THE TERM Bermuda triangle has entered

The Bermuda Triangle of Neonatal Neurology: Cerebral Palsy, Neonatal Encephalopathy, and Intrapartum Asphyxia Michael I. Shevell, MD, CM, FRCPC The terms cerebral palsy, neonatal encephalopathy, and intrapartum asphyxia are frequently used in pediatric neurology. This article presents concise, verifiable definitions for each of these entities based on our current understanding and formulates the nature of the interrelationships between them. The aim is to provide a level of clarity that will enhance diagnostic and pathogenetic precision and minimize conceptual misunderstanding. This should aid future therapeutic and research efforts in this important area. 2004 Elsevier Inc. All rights reserved. THE TERM Bermuda triangle has entered our lexicon as an eponymous synonym for mystery or confusion. Nominally denoting a largely open stretch of the Atlantic Ocean with its apices on Florida, Bermuda, and Puerto Rico, its lore is a seemingly disproportionate share of unexplained disappearances of ships and airplanes. Careful scrutiny of the actual record has revealed that the triangle is no more dangerous than any other equivalent stretch of open ocean and that a rational explanation (most commonly weather or human error) can explain the misfortunes that have occurred there. 1 Cerebral palsy (CP), neonatal encephalopathy, and intrapartum asphyxia are all concepts integral to an understanding of neonatal neurology. However, these terms are often used imprecisely, sowing confusion that can take on the appearance of a quagmire. This confusion hampers communication among health professionals and may convey erroneous impressions regarding clinical evolution and causality. However, like the actual Bermuda triangle of popular mythology, careful scrutiny can help clarify the relationships among these entities. Epidemiologic prevalence data highlight the scope of the problem. CP occurs in 1.5 to 2.5/1000 live births; 2 neonatal encephalopathy, in 1.8 to 7.7/1000 live births; 3 and intrapartum asphyxia, in 1.5 to 3.0/ 1000 live births. 4 These numbers must be considered in the context of an overall frequency of the full From the Departments of Neurology/Neurosurgery and Pediatrics, McGill University and Division of Pediatric Neurology, Montreal Children s Hospital, Montreal, Quebec, Canada. Address reprint requests to Michael Shevell, CM, FRCPC, Montreal Children s Hospital, Room A-514, 2300 Tupper Street, Montreal, Quebec, Canada H3H 1P3. 2004 Elsevier Inc. All rights reserved. 1071-9091/04/1101-0000$30.00/0 doi:10.1016/j.spen.2004.01.005 spectrum of neurodevelopmental disabilities of 5% to 7% of the pediatric population. 5 This article provides a systematic review of the consensus definitions of these 3 concepts, together with a brief survey of what we know about them. It then systematically explores the relationships between these concepts. CEREBRAL PALSY Cerebral palsy is a historical term first introduced into the medical literature in the latter half of the nineteenth century. 6 It is a clinically defined symptom complex that functions as a term of convenience and provides a shorthand way to communicate about a group of commonly encountered children with developmental disability. 2 Validity for the concept is imparted by a commonality of core features shared by the members of this group, including impairments, challenges, medical requirements, and rehabilitation needs. 7 Persons with CP display considerable variability in terms of severity 8 and comorbid conditions. 9 CP is but one type of childhood neurodevelopmental disability encountered in practice. A consensus definition for CP was not offered until 1958. 10 The most recent consensus definition defines CP as an umbrella term covering a group of non-progressive but often changing motor impairment syndromes secondary to lesions or anomalies of the brain arising in the early stages of its development. 11 Stated more simplistically, CP is a static, nonprogressive motor impairment of early onset that is cerebral in origin. Here, static and nonprogressive means that the process responsible for the neurologic deficits cannot be ongoing, with the infliction of additional injury or damage on the brain as time proceeds. 12 This effectively excludes neoplastic, neurodegenerative, and metabolic processes from the rubric of CP. 13 However, although the pathological lesions are nonprogressive, it is well recognized that the apparent clinical 24 Seminars in Pediatric Neurology, Vol 11, No 1 (March), 2004: pp 24-30

