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BACKGROUND: After a first-ever seizure, 6 months of seizure freedom is usually required before returning to driving a private motor vehicle, after which the annual risk of seizure recurrence has fallen to ≤20%. Stricter criteria apply for commercial driver's licence (CDL) holders, and a longer period of seizure freedom sufficient for the annual risk of recurrence to be <2% is recommended. However, CDL guidelines are based on little data with few studies having long-term follow-up. METHODS: 1714 patients with first-ever seizures were prospectively studied. Seizure recurrence was evaluated using survival analysis. The annual conditional risk of seizure recurrence was calculated for patients with first-ever unprovoked and acute symptomatic seizures, and according to the presence or absence of clinical, electroencephalogram (EEG) and neuroimaging risk factors for recurrence. RESULTS: The annual risk of recurrence for unprovoked first seizures did not fall below 2% until after 9 years of seizure freedom. The annual risk after 5 years of seizure freedom was still 3.9% (95% CI 1.8% to 6.1%) including for those without epileptiform abnormalities on EEG and with normal imaging. For acute symptomatic first seizures, the annual recurrence risk was 4.5% (95% CI 2.3% to 6.7%) after 1 year and fell below 2% only after 4 years of seizure freedom. CONCLUSIONS: For unprovoked and acute symptomatic first-ever seizure and CDL, a higher-than-expected annual seizure risk persists beyond the currently recommended seizure-free periods, even in those without risk factors for recurrence. Our data can inform decisions regarding a return to driving for CDL holders after first-ever seizure.
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A young man from Pakistan had his first-ever tonic-clonic seizure while playing cricket. Since age 12 years, he had reported involuntary jerks and tremulousness, sometimes with falls, particularly with bright lights. Family history included a brother who developed seizures with myoclonus in his mid-20s and parental consanguinity. Developmental history was normal. Examination identified cognitive impairment with action myoclonus. His clinical presentation raised suspicion of a progressive myoclonus epilepsy. MR scan of the brain showed white matter changes suggesting leucodystrophy with cortical atrophy. Electroencephalogram showed generalised epileptiform abnormalities with photoparoxysmal responses, including at low frequencies (1 Hz). Cortical hyperexcitability was confirmed with giant median somatosensory evoked potentials and long loop reflexes at rest. Multichannel electromyography showed action myoclonus with variable synchronous and asynchronous agonist and antagonist muscle activation with short-burst duration of 25-75 ms, and jerk-locked back-averaging showed premyoclonic potentials consistent with cortical myoclonus. Genetic sequencing identified a homozygous missense variant in the CLN6 gene (c.768C>G p.(Asp256Glu), confirming Kufs disease type A.
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Epilepsias Mioclónicas Progresivas , Mioclonía , Lipofuscinosis Ceroideas Neuronales , Masculino , Adulto , Humanos , Niño , Encéfalo , Electroencefalografía , Convulsiones , Electromiografía , Proteínas de la MembranaRESUMEN
OBJECTIVE: In Australia, 30% of newly diagnosed epilepsy patients were not immediately treated at diagnosis. We explored health outcomes between patients receiving immediate, deferred, or no treatment, and compared them to the general population. METHODS: Adults with newly diagnosed epilepsy in Western Australia between 1999 and 2016 were linked with statewide health care data collections. Health care utilization, comorbidity, and mortality at up to 10 years postdiagnosis were compared between patients receiving immediate, deferred, and no treatment, as well as with age- and sex-matched population controls. RESULTS: Of 603 epilepsy patients (61% male, median age = 40 years) were included, 422 (70%) were treated immediately at diagnosis, 110 (18%) received deferred treatment, and 71 (12%) were untreated at the end of follow-up (median = 6.8 years). Immediately treated patients had a higher 10-year rate of all-cause admissions or emergency department presentations than the untreated (incidence rate ratio [IRR] = 2.0, 95% confidence interval [CI] = 1.4-2.9) and deferred treatment groups (IRR = 1.7, 95% CI = 1.0-2.8). They had similar 10-year risks of mortality and developing new physical and psychiatric comorbidities compared with the deferred and untreated groups. Compared to population controls, epilepsy patients had higher 10-year mortality (hazard ratio = 2.6, 95% CI = 2.1-3.3), hospital admissions (IRR = 2.3, 95% CI = 1.6-3.3), and psychiatric outpatient visits (IRR = 3.2, 95% CI = 1.6-6.3). Patients with epilepsy were also 2.5 (95% CI = 2.1-3.1) and 3.9 (95% CI = 2.6-5.8) times more likely to develop a new physical and psychiatric comorbidity, respectively. SIGNIFICANCE: Newly diagnosed epilepsy patients with deferred or no treatment did not have worse outcomes than those immediately treated. Instead, immediately treated patients had greater health care utilization, likely reflecting more severe underlying epilepsy etiology. Our findings emphasize the importance of individualizing epilepsy treatment and recognition and management of the significant comorbidities, particularly psychiatric, that ensue following a diagnosis of epilepsy.
