Phase IV PROVE study: Perampanel in real-world clinical care of pediatric patients with epilepsy.

INTRODUCTION: The non-interventional Phase IV PROVE study (NCT03208660) assessed retention, efficacy, safety and tolerability, and perampanel dosing in patients with epilepsy during routine clinical care. This analysis evaluated final data from patients aged <4 years and 4-<12 years. METHODS: Data were obtained retrospectively from medical/pharmacy records of patients in the United States initiating perampanel after January 1, 2014, according to treating clinician recommendations. Retention rate was the primary endpoint. Secondary assessments included median percent changes in seizure frequency, seizure-freedom rates, investigator impression of seizure effect, and safety and tolerability. RESULTS: The Safety Analysis Set (SAS) included 41 patients (<4 years; mean maximum dose, 3.5 mg/day) and 203 patients (4-<12 years; mean maximum dose, 5.3 mg/day); 24-month retention rates were 35.7% (n = 5/14) and 42.0% (n = 47/112), respectively. In the Full Analysis Set, during Months 1-3, median percent reductions in seizure frequency were 33.3% (n = 8 [<4 years]) and 26.0% (n = 32 [4-<12 years]), and seizure-freedom rates were 12.5% in both groups (n = 1/8 and n = 4/32); patient numbers were low at later time points. Most patients showed improvements in seizure control (45.9% [<4 years] versus 52.4% [4-<12 years]) or no change (45.9% versus 34.5%) (SAS). Treatment-emergent adverse events (TEAEs) were reported in 12 (<4 years: 29.3%; most common, irritability [7.3%]) and 64 patients (4-<12 years: 31.5%; most common, aggression [6.9%]). CONCLUSIONS: Perampanel was generally well tolerated with <21% of TEAEs leading to withdrawal at 24 months, had favorable retention rates (≥50% and >35% at 12 and 24 months, respectively), and sustained efficacy in pediatric patients during routine clinical care.

Severe communication delays are independent of seizure burden and persist despite contemporary treatments in SCN1A+ Dravet syndrome: Insights from the ENVISION natural history study.

OBJECTIVE: Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment-resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. METHODS: ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent-reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6-2:0 years:months (Y:M; youngest), 2:1-3:6 Y:M (middle), and 3:7-5:0 Y:M (oldest). RESULTS: Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow-up was 17.5 months (range = .0-24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum-maximum] = 1.0 in the youngest [1.0-70.0] and middle [1.0-242.0] age groups and 4.5 [.0-2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size = .52, p = .024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. SIGNIFICANCE: In infants and young children with SCN1A+ DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age.

Prostate Adenocarcinoma Metastasis to the Rectal Submucosa and Mesorectal Lymph Node on 18 F-PSMA PET/CT.

ABSTRACT: We report a case of biopsy-proven prostate cancer metastasis to the rectum and presumed metastasis to a mesorectal lymph node, identified as radiotracer-avid lesions on prostate-specific membrane antigen PET/CT during workup for biochemically recurrent prostate cancer. This case adds to a growing number of atypical sites of metastatic prostate cancer being reported since the approval of prostate-specific membrane antigen PET/CT for staging of prostate cancer.

Effectiveness, safety and tolerability of perampanel by age group when used to treat people with focal and generalized epilepsy in clinical practice: The PERMIT Extension study.