BERMUDA TRIANGLE OF NEONATAL NEUROLOGY 25 manifestations may change against the backdrop of a maturing nervous system. 7 All individuals with CP have motor impairment characterized by objective, reproducible abnormalities on systematic examination. 14 This includes alterations in tone, posture, response to muscle stretch, and reflexes. 15 Clinically, this motor impairment may manifest as delayed acquisition of motor skills, clumsiness, and gait/ambulatory difficulties. Other neurologic disabilities (eg, epilepsy, mental retardation) often co-occur with CP yet are not necessary features for diagnosis or an invariable accompaniment. Universal agreement does not yet exist on the early onset component of the definition of CP. 7 The upper limit for inclusion of postnatal cases of acquired CP can vary considerably. 16 In addition, the initial age at which the diagnosis can be entertained is also not uniformly agreed on, given the potential for transitory early neurologic abnormalities that resolve on a second evaluation at a later date. 17 Symptomatically, early onset is manifested by early hand preference, motor delay, stiffness, or seizures. Traditionally, a long list of syndromic disorders or chromosomal abnormalities have been excluded from the concept of CP. 13 It is acknowledged that local idiosyncrasies may influence the precise context of this approach. What is agreed on is that neural tube defects and neuromuscular disorders, which may in themselves result in early-onset motor impairment syndromes, are excluded from the CP diagnostic label. From the foregoing, it is apparent that CP is conceptualized as a possible outcome. It is a quite heterogeneous entity with respect to pathogenesis, clinical manifestations, and evolution. 18 Although there may be a multiplicity of possible causes, 19 from a pathogenetic perspective what is shared is a congenital aberration or acquired injury to the maturing, not yet fully formed, central nervous system. The onset of this aberration or injury may be prenatal, perinatal, or postnatal in timing. Etiologically heterogeneous, clinical research in CP has traditionally focused on the identification of prenatal and perinatal risk factors for the later identification of CP. 20-22 This has permitted the elucidation of possible pathogenetic mechanisms. Uncertainty exists regarding the actual causal spectrum of CP and the relative contribution of the various causes. 5 Traditionally, the role and contribution of intrapartum asphyxia as an etiologic cause has been emphasized 23-25 with considerable obstetrical and medicolegal implications. 26 Recent advances in imaging technology, 27 the molecular understanding of neuroembryology, 28 and identifying specific deficits in the coagulation cascade 29 that exert a prothrombotic effect have worked jointly to increase etiologic yield. Understanding the causal spectrum of CP requires the systematic assessment of affected individuals together with the application of these advances to properly address the question of why a particular individual is so affected. 19 Recent studies have documented that the causal spectrum for CP is a function of the type of CP and gestational age. 19 Detailed investigations reveal a cause in most cases, with consensus that intrapartum asphyxia is a cause in only a minority of cases (certainly 20%, perhaps even as little as 10%). 19 Consensus has also been reached that intrapartum asphyxia of sufficient severity to cause later CP must produce evidence of a significant acute neonatal neurologic dysfunction (ie, neonatal encephalopathy). 30 Thus neonatal encephalopathy is a way station through which intrapartum asphyxia passes to yield later CP and is invariably present if intrapartum asphyxia is causal for this eventual outcome. NEONATAL ENCEPHALOPATHY Like CP, neonatal encephalopathy is also a clinically defined symptom complex. Neonatal encephalopathy is essentially a constellation of neurologic signs noted within the first 7 days after birth. It has been defined as a syndrome of disturbed neurologic function in the earliest days of life in the term infant manifested by difficulty with initiating and maintaining respiration, depression of tone and reflexes, sub-normal levels of consciousness and often by seizures. 31 It is manifested by acute neonatal neurologic dysfunction that remains the single best early clue that a newborn is potentially neurologically compromised and potentially at increased risk for later neurodevelopmental sequelae. 32 The severity of observed neonatal encephalopathy varies and can be graded as mild, moderate, or severe at the bedside according to the classification scheme of Sarnat and Sarnat first developed in 1976 (Table 1). 32 The grade is based on behavioral observations, response to handling, tone changes, the presence and frequency of seizures, and any evidence of brainstem dysfunction. Although

