First-ever seizure and eligibility for commercial motor vehicle driving.

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.

Long-term physical and psychiatric morbidities and mortality of untreated, deferred, and immediately treated epilepsy.

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.

Adult-onset Kufs disease.

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.

Mortality after a first-ever unprovoked seizure.

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.

First seizure from sleep: Clinical features and prognosis.

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.

Recognition and epileptology of protracted CLN3 disease.

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.

Markov modelling of treatment response in a 30-year cohort study of newly diagnosed epilepsy.

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.

Expert advice for prescribing cannabis medicines for patients with epilepsy-drawn from the Australian clinical experience.

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.

Risk factors and consequences of self-discontinuation of treatment by patients with newly diagnosed epilepsy.

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 3.0 years (interquartile range [IQR]: 1.2-6.0). Seventy eight (16.0%) self-discontinued ASM therapy after a median treatment duration of 1.4 years (IQR: 0.4-2.9), and after a median duration of seizure freedom of 11.8 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] = 0.44, 95% confidence interval [CI]: 0.23-0.83), presentation with seizure clusters (HR = 0.32, 95% CI: 0.14-0.69) and presentation with tonic-clonic seizures (HR = 0.36, 95% CI: 0.19-0.70). Patients with shorter interval since the last seizure (HR = 0.76, 95% CI: 0.66-0.86) were more likely to self-discontinue treatment. Sleep deprivation prior to seizures before diagnosis (HR = 1.80, 95% CI: 1.05-3.09) and significant alcohol or illicit drug use (HR = 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.

Revisiting an ancient legend: influence of the lunar cycle on occurrence of first-ever unprovoked seizures.

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.

Starting a new anti-seizure medication in drug-resistant epilepsy: Add-on or substitute?

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.

Temporal patterns in the first unprovoked seizure.

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 14-97 yr, median 39 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 (p < 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, p < 0.001) and during sleep (IRR 0.29, p < 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, p = 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.

Short- and long-term outcomes of immediate and delayed treatment in epilepsy diagnosed after one or multiple seizures.

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 39 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 (n = 363; adjusted hazard ratio [aHR] = 2.38, 95% confidence interval [CI]: 1.79-3.14, p < 0.001) and after one seizure (n = 235; aHR = 1.41, 95% CI: 0.995-1.99, p = 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] = 4), and in those diagnosed after one seizure the rates were 60% and 51% (NNT = 8). Of 380 patients with eligible follow-up (median 4.3 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.

Efficacy and tolerability of adjuvant perampanel: an Australian multicenter real-world observational study in refractory focal and generalized epilepsy syndromes.

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 12 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 12 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.

Treatment initiation decisions in newly diagnosed epilepsy-A longitudinal cohort study.

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.

The other side of the leaf: Seizures associated with synthetic cannabinoid use.

There has recently been a marked rise in the medicinal use of cannabis for epilepsy and multiple other conditions. While seizures have been reported in association with synthetic cannabinoids, the clinical features and prognosis have not been studied. Thirty patients with a history of seizures occurring within 24 h of synthetic cannabinoid use were identified from a first seizure clinic database in Perth, Western Australia between 2011 and 2016. Eight had a prior history of seizures, three related to synthetic cannabinoid use, with an additional three patients having risk factors for seizures. The presenting event was a tonic-clonic seizure in 27 patients (90%). "Kronic" was the synthetic cannabinoid used by 16 patients. Absorption was via smoking in all cases, with seizures occurring within 30 min of inhalation in 14 patients (46%). Electroencephalography (EEG) showed epileptiform abnormalities in 11%, and neuroimaging revealed epileptogenic lesions in 12%. Nine of 24 patients with follow-up had subsequent seizures, occurring in the setting of further synthetic cannabinoid use in two patients. This seizure recurrence rate is similar to seizures provoked by other acute systemic insults. In conclusion, smoking of some synthetic cannabinoids is associated with seizures, and this may relate to an intrinsic proconvulsant effect.

Efficacy and tolerability of adjuvant lacosamide: The role of clinical characteristics and mechanisms of action of concomitant AEDs.

