The "Bermuda Triangle" of Neonatal Neurology: Cerebral Palsy, Neonatal Encephalopathy, and Intrapartum Asphyxia
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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 misunderstand-
ing. This should aid future therapeutic and research efforts in this important area.
© 2004 Elsevier Inc. All rights reserved.
T HE TERM “Bermuda triangle” has entered
our lexicon as an eponymous synonym for
mystery or confusion. Nominally denoting a
spectrum of neurodevelopmental disabilities of 5% to
7% of the pediatric population.5
This article provides a systematic review of the
largely open stretch of the Atlantic Ocean with its consensus definitions of these 3 concepts, together
apices on Florida, Bermuda, and Puerto Rico, its with a brief survey of what we know about them.
lore is a seemingly disproportionate share of un- It then systematically explores the relationships
explained disappearances of ships and airplanes. between these concepts.
Careful scrutiny of the actual record has revealed CEREBRAL PALSY
that the triangle is no more dangerous than any
“Cerebral palsy” is a historical term first intro-
other equivalent stretch of open ocean and that a
duced into the medical literature in the latter half of
rational explanation (most commonly weather or
the nineteenth century.6 It is a clinically defined
human error) can explain the misfortunes that have symptom complex that functions as a “term of
occurred there.1 convenience” and provides a shorthand way to
Cerebral palsy (CP), neonatal encephalopathy, communicate about a group of commonly encoun-
and intrapartum asphyxia are all concepts integral tered children with developmental disability.2 Va-
to an understanding of neonatal neurology. How- lidity for the concept is imparted by a commonality
ever, these terms are often used imprecisely, sow- of core features shared by the members of this
ing confusion that can take on the appearance of a group, including impairments, challenges, medical
quagmire. This confusion hampers communication requirements, and rehabilitation needs.7 Persons
among health professionals and may convey erro- with CP display considerable variability in terms
neous impressions regarding clinical evolution and of severity8 and comorbid conditions.9 CP is but
causality. However, like the actual Bermuda trian- one type of childhood neurodevelopmental disabil-
gle of popular mythology, careful scrutiny can help ity encountered in practice.
clarify the relationships among these entities. A consensus definition for CP was not offered
Epidemiologic prevalence data highlight the scope until 1958.10 The most recent consensus definition
of the problem. CP occurs in 1.5 to 2.5/1000 live defines CP as “an umbrella term covering a group
births;2 neonatal encephalopathy, in 1.8 to 7.7/1000 of non-progressive but often changing motor im-
live births;3 and intrapartum asphyxia, in 1.5 to 3.0/ pairment syndromes secondary to lesions or anom-
1000 live births.4 These numbers must be considered alies of the brain arising in the early stages of its
in the context of an overall frequency of the full development.”11 Stated more simplistically, CP is
a static, nonprogressive motor impairment of early
onset that is cerebral in origin. Here, “static and
From the Departments of Neurology/Neurosurgery and Pe- nonprogressive” means that the process responsi-
diatrics, McGill University and Division of Pediatric Neurol- ble for the neurologic deficits cannot be ongoing,
ogy, Montreal Children’s Hospital, Montreal, Quebec, Canada. with the infliction of additional injury or damage
Address reprint requests to Michael Shevell, CM, FRCPC, on the brain as time proceeds.12 This effectively
Montreal Children’s Hospital, Room A-514, 2300 Tupper excludes neoplastic, neurodegenerative, and meta-
Street, Montreal, Quebec, Canada H3H 1P3.