26 MICHAEL I. SHEVELL Table 1. Neonatal Encephalopathy Mild Increased irritability Hyperexcitability Jitteriness Exaggerated Moro and tendon reflexes Sympathetic overreactivity Transient changes in tone ( 6 hours) Moderate Lethargy Hypotonia Diminished reflexes With or without associated seizures Severe Profound obtundation/coma Flaccid muscle tone Brainstem dysfunction Apnea Skew deviation, nystagmus, sucking and swallowing abnormalities Increased intracranial tension Seizures, frequently refractory largely lacking operationalization and validation, 33 this grading system for neonatal encephalopathy has proven useful as a predictor of later potential of survival and neurodevelopmental sequelae in both the intermediate and long term. 34,35 As a useful predictor, clinicians have relied on neonatal encephalopathy as a mechanism of influencing acute treatment intervention in conjunction with other objective markers, such as electroencephalography and neuroimaging. 36 Neonatal encephalopathy and CP also share an etiologically heterogeneous character. 31 There are a multiplicity of potential causes. Frequently, the term hypoxic ischemic encephalopathy is used synonymously with neonatal encephalopathy; however, this is inappropriate in the absence of certainty that intrapartum asphyxia is causal for the observed neonatal encephalopathy. 37,38 Little is actually known regarding the precise etiologic spectrum of neonatal encephalopathy; however, recent studies have identified significant antepartum and intrapartum risk factors, including small gestational age, maternal fever or viral illness, placental abnormalities, and severe preeclampsia. 39,40 The presence of neonatal encephalopathy suggests, but does not necessarily imply, a relatively recent antepartum or intrapartum compromise. Although the severity of neonatal encephalopathy relates directly to the risk of later adverse outcome, 41 observed improvement in the actual grade of neonatal encephalopathy acutely suggests enhanced individual resiliency and is a favorable prognostic indicator. 36 It is recognized that intrapartum asphyxia is but one cause of neonatal encephalopathy. Indeed, there is strong evidence to suggest that, as for CP, it is only an infrequent cause. 19,31 However, as noted earlier, neonatal encephalopathy at a moderate or severe level is a necessary antecedent to later CP if intrapartum asphyxia is causally responsible for the CP. INTRAPARTUM ASPHYXIA The definition of intrapartum asphyxia has two components. Asphyxia is defined as impaired respiratory gas exchange accompanied by the development of acidosis. Biochemically, the hallmarks are hypoxemia, hypercapnea, and, most important, metabolic acidosis, characterized by reduced bicarbonate and elevated negative base excess. Intrapartum refers to occurrence during the process of labor and parturition. The importance of intrapartum asphyxia is its potential, if sufficiently sustained and severe, to result in end organ (ie, central nervous system) injury. 42 Thus intrapartum asphyxia is conceptualized as a mechanism of acquired injury or pathogenesis. It is a process that can be incited by various events that then triggers a cascade of cellular and pathophysiologic responses that can then yield various possible short-term (eg, neonatal encephalopathy) and eventual (eg, CP) outcomes. 42 The significance of intrapartum asphyxia lies in the potential for its prevention and possible intervention to either avoid triggering the asphyxial cascade or modify it once it begins, thus reducing the risk of eventual neurodevelopmental sequelae. 42 These neurodevelopmental sequelae often have significant lifelong morbidity implications and attendant care costs at individual, familial, and societal levels. 43 Pragmatically, there are substantial medicolegal implications with respect to the 2 often-linked questions of (1) whether the inciting events themselves were foreseeable and perhaps preventable, and (2) whether the cause and its outcome could have been avoided by timely obstetrical intervention (ie, rapid delivery by one of various methods). 44 A particular challenge has been the ability to accurately and reliably diagnose intrapartum asphyxia. Simply put, at present there is no single gold standard for either clinical or laboratory diagnosis. 31 It is readily apparent that the single

