Frequency and causes of seizures

Seizures are common in mitochondrial disease, though a majority of patients do not have seizures. In one database of several hundred patients with mitochondrial cytopathies, about 40–50% have seizures.* This is probably an overestimate, because it was compiled at a referral institution taking care of patients with epilepsy as well as those with mitochondrial disorders.

There are no symptoms that doctors can use to forecast which patients with mitochondrial disease will develop seizures. Seizures are associated with a widely diverse group of mitochondrial disorders, suggesting that energy production for proper regulatory control within the central nervous system is extremely important. Seizures are seen in patients with:

• mitochondrial DNA mutations
• electron transport chain complex dysfunction
• cofactor deficiencies (Coenzyme Q10 deficiency)
• protein assembly defects (SURF mutation)
• substrate disorders (e.g., pyruvate dehydrogenase deficiency)
• mitochondrial DNA depletion syndromes (e.g., mitochondrial neurogastrointestinal encephalomyopathy).

Mutations in mitochondrial DNA that are often associated with seizures do not produce them in every patient. For instance, a mutation at the position 3243 in the mitochondrial DNA can produce the classic MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), but not all patients with this mutation have seizures

On the other hand, patients with the same symptoms may have different types of mitochondrial disease. For instance, some patients with the symptoms of MELAS and myoclonic seizures have a mutation at position 3243 in the mitochondrial DNA. Other patients with the same symptoms, including the same type of seizures, have a disorder involving complex III and IV in the electron transport chain.

Although many people with mitochondrial disease have seizures, not everyone with seizures has a mitochondrial disease. If a person has seizures along with disorders of several different organs without a clear cause, the doctor may suggest testing for mitochondrial disease, as outlined in Recognizing mitochondrial disease.

Seizure types

Patients with mitochondrial disease can experience a wide variety of seizure types. Some have a particular epilepsy syndrome with a single seizure type. Others have several types of seizures. Some patients have seizures that can be controlled by medication, but others have intractable seizures. To complicate the matter, some even have both real seizures and abnormal movements that look like seizures but are not. Some patients only have involuntary movements that are not seizures. The variability between patients and within types of mitochondrial diseases makes understanding the association between epilepsy and mitochondrial disease confusing and difficult for the physician.

Myoclonic seizures probably are the most frequent seizure type in mitochondrial disease. Other seizure types most often seen are:

• atypical absence
• tonic
• hypomotor (see below)

Many patients have multiple seizure types including clonic, tonic, and tonic-clonic. Patients with mitochondrial disease tend not to have classic childhood absence seizures or the multiple seizure types seen in Lennox-Gastaut syndrome.

More patients with mitochondrial disease have seizures that are intractable (difficult to control with medication) than patients with epilepsy not associated with another disorder. Greater intractability is typical of symptomatic epilepsy.

Patients whose mitochondrial disease is associated with a specific epilepsy syndrome will have predominantly the seizure types characteristic of that syndrome. For instance, infants that develop West syndrome (infantile spasms) have epileptic spasms as the predominant seizure type. Some of these infants have ongoing spasms well past 1 year of age. Ongoing spasms can be seen in patients without mitochondrial disease, but it seems to be more frequent in those with mitochondrial cytopathy.

Hypomotor seizures

Hypomotor seizures were described by epilepsy specialists at The Cleveland Clinic Foundation as decreased or absent behavioral activity without the emergence of new movements. Hypomotor seizures are not part of the International Classification of Epileptic Seizures, but this definition accurately describes what occurs in infants and individuals who are severely mentally impaired, in whom it is not possible to test consciousness. It is a common seizure type in patients with mitochondrial disease.

Epilepsia partialis continua

Epilepsia partialis continua has been defined as “regular or irregular clonic muscular twitches affecting a limited part of the body, occurring for a minimum of 1 hour, and recurring at intervals of no more than 10 seconds.” It is a rare seizure type that has been reported in patients with MELAS, in addition to other seizure types. It has also been seen in some patients with electron transport chain complex III dysfunction.

Electroencephalographic (EEG) findings

The most frequent EEG finding in a patient with a mitochondrial cytopathy is an independent spike seen in multiple brain regions over the left and right hemisphere, combined with a generalized slowing pattern. The discharges are usually moderate in amplitude, usually less than 200 microvolts. The background rhythm is usually slow for the patient's age. (Background slowing is common in patients with mitochondrial disease even if they do not have seizures, suggesting a mild to moderate encephalopathy.)

Generalized discharges are uncommon in patients with mitochondrial disease. They may be seen in less than 20% of patients.

Specific epilepsy syndromes

The two most common epilepsy syndromes associated with mitochondrial disease are West syndrome (infantile spasms) and Progressive Myoclonic Epilepsy.

West syndrome (infantile spasms)

Children with West syndrome and a mitochondrial cytopathy begin having seizures between 3 months and 1 year of age. Three characteristic findings lead to the diagnosis of this syndrome:

• a characteristic EEG pattern called hypsarrhythmia
• developmental delay or regression
• epileptic spasms

The EEG has a very chaotic, high-amplitude pattern with epileptiform discharges irregularly seen over both hemispheres. This EEG pattern is called hypsarrhythmia. The seizures, called epileptic spasms, are sudden, brief, tonic contractions of the trunk and limbs. The force is usually violent, but also may be mild, often with a crescendo increase in forceful movement. Spasms frequently occur in 1 to 30 clusters per day, with 10 to 150 spasms per cluster. They occur mostly when the infant is awake, or less often during an arousal from sleep. A cry may follow the end of the attack

Experience has shown that both adrenocorticotropic hormone (ACTH) and the ketogenic diet are often effective in stopping the spasms, but the EEG generally remains abnormal. Seizures usually return if ACTH treatment is discontinued. In some patients, the epileptic spasms return, but in other patients, different seizure types may develop.