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Epilepsia , Adulto , Humanos , Masculino , Femenino , Epilepsia/epidemiología , Epilepsia/terapia , Epilepsia/diagnóstico , Comorbilidad , Hospitalización , Incidencia , Modelos de Riesgos Proporcionales , Estudios RetrospectivosRESUMEN
INTRODUCTION: Epilepsy is one of the most common neurological conditions worldwide. Despite many antiseizure medications (ASMs) being available, up to one-third of patients do not achieve seizure control. Preclinical studies have shown treatment with sodium selenate to have a disease-modifying effect in a rat model of chronic temporal lobe epilepsy (TLE). AIM: This randomised placebo-controlled trial aims to evaluate the antiseizure and disease-modifying effects of sodium selenate in people with drug-resistant TLE. METHODS: This will be a randomised placebo-controlled trial of sodium selenate. One hundred and twenty-four adults with drug-resistant TLE and ≥4 countable seizures/month will be recruited. Outcomes of interest will be measured at baseline, week 26 and week 52 and include an 8-week seizure diary, 24-hour electroencephalogram and cognitive, neuropsychiatric and quality of life measures. Participants will then be randomised to receive a sustained release formulation of sodium selenate (initially 10 mg three times a day, increasing to 15 mg three times a day at week 4 if tolerated) or a matching placebo for 26 weeks. OUTCOMES: The primary outcome will be a consumer codesigned epilepsy-Desirability of Outcome Rank (DOOR), combining change in seizure frequency, adverse events, quality of life and ASM burden measures into a single outcome measure, compared between treatment arms over the whole 52-week period. Secondary outcomes will compare baseline measures to week 26 (antiseizure) and week 52 (disease modification). Exploratory measures will include biomarkers of treatment response. ETHICS AND DISSEMINATION: The study has been approved by the lead site, Alfred Hospital Ethics Committee (594/20). Each participant will provide written informed consent prior to any trial procedures. The results of the study will be presented at national and international conferences, published in peer-reviewed journals and disseminated through consumer organisations. CONCLUSION: This study will be the first disease-modification randomised controlled trial in patients with drug-resistant TLE. TRIAL REGISTRATION NUMBER: ANZCTR; ACTRN12623000446662.
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Epilepsia Refractaria , Epilepsia del Lóbulo Temporal , Adulto , Humanos , Animales , Ratas , Ácido Selénico , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Calidad de Vida , Resultado del Tratamiento , Epilepsia Refractaria/tratamiento farmacológico , Convulsiones , Ensayos Clínicos Controlados Aleatorios como Asunto , Ensayos Clínicos Fase II como AsuntoRESUMEN
Objectives: This article aims to critically review the literature on continuous electroencephalography (cEEG) monitoring in the intensive care unit (ICU) from an Australian and New Zealand perspective and provide recommendations for clinicians. Design and review methods: A taskforce of adult and paediatric neurologists, selected by the Epilepsy Society of Australia, reviewed the literature on cEEG for seizure detection in critically ill neonates, children, and adults in the ICU. The literature on routine EEG and cEEG for other indications was not reviewed. Following an evaluation of the evidence and discussion of controversial issues, consensus was reached, and a document that highlighted important clinical, practical, and economic considerations regarding cEEG in Australia and New Zealand was drafted. Results: This review represents a summary of the literature and consensus opinion regarding the use of cEEG in the ICU for detection of seizures, highlighting gaps in evidence, practical problems with implementation, funding shortfalls, and areas for future research. Conclusion: While cEEG detects electrographic seizures in a significant proportion of at-risk neonates, children, and adults in the ICU, conferring poorer neurological outcomes and guiding treatment in many settings, the health economic benefits of treating such seizures remain to be proven. Presently, cEEG in Australian and New Zealand ICUs is a largely unfunded clinical resource that is subsequently reserved for the highest-impact patient groups. Wider adoption of cEEG requires further research into impact on functional and health economic outcomes, education and training of the neurology and ICU teams involved, and securement of the necessary resources and funding to support the service.
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OBJECTIVES: Patients with a first-ever unprovoked seizure commonly have subsequent seizures and identifying predictors of recurrence has important management implications. Both prior brain insult and epileptiform abnormalities on electroencephalography (EEG) are established predictors of seizure recurrence. Some studies suggest that a first-ever seizure from sleep has a higher likelihood of recurrence. However, with relatively small numbers and inconsistent definitions, more data are required. METHODS: Prospective cohort study of adults with first-ever unprovoked seizure seen by a hospital-based first seizure service between 2000 and 2015. Clinical features and outcomes of first-ever seizure from sleep and while awake were compared. RESULTS: First-ever unprovoked seizure occurred during sleep in 298 of 1312 patients (23%), in whom the 1-year cumulative risk of recurrence was 56.9% (95% confidence interval [CI] 51.3-62.6) compared to 44.2% (95% CI 41.1-47.3, p < .0001) for patients with first-ever seizure while awake. First-ever seizure from sleep was an independent predictor of seizure recurrence, with a hazard ratio [HR] of 1.44 (95% CI 1.23-1.69), similar to epileptiform abnormalities on EEG (HR 1.48, 95% CI 1.24-1.76) and remote symptomatic etiology (HR 1.47, 95% CI 1.27-1.71). HR for recurrence in patients without either epileptiform abnormalities or remote symptomatic etiology was 1.97 (95% CI 1.60-2.44) for a sleep seizure compared to an awake seizure. For first seizure from sleep, 76% of second seizures also arose from sleep (p < .0001), with 65% of third seizures (p < .0001) also from sleep. Seizures from sleep were less likely to be associated with injury other than orolingual trauma, both with the presenting seizure (9.4% vs 30.6%, p < .0001) and first recurrence (7.5% vs 16.3%, p = .001). SIGNIFICANCE: First-ever unprovoked seizures from sleep are more likely to recur, independent of other risk factors, with recurrences also usually from sleep, and with a lower risk of seizure-related injury. These findings may inform treatment decisions and counseling after first-ever seizure.