OBJECTIVE: To assess the effectiveness and safety/tolerability of perampanel (PER) in people with epilepsy (PWE) treated in everyday clinical practice for focal and generalized seizures, both in the total cohort and by age group. METHODS: The PERMIT Extension study was a pooled analysis of data from PWE included in two large previous clinical practice studies (PERMIT and PROVE). Retention was assessed over 12 months. Effectiveness was assessed based on total seizures and by seizure type (focal and generalized) after 3, 6, and 12 months of PER treatment and at final follow-up (last observation carried forward; "last visit"); assessments included responder rate (≥50% seizure frequency reduction from baseline) and seizure freedom rate (no seizures since at least the previous visit). Safety/tolerability was assessed throughout PER treatment by evaluating adverse events (AEs). All assessments were conducted for the total population and by age category (<12, ≥12 to <18, ≥18 to <65, and ≥65 years at baseline). RESULTS: Full Analysis Set included 6,822 PWE (51.1% female; mean age, 36.9 years; mean duration of epilepsy 21.4 years) with 6,433, 4,648, and 6,233 PWE assessed for retention, effectiveness, and safety/tolerability, respectively. The majority of PWE (81.1%) were aged 18-64 at baseline, with 4.5% aged <12 years, 8.4% aged 12-17 years, and 5.9% aged ≥65 years. In the overall population, retention rates at 3, 6, and 12 months were 88.0%, 77.6%, and 61.4%, respectively; responder rates at 12 months were 58.5% for total seizures, 54.6% for focal seizures, and 77.7% for generalized seizures, and corresponding seizure freedom rates were 23.6%, 19.0%, and 51.3%, respectively. PER was effective regardless of age category, although effectiveness was greatest in PWE aged ≥65 years, for both focal and generalized seizures. In the overall population, the incidence of AEs was 49.2% and the most frequent AEs (≥5% of PWE) were dizziness/vertigo (13.4%), somnolence (8.8%), irritability (7.3%), and behavioral disorders (5.3%); AEs led to treatment discontinuation in 18.3% of PWE over 12 months. The incidence of AEs and the discontinuation rate due to AEs increased with increasing age (55.0% and 23.9%, respectively, in PWE aged ≥65 years). CONCLUSION: In this study, the largest pooled analysis of PER clinical practice data conducted to date, PER was shown to be effective and generally well tolerated when used to treat people with focal or generalized epilepsy in everyday clinical practice, regardless of age category. No new or unexpected side effects emerged following long-term use in the real-world setting.

Safety of Diazepam Nasal Spray in Pediatric Patients With Developmental Epileptic Encephalopathies: Results From a Long-term Phase 3 Safety Study.

Pediatric developmental epileptic encephalopathies are often refractory to treatment despite stable antiseizure therapy. The safety profile of diazepam nasal spray (Valtoco) as rescue therapy for seizure clusters was described in a long-term safety study. This post hoc analysis assessed safety and effectiveness within a subpopulation of patients with developmental epileptic encephalopathies. Of 163 treated patients, 64 were diagnosed with ≥1 pediatric developmental epileptic encephalopathy. Among the most common developmental epileptic encephalopathies were Rett syndrome (n = 16), Lennox-Gastaut syndrome (n = 9), and Dravet syndrome (n = 7). In the broad pediatric developmental epileptic encephalopathy group, 10.6% of seizure clusters were treated with a second dose, with similar proportions in the 3 individual encephalopathies. Across groups, treatment-emergent adverse event rates ranged from 66.7% to 100%. Only epistaxis (n = 2) was treatment-related and reported in >1 patient. In this long-term safety analysis in patients with developmental epileptic encephalopathies, diazepam nasal spray demonstrated a consistent safety profile, supporting its use in these hard-to-treat patients (ClinicalTrials.gov NCT02721069).

Efficacy of cannabidiol in convulsive and nonconvulsive seizure types associated with treatment-resistant epilepsies in the Expanded Access Program.

The cannabidiol (CBD) Expanded Access Program (EAP), initiated in 2014, provided CBD (Epidiolex) to patients with treatment-resistant epilepsy (TRE). In the final pooled analysis of 892 patients treated through January 2019 (median exposure = 694 days), CBD treatment was associated with a 46%-66% reduction in median monthly total (convulsive plus nonconvulsive) seizure frequency. CBD was well tolerated, and adverse events were consistent with previous findings. We used pooled EAP data to investigate the effectiveness of add-on CBD therapy for individual convulsive seizure types (clonic, tonic, tonic-clonic, atonic, focal to bilateral tonic-clonic), nonconvulsive seizure types (focal with and without impaired consciousness, absence [typical and atypical], myoclonic, myoclonic absence), and epileptic spasms. CBD treatment was associated with a reduction in the frequency of convulsive seizure types (median percentage reduction = 47%-100%), and nonconvulsive seizure types and epileptic spasms (median percentage reduction = 50%-100%) across visit intervals through 144 weeks of treatment. Approximately 50% of patients had ≥50% reduction in convulsive and nonconvulsive seizure types and epileptic spasms at nearly all intervals. These results show a favorable effect of long-term CBD use in patients with TRE, who may experience various convulsive and nonconvulsive seizure types. Future controlled trials are needed to confirm these findings.

