INTRODUCTION — Dravet syndrome (DS; OMIM # 607208), previously known as severe myoclonic epilepsy of infancy (SMEI), is a rare pediatric genetic epilepsy syndrome characterized by refractory epilepsy and neurodevelopmental problems beginning in infancy. Mutations in the alpha-1 subunit of the voltage-gated sodium channel (SCN1A) gene are identified in 70 to 80 percent of patients with DS.

Drug resistance is a well-recognized feature of seizures in this syndrome, and antiseizure medication therapies have overall limited efficacy. Nonetheless, every effort should be made to avoid seizure triggers and to control seizures and status epilepticus as best as possible. Pharmacologic therapy remains the mainstay of treatment, and ketogenic diet and neuromodulation are viable options in selected patients.

The goals of treatment are to reduce both the length and number of seizures and prevent status epilepticus, limit adverse effects of antiseizure medications to promote better neurocognitive development, and improve quality of life. The treatment recommendations below are generally consistent with those of a North American consensus panel on the diagnosis and management of DS.

The management and prognosis of DS will be reviewed here. The epidemiology, genetics, clinical features, and diagnosis of DS are reviewed separately. (See "Dravet syndrome: Genetics, clinical features, and diagnosis".)

AVOIDANCE OF SEIZURE TRIGGERS — Patients with DS are more sensitive to certain seizure triggers than the general epilepsy population, and anticipatory guidance about common triggers is an important component of management.

Approach to fever and hyperthermia — Fever and hyperthermia are well-known seizure triggers in patients with DS. We advise parents to try to avoid increases in body temperature by minimizing hot baths or excessive physical activity on warm days.

Oral or rectal antipyretics (eg, acetaminophen, ibuprofen) and prophylactic benzodiazepines may be used in the setting of fever, although prospective studies on the efficacy of prophylactic therapies for preventing seizures in patients with DS are lacking. A North American consensus panel on the diagnosis and management of DS reached strong consensus on use of antipyretics with both illness and vaccination and benzodiazepines with illness, but acknowledged limited evidence to support the practice [1]. Randomized trials of antipyretic therapy in otherwise healthy children with a history of febrile seizures have not shown any benefit compared with placebo. (See "Treatment and prognosis of febrile seizures", section on 'Antipyretics'.)

Caution is advised when administering acetaminophen in patients who are on valproate due to potential risk of hepatic injury. Antipyretic medications are ineffective for hyperthermia due to heatstroke and may exacerbate concomitant liver injury or coagulopathy. (See "Fever in infants and children: Pathophysiology and management" and "Heat stroke in children".)

Minimizing photic and pattern stimulation — Photic and pattern stimulation should be minimized in patients who demonstrate sensitivity to these triggers.

Although no methods have been systematically studied, possibly effective strategies include watching television from a distance in a lightened room, wearing sunglasses outdoors or blue lens glasses, and using a 100 Hz television screen rather than traditional 50 Hz screen [2]. Emotional stress and other recognized triggering factors should also be avoided when possible.

Vaccine-associated seizures — Post-vaccination seizures have been well described in children with an established diagnosis of DS as well as in children with a first-time febrile seizure who are later diagnosed with DS [3]. However, there is no compelling evidence that vaccines should be withheld or modified in patients with DS. Prophylactic antipyretics and benzodiazepines are commonly used at the time of vaccination and for 24 hours afterwards, although specific data on the effectiveness of this approach are lacking.

Observational data in children with DS indicate that vaccinations before or after disease onset do not affect clinical or intellectual outcomes [3-6]. As in healthy children, the risk of post-vaccination seizure likely varies according to the type of vaccine and the age of the child and may be highest in association with the measles, mumps, and rubella (MMR) vaccine [3]. Postvaccination seizures may also be seen in patients who do not develop fever, implicating an immune-mediated mechanism [7].

(See "Clinical features and evaluation of febrile seizures", section on 'Immunization'.)

ANTISEIZURE MEDICATION THERAPY — The most commonly used antiseizure medications in patients with DS include valproate, clobazam, topiramate, stiripentol, cannabidiol, fenfluramine, levetiracetam, and bromides (in some regions). Among these, stiripentol as an add-on therapy to clobazam as well as cannabidiol and fenfluramine have been evaluated in randomized trials. Notably, stiripentol has limited availability and is restricted in many countries [8,9].

