• Phenylketonuria
• Niemann-Pick disease
• Gaucher's disease
• Mucopolysaccharidoses
• Hepatic porphyria

Approximately 25% of patients have generalized or partial seizures. Infantile spasms and myoclonic seizures may occur.70 On the EEG, all patients have slowing, epileptiform discharges, or hypsarrhythmic patterns.71

Evaluation

Because newborns with PKU usually seem healthy, the diagnosis requires screening tests, which are mandated by law. Confirmatory tests are high plasma phenylalanine and normal or low plasma tyrosine concentrations.

Treatment

Treatment consists of dietary restriction of phenylalanine. The goal is to provide necessary but not excessive amounts of phenylalanine, typically 250 to 500 mg per day. The diet should be instituted immediately after birth and maintained throughout life to preserve cognitive and neuropsychologic function. Monitoring of plasma phenylalanine levels is required to gauge compliance and adequacy of the prescribed diet.

Antiepileptic drugs are given when necessary.

Adapted from: Schachter SC and Lopez MR. Metabolic disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;195–208.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Niemann-Pick disease is an autosomal-recessive lipidosis in which sphingomyelin (i.e., ceramide phosphorylcholine) accumulates in the lysosomes of reticuloendothelial cells.72 Several types have been identified. Types A and B result from a deficiency of acid sphingomyelinase. Types C and D are characterized by abnormal cholesterol esterification and transport out of the lysosome.

Clinical presentation

Type C is most associated with seizures. Two subtypes of type-C Niemann-Pick disease have been identified based on the temporal sequence of neurologic events, neurophysiologic abnormalities, and longevity.73

Neonates with type-C Niemann-Pick disease may be jaundiced at birth. Slowly progressive neurologic deterioration begins within 2 years. Partial, generalized tonic-clonic and atonic seizures may occur and are usually refractory to antiepileptic drugs.73 Hepatosplenomegaly is often present.

Evaluation

Laboratory testing may show pancytopenia from bone marrow infiltration. Sphingomyelinase activity is not reduced, but the cholesterol transport defect can be documented in cell culture.

Treatment

There is currently no specific treatment for any of the Niemann-Pick disease subtypes, and care is supportive.72

Adapted from: Schachter SC and Lopez MR. Metabolic disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;195–208.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Gaucher's disease is an autosomal-recessive lipidosis caused by a deficiency of acid b-glucosidase.72 Because acid b-glucosidase hydrolyzes glucocerebroside in lysosomes to glucose and ceramide, Gaucher's disease is characterized by the lysosomal accumulation of glucocerebrosides (primarily glucosylceramide).

Clinical presentation

There are three subtypes of Gaucher's disease. Types II and III involve the CNS. Patients with type II die in infancy, but type III, the juvenile form, may present in infancy or childhood.

Glucocerebroside accumulates in cells of the liver, spleen, lymph nodes, and bone marrow, leading to organomegaly, lymphadenopathy, and skeletal pain. Neurologic signs include ataxic gait, cognitive dysfunction, and partial and generalized tonic-clonic seizures.

Evaluation

The diagnosis is confirmed by the presence of characteristic cells on bone marrow aspiration and the lack of acid b-glucosidase activity in cell culture.

Treatment

There is no known effective treatment for the neurologic involvement in type III Gaucher’s disease.

Adapted from: Schachter SC and Lopez MR. Metabolic disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;195-208.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

The mucopolysaccharidoses are lysosomal storage disorders due to a lack of enzymes that normally degrade glycosaminoglycans. They are characterized by the intracellular accumulation and urinary excretion of glycosaminoglycans (i.e., mucopolysaccharides). The seven types of mucopolysaccharidoses are each distinguished by an excess of a particular urinary mucopolysaccharide.74

Clinical presentation

Inheritance is autosomal dominant, except for type II, which is x-linked.

Clinical features vary but generally include a characteristic coarse facies (i.e., thickened lips and open mouth), short height, bony abnormalities, mental retardation, corneal opacities, and hepatosplenomegaly.

Type III (Sanfilippo's syndrome) is the most common mucopolysaccharidosis. It has four subtypes. The onset of symptoms is usually after 2 years of age, followed by rapidly progressive neurologic and cognitive deterioration. Seizures occur in nearly half of patients.

Evaluation

The EEG shows nonspecific abnormalities, and neuroimaging studies reveal cortical atrophy and ventricular dilatation.

Laboratory studies confirm abnormalities on urine screening tests for glycosaminoglycans. Sophisticated cell culture or serum assays are available to evaluate patients for specific enzyme deficiencies.

