Chapter 591 Encephalopathies 2061

of the traumatic event, affected lower limb, pain out of proportion to inciting event, and changes in the overlying skin and blood
flow to the affected area suggest CPRS. Although sustained dystonia can produce pain or discomfort, CPRS should be considered in those who have a prominent component of pain and
recent history of trauma to the affected limb.
There are disorders unique to childhood that warrant exploration in this section. Benign paroxysmal torticollis of infancy is
characterized by recurrent episodes of cervical dystonia beginning
in the 1st months of life. The torticollis may alternate sides from
1 episode to the next and may also persist during sleep. Associated signs and symptoms include irritability, pallor, vomiting,
vertigo, ataxia, and occasionally limb dystonia. Family history is
often notable for migraine and/or motion sickness in first-degree
relatives. Despite the high frequency of spells, imaging studies are
normal, and the outcome is uniformly benign with resolution by
3 yr of age.
In alternating hemiplegia of childhood (AHC), episodic hemiplegia affecting either side of the body is the hallmark of the
disorder. However, patients are also affected by episodes of dystonia, ranging from minutes to days in duration. On average,
both features of the disorder commence at approximately 6 mo
of age. Episodic abnormal eye movements are observed in a large
proportion of patients (93%) with onset as early as the 1st week
of life. Thought to represent a migraine variant, AHC can similarly be triggered by fluctuations in temperature, certain foods,
or water exposure. Over time, epilepsy and cognitive impairment
emerge, and the involuntary movements change from episodic to
constant. Infantile onset and the paroxysmal nature of symptoms
early in the disease course are key features to this diagnosis.
Finally, although a diagnosis of exclusion, the presence of odd
movements or selective disability may indicate a psychogenic
dystonia in older children. There is considerable overlap in features of organic and psychogenic movement disorders, making
the diagnosis difficult to establish. For instance, both organic and
psychogenic movement disorders have the potential to worsen in
the setting of stress and may dissipate with relaxation or sleep.
History should include review of recent stressors, psychiatric
symptoms, and exposure to others with similar disorders. On
examination, a changing movement disorder, inconsistent motor
or sensory exam, or response to suggestion are supportive of a
possible psychogenic movement disorder. Early recognition of
this disorder may lessen morbidity caused by unnecessary diagnostic and interventional procedures.

TREATMENT
Children with generalized dystonia, including those with involvement of the muscles of swallowing, may respond to the anticholinergic agent trihexyphenidyl (Artane). Titration occurs slowly
over the course of months in an effort to limit untoward side
effects, such as urinary retention, mental confusion, or blurred
vision. Additional drugs that have been effective include levodopa,
and diazepam. Segmental dystonia such as torticollis often
responds well to botulinum toxin injections. Intrathecal baclofen
delivered through implantable constant infusion pump may be
helpful in some patients. Deep brain stimulation (DBS) with leads
implanted in the globus pallidus is most helpful for children with
severe primary generalized dystonia. Recent data suggests,
however, that DBS may also be of benefit in children with secondary dystonias, such as cerebral palsy.
In the case of drug-induced dystonias, removal of the offending agent and treatment with intravenous diphenhydramine typically suffice. For neuroleptic malignant syndrome, dantrolene
may be indicated.
BIBLIOGRAPHY

Please visit the Nelson Textbook of Pediatrics website at www.expertconsult.

com for the complete bibliography.

Chapter 591

Encephalopathies
Michael V. Johnston
Encephalopathy is a generalized disorder of cerebral function that
may be acute or chronic, progressive or static. The etiologies of
the encephalopathies in children include infectious, toxic (carbon
monoxide, drugs, lead), metabolic, genetic and ischemic causes.
Hypoxic-ischemic encephalopathy is discussed in Chapter 93.5.

591.1

Cerebral Palsy

Michael V. Johnston
See Chapters 33 and 91.2.
Cerebral palsy (CP) is a diagnostic term used to describe a
group of permanent disorders of movement and posture causing
activity limitation, that are attributed to nonprogressive disturbances in the in the developing fetal or infant brain. The motor
disorders are often accompanied by disturbances of sensation,
perception, cognition, communication, and behavior as well as
by epilepsy and secondary musculoskeletal problems. CP is
caused by a broad group of developmental, genetic, metabolic,
ischemic, infectious, and other acquired etiologies that produce
a common group of neurologic phenotypes. CP has historically
been considered a static encephalopathy, but some of the neurologic features of CP, such as movement disorders and orthopedic
complications including scoliosis and hip dislocation, can change
or progress over time. Many children and adults with CP function
at a high educational and vocational level, without any sign of
cognitive dysfunction.

EPIDEMIOLOGY AND ETIOLOGY

CP is the most common and costly form of chronic motor disability that begins in childhood, and recent data from the Centers
for Disease Control and Prevention indicate that the incidence is
3.6/1000 with a male/female ratio of 1.4/1. The Collaborative
Perinatal Project (CPP), in which approximately 45,000 children
were regularly monitored from in utero to the age of 7 yr, found
that most children with CP had been born at term with uncomplicated labors and deliveries. In 80% of cases, features were
identified pointing to antenatal factors causing abnormal brain
development. A substantial number of children with CP had
congenital anomalies external to the central nervous system
(CNS). Fewer than 10% of children with CP had evidence of
intrapartum asphyxia. Intrauterine exposure to maternal infection (chorioamnionitis, inflammation of placental membranes,
umbilical cord inflammation, foul-smelling amniotic fluid, maternal sepsis, temperature >38C during labor, urinary tract infection) was associated with a significant increase in the risk of CP
in normal birthweight infants. Elevated levels of inflammatory
cytokines have been reported in heelstick blood collected at birth
from children who later were identified with CP. Genetic factors
may contribute to the inflammatory cytokine response, and a
functional polymorphism in the interleukin-6 gene has recently
been associated with a higher rate of CP in term infants.
The prevalence of CP has increased somewhat due to the
enhanced survival of very premature infants weighing <1,000 g,
who go on to develop CP at a rate of approximately 15/100.
However, the gestational age at birth-adjusted prevalence of CP
among 2 yr old former premature infants born at 20-27 wk of
gestation has decreased over the past decade. The major lesions
that contribute to CP in this group are intracerebral hemorrhage
and periventricular leukomalacia (PVL). Although the incidence
of intracerebral hemorrhage has declined significantly, PVL
remains a major problem. PVL reflects the enhanced vulnerability

