Sex-based electroclinical differences and prognostic factors in epilepsy with eyelid myoclonia

Although a striking female preponderance has been consistently reported in epilepsy with eyelid myoclonia (EEM), no study has specifically explored the variability of clinical presentation according to sex in this syndrome. Here, we aimed to investigate sex-specific electroclinical differences and prognostic determinants in EEM. Data from 267 EEM patients were retrospectively analyzed by the EEM Study Group, and a dedicated multivariable logistic regression analysis was developed separately for each sex. We found that females with EEM showed a significantly higher rate of persistence of photosensitivity and eye closure sensitivity at the last visit, along with a higher prevalence of migraine with/without aura, whereas males with EEM presented a higher rate of borderline intellectual functioning/intellectual disability. In female patients, multivariable logistic regression analysis revealed age at epilepsy onset, eyelid myoclonia status epilepticus, psychiatric comorbidities, and catamenial seizures as significant predictors of drug resistance. In male patients, a history of febrile seizures was the only predictor of drug resistance. Hence, our study reveals sex-specific differences in terms of both electroclinical features and prognostic factors. Our findings support the importance of a sex-based personalized approach in epilepsy care and research, especially in genetic generalized epilepsies

Progressive myoclonus epilepsies-Residual unsolved cases have marked genetic heterogeneity including dolichol-dependent protein glycosylation pathway genes

Progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous rare diseases. Over 70% of PME cases can now be molecularly solved. Known PME genes encode a variety of proteins, many involved in lysosomal and endosomal function. We performed whole-exome sequencing (WES) in 84 (78 unrelated) unsolved PME-affected individuals, with or without additional family members, to discover novel causes. We identified likely disease-causing variants in 24 out of 78 (31%) unrelated individuals, despite previous genetic analyses. The diagnostic yield was significantly higher for individuals studied as trios or families (14/28) versus singletons (10/50) (OR = 3.9, p value = 0.01, Fisher's exact test). The 24 likely solved cases of PME involved 18 genes. First, we found and functionally validated five heterozygous variants in NUS1 and DHDDS and a homozygous variant in ALG10, with no previous disease associations. All three genes are involved in dolichol-dependent protein glycosylation, a pathway not previously implicated in PME. Second, we independently validate SEMA6B as a dominant PME gene in two unrelated individuals. Third, in five families, we identified variants in established PME genes; three with intronic or copy-number changes (CLN6, GBA, NEU1) and two very rare causes (ASAH1, CERS1). Fourth, we found a group of genes usually associated with developmental and epileptic encephalopathies, but here, remarkably, presenting as PME, with or without prior developmental delay. Our systematic analysis of these cases suggests that the small residuum of unsolved cases will most likely be a collection of very rare, genetically heterogeneous etiologies.Peer reviewe

The spectrum of epilepsy with eyelid myoclonia: delineation of disease subtypes from a large multicenter study

Objective Epilepsy with eyelid myoclonia (EEM) has been associated with marked clinical heterogeneity. Early epilepsy onset has been recently linked to lower chances of achieving sustained remission and to a less favorable neuropsychiatric outcome. However, much work is still needed to better delineate this epilepsy syndrome. Methods In this multicenter retrospective cohort study, we included 267 EEM patients from nine countries. Data on electroclinical and demographic features, intellectual functioning, migraine with or without aura, family history of epilepsy, and epilepsy syndromes in relatives were collected in each patient. The impact of age at epilepsy onset (AEO) on EEM clinical features was investigated, along with the distinctive clinical characteristics of patients showing sporadic myoclonia involving body regions other than eyelids (body-MYO). Results Kernel density estimation revealed a trimodal distribution of AEO, and Fisher-Jenks optimization disclosed three EEM subgroups: early onset (EO-EEM), intermediate onset (IO-EEM), and late onset (LO-EEM). EO-EEM was associated with the highest rate of intellectual disability, antiseizure medication refractoriness, and psychiatric comorbidities and with the lowest rate of family history of epilepsy. LO-EEM was associated with the highest proportion of body-MYO and generalized tonic-clonic seizures (GTCS), whereas IO-EEM had the lowest observed rate of additional findings. A family history of EEM was significantly more frequent in IO-EEM and LO-EEM compared with EO-EEM. In the subset of patients with body-MYO (58/267), we observed a significantly higher rate of migraine and GTCS but no relevant differences in other electroclinical features and seizure outcome. Significance Based on AEO, we identified consistent EEM subtypes characterized by distinct electroclinical and familial features. Our observations shed new light on the spectrum of clinical features of this generalized epilepsy syndrome and may help clinicians toward a more accurate classification and prognostic profiling of EEM patients