© 2004 Elsevier Inc. All rights reserved. bolic processes from the rubric of CP.13 However,
1071-9091/04/1101-0000$30.00/0 although the pathological lesions are nonprogres-
doi:10.1016/j.spen.2004.01.005 sive, 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 cause has been emphasized23-25 with considerable a maturing nervous system.7 obstetrical and medicolegal implications.26 Recent All individuals with CP have motor impairment advances in imaging technology,27 the molecular characterized by objective, reproducible abnormal- understanding of neuroembryology,28 and identi- ities on systematic examination.14 This includes fying specific deficits in the coagulation cascade29 alterations in tone, posture, response to muscle that exert a prothrombotic effect have worked stretch, and reflexes.15 Clinically, this motor im- jointly to increase etiologic yield. Understanding pairment may manifest as delayed acquisition of the causal spectrum of CP requires the systematic motor skills, clumsiness, and gait/ambulatory dif- assessment of affected individuals together with ficulties. Other neurologic disabilities (eg, epi- the application of these advances to properly ad- lepsy, mental retardation) often co-occur with CP dress the question of why a particular individual is yet are not necessary features for diagnosis or an so affected.19 invariable accompaniment. Recent studies have documented that the causal Universal agreement does not yet exist on the spectrum for CP is a function of the type of CP and “early onset” component of the definition of CP.7 gestational age.19 Detailed investigations reveal a The upper limit for inclusion of postnatal cases of cause in most cases, with consensus that intrapar- acquired CP can vary considerably.16 In addition, tum asphyxia is a cause in only a minority of cases the initial age at which the diagnosis can be enter- (certainly ⬍20%, perhaps even as little as tained is also not uniformly agreed on, given the ⬍10%).19 Consensus has also been reached that potential for transitory early neurologic abnormal- intrapartum asphyxia of sufficient severity to cause ities that resolve on a second evaluation at a later later CP must produce evidence of a significant date.17 Symptomatically, early onset is manifested acute neonatal neurologic dysfunction (ie, neonatal by early hand preference, motor delay, stiffness, or encephalopathy).30 Thus neonatal encephalopathy seizures. is a “way station” through which intrapartum as- Traditionally, a long list of syndromic disorders phyxia passes to yield later CP and is invariably or chromosomal abnormalities have been excluded present if intrapartum asphyxia is causal for this from the concept of CP.13 It is acknowledged that eventual outcome. local idiosyncrasies may influence the precise con- text of this approach. What is agreed on is that NEONATAL ENCEPHALOPATHY neural tube defects and neuromuscular disorders, Like CP, neonatal encephalopathy is also a clin- which may in themselves result in early-onset ically defined symptom complex. Neonatal en- motor impairment syndromes, are excluded from cephalopathy is essentially a constellation of neu- the CP diagnostic label. rologic signs noted within the first 7 days after From the foregoing, it is apparent that CP is birth. It has been defined as a “syndrome of dis- conceptualized as a possible outcome. It is a quite turbed neurologic function in the earliest days of heterogeneous entity with respect to pathogenesis, life in the term infant manifested by difficulty with clinical manifestations, and evolution.18 Although initiating and maintaining respiration, depression there may be a multiplicity of possible causes,19 of tone and reflexes, sub-normal levels of con- from a pathogenetic perspective what is shared is a sciousness and often by seizures.”31 It is mani- congenital aberration or acquired injury to the fested by acute neonatal neurologic dysfunction maturing, not yet fully formed, central nervous that remains the single best early clue that a new- system. The onset of this aberration or injury may born is potentially neurologically compromised be prenatal, perinatal, or postnatal in timing. and potentially at increased risk for later neurode- Etiologically heterogeneous, clinical research in velopmental sequelae.32 CP has traditionally focused on the identification The severity of observed neonatal encephalopa- of prenatal and perinatal risk factors for the later thy varies and can be graded as mild, moderate, or identification of CP.20-22 This has permitted the severe at the bedside according to the classification elucidation of possible pathogenetic mechanisms. scheme of Sarnat and Sarnat first developed in Uncertainty exists regarding the actual causal spec- 1976 (Table 1).32 The grade is based on behavioral trum of CP and the relative contribution of the observations, response to handling, tone changes, various causes.5 Traditionally, the role and contri- the presence and frequency of seizures, and any bution of intrapartum asphyxia as an etiologic evidence of brainstem dysfunction. Although
26 MICHAEL I. SHEVELL
Table 1. Neonatal Encephalopathy enhanced individual resiliency and is a favorable
Mild prognostic indicator.36
● Increased irritability It is recognized that intrapartum asphyxia is but
● Hyperexcitability one cause of neonatal encephalopathy. Indeed,
● Jitteriness
there is strong evidence to suggest that, as for CP,
● Exaggerated Moro and tendon reflexes
● Sympathetic overreactivity it is only an infrequent cause.19,31 However, as
● Transient changes in tone (⬍6 hours) noted earlier, neonatal encephalopathy at a moder-
Moderate ate or severe level is a necessary antecedent to later
● Lethargy CP if intrapartum asphyxia is causally responsible
● Hypotonia
for the CP.