OBJECTIVE: The objective of this study was to analyze the effectiveness and long-term tolerability of adjuvant lacosamide (LCM) in a multicenter cohort. We aim to assess outcomes of LCM-containing antiepileptic drug (AED) combinations based upon 'mechanism of action' (MoA) and patient's clinical features. METHODS: Consecutive patients commenced on LCM, with focal epilepsy were identified from three Australian hospitals. The 12-month efficacy endpoints were greater than 50% reduction in seizure frequency (responders) and seizure freedom. Tolerability endpoints were cessation of LCM for any reason, cessation due to side-effects and censoring due to inefficacy. Outcomes were assessed according to concomitant AEDs according to their MoA and the clinical risk factor profile. RESULTS: Three hundred ten patients were analyzed and followed for median 17.3months. Two hundred ninety-nine (97%) had drug-resistant epilepsy, and 155 (50%) had tried more than 7 AEDs at LCM commencement. Adjuvant LCM was associated with responder and seizure freedom rate of 29% and 9% respectively at 12months. Lower baseline seizure frequency, a prior 6-month period of seizure freedom at any time since epilepsy diagnosis and being on fewer concomitant AEDs were predictive of 12-month seizure freedom. Previous focal to bilateral tonic-clonic seizures (FBTCS), lower baseline seizure frequency, and concomitant AED reduction after LCM commencement were associated with improved LCM tolerability. No specific MoA AED combinations offered any efficacy or tolerability advantage. SIGNIFICANCE: Adjuvant LCM is associated with seizure freedom rates of 9% at 12months after commencement and is predicted by lower prior seizure frequency, a period of 6months or longer of seizure freedom since diagnosis and fewer concomitant AEDs. While the broad MoA of concomitant AEDs did not influence efficacy or tolerability outcomes, we have provided a framework that may be utilized in future studies to help identify optimal synergistic AED combinations.

Is the first seizure epilepsy--and when?

OBJECTIVE: Epilepsy has recently been redefined to include a single unprovoked seizure if the probability of recurrence is ≥60% over the following 10 years. This definition is based on the estimated risk of a third seizure after two unprovoked seizures, using the lower-limit 95% confidence interval (CI) at 4 years, and does not account for the initially high recurrence rate after first-ever seizure that rapidly falls with increasing duration of seizure freedom. We analyzed long-term outcomes after the first-ever seizure, and the influence of duration of seizure freedom on the likelihood of seizure recurrence, and their relevance to the new definition of epilepsy. METHODS: Prospective analysis of 798 adults with a first-ever unprovoked seizure seen at a hospital-based first seizure clinic between 2000 and 2011. The likelihood of seizure recurrence was analyzed according to the duration of seizure freedom, etiology, electroencephalography (EEG), and neuroimaging findings. RESULTS: The likelihood of seizure recurrence at 10 years was ≥60% in patients with epileptiform abnormalities on EEG or neuroimaging abnormalities, therefore, meeting the new definition of epilepsy. However, the risk of recurrence was highly time dependent; after a brief period (≤12 weeks) of seizure freedom, no patient group continued to fulfill the new definition of epilepsy. Of 407 patients who had a second seizure, the likelihood of a third seizure at 4 years was 68% (95% CI 63-73%) and at 10 years was 85% (95% CI 79-91%). SIGNIFICANCE: The duration of seizure freedom following first-ever seizure substantially influences the risk of recurrence, with none of our patients fulfilling the new definition of epilepsy after a short period of seizure freedom. When a threshold was applied based on the 10-year risk of a third seizure from our data, no first-seizure patient group ever had epilepsy. These data may be utilized in a definition of epilepsy after a first-ever seizure.

Are seizures in the setting of sleep deprivation provoked?

It is generally accepted that sleep deprivation contributes to seizures. However, it is unclear whether a seizure occurring in the setting of sleep deprivation should be considered as provoked or not and whether this is influenced by seizure type and etiology. This information may have an important impact on epilepsy diagnosis and management. We prospectively analyzed the influence of sleep deprivation on the risk of seizure recurrence in patients with first-ever unprovoked seizures and compared the findings with patients with first-ever provoked seizures. Of 1026 patients with first-ever unprovoked seizures, 204 (20%) were associated with sleep deprivation. While the overall likelihood of seizure recurrence was slightly lower in sleep-deprived patients with first-ever seizures (log-rank p=0.03), sleep deprivation was not an independent predictor of seizure recurrence on multivariate analysis. Seizure recurrence following a first-ever unprovoked seizure associated with sleep deprivation was far more likely than for 174 patients with a provoked first-ever seizure (log-rank p<0.0001). Our findings support the International League Against Epilepsy recommendation that seizures occurring in the setting of sleep deprivation should not be regarded as provoked.