Concomitant cannabidiol does not impact safety and effectiveness of diazepam nasal spray for seizure clusters: Post hoc analysis of a phase 3 safety study.

People with epilepsy may experience episodes of frequent seizure activity (seizure clusters, acute repetitive seizures), and benzodiazepines are the cornerstone of rescue treatment. Cannabidiol (CBD) can be used as an adjunctive treatment for epilepsy, and it may interact with other antiseizure drugs, such as benzodiazepines. Here, we examined the safety and effectiveness of intermittent use of diazepam nasal spray in patients with seizure clusters who also received CBD treatment. This analysis included data from patients aged 6 to 65 years enrolled in a phase 3, long-term safety study of diazepam nasal spray. Age- and weight-based dosing of diazepam nasal spray were administered during a 12-month treatment period. Concomitant CBD use was recorded, and treatment-emergent adverse events (TEAEs) were collected. Of 163 treated patients, 119 (73.0%) did not receive CBD, 23 (14.1%) received the US Food and Drug Administration-approved highly purified CBD and 21 (12.9%) received another form of CBD. On average, patients receiving highly purified CBD were younger and more likely to have epileptic encephalopathies, including Dravet syndrome or Lennox-Gastaut syndrome, than patients who received another CBD preparation or no CBD. Rates of TEAEs and serious TEAEs were greater in patients who received any form of CBD (90.9% and 45.5%, respectively) compared with no CBD (79.0% and 26.1%, respectively). However, the lowest rates of TEAEs attributed to diazepam nasal spray were reported in patients who received highly purified CBD (13.0%), and this result was maintained in those who received concomitant clobazam. Use of second doses of diazepam nasal spray, a proxy for effectiveness, was lowest in the highly purified-CBD group (8.2%) compared with the no-CBD (11.6%) and other-CBD groups (20.3%). These results suggest that CBD does not alter the safety and effectiveness of diazepam nasal spray and supports concomitant use in appropriate patients.

Second-line cannabis therapy in patients with epilepsy.

OBJECTIVE: Marijuana-based therapies (MBTs) have been shown to reduce seizure frequency in patients with severe and drug-resistant epilepsy (DRE). Pharmaceutical-grade CBD (EpidiolexⓇ) was approved by the FDA in 2018 for the treatments of Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS) and subsequently in 2020 for tuberous sclerosis complex (TSC). It is unclear what the utility would be in prescribing one type of MBT if a previous, alternative type failed. We conducted a retrospective study to determine if an alternative formulation of MBT reduces seizure frequency if the patient has not had a meaningful response from an initial MBT. We also investigated the clinical impact that a second MBT has on side effect profile. METHODS: We reviewed the charts of patients with DRE who were at least 2 years old and who took at least 2 different formulations of MBT, including a pharmacologic formulation of CBD (EpidiolexⓇ), artisanal marijuana, and/or a hemp-based formulation. We reviewed medical records in patients 2 years of age and older; however, subjects' historical data, such as age of first seizure onset, may be prior to the age of 2 years. We extracted data on demographics, type of epilepsy, history of epilepsy, medication history, seizure count, and drug side effects. Seizure frequency, side effect profiles, and predictors of responder status were evaluated. RESULTS: Thirty patients were identified as taking more than 1 type of MBT. Our findings suggest that seizure frequencies do not change significantly from baseline to after the first MBT and to after the second MBT (p = .4). However, we did find that patients with greater baseline seizure frequency were significantly more likely to respond to treatment after the second MBT (p = .03). To our second endpoint of side effect profile, we found that patients who experienced side effects after a second MBT had significantly greater seizure frequency compared to those who did not (p = .04). CONCLUSION: We found no significant seizure frequency reduction from baseline to after a second MBT in patients who tried at least 2 different formulations of MBT. This suggests a low probability of seizure frequency reduction with a second MBT therapy in patients with epilepsy who tried at least two different MBTs. While these findings need to be replicated in a larger sample, they suggest that clinicians should not delay care by trying alternative MBT formulations after a patient has already tried one. Instead, it may be more prudent to attempt an alternative class of therapy.

