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OBJECTIVE: Women of childbearing age with juvenile absence epilepsy (JAE) face treatment challenges due to limited access to safe and effective anti-seizure medications (ASMs). In a previous study we compared the effectiveness of levetiracetam (LEV) and lamotrigine (LTG) in women with idiopathic generalized epilepsy (IGE), highlighting a superiority of LEV in juvenile myoclonic epilepsy. In this study, we specifically reanalyzed, through a Bayesian approach and by expanding the previously published cohort, the comparative effectiveness of these ASMs as initial monotherapy in JAE. METHODS: We conducted a multicenter, retrospective, comparative effectiveness study on women of childbearing age diagnosed with JAE and prescribed LEV or LTG as the initial ASM. Inverse probability treatment weighting (IPTW) Bayesian Cox proportional hazard models were employed to evaluate treatment failure (TF) due to ineffectiveness and ASM retention. The patients' center of provenance and year of prescription were considered as random effect factors. Posterior probabilities and relative log-risk distribution were computed, and the distribution of posterior draws was analyzed to assess the evidence supporting LTG superiority over LEV. RESULTS: Of 123 patients, those treated with LTG (n = 67) demonstrated lower TF and higher ASM retention than those treated with LEV (n = 56), with the IPTW-weighted Bayesian Cox proportional hazards model showing a 99.2% posterior probability of LTG being superior on TF and a 99.5% probability on ASM retention. Additional analyses on ≥50% and ≥75% seizure reduction through IPTW-weighted Bayesian logistic regression largely confirmed these findings, whereas the two ASMs did not show evident differences in terms of seizure freedom. The two ASMs showed comparable safety profiles, with only a minority of patients discontinuing treatment due to side effects. SIGNIFICANCE: Bayesian reanalysis supports LTG as first-line monotherapy for JAE in women of childbearing age, emphasizing the importance of individualized treatment strategies in women with IGE. This study underscores the value of Bayesian methods in refining clinical research and treatment decisions.
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OBJECTIVE: Recent clinical trials have shown that cenobamate substantially improves seizure control in focal-onset drug-resistant epilepsy (DRE). However, little is known about cenobamate's performance in highly active (≥20 seizures/month) and ultra-refractory focal epilepsy (≥6 failed epilepsy treatments, including antiseizure medications [ASMs], epilepsy surgery, and vagus nerve stimulation). Here, we studied cenobamate's efficacy and tolerability in a "real-world" severe DRE cohort. METHODS: We conducted a single-center retrospective analysis of consecutive adults treated with cenobamate between October 2020 and September 2022. All patients received cenobamate through an Early Access Program. Cenobamate retention, seizure outcomes, treatment-emergent adverse events, and adjustments to concomitant ASMs were analyzed. RESULTS: Fifty-seven patients received cenobamate for at least 3 months (median duration, 11 months). The median cenobamate dose was 250 mg/day (range 75-350 mg). Baseline demographics were consistent with highly active (median seizure frequency, 60/month) and ultra-refractory epilepsy (median previously failed ASMs, nine). Most (87.8%) had prior epilepsy surgery and/or vagus nerve stimulation. Six patients stopped cenobamate due to lack of efficacy and/or adverse events. One patient died from factors unrelated to cenobamate. Among patients who continued cenobamate, three achieved seizure freedom (5.3% of cohort), 24 had a 75%-99% reduction in seizures (42.1% of cohort), and 16 had a 50%-74% reduction (28.1% of cohort). Cenobamate led to abolition of focal to bilateral tonic-clonic seizures in 55.6% (20/36) of patients. Among treatment responders, 67.4% (29/43) were treated with cenobamate doses of ≥250 mg/day. Three-fourths of patients reported at least one side-effect, most commonly fatigue and somnolence. Adverse events most commonly emerged at cenobamate doses of ≥250 mg/day. Side-effects were partially manageable by reducing the overall ASM burden, most often clobazam, eslicarbazepine, and perampanel. SIGNIFICANCE: Patients with highly active and ultra-refractory focal epilepsy experienced meaningful seizure outcomes on cenobamate. Emergence of adverse events at doses above 250 mg/day may limit the potential for further improvements in seizure control at higher cenobamate doses.