Initial therapy — Most patients with DS require two or more drugs to achieve reasonable seizure control, and choice of drugs should be individualized based on considerations of efficacy as well as side effects, tolerability, and access. We typically take a stepwise approach, using valproate as a first-line drug in most patients and then adding clobazam if seizures remain poorly controlled despite adequate valproate dosing and serum levels.

Valproate — Valproate is a broad-spectrum antiseizure medication that is widely prescribed in patients with DS and is considered a first-line antiseizure medication for DS by most epileptologists [10].

The rationale for use is based on expert opinion that valproate is effective in some patients with DS, extrapolation from clinical trials in children with both focal and generalized epilepsies of other etiologies, and its relatively favorable safety and tolerability profile. There have been no prospective studies of valproate in patients with DS.

In a retrospective survey of 99 children with DS in Japan, valproate was the most commonly used drug and was deemed to have excellent or moderate efficacy for the prevention of status epilepticus in 8 and 45 percent of patients, respectively [10]. It was felt to have no effect in the remaining patients. A similar survey study in Europe that included 274 patients with DS found that valproate was used by 86 percent of patients, most commonly in combination with clobazam and stiripentol [11].

Valproate is typically initiated at a dose of 10 to 15 mg/kg/day in two or three divided doses and increased to a target or maintenance dose of 25 to 60 mg/kg/day, depending on achieved blood levels, efficacy, and side effects.

Potential side effects include nausea and vomiting, weight gain, sedation, hair loss, pancreatitis, hyperammonemia, and blood dyscrasias. Valproate has multiple potential interactions with concomitant antiseizure medications and other medications (table 1). Routine monitoring of drug levels, complete blood count, liver function tests, and lipase is generally recommended (table 2). (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Valproate'.)

Children less than two years of age, patients with mitochondrial disease and other congenital metabolic disorders, and patients on multiple antiseizure medications have an increased risk of fulminant hepatic failure. Patients taking valproate are at risk of secondary carnitine deficiency, particularly those on a ketogenic diet, and increased monitoring of liver function tests is advised in this setting. (See "Ketogenic dietary therapies for the treatment of epilepsy", section on 'Antiseizure medication management'.)

Valproate is a known teratogen. Female patients and their caregivers should be informed of the risks associated with valproate use during pregnancy, the relative risks and benefits of alternative treatment options, and options for effective contraception [12]. (See "Seizures and epilepsy in children: Initial treatment and monitoring", section on 'Teratogenicity'.)

Adjunctive clobazam — Clobazam is our preferred first-line add-on therapy in patients with DS. It is a benzodiazepine with broad-spectrum anticonvulsant activity that is approved for use in most countries as an adjunctive antiseizure medication; in the United States, it has been approved since 2011 for patients with Lennox-Gastaut syndrome.

Similar to valproate, clobazam has been understudied in DS. Nevertheless, when used in combination with other therapies, clobazam does seem to help control seizures in these patients and is the second most commonly used drug, after valproate [10,13,14].

When used with stiripentol, clobazam levels typically increase by twofold, and most patients on both drugs require a reduction in clobazam dose [15,16]. Because of this interaction, we typically measure clobazam levels before stiripentol is initiated and monitor monthly levels until stable doses are achieved, then every six months thereafter.

Possible side effects include sedation, ataxia, behavioral disinhibition, and hypersalivation (table 3). Rare cases of Stevens-Johnson syndrome have been reported (table 4).

Assessment of response — As in other patients with epilepsy, patients with DS should be monitored closely for response and toxicity with any new therapy. (See "Seizures and epilepsy in children: Initial treatment and monitoring", section on 'Initiation of antiseizure medication therapy' and "Seizures and epilepsy in children: Initial treatment and monitoring", section on 'Follow-up and monitoring'.)

Most patients with DS can be assessed for response by history and clinical seizure frequency, without the need for serial electroencephalography (EEG) studies. Shortening of prolonged seizures and avoidance of status epilepticus are important goals.