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Convulsiones , Sueño , Adulto , Humanos , Estudios Prospectivos , Recurrencia , Convulsiones/diagnóstico , Convulsiones/epidemiología , Convulsiones/etiología , Factores de Riesgo , Pronóstico , Electroencefalografía/efectos adversosRESUMEN
OBJECTIVE: This study was undertaken to analyze phenotypic features of a cohort of patients with protracted CLN3 disease to improve recognition of the disorder. METHODS: We analyzed phenotypic data of 10 patients from six families with protracted CLN3 disease. Haplotype analysis was performed in three reportedly unrelated families. RESULTS: Visual impairment was the initial symptom, with onset at 5-9 years, similar to classic CLN3 disease. Mean time from onset of visual impairment to seizures was 12 years (range = 6-41 years). Various seizure types were reported, most commonly generalized tonic-clonic seizures; focal seizures were present in four patients. Progressive myoclonus epilepsy was not seen. Interictal electroencephalogram revealed mild background slowing and 2.5-3.5-Hz spontaneous generalized spike-wave discharges. Additional interictal focal epileptiform discharges were noted in some patients. Age at death for the three deceased patients was 31, 31, and 52 years. Molecular testing revealed five individuals were homozygous for c.461-280_677 + 382del966, the "common 1-kb" CLN3 deletion. The remaining individuals were compound heterozygous for various combinations of recurrent pathogenic CLN3 variants. Haplotype analysis demonstrated evidence of a common founder for the common 1-kb deletion. Dating analysis suggested the deletion arose approximately 1500 years ago and thus did not represent cryptic familial relationship in this Australian cohort. SIGNIFICANCE: We highlight the protracted phenotype of a disease generally associated with death in adolescence, which is a combined focal and generalized epilepsy syndrome with progressive neurological deterioration. The disorder should be suspected in an adolescent or adult patient presenting with generalized or focal seizures preceded by progressive visual loss. The common 1-kb deletion has been typically associated with classic CLN3 disease, and the protracted phenotype has not previously been reported with this genotype. This suggests that modifying genetic factors may be important in determining this somewhat milder phenotype and identification of these factors should be the subject of future research.
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Epilepsia Generalizada , Lipofuscinosis Ceroideas Neuronales , Humanos , Lipofuscinosis Ceroideas Neuronales/complicaciones , Lipofuscinosis Ceroideas Neuronales/diagnóstico , Lipofuscinosis Ceroideas Neuronales/genética , Australia , Convulsiones/diagnóstico , Genotipo , Glicoproteínas de Membrana/genética , Chaperonas Moleculares/genéticaRESUMEN
OBJECTIVE: Although increased mortality associated with epilepsy is well understood, data in patients after their first-ever seizure are limited. We aimed to assess mortality after a first-ever unprovoked seizure and identify causes of death (CODs) and risk factors. METHODS: A prospective cohort study was undertaken of patients with first-ever unprovoked seizure between 1999 and 2015 in Western Australia. Two age-, gender-, and calendar year-matched local controls were obtained for each patient. Mortality data, including COD, based on International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes, were obtained. Final analysis was performed in January 2022. RESULTS: One thousand two hundred seventy-eight patients with a first-ever unprovoked seizure were compared to 2556 controls. Mean follow-up was 7.3 years (range = .1-20). Overall hazard ratio (HR) for death after a first unprovoked seizure compared to controls was 3.06 (95% confidence interval [CI] = 2.48-3.79), with HRs of 3.30 (95% CI = 2.26-4.82) for those without seizure recurrence and 3.21 (95% CI = 2.47-4.16) after a second seizure. Mortality was also increased in patients with normal imaging and no identified cause (HR = 2.50, 95% CI = 1.82-3.42). Multivariate predictors of mortality were increasing age, remote symptomatic causes, first seizure presentation with seizure cluster or status epilepticus, neurological disability, and antidepressant use at time of first seizure. Seizure recurrence did not influence mortality rate. The commonest CODs were neurological, most relating to the underlying cause of seizures rather than being seizure-related. Substance overdoses and suicide were more frequent CODs in patients compared to controls and were commoner than seizure-related deaths. SIGNIFICANCE: Mortality is increased two- to threefold after a first-ever unprovoked seizure, independent of seizure recurrence, and is not only attributable to the underlying neurological etiology. The greater likelihood of deaths related to substance overdose and suicide highlights the importance of assessing psychiatric comorbidity and substance use in patients with first-ever unprovoked seizure.
