Levetiracetam + Clonazepam for MERRF Myoclonus: Promise but Need for More Proof

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Levetiracetam + Clonazepam for MERRF Myoclonus: Promise but Need for More Proof

If you or someone you know lives with myoclonic epilepsy with ragged-red fibers (MERRF)—a rare mitochondrial disorder causing sudden muscle jerks, seizures, and balance issues—you’ve probably wondered: What treatments really work? A 2018 study suggested combining two epilepsy drugs, levetiracetam (LEV) and clonazepam (CZP), might help. But new questions from a neurology expert highlight why we need more research to confirm these benefits.

The study, led by Su et al. and published in the Chinese Medical Journal, looked at 17 people with genetically confirmed MERRF (all with the m.8344A>G mutation, the most common cause of the condition). They found that using LEV and CZP together helped 12 of the 17 patients with myoclonus—better than using either drug alone or other epilepsy medications like valproic acid (VPA) or topiramate (TPM).

But Dr. Josef Finsterer, a neurologist at City Hospital Rudolfstiftung in Vienna and the Messerli Institute at the Veterinary University of Vienna, says this is just the start. In a 2019 response to the study, he raised critical points that affect how we trust and use these results.

1. Heteroplasmy: The Mutation Gap

Mitochondrial DNA mutations aren’t uniform—some cells have more of the mutation than others (a phenomenon called “heteroplasmy”). For MERRF, the m.8344A>G mutation is often most severe in muscle cells, which is why the study took DNA from muscle tissue. But Dr. Finsterer notes the team didn’t measure how much of the mutation was present in each patient’s muscle. This is a key gap: Higher mutation levels usually mean more severe symptoms, and could change how well drugs work. Without this data, we can’t tell if the LEV+CZP benefit is consistent across all mutation levels.

2. Valproic Acid: Toxicity or Natural Progression?

Two patients saw their symptoms worsen after taking VPA alone for 4 months. Dr. Finsterer points out VPA is known to damage mitochondria—the tiny structures that power our cells. This is especially dangerous for people with other genetic mutations (like POLG1) and has even caused fatal liver failure in some with mitochondrial disorders. The study authors think the worsening was from VPA’s toxicity, but they didn’t see obvious liver problems in these patients. Dr. Finsterer wants clarity: Was the decline from the drug, or just the disease progressing naturally?

3. Symptom Variability: Is This “Classic” MERRF?

MERRF is defined by four core symptoms: myoclonus, generalized seizures, ataxia (balance issues), and myopathy (muscle weakness). But in the study, only 3 of 17 patients had all four. Dr. Finsterer asks why—and notes the study didn’t share muscle biopsy results for all patients (only 11 had biopsies). Ragged-red fibers (damaged mitochondria seen under a microscope) are a hallmark of MERRF—without knowing if all patients had these, we can’t be sure the drug results apply to “classic” MERRF cases. Heteroplasmy might explain the missing symptoms: Less mutation = milder symptoms.

4. Missing Details: Family History, Other Drugs, and More

Dr. Finsterer also flags gaps that could skew conclusions:

  • No family history: 75% of mitochondrial disorders are maternally inherited—family ties might affect symptoms or drug response.
  • No other drugs: The study didn’t list medications patients took alongside epilepsy drugs, which could interact with LEV or CZP.
  • No extra symptoms: MERRF often causes migraines, hearing loss, or diabetes—these weren’t mentioned, but they can change how the body processes drugs.

The Authors’ Reply

The study authors responded to Dr. Finsterer’s points:

  • All patients were “sporadic” (no family history of MERRF), and DNA was taken from muscle.
  • They agree heteroplasmy is important but didn’t measure it here—something they plan to add in future work.
  • The VPA cases were due to an initial misdiagnosis. They think the worsening was from VPA’s mitochondrial toxicity but didn’t see liver issues.
  • Some patients took B vitamins or idebenone (a mitochondrial support drug) irregularly, but not everyone.

They also referenced a 2013 study by Mancuso et al. in Neurology that found most people with the m.8344A>G mutation don’t have full-blown MERRF: Only 35–45% have myoclonus, muscle weakness, or ataxia, and 25–35% have generalized seizures or hearing loss. Their patients matched this pattern.

What This Means for MERRF Patients

The LEV+CZP combo shows promise—12 of 17 patients had better myoclonus control. But Dr. Finsterer’s questions remind us that medical research is iterative. We need more data on heteroplasmy, clearer links between drug use and symptom changes, and full details on patient symptoms and other medications before we can say this combo is a sure thing. The study authors agree and plan to address these gaps in future work.

Dr. Josef Finsterer is a leading authority on mitochondrial disorders, with over 1,000 peer-reviewed publications. The original study and his response were published in the Chinese Medical Journal, a respected, peer-reviewed journal founded in 1887.

doi.org/10.1097/CM9.0000000000000042

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