, a claudin-5 punctate staining pattern is detected in the endothelial cytoplasm in vitro in cerebral endothelial (arrows). At 14 weeks, the punctate pattern starts to form interrupted linear tracks (arrowheads) that at 18 weeks (C) appear as nearly continuous thick bands (arrows). Scale cells. (40)(41)(42) Therefore, corticosteroids appear to exert a major bars: 15 mm in A and B and 10 mm in C. (Images courtesy of Dr Virgintino.) maturational effect on the BBB during a critical window of development late in gestation showed no difference in the expression of transmemand after birth. Corticosteroids most likely account for brane TJ proteins in blood vessels of germinal matrix, the marked decrease in BBB permeability observed after white matter, or cortex between 16 and 40 weeks of gesbirth in sheep (Fig 2) and other species. tation in humans. (32) On the other hand, the expression of ZO proteins increased between late gestation and the early neonatal period in both mouse and sheep brains.

Infection and Inflammation (33)(34) Specifically, expression of ZO-1, and of the Microorganisms can gain access into the brain parenchyma lower-molecular-weight isoforms of ZO-2 proteins were by directly breaching the BBB. (43)(44)(45) Escherichia higher at 90% than at 70% of gestation in fetal sheep, coli, Listeria monocytogenes, and group B streptococci and higher in newborn lambs than in late-gestation fetal are common bacterial pathogens causing disease in newsheep. (34) These results suggest that the expression of cyborn infants. The K1 type E coli and serotype III group tosolic TJ proteins may be a more specific marker of the B streptococci have specific virulence determinants that functional adversities, some of which are reviewed below. contribute to brain microvascular endothelial cell adhesion and invasion. (46)(47) These organisms appear to have a high capacity to penetrate the cerebrovascular endoCorticosteroids thelium and to result in large increases in BBB permeability In adult rats, adrenalectomy increased BBB permeability, in comparison with other organisms. Chorioamnionitis and corticosterone replacement reversed this effect on and sepsis are common clinical conditions that induce a systhe barrier. (35) Endogenous cortisol concentrations increase in the latter part of gestation. (36) The increase in temic inflammatory response in the fetus and newborn. plasma cortisol concentration correlates with a decrease (48) Systemic and local inflammatory mediators such as endotoxins, activated complement proteins, and proinin regional brain Ki permeability values for AIB between flammatory cytokines can bind to their receptors on 60% and 90% of gestation in the ovine fetus. (37) The various elements of the neurovascular unit. (49)(50) effect of antenatal corticosteroid treatment on BBB perActivation of the corresponding signaling cascades can dismeability was measured in ovine fetuses whose mothers rupt the expression and localization of TJ proteins, hence received four doses of 6 mg of dexamethasone every altering the integrity of the BBB. (51) Administering a sin12 hours over 48 hours, which was similar to a course of antenatal corticosteroids administered to pregnant gle dose of bacterial endotoxin intravenously to fetal sheep women who present in preterm labor. BBB permeability was associated with an increase in albumin concentration in the brain parenchyma, and intracarotid injections of a proinwas lower after antenatal corticosteroid administration at flammatory cytokine, tumor necrosis factor-a, resulted 60%, 70%, and 80% of gestation, but not at 90% of NeoReviews Vol.13 No.4 April 2012 e245

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in increases in BBB permeability in the cerebral cortex of newborn piglets. (52) These results indicate that BBB permeability increases after exposure to prenatal and/or perinatal systemic inflammation. (53) The associated opening of the BBB after infection and inflammation may facilitate access of cytokines and other neurotoxins present in the circulation into the brain parenchyma, which may exacerbate neuronal damage in preterm and term infants. (54)

Hypoxia, Ischemia, and Reperfusion Injury BBB integrity can be compromised after hypoxia, ischemia, and reperfusion injury to the CNS. (22) The blood-to-brain transfer constants for low-molecular-weight tracers such as sodium, urea, and sucrose increased after 30 minutes to 2 hours of complete ischemia to the newborn piglet brain.

(55)(56) The BBB remained intact after a short period of cerebral ischemia. However, the transfer coefficient increased by 59% to 107% in several brain regions of newborn piglets subjected to 8 minutes of cerebral ischemia followed by 4 hours of spontaneous perfusion after cardiopulmonary resuscitation. (57) The paracellular leak across the BBB increased with time and the severity of the insult.

(58) The effects of hypoxia and reoxygenation on BBB permeability and TJ protein expression were also examined in rat brains. (59)(60) The nonspecific transport of bloodborne proteins into the brain was increased, and the expression and localization of various TJ proteins and of nutrient and electrolyte transporters were disturbed under hypoxic or ischemic conditions. The cellular and molecular infrastructure of the neurovascular unit can be disrupted because of energy failure that results from oxygen and metabolite depletion, and because of the damaging effects of oxygen-free radicals and the local inflammatory cascades induced by hypoxic-ischemic injury to the tissues, as well.

Cessation of shear blood flow in the microcirculation leads to the adhesion of static leukocytes to the blood vessel walls and subsequent invasion and translocation of these cells across the neurovasculature into the brain parenchyma and exacerbating inflammation. (61)(62) The induction of perivascular inflammatory cascades with local and leukocyte-derived matrix metalloproteinase activation mediates BBB breakdown after transient focal cerebral ischemia and predisposes to hemorrhagic complications after reperfusion. (63)(64) Therefore, conditions commonly encountered in sick neonates could predispose to impaired BBB function in the perinatal period.

