Follow-up to low-dose fenfluramine for Sunflower syndrome: A non-randomized controlled trial.

AIM: This study reports on the long-term results for an initial cohort of patients with Sunflower syndrome who enrolled in an open-label study of low-dose fenfluramine as well as the short-term results of a second cohort. METHOD: We conducted a single-center, open-label study at the Massachusetts General Hospital. We analyzed the effect of fenfluramine on handwaving seizure frequency at monthly intervals during a 4-month core study period for the second patient cohort, and we evaluated the long-term (>2 years) effect of fenfluramine for the initial patient cohort. RESULTS: Eight of the 10 patients from the second cohort provided analyzable seizure data. These patients experienced a 33% median reduction in seizure frequency during the core study, as compared to the previously reported 79% for the initial cohort (n = 9). Of the seven patients from the first cohort who remain on fenfluramine in the extension study, five continue to experience benefit. Fenfluramine was overall well tolerated with minimal side effects, reduced appetite and fatigue being the primary adverse events, and no evidence of cardiac valvulopathy or pulmonary hypertension. INTERPRETATION: This study suggests fenfluramine can be an effective, durable, and well-tolerated antiseizure medication option for patients with Sunflower syndrome.

The long-term efficacy of cannabidiol in the treatment of refractory epilepsy.

OBJECTIVE: Cannabidiol (CBD) has been shown to reduce seizures among patients with refractory epilepsies of various etiologies in recent clinical trials and an expanded access program (EAP). Most studies report efficacy over short time periods (<1 year), with little published on longer term efficacy. Here, we investigate the efficacy of CBD for a treatment period of up to 60 months (median = 45.5 months). METHODS: We conducted a retrospective review of patient-reported seizure logs and medical records for 54 subjects with refractory epilepsy who enrolled in the Massachusetts General Hospital's open-label EAP for CBD as a new treatment for epilepsy. We analyzed the effect of CBD on seizure frequencies and concomitant antiepileptic drug (AED) use at 1 year after starting treatment and the most recent study visit. RESULTS: Our results indicate that CBD maintains its efficacy for controlling seizures from Year 1 to the most recent study visit. The percentage of seizure responders remained similar at these time points (41.7%-42.6%), and the seizure response rate was also maintained (p = .12). Efficacy was also seen over a broad dose range, and up to 50 mg/kg/day. CBD was particularly effective for controlling seizures in the setting of tuberous sclerosis complex and for reducing epileptic spasms and absence seizures. Although CBD use did not lead to an overall decrease in concomitant AEDs, most subjects reduced the dose of at least one concomitant AED compared to baseline. CBD was generally well tolerated, with drowsiness and diarrhea as the primary adverse reactions. SIGNIFICANCE: This study demonstrates CBD does not lose its efficacy in controlling seizures over a treatment period of up to 60 months. Taken alongside other results on the efficacy and tolerability of CBD in the treatment of refractory epilepsies, our results provide evidence that CBD is an effective, safe, and well-tolerated AED for long-term use.

Understanding Sunflower syndrome: Results of an online questionnaire.

OBJECTIVE: To characterize the clinical phenotype, treatments, and impact on quality of life of Sunflower syndrome. METHODS: A 138-question survey was created focusing on seizure description, disease course, treatment history, medical history, family history, and aspects of quality of life of individuals with Sunflower syndrome. The survey was administered to individuals with Sunflower syndrome who experience hand waving episodes (HWE) and/or their caregivers via Research Electronic Data Capture (REDCap). RESULTS: Sixty-eight responses were included in analysis. Seventy-one% of respondents were female. The mean age of participants was 13.6 years, with 84% of respondents under the age of 18. The average age of onset of HWE was 6.7 years. HWE frequency varied from a few episodes per week to multiple episodes per hour. Sixty-two% of participants experienced other seizure types. Participants had been on an average of 1.9 anti-seizure medications with varying efficacy. Other methods to reduce HWE included wearing a hat or sunglasses, hand holding, using special tinted lenses, and avoiding the sun and bright lights. Sixty-nine% of participants reported anxiety or depression related to their epilepsy, and 65% said their HWE affected their social life. SIGNIFICANCE: Sunflower syndrome is a highly stereotyped, refractory epilepsy which significantly impacts the lives of affected individuals. It remains underrecognized and poorly understood. These results characterize Sunflower syndrome in a large population of affected individuals and provides a basis for future research to better understand the epilepsy and improve clinical care.