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Sobredosis de Droga , Epilepsia Generalizada , Humanos , Estudios Prospectivos , Convulsiones , Causas de Muerte , Factores de Riesgo , RecurrenciaRESUMEN
Importance: Selection of antiseizure medications (ASMs) for epilepsy remains largely a trial-and-error approach. Under this approach, many patients have to endure sequential trials of ineffective treatments until the "right drugs" are prescribed. Objective: To develop and validate a deep learning model using readily available clinical information to predict treatment success with the first ASM for individual patients. Design, Setting, and Participants: This cohort study developed and validated a prognostic model. Patients were treated between 1982 and 2020. All patients were followed up for a minimum of 1 year or until failure of the first ASM. A total of 2404 adults with epilepsy newly treated at specialist clinics in Scotland, Malaysia, Australia, and China between 1982 and 2020 were considered for inclusion, of whom 606 (25.2%) were excluded from the final cohort because of missing information in 1 or more variables. Exposures: One of 7 antiseizure medications. Main Outcomes and Measures: With the use of the transformer model architecture on 16 clinical factors and ASM information, this cohort study first pooled all cohorts for model training and testing. The model was trained again using the largest cohort and externally validated on the other 4 cohorts. The area under the receiver operating characteristic curve (AUROC), weighted balanced accuracy, sensitivity, and specificity of the model were all assessed for predicting treatment success based on the optimal probability cutoff. Treatment success was defined as complete seizure freedom for the first year of treatment while taking the first ASM. Performance of the transformer model was compared with other machine learning models. Results: The final pooled cohort included 1798 adults (54.5% female; median age, 34 years [IQR, 24-50 years]). The transformer model that was trained using the pooled cohort had an AUROC of 0.65 (95% CI, 0.63-0.67) and a weighted balanced accuracy of 0.62 (95% CI, 0.60-0.64) on the test set. The model that was trained using the largest cohort only had AUROCs ranging from 0.52 to 0.60 and a weighted balanced accuracy ranging from 0.51 to 0.62 in the external validation cohorts. Number of pretreatment seizures, presence of psychiatric disorders, electroencephalography, and brain imaging findings were the most important clinical variables for predicted outcomes in both models. The transformer model that was developed using the pooled cohort outperformed 2 of the 5 other models tested in terms of AUROC. Conclusions and Relevance: In this cohort study, a deep learning model showed the feasibility of personalized prediction of response to ASMs based on clinical information. With improvement of performance, such as by incorporating genetic and imaging data, this model may potentially assist clinicians in selecting the right drug at the first trial.
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Aprendizaje Profundo , Epilepsia , Adulto , Inteligencia Artificial , Estudios de Cohortes , Epilepsia/diagnóstico , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Aprendizaje Automático , MasculinoRESUMEN
OBJECTIVE: Patients with epilepsy not uncommonly self-discontinue treatment with antiseizure medications (ASM). The rate, reasons for this, and consequences have not been well studied. METHODS: We analyzed self-discontinuation of ASM treatment in patients with recently diagnosed epilepsy via review of clinic letters and hospital correspondence in a prospective cohort of first seizure patients. RESULTS: We studied 489 patients with newly diagnosed and treated epilepsy (median age 41, range 14-88, 62% male), followed up for a median duration of 3.0â¯years (interquartile range [IQR]: 1.2-6.0). Seventy eight (16.0%) self-discontinued ASM therapy after a median treatment duration of 1.4â¯years (IQR: 0.4-2.9), and after a median duration of seizure freedom of 11.8â¯months (IQR: 4.6-31.8). Patients commonly self-discontinued treatment due to adverse effects (41%), perception that treatment was no longer required (35%), and planned or current pregnancy (12%). Patients who self-discontinued were less likely to have epileptogenic lesions on neuroimaging (hazard ratio [HR]â¯=â¯0.44, 95% confidence interval [CI]: 0.23-0.83), presentation with seizure clusters (HRâ¯=â¯0.32, 95% CI: 0.14-0.69) and presentation with tonic-clonic seizures (HRâ¯=â¯0.36, 95% CI: 0.19-0.70). Patients with shorter interval since the last seizure (HRâ¯=â¯0.76, 95% CI: 0.66-0.86) were more likely to self-discontinue treatment. Sleep deprivation prior to seizures before diagnosis (HRâ¯=â¯1.80, 95% CI: 1.05-3.09) and significant alcohol or illicit drug use (HRâ¯=â¯2.35, 95% CI: 1.20-4.59) were also associated with higher rates of discontinuation. After discontinuation, 51 patients (65%) experienced seizure recurrence, and 43 (84%) restarted treatment. Twenty two patients (28%) experienced a seizure-related injury after treatment discontinuation. SIGNIFICANCE: Self-initiated discontinuation of ASM treatment was not uncommon in patients with newly treated epilepsy. Reasons for discontinuation highlight areas for improved discussion with patients, including the chronicity of epilepsy and management strategies for current or potential adverse effects.