● Diminished reflexes
● With or without associated seizures
INTRAPARTUM ASPHYXIA
Severe
● Profound obtundation/coma The definition of intrapartum asphyxia has two
● Flaccid muscle tone components. Asphyxia is defined as impaired re-
● Brainstem dysfunction
spiratory gas exchange accompanied by the devel-
● Apnea
● Skew deviation, nystagmus, sucking and swallowing opment of acidosis. Biochemically, the hallmarks
abnormalities are hypoxemia, hypercapnea, and, most important,
● Increased intracranial tension metabolic acidosis, characterized by reduced bicar-
● Seizures, frequently refractory bonate and elevated negative base excess. Intrapar-
tum refers to occurrence during the process of
labor and parturition. The importance of intrapar-
largely lacking operationalization and validation,33 tum asphyxia is its potential, if sufficiently sus-
this grading system for neonatal encephalopathy tained and severe, to result in end organ (ie, central
has proven useful as a predictor of later potential of nervous system) injury.42
survival and neurodevelopmental sequelae in both Thus intrapartum asphyxia is conceptualized as
the intermediate and long term.34,35 As a useful a mechanism of acquired injury or pathogenesis. It
predictor, clinicians have relied on neonatal en- is a process that can be incited by various events
cephalopathy as a mechanism of influencing acute that then triggers a cascade of cellular and patho-
treatment intervention in conjunction with other physiologic responses that can then yield various
objective markers, such as electroencephalography possible short-term (eg, neonatal encephalopathy)
and neuroimaging.36 and eventual (eg, CP) outcomes.42 The significance
Neonatal encephalopathy and CP also share an of intrapartum asphyxia lies in the potential for its
etiologically heterogeneous character.31 There are prevention and possible intervention to either
a multiplicity of potential causes. Frequently, the avoid triggering the asphyxial cascade or modify it
term “hypoxic ischemic encephalopathy” is used once it begins, thus reducing the risk of eventual
synonymously with neonatal encephalopathy; neurodevelopmental sequelae.42 These neurode-
however, this is inappropriate in the absence of velopmental sequelae often have significant life-
certainty that intrapartum asphyxia is causal for the long morbidity implications and attendant care
observed neonatal encephalopathy.37,38 Little is costs at individual, familial, and societal levels.43
actually known regarding the precise etiologic Pragmatically, there are substantial medicolegal
spectrum of neonatal encephalopathy; however, implications with respect to the 2 often-linked
recent studies have identified significant antepar- questions of (1) whether the inciting events them-
tum and intrapartum risk factors, including small selves were foreseeable and perhaps preventable,
gestational age, maternal fever or viral illness, and (2) whether the cause and its outcome could
placental abnormalities, and severe preeclamp- have been avoided by timely obstetrical interven-
sia.39,40 The presence of neonatal encephalopathy tion (ie, rapid delivery by one of various meth-
suggests, but does not necessarily imply, a rela- ods).44
tively recent antepartum or intrapartum compro- A particular challenge has been the ability to
mise. Although the severity of neonatal encepha- accurately and reliably diagnose intrapartum as-
lopathy relates directly to the risk of later adverse phyxia. Simply put, at present there is no single
outcome,41 observed improvement in the actual gold standard for either clinical or laboratory di-
grade of neonatal encephalopathy acutely suggests agnosis.31 It is readily apparent that the single“BERMUDA TRIANGLE” OF NEONATAL NEUROLOGY 27
Table 2. American Academy of Pediatrics/American Table 4. American College of Obstetrics and
College of Obstetrics and Gynecology (1992) Gynecology (2002)
● Profound metabolic acidosis (pH ⬍7.0) Asphyxia
●Apgar 3 or lower beyond 5 minutes ● pH ⬍7.0; base deficit ⬎12 mmol/L
● Neonatal encephalopathy ● Moderate to severe neonatal encephalopathy
● Multiorgan system dysfunction ● CP: spastic, quadriparesis, dyskinetic, or mixed
