Mitochondrial Causes of Epilepsy: Evaluation, Diagnosis, and Treatment

Hannah E. Steele, MBBS, MRCP; Patrick F. Chinnery, PhD, FRCP, FRCPath


Semin Neurol. 2015;35(3):300-309. 

In This Article

When to Consider a Mitochondrial Disorder in a Patient With Epilepsy

It seems highly likely that epilepsy arising due to mitochondrial disease is underrecognized, given the estimated prevalence of mitochondrial disorders,[16] the oligosymptomatic basis of many patients with mitochondrial disease,[1,51] the often long diagnostic odyssey, and the impact of active investigation in other mitochondrial disorders.[51] Here, we flag clinical features that may indicate an underlying mitochondrial etiology in a patient with a seizure disorder. However, these are by no means diagnostic and alternative pathologies should also be contemplated in the diagnostic workup.

Clinical Features

Epilepsy in Association with Undiagnosed Multisystem Disease. Individuals with epilepsy and two or more of the clinical features below, without other unifying diagnosis, should be tested for the mt.3243A > G mutation in the first instance,[1] before moving on to consider other appropriate investigations, outlined later.

  • Cardiomyopathy

  • Deafness

  • Developmental delay or cognitive decline

  • Diabetes mellitus

  • Gastrointestinal disturbance (constipation and/or irritable bowel syndrome)

  • Migraine

  • Chronic progressive external ophthalmoplegia

  • Retinopathy

There should be a low threshold for POLG testing for people presenting with seizures and liver dysfunction.

Complex Childhood-onset Epilepsy. Individuals with childhood-onset epilepsy ultimately diagnosed with a respiratory chain defect often experience preceding symptoms of failure to thrive, psychomotor delay, ataxia;[8] encephalopathy, multiorgan symptomatology, or a fluctuating clinical course.[10] Furthermore, mitochondrial disorders are a recognized cause of epileptic encephalopathy:[44,52] conditions where the seizures themselves are thought to contribute to intellectual decline.

Family History. Our clinical experience mirrors reports of patients describing seemingly disparate clinical presentations in family members, which taken together, clinically suggest a unifying mitochondrial disorder.[4,5,7,10]

Features of the Epilepsy Itself

Status Epilepticus. Mitochondrial diseases are a key consideration in recurrent or refractory episodes of convulsive or nonconvulsive status epilepticus in adults or children.[4,7,8,23–25,28,33,39,42]

Epilepsia Partialis Continua. Epilepsia partialis continua is characterized by persistent focal seizures with retained consciousness. It is a feature of several mitochondrial disorders, including mt.3243A > G MELAS[4] (often in association with stroke like episodes) and AHS.[26] It can also occur with twinkle (C10orf12)[44] and POLG[39,42] mutations. Although it has been described on occasion in LS,[53] this does not appear to be a common feature of the disorder.[7,19,20]

Occipital Lobe Epilepsy. Occipital lobe epilepsy is an uncommon clinical presentation, affecting 2% to 13% of those with focal epilepsies.[54] Occipital lobe epilepsy can arise due to recognized electroclinical syndromes, as well as symptomatic causes;[55] however, seizures associated with mt.3243A > G MELAS and POLG have a clearly documented posterior predilection–particularly early in the disease course.[4,33,42]

Myoclonic Epilepsy. Myoclonic epilepsy is a cardinal feature of MERRF,[5,6] and widely recognized in other mitochondrial disorders.[10,56] Typically, mitochondrial myoclonic seizures are associated with clinical progression or other parameters of complex disease, setting them apart from the benign childhood and juvenile myoclonic epilepsies. Other causes of progressive myoclonic epilepsy should be considered.[57]

Recognized Electroclinical Syndrome. The following electroclinical syndromes have been reported in several cohorts to have a mitochondrial contribution:

  • Ohtahara syndrome[12,58]

  • West syndrome[12,59]

  • Landau–Kleffner syndrome[10,12,60]

  • Lennox–Gastaut syndrome[10,12]

Other electroclinical syndromes associated with mitochondrial diseases occur less frequently and are reviewed elsewhere.[9]

Investigative Features

Electroencephalogram. There is not a single "characteristic mitochondrial EEG." Indeed, the most frequently identified abnormalities are nonspecific and include generalized slowing (60%),[2,11] multifocal discharges, focal discharges or generalized discharges (all 40%).[2] Photosensitivity has been reported in patients with both MELAS and MERRF,[3,5] and although hyperventilation is safe in this patient cohort, it does not appear to increase the diagnostic yield.[36] Nonetheless, despite these nonspecific features, the EEG may show traits suggesting a mitochondrial disorder. These include:

  • EEG abnormalities with a posterior predilection[4,39,42]

  • Periodic lateralized epileptiform discharges (PLEDS) in children are suggestive of MELAS[4]

  • Focal high-voltage delta waves with polyspikes (FHDPS) may occur in acute stroke-like lesions in MELAS—although the other clinical features may prompt the diagnosis, rather than the EEG[61]

  • Rhythmic high amplitude delta with superimposed spikes and polyspikes (RHADS) strongly suggest POLG mutations causing AHS.[26,27]

Few definitive studies have examined EEG changes throughout the disease course, but progression is a feature.[39,61]

Neuroimaging. Brain imaging may be normal, particularly in nonsyndromic mitochondrial disease[11] or early in the disease course.[42] In one series, over half of patients with MERRF had normal cerebral imaging.[6] However, several features have been identified frequently in those with respiratory chain defects and seizures, including prominent and progressive cerebral atrophy,[5,6,8,10,11,42] cortical signal change,[5,6] stroke-like episodes,[4,5,6,33] and symmetrical extracortical lesions (such as signal change within the brainstem, basal ganglia, or thalamus).[11,39,42]