2062 Part XXVII The Nervous System

of immature oligodendroglia in premature infants to oxidative

stress caused by ischemia or infectious/inflammatory insults.
White matter abnormalities (loss of volume of periventricular
white matter, extent of cystic changes, ventricular dilatation,
thinning of the corpus callosum) present on MRI at 40 wk of
gestational age among former preterm infants are a predictor of
later CP.
In 2006, the European Cerebral Palsy Study examined prenatal and perinatal factors as well as clinical findings and results of
MRI in a contemporary cohort of more than 400 children with
CP. In agreement with the CPP study, more than half the children
with CP in this study were born at term, and less than 20% had
clinical or brain imaging indicators of possible intrapartum
factors such as asphyxia. The contribution of intrapartum factors
to CP is higher in some underdeveloped regions of the world.
Also in agreement with earlier data, antenatal infection was
strongly associated with CP and 39.5% of mothers of children
with CP reported having an infection during the pregnancy, with
19% having evidence of a urinary tract infection and 11.5%
reporting taking antibiotics. Multiple pregnancy was also associated with a higher incidence of CP and 12% of the cases in the
European CP study resulted from a multiple pregnancy, in contrast to a 1.5% incidence of multiple pregnancy in the study.
Other studies have also documented a relationship between multiple births and CP, with a rate in twins that is 5-8 times greater
than in singleton pregnancies and a rate in triplets that is 20-47
times greater. Death of a twin in utero carries an even greater risk
of CP that is 8 times that of a pregnancy in which both twins
survive and approximately 60 times the risk in a singleton pregnancy. Infertility treatments are also associated with a higher rate
of CP, probably because these treatments are often associated
with multiple pregnancies. Among children from multiple pregnancies, 24% were from pregnancies after infertility treatment
compared with 3.4% of the singleton pregnancies in the study.
CP is more common and more severe in boys compared to girls
and this effect is enhanced at the extremes of body weight. Male
infants with intrauterine growth retardation and a birthweight
less than the 3rd percentile are 16 times more likely to have CP
than males with optimal growth, and infants with weights above
the 97th percentile are 4 times more likely to have CP.

CLINICAL MANIFESTATIONS
CP is generally divided into several major motor syndromes
that differ according to the pattern of neurologic involvement,
neuropathology, and etiology (Table 591-1). The physiologic classification identifies the major motor abnormality, whereas the

topographic taxonomy indicates the involved extremities. CP is

also commonly associated with a spectrum of developmental
disabilities, including mental retardation, epilepsy, and visual,
hearing, speech, cognitive, and behavioral abnormalities. The
motor handicap may be the least of the childs problems.
Infants with spastic hemiplegia have decreased spontaneous
movements on the affected side and show hand preference at a
very early age. The arm is often more involved than the leg and
difficulty in hand manipulation is obvious by 1 yr of age. Walking
is usually delayed until 18-24 mo, and a circumductive gait is
apparent. Examination of the extremities may show growth
arrest, particularly in the hand and thumbnail, especially if the
contralateral parietal lobe is abnormal, because extremity growth
is influenced by this area of the brain. Spasticity refers to the
quality of increased muscle tone which increases with the speed
of passive muscle stretching and is greatest in antigravity muscles.
It is apparent in the affected extremities, particularly at the ankle,
causing an equinovarus deformity of the foot. An affected child
often walks on tiptoe because of the increased tone in the antigravity gastrocnemius muscles, and the affected upper extremity
assumes a flexed posture when the child runs. Ankle clonus and
a Babinski sign may be present, the deep tendon reflexes are
increased, and weakness of the hand and foot dorsiflexors is
evident. About one third of patients with spastic hemiplegia have
a seizure disorder that usually develops in the 1st yr or 2; approximately 25% have cognitive abnormalities including mental retardation. MRI is far more sensitive than CT for most lesions seen
with CP, although a CT scan may be useful for detecting calcifications associated with congenital infections. In the European CP
study, 34% of children with hemiplegia had injury to the white
matter that probably dated to the in utero period and 27% had
a focal lesion that may have resulted from a stroke. Other children with hemiplegic CP had had malformations from multiple
causes including infections (e.g., cytomegalovirus), lissencephaly,
polymicrogyria, schizencephaly, or cortical dysplasia. Focal cerebral infarction (stroke) secondary to intrauterine or perinatal
thromboembolism related to thrombophilic disorders, like the
presence of anticardiolipin antibodies, is an important cause of
hemiplegic CP (Chapter 594). Family histories suggestive of
thrombosis and inherited clotting disorders, such as factor V
Leiden mutation, may be present and evaluation of the mother
may provide information valuable for future pregnancies and
other family members.
Spastic diplegia is bilateral spasticity of the legs that is greater
than in the arms. Spastic diplegia is strongly associated with
damage to the immature white matter during the vulnerable
period of immature oligodendroglia between 20-34 wk of

Table 591-1 CLASSIFICATION OF CEREBRAL PALSY AND MAJOR CAUSES

MOTOR SYNDROME (APPROX % OF CP)

NEUROPATHOLOGY/MRI

Spastic diplegia (35%)

Periventricular leukomalacia
Periventricular cysts or scars in
White matter, enlargement of ventricles, squared of posterior ventricles

Spastic quadriplegia (20%)

Periventricular leukomalacia
Multicystic encephalomalacia
Cortical malformations
Stroke: in utero or neonatal
Focal infarct or cortical, subcortical damage
Cortical malformations

Hemiplegia (25%)

Extrapyramidal (athetoid, dyskinetic) (15%)

Asphyxia: symmetric scars in putamen and thalamus

Kernicterus: scars in globus pallidus, hippocampus
Mitochondrial: scaring globus pallidus, caudate, putamen, brainstem
No lesions: ? dopa-responsive dystonia

MAJOR CAUSES

Prematurity
Ischemia
Infection
Endocrine/metabolic (e.g., thyroid)
Ischemia, infection
Endocrine/metabolic, genetic/developmental
Thrombophilic disorders
Infection
Genetic/developmental
Periventricular hemorrhagic infarction
Asphyxia
Kernicterus
Mitochondrial
Genetic/metabolic

Chapter 591 Encephalopathies 2063

gestation. However, about 15% of cases of spastic diplegia result

from in utero lesions in infants who go on to delivery at term.
The 1st clinical indication of spastic diplegia is often noted when
an affected infant begins to crawl. The child uses the arms in a
normal reciprocal fashion but tends to drag the legs behind more
as a rudder (commando crawl) rather than using the normal fourlimbed crawling movement. If the spasticity is severe, application
of a diaper is difficult because of the excessive adduction of the
hips. If there is paraspinal muscle involvement, the child may be
unable to sit. Examination of the child reveals spasticity in the
legs with brisk reflexes, ankle clonus, and a bilateral Babinski
sign. When the child is suspended by the axillae, a scissoring
posture of the lower extremities is maintained. Walking is significantly delayed, the feet are held in a position of equinovarus, and
the child walks on tiptoe. Severe spastic diplegia is characterized
by disuse atrophy and impaired growth of the lower extremities
and by disproportionate growth with normal development of the
upper torso. The prognosis for normal intellectual development
for these patients is good, and the likelihood of seizures is
minimal. Such children often have learning disabilities and deficits in other abilities, such as vision, due to disruption of multiple
white matter pathways that carry sensory as well as motor
information.
The most common neuropathologic finding in children with
spastic diplegia is PVL, which is visualized on MRI in more than
70% of cases. MRI typically shows scarring and shrinkage in the
periventricular white matter with compensatory enlargement of
the cerebral ventricles. However, neuropathology has also demonstrated a reduction in oligodendroglia in more widespread
subcortical regions beyond the periventricular zones, and these
subcortical lesions may contribute to the learning problems these
patients can have. MRI with diffusion tensor imaging (DTI) is
being used to map white matter tracks more precisely in patients
with spastic diplegia, and this technique has shown that thalamocortical sensory pathways are often injured as severely as
motor corticospinal pathways (Fig 591-1). These observations
have led to greater interest in the importance of sensory deficits
Lateral

in these patients, which may be important for designing rehabilitative techniques.