BERMUDA TRIANGLE OF NEONATAL NEUROLOGY 27 Table 2. American Academy of Pediatrics/American College of Obstetrics and Gynecology (1992) Table 4. American College of Obstetrics and Gynecology (2002) Profound metabolic acidosis (ph 7.0) Apgar 3 or lower beyond 5 minutes Neonatal encephalopathy Multiorgan system dysfunction markers that have been identified and evaluated including fetal heart rate changes, meconium passage, Apgar scores, ph/base deficit, time to first breath or need for resuscitation, neonatal encephalopathy, other organ (ie, non central nervous system) dysfunction, electrophysiologic changes (ie, electroencephalography, evoked potentials), and imaging changes (eg, computed tomography, magnetic resonance imaging, magnetic resonance spectroscopy, diffusion-weighted imaging) have relatively low sensitivity and specificity for accurate diagnosis. 36,45 Many pathophysiologic processes other than intrapartum asphyxia may result in abnormalities in any of these single markers. To respond to this diagnostic challenge, emphasis has been placed on a constellation of signs (ie, the presence of multiple markers) to diagnose intrapartum asphyxia. Some of these signs are deemed essential; others, supportive. Some are diagnostic of asphyxia, and others are diagnostic of timing. Since 1992, 3 different consensus statements have addressed the diagnosis of intrapartum asphyxia (Tables 2, 3, and 4). 46-48 Experience has also shown that adverse events occurring during the intrapartum period do not occur in isolation and often reflect an antepartum predisposition for a fetus to respond inappropriately to the physiological stresses of normal labor and delivery. 49 All 3 consensus statements elaborated thus far share an emphasis on the concurrent observation and documentation of multiple markers to make a diagnosis of intrapartum asphyxia. These markers Table 3. International Cerebral Palsy Task Force (1999) Essential Moderate to severe neonatal encephalopathy ph 7.0 CP: spastic, quadraparetic, dyskinetic, or mixed Supportive Sentinel event Severe fetal heart rate changes Apgar lower than 6 beyond 5 minutes Multisystem dysfunction Evidence of acute cerebral involvement (electroencephalography/imaging) Asphyxia ph 7.0; base deficit 12 mmol/l Moderate to severe neonatal encephalopathy CP: spastic, quadriparesis, dyskinetic, or mixed Exclusion of other etiologies Intrapartum Sentinel event associated with labor Fetal heart rate changes: bradycardia, loss of variability, decelerations Apgar 3 or lower beyond 5 minutes Multisystem involvement Early imaging changes include neonatal encephalopathy, profound metabolic acidosis with precise cutoffs specified (ie, ph, base excess), multiple systemic involvement (typically renal), and depressed Apgar scores at and beyond 5 minutes of age. 46-48 The 2 more recent consensus criteria 47,48 have restricted the diagnosis of intrapartum asphyxia to only certain types of CP and provided additional supportive features of intrapartum timing and objective markers (ie, electroencephalography and/or imaging) of asphyxiation. The last consensus criterion 48 also calls for the careful search for and exclusion of other possible etiologies. The extent of this search and its mechanism is not specified, however. The restriction of intrapartum asphyxia to certain types of CP 47,48 is problematic in that it is put forward without the possibility of absolute verification. That is, a single case of intrapartum asphyxia resulting in an outcome other than spastic quadriparesis, dyskinetic, or mixed CP will render the scheme erroneous. Also it requires an eventual outcome (ie, a specific type of CP), 49 which may not be apparent for several years, as a means of diagnosing what is an acute process. Subsequent to intrapartum asphyxia, a range of possible outcomes exists, from normal through the entire spectrum of neurodevelopmental disability (eg, sensorineural hearing loss, developmental coordination disorder, attention deficit hyperactivity disorder, learning disability, global developmental delay, mental retardation, and CP), largely reflecting the dynamic interplay between the severity of asphyxia and the resiliency of the individual. 50 With respect to intrapartum asphyxia, it is apparent that the presence of multiple markers is a necessary precondition for diagnosis in the scheme of neonatal encephalopathy. For some infants with

28 MICHAEL I. SHEVELL Fig 1. Venn diagram illustrating relationships between neonatal encephalopathy, cerebral palsy, intrapartum asphyxia, non-cerebral palsy neurodevelopmental disability, and normality. intrapartum asphyxia, an antepartum precondition may predispose to intrapartum asphyxia occurrence. The threat of injury initiates a cellular and physiological cascade that reflects individual variation in resiliency and the capacity to adapt to this threat. Eventual outcomes are variable; CP is but one type of potential outcome of intrapartum asphyxia. RELATIONSHIPS From the foregoing, based on our present knowledge and understanding, it is possible to elaborate a number of statements regarding the interrelationships between CP, neonatal encephalopathy, and intrapartum asphyxia within the context of children encountered in practice (ie, those with and without neurodevelopmental disability). There relationships are shown schematically in Figure 1 and are listed below: 1. Some children with neonatal encephalopathy will have intrapartum asphyxia. 