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Chapter 15 Neurologic Manifestations of Systemic Disease
Child Neurology
Chapter 15
Neurologic Manifestations of Systemic Disease
John H. Menkes,
R
Burton W. Fink,
†
Carole G. H. Hurvitz,
‡
Carol B. Hyman,
§
Stanley C. Jordan, and
||
Frederick Watanabe
Departments of Neurology and Pediatrics, University of California, Los Angeles, UCLA School of Medicine, and Department of Pediatric Neurology, Cedars-Sinai Medical Center, Los Angeles,
California 90048;
R
Department of Pediatrics, University of California, Los Angeles, UCLA School of Medicine, Los Angeles, California 90048;
†
Department of Pediatrics, University of California, Los

Angeles, Center for the Health Sciences, and Department of Pediatric Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, California 90048;
‡
Department of Pediatrics, University of
Southern California School of Medicine, and Children's Hospital of Los Angeles, Cedars-Sinai Medical Center, Los Angeles, California 90048;
§
Department of Pediatrics, University of California, Los
Angeles, UCLA School of Medicine, and Department of Pediatric Nephrology and Transplant Immunology, Cedars-Sinai Medical Center, Los Angeles, California 90048; and
||
Department of Pediatrics,
University of California, Los Angeles, UCLA School of Medicine, and Center for Liver Diseases and Transplantation, Cedars-Sinai Medical Center, Los Angeles, California 90048
Metabolic Encephalopathies

Hypoxia and Hypoglycemia

Brain Death

Disorders of Acid–Base Balance

Disorders of Electrolyte Metabolism

Diagnosis of the Metabolic Encephalopathies
Neurologic Complications of Pulmonary Disease
Neurologic Complications of Gastrointestinal and Hepatic Disease

Hepatic Encephalopathy

Neurologic Complications of Liver Transplantation

Vitamin E Deficiency States

Whipple Disease
Neurologic Complications of Renal Disease

Uremia

Complications of Treatment of Chronic Uremia

Hemolytic Uremic Syndrome
Neurologic Complications of Cardiac Disease

Congenital Heart Disease
Obstructive Lesions

Coarctation of the Aorta

Cyanotic Congenital Heart Disease

Acquired Heart Disease
Neurologic Sequelae after Intervention Techniques

Cardiac Catheterization
Neurologic Complications of Hematologic Diseases

Anemia

Neonatal Polycythemia

Coagulation Disorders

Thrombocytopenic Purpuras

Neonatal Alloimmune Thrombocytopenia

Thrombotic Thrombocytopenic Purpura

Hemorrhagic Disease of the Newborn
Neurologic Complications of Neoplastic Disease

Leukemia

Neurologic Complications from Antineoplastic Agents

Lymphoma and Hodgkin Disease
Neurologic Complications of Endocrine Disorders

Thyroid Gland

Parathyroid Gland

Adrenal Gland

Pituitary Gland

Diabetes
Chapter References
METABOLIC ENCEPHALOPATHIES
Extracerebral diseases can interfere with normal brain function by impairing the necessary supply of oxygen and glucose or by disturbing the ionic environment of
neurons, glia, and cell processes.
Hypoxia and Hypoglycemia
Pathophysiology

Hypoxia-ischemia, hypoglycemia, and status epilepticus induce energy failure with consequent brain damage ( 1,2 and 3). The significant differences in the time
course and distribution of brain damage that result from these three insults are depicted in Table 15.1. Primary events involve the release of glutamate and other
excitatory amino acids and an increase in free cytosolic calcium concentration. Secondary ( downstream) events include activation of calcium-dependent protein
kinases and phosphorylases and hydrolysis of phospholipids with accumulation of diacylglycerides. The role of nitric oxide synthase, and free radical–mediated cell
damage, and the altered expression of growth factors, heat shock, and stress proteins in cell death resulting from energy failure, have been reviewed by Siesjö ( 4),
Choi (5), and Massa (6) (Fig. 15.1).
TABLE 15.1. Neurobiological differences among ischemia, hypoglycemia, and epilepsy
FIG. 15.1. Schematic diagram illustrating events resulting from energy failure. (DAG, diacylglycerides; FFA, free fatty acids; LPL, lysophospholipids; PAF, platelet
activating factor; NO, nitric oxide; XDH, XO, xanthine oxidase, reduced and oxidized forms.) (From Siesjö BK. A new perspective on ischemic brain damage? Prog
Brain Res 1993;96:1. With permission of the author.)
Cerebral function requires an adequate supply of oxygen and glucose. In adults, glucose is the only substrate oxidized by the brain, although under nonphysiologic
conditions such as starvation, structural proteins and lipids can be used as well. The brain of an infant or younger child can oxidize substrates other than glucose,
notably ketone bodies, and possibly glycerol and fatty acids ( 7,8). Glucose is supplied to the brain by the bloodstream and enters neurons and glia by facilitative
transport. Six isoforms of facilitated glucose transporters (GLUT) have been cloned and are expressed in brain. Quantitatively GLUT1 and GLUT3 are the most
important glucose transporters in brain. GLUT1 is expressed in the blood–brain barrier, whereas GLUT3 is the principal neuronal glucose transporter ( 9).
Compared with its rate of use, the glucose reserve of the brain, which is in the form of glycogen, is minute, and increased energy demands, as occur during a seizure,
necessitate an increased rate of glucose transport across the blood–brain barrier.
Approximately 85% of glucose used by the adult brain is oxidized to CO
2
either through the Krebs tricarboxylic acid cycle, or after conversion to a-amino acids, mainly
glutamic and aspartic acids. For these reactions, a constant oxygen supply (3.3 mL/100 g tissue per minute) is required. Glycolysis to lactate accounts for only
approximately 10% of glucose used by the adult brain. The brain of newborn infants has a lower cerebral oxygen consumption and converts a considerably greater
proportion of glucose to lactate and pyruvate (7). Values for cerebral metabolic rates for oxygen range from 0.4 to 1.3 mL/100 g per minute in term infants without
neurologic injury, and 0.06 to 0.54 mL/100 g per minute in apparently normal preterm infants of 26 to 32 weeks' gestation ( 10). These values reflect the increased
glycolytic ability of the immature brain and its reduced energy demands, in part a consequence of its reduced synaptic density. Reduced energy demands also explain
to some degree the relative resistance of the newborn brain to hypoglycemic and hypoxic damage. See Chapter 5 for a more extensive discussion of perinatal
asphyxia.
There is no constant relationship between blood glucose levels and the severity of neurologic symptoms, because the neurologic symptoms also reflect glucose levels
within the brain, tissue energy requirements, and the ability of brain to draw on anaerobic glycolysis and other substrates for its metabolic needs ( 8).
The quantity of oxygen used by the brain is a function of the cerebral blood flow and the concentration difference for oxygen between arterial and cerebral venous

blood. The principles involved in the measurement and calculation of brain oxygen consumption are discussed by Kety ( 11).
Neurologic symptoms can result from a reduction in arteriovenous oxygen difference. Such a reduction is seen in cyanotic congenital heart disease. According to
Tyler and Clark, cerebral disturbances are encountered when the arterial oxygen saturation is 60% or less, although considerable individual differences occur in the
degree to which the brain is susceptible to oxygen deprivation ( 12).
Cerebral anoxia also can result from reduced cerebral blood flow. The rate of cerebral blood flow depends on two factors: the pressure head (the difference between
the arterial and venous pressure) and the resistance to blood flow through the cerebral vasculature. In aortic stenosis and in breath-holding spells, reduction of
cerebral blood flow can induce neurologic symptoms, particularly syncope and seizures.
Several factors determine the extent and permanence of central nervous system (CNS) damage resulting from cerebral anoxia. These include the age of the subject,
body temperature, extent and duration of anoxia, and intracellular pH. Siesjö and Plum ( 13) and more recently by Auer and Siesjö (14) have reviewed the
pathophysiology of anoxic brain damage beyond the neonatal period.
Brain regions containing a high density of excitatory amino acid (e.g., glutamate) receptors are the most vulnerable to hypoxic-ischemic insult, a finding that can at
least partially account for patterns of hypoxic brain injury. This topic is more extensively covered in Chapter 5. The fact that damage from these insults can be
attenuated by pharmacologic blockage of excitatory neurotransmission with receptor antagonists has triggered the search for similar agents suitable for clinical use
(5). At present none are in general use in clinical situations.
Pathologic Anatomy
Bakay and Lee (15) and Auer and Siesjö (14) 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 involves glia and nerve fibers. The microscopic changes in neurons subjected to energy failure have been delineated by Auer and
Beneviste (16). 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. 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 ( 17). Brainstem nuclei are more likely to be involved in infants than in older
children.
When hypoxia is accompanied by hypotension, the ischemic lesions are concentrated along the arterial boundary zones of the cerebral cortex and cerebellum. With a
prolonged insult, ischemic lesions tend to become generalized.
In hypoglycemia, there is selective neuronal necrosis of the superficial cortical layers, the hippocampus, and dentate gyrus. The cerebral cortical lesions are most
conspicuous in the insular and the parieto-occipital cortices ( 18). The thalamus and nonneuronal elements are spared unless hypoglycemia is severe and prolonged
(19,20 and 21). Damage to Purkinje cells is less than occurs after hypoxia (16,22). Infarction or hemorrhage are usually absent, even after a severe hypoglycemic
insult (1). As occurs in hypoxia, the accumulation of excitatory neurotransmitters plays an important pathogenetic role in neuronal damage and death ( 1). The
predominant release of aspartate into extracellular fluid in response to hypoglycemia contrasts with the release of glutamate in hypoxia and may account for the
differences in the distribution of neuronal damage. The presence of acidosis, as occurs in hypercapnia, aggravates hypoglycemic neuronal damage, as does

concurrent hypoxia (22,23).
Clinical Manifestations
Hypoxia
A number of clinical features are shared by all metabolic encephalopathies ( 24). The earliest symptom is a gradual impairment of consciousness. In infants, this can
take the form of irritability, loss of appetite, and diminished alertness. Periods of hyperpnea can progress to Cheyne-Stokes respiration, a pattern of periodic breathing
in which hyperpnea regularly alternates with apnea. The eyes move randomly, but ultimately, as the coma deepens, they come to rest in the forward position.
When anoxia occurs acutely, consciousness is lost within seconds. In cyanotic congenital heart disease, anoxia can take the form of brief syncopal attacks, often after
crying, exertion, or eating, and most frequently occurring during the second year of life. Usually, at the onset of the attack, the child cries, then becomes deeply
cyanotic and gasps for breath. Generalized seizures can terminate the more severe cyanotic episodes.
Should oxygen supply be restored immediately, recovery is quick, but when anoxia lasts longer than 1 to 2 minutes, neurologic signs persist transiently or
permanently. These include impaired consciousness and decerebrate or decorticate rigidity. The prognosis for survival is relatively good for patients who after their
anoxic episode exhibit intact brainstem function as manifested by normal vestibular responses, normal respiration, intact doll's eye movements, and pupillary light
reactions (24).
The longer the duration of coma, the less likely the outlook for full recovery. In the series of Bell and Hodgson, which included all age groups, 17.5% of patients
comatose for longer than 24 hours could be discharged from the hospital, but 70% of these subjects experienced significant and permanent neurologic impairment
(25). There is fairly good evidence that some children who survive a major hypoxic episode without apparent neurologic residua are left with permanent
visuoperceptual deficits (26).
The electroencephalogram (EEG) is of assistance in predicting the outcome of coma after cardiorespiratory arrest. A phasic tracing early in the recovery period
indicates a good prognosis, whereas a flat EEG is never associated with full recovery except in cases of drug ingestion ( 27). Bilateral loss of cortical responses after
median nerve stimulation on the somatosensory-evoked potential (SSEP) test is one of the best prognosticators for a poor outcome. Initial preservation of the cortical
potentials does however not necessarily imply a good recovery ( 28,29). This is particularly true for small infants and serial SSEPs are indicated to ascertain whether
they continue to remain intact (30). In term neonates the positive predictive value of an abnormal SSEP is also excellent, but in premature infants a normal response
after stimulation of the median nerve had a poor predictive value with respect to normal outcome ( 30,31).
Near Drowning
In near drowning, the length of coma has even more significant prognostic implications than after cardiorespiratory arrest, and, as a rule, there is an all or nothing
outcome, with few children experiencing mild degrees of neurologic damage. None of the patients still comatose in 15 to 30 minutes after their rescue survived without
major neurologic residua, and 60% of subjects in this group died. In a Hawaiian series, all children who ultimately survived intact made spontaneous respiratory efforts
within 5 minutes of rescue, and the majority of those did so within 2 minutes (32). The experiences from several other centers are similar in that all children who still
required cardiopulmonary resuscitation on arrival at the hospital experienced permanent severe anoxic encephalopathy. Interestingly, the presence of convulsions
does not indicate a bad prognosis although their persistence beyond 12 hours does. Fields concurs with that observation and lists the following factors that predict

poor outcome: (a) submersion for more than 5 minutes; (b) serum pH below 7.0 at time of admission to the emergency room; (c) the need for cardiopulmonary
resuscitation in the emergency room; (d) a delay before the first postresuscitation gasp; and (e) poor initial neurologic evaluation on resuscitation ( 33). Immersion in
cold or icy water appears to give a better chance for survival ( 34).
SSEPs and an EEG obtained during the second 24 hours after the accident have been used as additional prognostic indicators ( 35).
Numerous treatment regimens, many of unproved benefit, have been used for cerebral salvage. These include induced hypothermia, barbiturate coma, and
intracranial pressure monitoring to control cytotoxic cerebral edema. None of these have been effective in improving the ultimate outcome ( 34,36). The neurologist
attending a near-drowning victim should keep in mind that hypoglycemia and hyperglycemia can cause further neurologic damage. Hyperthermia should be avoided
and seizures controlled, with phenytoin being the preferred anticonvulsant.
A postanoxic dystonic syndrome has been recognized in children. It appears 1 week to 36 months after the anoxic insult, and tends to worsen for several years.
Dysarthria and dysphagia are common. Neuroimaging studies reveal putaminal lesions in the majority of such cases. Treatment is generally ineffectual. The
pathophysiologic mechanism underlying this condition and the reason for its progression are totally unknown ( 37).
The persistent vegetative state (PVS) after near drowning is being seen with increasing frequency owing to the resuscitative facilities of most emergency rooms.
According to data compiled in California and reported in 1994, survival of children in PVS is dependent on their age. Median survival of infants younger than 1 year of
age was 2.6 years; of infants between 1 and 2 years, 4.2 years; and children between 2 and 6 years, 5.2 years ( 38). The same group of workers, reporting in 1999,
found that in the mid-1990s the mortality rate for infants in PVS was only one-third of those in the early 1980s. A smaller decrease in mortality rates was recorded for
children ages 2 to 10 years (38a). In the experience of Heindl and Laub 55% of children who are in PVS as a result of an anoxic event became conscious within 19
months of the injury. The quality of life was fairly good for those who recovered from PVS; 9% recovered completely, and another 52% became independent in
everyday life (39). After 9 months, less than 5% of children were able to recover from PVS (39). In the study of Ashwal and coworkers (38), children in PVS survive
somewhat longer in institutions than at home; other studies have shown converse results ( 40). A more extensive consideration of the PVS can be found in Chapter 8.
Hypoglycemia
The neonate does not show any specific symptoms of hypoglycemia. Table 15.2 outlines the clinical picture of symptomatic hypoglycemia in term neonates, as
recorded from a Scandinavian nursery (41).
TABLE 15.2. Symptoms of neonatal hypoglycemia in 44 newborn patients
a
Transient hypoglycemia has been observed in a relatively significant proportion of infants with intrauterine growth retardation, perinatal asphyxia, or other forms of
perinatal stress (42,43), and in neonates born to mothers with diabetes or toxemia (44). The incidence of neonatal hypoglycemia is difficult to ascertain because of the
different criteria used to define hypoglycemia and because of the varieties of feeding routines used in nurseries. Normal plasma glucose values during the first week
of life have been published (45). With hypoglycemia defined as glucose levels of 20 mg/dL or less, the condition was identified in 5.7% of cases at the University of
Illinois Hospital Nursery (46). The incidence is higher in low-birth-weight infants.
Symptoms of hypoglycemia may appear as early as 1 hour after birth, particularly in infants who are small for gestational age, but generally they are delayed until 3 to

