Monthly Seizure Frequency Research Articles

Clinical factors associated with work disability in epilepsy: A cross-sectional study at a tertiary referral hospital

ObjectiveThe impact of epilepsy on work disability remains unclear. The aim of this study was to determine the percentage of patients with epilepsy who are unemployed or on temporary or permanent disability leave and to analyze associated clinical factors. MethodsWe performed an observational cross-sectional study of consecutively recruited patients with epilepsy seen at a specialized epilepsy unit or admitted to the epilepsy monitoring unit of a tertiary referral hospital. We analyzed the percentage of patients who were actively employed, unemployed, and on temporary or permanent disability leave. The groups were compared for sociodemographic data (age, sex, marital status, and type of work), clinical data (type of epilepsy, disease duration, monthly seizure frequency, and presence of anxiety or depression), treatment-related factors, and quality of life. ResultsWe included 742 patients (53% male, mean age 44.3 ± 13.7 years old): 40.5% were employed, 29.2% were unemployed, 19% were on temporary disability leave, and 11.1% had a permanent work disability. Depressive symptoms and poorer quality of life were associated with unemployment (OR 2.3, p = 0.02 and OR 1.8, p = 0.01), temporary disability leave (OR 1.4, p = 0.05 and OR 1.7, p = 0.02), and permanent work disability (OR 1.9, p = 0.01 and OR 2.2, p = 0.01). Low-skilled work was also predictive of unemployment (OR 1.9, p = 0.04), temporary disability leave (OR 2.8, p = 0.03), and permanent work disability (OR 1.7, p = 0.04). A higher monthly seizure frequency was associated with permanent work disability (OR 2.01, p = 0.02). ConclusionLess than 50% of patients with epilepsy in our setting are working. Factors associated with unemployment and work disability are a higher frequency of seizures, low-skilled work, depressive symptoms, and poor quality of life.

Safety and Tolerability of Transdermal Cannabidiol Gel in Children With Developmental and Epileptic Encephalopathies

Developmental and epileptic encephalopathies (DEEs) are the most severe group of drug-resistant epilepsies. Alternatives to oral therapies are urgently needed to reduce seizures and improve developmental outcomes and comorbidities in this medically complex population. To assess the safety and tolerability of cannabidiol (CBD) transdermal gel in children with DEEs and to evaluate seizure frequency, sleep, and quality of life. This nonrandomized controlled trial was conducted in 2 centers in Australia and New Zealand from April 2018 to July 2019. Children and adolescents aged 3 to 18 years with DEEs who were receiving a stable regimen of 1 to 4 antiseizure medications were eligible for this study. After 1-month baseline and titration periods, patients entered a 5.5-month flexible-dosing maintenance period for a total of 6.5 months of treatment. Data were analyzed throughout the 6.5-month treatment period. Twice-daily applications of CBD transdermal gel at doses of 125 to 500 mg for 6.5 months. Safety and tolerability assessments included adverse events (AEs) and examination of skin. The outcome for seizures was the median percentage change from baseline in monthly (28-day) seizure frequency of focal impaired awareness seizures (FIAS) and tonic-clonic seizures (TCS) over 6.5 months. Of 48 patients (mean [SD] age, 10.5 [3.8] years; 26 [54%] boys), 29 (60%) had at least 1 treatment-related AE over 6.5 months; 44 of 46 treatment-related AEs (96%) were mild or moderate. Treatment-related AEs that occurred in at least 5% of patients were application-site dryness, application-site pain, and somnolence (each reported by 4 patients [8%]). The only treatment-related gastrointestinal AE was diarrhea, reported in a single patient. CBD treatment was associated with reductions in FIAS and TCS frequency. Analysis of the 33 patients with FIAS and TCS showed a median (interquartile range) monthly reduction in seizures of 58% (-5.3% to 81.8%) at 5 months and 43.5% (-23.8% to 57.5%) over the entire 6.5-month study period. Parents and caregivers noted improvements in social or interpersonal engagement and irritability (33 of 43 [77%] participants); alertness, energy, and sleep (23 of 43 [53%]); and cognition or concentration (20 of 43 [47%]). In this study, CBD transdermal gel was safe, well tolerated, and was associated with reductions in FIAS and TCS frequency and disease burden. ClinicalTrials.gov Identifier: ACTRN12618000516280.

