Objective
Epilepsy with generalized tonic–clonic seizures alone (GTCA) is a common but poorly characterized idiopathic generalized epilepsy (IGE) syndrome. Hence, we investigated electroclinical ...features, seizure outcome, and antiseizure medication (ASM) withdrawal in a large cohort of GTCA patients.
Methods
In this multicenter retrospective study, GTCA patients defined according to the diagnostic criteria of the International League Against Epilepsy (2022) were included. We investigated prognostic patterns, drug resistance at the last visit, and ASM withdrawal, along with their prognostic factors.
Results
We included 247 patients with a median (interquartile range IQR) age at onset of 17 years (13–22) and a median follow‐up duration of 10 years (IQR = 5–20). Drug resistance at the last visit was observed in 40 (16.3%) patients, whereas the median latency to achieve 2‐year remission was 24 months (IQR = 24–46.5) with a median number of 1 (IQR = 1–2) ASM. During the long‐term follow‐up (i.e., 202 patients followed ≥5‐years after the first ASM trial), 69 (34.3%) patients displayed an early remission pattern and 36 (17.9%) patients displayed a late remission pattern, whereas 16 (8%) and 73 (36.3%) individuals had no‐remission and relapsing–remitting patterns, respectively. Catamenial seizures and morning predominance of generalized tonic–clonic seizures (GTCS) independently predicted drug resistance at the last visit according to multivariable logistic regression. Treatment withdrawal was attempted in 63 (25.5%) patients, with 59 (93.7%) of them having at least a 12‐month follow‐up after ASM discontinuation. At the last visit, 49 (83%) of those patients had experienced GTCS recurrence. A longer duration of seizure freedom was the only factor predicting a higher chance of successful ASM withdrawal according to multivariable Cox regression.
Significance
GTCA could be considered a relatively easily manageable IGE syndrome, with a low rate of drug resistance and a high prevalence of early response to treatment. Nevertheless, a considerable proportion of patients experience relapsing patterns of seizure control, highlighting the need for appropriate counseling and lifestyle recommendations.
Objective
Perampanel, an antiseizure drug with α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor antagonist properties, may have a targeted effect in genetic epilepsies with overwhelming ...glutamate receptor activation. Epilepsies with loss of γ‐aminobutyric acid inhibition (e.g., SCN1A), overactive excitatory neurons (e.g., SCN2A, SCN8A), and variants in glutamate receptors (e.g., GRIN2A) hold special interest. We aimed to collect data from a large rare genetic epilepsy cohort treated with perampanel, to detect possible subgroups with high efficacy.
Methods
This multicenter project was based on the framework of NETRE (Network for Therapy in Rare Epilepsies), a web of pediatric neurologists treating rare epilepsies. Retrospective data from patients with genetic epilepsies treated with perampanel were collected. Outcome measures were responder rate (50% seizure reduction), and percentage of seizure reduction after 3 months of treatment. Subgroups of etiologies with high efficacy were identified.
Results
A total of 137 patients with 79 different etiologies, aged 2 months to 61 years (mean = 15.48 ± 9.9 years), were enrolled. The mean dosage was 6.45 ± 2.47 mg, and treatment period was 2.0 ± 1.78 years (1.5 months–8 years). Sixty‐two patients (44.9%) were treated for >2 years. Ninety‐eight patients (71%) were responders, and 93 (67.4%) chose to continue therapy. The mean reduction in seizure frequency was 56.61% ± 34.36%. Sixty patients (43.5%) sustained >75% reduction in seizure frequency, including 38 (27.5%) with >90% reduction in seizure frequency. The following genes showed high treatment efficacy: SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, POLG1, POLG2, and NEU1. Eleven of 17 (64.7%) patients with Dravet syndrome due to an SCN1A pathogenic variant were responders to perampanel treatment; 35.3% of them had >90% seizure reduction. Other etiologies remarkable for >90% reduction in seizures were GNAO1 and PIGA. Fourteen patients had a continuous spike and wave during sleep electroencephalographic pattern, and in six subjects perampanel reduced epileptiform activity.
Significance
Perampanel demonstrated high safety and efficacy in patients with rare genetic epilepsies, especially in SCN1A, GNAO1, PIGA, PCDH19, SYNGAP1, CDKL5, NEU1, and POLG, suggesting a targeted effect related to glutamate transmission.