Hypothermia Hypothermia can reduce disruption of the BBB after ischemia-reperfusion injury. Whole body hypothermia

during the first 6 hours of reperfusion reduced infarct volume and attenuated the increase in transfer of radiolabeled 3H-sucrose across the BBB after forebrain ischemia in adult rats. (65)(66) Moreover, postischemic hypothermia reduced the loss of structural basement membrane components and fibrinogen extravasation after reperfusion. (65) This suggests that transient postischemic hypothermia stabilizes the brain vasculature and reduces BBB disruption, in part, by preventing proteolytic degradation of regulatory basement membrane constituents and other elements of the neurovascular unit following ischemia-reperfusion injury. More studies are needed to clarify the effect of postischemic hypothermia on the developing BBB in fetal and/or neonatal models, particularly because hypothermia is currently an available therapy for hypoxic-ischemic encephalopathy in human infants. (67)

Hypercapnia, Acidosis, and Mechanical Ventilation Marked hypercapnia has been associated with increased BBB permeability to sucrose in fetal and newborn sheep. (68) Measurements of BBB permeability to AIB in surfactant-treated and ventilated premature lambs at 90% of gestation showed that increases in the duration of positive-pressure ventilation predispose to increases in regional BBB permeability. These alterations in barrier function occurred over relatively short time intervals of minutes to hours and were not attributable to changes in mean airway pressure. (69) The observed disruption of the BBB in the cerebral microvasculature associated with hypercapnia and ventilation-related increases in intrathoracic pressure have been attributed to perfusionrelated increases wall stress in the cerebral venules. (70)

Hyperosmolar Stress The intact BBB forms the first line of defense to protect the brain parenchyma from direct exposure to fluctuations in systemic osmolality. Exposure to an acute hyperosmotic stress also can impair the tightness of the developing BBB. The degree of barrier opening varies with the concentration of the solute and the type of hyperosmotic solution used. Experiments by Cserr and co-workers found barrier opening with degrees of hyperosmolality comparable to those encountered clinically in premature infants. (71) Stonestreet et al showed that BBB permeability increases with increases in plasma osmolality in fetal sheep and lambs, but only after a critical threshold is reached. The BBB became more resistant to the effects of hyperosmotic stress during development. (72)

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Hyperbilirubinemia Bilirubin is a small polar molecule that circulates mostly bound to albumin and in equilibrium with free unbound bilirubin in the serum. Diffusion of bilirubin across the BBB is a function of both the level of unbound bilirubin in the serum and the permeability of the BBB to bilirubin.

As described above, the BBB permeability to small polar molecules decreases after birth. Infusions of comparable amounts of bilirubin correlated with higher brain-toblood distribution ratios for bilirubin in 2-day-old than in 2-week-old piglets. (73) These findings were more pronounced in the cerebellum and brainstem than in the cerebral cortex of these animals. Clinical observations in newborn infants have shown that the unbound fraction of bilirubin in the serum to be more predictive of neurotoxicity than total bilirubin concentrations (74)(75) and that infants are at a higher risk for kernicterus at lower bilirubin levels in the first few hours after birth than later in postnatal life. (76) Conditions that disrupt the BBB are more likely to be associated with bilirubin-related neurotoxicity at any given serum bilirubin concentration. In an experimental model of hypercapnia-induced opening of the BBB, there was a 33% increment in cerebral deposition of bilirubin-albumin macrocomplexes at pCO2 levels of 67 mm Hg compared with normocapnic controls that had comparable serum bilirubin concentrations and bilirubin-albumin affinity. (77) Disruption of the BBB by inflammation or hypoxia-ischemia also could facilitate transport of bilirubin into the brain. (78) Premature infants are often exposed to systemic perinatal inflammation and to recurrent episodes of hypoxia and ischemiareperfusion. These insults in and by themselves, and in combination with increased BBB permeability for bilirubin, can exacerbate bilirubin-induced neuronal damage and place early-gestation preterm, and late preterm infants at higher risk for bilirubin-related neurotoxicity compared with term newborns. (79) Understanding the role of the BBB in the pathogenesis of kernicterus can help improve the assessment of risk for bilirubin-induced neurotoxicity in preterm and term newborn infants.

Intraventricular Hemorrhage Infants born prematurely are at an increased risk for intracranial hemorrhage, which adversely affects their neurodevelopment. (80) Germinal matrix hemorrhage progressing to intraventricular and/or intraparenchymal hemorrhage in the early postnatal period is the prototype of intracranial hemorrhage in preterm infants. (81) Extravasation of blood contained within the cerebral intravascular space into the subependymal, parenchymal, and/ or ventricular space represents a complete breakdown of

the BBB. Animal studies and postmortem analysis of tissues from human fetuses and preterm and term infants compared blood vessels in the germinal matrix with their counterparts in the cerebral cortex and white matter to understand the propensity of germinal matrix vessels to hemorrhage. The germinal matrix has higher blood vessel density than adjacent gray and white matter, and a large percentage of the surface area of germinal matrix vascular bed is formed of capillaries. (82) Germinal matrix blood vessels also possess fewer pericytes than the vasculature of the adjacent brain regions. (83) Germinal matrix venules and capillaries are more rounded and have large diameters and thin basement membranes and lack direct contact with perivascular structures along a large proportion of their circumference compared with vasculature in the cerebral cortex at the same gestational age. (84)(85) (86) This corresponds to higher surface tension per unit area and less support by the perivascular neuropil, and it places the germinal matrix capillaries at a higher risk of rupture under the same perfusion pressure. (87) The concentration of laminin and collagen V in the basement membranes of germinal matrix vessels increases significantly in the first four postnatal days in premature Beagle puppies.

(88) The increase in extracellular matrix components in the early postnatal period can add structural integrity to the germinal matrix vessels and decrease their susceptibility to rupture. Immunolocalization studies found staining patterns to be different between cortical and germinal matrix vessels to be different at 24 weeks’ postconceptional age. (89) Occludin and ZO-1 formed short, discontinuous strands in the germinal matrix vessels at 24 weeks, and long, more complex networks at later stages.