Add-on cannabidiol in patients with Dravet syndrome: Results of a long-term open-label extension trial.

Add-on cannabidiol (CBD) reduced seizures associated with Dravet syndrome (DS) in two randomized, double-blind, placebo-controlled trials: GWPCARE1Part B (NCT02091375) and GWPCARE2 (NCT02224703). Patients who completed GWPCARE1Part A (NCT02091206) or Part B, or GWPCARE2, were enrolled in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5. Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100mg/ml), titrated from 2.5 to 20mg/kg/day over a 2-week period, added to their existing medications. Based on response and tolerance, CBD could be reduced or increased to 30mg/kg/day. Of the 330 patients who completed the original randomized trials, 315 (95%) enrolled in this open-label extension. Median treatment duration was 444days (range = 18-1535), with a mean modal dose of 22mg/kg/day; patients received a median of threeconcomitant antiseizure medications. Adverse events (AEs) occurred in 97% patients (mild, 23%; moderate, 50%; severe, 25%). Commonly reported AEs were diarrhea (43%), pyrexia (39%), decreased appetite (31%), and somnolence (28%). Twenty-eight (9%) patients discontinued due to AEs. Sixty-nine (22%) patients had liver transaminase elevations >3× upper limit of normal; 84% were on concomitant valproic acid. In patients from GWPCARE1Part B and GWPCARE2, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to Week 156 was 45%-74% for convulsive seizures and 49%-84% for total seizures. Across all visit windows, ≥83% patients/caregivers completing a Subject/Caregiver Global Impression of Change scale reported improvement in overall condition. We show that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS.

Preoperative Heart Rate Variability During Sleep Predicts Vagus Nerve Stimulation Outcome Better in Patients With Drug-Resistant Epilepsy.

Objective: Vagus nerve stimulation (VNS) is an adjunctive and well-established treatment for patients with drug-resistant epilepsy (DRE). However, it is still difficult to identify patients who may benefit from VNS surgery. Our study aims to propose a VNS outcome prediction model based on machine learning with multidimensional preoperative heart rate variability (HRV) indices.Methods: The preoperative electrocardiography (ECG) of 59 patients with DRE and of 50 healthy controls were analyzed. Responders were defined as having at least 50% average monthly seizure frequency reduction at 1-year follow-up. Time domain, frequency domain, and non-linear indices of HRV were compared between 30 responders and 29 non-responders in awake and sleep states, respectively. For feature selection, univariate filter and recursive feature elimination (RFE) algorithms were performed to assess the importance of different HRV indices to VNS outcome prediction and improve the classification performance. Random forest (RF) was used to train the classifier, and leave-one-out (LOO) cross-validation was performed to evaluate the prediction model.Results: Among 52 HRV indices, 49 showed significant differences between DRE patients and healthy controls. In sleep state, 35 HRV indices of responders were significantly higher than those of non-responders, while 16 of them showed the same differences in awake state. Low-frequency power (LF) ranked first in the importance ranking results by univariate filter and RFE methods, respectively. With HRV indices in sleep state, our model achieved 74.6% accuracy, 80% precision, 70.6% recall, and 75% F1 for VNS outcome prediction, which was better than the optimal performance in awake state (65.3% accuracy, 66.4% precision, 70.5% recall, and 68.4% F1).Significance: With the ECG during sleep state and machine learning techniques, the statistical model based on preoperative HRV could achieve a better performance of VNS outcome prediction and, therefore, help patients who are not suitable for VNS to avoid the high cost of surgery and possible risks of long-term stimulation.

Adjunctive Perampanel in Older Patients With Epilepsy: A Multicenter Study of Clinical Practice.

