Child Neurology
7th Edition

HIE as it pertains to neonates is covered in Chapter 6, while localized arterial and venous disease are discussed in Chapter 13.

Hypoxia means reduced blood oxygen content, and ischemia means reduced tissue perfusion. They often go hand in hand because sustained changes in tissue oxygenation have secondary circulatory effects. Asphyxia means impaired gas exchange, as carbon dioxide accumulates as oxygen falls. Mild experimental hypoxemia increases electroencephalogram (EEG) delta activity, prolongs reaction times, and impairs psychological test performance (20).

Acute severe hypoxia impairs consciousness. The duration and severity of hypoxia determines the magnitude of injury and residual impairment, but other factors influence the extent of neural injury. Transient hypoxic episodes may be seen in heart disease, with cardiac arrhythmias, and respiratory problems. Experimentally induced transient hypoxia impairs oculomotor and visual function and can be accompanied by brief nonfocal seizures. These result in no detectable sequelae (21). Stephenson reports “anoxic motor convulsions” with asystole induced by ocular compression (22).

Mild to moderate oxygen desaturation (oxygen saturation in the 80% to 90% range) need not be harmful, especially if brief in duration. The Collaborative Home Infant Monitoring Evaluation (CHIME) study found that 43% of 306 healthy term babies had at least one 20-second episode of apnea or bradycardia without evidence of neurological abnormality (23).

Longer periods of hypoxia produce cellular injury. Neurons are more vulnerable than glial cells to hypoxia and hypoglycemia, and oligodendrocytes are generally more vulnerable than astrocytes (24). Neurons in certain areas of the brain such as the basal ganglia and the hippocampal CA1 pyramidal neurons are particularly vulnerable to asphyxial injury. By contrast, spinal cord neurons tolerate longer periods of occlusion than do cerebral neurons (25). The factors that determine the selective vulnerability of certain neuronal populations are still incompletely understood. They are reviewed in Chapter 6.

Bakay and Lee (43) and Auer and Siesjö (1) have described the basic pathologic alterations in the hypoxic brain. Structural damage can be limited to neurons or, if the hypoxia is more severe, it also can involve glia and nerve fibers. The microscopic changes in neurons subjected to energy failure have been delineated by Auer and Beneviste (44). As a rule, associated glial cell damage is proportional to neuronal damage. In gray matter, astrocytes swell as a result of cellular overhydration, whereas in white matter, the intercellular space enlarges because of extracellular edema and alterations in the walls of the cerebral capillaries. These pathological alterations are summarized in Table 17.4.

Areas most sensitive to hypoxia, as occurs after sudden cardiac arrest, are the middle cortical layers of the occipital and parietal lobes, the hippocampus, amygdala, caudate nucleus, putamen, anterior and dorsomedial nuclei of the thalamus, and cerebellar Purkinje cells (45). Brainstem nuclei are more likely to be involved in infants than in older children.

Brierley and coworkers have studied the time course of these pathologic changes in adult and juvenile monkeys. The earliest changes seen at the light microscopic level included loss of Nissl substance (ribosomes), eosinophilia, and nuclear changes—the “red dead neurons” (46,47). The nuclear changes may be pyknosis or karyorhexis (fragmentation). Necrosis is accidental and
requires no energy, whereas programmed cell death requires energy-dependent sequential activation of highly conserved proteins. Coagulation necrosis and disruption of tissue architecture—for example, infarction—is expected in the most hypoxic area, with PCD in peripheral areas, where energy supply permits the execution of preprogrammed cell death routines. Experimental stroke studies report caspase-mediated delayed cell death in the region outside maximal injury, with apoptotic features (48). Benjelloun and colleagues found prominent caspase expression in experimental neonatal stroke; it was rare in adults (49). Caspase expression was prominent in neurons and astrocytes in ischemic regions of the neonatal sheep brain (50).

Cardiac arrest or vascular obstruction of 15 minutes or more in duration is often followed by initially normal or supernormal cerebral blood flow that declines to subnormal values with regions devoid of perfusion. The causes of these progressive changes are unclear; they are common in children resuscitated from drowning or cardiac arrest with initial systemic pH values below 6.9 (51). In part, these changes can be due to increased cerebral vascular resistance with prolonged ischemia. Many other factors can contribute to this increased resistance, including release of intracellular potassium (52), increased blood viscosity, leukocyte margination, and mediators such as bradykinin and nitric oxide. Endothelial changes are often seen with prolonged ischemia and reperfusion (53,54). These processes can contribute to delayed encephalopathy and postanoxic deterioration. They could be part of the cerebral circulatory arrest seen in brain death, and they could be preventable.

Glucose is necessary for neuronal function. Lactate, pyruvate, and ketone bodies can partially support brain energy needs, but there is always a requirement for some glucose supply. Brain glucose content is less than blood glucose content and increases only slightly with hyperglycemia (125). This is because the delivery of glucose, lactate, and ketone bodies to the brain requires specific transporters, glucose and monocarboxylic acid transporter proteins (GLUTs and MCTs), respectively, and the number of transporter molecules available limits glucose penetration into cells. Neonates have less than half as many transporters per gram of brain tissue as adults (126). GLUT1 is located at the blood–brain barrier and GLUT3 at neuronal membranes (127). GLUT1 is the most widely distributed glucose transporter, with some expression being found in almost every organ. Mutations of GLUT1 produce a progressive encephalopathy with seizures appearing early in life, a condition covered in Chapter 1.

Increased body temperature is common in children, usually caused by infections. Children occasionally develop hyperthermia because of anesthesia-related malignant hyperthermia, drug effects, when sweating is impaired by extensive body casts and braces, or when children are left inside vehicles or covered in bed during hot weather (171). Children are more susceptible to heat illness than adults for many reasons, including a greater surface area to body mass ratio, a lower rate of sweating, and a slower rate of acclimatization. The drugs most often contributing to hyperthermia are cocaine and anticholinergic drugs. Life-threatening hyperthermia is less common; it can be seen with neuroleptic malignant syndrome (172), malignant hyperthermia (173), cocaine ingestion (174), and baclofen withdrawal (175). Baclofen withdrawal presents special problems because most such patients have intrathecal baclofen pumps that fail (176). The first sign of pump failure may be severe fever, tachycardia, and hypertension. There is no IV form of baclofen, but I have given such patients fluids, benzodiazepines, rectal baclofen, and cyproheptadine (177). Cocaine-induced hyperthermia is generally associated with exercise and/or warm ambient temperatures. Cocaine impairs sweating and cutaneous vasodilatation. It shares with Ecstasy and several other drugs the property of impairing subjective perception of overheating and need for fluids (174,178,179). Other drugs that can induce hyperthermia include zonisamide (180), topiramate (181), and less commonly, acetazolamide. Serotonin selective reuptake inhibitors (SSRIs) cause the serotonin syndrome,
which can be associated with fever and sweating (182) but rarely induce renal failure and collapse.

The prevention of heat illness is based on recognizing and modifying risk factors, which include environmental conditions, clothing, hydration, and acclimatization.

Encephalopathy is prominent early in the course of heat injury and is required for the diagnosis of heat stroke. It may progress to renal failure and multiple organ dysfunction with disseminated intravascular coagulation unless vigorously treated (183). Bytomski and Squire (179) cover special issues related to children.

Brain function and excitability are pH sensitive. The pH of body fluids is tightly regulated, and permeability barriers separate the central nervous system from body fluids. Those barriers are more permeable to carbon dioxide than to protons. Brain extracellular fluid contains more protons and free or total Mg⁺⁺ ions and less potassium than plasma; the intracellular compartments of neurons and astrocytes are quite different. The brain extracellular environment is regulated or programmed to contain more H⁺ than plasma or most bodily fluids. This relative acidity of the CSF and brain interstitial fluid is due to metabolic acid production (193).

Many voltage-gated ion channels in the nervous system are pH sensitive. Falling pH (acidosis) inhibits voltage-gated ion channels and glutamate-activated ion channels such as NMDA receptors (194,195). Since voltage-regulated calcium and sodium channels are more sensitive to pH than are potassium channels, increasing pH (alkalosis) increases calcium and sodium entry into neurons, making them more excitable. Acute metabolic disturbances, whether primarily pH changes or changes in electrolyte content of body fluids, often cause seizures and disturbances of consciousness. Respiratory alkalosis may have various causes, including liver disease and acute respiratory distress syndrome (ARDS), and may aggravate seizures from any cause. Respiratory alkalosis is more likely to increase glutamate release than metabolic alkalosis. In general, CSF pH fluctuates less than arterial pH and is well maintained unless changes are acute and severe. The neurological component of acid–base disturbances is nonspecific and poorly correlated with blood or spinal fluid pH.

