Management of Dravet syndrome is not limited to antiepileptic treatments. Indeed there is currently no cure for this syndrome. The only possible currently available treatment is a symptomatic treatment of the seizures. Comprehensive care of the patient aims to also consider and treat all other disorders.
Several pharmacological and non-pharmacological treatments can be used for Dravet syndrome patients. You should keep in mind that seizures are highly pharmacoresistant and their complete control cannot generally be achieved. So, persistence of some seizures is preferable to heavy and deleterious polytherapy.
It is reasonable to start continuous treatment as soon as the diagnosis of Dravet syndrome is strongly suspected. If you should need more clinical information on diagnosis, please refer to its dedicated section.
In addition or in substitution to pharmacological treatments, non-pharmacological treatments may be part of the therapeutic arsenal.
The following treatment algorithm published by Ch. Dravet and R. Guerrini can be helpful.
Valproate is usually the first-line treatment, 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 prevent or stop long-lasting seizures, in particular status epilepticus. Clonazepam and clobazam are the most frequently prescribed benzodiazepines in Dravet patients. 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.
Topiramate has been studied in open-label trials only (Nieto-Barrera et al., 2000; Coppola et al., 2002; Villeneuve et al., 2002; Grosso et al., 2005; Kröll Seger et al., 2006). 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. A slow titration facilitated a better tolerance.
The first classical chronic pharmacological treatment option after first seizures is valproate monotherapy. It is generally well tolerated but, in case of vomiting, close monitoring of valproate plasma concentration as well as biological constant should be performed to avoid risks of hepatic failure.
When seizures are no longer controlled by average valproate plasma concentration, three options are possible :
The first one is the polytherapy combination of valproate and clobazam. In case of failure, add stiripentol*. For Dravet syndrome patients with tonic-clonic seizure, the European Medecine Agency (EMA), the Canadian and Japanese Health Agencies recommend the combination of valproate, clobazam and stiripentol*.
The second is valproate and topiramate, as shown by Barrera et al. in 2003. In case of failure, clobazam can be added.
The third is to associate bromide to valproate.
As a remark, some authors like Ceulemans in 2004, propose limiting the chronic use of benzodiazepines because of their side-effects.
*Only available in EMA member states (full marketing authorisation 2014 following conditional marketing authorisation since 2007), Canada (2012) and Japan (2012). In some countries it has an orphan drug status.
Generally, even during therapy with recommended treatments, seizures are not totally controlled or, even if initially controlled, treatment loses efficacy over time. In this case a change of antiepileptic may be required. To avoid a too heavy and too complicated polytherapy approach, substitution of an antiepileptic rather than an addition should be considered. Clonazepam, zonisamide and levetiracetam in various combinations, with or without stiripentol, can be one of these alternative treatments.
Rectal diazepam :
Rectal diazepam (using the same solution as for intramuscular/intravenous injections) is the most popular solution worldwide, since it can be easily administered by parents and caregivers in a daily life setting (or out of a medical setting). However, adolescents and adults might tend to refuse it, finding it discomfiting. In some countries, ready to use preparations are available. The dose must be indicated by the current doctor, taking the patient’s age and weight into account. The seizure usually stops in the minutes following administration.
Oral / Nasal midazolam :
Oral / Nasal midazolam solution has recently been demonstrated to provide the same results (Mc Mullan et al, 2010), but is not available in all countries. It can be also used by parents and caregivers. They need to be informed of the exact way of putting the solution inside the mouth, where it is absorbed by the sublingual and cheek mucosa, in order to avoid the patient swallowing it. The seizure stops in the minutes following administration.
Other benzodiazepines :
Other benzodiazepines, such as clonazepam and lorazepam, have not been studied but are likely to have the same effect as midazolam when used orally in the same way.
When a convulsive seizure does not stop after this treatment approach, medical intervention is needed, either a mobile medical emergency or in the emergency room at the hospital.
Often pharmacological treatments are 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 its efficacy in clinical studies. Since each child is unique, what might work for some may not work for others.
The ketogenic diet 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 the ketogenic diet 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.
Vagus Nerve Stimulation (VNS) consists of the surgical implantation along the vagus nerve, in the neck, of a device similar to a pace-maker. This procedure has been shown useful in various pharmacoresistant epilepsy types but does not seem as advantageous for patients with Dravet syndrome (Zamponi et al, 2010)
Comprehensive care aims to prevent and/or treat problems other than seizures that come with Dravet syndrome (co-morbidities). Treatment may not eliminate these problems but may reduce their impact on patients and their families. This requires the collaboration between the physician and a multidisciplinary team who may give support to patients and their familes, allowing them the best quality of life possible. Providing this information in the Emergency parent’s protocol can be useful.
