Clinical manifestations

Presentation and course

Epilepsy can be the presenting symptom or occur during the course of most forms of mitochondrial respiratory chain disease, whether caused by mutations in mitochondrial DNA (mtDNA) or in genes encoded by nuclear DNA (nDNA) defects. No specific type of epilepsy characterizes mitochondrial disease, but an occipital lobe predilection, at least initially, is seen in several mtDNA- and nDNA-induced epilepsies. Myoclonus occurs in all types of mitochondrial disease, but whether this is purely cortical or brainstem or both is unclear, and both probably occur. Most commonly, the epilepsy in mitochondrial respiratory chain disease is symptomatic, multifocal, and, thus, secondary generalized epilepsy, combining focal and generalized features (05).

Because mitochondrial diseases often affect several tissues, it is common for epilepsy to occur together with other tissue manifestations, ie, as part of a syndrome. Specific mitochondrial syndromes in which epilepsy is a major feature include two linked to mtDNA mutations, myoclonus epilepsy with ragged-red fibers and mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, and epileptic syndromes caused by mutations in the nuclear-encoded POLG gene. These demonstrate the characteristic features of “mitochondrial epilepsy” and will be described in detail.

The International League Against Epilepsy Classification and Definition of Epilepsy Syndromes classifies mitochondrial epilepsies, in particular, MERRF, MELAS, and POLG-related epilepsies, as progressive myoclonus epilepsies, which are defined by (1) myoclonus, (2) progressive motor and cognitive impairment, (3) sensory and cerebellar signs, and (4) abnormal background slowing on EEG that (5) appear in an individual with prior normal development and cognition (46).

Myoclonus epilepsy with ragged-red fibers (MERRF). Epileptic seizures are one of the defining features of MERRF syndrome (14); others are myoclonus and the morphological hallmark of mitochondrial myopathy, namely, ragged-red fibers seen on muscle biopsy. Interestingly, there is also an association with multiple symmetrical lipomatosis. In an Italian cohort study, it was pointed out that myoclonus was an inconsistent feature of this disease and more associated with the presence of ataxia than epilepsy (31). In a clinical cross-sectional investigation on movement disorders on an Italian cohort of individuals with childhood-onset primary mitochondrial diseases, myoclonus was commonly observed in mitochondrial encephalopathies, mainly in MERRF, as predominant features at onset or appearing at follow-up in ataxic patients (34). In a German cohort study, the association between myoclonus and ataxia in adult subjects was insignificant, but a trend was observed (01).

Several different mtDNA mutations cause this syndrome. The first described was the m.8344 A>G in the mitochondrial tRNA gene for lysine. Subsequently, two more mutations in this gene were identified, and both appeared to cause the same clinical syndrome (m.8356T> C and m.8361G> A). Several other mutations have now been described, giving clinical syndromes in which myoclonic epilepsy occurs but which involve other features such as cardiomyopathy or diabetes mellitus (47). Indeed, overlap syndromes with features of both MERRF and MELAS are described, highlighting the marked phenotypic variability of mitochondrial disorders and the lack of consistent phenotype-genotype correlation. Nevertheless, the mutations in tRNA lysine cause a syndrome that is now well recognized and relatively frequent for an mtDNA disorder. More information is available in the article on myoclonus epilepsy with ragged-red fibers.

Patients can present with progressive myoclonus, and most have generalized tonic-clonic seizures (03; 25). The myoclonus may be indistinguishable from that seen in other progressive myoclonus epilepsies, eg, Unverricht-Lundborg or Lafora body disease. Myoclonic jerks may correlate with electroencephalographic (EEG) spike or polyspike activity, and suppression of epileptic activity following eye-opening has been seen. The myoclonus can be virtually constant but may also be intermittent, photosensitive, and intensified by action, such as writing, eating, etc. Focal clonic and atonic seizures have been reported (03). Visual or somatosensory symptoms may precede motor symptoms.

The generalized tonic-clonic seizures are generally amenable to traditional antiepileptic drugs, whereas the myoclonus may be relatively refractory and develop into continuous generalized myoclonus (03; 25). In addition to seizures, patients commonly develop ataxia, deafness, dementia, and a clinical myopathy (30).