Fenfluramine for seizures associated with Sunflower syndrome.

AIM: To determine the efficacy of fenfluramine on seizure frequency in patients with Sunflower syndrome. Secondary endpoints were changes in electroencephalogram (EEG) characteristics, cognitive functioning, executive functioning, and quality of life. METHOD: In this open-label study, patients underwent a 4-week baseline period, followed by 3 months of treatment. An oral solution of fenfluramine was administered twice daily for 3 months. The dose was titrated up to a maximum dose of 0.7mg/kg/day or 26mg/day. Cardiac safety was monitored by transthoracic echocardiogram and electrocardiogram. EEGs, abbreviated neuropsychological testing, and questionnaires were administered before starting the study medication and again at the end of the treatment period. RESULTS: Ten patients (eight females, two males; mean age 13y 4mo [SD 4y 11mo], range 7-24y) were enrolled in the study. Nine of the 10 patients completed the core study, eight of whom met the primary endpoint. There were no observations of cardiac valvulopathy or pulmonary hypertension during the study. INTERPRETATION: Treatment with low-dose fenfluramine resulted in a clinically significant reduction in seizure frequency, including hand-waving episodes. Fenfluramine may be an effective treatment option for patients with Sunflower syndrome. What this paper adds Nine patients with Sunflower syndrome were treated with fenfluramine. Eight patients were responders, displaying a ≥30% reduction in seizure activity. Six patients experienced a ≥70% reduction in hand-waving episodes. Improvements on electroencephalogram were observed after treatment with fenfluramine. None of the patients developed evidence of cardiac valvulopathy or pulmonary hypertension.

Cannabidiol in treatment of refractory epileptic spasms: An open-label study.

OBJECTIVE: This study aimed to evaluate clinical efficacy and safety of purified pharmaceutical cannabidiol (CBD) as an adjunctive therapy in refractory childhood-onset epileptic spasms (ES). METHODS: Nine patients with ES were enrolled in an Institutional Review Board (IRB)- and Food and Drug Administration (FDA)-approved expanded access investigational new drug trial. Patients received plant-derived highly purified CBD in oral solution in addition to their baseline medications at an initial dosage of 5 mg/kg/day, which was increased by 5 mg/kg/day every week to an initial target dosage of 25 mg/kg/day. Seizure frequency, adverse event, and parents' subjective reports of cognitive and behavioral changes were recorded after 2 weeks and 1, 2, 3, 6, 9, and 12 months of CBD treatment. Responder rates (percent of patients with >50% reduction in ES frequency from baseline) were calculated. Electrographic changes were studied in relation to CBD initiation and clinical response. RESULTS: Overall, the responder rates in 9 patients were 67%, 78%, 67%, 56%, 78%, 78%, and 78% after 2 weeks and 1, 2, 3, 6, 9, and 12 months of CBD treatment, respectively. Three out of nine patients (33%) were ES free after two months of treatment. Parents reported subjective improvements in cognitive and behavioral domains. Side effects, primarily drowsiness, were seen in 89% of patients (n = 8). Eight of the nine (89%) patients had electroencephalographic (EEG) studies prior to and after initiation of CBD. Three out of five patients (60%) had resolution in their hypsarrhythmia pattern. SIGNIFICANCE: Purified pharmaceutical CBD may be an effective and safe adjunctive therapy in refractory ES and may also be associated with improvements in electrographic findings.

Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex.

