Long-Term Outcomes of Tuberous Sclerosis Complex-Associated Non-functional Pancreatic Neuroendocrine Tumors: Should We Be More Conservative?

BACKGROUND: Hereditary syndromes such as tuberous sclerosis complex (TSC) account for 10% of pancreatic neuroendocrine tumors (PNETs). Surgical intervention is the current standard of care for sporadic PNETs (spPNETs) that are >2 cm in size. We compared the long-term outcomes of resected TSC-PNETs with patients with spPNETs. METHODS: We conducted a retrospective review of perioperative data and outcomes of TSC-PNETs compared with spPNETs. Inclusion criteria involved selecting patients whose tumors were no larger than 5.1 cm, the maximum size observed in the TSC-PNET group. RESULTS: Of the 347 patients resected for PNETs, 14 were TSC-PNETs and 241 were non-functional spPNETs. The median age for the whole cohort was 56 years (interquartile range [IQR] 21.0) and 47% were female. The median follow-up was 103.8 months (95% confidence interval [CI] 89.2-118.6). Specifically, 14 patients with TSC-PNETs and 194 patients with spPNETs were included. Compared with spPNETs, patients with TSC-PNETs were operated on at a younger age (24.0 vs. 57.5 years; p < 0.001), were more frequently multifocal (28.5% vs. 0.0%; p < 0.001), were more likely to undergo minimally invasive operations (78.6% vs. 24.3%; p < 0.001), and had more R1 resections (28.6% vs. 5.7%; p = 0.006). Local and distant tumor recurrence was only observed in the spPNET group. The 5-year mortality rates for the spPNET and TSC-PNET groups were 6.2% and 0.0%, respectively. No PNET-related deaths were observed among TSC-PNETs. CONCLUSION: None of the TSC-PNET patients recurred after a median follow-up of 78.0 months. The risk-benefit of aggressive pancreatic operations in TSC-PNET patients is still unclear and our findings suggest a conservative approach should be considered.

Long-term efficacy and safety of cannabidiol in patients with treatment-resistant epilepsies: Four-year results from the expanded access program.

OBJECTIVE: Cannabidiol (CBD) expanded access program, initiated in 2014, provided add-on CBD to patients with treatment-resistant epilepsies (TREs) at 35 US epilepsy centers. Prior publications reported results through December 2016; herein, we present efficacy and safety results through January 2019. METHODS: Patients received plant-derived highly purified CBD (Epidiolex®; 100 mg/ml oral solution), increasing from 2 to 10 mg/kg/day to tolerance or maximum 25-50 mg/kg/day dose, depending on the study site. Efficacy endpoints included percentage change from baseline in median monthly convulsive and total seizure frequency and ≥50%, ≥75%, and 100% responder rates across 12-week visit windows for up to 192 weeks. Adverse events (AEs) were documented at each visit. RESULTS: Of 892 patients in the safety analysis set, 322 (36%) withdrew; lack of efficacy (19%) and AEs (7%) were the most commonly reported primary reasons for withdrawal. Median (range) age was 11.8 years (range = 0-74.5), and patients were taking a median of three (range = 0-10) antiseizure medications (ASMs) at baseline; the most common ASMs were clobazam (47%), levetiracetam (34%), and valproate (28%). Median top CBD dose was 25 mg/kg/day; median exposure duration was 694 days. Median percentage reduction from baseline ranged 50%-67% for convulsive seizures and 46%-66% for total seizures. Convulsive seizure responder rates (≥50%, ≥75%, and 100% reduction) ranged 51%-59%, 33%-42%, and 11%-17% of patients across visit windows, respectively. AEs were reported in 88% of patients and serious AEs in 41%; 8% withdrew because of an AE. There were 20 deaths during the study deemed unrelated to treatment by the investigator. The most common AEs (≥20% of patients) were diarrhea (33%), seizure (24%), and somnolence (23%). SIGNIFICANCE: Add-on CBD was associated with sustained seizure reduction up to 192 weeks with an acceptable safety profile and can be used for long-term treatment of TREs.

Clinical presentation and evaluation of epilepsy with eyelid myoclonia: Results of an international expert consensus panel.