Spastic quadriplegia is the most severe form of CP because of
marked motor impairment of all extremities and the high association with mental retardation and seizures. Swallowing difficulties
are common as a result of supranuclear bulbar palsies, often
leading to aspiration pneumonia. The most common lesions seen
on pathologic examination or on MRI scanning are severe PVL
and multicystic cortical encephalomalacia. Neurologic examination shows increased tone and spasticity in all extremities,
decreased spontaneous movements, brisk reflexes, and plantar
extensor responses. Flexion contractures of the knees and elbows
are often present by late childhood. Associated developmental
disabilities, including speech and visual abnormalities, are particularly prevalent in this group of children. Children with spastic
quadriparesis often have evidence of athetosis and may be classified as having mixed CP.
Athetoid CP, also called choreoathetoid, extrapyramidal, or
dyskinetic CP, is less common than spastic cerebral palsy and
makes up about 15-20% of patients with CP. Affected infants are
characteristically hypotonic with poor head control and marked
head lag and develop variably increased tone with rigidity and
dystonia over several years. The term dystonia refers to the
abnormality in tone in which muscles are rigid throughout their
range of motion and involuntary contractions can occur in both
flexors and extensors leading to limb positioning in fixed postures. Unlike spastic diplegia, the upper extremities are generally
more affected than the lower extremities in extrapyramidal CP.
Feeding may be difficult, and tongue thrust and drooling may be
prominent. Speech is typically affected because the oropharyngeal
muscles are involved. Speech may be absent or sentences are
slurred, and voice modulation is impaired. Generally, upper
motor neuron signs are not present, seizures are uncommon, and
intellect is preserved in many patients. This form of CP is also
referred to in Europe as dyskinetic CP and is the type most likely
to be associated with birth asphyxia. In the European CP study,
76% of patients with this form of CP had lesions in the basal

Posterior thalamic
radiation

Fibers penetrating
the posterior limb
of internal capsule

ganglia and thalamus. Extrapyramidal CP secondary to acute

intrapartum near-total asphyxia is associated with bilaterally
symmetric lesions in the posterior putamen and ventrolateral
thalamus. These lesions appear to be the correlate of the neuropathologic lesion called status marmoratus in the basal ganglia.
Athetoid CP can also be caused by kernicterus secondary to high
levels of bilirubin, and in this case the MRI scan shows lesions
in the globus pallidus bilaterally. Extrapyramidal CP can also be
associated with lesions in the basal ganglia and thalamus caused
by metabolic genetic disorders such as mitochondrial disorders
and glutaric aciduria. MRI scanning and possibly metabolic
testing are important in the evaluation of children with extrapyramidal CP to make a correct etiologic diagnosis. In patients
with dystonia who have a normal MRI, it is important to have
a high level of suspicion for dihydroxyphenylalanine (DOPA)responsive dystonia (Segawa disease), which causes prominent
dystonia that can resemble CP. These patients typically have
diurnal variation in their signs with worsening dystonia in the
legs during the day; however this may not be prominent. These
patients can be tested for a response to small doses of l-dopa
and/or cerebrospinal fluid can be sent for neurotransmitter
analysis.

DIAGNOSIS
A thorough history and physical examination should preclude a
progressive disorder of the CNS, including degenerative diseases,
metabolic disorders, spinal cord tumor, or muscular dystrophy.
The possibility of anomalies at the base of the skull or other
disorders affecting the cervical spinal cord needs to be considered in patients with little involvement of the arms or cranial
nerves. An MRI scan of the brain is indicated to determine the
location and extent of structural lesions or associated congenital
malformations; an MRI scan of the spinal cord is indicated if
there is any question about spinal cord pathology. Additional
studies may include tests of hearing and visual function. Genetic
evaluation should be considered in patients with congenital malformations (chromosomes) or evidence of metabolic disorders
(e.g., amino acids, organic acids, MR spectroscopy). In addition
to the genetic disorders mentioned earlier that can present as CP,
the urea cycle disorder arginase deficiency is a rare cause of
spastic diplegia and a deficiency of sulfite oxidase or molybdenum cofactor can present as CP caused by perinatal asphyxia.
Tests to detect inherited thrombophilic disorders may be indicated in patients in which an in utero or neonatal stroke is suspected as the cause of CP.
Because CP is usually associated with a wide spectrum of
developmental disorders, a multidisciplinary approach is most
helpful in the assessment and treatment of such children.

TREATMENT

AP

Figure 591-1 Diffusion tensor image of white

Left
superior
oblique

2064 Part XXVII The Nervous System

matter pathways in the brains of 2 patients with

spastic diplegia on the right compared to a normal
child on the far left. Yellow fibers are corticospinal
pathways projected from the motor cerebral cortex
at the top downward into the brainstem, while the
red fibers are thalamocortical sensory fibers
projected from the thalamus upward to the cortex.
In the children with spastic diplegia, both the
corticospinal and thalamocortical pathways are
reduced in size, but the ascending thalamocortical
pathways are more affected. (From Nagae LM,
Hoon AH Jr, Stashinko E, et al: Diffusion tensor
imaging in children with periventricular
leukomalacia: variability of injuries to white
matter tracts, AJNR Am J Neuroradiol
28:12131222, 2007.)