● Exclusion of other etiologies
Intrapartum
● Sentinel event associated with labor
markers that have been identified and evaluated— ● Fetal heart rate changes: bradycardia, loss of
including fetal heart rate changes, meconium pas- variability, decelerations
sage, Apgar scores, pH/base deficit, time to first ● Apgar 3 or lower beyond 5 minutes
breath or need for resuscitation, neonatal enceph- ● Multisystem involvement
● Early imaging changes
alopathy, other organ (ie, non– central nervous sys-
tem) dysfunction, electrophysiologic changes (ie,
electroencephalography, evoked potentials), and
imaging changes (eg, computed tomography, mag-
include neonatal encephalopathy, profound meta-
netic resonance imaging, magnetic resonance spec-
bolic acidosis with precise cutoffs specified (ie,
troscopy, diffusion-weighted imaging)— have rel-
pH, base excess), multiple systemic involvement
atively low sensitivity and specificity for accurate
(typically renal), and depressed Apgar scores at
diagnosis.36,45 Many pathophysiologic processes
and beyond 5 minutes of age.46-48 The 2 more
other than intrapartum asphyxia may result in ab-
recent consensus criteria47,48 have restricted the
normalities in any of these single markers.
diagnosis of intrapartum asphyxia to only certain
To respond to this diagnostic challenge, empha-
types of CP and provided additional supportive
sis has been placed on a constellation of signs (ie,
features of intrapartum timing and objective mark-
the presence of multiple markers) to diagnose in-
ers (ie, electroencephalography and/or imaging) of
trapartum asphyxia. Some of these signs are
asphyxiation. The last consensus criterion48 also
deemed essential; others, supportive. Some are
calls for the careful search for and exclusion of
diagnostic of asphyxia, and others are diagnostic of
other possible etiologies. The extent of this search
timing. Since 1992, 3 different consensus state-
and its mechanism is not specified, however.
ments have addressed the diagnosis of intrapartum
The restriction of intrapartum asphyxia to cer-
asphyxia (Tables 2, 3, and 4).46-48 Experience has
tain types of CP47,48 is problematic in that it is put
also shown that adverse events occurring during
forward without the possibility of absolute verifi-
the intrapartum period do not occur in isolation and
cation. That is, a single case of intrapartum as-
often reflect an antepartum predisposition for a
phyxia resulting in an outcome other than spastic
fetus to respond inappropriately to the physiolog-
quadriparesis, dyskinetic, or mixed CP will render
ical stresses of normal labor and delivery.49
the scheme erroneous. Also it requires an eventual
All 3 consensus statements elaborated thus far
outcome (ie, a specific type of CP),49 which may
share an emphasis on the concurrent observation
not be apparent for several years, as a means of
and documentation of multiple markers to make a
diagnosing what is an acute process. Subsequent to
diagnosis of intrapartum asphyxia. These markers
intrapartum asphyxia, a range of possible outcomes
exists, from normal through the entire spectrum of
Table 3. International Cerebral Palsy Task Force (1999) neurodevelopmental disability (eg, sensorineural
Essential hearing loss, developmental coordination disorder,
● Moderate to severe neonatal encephalopathy attention deficit hyperactivity disorder, learning
● pH ⬍7.0 disability, global developmental delay, mental re-
● CP: spastic, quadraparetic, dyskinetic, or mixed tardation, and CP), largely reflecting the dynamic
Supportive
interplay between the severity of asphyxia and the
● Sentinel event
● Severe fetal heart rate changes resiliency of the individual.50
● Apgar lower than 6 beyond 5 minutes With respect to intrapartum asphyxia, it is ap-
● Multisystem dysfunction parent that the presence of multiple markers is a
● Evidence of acute cerebral involvement necessary precondition for diagnosis in the scheme
(electroencephalography/imaging)
of neonatal encephalopathy. For some infants with28 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 trapartum asphyxia. (Note that 4 and 5 are
may predispose to intrapartum asphyxia occur- equivalent statements.)