OBJECTIVE: The objective of this study was to determine areas of consensus among an international panel of experts for the clinical presentation and diagnosis of epilepsy with eyelid myoclonia (EEM; formerly known as Jeavons syndrome) to improve a timely diagnosis. METHODS: An international steering committee was convened of physicians and patients/caregivers with expertise in EEM. This committee summarized the current literature and identified an international panel of experts (comprising 25 physicians and five patients/caregivers). This international expert panel participated in a modified Delphi process, including three rounds of surveys to determine areas of consensus for the diagnosis of EEM. RESULTS: There was a strong consensus that EEM is a female predominant generalized epilepsy syndrome with onset between 3 and 12 years of age and that eyelid myoclonia must be present to make the diagnosis. There was a strong consensus that eyelid myoclonia may go unrecognized for years prior to an epilepsy diagnosis. There was consensus that generalized tonic-clonic and absence seizures are typically or occasionally seen in patients. There was a consensus that atonic or focal seizures should lead to the consideration of reclassification or alternate diagnoses. There was a strong consensus that electroencephalography is required, whereas magnetic resonance imaging is not required for diagnosis. There was a strong consensus to perform genetic testing (either epilepsy gene panel or whole exome sequencing) when one or a combination of factors was present: family history of epilepsy, intellectual disability, or drug-resistant epilepsy. SIGNIFICANCE: This international expert panel identified multiple areas of consensus regarding the presentation and evaluation of EEM. These areas of consensus may be used to inform clinical practice to shorten the time to the appropriate diagnosis.

Management of epilepsy with eyelid myoclonia: Results of an international expert consensus panel.

OBJECTIVE: There are limited data about the treatment and management of epilepsy with eyelid myoclonia (EEM). The objective of this study was to determine areas of consensus among an international panel of experts for the management of EEM (formerly known as Jeavons syndrome). METHODS: An international steering committee was convened of physicians and patients/caregivers with expertise in EEM. This committee summarized the current literature and identified an international panel of experts (comprising 25 physicians and five patients/caregivers). This panel participated in a modified Delphi process, including three rounds of surveys to determine areas of consensus for the treatment, other areas of management, and prognosis for EEM. RESULTS: There was a strong consensus for valproic acid as the first-line treatment, with levetiracetam or lamotrigine as preferable alternatives for women of childbearing age. There was a moderate consensus that ethosuximide and clobazam are also efficacious. There was a strong consensus to avoid sodium channel-blocking medications, except for lamotrigine, as they may worsen seizure control. There was consensus that seizures typically persist into adulthood, with remission occurring in <50% of patients. There was less agreement about other areas of management, including dietary therapy, lens therapy, candidacy for driving, and outcome. SIGNIFICANCE: This international expert panel identified multiple areas of consensus regarding the optimal management of EEM. These areas of consensus may inform clinical practice to improve the management of EEM. In addition, multiple areas with less agreement were identified, which highlight topics for further research.

Evaluating adult care in Dravet syndrome upon transferring from pediatrics in the U.S.: A caregiver-based survey study.

Patients with Dravet syndrome (DS) and their caregivers must navigate a complex process upon transitioning from pediatric to adult healthcare settings. Our study examines the state of care transfer of patients with DS in the U.S. A 34-question e-survey evaluating patient demographics, clinical features, and details of the transfer process was sent to caregivers of adults with DS (≥18 years old) residing in the U.S. through the Dravet Syndrome Foundation. Forty-six responses were included in the analysis. Twenty-nine patients (n = 29/46) did not undergo transfer of care - mostly because they were still followed by pediatric neurologists/epileptologists (71%), whereas 17 (n = 17/46) underwent transfer of care. Adult neurology/epilepsy teams providing care never/rarely included a multidisciplinary team (71%), addressed patients' self-advocacy capabilities (53%), or legal guardianship/end-of-life decision-making (59%). Adult neurology/epilepsy teams were considered very much attentive/available (63%), attentive and accommodating to patients with behavioral/cognitive issues (50%), and knowledgeable about caring for patients with intellectual disability/behavioral issues (63%), collaborating with caregivers (75%), and DS - especially in adults (50%). Most caregivers (62.5%) rated the transfer process as good, very good, or excellent. Patients with DS and their caregivers would benefit from more accessible transition programs, which would be ideally equipped to deliver care tailored to these patients' needs.

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.

Sporadic facial angiofibroma and sporadic angiomyolipoma mimicking tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a genetic syndrome due to mutations in either TSC1 or TSC2, leading to the development of hamartomatous tumours at multiple body sites, including facial skin (facial angiofibroma (FAF)), brain (cortical tubers) and kidney (angiomyolipoma (AML)). In this report, we describe an individual with minimal TSC clinical features, who had 'no mutation identified' (NMI) by prior genetic testing in a clinical laboratory. Our massively parallel sequencing (MPS) analysis of multiple samples from different body sites and tumours (including blood, saliva, normal skin, AML and FAF) revealed an extraordinary situation in which FAF and AML had completely independent inactivating biallelic variants in TSC2, not present in other matched samples. This suggests that the two different lesions (AML and FAF) are not due to the same underlying germline or mosaic mutation, rather both are likely sporadic events. This case demonstrates the relevance of thorough clinical examination, high-coverage MPS of multiple tumours and matched normal tissues, and appropriate genetic counselling for individuals with marginal TSC features and possible TSC1 or TSC2 mosaicism.