Ultimately, the treatment of CP must be prevention before it

occurs. The variable and often cryptic etiology of CP is

problematic in this regard. However, a recent study indicates that

prenatal treatment of the mothers with magnesium lowers the
prevalence of CP in their children at a corrected age of 2 yr.
A team of physicians from various specialties, as well as occupational and physical therapists, speech pathologists, social
workers, educators, and developmental psychologists provide
important contributions to the treatment of those children who
develop CP. Parents should be taught how to work with their
child in daily activities such as feeding, carrying, dressing, bathing,
and playing in ways that limit the effects of abnormal muscle
tone. They also need to be instructed in the supervision of a series
of exercises designed to prevent the development of contractures,
especially a tight Achilles tendon. Physical and occupational
therapies are useful for promoting mobility and the use of the
upper extremities for activities of daily living. Speech language
pathologists promote acquisition of a functional means of communications. These therapists help children to achieve their
potential, and often recommend further evaluations and adaptive
equipment.
Children with spastic diplegia are treated initially with the
assistance of adaptive equipment, such as walkers, poles, and
standing frames. If a patient has marked spasticity of the lower
extremities or evidence of hip dislocation, consideration should
be given to performing surgical soft tissue procedures that reduce
muscle spasm around the hip girdle, including an adductor tenotomy or psoas transfer and release. A rhizotomy procedure in
which the roots of the spinal nerves are divided produces considerable improvement in selected patients with severe spastic diplegia (Fig. 591-2). A tight heel cord in a child with spastic hemiplegia
may be treated surgically by tenotomy of the Achilles tendon.
Quadriplegia is managed with motorized wheelchairs, special
feeding devices, modified typewriters, and customized seating
arrangements. The function of the affected extremities in children
with hemiplegic CP can often be improved by therapy in which
movement of the good side is constrained with casts while the
impaired extremities perform exercises which induce improved
hand and arm functioning. This constraint-induced movement
therapy is effective in patients of all ages.
Several drugs have been used to treat spasticity, including the
benzodiazepines and baclofen. These medications have beneficial
effects in some patients, but can also cause side effects such as
sedation for benzodiazepines and lowered seizure threshold for
baclofen. Several drugs can be used to treat spasticity, including
oral diazepam (0.5-7.5 mg/dose, BID or QID), baclofen (0.2-2 mg/
kg/day, BID or TID) or dantrolene (0.5-10/kg/day, BID). Small
doses of levodopa (0.5-2 mg/kg/day) can be used to treat dystonia
or DOPA-responsive dystonia. Artane (trihexyphenidyl, 0.25 mg/
day, BID or TID and titrated upward) is sometimes useful for
treating dystonia and can increase use of the upper extremities
and vocalizations. Reserpine (0.01 g/kg/day, BID) or tetrabenzine (12.5-25 mg, BID or TID) can be useful for hyperkinetic
movement disorders including athetosis or chorea.
Intrathecal baclofen delivered with an implanted pump has
been used successfully in many children with severe spasticity,

Figure 591-2 Schematic representation of the

technique of selected dorsal rhizotomy. A, After
laminectomy, the dura is opened and the dorsal
spinal rootlets are exposed. The rootlets are
stimulated so that abnormal rootlet activity can
be identified. B, A proportion of rootlets are
transected. (From Koman LA, Smith BP, Shilt JS:
Cerebral palsy, Lancet 363:16191631, 2004.
Reproduced with permission from Wake Forest
University Orthopaedic Press.)

Chapter 591 Encephalopathies 2065

and can be useful because it delivers the drug directly around

the spinal cord where it reduces neurotransmission of afferent
nerve fibers. Direct delivery to the spinal cord overcomes the
problem of CNS side effects caused by the large oral doses
needed to penetrate the blood brain barrier. This therapy requires
a team approach and constant follow-up for complications of
the infusion pumping mechanism and infection. Botulinum toxin
injected into specific muscle groups for the management of spasticity shows a very positive response in many patients. Botulism
toxin injected into salivary glands may also help reduce the
severity of drooling, which is seen in 10-30% of patients with
CP and has been traditionally treated with anticholinergic agents.
Patients with rigidity, dystonia, and spastic quadriparesis sometimes respond to levodopa, and children with dystonia may
benefit from carbamazepine or trihexyphenidyl. Hyperbaric
oxygen has not been shown to improve the condition of children
with CP.
Communication skills may be enhanced by the use of Bliss
symbols, talking typewriters, electronic speech generating
devices, and specially adapted computers including artificial
intelligence computers to augment motor and language function.
Significant behavior problems may substantially interfere with
the development of a child with CP; their early identification
and management are important, and the assistance of a psychologist or psychiatrist may be necessary. Learning and attention deficit disorders and mental retardation are assessed and
managed by a psychologist and educator. Strabismus, nystagmus, and optic atrophy are common in children with CP; an
ophthalmologist should be included in the initial assessment.
Lower urinary tract dysfunction should receive prompt assessment and treatment.

BIBLIOGRAPHY

Please visit the Nelson Textbook of Pediatrics website at www.expertconsult.

com for the complete bibliography.

591.2

Mitochondrial Encephalomyopathies

Michael V. Johnston
See Chapters 81.4 and 603.4.
Mitochondrial encephalomyopathies are a heterogeneous group
of clinical syndromes caused by genetic lesions that impair energy
production through oxidative phosphorylation. The signs and
symptoms of these disorders reflect the vulnerability of the nervous
system, muscles and other organs to energy deficiency. Signs of
brain and muscle dysfunction (seizures, weakness, ptosis, external
ophthalmoplegia, psychomotor regression, hearing loss, movement
disorders, and ataxia) in association with lactic acidosis are prominent features of mitochondrial disorders. Cardiomyopathy and
diabetes mellitus can also result from mitochondrial disorders.
Children with mitochondrial disorders often have multifocal
signs that are intermittent or relapsing-remitting, often in association with intercurrent illness. Many of these disorders were
described as clinical syndromes before their genetics were understood. Children with mitochondrial encephalomyopathy with
lactic acidosis and strokelike episodes (MELAS) present with
developmental delay, weakness and headaches as well as focal
signs that suggest a stroke. Brain imaging indicates that injury
does not fit within the usual vascular territories. Children with
myoclonic epilepsy with ragged red fibers (MERRF) present with
myoclonus and myoclonic seizures as well as intermittent muscle
weakness. The ragged red fibers referred to in the name of this
disorder are clumps of abnormal mitochondria seen within
muscle fibers in sections from a muscle biopsy stained with
Gomori trichrome stain. NARP syndrome (neuropathy, ataxia
and retinitis pigmentosa), Kearn-Sayre syndrome (KSS) (ptosis,
ophthalmoplegia, heart block, Leigh disease (subacute necrotizing encephalomyelopathy), and Leber hereditary optic neuropathy (LHON) have also been defined as relatively homogeneous
clinical subgroups (Table 591-2). It is important to keep in mind
that mitochondrial disorders can be difficult to diagnose. They

Table 591-2 CLINICAL MANIFESTATIONS OF MITOCHONDRIAL ENCEPHALOMYOPATHIES

TISSUE

CNS

Nerve
Muscle

Eye

Heart
Blood
Endocrine
Kidney

SYMPTOMS/SIGNS

Regression
Seizures
Ataxia
Cortical blindness
Deafness
Migraine
Hemiparesis
Myoclonus
Movement disorder
Peripheral neuropathy
Ophthalmoplegia
Weakness
RRF on muscle biopsy
Ptosis
Pigmentary retinopathy
Optic atrophy
Cataracts
Conduction block
Cardiomyopathy
Anemia
Lactic acidosis
Diabetes mellitus
Short stature
Fanconi syndrome

MELAS

MERRF

+
+
+
+
+
+
+
+
+
+

+
+
+

NARP

+
+

+
+

KSS

LEIGH

LHON

+
+

+
+
+
+
+
+
+

+
+

+
+

+
+
+
+

+
+

+
+
+
+

KSS, Kearn-Sayre syndrome; LHON, Leber hereditary optic neuropathy; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes; MERRF, myoclonic epilepsy with
ragged red fibers; NARP, neuropathy, ataxia and retinitis pigmentosa; RRF, ragged red fibers.