24 hours. In approximately 25%, hypoglycemia does not become symptomatic until after 24 hours ( 41). An inconstant relationship exists between blood glucose levels
and hypoglycemic symptoms. Some infants with blood sugar levels between 20 and 30 mg/dL develop hypoglycemic symptoms, whereas others whose levels fall
below 20 mg/dL can remain asymptomatic (47). Evoked potentials have provided evidence for the critical value at which hypoglycemia affects the brain. SSEPs and
brainstem auditory-evoked potentials become abnormal in term infants when their blood sugar falls below 41.5 and 45.0 mg/dL, respectively ( 48). Visual-evoked
responses remain normal at these levels. A rapid compensatory increase in cerebral blood flow resulting from recruitment of previously unperfused capillaries
mediated by an increase in plasma epinephrine levels occurs at or below blood glucose values of 30 mg/dL ( 49,50 and 51). Magnetic resonance imaging (MRI)
studies can show patchy hyperintensities in the occipital periventricular white matter. These lesions tend to resolve with prompt therapy ( 51a). From the point of view
of a neurologist it therefore seems prudent that any blood glucose value of 45 mg/dL or less should be emergently corrected and followed closely to ensure
normoglycemia.
The clinical management of hypoglycemia in the neonates is beyond the scope of this text. The reader is referred to a flow diagram by Cornblath and Schwartz ( 52).
It is difficult to know what the outlook is in terms of neurologic and cognitive deficits for neonates who develop symptomatic hypoglycemia. This is because of
limitations of current definitions for neonatal hypoglycemia, our inability to determine at what glucose level hypoglycemia becomes symptomatic, and on the various
other risk factors, which complicate the clinical course of hypoglycemic infants and confound every study on neurodevelopmental outcome ( 53). From a multitude of
data derived from neonates without other major risk factors, who had severe hypoglycemia as a consequence of nesidioblastosis, it is clear that a significantly low
plasma glucose level that persists over a prolonged period of time can indeed result in major brain damage. The risks of asymptomatic neonatal hypoglycemia are
even more undefined, because low-birth-weight and stressed infants, the group with the highest incidence of hypoglycemia, are also subject to a variety of other
prenatal and perinatal risks, notably hypoxic ischemic encephalopathy ( 54).
When older infants and children develop symptomatic hypoglycemia, the condition presents with autonomic symptoms, which accompany a progressive impairment of
neurologic function. The serum glucose level at which symptoms appear varies, but any child with a blood glucose level of 46 mg/dL or less is suspect for
hypoglycemia (55). Autonomic symptoms are mainly caused by increased adrenaline secretion. They include anxiety, palpitations, pallor, sweating, irritability, and
tremors (55). During the initial stages, impaired neurologic function is manifested by dizziness, headache, blurred vision, somnolence, and slowed intellectual activity.
Transient cortical blindness is seen only rarely ( 56). In fact, if permanent blindness accompanies hypoglycemia, one must consider the diagnosis of congenital optic
nerve hypoplasia associated with hypopituitarism (see Chapter 4) (57). If hypoglycemia is prolonged, subcortical and diencephalic centers become inoperative. The
brainstem, the area most resistant to hypoglycemia, is the last to be affected.
Almost all children develop generalized or focal seizures during a severe hypoglycemic episode. With even more prolonged involvement, tonic extensor spasms and
shallow respirations develop. The response to intravenous glucose is immediate in patients who have not progressed to brainstem involvement. In children who have
experienced prolonged unconsciousness or repeated hypoglycemic attacks the prognosis for complete recovery is poor and approximately one-half of the patients
remain mentally retarded (58).
Not uncommonly, the clinician encounters a child whose first seizure occurred in the setting of suspected hypoglycemia, but who continues to experience seizures in
the absence of hypoglycemia. Although prolonged hypoglycemia can indeed induce hippocampal damage and thus set up a seizure focus, we believe that isolated

hippocampal damage is quite rare, and that, in the majority of such cases, both initial and subsequent seizures are unrelated to hypoglycemia. Transient hemiparesis
or aphasia has been seen in diabetic children, often in association with documented hypoglycemia. The cause of these focal deficits is unclear, but they could reflect
focal seizures followed by Todd's paralysis ( 59).
Brain Death
The Ad Hoc Committee on Brain Death from the Children's Hospital, Boston, has defined brain death:
Brain death has occurred when cerebral and brainstem functions are irreversibly absent. Absent cerebral function is recognized clinically as the lack of
receptivity and responsivity, that is, no autonomic or somatic response to any sort of external stimulation, mediated through the brainstem. Absent
brainstem function is recognized clinically when pupillary and respiratory reflexes are irreversibly absent. . . . Particularly in children, peripheral nervous
activity, including spinal cord reflexes, may persist after brain death; however, decorticate or decerebrate posturing is inconsistent with brain death ( 60).
Recommendations made by a special task force appointed to set guidelines for determining brain death have been published ( 61). Although it is generally recognized
that particular caution should be exerted when diagnosing brain death in small children, the task force further emphasized this age distinction by recommending
different brain death criteria for infants between 7 days and 2 months of age, between 2 months and 1 year, and older than 1 year. The period of observation before
declaration of brain death in the youngest group should be such that two examinations and EEGs to document electrocerebral silence are performed, separated by at
least 48 hours. In the group from 2 months to 1 year of age, the interval between the two examinations and EEGs can be reduced to 24 hours. Furthermore, a repeat
examination and EEG are not necessary in this group if radionuclide angiography demonstrates absent cerebral blood flow ( 62). In children older than 1 year, the task
force recommended the period of observation be a minimum of 12 hours, unless corroborating tests added further support to the diagnosis of brain death. When the
extent and reversibility of brain damage are difficult to assess because of the type of insult (e.g., hypoxic-ischemic encephalopathy), the observation period should be
extended to at least 24 hours.
Some authorities have challenged these recommendations and a survey of pediatric intensive care units shows substantial variability even within the same pediatric
intensive care unit with respect to criteria used by clinicians for the diagnosis of brain death ( 63). In a clinical and neuropathologic study of brain death, Fackler and
coworkers found no support for employing distinct brain death criteria for infants between 2 months and 1 year of age ( 64). Other investigators question the validity of
relying on the EEG to confirm brain death, because EEG activity is occasionally seen after brain death ( 65). Conversely, phenobarbital levels above 25 to 35 µL can
suppress EEG activity in neonates (66). The brainstem-auditory evoked response cannot be used as a confirmatory laboratory criterion of brain death. Its absence is
not predictive of brain death and persistence of peak I has occasionally been seen in brain dead infants ( 67). Although complete absence of cerebral blood flow is
considered irrefutable evidence of brain death, cerebral blood flow is extremely low in normal term or preterm newborns ( 10).
We believe that as more sophisticated imaging techniques such as xenon-enhanced computed tomography (CT), single photon emission computed tomography
(SPECT) (68), and positron emission tomography (PET) (69) are applied to the clinical evaluation of brain death in children, the criteria for making this diagnosis will
become refined and perhaps simplified.
An important aspect in diagnosing brain death is the documentation of apnea. During this procedure, it is vital to prevent hypoxemia. Administration of 100% oxygen
for 10 minutes is recommended before withdrawal of respiratory support. A catheter should be inserted into the endotracheal or tracheostomy tube, and oxygen be

continued at 6 L/minute during the test. The arterial pCO
2
level should be allowed to increase to 60 mm Hg. Patients who are hypothermic or receiving medications
that suppress respiration cannot be reliably tested using this procedure ( 70). When diabetes insipidus is seen, it reflects midbrain death ( 71).
Disorders of Acid–Base Balance
Pathology
Both pH and ionic concentrations within the CNS are controlled by the blood–brain barrier, which renders the brain relatively resistant to alterations in the electrolyte
composition of serum. In disorders of acid–base balance, the blood pH correlates poorly with the presence or severity of neurologic symptoms. This is because
cerebrospinal fluid (CSF) pH tends to fluctuate less than arterial pH, even with wide shifts in serum hydrogen ion concentrations. Resistance to shifts of systemic pH is
most pronounced in metabolic acidosis, less evident in metabolic and respiratory alkalosis, and least effective in respiratory acidosis. Homeostatic factors maintaining
the pH of CSF include alterations in cerebral blood flow, active transport of H
+
and HCO
3
–
, and carbon dioxide removal. These factors are reviewed by Plum and
Siesö (72). In respiratory acidosis, the pH of CSF deviates from normal as much as or more than arterial pH. This deviation often obscures the severity of acid–base
disturbance and suggests measurements of CSF pH in encephalopathies associated with ion imbalance are preferable to those of blood pH.
Clinical Manifestations
The neurologic picture of acid–base disorders is nonspecific. Children become progressively more obtunded, finally delirious, and comatose. Seizures are rare. Often,
the patient's clinical condition does not correlate well with either blood or CSF pH, although in patients with respiratory acidosis, neurologic symptoms are invariably
present when the pH of CSF decreases below 7.25.
Disorders of Electrolyte Metabolism
Sodium and Potassium
Disturbances of serum electrolytes can induce changes in the ionic composition of the intracellular and extracellular compartments of the brain. These changes can
have major effects on the excitability of the neural membrane and on the processing and transmission of neuronal signals. The membrane potential depends in part
on the ratio of intracellular and extracellular sodium and potassium concentrations. Major shifts in serum sodium concentrations disrupt cerebral function as a result of
altered osmolality of the cellular compartments. A normal potassium level is essential for the maintenance of the membrane potential. In contrast to the ease with
which fluctuations in serum sodium concentration affect intracerebral sodium, the concentration of extracellular potassium within the brain, as reflected by CSF levels,
varies little, even with such major shifts as those induced by intravenous infusions of potassium or by the administration of corticosteroids. It is, therefore, uncertain

what role potassium plays in the evolution of cerebral symptoms commonly associated with hyperkalemia or hypokalemia. The effect of potassium on muscular
function is reviewed in Chapter 14. The reader is also referred to a review by Katzman and Pappius (73) for a full discussion of the pathogenesis of cerebral
symptoms in electrolyte disorders and to a review by Strange on disorders of osmotic balance ( 74).
Hyponatremia
Low-sodium syndromes can result from an increase in body water with retention of a normal sodium store or can occur after reduction of sodium stores. The clinical
conditions associated with hyponatremia are outlined in Table 15.3.
TABLE 15.3. Clinic conditions producing abnormalities of sodium concentration
In the experience of Arieff and colleagues, the most common cause for symptomatic hyponatremia in the pediatric population was administration of hypotonic fluids
combined with extensive extrarenal loss of electrolyte-containing fluids ( 75). Oral water intoxication from increased intake of tap water during the summer months also
induces symptomatic hyponatremia (76). Neurologic symptoms of hyponatremia include headache, nausea, incoordination, delirium, and, ultimately, generalized or
focal seizures with apnea and opisthotonus ( 77,78). On autopsy, cerebral edema and transtentorial herniation are seen ( 75,76).
Generally, severe neurologic symptoms with permanent residua do not develop at sodium levels above 130 mEq/L, unless plasma sodium has decreased rapidly.
Some have advocated rapid correction of hyponatremia in a patient with neurologic symptoms using urea in conjunction with salt supplements and water restriction
(79). A too rapid correction of hyponatremia has been thought to play a role in the development of central pontine myelinolysis ( 80), a frequently fatal disorder
characterized clinically by confusion, cranial nerve dysfunction, and, in larger lesions, a “locked in” syndrome and quadriparesis. Pathologically, central pontine
myelinolysis is characterized by symmetric destruction of myelin at the center of the pons. The pontile demyelination can be visualized by MRI ( 81). According to
Brunner and colleagues, central pontine myelinolysis is more likely to develop when the initial sodium level is less than 105 mEq/L, when hyponatremia has
developed acutely, and when sodium levels are corrected too rapidly ( 82). Other investigators have challenged the concept that this condition is related to the rate of
correction of hyponatremia, and the optimal rate for correcting hyponatremia is still controversial ( 83). According to Keating and colleagues, an optimal rate of
correction is 2 to 3 mEq/L per hour (76).
Hypernatremia
Increased concentration of sodium in body fluids elevates fluid osmolality and induces severe cerebral manifestations. Major causes for hypernatremia are outlined in
Table 15.3.
Luttrell and Finberg have delineated the factors responsible for neurologic symptoms. These are subdural hematomas, venous and capillary congestion, and
hemorrhages, the last produced by shrinkage of the brain during dehydration ( 84).
Neurologic symptoms can also occur in the absence of any structural alteration and are probably the direct result of hyperosmolality. Symptoms are caused by
cerebral edema, which is particularly likely to occur with rapid rehydration and is caused by an elevated content of chloride and potassium in the brain ( 85,86).
Hypernatremia is generally seen in infants younger than 6 months of age. All have clear evidence of dehydration. Patients have varying degrees of impaired
consciousness and hyperpyrexia. Approximately one-third experience generalized convulsions and spasticity. Focal neurologic abnormalities, notably hemiparesis,
are seen in approximately 10% of patients. Finberg found subdural hematomas in many of his hypernatremic infants ( 87). In some, neurologic symptoms, notably

seizures, do not appear until 24 to 48 hours after the start of fluid therapy. These symptoms have been ascribed to cerebral edema and a lowered convulsive
threshold developing with rehydration of the brain ( 85).
The mortality of children who develop neurologic symptoms with hypernatremia ranges from 10% to 20%. Approximately one-third of survivors have permanent
sequels, notably seizures, spasticity, and mental retardation ( 88).
Chloride
Hypochloremia
A syndrome marked by anorexia, lethargy, failure to thrive, muscular weakness, and hypokalemic metabolic alkalosis was seen in infants who ingested a
chloride-deficient formula for the preceding 1 or more months (89,90). Serum chloride as low as 61 mEq/L and arterial pH values as high as 7.74 were recorded ( 89).
Usually, urinary chlorides were completely absent. Impaired growth of head circumference was documented in the majority of cases. Rehydration and chloride
supplementation reversed all symptoms and resulted in a marked acceleration of motor milestones and in complete or partial recovery of the decelerated skull growth.
Developmental testing in some of these children at 9 to 10 years of age indicated that children who had received this formula had significantly lower scores on the
Wechsler Intelligence Scale for Children (WISC) and significantly higher risks for receptive and expressive language disorders ( 91). We have recognized a clinical
picture of an expressive language delay, coupled with visuomotor deficits and an attention deficit disorder that often assumes the overfocused pattern (see Chapter
16). When the defect is more severe, the language and visuomotor problems can expand to a picture of generalized mental retardation, and the attention disorder can
exhibit autistic features (92). A similar condition has been seen in nursing infants whose mothers' milk was for unknown reasons deficient in chloride ( 93).
Calcium
Calcium is the major extracellular divalent cation. Both high and low serum calcium levels are associated with neurologic symptoms. Total calcium in serum is found in
three forms: protein bound, and therefore nondiffusible (30% to 55% of total); chelated (i.e., diffusible but nonionized; 15% of total); and ionized (remaining
percentage). Generally, the appearance of neurologic symptoms correlates well with levels of ionized calcium of 2.5 mg/dL or less. The concentration of CSF calcium
is normally approximately one-half that of serum calcium and represents the result of a secretory process, rather than the movement of diffusible and ionized calcium
from the serum. Changes in the CSF concentration are relatively small, although large alterations in serum calcium values overcome homeostatic mechanisms ( 73).
Hypocalcemia
The clinical picture of hypocalcemia and its causes varies with the age of the affected child. Some of the syndromes that produce hypocalcemia are outlined in Table
15.4.
TABLE 15.4. Conditions producing hypocalcemia, hypomagnesemia, and neurologic symptoms
Hypocalcemia was one of the more common causes of seizures during the neonatal period. The condition can be defined as a level of serum calcium below 7 mg/dL
or of ionized calcium below 3.5 mg/dL. It is commonly seen in the preterm neonate or in the stressed term neonate ( 106). Two forms of neonatal hypocalcemia are
encountered. One occurs during the first 2 days of life in premature and critically ill term infants. It is also seen in infants who have suffered perinatal asphyxia and in
infants of mothers with insulin-dependent diabetes. As many as 50% of very-low-birth-weight infants have serum calcium levels below 7 mg/dL ( 107). The exact
mechanism of this form of hypocalcemia is still obscure. Impaired vitamin D metabolism also has been excluded as a pathogenetic factor. Increased levels of

calcitonin have been suggested as an etiologic factor in the hypocalcemia of prematurity, but not in that seen in infants of diabetic mothers ( 108). Decreased
end-organ responsiveness, decreased calcium intake and absorption, and respiratory alkalosis are also believed to play a role ( 107). Less often, maternal
hyperparathyroidism, congenital absence of the parathyroid glands, or disturbed renal function induce neonatal hypocalcemia (see Table 15.4). The second form of
neonatal hypocalcemia is the classic neonatal tetany (late hypocalcemia), whose mechanism was first elucidated by Bakwin in 1937 ( 109). It occurs between the fifth
and tenth days of life and results in part from intake of cow's milk, which induces an increased phosphate load. In this form of hypocalcemia, hyperphosphatemia and
hypomagnesemia are commonly present (97). Additionally, low circulating parathyroid hormone levels are seen. With the widespread use of low-phosphate milk
formulas this condition has virtually disappeared. In the series of Lynch and Rust, congenital heart disease was seen in 47% of infants with hypocalcemic seizures,
and prematurity in 13%. Maternal hyperparathyroidism, idiopathic hypoparathyroidism, and DiGeorge syndrome were other causes. In 20% of infants there was no
obvious cause for the seizures (110).
Neonatal hypomagnesemia has been recorded in association with hypocalcemia resulting from maternal hyperparathyroidism ( 106). It can also be the result of a
selective malabsorption of magnesium (108) (see Table 15.4).
Hypocalcemic seizures can be focal, multifocal, or generalized. In the series of Lynch and Rust, multifocal clonic seizures were the most common. True tonic seizures
or tonic-clonic (grand mal) attacks are unusual, and the latter seizure type was not encountered by Lynch and Rust ( 110). In the interictal period, infants generally are
alert, and seizures without apparent loss of consciousness are not uncommon ( 97). Jitters were encountered in 35% of hypocalcemic infants in the 1971 series of
Cockburn and coworkers (97), and in 27% of infants in the series of Lynch and Rust (110). An increased extensor tone is relatively common, as are increased deep
tendon reflexes and ankle clonus. In contrast to neonates suffering from seizures owing to nonmetabolic causes, persistent focal neurologic deficits are not observed.
The classic signs of tetany seen in the older child are usually absent. Carpopedal spasm was rare, stridor owing to laryngospasm, and Chvostek's sign (a brief
contraction of the facial muscles elicited by tapping the face over the seventh nerve) was not noted in any of the hypocalcemic infants reported by Keen ( 111).
The EEG is frequently abnormal. It can demonstrate electroencephalo-graphic seizures ( 110).
The treatment of seizures caused by neonatal tetany consists primarily of the administration of calcium salts (see the section on neonatal seizures in Chapter 13). The
long-term outlook of infants who have experienced seizures owing to late hypocalcemia is generally good and in the absence of subsequent neurologic insults the
majority develop normally (97,110,111). Calcium deposition in necrotic areas of brains of stressed neonates has been related to the transient elevations of ionic
calcium after parenteral administration of calcium gluconate ( 112).
In older infants and in children, neurologic symptoms of hypocalcemia include tetany and seizures. Tetany is characterized by episodes of muscular spasms and
paresthesias mainly involving the distal portion of the peripheral nerves. Episodes appear abruptly and are precipitated by hyperventilation or ischemia. No alteration
of consciousness occurs. Carpopedal spasm and laryngospasm are the two most frequent examples of tonic muscular spasms. Chvostek's sign is not diagnostic of
tetany, because it is seen in healthy infants. Seizures can occur in the absence of tetany and are occasionally focal. Headaches and extrapyramidal signs are less
common and are confined to older children or adults with hypoparathyroidism ( 113). In this condition, CT scans can show symmetric bilateral punctate calcifications of
the basal ganglia, although only 50% show an association between this finding and the occurrence of extrapyramidal signs ( 113).
Pseudohypoparathyroidism is characterized by obesity, moon-shaped facies, mental retardation, cataracts, short, stumpy digits, enamel defects, and impaired taste