OBJECTIVE: Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder with highly variable expression. The most common neurologic manifestation of TSC is epilepsy, which affects approximately 85% of patients, 63% of whom develop treatment-resistant epilepsy. Herein, we evaluate the efficacy, safety, and tolerability of cannabidiol (CBD), a nonpsychoactive compound derived from the marijuana plant, as an adjunct to current antiepileptic drugs in patients with refractory seizures in the setting of TSC. METHODS: Eighteen of the 56 patients who have enrolled in our current expanded-access study of cannabidiol for patients with treatment-resistant epilepsy carry a diagnosis of TSC. After an initial baseline period of 1 month, patients began treatment with CBD. The initial dose of 5 mg/kg/day was increased by 5 mg/kg/day every week up to a maximum dose of 50 mg/kg/day, if tolerated. Weekly seizure frequencies, percent change in seizure frequencies, and responder rates were calculated during the 2nd, 3rd, 6th, 9th, and 12th month of treatment with CBD. RESULTS: The median weekly seizure frequency during the baseline period was 22.0 (interquartile range [IQR] 14.8-57.4), which decreased to 13.3 (IQR 5.1-22.1) after 3 months of treatment with cannabidiol. The median percent change in total weekly seizure frequency was -48.8% (IQR -69.1% to -11.1%) after 3 months of treatment. The 50% responder rates over the course of the study were 50%, 50%, 38.9%, 50%, and 50% after 2, 3, 6, 9, and 12 months of treatment with CBD, respectively. In patients taking clobazam concurrently with CBD (n = 12), the responder rate after 3 months of treatment was 58.3%, compared to 33.3% in patients not taking clobazam (n = 6). Twelve (66.7%) of 18 patients in this study experienced at least one adverse event thought possibly related to CBD; the most common adverse events were drowsiness (n = 8, 44.4%), ataxia (n = 5, 27.8%), and diarrhea (n = 4, 22.2%). SIGNIFICANCE: Although double-blind, placebo-controlled trials are still necessary, these findings suggest that cannabidiol may be an effective and well-tolerated treatment option for patients with refractory seizures in TSC.

Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy.

OBJECTIVE: Under an expanded access investigational new drug (IND) trial, cannabidiol (CBD) is being studied as a possible adjuvant treatment of refractory epilepsy in children. Of the 25 subjects in the trial, 13 were being treated with clobazam (CLB). Because CLB and CBD are both metabolized in the cytochrome P450 (CYP) pathway, we predicted a drug-drug interaction, which we evaluate in this article. METHODS: Thirteen subjects with refractory epilepsy concomitantly taking CLB and CBD under IND 119876 were included in this study. Demographic information was collected for each subject including age, sex, and etiology of seizures, as well as concomitant antiepileptic drugs (AEDs). CLB, N-desmethylclobazam (norclobazam; nCLB), and CBD levels were measured over the course of CBD treatment. CLB doses were recorded at baseline and at weeks 4 and 8 of CBD treatment. Side effects were monitored. RESULTS: We report elevated CLB and nCLB levels in these subjects. The mean (± standard deviation [SD]) increase in CLB levels was 60 ± 80% (95% confidence interval (CI) [-2-91%] at 4 weeks); the mean increase in nCLB levels was 500 ± 300% (95% CI [+90-610%] at 4 weeks). Nine of 13 subjects had a >50% decrease in seizures, corresponding to a responder rate of 70%. The increased CLB and nCLB levels and decreases in seizure frequency occurred even though, over the course of CBD treatment, CLB doses were reduced for 10 (77%) of the 13 subjects. Side effects were reported in 10 (77%) of the 13 subjects, but were alleviated with CLB dose reduction. SIGNIFICANCE: Monitoring of CLB and nCLB levels is necessary for clinical care of patients concomitantly on CLB and CBD. Nonetheless, CBD is a safe and effective treatment of refractory epilepsy in patients receiving CLB treatment.

Impact of pediatric epilepsy on sleep patterns and behaviors in children and parents.

