Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results.

OBJECTIVE: Since 2014, cannabidiol (CBD) has been administered to patients with treatment-resistant epilepsies (TREs) in an ongoing expanded-access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016. METHODS: Twenty-five US-based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2-10 mg/kg/d, titrated to a maximum dose of 25-50 mg/kg/d. Patient visits were every 2-4 weeks through 16 weeks and every 2-12 weeks thereafter. Efficacy endpoints included the percentage change from baseline in median monthly convulsive and total seizure frequency, and percentage of patients with ≥50%, ≥75%, and 100% reductions in seizures vs baseline. Data were analyzed descriptively for the efficacy analysis set and using the last-observation-carried-forward method to account for missing data. Adverse events (AEs) were documented at each visit. RESULTS: Of 607 patients in the safety dataset, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4-62). Median number of concomitant AEDs was 3 (range, 0-10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add-on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with ≥50%, ≥75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. CBD was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%). SIGNIFICANCE: Results from this ongoing EAP support previous observational and clinical trial data showing that add-on CBD may be an efficacious long-term treatment option for TRE.

Open-label use of highly purified CBD (Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes.

OBJECTIVE: We studied our collective open-label, compassionate use experience in using cannabidiol (CBD) to treat epilepsy in patients with CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes. METHODS: We included patients aged 1-30 years with severe childhood-onset epilepsy who received CBD for ≥10 weeks as part of multiple investigator-initiated expanded access or state access programs for a compassionate prospective interventional study: CDKL5 deficiency disorder (n = 20), Aicardi syndrome (n = 19), Dup15q syndrome (n = 8), and Doose syndrome (n = 8). These patients were treated at 11 institutions from January 2014 to December 2016. RESULTS: The percent change in median convulsive seizure frequency for all patients taking CBD in the efficacy group decreased from baseline [n = 46] to week 12 (51.4% [n = 35], interquartile range (IQR): 9-85%) and week 48 (59.1% [n = 27], IQR: 14-86%). There was a significant difference between the percent changes in monthly convulsive seizure frequency during baseline and week 12, χ2(2) = 22.9, p = 0.00001, with no difference in seizure percent change between weeks 12 and 48. Of the 55 patients in the safety group, 15 (27%) withdrew from extended observation by week 144: 4 due to adverse effects, 9 due to lack of efficacy, 1 withdrew consent, and 1 was lost to follow-up. SIGNIFICANCE: This open-label drug trial provides class III evidence for the long-term safety and efficacy of CBD administration in patients with treatment-resistant epilepsy (TRE) associated with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Adjuvant therapy with CBD showed similar safety and efficacy for these four syndromes as reported in a diverse population of TRE etiologies. This study extended analysis of the prior report from 12 weeks to 48 weeks of efficacy data and suggested that placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in these epileptic encephalopathies.

Dyshomeostatic modulation of Ca2+-activated K+ channels in a human neuronal model of KCNQ2 encephalopathy.

Mutations in KCNQ2, which encodes a pore-forming K+ channel subunit responsible for neuronal M-current, cause neonatal epileptic encephalopathy, a complex disorder presenting with severe early-onset seizures and impaired neurodevelopment. The condition is exceptionally difficult to treat, partially because the effects of KCNQ2 mutations on the development and function of human neurons are unknown. Here, we used induced pluripotent stem cells (iPSCs) and gene editing to establish a disease model and measured the functional properties of differentiated excitatory neurons. We find that patient iPSC-derived neurons exhibit faster action potential repolarization, larger post-burst afterhyperpolarization and a functional enhancement of Ca2+-activated K+ channels. These properties, which can be recapitulated by chronic inhibition of M-current in control neurons, facilitate a burst-suppression firing pattern that is reminiscent of the interictal electroencephalography pattern in patients. Our findings suggest that dyshomeostatic mechanisms compound KCNQ2 loss-of-function leading to alterations in the neurodevelopmental trajectory of patient iPSC-derived neurons.

The ketogenic diet in children 3 years of age or younger: a 10-year single-center experience.

The ketogenic diet (KD) is an effective treatment option for intractable epilepsy. Here, we reviewed the last 10 years of our experience with the KD and characterized its use in patients under 3 years of age. Medical records of all patients under the age of 3 years who were treated with the ketogenic diet from April 2004 to June 2014 were retrospectively reviewed. One hundred and nine patients with drug-resistant epilepsy were included. The mean age at the initiation of the KD was 1.4 ± 0.8 years old. The youngest patient was 3 weeks old. After 3 months, 39% (42/109) of patients responded to the KD and experienced more than 50% seizure reduction. Of those 42 patients, 20 (18%) achieved complete seizure control. Patients with a genetic etiology showed a better response to the KD in seizure reduction than the other patients (p = 0.03). Age at initiation of the KD was not related to eventual seizure outcome (p = 0.6). The KD continues to be an effective, safe, and well tolerated treatment option for infants with intractable epilepsy.

Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: Expanded access program results.