and olfaction. Calcifications of the basal ganglia are seen in approximately one-third of instances. The condition is seen more commonly in females and is caused by
an inability of renal tubules to respond to parathormone ( 103).
In neonates undergoing gastrostomy for various reasons, vitamin D malabsorption can lead to hypocalcemic seizures. This condition is treated by parenteral
administration of vitamin D (114). Tetanic seizures also can result from sodium phosphate enemas (115).
Hypercalcemia
Aside from hyperparathyroidism, which is rare, hypercalcemia of childhood takes two forms: mild hypercalcemia and the hypercalcemia elfin-facies syndrome
(Williams syndrome) (see Chapter 3). Patients with mild idiopathic hypercalcemia usually show a sudden failure to thrive between 3 and 7 months of age. The
condition is probably the result of excess vitamin D intake and is reversible with restriction of calcium and vitamin D intake.
Williams syndrome is covered in Chapter 3. Neonatal hypercalcemia also is seen in the presence of subcutaneous fat necrosis and blue diaper syndrome. The latter
is a rare familial disease in which hypercalcemia is associated with a defect in the intestinal transport of tryptophan. The blue diaper results from the oxidation of
indican, a tryptophan derivative (116). Neurologic symptoms are generally absent, although optic nerve hypoplasia has accompanied this condition.
Magnesium
Since the 1970s, it has become apparent that a number of symptomatic infants with combined hypocalcemia and hypomagnesemia respond only to the administration
of magnesium (117). This condition, termed congenital hypomagnesemia, is marked by recurrent tetany or convulsions, which commence during the first few weeks of
life and respond to administration of magnesium but not calcium. Blood magnesium levels can be as low as 0.04 mmol/L, as contrasted with mean normal levels of 0.8
mmol/L, with hypomagnesemia being defined as levels below 0.65 mmol/L (118). Although boys are overrepresented in reported cases, this condition is now believed
to be transmitted as an autosomal recessive disorder (119), and in one extended Bedouin family it has been mapped to the long arm of chromosome 9 (9q) (120). The
condition is caused by a selective defect in magnesium absorption in the small intestine ( 121). This is believed to result from a defect in a receptor or ion channel
(120). Symptomatic hypocalcemia also occurs and is believed to be secondary to impaired synthesis or secretion of parathyroid hormone, or end-organ
unresponsiveness to parathormone as a result of diminished activity of magnesium-dependent enzymes. When treated early and consistently, the outcome is good in
terms of neurodevelopment, but untreated children can die or experience permanent brain damage ( 119). Congenital hypomagnesemia is distinct from primary familial
hypomagnesemia, whose gene has been mapped to the long arm of chromosome 3 (122).
Hypomagnesemia also is seen in infants of diabetic mothers and in small-for-date infants. It has been described in conjunction with maternal hypoparathyroidism,
neonatal hepatic disease, and increased loss of magnesium, as might occur after repeated exchange transfusions.
In older infants or children, low plasma magnesium levels are encountered in malabsorption syndromes, prolonged diarrhea, rickets, protein energy malnutrition or
other forms of chronic malnourishment, and hypoparathyroidism (117,123).
Diagnosis of the Metabolic Encephalopathies
In most instances, the differential diagnosis of the metabolic encephalopathies rests on the clinical history and on laboratory examinations. The clinical and EEG
pictures tend to be nonspecific and usually reflect dulling of consciousness and a diffuse cerebral disorder. The examining physician, therefore, must go through the
differential diagnosis of impaired consciousness in an infant or child.

A history obtained quickly but competently is the first requirement for the differential diagnosis of coma. The physician must determine if loss of consciousness
occurred without warning or was preceded by other symptoms, such as an upper respiratory infection, gastrointestinal disturbances, headaches, or unsteady gait. If
the onset of unconsciousness was sudden, one has to consider acute poisoning, trauma, postictal stupor, or, less likely, an intracranial or subarachnoid hemorrhage.
Trauma and acute subdural and extradural hemorrhages secondary to trauma are unlikely in the absence of external injuries and retinal hemorrhages and in the
presence of a normal CT scan, whereas a normal CSF virtually excludes a subarachnoid hemorrhage. Focal neurologic signs are the rule in an intracerebral
hemorrhage. Poisoning is often difficult to exclude, particularly in a toddler, and warrants gastric lavage and blood screening for toxins in all undiagnosed cases of
coma. Making a diagnosis of postictal stupor is difficult after an unobserved convulsive attack unless one can elicit a history of a seizure disorder. Obstruction of the
ventricular system by an intraventricular tumor, and hemorrhage arising from a hemangiomatous malformation within the brainstem are rare causes for sudden loss of
consciousness.
When loss of consciousness is preceded by an illness, the diagnosis of metabolic encephalopathy, acute meningitis, encephalitis, or increased intracranial pressure
must be considered. Examination of the eye grounds for papilledema, neuroimaging studies, blood chemistries, and a lumbar puncture are required to distinguish
among the various entities. It is hazardous to arrive at a diagnosis of encephalitis in a patient who has normal CSF. Rather, one must consider other conditions. Acute
toxic encephalopathy and Reye syndrome are two entities, which are now relatively uncommon. They were characterized by vomiting, seizures, and prolonged loss of
consciousness. Because they have been postulated to have a viral cause, they are considered in Chapter 6.
NEUROLOGIC COMPLICATIONS OF PULMONARY DISEASE
In the past, neurologic problems in children with lung disease were encountered relatively infrequently, but with the recent advent of improved management for both
acute and chronic pulmonary disease, and hence prolonged survival, such disorders are being recognized increasingly.
Extracorporeal membrane oxygenation (ECMO) is being used in most medical centers to treat neonates with uncontrollable respiratory failure ( 124). 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. Even though there is a compensatory response anatomically mediated through the circle of Willis,
approximately one-fourth of infants demonstrate focal parenchymal lesions on postECMO MRI ( 125). 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 ( 126). These
abnormalities are demonstrable on head ultrasound studies performed during the course of ECMO ( 127). Additionally, there is a significant incidence of left
hemiparesis and left focal seizures. These deficits, seen during the neonatal period, however do not always translate into focal functional disabilities in later life. The
neurodevelopmental outcome of infants who had been placed on ECMO has been surveyed in several centers. Most studies record a handicap rate of approximately
20% to 30% (128,129). The underlying diagnosis necessitating ECMO is in part a predictor of the outcome. Children who required ECMO because of meconium
aspiration have higher developmental indices than those whose underlying diagnosis was sepsis ( 129), whereas children who develop bronchopulmonary dysplasia
after ECMO fare less well (130). Serial plasma lactate concentrations obtained during the procedure may help predict the developmental outcome ( 131), as may the
degree of abnormality seen on neuroimaging (132). The major causes of handicap are spastic quadriparesis, seizures, impaired cognitive functioning, and language

delay (128). Additionally, approximately 20% of children have abnormal hearing, most commonly a sensorineural hearing loss ( 133,134). This figure, obtained by
testing brainstem auditory-evoked potentials on ECMO-treated infants at the time of hospital discharge, may be falsely low, and at least in some infants hearing loss
appears to have a delayed onset and to be progressive (135). The sensorineural hearing loss seen in children postECMO treatment parallels an incidence of 37% of
generally bilateral sensorineural hearing loss in children with persistent fetal circulation who are not treated with ECMO. Although prolonged hyperventilation has
been implicated in this deficit, other factors are probably operative ( 136,137).
Theophylline is commonly used in the nursery for the treatment of apnea and in older children for 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 levels of 21 to 23 µg/mL ( 138,139). 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 (140). 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 the past, a progressive degenerative disease of the CNS was seen in premature infants with bronchopulmonary dysplasia or other forms of severe and chronic lung
disease who were receiving ventilatory support. This condition involved the cerebral cortex, brainstem, or basal ganglia ( 141). With improved control of the respirator
variables, which affect mechanical ventilation, this entity is no longer encountered.
A distinctive neuromuscular syndrome has been encountered in children who had been on prolonged ventilatory support and nondepolarizing neuromuscular blocking
agents. The condition is more common in the adult population and has been termed critical illness neuromuscular disease (142). Several overlapping syndromes are
subsumed under that term. Some patients suffer from an axonal motor neuropathy, whereas in others a defect at the neuromuscular junction or a myopathy can be
documented by electrophysiologic studies or biopsy ( 143). The clinical picture is similar and is highlighted by an inability of most such patients to be weaned from a
respirator. Neurologic examination discloses a quadriparesis with absent or reduced reflexes, a neuropathic or myopathic electromyography result (EMG), and normal
or only slightly elevated creatine kinase levels. Nerve conduction studies on patients with the axonal polyneuropathy show a mild slowing of motor velocity, and a
muscle biopsy shows grouped atrophy. In critical illness myopathy there is a type II muscle fiber atrophy ( 144). The cause or causes for the clinical picture are
obscure (145). Intravenous immune globulin has been suggested, but even without treatment affected children improve over the course of ensuing weeks or months.
The neurologic picture in chronic pulmonary disease (e.g., in advanced cystic fibrosis) results from hypoxia combined with carbon dioxide retention, and, to a lesser
degree, from chronic respiratory acidosis. Children develop progressively deepening lethargy that, often with the onset of a respiratory infection, progresses to coma.
Approximately 14% show papilledema, the consequence of increased intracranial pressure owing to chronic carbon dioxide retention, which induces dilatation of the
cerebral vasculature (146). Seizures are rare. With evolution of the encephalopathy, asterixis and multifocal myoclonus become prominent. Asterixis consists of
sudden flapping movements of the palms at the wrists (liver flap), most easily elicited when the arms are outstretched and the hands dorsiflexed.
During coughing paroxysms, such as are seen in cystic fibrosis, the most common neurologic complaints are lightheadedness and headache. Visual disturbances,
paresthesias, tremor, and speech disturbances are occasionally encountered ( 147). All symptoms are reversible.
NEUROLOGIC COMPLICATIONS OF GASTROINTESTINAL AND HEPATIC DISEASE

Hepatic Encephalopathy
When the liver is damaged by acute or chronic disease, a characteristic set of neuropsychiatric symptoms develops termed hepatic encephalopathy (HE). The
etiology of HE is still debated, but it is probably the consequence of systemic shunting of gut-derived constituents, caused by the impaired extraction by the failing
liver (148,149).
Pathology and Pathogenesis
The morphologic changes in the brain are dominated by astrocytic alterations. The principal microscopic abnormalities include enlargement and increase in the
number of protoplasmic astrocytes. These cells (Alzheimer II cells) are astrocytes with an enlarged, pale nucleus, and a marked diminution in glial fibrillary acidic
protein. They are found throughout the cerebral cortex, basal ganglia, brainstem nuclei, and Purkinje layer of the cerebellum. They are most prominent in the chronic
forms of liver disease and in patients dying after prolonged periods of coma ( 150). Neuronal changes are generally not seen. Less often, central pontine myelinolysis
has been noted in children with hepatic failure ( 151).
According to current consensus HE is multifactorial ( 152,152a). The two most important factors in its pathogenesis are increased plasma and brain concentrations of
ammonia and increased GABAergic neurotransmission.
Ammonia has been known to be neurotoxic for several decades. When astrocyte cultures are exposed to ammonia, they are transformed to Alzheimer II cells. From a
neurophysiologic point of view, ammonia enhances neuronal inhibition, either by acting directly on the GABA
A
receptor complex and increasing selectively the binding
of agonist ligands, or by promoting astrocytic synthesis of substances that activate the GABA
A
receptor complex (152).
However, approximately 10% of patients with HE have normal or only moderately elevated blood ammonia levels ( 153), and electrophysiologic experiments have
shown that at the ammonia concentrations seen in hepatic failure, (0.5 to 2 mM), ammonia blocks the formation of hyperpolarizing inhibitory postsynaptic potentials,
thus impairing postsynaptic inhibitory processes and increasing excitatory neurotransmission ( 154). These effects contrast with the clinical picture of hepatic coma,
making it evident that hyperammonemia is not solely responsible for HE.
Increased GABA-mediated neurotransmission contributes significantly to the manifestations of HE. Primarily studied in chronic liver disease, GABAergic transmission
is probably also affected in acute HE. Several mechanisms have been proposed. These include an increased availability of GABA in synaptic clefts, the result of
ammonia-induced abnormalities in glial function, leading to decreased GABA reuptake, increased levels of benzodiazepine receptor agonists ( 155), loss of
presynaptic feedback inhibition of GABA release caused by a decrease in the number of GABA
B
receptors, or increased transfer of GABA from blood to brain ( 154).
Studies in both animal models and humans with HE have demonstrated transient improvement in mental status after administration of flumazenil, a benzodiazepine

antagonist (156). The exact mechanism for improvement is unclear; it has been suggested that several, mostly unidentified endogenous or food-derived
benzodiazepine-like substances act as ligands for the receptor ( 157).
Additional metabolic disturbances may contribute to the evolution of HE. High levels of ammonia can increase glutamine synthesis. Although glutamine itself is not
neurotoxic, its metabolite alpha-ketoglutarate is. Furthermore, the increased synthesis of glutamine depletes the available amounts of alpha-ketoglutarate, reducing
the concentration of high-energy phosphates, and slowing the reactions in the Krebs tricarboxylic acid cycle. Decreased oxygen consumption and glucose metabolism
are probably secondary to HE rather than causative (152).
Evidence for the synergistic role of other neurotoxins such as mercaptans, short-chain fatty acids, and phenols, and the generation of false neurotransmitters such as
octopamine is currently less strong (152). Additionally, liver failure induces profound multisystem disturbances, which, in turn, can further impair neurologic function
(158).
Clinical Manifestations
HE can occur in two forms: acutely, as in fulminant hepatic failure, and as a chronic, progressive encephalopathy. In children, acute hepatic failure is primarily
responsible for clinically important HE. The most common predisposing causes are acute infectious hepatitis, ingestion of drugs (e.g., valproic acid, acetaminophen,
isoniazid, halothane) or toxins (e.g., mushroom poisoning) ( 159), or Wilson disease (160). In infancy, galactosemia, fructosemia, or tyrosinemia can present as
fulminant hepatic failure (see Chapter 1). In the past, Reye syndrome and hemorrhagic shock syndrome presented with fulminant liver failure (see Chapter 6).
The onset of the encephalopathy usually coincides with a deterioration of the general clinical condition. The principal signs and symptoms of hepatic coma are related
to disorders of consciousness. The stages of HE are outlined in Table 15.5. It is of the utmost importance that the first signs of encephalopathy are recognized.
Because the first evidence of encephalopathy can be outbursts of violent agitation or uncharacteristic behavior, the early stage of HE is frequently misdiagnosed. The
progression from stage I to stage IV can be exceedingly rapid. Hyperventilation can develop during stages II and III and can lead to alkalosis, low serum pCO
2
, and a
further deterioration of mental status. A fine tremor and more characteristically coarse flapping movements, termed asterixis, can be present in stages I and II,
respectively, whereas decorticate and decerebrate postural responses accompany stage IV of HE. Choreic movements, a fluctuating rigidity of the limbs, dystonia,
and periods of noisy delirium are particularly frequent in children ( 161).
TABLE 15.5. Signs and symptoms of hepatic encephalopathy
Cerebral edema is a prominent part of the clinical picture of acute HE and is the principal cause of death, with brainstem herniation found in up to 80% of patients
dying in fulminant hepatic failure ( 162). The cause of cerebral edema is unknown, and it is believed to be both vasogenic and cytotoxic, with the latter being more
important. In vasogenic edema, there is a toxin-induced breakdown of the blood–brain barrier, with leakage of serum proteins through the capillary endothelium into
the brain parenchyma. The cytotoxic aspects of cerebral edema result from an impaired cellular osmoregulation, which results in intracellular accumulation of fluids,
mainly within astrocytes (163).
Although severe liver disease is a prerequisite for the appearance of HE, ascites, jaundice, edema, or hepatomegaly do not invariably accompany the neurologic

involvement. In fact, frequently, as irreversible liver failure supervenes, previously elevated serum transaminase levels decrease rapidly, the coagulopathy worsens,
the initially enlarged liver shrinks, and the total bilirubin climbs while the conjugated portion decreases.
In a majority of patients, the EEG shows paroxysmal and diffuse bursts of high-voltage slow-wave activity, a pattern that is not specific for HE but is highly indicative of
one of the metabolic encephalopathies. Triphasic waves, characteristic for HE, are common in adults but rare in children. Clinical or EEG evidence of seizures is
associated with a poor outcome (164).
Treatment and Prognosis
The advent of successful liver transplantation has revolutionized the management, treatment, and prognosis of children with liver failure and HE ( 165). Liver
transplantation now offers a success rate of between 55% and 89% (166). Therefore, the child with HE requires meticulous medical management until either the liver
resumes adequate function or a replacement organ is found. Management of the precipitating event, dietary protein restriction, avoidance of constipation, and
alteration of the intestinal flora are the major aspects of the therapeutic regimen ( 167). The therapeutic value of flumazenil, a benzodiazepine antagonist, appears to
be minimal in the pediatric population (168). Response to flunazenil is transient; the medication may precipitate an anaphylactic reaction. For a comprehensive
discussion of the therapy of hepatic failure, the interested reader is referred to reviews by Jalan ( 149), Sherlock (153), and Devictor (169).
The neurologist involved in the treatment of the child in HE should consider that neurologic symptoms can result from six complications: hypoglycemia, sepsis,
intracranial bleeding as a consequence of a coagulopathy, renal failure (seen in approximately one-half of patients with hepatic failure), electrolyte disturbances
(notably hyponatremia, hypokalemia, and hypocalcemia), and cerebral edema. Because cerebral edema mainly occurs on a cytotoxic basis, corticosteroids have no
role in the management. The best course of management is by fluid restriction and assisted hyperventilation. Minimizing stimulation (lights, sound, endotracheal
suctioning) avoids sharp increases in intracranial pressure that may become sustained and recalcitrant to therapeutic measures. Short-acting narcotics (fentanyl) can
be administered to further blunt intracranial pressure increase from stimulation. The judicious use of osmotic diuretics, such as mannitol, is recommended ( 153).
Hypothermia and barbiturate coma have been advocated, but should only be used if intracranial pressure is monitored. Extradural or subdural monitoring devices are
increasingly used for children in stages III or IV ( 169). These allow management of intracranial pressure and permit documentation of cerebral hypoperfusion and the
rapid fluctuations of intracranial pressure encountered during the transplant procedure ( 170). Placement requires an experienced neurosurgeon and may call for
simultaneous administration of fresh frozen plasma. In the experience of Blei and coworkers, a potentially fatal hemorrhage was the most common complication of
cerebral pressure monitoring in fulminant hepatic failure ( 171).
Liver transplantation is the definitive treatment in patients with acute or chronic hepatic failure, and in several major centers, including our own, results have been
encouraging both in terms of survival rate and posttransplant complications. The decision on which patients to transplant and when surgery is to be done is beyond
the scope of this text. Suffice it to say that the mortality of patients in stage IV HE is 63% to 80%. In particular, patients who have developed cerebral edema fare
badly and are not suitable candidates for liver transplant ( 172). In the experience of the Children's Hospital of Pittsburgh, 70% of children who developed cerebral
edema as demonstrated by CT scan died, and 15% were left with severe to profound neurologic deficits. The remainder was left with moderate deficits that prevented
them from an independent lifestyle (172). Sustained increases in intracranial pressure resulting in diminished cerebral perfusion pressure (less than 40 torr for more
than 2 hours) is generally accepted as a contraindication to liver transplantation ( 173). In addition, the cause of hepatic failure and a variety of other prognostic

