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

Management of Mitochondrial Epilepsy

Supportive Care

As seizures in mitochondrial disorders may be triggered, or exacerbated, by metabolic disturbance, physicians should aim to regulate the biochemical milieu by ensuring appropriate hydration, normalizing blood glucose, managing acidosis, and treating concomitant infections where present.[66]

Mitochondrial "cocktail" therapy consisting of co-enzyme Q10, vitamin B complex, vitamins C and E, and L-carnitine has been used to treat a variety of respiratory chain defects. In one study, the carers of 48 children with seizures and a RCD were asked to report changes in seizure rate, behavior, and development.[12] Although 75% reported improvements, the study was not primarily designed to assess drug efficacy. Furthermore, the 2012 Cochrane review did not identify any evidence-based disease modifying treatments for mitochondrial disease.[67]

The remaining sections therefore focus on the symptomatic treatment of seizures arising in the context of respiratory chain disorders.

Antiepileptic Drugs

There are few high quality trials to inform best use of antiepileptic medications in mitochondrial disease specifically. However, in common with epilepsies arising from other causes, the choice of medication should largely depend upon whether the seizure disorder has a focal or generalized onset.

A wide range of antiepileptic drugs (AEDs) are used to control seizures in mitochondrial disease, including carbamazepine, clobazam, clonazepam, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, topiramate, and sodium valproate. Many patients are on more than a single drug.[8,11] Furthermore, treatment efficacy is difficult to assess due to the lack of trials and the heterogeneous nature of seizures in mitochondrial disease, which are often progressive.

In one series of adults and children, those with seizures were identified from a population with diagnosed respiratory chain disorders. Of these, 72% were "easily controlled" with AEDs and 28% were refractory.[2] In contrast, other series report that 5 to 15% achieve seizure freedom with antiepileptic medication,[8,11] highlighting the highly variable prognosis. Although this probably reflects different patient selection methods between series, it serves to emphasize that seizure freedom is a realistic and achievable goal for select patients with RCDs.

In addition to considering efficacy, clinicians should be aware of potential interactions between antiepileptic medications and mitochondrial function. Although many are described, most have no implications for widespread clinical practice.[68] The exception to this is use of sodium valproate use in those with a polymerase gamma (POLG) mutation, which may precipitate irreversible liver failure. Consequently, there is a move to screen for POLG mutations before starting it in children with refractory epilepsy.[28] It seems appropriate to test adults in appropriate clinical circumstances.

Intensive Care Support

Status epilepticus or epilepsia partialis continua may require intensive care support for induction of anesthetic coma. There is no evidence base to guide specific treatment, and it is likely that a combination of antiepileptic medications will be used. Magnesium infusion is recommended as a treatment for super-refractory status epilepticus[69] and its use in status epilepticus due to recessive POLG mutations has been described in two cases, both of whom showed improvement in seizure control.[70]

The prognosis following intensive care unit (ICU) admission for seizures has not been well reported in the context of mitochondrial disease specifically. In a series of 11 patients with mitochondrial disorders admitted to an ICU with seizures, 4 died, suggesting the prognosis is poor.[71] This is largely in keeping with figures reported elsewhere for the outcome of individuals following status epilepticus.[72] Therefore, end-of-life care is a salient issue to consider for such patients, even while active management is ongoing.

Ketogenic Diet

The ketogenic diet has an increasing evidence base for use in mitochondrial disease and may have applications in the treatment of seizure disorders arising due to either nuclear or mitochondrial DNA defects.[8,12,73,74] Predicting who will respond to ketogenic diet is not currently possible. However, in one study, 75% of individuals had a reduction in seizures of more than 50%, and half of people became seizure free.[12] Furthermore, ketogenic diet may be a useful adjunct to traditional pharmaceutical agents in the acute setting,[73,75] although this effect is not universal and reporting bias is likely to be evident.[42] Whether the ketogenic diet modifies the prognosis or disease course of mitochondrial disease is currently unknown. Specialist dietician input is required, and further support can be found from Matthew's Friends (in the UK)–a support group for those embarking on the ketogenic diet.[76]

Surgical Management

The current evidence base for the surgical management of mitochondrial seizures is limited to case reports and small case series. In the case of vagus nerve stimulation, five children with an electron transport chain deficiency did not experience seizure reduction following vagus nerve stimulator implantation.[77] However, the patient population was small and heterogeneous, both in terms of the underlying genetic etiology and the seizure type. As such, it has limited ability to guide clinical application.

Traditional epilepsy surgery programs are usually inappropriate for those with mitochondrial disorders. However, palliative hemispherectomy in AHS has been described,[29] which enabled a patient to leave intensive care and die at home. The report was well received[78,79] and as refractory seizures are a common end-stage feature of mitochondrial disease, select cases may benefit from such an approach.

Palliative Care

As mentioned, many mitochondrial disorders cause premature death,[7,8,24] and for those with seizures, many deaths occur due to neurologic decompensation.[8] Accordingly, palliative care requirements should be anticipated by the clinical team.[80,81]