2066 Part XXVII The Nervous System

often present with novel combinations of signs and symptoms

due to high mutation rates for mitochondrial DNA (mtDNA),
and the severity of disease varies from person to person.
Mitochondrial diseases can be caused by mutations of nuclear
DNA (nDNA) or mtDNA (Chapters 75, 80, and 81). Oxidative
phosphorylation in the respiratory chain is mediated by 5 intramitochondrial enzyme complexes (complexes I-V) and 2 mobile
electron carriers (coenzyme Q and cytochrome c) that are responsible for producing the adenosine triphosphate (ATP) required for
normal cellular function. The maintenance of oxidative phosphorylation requires coordinated regulation of nuclear DNA and
mitochondrial DNA genes. Human mtDNA is a small (16.6 kb),
circular, double-stranded molecule that has been completely
sequenced and encodes 13 structural proteins, all of which are
subunits of the respiratory chain complexes, as well as 2 ribosomal
RNAs and 22 tRNAs needed for translation. The nuclear DNA is
responsible for synthesizing approximately 70 subunits, transporting them to the mitochondria via chaperone proteins, ensuring
their passage across the inner mitochondrial membrane, and coordinating their correct processing and assembly. Diseases of mitochondrial oxidative phosphorylation can be divided into 3 groups:
(1) defects of mtDNA, (2) defects of nDNA, and (3) defects of
communication between the nuclear and mitochondrial genome.
mtDNA is distinct from nDNA for the following reasons: (1)
its genetic code differs from nDNA, (2) it is tightly packed with
information because it contains no introns, (3) it is subject to
spontaneous mutations at a higher rate than nDNA, (4) it has less
efficient repair mechanisms, and (5) it is present in hundreds or
thousands of copies per cell and is transmitted by maternal inheritance. mtDNA is contributed only by the oocyte in the formation
of the zygote. If a mutation in mtDNA occurs in the ovum or
zygote, it may be passed on randomly to subsequent generations
of cells. Some receive few or no mutant genomes (normal or wildtype homoplasmy), while others receive a mixed population of
mutant and wild-type mtDNAs (heteroplasmy), and still others
receive primarily or exclusively mutant genomes (mutant homoplasmy). The important implications of maternal inheritance and
heteroplasmy are as follows: (1) inheritance of the disease is
maternal, but both sexes are equally affected; (2) phenotypic
expression of an mtDNA mutation depends on the relative proportions of mutant and wild-type genomes, with a minimum critical number of mutant genomes being necessary for expression
(threshold effect); (3) at cell division, the proportional distribution
may shift between daughter cells (mitotic segregation), leading to
a corresponding phenotypic change; and (4) subsequent generations are affected at a higher rate than in autosomal dominant
diseases. The critical number of mutant mtDNAs required for the
threshold effect may vary, depending on the vulnerability of the
tissue to impairments of oxidative metabolism as well as on the
vulnerability of the same tissue over time that may increase with
aging. In contrast to maternally inherited disorders due to mutations in mtDNA, diseases resulting from defects in nDNA follow
mendelian inheritance. Mitochondrial diseases caused by defects
in nDNA include defects in substrate transport (plasmalemmal
carnitine transporter, carnitine palmitoyltransferase I and II, carnitine acylcarnitine translocase defects), defects in substrate oxidation (pyruvate dehydrogenase complex, pyruvate carboxylase,
intramitochondrial fatty acid oxidation defects), defects in the
Krebs cycle (-ketoglutarate dehydrogenase, fumarase, aconitase
defects), and defects in the respiratory chain (complexes I-V)
including defects of oxidation/phosphorylation coupling (Luft
syndrome) and defects in mitochondrial protein transport.
Diseases caused by defects in mtDNA can be divided into
those associated with point mutations that are maternally inherited (e.g., LHON, MELAS, MERRF, and NARP syndromes) and
those due to deletions or duplications of mtDNA that reflect
altered communication between the nucleus and the mitochondria (KSS; Pearson syndrome, a rare severe encephalopathy with
anemia and pancreatic dysfunction; and progressive external

ophthalmoplegia [PEO]). These disorders can be inherited by

sporadic, autosomal dominant, or recessive mechanisms and
mutations in multiple genes, including mitochondrial mtDNA
polymerase catalytic subunit (POLG) have been identified.
POLG mutations have also been identified in patients with
Alpers-Huttenlocher syndrome which causes a refractory seizure
disorder and hepatic failure. Other genes that regulate the supply
of nucleotides for mtDNA synthesis have been associated with
severe encephalopathy and liver disease, and new disorders are
being identified that result from defects in the interactions
between mitochondria and their milieu in the cell.

MITOCHONDRIAL MYOPATHY, ENCEPHALOPATHY, LACTIC

ACIDOSIS, AND STROKELIKE EPISODES (MELAS)
Children with MELAS may be normal for the 1st several years,
but they gradually display delayed motor and cognitive development and short stature. The clinical syndrome is characterized by
(1) recurrent strokelike episodes of hemiparesis or other focal
neurologic signs with lesions most commonly seen in the posterior
temporal, parietal, and occipital lobes (CT or MRI evidence of
focal brain abnormalities); (2) lactic acidosis, ragged red fibers
(RRF), or both; and (3) at least 2 of the following: focal or generalized seizures, dementia, recurrent migraine headaches, and vomiting. In 1 series, onset was before age 15 yr in 62% of patients, and
hemianopia or cortical blindness was the most common manifestation. Cerebrospinal fluid protein is often increased. The MELAS
3243 mutation on mtDNA can also be associated with different
combinations of exercise intolerance, myopathy, ophthalmoplegia, pigmentary retinopathy, hypertrophic or dilated cardiomyopathy, cardiac conduction defects, deafness, endocrinopathy
(diabetes mellitus), and proximal renal tubular dysfunction. Two
patients have also been described with bilateral rolandic lesions
and epilepsia partialis continua associated with mitochondrial
DNA mutations at 10158T>C and 10191T>C. MELAS is a progressive disorder that has been reported in siblings. It is punctuated with episodes of stroke leading to dementia (Chapter 603.4).
Regional cerebral hypoperfusion can be detected by singlephoton emission CT (SPECT) studies and MR spectroscopy can
detect focal areas of lactic acidosis in the brain. Neuropathology
may show cortical atrophy with infarct-like lesions in both cortical and subcortical structures, basal ganglia calcifications, and
ventricular dilatation. Muscle biopsy specimens usually show
RRF. Mitochondrial accumulations and abnormalities have been
shown in smooth muscle cells of intramuscular vessels and of
brain arterioles and in the epithelial cells and blood vessels of the
choroid plexus, producing a mitochondrial angiopathy. Muscle
biochemistry shows complex I deficiency in many cases; however,
multiple defects have also been documented involving complexes
I, III, and IV. Targeted molecular testing for specific mutations or
sequence analysis and mutation scanning are generally used to
make a diagnosis of MELAS when clinical evaluation suggests
the diagnosis. Because the number of mutant genomes is lower
in blood than in muscle, muscle is the preferable tissue for examination. Inheritance is maternal, and there is a highly specific,
although not exclusive, point mutation at nt 3243 in the
tRNALeu(UUR) gene of mtDNA in 80% of patients. An additional
7.5% have a point mutation at nt 3271 in the tRNALeu(UUR) gene.
A 3rd mutation has been identified at nt 3252 in the tRNALeu(UUR)
gene. The prognosis in patients with the full syndrome is poor.
Therapeutic trials reporting some benefit have included corticosteroids, coenzyme Q10, nicotinamide, riboflavin, and L-arginine
and preclinical studies reported some success with resveratrol.