Perampanel in real-world clinical care of adolescent and adult patients with epilepsy: Results from the retrospective Phase IV PROVE Study.

PURPOSE: Report final data from adolescent (12-<18 years) and adult (≥18 years) patients from PROVE (NCT03208660), a multicenter, retrospective, non-interventional, Phase IV study to assess retention, efficacy, safety, and dosing of perampanel in patients with epilepsy during routine clinical care. METHODS: Data were retrospectively collected from medical/pharmacy records of patients in the US initiating perampanel after January 1, 2014, according to treating clinicians' recommendation. Retention rate was the primary efficacy endpoint. Secondary endpoints included median percent changes in seizure frequency, seizure-freedom rates, investigator's impression of seizure effect, and treatment-emergent adverse events (TEAEs). RESULTS: The Safety Analysis Set (SAS) included 294 adolescents and 1157 adults (median maximum perampanel dose, 6.0 mg/day). In patients eligible for inclusion in the retention rate analysis, 24-month retention rates were 53.5% (n=91/170) in adolescents and 47.8% (n=354/741) in adults. In patients with available efficacy data during Months 10-12, median percent seizure frequency reductions were 79.3% (n=20) in adolescents and 70.8% (n=92) in adults. Most patients in the SAS with seizure-effect data experienced an improvement in seizures at the last follow-up time point (adolescents, 51.4% [n=128/249]; adults, 52.3% [n=506/967]). TEAEs occurred in 113 adolescents (38.4%; most common, aggression [6.5%]) and 512 adults (44.3%; most common, dizziness [9.2%]). CONCLUSION: Perampanel demonstrated favorable retention rates and sustained efficacy (up to 2 years) in adolescent and adult patients during routine clinical care; no new safety signals were observed. GOV IDENTIFIER: NCT03208660 (https://clinicaltrials.gov/ct2/show/NCT03208660).

PROVE-Phase IV Study of Perampanel in Real-World Clinical Care of Patients with Epilepsy: Interim Analysis in Pediatric Patients.

PROVE is a retrospective, phase IV study assessing retention, dosing, efficacy, and safety of perampanel when administered to patients during routine clinical care. We report an interim analysis of preadolescent (1 to <12 years) and adolescent (12 to <18 years) patients. Data were obtained from medical records of patients with epilepsy initiating perampanel after January 1, 2014; cut-off date for this analysis was October 10, 2018. Overall, 151 preadolescent and 183 adolescent patients were included. Retention rates following 24 months on perampanel were 42.5% (preadolescent subgroup; n = 31/73) and 55.7% (adolescent subgroup; n = 54/97). Treatment-emergent adverse events occurred in 53 (35.1%) preadolescent (most common: aggression, irritability, and somnolence) and 78 (42.6%) adolescent patients (most common: somnolence, aggression, and dizziness). These data indicate that daily oral doses of perampanel are generally well tolerated during routine clinical care, with favorable retention rates for ≤2 years, in patients aged 1 to <18 years.

PROVE: Retrospective, non-interventional, Phase IV study of perampanel in real-world clinical care of patients with epilepsy.

OBJECTIVE: To assess retention, dosing, efficacy, and safety of perampanel in a large cohort of patients with epilepsy during routine clinical care. METHODS: PROVE was a retrospective, non-interventional Phase IV study (NCT03208660). Data were obtained retrospectively from the medical records of patients in the United States initiating perampanel after January 1, 2014, according to treating clinicians' recommendation. Retention rate was the primary efficacy endpoint. Secondary efficacy endpoints included median percent changes in seizure frequency per 28 days from baseline, seizure-freedom rate, and overall investigator impression of seizure effect. Safety endpoints included incidence of treatment-emergent adverse events (TEAEs). Efficacy and safety were also assessed according to baseline use of enzyme-inducing antiseizure medications (EIASMs). RESULTS: Overall, 1703 patients were enrolled and included in the Safety Analysis Set (SAS; ≥1 baseline EIASMs, n = 358 [21.0%]; no baseline EIASMs, n = 1345 [79.0%]). Mean (standard deviation [SD]) cumulative duration of exposure to perampanel was 17.4 (15.7) months; mean (SD) daily perampanel dose was 5.6 (2.7) mg. The most frequent perampanel titration intervals were weekly (23.4%) and every 2 weeks (24.7%). Across the SAS, 24-month retention rate was 48.1% (n = 501/1042). Based on overall investigator impression at the end of treatment, 51.9%, 35.8%, and 12.3% of patients in the SAS experienced improvement, no change, or worsening of seizures, respectively. TEAEs occurred in 704 (41.3%) patients; 79 (4.6%) had serious TEAEs. The most common TEAE was dizziness (7.3%). There was some variation in efficacy according to EIASM use, while retention rates and safety were generally consistent. SIGNIFICANCE: In this final analysis of >1700 patients with epilepsy receiving perampanel in routine clinical care, favorable retention and sustained efficacy were demonstrated for ≥12 months.