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Epilepsia Resistente a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Epilepsias Parciais , Adulto , Humanos , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Estudos Retrospectivos , Epilepsias Parciais/tratamento farmacológico , ConvulsõesRESUMO
BACKGROUND: Pathogenic variants in the GAP activity towards RAGs 1 (GATOR1) complex genes (DEPDC5, NPRL2, NPRL3) cause focal epilepsy through hyperactivation of the mechanistic target of rapamycin pathway. We report our experience using everolimus in patients with refractory GATOR1-related epilepsy. METHODS: We performed an open-label observational study of everolimus for drug-resistant epilepsy caused by variants in DEPDC5, NPRL2 and NPRL3. Everolimus was titrated to a target serum concentration (5-15 ng/mL). The primary outcome measure was change in mean monthly seizure frequency compared with baseline. RESULTS: Five patients were treated with everolimus. All had highly active (median baseline seizure frequency, 18/month) and refractory focal epilepsy (failed 5-16 prior anti-seizure medications). Four had DEPDC5 variants (three loss-of-function, one missense) and one had a NPRL3 splice-site variant. All patients with DEPDC5 loss-of-function variants had significantly reduced seizures (74.3%-86.1%), although one stopped everolimus after 12 months due to psychiatric symptoms. Everolimus was less effective in the patient with a DEPDC5 missense variant (43.9% seizure frequency reduction). The patient with NPRL3-related epilepsy had seizure worsening. The most common adverse event was stomatitis. CONCLUSIONS: Our study provides the first human data on the potential benefit of everolimus precision therapy for epilepsy caused by DEPDC5 loss-of-function variants. Further studies are needed to support our findings.
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Epilepsia Resistente a Medicamentos , Epilepsias Parciais , Epilepsia , Humanos , Everolimo/efeitos adversos , Epilepsias Parciais/tratamento farmacológico , Epilepsias Parciais/genética , Proteínas Ativadoras de GTPase/genética , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia Resistente a Medicamentos/genéticaRESUMO
Autosomal dominant epilepsy with auditory features (OMIM 600512) is characterised by focal seizures with distinctive auditory auras and/or ictal aphasia. We describe a 17-year-old girl with recurrent attacks of ictal aphasia and rare nocturnal convulsions. She had a four-generation paternal family history of epilepsy. Her father and aunt perceived bells ringing at the onset of seizures. Sequence analysis of the leucine-rich glioma-inactivated 1 (LGI1) gene identified a novel heterozygous variant in the proband and her father. LGI1-related genetic epilepsy has a benign clinical course with a favourable response to anti-seizure medications. Auditory or vertiginous seizures may be mistaken for peripheral audio-vestibular symptoms, while complex auditory ictal symptoms may be misattributed to primary psychiatric disorders. Recognising this distinctive inherited syndrome should prompt targeted analysis of the LGI1 gene.
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Afasia , Epilepsia , Glioma , Adolescente , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , LeucinaRESUMO
OBJECTIVE: Epilepsy with generalized tonic-clonic seizures alone (GTCA) is the least studied syndrome within the idiopathic generalized epilepsy (IGE) spectrum. We characterize a large cohort of adult patients with GTCA to understand natural history and drug responsiveness. METHODS: In this retrospective single-center study using our epilepsy electronic record, we evaluated clinical characteristics, seizure outcomes, anti-seizure medication (ASM) response including seizure recurrence after ASM withdrawal, and sex differences in a cohort of GTCA patients aged ≥17 years. RESULTS: Within a cohort of 434 IGE patients, 87 patients (20â¯%) with GTCA were included. The mean age was 34.9 years (range 17-73 years). Forty-six patients (52.8â¯%) were females. Seventy-two patients (82.8â¯%) were seizure-free and 15 (17.2â¯%) had active epilepsy over the previous 12 months. Thirty-four patients (39.1â¯%) had ≤5 lifetime seizures, aligning with a prior definition of 'oligoepilepsy'. Sixty-five patients (74.7â¯%) were treated with monotherapy, 19 (21.8â¯%) were treated with polytherapy, and three were not taking any ASM. Levetiracetam (37.9â¯%) was the most commonly prescribed ASM, followed by lamotrigine (32.1â¯%) and valproate (31â¯%). Seventeen patients (19.5â¯%) attempted to withdraw their ASM. The rate of seizure recurrence after ASM withdrawal was 88.2â¯% (15/17), including two patients who relapsed more than 20 years after ASM discontinuation. Females had more seizures in their lifetime and had trialed more ASM compared to males. SIGNIFICANCE: GTCA has a relatively good prognosis, with most patients becoming seizure-free on monotherapy. The high rate of seizure recurrence after ASM withdrawal supports lifetime seizure susceptibility. We found potential sex differences in seizure outcomes and ASM response, although further research is needed to validate this finding.
