Pathogenesis and Pathophysiology. CNS locations affected by Alpers' disease are the same as those of Leigh's
disease, but in reverse order: most severe in cerebral cortex, then cerebellum, basal ganglia, and brain stem. Lesions show diffuse neuronal degeneration, characteristic spongiform or microcystic degeneration, and, in common with Leigh's disease, gliosis, necrosis, and capillary proliferation. y Biochemical abnormalities have not been specific and have included decreased pyruvate dehydrogenase activity, decreased utilization of pyruvate and NADH, and citric acid cycle dysfunction. The genetic abnormality and mechanism of transmission is unknown. It is even disputed whether Alpers' disease is a mitochondrial disease at all. The cortical spongy degeneration appears similar to that of adult Creutzfeldt-Jakob disease, now recognized as a prion disease.
Epidemiology and Risk Factors. The epidemiology is unclear, because the recognition of the syndrome has been unclear, and there is no known gene defect despite the familial occurrence.
Clinical Features and Associated Disorders. Age at onset and duration are similar to those of Leigh's disease. However, there is usually psychomotor delay before the abrupt onset of seizures.y The seizures may be focal status epilepticus and epilepsia partialis continua, but they evolve into multifocal myoclonus. Areflexia and hypotonia are initially present, with some signs of spasticity later. Ataxia and nystagmus may worsen, with all other neurological signs and symptoms, during infections. Approximately 40 percent of patients have associated hepatic dysfunction. The course is rapidly progressive after onset of seizures. Blindness and optic atrophy occur late.
Differential Diagnosis. This includes any of the infantile or late infantile progressive encephalopathies with primary involvement of cortical gray matter and presentation with refractory epilepsy. Probably the most common of these diseases is neuronal ceroid lipofuscinosis (Jansky- Bielschowsky or Batten-Spielmeyer-Vogt presentations), which can be ruled out by looking for appropriate inclusion bodies in skin, conjunctival, or full-thickness rectal (ganglion cell) biopsy specimens with electron microscopy. Another mitochondrial disease with severe epilepsy is the myoclonic epilepsy and ragged red fibers (MERRF) syndrome (see subsequent section). Other storage diseases at this age, such as atypical GM 2 -gangliosidosis (Tay-Sachs disease, Sandhoff's disease), infantile sialidosis, and galactosialidosis, could be diagnosed by testing for lysosomal enzyme activity, preferably on cultured skin fibroblasts, rather than blood. Other rare causes of a progressive encephalopathy with refractory seizures at this age, but important because they are treatable and reversible, are later-onset pyridoxine dependency and nonketotic hyperglycinemia (both usually neonatal-onset diseases), biotinidase deficiency, and disorders of biogenic amine metabolism, such as folate-responsive seizures. Sulfite oxidase deficiency and Menkes' disease usually present earlier in infancy. The former can be screened for by a commercially available sulfite oxidase urine dipstick test; the latter, by measuring serum copper and ceruloplasmin. Extremely rare at this age are slow virus (subacute sclerosing panencephalitis) diseases. Within the differential diagnosis are epileptic syndromes that appear to be progressive at the onset but that usually plateau into developmental arrest and retardation. These include the syndrome of severe myoclonic epilepsy and the Lennox-Gastaut syndrome.
Evaluation. Because there is no one pathognomonic clinical sign or laboratory study, Alpers' disease is a diagnosis of exclusion. Therefore, all rapidly progressive infantile encephalopathies need to be excluded by clinical story and/ or laboratory tests. Measurement of amino acids, organic acids, lactate, and pyruvate should be done in CSF as well as in blood. Mitochondrial biochemical and DNA studies should be performed, looking specifically for the MERRF mutation, as well as functional neuroimaging studies (i.e., MR spectrometry, single photon emission computed tomography [SPECT], and PET if available), to garner evidence for defective energy metabolism and oxidative phosphorylation and to determine the biochemical geography. In Alpers' disease electroencephalograms (EEGs) are markedly abnormal, showing a diffuse encephalopathy. A characteristic electroencephalographic pattern consists of high-voltage, very slow delta waves mixed with low-voltage polyspikes. Serial visual evoked potentials extinguish over time. Structural neuroimaging studies (Ct, MRI) show progressive marked cortical atrophy. Results of liver function tests are abnormal at the onset of seizures, before clinical features of hepatic degeneration.
Management. There is no specific treatment. The broad-spectrum approach described earlier for Leigh's disease should be applied in order not to miss a treatable progressive encephalopathy. A trial of pyridoxine, 50 mg twice a day orally can be done to rule out pyridoxine- dependent/deficient seizures. If the serum and CSF glycine levels are elevated, the glycine cleavage enzyme activity should be assessed by liver biopsy in a laboratory qualified to do this test; and treatment should be started with dextromethorphan, leucovorin, and sodium benzoate for nonketotic hyperglycinemia. In symptomatic treatment of the seizures, valproic acid should be avoided, because the risk of accelerating the course and a resultant fatal toxic hepatitis is very high. Other treatments of refractory, non- surgically treatable epilepsy at this age, such as adrenocorticotropic hormone or prednisone, ketogenic diet, and intravenous IgG, are unproven and may be harmful.
Prognosis and Future Perspectives. This is a fatal disease. Future treatment approaches depend on the elucidation of the underlying biochemical and molecular pathogenesis.
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