Final results from a Phase 3, long-term, open-label, repeat-dose safety study of diazepam nasal spray for seizure clusters in patients with epilepsy.

OBJECTIVE: A Phase 3 open-label safety study (NCT02721069) evaluated long-term safety of diazepam nasal spray (Valtoco) in patients with epilepsy and frequent seizure clusters. METHODS: Patients were 6-65 years old with diagnosed epilepsy and seizure clusters despite stable antiseizure medications. The treatment period was 12 months, with study visits at Day 30 and every 60 days thereafter, after which patients could elect to continue. Doses were based on age and weight. Seizure and treatment information was recorded in diaries. Treatment-emergent adverse events (TEAEs), nasal irritation, and olfactory changes were recorded. RESULTS: Of 163 patients in the safety population, 117 (71.8%) completed the study. Duration of exposure was ≥12 months for 81.6% of patients. There was one death (sudden unexpected death in epilepsy) and one withdrawal owing to a TEAE (major depression), both considered unlikely to be related to treatment. Diazepam nasal spray was administered 4390 times for 3853 seizure clusters, with 485 clusters treated with a second dose within 24 h; 53.4% of patients had monthly average usage of one to two doses, 41.7% two to five doses, and 4.9% more than five doses. No serious TEAEs were considered to be treatment related. TEAEs possibly or probably related to treatment (n = 30) were most commonly nasal discomfort (6.1%); headache (2.5%); and dysgeusia, epistaxis, and somnolence (1.8% each). Only 13 patients (7.9%) showed nasal irritation, and there were no relevant olfactory changes. The safety profile of diazepam nasal spray was generally similar across subgroups based on age, monthly usage, concomitant benzodiazepine therapy, or seasonal allergy/rhinitis. SIGNIFICANCE: In this large open-label safety study, the safety profile of diazepam nasal spray was consistent with the established profile of rectal diazepam, and the high retention rate supports effectiveness in this population. A second dose was used in only 12.6% of seizure clusters.

Consensus Statement for the Management and Treatment of Sturge-Weber Syndrome: Neurology, Neuroimaging, and Ophthalmology Recommendations.

BACKGROUND: Sturge-Weber syndrome (SWS) is a sporadic, neurocutaneous syndrome involving the skin, brain, and eyes. Because of the variability of the clinical manifestations and the lack of prospective studies, consensus recommendations for management and treatment of SWS have not been published. OBJECTIVE: This article consolidates the current literature with expert opinion to make recommendations to guide the neuroimaging evaluation and the management of the neurological and ophthalmologic features of SWS. METHODS: Thirteen national peer-recognized experts in neurology, radiology, and ophthalmology with experience treating patients with SWS were assembled. Key topics and questions were formulated for each group and included (1) risk stratification, (2) indications for referral, and (3) optimum treatment strategies. An extensive PubMed search was performed of English language articles published in 2008 to 2018, as well as recent studies identified by the expert panel. The panel made clinical practice recommendations. CONCLUSIONS: Children with a high-risk facial port-wine birthmark (PWB) should be referred to a pediatric neurologist and a pediatric ophthalmologist for baseline evaluation and periodic follow-up. In newborns and infants with a high-risk PWB and no history of seizures or neurological symptoms, routine screening for brain involvement is not recommended, but brain imaging can be performed in select cases. Routine follow-up neuroimaging is not recommended in children with SWS and stable neurocognitive symptoms. The treatment of ophthalmologic complications, such as glaucoma, differs based on the age and clinical presentation of the patient. These recommendations will help facilitate coordinated care for patients with SWS and may improve patient outcomes.