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Anticonvulsivantes , Epilepsia , Adulto , Anticonvulsivantes/uso terapéutico , Epilepsia/inducido químicamente , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Masculino , Estudios Prospectivos , Factores de Riesgo , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológicoRESUMEN
There is international interest for consensus advice for prescribers working in the field of drug resistant epilepsy intending to trial potential therapies that are nonregistered or off-label. Cannabinoids are one such therapy. In 2017, the New South Wales State Government (Australia) set up a cannabinoid prescribing guidance service for a wide variety of indications, based on known pharmacology together with the relevant new literature as it became available. Increasing interest in cannabis medicines use outside this State over the following 5 years together with a paucity of registration-standard clinical trials, lack of information around dosing issues, drug interactions and biological plausibility meant there remained a large unmet need for such advice. To address the unmet need in epilepsy, and until medicines were registered or regulator quality data were available, it was agreed to bring together a working group comprising paediatric and adult epilepsy specialists, clinical pharmacists., clinical pharmacologists and cannabis researchers from across Australia to develop interim consensus advice for prescribers. Although interim, this consensus advice addresses much of the current practice gap by providing an informed overview of the different cannabis medicines currently available for use in the treatment of epilepsy in paediatric and adult settings, with information on dose, drug interactions, toxicity, type of seizure and frequency of symptom relief. As such it supplements the limited evidence currently available from clinical trials with experience from front-line practice. It is expected that this consensus advice will be updated as new evidence emerges and will provide guidance for a subsequent Guideline.
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Cannabinoides , Cannabis , Epilepsia , Alucinógenos , Adulto , Analgésicos/uso terapéutico , Australia , Cannabinoides/farmacología , Niño , Epilepsia/tratamiento farmacológico , Humanos , Convulsiones/tratamiento farmacológicoRESUMEN
BACKGROUND AND OBJECTIVES: Our aim was to study the development of pure sleep epilepsy after a first-ever seizure from sleep in adults. METHODS: This was a prospective observational study of patients seen at a tertiary hospital-based first seizure clinic between 2000 and 2011. Adults with a first-ever unprovoked seizure from sleep were consecutively recruited. All patients were followed up at least once after the initial seizure, and those not requiring regular clinical review were contacted every 1 to 2 years. The timing and pattern of subsequent seizures and potential predictors of future awake seizures were analyzed. RESULTS: Two hundred thirty-nine adults with a first-ever unprovoked seizure from sleep were identified. Sixty-one percent were male; mean age was 43 years (range 14-88 years); and median follow-up of 8.8 years (range 2 months-18 years). Of the 174 patients who had recurrent seizures, 130 patients (75%) had their second seizure from sleep, and of these, 76 of 94 (81%) also had their third seizure from sleep. Eighty-nine patients (37%) developed awake seizures during follow-up. In half of these patients, the awake seizure occurred within 2 years of the initial seizure. The risk of an awake seizure within 1 year of a first-ever seizure from sleep was 13.9% (95% CI 9.4%-18.3%), falling to 2.0% to 5.3% per year after 3 years. The risks of an awake seizure within 1 year of a second or third consecutive sleep seizure were 9.9% (95% CI 4.6%-15.3%) and 8.7% (95% CI 2.0%-15.4%), respectively, and similarly decreased with time. DISCUSSION: Most initial seizure recurrences after a first-ever sleep seizure occur during sleep. While more than one-third eventually had awake seizures, the annual risk of an awake seizure was ≤14% and decreased with time, albeit with a small ongoing risk of between 2% and 5% per year. These findings may be used in counseling patients with seizures from sleep and to inform driving recommendations.
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Epilepsia Refleja , Narcolepsia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Convulsiones/epidemiología , Sueño , Adulto JovenRESUMEN
PURPOSE: Following a single seizure, or recent epilepsy diagnosis, it is difficult to balance risk of medication side effects with the potential to prevent seizure recurrence. A prediction model was developed and validated enabling risk stratification which in turn informs treatment decisions and individualises counselling. METHODS: Data from a randomised controlled trial was used to develop a prediction model for risk of seizure recurrence following a first seizure or diagnosis of epilepsy. Time-to-event data was modelled via Cox's proportional hazards regression. Model validity was assessed via discrimination and calibration using the original dataset and also using three external datasets - National General Practice Survey of Epilepsy (NGPSE), Western Australian first seizure database (WA) and FIRST (Italian dataset of people with first tonic-clonic seizures). RESULTS: People with neurological deficit, focal seizures, abnormal EEG, not indicated for CT/MRI scan, or not immediately treated have a significantly higher risk of seizure recurrence. Discrimination was fair and consistent across the datasets (c-statistics: 0.555 (NGPSE); 0.558 (WA); 0.597 (FIRST)). Calibration plots showed good agreement between observed and predicted probabilities in NGPSE at one and three years. Plots for WA and FIRST showed poorer agreement with the model underpredicting risk in WA, and over-predicting in FIRST. This was resolved following model recalibration. CONCLUSION: The model performs well in independent data especially when recalibrated. It should now be used in clinical practice as it can improve the lives of people with single seizures and early epilepsy by enabling targeted treatment choices and more informed patient counselling.