Complete control of routine seizures (ie, short daily generalized tonic clonic, absence, myoclonic, and focal onset seizures) is rarely achieved. While brief periods of seizure freedom can occur during childhood for several months at a time, most children will have recurrent seizures despite optimal drug and dietary management. Longer periods of seizure freedom are more commonly seen in adults than in children.

Patients who fail first two drugs — The approach to patients with poor seizure control or intolerance to first-line therapy with valproate and clobazam is individualized. Options include additional broad-spectrum antiseizure medications (table 5) as well as non-pharmacologic therapies, including dietary therapy (eg, ketogenic diet) and surgical therapies (eg, vagus nerve stimulation). (See 'Ketogenic diet' below and 'Surgical therapies' below.)

Among the broad-spectrum antiseizure medications, topiramate and stiripentol are considered second line, while levetiracetam, cannabidiol (pharmaceutical), and fenfluramine are considered third-line drugs. This order may change with a forthcoming international consensus guideline; cannabidiol (pharmaceutical) and fenfluramine are newer therapies that have been rigorously studied and approved for patients with DS older than two years of age. Some experts argue that cannabidiol and fenfluramine should be considered at any point in the treatment pathway for patients with DS two years and older with high seizure burden, given their established safety and efficacy in DS [17].

Sodium channel blocking drugs should generally be avoided. (See 'Drugs to avoid' below.)

Topiramate — Topiramate is a broad-spectrum antiseizure medication with some evidence of efficacy in patients with DS [18-22]. It is therefore a reasonable add-on therapy in patients with poorly controlled generalized or focal seizures despite first-line therapies.

In small observational studies in patients with DS, topiramate has been associated with ≥50 percent reduction in seizures in 50 to 85 percent of patients, including 16 to 18 percent remaining seizure-free for approximately one year [18-22]. Side effects were observed in approximately 15 percent of patients, most commonly anorexia, weight loss, behavioral disturbances, emotional and language regression, and renal stones.

Topiramate is typically started at 0.5 to 2 mg/kg per day and subsequently titrated up to 8 to 12 mg/kg per day depending on efficacy, and side effects. We do not routinely monitor topiramate drug levels.

The potential for drug interactions with topiramate is generally low. Clinical monitoring of body weight and serum bicarbonate is advised given the risk of nephrolithiasis, which may be increased in patients on the ketogenic diet. (See "Ketogenic dietary therapies for the treatment of epilepsy", section on 'Adverse effects' and "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Topiramate'.)

Stiripentol — Stiripentol is an allosteric modulator of the gamma-aminobutyric acid A (GABA-A) receptor with direct activating effects [23]. It also inhibits cytochrome P450 enzymes, thereby increasing blood levels of some antiseizure medications, especially clobazam, valproate, and fenfluramine [24]. The drug is available for clinical use in Canada, Europe, and Japan under an orphan drug designation. The US Food and Drug Administration (FDA) approved stiripentol in 2018 for treatment of seizures associated with DS in patients two years of age and older taking clobazam [25].

Like topiramate, stiripentol is considered a preferred second-line medication for DS in children with an inadequate response to first-line therapies. Stiripentol should be used in combination with valproate and clobazam, as there is no evidence to support its use as monotherapy.

Stiripentol has been evaluated in two multicenter, placebo-controlled randomized trials in patients with DS [26-28].

●In the first trial, 42 patients with DS who were randomly assigned to receive either stiripentol (50 mg/kg/day) or placebo as add-on therapy to clobazam and valproate [26]. After two months, patients in the stiripentol group had significantly improved seizure control as assessed by both the proportion of patients with ≥50 percent reduction in clonic and tonic-clonic seizures (71 versus 5 percent) and the number of patients free of these seizure types (9 versus 0). Side effects (eg, drowsiness, loss of appetite, weight loss) were seen in all patients treated with stiripentol and in 25 percent of those who received placebo [26].

●Unpublished data from a second trial of similar design in 22 patients with DS have been reported in abstract form [27] and as part of a patient-level meta-analysis [29]. The response rate was again greater with stiripentol compared with placebo (63 versus 9 percent with ≥50 percent reduction in clonic and tonic-clonic seizures, three versus one patient seizure free). Side effects were not reported.