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). The defining features of this syndrome are the finding of lactic acidosis and the occurrence of stroke-like episodes (41; 33; 09). Diabetes, deafness, progressive external ophthalmoplegia, gastroenteropathy and cyclical vomiting, failure to thrive, myopathy, and peripheral neuropathy also occur with variable frequency (08). Several different mtDNA mutations can cause the syndrome, but one, the m.3243A>G in the tRNA for leucine (UUR), is by far the commonest (15). This mutation can cause MELAS, with stroke-like episodes and epilepsy, or more benign phenotypes, such as maternally inherited diabetes, deafness, and encephalopathy or progressive external ophthalmoplegia with a proximal myopathy (09). More information is available in the article on MELAS.

Epilepsy occurs primarily in the group of patients who develop stroke-like lesions, and seizures are often preceded by, or associated with, migraine-like headache. Stroke-like lesions evolve gradually (23) and show a predilection for the occipital and temporal lobes, and seizure semiology often reflects disturbances in these locations. MRI shows evolving lesions that appear to reflect initial cellular damage followed by vasogenic edema (52). Why certain areas of the brain are targeted is still an unanswered question. However, there is a growing acceptance that they represent seizure activity (09). Once initiated, seizures increase the metabolic demand placed on neurons, exposing patients to a risk of further damage and, therefore, further seizures.

In a review of 110 reported cases of MELAS in which stroke-like episodes were a defining feature, 38% had myoclonus, and 96% had seizures (19). In 28% of the cases, seizures were the initial clinical manifestation. Both generalized and focal seizures were seen (26 of 42), and in 10 of 42 patients, generalized epilepsy was defined, including one patient with absence seizures (18). The commonest type of partial seizures found were motor, followed by visual and temporal lobe seizures. Status epilepticus occurred in six of 42 patients in this series, but clinical experience shows that status epilepticus is frequent in patients with MELAS and similar mitochondrial disorders and can be the initial presentation.

In a study of Italian patients with the m.3243A>G mutation, seizures were the second most common presenting complaint, but they were present in only 18% (31). Although seizures were again significantly associated with stroke-like episodes, the differences between this study and the one from 1994 reflect the extended range of phenotypes now associated with this mutation and the greater impact of more common features such as diabetes and deafness on the presentation of this mitochondrial phenotype. Interestingly, this study of 126 m.3243A>G carriers demonstrated a significantly greater number of males with stroke-like episodes.

When present, myoclonic seizures appear less severe and less common than in patients with MERRF. Noticeably, there may be overlap syndromes between MELAS and MERFF. In a later publication, interictal EEG changes in MELAS patients were localized to the parieto-occipital regions or as diffuse sharp wave paroxysms, whereas EEG discharges associated with partial motor seizures had a congruous frontocentral location (04). The age of epilepsy debut may likely influence the seizure semiology in MELAS, with absence seizures reflecting young age, whereas a complex partial status epilepticus with regional epileptic activity in the right posterior quadrant occurred in late-onset MELAS (26).

Other mtDNA mutations. Over 150 mutations in mtDNA have been described, and mutations in mitochondrial tRNA genes are particularly common. Many cause syndromes that also include epilepsy. However, these are rare compared with the syndromes described above, and the epilepsy that evolves does not differ significantly from what is described in the MERRF and MELAS sections.

POLG-related syndromes. The POLG gene encodes the catalytic subunit of the mitochondrial DNA polymerase, the enzyme that replicates mtDNA. Mutations in this nuclear gene can either induce qualitative mtDNA defects (multiple mtDNA deletions or point mutations) or quantitative loss of mtDNA, known as depletion. Moreover, mutations in this gene appear to be common and give rise to a variety of disorders ranging from infantile hepatocerebral disease, such as Alpers syndrome; myoclonic epilepsy, myopathy and sensory ataxia and the ataxia neuropathy spectrum; parkinsonism; and progressive external ophthalmoplegia (29; 16; 22; 54; 17).

Alpers-Huttenlocher syndrome comprises refractory seizures, psychomotor retardation, and liver involvement and is caused by a variety of different mutations in the POLG gene (12; 38). Initial presentation is most often with status epilepticus that can be focal (epilepsia partialis continua) or generalized and from which the child might never recover. Mental retardation can be present before the onset of seizures, or begin thereafter. Liver failure, perhaps the least consistent feature, may be present at onset or it may only develop during the terminal illness. The majority of children with this disease die within a few months of onset, but some survive several years, usually profoundly affected. Elevated lactate in blood or CSF is an inconsistent feature. MRI shows a predilection for involvement of the occipital lobes.

