dravet syndrome MANAGEMENT

At present there is no cure for Dravet syndrome. However, it is possible to reduce the number and the severity of seizures with pharmacological treatments (Anti-Epileptic Drugs: AEDs) and by avoiding triggering factors.
Treatment of Dravet syndrome requires comprehensive management. In addition to medication, other non-pharmacological treatments may be helpful, along with comprehensive care measures. Families and caregivers play a critical role.

TREATMENT

All treatments should be taken under the supervision of a medical doctor who is familiar with Dravet syndrome. Many anti-epileptic treatments are available worldwide, but some may not be available or officially approved in every country. All initiation change or modification of anti-epileptic treatment must only be made with the approval of the prescriber who regularly follows the patient.

Several pharmacological and non-pharmacological treatments can be used for patients with Dravet syndrome whose seizures are highly pharmacoresistant, making it difficult to achieve seizure freedom.

It is reasonable to start an appropriate treatment as soon as the diagnosis of Dravet syndrome is strongly suspected. If you require more clinical information on diagnosis, please refer to the dedicated section.

Seizure freedom is hard to achieve, as the intractability of seizures is the hallmark of the disease. Pharmacological treatment is nevertheless the mainstay of disease management, and several anti-epileptic drugs are available. Current practice in management of Dravet syndrome continues to optimize anti-epileptic treatment for seizure control while minimizing side effects. The following treatments are recommended by the last panel recommendations (Cross et al. 2019):

Algorithm of treatment (adapted from Cross et al. 2019)

In 2019, a board of international experts updated the treatment algorithm including newly approved drugs cannabidiol (FDA: 2018; EMA: 2019) and fenfluramine (FDA: 2019) (Cross et al. 2019).

1. pharmacological

STIRIPENTOL

Stiripentol (STP) is the first treatment that has demonstrated its efficacy in patients with Dravet syndrome in two randomised, double-blind, placebo-controlled trials, STICLO France (Chiron et al., 2000) and STICLO Italy (Guerrini et al., 2002). It is used as an add‑on therapy to clobazam and valproate for patients with Dravet syndrome to treat generalised tonic-clonic seizures when these are not adequately controlled by clobazam and valproate. Efficacy and safety have been evaluated for more than 20 years (Chiron et al. 2019).

VALPROATE

Valproate (VPA) is an anti-epileptic drug widely used to treat epilepsy. It is usually the first-line treatment for patients with Dravet syndrome, notably for preventing the recurrence of febrile seizures. Even though well-controlled and long-term efficacy studies are lacking, valproate is widely used in Dravet patients.

BENZODIAZEPINES

Benzodiazepines (BZD) are a class of psychoactive drugs widely used to treat anxiety, insomnia, agitation and also epilepsy. BZD prevent or stop long-lasting seizures, in particular status epilepticus. Clonazepam and clobazam are the most frequently prescribed benzodiazepines in patients with Dravet syndrome. Clobazam is usually combined with valproate for the long-term treatment of the disease, while clonazepam, available as a solution for injection, is often used as a rescue medication in the hospital setting in order to end long-lasting seizures. Some authors, including Ceulemans in 2004, propose limiting the chronic use of benzodiazepines because of their side-effects.

CANNABIDIOL

Cannabidiol (CBD) (highly purified) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut and Dravet syndrome in four randomised controlled trials. While the mechanism of action of CBD underlying the reduction of seizures in humans is unknown, CBD possesses affinity for multiple targets, across a range of target classes, resulting in functional modulation of neuronal excitability, relevant to the pathophysiology of many disease types, including epilepsy (Gray et al. 2020).
CBD was approved in the USA in 2018 and in Europe in 2019.

FENFLURAMINE

Fenfluramine (FFA) was previously used in combination with phentermine as an appetite suppressor, but because of cardiac side effects (valvular hypertrophy) and pulmonary hypertension when used at high dosages, it was withdrawn from the market in 1997. Fenfluramine has a high affinity for serotonin receptors in the brain (especially 5HT 2A and 2C), leading to a higher serotonin concentration. In 1996, Boel and Casaer published a first article showing that low dose fenfluramine was beneficial in children with refractory epilepsy. Later, fenfluramine was tested on Dravet syndrome patients, including two prospective, double-blind, placebo-controlled trials that show efficacy and safety. FFA was approved in the USA in 2020.

Also used

Several antiepileptic drugs are used to treat patients with Dravet syndrome like Topiramate, Bromide, Levetiracetam… Their use depends on their local availability.

Should you need information regarding recommended treatments for Dravet syndrome patients in your country please refer to your local health authorities’ guidelines or to the specialist who is regularly following the patient.