Tuberous sclerosis complex-associated nonfunctional pancreatic neuroendocrine tumors: Management and surgical outcomes.

We aimed to further characterize pancreatic involvement in tuberous sclerosis complex (TSC), with a focus on management of TSC-associated nonfunctional pancreatic neuroendocrine tumors (PNETs). This was a retrospective chart review of a large cohort of TSC patients. A total of 637 patients with a confirmed diagnosis of TSC were seen at the Herscot Center for Tuberous Sclerosis Complex at Massachusetts General Hospital. Of the 637 total patients with a confirmed diagnosis of TSC, 28 patients were found to have varying pancreatic findings ranging from simple-appearing cysts to well-differentiated PNETs. Thirteen of the 28 patients had PNET confirmed on pathology; 10 of these tumors were resected at Massachusetts General Hospital. None of the patients had serious perioperative or postoperative complications; only one of the patients had a recurrence following resection. As roughly 4.4% of our TSC patient population had pancreatic involvement, surveillance abdominal imaging should include evaluation of the pancreas instead of limiting to a renal protocol. Additionally, given the low risk of complications and recurrence combined with documented risk of metastasis in TSC-associated PNET, TSC patients with pancreatic lesions suspicious for PNETs should be considered as surgical candidates.

Long-term cannabidiol treatment for seizures in patients with tuberous sclerosis complex: An open-label extension trial.

OBJECTIVE: To evaluate the long-term safety and efficacy of add-on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC) in the open-label extension (OLE) of the randomized, placebo-controlled phase 3 trial GWPCARE6 (NCT02544763). Results of an interim (February 2019 data cut) analysis are reported. METHODS: Patients who completed the randomized trial enrolled to receive CBD (Epidiolex® in the United States; Epidyolex® in the EU; 100 mg/mL oral solution). The initial target dose was 25 mg/kg/day, which, based on response and tolerability, could be decreased or increased up to 50 mg/kg/day. The primary end point was safety. Key secondary end points included percentage reduction in TSC-associated (countable focal and generalized) seizures, responder rates, and Subject/Caregiver Global Impression of Change (S/CGIC). RESULTS: Of 201 patients who completed the randomized phase, 199 (99%) entered the OLE. Mean age was 13 years (range, 1-57). At the time of analysis, 5% of patients had completed treatment, 20% had withdrawn, and 75% were ongoing. One-year retention rate was 79%. Median treatment time was 267 days (range, 18-910) at a 27 mg/kg/day mean modal dose. Most patients (92%) had an adverse event (AE). Most common AEs were diarrhea (42%), seizure (22%), and decreased appetite (20%). AEs led to permanent discontinuation in 6% of patients. There was one death that was deemed treatment unrelated by the investigator. Elevated liver transaminases occurred in 17 patients (9%) patients; 12 were taking valproate. Median percentage reductions in seizure frequency (12-week windows across 48 weeks) were 54%-68%. Seizure responder rates (≥50%, ≥75%, 100% reduction) were 53%-61%, 29%-45%, and 6%-11% across 12-week windows for 48 weeks. Improvement on the S/CGIC scale was reported by 87% of patients/caregivers at 26 weeks. SIGNIFICANCE: In patients with TSC, long-term add-on CBD treatment was well tolerated and sustainably reduced seizures through 48 weeks, with most patients/caregivers reporting global improvement.

Electroencephalographic changes in purified pharmaceutical cannabidiol therapy.