indicators must be considered (174). In particular, the longer the interval between the onset of jaundice and the development of HE, the worse the outcome ( 175). As
a rule, somatosensory-evoked potentials are superior to EEG in terms of prognosis, and a lack of a thalamocortical potential presages a poor outcome ( 176).
Neurologic Complications of Liver Transplantation
Neurologic complications of liver transplantation occur in 30% to 60% of patients. They can be categorized into problems related to the underlying disease, problems
related to the transplant procedure, side effects of immunosuppressive drugs, and neurologic complications arising from immunosuppression ( 177).
In the pediatric age group infectious complications resulting from immunosuppression are the most common. These may take the form of acute meningitis, subacute
chronic meningitis, a meningoencephalitis, or a brain abscess. Conti and Rubin provide a timetable for the occurrence of infections in the transplant patient ( 178).
Opportunistic infections of the CNS during the first month after transplantation are rare. Between 1 and 6 months after transplantation, the risk for CNS infections is
the greatest. The organisms responsible for these infections differ from those causing infections in the immunocompetent child. Organisms include herpesvirus,
cytomegalovirus, Listeria monocytogenes, Aspergillus, and Nocardia (178). At 6 months posttransplant, patients are at risk for cryptococcal meningitis and
cytomegalovirus. The most common organism to cause acute meningitis in the immunocompromised child is Listeria monocytogenes. Cryptococcus, Listeria, and
Mycobacterium tuberculosis can be responsible for subacute infections. Abscess is most commonly caused by Aspergillus, Nocardia, and toxoplasmosis.
Neurologic symptoms can also result from the use of immunosuppressive agents. Cyclosporine induces neurologic symptoms in some 10% to 25% of patients ( 179).
The most common neurologic symptom is tremor. This can be caused by sympathetic activation, a leukoencephalopathy, or can be a part of generalized cerebellar
dysfunction (180). Less often, one can observe seizures. In some patients these appear to be related to metabolic derangements, notably hypomagnesemia. Seizures
are more likely to occur with the intravenous form of cyclosporine (Sandimmune) than with the oral form of the drug. The neurologic consultant is often asked whether
to start anticonvulsant therapy and which anticonvulsant is most appropriate. By inducing the hepatic P450 system most anticonvulsants interfere with the metabolism
of immunosuppressive agents, thus increasing their required dosage. Benzodiazepines, gabapentin, and valproate are the drugs of choice in that they tend to have a
lesser effect on cyclosporine metabolism (177).
Other serious complications include cerebellar symptoms, mental confusion, polyneuropathy, a motor spinal cord syndrome, thromboembolic phenomena, visual
hallucinations, and transient cortical blindness. Neuroimaging studies disclose diffuse white matter abnormalities and the EEG reveals diffuse slowing. The CSF is
generally normal (181,182). An encephalopathy, characterized by confusion, cortical blindness, quadriparesis, seizures, intracranial hemorrhage, and coma, also has
been encountered (182,183 and 184). It is often reversed after discontinuation or reduction of the immune suppressant and has been linked to low serum cholesterol
levels in that hypocholesterolemia upregulates the low-density lipoprotein receptor, which increases intracellular transport of cyclosporine ( 185,186). A
dose-dependent myopathy has been encountered some 5 to 25 months after initiation of cyclosporine therapy ( 187). In a small proportion of patients cyclosporine
induces a hemolytic uremic syndrome or thrombotic thrombocytopenic purpura with ensuing neurologic symptoms ( 188,189).
Tacrolimus is a potent new immunosuppressant, which is used increasingly in children. The spectrum and incidence of neurotoxicity is similar to that of cyclosporine.
A severe postural tremor and, less frequently, mutism and speech apraxia and seizures are the most common manifestations ( 190,191). Headaches are also
commonly seen, especially early after transplantation, a time when immunosuppression is highest. OKT3 is a monoclonal murine IgG immunoglobulin used for short
courses in severe acute organ rejection. This agent can induce a sterile CSF pleocytosis. Symptoms include fever, headache, photophobia, meningism, cerebral

edema, and transient hemiparesis. They are reversed by cessation of OKT3 treatment (192,193).
At dosages required for immune suppression, corticosteroids may induce mental status changes, a steroid myopathy, cerebrovascular changes owing to hypertension,
and pseudotumor cerebri, which can develop after corticosteroid withdrawal. Neurologic complications of the other immunosuppressive agents are covered by Walker
and Brochstein (179). A primary CNS lymphoma is seen in some 2% of organ transplant patients.
The clinical picture of these various complications most often takes the form of an encephalopathy, characterized by changes in mental status. This picture was
encountered in 50% of children in the University of Pittsburgh hepatic transplant series of Martinez and coworkers ( 194). The most important causes were infections,
intracranial bleeds, and metabolic abnormalities. Seizures were seen less often (33% of children), and focal neurologic deficits occurred in 13%. Parkinsonian
symptoms of bradykinesia and hypokinesia, cog-wheel rigidity, and resting tremor have been noted after bone marrow transplantation ( 195). In the series of Martinez
and colleagues, the most common pathologic findings in children dying after having undergone a liver transplantation were cerebral edema, a variety of ischemic and
hemorrhagic vascular lesions, and infections, mainly caused by cytomegalovirus, aspergillosis, and candidiasis ( 194). A liver transplant series reported from the
University of California, Los Angeles, UCLA School of Medicine shows similar neuropathologic sequelae ( 196). Aspergillosis of the CNS is a particularly common
infection in immunocompromised children. In the University of California, Los Angeles, UCLA School of Medicine series, 1.1% of adult and pediatric patients had
disseminated aspergillosis with multiple brain abscesses. Solitary or multiple subcortical infarctions of the cerebral hemispheres or cerebellum and meningeal
involvement are other common features of aspergillosis. The diagnosis could not be made during the lifetime in more than one-half of the cases, and blood culture
results are generally negative (197). Central pontine myelinolysis and focal pontine leukoencephalopathy also have been encountered. Central pontine myelinolysis is
most commonly seen in liver transplant recipients, but it has also been seen after renal transplant ( 198,199). Focal pontine leukoencephalopathy refers to a
pathologic picture of multiple microscopic foci of vacuolization, necrosis, calcification, and axonal injury of the pontocerebellar or corticospinal tracts of the basis
pontis (196). Neither of these conditions was diagnosed during the lifetime of the patient ( 199). In most instances, clinicopathologic correlation is difficult and the
factors that lead to one or the other neuropathologic abnormality are obscured by the multiplicity of complications that befall transplant patients before their demise.
The neurologic consequences of the transplant procedure are related to the major fluid and electrolyte shifts that can occur during the course of the operation. All
these factors contribute to the neurologic mortality associated with liver failure. Intracranial hemorrhage secondary to coagulopathy and severe ischemic injury
secondary to hypoperfusion are uncommon but devastating consequences. Patients with fulminant hepatic failure can continue to experience encephalopathy and
life-threatening cerebral edema for several days after the transplant. Intraoperative intracranial pressure may increase secondary to the stress of surgery, supine
operating position, or fluid shifts. Rapid shifts in sodium concentrations in the perioperative period have been associated with the development of central pontine
myelinolysis (194).
Children who are long-term survivors of liver transplantation after chronic hepatic failure are at greater risk for intellectual and neuropsychological deficits than are
children with other chronic illnesses. Whether this is an effect on cognitive functioning of the pretransplant hepatic disease or the posttransplant immune suppressant
therapy remains to be established (200).
Vitamin E Deficiency States
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 (201). Generally, vitamin E deficiency induces a spinocerebellar degeneration, resembling that seen in spinocerebellar (Friedreich's) ataxia. This
picture is seen in a variety of conditions marked by chronic malabsorption ( 202). Thus, children with chronic cholestatic liver disease can develop a syndrome
characterized by areflexia, gait disturbance, decreased proprioception and vibratory sensation, and gaze paresis ( 203). Dystonia is seen less commonly (162). Nerve
conduction velocities and nerve action potential amplitudes are decreased ( 204). In most instances, serum vitamin E levels have been low. 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 (205). A similar clinical picture is encountered in abetalipoproteinemia. Here, too, vitamin E levels can be strikingly reduced (see Chapter 1). 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 ( 206).
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 ( 207). 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 (208,209). The neuropathologic picture of vitamin E deficiency regardless of cause resembles that previously 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 (210,211). 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 ( 212). Ultrastructural evidence of
electron-dense accumulations in muscle fibers also has been reported ( 213,214).
Inflammatory bowel disease (Crohn's disease) is usually unaccompanied by neurologic complications unless an associated vitamin E deficiency exists. Prolonged use
of metronizadole (Flagyl) for the treatment of the condition can result in a clinical or subclinical sensory polyneuropathy or a combined sensory-motor polyneuropathy.
When subjects with inflammatory bowel disease undergo MRI studies, a large proportion demonstrate increased signal in white matter. These changes are
unaccompanied by neurologic symptoms and their clinical significance, if any, is still uncertain ( 215).
The association of celiac disease with a seizure disorder, notably with complex partial seizures, and bilateral occipital or fronto-occipital calcifications has been
encountered with some frequency in Europe and Latin America (216). In many instances the distribution of the calcifications resembles that seen in Sturge-Weber
disease. Folate deficiency has been documented in some patients, whereas in others there has been nephrogenic diabetes insipidus. The nature of this condition is
unknown. Seizures are treated with anticonvulsants and a gluten-free diet ( 217).
Whipple Disease
Whipple disease, with or without nervous system involvement, although usually a disease of middle-aged men, has been encountered in children ( 218). Adults can
have one of three patterns of CNS involvement. The most common pattern consists of myoclonus, ataxia, and ocular abnormalities with progressive dementia. The
second pattern is hypothalamic dysfunction, notably sleeping and waking disturbances, and polydipsia. Additionally, there are abnormalities of gaze and dementia. In
the third pattern, no clinically evident neurologic deficits are seen, but at autopsy, periodic acid–Schiff-positive material is stored in the brain ( 219). The diagnosis and

treatment of Whipple disease is beyond the scope of this text.
NEUROLOGIC COMPLICATIONS OF RENAL DISEASE
Uremia
Pathology
The pathogenesis of cerebral symptoms in uremia is still unknown and it is generally accepted that several toxins are responsible. Urea is the most studied of these. It
has been known for some time that the severity of cerebral symptoms correlates poorly with levels of serum urea, and hemodialysis sometimes reverses symptoms
without lowering blood urea (220). Creatinine, p-cresol, the guanidines, and parathormone may each be responsible for some aspect of the various neurologic
symptoms encountered in uremia, notably the peripheral neuropathy and the myopathy ( 221,222). Cerebral blood flow studies have shown a defect in oxygen use. In
part, this defect might be caused by nonspecific increases in brain permeability and disordered membrane function, which could allow toxic products, possibly a
variety of organic acids, to enter the brain. These acids could alter the function of the sodium-potassium ion pump. Disorders in blood and CSF electrolytes can
aggravate the clinical picture, as can bouts of acute hypertensive encephalopathy ( 223). The neurologic symptoms in uremia have been reviewed by Fraser and Arieff
(224).
Clinical Manifestations
The principal neurologic symptoms of uremia are abnormalities in mental status, tremor, myoclonus, asterixis, convulsions, and muscle cramps ( 105,225). Peripheral
nerve involvement is common in patients with uremia. Most frequently, it takes the form of a polyneuropathy. This can be a symptomatic mixed motor and sensory
neuropathy, or it can be subclinical, detected only by nerve conduction studies. In one report, 76% of uremic children had a significantly reduced peroneal motor
nerve conduction velocity without any clinical evidence of neuropathy ( 226). When symptoms develop, they begin with sensory abnormalities in the lower extremities.
The condition can progress slowly to total flaccid quadriplegia. Nerve biopsy can reveal primarily an axonal neuropathy, progressive axonal neuropathy with
secondary demyelination, or predominantly demyelinating neuropathy ( 227). Less commonly, patients develop a mononeuropathy, cranial nerve palsies, and
choreoathetosis. Restless legs syndrome is seen in a large proportion of uremic patients ( 228). Signs of hypocalcemia and hypomagnesemia are often present. On
rare occasions, one can encounter a primary myopathy (229).
In hypertensive encephalopathy, such as occurs with acute glomerulonephritis, patients develop symptoms and signs of increased intracranial pressure, with
headache, vomiting, disturbance of vision, and papilledema. Seizures and transient focal cerebral syndromes, including hemiparesis and cortical blindness, are also
common.
As a rule, developmental quotients of children who develop chronic renal failure before 1 year of age are more affected than those of children who go into uremia after
3 years of age (230). In the experience of McGraw and Haka-Ikse, more than 50% of patients with chronic renal failure present since infancy had significant
developmental delay (231). This is accompanied by a significant reduction in the head circumference.
Neuroimaging studies of the brain of patients with end-stage uremia reveal a high incidence of cerebral atrophy, suggesting an adverse effect of uremia on brain
development (232). MRI of patients with cortical blindness demonstrates increased signals in occipital white matter and cortex on T2-weighted images. These tend to
resolve over the ensuing weeks (233).

Treatment and Prognosis
Treatment of uremia involves correction of electrolyte disturbance and maintenance of normal plasma composition. These have been greatly assisted by the use of
dialysis. In some instances, neurologic symptoms can become aggravated after peritoneal dialysis or hemodialysis. Some workers have suggested that urea in the
brain does not equilibrate freely with urea in blood, so that water enters the brain along an osmotic gradient. This is generally referred to as the
dialysis-dysequilibrium syndrome. Gradual changes in blood electrolytes and earlier dialysis prevent some neurologic complications. In general, motor symptoms tend
to improve once blood urea levels are lowered, whereas sensory symptoms tend to remain fixed. The sensory neuropathy does, however, respond dramatically to
renal transplant (234). The correction of anemia by means of recombinant erythropoietin improves intellectual function ( 235).
Successful renal transplantation is associated with acceleration in head growth and improved intellectual functioning. Improvement can continue for more than 1 year
after the transplant (236,237). Nevertheless, prospective studies of children with moderate to severe congenital renal disease indicate that both cognitive and motor
developmental delay is common. This delay reflects, in part, a toxic effect of uremia on brain growth and maturation, and, in part, chronic malnutrition, the various
metabolic disturbances, and also an antecedent brain malformation. In the series of Bock and coworkers, approximately one-half of infants with congenital renal
disease maintained normal development. In the remainder, development was delayed or deteriorated. Neither the cause for the renal disease, nor its severity
influenced the neurologic or cognitive status ( 238).
Treatment of convulsions in uremic patients depends on the cause of the seizures. Seizures accompanying the dysequilibrium states are usually self-limiting and
often can be prevented by close supervision of dialysis. Chronic seizures are best treated with phenobarbital or phenytoin, with recognition that serum protein binding,
particularly for phenytoin, is reduced in uremia. As a result, both therapeutic and toxic effects of the drug are encountered at lower serum levels than of patients with
normal renal function. Nevertheless, anticonvulsant activity can usually be achieved with the usual doses, because the free fraction of phenytoin remains unchanged
(239). No modification of carbamazepine clearance or bioavailability has been observed. In renal failure, the free fraction of valproate increases two- to threefold.
However, the intrinsic metabolism of the drug is reduced so that the actual clearance remains normal. The metabolism of the various benzodiazepines is unaffected.
Both phenytoin and phenobarbital are known to hasten the metabolism of corticosteroids and the immunosuppressant drugs cyclosporine and FK506. This causes
ineffective immunosuppression in renal transplant recipients and reduced cadaver allograft survival ( 240). Hence, Wassner and coworkers have suggested that
anticonvulsants not be administered to patients right after transplant unless absolutely essential, and if they are given, corticosteroid dosage should be increased
accordingly (240). Alternatively, a benzodiazepine can be used. The various drug interactions are considered by Cutler ( 241). (See Chapter 13 for a discussion of
anticonvulsant therapy of patients with renal failure.)
Complications of Treatment of Chronic Uremia
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 ( 242). 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 are now less common (242). 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 the damaged kidneys, because bilateral nephrectomy resulted in complete relief of headaches in 70% of subjects despite continued dialysis ( 243).
Cerebral hemorrhages and central retinal vein occlusion are less common complications of hemodialysis ( 244).
With repeated dialyses, a variety of syndromes are encountered that have been attributed to a deficiency of vitamins or other nutritional factors. These include a
peripheral sensorimotor neuropathy (burning feet or restless legs syndrome) ( 242), central pontine myelinolysis (151), Wernicke encephalopathy ( 245), and leg
cramps. Restless legs syndrome and leg cramps respond to vitamin supplementation; in particular, leg cramps respond to vitamin E or quinine ( 246).
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 (247). Untreated, the condition usually terminates in death within a few years ( 248). Though initially
reported only in patients on chronic dialysis, the syndrome is now known to occur in patients with chronic renal failure who have never undergone dialysis ( 249).
The role of aluminum in causing dialysis dementia is well established ( 250). The metal enters the body not only through dialysis fluid, but also orally, in the form of
various aluminum resins taken by many uremic patients (251), and even through some infant formulas (252,253). Furthermore, citrates promote aluminum absorption,
and the elevated parathormone levels, often found in uremic individuals, promote entry of aluminum into the body and brain ( 254). Discontinuation of aluminum gel
(255), chelation of aluminum by deferoxamine (256), and parathyroidectomy (257) have all been reported to reverse dialysis dementia.
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 (258,259). 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 (260).
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 (261) and viral infections with
cytomegalovirus and herpes simplex (262). In an autopsy study on renal transplant patients, 58% of subjects who succumbed to infection died of bacterial infection,
27% of fungal infection and 6% of viral infection ( 263). 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 are similar to those encountered after hepatic transplants, but appear to be less frequent ( 264). Side effects of
FK506 and OKT3 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 ( 265).
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 (266,267 and 268).
Hemolytic Uremic Syndrome
Hemolytic uremic syndrome, a heterogeneous group of disorders, shares the following features: microangiopathy, hemolytic anemia, and thrombocytopenia. Because
it now appears that 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, hemolytic uremic syndrome is considered in Chapter 6. Secondary hemolytic
uremic syndrome, resulting from a variety of drugs, notably cyclosporine, is seen mainly in adults.
NEUROLOGIC COMPLICATIONS OF CARDIAC DISEASE
In addition to the neurologic effects of hypoxia, cerebral complications can be encountered in a significant proportion of children with congenital or acquired heart
disease. Such complications can be classified into those that occur as a consequence of the anatomic abnormality, and those that are at risk to develop after the
treatment of such congenital or acquired abnormalities.
Congenital Heart Disease
Left-to-Right Shunts
Patients with uncomplicated atrial septal defects, ventricular septal defects, or patent ductus arteriosus are, in the main, not at risk for neurologic complications. This
is based on the basic physiology of a left-to-right shunt in which the pulmonary circuit serves as a buffer against insult to the brain. However, should patients with such
lesions not be operated on and develop pulmonary vascular disease, the Eisenmenger's complex, a shunt reversal can develop, with consequent direct
communication between the right side of the heart and the systemic circulation. This flow reversal puts the patient at risk for a cerebral embolus.
Cerebral embolization also can occur as a consequence of bacterial endocarditis. Currently, most cases of bacterial endocarditis are caused by congenital heart
disease, notably ventricular septal defect and patent ductus arteriosus. Bacterial endocarditis has not been reported in a secundum atrial septal defect. Because the
vegetations in a ventricular septal defect tend to occur on the right ventricular side, neurologic accidents secondary to this form of a congenital heart disease are rare.
In the patient with a patent ductus arteriosus, vegetations also can occur on the pulmonary artery side but with a potential extension into the aorta. Children with
unrepaired atrial septal defects are at risk for paradoxical emboli. In this defect the right and left atrial pressures are generally equal. However, when intrathoracic
pressures increase, the usual left-to-right shunt can then be reversed into a shunt from the right atrium to the left atrium. This exposes the patient to the possibility of
an emboli, septic or otherwise, being routed to the brain with potential neurologic sequelae ( 269,270).
On the whole, with the widespread prophylactic use of antibiotics for dental surgery and for the treatment of bacterial infections, and with progressively earlier surgical
correction of most cardiac malformations, bacterial endocarditis is rarely seen ( 270).
The clinical picture of cerebral embolization can be a sudden disturbance of consciousness, hemiparesis, seizures, or aphasia. Most patients show hematuria, the
result of embolization to the kidneys. Rarely, cerebral embolization is the first sign of bacterial endocarditis or secondary to the presence of immune complex.
The diagnosis of the cerebral embolization rests on the demonstration of sepsis by means of repeated blood cultures. Large intracardiac vegetations can be detected

