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 >38°C 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 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 child’s problems.

Table 591-1 CLASSIFICATION OF CEREBRAL PALSY AND MAJOR CAUSES

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

Figure 591-1 Diffusion tensor image of white 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 28:1213–1222, 2007.)

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 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

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.

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 363:1619–1631, 2004. Reproduced with permission from Wake Forest University Orthopaedic Press.)

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 µg/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, 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.

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 single-photon 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 tRNA^Leu(UUR) gene of mtDNA in ≈80% of patients. An additional 7.5% have a point mutation at nt 3271 in the tRNA^Leu(UUR) gene. A 3rd mutation has been identified at nt 3252 in the tRNA^Leu(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 to a maternally inherited homoplasmic m.14674T>C mt-tRNA^Glu 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-tRNA^Glu 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 tRNA^Lys gene of mtDNA. Additional patients have been reported with a T to C mutation at nt 8356 in the tRNA^Lys 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 E₁α 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 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 adult–onset 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).

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 organ-specific 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. 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 re-evaluation 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).