Autoimmune-associated epilepsy in an outpatient epilepsy clinic: A retrospective study

Purpose: To analyse cases with suspected autoimmune-associated epilepsy (AAEp) and to compare them to patients with acute symptomatic seizures secondary to autoimmune encephalitis (ASS-AEn). Methods: Single-centre retrospective analysis of patients with suspected AAEp seen in an outpatient epilepsy clinic between 2014 and 2021. Differences according to autoimmune testing results and their responsiveness to immunotherapy were assessed and compared with our cohort of patients with ASS-AEn. Results: A total of 30 patients were included: 18 women (60%); mean age 28.2 years at seizure-onset. AAEp was diagnosed in 14 (46.6%), on the basis of antineuronal antibodies, CSF pleocytosis/OCB (oligoclonal bands), MRI with neuroinflammation, and/or PET hypermetabolism. Thirteen patients (43.3%) received immunotherapy, of whom 5 responded (38.4%). Delay between epilepsy-onset and autoimmune testing was longer in patients with negative autoimmune-testing and in non-responders. Viral prodrome (P < .035), associated neurological signs/symptoms and MRI showing neuroinflammation were more common in responders. ASS-AEn patients were older (P < .019), and more frequently presented coexisting neurological signs/symptoms (P < .0001), antineuronal cell-surface antibodies (P < .009), neuroinflammation on MRI, PET hypermetabolism (P < .01), CSF pleocytosis (P < .047), and higher APE (antibody prevalence in epilepsy)/RITE (response to immunotherapy in epilepsy)-scores (P < .022/P < .004). Drug-refractoriness (P < .033) was more common in AAEp. ASS-AEn received immunotherapy more frequently, with better outcomes. Diagnosis and treatment delay were longer in AAEp (P < .0001). Conclusion: Isolated/chronic AAEp is a rare, drug-resistant epileptic-disorder. Early diagnosis is essential for immunotherapy. However, diagnostic and therapeutic delay is longer in AAEp than in ASS-AEn. This may indicate that currently there is less capacity to detect AAEp than ASS-AEn. Resumen: Objetivo: Analizar los casos con sospecha de epilepsia asociada a autoinmunidad (EAA). Compararlos con pacientes con crisis epilépticas sintomáticas agudas a encefalitis autoinmunes (CSA-EA). Métodos: Estudio unicéntrico-retrospectivo de pacientes con sospecha de EAA de una consulta monográfica de epilepsia (2014–2021). Análisis de sus diferencias según resultados del estudio de autoinmunidad y respuesta a tratamiento inmunosupresor. Comparación con una cohorte hospitalaria de pacientes con CSA-EA. Resultados: Se incluyeron 30 pacientes: 18 mujeres (60%); edad media = 28.2 años al debut. Fueron diagnosticados de EAA 14 (46.6%), en base a anticuerpos antineuronales, pleocitosis/BOC (bandas oligoclonales) en LCR, neuroinflamación en RM y/o hipermetabolismo en PET cerebral. Trece (43.3%) recibieron inmunosupresión, respondiendo 5 (38.4%). El retraso diagnóstico fue mayor en pacientes con resultados negativos y en no respondedores. El pródromos pseudoviral (p < 0.035), la coexistencia de signos/síntomas neurológicos y la neuroimagen inflamatoria fueron más frecuentes en respondedores. Los pacientes con CSA-EA fueron mayores (p < 0.019) y presentaron más frecuentemente otros signos/síntomas neurológicos (p < 0.0001), anticuerpos anti-superficie neuronal (p < 0.009), neuroinflamación en RM, hipermetabolismo en PET (p < 0.01), pleocitosis (p < 0.047) y puntuaciones APE(antibody prevalence in epilepsy)/RITE(response to immunotherapy in epilepsy) más altas (p < 0.022/p < 0.004). La farmacorrefractariedad (p < 0.033) fue más común en EAA. Las CSA-EA recibieron inmunosupresión más frecuentemente, con mejores resultados. El retraso diagnóstico-terapéutico fue mayor en la EAA (p < 0.0001). Conclusión: La EAA constituye una epilepsia infrecuente pero farmacorrefractaria. Su diagnóstico precoz es esencial para su tratamiento; sin embargo, existe un retraso diagnóstico-terapéutico mayor que en las CSA-EA, pudiendo ello indicar que actualmente se dispone de menor capacidad para detectar EAA que CSA-EA

Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry

Background: Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy. Methods: We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors. Findings: Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10\ub73%) of 1381 pregnancies for valproate, 19 (6\ub75%) of 294 for phenobarbital, eight (6\ub74%) of 125 for phenytoin, 107 (5\ub75%) of 1957 for carbamazepine, six (3\ub79%) of 152 for topiramate, ten (3\ub70%) of 333 for oxcarbazepine, 74 (2\ub79%) of 2514 for lamotrigine, and 17 (2\ub78%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0\ub70140), lamotrigine (p=0\ub70145), phenobarbital (p=0\ub70390), and valproate (p<0\ub70001). After adjustment, multivariable analysis showed that the prevalence of major congenital malformations was significantly higher for all doses of carbamazepine and valproate as well as for phenobarbital at doses of more than 80 mg/day than for lamotrigine at doses of 325 mg/day or less. Valproate at doses of 650 mg/day or less was also associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250\u20134000 mg/day (odds ratio [OR] 2\ub743, 95% CI 1\ub730\u20134\ub755; p=0\ub70069). Carbamazepine at doses of more than 700 mg/day was associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250\u20134000 mg/day (OR 2\ub741, 95% CI 1\ub733\u20134\ub738; p=0\ub70055) and oxcarbazepine at doses of 75\u20134500 mg/day (2\ub737, 1\ub717\u20134\ub780; p=0\ub70169). Interpretation: Different antiepileptic drugs and dosages have different teratogenic risks. Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs. These findings facilitate rational selection of these drugs, taking into account comparative risks associated with treatment alternatives. Data for topiramate and phenytoin should be interpreted cautiously because of the small number of exposures in this study. Funding: Bial, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, the Netherlands Epilepsy Foundation, and Stockholm County Council