Use of levetiracetam in treating epilepsy associated with other medical conditions

Objective - This prospective, open-label study was conducted to evaluate the effectiveness, tolerability, and safety of levetiracetam in patients with epilepsy in whom unfavorable metabolism, complex drug interactions, or direct toxic effects of antiepileptic drugs (AEDs) had caused a worsening of comorbid conditions. Methods - Study design included the introduction of levetiracetam, discontinuation of other AEDs, and a serial assessment comprising electroencephalograms and blood tests at baseline and 2, 6, and 12 months. Of 21 patients, 16 had partial and five generalized epilepsy. Concomitant pathologies were gastroenterological (six), vascular (four), endocrinological (four), or complex conditions including hematological (four) or dermatological (three) disease. A change of regimen was necessitated by drug-drug interactions in four patients, direct real or potential toxic effects of previous AEDs in 13, and a combination of interactions/toxic effects in four. Results - After 12 months, 12 patients were seizure-free, nine had reductions in seizure frequency of 50-75%, and improvement in concomitant medical conditions was observed. No side effects were reported. Conclusion - Levetiracetam appears to be effective, well tolerated, and safe in patients with epilepsy and other medical conditions that are difficult to manage because of drug interactions or AED-related side effects. © Blackwell Munksgaard 2005

Use of levetiracetam in treating epilepsy associated with other medical conditions

Objective - This prospective, open-label study was conducted to evaluate the effectiveness, tolerability, and safety of levetiracetam in patients with epilepsy in whom unfavorable metabolism, complex drug interactions, or direct toxic effects of antiepileptic drugs (AEDs) had caused a worsening of comorbid conditions. Methods - Study design included the introduction of levetiracetam, discontinuation of other AEDs, and a serial assessment comprising electroencephalograms and blood tests at baseline and 2, 6, and 12 months. Of 21 patients, 16 had partial and five generalized epilepsy. Concomitant pathologies were gastroenterological (six), vascular (four), endocrinological (four), or complex conditions including hematological (four) or dermatological (three) disease. A change of regimen was necessitated by drug-drug interactions in four patients, direct real or potential toxic effects of previous AEDs in 13, and a combination of interactions/toxic effects in four. Results - After 12 months, 12 patients were seizure-free, nine had reductions in seizure frequency of 50-75%, and improvement in concomitant medical conditions was observed. No side effects were reported. Conclusion - Levetiracetam appears to be effective, well tolerated, and safe in patients with epilepsy and other medical conditions that are difficult to manage because of drug interactions or AED-related side effects. \ua9 Blackwell Munksgaard 2005

EEG/fMRI study of ictal and interictal epileptic activity: Methodological issues and future perspectives in clinical practice