Gastroenteritis is associated with clusters of seizures, even in the absence of fever. The first reports of this association came from Asia (276), but I have seen cases every year since 1998 that were not limited to children of Asian background (277). Typically, a previously normal child less than
five years old begins to have GI symptoms, has a cluster of seizures with lethargy and perhaps ataxia, and recovers completely in 48 hours or so. EEG during the seizure cluster is normal or a bit slow. Encephalopathy often accompanies the seizures (278). Rotavirus is the cause in some cases (279). Rotavirus also may produce an encephalopathy with or without CSF pleocytosis. In the experience of Goldwater and coworkers, the presence of CSF pleocytosis is associated with a better outcome (280). Rotavirus also has been associated with the syndrome of hemorrhagic shock and encephalopathy (281).

Wheat, rye, and barley proteins induce celiac disease, an autoimmune type of gastrointestinal disorder, in genetically susceptible persons. Subjects with celiac disease can present with cerebellar ataxia, less often with progressive myoclonic ataxia, myelopathy, or cerebral, brainstem and peripheral nerve involvement (282,283). In many cases, there is no overt malabsorption or growth problem. Epilepsy, which is frequently associated with occipital lobe calcifications, also is encountered—even in patients who are not malnourished (284)—as is an inflammatory white matter disease resembling multiple sclerosis (285). Although neurologic complications of celiac disease are generally restricted to adult subjects, children with celiac disease are at greater risk for developing learning disorders, ADHD, and headaches than control subjects (286). Patients develop various antibodies, including antigliadin, antiendomysial, and antitissue transglutaminase antibodies (anti-tTG), of which anti-tTG may be the most specific for the condition (287).

The recognition that vitamin E deficiency is associated with a number of neurologic manifestations points to the important role played by vitamin E in normal neurologic function. Generally, vitamin E deficiency induces a spinocerebellar degeneration, resembling that seen in spinocerebellar (Friedreich) ataxia. This picture is seen in a variety of conditions marked by chronic malabsorption such as occurs in chronic cholestatic liver disease (288), cystic fibrosis, short gut, blind loop, and other intestinal syndromes (289).

Children with chronic cholestatic liver disease can develop a syndrome characterized by areflexia, gait disturbance, decreased proprioception and vibratory sensation, and gaze paresis (290). Dystonia is seen less commonly (291). Nerve conduction velocities and nerve action potential amplitudes are decreased (292). In most instances, serum vitamin E levels have been low (293). In one series, 80% of children older than 5 years of age with chronic cholestasis and vitamin E deficiency developed clinically significant neurologic abnormalities, with areflexia being the earliest sign (294). A similar clinical picture is encountered in abetalipoproteinemia (295). Here, too, vitamin E levels can be strikingly reduced (see Chapter 1). However, a normal serum vitamin E level does not exclude a deficiency in the vitamin because hyperlipidemia can produce a false elevation in serum vitamin E levels. The ratio of vitamin E to total serum lipids (cholesterol, triglycerides, and phospholipids) is considered a better indicator of vitamin E deficiency. Oral vitamin E in large doses is usually satisfactory treatment, but some patients with severe problems require injectable forms of the vitamin (292,296).

A rare autosomal recessive disorder is caused by mutations in the gene for the alpha-tocopherol transfer protein. This protein incorporates alpha-tocopherol into lipoprotein particles during their assembly in liver cells. The defect results in a decrease in serum vitamin E levels (297,298). Several allelic variants have been recognized. In some, the clinical picture resembles that of spinocerebellar ataxia with peripheral neuropathy; in others, ataxia is accompanied by retinitis pigmentosa. The age of onset can be as early as the first decade, and the disease is relentlessly progressive. Vitamin E in large doses (400 to 1,200 IU) can stabilize or improve neurologic symptoms (299). However, a few patients have developed new neurologic symptoms while receiving vitamin E and maintaining satisfactory serum vitamin E levels (300). As a rule, the earlier treatment is begun the better the outcome.

The neuropathologic picture of vitamin E deficiency regardless of cause resembles that described for vitamin E deficiency in rats and monkeys. It includes a loss of large diameter myelinated sensory axons in the spinal cord and peripheral nerves, with spheroid formation. These findings are most pronounced in the posterior columns (301). The tocopherol content of biopsied peripheral nerve is reduced in vitamin E–deficient patients with peripheral neuropathy. In some cases, chemical changes precede anatomic evidence for peripheral nerve degeneration (302). Ultrastructural evidence of electron-dense accumulations in muscle fibers also has been reported (303,304).

Inflammatory bowel disease (Crohn disease and ulcerative colitis) is associated with an increased risk of cerebral venous thromboses, especially during times of crisis (295,296). Kao and colleagues describe four children who developed sinovenous thrombosis coinciding with flare-ups of their ulcerative colitis (305). Markers of coagulation and fibrinolysis are often abnormal in patients with inflammatory bowel disease (306). Cerebral vasculitis is associated with Crohn disease (307), and inflammatory bowel disease is associated with higher incidence of neuropathy, myelopathy, and myopathy more so than with other
illnesses (308). Not all cases can be explained by intestinal malabsorption and an associated vitamin E deficiency. Prolonged use of metronizadole (Flagyl) for the treatment of the condition can result in a clinical or subclinical sensory polyneuropathy or a combined sensorimotor polyneuropathy.

White matter lesions similar to those of multiple sclerosis have been seen in Crohn disease patients who were treated with the tumor necrosis factor antagonists etanercept and infliximab (309).

The association of ileal lymphoid nodular hyperplasia (ILNH) with regressive autism is covered in Chapter 18.

Whipple disease is an unusual systemic illness caused by the culture-resistant organism Tropheryma whipplei. Although usually a disease of middle-aged men, the condition has been encountered in children; it causes CNS symptoms with or without obvious gastrointestinal disease (310,311). These include cognitive changes, supranuclear gaze palsy, altered consciousness, oculomasticatory and oculofacial skeletal myorhythmia, myoclonus, ataxia, and cranial nerve abnormalities (311). Some patients have CSF pleocytosis. Diagnosis usually requires brain or intestinal biopsy (312). The treatment of Whipple disease is beyond the scope of this text.

Changes in intra-abdominal pressure can influence intracranial pressure, primarily through effects on cerebral venous pressure. Citerio and coworkers showed that placing weights on the abdomen of patients with head trauma produced measurable increases in intracranial pressure (313). Intra-abdominal pressure can be significant with ascites and other abdominal fluid collections (314) and may contribute to the evolution of pseudotumor cerebri in very obese patients (315).

Generalized encephalopathy complicates acute pancreatitis in up to one-third of cases (316,317). Features include confusion, depression of consciousness, and occasionally asymmetrical weakness. There can be slowing of the EEG. White matter lesions are sometimes evident on MRI studies (316). If the pancreatitis subsides, neurologic recovery is likely.

Intussusception is relatively common in early childhood, but its diagnosis can be difficult. The classical triad of abdominal pain, currant jelly stools, and palpable abdominal mass is seen in less than one-half of patients. Whereas lethargy in gastrointestinal disorders is unexpected, approximately one-half of patients present with the symptom. Lethargy is common in volvulus as well and is seen occasionally in bowel obstruction (318,319). Many have speculated that intestinal bacteria enter the circulation when the bowel is ischemic; however, blood cultures are usually negative, and the mechanism of brain dysfunction in this condition is unknown. In a few cases, lethargy can be so profound as to prompt lumbar puncture, neurologic consultation, and brain imaging studies (320,321).

Liver damage by acute or chronic disease initiates a characteristic set of neuropsychiatric symptoms termed hepatic encephalopathy (HE), a condition that was first delineated in 1952 by Adams and Foley (322). It is variable in severity and multifactorial in etiology (323,324).

As a consequence of the various methods of therapy currently available for what at one time was considered an irreversible renal disease, various neurologic complications have been encountered.

Generally, neurologic complications are seen more frequently after hemodialysis than after peritoneal dialysis (424). Restlessness, headache, nausea, and vomiting are relatively common after more extreme adjustments of urea levels or acidosis. Seizures followed by impaired consciousness were seen in some 8% of patients subjected to dialysis before 1965, but they are now less common (424). These symptoms have been attributed to the osmotic gradient established when, as a consequence of the blood–brain barrier, urea is removed more rapidly from the blood than from the brain. Headaches also can be caused by impaired vascular regulation by damaged kidneys because bilateral nephrectomy resulted in complete relief of headaches in 70% of subjects despite continued dialysis (425).