Objective
Due to the high clinical heterogeneity of epilepsy, there is a critical need for novel metrics aimed at capturing its biological and phenotypic complexity. Frailty is increasingly ...recognized in various medical disciplines as a useful construct to understand differences in susceptibility to adverse outcomes. Here, we develop a frailty index (FI) for patients with epilepsy (PwE) and explore its association with demographic and clinical features.
Methods
In this cross‐sectional study, we consecutively enrolled 153 PwE from an outpatient epilepsy clinic. Participants were assessed for various health deficits to calculate the FI. Associations between FI and demographic/clinical features, antiseizure medications (ASMs), and patient‐reported outcomes were analyzed using general linear models and Spearman correlation.
Results
The median age at the time of study visit was 47 years (interquartile range = 33–60), and 89 (58.2%) patients were females. Multiple linear regression revealed that the developed 33‐item FI showed an independent association with age, female sex, higher body mass index, family history of epilepsy, intellectual disability, and the number of ASMs used. A robust analysis of covariance showed higher FI levels in patients using cytochrome P450 3A4‐inducer ASMs. We found a moderate positive correlation between FI and psychological distress, lower quality of life, and physical frailty, measured by the Hospital Anxiety and Depression Scale, Quality of Life in Epilepsy Inventory‐10, and handgrip strength, respectively. Finally, a weak association was observed between higher FI scores and an increased number of epileptic falls.
Significance
This study highlights the significance of frailty as a comprehensive health measure in epilepsy. It suggests that frailty in this specific population is not only a manifestation of aging but is inherently linked to epilepsy and treatment‐related factors. Future research is warranted to validate and refine the FI in diverse epilepsy populations and investigate its impact on specific adverse outcomes in longitudinal studies.
Regulatory agencies have recently discouraged the prescription of topiramate (TPM) to women of childbearing potential with epilepsy due to growing evidence of the teratogenic and neurodevelopmental ...risks associated with its use during pregnancy. It remains, however, unclear whether the use of TPM in this population can be supported to some extent by its high effectiveness. In this multicenter, retrospective, cohort study performed at 22 epilepsy centers, we investigated the comparative effectiveness of TPM and levetiracetam (LEV) given as first‐line antiseizure medication in a cohort of women of childbearing potential with idiopathic generalized epilepsy (IGE). A total of 336 participants were included, of whom 24 (7.1%) received TPM and 312 (92.9%) LEV. Women treated with TPM had significantly higher risks of treatment failure and treatment withdrawal and were less likely to achieve seizure freedom at 12 months compared to women treated with LEV. In conclusion, this study highlighted a low tendency among clinicians to use TPM in women of childbearing potential with IGE, anticipating the recently released restrictions on its use. Furthermore, the available data on effectiveness do not appear to support the use of TPM in this population.
•PERMIT is the largest pooled analysis of perampanel (PER) clinical practice data•A post-hoc analysis was done of 156 patients from PERMIT with myoclonic seizures•12-month responder and seizure ...freedom rates were 89.5% and 68.8%, respectively•Adverse events occurred in 46.8% of patients and led to discontinuation of 14.0%•These real-world findings support the use of PER for myoclonic seizures
Purpose: To investigate the effectiveness, safety and tolerability of perampanel (PER) in treating myoclonic seizures in clinical practice, using data from the PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) study.
Methods: PERMIT was a pooled analysis of 44 real-world studies from 17 countries, in which patients with focal and generalised epilepsy were treated with PER. This post-hoc analysis included patients with myoclonic seizures at baseline. Retention and effectiveness were assessed after 3, 6, and 12 months; effectiveness was additionally assessed at the last visit (last observation carried forward). Effectiveness assessments included responder rate (≥50% seizure frequency reduction from baseline) and seizure freedom rate (no seizures since at least the prior visit). Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs.
Results: 156 patients had myoclonic seizures (59.0% female; mean age, 32.1 years; idiopathic generalised epilepsy, 89.1%; Juvenile Myoclonic Epilepsy, 63.1%; monthly median myoclonic seizure frequency interquartile range, 1.7 1.0–10.0; mean standard deviation prior antiseizure medications, 2.9 2.6). Retention was assessed for 133 patients (mean time, 12.1 months), effectiveness for 142, and safety/tolerability for 156. Responder and seizure freedom rates were, respectively, 89.5% and 68.8% at 12 months, and 85.9% and 63.4% at the last visit. Incidence of AEs was 46.8%, the most frequent being dizziness/vertigo (19.2%), irritability (18.6%) and somnolence (9.6%). AEs led to discontinuation of 14.0% of patients over 12 months.