BACKGROUND: Since 2014, patients with severe treatment-resistant epilepsies (TREs) have been receiving add-on cannabidiol (CBD) in an ongoing, expanded access program (EAP), which closely reflects clinical practice. We conducted an interim analysis of long-term efficacy and tolerability in patients with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) who received CBD treatment through December 2016. METHODS: Children and adults with LGS/DS taking stable doses of antiepileptic drugs (AEDs) at baseline were included from 25 EAP sites across the United States. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received a pharmaceutical formulation of highly purified CBD (Epidiolex®; 100 mg/mL) in oral solution at 2-10 mg/kg/day, titrated until tolerability limit or a maximum dose of 25-50 mg/kg/day. Patient visits were every 2-4 weeks. The percentage change from baseline in median monthly convulsive (ie, major motor) and total seizures was evaluated at 12-week intervals through 96 weeks. The percentages of patients who had ≥50%, ≥75%, and 100% reduction in monthly seizures relative to the baseline period were also evaluated. Adverse events (AEs) were monitored and summarized for the safety analysis set (SAS) through 144 weeks. RESULTS: Of the 607 patients in the SAS, 58 had DS and 94 had LGS (N = 152); 455 patients had other TREs. Twenty-eight percent of LGS/DS patients withdrew, primarily owing to lack of efficacy (20%). LGS/DS patients were taking a median of 3 (0-10) concomitant AEDs. Median treatment duration was 78.3 (range, 4.1-146.4) weeks. Between weeks 12 and 96, median CBD dose ranged from 21 to 25 mg/kg/day. At 12 weeks, add-on CBD reduced median monthly major motor seizures by 50% and total seizures by 44%, with consistent reductions in both seizure types through 96 weeks. At 12 weeks, the proportions of patients with ≥50%, ≥75%, and 100% reductions in major motor seizures were 53%, 23%, and 6%; the proportions with corresponding reductions in total seizures were 46%, 26%, and 5%. Responder rates for both seizure types were consistent through 96 weeks. CBD had an acceptable safety profile; the most common AEs were somnolence (30%) and diarrhea (24%). CONCLUSIONS: Results from this interim analysis support add-on CBD as an effective long-term treatment option in LGS or DS.

Severe peri-ictal respiratory dysfunction is common in Dravet syndrome.

Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. Patients with DS have a high risk of sudden unexplained death in epilepsy (SUDEP), widely believed to be due to cardiac mechanisms. Here we show that patients with DS commonly have peri-ictal respiratory dysfunction. One patient had severe and prolonged postictal hypoventilation during video EEG monitoring and died later of SUDEP. Mice with an Scn1aR1407X/+ loss-of-function mutation were monitored and died after spontaneous and heat-induced seizures due to central apnea followed by progressive bradycardia. Death could be prevented with mechanical ventilation after seizures were induced by hyperthermia or maximal electroshock. Muscarinic receptor antagonists did not prevent bradycardia or death when given at doses selective for peripheral parasympathetic blockade, whereas apnea, bradycardia, and death were prevented by the same drugs given at doses high enough to cross the blood-brain barrier. When given via intracerebroventricular infusion at a very low dose, a muscarinic receptor antagonist prevented apnea, bradycardia, and death. We conclude that SUDEP in patients with DS can result from primary central apnea, which can cause bradycardia, presumably via a direct effect of hypoxemia on cardiac muscle.

Seizure Outcomes in Children Following Electrocorticography-Guided Single-Stage Surgical Resection.

BACKGROUND: In children with abnormal imaging, single-stage epilepsy surgery is an attractive alternative to the two-stage approach that relies on invasive recording of seizures. Implanted electrodes carry risks of their own and extend hospitalization, but the efficacy of one-stage resections in a variety of pathologies and cerebral locations is not well established. We report our center's experience with single-stage epilepsy surgery guided by intraoperative electrocorticography (ECoG). METHODS: We retrospectively analyzed 130 consecutive patients who underwent single-stage epilepsy surgery before age 19 years and had at least a two-year follow-up. Intraoperative ECoG was available for review in 113. Patients were considered seizure-free if they were continuously Engel Class I up to the two-year postoperative mark. ECoG findings were classified according to the presence of interictal attenuation, spikes, both, or neither. Complications and hospital length of stay were evaluated. RESULTS: Eighty percent of 130 patients were seizure-free at two years. All but one had an abnormal MRI. Patients with tumor had a better seizure outcome than patients with cortical malformation. Frontal resections had worse outcome, especially among tumors. Intraoperative ECoG revealed both attenuation and spikes in 48%, attenuation only in 23%, spikes only in 20%, and neither in 9%. The complication rate was 6.9%, with no major neurological complications. The average length of stay was 5.7 nights. CONCLUSIONS: With ECoG-guided single-stage surgery, we achieved results comparable with other pediatric surgical series and with a low complication rate. An extensive two-stage approach may not be required when there is a lesion on imaging and other information is concordant, even when the MRI abnormality is subtle and unclearly delineated. Frontal foci may present a challenge because of their proximity to "eloquent" nonresectable cortex or critical structures.