Purpose: Electroencephalography/functional magnetic resonance imaging (EEG/fMRI) has been proposed recently as a tool to study electrophysiological activity and, consequently, detect brain regions activated during epileptiform EEG abnormalities. The purpose of the study was to review our two-year experience with studying ictal and interictal activities in patients with epilepsy. Methods: Using EEG/fMRI, we studied hemodynamic changes associated with ictal and interictal EEG abnormalities in 43 patients with partial (31 cases) or generalized (12 cases) epilepsy. Using two different paradigms (block design and event-related design), we studied several forms of EEG activity consisting of (i) interictal abnormalities constantly elicitable by specific stimulation (8 cases); (ii) focal and generalized interictal activity, such as focal spikes or typical and atypical generalized spike-and-wave discharges (18 cases); and (iii) focal and generalized ictal electro-clinical activity, such as tonic seizures or pseudo-absences in frontal lobe epilepsy, typical absences in idiopathic generalized epilepsy, complex partial seizures in temporal lobe epilepsy, and perisylvian seizures in special syndromes (17 patients). Results: EEG/fMRI revealed clear hemodynamic changes related to EEG abnormalities in 21 patients. In 18 of these patients, the changes were highly concordant with electro-clinical findings. In the remaining 22 patients, fMRI analysis data failed to show activation or deactivation clusters, probably owing either to lack or inadequate amount of temporal distribution of abnormal EEG activity, or to intrinsic methodological problems. Conclusions: By defining the electro-clinical and hemodynamic correlates of EEG activity, fMRI may shed light on the neurophysiological mechanisms underlying epileptic phenomena. However, as several methodological issues have yet to be addressed, further studies are warranted to assess the reliability and usefulness of EEG/fMRI in clinical practice. © 2006 International League Against Epilepsy

Idiopathic generalized epilepsy and café-au-lait macules as the predominant features in NF1 mild form

Neurofibromatosis type 1 (NF1) is a complex autosomal dominant neurocutaneous disorder with a variable phenotype involving multiple body systems. It is due to a mutation in the NF1 gene, which results in the production of abnormal neurofibromin protein. According to the National Institutes of Health diagnostic criteria, hyperpigmented skin markings or café-au-lait macules (CALMs), axillary freckling, Lisch nodules, and neurofibromas are characteristic NF1 features. A milder phenotype, apparently manifesting with only pigmentary skin changes, has recently been associated with the c.2970_2972 in-frame deletion. Although neurological findings, including epilepsy and neurocognitive deficits, have been frequently described as a part of the classic NF1 form, they have not been properly characterized in this milder variant. We report for the first time the case of a patient harboring the c.2970_2972del of the NF1 gene and presenting with CALMs, idiopathic generalized epilepsy, and transient brain MRI alterations (so-called “unidentified bright objects”)

Switch from originator to equivalent drug in the era of generic antiepileptic drugs: study of keppra versus epitiram clinical equivalence

OBJECTIVES: Generic antiepileptic drugs represent a measure to maximize cost saving. Levetiracetam (LEV) is one of most commonly used and effective antiepileptic drugs. The objective of our work was to demonstrate the effectiveness and safety of overnight switch from monotherapy with Keppra (original drug) to epitiram (generic drug) at the same dose. METHODS: In our observational study, we consecutively enrolled 37 seizure-free patients with epilepsy who expressed the wish to switch to a generic drug for economic reasons. During the 6-month evaluation period, we assessed treatment efficacy, tolerability, compliance, and intersubject variability of LEV serum concentration. At each visit, clinical and neurological examination, scales, video-electroencephalogram, and blood sample analysis to evaluate LEV plasma level were performed. RESULTS: A total of 36 of 37 enrolled patients switched from Keppra to epitiram, which was administered at the same dose in monotherapy. Three of 36 patients dropped out during follow-up for adverse events. The other 33 subjects had neither seizures nor adverse events. No significant differences in electroencephalogram features and scale scores were revealed; the intersubject variability of LEV serum concentration did not differ significantly at follow-up evaluation (P = 0.53). All the patients expressed good clinical personal impression and continued to take epitiram. The switchback rate was 8 %. CONCLUSIONS: The switch from Keppra to epitiram was easy and safe in our population, and epitiram can be considered as effective and tolerable as Keppra. Only a slight, non-statistically significant variability in LEV serum concentration was documented after the switch from Keppra to epitiram. Larger epileptic populations should be studied to confirm these results