Consistent safety and tolerability of Valtoco® (diazepam nasal spray) in relationship to usage frequency in patients with seizure clusters: Interim results from a phase 3, long-term, open-label, repeat-dose safety study.

OBJECTIVE: Need for rescue therapy differs among patients with seizure clusters. Diazepam nasal spray is approved to treat seizure clusters in patients with epilepsy ≥6 years of age. This analysis used interim data from a phase 3 safety study to assess safety profile and effectiveness of diazepam nasal spray using average number of doses/month as a proxy measurement. METHODS: This phase 3, open-label, repeat-dose, safety study of diazepam nasal spray enrolled patients (6-65 years) with epilepsy and need of benzodiazepine rescue. Patients were stratified by average number of doses/month (<2, moderate frequency; 2-5, high frequency; >5, very-high frequency). Safety was evaluated based on treatment-emergent adverse events (TEAEs), assessed nasal irritation, and olfaction. The proportion of treatments given as a second dose was used as an exploratory proxy for effectiveness. RESULTS: Of 175 enrolled patients (data cutoff, October 31, 2019), 158 received ≥1 dose of diazepam nasal spray. Frequency of use was moderate in 43.7% of patients, high in 50.6% of patients, and very high in 5.7% of patients. Patients treated 3397 seizure episodes (moderate frequency, 14.2%; high frequency, 59.9%; very high frequency, 25.8%). Nasal discomfort was the most common treatment-related TEAE in all groups. No notable changes in nasal irritation or olfaction were observed. Second doses represented only 2.5%, 7.5%, and 17.2% of all doses in the moderate-, high-, and very-high-frequency groups, respectively. Overall retention rate was 82.9%, without an observed relationship to frequency of use. SIGNIFICANCE: Frequency of dosing diazepam nasal spray had little impact on the safety/tolerability profile across a range of <2 to >5 doses/month. Effectiveness was suggested for all dosing frequencies by the high proportion of seizure clusters not treated with a second dose. These results support the utility, safety profile, and effectiveness of diazepam nasal spray across frequencies of seizure cluster burden.

Evaluation of diazepam nasal spray in patients with epilepsy concomitantly using maintenance benzodiazepines: An interim subgroup analysis from a phase 3, long-term, open-label safety study.

OBJECTIVE: Diazepam nasal spray (Valtoco), indicated for acute treatment of frequent seizure activity (seizure clusters) in patients with epilepsy ≥6 years of age, is designed to be a rapid, noninvasive, socially acceptable route of administration. This interim analysis evaluated the safety profile of diazepam nasal spray in patients with and without concomitant use of benzodiazepines, with use of a second dose for a seizure cluster as a proxy for effectiveness. METHODS: A long-term, phase 3, open-label safety study enrolled patients with epilepsy who had seizures despite a stable antiseizure medication regimen. RESULTS: Among 175 patients enrolled by October 31, 2019, a total of 158 were treated with diazepam nasal spray (aged 6-65 years; 53.8% female). Of those, 119 (75.3%) received concomitant benzodiazepines (60, chronic; 59, intermittent); 39 (24.7%) did not. Use of a second dose was similar in patients using chronic concomitant benzodiazepines (second dose in 11.1% [144/1299]) and those with no concomitant benzodiazepines (second dose in 10.3% [41/398]). Treatment emergent adverse events (TEAEs) occurred for 80.0% with chronic use of concomitant benzodiazepines and 61.5% without. Cardiorespiratory depression was not reported, and no serious TEAEs were treatment related. Study retention was high: 83.3% in the chronic benzodiazepine group and 76.9% in the no-benzodiazepine group. Findings were similar in a sub-analysis of patients who were (n = 44) or were not (n = 75) taking clobazam. SIGNIFICANCE: This analysis of patients from a long-term study shows a similar safety profile of diazepam nasal spray in patients with and without concomitant benzodiazepines, and consistent with the established profile for diazepam. Use of a single dose of diazepam nasal spray and high study retention rates suggest the effectiveness of diazepam nasal spray in patients irrespective of chronic daily benzodiazepine use. Results were similar in the clobazam sub-analysis. These results support the safety and effectiveness of diazepam nasal spray in patients with concomitant benzodiazepine use.