Myoclonic epilepsy, myopathy, and sensory ataxia (MEMSA). This spectrum of disorders, which covers the disorder previously described as spinocerebellar ataxia with epilepsy, usually starts in the teenage years, either with ataxia or epilepsy and typically without ophthalmoplegia (note that long-term survivors of MEMSA can additionally develop progressive external ophthalmoplegia) (45). All patients eventually develop ataxia if they survive. It has been suggested that approximately 80% of patients develop epilepsy (11), but this must be interpreted with caution because patients with MEMSA can develop an explosive and fatal epilepsy more than 30 years after presenting with ataxia. Although several POLG mutations are described as causing this disease that presents later than Alpers, the two most common are the c.1399G>A that gives p.A467T and the c.2243G>C that gives p.W748S. The MELAS phenotype may also develop with certain POLG mutations.

Epilepsy is the presenting symptom of MEMSA in approximately 65% of patients (11). Occipital lobe epileptic features are the initial symptoms in the majority, and seizure phenomena include flickering colored light that may persist for weeks, months, or even years; ictal visual loss; nystagmus or ocular clonus; dysmorphopsia; micro-/macropsia; and palinopsia, often combined with headache or emesis. Refractory simple partial seizures with visual symptoms in one visual hemifield occurring daily for weeks, months, or even years have been seen in over 50% of cases, and the epileptic origin of these symptoms could be substantiated by ictal EEG.

All patients with epilepsy develop focal clonic or myoclonic seizures, most often involving an arm, shoulder, neck, or head and manifesting as simple partial motor seizures that often continue on to focal motor status (epilepsia partialis continua). Occasionally, persisting focal or generalized myoclonic jerks can be observed. Motor simple partial seizures are sometimes accompanied by a clear epileptic EEG correlate, sometimes with rhythmic focal slowing of the contralateral, posterior hemispheric quadrant or the occipital electrodes. No clear correlation between frequency of focal clonic movements of arm-shoulder-head and frequency of occipital slow waves is seen, but EEG changes can be considered epileptiform in nature. Complex partial seizures with motor symptoms occur in more than 50% of patients and may be underreported. Generalized tonic-clonic seizures, all considered secondary generalized tonic-clonic seizures, occur in more than 90% of cases (13). All patients who develop epilepsy develop status epilepticus, and this can begin explosively several decades after disease onset. Status epilepticus can also be the presenting seizure phenomenon, although the median time from onset of epilepsy to the first status epilepticus is 2 months.

EEG showing occipital slow-wave and epileptic activity occurs as an early feature in the majority of patients. Ictal registrations reveal either severe general slowing, with or without epileptic activity, or, as in the majority of patients, consistent focal occipital or temporo-occipital epileptic discharges.

Other nuclear gene defects. Although many mitochondrial nuclear gene defects can cause epilepsy, those due to POLG mutation are, by far, the best described. Nevertheless, a similar syndrome with epilepsy and encephalopathy is seen with an early-onset disease due to mutations in the mitochondrial helicase Twinkle (28), and it is highly likely that other nDNA defects, particularly those having a similar role to POLG and Twinkle (ie, involved in mtDNA homeostasis), will also be associated with similar clinical syndromes. Epilepsy is also common in pediatric disorders, such as Leigh syndrome, which are caused by defects in complex I or IV. Initial presentation with an epileptic seizure is well recognized, but as above, no particular seizure type is indicative of one of these disorders. Diseases associated with defects of ubiquinone biosynthesis are also potent causes of epilepsy, particularly those caused by mutations in ADCK3 (57).

Prognosis and complications

A wide spectrum of phenotypes are associated with mtDNA diseases, and the same mutation, eg, the common m.3243A>G, can give rise not only to MELAS but also to diabetes, deafness, progressive external ophthalmoplegia, other endocrine disturbances, myopathy, gastroparesis, and cyclical vomiting. It is essential, therefore, that clinical follow-up recognizes this fact and that screening protocols are instituted. Mitochondrial syndromes such as MELAS, MERRF, and POLG-related epilepsy are progressive and associated with poor prognosis and shortened lifespan. MELAS, as the name implies, is associated with stroke-like episodes that predispose to seizures and status epilepticus. Cardiomyopathy and diabetes mellitus are complications of MELAS that occur with relatively high frequency, and these must be actively sought and treated (37). MERRF is less aggressive, but it is also associated with sudden death that might be cardiac in origin.

