Disorders of mitochondrial function and metabolism result in energy failure producing varying severity of symptoms (1–3). The central nervous system is particularly susceptible to mitochondrial defects and neurologic manifestations are frequently seen in mitochondrial disorders (4, 5).

Seizures are particularly common in mitochondrial disorders such as polymerase gamma (POLG) mutations, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), and myoclonic epilepsy with ragged-red fibers (MERRF) (6–9). Published information on specific seizure semiology and electroencephalogram (EEG) findings in mitochondrial disorders is limited compared to what is known about other genetic and metabolic epilepsies, likely owing to the significant variability between and within specific mitochondrial disorders (10). While seizures are not unique to a mitochondrial etiology (11–13), it has been previously noted that EEG abnormalities in these disorders tend to have a posterior cerebral predilection (14–16). Within the central nervous system, mitochondrial dysfunction frequently results in structural injury, which can manifest as characteristic neuroimaging abnormalities (17, 18). The time to diagnosis can be variable and in some cases may take years when presentations are atypical or when symptoms and diagnostic studies are non-specific. Treatment of these disorders is limited and mainly comprised of utilization of nutritional therapies aimed to increase the metabolic substrates used in mitochondrial processes (19). These nutraceutical therapies, sometimes referred to as the “mitochondrial cocktail,” are unproven at present with limited evidence-based support of their use.

The main objective of this study was to evaluate the EEG, clinical, and radiologic progression of disease in patients with epilepsy due to mitochondrial cytopathies in order to identify features, which may help the clinician more readily diagnose these disorders. A secondary objective was to study nutraceutical therapy use in relationship to disease progression.

This retrospective study was performed using the Mayo Clinic Mitochondrial Disease Database from January 2011 to December 2019. Records were reviewed for diagnosis, history of epilepsy, laboratory investigations, and available raw EEG and MRI studies. Patients were classified based on previously published diagnostic criteria as having a definite, probable, or possible mitochondrial disorder (20–23).

Patients with a definite, genetically confirmed diagnosis of mitochondrial disorder were included. Patients without confirmatory testing or where there was diagnostic ambiguity were excluded. Additional inclusion criteria included history of seizures and EEG and MRI studies performed at our institution. Patients were excluded if any of the inclusion criteria were missing or if medical records were limited.

Information extracted from the medical record included seizure history and semiology, anti-seizure therapies and side effects, laboratory investigations, including genetic testing and tissue biopsy results, EEG and neuroimaging findings, use of nutraceuticals/supplements, and disposition at last follow-up. Seizure semiology was classified based upon the most recent International League Against Epilepsy (ILAE) classification schema (24, 25).

Electroencephalogram studies were graded based on the degree and location of abnormalities and rated as either normal or demonstrating mild, moderate, or severe abnormalities using the Mayo Clinic EEG classification system, which assigns a dysrhythmia score of 1 through 3 (1 = mild, 2 = moderate, and 3 = severe). This included pediatric EEG recordings, which were reviewed and interpreted with attention to age-expected findings in children. “Mild” was defined as background slowing of 7–8 Hertz (Hz) or intermittent slowing in the theta range (5–7 Hz); “moderate” if there was a mixture of frequent delta-theta slowing (<4 Hz up to 7 Hz) or if there was a mild-to-moderate asymmetry of the background (<50% difference in amplitude between homologous regions); and “severe” if any of the following were present: focal or diffuse delta slowing (<4 Hz), severe background asymmetry (>75% difference in amplitude between homologous regions), epileptiform abnormalities [spikes, spike and wave, and sharp wave discharges, lateralized periodic discharges (LPDs) or generalized periodic discharges (GPDs), and periodic sharp wave complexes], or recorded seizures or status epilepticus. The locations of EEG abnormalities were noted and categorized as focal, multifocal (focal abnormalities in more than two regions), or generalized.

Magnetic resonance imaging studies were reviewed by one study author (GL) and abnormalities noted based on location, imaging sequence [T2/fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI)], abnormal contrast enhancement, and presence or absence of cortical laminar necrosis, atrophy, or encephalomalacia.

Electroencephalogram and MRI results were evaluated for anatomic concordance, defined as colocalization on studies, comparing studies obtained within 30 days of each other. Serial EEG and MRI studies were also evaluated for disease progression, defined as the presence of new abnormalities compared to previous studies.

Functional status was assigned based on initial and last documented encounters, using the modified Rankin scale (mRS), with a score of 0 (no symptoms), 1 (no significant disability), 2 (slight disability), 3 (moderate disability), 4 (moderate-to-severe disability), 5 (severe disability), or 6 (death). Patient disposition was determined at last known follow-up based on notes or communications contained in the medical record.

This study was approved by the Mayo Clinic Foundation Institutional Review Board.

A total of 164 unique patient records were reviewed with 144 patients excluded for the following reasons: limited/missing clinical information (n = 22), absence of seizures (n = 113), or diagnosis of a probable or possible mitochondrial disorder (n = 9).

Diagnoses in excluded patients included MELAS (m.3243A>G variant) (n = 28), chronic progressive external ophthalmoplegia (CPEO)/Kearns–Sayre syndrome (KSS) (n = 14), Leber hereditary optic neuropathy (LHON) (n = 5), neuropathy, ataxia, and retinitis pigmentosa (NARP) (n = 2), and Leigh syndrome (n = 2). In an additional 34 patients without seizure, the diagnosis was based on history and laboratory findings without genetic confirmation.

Table 1 shows details on the 20 patients that fulfilled inclusion criteria. The mean age at initial evaluation was 23 years (median 21.5 years, SD 14.3 years) with 6 males and 14 females. Two kindred pairs were included (one sibling pair and one parent–child pair). The most common diagnoses were MELAS (n = 12) and POLG1 (n = 3). Evaluation of epilepsy was the most common initial visit indication (n = 14), followed by genetics evaluation (n = 2), developmental delay (n = 2), and headache evaluation (n = 2).