Cerebral hemorrhages and central retinal vein occlusion are less common complications of hemodialysis (426).

With repeated dialyses, a variety of syndromes are encountered. Dialysis generally has little effect on brain water or on EEG (427). However, hemodialysis produces cytokine release (428), and patients may have headaches (429) or severe fatigue at the end of a session. As well, they may develop areas of osmotic demyelination or myelinolysis, notably central pontine myelinolysis (430). With time, these lesions generally disappear (431). Nutrition is a concern, and a few chronic dialysis patients have developed Wernicke’s encephalopathy (432) that has been attributed to a deficiency of vitamins or other nutritional factors. Other nutritional deficiency syndromes include a peripheral sensorimotor neuropathy (burning feet or restless legs syndrome) (424) and leg cramps. Restless legs syndrome and leg cramps respond to vitamin supplementation; in particular, leg cramps respond to vitamin E, quinine, or to treatment with L-DOPA or dopamine agonists (433,434).

Eventually, almost all patients on chronic dialysis develop some electrophysiologic abnormalities, but these may be asymptomatic (435). Less often, patients develop mononeuropathy, cranial nerve palsies including optic neuropathy (436), and choreoathetosis. Patients may develop mononeuropathies resulting from placement of arteriovenous fistulas, including a rare but catastrophic ischemic monomelic neuropathy (437). Dialysis dementia is characterized by rapidly progressive speech disturbance, myoclonus, asterixis, seizures, and personality changes. Impaired bulbar function, weakness, and diffuse EEG abnormalities also can be seen (438). Untreated, the condition usually terminates in death within a few years (439). The role of aluminum in causing dialysis dementia is well established, and with modern techniques of water purification, this syndrome can be avoided (440).

A progressive encephalopathy with a clinical picture similar to dialysis dementia has been recognized in children who developed chronic renal insufficiency before 1 year of age and who have not been dialyzed. It is characterized by developmental delay, the evolution of microcephaly, seizures, hypotonia, and involuntary movements, including chorea and tremor (441,442). Various causes have been suggested for this clinical picture, including the oral ingestion of aluminum in the form of aluminum hydroxide, chronic malnutrition, and the neurotoxic effects of chronic renal failure during a vulnerable period of brain growth.

Another syndrome that is clinically indistinguishable from dialysis dementia is occasionally seen in uremic
patients who develop acute hypercalcemia. It is easily reversed by normalizing calcium levels (443). The reversible posterior encephalopathy syndrome, mentioned in the preceding section, is common in children with glomerulonephritis and other rapidly evolving nephropathies. Seizures, cortical blindness, and unilateral motor deficits may accompany this. The patient may have normal or increased CSF pressure, normal fundi, or papilledema (444). Most children make a full neurologic recovery. The treatment of seizures associated with reversible posterial encephalopathy is usually not difficult; most patients respond to moderate doses of standard anticonvulsants.

The neurologic complications attending renal homotransplants are mainly the result of immunosuppressive therapy. Like the complications after hepatic transplants, considered earlier in this chapter, they include a variety of infections, notably fungal infections resulting from Aspergillus or Candida (445) and viral infections with cytomegalovirus and herpes simplex (446). The infectious and other complications of renal transplants are similar to those seen with liver transplants. Infection is the most frequent cause of late death in transplant patients.

In autopsy studies on renal transplant patients collected between 1968 and 1991, 58% of subjects who succumbed to infection died of bacterial infection, 27% of fungal infection, and 6% of viral infection (447). The clinical picture of these secondary infections is highlighted by disturbances of behavior and seizures. Fungal infections, in particular, are seen in children who have been on prolonged immunosuppressive therapy, and their appearance is unrelated to preexisting treatment with antibiotics. It is often difficult to establish an antemortem diagnosis. Imaging studies should be performed before lumbar puncture, which can be dangerous in the presence of a large brain abscess.

The neurologic complications of cyclosporine therapy for renal transplants are similar to those encountered after hepatic transplants but appear to be less frequent (448). Side effects of other immunosuppressants are covered in the section on liver transplantation.

Symptomatic hypoglycemia can develop in infants or children a few months to several years after transplantation. The etiology is probably multifactorial, but in the series of Wells and coworkers, almost all affected patients were receiving propranolol when they developed hypoglycemia. In such cases, propranolol should be discontinued and frequent feedings initiated (449).

Approximately 6% of renal homograft recipients, followed for up to 8 years, have developed neoplasms. The majority of these neoplasms has involved the CNS and includes reticulum cell sarcomas, lymphomas, and less commonly, Hodgkin disease (450,451).

Patients with chronic renal failure can develop nonconvulsive status epilepticus if they receive large doses of cephalosporins (452). The incidence of nonconvulsive seizures is increased in patients on chronic dialysis (453).

Hemolytic uremic syndrome, a heterogeneous group of disorders, is marked by microangiopathy, hemolytic anemia, and thrombocytopenia (454). Up to one-half of patients have neurologic symptoms, and some are left with permanent sequelae due to strokes and hemorrhages. A focally abnormal EEG may be prognostically useful (455). The classic or primary hemolytic uremic syndrome seen in infants or young children is in part the consequence of endothelial damage resulting from an infection, principally with the verotoxin-producing Escherichia coli, 0157:H7. Secondary hemolytic uremic syndrome, resulting from a variety of drugs, notably cyclosporine, is seen mainly in adults.

The neurologic symptoms of hypoparathyroidism and hyperparathyroidism are the direct or indirect result of disordered calcium metabolism and are, therefore, considered
in the section dealing with the disturbances of electrolyte metabolism.

Neurologic symptoms accompanying disorders of the adrenal gland are usually the result of disturbed serum electrolytes and osmolarity. They are referred to in another portion of this chapter. Adrenoleukodystrophy is discussed in Chapter 3. Addison’s disease or adrenal insufficiency may be a feature of adrenoleukodystrophy or may have other etiologies. It has been associated with catatonia, vertigo, chorea, and papilledema (516). Some patients have encephalopathy, autoimmune thyroiditis, and adrenal insufficiency (517).

Allgrove syndrome is a rare, progressive autosomal recessive disorder that usually becomes symptomatic by age 10. Patients have adrenocorticotropic hormone (ACTH)–resistant adrenal insufficiency, achalasia, alacrima, hyperpigmentation, and hypoglycemia. Most subjects have mental retardation, pyramidal signs, ataxia, and other neurologic impairment (518). This disorder is due to mutations of the aladin or AAAS gene, whose function is unknown (519,520,520a).

Neurologic symptoms associated with disorders of pituitary function can result from direct involvement of the perisellar and hypothalamic regions by a mass originating from the pituitary gland or neighboring structures (see Chapter 11). Less commonly, the neurologic picture evolves in conjunction with direct trauma or a destructive lesion affecting this area, such as occurs with histiocytosis X, sarcoidosis, or other granulomatous diseases.

MRI is superior to CT scans for detecting small masses in these regions. Cacciari and coworkers found that girls with precocious puberty who had its onset before age 2 are more likely to have lesions suggestive of hypothalamic hamartoma than those with precocious puberty of later onset, whose MRIs are generally normal (521). Reporting on a larger patient series, Ng and colleagues found that the age of onset of precocious puberty did not predict MRI results (522).

MRI is also useful in the evaluation of growth hormone deficiency (523,524,525). In a series of Agyropoulou and colleagues, approximately one-half of growth hormone–deficient children showed an interruption of the pituitary stalk with a gland of normal size (526). The significance of this finding is not clear, but interruption of the pituitary stalk can result from head injury, a prenatal developmental defect, or a perinatal insult (526,527). The likelihood of pituitary stalk interruption is greater when multiple hormones are deficient. In those cases, the adenohypophysis also is often absent or reduced in size (525). Other pituitary disorders are rarely associated with neurologic dysfunction. However, acromegaly is frequently accompanied by hypertrophic neuropathy (528) and lymphocytic or granulomatous hypophysitis (529). The latter condition can cause headache and visual field defects (530).

The Laurence-Moon-Bardet-Biedl syndrome is a clinically and genetically heterogeneous autosomal recessive disorder. As first described by Laurence and Moon, the condition is characterized by mental retardation, spinocerebellar ataxia, retinitis pigmentosa, progressive spastic paraparesis, and hypogonadism (531). Patients subsequently described by Bardet and Biedl suffered from mental retardation, retinitis pigmentosa, hypogonadism, obesity, and polydactyly (532). This group of disorders is clinically and genetically heterogeneous and has now been linked to at least eight different gene loci (533); most genes are associated with cilia, flagella, or centrioles. Inheritance is generally autosomal recessive. The Bardet-Biedl and Usher syndromes are the most prevalent syndromic forms of retinitis pigmentosa (RP) in North America; together, they make up almost a one-fourth of all RP patients (534).

