CHAPTER 185 Neurodegenerative Disorders (Childhood Dementia)
Children typically acquire developmental milestones in a variable but predictable sequence (see Chapter 7). Rarely, children present with stagnation of development or frank loss of previously acquired skills. These entities are referred to as neurodegenerative disorders.
Primary degenerative diseases of the nervous system are usually hereditary or metabolic processes. Their onset is often insidious with gradual progression over weeks, months, or years. Typically, they are symmetrical in their manifestations. Symptoms may target either gray matter structures or white matter tracts.
ACQUIRED ILLNESSES MIMICKING DEGENERATIVE DISEASES
Children with poorly controlled epilepsy may be continuously in either an ictal or a postictal state. They may appear stuporous. The antiepileptic regimen may be contributing to the lack or loss of developmental abilities. Antiepileptic drugs that are sedating or affect mood, memory, motivation, or attention may contribute to school failure. Use of high doses or multiple anticonvulsants may compound this problem. Readjustment of medications or achievement of better control returns the child to his or her previous level of functioning.
Other chronic drug use or overuse (sedatives, tranquilizers, anticholinergics) can bring about progressive mental confusion, lethargy, and ataxia (see Chapter 45). Intoxications with metals, such as lead, may cause chronic learning difficulties or may present acutely with irritability, listlessness, anorexia, and pallor, progressing to fulminant encephalopathy. Vitamin deficiency of thiamine, niacin, vitamin B12, and vitamin E can produce encephalopathy, peripheral neuropathy, and ataxia. Congenital and acquired hypothyroidism impairs intelligence and retards developmental progress. Unrecognized congenital hypothyroidism produces irreversible damage if it is not treated immediately after birth (see Chapter 175).
Structural brain diseases, such as hydrocephalus and slowly growing tumors, may mimic dementia. Certain indolent brain infections, such as rubeola (measles causing subacute sclerosing panencephalitis), rubella (German measles), syphilis, prion disease, and some fungi, cause mental and neurologic deterioration over months and years. Congenital human immunodeficiency virus (HIV) infection causes failure of normal development and regression of acquired skills.
Emotional disorders, such as depression and severe psychosocial deprivation in infancy, can give rise to apathy and failure to attain developmental milestones (see Chapter 21). Children with autism spectrum disorder may go through a phase of developmental stagnation or disintegration at about 12 to 18 months of age after a period of early normal milestones. Depression in older children can lead to blunting of affect, social withdrawal, and poor school performance, which raise the question of encephalopathy and dementia.
HEREDITARY AND METABOLIC DEGENERATIVE DISEASES
Degenerative diseases may affect gray matter (neuronal degenerative disorders), white matter (leukodystrophies), or specific, focal regions of the brain. Many white and gray matter degenerative illnesses result from enzymatic disorders within subcellular organelles, including lysosomes, mitochondria, and peroxisomes. Disorders of lysosomal enzymes typically impair metabolism of brain sphingolipids and gangliosides. These enzyme deficiencies have classic patterns of expression (Niemann-Pick disease, Gaucher disease, Tay-Sachs disease). The same enzymatic deficiency may produce unusual clinical syndromes that differ greatly from the classic patterns. The age at onset, rate of progression, and neurologic signs may vary. For this reason, any patient with a degenerative neurologic condition of unknown cause should have leukocytes or skin fibroblasts harvested for measurement of a standard battery of lysosomal, peroxisomal, and mitochondrial enzymes (see Chapters 56 and 57).
Gray matter degeneration (neuronal degeneration) is characterized early by dementia and seizures. This group of gray matter disorders, which cause slowly progressive loss of neuronal function, is separated into disorders with and disorders without accompanying hepatosplenomegaly. Most are autosomal recessive traits except for Hunter syndrome (sex-linked recessive), Rett syndrome (sex-linked dominant), and the mitochondrial encephalopathies (nuclear or mitochondrial DNA defects).