As described above, cerebral cortical vessels showed a continuous pattern at both ages. This suggests that TJs in germinal matrix vessels continue to mature during the third trimester. Because TJs do not provide much of tensile strength, immaturity of the endothelial TJ per se is not likely to account for the propensity for hemorrhage in premature infants. (84) Maturation of TJs may parallel other maturational changes that reduce the propensity of the germinal matrix to bleed at more mature gestational ages. A surge in corticosteroids or other hormones in the immediate postnatal period may also contribute to the maturation of vessel wall support or other structures that reduce vulnerability of germinal matrix vessels to bleed. However, it is noteworthy that these studies are limited by confounding exposure of premature infants to a number of prenatal and postnatal variables including antenatal steroids, mechanical ventilation, and others factors that may alter cerebral hemodynamics, and the structure, function, and maturation of the BBB, as well.

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Therefore, the contributions of the neurovascular unit to intracranial hemorrhage and to subsequent brain damage in premature infants require further investigation.

Conclusions The BBB appears to develop as soon as cerebral microvasculature begins to form during early embryonic development. TJ proteins are expressed very early in fetal development, and the BBB is present and functional early in fetal life. Measures of BBB permeability throughout gestation revealed a significant degree of functional tightness to develop during early to midgestation. The tightness of the barrier continues to increase gradually and, to a lesser degree, during mid to late gestation and in the newborn period. The condition of the basolateral environment of the cerebral microvasculature can modify BBB properties by modulating the expression of the endothelial TJs and other biochemical properties of the endothelium. Maturation of the BBB in late gestation correlates positively with increases in endogenous corticosteroid levels and with exposure to exogenous corticosteroids. Several adverse fetal and neonatal conditions can alter the structure and function of the BBB. Understanding the role of the BBB in the pathophysiology of developmental brain disorders can help advance the management of these disease conditions and improve the neurodevelopmental outcomes of high-risk preterm and term newborn infants.

ACKNOWLEDGMENTS. Work on which this chapter is based was supported by National Institutes of Health (NIH) grants P50 HD11343, R01-HD34618, and 1R01-HD-057100.

American Board of Pediatrics Neonatal–Perinatal Content Specifications • Recognize the neonatal systemic complications and vascular redistribution of blood flow caused by perinatal hypoxia or asphyxia.

• Know the factors that affect the biological properties of bilirubin, including its solubility and tissue distribution.

• Know the mechanisms by which bilirubin enters the brain and causes damage.

• Know the normal developmental course of neuronal proliferation, migration, and myelination and the factors affecting these.

• Know the risk factors for development, proposed mechanisms, clinical and laboratory features, and diagnosis of periventricular-intraventricular hemorrhage.

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2000;10(1):113–126 63. Krizanac-Bengez L, Hossain M, Fazio V, Mayberg M, Janigro D. Loss of flow induces leukocyte-mediated MMP/TIMP imbalance in dynamic in vitro blood-brain barrier model: role of proinflammatory cytokines. Am J Physiol Cell Physiol. 2006;291(4): C740–C749 64. Hung YC, Chen TY, Lee EJ, et al. Melatonin decreases matrix metalloproteinase-9 activation and expression and attenuates reperfusion-induced hemorrhage following transient focal cerebral ischemia in rats. J Pineal Res. 2008;45(4):459–467 65. Baumann E, Preston E, Slinn J, Stanimirovic D. Postischemic hypothermia attenuates loss of the vascular basement membrane proteins, agrin and SPARC, and the blood-brain barrier disruption after global cerebral ischemia. Brain Res. 2009;1269:185–197 66. Huang ZG, Xue D, Preston E, Karbalai H, Buchan AM. Biphasic opening of the blood-brain barrier following transient focal ischemia: effects of hypothermia. Can J Neurol Sci. 1999;26 (4):298–304 67. Shankaran S, Laptook AR, Ehrenkranz RA, et al; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353(15): 1574–1584 68. Evans CA, Reynolds JM, Reynolds ML, Saunders NR. The effect of hypercapnia on a blood-brain barrier mechanism in foetal and new-born sheep. J Physiol. 1976;255(3):701–714 69. Stonestreet BS, McKnight AJ, Sadowska G, Petersson KH, Oen JM, Patlak CS. Effects of duration of positive-pressure ventilation on blood-brain barrier function in premature lambs.

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71. Cserr HF, DePasquale M, Patlak CS. Volume regulatory influx of electrolytes from plasma to brain during acute hyperosmolality.

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Core Concepts : Development of the Blood-Brain Barrier Shadi N. Malaeb, Susan S. Cohen, Daniela Virgintino and Barbara S. Stonestreet Neoreviews 2012;13;e241 DOI: 10.1542/neo.13-4-e241

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Fetal Intracerebral Mass With Major Perinatal Implications Meredith Giffin, Barbara Brennan and Bosco A. Paes Neoreviews 2012;13;e251 DOI: 10.1542/neo.13-4-e251

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://neoreviews.aappublications.org/content/13/4/e251

Neoreviews is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since . Neoreviews is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright Š 2012 by the American Academy of Pediatrics. All rights reserved. Print ISSN: .

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index of suspicion in the nursery

Fetal Intracerebral Mass With Major Perinatal Implications Case Presentation

The reader is encouraged to write possible diagnoses for each case before turning to the discussion.

We invite readers to contribute case presentations and discussions.

Please inquire first by contacting Dr. Philip at aphilip@stanford.edu.

Author Disclosure Drs Giffin, Brennan, and Paes have disclosed no financial relationships relevant to this case. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.

