March was a busy month for Dravet research! Here we highlight 4 studies on SCN1A variants (including the latest hot topic, mosaicism, and how mutations relate to cognitive impairment); a review of medications used for Dravet (co-authored by one of our very own Medical Advisory Board members); a new transcutaneous VNS device; a small study on vaccines and seizures, and perhaps the greatest overview of potential SUDEP mechanisms published to date. Enjoy!

1. Surovy, M. et. al. (April 2016). Novel SCN1A Variants in Dravet Syndrome and Evaluating a Wide Approach of Patient Selection.

General Physiology and Biophysics. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/27045673.

SCN1A mutations are found in up to 80% of patients with Dravet syndrome. But do they occur in other epilepsies? If so, how often? This study looked for SCN1A mutations in 52 patients diagnosed with Dravet syndrome (DS), GEFS+, and similar types of epilepsies and found that SCN1A mutations were found almost exclusively in the Dravet syndrome patients. No disease-causing mutations were identified in any of the non-DS patients in this cohort. While there are certainly cases of SCN1A mutations in patients with diagnoses other than Dravet, this study supports the theory that those are exceptions, rather than the rule, and underscores the link between SCN1A and the Dravet phenotype. (Remember, phenotype refers to how a patient presents clinically, while genotype refers to the genetic makeup of the patient.)

2. Lal, D., et. al. (Mar 2016). Evaluation of Presumably Disease Causing SCN1A Variants of Common Epilepsy Syndromes.

PLOS One. Volume 11 Issue 13. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4798642/

As genetic testing results become more widely accessed and published, there is concern that SCN1A mutations which have been reported as disease-causing in the literature may be found in subsequent individuals and may not necessarily be disease-causing. This study reviewed 448 cases of epilepsy (not just Dravet syndrome) and 777 healthy controls in Europe. They found 8 SCN1A mutations that had been reported as disease-causing in the literature. After further review of the inheritance patterns, clinical characteristics, and other genetic mutations in the patients, the authors determined that 7 of those 8 SCN1A mutations could not be positively identified as disease-causing in the patients. This highlights the difficulty in determining whether SCN1A variants found by testing labs are truly pathogenic (disease-causing) or of unknown significance.

3. Sharkia, R. et. al. (Mar 2016). Parental Mosaicism in Another Case of Dravet Syndrome Caused by a Novel SCN1A Deletion: A Case Report.

Journal of Medical Case Reports, Volume 10 Issue 67. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4810572/

Most SCN1A mutations in Dravet syndrome are “de novo,” meaning they are not found in the parents but rather are new to the patient. However, as testing techniques become more sensitive, researchers are discovering a growing number of cases where the patient’s mutation is actually inherited from the parent but the mutation is present in such a small percentage of the parent’s cells that it is not detected on initial screening (mosaicism). This article presents one such example. Two sisters with Dravet syndrome were found to have the same SCN1A mutation but the mutation was not detected by Sanger sequencing in the parents. For two siblings to have the exact same mutation, some sort of inheritance is highly likely. The authors were not able to test for the mutation in the father’s semen or other tissues to determine what type of mosaicism was present. It is possible the mutation was present in the sperm or eggs, or in such a low level in the parents’ blood that the limits of Sanger sequencing could not detect the mutation. It highlights the need to proceed with caution in counseling parents on reproduction after a child with Dravet syndrome, even when the mutation appears to be de novo.

4. Bender, A., et. al. (Mar 2016). Cognitive Deficits Associated with NaV1.1 Alterations: Involvement of Neuronal Firing Dynamics and Oscillations.

PLOS One. Volume 11 Issue 3. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792481/

SCN1A codes for the voltage-gated sodium (Na) ion channel Nav1.1. Seizures are a widely recognized result of mutations in SCN1A, but the cognitive impairment seen in patients is more difficult to attribute to these mutations. This study examined brain rhythms in rats with SCN1A mutations and found that the neurons in these rats fired differently from those in healthy rats. Theta rhythm and fast-firing properties were affected, and the rats did not perform as well as their healthy controls on memory tasks. This suggests that sodium ion channel mutations themselves (rather than medications or seizures) may affect brain rhythms, which may disrupt information processing.

5. Wallace, A., et. al. (Mar 2016). Pharmacotherapy for Dravet Syndrome.

Pediatric Drugs. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/26966048

If you wonder what the most common treatments for Dravet syndrome are, look no further. This is an excellent review of the prominent pharmacotherapy options and briefly touches on medications used for comorbidities such as ADHD associated with Dravet. Sodium valproate (Depakote) and clobazam (Onfi) are first-line treatments, with evidence that topiramate (Topamax), levetiracetam (Keppra), stiripentol (Diacomit), and the ketogenic diet are helpful as well. Fenfluramine and others show promise. Medications that are not recommended include sodium channel blockers such as carbamazepine (Tegretol) and lamotrigine (Lamictal).

