May and the first part of June saw a surge in Dravet syndrome publications. Nearly half of those publications were from one journal, The Canadian Journal of Neurological Sciences. This journal ran a 23-page series of 5 articles focused on Dravet featuring an introduction and conclusion by Dr. Charlotte Dravet, sandwiching three articles on diagnosis and long term course of the disease, management, stress on families, and needs of patients and families. The articles and their abstracts were so well written I have included most of them in their unedited form below.
In addition to the series of articles on Dravet syndrome, there were 2 basic science articles (GABAA manipulation/EEG recordings and an SCN8A study on cannabidiol) as well as 3 new clinical research studies (fenfluramine follow-up, stiripentol in adults, and a case of mild Dravet due to a frameshift mutation.) Enjoy!
Canadian Journal of Neurological Sciences Series of Dravet Articles:
1. Dravet, C. (Jun 2016). Dravet Syndrome: Addressing the Needs of Patients and Families: Introduction. Canadian Journal of Neurological Sciences, vol. 43(S3).
Charlotte Dravet, who first characterized Dravet syndrome, reviews the incidence, management, and characteristics of patients with a focus on family needs.
2. Connolly, M.B. (Jun 2016) Dravet Syndrome: Diagnosis and Long-Term Course. Canadian Journal of Neurological Sciences, vol.43(S3).
Dravet syndrome is one of the most severe epilepsy syndromes of early childhood, and it comes with very high morbidity and mortality. The typical presentation is characterized by hemiclonic or generalized clonic seizures triggered by fever during the first year of life, followed by myoclonic, absence, focal and generalized tonic-clonic seizures. Non-convulsive status epilepticus and epileptic encephalopathy are common. Development is normal in the first year of life, but most individuals eventually suffer from intellectual impairment. Dravet syndrome is associated with mutations in the sodium channel alpha1 subunit gene (SCN1A) in 70-80% of individuals. SCN1A mutation results in inhibition of the GABAergic inhibitory interneurons, leading to excessive neuronal excitation. The “interneuron hypothesis” is the current most accepted pathophysiological mechanism of Dravet syndrome. The mortality rate is increased significantly in Dravet syndrome. Ataxia, a characteristic crouched gait and Parkinson’s symptoms may develop in some individuals. It is likely that Dravet syndrome is underdiagnosed in adults with treatment-resistant epilepsy. Early diagnosis is important to avoid anti-seizure medications that exacerbate seizures.
3. Wirrell, E. (Jun 2016). Treatment of Dravet Syndrome. Canadian Journal of Neurological Sciences, 43(S3).
Dravet syndrome is among the most challenging electroclinical syndromes. There is a high likelihood of recurrent status epilepticus; seizures are medically refractory; and patients have multiple co-morbidities, including intellectual disability, behaviour and sleep problems, and crouch gait. Additionally, they are at significant risk of sudden unexplained death. This review will focus predominantly on the prophylactic medical management of seizures, addressing both first-line therapies (valproate and clobazam) as well as second-line (stiripentol, topiramate, ketogenic diet) or later options (levetiracetam, bromides, vagus nerve stimulation). Sodium channel agents-including carbamazepine, oxcarbazepine, phenytoin and lamotrigine-should be avoided, as they typically exacerbate seizures. Several agents in development may show promise, specifically fenfluramine and cannabidiol, but they need further evaluation in randomized, controlled trials. In addition to prophylactic treatment, all patients need home-rescue medication and a status epilepticus protocol that can be carried out in their local hospital. Families must be counselled on non-pharmacologic strategies to reduce seizure risk, including avoidance of triggers that commonly induce seizures (including hyperthermia, flashing lights and patterns). In addition to addressing seizures, holistic care for a patient with Dravet syndrome must involve a multidisciplinary team that includes specialists in physical, occupational and speech therapy, neuropsychology, social work and physical medicine.
4. Camfield, P. Camfield, C., Nolan, K. (Jun 2016). Helping Families Cope with the Severe Stress of Dravet Syndrome. Canadian Journal of Neurological Sciences, vol.43(S3).
A child with Dravet syndrome shakes family life to the core. Dravet syndrome usually has three phases: (1) up to 1-1½ years: with episodes of febrile status epilepticus but normal development; (2) age 1½ to ~6-10 years: with frequent seizures of varying types, developmental stagnation, behavioural and sleep problems; (3) after ~10 years: improvement in seizures, deteriorating gait, intellectual disability but some developmental gains. Complete seizure control is rare-simply prescribing medication is inadequate to help families. Based on structured interviews with 24 families and confirmed by more informal discussions with other families, we suggest strategies for coping with this catastrophe. A child with Dravet syndrome usually means that one parent cannot work-financial pressures should be anticipated. In Stage 1, the approach to status should include a written protocol. An indwelling catheter for rapid venous access may be helpful. In Stage 2, assistance finding qualified babysitters is required, and the extended family needs encouragement to help. Appropriate equipment, rescue medication and protocols should travel with the child. Siblings may benefit from a system of one parent “on call.” An internet support group provides an invaluable lifeline. In Stage 3, family isolation may be extreme-respite care and personal time for parents are important. Death from status, accidents and SUDEP (sudden unexplained death in epilepsy) occurs in 15%. Fear of SUDEP needs to be addressed. Moving from paediatric to adult care is frightening; an epilepsy transition clinic is useful. Attention to these realities may improve the quality of life for both child and family.
