Monday, February 20, 2017

Epilepsy in MELAS

Lee HN, Eom S, Kim SH, Kang HC, Lee JS, Kim HD, Lee YM. Epilepsy Characteristics and Clinical Outcome in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS). Pediatr Neurol. 2016 Nov;64:59-65.

Epileptic seizures in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) are heterogeneous with no pathognomonic features. We reviewed epilepsy characteristics and clinical outcome exclusively in a pediatric population.
Twenty-two children and adolescents (13 males) with confirmed mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes due to mitochondrial DNA A3243G mutation and epilepsy were recruited. Clinical data including seizure semiology, treatment response, neuroimaging findings, and electroencephalography were analyzed. We also examined the effect of the age at seizure onset and initial symptoms on the clinical variables.
Seizure semiology and electroencephalography abnormalities showed no syndrome-specific findings. Focal seizures occurred in 21 of 22 subjects (95.5%), whereas generalized seizures developed in seven of 22 subjects (31.8%). Twenty of 22 subjects (90.9%) achieved partial to complete reduction of clinical seizures for more than one year with a combination of more than two antiepileptic drugs. The subgroup with earlier seizure onset presented significantly earlier and showed significantly higher rates of drug-resistant epilepsy compared with the late onset group, although there were no significant differences in the initial symptoms. The subjects with severe epileptic conditions tended to have more severe clinical dysfunction and more severe organ involvement.

Both focal and generalized seizures occurred in patients with MELAS. Epilepsy in this population is drug resistant, but a certain degree of clinical seizure reduction was achievable with antiepileptic drugs, with more favorable outcomes than historically expected. Close observation and active epilepsy treatment of individuals with MELAS episodes and earlier seizure onset might improve the prognosis.

From the article

Epilepsy is quite common throughout the MELAS disease course,  but not all individuals initially manifest with seizures. Our data are consistent with previous studies in terms of age at first presentation and at first seizure.  Twelve of our 22 patients (54.5%) initially presented with seizures, reconfirming that epileptic seizures were the most common presenting symptom in patients with MELAS. Subsequently, all subjects experienced seizure events…

MELAS may respond to traditional antiepileptic drugs but is generally refractory.  Epileptic seizures in MELAS can be difficult to treat for several reasons, including recurrent unexpected acute lesions induced by stroke-like episodes with resultant neuronal hyperexcitability, focal hyperemia, inflammation, necrosis, edema,  and epileptogenetic primary mitochondrial dysfunction.  The choice of antiepileptic drugs is complicated because of the high potential of mitochondrial toxicity associated with valproic acid, carbamazepine, phenytoin, and phenobarbital.  Most studies focused on describing EEG characteristics or showing progressive ongoing courses of each case series.  Lee et al.  reported detailed treatment outcomes of a combination of antiepileptic drugs in 46 infants with syndromic and nonsyndromic mitochondrial diseases. When we further investigated, partial to complete seizure reduction for more than 1 year was achievable with combinations of more than two antiepileptic drugs, somewhat more favorable than historically expected and relatively better than the study by Lee et al.  Four of 22 patients (18.2%) achieved complete seizure freedom for at least one year, 16 of 22 patients (72.7%) achieved ≥50% seizure reduction, and only two patients (9.1%) showed no change from baseline at the last clinic visit, appearing quite promising. Treatment of drug-resistant epilepsy requires complex decision making to balance the risks and benefits of applying multiple drugs in this complicated patient population with ongoing multiorgan involvement; however, our data suggest active epilepsy treatment is possible, which may lead to better quality of life for both patients and their caregivers.

Having determined that temporary partial to complete seizure reduction is achievable by antiepileptic treatment, we further investigated factors that may affect outcomes, including the age of seizure onset and initial presenting symptom. The subgroup analyses confirmed heterogeneity of seizure types and EEG abnormalities, which was not affected by the age of seizure onset or initial presenting symptoms. Patients with earlier seizure onset presented at significantly younger ages (5.4 ± 2.4 vs 11.1 ± 2.8 years, P < 0.001) and showed significantly higher rates of drug-resistant epilepsy (83% vs 40%, P = 0.017). There was no significant difference in initial presenting symptoms. Patients with earlier seizure onset also tended to take higher numbers of antiepileptic drugs and exhibited lower rates of clinical seizure reduction with treatment, yet with no statistical significance. From these results, we may assume that in the pediatric MELAS population, seizures at a younger age might indicate underlying brain dysfunction at an earlier age, as demonstrated by our EEG results, and which subsequently leads to earlier diagnosis. An earlier beginning to the epileptic process and ongoing encephalopathy may also result in worse treatment outcomes, as in our data. Special attention and active epilepsy treatment is thus required in children presenting with seizure at earlier ages. Physicians who treat children with MELAS should be prepared to detect early signs of clinical seizures and plan subsequent treatment for best management.

1 comment:

  1. osef Finsterer, Sinda Zarrouk-Mahjoub. Epilepsy in MELAS. Pediatric Neurology. In press.

    Since some of the antiepileptic drugs (AEDs) can be mitochondrion-toxic, in particular valproic acid, carbamazepine, phenytoin, and barbiturates, we should consider how often these AEDs were utilized and how seizure control in these patients compared with those taking less mitochondrion-toxic AEDs. Did the MELAS phenotype deteriorate upon administration of mitochondrion-toxic AEDs in any of the patients? For status epilepticus, administration of mitochondrion-toxic AEDs may be inevitable. How many patients experienced a status epilepticus and how many received mitochondrion-toxic AEDs during these conditions would be of interest.

    Two patients in the series had been treated with a ketogenic diet. Was ketogenic diet the exclusive antiepileptic treatment in these patients or used in conjunction with AEDs? Was seizure control of the ketogenic diet patients better than that of individuals not on the diet?

    Seizures in MELAS may or may not be associated with stroke-like episodes. In how many patients were seizures associated with the occurrence of a stroke-like episode? Did those with stroke-like episodes receive l-arginine and did this agent also have a beneficial effect on seizure frequency?

    How many patients had intractable epilepsy? Did any of the patients undergo epilepsy surgery or receive a vagus nerve stimulator?

    The mean follow-up period was 5.5 years. In how many did seizure control improve or deteriorate during follow-up?

    We should be informed in how many patients the family history was positive for epilepsy, in how many it was positive for MELAS, in how many the diagnosis was confirmed by genetic investigations, in how many by biochemical investigations, and in how many by immunohistological investigations.

    In two patients MELAS presented with headache. How was the headache classified? Did either of these individuals have a history of migraine or migraine-like headache, frequently associated with MELAS? Migraine-like headache in MELAS may respond to l -arginine, midazolam, or steroids. Which treatment was prescribed to these two patients?

    The authors report 20 patients with ischemic stroke. Secondary stroke prophylaxis often includes administration of acetyl salicylic acid, clopidogrel, or oral anticoagulation with vitamin K antagonists or direct oral anticoagulants. Were any of these agents administered? Recently, acetyl salicylic acid has been shown to be mitochondrion-toxic with a potentially deleterious effect in individuals with MELAS.

    Nine patients experienced cardiomyopathy and arrhythmia. Which type of cardiomyopathy was diagnosed in these nine patients? How many had hypertrophic, dilative, or restrictive cardiomyopathy and how many had noncompaction?

    Overall, this interesting study could profit from providing more data about the family history, the diagnosis of MELAS, and the relation of seizures with stroke-like episodes. We should be informed about the type of AED treatment in more detail to assess if mitochondrion-toxic AEDs were given and if they further deteriorated the MELAS phenotype.