Phenotypes of Dravet Syndrome.

Researchers from the University of Washington in Seattle studied selective heterozygous and homozygous deletions of the voltage gated sodium channel (Nav1.1) in parvalbumin (PV) or somato-statin (SST) expressing interneurons.

Alleged cases of vaccine encephalopathy rediagnosed years later as Dravet syndrome.

Dravet syndrome is a rare epileptic encephalopathy linked to mutations in SCN1A (neuronal sodium channel α1 subunit) and characterized by an onset in infancy with polymorphous seizure types and developmental decline. It was reported recently that a proportion of patients previously diagnosed with alleged vaccine encephalopathy might possess SCN1A mutations and clinical histories that enabled a diagnosis of Dravet syndrome, but these results have not been replicated. We present here the cases of 5 children who presented for epilepsy care with presumed parental diagnoses of alleged vaccine encephalopathy caused by pertussis vaccinations in infancy. Their conditions were all rediagnosed years later, with the support of genetic testing, as Dravet syndrome. We hope that these cases will raise awareness of Dravet syndrome among health care providers who care for children and adolescents and aid in earlier recognition and diagnosis.

Ictal asystole and anti-N-methyl-D-aspartate receptor antibody encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is a recently identified autoimmune disorder that is increasingly recognized in children. Most cases occur in girls and women and may be paraneoplastic with an associated ovarian teratoma. Characteristic clinical features include neuropsychiatric symptoms, dyskinesias, decreased consciousness, and autonomic instability. We report the first case of asystole associated with temporal lobe seizures in this disorder and highlight the need for careful monitoring for this potentially fatal complication. A 15-year-old previously healthy girl presented with focal seizures and personality changes that progressed to periods of agitation and confusion alternating with catatonia. Anti-NMDAR antibodies were detected in the cerebrospinal fluid and serum. Twenty-six days after initial presentation, new seizures developed characterized by bradycardia and oxygen desaturation. Continuous video-electroencephalogram monitoring captured 3 seizures with left-temporal onset and associated asystole. An ovarian teratoma was diagnosed by pelvic ultrasound and computed tomography, and surgical resection was followed by gradual improvement in her neuropsychiatric symptoms. Treatment with phenobarbital beginning on day 26 lead to the cessation of seizures. However, asymptomatic bradycardia and pauses of 3 seconds continued. After insertion of a demand pacemaker on day 46, there were no further cardiac events. The patient was also treated with 2 courses of intravenous immunoglobulin. Outpatient follow-up at 4 months revealed near-complete neurologic recovery and no cardiac events. To our knowledge, ictal asystole has not previously been described as a complication of anti-NMDAR encephalitis; it is a preventable cause of death in this emerging pediatric disorder, which presents with protean symptoms and is easily misdiagnosed.

Child Neurology: Dravet syndrome: when to suspect the diagnosis.

Dravet syndrome (DS), previously known as severe myoclonic epilepsy in infancy (SMEI), is an epileptic encephalopathy that presents with prolonged seizures in the first year of life. The seizures often occur with fever or illness, and are frequently initially categorized as febrile seizures. The correct diagnosis of DS and appropriate follow-up are typically delayed. The EEG is normal at onset, and neuroimaging reveals no structural lesion. Early development is normal, but signs of regression appear in the second year of life and are often accompanied by convulsive status epilepticus, alternating hemiconvulsions, and myoclonic seizures. Diagnosis can be confirmed by genetic testing that is now available, and shows mutations within the SCN1A gene. Early recognition and diagnosis of DS and management with appropriate anticonvulsants and treatment plan may reduce the seizure burden and improve long-term developmental outcome.

When do seizures usually improve with the ketogenic diet?

PURPOSE: Parents often expect immediate seizure improvement after starting the ketogenic diet (KD) for their children. The purpose of this study was to determine the typical time to seizure reduction as well as the time after which it was unlikely to be helpful in those children started on the KD. METHODS: Records of all children started on the KD at Johns Hopkins Hospital, Baltimore (n = 83) and Children's Memorial Hospital, Chicago (n = 35) from November 2003 to December 2006 were examined to determine the first day in which seizures were reportedly improved. RESULTS: Of the 118 children started on the KD, 99 (84%) had documented seizure reduction. The overall median time to first improvement was 5 days (range: 1-65 days). Seventy-five percent of children improved within 14 days. In those children who were fasted at KD onset, the time to improvement was quicker (median 5 vs. 14 days, p < 0.01) with a higher percentage improving within 5 days (60% vs. 31%, p = 0.01). No difference was identified between fasting and nonfasting in regards to long-term outcomes, however. DISCUSSION: The KD works quickly when effective, typically within the first 1-2 weeks. Starting the KD after a fasting period may lead to a more rapid, but equivalent long-term seizure reduction, confirming prior reports. If the KD has not led to seizure reduction after 2 months, it can probably be discontinued.