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Anticonvulsivantes , Epilepsia , Anticonvulsivantes/uso terapéutico , Australia , Epilepsia/tratamiento farmacológico , Epilepsia/epidemiología , Humanos , Probabilidad , Convulsiones/tratamiento farmacológico , Convulsiones/epidemiologíaRESUMEN
People with epilepsy have variable and dynamic trajectories in response to antiseizure medications. Accurately modelling long-term treatment response will aid prognostication at the individual level and health resource planning at the societal level. Unfortunately, a robust model is lacking. We aimed to develop a Markov model to predict the probability of future seizure-freedom based on current seizure state and number of antiseizure medication regimens trialled. We included 1795 people with newly diagnosed epilepsy who attended a specialist clinic in Glasgow, Scotland, between July 1982 and October 2012. They were followed up until October 2014 or death. We developed a simple Markov model, based on current seizure state only, and a more detailed model, based on both current seizure state and number of antiseizure medication regimens trialled. Sensitivity analyses were performed for the regimen-based states model to examine the effect of regimen changes due to adverse effects. The model was externally validated in a separate cohort of 455 newly diagnosis epilepsy patients seen in Perth, Australia, between May 1999 and May 2016. Our models suggested that once seizure-freedom was achieved, it was likely to persist, regardless of the number of antiseizure medications trialled to reach that point. The likelihood of achieving long-term seizure-freedom was highest with the first antiseizure medication regimen, at approximately 50%. The chance of achieving seizure-freedom fell with subsequent regimens. Fluctuations between seizure-free and not seizure-free states were highest earlier on but decreased with chronicity of epilepsy. Seizure-freedom/recurrence risk tables were constructed with these probability data, similar to cardiovascular risk tables. Sensitivity analyses showed that the general trends and conclusions from the base model were maintained despite perturbing the model and input data with regimen changes due to adverse effects. Quantitative comparison with the external validation cohort showed excellent consistency at Year 1, good at Year 3 and moderate at Year 5. Quantitative models, as used in this study, can provide pertinent clinical insights that are not apparent from simple statistical analysis alone. Attaining seizure freedom at any time in a patient's epilepsy journey will confer durable benefit. Seizure-freedom risk tables may be used to individualize the prediction of future seizure control trajectory.
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Anticonvulsivantes , Epilepsia , Anticonvulsivantes/uso terapéutico , Estudios de Cohortes , Epilepsia/diagnóstico , Epilepsia/tratamiento farmacológico , Humanos , Convulsiones/tratamiento farmacológico , Resultado del TratamientoRESUMEN
BACKGROUND: The mythical effect of the lunar cycle on seizures has been debated over time. Previously healthy individuals presenting with first-ever seizures in whom investigations are negative often invoke questions about potential reasons including a full moon. AIMS: To determine whether there is a temporal relationship between the occurrence of the first-ever unprovoked seizure and the lunar cycle. METHODS: We studied adults who presented with a first-ever unprovoked seizure to two tertiary centres in Australia. Seizure onset time was obtained from the emergency department and ambulance documentations. We used Poisson regression modelling and incidence rate ratios (IRR) to determine whether seizures have a preponderance for a particular lunar phase. We performed further analysis on 'first seizure epilepsy' and 'first seizure not epilepsy' subgroups based on the International League Against Epilepsy criteria for a diagnosis of epilepsy after a single unprovoked seizure. RESULTS: We analysed 1710 patients (38% females; median age 39 years), of whom 18% had epileptiform abnormalities on electroencephalogram (EEG) and potentially epileptogenic lesions were detected on neuroimaging in 28%. Based on the EEG and imaging findings, 684 (40%) patients were categorised as 'first seizure epilepsy' and 1026 (60%) 'first seizure not epilepsy'. The whole cohort and subgroup analysis demonstrated no significant difference in the seizure occurrence among the four lunar quarters. CONCLUSIONS: First unprovoked seizures are not influenced by the lunar cycle. Patients pondering the cause of their first-ever unprovoked seizure can be reassured that the full moon was not responsible.
