Seizures, Fits…Still Fighting Dravet Syndrome Bravely
Every year ‘International Dravet Syndrome Awareness Day’ is being commemorated on 23 June to create awareness about this epileptic, genetic dysfunction of brain across the globe.
Dravet syndrome was named after its French discoverer Dr. Charlotte Dravet in 1978 earlier known as Severe Myoclonic Epilepsy of Infancy (SMEI). Let us have a look at how this rare form of epilepsy with prolonged seizures is tainting the life of innocent kids.
Dravet syndrome is rare, genetic, epileptic, neurodevelopmental disorder of brain which encompasses a spectrum of disorders with the characteristic onset of seizures during the first year of life. The seizures can last for more than five minutes requiring urgent medical intervention.
The syndrome later in second to fourth year develops various developmental disorders. In spite of having 85% chance of survival, these children always live at a higher risk of sudden unexplained death in epilepsy (SUDIP).
Worldwide birth prevalence of Dravet syndrome is approximately 1 in every 20,000 to 40,000 infants.
Dravet Syndrome: Understanding the Disease
Dravet syndrome is a severe, genetic disorder that occurs mainly due to a mutation or deletion in the SCN1A gene. In about 90% cases, mutations are not inherited from the parents. SCN1A is sodium voltage-gated channel alpha subunit 1. They give instruction for making sodium channels which helps in transporting sodium ions into cells.
Figure 1. Mutations of voltage‐gated Na+ channel Nav1.1 gene in intractable childhood epilepsies with frequent GTC (Photo credit: Brain. 2003 Mar;126(Pt 3):531-46).
Therefore, they play a crucial role in enabling the cells to generate and transmit electric signals. These sodium channels are found in brain and muscles. Mutations in the SCN1A gene might cause abnormal functioning of the sodium ion channels in the brain thereby, leading to the neurodevelopmental dysfunction of the brain, Dravet syndrome.
In families with the history of SCN1A mutation, autosomal dominant inheritance has been seen. They often shows Generalized epilepsy with Febrile Seizure plus (GEFS+) which means these children may have febrile seizures even after the age of 6 years at which usually febrile convulsions stop.
In some cases, especially in females, PCDH19 gene mutation causes Dravet syndrome causing cognitive impairment.
The Dravet syndrome is often stimulated by high temperature or fever. It is characterized by prolonged febrile or non-febrile seizures which lead to intellectual and motor deficits and behavioural disorders like hyperactivity, impulsiveness.
Providing Relief from Dravet Syndrome
Dravet syndrome is the type of epilepsy which is most resistant to the currently available medications of epilepsy. It is diagnosed by the electroencephalography (EEG) data which measure the electrical activity of the brain. In the patients, it shows poly-spike waves with the slowdown of background activity.
Figure 2. Brain MRI findings in adults with Dravet syndrome and SCN1A mutation (photo credit: Brain. 2011 Oct;134(Pt 10):2982-3010. doi: 10.1093/brain/awr129).
Currently available treatment only helps to control the epileptic seizures. Initially, sodium valproate (Epilim) and topiramate (Topomax) were deployed for the treatment. These were the primary drugs used for the treatment of epilepsy.
In case of prolonged seizures benzodiazapine are effective as a rescue medicine to stop seizures. Anticonvulsant drugs like clobazam, stiripentol, clonazepam, leviteracetam are also given for the treatment of Dravet syndrome. Stiripentol has been granted Orphan Drug status in Unites States.
Figure 3. Drugs used for symptomatic treatment of Dravet syndrome.
Being the most resistant form of epilepsy, combination of stiripentol along with sodium valproate, clobazam given to the children having Dravet syndrome to relief from seizures are most effective. In an efficacy evaluation this combination has been shown to decrease overall seizure rate by 70%.
Ketogenic diet which is high in fats and low in carbohydrates given as supplementary with the medications are also beneficial for the Dravet syndrome patients.