OBJECTIVE: Evaluate electroencephalographic changes in patients receiving purified pharmaceutical cannabidiol (CBD). METHODS: A total of 104 EEG studies from 52 patients with pediatric-onset refractory epilepsy, who were enrolled in the FDA-approved expanded access investigational new drug program, were retrospectively analyzed for electroencephalographic changes in the background, interictal epileptiform discharges (IEDs), ictal findings, and sleep architecture after CBD treatment. RESULTS: Patients were between 18 months and 52 years of age. After CBD treatment, 88.4% (46/52) of patients had EEG changes. Eighty-nine percent of these patients had changes in their background, 74% in IEDs, 46% in ictal findings, and 17% in sleep architecture. Seven out of 52 patients had modified hypsarrhythmia on their pre-treatment EEG. The pattern resolved in 2/7 patients (29%), diminished in prevalence in 4/7 (57%) subjects, and remained unchanged in 1/7 (14%) cases. Electrographic improvement was seen in 70% (32/46) of the patients, and worsening in 7% (3/46) of the cases. At the post-CBD EEG, 83% had a reduction in the frequency of the most predominant seizure type, and 25% reported subjective cognitive improvement. Of these patients, 88% (p = 0.09) and 92% (p = 0.45) had corresponding EEG changes, respectively. CONCLUSION: Our results revealed electrographic changes in association with the CBD treatment. Despite these changes, a substantial association between specific electrographic findings and clinical outcomes was not established.

Subependymal giant cell astrocytomas are characterized by mTORC1 hyperactivation, a very low somatic mutation rate, and a unique gene expression profile.

Subependymal giant-cell astrocytomas (SEGAs) are slow-growing brain tumors that are a hallmark feature seen in 5-10% of patients with Tuberous Sclerosis Complex (TSC). Though histologically benign, they can cause serious neurologic symptoms, leading to death if untreated. SEGAs consistently show biallelic loss of TSC1 or TSC2. Herein, we aimed to define other somatic events beyond TSC1/TSC2 loss and identify potential transcriptional drivers that contribute to SEGA formation. Paired tumor-normal whole-exome sequencing was performed on 21 resected SEGAs from 20 TSC patients. Pathogenic variants in TSC1/TSC2 were identified in 19/21 (90%) SEGAs. Copy neutral loss of heterozygosity (size range: 2.2-46 Mb) was seen in 76% (16/21) of SEGAs (44% chr9q and 56% chr16p). An average of 1.4 other somatic variants (range 0-7) per tumor were identified, unlikely of pathogenic significance. Whole transcriptome RNA-sequencing analyses revealed 190 common differentially expressed genes in SEGA (n = 16, 13 from a prior study) in pairwise comparison to each of: low grade diffuse gliomas (n = 530) and glioblastoma (n = 171) from The Cancer Genome Atlas (TCGA) consortium, ganglioglioma (n = 10), TSC cortical tubers (n = 15), and multiple normal tissues. Among these, homeobox transcription factors (TFs) HMX3, HMX2, VAX1, SIX3; and TFs IRF6 and EOMES were all expressed >12-fold higher in SEGAs (FDR/q-value < 0.05). Immunohistochemistry supported the specificity of IRF6, VAX1, SIX3 for SEGAs in comparison to other tumor entities and normal brain. We conclude that SEGAs have an extremely low somatic mutation rate, suggesting that TSC1/TSC2 loss is sufficient to drive tumor growth. The unique and highly expressed SEGA-specific TFs likely reflect the neuroepithelial cell of origin, and may also contribute to the transcriptional and epigenetic state that enables SEGA growth following two-hit loss of TSC1 or TSC2 and mTORC1 activation.

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.

Long-term safety and efficacy of add-on cannabidiol in patients with Lennox-Gastaut syndrome: Results of a long-term open-label extension trial.

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy that is often treatment resistant. Efficacy and safety of add-on cannabidiol (CBD) to treat seizures associated with LGS was demonstrated in two randomized controlled trials (RCTs). Patients who completed the RCTs were invited to enroll in this long-term open-label extension (OLE) trial, GWPCARE5 (NCT02224573). We present the final analysis of safety and efficacy outcomes from GWPCARE5. METHODS: Patients received plant-derived highly purified CBD (Epidiolex in the United States; Epidyolex in the European Union; 100 mg/ml oral solution), titrated to a target maintenance dose of 20 mg/kg/day over 2 weeks. Based on response and tolerability, CBD could then be reduced or increased up to 30 mg/kg/day. RESULTS: Of 368 patients with LGS who completed the RCTs, 366 (99.5%) enrolled in this OLE. Median and mean treatment duration were 1090 and 826 days (range = 3-1421), respectively, with a mean modal dose of 24 mg/kg/day. Adverse events (AEs) occurred in 96% of patients, serious AEs in 42%, and AE-related discontinuations in 12%. Common AEs were convulsion (39%), diarrhea (38%), pyrexia (34%), and somnolence (29%). Fifty-five (15%) patients experienced liver transaminase elevations more than three times the upper limit of normal; 40 (73%) were taking concomitant valproic acid. Median percent reductions from baseline ranged 48%-71% for drop seizures and 48%-68% for total seizures through 156 weeks. Across all 12-week visit windows, 87% or more of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale. SIGNIFICANCE: Long-term add-on CBD treatment had a similar safety profile as in the original RCTs. Sustained reductions in drop and total seizure frequency were observed for up to 156 weeks, demonstrating long-term benefits of CBD treatment for patients with LGS.