Fever is one of the most frequent triggering factors in Dravet syndrome, particularly in young children. It is noteworthy that often the temperature does not reach a level of true fever and may provoke seizures when it rises slightly (from 37 to 38 ° Celsius for example). This “fever” has a number of causes but is often related to infection.
There is a general sense that Dravet syndrome patients 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 aware not to exceed reasonable doses because of the risk of hepatic toxicity due to interactions with the antiepileptic drugs.
Even if these patients are fever-sensitive, it is impossible to eliminate all infectious illnesses. They need to have a social life that is as normal as possible and should not be “isolated”.
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% of the studied Dravet syndrome patients 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 may it be the cause of the epilepsy.
It is important to keep in mind that infectious diseases such as measles, rubella, mumps, pertussis, and influenza may be severe trigger seizures and even cause neurological complications. If vaccination is a way to prevent an 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. It occured in one third of the vaccine-related seizures in a study of 19 patients. For this reason, prevention is not currently possible.
The degree of severity and the nature of the cognitive decline should be documented by aged-adapted standardised testing. This testing allows an understanding of the specific deficits, but also the real abilities of the child and the respective roles of epilepsy and treatment. It can be carried out as soon as the diagnosis is established and at intervals throughout the patient’s life. The results are taken into account by the family and the medical team for school integration and implementation of rehabilitative therapies: speech therapy, psychomotricity, and ergotherapy.
If available in your country, the help of a cognition specialist can be valuable to develop an early appropriate management plan and optimize cognitive progression.
Behavioural and psychological issues are always observed in Dravet syndrome patients and impact their family and social life.
These factors vary from one child to another and may include hyperactivity, repetitive behaviour, opposition behaviour and problems with social interaction.
A short attention span especially when associated with hyperactivity can make life dangerous for these patients – they may not perceive a situation as risky.
Stereotypic activities are repetitive movements and behaviours that may interfere with structured play as well as with learning activities.
Oppositional behaviour may make Dravet patients difficult to manage at home and in public. Some oppositional behaviour may be linked to language impairment and poor communication.
For the same reasons, many Dravet syndrome patients have difficulties interacting appropriately with children of their own age, which can lead to withdrawal and isolation. They may prefer the company of adults. Overly trusting and friendly behaviour towards adults may lead them to danger.
These problems often worsen in adolescence, particularly in patients who do not have severe cognitive impairment and become aware of their differences with those of the same age.
Pedagogic, behavioural and psychological measures that can be used depend on the structures and specialists in different countries.
Special classes, individual help in mainstream classes, out-of-school social and educational settings, sport practice, and group leisure activities, are some of the possible solutions.
Either psychotherapy or, at least, psychological support should also be offered.
In adulthood, few patients can engage in simple work in a sheltered structure. Specialized institutions for mentally retarded patients, when possible, can be positively received by patients and alleviate the burden for the family.
In all cases it is important that physicians and professionals are aware of all these problems, take time to listen to patients and families, without forgetting siblings, to help them find the best possible solutions and, finally, to accompany them in the acceptance of the disease.
Dravet patients may experience difficulties with sleep. Problems may include excessive sleepiness or difficulty falling asleep, maintaining sleep or awakening very early.
There are many causes, including unrecognized seizures or side effects from some anti-epileptic drugs, which may be improved through dose adjustment and spreading out doses during the day. Sleep-inducer drugs may help falling asleep.
Most feeding disorders such as anorexia or loss of appetite are a consequence of anti-epileptic drug treatment. Dose adjustments may not be easy because of the risk of more seizures. Sometimes a psychologist can be helpful.
In rare patients, anorexia, failure to thrive or loss of weight are independent from antiepileptic drugs and are so worrying that gastrostomy becomes necessary.
Dravet syndrome patients are often subject to motor impairment and postural change. These issues may become particularly important during adolescence.
Fine motor skills are impacted from the first years, making children clumsy, especially if they have ictal and interictal myoclonic jerks. Difficulties with fine motor skills may impact all daily life activities and also reading, writing and drawing. They can be attenuated by psychomotricity therapy.
Gait tends to deteriorate from about nine to ten years of age, associated with pes planus-valgus and, sometimes, cyphoscoliosis. From adolescence, the most severely affected patients gradually develop a special crouch pattern when they walk. These patients may have difficulty walking long distances, although usually they maintain the ability to walk around the house and for short distances.
Motor impairment can be attenuated by physiotherapy but needs to be followed up by an orthopaedist who will possibly prescribe custom orthesis and, rarely, surgical intervention.