Green and colleagues reviewed the syndrome in 28 Newfoundland patients (535); all had severe retinal dystrophy, but only 2 had typical RP. Obesity was seen in 96%, 58% had polydactyly, and 41% were mentally retarded. Many affected males had hypogonadism. Beales and coworkers studied 109 English patients and their families (536). In addition to the previously known signs and symptoms, they also identified neurologic, speech, and language deficits and behavioral traits, facial dysmorphism, and dental anomalies. Unaffected relatives had a significant incidence of renal anomalies and renal cell carcinoma. Beales and coworkers revised the diagnostic categorization to emphasize the phenotypical overlap with the disorder originally described by Laurence and Moon and proposed a unifying label: polydactyly-obesity-kidney-eye syndrome (536). Similar disorders are common in Arabs; many patients also have aminoaciduria and progressive renal failure as well as progressive visual failure (537). Most patients with the Bardet-Biedl and related syndromes have normal pituitary function; some, especially males, have hypothalamo-pituitary dysfunction, which is most marked in the realm of gonadotropins and gonadal function (538).

The Bardet-Biedl syndrome must be distinguished from the Alström syndrome, a condition in which RP, hypogonadism, obesity, and sensorineural hearing loss also are inherited in an autosomal recessive manner (539,540). The Biemond type II syndrome of iris coloboma, mental retardation, obesity, hypogenitalism, and postaxial polydactyly also is similar (541), as is the McKusick-Kaufman syndrome of hydrometrocolpos, hydronephrosis, postaxial polydactyly, and sometimes, Hirschsprung disease (542). The Online Mendelian Inheritance in Man (OMIM) Web site provides a good summary of these disorders and is regularly updated.

Polydactyly also is encountered as part of the various orofaciodigital syndromes (543,544). These disorders are often accompanied by cerebral defects, including callosal dysgenesis, heterotopic gray matter, hydrocephalus, and various posterior fossa anomalies, including agenesis or hypoplasia of the cerebellar vermis, or Dandy-Walker syndrome (545,546).

A syndrome of cerebral gigantism (Sotos syndrome), first described by Sotos in 1964 (547), is not rare. Sotos syndrome is associated with mental retardation and relatively distinctive facies with frontal bossing, hypertelorism, macrocrania, and prognathism. Birth weights usually exceed the 90th percentile, and growth is excessive in the first 4 to 5 years of life. Epilepsy and sexual precocity may be present (548). Cortical malformations can be demonstrated by MRI (549). School and learning difficulties are common, even if IQs fall in the normal range (550). These patients tend to improve as they become older.

The neuroimaging findings of Sotos syndrome often permit differentiation from other mental retardation syndromes with macrocephaly (549). In Sotos syndrome, the ventricles are almost always abnormal: Most common is a prominence of the trigone (90%), followed by prominence of the occipital horns (75%) and ventriculomegaly (63%). Various midline abnormalities also are noted; in particular, anomalies of the corpus callosum are quite common.

Most reported cases of Sotos syndrome have been sporadic and probably represent new mutations. Defects of NSD1, a gene that codes for what appears to be a transcriptional intermediary factor, are found in more than 70% of cases of Sotos syndrome. De Boer and coworkers (551) found that facial appearance correlated with NSD1 gene status patients with Sotos phenotypes. The best predictors for a NSD1 alteration were frontal bossing, down-slanted palpebral fissures, pointed chin, and overgrowth. Patients with NSD1 defects were more likely to have cardiac and feeding problems. No abnormality of pituitary hormone secretion has been found in Sotos syndrome.

The phenotypically overlapping but less common Weaver syndrome is marked by accelerated growth and osseous maturation, unusual craniofacial appearance, hoarse and low-pitched cry, and hypertonia with camptodactyly (552,553). Opitz and colleagues (553) reviewed the Sotos and Weaver syndromes and discussed the possibility that they represent a single genetic entity. From a phenotypic point of view, Weaver syndrome has more conspicuous contractures and a facial appearance that generally differs from that in Sotos syndrome. NSD1 mutations are found in some patients with Weaver syndrome (554) as well as in a small minority of patients with the Beckwith-Wiedemann syndrome (BWS), another overgrowth syndrome (555). The cardinal features of the latter disorder are exomphalos, macroglossia, and neonatal gigantism. BWS patients are at increased risk of developing specific tumors, such as Wilms tumor, hepatoblastoma, and neuroblastoma (556). BWS also is covered in Chapter 4.

Septo-optic dysplasia (SOD) is a common congenital anomaly syndrome often associated with hypopituitarism and poor adrenal response to stress (557). It a heterogeneous disorder that varies greatly in severity and is loosely defined by any combination of optic nerve hypoplasia, pituitary gland hypoplasia, and midline abnormalities of the brain, including absence of the corpus callosum and septum pellucidum (558,559). As it frequently includes large defects of the cerebral mantle (schizencephaly), callosal defects, seizures, visual handicap, and variable degrees of mental retardation, the condition is covered in Chapter 5.

Growth failure is commonly seen in children who are severely retarded or who have other forms of serious and long-standing brain dysfunction. In the series of Castells and associates (560), the IQs of all children so affected were below 60, and the majority had severe microcephaly and a retarded bone age. In view of an impaired growth hormone response to a variety of stimuli, hypothalamic function appears to be faulty in at least some of these patients.

Several conditions in which delayed growth accompanies mental retardation have been described. Many of these also are associated with other neurologic features and with chromosomal disorders (see Chapter 4 for a more extensive discussion).

Of the neurologic complications of diabetes in children, the most common is an asymptomatic peripheral neuropathy. Its mechanism is discussed by Winegrad (561). Careful neurologic examination of juvenile diabetic patients can reveal slight distal weakness in the lower extremities, wasting of the interossei muscles, and diminished deep tendon reflexes. Conduction velocity in the peroneal nerve is abnormally slow in 11% of diabetic children between 8 and 15 years of age, even in the absence of clinical signs for peripheral neuropathy (562). Sensory changes are the most common electrophysiological findings. Somatosensory-evoked potentials from peroneal nerve stimulation are abnormal in some asymptomatic juvenile diabetics, suggesting additional abnormalities in spinal afferent transmission (563). The risk of diabetic neuropathy increases with patient age, duration of diabetes, and amount of hyperglycemia (564,565). In a study published in 1987, Kruger and colleagues found that proximal diabetic neuropathy was much better correlated with poor diabetic control than was peroneal or more distal neuropathy (566). This study confirmed the work of Hoffman and colleagues, which indicates that duration of diabetes, patient age, and diabetic control each significantly and independently influence the prevalence of delayed motor conduction in diabetic patients aged 6 to
23 years (565). Moreover, the presence of retinopathy in these patients correlates closely with the conduction velocity. Symptomatic diabetic polyradiculopathy is rare in juvenile diabetes (566,568). Nocturnal abdominal, leg, or foot pain may be troublesome. It can develop after rapid achievement of glycemic control. This is called insulin neuritis, and it occurs in type II diabetes as well (569). Diabetic cranial nerve palsies have not been seen in children.

Cognitive impairment may be seen in children whose diabetes begins before age 5 and who have frequent hypoglycemic episodes (570). Hypoglycemic episodes after age 5 are less clearly linked to cognitive impairment. A group of 90 Australian children with type I diabetes scored lower than control children on measures of intelligence, attention, processing speed, long-term memory, and executive skills. These effects were greatest in children whose diabetes began before age 4 (571).

Neurologic symptoms also are seen in diabetic coma, in the course of treatment of diabetic ketoacidosis, and in hyperosmolar nonketotic diabetic coma. The cause of neurologic impairment in diabetic ketoacidosis (DKA) is not well understood. Kety reported in 1948 that cerebral oxygen uptake was significantly reduced during DKA in adults despite increased cerebral blood flow and normal arterial oxygen saturation (572). The extent of decrease in cerebral oxygen uptake correlated with the degree of obtundation. The correlation between state of consciousness and pH was much weaker, and patients can remain alert even though there is marked acidosis during DKA (573). The concentration of ketone bodies, spinal fluid pH, and the degree of hyperosmolality also correlate poorly with mental status (574). It appears, therefore, that a multitude of factors, including brain intracellular pH, impaired oxygen use, hyperosmolality, and disseminated intravascular coagulation inducing localized areas of cerebral hyperperfusion act jointly to cause the depression of sensorium.