REVERSIBLE INFANTILE CYTOCHROME C OXIDASE

DEFICIENCY MYOPATHY
A reversible form of severe neuromuscular weakness and hypotonia in infants was recently characterized and found to be due

Chapter 591 Encephalopathies 2067

to a maternally inherited homoplasmic m.14674T>C mt-tRNAGlu

mutation associated with a deficiency of cytochrome c oxidase
(COX) in 17 patients from 12 families. Affected children presented within the 1st few weeks of life with hypotonia, severe
muscle weakness and very elevated serum lactate levels, and they
often required mechanical ventilation. However, feeding and psychomotor development were not affected. Muscle biopsies taken
from these children in the neonatal period show ragged red fibers
and deficient COX activity, but these findings disappeared within
5-20 mo when the infants recovered spontaneously. It was difficult to distinguish these infants from those with lethal mitochondrial disorders without waiting for them to improve. The
mechanism for this recovery has not been established, but it may
reflect a developmental switch in mitochondrial RNAs later in
infancy. This reversible disorder has been observed only in COX
deficiency associated with the 14674T>C mt-tRNAGlu mutation,
so it has been suggested that infants with this type of severe
weakness in the neonatal period be tested for this mutation to
help with prognosis.

MYOCLONUS EPILEPSY AND RAGGED RED FIBERS (MERRF)

This syndrome is characterized by progressive myoclonic epilepsy, mitochondrial myopathy, and cerebellar ataxia with dysarthria and nystagmus. Onset may be in childhood or in adult life,
and the course may be slowly progressive or rapidly downhill.
Other features include dementia, sensorineural hearing loss, optic
atrophy, peripheral neuropathy, and spasticity. Because some
patients have abnormalities of deep sensation and pes cavus, the
condition may be confused with Friedreich ataxia. A significant
number of patients have a positive family history and short
stature. This condition is maternally inherited.
Pathologic findings include elevated serum lactate concentrations, RRF on muscle biopsy, and marked neuronal loss and
gliosis affecting, in particular, the dentate nucleus and inferior
olivary complex with some dropout of Purkinje cells and neurons
of the red nucleus. Pallor of the posterior columns of the spinal
cord and degeneration of the gracile and cuneate nuclei occur.
Muscle biochemistry has shown variable defects of complex III,
complexes II and IV, complexes I and IV, or complex IV alone.
More than 80% of cases are caused by a heteroplasmic G to A
point mutation at nt 8344 of the tRNALys gene of mtDNA. Additional patients have been reported with a T to C mutation at nt
8356 in the tRNALys gene. Targeted mutation analysis or mutation analysis after sequencing of the mitochondrial genome are
used to diagnosis MERRF.
There is no specific therapy, although coenzyme Q10 appeared
to be beneficial in a mother and daughter with the MERRF mutation. The anticonvulsant levetiracetam has been reported to help
reduce myoclonus and myoclonic seizures in this disorder.

LEIGH DISEASE (SUBACUTE NECROTIZING

ENCEPHALOMYOPATHY)
There are several known genetically determined causes of Leigh
disease: pyruvate dehydrogenase complex deficiency, complex I or
II deficiency, complex IV (COX) deficiency, complex V (ATPase)
deficiency, and deficiency of coenzyme Q10. These defects may
occur sporadically or be inherited by autosomal recessive transmission, as in the case of COX deficiency; by X-linked transmission, as in the case of pyruvate dehydrogenase E1 deficiency; or
by maternal transmission, as in complex V (ATPase 6 nt 8993
mutation) deficiency. About 30% of cases are due to mutations
in mtDNA. Leigh disease is a progressive degenerative disorder,
and most cases become apparent during infancy with feeding and
swallowing problems, vomiting, and failure to thrive. Delayed
motor and language milestones may be evident, and generalized
seizures, weakness, hypotonia, ataxia, tremor, pyramidal signs,
and nystagmus are prominent findings. Intermittent respirations

with associated sighing or sobbing are characteristic and suggest

brainstem dysfunction. Some patients have external ophthalmoplegia, ptosis, retinitis pigmentosa, optic atrophy, and decreased
visual acuity. Abnormal results on CT or MRI scan consist of
bilaterally symmetric areas of low attenuation in the basal ganglia
and brainstem as well as elevated lactic acid on MR spectroscopy.
Pathologic changes consist of focal symmetric areas of necrosis in
the thalamus, basal ganglia, tegmental gray matter, periventricular
and periaqueductal regions of the brainstem, and posterior
columns of the spinal cord. Microscopically, these spongiform
lesions show cystic cavitation with neuronal loss, demyelination,
and vascular proliferation. Elevations in serum lactate levels are
characteristic and hypertrophic cardiomyopathy, hepatic failure
and rental tubular dysfunction can occur. The overall outlook is
poor, but a few patients experience prolonged periods of remission. There is no definitive treatment for the underlying disorder,
but a range of vitamins including riboflavin, thiamine, and coenzyme Q are often given to try to improve mitochondrial function.
Biotin, creatine, succinate, and idebenone as well as a high-fat diet
have also been used, but phenobarbital and valproic acid should
be avoided due to their inhibitory effect on the mitochondrial
respiratory chain.

NARP SYNDROME
This maternally inherited disorder presents with either Leigh
syndrome or with neurogenic weakness and neuropathy, ataxia,
and retinitis pigmentosa (NARP syndrome) as well as seizures. It
is due to a point mutation at nt 8993 within the ATPase subunit
6 gene. The severity of the disease presentation appears to have
close correlation with the percentage of mutant mtDNA in leukocytes. There is no treatment.

LEBER HEREDITARY OPTIC NEUROPATHY (LHON)

LHON is characterized by onset usually between the ages of 18
and 30 yr of acute or subacute visual loss caused by severe bilateral optic atrophy, although children as young as 5 yr have been
reported to have LHON. At least 85% of patients are young
men. An X-linked factor may modulate the expression of the
mitochondrial DNA point mutation. The classic ophthalmologic
features include circumpapillary telangiectatic microangiopathy
and pseudoedema of the optic disc. Variable features may include
cerebellar ataxia, hyperreflexia, Babinski sign, psychiatric symptoms, peripheral neuropathy, or cardiac conduction abnormalities (pre-excitation syndrome). Some cases have been associated
with widespread white matter lesions as seen with multiple sclerosis. Lactic acidosis and RRF tend to be conspicuously absent
in LHON. More than 11 mtDNA point mutations have been
described, including a usually homoplasmic G to A transition at
nt 11,778 of the ND4 subunit gene of complex I. The latter leads
to replacement of a highly conserved arginine residue by histidine
at the 340th amino acid and accounts for 50-70% of cases in
Europe and >90% of cases in Japan. Certain LHON pedigrees
with other point mutations are associated with complex neurologic disorders and may have features in common with MELAS
syndrome and with infantile bilateral striatal necrosis. One
family has been reported with pediatric onset of progressive
generalized dystonia with bilateral striatal necrosis associated
with a homoplasmic G14459A mutation in the mtDNA ND6
gene, which has also been associated with LHON alone and
LHON with dystonia.