Acute encephalopathy and status epilepticus have a high mortality in patients with POLG-related epilepsy. More than 70% of patients who develop status epilepticus die, compared with none of those who do not develop epilepsy. Because POLG mutations lead to defects in mtDNA, POLG-related disease manifests almost the same spectrum of phenotypes as mtDNA disease. Interestingly, however, neither diabetes nor cardiomyopathy is common.

In a review of 182 adult patients with mitochondrial disease attending a specialized clinic, the prevalence of epilepsy was 23.1%, and the most common genotypes involved those caused by the m.3243A>G and m.8344A>G mtDNA mutations. The prevalence was 34.9% with m.3243A>G and 92.3% with m.8344A>G (especially myoclonus). Interestingly, however, the standardized mortality ratio, which was high for the whole group (2.86), did not differ between those with epilepsy and those without (56).

Biological basis

Etiology and pathogenesis

Mitochondria are organelles with multiple functions, of which ATP production is arguably the most important. The pathway that generates ATP, the mitochondrial respiratory chain, is controlled by two genomes--one in the mitochondrion itself, mitochondrial DNA (mtDNA), and the other the nuclear genome DNA (nuclear DNA). Mitochondrial disease can arise from mutations occurring in either genome, and inheritance is, therefore, complex, with maternal, recessive, dominant, and X-linked transmission all possible.

In classical genetics, the concepts of heterozygous (each gene copy has a different sequence) and homozygous (both gene copies have an identical sequence) are used. Dominant disorders arise when a mutation in one gene copy is sufficient to cause disease, and recessive disorders require mutations affecting both copies. In mitochondrial genetics, the situation is complicated by the presence of multiple genomes and uneven tissue distribution (32). Mutations can affect a percentage of mtDNA copies, from less than 1% to more than 99%. In homoplasmy (cf. homozygous), all copies in an individual have the same sequence; in heteroplasmy (cf. heterozygous), there are mtDNA with two different sequences, eg, one with a mutation and one normal. In addition, the level of mutation in one tissue can differ dramatically from another based on factors such as whether the cell retains the capacity to divide and, therefore, select against cells with impaired energy metabolism. In many mtDNA disorders, particularly those in which the defect is unknown, this will mean that it is not possible to use white blood cells, which retain the capacity to divide, as a source of genetic material because the level can fall below the level of detection.

Neurons heavily depend on aerobic metabolism to uphold membrane polarization through ion channels. The intricate association between epilepsy and cerebral metabolism underscores the significance of ATP depletion resulting from impaired oxidative phosphorylation in the genesis of seizures in primary mitochondrial diseases. Dysfunction in membrane channels and Na+/K+ ATPase activity leads to the loss of neuron hyperpolarization. Additionally, defective mitochondrial metabolism contributes to heightened cell excitation by (1) diminishing GABA-mediated inhibition due to the loss of inhibitory interneurons, particularly in the occipital cortex; (2) suppressing the activity of inhibitory neurons in the hippocampus; and (3) increasing glutamate release in the synaptic space by astrocytes (24; 43; 51).

Notably, interneurons, especially those affected by complex I and complex IV defects, appear more vulnerable to oxidative phosphorylation dysfunction (24; 43). A metabolic interplay between astrocytes and neurons, facilitated by a lactate shuttle, is proposed to primarily meet the energetic demands of neurons, particularly during periods of high synaptic activity (13). A “dual neuronal-astrocytic hypothesis” posits that oxidative phosphorylation deficiency, coupled with the downregulation of glutamine synthetase, reduces GABA recycling in astrocytes. This astrocytic metabolic shutdown, combined with the loss of inhibitory interneurons, contributes to the formation of a hyperexcitable network that supports seizure generation (42).