An algorithmic approach to preoperative studies and patient selection for hemispheric disconnection surgery: a literature review.

Hemispheric disconnection surgery (HDS) is one of the most effective surgical options for appropriate candidates with medically-refractory epilepsy (MRE) in whom most or all seizures arise from diffuse areas within a single hemisphere. While there are several well-accepted indications for HDS, there are additional patients who may benefit from HDS. However, there are no standardized recommendations for how preoperative studies should be used to identify appropriate candidates for HDS. We aimed to propose an algorithmic approach for presurgical evaluation in order to guide appropriate implementation of HDS for either cure or palliation of severe MRE in infants, children, and adults. We performed a qualitative review of the literature using PubMed, the Cochrane Library, and Google Scholar to select primary articles addressing imaging modalities used for the presurgical evaluation of patients with MRE being considered for HDS. In total, we identified 126 articles that met our inclusion criteria. We propose a framework to guide candidate selection for HDS that incorporates various elements of the clinical presentation, electroencephalographic analysis, and neuroimaging. While this approach still requires prospective validation, the authors feel it is grounded in a synthesis of the best available evidence in the literature and informed by expert opinion. HDS is a powerful tool in the armamentarium of experienced multi-disciplinary epilepsy centers to treat patients with severe MRE arising from diffuse areas constrained to a single hemisphere. The under-utilization of epilepsy surgery may be, in part, remedied by establishing evidence-based pathways for presurgical analyses to determine surgical candidacy.

Rare homozygous nonsense variant in AIMP1 causing Early Onset Epileptic Encephalopathy with Burst Suppression (EOEE-BS).

Pathogenic variants in AIMP1 gene are rare causes of neurologic disorders. Homozygous frameshift and nonsense variants in AIMP1 have been described in severe neurodegenerative disease. This is the third report of a homozygous nonsense variant in AIMP1 [c.115 C > T (p.Gln39*)] in a girl with severe neonatal onset epileptic encephalopathy. Like the two other cases reported, our patient is also of Filipino descent. Clinical features include microcephaly, poor visual motor development, shallow breathing, severe hypertonia in extremities, severe global developmental delay, poor gag and suck reflex, failure to thrive in the neonatal period, and early onset intractable seizures. Brain MRI showed hypoplasia of corpus callosum as well as cerebellar vermis, global volume loss and diminished myelination for her age. Electroencephalogram at four months of age showed background consisting of synchronous and asynchronous intervals of burst suppression with intermittent multifocal spikes predominantly in the bi-temporal region, suggestive of Early Onset Epileptic Encephalopathy with Burst Suppression (EOEE-BS) which has not been previously associated with the c.115 C > T variant in AIMP1. Of note, she presented to us in super refractory status epilepticus which was eventually controlled after administration of ketogenic diet and Epidiolex (cannabidiol). This report expands the genetic landscape of EOEE-BS. This is the first case of this specific variant in which Epidiolex was administered, which along with Ketogenic diet aided in controlling patient's super refractory status epilepticus.

Attitudes and knowledge about cannabis and cannabis-based therapies among US neurologists, nurses, and pharmacists.

Use of cannabinoid therapies is on the rise in the United States, but responses of healthcare professionals and their knowledge of these therapies have been mixed. More information is needed about factors associated with healthcare professionals' attitudes and knowledge about medical cannabis. We conducted an online survey of US-based neurologists, nurse practitioners (NPs)/nurses, and pharmacists in August-September of 2018 (n = 451). We constructed perceived knowledge and attitudes scales and a knowledge index from multiple items and assessed state cannabis laws, participant's sociodemographics, workplace type and policies, and patient population. We used ordinary least-squares regression to examine associations among study variables. Over 80% of participants supported use and legalization of medical cannabis, especially cannabidiol (CBD) for epilepsy and when prescribed by a medical provider, but 40-50% (depending on item) felt unfamiliar with cannabinoid pharmacology and clinical applications. A total of 43% favored legal recreational cannabis. Pharmacists scored higher on the knowledge test than neurologists and NPs/nurses, but NPs/nurses had more favorable attitudes than neurologists and higher perceived knowledge than pharmacists. Both knowledge indicators predicted attitudes. State cannabis access and favorable workplace policies were associated with higher knowledge and more favorable attitudes. Healthcare professionals see potential in cannabis therapies but report significant knowledge gaps. Professional cannabinoid education is needed to address growing patient and provider demand for knowledge about cannabinoid therapies.