A 27-year-old G3A2L0 woman is referred to the Maternal Fetal Medicine clinic after a routine third-trimester ultrasound in a community setting shows an intracerebral mass at 30 weeks’ gestational age (GA). The mother is healthy other than being a chronic carrier of hepatitis B. She is blood type B positive with a negative antibody screen. She previously had two first-trimester therapeutic abortions, and this is her first pregnancy with her current partner. The pregnancy was uneventful with a negative integrated prenatal screen and ultrasounds with normal results at 14 and 20 weeks’ GA. Mild maternal thrombocytopenia was detected throughout the pregnancy (lowest platelet count 97 109/L) with reported increased bruising. There is no family history of bleeding disorders in either her or her partner’s family.

The findings on physical examination are normal with no signs of bleeding, bruising, or petechiae. A complete blood cell count shows a hemoglobin level of 11.3 g/dL (113 g/L) and a platelet count of 124 103/mL (124 109/L). A repeat ultrasound confirms a large complex intracerebral mass with hypoechoic areas suggestive of cysts as well as echogenic portions that were felt to be either solid or to represent bleeding with clots. The composition of the mass is clarified by maternal MRI at 31 weeks’ GA, which shows a large cystic complex lesion measuring 5.0 3.8 4.5 cm (Fig 1). There is a solid component that shows blooming on the susceptibility-weighted imaging sequence, suggestive of blood products, clot, or calcification, but an underlying neoplastic process or vascular anomaly cannot be excluded.

A repeat ultrasound is performed 10 days later at 32 weeks’ GA in conjunction with a biophysical profile for follow-up of the mass. The mass has increased in size to 5.6 4.3 4.5 cm with midline shift and possible compression of the left choroid plexus (Fig 2). Parental platelet antigen results are still pending. However, given the increasing mass size, an empirical decision is made to treat the patient as if she had a bleeding disorder.

She is hospitalized 3 days later and treated with betamethasone to enhance fetal lung maturity and reduce the risks of neonatal mortality and intraventricular hemorrhage. Intravenous immunoglobulin (IVIG) (1g/kg) and prednisone 50 mg is administered daily for two consecutive days for the management of a probable bleeding disorder.

A male infant, weighing 2,179 g, is delivered by caesarean delivery at 33 weeks’ GA with Apgar scores of 8 and

Figure 1. MRI of the maternal pelvis at 31 weeks’ GA without gadolinium. Large complex cystic lesion (arrow) in the frontoparietal region of the left cerebral hemisphere of the fetus with characteristics suggestive of blood products. Solid amorphous component attached to the anterior wall (small arrow) most likely a clot or calcification.

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Figure 2. Ultrasound of fetal head in utero performed at 32 weeks. There is a complex mass (arrow) in the left parietal region measuring 5.6 3 4.3 3 4.5 cm.

There is a midline shift with possible compression of the left choroid plexus.

8 at 1 and 5 minutes, respectively. The pediatric team is in attendance and matched, compatible platelets are available for immediate transfusion if necessary. The platelet count at birth is 5 103/mL (5 109/L). The infant is transferred to the NICU and briefly receives continuous positive airway pressure for transient respiratory distress. Two single-donor, irradiated, platelet transfusions (human platelet antigen [HPA] 1b/1b; 10 mL/kg) are administered on successive days with IVIG (1 g/kg), and the platelet count stabilized at 200 103/mL (200 109/L).

The findings of a complete newborn examination, including a full neurological assessment, are normal. An MRI shows a 5.4 6.0 4.7 cm intraparenchymal cyst located in the territory of the left middle cerebral artery consistent with an evolving hemorrhage (Fig 3). Midline shift is mild with insignificant parenchymal compression. Multiple, small hematomas are evident, mainly in the cerebellum, and few are noted within the cortical parenchyma. Neurosurgery and neurology are consulted. The risks and

benefits of surgical intervention are thoroughly discussed with the parents and the allied health care professional team, but surgical intervention is deemed unnecessary in the absence of raised intracranial pressure and neurological deficits versus the operative risk of further extension and complications from the existing intracranial hemorrhage (ICH). Based on the location and size of the hemorrhage, long-term spastic hemiplegia, right homonymous hemianopia, and epilepsy are prognosticated. The infant is successfully discharged to a level 2 nursery at 13 days of life with planned follow-up.

Case Discussion A differential diagnosis of neonatal alloimmune thrombocytopenia, severe idiopathic thrombocytopenia, a hereditary platelet disorder, anatomical abnormality, intracerebral tumor, and a spectrum of congenital infections (toxoplasmosis, rubella, cytomegalovirus, herpes) was considered. The absence of maternal history, negative serology, and normal fetal anatomical profile, apart from the localizing lesion, made the diagnosis of viral infection less likely. Congenital brain tumors are rare; the most common are intracranial teratomas, which comprise 50% of all lesions followed by astrocytomas, choroid plexus papillomas, ependymomas, and other primitive tumors. (1) Contrast-enhanced MRI with T1- and T2-weighted imaging helps to define the location, components of the lesion, compression of the ventricular system, midline deviation, and coexisting hydrocephalus. However, differentiation may still prove difficult, and, moreover, hemorrhage can masquerade as a tumor. After maternal treatment was commenced antenatally, the parental HPA status

Figure 3. MRI of the neonatal brain without gadolinium, performed on the third day after birth. Large hematoma (arrow) in the left hemisphere that is predominantly cystic, with fluid-filled levels. The dark signal-intense rim is consistent with hemosiderin deposition.

Within the left anterolateral aspect of the mass is a lobulated component in keeping with denatured (extracellular methemoglobin) blood products. A local mass effect is seen with gyral crowding and partial effacement of the left lateral ventricle.

revealed an incompatibility; maternal HPA-1b/1b, paternal HPA-1a/1a, and the infant was later found to have HPA-1a/1b.