BackgroundClinical data regarding use of newer antiseizure medications (ASMs) in an older population are limited. In randomized-controlled, placebo-controlled trials, older patients are under-represented, and protocols deviate markedly from routine clinical practice, limiting the external validity of results. Studies performed in a naturalistic setting are a useful complement to characterize the drug profile. Perampanel is a third-generation ASM and the first and only non-competitive alfa-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor antagonist.ObjectiveThe aim of this study was to assess the effectiveness and tolerability of adjunctive perampanel over a 1‐year period in a population of older patients with epilepsy treated in a real-world setting.MethodsOlder (≥ 65 years of age) patients prescribed add-on perampanel at 12 Italian epilepsy centers were retrospectively identified. Seizure occurrence, adverse events (AEs), and drug withdrawal were analyzed. Effectiveness outcomes included the rates of seizure response (≥ 50% reduction in baseline monthly seizure frequency), seizure freedom, and treatment discontinuation. Safety and tolerability outcomes were the rate of treatment discontinuation due to AEs and the incidence of AEs.ResultsA total of 92 patients with a median age of 69 (range 65–88) years were included. The median daily dose of perampanel at 12 months was 6 mg (interquartile range 4–6 mg). At 12 months, 53 (57.6%) patients were seizure responders, and 22 (23.9%) patients were seizure free. Twenty (21.7%) patients discontinued perampanel; the reasons for treatment withdrawal were insufficient efficacy (n = 6/20; 30.0%), AEs (n = 12/20; 60.0%), and a combination of both (n = 2/20; 10%). The most common AEs included irritability (8.7%), somnolence (4.3%), and dizziness/vertigo (4.3%). The rate of behavioral and psychiatric AEs was higher in patients with history of psychiatric comorbidities (p = 0.044). There were no differences in the occurrence of behavioral and psychiatric AEs according to the concomitant use of levetiracetam (p = 0.776) and history of cognitive decline (p = 0.332).ConclusionsAdjunctive perampanel was associated with improvement in seizure control and good tolerability in a real-life setting and can represent a viable therapeutic option in older patients with epilepsy.

Differential risks of changes in seizure frequency with transitions between hormonal and non-hormonal contraception in women with epilepsy: A prospective cohort study

This prospective, observational, cohort study of 101 women with epilepsy (WWE) assesses the seizure safety of systemic hormonal contraception (HC) versus non-HC (NHC). It reports risks of changes in seizure frequency associated with transition from NHC to HC relative to HC to NHC for (1) proportions of WWE with ≥50% increase and decrease in seizure frequency, (2) changes in seizure frequency, (3) changes in seizure severity, and 4) changes in AED regimen during the study. In comparing NHC to HC versus HC to NHC, NHC to HC had greater risk of ≥50% increase in seizure frequency: RR = 1.98 (1.07–3.64), p = 0.03 and lower risk of ≥50% decrease in seizure frequency: RR = 0.42 (0.22 = 0.83), p = 0.01. These risks were particularly notable for oral contraceptive pill: RR = 2.91 (1.26–6.72), p = 0.01 and RR = 0.54 (0.30–0.97), p = 0.04, respectively. Median monthly seizure frequency (MMSF) increased 302.0% (p = 0.0019) with transition from NHC to HC. MMSF decreased 81.9% with change from HC to NHC (p = 0.001). RR for change in seizure type from milder to more severe type was greater for NHC to HC: RR = 3.32 (1.07–10.27), p = 0.04. Change in AED regimen was not a significant factor. The findings suggest further prospective study to assess whether HC, especially oral contraceptive pill, poses a greater risk of increased seizures than NHC.

Deep Brain Stimulation for Refractory Focal Epilepsy: Unraveling the Insertional Effect up to Five Months Without Stimulation

IntroductionFollowing electrode implantation, a subgroup of patients treated with deep brain stimulation (DBS) for focal epilepsy exhibits a reduction of seizure frequency before stimulation is initiated. Microlesioning of the target structure has been postulated to be the cause of this “insertional” effect (IE). We examined the occurrence and duration of this IE in a group of patients with focal epilepsy following electrode implantation in the anterior nuclei of the thalamus (ANT) and/or nucleus accumbens (NAC) for DBS treatment. Materials and MethodsChanges in monthly seizure frequency compared to preoperative baseline were assessed one month (14 patients) and five months (four patients) after electrode implantation. A group analysis between patients with implantation of bilateral ANT-electrodes (four patients), NAC-electrodes (one patient) as well as ANT and NAC-electrodes (nine patients) was performed. ResultsIn this cohort, seizure frequency decreased one month after electrode implantation by 57.1 ± 30.1%, p ≤ 0.001 (compared to baseline). No significant difference within stimulation target subcohorts was found (p > 0.05). Out of the four patients without stimulation for five months following electrode insertion, three patients showed seizure frequency reduction lasting two to three months, while blinded to their stimulation status. ConclusionAn IE might explain seizure frequency reduction in our cohort. This effect seems to be independent of the number of implanted electrodes and of the target itself. The time course of the blinded subgroup of epilepsy patients suggests a peak of the lesional effect at two to three months after electrode insertion.