by echocardiography. Diffusion-weighted MRI and conventional MRI can demonstrate increased signal consistent with cerebral ischemia resulting from embolization.
Treatment consists of parenteral antibacterial therapy against the invading organism, most commonly a- or g-streptococcus or staphylococcus ( 270).
OBSTRUCTIVE LESIONS
In the obstructive lesions category, we consider the complications of aortic stenosis, pulmonary stenosis, and coarctation of the aorta. Each of these three lesions can
be responsible for bacterial endocarditis and subsequent cerebral vascular or peripheral embolization, although the incidence of that process in pulmonary stenosis is
extremely low.
Unique to aortic stenosis is the potential for an acutely decreasing cardiac output with reduced coronary artery flow leading to an arrhythmia such as ventricular
tachycardia or fibrillation. Such an event in turn leads to diminished cerebral blood flow and the risk of seizures resulting from cerebral hypoxia.
Coarctation of the Aorta
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 ( 271). 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 12.
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 ( 272,273).
Spinal cord damage can result in residua ranging from mild weakness to complete paraplegia, with transection usually at the midthoracic level.
Somatosensory-evoked potentials (SSEP) after posterior tibial nerve stimulation can be monitored during surgery to detect spinal cord ischemia ( 274).
Cyanotic Congenital Heart Disease
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 ( 275). The EEG during
such an attack shows high-voltage slow-wave activity, but no spike discharges ( 276). 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 seen in older children, usually those older than 2 years of age. 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. The risk of brain abscess is proportional to the degree of

cyanosis (277). The diagnosis and treatment of brain abscesses in children with cyanotic heart disease are discussed more extensively in Chapter 6.
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 ( 278,279). Dehydration, fever, and iron deficiency anemia also play a role in the evolution of cerebrovascular accidents in nonsurgical patients
(280) (see Chapter 12).
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 ( 281).
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 6).
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 ( 282).
Prolonged hypoxemia with pO
2
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.
Additionally, a variety of developmental CNS anomalies can accompany many types of congenital heart disease. In a survey of children scheduled to undergo open
heart surgery, preoperative neurologic evaluation found neurologic and neurobehavioral abnormalities in more than one-half of the group. One-third of subjects were
microcephalic, and 44% were hypotonic (282a). The incidence of the neurologic abnormalities in the various major types of congenital heart disease is outlined in
Table 15.6. Malformations of the CNS are seen in approximately 7% of children with congenital heart disease ( 283) (Table 15.6). In the original study, published in
1975, the highest incidence of CNS anomalies was seen in children with patent ductus arteriosus and atrial septal defects. In part, this may have reflected the fact that
it was the CNS anomalies, rather than what in most instances was a mild cardiac defect, that brought the children to their doctors' attention. A high incidence of CNS
anomalies is seen also in patients with the hypoplastic left-sided heart syndrome ( 284). A significant proportion of infants who have both congenital heart disease and
a CNS malformation have chromosomal anomalies such as Down syndrome or a well-established syndrome such as congenital rubella, Cornelia de Lange, or
Rubinstein-Taybi.
TABLE 15.6. Incidence of neurologic abnormalities in various types of congenital heart disease
a
Acquired Heart Disease
Cardiomyopathy

This diagnosis applies to patients whose hearts are uncommonly dilated (dilated cardiomyopathy) or demonstrate an abnormal hypertrophy, generally of the
ventricular septum itself. The latter condition has been termed asymmetric septal hypertrophy, hypertrophic cardiomyopathy, or idiopathic hypertrophic subaortic
stenosis. Dilated cardiomyopathy can be the aftermath of acute myocarditis or may be idiopathic. In the presence of a chronically dilated heart, there can be stasis
and clot formation, and the potential for emboli into the systemic circuit and the subsequent risk of a cerebral vascular accident. Hypertrophic cardiomyopathy can
cause subtle or acute decrease in left ventricular output, decreased coronary blood flow, ventricular arrhythmia, syncope, and the potential of hypoxic brain damage.
Rheumatic Fever
Once a relatively common condition, rheumatic fever has gone through a phase of near nonrecognition, followed by a resurgence in the 1980s, and more recently a
quiescence. The principal neurologic complications of acute rheumatic fever and rheumatic heart disease are Sydenham chorea (see Chapter 7) and cerebral
embolization secondary to bacterial endocarditis or cardiac arrhythmias.
Arrhythmias
It is well known that ventricular arrhythmias may develop during the postoperative period in patients who have undergone open heart surgery in which the ventricle
has been involved in the repair, such as tetralogy of Fallot, truncus arteriosus, or ventricular septal defect. The neurologist must remember that ventricular tachycardia
can progress to fibrillation and to cardiac arrest with cerebral hypoxia.
The same sequence of events can occur in the patient with ventricular ectopy unrelated to surgery. Clinically, the presenting symptom is one of syncope. The
differential diagnosis between cardiac and primary neurologic causes for syncope is considered in Chapter 13.
Neurologic complications caused by hypertension, whether due to renal disease or to essential hypertension, are discussed more fully in a text on adult neurology.
The interested reader is referred to a review by Wright and Mathews on hypertensive encephalopathy in a pediatric population ( 285). The condition is rare and
generally develops in association with renal disease. As a rule, the percentage increase over base blood pressure rather than the actual magnitude of the level
determines the development of neurologic symptoms. The most common presenting symptoms are focal or generalized seizures, headaches, and impaired vision. In
the series of Wright and Mathews, papilledema was seen in approximately one-third of children whose discs were examined ( 285). Imaging studies are nonspecific or
can demonstrate white matter hypodensity on CT, whereas MRI can show focal cortical and white matter increased signal on T2-weighted images. A reduction of the
hypertension by 20% to 25% is usually adequate to improve or reverse neurologic symptoms within 24 to 48 hours.
The association of hypertension with lower motor neuron facial nerve palsy has been noted by several clinicians ( 286). The association of hypertension with
pheochromocytoma and neurofibromatosis or pheochromocytoma with von Hippel–Lindau disease is also well recognized (see Chapter 11). Other neurologic
conditions in which hypertension is not uncommon include familial dysautonomia, Guillain-Barré syndrome, increased intracranial pressure, and various viral diseases
that can affect the brainstem, classically poliomyelitis.
A reversible syndrome of headache, altered mental status, seizures, and loss of vision due to cortical blindness is associated with hypertension, particularly with a
rapid increase in blood pressure. It can occur in the setting of severe renal disease or in association with chemotherapy or immunosuppressant therapy ( 287,288).
MRI demonstrates hypointense T1 and hyperintense T2 signal involving gray and white matter mainly in the posterior regions ( Fig. 15.2) (289). The condition has
been termed occipital parietal encephalopathy. Its pathophysiology is similar to that of hypertensive encephalopathy in that the condition results when systemic blood

pressure exceeds the autoregulatory capacity of the cerebral vasculature, with consequent breakdown of the blood–brain barrier and transudation of fluid into the
brain. It is believed that the relative lack of sympathetic innervation of the posterior circulation may predispose the parietal occipital region to vasodilation and
breakdown of the blood–brain barrier (290). The condition is reversible on lowering the blood pressure or discontinuation of immune suppressants.
FIG. 15.2. Occipital parietal encephalopathy. This T1-weighted axial magnetic resonance image demonstrates increased signal in the right occipital parietal region.
The patient was a 9-year-old girl with chronic renal disease on home peritoneal dialysis. She developed status epilepticus after apparent fluid overload. On
admission, her blood pressure was 195/140. She had hypotonia in the right upper extremity, and hypertonia in the other extremities. There was no papilledema.
(Courtesy of Dr. Franklin G. Moser, Department of Radiology, Cedars-Sinai Medical Center, Los Angeles.)
Systemic hypertension is seen in the neonate, most commonly in association with bronchopulmonary dysplasia, and can result in cerebrovascular accidents ( 291).
Sudden reduction of the hypertension, such as follows the use of captopril, has resulted in seizures or the development of an intracranial hemorrhage, in which case
the neurologic status improves concurrent with an increase in systolic blood pressure ( 292).
Congestive heart failure in neonates has been observed secondary to large cerebral arteriovenous malformations (see Chapter 12). Although arteriovenous
malformations are readily delineated by neuroimaging studies, their clinical recognition is often difficult. Audible bruits over the cranium can be heard in many of these
patients, but also are heard in approximately 15% of healthy infants younger than 1 year of age. Cutaneous abnormalities around the head and neck and dilated neck
veins are perhaps more reliable indications of the diagnosis.
NEUROLOGIC SEQUELAE AFTER INTERVENTION TECHNIQUES
Cardiac Catheterization
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. In children, thromboembolic complications predominate and appear most commonly when the
procedure is performed in the first few months of life.
Neurologic Complications of Cardiac Surgery
Since the 1960s we have witnessed improved diagnostic techniques and an increased aggressiveness in the surgical approach to the management of the child with
heart disease. As a result, the incidence of neurologic complications attending cardiac surgery has become better defined. Also, improved survival of more serious
types of heart disease has been accompanied by a more noticeable number of children with neurologic defects ( 293).
The basic technique of open heart surgery initially isolated the heart for surgical repair and, at the same time, protected the other organs. Research demonstrated that
lowering body temperatures permitted a longer time of perfusion with continued protection of the organs. Shortly thereafter, the technique of profound hypothermia
with circulatory arrest was developed. With this technique, the patient's body temperature is decreased to 15° to 17° C. The blood volume is stored in the oxygenator
compartment of the heart-lung system. Experimental work suggests that a window of safety for this technique is 1 hour ( 294,295 and 296).
After repair, the blood is returned to the patient, the patient gradually rewarmed, and the surgical procedure completed. The parameters of this technique, in addition

to standard open heart surgical techniques, expose the patient to hypoxic-ischemic encephalopathy. Vanucci and colleagues have pointed out that this can be a
sequel to inadequate blood flow to vital regions of the brain. The various causes include prolonged cardiac arrest beyond the perceived safety margin, intraoperative
or postoperative systemic hypoxia and hypotension, and cerebral vascular occlusive insults secondary to thrombi or embolization ( 297).
Clinically, one may see seizures in the immediate postoperative period. Rappaport and coworkers, in a selected group of patients with transposition of the great
arteries, spoke to the recognition of seizures and the potential risk of long-term neurologic and developmental sequelae ( 298). Although studying a different subset of
patients, Uzark and colleagues reported on a group of patients with single ventricle undergoing the Fontan procedure with no deficiency in intellectual development,
but for some deficits in visual motor integration ( 299). These patients, however, did not require circulatory arrest and were cyanotic before the onset of surgical
intervention.
Actual figures on the incidence of neurologic complication after cardiac surgery vary, depending on the care and detail of the neurologic evaluation and on the period
during which the series was collected. Currently, they range between 5% and 25%. Sotaniemi, reporting in 1980 on 100 consecutive patients who underwent open
heart surgery, found a 37% incidence of postoperative cerebral disorders. In his experience, the incidence of cerebral complications was proportional to the duration
of cardiac bypass (300). It must be pointed out, however, that many factors, such as cross clamp time, complete or partial circulatory arrest, blood gas manipulation,
and brain hypothermia, affect the supply and demand of oxygen in cerebral tissue. Thus, conclusions as to the cause of these complications must be drawn carefully
and related specifically to the techniques used at a specific institution at a specific time.
Ferry divided the neurologic complications into acute and chronic forms ( 301). In the pediatric population the most prominent of the acute complications are focal and
generalized seizures, intracranial hemorrhage, and spinal cord infarction ( 302).
Neuropathologic changes, when present, have been attributed to impaired cerebral blood flow, hypoxia or hypotension, reduced microvascular perfusion consequent
to gas, microparticulate, or platelet embolization, a nonpulsatile blood flow, and the altered rheologic states of cardiopulmonary bypass and hypothermia ( 303).
Several factors are responsible for impaired cerebral blood flow. Hypotensive episodes can be related to the surgical procedure. Additionally, considerable evidence
suggests that hypothermia, when used with cardiopulmonary bypass, produces a marked reduction in cerebral blood flow ( 304). Additionally, during deep hypothermia
there si a loss of cerebrovascular autoregulation. The reduction in cerebral blood flow is not immediately reversible postoperatively, and brain oxygenation remains
impaired for some time after rewarming (305).
During the immediate postoperative period, major neurologic deficits include alterations of consciousness, behavioral changes, and defects in intellectual function,
particularly in recent memory and in those modalities that pertain to perception and synthesis of visual patterns. Additionally, we and several other groups have
observed a curious dyskinesia, which is frequently localized to the orofacial region and can be accompanied by developmental delay ( 306,307). In the large series of
Medlock and coworkers, involuntary movements were seen in 1.2%; in other series, the incidence ranged from 1.1% to 18.0% ( 307). On neuropathologic examination,
there is marked neuronal loss and gliosis in the globus pallidus, chiefly in the lateral segment ( 308). The cause for the dyskinesia is unknown. In the majority of
children the involuntary movements improve in the course of several days to 3 weeks and ultimately clear completely.
When intraoperative hypoxic or hypotensive brain damage has been extensive, patients do not recover consciousness postoperatively. They often experience focal or
generalized seizures. On examination they are in extensor rigidity with papilledema and fixed, dilated pupils. Focal signs can be evident, even though autopsy reveals

widespread anoxic changes throughout both hemispheres. Symptoms of cerebral emboli include hemiplegia, visual field defects, and seizures. These deficits are not
likely to resolve spontaneously, and permanent residua are not unusual ( 302). As many patients undergo surgical repair in the early neonatal period or in infancy,
signs of cerebral compromise are even more difficult to detect.
As is the case after renal or hepatic transplantation, neurologic sequelae of heart transplantation can be divided into perioperative and late complications.
The perioperative complications are those encountered with cardiopulmonary bypass surgery and hypothermia and have already been cited. Late complications are
related to chronic immunosuppressants and include opportunistic intracranial infection and, less commonly, lymphoproliferative disorders, and the complications that
attend the use of cyclosporine and other immunosuppressive agents (309,310).
Chronic Complications
Evidence exists that prolonged hypoxia adversely affects the developing nervous system. Chronic hypoxia in children with cyanotic congenital heart disease is
associated with motor dysfunction, poor attention span, and low academic achievement ( 311). In the experience of Bellinger and colleagues, the incidence of
developmental sequelae is greater the longer the duration of circulatory arrest ( 312). Neurocognitive abnormalities occur less frequently in children operated on
before 14 months of age, as compared with those who undergo surgery later. Newburger and associates also found that the age at which major cardiac surgery is
performed correlates inversely with cognitive function ( 313). These data suggest that postponement of repair in a child with cyanotic congenital heart disease is
associated with progressive impairment of cognitive abilities.
Attacks of syncope occasionally occur in unrepaired patients with tetralogy of Fallot, or after placement of a Blalock-Taussig shunt. This condition, called the
subclavian steal syndrome, is caused by obstruction in the proximal portion of the vertebral artery and consequent siphoning off of blood from the vertebral-basilar
system into the subclavian and subsequently the pulmonary artery. This shunt can be demonstrated by arteriography ( 314).
Injuries to the brachial plexus can result from traction in the course of surgery. A postoperative polyneuropathy has been rarely encountered, but is mainly seen in
adults. This complication may be related to the duration of induced hypothermia. Unilateral or, more rarely, bilateral phrenic nerve injury with ensuing diaphragmatic
paralysis and respiratory insufficiency is an uncommon complication of cardiac surgery. Approximately one-half of the children require diaphragmatic plication ( 315).
NEUROLOGIC COMPLICATIONS OF HEMATOLOGIC DISEASES
Anemia
Neurologic symptoms accompanying anemia usually result from cerebral hypoxia. They include irritability, listlessness, and impaired intellectual function. The
relationship between the various red blood cell disorders and cerebrovascular accidents has been reviewed by Grotta ( 316).
The effects on neurodevelopmental outcome of chronic iron deficiency anemia experienced during the first 2 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 3 months. Correction of the iron deficiency failed to improve the performance scores ( 317). Similar results have been obtained
from other parts of the world (318). Like the effects of lead, these results are confounded by a variety of environmental, particularly socioeconomic factors ( 318).
Some of these aspects are covered in Chapter 16.
Congenital Aplastic Anemia (Fanconi's Anemia)