A number of deaths from irreversible cerebral edema have occurred in the course of apparently adequate treatment of DKA (575). About 1% of pediatric cases of DKA are associated with clinically obvious cerebral edema with compression of cerebral cisterns (576,577). These patients have significant mortality and risk of residual impairment (577) and often respond poorly to treatment (578). Neither the use of bicarbonate, nor the rate of decline of glucose, or excessive secretion of antidiuretic hormone, or the rate of fluid administration is responsible for the development of cerebral edema (579).

Duck and colleagues have proposed that a rapid reduction of blood hyperosmolality with treatment and a slower change in the cerebral hyperosmolality owing to the presence of substances termed idiogenic osmoles can result in the entrance of water into the brain and consequent cerebral edema (576). Van der Meulen and coworkers hypothesized that cell swelling during treatment of diabetic ketoacidosis results from conditions favoring the activation of the sodium-potassium exchanger, a plasma-membrane transport system that regulates cytoplasmic pH. Apparently, weak organic acids, such as ketoacids and free fatty acids, present in cytoplasm, are known to activate the exchanger, which, in the presence of extracellular sodium, leads to cell swelling (580). These theories all assume that cerebral edema is primarily intracellular. However, recent diffusion-perfusion MRI studies cast serious doubt on this concept (581). Glaser and colleagues studied 14 children during treatment for DKA and after recovery, using apparent diffusion coefficients (ADCs) and measures of cerebral perfusion. They found significantly elevated ADCs in all regions except the occipital gray matter, where it was decreased. Mean transit times were decreased, and the perfusion data suggested increased cerebral blood flow during DKA with normalization in the follow-up study. However, none of their patients had compression of cisterns or clinical evidence of cerebral edema, suggesting that symptomatic cerebral edema develops when a “second hit” is added to the initial clinically silent changes documented by Glaser and colleagues (581). The increased ADCs found in all patients during the acute stage suggest increased extracellular or interstitial fluid (vasogenic edema). The difference between increased extracellular fluid and blood flow in most brain regions and simultaneous decreases in ADC and perfusion in the occipital gray matter brings us back to reversible posterior encephalopathy, so common in renal disease and in patients on immunosuppressant treatment. The posterior cerebral circulation could be ischemic at the same time that excessive perfusion and extracellular fluid accumulation occurs in the carotid territory. This disparity can be explained by the different sympathetic innervations of the vertebro-basilar and carotid circulations (582). Our understanding of regional differences in cerebral autoregulation and autonomic control remains very limited, but if cerebral edema indeed results from hypoxic injury and cytotoxic mediators, additional treatment in addition to insulin and fluids could be of help (579).

Prediction and diagnosis of cerebral edema is difficult because characteristic clinical or biochemical features are lacking, and neuroimaging studies indicate that subclinical cerebral edema is fairly common during therapy of diabetic ketoacidosis in the pediatric age group but uncommon in patients over age 20 years (578). Rather, a patient’s failure to recover consciousness, despite adequate treatment with insulin and fluids, will suggest the presence of cerebral edema.

Dexamethasone has been used in treatment of cerebral edema, but in my experience, it is usually given too late to be effective. Mannitol, administered as soon as cerebral edema is diagnosed, might be more beneficial (583). In any case, the incidence of death or neurologic handicap is quite high even with the most expert care.

Nonketotic hyperosmolal diabetic coma is rare in children. Neurologic symptoms are believed to result from
brain swelling, but this is surely an oversimplification (584). In addition to impaired consciousness, patients can develop hemiparesis and generalized or focal seizures. Movement disorders, including eye movement disorders such as opsoclonus-myoclonus, may accompany nonketotic hyperglycemic coma or stupor more often in adults than in children (585).

Nonketotic hyperglycemic coma has been treated successfully with low-dose insulin infusion while intracranial pressure is monitored (586).

The neurologic complications of hypoglycemia are discussed at another point in this chapter.

The Wolfram syndrome is an autosomal recessive syndrome of early onset diabetes, progressive optic atrophy, sensorineural hearing loss, anosmia, ataxia, and peripheral neuropathy (587,588). Insulin-dependent diabetes mellitus and bilateral progressive optic atrophy are necessary to make this diagnosis. Both may present in childhood, adolescence, or early adult life; diabetes mellitus usually comes first. Other neurologic symptoms in Wolfram homozygotes include hearing loss, urinary retention, ataxia, peripheral neuropathy, mental retardation, dementia, and psychiatric illnesses (588).

Lipoatrophic diabetes or congenital generalized lipodystrophy, the Berardinelli-Seip syndrome, is a rare autosomal recessive disease characterized by a near total absence of adipose tissue from birth or early infancy and severe insulin resistance. Other features include acanthosis nigricans, accelerated linear growth, muscular hypertrophy, hepatomegaly, and mild mental retardation (589). This syndrome is usually due to mutations in BSCL2, the gene encoding seipin, an integral membrane protein of the endoplasmic reticulum (590). Mutations in this gene also are associated with a form of hereditary spastic paraparesis accompanied by amyotrophy of the hand muscles (Silver syndrome).

Neurologic symptoms accompanying anemia usually result from cerebral hypoxia. They include irritability, listlessness, and impaired intellectual function. The relationship between the various hemoglobinopathies, coagulopathies, and stroke is reviewed by Grotta and coworkers (591) and by Chan and deVeber (592).

The effects on neurodevelopmental outcome of chronic iron deficiency anemia experienced during the first two years of life have been a matter of some debate. In the Chilean experience of Walter and colleagues, developmental test performance, particularly on language items, was impaired in children whose hemoglobin values had been below 10.5 g for more than three months. Correction of the iron deficiency failed to improve the performance scores (593). Similar results have been obtained from other parts of the world. Costa Rican children treated for iron deficiency anemia as infants still showed significant cognitive differences from controls at age 5, when all had normal hematological indices (594). Iron supplementation of relatively healthy elementary school children with iron deficiency anemia improved their cognitive function; this improvement correlated poorly with changes in hemoglobin (595). Supplementation of Third World infants with iron and zinc improves behavior and increases exploratory activity without measurable effects on hemoglobin (596). It is likely that iron has some effects on the brain independent of its red cell function and that chronic anemia of any cause has mild negative effects on development. Like the effects of lead, these results are confounded by a variety of environmental and particularly socioeconomic factors (597). Some of these aspects are covered in Chapter 18.

Idiopathic thrombocytopenic purpura (ITP) of childhood is usually an acute self-limited disorder. It may evolve into a chronic condition with remissions and exacerbations and a significant risk of CNS hemorrhage, greatest at the time of febrile illnesses (700). Chronic ITP, especially when complicated by multiple intracranial hemorrhages, can be associated with mental handicap (701), and patients also may have ischemic strokes. Mononeuritis multiplex due to nerve hemorrhages has been encountered (702). In patients with the chronic form of ITP, learning disorders and behavioral problems are common, and significant EEG abnormalities are seen in approximately 50% of cases. Minute, multiple capillary bleeding is believed to account for these findings (701). The treatment of thrombocytopenia is reviewed by Kaplan and Bussel (700).

The thrombocytopenia-absent radius or tetraphocomelia syndrome (703) is usually associated with normal intelligence, but patients may have abnormalities of the cerebellar vermis or corpus callosum (704). CNS hemorrhage from thrombocytopenia is more often subdural or subarachnoid than within the brain substance, but may occur in any location.

Neonatal alloimmune thrombocytopenia is caused by infants having platelet antigen that differs from that of their mothers. Alloimmunization occurs during pregnancy, thereby inducing a transient severe thrombocytopenia. CNS hemorrhages develop in 10% to 15% of infants (705). The thrombocytopenia is transient, and maternal platelet transfusion or intravenous IgG improves the platelet count. A mother who has had one infant with
this condition is at high risk for thrombocytopenia in subsequent pregnancies, and the likelihood of intracranial bleeding increases in later pregnancies as well.

In thrombotic thrombocytopenic purpura (TTP), a rare and occasionally familial condition usually confined to adult life, platelet aggregation in the microvasculature results in intracapillary and intra-arteriolar thrombi that are widespread throughout the brain. Rarely, thrombosis can involve the middle cerebral artery or other large arteries (706). The thromboses result in cerebral ischemia and a variety of neurologic symptoms. These have been reviewed by Lawlor and coworkers (707). The condition responds promptly to plasma exchange (708). TTP is related to the HELLP (hemolytic anemia, elevated liver enzymes, and low platelet count) syndrome of pregnancy, in which liver dysfunction is usually more prominent than neurologic symptoms (709), and to hemolytic uremic syndrome, an entity in which platelet aggregation occurs in the microvasculature.

