Epilepsy is a common feature of several rare neurological diseases. Seizures in this group of diseases are often resistant to treatment and selecting an appropriate antiseizure medication is usually challenging. Moreover, controlled clinical trials and observational studies are rare, limiting evidence-based guidance. This highlights the need for proper guidelines and/or consensus statements in this field.
Two recent articles approached this topic, a consensus statement on the management of seizures in patients with primary mitochondrial diseases by Mancuso et al. and a a literature review of treatment guidelines focusing on Rett syndrome and tuberous sclerosis complex by Amin et al.
Regarding primary mitochondrial diseases (PMD), epilepsy is one of the most common features of central nervous system involvement, with approximately 20%–50% of patients experiencing seizures during the disease course. The statement highlights the need for specific protocols for good management of seizures and the importance of epilepsy specialist referral. Previous studies on this topic are endorsed, namely “Safety of drug use in patients with a PMD: an international Delphi-based consensus” (PMID: 32030781) and NICE guidelines (NG217, published in April 2022).All analysed treatments were considered generally safe to use in PMD, with the main safety concerns being the use of valproic acid in POLG disease, vigabatrin in patients with γ-aminobutyricacidtransaminase deficiency and topiramate in patients at risk for renal tubular acidosis. Therefore, it was strongly endorsed the adoption of the NICE guidelines for the management of seizures and status epilepticus in adults and children (above 28 days) diagnosed with a PMD.
Regarding Rett syndrome, there is a cumulative risk of developing epilepsy of approximately 90% over the lifespan, with the occurrence and remission of seizures being highly heterogeneous. There were only three guidelines with recommendations for symptomatic treatment of seizures. Seven different medications were included in treatment recommendations, of which sodium valproate had the highest number of positive recommendations. No recommendations for a specific line of treatment were made. Two positive recommendations specifically for the treatment of myoclonic seizures were made (one for levetiracetam and one for topiramate).
Regarding tuberous sclerosis complex (TSC), many individuals initially manifest with infantile spasms, but it has also been associated with most other seizure types. There were 22 guidelines identified for TSC. Vigabatrin had the highest number of positive recommendations and was recommended for infantile spasms. The other medications which received a high number of positive recommendations were adrenocorticotropic hormone (ACTH), topiramate, prednisolone and sodium valproate. Cannabidiol and sirolimus both received negative recommendation. Regarding treatment lines, the highest number of recommendations for first line was for vigabatrin and for second-line was ACTH.
The authors considered that updated treatment guidelines are urgently needed, mainly for Rett syndrome but also for TSC, focusing on specific lines of treatments and key areas still not addressed (e.g. Sudden Unexpected Death in Epilepsy).
Both articles underlined the difficulties and the need for the development of international high-quality and comprehensive consensus-based guidance for the management of seizures in patients with rare neurological diseases.
Key Points:
- The NICE guidelines for the management of seizures and status epilepticus in adults and children diagnosed with primary mitochondrial diseases are strongly endorsed by an international consensus with the only exception of valproic acid which is contraindicated in POLG patients.
- Despite recommendations for several treatments, there was insufficient evidence for a specific line of treatment in Rett syndrome.
- Vigabatrin has the most recommendations as the first line treatment for infantile spasms in tuberous sclerosis complex, with adrenocorticotropic hormone (ACTH), topiramate, prednisolone and sodium valproate also receiving a high number of positive recommendations.
- More robust evidence is needed for the specific management of seizures in patients with rare neurological disease.
References:
Amin S, Ruban-Fell B, Newell I, et al. Treatment guidelines for rare, early-onset conditions associated with epileptic seizures: a literature review on Rett syndrome and tuberous sclerosis complex. Orphanet J Rare Dis. 2024;19(1):89. Published 2024 Feb 26. doi:10.1186/s13023-023-02994-xhttps://pubmed.ncbi.nlm.nih.gov/38409029/
Mancuso M, Papadopoulou MT, Ng YS, et al. Management of seizures in patients with primary mitochondrial diseases: consensus statement from the InterERNs Mitochondrial Working Group. Eur J Neurol. Published online April 4, 2024. doi:10.1111/ene.16275https://pubmed.ncbi.nlm.nih.gov/38576261/
Co-authors:
Michelangelo Mancuso, Neurological Institute, University of Pisa
Kailash Bhatia, UCL Queen Square Institute of Neurology, University College London
Publish on behalf of the Coordinating Panel on Rare Neurological Disease