TOPIRAMATE

Topiramate (TPM) has been studied in open-label trials only (Nieto-Barrera et al. 2000; Coppola et al. 2002; Kröll Seger et al. 2006; Morimoto et al. 2017). Results showed that a ≥50% reduction of seizures occurred in 50 to 85% of patients, of whom 16 to 18% were seizure-free for a period of 11 to 13 months. Fifteen percent of patients experienced side effects, mainly anorexia and weight loss but also behavioural disturbances, emotional and language regression. Slow titration facilitated better tolerance.

BROMIDE

Bromide is the oldest anti-epileptic drug and is still widely used in Germany and Japan. Studies have shown significant results regarding convulsive seizures and status epilepticus (Oguni et al. 1994; Tanabe et al. 2008).

LEVETIRACETAM

Levetiracetam (LEV) was evaluated as add-on therapy in a multicentre, open-label trial in 28 patients over a 6- to 36-month period (Striano et al., 2007). In the 23 patients who completed the trial, responders were 64.2%, 60%, 60% and 44.4% for tonic-clonic, myoclonic, focal and absence seizures, respectively. Eighteen percent of patients withdrew from the study for side effects such as irritability, cutaneous rash, worsening of myoclonic seizures and thrombocytopenia.

2. EMERGING TREATMENT

Gene therapy

Gene therapy is a novel approach that uses a vector (i.e. virus) to introduce a new version of a gene into a patient’s body.

Gene therapy is used in laboratory animals for research, or to create genetically modified crops or cells that can produce molecules or enzymes for medications. Its use in humans as a potential therapy is still in the early phases of development.

Dravet syndrome and other epilepsy disorders are challenges for gene therapy. The SCN1A gene is too large for many vectors, so gene replacement therapy is currently not possible.

Individuals with Dravet syndrome typically have a second healthy copy of the SCN1A gene, so the most promising area for gene therapy seems to be a combination of two approaches: increasing the production of the healthy gene and suppressing the mutated gene. It is not yet known how and when this can be done.

The aim is to develop modified virus vectors that will be able to deliver a healthy copy of the SCN1A gene to affected neurons in mouse models of Dravet syndrome. This project is currently in progress.

3. RESCUE MEDICATIONS

A component of the phenotype of Dravet syndrome is prolonged convulsive seizures, often requiring emergency care at hospitals. It is established that earlier treatment of seizures will reduce the likelihood of status epilepticus and consequent admission to hospital. Standard emergency treatment is recommended for tonic-clonic seizures lasting more than 5 minutes. (Trinka et al. 2015)

Common first line emergency medications recommended for home or hospital use are Benzodiazepines. Various formulations are available that offer different routes of administration, depending on the patient, the type of seizure and who is available to give the medication: rectal Diazepam, buccal and Nazal Midazolam or other benzodiazepines like Clonazepam or Lorazepam.

In 2019, Cross et al. proposed au protocol for the treatment of prolonged seizures in association with Dravet syndrome (Cross et al. 2019). When a convulsive seizure does not stop after first line emergency treatment administration, medical intervention is needed.

Emergency protocol (adapted from Cross et al. 2019)

4. to avoid

Sodium channel blockers have been shown to worsen seizures in patients with Dravet syndrome (de Lange et al. 2018) and therefore should be avoided (Wirrell et al. 2017).

  • Lamotrigine
  • Carbamazepine
  • Vigabatrin

In 2018, De Lange et al have shown that the use of contraindicated medications, defined as sodium channel blockers: lamotrigine, phenytoin, carbamazepine, oxcarbazepine, vigabatrin, in the first 5 years of disease may have negative impacts on the cognitive outcomes of patients with Dravet syndrome. These drugs should be avoided.

Should you wish more information, please refer to your local health authorities’ guidelines or to the specialist who is regularly following the patient.

ketogenic diet and vagus nerve stimulation

Pharmacological treatments are often not sufficient to control seizures.

Some non-pharmacological treatments may be considered, such as ketogenic diet and vagus nerve stimulation, knowing that only the ketogenic diet has proven efficacy in clinical studies. Since each child is unique, what works for some may not work for others.

1. Ketogenic Diet

A ketogenic diet (KD) is a high-fat, adequate-protein, low-sugar diet. The diet forces the body to burn fats rather than sugars. Normally, sugars contained in food are converted into glucose, which is then transported around the body and is particularly important in fuelling brain function.

Generally, in ketogenic diets the fat/carbohydrate and protein ratio is 4:1. Several variants of this diet exist, such as the Atkins diet (fat/carbohydrate and protein ratio of 3:1), or the modified Atkins diet (fat/carbohydrate and protein ratio of 1:1). A ready-to-feed formula may be useful for maintaining this diet.