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.

Sunflower syndrome: a poorly understood photosensitive epilepsy.

Sunflower syndrome is a rare photosensitive epilepsy which has received little attention in recent medical literature. The historical cases documenting the epilepsy's stereotyped handwaving motion in front of light characterized the behavior as self-inducing seizures via mimic of stroboscopic effect. However, the relationship between handwaving episodes and attendant generalized electroencephalogram abnormalities, and an appreciation of the compulsive attraction the sun and other light sources hold for these patients, suggest the handwaving motion may be a part of the seizure rather than a mechanism of self-induction. The lack of awareness of Sunflower syndrome often leads to misdiagnosis. The seizures are often refractory to traditional anticonvulsant medication, and patients resort to behavioral intervention, such as hats and sunglasses, to reduce handwaving episodes. Further study is required to determine the syndrome's natural history and to identify more effective treatment options. WHAT THIS PAPER ADDS: Sunflower syndrome is a rare condition that is often misdiagnosed. Awareness of the clinical and electroencephalogram characteristics of Sunflower syndromemay reduce the prevalence of misdiagnosis.

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.

Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome.

BACKGROUND: The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period. RESULTS: The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, -22.8 percentage points; 95% confidence interval [CI], -41.1 to -5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient's overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group. CONCLUSIONS: Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. (Funded by GW Pharmaceuticals; ClinicalTrials.gov number, NCT02091375 .).

Cannabidiol efficacy independent of clobazam: Meta-analysis of four randomized controlled trials.

OBJECTIVE: The efficacy of cannabidiol (CBD) with and without concomitant clobazam (CLB) was evaluated in stratified analyses of four large randomized controlled trials, two in Lennox-Gastaut syndrome, and two in Dravet syndrome. METHODS: Each trial of CBD (Epidiolex® in the US; Epidyolex® in the EU; 10 and 20 mg/kg/day) was evaluated by CLB use. The treatment ratio was analyzed using negative binomial regression for changes in seizure frequency and logistic regression for the 50% responder rate, where the principle analysis combined both indications and CBD doses in a stratified meta-analysis. Pharmacokinetic data were examined for an exposure/response relationship based on CLB presence/absence. Safety data were analyzed using descriptive statistics. RESULTS: The meta-analysis favored CBD vs. placebo regardless of CLB use. The treatment ratio (95% CI) of CBD over placebo for the average reduction in seizure frequency was 0.59 (0.52, 0.68; P < .0001) with CLB and 0.85 (0.73, 0.98; P = .0226) without CLB, and the 50% responder rate odds ratio (95% CI) was 2.51 (1.69, 3.71; P < .0001) with CLB and 2.40 (1.38, 4.16; P = .0020) without CLB. Adverse events (AEs) related to somnolence, rash, pneumonia, or aggression were more common in patients with concomitant CLB. There was a significant exposure/response relationship for CBD and its active metabolite. CONCLUSIONS: These results indicate CBD is efficacious with and without CLB, but do not exclude the possibility of a synergistic effect associated with the combination of agents. The safety and tolerability profile of CBD without CLB show a lower rate of certain AEs than with CLB.

Ictal EEG in sunflower syndrome: Provoked or unprovoked seizures?

Sunflower syndrome (SS) is a rare, photosensitive epilepsy characterized by an attraction to light and highly stereotyped seizures with associated hand-waving (HW). It is controversial whether HW is part of the seizure or a provoking factor; therefore, we aimed to characterize the ictal electroencephalogram (EEG) in patients with SS. Video-EEG (vEEG) and charts of five patients with SS with HW during vEEG from Massachusetts General Hospital's Pediatric Epilepsy Program were reviewed and analyzed. In four out of five patients, the ictal EEG showed high amplitude (500-700 µV) 3-4 Hz generalized spike/polyspike-and-slow wave discharges, lasting 1.63-24.41 s. One hundred and twelve of 126 HW episodes, correlating to epileptiform activity (vEEG), had a lag time of less than 1.00 s (88.89%) between onset of HW and appearance of epileptiform activity. This suggests that HW does not induce seizure activity. Awareness of the ictal EEG features of this syndrome is important, as patients are frequently described as "self-inducing" their seizures.

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.