The Humanistic and Economic Burden of Pediatric Focal Seizures in the United States.

OBJECTIVE: To better understand the humanistic and economic burden of focal seizures in children 2-12 years old. METHODS: We conducted a targeted literature review by searching MEDLINE for English-language publications reporting on children 2-12 years old with focal seizures published in the United States since 2008. RESULTS: Thirty-five publications were included. Incidence of focal seizures was 23.2 to 47.1 per 100,000 children per year; prevalence was 2.0 per 1,000 children, and ranged from 1.6 - 2.6 per 1,000 in patients of any age. Life expectancy was 47.3-61.8 years among children 3-12 years old. Patients took several antiepileptic drugs and experienced frequent seizures, sleep disorders, mood disorders, migraine, and seizure-related injuries (eg, bone fractures, sprains, open wounds). Children with focal seizures scored below average on cognitive assessments and up to 42%, 16%, and 19% had depression, anxiety, and attention-deficit disorder, respectively. Patients of any age had about 10 outpatient visits (2 epilepsy-related), 2 inpatient visits (less than 1 epilepsy-related), and 24 procedures (1 epilepsy-related) per year. Medication adherence was low: only half of pediatric patients maintained ≥90% adherence over 6 months. Annual total health care costs among patients of any age ranged from $18,369 - 38,549; first-year total health care costs for children were $19,883. CONCLUSIONS: Incidence and prevalence of focal seizures is high and the humanistic and economic burdens are significant. Future studies focused exclusively on children with focal seizures are needed to more precisely describe the burden. We also suggest further research and implementation of methods to improve medication adherence as an approach to lessen burden on these young patients.

Pharmacokinetics and safety of VALTOCO (NRL-1; diazepam nasal spray) in patients with epilepsy during seizure (ictal/peri-ictal) and nonseizure (interictal) conditions: A phase 1, open-label study.

OBJECTIVE: To assess pharmacokinetics and safety of diazepam nasal spray (NRL-1; VALTOCO®) in pediatric and adult patients with epilepsy in seizure and nonseizure states. METHODS: A single dose of diazepam nasal spray (5, 10, 15, or 20 mg based on weight) was administered during each of two conditions (ictal/peri-ictal and interictal condition) to patients 6-65 years old with partial or generalized epilepsy with motor seizures or seizures with clear alteration of awareness; a second dose was permitted if needed for persistent seizures. Dosing could be interictal or ictal/peri-ictal first, with a washout of ≥14 days. Blood samples for pharmacokinetic analysis were taken at prespecified time points. Treatment-emergent adverse events (TEAEs), sedation, nasal irritation, nasal mucosal pain, and olfactory changes were assessed. RESULTS: Of 57 patients in the study (mean age = 28.1 years [range = 6-59], 54.4% female, 80.7% white), 49 were included in the primary pharmacokinetic analyses. Diazepam pharmacokinetic profiles were similar under both conditions, with approximately 2-hour median time to mean (SD) maximum plasma concentrations of 164 (88) and 189 (110) ng/mL for ictal/peri-ictal and interictal conditions, respectively; drug exposure during the first 6 hours postdosing was 532 (313) and 615 (368) h•ng/mL, respectively. Seventeen patients (29.8%) reported TEAEs, of whom eight (14%) had treatment-related TEAEs, with those reported in ≥2 patients being dysgeusia (n = 3, 5.3%) and nasal discomfort (n = 2, 3.5%). One patient had serious TEAEs (recurrent seizures, metabolic encephalopathy), which were deemed unrelated to study treatment. No changes in respiratory rate were observed, nor were there clinically relevant changes in sedation, olfaction, nasal irritation, or acute nasal mucosal pain. SIGNIFICANCE: The epileptic conditions (ictal/peri-ictal, interictal) had minimal impact on diazepam nasal spray pharmacokinetics in patients with epilepsy. Therefore, diazepam nasal spray can be administered ictally and interictally. Diazepam nasal spray safety was consistent with the profile of diazepam.