Deficiency of the Von Willebrand factor cleaving metalloprotease, ADAMTS-13, is often associated with TTP (710), and familial TTP is due to mutations of the ADAMTS13 gene mapped to chromosome 9 and coding for a metalloproteinase (711,712). The condition can present in the newborn period (707).

Hemorrhagic disease of the newborn is associated with a deficiency in vitamin K. It is most common in fully breast-fed infants who received no vitamin K after birth and in infants of mothers taking various anticonvulsants (713). Early and late forms of the condition have been described. In the early form of the disease, onset of bleeding occurs during the first day of life. Infants usually present with gastrointestinal bleeding. The peak age for the late form is 4 weeks. In the German series of Sutor and colleagues, 58% of infants had intracranial hemorrhage (714). Vitamin K–related prothrombin complex deficiency may develop after the newborn period, in which case CNS hemorrhages are frequent and devastating (715).

Neurologic complications occur in up to 10% of children with Henoch-Schonlein purpura, a self-limited disorder with hypertension, renal disease, and vasculitis. Immune complexes, mainly of IgA and C3, are deposited in various organ systems (716). Patients have nonthrombocytopenic purpura, arthritis or arthralgia, abdominal pain that may be complicated by intussusception, and glomerulonephritis. The disease is usually self-limited and lasts a few weeks but can recur. Most patients recover completely; prognosis generally depends on the severity of renal involvement. Neurologic complications occur in 1% to 8% of patients with Henoch-Schoenlein purpura, usually as a result of hypertension, vasculitis, or renal involvement (716a). The most frequently seen neurologic manifestations are headaches and mental status changes. Cerebral vasculitis can lead to ischemic strokes and intracerebral hemorrhage. A reversible encephalopathy typical of RPE (717), ataxia, and peripheral neuropathy also have been described (718). Other complications include seizures and focal neurologic deficits, notably hemiparesis, aphasia, chorea, ataxia, and cortical blindness. Peripheral nervous system involvement, manifested by a mononeuropathy (719), and polyradiculoneuropathy can be encountered as well (720).

Pernicious anemia is a classical hematologic syndrome that may present with neurologic symptoms. Childhood pernicious anemia is a rare but treatable cause of sensory ataxia (721). The various cobalamin-deficient and cobalamin-responsive states are covered in Chapter 1. Nutritional deficiencies of vitamin B₁₂ are important; macrobiotic diets and maternal B₁₂ deficiency may cause hematologic and neurologic problems in infants (722). Nitrous oxide, used for anesthesia or as a recreational drug, may cause dramatic neurologic symptoms in patients with unsuspected B12 deficiencies (723,724) because nitrous oxide oxidizes the cobalt prosthetic group, irreversibly inactivating the vitamin.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired genetic disorder with complement-mediated hemolysis and clonal expansion of affected cells of various hematopoietic lineages probably derived from an abnormal multipotential hematopoietic stem cell (725). Nocturnal hemolysis causes the classical dark urine on arising. Some patients have cerebral venous or arterial occlusions (726). PNH is one of the causes for moyamoya syndrome (727).

The sideroblastic anemias are a heterogeneous group of disorders with two common features: ring sideroblasts in the bone marrow (abnormal normoblasts with excessive mitochondrial iron) and impaired heme biosynthesis. Mitochondrial dysfunction underlies all of these anemias. Some are hereditary; others are due to toxins, such as lead. Several of the hereditary forms are associated with
neurologic disease. Mitochondrial myopathy with lactic acidosis and sideroblastic anemia (MLSA) typically begins with progressive exercise intolerance during childhood, with lactic academia and onset of sideroblastic anemia around adolescence (728,729). An unusual X-linked nonprogressive spinocerebellar ataxia of early onset is associated with mild anemia in the anemia, sideroblastic, and spinocerebellar ataxia (ASAT) syndrome, due to mutation of the ABCB7 gene at Xq13.1 (730). Sideroblastic anemia associated metabolic myopathy and an axonal neuropathy that sometimes causes fatal respiratory failure also have been reported (731).

With the advent of effective antileukemic chemotherapy and, hence, longer patient survival, neurologic complications in acute leukemia have become more common, and their diagnosis and treatment have become major medical problems (732). Neurologic complications are of two kinds: those attending the disease and those resulting from the therapy used to control the disease.

A number of neurologic disorders result from the agents used in the treatment of leukemia. These are reviewed by Plotkin and Wen (780) and Armstrong and Gilbert (781). Acute encephalopathy with convulsions and coma may complicate induction chemotherapy for childhood leukemia (782). Disseminated leukoencephalopathy develops in some children treated with methotrexate (MTX) and cranial irradiation (783). This condition is most common with high doses of MTX or with intrathecal MTX. Patients may have mental status changes, obtundation, hemiplegia, ataxia, and evidence of cortical involvement such as seizures, aphasia, and hemianopia. On imaging studies, the lesions are usually subcortical and most prominent in the periventricular regions, but neither the imaging, the clinical, nor the CSF picture is entirely specific (784,785) (Fig. 17.5A,B). In the series of Rollins and coworkers, the abnormalities observed on diffusion-weighted imaging appeared to correlate best with the clinical deficits (786). Some patients with this entity die, others recover completely, and others yet are left with residual injury but may tolerate subsequent courses of MTX without additional problems. The variability in patient course and inability to validate this diagnosis makes the reports of “reversal of MTX neurotoxicity” with aminophylline and/or high-dose folinic acid difficult to evaluate (787). Even though there
are theoretical reasons that folinic acid (leucovorin) might be helpful (788), I have used it in two cases, without definite benefit.

White matter disease is not the only neurologic syndrome associated with MTX treatment. Lumbar radiculopathy and paraplegia (789,790), ataxia, and confusion without imaging changes have been seen. Leukemic children have an increased risk of both reversible posterior encephalopathy (RPE) (372) and acute disseminated encephalomyelitis (ADEM), a highly variable entity further discussed in Chapter 8 (791,792).

Vincristine is used widely to induce the initial remission. Its neurologic side effects mainly are a dose-dependent peripheral neuropathy, with the drug’s initial effect being on the muscle spindle (793). The Achilles tendon reflexes are depressed or lost in almost all patients. Less often, paroxysmal abdominal pain, weakness of the distal musculature of the lower extremities, and paresthesias in a stocking-glove distribution occur. Cranial nerve involvement, usually optic neuritis, ptosis, ophthalmoplegia, and facial palsy, has been noted less often and almost always in association with peripheral muscle weakness and atrophy. Autonomic disturbances, including constipation, paralytic ileus, bladder atony, and orthostatic hypotension, also have been encountered. The isolated appearance of cranial nerve signs in a leukemic child who has been treated with vincristine should suggest meningeal infiltration rather than a side effect of vincristine therapy.

The inadvertent intrathecal administration of vincristine results in an ascending and generally fatal myeloencephalopathy (794). Early irrigation of CSF and treatment with glutamic acid occasionally arrests the process (794,795). Vincristine produces a severe, even fatal, neuropathy in patients with hereditary neuropathies in the Charcot-Marie-Tooth family (CMT) (796,797) and in patients receiving vincristine together with itraconazole (798). Itraconazole is useful for fungal infection but is a potent inhibitor of CYP3A4, one of the families of cytochrome P450 mono-oxygenases. Several reports indicate that glutamic acid decreases vincristine neuropathy in patients (799). Painful neuropathies due to vincristine or paclitaxel also may be treated with gabapentin (800) or ethosuximide (801).

Cisplatin induces a peripheral neuropathy in addition to many other toxic symptoms. Cisplatin neuropathy is dose-dependent and at times does not appear until after treatment has ended (802). Muscle cramps and Lhermitte’s sign, a sudden electric-like sensation spreading down the body or into the limbs on flexion of the neck, can appear after cisplatin treatment (803). The drug usually affects large sensory fibers and can cause sensory ataxia. Strength is usually spared. Nerve conduction studies show evidence of a sensory axonopathy. Hearing loss is common. Cisplatin may contribute to vascular syndromes, including stroke.

Intrathecal Ara-C is sometimes followed by aseptic meningitis and/or myelopathy (804). It also can be associated with encephalopathy, seizures, and cranial nerve deficits; it can induce a significant neuropathy as well, although it does so less commonly than does vincristine (805,806). The drug is best known for its cerebellar toxicity, which can be permanent, and is seen more frequently in adults than in children (807).

