Dravet syndrome

Overview

Dravet syndrome is a rare and severe form of epilepsy. At some point before age 1, children with Dravet syndrome begin to have frequent, prolonged seizures that are difficult to control with standard epilepsy treatments.

At first, children with Dravet syndrome appear healthy and develop normally. As the seizures continue, cognitive and motor development may slow or stop. The severity of the developmental delay varies from child to child. In some children, cognitive delays may go through periods of improvement, although most patients have some degree of lifelong disability.

Current treatment options for Dravet syndrome include medications, special diets and an implantable device called a vagal nerve stimulator. It is often very challenging to find a treatment or combination of treatments that completely controls the seizures. Research to uncover new treatments is underway, and children who don't improve with available therapies may be eligible for clinical trials.

Recent studies suggest Dravet syndrome affects around 1 in 15,000 children. Three percent to 8 percent of children who have seizures in their first year of life are eventually diagnosed with the syndrome.

Causes

More than 80 percent of Dravet syndrome patients have a mutation in a gene called SCN1A. This mutation affects the sodium channels in the brain, which are important for regulating the firing of nerve cells. Other genetic mutations may also cause Dravet.

These mutations usually occur spontaneously during fetal development and are not inherited from a parent. However, there are rare cases of families with more than one affected child.

Signs & symptoms

The first sign of Dravet syndrome is usually a convulsive seizure that is triggered by a fever, typically around 5 to 8 months of age. First, the body stiffens, then one or both sides of the body start to jerk repeatedly.

Children with Dravet syndrome go on to have other types of seizures in the weeks or months after the first event. The seizures tend to be long (more than two minutes) and difficult to control with medication. They may be triggered by infections, changes in body temperature, flashing lights or other visual stimuli, and emotional stress or excitement.

Between the ages of 1 and 5 years, many children begin to show signs of developmental delay as well as other health issues that have been associated with Dravet syndrome. These can include:

• Poor coordination
• Unsteady gait
• Slow speech development
• Behavioral issues such as hyperactivity, irritability and traits associated with autism
• Frequent infections
• Slow growth and poor weight gain

Diagnosis

Many children with Dravet syndrome are initially misdiagnosed, since the diagnosis depends on the child's history of seizures and other symptoms that emerge as seizures progress. Another complication is that the usual tests used to evaluate epilepsy — magnetic resonance imaging (MRI) and electroencephalography (EEG) — appear normal at first in babies with Dravet syndrome. Experts believe some children are never correctly diagnosed.

In particular, Dravet syndrome may be first mistaken for febrile seizures, a common type of childhood seizure triggered by a fever. Unfortunately, medications used to treat febrile seizures can worsen seizures in children with Dravet.

Experts recommend genetic testing for children who have had any of the following:

• Two or more prolonged (more than 10 minutes) seizures by age 1
• One prolonged seizure and a hemi-clonic seizure (seizure causing rhythmic jerking in one side of the body) by age 1
• Two seizures that affect alternating sides of the body
• Seizure onset before 18 months of age, followed by myoclonic seizures (isolated jerking of a muscle or muscle group), absence seizures (brief periods when the child appears to stare into space, also called petit mal seizures) or both types

Genetic blood tests can screen for SCN1A mutations and a few other mutations linked to Dravet syndrome. However, these tests are not 100 percent conclusive, since they do not screen for all mutations that cause Dravet syndrome and because SCN1A mutations can also cause other, less severe forms of epilepsy. Some cases of Dravet syndrome do not have a clear genetic cause.

There is a strong chance that children who meet most of the following criteria have Dravet syndrome, even if they do not have an SCN1A mutation:

• Normal development before the first seizure
• Two or more seizures, with or without fever, before age 1
• Two or more seizures that last more than 10 minutes
• Myoclonic, hemi-clonic or tonic-clonic seizures
• Seizures that do not respond to epilepsy medications, with seizures continuing past age 2

Treatment

Because Dravet syndrome is so rare, it can be difficult to find a pediatric neurologist who has experience in treating it. The Dravet Syndrome Foundation maintains a searchable listing of physicians who have treated patients with Dravet syndrome and related epilepsies. To search the site, visit www.dravetfoundation.org.