Because this diet must be strictly calculated and consumed, it requires clear understanding by the family, real compliance by the child, and permanent collaboration between the family and their doctor.

Several studies have demonstrated the efficacy of the ketogenic diet in patients with Dravet syndrome, resulting in a significant reduction (50%-100%) of the seizure frequency in 65% of children , accompanied by an improvement of behaviour, and allowing for a reduction in use of AEDs (Laux et al. 2013).

Currently, Ketogenic diet is considered as a good treatment option when three or four anti-epileptic drugs have failed.

These diets should only be initiated and undertaken under the supervision of a doctor knowledgeable about Dravet syndrome and the ketogenic diet, and with the assistance of a dietician.

The Charlie Foundation for Ketogenic Therapies was founded in 1994 to provide information about diet therapies for people with epilepsy, other neurological disorders and tumorous cancers.

Link to Charlie’s Foundation https://charliefoundation.org/

2. Vagus Nerve Simulation

The Vagus nerve is a special nerve that carries motor impulses from the brain to several organs (lungs, heart, intestines, blood vessel, etc.) and sensations from these organs back to the brain. Vagal stimulation may regulate epileptic seizures by an unknown mechanism of action.

Vagus Nerve Stimulation (VNS) consists of the surgical implantation along the vagus nerve, in the neck, of a device similar to a pacemaker. This procedure has been shown useful in various pharmacoresistant types of epilepsy, but its efficacy is not well documented for patients with Dravet syndrome (Zamponi et al. 2011).

In a meta-analysis including 68 patients across 13 studies, Dibué-Adjei et al. 2017 concluded that 53% of patients experienced a ≥50% reduction of seizures. Patients also occasionally benefit in terms of alertness, communication, quality of life and life skills.

Vagus nerve stimulation

emergency protocol

Dravet syndrome can deeply affect family life, especially when the child presents long-lasting convulsive seizures that can require hospitalisation.


The following approaches can be useful in case of emergency:

  • Write an emergency protocol for parents to give to emergency medical health services, in which you detail the medications that the Dravet patient is currently receiving, the disease he/she is suffering from and what treatments to avoid.
  • Propose the “on watch parent” idea. One “parent on call” accompanies the Dravet child to the emergency room while the other parent, or another designated adult, stays with any other children so that they can continue their activities and avoid the trauma of hours spent in a hospital environment.
  • To avoid long-lasting seizures or status epilepticus, provide guidance on the proper usage of emergency benzodiazepines, according to the available form in your country, using information provided in the Emergency seizure treatment section.
  • Advise parents to take the following items every time they leave home:

comprehensive care

Comprehensive care aims to prevent and/or treat problems other than seizures that come with Dravet syndrome (comorbidities). Treatment may not eliminate these problems but may reduce their impact on patients and their families. This requires collaboration between the doctor and a multidisciplinary team who can give support to patients and their families, enabling them to have the best quality of life possible. Providing this information in the Emergency parent’s protocol can be useful.

1. FEVER AND VACCINATION

Fever is one of the most frequent trigger factors in Dravet syndrome, particularly in young children. It is noteworthy that temperature does not always reach the level of fully-fledged fever and may provoke seizures when it rises only slightly (from 37 to 38° Celsius for example). This “fever” has several possible causes but is often related to infection.

INFECTIONS AND FEVER

There is a general sense that patients with Dravet syndrome are prone to infections although they do not have any known immunological deficiency. Common infections affect mainly upper respiratory tracts, lungs and urinary tracts. They should be appropriately treated, with or without antibiotics.

A correct dose of antipyretic medication (for example, acetaminophen or ibuprofen) is usually effective to decrease temperature. Be careful not to exceed reasonable doses because of the risk of hepatic toxicity due to interactions with anti-epileptic drugs.

Although these patients are fever-sensitive and precautions should be taken, it is impossible to eliminate all infectious illnesses. Patients need to have a social life that is as normal as possible and should not be “isolated”.

VACCINATION

Parents often fear that vaccination may trigger seizures, especially since:

  • One of the side effects of certain vaccines can be to cause fever
  • Fever in some children with epilepsy can trigger a seizure
  • The first epileptic episode for Dravet syndrome is often triggered by a fever

However, it is highly recommended to vaccinate these children to protect them from serious infectious diseases. After a vaccination, it may be reasonable to routinely give an antipyretic medication for fever prevention. Otherwise the child’s temperature should be monitored and, if fever develops, antipyretics can be given promptly.