L-Asparaginase, an enzyme used in induction therapy for acute leukemia, has been associated with a variety of adverse reactions affecting the nervous system (808). The most serious of these complications, seen in 1% to 2% of children, are intracranial thromboses and hemorrhagic infarcts, which result in headache, obtundation, focal seizures, and hemiparesis (809). Symptoms occur a few weeks after L-asparaginase initiation and are believed to result from the enzyme-inducing deficiencies of antithrombin, plasminogen, and fibrinogen, with a subsequent disruption of plasma hemostasis. Because thrombosis of the cerebral veins or dural sinuses is common under these circumstances, MRI or angiography is required to establish the diagnosis. Administration of fibrinogen or fresh frozen plasma is the usual treatment. For unclear reasons, the risk of recurrence with further L-asparaginase therapy is low (810). The drug is yet another cause for the reversible posterior encephalopathy syndrome (811).

The immediate and long-term effects of radiation therapy are covered in Chapter 11.

Oppenheim proposed in 1883 that some neurologic disorders were due to release of toxic substances from distant cancers (811a). Some paraneoplastic syndromes, such as the Lambert-Eaton myasthenic syndrome, are so stereotyped that physicians may identify them from clinical observation. This syndrome, mostly seen in adults with small cell lung cancer, produces abnormal fatigability and proximal weakness in the absence of the bulbar involvement characteristic of myasthenia (812). Unlike myasthenia, tendon reflexes are often absent and may return with exercise. This autoimmune disorder can be treated by treating the tumor, if present, or by immunosuppressant measures. It is seen in children with leukemia and lymphoproliferative disorders (813) and in some children with autoimmune disease and no tumor (814).

Opsoclonus is a disorder of saccadic stability, often associated with myoclonus and cerebellar dysfunction, a clinical picture that is collectively termed the opsoclonus-myoclonus (OM) syndrome. The condition is a frequent accompaniment to neuroblastomas and other tumors of neural crest origin, such as ganglioneuroma and ganglioneuroblastoma. It is covered in Chapter 8.

Primary CNS lymphoma is rare in children, and the neurologic complications of lymphomas generally result from an infiltration of the CNS and meninges. Symptoms and signs of increased intracranial pressure are present. A peripheral neuropathy also has been encountered (815). CNS involvement often presages a fatal outcome (816), and at diagnosis, it is encountered in approximately 20% of children with Burkitt lymphoma and develops despite prophylactic therapy (817). Paraplegia resulting from spinal cord compression, cranial neuropathies, and meningeal infiltration are the most common abnormalities. With intensive multidrug chemotherapy, the prognosis for 5-year survival has improved considerably (818).

Neurologic complications of Hodgkin disease are relatively unusual in childhood. They can take the form of infiltrations along the floor of the cranial cavity and the overlying meninges with an extension to the cranial nerves. Intracranial granulomas are rare (819). Progressive multifocal encephalopathy, an acute disseminated demyelination, also can be encountered in Hodgkin disease and lymphosarcoma.

A variety of developmental CNS anomalies can accompany many types of congenital heart disease. Malformations of the CNS are seen in approximately 7% of children with congenital heart disease (820). In a survey of children scheduled to undergo open-heart surgery, preoperative evaluation found neurologic and neurobehavioral abnormalities in more than one-half of the group. One-third of subjects were microcephalic, and 44% were hypotonic (821). The incidence of the neurologic abnormalities in the various major types of congenital heart disease is outlined in Table 17.16. A high incidence of CNS anomalies also is seen in patients with the hypoplastic left-sided heart syndrome (822). Trisomies 11, 18, and 21 are accompanied by both neurologic and cardiac dysfunction. About 40% of children with Down syndrome have congenital heart disease, most often endocardial cushion defects. Several of the contiguous gene syndromes such as the velocardiofacial syndrome, the DiGeorge syndrome, Rubinstein-Taybi syndrome, and the Williams syndrome have a high incidence of congenital heart disease. These conditions are covered in Chapter 4.

The association of coarctation of the aorta with intracranial arterial aneurysms is well documented. Although intracranial arterial aneurysms are seen in only a small percentage of children with coarctation, they account for approximately one-fourth of aneurysms in childhood (825). Like arterial aneurysms in general, these are located around the circle of Willis and its major branches, particularly the anterior communicating artery. Arterial aneurysms are more fully discussed in Chapter 13.

A rare complication of surgery for repair of the coarctation is spinal cord damage. The nature of the repair requires occlusion proximally and distally to the site of the coarctation. Generally, children with fewer collateral vessels and the longest period of aortic occlusion are more disposed to this complication. Other factors, including the degree of compromise to the circulation of the spinal cord and variations in the anatomy of the blood supply to the spinal cord, play important roles (826,827).

The residua from spinal cord damage range from mild weakness and a picture resembling anterior spinal artery syndrome to complete paraplegia, with transection usually at the midthoracic level. Somatosensory-evoked potentials after posterior tibial nerve stimulation can be monitored during surgery to detect spinal cord ischemia (828). MRI studies can demonstrate a midthoracic hydromyelia.

Cyanotic congenital heart disease includes the traditional five T’s, namely, transposition of the great arteries, tetralogy of Fallot, truncus arteriosus, tricuspid atresia, and total anomalous pulmonary venous connection. Generally speaking, each of these lesions allows a connection between systemic venous blood passing into the heart and the cerebral circulation without the lungs acting as an intervening filter. As such, any peripheral infection could cause a neurologic event such as a brain abscess or a cerebral vascular accident.

Unique to the patient with tetralogy of Fallot is the additional risk of an acute hypoxic episode, known as “TET” spells. These result from a sudden increase in the infundibular stenosis, which then increases the flow of hypo-oxygenated blood from the right ventricle through the ventricular septal defect to the aorta and into the cerebral circulation. Attacks occur most frequently between 6 months and 3 years of age and are precipitated by crying, dehydration, and fever. Many attacks occur shortly after the child wakes up. In approximately one-half of the children, severe cyanotic attacks are followed by a generalized convulsion (829). The EEG during such an attack shows high-voltage slow-wave activity, but no spike discharges (830). These spells may be transient and short-lived. However, frequent spells lead to repeated cerebral insults and have the potential for permanent diminished cerebral function.

Brain abscesses are usually seen in children older than 2 years of age. Most often they occur as a complication of cyanotic congenital heart disease, sinus infections, or central lines. Early repair of most types of cyanotic cardiac lesions has reduced the incidence of brain abscess. Those with a residual right-to-left shunt remain at risk for this complication, however, and the risk of brain abscess is proportional to the degree of cyanosis (831). Anaerobic mouth organisms are the most common flora in immunocompetent patients without central lines. In the preimaging era, the distinction between ischemic stroke and abscess was often difficult. Patients with cyanotic heart disease have an increased risk of both complications. This distinction between the two diagnoses can generally be made with MR scanning (832). The mortality rate of brain abscess has improved greatly with the introduction of CT scanning (833). Prior to then, the diagnosis was frequently difficult. Fever generally is absent; only 20% of children with brain abscess seen at Boston Children’s Hospital between 1981 and 2000 were febrile. Seizures were present in 27%, and 49% reported headaches. Thirteen patients (24%) in this series died, and of the survivors who returned for follow-up, more than one-half had epilepsy, cognitive, or motor handicaps. Almost all abscesses were in the cerebral hemispheres; 67% had single abscesses. Nearly all patients received both antibiotics and some type of surgical procedure. Eleven patients, seven of whom died, had fungal abscesses. Seven of the fungal abscess patients were immunosuppressed. No fungal abscesses had been seen at that institution before 1980 (833). Abscesses smaller than 2 cm in diameter in immunocompetent patients in good condition can often be successfully treated without surgery, as long as the elimination of the abscess is confirmed radiologically (834).

The diagnosis and treatment of brain abscesses in children with cyanotic heart disease are discussed more extensively in Chapter 7.

Any patient with inoperable cyanotic heart disease is at risk for progressive hemoconcentration with a potential increase in hematocrit to the high 60s or low 70s. This results in a small but recognizable risk of a cerebral vascular accident secondary to either embolic phenomenon or intrinsic vascular occlusion. The majority of cerebral infarcts in such children are caused by vascular occlusions, most often in the distribution of the middle cerebral artery.
Venous thrombi are more common than arterial occlusions (835,836). Dehydration, fever, and iron deficiency anemia also play a role in the evolution of cerebrovascular accidents in nonsurgical patients (837).