This autosomal recessive syndrome probably represents several genetically distinct entities whose molecular biology is incompletely delineated. The syndrome is
characterized by the inadequate proliferation or differentiation of hematopoietic stem cells. Clinically, it is marked by association of pancytopenia and bone marrow
hypoplasia with a variety of congenital anomalies ( 319). These include skeletal defects, growth retardation, microcephaly, microphthalmus, ptosis, facial weakness,
strabismus, deafness, and malformations of ears, kidneys, and heart (320). Generalized hyperpigmentation, and café-au-lait spots are seen in 51% and 23% of
children, respectively. Both types of skin lesions can be present also. Approximately 20% of children with Fanconi's anemia develop malignancies ( 321).
Hereditary Hemoglobinopathies
Sickle Cell Disease
Sickle cell disease results from a genetic, structural abnormality of hemoglobin that is found predominantly in individuals of African ancestry but also may be found in
individuals of Mediterranean, Indian, and mideastern descent. In the United States it occurs mainly in blacks (approximately 1 in 600) and in Hispanics of Caribbean
or South American origins. Sickle cell in the homozygous state (SS) or in combination with another hemoglobin disorder may result in significant morbidity and
mortality. Because neurologic problems are among the most frequent and devastating complications and in many instances can be prevented, present-day
management is directed toward their prevention (322,323).
Serious neurologic problems occur primarily in patients with SS or S Beta
0
thalassemia (at least 29%) and less frequently in those with SC disease (approximately
5%) or S Beta
+
thalassemia (322,324,325 and 326). At least 25% of children with sickle cell have evidence of sickle-related neurovascular disease during the first
decade of life and some are younger than 2 years of age at diagnosis ( 327,328). MRI was found to be positive for prior infarctions in 10% of patients aged 1 to 4 years
with no history of CNS symptoms (328). Findings of the Cooperative Study of Sickle Cell Disease suggest that neurovasculopathy is present by 6 years of age in most
children who will be affected (324,329). The magnitude of CNS-related problems is much greater than the incidence of overt stroke, reported to be 5.5% to 12.0%
(324,329). When a group of 312 children with sickle cell disease, with and without a history of CNS symptoms, were screened with brain MRI, 13% with no prior
history of CNS problems were shown to have brain abnormalities (silent stroke) ( 329). Another group of children without prior stroke was studied, beginning at 12
months of age, by age appropriate neurologic and neuropsychological test procedures, and those with positive findings had a high incidence of abnormalities
identified by MRI, MR angiography or transcranial Doppler ultrasonography (TCD) ( 330). The addition of positron emission tomography and single photon emission
CT to anatomic imaging identified an even greater number with neuronal damage (331,332).
Sickle hemoglobin causes neurovasculopathy by changing the shape and rheology of the red cell ( 333). Sickle red cells are more adherent to the endothelium than
normal red cells even when the hemoglobin is oxygenated. When it is deoxygenated, the process is markedly enhanced and the red cells become rigid and sickle in
shape. There is evidence that under intra-arterial pressure the jet stream of blood containing sickle cells is sufficient to cause endothelial damage and start
thrombosis (334). Intimal proliferation occurs, narrowing the vascular lumen ( 334). Blood flow, which is more rapid than normal because of the anemia, is even more

rapid through the narrower lumen, bombarding the distal endothelium with sickle cells at an increasingly higher rate ( 334). The reason the young child is especially
susceptible to CNS damage from sickling may be that the higher oxygen requirement of the child's brain necessitates a much higher blood flow than is required by the
older child or adult (335).
Neuropathologic findings include widespread narrowing of the major cerebral arteries, smaller vessels, and distal microvasculature as a result of endothelial
proliferation. This is sometimes accompanied by focal dilatation, thrombosis, neovascularization, and hemorrhage ( 327,334,335). Most infarcts are located in the
major arterial border zones, confirming that the primary pathogenic mechanism is large vessel disease with distal hypoperfusion, and that distal small vessel disease
accounts for only a minority of symptoms of cerebral ischemia (Fig. 15.3A) (336,337). Occlusion or segmental narrowing of the larger arteries or veins can be
demonstrated by MRI and MR angiography (Fig 15.3B) (338). Both large and small vessel disease usually occur in combination ( 334). Neovascularization may
present a pattern of moyamoya (335,339). Cerebral infarction is the most frequent complication and occurs most often in children ( 340,341), whereas intracranial
hemorrhage affects more adults than children. Both processes can occur simultaneously ( 324,334). Intracranial hemorrhage in children is usually subarachnoid and
has a higher mortality than infarction ( 340). Hemorrhage may result from an aneurysm in the circle of Willis and be amenable to surgery ( 341). In a neuropathologic
study, infarcts were found in 50% of autopsied brains and were most extensive in the distal perfusion areas of the internal carotid arteries, particularly in the boundary
zone between the anterior and middle cerebral artery boundary zone ( 342). For patients with a history of overt stroke, lesions were typically in the cortex and deep
white matter, whereas in patients with silent stroke they were confined to the deep white matter ( 329). The most common areas of infarction and ischemia were frontal
lobe (78%), parietal lobe (51%), and temporal lobe (15%). Lesions in the occipital lobe, cerebellum, and brainstem were uncommon. Among patients with lesions of
infarction and ischemia, both hemispheres were affected in 60%, and 20% each had an affected right or left hemisphere. Generalized, focal, or both kinds of atrophy
were present in 30 (14%) of SS patients and 5 (5%) of SC patients. Twenty of these also had lesions of infarction and ischemia ( 329).
FIG. 15.3 A: Sickle cell disease. This T2-weighted axial magnetic resonance image (2,000/80/1) demonstrates extensive patchy hyperintensity bilaterally in the
distribution of the middle cerebral artery. The lesions are consistent with the clinical history of repeated episodes of stroke in this 9-year-old girl. (Courtesy of Dr. John
Curran, Department of Radiology, UCLA Center for the Health Sciences, Los Angeles.) B: Magnetic resonance angiography in the same child demonstrates a severe
loss of arterial supply in the middle cerebral artery distribution bilaterally. (Courtesy of Dr. John Curran, Department of Radiology, UCLA Center for the Health
Sciences, Los Angeles.)
Neurologic problems may be acute or chronic. The acute problems are emergencies and require immediate diagnosis and treatment. They include bacterial
meningitis, the consequences of increased susceptibility to infection, overt stroke, or transient focal signs or symptoms of neurologic deficit. Stroke is the most
frequent and can occur as an isolated event or in combination with a sickle cell crisis, especially after a transient ischemic attack or acute chest syndrome, infection,
transfusion, or other systemic illness. Findings include changes in sensorium, focal seizures, aphasia, hemiparesis, transient weakness or inability to move an
extremity, paresthesia of an extremity, ataxia, and homonymous hemianopia. Spinal cord infarction, mononeuropathies, and multiple cranial neuropathies also have
been reported (343). These findings can be irreversible or transient, but those that are transient may be caused by vasospasm and in most instances precede an
overt clinical stroke (324). Chronic neurologic symptoms include headaches and the residua of prior infarcts or brain hypoperfusion such as seizures and a variety of
cognitive deficits including short attention span, delayed speech development, behavior and school learning problems. Cognitive deficits occur more frequently in

children with sickle cell than in their siblings or in other healthy children ( 326). Imaging studies have confirmed that many of the children with cognitive deficits had
experienced silent strokes (326,329,330,341). Seizures can result from an acute infarction or be part of a chronic process often in association with other neurologic
abnormalities. Severe headaches can occur with intracranial hemorrhage, be related to increased cerebral blood flow, or be unrelated to sickle cell disease ( 322,344).
Diagnostic procedures include a careful history of prior events as well as of the acute problem, neurologic examination, and neural imaging studies. Bacterial
meningitis needs to be considered. Neurologic examination may fail to elicit subtle evidence of frontal or temporal lobe disease or extension of a previous infarction
(345). Transcranial Doppler ultrasonography (TCD) can identify large vessel stenosis and has been found to be useful as a screening procedure to identify those
children who are at high risk for future infarction, including those with no prior history of CNS disease ( 323,329,330). A flow velocity of 200 cm/second or greater in the
internal carotid or middle cerebral artery is considered to be positive. In a controlled trial of 130 children identified as high risk by TCD there was a 92% decrease in
the incidence of first stroke in those treated with transfusion compared with the observation group ( 346).
Imaging studies using gadolinium as contrast medium appear to be safe and can identify both large and small vessel disease, areas of ischemia and infarction, and
atrophy (see Fig. 15.3A and Fig. 15.3B). Angiography using high-viscosity radiopaque dyes is contraindicated, however, because of a 5% risk of inducing infarction
(328,333). After a stroke the MRI becomes positive within 2 to 4 hours in 90% of patients ( 347). Positron emission tomography (PET) and single photon emission CT
(SPECT) may identify lesions not found by the other techniques and can be useful in monitoring the effectiveness of therapy ( 332). The EEG can reveal slow-wave
foci. Hyperventilation, normally a routine part of an EEG procedure, can trigger a neurologic deficit in children with sickle cell by inducing cerebral arteriolar
constriction and consequent cerebral edema (348). Unfortunately, no single test identifies all patients with CNS pathology.
Clinical stroke, whether the symptoms persist or are transient, must be treated with immediate transfusion, preferably exchange transfusion, using blood
phenotypically matched at least for Kell and Rh subgroups, if available. Untreated, there is a greater than 65% likelihood of recurrent cerebral infarctions, with
progressively more extensive clinical deficits occurring within the next 36 months ( 324). The patient should remain on transfusion therapy to suppress the hemoglobin
S level to less than 20% because with levels of 30% or greater there is a significant recurrence rate ( 347,349). In some instances, the moyamoya syndrome can be
reversed or improved by transfusion. Although red cell transfusion is the only effective therapy at present, in the future it may be replaced by anti-sickling agents,
some of which are under development (350,351). Hydroxyurea has not been shown to be effective in preventing stroke, and neurologic complications have occurred
after bone marrow transplant.
For unknown reasons children with sickle cell disease have an increased risk of developing lead neuropathy when exposed to the metal ( 352).
Sickle Cell Trait
There have been case reports of cerebral vascular occlusive events in sickle cell trait, but convincing evidence of an etiologic role for the hemoglobinopathy is lacking
(353,354).
Congenital Hemolytic Anemia
Several forms of congenital hemolytic anemia have been associated with neurologic deficits, most commonly developmental retardation. In all of these forms, an
enzymatic defect affects red cell glycolysis. Muscle glycolysis also can be defective. In the most common of these disorders (pyruvate kinase deficiency), neurologic
symptoms result from kernicterus as a consequence of severe neonatal jaundice. Deficiency of erythrocyte phosphoglycerate kinase, an X-linked disorder, causes

hemolytic anemia of variable severity and is accompanied by a slowly progressive extrapyramidal disease characterized by a resting tremor, dystonic posturing of the
extremities, and hyperlordosis (355). When the enzyme defect affects both red cells and muscle, patients also can present with recurrent myoglobinuria, mental
retardation, and a seizure disorder. In some no apparent hemolytic anemia is seen ( 356). Triosephosphate isomerase deficiency also is accompanied by a
progressive neurologic disorder with onset in infancy ( 357). Symptoms and signs are variable. They include dystonia, tremor, and involvement of the spinal motor
neurons and pyramidal tract. Intellectual development is usually normal ( 358). In other families the clinical picture is one of chronic hemolytic anemia, myopathy, and
mental retardation (359). Muscle biopsy can show abnormalities in mitochondrial structure ( 360).
Thalassemia
In thalassemia, neurologic symptoms are rare, but one-third of patients, homozygous for b-thalassemia, have myalgia, a myopathy with weakness and wasting of the
proximal muscles in the lower extremities, hyporeflexia, and a myopathic EMG pattern (361). On muscle biopsy a moderate variation in fiber size is seen, with fiber
atrophy and preponderance of type 1 fibers ( 362). Because in many such children serum vitamin E levels are low, treatment with the vitamin should be considered.
High-dose deferoxamine, used for iron chelation in patients with thalassemia and congenital hypoplastic anemia, can lead to visual and auditory neurotoxicity
characterized by decreased visual acuity, loss of color vision, deafness, and abnormal visual and auditory-evoked potentials. Partial or complete recovery can be
seen after discontinuation of the drug ( 363).
Occasionally, one encounters spinal cord compression as a consequence of extramedullary hematopoiesis. Neuroimaging studies demonstrate an extradural block.
Localized irradiation is recommended for this complication ( 364).
The association of mental retardation and a-thalassemia was first reported by Weatherall and coworkers ( 365). Two distinct syndromes have been recognized. In one
group extensive deletions of the short arm of chromosome 16 could be detected. These subjects exhibit mild to moderate mental retardation accompanied by a variety
of dysmorphic features. The other group is an X-linked condition in whom mental retardation is more severe. In these children the clinical features have been striking.
They include microcephaly, hypertelorism, midface hypoplasia with a pouting lower lip, and hypotonia ( Fig. 15.4A). Anemia is usually not severe, and this syndrome
can best be diagnosed by demonstrating the presence of hemoglobin H in red cells. All affected cases have been male, and the condition is believed to be transmitted
as an X-linked trait (366). We suspect that this entity is not at all rare, but the anemia is frequently not marked and hemoglobin H is not invariably detected by
electrophoresis and requires special staining techniques. For this purpose, fresh venous blood is incubated for at least 4 hours or preferably overnight at room
temperature, with an equal volume of 1% brilliant cresyl blue in 0.9% saline. Inclusions are seen in 0.8% to 40.0% of cells ( Fig. 15.4B) (367). Hemoglobin H disease
has a relatively high prevalence in Asians; it is seen sporadically in Mediterranean populations. Optimally, severely retarded male subjects in these ethnic groups
should be screened for the presence of hemoglobin H.
FIG. 15.4 A: Eight-year-old boy with hemoglobin H disease. He has hypotonia, seizures, and severe mental retardation. Appearance is marked by microcephaly,
relative hypertelorism, depressed nasal bridge, a pouting lower lip, and a small triangular nose with anteverted nares. B: Blood smear stained with 1% brilliant cresyl
blue, showing hemoglobin H inclusions. (Courtesy of Drs. Richard Gibbons and Douglas R. Higgs, MRC Molecular Haematology Unit, John Radcliffe Hospital, Oxford,
England.)
Neonatal Polycythemia