rence. The threat of injury initiates a cellular and 6. Most children with later CP will not have
physiological cascade that reflects individual vari- previous intrapartum asphyxia.
ation in resiliency and the capacity to adapt to this 7. Most children with later CP will not have
threat. Eventual outcomes are variable; CP is but previous neonatal encephalopathy.
one type of potential outcome of intrapartum as- 8. All children with CP will have a neurodevel-
phyxia. opmental disability.
9. Some children with a later non-CP neurode-
RELATIONSHIPS velopmental disability will have had previous
From the foregoing, based on our present knowl- intrapartum asphyxia.
edge and understanding, it is possible to elaborate 10. Some children with a later non-CP neurode-
a number of statements regarding the interrelation- velopmental disability will have had previous
ships between CP, neonatal encephalopathy, and neonatal encephalopathy but no intrapartum
intrapartum asphyxia within the context of children asphyxia.
encountered in practice (ie, those with and without 11. Most children with a later non-CP neurodevel-
neurodevelopmental disability). There relation- opmental disability will not have had previous
ships are shown schematically in Figure 1 and are neonatal encephalopathy.
listed below: 12. Some normal children will have had previous
1. Some children with neonatal encephalopathy intrapartum asphyxia.
will have intrapartum asphyxia. 13. Some normal children will have had previous
2. All children with intrapartum asphyxia will neonatal encephalopathy but no intrapartum
have neonatal encephalopathy. asphyxia.
3. Some children with intrapartum asphyxia will The relationships between causes, neonatal pre-
develop later CP. sentation, and outcome are also shown schemati-
4. Some children with neonatal encephalopathy cally in Figure 2. This figure highlights that fetal
and no intrapartum asphyxia will develop later predisposing conditions may or may not exist as an
CP. antecedent of possible intrapartum asphyxia. A
5. Some children with later CP will have had multitude of possible causes other than intrapartum
previous neonatal encephalopathy and no in- 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 out- occurrence of asphyxia and modify eventual out-
comes subsequent to neonatal encephalopathy, comes need to be identified. Identification of such
ranging from normality to CP to a non-CP neuro- predisposing conditions, reliable diagnostic mark-
developmental disability. Causes other than those ers, and mechanisms of resiliency, coupled with
operating through intrapartum asphyxia and/or elaboration of the cellular and physiological cas-
neonatal encephalopathy may also result in CP and cade in response to injury, will provide potential
non-CP neurodevelopmental disability. means for intervention both acutely and in the long
term. Ancillary to this will be improvement in
CONCLUSION maternal/fetal health promotion and health service
Improving the clarity and understanding of key delivery to the affected population, which will both
terminology and concepts, together with their in- reduce the number of those affected and minimize
terrelationships, will help us focus our future ef- the impacts at multiple levels of neurodevelopmen-
forts more sharply. Better means and mechanisms tal disability.
(ie, markers) for reliable, earlier, and more certain
ACKNOWLEDGMENTS
diagnosis are needed. Clarification of interrelation-
ships will depend on the application of these mark- The author thanks Alba Rinaldi for secretarial assistance in
preparing this manuscript and the Montreal Children’s Hospital
ers to the clinical situation and on the performance Foundation for support during the writing of this manuscript.
of longitudinal studies that more sharply define The author is a Chercheur Boursier Clinicien (Clinical Research
possible outcomes. Factors that predispose to the Scholar) of the Fonds de Recherche en Sante du Quebec.
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