Conclusion: PER was associated with reduction in myoclonic seizure frequency in patients with myoclonic seizures treated in everyday clinical practice.
Objective
To investigate the functional and structural brain correlates of eyelid myoclonus and absence seizures triggered by eye closure (eye closure sensitivity ECS).
Methods
Fifteen patients with ...eyelid myoclonus with absences (EMA, Jeavons syndrome), 14 patients with idiopathic generalized epilepsies (IGE) without ECS, and 16 healthy controls (HC) underwent an electroencephalography (EEG)‐correlated functional magnetic resonance imaging (fMRI) and voxel brain morphometry (VBM) protocol. The functional study consisted of 30‐second epochs of eyes‐open and eyes‐closed conditions. The following EEG events were marked and the relative fMRI maps obtained: (1) eye closure times, (2) spontaneous blinking, and (3) spontaneous and eye closure–triggered spike and wave discharges (SWD; for EMA and IGE). Within‐group and between‐groups comparisons were performed for fMRI and VBM data as appropriate.
Results
In EMA compared to HC and IGE we found: (1) higher blood oxygenation level–dependent (BOLD) signal related to the eye closure over the visual cortex, the posterior thalamus, and the network implicated in the motor control of eye closure, saccades, and eye pursuit movements; and (2) increments in the gray matter concentration at the visual cortex and thalamic pulvinar, whereas decrements were observed at the bilateral frontal eye field area. No BOLD differences were detected when comparing SWD in EMA and IGE.
Interpretation
Results demonstrated altered anatomo‐functional properties of the visual system in EMA. These abnormalities involve a circuit encompassing the occipital cortex and the cortical/subcortical systems physiologically involved in the motor control of eye closure and eye movements. Our work supports EMA as an epileptic condition with distinctive features and provides a contribution to its classification among epileptic syndromes. Ann Neurol 2014;76:412–427
Tremor is a common movement disorder that can be induced by medications, including valproate, which is used for the treatment of epilepsy. However, the clinical and neurophysiological features of ...valproate-induced tremor are still under-investigated. We performed a clinical and kinematic assessment of valproate-induced tremor by considering tremor body distribution and activation conditions. We investigated possible correlations between demographic and clinical data and kinematic features. Valproate-induced tremor results were also compared with those collected in a large sample of patients with essential tremor. Sixteen valproate-induced tremor patients and 93 essential tremor patients were enrolled. All participants underwent a standardised neurological examination and video recording. Patients also underwent an objective assessment of postural, kinetic and rest tremor of the upper limbs and head tremor through kinematic analysis. Nonparametric tests were used for statistical comparisons between the two groups. Clinical evaluation showed a higher occurrence of rest tremor as well as head or voice, and lower limb involvement in patients with valproate-induced tremor. Kinematic analysis showed a substantial variability in the tremor features of patients with valproate-induced tremor. Compared to essential tremor, we found a higher occurrence of rest tremor of the upper limbs and the involvement of more body segments in valproate-induced tremor patients. Valproate-induced tremor has distinctive clinical and kinematic features, which may suggest that valproate interferes with the cerebellar functions.
Objective
Autosomal dominant cortical myoclonus and epilepsy (ADCME) is characterized by distal, fairly rhythmic myoclonus and epilepsy with variable severity. We have previously mapped the disease ...locus on chromosome 2p11.1‐q12.2 by genome‐wide linkage analysis. Additional pedigrees affected by similar forms of epilepsy have been associated with chromosomes 8q, 5p, and 3q, but none of the causing genes has been identified. We aim to identify the mutant gene responsible for this form of epilepsy.
Methods
Genes included in the ADCME critical region were directly sequenced. Coimmunoprecipitation, immunofluorescent, and electrophysiologic approaches to transfected human cells have been utilized for testing the functional significance of the identified mutation.
Results
Here we show that mutation in the α2‐adrenergic receptor subtype B (α2B‐AR) is associated with ADCME by identifying a novel in‐frame insertion/deletion in 2 Italian families. The mutation alters several conserved residues of the third intracellular loop, hampering neither the α2B‐AR plasma membrane localization nor the arrestin‐mediated internalization capacity, but altering the binding with the scaffolding protein spinophilin upon neurotransmitter activation. Spinophilin, in turn, regulates interaction of G protein coupled receptors with regulator of G protein signaling proteins. Accordingly, the mutant α2B‐AR increases the epinephrine‐stimulated calcium signaling.
