The metabolic hypothesis is more likely than the epileptogenic hypothesis to explain stroke-like lesions
1Krankenanstalt Rudolfstiftung, Messerli Institute, Vienna, 1180, Austria.
Abstract:
Stroke-like episodes (SLEs) are a hallmark of mitochondrial encephalopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome but occur in other mitochondrial disorders (MIDs) as well. The morphological equivalent of the SLE is the stroke-like lesion (SLL) on magnetic resonance imaging (MRI). The pathophysiology of SLLs is under debate, but several hypotheses have been raised to explain the phenomenon. Of these, the metabolic, epileptogenic, and vascular hypotheses are the most frequently discussed. There are several arguments for and against these hypotheses, but a consensus has not been reached which of them provides the correct explanation. A recent consensus statement generated by a panel of experts applying the Delphi method, favoured the epileptogenic hypothesis and recommended treatment of SLEs with antiepileptic drugs, irrespective if the patient presented with a seizure or epileptiform discharges on electroencephalography (EEG) or not. We disagree with this general procedure and provide the following arguments against the epileptogenic hypothesis: 1. not each SLE is associated with seizures. 2. epileptiform discharges may be absent on EEG during a SLE. 3. SLLs are not restricted to the cortex. 4. antiseizure-drugs (ASDs) may not prevent the progression or recurrence of a SLL. 5. ASDs may terminate seizures but no other phenotypic feature of a SLE. 6. patients already under ASDs are not immune from developing a SLL. 7. SLLs usually last longer than seizures. 8. no animal model supports the epileptogenic hypothesis. The strongest arguments for the metabolic hypothesis are that SLLs are not confined to a vascular territory, that the oxygen-extraction fraction within a SLL is reduced, and that there is hypometabolism within a SLL on FDG-PET. SLLs may respond to antioxidants, NO-precursors, steroids, or the ketogenic diet. ASDs should be applied only if there is clinical or electrophysiological evidence of seizure-activity.
Insights
Stroke-like episodes (SLEs) in mitochondrial disorders are debated. The metabolic hypothesis, supported by imaging and treatment responses, is favored over the epileptogenic hypothesis for understanding stroke-like lesions (SLLs).
Area of Science:
- Neurology
- Mitochondrial Diseases
- Neuroimaging
Background:
- Stroke-like episodes (SLEs) are characteristic of MELAS syndrome and other mitochondrial disorders (MIDs).
- The underlying pathophysiology of stroke-like lesions (SLLs) observed in MRI remains debated, with metabolic, epileptogenic, and vascular hypotheses proposed.
- A recent Delphi consensus favored the epileptogenic hypothesis, recommending antiepileptic drug (ASD) treatment regardless of seizure activity.
Purpose of the Study:
- To critically evaluate the epileptogenic hypothesis for SLLs in MIDs.
- To present arguments supporting the metabolic hypothesis for SLL pathogenesis.
- To advocate for a more targeted approach to ASD use in SLEs.
Main Methods:
- Review and critique of existing literature and hypotheses regarding SLLs.
- Analysis of clinical observations and imaging findings (MRI, FDG-PET).
- Evaluation of treatment responses to various interventions.
Main Results:
- Arguments against the epileptogenic hypothesis include the frequent absence of seizures or epileptiform discharges, SLLs outside the cortex, limited efficacy of ASDs, and lack of supporting animal models.
- Evidence supporting the metabolic hypothesis includes SLLs not being confined to vascular territories, reduced oxygen extraction, and hypometabolism on FDG-PET.
- SLLs have shown positive responses to antioxidants, NO-precursors, steroids, and ketogenic diets.
Conclusions:
- The epileptogenic hypothesis does not fully explain SLLs in MIDs.
- The metabolic hypothesis offers a more comprehensive explanation for SLLs.
- ASDs should be reserved for cases with clear clinical or electrophysiological evidence of seizure activity.
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