Publications

Abstract

  • Long-term Efficacy and Safety of Add-on Cannabidiol (CBD) in Patients with Treatment-Resistant Epilepsies (TRE): 4-year Results from the Expanded Access Program (EAP) icnapedia.org/abstracts-icnc2020#posters poster#223   (10/2020) (link)
  • Visual Memory is improved in children 1 year after epilepsy surgery on the right hemisphere. Presented at the 2019 Annual Meeting of the American Epilepsy Society on Dec 8, 2019: Baltimore, Maryland. Rationale: In order to test for language and verbal memory in children, neuropsychological assessment, intracarotid sodium amytal testing (Wada test), or functional MRI or a combination thereof are done. In resource-limited centers or if the ability of the patients to participate in testing are limited, neuropsychological assessment may be the most viable option.  Methods: We retrospectively reviewed the neuropsychological assessment profile of patients below 18 years old pre- and post-epilepsy surgery. We identified 4 right-handed patients who underwent neuropsychological testing prior to surgeries involving the right hemisphere. We reviewed their verbal memory scores and visual memory scores using the California Verbal Learning Test- Children's Version (CVLT-C) and Children's Memory Scale (CMS), respectively.  Results: We found that there was no change in the verbal memory before and after surgery. There was however an improvement in the visual memory as seen in the CMS Dot Locations Learning and CMS Dot Locations Long Delay scores.  Conclusions: Memory decline post-surgery is often attributed to resection of a functional hippocampus in the language-dominant temporal lobe. In our patients, improvement in visual memory post-surgery was seen in the resection involving the non-language dominant hemisphere. (12/2019) (link)
  • Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded accress 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. Keywords: cannabidiol; efficacy; expanded access program; seizures; tolerability; treatment-resistant epilepsy. © 2018 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy. (08/2018) (link)
  • Seizure burden and hydrocephalus as factors in considering brain surgery for pediatric patients with tuberous sclerosis complex Rationale: Children with tuberous sclerosis complex (TSC) carry a significant seizure burden due to cortical tubers and subependymal giant cell astrocytomas (SEGA). The timing and indication for surgery remains a clinical dilemma. Methods: We report 3 TSC patients  who were considered for surgery due to high seizure burden and hydrocephalus.  Results: Patient  #1 was a term newborn female in focal status epilepticus since 15 minutes of life with 50-100 daily seizures lasting up to 20 minutes. She was on topiramate, phenobarbital, lacosamide, midazolam, and pentobarbital. Burst suppression was induced but status epilepticus recurred upon weaning the drips. MRI demonstrated a large left frontoparietal giant cell astrocytoma (Figure 1).  Hemispherectomy was deferred due to the risk of high mortality and the patient’s young age. The mother decided to withdraw support on day 23. She was heterozygous for a pathogenic variant of the TSC1 gene with exon 1 deletion.Patient #2 is a 2 yo boy who presented with a large left frontal subependymal mass causing hydrocephalus soon after birth. Biopsy confirmed SEGA. A VP shunt was placed and Everolimus was started. Renal ultrasound and echocardiogram did not reveal TSC-related tumors. He was heterozygous for a pathogenic variant of the TSC2 gene with c.4928A>G; p.Asn1643Ser. He was profoundly delayed but was seizure-free until 16 months of age when he began having brief intermittent rhythmic extremity twitching. Partial resection of the SEGA was performed at age 2. Post-operatively, he developed status epilepticus and paroxysmal sympathetic hyperactivity. He is on  Keppra, Valproic acid, Gabapentin and Diazepam and has 6-8 brief tonic seizures daily. Patient #3 is an 8 yo girl with tonic clonic seizures at 5 weeks of age. MRI showed multiple cortical/ subcortical tubers and a SEGA. Renal ultrasound showed bilateral renal angiomyolipomas. Echocardiogram showed small rhabdomyomas. She had 3 seizures daily but sustained head injuries from drop attacks despite wearing a helmet. She was on Oxcarbazepine, Valproic acid, Vigabatrin, Zonisamide, and Lacosamide. Repeat brain MRI showed subependymal nodules and multiple cortical/subcortical tubers, most prominent in the right frontal lobe. There were epileptic spasms with asymmetric bilateral arm extension with head turn to the right and initial EEG change in the right frontal region. Interictally, there were focal epileptiform discharges in the right frontal and temporal regions. Ictal SPECT showed right frontal hyperperfusion. Intracranial strip electrodes placed radially on the frontal tubers did not confirm them as ictal onset-zones and the EEG changes appeared to be diffuse.  Corpus callosotomy was performed to reduce the drop attacks. At 3 months post-op, she had no recurrent drop attacks, dyscognitive or tonic clonic seizures. She continued to have myoclonic seizures every other day and is more alert and doing better at school. Conclusions: The approach to managing epilepsy in children with TSC is highly individualized. The decision to consider surgery is based on seizure burden and clinical sequelae of TSC-related brain lesions. These three cases demonstrate that surgery, in conjunction with medication management, can help decrease seizure burden and improve quality of life.  (12/2017) (link)