Subsequent observational studies have reported similar efficacy, with response rates ranging from 61 to 89 percent [13,14,30-32], as well as reductions in seizure length, frequency of status epilepticus, frequency of hospitalizations, and frequency of rescue medication use [33]. Long-term follow-up data suggest that the benefit of stiripentol persists into adulthood [34].

The largest published experience in the United States consists of a retrospective study of data submitted by 13 pediatric neurologists who had prescribed stiripentol to 82 children with DS over a seven-year period [31]. The median number of antiseizure medications tried before stiripentol was seven, and over half of patients had been treated with a dietary therapy such as the ketogenic diet. The most common drug combination (n = 48) was stiripentol, valproate, and clobazam, plus a median of one additional drug. In these patients, overall seizure frequency was reduced in 63 percent, unchanged in 33 percent, and increased in 4 percent compared with baseline. Overall efficacy appeared to be slightly better in the group treated with stiripentol and clobazam but not valproate (n = 35) and lower among those treated with stiripentol without concurrent clobazam.

The starting dose for stiripentol is listed at 50 mg/kg per day, administered in two or three divided doses, but some experts start at 25 mg/kg per day. The dose can be increased in increments of 10 mg/kg per day every one to two weeks to a maximum total daily dose of 3000 mg. The typical tolerated dose in children is 75 mg/kg per day [35], although some children may require up to 100 mg/kg per day. In a retrospective study of 82 children with DS, stiripentol adverse effects were reported as mild and not requiring treatment discontinuation in the majority; the most common were sedation (18 percent) and decrease in appetite (8.5 percent) [31].

There are fewer data for stiripentol dosing in adults with DS. Findings from one small study of adult patients with DS who started stiripentol in childhood or adolescence suggested that 25 to 30 mg/kg per day is better tolerated by adults [34]. Another study suggested that stiripentol-naïve adults may tolerate even lower doses (15 to 25 mg/kg per day) [36]. This study also showed that some adults on concomitant stiripentol and valproate developed a hyperammonemic encephalopathy, which could be managed with carnitine in some of them.

Stiripentol has also been used in combination with perampanel by some experts to treat DS. When this combination is used, it is important to monitor perampanel serum levels and to follow for signs of perampanel toxicity, given that stiripentol may increase perampanel serum levels [37]. Comprehensive information on drug-drug interactions can be determined using the Lexicomp drug interactions tool.

Levetiracetam — Levetiracetam has broad-spectrum anticonvulsant activity for both generalized and focal epilepsies and has been used with variable success in patients with DS who have failed other therapies.

In one prospective multicenter study, 28 patients with DS (mean age 9.4 years, 57 percent with an alpha-1 subunit of the voltage-gated sodium channel [SCN1A] mutation) were treated with levetiracetam for an initial 5- to 6-week titration period and then a 12-week evaluation phase [38]. Response rate (≥50 percent reduction in seizure frequency) was 64 percent for tonic-clonic seizures, 60 percent for myoclonic seizures, 60 percent for focal seizures, and 44 percent for absence seizures. Subsequent studies have reported less favorable results, however, with response rates ranging from 11 to 30 percent [14,39].

Levetiracetam has minimal drug interaction potential and is generally well tolerated, although it can be associated with behavioral side effects including irritability, aggression, and depression in some patients. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Levetiracetam'.)

Cannabidiol — The potential antiseizure effects of cannabis (marijuana) have generated significant interest in the epilepsy patient community and in patients with DS specifically.

Cannabidiol (pharmaceutical) is the component of cannabis most commonly investigated in medical studies. Preliminary support for its potential efficacy in DS was provided by open-label trial of cannabidiol in patients with intractable epilepsy that included 32 patients with DS [40]. In a post hoc analysis, 50 percent of these patients had a ≥50 percent decrease in frequency of motor seizures, including one patient who was free from motor seizures.