Treatment

Treatment is symptomatic. Enzyme replacement by bone marrow transplantation has produced systemic improvement in selected patients but has not prevented neurologic deterioration.

Adapted from: Schachter SC and Lopez MR. Metabolic disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;195–208.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

The porphyrias are caused by inherited deficiencies of enzymes involved in heme synthesis.75 Heme is used in the bone marrow to make hemoglobin and in the liver to make cytochrome P-450 enzymes. The hepatic synthesis of heme is largely regulated by d-aminolevulinic acid (ALA) synthase, an inducible enzyme.

The symptoms and signs of the porphyrias result from the accumulation of toxic metabolites. They are classified either as erythropoietic and hepatic or on the basis of the specific enzyme deficiency.

Seizures and other neurologic manifestations only occur in the hepatic group, in which the porphyrin precursors ALA and porphobilinogen (PBG) accumulate.76 Both compounds have been implicated as directly neurotoxic.77

Three acute hepatic porphyrias, all autosomal dominant, are associated with seizures:78

• acute intermittent porphyria (AIP)
• hereditary coproporphyria (HCP)
• variegate porphyria (VP)

HCP and VP are much less common than AIP. They present similarly except that HCP and VP are also associated with cutaneous photosensitivity.

Patients with AIP have approximately 50% reduction of PBG deaminase activity.75 This condition is particularly prevalent in Northern Europe, especially Finland.79 When the demand for hepatic heme synthesis is increased, the reduced PBG deaminase activity leads to the accumulation of ALA and PBG in the liver, plasma, and urine.78 Some of the PBG and ALA is converted to porphyrin.

AIP can be precipitated by:80

• drugs that induce hepatic ALA synthase (e.g., enzyme-inducing antiepileptic drugs)
• drugs that inhibit PBG deaminase (e.g., sulfonamide antibiotics)
• hormones (e.g., estrogen, progesterone and its metabolites, and oral contraceptives)
• alcohol
• reduced caloric intake
• intercurrent infections
• major surgery

Clinical presentation

Clinical manifestations can persist for days to weeks and may be preceded by nonspecific symptoms.76 The most common acute symptom is abdominal pain, often severe enough to require narcotic analgesia. The pain is sometimes accompanied by nausea, vomiting, ileus, and constipation.

Sympathetically mediated signs include tachycardia, hypertension, sweating, and tremors. Sleep disturbance, anxiety, delirium, hallucinations, depressed mood, and paranoid delusions may be present.81,82 Lethargy and coma occur rarely. Peripheral motor neuropathies may lead to foot or wrist drops.

Seizures associated with AIP occur either as a direct neurologic manifestation of the condition or from hyponatremia, which may result from SIADH, vomiting, diarrhea, or poor oral intake. Some studies suggest that focal and generalized seizures occur in nearly one-third of pediatric cases and up to 20% of adult cases.83-85 By contrast, a study of patients registered at the National Porphyria Center in Sweden found that the lifetime prevalence of AIP-associated seizures was 2.2% of all those with known AIP and 5.1% of all those with manifest AIP.86

Evaluation

The diagnosis may be suspected based on the clinical presentation and may be confirmed by the presence of photosensitive porphyrins in the urine and reduced monopyrrole PBG deaminase in red blood cells.81,87

Treatment

After a definitive diagnosis, treatment of acute attacks consists of

• narcotic analgesia for pain (see below)
• symptomatic therapy of nausea, anxiety, and restlessness
• oral or intravenous glucose
• Intravenous hematin or heme arginate (to reverse the induction of ALA synthase and thereby reduce the production and accumulation of ALA and PBG78,88,89)

Drugs known to precipitate AIP must be avoided,78,90 particularly when treating seizures, pain, and acute anxiety attacks. Hahn et al. used a cell-culture model of primary chicken embryo liver cells, which maintain intact heme synthesis and regulation, to study the effects of several of the more recently approved antiepileptic drugs on porphyrin accumulation.91 Based on the results, they recommended vigabatrin or gabapentin, for which success was reported anecdotally,92 but not felbamate, lamotrigine, or tiagabine, as possible treatments for seizures in patients with porphyria.

Similar animal studies have suggested that patients with acute porphyrias may be at greater risk for developing porphyric attacks when treated with certain medications:

Complete recovery from attacks is the rule, although neuropathic deficits may take months to resolve.

Adapted from: Schachter SC and Lopez MR. Metabolic disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;195-208.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.