Moreover, ATP depletion may result in structural damage to the brain, creating epileptogenic foci. For instance, intrauterine white matter loss in neonatal encephalopathy forms of pyruvate dehydrogenase complex deficits or stroke-like lesions in MELAS or POLG-related diseases exemplify this phenomenon (24; 43).

Finally, seizures themselves can initiate mitochondrial dysfunction, establishing a self-perpetuating cycle. Severe episodes of seizure exacerbation may lead to the development of stroke-like lesions and status epilepticus (53; 45). Although the underlying mechanism of stroke-like episodes remains unclear, they are generally perceived as manifestations of prolonged and aberrant ictal activity (17).

Epidemiology

Primary mitochondrial diseases are the most common inherited metabolic diseases. Studies in the United Kingdom showed that 9.2 in 100,000 people of working age (over 16 and under 60/65 years of age, female/male) had a clinically manifest mtDNA disease, and a further 16.5 in 100,000 children and adults younger than retirement age were at risk of developing one (48). Studies from Sweden showed that the incidence of mitochondrial encephalomyopathies in preschool children (under 6 years of age) was one in 11,000 (06), and in Australia, an estimated minimum birth prevalence of 6.2 in 100,000 was found (49). These figures are based only on patients with known mtDNA mutations; there is no way of estimating how many more mutations are still to be discovered, but several new mtDNA mutations are published each year. In a major study published in 2008, Elliott and colleagues determined the frequency of 10 mtDNA mutations in 3168 neonatal-cord blood samples from sequential live births and found that at least one in 200 healthy humans harbors a pathogenic mtDNA mutation that potentially causes disease in the offspring of female carriers (10).

Prevention

There are no studies dealing with this issue. In practice, however, because of the clear danger for status epilepticus, there is a very low threshold for initiating anticonvulsant treatment in patients with the m.3243A>G and POLG mutations.

Differential diagnosis

Epilepsy as the only manifestation of syndromic mitochondrial disorders is highly unusual. The differential diagnosis depends on the other features present, eg, stroke-like episodes, myopathy, progressive myoclonic epilepsy, and lactic acidosis.

Stroke-like episodes are highly suggestive of mitochondrial etiology (occur in MELAS and POLG-related disease, but also other mtDNA disorders and even other metabolic conditions), but stroke occurring in isolation is more likely to be an ischemic stroke, which can also be associated with secondary epilepsy.

A combination of myopathy and epilepsy should prompt the clinician to consider primary mitochondrial disease as the primary diagnosis. The combination of myopathy and mental retardation gives a wider differential diagnosis that includes congenital muscular and myotonic dystrophies; refer to general muscle tracts for more information.

Progressive myoclonic epilepsy can occur with Unverricht-Lundborg disease, Lafora body disease, neuronal ceroid lipofuscinosis, and sialidosis.

Lactic acidosis is a hallmark of primary mitochondrial disease but can also occur in other metabolic diseases, such as very long-chain acyl-CoA dehydrogenase deficiency and early-onset trifunctional enzyme deficiency.

Diagnostic workup

Diagnosing primary mitochondrial diseases involves following the standard protocol of clinical suspicion and conducting additional laboratory tests (50; 39). The diverse presentation of epilepsy in these diseases challenges the misconception that the presence of myoclonic seizures or severe epileptic encephalopathy should automatically trigger suspicion of a mitochondrial disorder. Even experienced neurologists find the identification of mitochondrial epilepsy to be a complex task.

In mitochondrial medicine, the initial focus is on obtaining a thorough family history, paying meticulous attention to subtle and seemingly nonspecific indicators within the family, termed "mitochondrial red flags." These indicators encompass various conditions, such as short stature, diabetes, migraine, hearing loss, ataxia, exercise intolerance, progressive external ophthalmoplegia, cardiomyopathies, and psychiatric disorders. A positive family history in the maternal lineage strongly suggests an association with mtDNA-related disorders. Regardless of familial background, consideration of a primary mitochondrial disease is warranted in cases with seemingly disparate involvement of two or more tissues.

Elevated lactate levels in blood or cerebrospinal fluid are common but inconsistent findings, even in cases of MELAS. Raised lactate levels are associated with the presence of stroke-like episodes, increasing the risk of epilepsy in patients with the m.3243A>G mutation (31). However, caution is advised in interpreting elevated CSF lactate levels, as they can also result from seizure activity and certain infections. Biomarkers such as fibroblast growth factor-21 (FGF-21) and growth differentiation factor 15 (GDF-15) show significantly higher expression in mitochondrial dysfunction, with circulating GDF-15 considered the best standalone biomarker for diagnosing mitochondrial dysfunction (21).