PURPOSE: Disrupted sleep patterns in children with epilepsy and their parents are commonly described clinically. A number of studies have shown increased frequency of sleep disorders among pediatric epilepsy patients; however, few have characterized the association between epilepsy and parental sleep quality and household sleeping arrangements. The purpose of this study was to explore the effect of pediatric epilepsy on child sleep, parental sleep and fatigue, and parent-child sleeping arrangements, including room sharing and cosleeping. METHODS: Parents of children 2 to 10 years of age with and without epilepsy completed written questionnaires assessing seizure history, child and parent sleep, and household sleeping arrangements. Children's Sleep Habits Questionnaire (CSHQ) scores were used to evaluate sleep disturbances for the child. The Pittsburgh Sleep Quality Index (PSQI) and the Iowa Fatigue Scale (IFS) were used to evaluate parental sleep and fatigue, respectively. The Early Childhood Epilepsy Severity Scale (E-Chess) was used to assess epilepsy severity. KEY FINDINGS: One hundred five households with a child with epilepsy and 79 controls participated in this study. Households with a child with epilepsy reported increased rates of both parent-child room sharing (p < 0.001) and cosleeping (p = 0.005) compared to controls. Children with epilepsy were found to have greater sleep disturbance by total CSHQ score (p < 0.001) and the following subscores: parasomnias (p < 0.001), night wakings (p < 0.001), sleep duration (p < 0.001), daytime sleepiness (<0.001), sleep onset delay (p = 0.009), and bedtime resistance (p = 0.023). Parents of children with epilepsy had increased sleep dysfunction (p = 0.005) and were more fatigued (p < 0.001). Severity of epilepsy correlated positively with degree of child sleep dysfunction (0.192, p = 0.049), parental sleep dysfunction (0.273, p = 0.005), and parental fatigue (0.324, p = 0.001). Antiepileptic drug polytherapy was predictive of greater childhood sleep disturbances. Nocturnal seizures were associated with parental sleep problems, whereas room sharing and cosleeping behavior were associated with child sleep problems. Within the epilepsy cohort, 69% of parents felt concerned about night seizures and 44% reported feeling rested rarely or never. Finally, 62% of parents described decreased sleep quality and/or quantity with cosleeping. SIGNIFICANCE: Pediatric epilepsy can significantly affect sleep patterns for both the affected child and his or her parents. Parents frequently room share or cosleep with their child, adaptations which may have detrimental effects for many households. Clinicians must not only be attentive to the sleep issues occurring in pediatric patients with epilepsy, but also for the household as a whole. These data provide evidence of a profound clinical need for improved epilepsy therapeutics and the development of nocturnal seizure monitoring technologies.

Characterizing Sunflower syndrome: a clinical series.

To characterize the clinical phenotype of Sunflower syndrome. Sunflower syndrome is a rare photosensitive epilepsy syndrome characterized by highly stereotyped seizures, photosensitivity, and heliotropism. We retrospectively reviewed the medical records of patients seen in the Massachusetts General Hospital for Children (MGHfC) pediatric epilepsy program with a history of Sunflower syndrome. Twenty-four patients were identified; 18 were female. At the time of initial MGHfC evaluation, patients' ages ranged from 6.4 to 25 years, with a median age of 11.5 years. All patients presented with hand-waving episodes (HWEs), although one patient no longer demonstrates this, but now has eye blinking episodes on exposure to light. Four have associated eye fluttering as a component of their most prevalent light-induced seizures. The average age at onset of HWEs was six years. Seventeen developed other symptoms prior to the onset of HWEs. The most prevalent symptom was an attraction to light and possible absence seizures. Light-induced seizures were generally refractory to broad-spectrum antiepileptic drugs (AEDs). Only three patients had a reduction of HWEs with the use of AEDs. Several non-pharmacological strategies reduced seizure frequency, however, efficacy varied. These non-pharmacological strategies included avoiding stimulus, focusing on other tasks, and occupying or restraining the hand that was involved in hand-waving. The use of tinted glasses reduced seizure frequency in 17 patients, however, no patient achieved seizure freedom. Twenty-two patients had available EEGs, 20 of which showed interictal epileptiform discharges. Additionally, many of the patients experienced a negative impact on their self-concept due to anxiety, depression, or negative interactions with peers. Sunflower syndrome is a generalized, pharmacoresistant epilepsy with childhood onset and remains poorly understood. To improve clinical care and scientific understanding, long-term prospective research exploring the natural history, etiology, and effective treatments for Sunflower syndrome should be conducted. [Published with video sequence].

Efficacy of cannabidiol in subjects with refractory epilepsy relative to concomitant use of clobazam.