Quantifying the burden of disease in patients with Lennox Gastaut syndrome.

Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy but there is limited literature characterizing the disease burden despite this being crucial for disease management strategies, and for designing and interpreting clinical trials. We searched the Vagus Nerve Stimulation (VNS) Therapy Patient Outcome Registry including over 7000 patients with drug‑resistant epilepsy (DRE). Propensity Score Matching (PSM) matched LGS-DRE patients and non-LGS-DRE patients and frequencies of individual seizure types were assessed. The PSM population included 705 and 1410 DRE patients with and without LGS. 40% of the LGS-DRE group had polypharmacy with 3 antiseizure medications (ASM) while 42% in non-LGS-DRE had polypharmacy with 2 ASMs. Median total monthly seizure frequency was over double in the LGS group: 90 (IQR, 28-312) versus 40 (IQR, 10-150); p<0.001. This analysis suggests that seizure frequency in LGS patients who later receive VNS is more than double than in non-LGS DRE patients with mostly bilateral tonic-clonic seizures contributing to this difference. Furthermore, ASM burden with poorer seizure control may be greater in LGS patients, however data collection ceased in 2003 and therefore does not take recent ASMs approved for LGS into account. This analysis offers quantitative insight into the burden of disease in patients with LGS.

Brivaracetam as add-on treatment in focal epilepsy: A real-world time-based analysis.

The study assessed the clinical response to add-on brivaracetam (BRV) in real-world practice by means of time-to-baseline seizure count methodology. Patients with focal epilepsy who were prescribed add-on BRV were identified. Primary endpoint was the time-to-baseline seizure count defined as the number of days until each patient experienced the number of focal seizures that occurred in the 90days before BRV initiation. Subgroup analysis was performed according to levetiracetam (LEV) status (naive vs prior use). Three-hundred eighty-seven patients were included. The overall median time-to-baseline seizure count was 150 (95% confidence interval [CI] = 130-175) days. The median time-to-baseline seizure count was 198 (lower limit of 95% CI = 168) days for LEV-naive patients, 126 (95% CI = 105-150) days for patients with prior LEV use and withdrawal due to insufficient efficacy, and 170 (95% CI = 128-291) days for patients who discontinued LEV due to adverse events (P=.002). The number of prior antiseizure medications (adjusted hazard ratio [adj HR]=1.07, 95% CI = 1.02-1.13, P=.009) and baseline monthly seizure frequency (adj HR=1.004, 95% CI = 1.001-1.008, P=.028) were independently associated with the primary endpoint. Add-on BRV improved seizure control in LEV-naive and LEV-prior patients. The time-to-baseline seizure count represents an informative endpoint alongside traditional study outcomes and designs.

Adjunctive cenobamate for the treatment of focal onset seizures in adults with epilepsy: a critical review

ABSTRACT Introduction Uncontrolled epilepsy has persisted despite development of numerous antiseizure medications (ASMs) over the past 25 years, and more effective treatments are needed. Cenobamate is a new ASM approved in the US for treatment of adults with focal onset seizures. Areas covered This review outlines cenobamate study results from preclinical animal models through phase 2 and 3 clinical studies. Topics include mechanisms of action, pharmacokinetics, efficacy, and safety of cenobamate. Information on dosing, tolerability, and special populations are included to help healthcare providers understand this new ASM. Expert opinion Adjunctive cenobamate shows a high level of efficacy in patients with refractory focal epilepsy compared to that reported for other ASMs. Most notable are reductions in monthly seizure frequency (up to 55%) and unprecedented seizure-free rates (up to 28%) with cenobamate in patients with refractory epilepsy despite the concomitant use of 1-3 ASMs. Cenobamate was generally safe and well-tolerated, with a safety profile similar to other ASMs. Due to 3 early cases of DRESS, however, the cenobamate starting dose was lowered and titration rate slowed; no additional cases occurred. If efficacy responses in real-world use reflect what have been observed in clinical studies, cenobamate would be a welcome new treatment option.

Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy: A Canadian Experience.

To describe the experience with Anterior Nucleus of the Thalamus-Deep Brain Stimulation (ANT-DBS) for the treatment of epilepsy at a Canadian Center. All patients who underwent ANT-DBS implantation between 2013 (first patient implanted at our center) and 2020 were included. These patients had therapy-resistant epilepsy (TRE), were not candidates for resective surgery, and failed vagus nerve stimulation (VNS) treatment. Baseline of monthly seizure frequency was calculated within 3 months prior to VNS placement. Monthly seizure frequency was assessed at different points along the timeline: 3 months before ANT-DBS implantation as well as 3, 6, 12, 24, 36, 48, 60, and 72 months after ANT-DBS device placement. At each time point, seizure frequency was compared to baseline. Six patients were implanted with ANT-DBS. Three (50%) patients had multifocal epilepsy, one (16.6%) had focal epilepsy, and two (33.4%) had combined generalized and focal epilepsy. Two patients with multifocal epilepsy experienced a seizure reduction >50% in the long-term follow-up. Three (50%) patients did not showed improvement: two with combined generalized and focal epilepsy and one with focal epilepsy. There were not surgical or device-related side effects. Two (33.3%) patients presented mild and transient headaches as a stimulation-related side effect. ANT-DBS is an effective and safe treatment for focal TRE. Our experience suggests that patients with multifocal epilepsy due to regional lesion may benefit from ANT-DBS the most. Further investigations are required to determine optimal parameters of stimulation.

Repetitive transcranial magnetic stimulation in drug-resistant idiopathic epilepsy of dogs: A noninvasive neurostimulation technique.

BackgroundAlthough repetitive transcranial magnetic stimulation (rTMS) has been assessed in epileptic humans, clinical trials in epileptic dogs can provide additional insight.ObjectivesEvaluate the potential antiepileptic effect of rTMS in dogs.AnimalsTwelve client‐owned dogs with drug‐resistant idiopathic epilepsy (IE).MethodsSingle‐blinded randomized sham‐controlled clinical trial (dogs allocated to active or sham rTMS) (I) and open‐labeled uncontrolled clinical trial (dogs received active rTMS after sham rTMS) (II). Monthly seizure frequency (MSF), monthly seizure day frequency (MSDF), and number of cluster seizures (CS) were evaluated for a 3‐month pre‐TMS and post‐rTMS period and safety was assessed. The lasting effect period of rTMS was assessed in each dog treated by active stimulation using the MSF ratio (proportion of post‐TMS to pre‐rTMS MSF) and treatment was considered effective if the ratio was <1.ResultsNo adverse effects were reported. In trial I, MSF and MSDF decreased significantly (P = .04) in the active group (n = 7). In the sham group (n = 5), no significant changes were found (P = .84 and .29, respectively). Cluster seizures did not change significantly in either group. No significant differences were detected between the groups. In trial II, previously sham‐treated dogs (n = 5) received active rTMS and significant decreases in MSF and MSDF were noted (P = .03 and .008, respectively). The overall effect of rTMS lasted for 4 months; thereafter, the MSF ratio was >1.Conclusions and Clinical ImportanceRepetitive transcranial magnetic stimulation may be a safe adjunctive treatment option for dogs with drug‐resistant IE, but large‐scale studies are needed to establish firm conclusions.

Cannabidiol-enriched oil in children and adults with treatment-resistant epilepsy-does tolerance exist?