KEARNS-SAYRE SYNDROME (KSS)

The criteria for KSS include a triad of (1) onset before age 20 yr,
(2) progressive external ophthalmoplegia (PEO) with ptosis, and
(3) pigmentary retinopathy. There must also be at least 1 of the
following: heart block, cerebellar syndrome, or cerebrospinal

2068 Part XXVII The Nervous System

fluid protein >100 mg/dL. Other nonspecific but common features include dementia, sensorineural hearing loss, and multiple
endocrine abnormalities, including short stature, diabetes mellitus, and hypoparathyroidism. The prognosis is guarded, despite
placement of a pacemaker, and progressively downhill, with
death resulting by the 3rd or 4th decade. Unusual clinical presentations can include renal tubular acidosis and Lowe syndrome.
There are also a few overlap cases of children with KSS and
strokelike episodes. Muscle biopsy shows RRF and variable
COX-negative fibers. Most patients have mtDNA deletions, and
some have duplications. These may be new mutations accounting
for the generally sporadic nature of KSS. A few pedigrees have
shown autosomal dominant transmission. Patients should be
monitored closely for endocrine abnormalities, which can be
treated. Coenzyme Q has been reported anecdotally to have some
beneficial effect and positive effects of folinic acid for low folate
levels has been reported. A report of positive effects of a cochlear
implant for deafness has also appeared.
Sporadic PEO with RRF is a clinically benign condition characterized by adolescent or young adultonset ophthalmoplegia,
ptosis, and proximal limb girdle weakness. It is slowly progressive and compatible with a relatively normal life. The muscle
biopsy material demonstrates RRF and COX-negative fibers.
Approximately 50% of patients with PEO have mtDNA deletions, and there is no family history.

REYE SYNDROME
This encephalopathy, which has become uncommon, is associated
with pathologic features characterized by fatty degeneration of
the viscera (microvesicular steatosis) and mitochondrial abnormalities and biochemical features consistent with a disturbance
of mitochondrial metabolism (Chapter 353).
Recurrent Reye-like syndrome is encountered in children with
genetic defects of fatty acid oxidation, such as deficiencies of the
plasmalemmal carnitine transporter, carnitine palmitoyltransferase I and II, carnitine acylcarnitine translocase, medium- and
long-chain acyl-CoA dehydrogenase, multiple acyl-CoA dehydrogenase, and long-chain L-3 hydroxyacyl-CoA dehydrogenase or
trifunctional protein. These disorders are manifested by recurrent
hypoglycemic and hypoketotic encephalopathy, and they are
inherited in an autosomal recessive pattern. Other potential
inborn errors of metabolism presenting with Reye syndrome
include urea cycle defects (ornithine transcarbamylase, carbamyl
phosphate synthetase) and certain of the organic acidurias (glutaric aciduria type I), respiratory chain defects, and defects of
carbohydrate metabolism (fructose intolerance).
BIBLIOGRAPHY

Please visit the Nelson Textbook of Pediatrics website at www.expertconsult.

com for the complete bibliography.

591.3

Other Encephalopathies

Michael V. Johnston

HIV ENCEPHALOPATHY
Encephalopathy is an unfortunate and common manifestation in
infants and children with HIV infection (Chapter 268). Neurologic
signs in congenitally infected patients may appear during early
infancy or may be delayed to as late as 5 yr of age. The primary
features of HIV encephalopathy include an arrest in brain growth,
evidence of developmental delay, and the evolution of neurologic
signs including weakness with pyramidal tract signs, ataxia,
myoclonus, pseudobulbar palsy, and seizures. However, the introduction of highly active antiretroviral therapy (HAART) and
CNS-penetrating antiretroviral regimens for perinatally infected

children has been associated with a 10-fold decrease in the incidence of HIV encephalopathy starting in 1996. Introduction of
HAART for children has also resulted in an increase in CD4 T-cell
count and a reduction in opportunistic infections and organspecific diseases including wasting syndrome, thrombocytopenia,
cardiomyopathy, and lymphoid interstitial pneumonia. High
CNS-penetrating regimens are associated with 74% reduction in
the risk of death in children with a diagnosis of HIV encephalopathy compared to low CNS-penetrating drugs.

LEAD ENCEPHALOPATHY
See Chapter 702.

BURN ENCEPHALOPATHY
An encephalopathy develops in about 5% of children with significant burns in the 1st several weeks of hospitalization (Chapter
68). There is no single cause of burn encephalopathy but rather
a combination of factors that include anoxia (smoke inhalation,
carbon monoxide poisoning, laryngospasm), electrolyte abnormalities, bacteremia and sepsis, cortical vein thrombosis, a concomitant head injury, cerebral edema, drug reactions, and
emotional distress. Seizures are the most common clinical manifestation of burn encephalopathy, but altered states of consciousness, hallucinations, and coma may also occur. Management of
burn encephalopathy is directed to a search for the underlying
cause and treatment of hypoxemia, seizures, specific electrolyte
abnormalities, or cerebral edema. The prognosis for complete
neurologic recovery is generally excellent, particularly if seizures
are the primary abnormality.

HYPERTENSIVE ENCEPHALOPATHY
Hypertensive encephalopathy is most commonly associated with
renal disease in children, including acute glomerulonephritis,
chronic pyelonephritis, and end-stage renal disease (Chapters 439
and 529). In some cases, hypertensive encephalopathy is the
initial manifestation of underlying renal disease. Marked systemic
hypertension produces vasoconstriction of the cerebral vessels,
which leads to vascular permeability, causing areas of focal cerebral edema and hemorrhage. The onset may be acute, with seizures and coma, or more indolent, with headache, drowsiness
and lethargy, nausea and vomiting, blurred vision, transient cortical blindness, and hemiparesis. Examination of the eyegrounds
may be nondiagnostic in children, but papilledema and retinal
hemorrhages may occur. MRI often shows increased signal intensity in the occipital lobes on T2 weighted images, which is known
as posterior reversible leukoencephalopathy (PRES) and may be
confused with cerebral infarctions. These high signal areas may
appear in other regions of the brain as well. Treatment is directed
at restoration of a normotensive state and control of seizures with
appropriate anticonvulsants.

