Mortality in Dravet syndrome: A review

Shmuely, Sharon; Sisodiya, Sanjay M.; Gunning, W. Boudewijn; Sander, Josemir W.; Thijs, Roland D.

doi:10.1016/j.yebeh.2016.09.007

Cited by 142 publications

(150 citation statements)

References 54 publications

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“…1 Incidence estimates range from 1 in 15 700 to 40 000 infants, [2][3][4][5] and early mortality is high, with sudden unexplained death in epilepsy (SUDEP) and status epilepticus as the leading causes of death. 6,7 DS results from mutations in the gene encoding the α1 subunit of the voltage-gated sodium channel (Nav1.1) encoded by SCN1A in 70%-80% of cases, whereas mutations in other voltagegated sodium channel subunits as well as other ion channels can also cause DS. [8][9][10][11][12] Seizures in DS are often drug resistant.…”

Section: Introductionmentioning

confidence: 99%

Long‐term cannabidiol treatment in patients with Dravet syndrome: An open‐label extension trial

Devinsky¹,

et al. 2018

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Summary Objective Add‐on cannabidiol (CBD) significantly reduced seizures associated with Dravet syndrome (DS) in a randomized, double‐blind, placebo‐controlled trial: GWPCARE1 Part B (NCT02091375). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or a second placebo‐controlled trial, GWPCARE2 (NCT02224703), were invited to enroll in a long‐term open‐label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient‐reported outcomes from GWPCARE5. Methods Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2‐week period, with their existing medications. Based on response and tolerance, CBD could be reduced or increased up to 30 mg/kg/d. Results By November 2016, a total of 278 patients had completed the original randomized trials, and 264 (95%) enrolled in this open‐label extension. Median treatment duration was 274 days (range 1‐512) with a mean modal dose of 21 mg/kg/d, and patients received a median of 3 concomitant antiepileptic medications. Adverse events (AEs) occurred in 93.2% of patients and were mostly mild (36.7%) or moderate (39.0%). Commonly reported AEs were diarrhea (34.5%), pyrexia (27.3%), decreased appetite (25.4%), and somnolence (24.6%). Seventeen patients (6.4%) discontinued due to AEs. Twenty‐two of the 128 patients from GWPCARE1 (17.2%), all taking valproic acid, had liver transaminase elevations ≥3 times the upper limit of normal. In patients from GWPCARE1 Part B, the median reduction from baseline in monthly seizure frequency assessed in 12‐week periods up to week 48 ranged from 38% to 44% for convulsive seizures and 39% to 51% for total seizures. After 48 weeks of treatment, 85% of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale. Significance This trial shows that long‐term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment‐resistant DS.

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Section: Introductionmentioning

confidence: 99%

Long‐term cannabidiol treatment in patients with Dravet syndrome: An open‐label extension trial

Devinsky¹,

et al. 2018

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“…Recently, the US Food and Drug Administration (FDA) approved a purified preparation of CBD, Epidiolex, for the treatment of two severe, intractable childhood epilepsies: Dravet syndrome and Lennox-Gastaut syndrome. 7 Thus, the introduction of CBD in the management of Dravet syndrome offers new hope for improved therapeutic outcomes for patients afflicted by this devastating condition. [1][2][3][4] Dravet syndrome is a rare pediatric encephalopathy that typically presents during infancy with seizures provoked by fever, subsequently progressing to pleomorphic afebrile seizure types.…”

Section: Introductionmentioning

confidence: 99%

Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions

et al. 2019

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Objective: Cannabidiol (CBD) has been approved by the US Food and DrugAdministration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox-Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first-line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam. Methods: We examined whether CBD inhibits human CYP3A4 and CYP2C19 mediated metabolism of clobazam and N-desmethylclobazam (N-CLB), respectively, and performed studies assessing the effects of CBD on brain and plasma pharmacokinetics of clobazam in mice. We then used the Scn1a +/− mouse model of Dravet syndrome to examine how CBD and clobazam interact. We compared anticonvulsant effects of CBD-clobazam combination therapy to monotherapy against thermally-induced seizures, spontaneous seizures and mortality in Scn1a +/− mice. In addition, we used Xenopus oocytes expressing γ-aminobutyric acid (GABA) A receptors to investigate the activity of GABA A receptors when treated with CBD and clobazam together. Results: CBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N-CLB. Combination CBD-clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a +/− mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub-anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABA A receptor activation.

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“…In addition, data from pediatric populations may not be applicable for adults due to the self‐limiting nature of some syndromes (eg, autosomal dominant familial neonatal seizures). Moreover, some conditions, such as Dravet syndrome, have a high rate of early mortality, so that not all individuals survive to adulthood …”

Section: Introductionmentioning

confidence: 99%

Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability

et al. 2019

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Objective To determine the diagnostic yield of a commercial epilepsy gene panel in adults with chronic epilepsy and accompanying intellectual disability, given that genetic evaluation is often overlooked in this group of patients. Methods This is a cross‐sectional study analyzing the results of epilepsy gene panels including up to 185 genes in adult epilepsy patients with intellectual disability, according to Diagnostic and Statistical Manual of Mental Disorders, fifth edition. Patients with acquired structural brain abnormalities or known chromosomal abnormalities were excluded. Results From approximately 600 patients seen from January 2017 to June 2018 at a single academic epilepsy center, 64 probands and two affected relatives (32 males, mean age = 31 years ± 10) were selected and clinically tested. Fourteen probands (14/64 = 22%; four males, mean age = 32 years ± 10) were found to have pathogenic or likely pathogenic variants in the following genes: SCN1A, GABRB3, UBE3A, KANSL1, SLC2A1, KCNQ2, SLC6A1, HNRNPU, STX1B, SCN2A, PURA, and CHD2. Six variants arose de novo, and the inheritance was not determined in eight. Nine probands (64%) had severe or profound intellectual disability, and five (35%) had autistic features. Eight patients (57%) had a diagnostic change from presumptive clinical diagnosis prior to genetic testing. Significance We were able to demonstrate that a commercial epilepsy gene panel can be an important resource in clinical practice, identifying the etiology in 22% of adults with epilepsy and intellectual disability. The diagnostic yield is similar to previously reported pediatric cohorts. Larger samples would be required to evaluate the more prevalent genotypes among adult epilepsy patients.

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Mortality in Dravet syndrome: A review

Cited by 142 publications

References 54 publications

Long‐term cannabidiol treatment in patients with Dravet syndrome: An open‐label extension trial

Long‐term cannabidiol treatment in patients with Dravet syndrome: An open‐label extension trial

Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions

Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability

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