AimTo evaluate the long-term effectiveness of cannabidiol (CBD)-enriched oil for the treatment of refractory epilepsy and to assess the development of tolerance to its anti-seizure effect. MethodsA prospective study of 92 consecutive patients (age 1–37 years, mean-11.8 years) with treatment resistant epilepsy who were treated with cannabis oil extract (CBD/tetrahydrocannabinol [THC] ratio of 20:1). Mean monthly seizure frequency was reported by the patients/their parents during monthly clinic visits. Tolerance was defined as either the need to increase the dose by ≥30% due to reduced treatment efficacy or as an increase of ≥30% in mean monthly seizure frequency in patients treated for at least 3 months with no change in other anti-seizure medications. ResultsMean follow-up time was 19.8 ± 12.5 months (range 3–45). Mean CBD dose was 11.3 (4–38) mg/kg/day. Twenty-nine (31%) patients discontinued treatment due to lack of effect or adverse reactions, which were reported in 51% (47/87) of the patients. Overall responder rate (>50% seizures reduction) was 54%, whereas 8 patients (9%) became seizure-free. Eighty-four patients were included in the tolerance analysis. Tolerance was observed in 21 (25%) patients after a mean duration of 7.3 ± 5.4 months of CBD-enriched oil treatment. There was a negative correlation between epilepsy duration and tolerance development (p = 0.038). ConclusionsWe report for the first time the plausible appearance of tolerance to cannabidiol-enriched oil. This may limit treatment efficacy in the long-term clinical management of refractory epilepsy in both pediatric and adult population. Further studies are needed to investigate potential mechanisms.

Efficacy of medium chain triglyceride oil dietary supplementation in reducing seizure frequency in dogs with idiopathic epilepsy without cluster seizures: a non-blinded, prospective clinical trial

BackgroundDespite appropriate antiseizure drug (ASD) treatment, around two-thirds of dogs with idiopathic epilepsy (IE) have seizures long-term and 20–30per cent of affected dogs remain poorly controlled.MethodsThe current study aim is...

Effectiveness of cannabidiol in a prospective cohort of children with drug-resistant epileptic encephalopathy in Argentina

ObjectiveWe report our preliminary findings regarding effectiveness, safety, and tolerability of cannabidiol (CBD) added to antiepileptic therapy in a cohort of children with drug-resistant epileptic encephalopathies (EEs) with a mean follow-up of 8.5 months (range, 3–12 months). MethodsA prospective cohort study was designed with the aim of assessing the effectiveness, safety, and tolerability of the addition of CBD to standard antiseizure medications (ASMs) in children with drug-resistant EE enrolled at a single center (Neurology Department, Hospital de Pediatría "Juan P. Garrahan", Buenos Aires, Argentina). ResultsFifty patients were enrolled between October 2018 and October 2019, 49 of whom had a follow-up of at least 3 months at the time this interim analysis was performed. Mean age at enrollment was 10.5 years (range 2–16). Median age at first seizure was 7 months. Up to the last visit of each patient (follow-up 3–12 months) 39/49 children (80 %) had responded to treatment with a decrease in seizure frequency. Overall, 77.6 % of the patients had a seizure reduction of at least 25 %, 73.5 % had a ≥ 50 % reduction, and 49 % had a ≥ 75 % reduction. Mean monthly seizure frequency was reduced from 959 to 381 (median decrease from 299 to 102, range, 38–1900; median decrease 66 %, p < 0.001). All adverse effects were mild or moderate. The most common adverse effect was drowsiness (in 32 %), usually reversed by adjusting clobazam dose (in 12 children). ConclusionIn children with drug-resistant EEs, CBD oil as an adjuvant therapy to antiepileptic therapy seems safe, well tolerated, and effective.

&lt;p&gt;Cannabinoids in the Treatment of Epilepsy: Current Status and Future Prospects&lt;/p&gt;