Polycythemia, as defined by a venous hematocrit of more than 65% during the first week of life, and hyperviscosity occur in 1% to 4% of newborns and up to 40% of
affected infants have long-term neurologic and developmental sequelae.
Neurologic symptoms from neonatal polycythemia are generally thought to result from reduced cerebral blood flow caused by increased blood viscosity. This in turn
leads to cerebral hypoxia and ischemia. Rosenkrantz and coworkers have postulated that the elevation of arterial oxygen content in infants with polycythemia
compensates for the reduced cerebral blood flow and allows for normal oxygen delivery to the brain. On the basis of animal experiments they suggest that the
decreased plasma glucose fraction of blood in polycythemic animals results in a reduced glucose delivery to the brain and consequently a reduction in glucose
metabolism (368). These experimental studies are supported by clinical data that show that polycythemic infants with concurrent hypoglycemia tend to experience
more neurologic and developmental deficits than normoglycemic infants (369).
The most frequently encountered signs and symptoms of neonatal polycythemia are headache, paresthesias, vertigo, tinnitus, seizures, and visual disturbances.
Intracranial hemorrhage is seen on rare occasions (370). We also have seen thrombotic cerebrovascular accidents in neonates with unrecognized or poorly treated
polycythemia. In one prospective study, 38% of newborns with polycythemia and the neonatal hyperviscosity syndrome had evidence of motor and neurologic
abnormalities at 1 to 3 years of age. As has already been cited, in the experience of Black and coworkers the presence of hypoglycemia posed an additional risk and
raised this figure to 55% (371). Peripheral neuropathy has been noted also. It probably is not an unusual complication, but can only be detected by electrodiagnostic
studies (372). Controlled studies show that partial exchange transfusions reverse many of the physiologic abnormalities and improve most symptoms, but do not
improve the long-term neurologic and developmental outcome (373). The relatively poorer outcome of polycythemic infants could in part reflect the high incidence of
antecedent fetal disorders in this group.
Coagulation Disorders
Intracranial hemorrhage is the leading cause of death in hemophilia owing to factor VIII deficiency ( 374). Up to 10% of subjects experience an intracranial
hemorrhage; in approximately one-half, trauma is documented. Also in approximately one-half, the site of bleeding is within the subdural or epidural spaces.
Subgaleal bleeding is the most common hemorrhagic complication in vaginally delivered hemophilic infants. The majority of infants with subgaleal hemorrhage were
delivered by vacuum extraction (375). After head trauma, neurologic symptoms tend to develop after a symptom-free interval that can last several hours to 4 or more
days, attesting to the importance of indolent bleeding in the hemophiliac child. A CT scan should therefore be performed; in most instances it discloses the site and
extent of the bleeding (376). Martinowitz and coworkers advise immediate replacement of missing factor and evacuation of any clot, if no improvement occurs within a
few hours (374). The rationale behind surgery is that an intracranial hemorrhage activates the fibrinolytic system, promoting the breakdown of the clot and subsequent
rebleeding. These authors also recommend antifibrinolytic therapy with tranexamic acid (0.1 to 0.15 g/kg per day). Whenever a lumbar puncture is indicated, it should
be deferred until factor VIII replacement therapy has been completed to avoid epidural or subarachnoid bleeding ( 377). Although CNS bleeding caused by coagulation
defects is rare in the newborn period, coagulation studies should be obtained in any infant who has experienced an intracranial hemorrhage ( 378). A spinal extradural
hematoma is a less common neurologic complication of hemophilia (379).
Patients with factor IX (plasma thromboplastin antecedent) deficiency have a clinical picture essentially identical to that of factor VIII deficiency. Intracranial
hemorrhages occur rarely but apparently spontaneously in this condition, as well as in factor VII deficiency and in the von Willebrand diseases ( 380,381). The

neurologic complications of acquired immunodeficiency syndrome seen in some hemophiliac children are covered in Chapter 6.
Thrombocytopenic Purpuras
In young children, idiopathic thrombocytopenic purpura occurs as an acute, self-limiting disorder. Less often it is a chronic disease with remissions and exacerbations.
Intracranial hemorrhages are rare in both entities. In patients with the chronic form, 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 ( 382). Generally, the febrile
thrombocytopenic child is at a significant risk for intracranial hemorrhage.
Neurologic complications occur in 1% to 8% of patients with Schönlein-Henoch purpura, usually as a result of hypertension, vasculitis, or renal involvement ( 383). The
most frequently seen neurologic manifestations are headaches and mental status changes ( 384). Other complications include seizures and focal neurologic deficits,
notably hemiparesis, aphasia, chorea, ataxia, and cortical blindness. Peripheral nervous system involvement, manifested by a mononeuropathy ( 385), and
polyradiculoneuropathy can be encountered also ( 384).
Neonatal Alloimmune Thrombocytopenia
Neonatal alloimmune thrombocytopenia is caused by infants having platelet antigen that differs from that of their mothers' and alloimmunization occurs during
pregnancy inducing a transient severe thrombocytopenia. CNS hemorrhages develop in 10% to 15% of infants ( 386). The thrombocytopenia is transient, but maternal
platelet transfusion or intravenous IgG improves the platelet count. Subsequent pregnancies of a mother who has had one infant with this condition are at high risk for
thrombocytopenia, and the likelihood of intracranial bleeding increases in later pregnancies.
Thrombotic Thrombocytopenic Purpura
In thrombotic thrombocytopenic purpura, 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
(387). The thromboses result in cerebral ischemia and a variety of neurologic symptoms. These have been reviewed by Lawlor and coworkers ( 388). The condition
responds promptly to plasma exchange (388). Thrombotic thrombocytopenic purpura is related to hemolytic uremic syndrome, an entity in which platelet aggregation
occurs in the microvasculature. Hemolytic uremic syndrome is covered in Chapter 6.
Hemorrhagic Disease of the Newborn
Hemorrhagic disease of the newborn can result in intracerebral and subarachnoid hemorrhage or in the evolution of a subdural hematoma ( 389). The condition is
most often encountered in fully breast-fed infants who failed to receive prophylactic vitamin K after birth ( 390). 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 ( 391). The peak
age for the late form is 4 weeks. In the German series of Sutor and colleagues, 58% of infants had intracranial hemorrhage ( 392). Mothers who are receiving
anticonvulsant medications are particularly prone to bearing offspring with symptomatic hemorrhagic disease ( 393).
Intracranial hemorrhage is commonly seen in the framework of the hemorrhagic disease that accompanies disseminated intravascular coagulation, a condition that
complicates a variety of serious illnesses in the newborn.
NEUROLOGIC COMPLICATIONS OF NEOPLASTIC DISEASE

This section deals only with neoplastic disease that arises outside the nervous system. Primary tumors of the nervous system are discussed in Chapter 10.
Leukemia
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. Neurologic complications are of two kinds: those attending the disease and those resulting
from the therapy used to control the disease.
Central Nervous System Leukemia
Some controversy exists as to what constitutes CNS leukemia. The Children's Cancer Group (CCG) considers the diagnosis of CNS leukemia to be established when
the CSF cell count is greater than 5 and lymphoblast cells are found on microscopic examination or on cytospin counts ( 394).
Pathology
Neurologic complications result from leukemic infiltrations of the meninges, brain, and cranial or peripheral nerves or from intracranial hemorrhage and infections. In
one neuropathologic study, published in 1978, CNS lesions were found in 93% of children who died from leukemia ( 395). The present incidence of CNS lesions is
undoubtedly much lower. The most common lesion in the 1978 study was cerebral atrophy, seen in 65%, followed in frequency by leptomeningeal infiltrations and
various forms of hemorrhage.
Meningeal leukemia (CNS leukemia) is seen in all types of acute leukemia and can occur at any stage of the disease. It is generally thought that CNS leukemia
results from the entrance into the CNS of leukemic cells from the blood as a consequence of petechial hemorrhages and a failure of systemically administered
chemotherapeutics to cross the blood–brain barrier. Leukemic cells are first seen in the walls of the superficial arachnoid veins. Cells then extend into the deeper
arachnoid vessels, from there into the CSF, and finally they penetrate the vessel walls and invade brain parenchyma. The pathology of CNS leukemia and the
neurologic complications of therapy have been reviewed by Price ( 396).
Clinical Manifestations
At the time when leukemia is first diagnosed, approximately 4% to 5% of children have CNS involvement ( 397). More frequently, CNS involvement occurs in the late
stages of the disease and is frequently present at relapse. Presenting symptoms and signs of CNS leukemia are shown in Table 15.7. These include signs of
increased intracranial pressure with vomiting, headache, and papilledema. Seizures are less frequent. Although nuchal rigidity was not noted by Hardisty and Norman
(398), we have found it on numerous occasions. Cranial nerve palsies are relatively common and result from leukemic infiltration of the basilar meninges. Nerves most
commonly affected are the facial, abducens, and auditory. In the series of Ingram and coworkers facial nerve palsy was seen in over 90% of children who developed
cranial nerve palsies as a part of the first CNS relapse ( 399). Increased appetite and sudden weight gain, an indication of hypothalamic infiltration, have also been
noted (398). Rarely, epidural spinal cord compression is seen at the time of diagnosis ( 400). This complication can be treated effectively with systemic chemotherapy
and local radiation. The hyperleukocytosis that occurs in chronic myelogenous leukemia and is occasionally encountered in acute lymphoblastic leukemia can induce
a leukostatic syndrome. Neurologic signs include papilledema, hearing loss, impaired vestibular function, and a variety of focal neurologic deficits. Symptoms respond
promptly when the leukocyte level is lowered (401).
TABLE 15.7. Presenting symptoms and signs in 50 episodes of central nervous system leukemia occurring in 29 patients

CNS relapse after complete remission occurs in 6% to 8% of children with acute lymphoblastic leukemia. With the more recent treatment protocols, 64.5% of children
with acute lymphoblastic leukemia who experienced CNS relapse were in apparently complete hematologic remission. Of these children, only 29% had neurologic
signs and symptoms, and the diagnosis was made by examination of the CSF (397).
Diagnosis
The CSF cell count is generally increased. The sugar content is reduced in approximately 60% of cases, and the protein content is increased in approximately 50% of
children who present with CNS symptoms (402). CT scans of the skull often show splitting of the sutures. MRI studies can demonstrate meningeal enhancement,
particularly after the infusion of gadolinium ( 402a).
Prophylaxis and Treatment
Because leukemic cells are sequestered in the CNS even in the absence of overt clinical or CSF manifestations of CNS leukemia, CNS treatment is delivered as an
early part of intervention ( 403). The optimal treatment for CNS leukemia is still under debate. CNS leukemia is usually sensitive to chemotherapy and there has been
a trend to use intensive intrathecal chemotherapy and individualized systemic therapy with blood level monitoring of chemotherapeutic agents ( 404). Such a regimen
prevents overt CNS leukemic manifestations in some 90% of cases and in part has contributed to the dramatic increase in long-term survival ( 405).
The presence of CNS leukemia at the time of diagnosis is an ominous prognostic sign, even though with intensive therapy most of these children go into temporary
remission. The ultimate outlook for children who experience a CNS relapse after their initial remission is not good, even when the diagnosis is made by routine lumbar
puncture in an asymptomatic patient (406). Treatment requires intensive systemic chemotherapy using multiple agents, intrathecal therapy, and craniospinal
irradiation. Using such a protocol on a series of 20 children, Ribeiro and his group managed to achieve a second complete remission in all, with a 5-year second
complete remission rate of 70% (407). The CCG has reported a 48% 5-year remission rate after CNS relapse ( 408). It is evident that the ideal therapy has yet to be
devised.
Both acute and long-term complications of CNS prophylaxis are encountered when a combination of intrathecal therapy and cranial irradiation is used.
Neurologic complications seen in the course of intracranial irradiation include headache and, on rare occasion, seizures. These side effects have become uncommon
with the lower radiation doses currently in use. On MRI a transient, diffusely increased signal is seen on T2-weighted images. This finding probably reflects vasogenic
edema (409). A transient episode of somnolence of fever has been seen 6 to 8 days after cranial irradiation. This condition clears spontaneously. It may be a
predictor of later neuropsychological deficits ( 410).
A subacute leukoencephalopathy is seen as a late effect of therapy, particularly after the combination of intrathecal methotrexate and CNS irradiation ( 411,412). The
condition is caused by a polyoma virus (the JC virus), which is normally acquired at an early age, and becomes reactivated to cause a lytic infection of oligodendroglia
that induce demyelination. The clinical picture is one of a rapid evolution of dementia, spasticity, and ataxia developing in the course of several days to weeks. Focal
neurologic signs, including hemiparesis and blindness, also can be noted. Seizures and changes in consciousness are not uncommon ( 413). The condition can be
fatal or can gradually resolve, with partial recovery of neurologic function. A polymerase chain reaction assay on CSF has been used to detect the presence of viral
DNA (414).
Delayed effects appear several months to years after CNS prophylaxis and are marked focal neurologic signs, notably seizures of hemiparesis. Although clinical and

neuroimaging correlates are poor, MRI shows progressive focal, multifocal, or diffusely increased signal in white matter ( 415). Additionally, CT scans reveal a
calcifying microangiopathy (416). Changes are frequently bilateral and are most pronounced in the putamen and internal capsule, but also can affect the cerebral and
cerebellar cortex (417). The cortical calcifications can resemble the “railroad tracks” of Sturge-Weber syndrome. They are most likely to be seen in children who
received prophylactic irradiation before 5 years of age.
On rare occasions, one encounters isolated optic atrophy as a consequence of the combined use of cranial irradiation and chemotherapy ( 418). In addition, a large
proportion of children develops secondary malignancies with a sevenfold increase in all second malignancies, and a 22-fold increase in the incidence of brain tumors
over the general population (419).
Long-term follow-up of leukemic children has uncovered deficits in such areas as overall intellectual functioning, academic achievement, attention, concentration, and
short-term memory (420). These deficits are more severe after cranial irradiation than after intrathecal or systemic methotrexate and are particularly evident in
children treated before 3 to 5 years of age. They can progress over time ( 421,422,423 and 424). Intensive intrathecal and systemic chemotherapy also has the
potential to lead to long-term neuropsychological deficits. The mechanism for the cognitive deficits is not clear.
In apparently asymptomatic children who have undergone treatment for leukemia, the incidence of neuroimaging abnormalities can be as high as 75%. Most
commonly, there is cerebral atrophy. MRI studies can show increased white matter signal on T2-weighted images ( 425). On positron emission tomography cerebral
white matter glucose metabolism is reduced in subjects who had been treated with a combination of cranial irradiation and intrathecal chemotherapy, but was normal
in those who had received intrathecal therapy alone. Metabolic rates in cortical and subcortical gray matter are reduced, regardless of the mode of therapy ( 426).
Radiation injury to the brain is more extensively covered in Chapter 10.
The use of immunosuppressants in the treatment of leukemia predisposes the child to a variety of infectious agents that can invade the CNS. Of the various viral
encephalitides, herpes zoster, cytomegalovirus, and herpes simplex are the most common (402). Atypical subacute sclerosing panencephalitis also has been
encountered with or without antecedent measles (427). Other infections of the CNS can be caused by a variety of organisms: Staphylococcus aureus, Pseudomonas,
Escherichia coli, and a variety of fungi, most commonly, Candida and Cryptococcus.
More recently, with CNS leukemia on the wane because of preventive therapy, other destructive lesions have been found in the brains of leukemic children who come
to autopsy (395,428). As has already been noted, progressive multifocal encephalopathy, a condition that is not rare in immunocompromised individuals or in adults
who experience malignant tumors, has been seen in children with acute leukemia. Central pontine myelinolysis, another disorder more familiar to the nonpediatric
neurologist, also has been described in childhood leukemia ( 429).
CNS involvement also occurs in acute nonlymphoblastic leukemia, a heterogeneous group of malignancies that accounts for some 20% of childhood leukemia and
that is commonly accompanied by chromosome abnormalities (430). CNS involvement at diagnosis is more common in acute nonlymphoblastic leukemia than in acute
lymphoblastic leukemia. At the time of diagnosis some 5% to 15% have abnormal CSF. Neurologic symptoms at time of diagnosis are rare and are mainly seen in
infants. CNS prophylaxis appears to have little effect on the incidence of CNS relapse, and the overall prognosis is not as good as for acute lymphoblastic leukemia
(431).
Neurologic Complications from Antineoplastic Agents

A number of neurologic disorders results from the agents used in the treatment of leukemia. These are reviewed by Allen ( 432) and Pizzo and colleagues (433).
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 (434). 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. It is an
indication to perform a diagnostic lumbar puncture (435). Another common side effect is jaw pain, seen with the first dose of vincristine. The CSF is normal in
vincristine neuropathy (435,436). Motor and sensory nerve conduction times are usually normal, even when the neuropathy is severe ( 437). Vincristine neuropathy is
largely reversible on discontinuation of the drug. Less often, an episode of seizures and coma accompanies or follows a course of vincristine therapy ( 438). The
inadvertent intrathecal administration of vincristine results in an ascending and generally fatal myeloencephalopathy ( 439). Early irrigation of CSF and treatment with
glutamic acid occasionally arrests the process (440,441).
Intrathecal methotrexate can induce at least two distinct neurologic disorders ( 442). Most common is a chemical arachnoiditis with fever, headaches, back pain, and
nuchal rigidity. A more serious complication is the development of a transient or persistent paraparesis or paraplegia ( 443).
L-asparaginase, an enzyme used in induction therapy for acute leukemia, has been associated with a variety of adverse reactions affecting the nervous system ( 444).
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 (445,446). Symptoms occur a few weeks after L-asparaginase initiation and are believed to result from the enzyme's causing
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 (447). An acute brain syndrome has been encountered also
(444).
A number of other antineoplastic agents can induce neurologic complications in children with neoplastic disease.
Cisplatin, a drug used against neuroblastoma, osteosarcoma, and other tumors, can produce a high-frequency hearing loss, particularly in young children ( 448). As
deduced from animal studies, damage is the result of destruction of hair cells in the organ of Corti ( 449). A sensory peripheral neuropathy also has been attributed to
cisplatin (450).
On rare occasions, the use of cytosine arabinoside is associated with paraplegia, blindness, and a peripheral neuropathy ( 451). With high-dose arabinoside, the
incidence of CNS toxicity increases. Complications include cerebellar signs, seizures, and a leukoencephalopathy. Symptoms usually become apparent within 24
hours after the last treatment, and in some instances are irreversible ( 452). Postmortem examination on some of these patients has disclosed evidence of cerebellar
degeneration, characterized by a depletion of Purkinje cells ( 453).
Fluorouracil, a pyrimidine analogue that interferes with DNA synthesis, can cause cerebellar injury with ensuing dysfunction of gait and coordination. These symptoms

are reversible with discontinuation of the drug ( 451).
In patients receiving phenytoin and undergoing a combined chemotherapeutic treatment program, particularly those who receive methotrexate, serum phenytoin levels
can decrease, thereby lowering the seizure threshold. The exact cause of this interaction is unknown, but is believed to involve increased phenytoin clearance ( 454).
Bone marrow transplantation is being performed increasingly for leukemia, as well as for aplastic anemia and a variety of inborn errors of metabolism ( 455). The
complications are similar to those encountered after other organ transplants.
In a series published in 1984, 59% of children receiving bone marrow transplants developed neurologic complications, notably cerebrovascular accidents and CNS
infections (meningitis or meningoencephalitis). Herpes zoster infections were seen in 23% ( 456). Aspergillosis, Listeria monocytogenes, and cytomegalovirus also can
be encountered. Cerebrovascular complications are usually the consequence of endocarditis ( 457). Rare neuromuscular complications of chronic graft-versus-host
disease after bone marrow transplantation include myasthenia gravis ( 458) and an inflammatory myopathy (459). The side effects of immune suppressant therapy are
covered in the section on hepatic transplants.
The long-term effects of chemotherapy and total body irradiation before bone marrow transplantation have been studied extensively. Generally, the younger the child
and the greater the dose of irradiation, the more likely a developmental delay. In addition, there are delayed growth and endocrine abnormalities.
Lymphoma and Hodgkin Disease
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 ( 460). When present, CNS involvement often presages
a fatal outcome (461). CNS involvement at diagnosis is encountered in approximately 20% of children with Burkitt lymphoma and develops despite prophylactic
therapy (462). 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 ( 463).
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 ( 464). Progressive multifocal encephalopathy, an acute disseminated
demyelination, can also be encountered in Hodgkin disease and lymphosarcoma.
NEUROLOGIC COMPLICATIONS OF ENDOCRINE DISORDERS
Thyroid Gland
Pathology
The brain and thyroid act on each other reciprocally. The anterior hypothalamus controls the thyrotropic function of the pituitary by regulating thyroid-stimulating
hormone secretion, which in turn is under feedback control by blood thyroxine or T
3
concentrations. Thyroid hormone regulates the various processes, which are part
of the final stage of brain differentiation. These include dendritic arborization, axonal growth, synaptogenesis, neuronal migration, and myelination. A review of the
role of thyroid hormone in brain development and of the molecular basis of the various actions of thyroid hormone in the developing brain is far beyond the scope of