The incidence of neonatal alloimmune thrombocytopenia (NAIT) is w0.7 in 1000 pregnancies. (2) It is the most common cause of severe thrombocytopenia in fetuses and neonates and of ICH in the newborn.

(3) NAIT is defined as thrombocytopenia and bleeding in a fetus or neonate caused by maternal antibodies directed against fetal platelet antigens inherited from the father. Human platelet antigen-1a (HPA-1a) is the most frequently involved antigen. Fetal platelet antigens are expressed as early as 16 weeks and enter the maternal circulation through poorly understood mechanisms. Unlike hemolytic disease of the newborn, in which index cases are usually unaffected, NAIT can have severe sequelae even in the initial pregnancy.

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The incidence of ICH in fetuses with HPA-1a antigen alloimmunization is w20%. (4) Most hemorrhages occur antenatally (80%) with 32% presenting before 30 weeks’ GA. (4) NAIT in a first-born child is usually unanticipated and diagnosed at birth because of skin bruising, petechiae, and moderately severe thrombocytopenia (platelet count <50 103/mL [50 109/L]).

ICH is generally identified by cerebral ultrasound as part of the NAIT workup. Our case is unique in that the fetal ICH led to the diagnosis of NAIT rather than vice versa. It is not standard practice with uncomplicated pregnancies to have routine third-trimester ultrasounds and the rationale remained undetermined.

Regardless, the intracerebral findings instigated a diagnostic assessment and may have saved this child’s life.

Antenatal therapy for known NAIT includes fetal transfusion of antigencompatible platelets, maternal IVIG, and corticosteroids. Recent trends favor the use of the latter two, noninvasive therapies, in the absence of solid evidence from randomized, placebocontrolled trials. With recognized NAIT either apheresis, leuko-reduced, plasma-depleted, irradiated, maternal platelets, or HPA-1a- and HPA-5bnegative stocked platelets are optimum for newborn treatment and should be made immediately available at birth.

IVIG (1–2 g/kg total dose) given on successive days with or without steroids is also of benefit but with a slower response time. Random donor platelets have proven useful and are advocated while awaiting the arrival of compatible platelets. (5) Algorithms for the diagnosis of NAIT and neonatal management are summarized in recent reviews. (2)(6)

A useful predictor of the severity of thrombocytopenia and future occurrence of ICH with HPA-1a alloimmunization is the presence of fetal ICH in a sibling, (4) but this finding is inconsistent across studies.

(7) The rate of ICH recurrence in future pregnancies ranges between 72% and 79%. (4) More recently, blood group A phenotype compared with group O was found to be associated with a 2-fold higher risk of severe NAIT. (8)

Lessons for the Clinician This case illustrates that, although NAIT is relatively rare, it needs to be considered in any otherwise well fetus or neonate who presents with ICH. Multidisciplinary care involving maternal fetal medicine, radiology, hematology, and the neonatal intensive care team is essential. Major discussion should ensue when NAIT is suspected antenatally but cannot be confirmed in a timely fashion; risks of elective preterm birth must be weighed against the risk of ongoing bleeding in utero. Close monitoring and regular fetal surveillance must be undertaken in a tertiary care service where maternal treatment is optimized and compatible platelets are readily available through the transfusion service to achieve favorable maternal-fetal outcomes. In all cases of ICH, neurodevelopmental follow-up is essential because long-term sequelae are likely. Once a diagnosis of NAIT is established, all future pregnancies should be screened and supervised in an advanced perinatal unit.

(Meredith Giffin, MD, Barbara Brennan, MD, MSc, PhD, FRCSC, Bosco A. Paes, MBBS, FRCPI, FRCPC, FAAP, McMaster University, Hamilton, ON, Canada.)

American Board of Pediatrics Neonatal–Pernatal Medicine Content Specifications • Know the clinical and laboratory manifestations and management of neonatal thrombocytopenia and thrombocytosis.

• Know the risk factors for and the evaluation and management of a fetus or infant with prenatal vascular brain injury.

References 1. Parmar HA, Pruthi S, Ibrahim M, Gandhi D. Imaging of congenital brain tumors. Semin Ultrasound CT MR. 2011;32(6):578–589 2. Symington A, Paes B. Fetal and neonatal alloimmune thrombocytopenia: harvesting the evidence to develop a clinical approach to management. Am J Perinatol. 2011;28 (2):137–144 3. Bussel JB, Zacharoulis S, Kramer K, McFarland JG, Pauliny J, Kaplan C. Clinical and diagnostic comparison of neonatal alloimmune thrombocytopenia to non-immune cases of thrombocytopenia. Pediatr Blood Cancer. 2005;45(2):176–183 4. Spencer JA, Burrows RF. Feto-maternal alloimmune thrombocytopenia: a literature review and statistical analysis. Aust N Z J Obstet Gynaecol. 2001;41(1):45–55 5. Kiefel V, Bassler D, Kroll H, et al. Antigenpositive platelet transfusion in neonatal alloimmune thrombocytopenia (NAIT). Blood.

2006;107(9):3761–3763 6. Arnold DM, Smith JW, Kelton JG. Diagnosis and management of neonatal alloimmune thrombocytopenia. Transfus Med Rev. 2008;22(4):255–267 7. Radder CM, Brand A, Kanhai HH. Will it ever be possible to balance the risk of intracranial haemorrhage in fetal or neonatal alloimmune thrombocytopenia against the risk of treatment strategies to prevent it?