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Epilepsia , Luna , Adulto , Electroencefalografía , Femenino , Humanos , Incidencia , Masculino , Convulsiones/diagnóstico , Convulsiones/epidemiologíaRESUMEN
PURPOSE: To explore the efficacy and tolerability of adjuvant perampanel (PER) and their associated risk factors in late add-on drug-resistant epilepsy. METHOD: Retrospective multicenter 'real-world' observational study. Consecutively identified patients commenced on PER, with mixed epilepsy syndromes, from nine Australian epilepsy centers. Primary efficacy endpoints were at least 50% reduction in seizure frequency (responders), seizure freedom, and retention at 6 and 12â¯months, following a 3-month titration period. Tolerability endpoints were cessation of PER for any reason, cessation of PER due to treatment-emergent adverse events (TEAE), or cessation due to inefficacy. Outcomes were assessed for a-priori risk factors associated with efficacy and tolerability. RESULTS: Three-hundred and eighty seven adults were identified and followed up for a median of 12.1 months (IQR 7.0-25.2). Focal epilepsy accounted for 79.6% (FE), idiopathic generalized epilepsy (IGE), 10.3% and developmental epileptic encephalopathy (DEE) 10.1%, of the cohort. All patients had drug-resistant epilepsy, 71.6% had never experienced six months of seizure freedom, and the mean number of antiepileptic medications (AEDs) prior to starting PER was six. At 12â¯months, with missing cases classified as treatment failure, retention was 40.0%, responder 21.7%, and seizure freedom 9.0%, whereas, using last outcome carried forward (LOCF), responder and seizure freedom rates were 41.3% and 14.7%, respectively. Older age of epilepsy onset was associated with a marginal increase in the likelihood of seizure freedom at 12-month maintenance (OR 1.04, 95% CI 1.02, 1.06). Male sex (adjusted OR [aOR] 2.06 95% CI 1.33, 3.19), lower number of prior AEDs (aOR 0.84, 95% CI 0.74, 0.96) and no previous seizure-free period of at least 6-month duration (aOR 2.04 95% CI 1.21, 3.47) were associated with retention. Perampanel combined with a GABA receptor AED was associated with a lower responder rate at 12 months but reduced cessation of PER. The most common TEAEs were neuropsychiatric (18.86%), followed by dizziness (13.70%), and sleepiness (5.68%). CONCLUSIONS: Adjuvant PER treatment, even in late-add on drug-resistant epilepsy is an effective and well-tolerated treatment for drug-resistant epilepsy.
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Epilepsia Refractaria , Epilepsia Generalizada , Síndromes Epilépticos , Adulto , Anciano , Anticonvulsivantes/uso terapéutico , Australia , Epilepsia Refractaria/tratamiento farmacológico , Quimioterapia Combinada , Epilepsia Generalizada/tratamiento farmacológico , Síndromes Epilépticos/tratamiento farmacológico , Humanos , Masculino , Nitrilos , Piridonas/uso terapéutico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVES: To compare the outcomes between immediate and deferred treatments in patients diagnosed after one or multiple (two or more) seizures. METHODS: Our observational study investigated seizure recurrence and 12-month seizure remission in patients with newly diagnosed epilepsy, comparing immediate to deferred treatment in patients diagnosed after one seizure or after two or more seizures. RESULTS: Of 598 patients (62% male, median age 39â¯years), 347 (58%) were treated at diagnosis and 251 (42%) received deferred or no treatment. Seizure recurrence was higher with deferred treatment both in patients diagnosed after two or more seizures (nâ¯=â¯363; adjusted hazard ratio [aHR]â¯=â¯2.38, 95% confidence interval [CI]: 1.79-3.14, pâ¯<â¯0.001) and after one seizure (nâ¯=â¯235; aHRâ¯=â¯1.41, 95% CI: 0.995-1.99, pâ¯=â¯0.05). Cumulative seizure recurrence rates at two years in patients diagnosed after two or more seizures were 73% with deferred treatment and 49% with immediate treatment (risk-factor-corrected number-needed-to-treat [NNT]â¯=â¯4), and in those diagnosed after one seizure the rates were 60% and 51% (NNTâ¯=â¯8). Of 380 patients with eligible follow-up (median 4.3â¯years), 287 (76%) had been in seizure remission for at least one year and 211 (56%) remained in remission at last follow-up. Long-term remission rates were similar between immediate and deferred treatments, and between patients diagnosed after one seizure and those with two or more seizures. SIGNIFICANCE: Immediate rather than deferred treatment was less likely to influence seizure recurrence in patients diagnosed with epilepsy after a single seizure than in those diagnosed after two or more seizures, and showed no differences in long-term seizure freedom.