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Anticonvulsivantes , Epilepsia Generalizada , Convulsões , Humanos , Adulto , Feminino , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Adolescente , Anticonvulsivantes/uso terapêutico , Estudos Retrospectivos , Idoso , Convulsões/tratamento farmacológico , Convulsões/fisiopatologia , Epilepsia Generalizada/tratamento farmacológico , Epilepsia Generalizada/fisiopatologia , Centros de Atenção Terciária , Resultado do TratamentoRESUMO
OBJECTIVE: We retrospectively explored patients with drug-resistant epilepsy (DRE) who previously underwent presurgical evaluation to identify correlations between surgical outcomes and pathogenic variants in epilepsy genes. METHODS: Through an international collaboration, we evaluated adult DRE patients who were screened for surgical candidacy. Patients with pathogenic (P) or likely pathogenic (LP) germline variants in genes relevant to their epilepsy were included, regardless of whether the genetic diagnosis was made before or after the presurgical evaluation. Patients were divided into two groups: resective surgery (RS) and non-resective surgery candidates (NRSC), with the latter group further divided into: palliative surgery (vagus nerve stimulation, deep brain stimulation, responsive neurostimulation or corpus callosotomy) and no surgery. We compared surgical candidacy evaluations and postsurgical outcomes in patients with different genetic abnormalities. RESULTS: We identified 142 patients with P/LP variants. After presurgical evaluation, 36 patients underwent RS, while 106 patients were NRSC. Patients with variants in ion channel and synaptic transmission genes were more common in the NRSC group (48â¯%), compared with the RS group (14â¯%) (p<0.001). Most patients in the RS group had tuberous sclerosis complex. Almost half (17/36, 47â¯%) in the RS group had Engel class I or II outcomes. Patients with channelopathies were less likely to undergo a surgical procedure than patients with mTORopathies, but when deemed suitable for resection had better surgical outcomes (71â¯% versus 41â¯% with Engel I/II). Within the NRSC group, 40 underwent palliative surgery, with 26/40 (65â¯%) having ≥50â¯% seizure reduction after mean follow-up of 11 years. Favourable palliative surgery outcomes were observed across a diverse range of genetic epilepsies. SIGNIFICANCE: Genomic findings, including a channelopathy diagnosis, should not preclude presurgical evaluation or epilepsy surgery, and appropriately selected cases may have good surgical outcomes. Prospective registries of patients with monogenic epilepsies who undergo epilepsy surgery can provide additional insights on outcomes.
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OBJECTIVE: Refractory idiopathic generalised epilepsy (IGE; also known as genetic generalised epilepsy) is a clinical challenge due to limited available therapeutic options. While vagus nerve stimulation (VNS) is approved as an adjunctive treatment for drug-resistant focal epilepsy, there is limited evidence supporting its efficacy for refractory IGE. METHODS: We conducted a single-centre retrospective analysis of adult IGE patients treated with VNS between January 2003 and January 2022. We analysed the efficacy, safety, tolerability, stimulation parameters and potential clinical features of VNS response in this IGE cohort. RESULTS: Twenty-three IGE patients were implanted with VNS between January 2003 and January 2022. Twenty-two patients (95.65%) were female. The median baseline seizure frequency was 30 per month (interquartile range [IQR]= 140), including generalised tonic-clonic seizures (GTCS), absences, myoclonus, and eyelid myoclonia with/without absences. The median number of baseline anti-seizure medications (ASM) was three (IQR= 2). Patients had previously failed a median of six ASM (IQR= 5). At the end of the study period, VNS therapy remained active in 17 patients (73.9%). amongst patients who continued VNS, thirteen (56.5% of the overall cohort) were considered responders (≥50% seizure frequency reduction). Amongst the clinical variables analysed, only psychiatric comorbidity correlated with poorer seizure outcomes, but was non-significant after applying the Bonferroni correction. Although 16 patients reported side-effects, none resulted in the discontinuation of VNS therapy. SIGNIFICANCE: Over half of the patients with refractory IGE experienced a positive response to VNS therapy. VNS represents a viable treatment option for patients with refractory IGE, particularly for females, when other therapeutic options have been exhausted.
