Epilepsy Talk

Dravet Syndrome — New Hope Through Research | August 25, 2013

Severe Myoclonic Epilepsy of Infancy was first described by Dravet in 1978.

In 1992, Dravet and colleagues found at least 172 published cases. Since then there have been numerous new cases.

Dravet Syndrome, also known as Severe Myoclonic Epilepsy of Infancy (SMEI), is a rare and catastrophic form of intractable epilepsy that begins in infancy.

Mutations of the SCN1A gene cause 79% of diagnosed cases of Dravet Syndrome.

The mystery of  Dravet Syndrome is that this rare genetic epileptic encephalopathy (dysfunction of the brain) happens in an otherwise healthy infant.

It appears during the first year of life with frequent febrile seizures — fever-related seizures that, by definition, are rare beyond age 5.

The first seizure is often associated with a vaccination at six months of age.

Between one and four years of age, children develop other seizure types including atypical absence, involuntary, rapid eye movement and non-convulsive seizures.

Seizures are intractable (uncontrollable) and combination drug therapy is necessary for acceptable seizure control.

Some anti-epileptic drugs often have an aggravating effect, exacerbate seizures and should be avoided. Examples include, carbamazepine and lamotrigine.

However, some drugs that have proved to be more effective, (although only relatively so), are topiramate, valproate, benzodiazepines and more recently, stiripentol.

Intravenous use of immunoglobulins can be useful.

In most cases, surgery is not indicated.

As children with Dravet Syndrome get older, their decline in cognitive function stabilizes, and in many, it improves slightly.

Frequently referred to as a sodium channelopathy, this intractable epilepsy is characterized by unilateral (one-sided) clonic or tonic clonic (grand mal) seizures that are prolonged (5 minutes) or progress to status epilepticus (30 minutes) and require emergency management.

In FS and GEFS+, there is usually a family history of febrile seizures or epilepsy, and these forms of epilepsy are inherited within the affected families in a genetically dominant pattern.

But, no association between obstetric complications or perinatal abnormality and severe myoclonic epilepsy in infancy has been reported.

In contrast, patients with SMEI usually have an SCN1A gene mutation that is “de novo”, meaning that it is NOT inherited from their parents.

Most, but not all, patients, test positive for a mutation in the SCN1A gene, and the presence of the SCN1A mutation usually means a diagnosis of a Dravet Spectrum Disorder.

Individuals with Dravet Syndrome face a higher incidence of SUDEP (sudden unexplained death in epilepsy) and have associated conditions, which also need to be properly treated and managed.

These conditions include:

Behavioral and developmental delays

Delayed language and speech issues

Movement and balance issues

Sensory integration disorders

Disruptions of the autonomic nervous system (which regulates things such as body temperature and sweating)

Chronic infections

Growth and nutrition issues

Sleeping difficulties

Orthopedic conditions

Earmarks of the syndrome include:

Seizures of various types beginning in the first 12 months of life

Seizures begin as febrile, but later also appear without a fever

Episodes of status epilepticus (prolonged seizures)

Seizures do not respond to standard anticonvulsant drugs

Normal initial development, then a slows or stagnation in the second year of life

Myoclonic seizures which occur around the age 18 months of age

Synonyms:

Febrile seizures

Severe myoclonic epilepsy in infancy (SMEI)

Polymorphic epilepsy in infancy (PMEI)

Epilepsy with different types of seizures

Disorder subdivisions

Genetic epilepsy with febrile seizures plus (GEFS+)

Severe myoclonic epilepsy borderline (SMEB)

Intractable childhood epilepsy with generalized tonic clonic seizures

ICE-GTC

Also, it is essential to avoid the most aggravating triggers: infectious diseases and hyperthermia.

Diagnostic Criteria:

Dravet Syndrome is diagnosed clinically based on seizure history, clinical aspects, neurologic examination, EEG pattern and observation.

Subsequently, genetic testing of the SCN1A gene can confirm the diagnosis in the majority of cases.

However, a mutated SCN1A gene can’t be identified in approximately 20% of the patients who meet the diagnostic criteria of the syndrome.

Therefore it’s possible that other genes might be involved.

Brain imaging studies have occasionally shown diffuse atrophy, but no specific abnormalities have emerged and the majority of patients have shown no abnormalities on CT or MRI scanning.

But, there are now commercially available blood tests which can screen for an SCN1A gene mutation that may be ordered by your doctor.

However, current technology may not detect all mutations.

Some screening labs also test for SCN2A, GABRG2, and PCDH19 mutations that may cause Dravet Syndrome and related epilepsies.

Is There Any Treatment?

Seizures in Dravet Syndrome are difficult to control, but can be reduced by anticonvulsant drugs.

A Ketogenic Diet, high in fats and low in carbohydrates, also may be beneficial. 

What Research Is Being Done?

The National Institutes of Health (NIH) is recruiting patients for Dravet Syndrome clinical trials at the NIH Clinical Center .

There also clinical trials being held throughout the U.S. and worldwide.

Study of the genetic defects responsible for Dravet Syndrome and related disorders is expected to lead to the development of effective drug therapies.

How Common Are Dravet Spectrum Disorders?

These diseases occur equally in both genders, and have no geographic or ethnic boundaries.

Although males are more often affected than females, in the ratio of 2 to 1.

Febrile seizures are very common, occurring in up to 4 out of 100 children at some point in childhood.

Most children who have febrile seizures do not have a Dravet Spectrum Disorder or any other inherited form of epilepsy.

New Hope For Adults With Dravet Spectrum Disorders.

A recent study led by the Epilepsy Society’s head of genetics, Professor Sanjay Sisodiya, has thrown new light on the development of the condition in adult life and the way it can be managed.