When caring for children with Dravet syndrome, our main goals are to achieve the best possible control of the seizures, prevent a dangerous type of seizure called status epilepticus, and improve the child's and family's quality of life.

To reduce the frequency and severity of the seizures, patients must avoid seizure triggers and take medications. A ketogenic diet — low in carbohydrates and high in fats — may also help. Surgery is generally not recommended, but an implantable device called a vagal nerve stimulator may reduce seizures in some cases.

Working with experts such as a speech therapist, physical therapist and occupational therapist can help improve patients' motor and cognitive development. Psychological and social support for the whole family is also important.

Seizure Trigger Avoidance

People with Dravet syndrome tend to be more sensitive to seizure triggers than those with other types of epilepsy, so it's important to avoid these common triggers:

• Overheating (usually from hot baths or exercise)
• Sudden temperature changes in the environment (hot or cold)
• Fevers (should be treated with fever reducers such as ibuprofen or acetaminophen)
• Flashing lights
• Visual patterns such as stripes and other contrasting patterns
• Stress or overexcitement

Vaccines may sometimes trigger a seizure. Your child's doctor may recommend giving your child a fever reducer before a vaccination and for 24 hours afterward to prevent vaccine-related fever.

Medications

Every Dravet patient is different, and medications that work for one child may not work for another. Generally, we introduce medications in a systematic order, beginning with those that have helped the largest number of Dravet syndrome patients, to determine what treatment regimen works best for each individual child.

The following medications are first-line treatments for Dravet syndrome, meaning they've benefitted more patients:

• Clobazam (Onfi, Frisium, Urbanyl)
• Valproic acid (Depakote, Depakene, Epilim, Epival)
• Topiramate (Topamax)

If first-line treatments fail, your child's neurologist may try second-line medications:

• Stiripentol (Diacomit)
• Levetiracetam (Keppra)

Some common epilepsy drugs can worsen seizures in people with Dravet and should be avoided. These include:

• Carbamazepine (Tegretol, Carbatrol)
• Oxcarbazepine (Trileptal)
• Lamotrigine (Lamictal)
• Phenytoin (Dilantin, Epanutin)
• Vigabatrin (Sabril, Sabrilan, Sabrilex)

Children who experience status epilepticus — life-threatening seizures that last longer than five minutes or that continue one after the other — must be treated with so-called rescue medications to try to stop the seizure. Your child's doctor may prescribe a rescue medication — typically a benzodiazepine, such as diazepam (Diastat), midazolam or lorazepam — to have on hand in case of status epilepticus.

Ketogenic Diet

The high-fat, low-carbohydrate ketogenic diet can be helpful for some children with Dravet syndrome, especially if their seizures aren't responding to medication. Studies have shown that 60 percent to 71 percent of Dravet patients have less frequent seizures while on the diet. Some research also suggests that a ketogenic diet is linked to improvements in behavior and cognition.

Ketogenic diets are designed by the patient's neurologist and a dietitian experienced in Dravet syndrome.

Vagal Nerve Stimulation

Vagal nerve stimulation may be considered if medications aren't working. Vagal nerve stimulation involves implanting a small device in the child's neck, around the vagus nerve. The device sends regular, mild electric signals from the vagus nerve up to the brain, which may interrupt a seizure or prevent one from starting.

Experimental Treatments

Researchers at UCSF and other institutions are actively seeking new treatments for Dravet syndrome. If standard treatment options fail, your child's doctors may discuss trying an experimental drug.

Currently, UCSF is leading a clinical trial of two doses of fenfluramine hydrochloride (ZX008). An earlier study found that the higher dose reduced patients' monthly seizures by 64 percent on average. For more information, please visit http://clinicaltrials.ucsf.edu/trial/NCT02682927.