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Epilepsia Resistente a Medicamentos , Epilepsia Generalizada , Mioclonia , Estimulação do Nervo Vago , Adulto , Humanos , Feminino , Masculino , Estimulação do Nervo Vago/métodos , Estudos Retrospectivos , Epilepsia Generalizada/terapia , Epilepsia Resistente a Medicamentos/terapia , Convulsões , Imunoglobulina E , Resultado do Tratamento , Nervo VagoRESUMO
Epilepsy surgery should be considered in all patients with drug-resistant focal epilepsy. The diagnostic presurgical evaluation aims to delineate the epileptogenic zone and its relationship to eloquent brain regions. Genetic testing is not yet routine in presurgical evaluations, despite many monogenic causes of severe epilepsies, including some focal epilepsies. This review highlights genomic data that may inform decisions regarding epilepsy surgery candidacy and strategy. Focal epilepsies due to pathogenic variants in mechanistic target of rapamycin pathway genes are amenable to surgery if clinical, electroencephalography and imaging data are concordant. Epilepsy surgery outcomes are less favourable in patients with pathogenic variants in ion channel genes such as SCN1A. However, genomic data should not be used in isolation to contraindicate epilepsy surgery and should be considered alongside other diagnostic modalities. The additional role of somatic mosaicism in the pathogenesis of focal epilepsies may have implications for surgical planning and prognostication. Here, we advocate for including genomic data in the presurgical evaluation and multidisciplinary discussion for many epilepsy surgery candidates. We encourage neurologists to perform genetic testing in patients with focal non-lesional epilepsy, epilepsy in the setting of intellectual disability and epilepsy due to specific malformations of cortical development. The integration of genomics into the presurgical evaluation assists selection of patients for resective surgery and fosters a personalised medicine approach, where precision or targeted therapies are considered alongside surgical procedures.
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Epilepsia Resistente a Medicamentos , Epilepsias Parciais , Epilepsia , Epilepsia Resistente a Medicamentos/cirurgia , Eletroencefalografia , Epilepsias Parciais/diagnóstico , Epilepsia/diagnóstico , Epilepsia/genética , Epilepsia/cirurgia , Genômica , Humanos , Imageamento por Ressonância MagnéticaRESUMO
The mechanistic target of rapamycin signalling pathway serves as a ubiquitous regulator of cell metabolism, growth, proliferation and survival. The main cellular activity of the mechanistic target of rapamycin cascade funnels through mechanistic target of rapamycin complex 1, which is inhibited by rapamycin, a macrolide compound produced by the bacterium Streptomyces hygroscopicus. Pathogenic variants in genes encoding upstream regulators of mechanistic target of rapamycin complex 1 cause epilepsies and neurodevelopmental disorders. Tuberous sclerosis complex is a multisystem disorder caused by mutations in mechanistic target of rapamycin regulators TSC1 or TSC2, with prominent neurological manifestations including epilepsy, focal cortical dysplasia and neuropsychiatric disorders. Focal cortical dysplasia type II results from somatic brain mutations in mechanistic target of rapamycin pathway activators MTOR, AKT3, PIK3CA and RHEB and is a major cause of drug-resistant epilepsy. DEPDC5, NPRL2 and NPRL3 code for subunits of the GTPase-activating protein (GAP) activity towards Rags 1 complex (GATOR1), the principal amino acid-sensing regulator of mechanistic target of rapamycin complex 1. Germline pathogenic variants in GATOR1 genes cause non-lesional focal epilepsies and epilepsies associated with malformations of cortical development. Collectively, the mTORopathies are characterized by excessive mechanistic target of rapamycin pathway activation and drug-resistant epilepsy. In the first large-scale precision medicine trial in a genetically mediated epilepsy, everolimus (a synthetic analogue of rapamycin) was effective at reducing seizure frequency in people with tuberous sclerosis complex. Rapamycin reduced seizures in rodent models of DEPDC5-related epilepsy and focal cortical dysplasia type II. This review outlines a personalized medicine approach to the management of epilepsies in the mTORopathies. We advocate for early diagnostic sequencing of mechanistic target of rapamycin pathway genes in drug-resistant epilepsy, as identification of a pathogenic variant may point to an occult dysplasia in apparently non-lesional epilepsy or may uncover important prognostic information including, an increased risk of sudden unexpected death in epilepsy in the GATORopathies or favourable epilepsy surgery outcomes in focal cortical dysplasia type II due to somatic brain mutations. Lastly, we discuss the potential therapeutic application of mechanistic target of rapamycin inhibitors for drug-resistant seizures in GATOR1-related epilepsies and focal cortical dysplasia type II.