Gray Matter Degenerative Diseases with Visceromegaly
Mucopolysaccharidoses are caused by defective lysosomal hydrolases resulting in the accumulation of mucopolysaccharides within lysosomes. Abnormally large amounts are excreted in the urine. The clinical manifestations include dwarfism, kyphoscoliosis, coarse facies, hepatosplenomegaly, cardiovascular abnormalities, and corneal clouding. Neurologic involvement is seen in mucopolysaccharidosis types I H (Hurler syndrome), II (Hunter syndrome), III (Sanfilippo syndrome), and VII. Children with Hurler syndrome, the most severe of these illnesses, appear normal during the first 6 months of life, then develop the characteristic skeletal and neurologic features. Mental deficiency, spasticity, deafness, and optic atrophy are progressive. Hydrocephalus frequently occurs because of obstruction to CSF flow by thickened leptomeninges.
Mucolipidosis II (I-cell disease), mucolipidosis III, GM1 gangliosidosis, fucosidosis, and mannosidosis resemble Hurler syndrome clinically but do not exhibit excess excretion of mucopolysaccharides and involve different disorders in lysosomal hydrolases. The diagnosis is confirmed by analysis of enzymes in white blood cells, serum, and skin fibroblasts.
Classic Niemann-Pick disease is caused by a deficiency of the enzyme sphingomyelinase. Sphingomyelin accumulates in foam cells of the reticuloendothelial system of the liver, spleen, lungs, and bone marrow. It also distends neurons of the brain. Intellectual retardation and regression, myoclonic seizures, hypotonia, hepatosplenomegaly, jaundice, and sometimes retinal cherry-red spots are noted within the first year of life. The diagnosis is confirmed by finding foam cells in the bone marrow and sphingomyelinase deficiency in leukocytes and skin fibroblasts.
Although the most common form of Gaucher disease is an indolent illness of adults, there is a rapidly fatal infantile form featuring severe neurologic involvement caused by deficiency of the enzyme glucocerebrosidase. Glucoceramide accumulates in the liver, spleen, and bone marrow. The characteristic neurologic signs are neck retraction, extraocular palsies, trismus, difficulty swallowing, apathy, and spasticity. Gaucher cells are found in bone marrow, and the level of serum acid phosphatase is increased.
Gray Matter Degenerative Disease without Visceromegaly
Tay-Sachs disease (GM2 gangliosidosis) is caused by deficiency of hexosaminidase A and results in the accumulation of GM2 ganglioside in cerebral gray matter and cerebellum. Infants are normal until 6 months of age, when they develop listlessness, irritability, hyperacusis, intellectual retardation, and a retinal cherry-red spot. The ganglion cells of the retina and macula are distended with ganglioside and appear as a large area of white surrounding a small red fovea that is not covered by ganglion cells. Within months, blindness, convulsions, spasticity, and opisthotonos develop.
Rett syndrome is a common neurodevelopmental disorder affecting only females with onset at about 1 year of age. It is characterized by the loss of purposeful hand movements and communication skills; social withdrawal; gait apraxia; stereotypic repetitive hand movements that resemble washing, wringing, or clapping of the hands; and acquired microcephaly. The illness plateaus for many years before seizures, spasticity, and kyphoscoliosis develop. The etiology is a mutation on an X chromosome gene coding for a transcription factor called methyl-CpG-binding protein 2. The exact phenotype is influenced by whether the mutation is missense or truncating and on the pattern of X chromosome inactivation in the individual patient.
Neuronal ceroid lipofuscinosis is a family of genetic diseases characterized histologically by the accumulation of autofluorescent hydrophobic proteins and esterified dolichol lipopigments in lysosomes. The original infantile form of neuronal ceroid lipofuscinosis (NCL1) is palmitoyl protein thioesterase deficiency (gene at the 1p32 locus), the late infantile form (NCL2) is pepstatin-resistant proteinase deficiency (gene at the 11p15.5 locus), and the original juvenile form (NCL3) is a defect in a gene (locus 16p11.2-12.3) whose product, the NCL3 protein, still lacks functional characterization. The clinical features are dementia, retinal degeneration, and severe myoclonic epilepsy. Visceral symptoms, despite the presence of the storage process, are absent. The disease may present at any age.