Vox Sang. 2003;84:318–325 8. Ahlen MT, Husebekk A, Killie MK, Kjeldsen-Kragh J, Olsson ML, Skogen B. The development of severe neonatal alloimmune thrombocytopenia due to anti-HPA-1a antibodies is correlated to maternal ABO genotypes. Clin Dev Immunol. 2012;2012:156867

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Fetal Intracerebral Mass With Major Perinatal Implications Meredith Giffin, Barbara Brennan and Bosco A. Paes Neoreviews 2012;13;e251 DOI: 10.1542/neo.13-4-e251

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Strip of the Month: April 2012 Maurice L. Druzin and Nancy Peterson Neoreviews 2012;13;e254 DOI: 10.1542/neo.13-4-e254

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://neoreviews.aappublications.org/content/13/4/e254

Neoreviews is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since . Neoreviews is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright Š 2012 by the American Academy of Pediatrics. All rights reserved. Print ISSN: .

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Strip of the Month: April 2012 Maurice L. Druzin, MD,*

Electronic Fetal Monitoring Case Review Series

Nancy Peterson, RNC,

Electronic fetal monitoring (EFM) is a popular technology used to establish fetal well-being.

Despite its widespread use, terminology used to describe patterns seen on the monitor has not been consistent until recently. In 1997, the National Institute of Child Health and Human Development (NICHD) Research Planning Workshop published guidelines for interpretation of fetal tracings. This publication was the culmination of 2 years of work by a panel of experts in the field of fetal monitoring and was endorsed in 2005 by both the American College of Obstetricians and Gynecologists (ACOG) and the Association of Women’s Health, Obstetric and Neonatal Nurses (AWHONN). In 2008, ACOG, NICHD, and the Society for Maternal-Fetal Medicine reviewed and updated the definitions for fetal heart rate patterns, interpretation, and research recommendations. Following is a summary of the terminology definitions and assumptions found in the 2008 NICHD workshop report. Normal values for arterial umbilical cord gas values and indications of acidosis are defined in Table 1.

†

PNNP, MSN, IBLC

Author Disclosure Dr Druzin and Ms Peterson have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device.

Assumptions From the NICHD Workshop • Definitions are developed for visual interpretation, assuming that both the fetal heart rate (FHR) and uterine activity recordings are of adequate quality.

• Definitions apply to tracings generated by internal or external monitoring devices.

• Periodic patterns are differentiated based on waveform, abrupt or gradual (eg, late decelerations have a gradual onset, and variable decelerations have an abrupt onset).

• Long- and short-term variability are evaluated visually as a unit.

• Gestational age of the fetus is considered when evaluating patterns.

• Components of fetal heart rate FHR do not occur alone and generally evolve over time.

Definitions Baseline FHR • Approximate mean FHR rounded to increments of 5 beats per minute in a 10-minute segment of tracing, excluding accelerations and decelerations, periods of marked variability, and segments of baseline that differ by >25 beats per minute.

• In the 10-minute segment, the minimum baseline duration must be at least 2 minutes (not necessarily contiguous) or the baseline for that segment is indeterminate.

• Bradycardia is a baseline of <110 beats per minute; tachycardia is a baseline of >160 beats per minute.

• Sinusoidal baseline has a smooth sine wave–like undulating pattern, with waves having regular frequency and amplitude.

Baseline Variability • Fluctuations in the baseline FHR of ‡2 cycles per minute, fluctuations are irregular in amplitude and frequency, fluctuations are visually quantitated as the amplitude of the peak to trough in beats per minute.

• Classification of variability: Absent: Amplitude range is undetectable.

Minimal: Amplitude range is greater than undetectable to 5 beats per minute.

Moderate: Amplitude range is 6 to 25 beats per minute.

Marked: Amplitude range is >25 beats per minute.

*Charles B. and Ann L. Johnson Professor of Obstetrics; Chief, Division of Maternal-Fetal Medicine; Co-Medical Director, Mid-Coastal California Perinatal Outreach Program, Stanford University School of Medicine, Palo Alto, CA. † Director of Perinatal Outreach, Stanford University, Palo Alto, CA.

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Table 1.

Arterial Umbilical Cord Gas Values a

Normal Range Respiratory acidosis Metabolic acidosis Mixed acidosis

pH

Pco2 (mm Hg)

Po2 (mm Hg)

Base Excess

‡7.20 (7.15 to 7.38) <7.20 <7.20 <7.20

<60 (35 to 70) >60 <60 >60

‡20

£L10 (L2.0 to L9.0) £L10 ‡L10 ‡L10

Variable Variable Variable

a

Normal ranges from Obstet Gynecol Clin North Am. 1999;26:695.

Accelerations • Abrupt increase in FHR above the most recently determined baseline.

• Onset to peak of acceleration is <30 seconds, acme is ‡15 beats per minute above the most recently determined baseline and lasts ‡15 seconds but <2 minutes.

• Before 32 weeks’ gestation, accelerations are defined by an acme ‡10 beats per minute above the most recently determined baseline for ‡10 seconds.

• Prolonged acceleration lasts ‡2 minutes but <10 minutes.

Late Decelerations • Gradual decrease in FHR (onset to nadir ‡30 seconds) below the most recently determined baseline, with nadir occurring after the peak of uterine contractions.

• Considered a periodic pattern because it occurs with uterine contractions.

Early Decelerations • Gradual decrease in FHR (onset to nadir ‡30 seconds) below the most recently determined baseline, with nadir occurring coincident with uterine contraction.

• Also considered a periodic pattern.

Variable Decelerations • Abrupt decrease in FHR (onset to nadir <30 seconds).

• Decrease is ‡15 beats per minute below the most recently determined baseline lasting ‡15 seconds but <2 minutes.

• May be episodic (occurs without a contraction) or periodic.

Prolonged Decelerations • Decrease in the FHR ‡15 beats per minute below the most recently determined baseline lasting ‡2 minutes but <10 minutes from onset to return to baseline.