OBJECTIVE: To evaluate the efficacy of open-label, highly purified cannabidiol (CBD, Epidiolex®) in treating refractory epilepsy relative to the concomitant use of clobazam (CLB) as well as the clinical implications of changes in CLB and norclobazam (nCLB) levels. METHODS: Data were examined retrospectively, in patients who either used CBD with concomitant CLB or without concomitant CLB after two months of treatment with CBD and at the point of best seizure control within the first year of treatment with CBD. Responder rates (percentage of subjects with a 50 % or greater reduction in weekly seizures from their baseline) and mean reduction in weekly seizure frequency were calculated and compared between those who concomitantly used CLB and those who did not. The relationship between the change in CLB and nCLB levels and change in mean weekly seizure frequency was also investigated within the group of subjects using concomitant CLB and CBD. RESULTS: We analyzed data from 47 subjects between the ages of 2.5-51 years. There was no significant difference between the concomitant CLB (n = 32) and no concomitant CLB (n = 15) groups in terms of demographics (age (p = 0.4344), race (p = 1.0000), sex (p = 0.7507)) or most epilepsy characteristics (underlying condition (all p > 0.05), mean baseline seizure frequency (p = 0.6483)). There was only one significant difference between groups regarding seizure types (more subjects with epileptic spasms in concomitant CLB group (p = 0.0413)). Concomitant AED usage was not significantly different in the two groups (all p > 0.05). Mean reduction in weekly seizure frequency was greater at the best point of seizure control within the first year than at two months of treatment with CBD, regardless of concomitant CLB usage (all p > 0.05). There was no significant difference in reduction of mean weekly seizure frequency between those who took concomitant CLB and those who did not at either time point (all p > 0.05). There was a significantly greater responder rate for subjects taking CBD and CLB than those taking CBD without CLB only at the point of best seizure control within the first year of CBD treatment (p = 0.0240). There was no strong, significant correlation between change in nCLB or CLB levels and change in seizure frequency at either time point (all |p|<0.22). SIGNIFICANCE: With or without concomitant CLB, CBD can be effective in reducing seizure frequency. Changes in nCLB and CLB levels do not have a clinically significant correlation with changes in weekly seizure frequency for those taking CBD with CLB.

Epilepsy in Angelman syndrome: a questionnaire-based assessment of the natural history and current treatment options.

PURPOSE: Angelman syndrome (AS) commonly presents with epilepsy (>80%). The goal of this study was to examine the natural history and various treatments of epilepsy in AS in a large population. METHODS: A detailed electronic survey containing comprehensive questions regarding epilepsy in AS was conducted through the Angelman Syndrome Foundation. RESULTS: There were responses from 461 family members of individuals with AS, of whom 86% had epilepsy (60% with multiple seizure types), the most common being atonic, generalized tonic-clonic, absence, and complex partial. Partial-onset seizures only were reported in 11% of those with epilepsy. Epilepsy was most common among those with maternal deletions and unknown subtypes, with catastrophic epilepsies present in only these two subtypes. These epilepsies were refractory to medication, with only 15% responding to the first antiepileptic drug (AED). The most commonly prescribed AED were valproic acid and clonazepam, but lamotrigine and levetiracetam appeared to have similar efficacy and tolerability. DISCUSSION: This is the largest study to date assessing epilepsy in AS. Although epilepsy in AS is considered a generalized epilepsy, there was a high prevalence of partial seizures. There are few previous data regarding the use of newer AED in AS, and the results of this study suggest that these newer agents, specifically levetiracetam and lamotrigine, may have efficacy similar to that of valproic acid and clonazepam, and that they appear to have similar or better side-effect profiles. Nonpharmacologic therapies such as dietary therapy and vagus nerve stimulation (VNS) also suggest favorable efficacy and tolerability, although further studies are needed.

Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.

BACKGROUND: Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. METHODS: In this open-label trial, patients (aged 1-30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. RESULTS: Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death-a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30.0 (IQR 11.0-96.0) at baseline and 15.8 (5.6-57.6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36.5% (IQR 0-64.7). INTERPRETATION: Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound. FUNDING: GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.