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OBJECTIVES: To determine the clinical features and anti-seizure medication (ASM) strategies associated with an unanticipated substantial improvement in seizure control in patients with drug-resistant epilepsy (DRE). METHODS: This retrospective analysis of patients attending a tertiary care epilepsy clinic between 2008 and 2017 identified all patients with active DRE (at least 1 seizure per month for 6 months, despite treatment with 2 different ASMs). All treatment interventions were recorded from when DRE was first identified to the end of the study. The primary end points were seizure freedom or meaningful reduction in seizure frequency (greater than 75 %) sustained for at least 12 months after a treatment intervention. RESULTS: Three hundred and twenty-two patients were included in the analysis. Overall, 10 % became seizure free following ASM adjustment and an additional 10 % had a greater than 75 % improvement in seizure control (median follow-up, 4 years). An ASM introduction was ten times more likely than an ASM dose increase to improve seizure control. Combined focal and generalized epilepsy, intellectual disability and prior treatment with more than 5 ASMs were more frequently observed in those with continued pharmacoresistance. ASM responders were more likely to have primary generalized epilepsy. Rational polytherapy (combining ASMs with different mechanisms of action) was almost ubiquitous amongst ASMs responders (95 % taking at least 2 drugs with different mechanistic targets). Of the ASM additions that heralded improved seizure control, 85 % were maintained at submaximal doses. CONCLUSIONS: This retrospective analysis of a large number of 'real-world' patients provides evidence to persist with ASM trials in DRE. Early rotation of ASMs if a clinical response is not observed at a substantial dose and rational ASM polytherapy may yield better clinical outcomes in patients with DRE, although a prospective study would need to be conducted to validate these findings.
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Epilepsia , Preparações Farmacêuticas , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Convulsões/tratamento farmacológicoRESUMO
Historically, electromyography (EMG) is utilized early in the diagnostic evaluation of neuromuscular disorders, but its importance may be diminishing with more sophisticated genetic, imaging and immunohistochemistry investigations now available. In the present study, the diagnostic yield of EMG at predicting pathological abnormalities confirmed by muscle biopsy was determined at our neuroscience center. A retrospective study of consecutive cases reviewed at neuromuscular multidisciplinary meetings between 2007 and 2016 identified patients who had EMG and muscle biopsy as part of their diagnostic evaluation. EMG and biopsy findings were categorized as myopathic, neurogenic or normal. The diagnostic accuracy was determined by calculating the concordance between EMG and pathological findings. Of the 175 cases included in the analysis, there was definite concordance between EMG and muscle biopsy findings in 134 cases (76.6%). Abnormal EMG produced sensitivity of 87% and specificity of 65% for abnormal muscle biopsy. Seventeen patients had a normal EMG and an abnormal muscle biopsy, of which 6 had histopathological findings consistent with mitochondrial myopathy, central core myopathy or glycogen storage disorder. Conflicting EMG and muscle biopsy findings were observed in 10 cases. Inclusion body myositis, chronic neuromuscular disorders and dual pathologies were associated with discordant findings. This study demonstrates that EMG has accurate predictive value in diagnosing neuromuscular disorders at our neuroscience center. EMG retains a vital role, particularly in initial diagnostic evaluations of neuromuscular disorders.
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Doenças Neuromusculares , Biópsia , Eletromiografia , Humanos , Músculos , Doenças Neuromusculares/diagnóstico , Estudos RetrospectivosRESUMO
Discordant elevations of cerebrospinal fluid (CSF) human immunodeficiency virus (HIV) ribonucleic acid (RNA) in chronically treated patients known as 'CSF escape' may present as acute encephalitis. Infectious encephalitis caused by herpes simplex virus (HSV) and other neurotropic viruses have been identified as potential triggers of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Autoantibody-mediated encephalitis has been infrequently reported in HIV infected patients and may mimic HIV encephalitis. We report two adults infected with HIV presenting with encephalopathy and seizures. Case 1 had a monophasic encephalopathy with detection of NMDAR antibodies in the context of HIV CSF escape. There was a clinical response to immunotherapy and anti-retroviral therapy adjustment. Case 2 initially presented in non-convulsive status epilepticus associated with HIV CSF escape. He responded to treatment with anti-epileptic drugs and anti-retroviral therapy alteration, but had two further neurological relapses. NMDAR antibodies were detected during the relapses and a clinical response was observed following treatment with immunotherapy. Clinicians should consider autoimmune encephalitis in HIV infected patients presenting with encephalopathy and seizures, particularly in cases with concomitant HIV CSF escape.