Mitochondrial diseases represent a clinically heterogeneous group of disorders that fundamentally share a disturbance in oxidative phosphorylation (adenosine triphosphate [ATP] synthesis) (see Chapter 57). Abrupt symptoms are often manifest concurrent with periods of physiologic stress such as febrile illness or fasting. Specific genetic diagnoses are often difficult to identify because clinical features are pleotropic within individual defects, overlap between different defects, and because analysis of mitochondrial protein function is technically demanding. Specific syndromes include MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes); MERRF (myoclonus, epilepsy, and ragged red fibers), which includes dementia, hearing loss, optic nerve atrophy, ataxia, and loss of deep sensation; and NARP (neuropathy, ataxia, and retinitis pigmentosa).
Degenerative Diseases of the White Matter (Leukodystrophies)
The prominent signs of diseases affecting primarily white matter are spasticity, ataxia, optic atrophy, and peripheral neuropathy. Seizures and dementia are late manifestations. Life expectancy ranges from months to a few years.
Metachromatic leukodystrophy is an autosomal recessive lipidosis caused by deficiency of arylsulfatase. Demyelination of the CNS and peripheral nervous system occurs. Children present between 1 and 2 years of age with stiffening and ataxia of gait, spasticity, optic atrophy, intellectual deterioration, absent reflexes, up-going toes, increased CSF protein, and slowing of motor nerve conduction velocity.
Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive lipidosis caused by a deficiency of galactocerebrosidase. It begins at 6 months of age and includes extreme irritability, macrocephaly, hyperacusis, and seizures. Demyelination of the CNS and peripheral nervous system results in upper and lower motor neuron signs.
Adrenoleukodystrophy is a sex-linked, recessively inherited disorder associated with progressive central demyelination and adrenal cortical insufficiency (see Chapter 178). It is caused by an impaired capacity of a subcellular organelle, the peroxisome, to degrade saturated unbranched very long chain fatty acids, particularly hexacosanoate (C26:0). The most common presentation occurs in boys in early school years who develop subtle behavioral changes and intellectual deterioration, followed by cortical visual and auditory deficits and a stiff gait. Later, spastic quadriparesis, coma, and seizures supervene. Symptomatic adrenocortical insufficiency with fatigue, vomiting, and hypotension develops in 20% to 40% of patients, usually at the same time as the neurologic illness. The disease can present with slowly progressive paraplegia in young men, which is called adrenomyeloleukodystrophy. The diagnosis is established by finding an elevated hexacosanoate level in plasma lipids and typical abnormalities of neuroimaging.
Degenerative Diseases with Focal Manifestations
Some neurodegenerative disorders have predilections to target specific regions or systems within the neuraxis, producing symptoms referable to the affected region. Ataxia indicates disease of the cerebellum or spinocerebellar pathways. Abnormalities of extraocular movement or respiration indicate disease of the brainstem. Choreoathetosis or dystonia indicates disease of the motor basal ganglia. Paraplegia indicates disease of the spinal cord. Hereditary degenerative diseases can cause ataxia (see Table 183-1).
Cerebellar Pathways
Friedreich ataxia is a relentlessly progressive, autosomal recessive disorder that manifests in the early teenage years with ataxia, dysmetria, dysarthria, pes cavus, hammer toes, diminished proprioception and vibration, diminished or absent reflexes, up-going toes, kyphoscoliosis, nystagmus, and a hypertrophic cardiomyopathy. It is caused by a homozygous GAA expansion of 120 to 1700 trinucleotide repeats of the first intron of the frataxin gene on chromosome 9. The GAA repeats are unstable on transmission. The size of the GAA expansion determines the frequency of cardiomyopathy and loss of reflexes in the upper limbs.