This retrospective series of patients with mitochondrial disorders and epilepsy demonstrated an increasing predominance of posterior imaging and EEG abnormalities. Focal seizures, particularly with visual phenomena, were the most frequently seen, correlating with focal lesions commonly found in our cohort. As expected, patients with the same genetic variant had variable disease manifestations and clinical course.

On EEG studies, seizures and epileptiform abnormalities most commonly localized to the posterior temporal, parietal, and occipital regions. This proclivity for the posterior cerebral regions in mitochondrial disorders has been previously described and early recognition of such findings should suggest the possibility of a mitochondrial cytopathy (7, 15, 26).

Our findings are supported by previous patient series and literature reviews on epilepsy features in mitochondrial disorders (Table 3) (8, 10, 16, 28–31). Focal seizures were the predominant seizure type in our series, which is in agreement with the previous review by Anagnostou et al. in POLG and a recent case series in MELAS by Li et al. (10, 28). In a series of 19 patients with POLG1, occipital rhythmic slowing was present in 7 patients and occipital interictal discharges was present in 18 patients, demonstrating an occipital predilection in POLG (15). This finding, as seen in our study over the disease course, is concordant with electrophysiologic data reported by other authors (10, 16, 28, 29). Occipital status epilepticus and occipital seizures have also been previously reported in MELAS; this manifestation may precede other clinical signs of the disease and serve as a potential diagnostic clue (29, 32, 33). Similarly, in our series, MRI abnormalities frequently involved the posterior head regions, often in concordance with EEG findings, which is in agreement with other series (18, 34, 35).

The most common mitochondrial disorder in our cohort was MELAS. Clinically, this diagnosis should be considered in an individual, particularly a young individual, with recurrent stroke-like episodes of unclear etiology. Stroke in MELAS is hypothesized to result from a combination of impaired oxidative phosphorylation, abnormal nitric oxide homeostasis, and vascular endothelial dysfunction (36–38). Oxidative stress leads to abnormal calcium homeostasis producing neuronal hyperexcitability (39, 40). The resultant localized cortical dysfunction and cerebral edema in acute and recovering cerebral infarcts increases the risk for seizure. Seizures then lead to increased free radical production within dysfunctional mitochondria, predisposing to further oxidative damage (5). With prolonged seizures, this process may lead to cortical laminar necrosis, which is manifested in the acute phase as T2 hyperintense or DWI hyperperfusion signal in the cortical ribbon on MRI (37, 41). The combination of local cortical injury and ongoing seizures then could produce a structural lesion (i.e., encephalomalacia, gliosis, etc.) predisposing to future seizure activity.

Inexorable progression was seen in our patients, with recurrent seizures, stroke-like episodes, and further brain injury, leading to continued functional decline. The majority developed moderate-to-severe disability or death, with eight patients deceased, of which seven deaths were attributable to their underlying mitochondrial disorder.

The treatment of seizures in patients with mitochondrial disorders is challenging. There is known mitochondrial toxicity from several ASMs, notably, valproic acid, phenytoin, and phenobarbital (42, 43). In our series, it was rare for patients to not have tried two or more ASMs including valproic acid, phenytoin, and phenobarbital. Interestingly, two patients were not started on ASM while seen at our institution, despite recurrent seizures. The reason documented for both was patient/family preference. The clinical course of the epilepsy in this cohort was unfortunately dismal, with the majority experiencing intractability and two of whom died from complications of super-refractory status epilepticus.

We found no evidence of efficacy of nutraceutical supplementation in our cohort, with the majority experiencing significant progression and exacerbations despite treatment. Compliance with the mitochondrial cocktail was difficult to assess based on chart review alone, which limited our ability to be certain as to the futility of therapy. These regimens can be difficult to maintain and are cost prohibitive. Some authors report the benefits of arginine and citrulline during acute attacks in MELAS to mitigate cortical injury by free radical reduction (36, 44, 45). Indeed, our practice is to include arginine in the regimen of patients with MELAS and provide additional supplementation during a stroke-like episode. However, the results of this retrospective review are sobering as to the potential for response to nutritional therapies in these patients. The use of other supplements has not been shown to alter disease course in mitochondrial disorders (45). A prospective clinical trial would be necessary to definitively evaluate the efficacy of supplement use in mitochondrial disorders.

There are several limitations of this study. As this study was retrospective, we were limited to information contained within the medical record. A large number of patients were excluded due to missing or incomplete records. We only included those with genetically confirmed disease, thus further reducing our sample size and potentially limiting our cohort to the most severely affected. Our small series was heavily weighted toward patients with MELAS, which could have skewed our findings and interpretation.

This retrospective series reviewed the clinical course of 20 patients with mitochondrial disorders and epilepsy. Most patients had EEG and neuroimaging abnormalities over the posterior head regions or showed progression to involvement of these regions over time. Seizures with visual symptoms occurred frequently. The presence of posterior predominant EEG and MRI abnormalities of unclear etiology should increase clinical suspicion of a mitochondrial disorder, particularly in an adult patient presenting with occipital status epilepticus. Our results raise question as to the efficacy of nutraceutical therapy for these diseases. A larger prospective study would be helpful to further clarify the optimal medical management of patients with mitochondrial disorders and epilepsy.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by Mayo Clinic IRB. Written informed consent from the participants' legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.

AF wrote the first draft of the manuscript, collected, analyzed and interpreted data, and revised the manuscript. GL collected and interpreted data and revised the manuscript. RG and JB revised the manuscript and gave final approval. All the authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.