Decelerations are tentatively called recurrent if they occur with ‡50% of uterine contractions in a 20-minute period.

Decelerations occurring with <50% of uterine contractions in a 20-minute segment are intermittent.

Sinusoidal Fetal Heart Rate Pattern • Visually apparent, smooth sine wave–like undulating pattern in the baseline with a cycle frequency of 3 to 5 per minute that persists for ‡20 minutes.

Uterine Contractions • Quantified as the number of contractions in a 10-minute window, averaged over 30 minutes.

Normal: £5 contractions in 10 minutes.

Tachysystole: >5 contractions in 10 minutes.

Interpretation A 3-tier FHR interpretation system has been recommended as follows: • Category I FHR tracings: normal, strongly predictive of normal fetal acid-base status and require routine care. These tracings include all of the following: Baseline rate: 110 to 160 beats per minute Baseline FHR variability: Moderate Late or variable decelerations: Absent Early decelerations: Present or absent Accelerations: Present or absent • Category II FHR tracings: indeterminate, require evaluation and continued surveillance and reevaluation.

Examples of these tracings include any of the following:

Bradycardia not accompanied by absent variability Tachycardia Minimal or marked baseline variability Absent variability without recurrent decelerations Absence of induced accelerations after fetal stimulation Recurrent variable decelerations with minimal or moderate variability Prolonged decelerations NeoReviews Vol.13 No.4 April 2012 e255

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Recurrent late decelerations with moderate variability Variable decelerations with other characteristics, such as slow return to baseline • Category III FHR tracings: abnormal, predictive of abnormal fetal acid-base status and require prompt intervention. These tracings include the following: Absent variability with any of the following: ■ Recurrent late decelerations ■ Recurrent variable decelerations ■ Bradycardia Sinusoidal pattern

Data from Macones GA, Hankins GDV, Spong CY, Hauth J, Moore T. The 2008 National Institute of Child Health and Human Development workshop report on electronic fetal monitoring. Obstet Gynecocol. 2008;112:661–666 and American College of Obstetricians and Gynecologists.

Intrapartum fetal heart rate monitoring: nomenclature, interpretation, and general management principles. ACOG Practice Bulletin No. 106. Washington, DC: American College of Obstetricians and Gynecologists; 2009.

We encourage readers to examine each strip in the case presentation and make a personal interpretation of the findings before advancing to the expert interpretation provided.

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Case Presentation History A 21-year-old, G 1, P 0 at 38 1/7 weeks’ gestation presents to her provider’s office in the morning for complaints of decreased fetal movement since 6 pm the prior evening. A nonstress test done in the office is nonreactive (<2 accelerations in 20 min). A nonreactive nonstress test requires additional testing to determine the etiology of decreased fetal movement. The patient

is sent to the labor and delivery department for further evaluation and possible induction of labor. Prenatal history is unremarkable. Her admission vital signs are blood pressure 114/87, 84, and temperature was not documented. Prenatal labs are within normal limits, and GBS was negative. A cervical exam was 2 to 3 cm, 90% effaced, and vertex 1/ 2 station. An FHR admission tracing is obtained shortly after admission to labor and delivery (Fig 1).

Figure 1. EFM Strip #1.

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Figure 1. EFM Strip #1.

Findings on EFM Strip #1 are: • Variability: Absent • Baseline rate: Indeterminate because of sinusoidal pattern • Episodic patterns: None • Periodic patterns: None • Uterine contractions: Every 2 ½ to 3 minutes lasting 30 to 60 seconds, mild to moderate by palpation • Interpretation: Category III tracing • Differential diagnosis: Abnormal FHR tracing, sinusoidal pattern • Action: A sinusoidal pattern is a visually apparent, smooth, sine wave–like undulating pattern in FHR baseline with a cycle frequency of 3 to 5 per minute that persists for ‡20 minutes. In conjunction with decreased fetal movement, a sinusoidal pattern points to a fetus that is likely, anemic and possibly hypoxic. In addition, this pattern is associated with fetal infection (sepsis, cytomegalovirus), chorioamnionitis, cardiac anomalies, and gastroschisis. (1) Whenever an abnormal admission tracing is observed, the possibility of a previous hypoxic insult or a congenital anomaly should be considered. Regardless of the pathophysiology, this pattern should prompt an immediate assessment of fetal well-being by the physician. An initial assessment

should include maternal and fetal risk factors for anemia and hypoxia such as maternal blood type and Rh status, history of preeclampsia, abruption, infection, and trauma (motor vehicle accidents, falls, domestic violence directed at the abdomen).

In this case, the patient denies any risk factors. Her physical examination is unremarkable, abdomen is soft with no tenderness, and patient reports a pain score of 0/10. No vaginal bleeding is noted. Category III tracings are abnormal, which most often requires prompt delivery. However, the physician in this case decides to proceed to an induction of labor. An intravenous line is started with lactated ringers solution, and the patient is given an initial 1000-mL bolus followed by an oxytocin infusion at 1 MU per minute. A Kleihauer-Betke test is ordered to determine the presence and amount of fetal cells in the maternal blood stream to rule out a fetomaternal hemorrhage. Interventions should include O2 per rebreather mask at 10 L and lateral maternal positioning to improve fetal oxygenation and blood flow. The neonatal team, anesthesia, and surgical staff should also be alerted to the potential for an urgent cesarean delivery should the fetal condition worsen.

Two hours later, the following tracing is obtained (Fig 2).

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Figure 2. EFM Strip #2.

Findings on EFM Strip #2 are: • Variability: Minimal • Baseline rate: Indeterminate because of sinusoidal pattern • Episodic patterns: None • Periodic patterns: None • Uterine contractions: Every 2 to 2.5 minutes, 30 to 40 seconds, mild by palpation • Interpretation: Category III • Differential Diagnoses: Same

• Action: Continue with above interventions. Physician performs another cervical exam and finds the cervix at 5 cm. An amniotomy reveals meconium-stained fluid.