Imaging techniques such as MRI can reveal patterns suggesting a mitochondrial etiology, although they are not diagnostic. Dystrophic calcification, especially affecting the basal ganglia, is seen in MELAS but also in Kearns-Sayre syndrome. MR spectroscopy and PET scanning provide additional information on brain metabolism and ATP production.

Seizures may be the initial feature of primary mitochondrial diseases, particularly in pediatric patients with nDNA mutations. However, they are often part of a multisystem presentation and can occur throughout the disease course. Mitochondrial epilepsy often exhibits multifocal characteristics, involving both focal and generalized features. Clear syndromic epilepsy can be found in specific phenotypes. Status epilepticus, especially in the form of epilepsia partialis continua, should raise suspicion of a stroke-like episode, which is commonly associated with MELAS syndrome or POLG-related disorders (56; 43).

EEG alterations, typically in the form of abnormal background activity with occipital predilection, are not pathognomonic but are commonly observed in patients with mitochondrial disease and a history of seizures (51; 13).

For patients with early-onset epilepsy, a history of tonic seizures, and disorganized background activity in EEG traces, preliminary nuclear gene testing is recommended. Next-generation sequencing covering known nuclear mitochondrial genes is preferred, avoiding single-gene testing due to genetic pleiotropy and syndromic overlapping. Patients with myoclonic seizures, particularly those with neuromuscular disorders, may warrant diagnostic testing for m.8344A>G (MERRF mutation). In cases of a history of status epilepticus or seizures associated with specific symptoms, such as hearing loss, short stature, endocrine disorders, or migraine, screening for m.3243A>G (MELAS mutation) is recommended. If primary mitochondrial disease is strongly suspected and blood testing for common mtDNA point mutations is negative, assessing mtDNA in another tissue, such as urine, may be informative, especially for MELAS suspicion. Tissues investigated when blood or urine genetic tests yield negative or inconclusive results typically include skeletal muscle and skin fibroblasts. Skeletal muscle biopsy often reveals abnormalities, even in the absence of clinical myopathy. The presence of mitochondrial accumulation (ragged-red fibers) or fibers lacking complex IV activity (cytochrome oxidase negative fibers) suggests mitochondrial respiratory chain disease. Muscle or fibroblasts can be utilized for biochemical measurements of respiratory complexes and studies of mtDNA.

Management

General recommendations. Although there are generally no disease-modifying therapies for most primary mitochondrial diseases, some exceptions, known as "treatable forms," warrant recognition. Notable instances include disorders related to coenzyme Q10 (ubiquinone) biosynthesis, which may show partial improvement with high-dose supplementation. Additionally, conditions arising from mutations in the ACAD9 gene leading to complex I deficiencies, marked by seizures, may respond positively to riboflavin (vitamin B2) supplementation (44). Similarly, Leigh or Leigh-like syndromes resulting from biotinidase deficiency or thiamine transporter 2 deficiency may exhibit responsiveness to biotin (vitamin B8) or thiamine (vitamin B1) administration, respectively (27).

In 2017, the Mitochondrial Medicine Society issued a consensus-based statement emphasizing the importance of a low threshold for obtaining an EEG registration in patients displaying alterations in their cognitive state and repetitive stereotypical spells (40). A 2020 international Delphi-based consensus on the safety of drug use in patients with primary mitochondrial disease, including anti-seizure drugs, was published (07). Although epilepsy in primary mitochondrial disease should generally be treated similarly to non-mitochondrial epilepsy, caution is advised when using drugs with known mitochondrial toxicity, such as sodium valproate, particularly in patients with POLG mutations, due to the risk of hepatic failure and seizure aggravation. The 2017 consensus emphasizes that no combination of antiseizure medication has been proven superior (40).

