Mitochondrial toxicity of antiepileptic drugs and their tolerability in mitochondrial disorders

Abstract

Mitochondrial-toxic AEDs may trigger or worsen an MID or may be even fatal in single cases. The AED with the most well-known mitochondrial toxicity is valproic acid (VPA), which has been known to exhibit a deleterious effect in patients with POLG1 mutations and patients with myoclonic epilepsy with ragged red fibers syndrome and VPA should only be applied in MIDs in case of a drug-resistant status epilepticus. AEDs other than VPA, which may affect the mitochondrial metabolism, include phenobarbital, carbamazepine, phenytoin, oxcarbazepine, ethosuximide, zonisamide, topiramate, gabapentin and vigabatrin. AEDs which interfere with mitochondrial function should be avoided whenever justifiable to the patient's well-being. Collateral beneficial effects of AEDs should also influence their choice in MIDs.

Prevention of Epilepsy by Low-Dose Artesunate + Esomeprazole-Furosemide Sequential Therapy.

“…[55] [56] Whereas present AEDs may induce cognitive dysfunction, metabolic syndrome/vascular stress, [57][58] [59] our present report shows that sequential therapy with artesunate + esomeprazole and furosemide may enhance cognition most probably by decreasing markers of vascular stress and preventing the metabolic syndrome which may upregulate epileptogenesis. This effect may largely be explained by these agents upregulating mitochondrial biogenesis.…”

Therapeutic Strategies for Mitochondrial Disorders

“…Valproate encephalopathy or fatal hepatopathy may be consequences of the toxic effect of valproate. 114 Particularly, in patients carrying POLG1 mutations, valproic acid must be avoided. Testing for POLG1 mutations even emerges to become a standard of care before applying valproate for pediatric epilepsy.…”

When should MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis?

“…MELAS management also includes additional therapy for its complications, such as, cardiac disease (standard pharmacologic therapy), diabetes mellitus (dietary modification, oral hypoglycemic agents and/or insulin therapy), deafness (hearing devices and cochlear implantation) or epilepsy (traditional antiepileptic treatment) 25,58,60 . Because febrile illnesses may trigger acute exacerbations, MELAS patients should receive standard childhood vaccinations, flu vaccine, and pneumococcal vaccine 25,55 .…”

“…In addition, toxins or drugs that had potential to cause mitochondrial dysfunction or lesion, such as aminoglycoside antibiotics, linezolid, aspirin, Zidovudine, cigarettes or alcohol consumption, should be recognized and avoided 55,58 . Valproic acid for seizure treatment (high risk by carnitine uptake inhibition) and dichloroacetate for acute stroke-like episodes (high risk for peripheral neuropathy) are not recommended 58,60 . Exercise (endurance and resistance training) is helpful in MELAS as well other mitochondrial diseases 58 .…”