The patient reports her pain at a 2/10 and requests an epidural.

Approximately 2.5 hours later, the patient’s pain level is 0/0, and she has progressed to 8 cm, 90% effaced, and 1 station. Her vital signs are temperature 98.8, blood pressure 130/83, and HR 74. The following tracing is obtained (Fig 3).

Figure 3. EFM Strip #3.

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Figure 3. EFM Strip #3.

Findings on EFM Strip #3 are: • • • • •

Variability: Minimal Baseline rate: 145, slight undulating pattern Episodic patterns: None Periodic patterns: None Uterine contractions: Tachysystole pattern, strong by palpation • Interpretation: Category II • Differential Diagnosis: Same • Action: Sinusoidal patterns are not always symmetrical and continuous but may be intermittent. There are two types of sinusoidal patterns: benign, or sometimes called pseudosinusoidal, and pathological. Benign patterns are

commonly seen after maternal narcotic administration (especially butorphanol and fentanyl), during fetal sleep, or during fetal thumb sucking and generally resolve within a short period of time to a normal pattern with accelerations and normal variability. (1) However, in this case, after more than 3 hours, there are still no accelerations or fetal movement, making this pattern more likely to be pathologic in nature.

The oxytocin is discontinued, and another bolus of 500 mL is given in an effort to space out contractions, thereby improving blood flow and oxygenation to the fetus. The fetal tracing from 2 hours later is shown in Fig 4.

Figure 4. EFM Strip #4. e260 NeoReviews Vol.13 No.4 April 2012

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Figure 4. EFM Strip #4.

Findings on EFM Strip #4 are: • • • • •

Variability: Minimal Baseline Rate: 165 Episodic patterns: None Periodic patterns: Variable, early and late deceleration Uterine contractions: Every 2 to 3 minutes, intensity and tone per palpation • Interpretation: Category II • Differential Diagnosis: Same • Action: Although this pattern appears to have improved somewhat, there are still no accelerations, and the

variability is diminished. Combination deceleration patterns like this are fairly common in this stage of labor, with head and cord compression causing a vagal response. Another cervical examination finds the cervix to be completely dilated and the head at a þ1 station.

The Kleihauer-Betke results document that this fetus has 9% fetal cells in the maternal blood. Because the reference range is <1%, this result verifies that there has been a significant fetomaternal hemorrhage.

The patient was instructed to begin pushing. Two hours later, the following tracing was obtained (Fig 5).

Figure 5. EFM Strip #5.

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Figure 5. EFM Strip #5.

• • • • •

Variability: Minimal Baseline Rate: 165 Episodic patterns: None Periodic patterns: Recurrent variable decelerations Uterine Contractions: Every 2 minutes, palpate for intensity and tone • Interpretation: Category II • Action: Recurrent variable decelerations are very common in the second stage of labor because of cord compression. Fortunately, this patient is close to delivery, and the fetus has tolerated the labor well despite a significant bleed. Staff members need to remain hypervigilant and prepared to expedite the delivery if the fetal condition worsens. The NICU team should be requested to attend the delivery and be informed of history of significant fetomaternal bleed, sinusoidal FHR pattern, and potential need for blood transfusion and volume replacement.

Outcome Thirty minutes later, the patient had a normal spontaneous vaginal delivery of an 8-lb, 4-oz girl with a compound arm presentation. Apgars were 7 and 9 at 1 and 5 minutes, respectively. The placenta was noted to be bilobed with meconium staining and was sent to pathology. Unfortunately, cord gases were unavailable. The NICU team was present for the delivery. The baby was slightly pale, asymptomatic with normal vital signs, no active bleeding, and a normal physical examination. A hematocrit was sent to the laboratory and found to be 21.7.

According to the Kleihauer-Betke test result of 9% fetal cells present in the maternal blood, this represents an approximate blood loss of 300 mL. One might question why this fetus is still alive after such a large amount of blood loss. It is important to note that this test does not reflect the timing or acuity of a bleed. In fact, fetal blood cells disappear gradually (over 5 weeks) from the maternal circulation after a fetomaternal bleed. (2) Therefore, fetal cells that have accumulated in the maternal blood over the course of several weeks, representing a chronic loss, is more likely tolerated better by the fetus than an acute bleed. (2) Evidence from studies performed on sheep fetuses with slow hemorrhages has demonstrated that intravascular volume was restored to normal within 3 hours because of the redistribution of fluid and proteins from the interstitial space, preventing cardiovascular collapse. (2)(3) The fact that this infant not only survived such an insult but also had a good outcome provides evidence that this was most likely a chronic fetomaternal hemorrhage that had resolved.

References 1. Modanlou HD, Murata Y. Sinusoidal heart rate pattern: reappraisal of its definition and clinical significance. J Obstet Gynaecol Res. 2004;30(3):169–180 2. Wylie BJ, D’Alton ME. Fetomaternal hemorrhage. Obstet Gynecol. 2010;115(5):1039–1051 3. Brace RA, Cheung CY. Fetal blood volume restoration following rapid fetal hemorrhage. Am J Physiol. 1990;259(2 Pt 2): H567–H573

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Strip of the Month: April 2012 Maurice L. Druzin and Nancy Peterson Neoreviews 2012;13;e254 DOI: 10.1542/neo.13-4-e254

Updated Information & Services

including high resolution figures, can be found at: http://neoreviews.aappublications.org/content/13/4/e254

References

This article cites 3 articles, 0 of which you can access for free at: http://neoreviews.aappublications.org/content/13/4/e254#BIBL

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