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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. Several alterations of mitochondrial function produce this clinical syndrome.
Children with poorly controlled epilepsy may be continuously in either an ictal or a postictal state and may appearstuporous because of their epileptic encephalopathy. Antiepileptic drugs that are sedating or affect mood, memory,motivation, or attention may contribute to the lack or lossof developmental abilities and school failure. Use of highdoses or multiple anticonvulsants may compound thisproblem.
Chronic drug use or overuse (sedatives, tranquilizers, anticholinergics) can bring about progressive confusion, lethargy, and ataxia. Intoxications with heavy 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 cognition and retards developmental progress. Unrecognized congenital hypothyroidism produces irreversible damage if it is not treated immediately after birth (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, and some fungal infections, cause neurologic deterioration over months and years. Congenital human immunodeficiency virus infection causes failure of normal development and regression of acquired skills.
Psychiatric disorders, such as depression and severe psychosocial deprivation in infancy, can give rise to apathy andfailure to attain developmental milestones (Chapter 21). Children with autism spectrum disorder may go througha phase of developmental stagnation or disintegration atabout 12 to 18 months of age after a period of early normal milestones. Depression in older children can lead toblunting of affect, social withdrawal, and poor school performance, which raise the question of encephalopathy ordementia.
The skin, teeth, hair, nails, and brain are derived embryologically from ectoderm. Abnormalities of these surface structures may indicate abnormal brain development. Not all of the so-called neurocutaneous disorders have characteristic cutaneous lesions, however, and not all are of ectodermal origin. Neurofibromatosis (types 1 and 2), tuberous sclerosis, Sturge-Weber syndrome, von Hippel–Lindau disease, and ataxia-telangiectasia are the most common of the more than 40 neurocutaneous disorders.
Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is an autosomal-dominant disorder with an incidence of approximately 1 in 3000. It is caused by mutations of the NF1 gene, which codes for a tumor suppressor gene, neurofibromin. Neurofibromin is a major negative regulator of a key signal transduction pathway, the Ras pathway. Mutations results in increased downstream mitogenic signaling. Somatic mosaicism, in which an abnormality in one copy of the NF1 gene is present in some cells but not others, indicates a post-zygotic mutation and is called segmental neurofibromatosis.
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