Ataxia-telangiectasia is an autosomal recessive genetic disorder of DNA repair that produces a neurologic disorder, immunologic deficiency, lymphoid malignancy, and gonadal dysgenesis (see Chapter 73). The basic pathologic defect is an inability to respond properly to homologous double-stranded DNA breaks by either DNA repair or induction of apoptosis due to a lack of the ATM protein (a DNA-binding protein kinase related to kinases involved in cell cycle progression and response to DNA damage). The ATM gene is a large gene on 11q22-23. Most mutations of the gene are unique and nonsense. Most patients are compound heterozygotes. In 80% of cases, a genetic diagnosis can be made by failure to detect the ATM protein on Western blot.
The neurologic symptoms manifest between 1 and 2 years of age with progressive ataxia, dystonia, chorea, swallowing difficulty, poor facial movements, and severe abnormalities of saccadic and pursuit eye movements. Most characteristically, patients develop oculomotor apraxia, a disorder in which the child visually tracks by making head movements to compensate for the inability to generate saccadic eye movements. Intellect is preserved. Patients are wheelchair bound in childhood. The external hallmark of the disease, conjunctival telangiectasia, does not manifest until about 5 years of age. Telangiectases also develop on the ear, malar face, neck, elbows, knees, hands, and feet. In addition, prematurely gray hair and atrophic skin develop in patients. Recurrent sinopulmonary infections are a problem in some patients from infancy. Thirty percent of patients die of lymphoreticular cancers. Laboratory clues to the diagnosis include elevation of blood alpha-fetoprotein levels and depression of blood IgA and circulating T-cell levels. Patients with IgA deficiency are at risk of anaphylaxis after blood transfusion that includes IgA. There is presently no therapy for the disease or its symptoms.
Lesch-Nyhan syndrome is a sex-linked recessive disorder caused by deficiency of hypoxanthine-guanine phosphoribosyltransferase, leading to the formation of excess uric acid. Infants appear normal until late in the first year of life, when they exhibit psychomotor retardation, choreoathetosis, spasticity, and severe self-mutilation. These patients never achieve ambulation. Gouty arthritis and renal calculi with renal failure occur. Hyperuricemia and renal complications are treated with allopurinol, a xanthine oxidase inhibitor, but no effective treatment for the neurologic disease is available.
Wilson disease is a treatable, degenerative condition that exhibits signs of cerebellar and basal ganglia dysfunction. It is an autosomal recessive inborn error of copper metabolism. Serum ceruloplasmin levels are low. Abnormal copper deposition is found in the liver, producing cirrhosis; in the peripheral cornea, producing a characteristic green-brown (Kayser-Fleischer) ring; and in the CNS, producing neuronal degeneration and protoplasmic astrocytosis. Neurologic symptoms characteristically begin in the early teenage years with dysarthria, dysphasia, drooling, fixed smile, tremor, dystonia, and emotional lability. MRI shows abnormalities of the basal ganglia. Treatment is with a copper-chelating agent, such as oral penicillamine.
Brainstem
Subacute necrotizing encephalomyelopathy, or Leigh disease, is a neuropathologically defined, degenerative inherited CNS disease primarily involving the periaqueductal region of the brainstem, caudate, and putamen. Symptoms usually begin before 2 years of age and consist of hypotonia, feeding difficulties, respiratory irregularity, weakness of extraocular movements, and ataxia. Blood and CSF lactate and pyruvate levels are elevated. Different disorders of mitochondrial function can produce this clinical syndrome. Decreased pyruvate carboxylase or pyruvate dehydrogenase activity, biotinidase deficiency, and cytochrome c oxidase deficiency have been identified as causative in some cases. Vitamin therapies have been attempted but with little success except in children with biotinidase deficiency. Many degenerative encephalopathies defy diagnosis despite extensive laboratory analysis. The diagnosis of leukodystrophy usually can be made confidently on the basis of extensive cerebral white matter changes on CT or MRI. The diagnosis of hereditary or metabolic gray matter encephalopathy, when histologic and biochemical studies are normal, is much less secure. Acquired lesions (infectious, inflammatory, vascular, or toxic) are difficult to exclude completely. Brain biopsy is not likely to be helpful, unless specific lesions are shown on neuroimaging.