6. Wong, P.T.Y, et. al. (Jan. 2016). Prevalence and Characteristics of Vaccination Triggered Seizures in Dravet Syndrome in Hong Kong: A Retrospective Study.

Pediatric Neurology. Retrieved from http://www.pedneur.com/article/S0887-8994(15)30264-2/abstract

Many parents of patients with Dravet syndrome report that seizures occur as a result of a vaccination. This study examined the records of 54 patients with Dravet syndrome and found that 32% of the patients experienced a seizure within 48 hours of vaccination. The abstract does not limit this response to the first seizure. Because nearly 1/3 of patients had a correlation between seizures and vaccination, the authors suggest the development of guidelines and protocols for the prevention of vaccine-related seizures in children with recurrent febrile seizures under 12 months of age who are suspected of having Dravet syndrome.

7. Bauer, S., et. al. (Mar 2016). Transcutaneous Vagus Nerve Stimulation (tVNS) for Treatment of Drug-Resistant Epilepsy: A Randomized, Double-Blind Clinical Trial (cMPsEo2).

Brain Stimulation. Retrieved from http://www.brainstimjrnl.com/article/S1935-861X(15)01225-5/abstract

Vagus Nerve Stimulators (VNS’s) have been used with varying success in Dravet syndrome. These devices are invasively implanted in the chest, with electrodes running up to the vagus nerve in the neck. The devices deliver electrical impulses to the vagus nerve at varying frequencies and intensities to interrupt abnormal electrical firing. This article summarizes the data from a less invasive tVNS, which is placed over the skin near the ear conch. The results showed promise, with decreased seizures over 20 weeks in the group with higher frequency stimulation than the control group, but the results are somewhat confounded by a higher intensity (amplitude) in the lower frequency group than in the high frequency group. If proven beneficial, this could be a much more reasonable option for Dravet syndrome than the invasive traditional VNS.

8. Dlouhy, B., et. al. (Apr 2016). Sudden Unexpected Death in Epilepsy: Basic Mechanisms and Clinical Implications for Prevention.

Journal of Neurology, Neurosurgery, and Psychiatry. Volume 87 Issue 4. Retrieved from http://jnnp.bmj.com/content/87/4/402.long

Perhaps the most comprehensive study of SUDEP yet, this article is a must-read in its entirety. Although it is not Dravet-specific, it covers nearly every hypothesis for mechanisms of SUDEP presented thus far in an easy-to-read manner. Highlights include:
12 of 15 cases of witnessed SUDEP followed tonic clonic seizures. 12 of 15 witnesses noted the patient had difficulty breathing, suggesting a respiratory component to SUDEP. 7 of those 15 cases occurred in bed.

11 of 16 SUDEP cases that occurred in an Epilepsy Monitoring Unit had corresponding video EEG (VEEG). All 11 of those cases had a confirmed generalized tonic clonic seizure immediately preceeding death. Of those 11 VEEG cases, 9 included heart rate and respiratory monitoring.
“Seizures were followed by a short period of normal or increased heart and respiratory rates, after which there was ‘early postictal parallel collapse of respiratory and cardiac rates, which was observed in every patient during the first 3 min postictally’. This was accompanied by postictal generalized EEG suppression (PGES). The early cardiorespiratory collapse was terminal in three of the patients. In the remaining six patients, there was transient restoration of cardiac function associated with abnormal and possibly ineffective respiration, likely aggravated by the prone position. Respiration then progressively deteriorated until terminal apnoea occurred, followed by terminal asystole. In every case, terminal apnoea occurred first, and the heart rate continued for a variable period of time before terminal asystole.”

13 of 14 cases where position of the patient could be determined showed the patient in a prone position prior to cardiorespiratory rest, often with the face tilted to one side.

The article goes on to evaluate potential mechanisms including respiratory changes; cardiac changes; electrocerebral shutdown; general susceptibility; and other molecular mechanisms of SUDEP. In terms of preventing SUDEP, the authors note that postictal nursing intervention is associated with a reduced period of respiratory dysfunction and oxygen desaturation, and supervision at night was beneficial in preventing SUDEP. The authors generalize these findings and suggest that monitors and alarms may well be beneficial in our population, by reducing respiratory dysfunction and allowing for resuscitatory measures, thereby preventing SUDEP.