Pharmacological intervention. Levetiracetam is considered a safe and primary treatment, particularly for myoclonus, notably in cases of MERRF, and can be complemented with benzodiazepines like clonazepam or clobazam, which have demonstrated efficacy. Lamotrigine is both safe and effective, although caution is advised as it might exacerbate myoclonic seizures. Zonisamide and lacosamide have been reported as safe and beneficial options, especially in individuals with MELAS or those experiencing drug-resistant seizures. Other viable choices include gabapentin, oxcarbazepine, rufinamide, and stiripentol. Although some mitochondrial patients have been treated with oxcarbazepine, phenytoin, or phenobarbital, their potential toxicity and adverse impact on myoclonus should prompt clinicians to explore alternative pharmacological options. Invariably, a considerable number of patients require multiple antiseizure drugs to attain seizure control, and a significant portion of individuals with mitochondrial epilepsy eventually develop resistance to therapy (40; 55).

Nonpharmacological interventions. Given the prevalence of drug-resistant epilepsy in many patients, alternative therapeutic approaches are often explored. Reports have been documented on the use of vagal nerve stimulation, deep brain stimulation, and palliative surgery. However, the effectiveness of vagal nerve stimulation in seizure control remains unclear, as indicated in studies such as the one by Arthur and colleagues in 2007 (02). On the other hand, corpus callosotomy has demonstrated a reduction in seizure frequency in 10 pediatric patients with drug-resistant epilepsy (35).

The ketogenic diet has emerged as a widely adopted nonpharmacological option for individuals with mitochondrial intractable epilepsy. This low-carbohydrate, high-fat diet promotes fatty-acid utilization through beta-oxidation, leading to the production of ketone bodies. This process has shown beneficial outcomes by stimulating mitochondrial biogenesis, enhancing oxidative phosphorylation functioning, and reducing oxidative stress. The ketogenic diet contributes to a decrease in glutamate levels in the synaptic space and the elevation of decanoic acid, a fatty acid known to reduce neuronal excitation. Additionally, the metabolism of ketone bodies supports ATP production, partially circumventing the activity of complex I. Therefore, individuals with complex I deficiencies are considered potential candidates for ketogenic diet treatment (58).

A systematic review has highlighted the high efficacy of the ketogenic diet in seizure control among patients with mitochondrial disease, predominantly in the pediatric population. However, 65% of cases reported adverse effects, including headache, lethargy, rhabdomyolysis, and lactic acidosis (58). In a prospective study from China, a ketogenic diet demonstrated significant seizure reduction, with 31.8% of participants achieving 50% or greater reduction after 1 month, increasing to 40.9% at 3 months, particularly in patients with MELAS or pathogenic variants in mtDNA. Although the ketogenic diet has proven to be safe and effective for seizure control in primary mitochondrial diseases, especially MELAS and mtDNA pathogenic variants, caution is advised in cases of mitochondrial myopathy related to mtDNA multiple deletions. Despite limited data for general guidelines, it is recommended to consider a ketogenic diet in patients with resistant mitochondrial epilepsy, under the supervision of an experienced team (58; 20).

Stroke-like episodes and status epilepticus. In 2019, a consensus-based statement on the management of stroke-like episodes emphasized the importance of prompt treatment with benzodiazepines for patients displaying suggestive signs and a history of previous episodes (36). On arrival at the emergency department, immediate initiation of intravenous antiseizure therapy is recommended. Levetiracetam is the preferred choice (20 to 40 mg/kg, max 4500 mg), although alternatives such as phenytoin, phenobarbitone, or lacosamide can also be considered. Due to limited evidence, L-arginine is not recommended for the treatment of stroke-like episodes (36). A prospective randomized controlled trial is deemed necessary to evaluate the efficacy of various compounds in treating or preventing stroke-like episodes.

As mentioned earlier, status epilepticus is generally linked with stroke-like episodes. If necessary, midazolam is recommended as the primary option for general anesthetics in the management of refractory status epilepticus in primary mitochondrial diseases. Continuous EEG monitoring is essential, and a quick and aggressive approach to treatment is advised. Propofol is not contraindicated. In cases of convulsive status epilepticus, adherence to local status epilepticus guidelines is recommended (36). Positive responses have been reported with alternative interventions, including the use of perampanel, corticosteroids, ketamine, immunoglobulin, and magnesium infusion.

Special considerations

Pregnancy

There is little information concerning pregnancy and most types of primary mitochondrial diseases, including MELAS, MERRF, and POLG-related diseases.