2. All children with intrapartum asphyxia will have neonatal encephalopathy. 3. Some children with intrapartum asphyxia will develop later CP. 4. Some children with neonatal encephalopathy and no intrapartum asphyxia will develop later CP. 5. Some children with later CP will have had previous neonatal encephalopathy and no intrapartum asphyxia. (Note that 4 and 5 are equivalent statements.) 6. Most children with later CP will not have previous intrapartum asphyxia. 7. Most children with later CP will not have previous neonatal encephalopathy. 8. All children with CP will have a neurodevelopmental disability. 9. Some children with a later non-cp neurodevelopmental disability will have had previous intrapartum asphyxia. 10. Some children with a later non-cp neurodevelopmental disability will have had previous neonatal encephalopathy but no intrapartum asphyxia. 11. Most children with a later non-cp neurodevelopmental disability will not have had previous neonatal encephalopathy. 12. Some normal children will have had previous intrapartum asphyxia. 13. Some normal children will have had previous neonatal encephalopathy but no intrapartum asphyxia. The relationships between causes, neonatal presentation, and outcome are also shown schematically in Figure 2. This figure highlights that fetal predisposing conditions may or may not exist as an antecedent of possible intrapartum asphyxia. A multitude of possible causes other than intrapartum asphyxia exists to explain neonatal encephalopa-

BERMUDA TRIANGLE OF NEONATAL NEUROLOGY 29 Fig 2. Schematic diagram illustrating relationships between fetal status, intrapartum asphyxia, neonatal encephalopathy, and eventual outcome. thy. There also exists a multitude of possible outcomes subsequent to neonatal encephalopathy, ranging from normality to CP to a non-cp neurodevelopmental disability. Causes other than those operating through intrapartum asphyxia and/or neonatal encephalopathy may also result in CP and non-cp neurodevelopmental disability. CONCLUSION Improving the clarity and understanding of key terminology and concepts, together with their interrelationships, will help us focus our future efforts more sharply. Better means and mechanisms (ie, markers) for reliable, earlier, and more certain diagnosis are needed. Clarification of interrelationships will depend on the application of these markers to the clinical situation and on the performance of longitudinal studies that more sharply define possible outcomes. Factors that predispose to the occurrence of asphyxia and modify eventual outcomes need to be identified. Identification of such predisposing conditions, reliable diagnostic markers, and mechanisms of resiliency, coupled with elaboration of the cellular and physiological cascade in response to injury, will provide potential means for intervention both acutely and in the long term. Ancillary to this will be improvement in maternal/fetal health promotion and health service delivery to the affected population, which will both reduce the number of those affected and minimize the impacts at multiple levels of neurodevelopmental disability. ACKNOWLEDGMENTS The author thanks Alba Rinaldi for secretarial assistance in preparing this manuscript and the Montreal Children s Hospital Foundation for support during the writing of this manuscript. The author is a Chercheur Boursier Clinicien (Clinical Research Scholar) of the Fonds de Recherche en Sante du Quebec. 1. http://www.unmuseum.org/triangle.htm 2. Kuban KCK, Leviton A: Cerebral palsy. N Engl J Med 330:188-195, 1994 3. Badawi N, Keogh JM, Dixon G, et al: Developmental outcomes of newborn encephalopathy in the term infant. Indian J Pediatr 8:527-530, 2001 4. Robertson NJ, Edwards AD: Recent advances in developing neuroprotective strategies for perinatal asphyxia. Curr Opin Pediatr 10:575-580, 1998 REFERENCES 5. Canadian Institute of Child Health: The Health of Canada s Children (ed 3). Ottawa, Ontario, author, 2000 6. Ingram TTS: A historical view of the definition and classification of the cerebral palsies, in Stanley F, Alberman F (eds): The Epidemiology of the Cerebral Palsies. London, Spastics International Medical Publications, 1984, pp 1-11 7. Stanley F, Blair D, Alberman E: What are the cerebral palsies? in Cerebral Palsies: Epidemiology & Causal Pathways. London, MacKeith, 2000, pp 8-13

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