Dravet syndrome has sometimes been mistakenly identified as a “vaccine encephalopathy” because the initial seizures appeared soon after a vaccination. But retrospective studies demonstrated that 92% (Berkovic et al. 2006) of the studied patients with Dravet syndrome who had their first seizure after a vaccination carried an SCN1A mutation. It is reasonable to think that vaccination may trigger an epileptic seizure episode in infants who are likely to have them anyway, but on no account is it the cause of epilepsy.

It is important to keep in mind that infectious diseases such as measles, rubella, mumps, pertussis, and influenza may trigger severe seizures and even cause neurological complications. If vaccination is a method of preventing infection, then it should not be excluded.

Vaccination may be followed by seizures even when there is no change in temperature, although the mechanisms driving this remain obscure. In a retrospective evaluation of 70 patients with Dravet syndrome and SCN1A mutation, seizures following vaccination were reported in 19 patients (27%) and for 9 (47%) of them, seizures were not accompanied by fever (Tro-Baumann et al. 2011). For this reason, prevention is not currently possible.

With regards to recommendations for vaccination of children with Dravet syndrome, the Dravet syndrome chapter in the “Epileptic syndromes in infancy, childhood and adolescence” book (5th edition 2013), Bureau et al state to “not inject vaccine when the child is ill or febrile and to give antipyretics before and after the vaccination, associated with benzodiazepines for one week”.

2. OTHER SEIZURE-TRIGGERING FACTORS

Dravet syndrome patients are sensitive to various stimuli that may trigger seizures.

PHOTOSENSITIVITY
TEMPERATURE SENSITIVITY
OTHER SITUATIONS
PATTERN SENSITIVITY

PHOTOSENSITIVITY

Some patients with Dravet syndrome may have seizures triggered by bright flashing lights, such as strobe lights, sun reflected from the water at the beach, or moving through the branches of trees. For others, flashing colours and shapes may play an important role, such as in video games or cartoons.

The following remarks may be useful for these patients:
• Avoid bright lights that flicker.
• Limit the time spent in front of television and other electronic screens and reduce contrast. Sit as far away from screens as possible and keep the lights on in the room. Avoid looking at screens in the dark.
• Regular sunglasses may be helpful outside, but not sufficient on their own.

A Japanese study suggested that certain wavelengths might cause the triggering of seizures. This study on patients with Dravet syndrome with photosensitivity and self-induced seizures showed that an appropriate filter of 600-700 nm light waves gradually reduced photosensitivity and inhibited flickering hand movement and forced eye closure-induced seizures (Takayashi et al. 1995). These results were confirmed by a large Italian study of photosensitive patients with various types of epilepsy (Verrotti et al. 2012).

According to this data, we strongly suggest that patients who are light sensitive and, even more so, those with self-induced seizures, wear glasses that stop seizure-triggering light waves specific to the patient. It is also important that these glasses provide lateral protection to stop side lights from reaching the eye.
This suggestion is also valid for patients who are sensitive to non-flickering environmental light and experience seizures when they go outside or are in a well-lit place.

TEMPERATURE SENSITIVITY

A slight increase in body temperature can be a seizure-triggering factor. This is often provoked by infectious diseases.

However, increased body temperature may occur in other situations: excessive or prolonged physical activity, immersion in hot water, environmental heat, etc. It may be sensible to avoid intensive sports, hot environments (hot rooms, hot cars etc.), hot baths and to opt for air-conditioned environments. But parents cannot always prevent their children from being exposed to these types of environments. Control of body temperature using cooling vests has no established value.

OTHER SITUATIONS

Excitation and emotions can also be trigger factors.

They are reported by many parents who are afraid when their children participate in celebrations such as birthdays, Christmas, school parties, etc.

Stressful situations may also be responsible for seizures: separation, change of people and environment, first days at school, criticism, etc. Sometimes this can disrupt education and promote a tendency to misbehave, or even become “poorly behaved children”.

The role of doctors and of medical teams is to reassure parents by putting the risk of such provoked seizures in perspective.

PATTERN SENSITIVITY

Visual patterns may trigger seizures in some patients. They consist of various designs such as regular geometric patterns, lines, dots, or contrasted surfaces, which are found widely in many environments: clothes, roof tiles, escalators, pavements, windows, letters in children’s books, TV screens, etc.

Affected patients may or may not also be photosensitive. Pattern sensitivity is generally not suppressed but only attenuated by wearing special glasses for photosensitivity.

Although it is not always easy to avoid patterns, there is another solution which involves completely masking one eye. However, it is not well tolerated by patients and can only be used for short periods of time to facilitate some activities (e.g. reading).

EXAMPLE OF PATTERNS