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Epilepsia , Tiempo de Tratamiento , Adulto , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Epilepsia/terapia , Femenino , Humanos , Masculino , Recurrencia , Convulsiones/tratamiento farmacológico , Convulsiones/terapiaRESUMEN
OBJECTIVE: Cyclic phenomena in epilepsy are well recognized. We investigated a multicenter cohort of unprovoked first seizure presentations to determine whether seizures have a preponderance to occur in: a particular time of the day, a particular day of the week, a particular month of the year, day time versus night time, and wakefulness versus sleep. METHODS: We retrospectively studied adults who presented with a first-ever unprovoked seizure to the First Seizure Clinic at two tertiary centers in Australia. Seizure onset time was obtained from the emergency department and ambulance documentations. Electro-clinical and neuroimaging findings were reviewed. We used histograms and Poisson regression modeling to determine whether seizures have a preponderance to occur at a particular time and calculated incidence rate ratios (IRR). We performed further analysis on patients with "first seizure epilepsy" and "first seizure not epilepsy" based on the ILAE criteria for a diagnosis of epilepsy after a single unprovoked seizure, as well as comparing patients that could be categorized as having a generalized-onset seizure versus those with focal-onset seizures. RESULTS: We analyzed 1724 patients (38% females; age range 14-97â¯yr, median 39â¯yr), of whom 18% had epileptiform abnormalities on EEG and potentially epileptogenic lesions were detected on neuroimaging in 28%. Whole cohort analysis shows the incidence rate ratios (IRR) of seizures varied significantly across the 24-hour clock-time of the day (pâ¯<â¯0.001), peaking at hour 12 (IRR 3.18). The first unprovoked seizure was significantly less likely to be reported during the night (IRR 0.61, pâ¯<â¯0.001) and during sleep (IRR 0.29, pâ¯<â¯0.001). Both the "first seizure epilepsy" and "first seizure not epilepsy" subgroups' analysis demonstrated similar patterns. An infraradian pattern was also noted with seizures most likely to occur in May (IRR 1.29, pâ¯=â¯0.02). Both "first seizure epilepsy - generalized" and "first seizure epilepsy - focal" groups had a preponderance for seizures to occur during the day versus night and wakefulness as opposed to sleep, but the association was more robust for generalized seizures. CONCLUSIONS: Our results suggest that temporal patterns are seen in patients with first-ever unprovoked seizures, including those that meet contemporary criteria for epilepsy. These results raise the possibility that first unprovoked seizures have intrinsic rhythmicity similar to epileptic seizures.
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Electroencefalografía , Epilepsia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Australia , Epilepsia/complicaciones , Epilepsia/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Convulsiones/epidemiología , Adulto JovenRESUMEN
OBJECTIVES: Randomized studies in drug-resistant epilepsy (DRE) typically involve addition of a new anti-seizure medication (ASM). However, in clinical practice, if the patient is already taking multiple ASMs, then substitution of one of the current ASMs commonly occurs, despite little evidence supporting this approach. METHODS: Longitudinal prospective study of seizure outcome after commencing a previously untried ASM in patients with DRE. Multivariable time-to-event and logistic regression models were used to evaluate outcomes by whether the new ASM was introduced by addition or substitution. RESULTS: A total of 816 ASM changes in 436 adult patients with DRE between 2010 and 2018 were analyzed. The new ASM was added on 407 (50.1%) occasions and substituted on 409 (49.9%). Mean patient follow-up was 3.2 years. Substitution was more likely if the new ASM was enzyme-inducing or in patients with a greater number of concurrent ASMs. ASM add-on was more likely if a γ-aminobutyric acid (GABA) agonist was introduced or if the patient had previously trialed a higher number of ASMs. The rate of discontinuation due to lack of tolerability was similar between the add-on and substitution groups. No difference between the add-on and substitution ASM introduction strategies was observed for the primary outcome of ≥50% seizure reduction at 12 months. SIGNIFICANCE: Adding or substituting a new ASM in DRE has the same influence on seizure outcomes. The findings confirm that ASM alterations in DRE can be individualized according to concurrent ASM therapy and patient characteristics.
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Anticonvulsivantes/uso terapéutico , Epilepsia Refractaria/tratamiento farmacológico , Sustitución de Medicamentos/estadística & datos numéricos , Quimioterapia Combinada/estadística & datos numéricos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Modelos Logísticos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
OBJECTIVE: To examine the factors and reasons influencing treatment initiation decisions in patients with newly diagnosed epilepsy. METHODS: We assessed antiseizure medication initiation decisions in adults with newly diagnosed epilepsy seen at first seizure clinics in Western Australia between 1999 and 2016 and followed to 2018. RESULTS: Of 610 patients (median age 40 years, 61.0% male), 426 (69.8%) were diagnosed after two or more seizures and 184 (30.2%) after a single seizure with risk factors for recurrence. Treatment was commenced in 427 patients (70.0%) at diagnosis, 112 (18.4%) during follow-up, mostly after further seizures, whereas 71 (11.6%) remained untreated at last follow-up. Elders (≥65 years, odds ratio [OR] = 3.06, 95% confidence interval [CI]: 1.62-5.80), more seizures (OR = 3.48, 95% CI: 2.03-5.96), and epileptogenic lesions on neuroimaging (OR = 2.15, 95% CI: 1.26-3.68) had a higher likelihood of treatment at diagnosis. Patients with less than one seizure per year within the preceding year (OR = 0.40, 95% CI: 0.21-0.73) and of higher socioeconomic status (OR = 0.985, 95% CI: 0.977-0.994) were less likely to be treated. For 93 patients (15.2%), treatment was not recommended at diagnosis, most commonly because only a single seizure had occurred. Ninety patients (14.8%) declined recommended treatment, mostly because they were unconvinced of the need for treatment or the diagnosis. SIGNIFICANCE: Thirty percent of adults with newly diagnosed epilepsy were not immediately treated. Treatment initiation in this real-world cohort was influenced by age, number of seizures prior to diagnosis, imaging findings, patient preferences, and socioeconomic status.