Figure 4. Example of anticonvulsant drugs with negative impact on Dravet syndrome.
Due to the whole spectrum of disorders associated with the Dravet syndrome, the standard protocol for the disease is very difficult to set. Some anticonvulsant drugs impact negatively in case of Dravet syndrome like gabapentin, vigabatrin, tiagabine.
A Girl Who Revolutionized “Medical Marijuana”
The parents of an American girl Charlotte Figi found a miraculous remedy for her daughter’s Dravet syndrome in the Stanley brothers’ unique strain of cannabis which was developed by cross breeding a strain of marijuana with industrial hemp. It was low in its psychoactive ingredient- tetrahydrocannabionol (THC) and high in its therapeutic component- cannabidiol (CBD).
Her recovery set an example of the miraculous therapeutic potential of that medical marijuana which is now popularly known as ‘Charlotte’s Web’.
The medical legalization of Charlotte’s Web is currently under process. It is marketed as dietary supplement in US under federal law and medical cannabis under state laws.
No FDA Approved Drug yet ……Efforts for Still Incurable Dravet Syndrome
“Medical Marijuana”….the hope
UK based GW Pharmaceuticals’ cannabis based drug- Epidiolex has showed positive results lately in its Phase III clinical trial in which it significantly reduced the frequency of convulsive seizures in Dravet syndrome affected children.
Among the 120 randomly selected patients, Epidiolex were given to 61 patients and rest were treated with placebo. Epidiolex achieved 39% median reduction in monthly convulsive seizures compared to only 13% reduction in placebo treated patients.
Epidiolex has received Orphan Drug designation from European Medicines Agency (EMA).
A Dotted Father’s Dedication
Daniel Fischer, CEO and Founder of the Atlanta startup Intellimedix and a father of a little girl with Dravet syndrome collaborated with The Epilepsy Foundation and the giant drugmaker, Pfizer to screen the potential investigational drugs identified by Intellimedix for the treatment of Dravet syndrome.
Promising Investigational Drugs
California based pharmaceutical company; Zogenix Inc. has started the second Phase III clinical trial for its lead candidate- ZX008. It is a low dose fenfluramine liquid solution indicated for the adjunctive treatment of seizures in children with Dravet syndrome.
ZX008 has been granted orphan drug status in US and Europe and Fast Track Designation in the US for the treatment of Dravet syndrome.
The research concludes: “These findings support the long-term control of convulsive seizures by low-dose fenfluramine, while being well tolerated in this cohort of patients with Dravet syndrome.”
Indian Efforts…..Diagnosing Dravet Syndrome
Diagnosis of Dravet syndrome by the EEG findings is the most common way of detecting the disease in children.
Hyderabad based DNA Labs India provides genetic Dravet syndrome panel NGS panel. Next Generation Sequencing (NGS) has gained much limelight these days as a powerful tool for the identification of causative mutations in rare genetic diseases and as a genetic diagnostics. By utilizing the genome sequencing process they detect every type of mutation causing variant.
Bangalore based MedGenome Labs Pvt Ltd offers Dravet Syndrome Gene Panel which is a genetic testing for Dravet syndrome. The gene tested in the panel are given below;
It is very unfortunate that decades after the discovery of the Dravet syndrome, it is still standing incurable.
This rare and therapy-resistant epilepsy syndrome still make the few minutes feel like ages for the parents of children with Dravet syndrome when they see their kid during seizures. Still those parents are waiting for the medication to arrive which can cure their child.
There is an urgent need to promote the research and development of compounds for Dravet syndrome. Apart from Dravet syndrome those drugs may broadly benefit the epilepsy community.
Several foundations are also working closely with the companies across the globe to combat Dravet syndrome and to accelerate the efforts to address this unmet medical need. Let us hope for some breakthrough medication soon in the nearby future.
Featured Image credit: Artificially Coloured MRI Scan Of Human Brain. © Daisy Daisy (BigStock Photo ID: 4636020)