Twenty-two adults aged 20-66 with Dravet Syndrome were studied, including 10 women.

Researchers reviewed their clinical history, seizure types and frequency, anti-epileptic drugs (AEDs), cognitive and social development.

In 60% of patients, SCN1A structural variation was found with one patient showing three mutations of the gene.

Common features in adult Dravet Syndrome were multiple seizure types in spite of several different AEDs, and change in seizures according to age.

In 50% of cases, fever sensitivity persisted into adulthood and across the study there was cognitive and motor impairment.

After the age of 40, some patients developed dysphagia, or difficulty in swallowing.

However a correct diagnosis in adult life made an impact at several levels.

Said Professor Sisodiya: “We were able to follow-up three patients for a sufficient length of time after drug changes to see improved seizure control even after years of drug resistance.

And for two patients better control led to a significant improvement in cognitive performance and quality of life.”

Now, clues to Dravet Syndrome’s origins and possible treatment show promise.

A new stem cell-based approach to studying epilepsy has yielded a surprising discovery about what causes one form of the disease, and may help in the search for better medicines to treat all kinds of seizure disorders.

The findings, reported by a team of scientists from the University of Michigan Medical School and colleagues, used in an “epilepsy in a dish” technique.

By turning skin cells of epilepsy patients into stem cells, and then turning those stem cells into neurons, or brain nerve cells, the team created a miniature testing ground for epilepsy.

They could even measure the signals that the cells were sending to one another, through tiny portals called sodium channels.

In neurons derived from the cells of children who have Dravet Syndrome, the researchers reported abnormally high levels of sodium current activity.

They saw spontaneous bursts of communication and “hyperexcitability” that could potentially set off seizures.

Neurons made from the skin cells of people without epilepsy showed none of this abnormal activity.

Because the cells came from patients, they contained the hallmark seen in most patients with Dravet Syndrome: a new mutation in SCN1A, the gene that encodes the crucial sodium channel protein called Nav1.1.

That mutation reduces the number of channels to half the normal number in patients’ brains.

More Good News

“With this technique, we can study cells that closely resemble the patient’s own brain cells, without doing a brain biopsy,” says senior author and team leader Jack M. Parent, M.D., professor of neurology at U-M and a researcher at the VA Ann Arbor Healthcare System.

“It appears that the cells are overcompensating for the loss of channels due to the mutation. These patient-specific induced neurons hold great promise for modeling seizure disorders, and potentially screening medications.”

With the new paper, Parent, postdoctoral fellow Yu Liu, Ph.D. and their collaborators Lori Isom, Ph.D., professor of Pharmacology and of Molecular and Integrative Physiology at U-M, and Miriam Meisler, Ph.D., Distinguished University Professor of Human Genetics at U-M, report striking discoveries about what is happening at the cell level in the neurons of Dravet Syndrome patients with a mutated SCN1A gene.

They found that the neurons didn’t show the telltale signs of hyperexcitability in the first few weeks after they were made — consistent with the fact that children with Dravet Syndrome often don’t suffer their first seizures until they are several months old.

“In addition, reproduction of the hyperactivity of epileptic neurons in these cell cultures demonstrates that there is an intrinsic change in the neurons that does not depend on input from circuits in the brain,” says co-author Meisler.

Since many Dravet patients don’t respond to current epilepsy medications, the search for new options and new medications is more urgent.

“Working with patient families, and translating our sodium channel research to a pediatric disease, has made our basic science work much more immediate and critical,” says Isom, who serves on the scientific advisory board of the Dravet Syndrome Foundation, along with Meisler.

The team is now working toward screening specific compounds for seizure-calming potential in Dravet Syndrome by testing their impact on the cells in an “epilepsy in a dish” model.

Parent and his colleagues hope to identify drugs that affect certain aspects of sodium channels, to see if they can dampen the sodium currents and calm hyperexcitability.

The team is exploring new techniques that can make this process faster, using microelectrodes and calcium-sensitive dyes.

They also hope to use the model to study potential drugs for non-genetic forms of epilepsy.

The U-M team’s research wouldn’t be possible without the participation of patients with Dravet Syndrome and other genetic forms of epilepsy, and their parents.

More than 100 of them have joined the International Ion Channel Epilepsy Patient Registry, which is based at U-M and Miami Children’s Hospital and co-funded by the Dravet Syndrome Foundation and the ICE Epilepsy Alliance.

Meanwhile, patients with other genetically based neurological diseases can also help U-M scientists discover more about their conditions, by taking part in other efforts to create induced neurons from skin cells.

Parent and his team have worked with several other U-M faculty to create stem cell lines from skin cells provided by patients with other diseases including forms of ataxia and lysosmal storage (a metabolic) disease.

As researchers and doctors learn more about these disorders, and awareness about the clinical spectrum broadens, the number of people diagnosed with Dravet Spectrum Disorders is increasing.

This, at least, gives us reason for hope.

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Another article of interest: OBTAINING EPIDIOLEX™ IN THE U.S. http://www.dravetfoundation.org/dravet-syndrome/consider-dravet/obtaining-epidiolex

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Resources:

http://www.dravetfoundation.org/dravet-syndrome/what-is-dravet-syndrome

http://www.dravetfoundation.org/dravet-syndrome/medical-information/diagnosis-testing

http://www.ninds.nih.gov/disorders/dravet_syndrome/dravet_syndrome.htm

http://www.webmd.com/epilepsy/dravet-syndrome

http://dravet.org/about-dravet/what-is-dravet

http://www.dravet.com/dravet1uk.htm

http://www.rightdiagnosis.com/d/dravet_syndrome/symptoms.htm

http://www.epilepsysociety.org.uk/Forprofessionals/Dravetsyndrome

http://www.medicalnewstoday.com/releases/263956.php

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