  • Long-term Efficacy and Safety of Cannabidiol (CBD) in Children and Adults with Treatment Resistant Epilepsies (TRE) Rationale: Initial data suggest that add-on CBD may be efficacious in patients with TRE. The long-term effectiveness and safety of add-on CBD in patients with TRE enrolled in an Expanded Access Program (EAP) and treated for >10 weeks between January 2014 and December 2016 were assessed. Methods: During the 4-week baseline period, parents/caregivers kept seizure diaries of all countable seizures. Patients received a plant-derived pharmaceutical formulation of CBD (100 mg/mL) in oral (sesame oil) solution (Epidiolex: GW Pharmaceuticals) at a gradually increasing dose from 2–10 mg/kg/day to tolerance or a maximum dose of 25–50 mg/kg/day, depending on the site (median dose: 25 mg/kg/day [IQR: 15-25] at 12 weeks; 25 mg/kg/day [IQR: 21-30] at 96 weeks). Patients were seen every 2–4 weeks during the first 12 weeks and at 3–6-month intervals thereafter. Efficacy endpoints were percentage change from baseline in convulsive and total seizures and ≥25%, ≥50%, and ≥100% responder rates. Adverse events (AEs) were recorded. Results: Of all U.S. EAP patients with efficacy data (N=580), 136 (23%) withdrew during the study period; the top reasons were lack of efficacy for 87 (15%) and AEs for 25 (4%). Results are presented for patients on CBD >10 weeks: 542 patients comprise the safety set with median (Q1, Q3) treatment duration of 54 weeks (27, 100) and 523 patients comprise the efficacy set. Mean (min, max) age was 13.0 y (0.4, 62.1); 23% were ≥18 y. Median (Q1, Q3) number of concomitant antiepileptic drugs was 3 (2, 4). Baseline monthly median (Q1, Q3) seizure frequency was 40 (12, 112) for convulsive and 72 (22, 196) for total seizures. Median percentage changes in convulsive and total seizures were consistent at Weeks 12, 24, 48, 72, and 96 (Table 1). For both convulsive and total seizures, the ≥50%, ≥75%, and 100% responder rates were also consistent across the five time points.Most common AEs in this subset of patients on CBD >10 weeks are summarized in Table 2. Abnormal liver AEs were reported in 11% of patients. All causality serious AEs were reported in 35% of patients; most common were convulsion (10%), status epilepticus (8%), and pneumonia (5%). Eight patients died, considered unrelated to treatment. In patients treated for <10 weeks and not included in this analysis, there were 4 deaths (including 1 prior to starting CBD), considered unrelated to treatment. Across the entire CBD development program, common adverse reactions are somnolence, decreased appetite, diarrhea, pyrexia, fatigue, lethargy,  rash, nasopharyngitis, and pneumonia.  Dose-related reversible elevation of liver transaminases without elevation of bilirubin is an identified adverse reaction of special interest for CBD. Conclusions: The EAP is an ongoing study reflective of real-world clinical practice. To date, CBD has been generally well-tolerated. This study supports previous observational and randomized controlled trial data showing add-on CBD may be an efficacious long-term treatment option for TRE. Funding: Funded by GW Research Ltd. (11/2017) (link)
  •   Vagal Nerve Stimulation for Super Refractory Status Epilepticus in children Rationale: Super- refractory status epilepticus (SRSE) is defined as persistent seizures or recurrence of seizures 24 hours after anesthetic anti-seizure agents are started. There are a few reports on the use of Vagal Nerve Stimulation (VNS) in refractory status epilepticus in children (1,2). We asked the question whether VNS can be used as an adjunctive therapy in SRSE. We report on a 10-month-old boy with hypoxic-ischemic encephalopathy s/p "partial" right temporal lobe resection, a 28-month-old boy with a nearly homoplasmic m.11778G>A mutation and progressive mitochondrial encephalopathy, and a 6-year-old boy with left mesial temporal sclerosis, who was unable to undergo epilepsy surgery. They were in SRSE and were implanted with VNS after either surgical or medication failure. Methods: Retrospective chart review of EEGs to confirm electroclinical and electrographic seizures, hospitalization, and follow-up records were done. The primary endpoint was reduction in number of anti-seizure medications. The secondary endpoint was reduction in the number of anti-seizure medications. Results: At 2 year follow-up, there was 100% seizure reduction in patients 1 and 3, and 50% reduction in patient 2 who has the progressive mitochondrial encephalopathy and is currently undergoing epilepsy surgery evaluation. There was a mean reduction of 2 anti-seizure medications at 2-year follow-up. The total number of medications decreased from 4 to 2, 8 to 5, and 6 to 5, respectively. Conclusions: The poor response of patient 2 is likely due to his progressive mitochondrial disease. Arthur (3) and colleagues have reported no response to VNS therapy in 5 patients with mitochondrial disease. The good response of patients 1 and 3 point to a potential role for VNS as an adjunctive therapy in patients who failed surgical intervention or anti-seizure medications as seen at 2 year follow-up. The lag time in the response to VNS makes it a poor option in hyperacute cases where early cessation of seizures is the goal. For patients who are epilepsy surgery candidates, epilepsy surgery should remain as the primary treatment option. 1De Herdt V et al, European Paediatric Neurology Society, 2009 (13); 286-289 2Winston K et al, Pediatric Neurosurgery, 2001; 34: 190-192 3Arthur TM et al, Mitochondrion, 2007; 7(4): 279-283 (11/2016) (link)