This week’s blog, by Margarita Delgado Thompson, has been chosen from the essays submitted to our 2016 Student Voice Essay Competition. It makes a very interesting read.
Rare syndromes are leading research for chronic health conditions that impact millions of people worldwide. This paper uses the example of Dravet syndrome, a rare genetic epileptic encephalopathy, to show how research into this rare disease, may result in a novel treatment for people living with intractable epilepsy. Rare syndromes provide researchers with three qualities ideal for research: genetically mutated animal models for initial testing, clear diagnostic criteria for inclusion in a study, and motivated patients looking for a solution to devastating diseases.
Epilepsy: a need for treatment
Epilepsy is one of the most common neurological diseases, it affects over 50 million people worldwide (1). Epilepsy is defined by Fisher et.al. as a “family of disorders, having in common an abnormally increased predisposition to seizures” (2). In addition to seizures, patients with epilepsy can suffer from cognitive delays and psychosocial problems including: anxiety, depression and negative stigma (2). The primary treatment for epilepsy is antiepileptic medicines to control seizures:
“The lack of absolutes is frustrating while trying to find a solution to the seizures. Treatment revolves around experimenting with various medications and weighing results with the side effects. It can take years to find what combinations work the best.” – Dennis, father of a child living with epilepsy (D. Dickson 2016, personal communication, 2 November).
One third of patients have refractory epilepsy, which cannot be controlled by medication, these patients and their families are constantly looking for solutions.
The rare syndrome
As Fisher et.al.’s definition states, epilepsy is not a single disease, but a family of conditions; within this family are a number of rare genetic syndromes that manifest with refractory seizures and other symptoms (2). One example is Dravet syndrome, a genetic channelopathy caused by a mutation in the SCN1A gene (3). Dravet syndrome begins with febrile and afebrile clonic and tonic-clonic seizures in the first year of life (4). It develops to other types of seizures, which are usually unresponsive to treatment (3). Children with Dravet syndrome develop mental delays, cognitive impairments and personality disorders by the age of 2, there is a theory that the epileptiform abnormalities in the brain causes these cognitive impairments (3). Dravet syndrome impacts 1.4% of children with epilepsy under the age of 15 and one in 20,000-30,000 live births (3). Around 14-16 years the seizures tend to decrease, but patients need full time care for the rest of their lives and are at high risk for sudden unexpected death in epilepsy (SUDEP) as well as lethal status epilepticus (4).
Because of the gap in effective treatments for intractable epilepsy, drug companies and charities are searching for new options. One of the innovative treatments is Epidiolex, a purified plant based cannabinoid, cannabidiol (CBD), produced by GW Pharmaceutical UK (5).
Enthusiasm surrounding cannabis use for intractable epilepsy began with the case report of Charlotte Figi, diagnosed with Dravet syndrome (6). After failing antiepileptic drugs and the ketogenic diet, her mother looked into cannabis, which has historically been used as an antiepileptic (6). She worked closely with cultivators, doctors and the Colorado state legislature, and began to give her daughter extract from the marijuana plant specially cultivated to produce an oil with a high concentration of cannabidiol, a non-psychoactive compound of marijuana (6). The results of the case study surprised the epilepsy community, Charlotte had a 90% reduction in tonic-clonic seizures and her behavior and cognition improved, so that the 5 year old began to walk and talk for the first time (6). Many families have followed the Figi family and attempted to find legal sources of the plant christened “Charlotte’s Web”. The new drug Epidiolex promises a cannabidiol source, similar to Charlotte’s Web, that is controlled for potency and quality will be clinically tested for effectiveness and safety (6).
Epidiolex is currently in phase 3 of clinical testing, patients with Dravet syndrome take the drug and it is compared to patients taking the placebo (7). Epidiolex received orphan drug status from the European Medicines Agency and the US Food and Drug Administration (8). The current results from the phase three trial found that Epidiolex decreased convulsive seizures by 39% compared to the placebo, and it is generally well tolerated (8). GW Pharmaceuticals states that they are currently focusing trials on rare electroclinical syndromes, including Dravet syndrome and Lennox-Gastaut syndrome, both of which have poor prognoses for seizure control and limited treatment options; but they hope to expand to other orphan seizure disorders and ultimately to all intractable epilepsies (5). A program has already begun in the US for a compassionate use program, where children and young adults with intractable epilepsy, who do not qualify for the clinical trial, may take the medication (9).
Why research rare syndromes?
In order for new medications to be used there is a stringent series of tests, to make sure that the drug is safe and effective, this can take up to 10-15 years (10). Rare syndromes have several advantages that make them ideal to study.