In a follow-up multicenter trial, 120 children and young adults with DS were randomly assigned to receive oral cannabidiol solution (20 mg/kg/day) or placebo, in addition to standard antiseizure medication treatment [9]. From baseline to 14 weeks, the median convulsive seizure frequency decreased from 12.4 to 5.9 per month in the cannabidiol group and from 14.9 to 14.1 in the placebo group (adjusted median difference in relative seizure reduction 23 percent, 95% CI 5-41). There was no difference in nonconvulsive seizure frequency. Several other efficacy endpoints favored cannabidiol, including total seizure frequency and global caregiver impression scores. Adverse effects were more common in the cannabidiol group, most notably diarrhea (31 versus 10 percent), somnolence (36 versus 10 percent), and fatigue (20 versus 3 percent). Increased liver function tests were observed in children taking concurrent valproic acid. One potential limitation of the trial is that the disparity in side effects and differences in palatability between cannabidiol and placebo preparations may have affected blinding of caregivers, who were responsible for reporting seizure frequency.

Based upon these data, and clinical trials of cannabidiol in children with Lennox-Gastaut syndrome, the US Food and Drug Administration approved cannabidiol (pharmaceutical) for the treatment of seizures associated with DS and Lennox-Gastaut syndrome in June 2018 [41]. In addition, the United Kingdom National Institute for Health and Care Excellence (NICE) guidelines recommend cannabidiol with clobazam as an option for treating seizures associated with DS for people who are two years of age and older [42]. NICE recommends checking the frequency of convulsive seizures every six months and stopping cannabidiol if the frequency is not reduced by at least 30 percent when compared with the six months prior to treatment. However, there is no evidence to support the use of cannabidiol as a first-line agent or as monotherapy for this indication.

Cannabidiol (pharmaceutical) is an oral solution (100 mg/mL) [43]. The initial dose is 2.5 mg/kg twice daily by mouth. The dose can be increased after one week to the suggested maintenance dose of 5 mg/kg twice daily, and may be increased, if needed for further seizure control, up to a maximum of 10 mg/kg twice daily (total 20 mg/kg per day). In a randomized controlled trial of over 190 children with DS, the reduction in convulsive seizure frequency compared with placebo was similar for cannabidiol 10 mg/kg per day and cannabidiol 20 mg/kg per day, while safety and tolerability were better with the lower dose [44]. We therefore typically use cannabidiol up to a maximum dose of 10 mg/kg per day. However, higher doses may be used in select cases depending on individual efficacy and tolerability.

The most common adverse reactions with cannabidiol are somnolence, decreased appetite, transaminase elevations, diarrhea, fatigue, malaise, insomnia and other sleep problems, and infections.

Serum transaminase (alanine transaminase [ALT] and aspartate transaminase [AST]) and total bilirubin levels should be obtained at baseline and then at one, three, and six months after starting treatment, and periodically thereafter as clinically indicated, or within one month of change in cannabidiol dosing or with changes in other medications that affect liver function [43]. Cannabidiol should be discontinued or interrupted if symptoms or signs of liver dysfunction develop.

The pharmacokinetics of purified cannabidiol were evaluated by a randomized controlled trial that included 34 children with DS who were randomly assigned to three different doses of cannabidiol (5, 10, or 20 mg/kg per day) or placebo taken twice daily [45]. Cannabidiol did not affect levels of concurrent antiseizure medications except for the active clobazam metabolite, N-desmethylclobazam. The levels of N-desmethylclobazam increased regardless of the specific cannabidiol dosing; however, this phenomenon was not seen in patients who were also using stiripentol. All three doses of cannabidiol were well tolerated.

In a long-term open-label extension trial, add-on therapy with cannabidiol (pharmaceutical) had an acceptable safety profile and decreased the frequency of total and convulsive seizures up to 156 weeks of treatment [46]. Additional studies are required to assess whether tetrahydrocannabinol (THC)-containing cannabidiol preparations are safe and effective in this population of patients [47].

Fenfluramine — The antiobesity drug fenfluramine, which was withdrawn from the market in 2001 due to an association with cardiac valve injury and pulmonary hypertension [48], was approved by the FDA in June 2020 for the treatment of seizures associated with DS in patients age two years and older [49]. It is not clear how fenfluramine may control seizures. One possible mechanism is via modulation of N-methyl-D-aspartate receptor (NMDAR)-mediated excitation [50], and another is through serotonergic effects.