A cerebrovascular accident is marked by a sudden onset of hemiplegia or aphasia. Seizures can accompany the acute episode; in some 10% of children, they can follow the cerebrovascular accident after a latent period of 6 months to 5 years. Approximately 20% of children, particularly those who incur a cerebrovascular accident during the early years of life, are left mentally retarded (838).

The differential diagnosis of hemiplegia and seizures in a child with cyanotic congenital heart disease is discussed in the section on brain abscess (see Chapter 7). We should point out that in cyanotic children, funduscopy is of little help in ascertaining the presence of increased intracranial pressure. Retinal changes consisting of dilated and tortuous veins and blurring of the disc margins can be observed in the majority of these children. This retinopathy is related to decreased oxygen tension and secondary polycythemia, rather than to retention of carbon dioxide or increased venous pressure (839).

Prolonged hypoxemia with pO₂ levels less than 25 torr in a patient with as yet unoperated cyanotic heart disease can lead to acidosis and potential cerebral vascular deficiencies. The symptoms may be seizures and, on a long-term basis, diminution in intellectual capability.

Cardiac catheterization, originally primarily a diagnostic tool, now serves as both an avenue for diagnosis and treatment. Common to both purposes is the introduction of sheaths, catheters, balloons, and devices into arteries and veins. As a result, a significant risk exists of vessel compromise or occlusion and clot formation with emboli and air emboli. Further, the implanting of devices into the patent ductus arteriosus, atrial septum, and other vessels presents a nidus for thrombus, clots, and emboli. Neurologic complications rarely attend cardiac catheterization. When complications do develop in children, thromboembolic events predominate and appear most commonly when the procedure is performed in the first few months of life. Seizures and brachial plexus injuries also have been reported (850).

Extracorporeal membrane oxygenation (ECMO) is being used in most medical centers to treat neonates with uncontrollable respiratory failure. This invasive, technically complicated procedure is designed to functionally bypass the lungs. It requires systemic anticoagulation and generally necessitates ligation of the right common carotid artery, the right internal jugular vein, or both. The carotid artery can be reconstructed after ECMO, but the efficacy of this procedure is unproven (890). Venovenous ECMO involves cannulation of only the jugular vein, sparing the carotid artery and maintaining pulsatile flow, which is lacking in venoarterial ECMO. Venovenous ECMO provides less cardiovascular support.

ECMO survival rates depend greatly on diagnosis; infants with persistent pulmonary hypertension (PPHN)
and meconium aspiration syndrome do best, while those with cardiac conditions and congenital diaphragmatic hernia generally require more time on ECMO and have the highest mortalities (891). Even though there is a compensatory response that is anatomically mediated through the circle of Willis, approximately one-fourth of infants demonstrate focal parenchymal lesions on post-ECMO MRI (892). As a rule, these are right-sided ischemic lesions and contralateral hemorrhagic lesions consistent with hyperperfusion of the left cerebral hemisphere. In the experience of Mendoza and her group, 83% of ischemic lesions involved the right side, and 70% of the hemorrhagic lesions occurred solely or predominantly on the side opposite the carotid ligation (893). These abnormalities are demonstrable on head ultrasound studies performed during the course of ECMO (894). Additionally, there is a significant incidence of left hemiparesis and left focal seizures, and occasionally, a subclavian steal has been documented (895). Children must be anticoagulated during ECMO, which increases the risk of intraventricular hemorrhage (IVH). These deficits, seen during the neonatal period, however, do not always translate into focal functional disabilities in later life.

Follow up of ECMO patients has been relatively encouraging: Nield and colleagues studied cognitive function in 108 ECMO survivors at age 43 months (896). Sixty percent functioned in the normal range, including three children with obvious neurologic deficits. Eighty percent of those patients had relatively favorable conditions (meconium aspiration syndrome, sepsis, and PPHN). Hamrick and coworkers studied a less favorable group: 53 infants who required ECMO after cardiac surgery (897), most often because they could not be weaned from bypass. Eleven of 12 who had cardiac arrest before ECMO did not survive. Only 14 children survived; 10 of these functioned at their age levels. Three of the four with overt neurologic handicaps had hemorrhage and periventricular white matter abnormalities documented during the acute illness. On the other hand, five of the ten good outcome children also had abnormal imaging studies during the acute phase. Severe CNS hemorrhage led to withdrawal of support in one-fourth of nonsurvivors. Davis and colleagues reviewed outcomes in 73 neonates who received ECMO for congenital diaphragmatic hernia in the United Kingdom between 1991 and 2000 (898). Twenty-seven, or 37%, survived to age 1, and only six survivors were found to be neurodevelopmentally normal.

Asthma and epilepsy are common episodic disorders; hypoxic seizures may occur during asthma attacks (899), or patients may lose consciousness from cough syncope (900). If these episodes occur only with asthma attacks, they are rarely epileptic in nature. Children with mild to moderate asthma are usually similar to controls on neuropsychologic testing (901), although those with many school absences often do poorly academically. Children with sleep apnea and sleep-disordered breathing seem to have more cognitive and behavior problems than those with asthma (902,903). Even if sleep apnea cannot be documented, children with disrupted sleep score below controls on neurocognitive tests (904). Adult criteria for sleep apnea apply poorly to children, many of whom have frequent arousals and oxygen desaturation with very rare apneas (905). The association of sleep-disordered breathing with chronic headache, stroke, inflammation, and elevated C-reactive protein (CRP) has been mentioned (615,905a).

Theophylline is commonly used for the treatment of asthma and other pulmonary conditions. The major neurologic complication of theophylline therapy is the appearance of seizures, which are seen in all age groups and are generally accompanied by elevated theophylline levels, although seizures have been observed at therapeutic or low toxic levels (906). Seizures can be focal or generalized. When they are focal, one should suspect an underlying focal cerebral lesion. Theophylline-induced seizures are often difficult to control with anticonvulsants, and in some instances, a toxic encephalopathy and permanent brain damage can ensue (907). Seizures are best avoided by careful monitoring of serum theophylline levels, and it would appear wise not to use the medication for the treatment of reactive airway disease in children who have an abnormally low seizure threshold.

In some children recovering from an acute episode of asthma, a flaccid paralysis resembling poliomyelitis has been encountered. This condition, first reported from Australia in 1974 (908), has been termed Hopkins syndrome. No consistent virus has been cultured from such patients, who generally have been successfully vaccinated against poliomyelitis. The disorder primarily involves the anterior horn cells. A rapid progression of paralysis usually affects one limb, leaving the child with a severe and permanent weakness. Sensation is preserved; the CSF usually shows moderate mononuclear pleocytosis, and the protein content can be slightly elevated (909). MR changes in the anterior horn have been documented (910). Some of the children have evidence for an underlying immune deficiency (911).

Another cause of amyotrophy associated with asthma is Hirayama disease (912), which is characterized by dilated posterior cervical venous plexuses, eosinophilia, and high serum IgE titers and high titer to mite antigens. A related and more symmetrical myelopathy associated with atopic dermatitis and allergy to mites (mite myelopathy) and observed in both children and adults has been reported only from Japan (913,914).

Pulmonary arteriovenous fistulas may be part of the Osler-Weber-Rendu syndrome (915) or may be sporadic congenital anomalies (916). In either case, they may permit emboli from the body to enter the cerebral circulation, and they pose a risk for brain abscess (917). The Osler-Weber-Rendu syndrome or hereditary hemorrhagic telangiectasia is a dominantly inherited and highly variable syndrome with telangiectases and arteriovenous malformations of skin, mucosa, and viscera. This condition is considered in Chapter 13.

Chronic lung disease, such as cystic fibrosis, may be complicated by pseudotumor cerebri (918). In some instances, pseudotumor cerebri can be explained by hypovitaminosis A, which commonly accompanies cystic fibrosis. However, a bulging fontanel in infants with cystic fibrosis is rarely due to vitamin A deficiency (919), and papilledema, confusion, and asterixis are common in older children with respiratory failure and carbon dioxide retention from any cause (920). Rapid correction of hypercapnia may cause seizures in patients (921). Hypophosphatemia may be a factor in this complication of mechanical ventilation (921).

Bolton first described polyneuropathy associated with sepsis and ICU care in 1984 (922). Sepsis and multiorgan failure trigger a symmetrical polyneuropathy that often produces ventilatory muscle weakness but generally spares eye, face, and head movements (923). Patients may have received steroids, but they are not central to this complication of the sepsis syndrome. Electrodiagnostic studies show normal conduction velocities, reduced compound muscle action potential amplitude, and eventual muscle denervation changes. If sepsis and organ failure are controlled, prognosis for recovery is good. Van Mook and Hulsewe-Evers provide a good review of this common syndrome (924).