Cannabidiol (CBD) is one of the prominent phytocannabinoids found in Cannabis sativa, differentiating from Δ9-tetrahydrocannabinol (THC) for its non-intoxicating profile and its antianxiety/antipsychotic effects. CBD is a multi-target drug whose anti-convulsant properties are supposed to be independent of endocannabinoid receptor CB1 and might be related to several underlying mechanisms, such as antagonism on the orphan GPR55 receptor, regulation of adenosine tone, activation of 5HT1A receptors and modulation of calcium intracellular levels. CBD is a lipophilic compound with low oral bioavailability (6%) due to poor intestinal absorption and high first-pass metabolism. Its exposure parameters are greatly influenced by feeding status (ie, high fat-containing meals). It is mainly metabolized by cytochrome P 450 (CYP) 3A4 and 2C19, which it strongly inhibits. A proprietary formulation of highly purified, plant-derived CBD has been recently licensed as an adjunctive treatment for Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS), while it is being currently investigated in tuberous sclerosis complex. The regulatory agencies’ approval was granted based on four pivotal double-blind, placebo-controlled, randomized clinical trials (RCTs) on overall 154 DS patients and 396 LGS ones, receiving CBD 10 or 20 mg/kg/day BID as active treatment. The primary endpoint (reduction in monthly seizure frequency) was met by both CBD doses. Most patients reported adverse events (AEs), generally from mild to moderate and transient, which mainly consisted of somnolence, sedation, decreased appetite, diarrhea and elevation in aminotransferase levels, the last being documented only in subjects on concomitant valproate therapy. The interaction between CBD and clobazam, likely due to CYP2C19 inhibition, might contribute to some AEs, especially somnolence, but also to CBD clinical effectiveness. Cannabidivarin (CBDV), the propyl analogue of CBD, showed anti-convulsant properties in pre-clinical studies, but a plant-derived, purified proprietary formulation of CBDV recently failed the Phase II RCT in patients with uncontrolled focal seizures.

Ending the pain of children with severe epilepsy? An audit of the impact of medical cannabis in 10 patients

Background Scientific and anecdotal evidence suggest that whole plant cannabis extracts are effective in reducing seizure frequency in individuals with a range of epileptic etiologies. We report a case series of 10 individuals using CBMPs in the UK to treat their conditions. Methods In this retrospective study, we report on patients (aged 2-48) with severe, intractable, childhood onset epilepsies using combined cannabinoid therapy. Carers of patients provided details through the charity ‘End our Pain’ and these data were subsequently analysed. Our primary objective was to assess changes in monthly seizure frequency pre and post initiation of CBMPs. We also report on previous and current AED, CBD:THC daily dose, quality of life and financial costs associated with CBMP private prescription. Change in monthly seizure frequency were assessed using a Wilcoxon Signed-ranks test. Results Of the 10 patients enrolled in the study there was an 97% mean reduction in monthly seizure frequency post initiation of CBMPs which was statistically significant (Z = 0, p &lt; 0·01). We showed a reduction in AED use following initiation of CBMPs from a mean of 8 (±5·98) to 1 (±1·05). All patients were using either Bedrolite or Bedica (Bedrocan International) as their CBMP. Individual daily doses of THC ranged from 6·6mg – 26·5mg and for CBD, 200 mg – 550 mg. Average monthly cost of CBMP was £1816·20. Interpretation Our findings suggest a combination of CBD and THC based products are effective in reducing seizure frequency in a range of epileptic conditions. We highlight the inefficacy of the healthcare system in supporting these patients who bare great personal and financial burdens. We encourage specialist physicians and relevant bodies to permit greater ease of access of these medications to those patients where efficacy has been shown.

The safety, tolerability, and effectiveness of PTL-101, an oral cannabidiol formulation, in pediatric intractable epilepsy: A phase II, open-label, single-center study

IntroductionSeveral works have reported on the antiepileptic impact of cannabis-based preparations in patients with treatment-resistant epilepsy (TRE). However, current formulations suffer from low bioavailability and side effects. PTL-101, an oral formulation containing highly purified cannabidiol (CBD) embedded in seamless gelatin matrix beadlets was designed to enhance bioavailability and maintain a constant gastrointestinal transit time. MethodsThis phase II, prospective study was open to pediatric patients with TRE on stable antiepileptic drugs' (AEDs) doses, who experienced ≥4 seizures within four weeks of enrolment and with a history of ≥4 AEDs failing to provide seizure control. Following a 4-week observation period, patients began a 2-week dose-titration phase (up to ≤25mg/kg or 450mg, the lower of the two), followed by a 10-week maintenance treatment period. Caregivers recorded seizure frequency, type, and severity and ranked their global impressions after 7 and 12weeks of treatment. Responders were those showing a ≥50% reduction from baseline monthly seizure frequency. Safety assessments monitored vital signs, adverse effects, physical and neurological exams, and laboratory tests. ResultsSixteen patients (age: 9.1±3.4) enrolled in the study; 11 completed the full treatment program. The average maintenance dose was 13.6±4.2mg/kg. Patient adherence to treatment regimens was 96.3±9.9%. By the end of the treatment period, 81.9% and 73.4±24.6% (p<0.05) reductions from baseline median seizure count and monthly seizure frequency, respectively, were recorded. Responders' rate was 56%; two patients became fully seizure-free. By study end, 8 (73%) caregivers reported an improved/very much improved condition, and 9 (82%) reported reduced/very much reduced seizure severity. Most commonly reported treatment-related adverse effects were sleep disturbance/insomnia, (4 (25.0%) patients), followed by somnolence, increased seizure frequency, and restlessness (3 patients each (18.8%)). None were serious or severe, and all resolved. ConclusionsPTL-101 was safe and tolerable for use and demonstrated a potent seizure-reducing effect among pediatric patients with TRE.