Interpretation
The identified mutation is responsible for ADCME, as the loss of α2B‐AR/spinophilin interaction causes a gain of function effect. This work implicates for the first time the α‐adrenergic system in human epilepsy and opens new ways of understanding the molecular pathway of epileptogenesis, widening the spectrum of possible therapeutic targets. ANN NEUROL 2014;75:77–87
Sunflower syndrome (SFS) is a rare childhood-onset generalized epilepsy characterized by photosensitivity, heliotropism, and drug-resistant stereotyped seizures maybe self-induced by hand-waving ...maneuvers. Data on the long-term prognosis are scantly and evidence over best treatment strategies is lacking.
We retrospectively describe the electroclinical features, and therapeutic response in a group of 21 patients with SFS, without intellectual disability.
16 patients were female (67%), with a median age at onset of 7 years. In all patients, ictal episodes began with sun-staring, and hand-waving in front of the sunlight, accompanied by brief typical absence seizures. 17 patients (81%) showed interictal EEG abnormalities, mainly characterized by spike and polyspike-and-wave discharges. Ictal epileptiform activity occurred approximately less than one second after the start of hand-waving. At the last follow-up (median length 8.2 years), 12 patients (57%) were drug-resistant. Nine of them (75%) achieved seizure control with the use of tainted lenses, either alone or compared with anti-seizure medications (ASM). Disappearance of seizures was associated with EEG improvement/normalization when tinted glasses were used during EEG recordings.
While the clinical and EEG characteristics of SFS are well defined, the best therapeutic approaches are still under debate. Our data confirms a high rate of drug-resistance and frequent need of polytherapy. Of note, in drug-resistant patients, lenses (but not ASM) were able to suppress PPR in our patients while wearing lenses. Regarding the role of lenses, we do not only rely on the PPR reduction but also clinically by the reduction of seizures.
Although additional data are needed, lenses seem to have a powerful potential role for the management of SFS.
IMPORTANCE: After the recent limitations to prescribing valproate, many studies have highlighted the challenging management of female patients of reproductive age with idiopathic generalized epilepsy ...(IGE). However, no study, to the authors’ knowledge, has addressed the comparative effectiveness of alternative antiseizure medications (ASMs) in these patients. OBJECTIVE: To compare the effectiveness and safety of levetiracetam and lamotrigine as initial monotherapy in female patients of childbearing age with IGE. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, retrospective, comparative effectiveness cohort study analyzing data from patients followed up from 1994 to 2022. Patients were recruited from 22 primary, secondary, and tertiary adult and child epilepsy centers from 4 countries. Eligible patients were female individuals of childbearing age, diagnosed with IGE according to International League Against Epilepsy (2022) criteria and who initiated levetiracetam or lamotrigine as initial monotherapy. Patients were excluded due to insufficient follow-up after ASM prescription. EXPOSURES: Levetiracetam or lamotrigine as initial monotherapy. MAIN OUTCOMES AND MEASURES: Inverse probability of treatment weighting (IPTW)–adjusted Cox proportional hazards regression was performed to compare treatment failure (TF) among patients who received levetiracetam or lamotrigine as initial monotherapy. RESULTS: A total of 543 patients were included in the study, with a median (IQR) age at ASM prescription of 17 (15-21) years and a median (IQR) follow-up of 60 (24-108) months. Of the study population, 312 patients (57.5%) were prescribed levetiracetam, and 231 (42.5%) were prescribed lamotrigine. An IPTW-adjusted Cox model showed that levetiracetam was associated with a reduced risk of treatment failure after adjustment for all baseline variables (IPTW-adjusted hazard ratio HR, 0.77; 95% CI, 0.59-0.99; P = .04). However, after stratification according to different IGE syndromes, the higher effectiveness of levetiracetam was confirmed only in patients with juvenile myoclonic epilepsy (JME; IPTW-adjusted HR, 0.47; 95% CI, 0.32-0.68; P < .001), whereas no significant differences were found in other syndromes. Patients treated with levetiracetam experienced adverse effects more frequently compared with those treated with lamotrigine (88 of 312 28.2% vs 42 of 231 18.1%), whereas the 2 ASMs had similar retention rates during follow-up (IPTW-adjusted HR, 0.91; 95% CI, 0.65-1.23; P = .60). CONCLUSIONS AND RELEVANCE: Results of this comparative effectiveness research study suggest the use of levetiracetam as initial alternative monotherapy in female patients with JME. Further studies are needed to identify the most effective ASM alternative in other IGE syndromes.
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