By Kimberly Pargeon, MD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Pargeon reports no financial relationships relevant to this field of study.

SYNOPSIS: In a prospective study of 182 consecutive patients at a specialized mitochondrial clinic in the United Kingdom, followed for more than 7 years, recording the initial prevalence of epilepsy, and subsequently tracking occurrences of new seizure activity, status epilepticus, stroke-like episodes, and death during the follow-up period, epilepsy was found to be a common feature of these disorders.

SOURCE: Whittaker RG, et al. Epilepsy in adults with mitochondrial disease: A cohort study. Ann Neurol 2015;78:949-957.

Mitochondria are the main source of cellular adenosine triphosphate via oxidative phosphorylation. Thus, highly energy-dependent tissues are most vulnerable in mitochondrial diseases, including skeletal muscle and the central nervous system.1 Mitochondrial diseases can be caused by a variety of mutations of mitochondrial DNA or nuclear genes. As such, mitochondrial diseases may manifest as many different syndromes, of which seizures may be a common phenotypic feature.

This report is one of the first large-scale cohort studies of the prevalence and classification of epilepsy in adult patients with well-defined mitochondrial disease. One-hundred eighty-two consecutive patients were recruited at a specialized mitochondrial clinic in the United Kingdom from 2005 to 2008 and followed prospectively over 7 years. The mean age at recruitment was 37.8 years, and all had genotyped disease. Patients were initially screened for a current or past history of epilepsy, defined as more than one unprovoked seizure or status epilepticus. Active epilepsy was defined as at least one seizure or status epilepticus in the past year. Outcome measures included a new diagnosis of epilepsy, seizure-related morbidities (status epilepticus or stroke-like events), and death.

Of the initial 182 patients, 42 (23.1%) had a history of epilepsy across all genotypes with 35 (19.2%) having active epilepsy at inclusion. The mean age of epilepsy onset was 29.4 years and was a feature in eight different genotypes. The most commonly represented genotype was the m.3243A>G mutation, which included 63 patients, 22 (34.9%) of whom had epilepsy, over half of which reported focal motor seizures (54.5%). This mutation commonly leads to the syndrome Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS), characterized by encephalopathy, stroke-like episodes, and epilepsy, the latter of which may be partial or generalized seizures, including status epilepticus.2 One patient also presented with a rare but devastating MELAS-like phenotype involving a m.12147G>A mutation, presenting as encephalopathy, stroke-like episodes, and focal status epilepticus.

Another more commonly represented genotype was the m.8344A>G point mutation, which included 13 patients, 12 of whom had epilepsy (92.3%). This mutation presents as the syndrome Myoclonic Epilepsy with Ragged Red Fibers (MERRF), with the primary clinical features including ataxia, myopathy, and myoclonic epilepsy with photosensitivity.2 Not surprising, all 12 patients had myoclonic seizures, although two also had infrequent photosensitive tonic-clonic seizures. Of the remaining genotypes, epilepsy was noted in three of 13 patients with recessive POLG mutations; one of 14 with multiple mtDNA deletions; one with a recessive TRIT1 missense mutation; and one with the m.8993T>G mutation, which is often associated with Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) syndrome. There were 15 additional genotypes in which no epilepsy was reported.

For the 7-year follow up period, three patients subsequently developed epilepsy, all carrying the m.3243A>G mutation and each occurring in the context of a stroke-like episode. The risk of developing epilepsy with this mutation was approximated at 1.2% per year. Risk of seizures with other genetic mutations could not be estimated. Regarding other outcome measures, four patients developed stroke-like episodes, all with the m.3243A>G mutation, including the three with newly developed epilepsy. Status epilepticus was seen in five patients with m.3243A>G mutations and the one with m.12147G>A mutation, all in the setting of a stroke-like episode but none in the follow-up period. Finally, 20 patients died during the follow-up period, five of whom had epilepsy. The approximate case fatality rates for those with and without epilepsy were similar (1.66% vs 1.60%), suggesting epilepsy did not significantly affect mortality.


The primary finding is that epilepsy is common in adults with mitochondrial disease with an initial prevalence of 23.1% in this cohort; however, there were clear differences among the different genotypes. Not surprising, about a third (34.9%) of those with the m.3243A>G mutation, the most common genotype, and nearly all (92.3%) of those with the m.8344A>G point mutation had epilepsy, but for those genotypes where few patients were included, prevalence was difficult to discern. The real question is why epilepsy is seen more preferentially in some mitochondrial disorders. For some, complex I defects in the mitochondrial respiratory chain seem to be more commonly associated with epilepsy as compared to others.1 Further, there can be interplay between mitochondrial dysfunction and seizure activity. Mitochondrial dysfunction leads to decreased intracellular ATP levels, causing energy depletion in susceptible cells. Dysfunction can also affect calcium modulation, leading to increased glutamate release and excitotoxic effects, ultimately leading to seizures.1,3 Finally, once seizures have started, they can increase energy demands of already taxed cells, which if not controlled, can lead to further damage as stroke-like episodes. Stroke-like episodes are seen more commonly in MELAS and POLG-related diseases, in which complex I deficiency is often seen.1 The key in patients with vulnerable genotypes is to treat seizures aggressively at initial onset to prevent progression to status epilepticus, while avoiding potentially toxic therapies, such as valproate.


  1. Bindoff LA, Engelsen BA. Mitochondrial diseases and epilepsy. Epilepsia 2012;53(Suppl 4):92-97.
  2. Finsterer J, Mahjoub SZ. Epilepsy in mitochondrial disorders. Seizure 2012;21:316-321.
  3. Kang HC, et al. Mitochondrial disease and epilepsy. Brain Dev 2013;35:757-761.