The FDA approval was based upon the findings of two trials [8,51]. The potential benefit of fenfluramine is illustrated by a 14-week trial that randomly assigned 119 patients (mean age 9 years) in a 1:1:1 ratio to fenfluramine 0.7 mg/kg per day, fenfluramine 0.2 mg/kg per day, or placebo [8]. Compared with the placebo group, patients assigned to the higher dose of fenfluramine had a median reduction in monthly convulsive seizure frequency of 62 percent, while those assigned to the lower dose of fenfluramine had a median reduction of 32 percent. Fenfluramine was also well tolerated and effective as an add-on in patients with DS who were receiving stiripentol. This observation arose from a 15-week multicenter trial of 87 children with DS who continued to have seizures despite antiseizure regimens that included stiripentol [51]. Patients were randomly assigned to fenfluramine (0.4 mg/kg per day, maximum of 17 mg per day) or to placebo. Compared with the placebo group, patients treated with fenfluramine achieved a 54 greater reduction in mean monthly convulsive seizure frequency. Subsequent open-label extension study data showed that the benefit of fenfluramine continues to provide clinically meaningful reductions in convulsive seizures was sustained over two years: 62 percent of patients had a ≥50 percent decrease in monthly convulsive seizure frequency, and 37 percent of patients had a ≥75 percent decrease in this measure [52,53].

Fenfluramine is an oral solution (2.2 mg/mL). The starting and initial maintenance dose is 0.1 mg/kg given twice daily, which can be increased weekly as needed and tolerated [54]. For patients not on concomitant stiripentol, the maximum daily dose of fenfluramine is 0.35 mg/kg twice daily, not to exceed a total daily dose of 26 mg. For patients taking who are taking concomitant stiripentol, the maximum daily maintenance dose of fenfluramine is 0.2 mg/kg twice daily, not to exceed a total daily dose of 17 mg.

While generally well tolerated, adverse effects of fenfluramine in these trials included fatigue, lethargy, somnolence, diarrhea, loss of appetite, pyrexia, and loss of weight [8,51]. No patients developed valvular heart disease or pulmonary hypertension during the trials. In an earlier study that followed 10 patients with DS treated with adjunct fenfluramine, two patients developed mild thickening of one or two cardiac valves without clinical significance and none developed pulmonary hypertension over a mean follow-up of 16 years [55]. In the United States, fenfluramine will be available only through a risk evaluation and mitigation strategy (REMS) program [54]. Evaluation with echocardiography is required before treatment, every six months during treatment, and once three to six months after treatment to monitor for valvular heart disease and pulmonary hypertension. Further study is needed to determine the long-term safety of fenfluramine for DS, particularly its effect on cardiac valve function.

Bromides — Clinical experience and limited published data suggest that bromides, one of the oldest classes of antiseizure medications, may be effective for seizures in patients with DS, but lack of availability has limited clinical use and further study [56,57]. Side effects are usually mild and include somnolence, decreased appetite, and skin rash.

Drugs to avoid — Sodium channel blocking drugs such as carbamazepine and its analogs (oxcarbazepine and eslicarbazepine), lamotrigine, and phenytoin may aggravate seizures in patients with DS and should generally be avoided [58-63]. In addition, use of these drugs for patients with DS may be associated with worse cognitive outcomes [64]. Phenytoin has also been reported to trigger paroxysmal movement disorders in some patients [62,63]. However, phenytoin has been used, without apparent adverse effects, to abort status epilepticus in patients with DS. It is still unclear if this drug should be avoided in emergency situations.

Rare patients do seem to benefit from sodium channel blocking drugs, and seizures may even worsen when these drugs are removed [65].

Seizure action plan — All patients with DS should be provided with a seizure action plan (ie, emergency protocol), which should be individualized but often includes use of rescue benzodiazepines. A copy should be provided to the child's school and other caretakers.

The seizure action plan should indicate when home rescue therapy begins and ends and when emergency medical services should be called to transport the patient to an emergency department. At a minimum, rescue medication should be given within three to five minutes of the onset of a convulsive seizure; in patients with a recent history of prolonged convulsive seizures, rescue medication should be given at the time of convulsive seizure onset. A full dose may be repeated five to ten minutes after the initial dose in patients with ongoing seizure activity.