Basic Science Research:
GABA and Depolarization
Kurbatova, P., et. al. (May 2016). Dynamic Changes of Depolarizing GABA in a Computational Model of Epileptic Brain: Insight for Dravet Syndrome. Experimental Neurology.
Much like sodium ion channels, GABA receptors allow charged ions into and out of the cell depending on their activation state. However, unlike sodium ion channels, which allow positive sodium ions (Na+) into the cell when they are activated, GABAA receptors allow negative chlorine ions (Cl–) into the cell. This results in an inhibitory effect on the neuron, rather than an excitatory effect. Interneurons contain GABAA and are thus usually inhibitory. This study used a mass of various types of neurons hooked up to a simplified EEG to determine how changes in polarization via GABAA receptors affect the EEG. They were able to mimic the EEG patterns in 4 DS patients, both during and between seizures, just by adjusting the polarization via GABAA. This is important because it suggests a major role for the receptors in Dravet syndrome.
Resurgent Currents, CBD, and SCN8A
Patel, RR., et. al. (June 2016). Aberrant epilepsy-associated mutant Nav1.6 sodium channel activity can be targeted with cannabidiol.
Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/27267376
There are several genes that code for voltage-gated sodium channels, including SCN1A (which codes for the sodium ion channel Nav1.1), SCN2A (which codes for the sodium ion channel Nav1.2), and SCN8A (which, oddly, codes for Nav1.6, not Nav1.8 like you might think.) The electrical activity of each sodium ion channel is complex and consists of phases of activation, inactivation, and, sometimes, resurgent currents. Resurgent currents are an odd phenomena seen in several mutated models of sodium channels, in which abnormal electrical currents are seen after a channel should have returned to its resting state. It is increasingly believed that these resurgent currents contribute to the over-excitability seen in mutated neurons. The researchers found resurgent currents in cells with two different mutations in SCN8A, but not in cells with one SCN1A mutation. They then applied cannabidiol (CBD) to the cells with SCN8A mutations and were able to reduce resurgent currents and the overall action potential of certain types of neurons. They conclude that CBD may be reducing seizures through its work on sodium ion channel resurgent currents.
Ceulemans, B., et. al. (May 2016). Five-year Extended Follow-up Status of 10 Patients with Dravet Syndrome Treated with Fenfluramine.
In 2012, a study on 12 DS patients treated with fenfluramine was published. This article is a 5-year follow-up of those original patients. 10 patients continued treatment with a mean age of 24 years, a mean dose of 0.27mg/kg/day, and a mean treatment period of 16.1 years. 3/10 patients were seizure free for all 5 years of the study and 4 more patients had seizure free periods of at least 2 years. Two patients had mild cardiac valve thickening that was not deemed clinically significant. Looking at both studies combined, no patient has developed any signs or symptoms of cardiac valvulopathy or pulmonary hypertension, suggesting low-dose fenfluramine is both safe and effective.
Stiripentol in Adults
Balestrini, S., Sisodiya, SM. (May 2016). Audit of Use of Stiripentol in Adults with Dravet Syndrome. Annals of Clinical and Tranlational Neurology.
As more and more adults are being diagnosed with Dravet, and more children are transitioning to adulthood, it is important to evaluate whether the most effective treatments for children continue to be the most effective treatments for adults. This small study looked at 13 adult subjects in London on stiripentol. Compared with studies on children with DS, they found a lower responder rate and similar side effect profile. Stiripentol was still fairly effective and well tolerated, suggesting it is a reasonable treatment option for adults.
Frameshift with Mild Result
Jiang, P., et. al. (Jul 2016). Dravet Syndrome with Favourable Cognitive and Behavioral Development due to a Novel SCN1A Frameshift Mutation. Clinical Neurology and Neurosurgery, vol.146.
Frameshift mutations, which alter a large portion of the protein, should theoretically result in severe sodium ion channel dysfunction. As has been seen before, however, the type of mutation does not always affect clinical outcome. This article reports a patient with Dravet syndrome who has a frameshift mutation in their SCN1A gene, but who has normal expressive language (speech) and mild motor clumsiness. This suggests there are other mechanisms behind how mutations (genotype) affect clinical outcome (phenotype).