Before any human testing can begin, medications are first tested on animal models, to assess efficacy, safety and toxicity (10). Because epilepsy is a family of disorders, researchers have found it difficult to create an animal model that represents all forms of epilepsy. At a conference led by the National Institute of Neurological Disorders and Stroke in 2001 the conclusion was that researchers need new in vitro and in vivo models for chronic epilepsy (11). Dravet syndrome promises a solution. Patients with Dravet syndrome have a specific defect in the SCN1A gene, this has allowed scientists to create a line of zebra fish and other animals, which have the same genetic mutation (12). Also researchers have managed to take skin cells from patients with Dravet syndrome and turn them back to pluripotent stem cells and allow them to differentiate into neurons (12). These genetic models allow drug companies to test drugs and have allowed researchers to use the neurons to investigate the mechanism that causes the brain to be prone to seizures, epileptogenesis (12).
After preclinical testing, drugs start clinical trials, phase three clinical trials use patients that are affected by the target condition to compare new treatments to a placebo (7). In order for a randomized control trial to produce statistically significant data with the lowest possible risk of confounding, researchers need a homogenous population (7). Therefore the population needs to have clear diagnostic criteria (13). Because epilepsy is so varied, getting a homogenous population is difficult; however, Dravet syndrome has a clear genetic test, which makes these patients a homogenous group.
The other goal of randomized control trials is generalizing them to a larger population (7). Because Dravet syndrome manifest with epileptic seizures like other epilepsies, researchers can do future testing to see whether a drug, which is effective for Dravet syndrome, can be generalized to other epilepsies.
Another example of this phenomenon is a specific subset of patients with Alzheimer’s disease, who develop the disease early because of a genetic mutation (14). Scientists are using these patients as models to examine how the disease advances and investigate possible treatments (14). These patients are a homogenous group that are diagnosed using a genetic test, compared to most Alzheimer’s patient who can only confirm a diagnosis post-mortem (14). The genetic test can also identify the patients early before they begin to present with symptoms, allowing researchers to study the disease development (14).
Clinical trial participants need to be invested in the research, there has to be a high rate of compliance and follow through (7, 13). The Dravet syndrome community is spurred to find a treatment by the devastating prognosis of the condition: the intractable seizures continue and children with Dravet syndrome will need full time care for the rest of their lives (4). Dravet syndrome is also life threatening, patients have a high rate of SUDEP and a risk of status epilepticus (8). In 2013 patients, family and friends raised money to fund a £22,000 research grant to look at a possible causes of SUDEP (15). The dedication to find answers encourages patients to participate and follow through with new clinical trials.
This essay shows that rare syndromes provide researchers with three qualities ideal for research: animal models for initial testing, clear diagnostic inclusion criteria, and motivated patients looking for a solution to devastating diseases.
In 1983 the US Orphan Drug Act was enacted to encourage research into diseases that had previously been ignored by pharmaceutical companies because of poor profits (16). Now, there is hope that research involving rare disease syndromes like Dravet and familial early onset Alzheimer’s will bring answers to questions about common conditions like epilepsy and Alzheimer’s.
“Epilepsy is going everyday, since [the day]… [you have] your first seizure [you think] about nothing but epilepsy every second of everyday. Epilepsy is fear for your life and the fear of SUDEP.” – Katie, patient living with intractable seizures (K. Dickson 2016, personal communication, 2 November).
Millions of people, like Katie and her father, are waiting for research to be completed on new drugs like Epidiolex, hoping that one of these drugs will be the answer and thanking the Dravet community for participating in these life-changing trials.
Thank you to my friends from the Epilepsy Foundation of Texas support group who consented to their quotes being included in this paper.
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- 11. Frazin N, editor Models for Epilepsy & Epileptogenesis. Curing Epilepsy: Focus on the Future; 2000: National Institute of Neurological Disorders and Stroke.
- 12. Liaison OoCaP. Curing the epilepsies: the promise of research. In: Stroke NIoNDa, editor. Bethesda, Maryland: National Institutes of Health; 2013.
- 13. Haynes RB. Clinical epidemiology : how to do clinical practice research. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2006. xv, 496 p. p.
- 14. Child D. The Truth about Dementia, presented by Angela Rippon. London: BBC; 2016. p. 59 min.
- 15. Anon. About Us- Dravet Syndrome UK Chesterfield, UK: Dravet Syndrome UK; 2013 [Available from: http://www.dravet.org.uk/what-is-dravet-syndrome/about-us/.
- 16. Orphan Drug Act of 1983. Sect. Chapter I, suchapter D (1983).