AUTOIMMUNE ENCEPHALITIS
Limbic encephalitis is an inflammatory syndrome manifested by
memory loss, temporal lobe seizures, and affective symptoms.
Neuronal antibodies (VGKC, GAD) that may be paraneoplastic
(neuroblastoma) or idiopathic are present. The outcome is poor.
Anti-NMDAR (N-methyl-D aspartate receptor) encephalitis is
manifested by mood, personality and behavioral changes, and
seizures, dyskinesias, and sleep disturbances. Ovarian teratomas
or idiopathic mechanisms may be present.

RADIATION ENCEPHALOPATHY
Acute radiation encephalopathy is most likely to develop in
young patients who have received large daily doses of radiation.

Chapter 592 Neurodegenerative Disorders of Childhood 2069

Excessive radiation injures vessel endothelium, resulting in

enhanced vascular permeability, cerebral edema, and numerous
hemorrhages. The child may suddenly become irritable and
lethargic, complain of headache, or present with focal neurologic
signs and seizures. Patients occasionally develop hemiparesis due
to an infarct secondary to vascular occlusion of the cerebral
vessels. Steroids are often beneficial in reducing the cerebral
edema and reversing the neurologic signs. Late radiation encephalopathy is characterized by headaches and slowly progressive
focal neurologic signs, including hemiparesis and seizures. Exposure of the brain to radiation for treatment of childhood cancer
increases the risk of later cerebrovascular disease, including
stroke, moyamoya disease, aneurysm, vascular malformations,
mineralizing microangiopathy and strokelike migraines. Some
children with acute lymphocytic leukemia treated with a combination of intrathecal methotrexate and cranial irradiation develop
neurologic signs months or years later; signs consist of increasing
lethargy, loss of cognitive abilities, dementia, and focal neurologic
signs and seizures (Chapter 488). The CT scan shows calcifications in the white matter, and the postmortem examination
demonstrates a necrotizing encephalopathy. This devastating
complication of the treatment of leukemia has prompted reevaluation and reduction in the use of cranial radiation in the
treatment of these children.

ZELLWEGER SYNDROME (CEREBROHEPATORENAL

SYNDROME [CHRS])
This rare, lethal disorder is inherited as an autosomal recessive
trait. It represents the prototype of a group of peroxisomal disorders that have overlapping symptoms, signs, and biochemical
abnormalities (Chapter 80.2). The cause of the severe neurologic
abnormalities is related to an arrest of migrating neuroblasts
during early development, resulting in cerebral pachygyria with
neuronal heterotopia (Chapter 585.7).
BIBLIOGRAPHY

Please visit the Nelson Textbook of Pediatrics website at www.expertconsult.

com for the complete bibliography.

course are the hallmarks of grey matter disorders. A precise history

confirms regression of developmental milestones, and the neurologic examination localizes the process within the nervous system.
Although the outcome of a neurodegenerative condition is usually
fatal and available therapies are often limited in effect, it is important to make the correct diagnosis so that genetic counseling may
be offered and prevention strategies can be implemented. Bone
marrow transplantation and other novel therapies may prevent the
progression of disease in certain presymptomatic individuals. For
all conditions in which the specific enzyme defect is known, prevention by prenatal diagnosis (chorionic villus sampling or amniocentesis) is possible. Carrier detection is also often possible by
enzyme assay. Table 592-1 summarizes selected inherited neurodegenerative and metabolic disorders by their age of onset.

592.1

Sphingolipidoses

Jennifer M. Kwon
The sphingolipidoses are characterized by intracellular storage of
lipid substrates resulting from defective catabolism of the sphingolipids comprising cellular membranes (Fig. 592-1). The sphingolipidoses are subclassified into 6 categories: Niemann-Pick
disease, Gaucher disease, GM1 gangliosidosis, GM2 gangliosidosis, Krabbe disease, and metachromatic leukodystrophy. NiemannPick disease and Gaucher disease are discussed in Chapter 80.4.

GANGLIOSIDOSES (CHAPTER 80.4)

Gangliosides are glycosphingolipids, normal constituents of
the neuronal and synaptic membranes. The basic structure of
GM1 ganglioside consists of an oligosaccharide chain attached
to a hydroxyl group of ceramide and sialic acid bound to
galactose. The gangliosides are catabolized by sequential cleavage
of the sugar molecules by specific exoglycosidases. Abnormalities
in catabolism result in an accumulation of the ganglioside
within the cell. Defects in ganglioside degradation can be
classified into 2 groups: the GM1 gangliosidoses and the GM2
gangliosidoses.

GM1 Gangliosidoses

Chapter 592

Neurodegenerative Disorders
of Childhood
Jennifer M. Kwon
Neurodegenerative disorders of childhood encompass a large,
heterogeneous group of diseases that result from specific genetic
and biochemical defects, chronic viral infections, and varied
unknown causes. Children with suspected neurodegenerative disorders were once subjected to brain and rectal (neural) biopsies,
but with modern neuroimaging techniques and specific biochemical and molecular diagnostic tests, these invasive procedures are
rarely necessary. The most important component of the diagnostic
investigation continues to be a thorough history and physical
examination. The hallmark of a neurodegenerative disease is
regression and progressive deterioration of neurologic function
with loss of speech, vision, hearing, or locomotion, often associated with seizures, feeding difficulties, and impairment of intellect.
The age of onset, rate of progression, and principal neurologic
findings determine whether the disease affects primarily the white
or the gray matter. Upper motor neuron signs and progressive
spasticity are the hallmarks of white matter disorders; convulsions,
intellectual, and visual impairment that occur early in the disease

The 3 subtypes of GM1 gangliosidoses are classified according to

age at presentation: infantile (type 1), juvenile (type 2), and adult
(type 3). The condition is inherited as an autosomal recessive trait
and results from a marked deficiency of acid -galactosidase. This
enzyme may be assayed in leukocytes and cultured fibroblasts.
The acid -galactosidase gene has been mapped to chromosome
3p14.2. Prenatal diagnosis is possible by measurement of acid
-galactosidase in cultured amniotic cells.
Infantile GM1 gangliosidosis presents at birth or during the
neonatal period with anorexia, poor sucking, and inadequate
weight gain. Development is globally retarded, and generalized
seizures are prominent. The phenotype is striking and shares
many characteristics with Hurler syndrome. The facial features
are coarse, the forehead is prominent, the nasal bridge is depressed,
the tongue is large (macroglossia), and the gums are hypertrophied. Hepatosplenomegaly is present early in the course as a
result of accumulation of foamy histiocytes, and kyphoscoliosis
is evident because of anterior beaking of the vertebral bodies. The
neurologic examination is dominated by apathy, progressive
blindness, deafness, spastic quadriplegia, and decerebrate rigidity.
A cherry red spot in the macular region is visualized in approximately 50% of cases. The cherry red spot is characterized by an
opaque ring (sphingolipid-laden retinal ganglion cells) encircling
the normal red fovea (Fig. 592-2). Children rarely survive beyond
age 2-3 yr, and death is due to aspiration pneumonia.
Juvenile GM1 gangliosidosis has a delayed onset beginning
about 1 yr of age. The initial symptoms consist of incoordination, weakness, ataxia, and regression of language. Thereafter,