this book. The interested reader is referred to reviews by Dussault and Ruel ( 465), Bernal and Nunez (466), Oppenheimer and Schwartz (467), and Burrow and
colleagues (468).
In essence, thyroid hormones act almost ubiquitously, but the brain's responsiveness to them is maximal during the last stages of development and maturation. During
this period thyroid hormones interact with specific receptors to alter genomic activity and affect synthesis of a variety of brain-specific proteins. In the human fetus,
thyroxine is synthesized after 10 to 14 weeks' gestation. Because maternal thyroxine is unable to cross the placenta to any significant degree, an inability of the fetus
to initiate or maintain thyroid synthesis can affect brain development during the latter part of gestation ( 469). Therefore, the degree of thyroid deficiency suffered by
the athyrotic fetus influences the extent of intellectual retardation.
Structural abnormalities in the brain of hypothyroid individuals often incorporate characteristics of the immature organ. Both cerebrum and cerebellum partake of the
developmental delay. As a consequence of increased neuronal cell death and defective oligodendrocyte differentiation, cortical neurons are smaller and fewer, axons
and dendrites are hypoplastic, and myelination is retarded.
Hypothyroidism
Clinical Manifestations
The clinical picture of hypothyroidism depends on the degree of thyroid insufficiency and the time of its onset. With respect to neurologic symptoms, five clinical forms
can be distinguished: (a) neonatal nongoitrous hypothyroidism, (b) congenital goitrous hypothyroidism, (c) goitrous hypothyroidism with deafness (Pendred
syndrome), (d) endemic cretinism, and (e) congenital thyroid deficiency with muscular hypertrophy (Kocher-Debré-Sémélaigne syndrome).
In neonatal nongoitrous hypothyroidism, the thyroid gland is absent or too small to keep the patient euthyroid. At birth, symptoms of hypothyroidism are difficult to
detect. Affected infants tend to have a prolonged gestation and a birth weight greater than 4 kg. They also tend to have prolonged neonatal jaundice, abdominal
distention, a large posterior fontanelle, mottling of the skin, and decreased motor activity. Osseous development is often retarded, and an umbilical hernia is present
in approximately one-half of affected infants (470). Sensorineural hearing loss is present in at least 10% of these infants ( 471). Auditory brainstem-evoked responses
can indicate a delayed wave I (472). The cause of the hearing loss is believed to result from developmental abnormalities of the cochlea.
Symptoms become more clear-cut by the second month of life. By then, infants are more obviously placid, with diminished spontaneous movements, generalized
hypotonia, and a husky, grunting cry. The head appears large with coarse, lusterless hair and widely open sutures and fontanelle ( Fig. 15.5). Motor and intellectual
development is delayed. One-third of patients are spastic, uncoordinated, and experience cerebellar ataxia ( 473). The EEG also reflects delayed development of the
brain (474).
FIG. 15.5. Congenital hypothyroidism. Five-month-old child presenting with developmental delay and hypotonia. Note the immature facies and coarse hair.
Additionally, the anterior fontanelle was enlarged, the posterior fontanelle was still patent, and there was a hoarse cry and an umbilical hernia. A history of diminished
motor activity was elicited also.
When hypothyroidism develops after 3 years of age, intelligence is not irreversibly damaged. Impaired memory, poor school performance, and generalized slowing of
movement and speech are prominent. The muscles are weak and pseudohypertrophic. A significant reduction in the speed of muscular contraction and relaxation can
be demonstrated by EMG and can be visible on neurologic examination.

At least nine major defects in the biosynthesis, storage, secretion, delivery, and use of thyroid hormone have been delineated. These entities are transmitted as
autosomal recessive traits and are responsible for congenital goitrous hypothyroidism. The association of sensorineural deafness with goitrous hypothyroidism,
Pendred syndrome, is transmitted as an autosomal recessive disorder (475,476). The condition accounts for an estimated 7.5% of childhood deafness.
Endemic cretinism is by far the most prevalent form of hypothyroidism, affecting some 800 million people, mainly in Third World countries ( 477). It results from dietary
iodine deficiency, which induces maternal hypothyroidism and deficient transfer of thyroid hormone across the placenta with ensuing fetal hypothyroidism. The
neurologic picture includes a small head circumference, mental retardation, pyramidal tract signs, extrapyramidal deficits, notably focal or generalized dystonia, and a
characteristic gait. The gait, which resembles that of parkinsonian patients, is marked by slow turning and reduced arm swing. Stance is broad based with flexion of
hips and knees and knock-knees. Deafness, resulting from cochlear damage, is seen in as many as 90% of children with endemic cretinism, and in some areas of the
world can be the sole neurologic abnormality ( 477,478).
The CT scan discloses calcifications of the basal ganglia in 30% of subjects, principally those with severe and long-standing hypothyroidism. MRI demonstrates
widening of the sylvian fissures, a nonspecific developmental abnormality, and hyperintensity of the globus pallidus and substantia nigra on T1-weighted images
(479). The selective vulnerability of these areas to thyroid deficiency has been postulated to reflect the density of T
3
receptors (480).
Supplementation of the maternal diet with iodine before the third trimester of pregnancy improves neurologic and psychological development in offspring. Treatment
with iodine during the first two trimesters of pregnancy prevents the development of neurologic symptoms. Treatment during the third trimester is ineffective. These
observations confirm experimental work showing the importance of thyroid hormone in neural differentiation and synaptogenesis ( 481).
Kocher, in 1892 (482), and Debré and Sémélaigne, in 1935 (483), described infants with an unusual combination of diffuse muscular hypertrophy and congenital
thyroid deficiency. The muscular hypertrophy is unexplained, for neither fiber enlargement nor an infiltrative process has been found with light or electron microscopy
(484,485).
Transient hypothyroxinemia is common in premature infants and is believed to reflect hypothalamic-pituitary immaturity. In the study of Reuss and colleagues preterm
infants whose blood thyroxine concentrations were more than 2.6 standard deviations below the mean were at increased risk for cerebral palsy and developmental
delay (486).
Diagnosis
The diagnosis of congenital hypothyroidism is often considered in a child with developmental retardation. The infantile facies, protuberant abdomen, and dry hair and
skin evoke the suspicion of the condition (487). The diagnosis can be confirmed by documenting retarded osseous development, delayed growth, and infantile bodily
proportions. More specific are the determination of serum T
4
and T
3

concentrations and an elevated thyroid-stimulating hormone level.
Treatment and Prognosis
Synthetic levothyroxine (Synthroid) is the accepted treatment of hypothyroidism. When treatment is started within the first weeks of life, somatic growth and head
circumference is normal (488), but the prognosis for mental function is less clear-cut.
A meta-analysis of published data has concluded that in all studies there was a trend toward lower IQ and poorer motor skills in infants with congenital hypothyroidism
as compared with controls (489). The most important independent risk factor for eventual outcome was the severity of congenital hypothyroidism at the time of
diagnosis as defined by the initial T
4
level and skeletal maturation. Age at start of treatment, dose of T
4
and plasma T
4
during treatment was less important in
determining eventual cognitive development. It should be noted, however, that in the studies included for analysis the mean age specified for the start of treatment
ranged from 16 to 32 days (489). Children with congenital hypothyroidism who remain hypothyroid for the first 3 months of life frequently suffer residual cerebellar
deficits and speech defects (490,491). One curious complication of excessive thyroid therapy for cretinism is the development of craniosynostosis ( 492).
Hyperthyroidism
Clinical Manifestations
The association of hyperthyroidism with neuromuscular disease is much more frequent in adults than in children. The condition is more common in girls than in boys;
a quoted gender ratio is 6:1. Neuromuscular disorders seen in the course of hyperthyroidism include exophthalmic ophthalmoplegia, thyrotoxic myopathy, myasthenia
gravis, and periodic paralysis (493). Cerebral symptoms begin insidiously and at first are nonspecific. The child is irritable, nervous, and unable to concentrate, has a
short attention span, and does poorly in school. Exophthalmos is the most characteristic sign. It can be unilateral early in the disease, and when severe is
accompanied by papilledema and central scotomata. The chorea of hyperthyroidism can be continuous or paroxysmal ( 494) and can be related to hypersensitivity of
brain dopamine receptors in this condition ( 495). Tremor and increased deep tendon reflexes are seen in the more toxic children, and seizures, usually generalized,
are encountered in a small proportion of children ( 496). Presentation in status epilepticus and coma also has been encountered ( 497). In some instances, previously
diagnosed epilepsy can become more difficult to control. Cranial nerve palsies are rarely seen in childhood hyperthyroidism. Thyrotoxicosis is occasionally associated
with myasthenia gravis or with familial periodic paralysis (see Chapter 14).
Congenital hyperthyroidism is rare. Most commonly it is seen in offspring of hyperthyroid mothers. Although usually transient, the condition can persist for several
years. Affected infants can develop craniosynostosis, and long-term follow-up shows that a high proportion of infants with long-standing neonatal Graves disease has
residual hyperactivity and major visuomotor deficits (498).

A gain of function mutation in the thyrotropin receptor gene also leads to congenital hyperthyroidism ( 499). This condition is probably responsible for the majority of
infants with congenital hyperthyroidism whose mothers do not have Graves disease.
Diagnosis
In thyrotoxic children, the thyroid gland is nearly always enlarged. Radioactive iodine uptake is increased, and the concentrations of serum T
4
and T
3
are elevated.
Measurement of the proportion of free to bound T
4
confirms the diagnosis.
Thyroiditis, which can simulate thyrotoxicosis, is suggested by the presence of a symptomatic goiter in an euthyroid child. The clinical manifestations of thyroiditis can
vary from symptoms suggesting hyperthyroidism to symptoms of hypothyroidism.
Treatment
Thyrotoxicosis is treated with propylthiouracil or methimazole. Details of treatment are beyond the scope of this text. Once thyroid function returns to normal,
neuromuscular and most other neurologic symptoms remit.
Parathyroid Gland
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.
Adrenal Gland
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 2. The association of catatonia, vertigo, chorea, and papilledema with Addison disease
also has been recorded (500).
A syndrome of adrenal insufficiency, absent tears, and achalasia with addisonian skin pigmentation and hypoglycemia goes under the name of Allgrave syndrome.
Symptoms usually develop before 5 years of age and include achalasia, mental retardation, microcephaly, optic atrophy, nerve deafness, ataxia, and increased
muscle tone (501).
Pituitary Gland
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 10). 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, and other granulomatous diseases.

MRI is preferable to CT scans for detecting small masses in these regions. Using MRI, girls with precocious puberty having its onset before 2 years of age were found
to harbor a lesion suggestive of a hypothalamic hamartoma. When precocious puberty had a later onset the MRI was normal ( 502).
MRI is employed also in the evaluation of patients with growth hormone deficiency. In a series of Agyropoulou and colleagues, approximately one-half of these
children showed an interruption of the pituitary stalk. 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 ( 503,504). The incidence of these abnormalities is even higher when there are multiple pituitary deficiencies ( 502).
Neurologic complications of other pituitary disorders are rare, although a hypertrophic neuropathy is a distinct complication of acromegaly ( 505).
The Laurence-Moon-Bardet-Biedl syndrome is a clinically and genetically heterogeneous autosomal disorder. As first described by Laurence and Moon, the condition
is characterized by mental retardation, spinocerebellar ataxia, retinitis pigmentosa, progressive spastic paraparesis, and hypogonadism ( 506). Patients subsequently
described by Bardet and Biedl suffered from mental retardation, retinitis pigmentosa, hypogonadism, obesity, and polydactyly ( 507). In the series of Green and
coworkers, retinal dystrophy and renal abnormalities were present in all patients, obesity was seen in 96%, polydactyly in 58%, and mental retardation in 41% ( 508).
The condition is common in Arabs, and aminoaciduria and end-stage renal failure is seen in a significant proportion of patients. Visual failure is progressive ( 509).
Although pituitary dysfunction has been held responsible for the hypogonadism, recent immunocytologic and histologic studies have failed to show any pituitary
abnormalities (510). At least four genetic loci are associated with this condition. The genes for this condition in European families studied by Bruford and colleagues
were linked to chromosomes 11, 15, and 16 (511). In Arab families, the gene for the Bardet-Biedl syndrome has been localized to the long arm of chromosome 16
(16q21). However, in another pedigree all three of these loci were excluded, an indication of the genetic heterogeneity of the Bardet-Biedl syndrome ( 511,512). The
Bardet-Biedl syndrome should be distinguished from the Alström syndrome, an autosomal recessive condition in which retinitis pigmentosa, hypogonadism, and
obesity are accompanied by a sensorineural hearing loss ( 513).
Polydactyly also is seen as part of the various orofaciodigital syndromes. These entities are frequently accompanied by a variety of brain defects. These include
agenesis of the corpus callosum, hydrocephalus, heterotopic gray matter, and various congenital anomalies of the posterior fossa, notably agenesis or hypoplasia of
the cerebellar vermis, or Dandy-Walker syndrome ( 514).
A syndrome of cerebral gigantism (Sotos syndrome), first described by Sotos in 1964 (515), does not appear to be rare. Patients are generally mentally retarded and
their facies are unusual, with frontal bossing, hypertelorism, macrocrania, and prognathism. Birth weights are commonly above the 90th percentile, and for the first 4
to 5 years, children experience a growth spurt that subsequently subsides. Convulsions and sexual precocity are occasionally present. Most cases are sporadic, but
transmission as a dominant trait has been reported in several families. In addition to mental retardation, which is found in more than 80% of cases, perceptual
handicaps are common in subjects with apparently normal IQs (516). Abnormalities of cortical architecture have been documented on autopsy and by MRI studies
(517). Plasma growth hormone levels are normal and the cause for this syndrome is unknown (518). Sotos syndrome has been associated with fragile X syndrome
(519).
Hypopituitarism can be seen in septo-optic dysplasia (De Morsier syndrome), a condition characterized by optic nerve hypoplasia and absence of the septum
pellucidum (see Chapter 4). It also can be associated with a number of neurologic abnormalities, notably seizures, nystagmus, and varying degrees of mental
retardation (see Chapter 4).

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 (520), 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 are also associated with other neurologic features
and with chromosomal disorders (see Chapter 3 for a more extensive discussion).
Diabetes
Of the neurologic complications of diabetes in children, the most common is peripheral neuropathy. The mechanism for this disorder has been reviewed by Winegrad
(521). This condition is usually asymptomatic, although careful neurologic examination of 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 ( 522). Somatosensory-evoked potentials to bilateral peroneal nerve
stimulation are also abnormal in a significant percentage of neurologically asymptomatic juvenile diabetic patients, suggesting an additional defect in spinal afferent
transmission (523). The presence of a neuropathy correlates with the duration of the diabetes and is more commonly seen in children whose disease has been under
poor control (522,524). This view is confirmed by a more recent study, 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 ( 525). Moreover, the presence of retinopathy in these
patients correlates closely with the conduction velocity.
Although polyradiculopathy is a complication primarily of adult diabetics, in rare instances it can be seen in juvenile diabetics ( 526). Pain, dysesthesia, and weakness
are the primary complaints. Clinical and EMG evidence point to involvement of multiple nerve roots or proximal segmental nerves.
Involvement of the cranial nerves and cerebrovascular disease are not encountered in diabetic children, although some authors believe that acute and transient
hemiparesis may be a complication of juvenile insulin-dependent diabetes ( 527). We have not observed involvement of the cranial nerves or cerebral vascular
disease in diabetic children.
When diabetes has its onset before 5 years of age and especially when it is complicated by episodes of severe hypoglycemia resulting in seizures, the condition is
associated with a mild impairment of psychomotor efficiency, attention, and verbal skills ( 527a). When diabetes develops after 5 years of age, hypoglycemia does not
appear to affect cognitive function (528).
Neurologic symptoms 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 is not well understood. For some time, it has been known that under these circumstances cerebral oxygen uptake is
reduced by 40% (529), and that cerebral blood flow is decreased, but the role of the various metabolic abnormalities present in diabetic coma in causing these
changes has not been completely clarified.
It is unlikely that accumulation of ketone bodies is solely responsible, as the CSF concentrations of b-hydroxybutyrate and acetoacetate vary widely when obtundation
first becomes apparent (530). In severely acidotic patients CSF pH is normal or even elevated. Hyperosmolality per se also does not correlate well with the patient's
state of alertness. 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 diabetic ketoacidosis ( 531). In the experience
of Bello and Sotos, the incidence of this complication was 0.7% of children presenting in diabetic ketoacidosis. Patients who experience this complication are younger
and more likely to have new onset diabetes. They have had a longer duration of ketoacidosis and a higher serum glucose level than those who do not develop
cerebral edema (532).
The pathophysiology that leads to this complication is not entirely clear. 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 (533). 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 (534). Neither the use of bicarbonate nor the rate of decline of glucose, or excessive secretion of antidiuretic hormone, or the rate of fluid administration are
responsible for the development of cerebral edema. Rather, it could represent vasogenic edema, the result of damage to the capillary endothelium and an increased
reactivity of the immature cerebral vasculature (531).
Prediction and diagnosis of this complication 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 ( 535). Rather, the patient's failure to recover
consciousness, despite adequate treatment with insulin and fluids, suggests the presence of cerebral edema. The presence of high blood sugar levels and
hyperpyrexia should alert the clinician to the imminence of cerebral edema. Duck and Wyatt suggest that excessive secretion of vasopressin exacerbates brain
swelling and recommend limiting the rate of fluid administration ( 536). Dexamethasone has been used in treatment of cerebral edema, but in our experience, it is
usually given too late to be effective. Mannitol, administered as soon as cerebral edema is diagnosed, might be more beneficial ( 537). In any case, early intervention
is effective, even though 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 ( 538). In addition to impaired
consciousness, patients can develop hemiparesis and generalized or focal seizures. This condition has been treated successfully with low-dose insulin infusion while
intracranial pressure is monitored (539).
The neurologic complications of hypoglycemia are discussed at another point in this chapter.
A familial syndrome of juvenile diabetes mellitus and optic atrophy has been reported sporadically since 1938. The condition is transmitted as a recessive trait and is
marked by early onset of diabetes, subsequent evolution of optic atrophy, a sensorineural hearing loss, ataxia, peripheral neuropathy, and anosmia (Wolfram
syndrome) (540).
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