Long-term efficacy and safety of lacosamide and levetiracetam monotherapy in elderly patients with focal epilepsy: A retrospective study

ObjectivesEpilepsy management in elderly patients is often complex because of several concomitant comorbidities that may limit the use of some antiepileptic drugs (AEDs). Levetiracetam (LEV) is a second-generation AED widely used in elderly patients with epilepsy while lacosamide (LCM), which has been recently approved in European Union (EU) as monotherapy for the treatment of focal onset seizures, is affected by a scarcity of data in such frail population. This study is aimed at assessing the efficacy and the tolerability of LCM as monotherapy in elderly patients affected by focal onset epilepsy compared with those receiving LEV. MethodsA retrospective chart review of patients aged ≥65 years suffering from focal onset seizures, with or without secondary generalization on LCM monotherapy or LEV monotherapy, was performed. Data regarding demographic characteristics, seizure type and etiology, LCM and LEV daily dose, number of lifetime AEDs, seizure frequency at baseline and at 12 months of follow-up, and seizure freedom rates were reported. ResultsIn this observational retrospective study, 22 patients on LCM (10 males, 12 females, mean age: 76.23 ± 7.5) and 24 patients on LEV (10 males, 14 females, mean age: 73.58 ± 6.39) were enrolled. Mean LCM daily dose was 204.51 ± 88.51 mg and mean LEV daily dose was 1281.25 ± 378.15 mg. All patients had comorbidities on chronic treatment. At 12 months of follow-up, mean monthly seizure frequency reduced from 4.23 ± 8.53 to 0.33 ± 0.9 (p < .001) in LCM group and from 2.29 ± 6.11 to 0.2 ± 0.81 (p < .001) in LEV group. Furthermore, 16/22 (72.7%) LCM patients were seizure-free at 12 months of follow-up while seizure freedom was achieved by 17/24 (70.8%) patients in LEV group. Discussion and conclusionEpilepsy management in elderly patients is often challenging. In this retrospective real-life study, the efficacy and the tolerability of LCM as monotherapy was favorable even at low doses in older patients and comparable with LEV with a high rate of long-term seizure freedom. Considering the frequent comorbidities and the risk of drug–drug interactions, LCM monotherapy may be a valuable option in elderly patients with focal onset epilepsy because of its favorable pharmacokinetic profile.

External trigeminal nerve stimulation: A long term follow up study

PurposeExternal trigeminal nerve stimulation is an emerging noninvasive therapy for drug resistant epilepsy (DRE). The aim of this study is to describe the long-term outcome of a series of patients treated with eTNS. MethodsWe present a retrospective observational study of patients with DRE who received eTNS treatment, comparing the monthly seizure frequency during the 3-months period before eTNS initiation with the monthly seizure frequency at 6, 12, 24, 36 and 48 months after eTNS. We analyze the responder rate, the retention rate and the tolerability. Results17 patients with highly drug-resistant epilepsy were included. Mean follow-up was 2194 [6–56] months. The responder rate was 35% at 6 months and 12 months, 23% at 24 months, 19% at 36 months, and 14% at 48 months. Retention rates at the same periods were 88%, 53%, 41%, 37.5% and 28.5%. There were no reports of serious adverse events. Four patients reported improvement in sleep and better mood. ConclusionThe effectivity of eTNS is similar to some of the new treatments available, with a retention rate of 52% in the first year and 285% at 4 years. Tolerability is excellent with only mild effects reported by a minority of patients.