West syndrome can occur in patients with mitochondrial DNA mutations, electron transport chain complex dysfunction, and substrate metabolism abnormalities:

• Leigh syndrome, caused by either the mutation at position 8993 (T > G) in the mitochondrial DNA or a complex IV dysfunction
• MELAS mutation 3243 (A > G)
• pyruvate dehydrogenase deficiency
• complex I dysfunction
• dysfunctions of complex III, combinations of complex III/IV, or multiple complex I, III, and IV dysfunctions

Progressive myoclonic epilepsies

The progressive myoclonic epilepsies are a group of rare disorders characterized by

• myoclonic seizures
• tonic-clonic seizures
• gradually worsening neurologic dysfunction, often dementia and ataxia (poor coordination)

Two mitochondrial syndromes most often associated with this epilepsy syndrome are MERRF (myoclonic epilepsy associated with ragged-red fibers) and MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). The same symptoms often occur in patients with electron transport chain dysfunctions, and in many other people with mitochondrial disease and seizures, but they are not routinely classified into this epilepsy syndrome.

MERRF

The diagnosis of MERRF is based on the features of myoclonic and generalized seizures, ataxia, and ragged-red fibers in the muscle biopsy. The disease usually first appears during childhood, but can occur during adolescence. Myoclonus is often the first symptom, followed by generalized epilepsy. The child’s early development is usually normal, but patients with progressive symptoms invariably become demented. However, not all patients with MERRF have progressive myoclonus epilepsy.

Other common features are hearing loss, peripheral nerve disease, short stature, exercise intolerance, and impaired vision from damage to the optic nerve. Less common findings include cardiomyopathy, pigmentary retinopathy, pyramidal signs, ophthalmoparesis, and multiple lipomas.

About 80–90% of patients with MERRF have a family history suggesting inheritance through the mother, but not all maternal relatives are affected and not all those who are affected have the full MERRF syndrome.

The most common mutation in MERRF (over 80% of patients), is at position 8344 (A>G) in the mitochondrial DNA. This mutation has also been associated with other disorders (isolated myopathy, multiple lipomas, cardiac arrhythmia of Wolff-Parkinson-White, spinocerebellar degeneration, and Leigh syndrome). Less frequent point mutations of 8356 (T>C) and 8363 (G>A) are also seen in the mitochondrial DNA. These mutations occur in the transfer RNA encoding lysine, designated the MTTK gene.

The EEG findings in MERRF include background slowing, focal epileptiform discharges, and atypical spike- or sharp-and-slow-wave discharges that have a variable association with myoclonic seizures. These discharges generally are normalized or suppressed during sleep.

MELAS

Less frequently than MERRF, the mitochondrial cytopathy syndrome of MELAS has been associated with the syndrome of progressive myoclonic epilepsy. Typically, onset is in childhood. Early childhood development is usually normal, but short stature is common. Symptoms most often appear between ages 2 and 10 years, but can be delayed until age 40. They rarely begin younger or older than 2 to 40 years.

Usually, the first symptoms are

• seizures
• headaches
• vomiting
• anorexia (loss of appetite)

Exercise intolerance or weakness of the arms or legs also is common.

Seizure types may include generalized myoclonic, focal clonic, and generalized tonic-clonic. Epilepsia partialis continua has also been reported in this syndrome. Myoclonus is less common. In one group of patients with MELAS, the seizures were reported to evolve into partial or generalized status epilepticus.

Seizures are often associated with metabolic stroke-like episodes. The cumulative effects of the stroke-like episodes gradually impair motor abilities, vision, and thinking, often by young adulthood.

Less common symptoms include ataxia (poor coordination), episodes of coma, damage to heart muscle (cardiomyopathy), vision disorders (damage to the optic nerve, pigmentary retinopathy, or ophthalmoplegia), diabetes mellitus, unwanted hair growth (hirsutism), disorders of the digestive tract, and kidney disease.

About 80% of patients with MELAS have a point mutation at position 3243 (A>G) in the mitochondrial DNA. Mutations at position 3271 (T>G) and 3252 (A>G) have been described in about 7.5% to 10% of patients. All these mutations are found within the MTTL1 gene or transfer RNA encoding for leucine, encoded within the mitochondrial DNA. At least nine other rare point mutations and a 4-bp deletion in seven additional genes also have been associated with MELAS. Several nuclear DNA mutations in complex I of the electron transport chain also may give rise to MELAS.

Interestingly, a few patients have been found who have the 3243 (A>G) mutation but symptoms of MERRF rather than MELAS, suggesting an overlap of features between the two syndromes.

Patients with MELAS have been studied by EEG during the acute period following a stroke-like event. During this period the EEG usually shows focal high-voltage delta waves with polyspikes. Later, focal spikes or sharp waves and 14- and 6-Hertz positive bursts are frequently seen.

During the more chronic stages of the MELAS syndrome, the EEG may show only a generalized delta slowing, without epileptic discharges.

* Saneto R., presented at the meeting of the United Mitochondrial Disease Foundation/Mitochondrial Medicine Society (UMDF/MMS) in Dallas, Texas, 2002.

By Russell P. Saneto, D.O., Ph.D., Children’s Hospital and Regional Medical Center/University of Washington School of Medicine, Seattle, WA.

Topic Editor: Russell P. Saneto, D.O., Ph.D.
Last Reviewed:6/25/04