Depending on the age of the patient, clinician and family/caregiver preferences, and regional availability, home rescue therapy may consist of rectal diazepam, buccal midazolam, or intranasal midazolam. Home rescue therapy and school action plans are discussed in more detail separately. (See "Seizures and epilepsy in children: Refractory seizures", section on 'Home rescue therapy (transmucosal antiseizure medications)'.)

KETOGENIC DIET — The ketogenic diet is a viable option for motivated patients, families, and caregivers with access to an experienced multidisciplinary team. (See "Ketogenic dietary therapies for the treatment of epilepsy".)

Although randomized trials have not been performed, observational studies have consistently shown significant benefit of the diet in patients with DS, with response rates ranging from 60 to 71 percent [14,66-69]. Some studies have also suggested improvement in behavior and cognition [67,69] as well as in electroencephalography (EEG) features [66,68]. Overall, the efficacy of the diet compares favorably with other options (eg, additional drugs, vagus nerve stimulation) in patients with poorly controlled seizures [14].

Provision of the ketogenic diet requires supervision by an experienced dietician and neurologist, ideally in the context of a multidisciplinary program with additional endocrinology, psychology, and social work support. The most commonly reported side effects include nausea and vomiting, constipation, dyslipidemia, and nephrolithiasis. Important contraindications to the diet include disorders of fatty acid transport or beta-oxidation and select mitochondrial cytopathies. (See "Ketogenic dietary therapies for the treatment of epilepsy", section on 'Contraindications' and "Ketogenic dietary therapies for the treatment of epilepsy", section on 'Implementation'.)

Less restrictive dietary therapies such as the modified Atkins diet and low glycemic index diet have also been used with some success in patients with refractory epilepsy, but there is less supporting evidence available specifically in patients with DS. (See "Ketogenic dietary therapies for the treatment of epilepsy", section on 'Indications'.)

Use of diet therapies should be reviewed in older patients who will be transitioned to an adult epilepsy program. Although diet therapy clinics are somewhat common in pediatric centers, they are far less common in adult epilepsy programs [1].

SURGICAL THERAPIES — Patients with DS are not usually candidates for resective epilepsy surgery based on the multifocal and generalized nature of disorder [70].

Neuromodulation techniques (eg, vagus nerve stimulation [VNS], deep brain stimulation [DBS]) are potential options in patients with DS, although the available data are limited and somewhat mixed.

●Vagus nerve stimulation – An early retrospective study of VNS in eight patients with DS and medically intractable seizures found a mean reduction in seizure frequency of 12 percent at 3 months, 6 percent at 6 months, and 31 percent at 12 months [71]. Five of eight patients experienced some reduction in seizure burden (33 to 61 percent) at 12 months [71]. These results are similar to the overall efficacy of VNS in other epilepsy syndromes. (See "Vagus nerve stimulation therapy for the treatment of epilepsy", section on 'Patient selection'.)

Subsequent studies have been less encouraging, however. In a retrospective study from Norway, only 1 of 13 patients with DS who received VNS showed a significant seizure-reducing effect [70]. Similarly, a long-term study on VNS for refractory epilepsy in 347 children in Europe reported response rates (≥50 reduction in seizure frequency from baseline) in patients with DS of 12.5 percent (2 out of 16) at 6 months; 25 (5 out of 20) at 12 months; and 38.5 percent (5 out of 13) at 24 months [72].

●Deep brain stimulation – DBS has been understudied in patients with DS. The evidence is limited to case reports of patients treated with subthalamic or anterior thalamic stimulation showing mixed responses [73,74]. It is therefore not yet possible to draw conclusions on the effectiveness of DBS in these patients.

COMORBID PROBLEMS

Motor impairment — Management of motor impairment in patients with DS is primarily nonpharmacologic. Patients may benefit from physical and occupational therapy. Orthopedic problems, such as kyphosis, scoliosis, and foot deformities, are managed in conjunction with orthopedics and physiatry.

Levodopa/carbidopa might have a role in the treatment of parkinsonian features in young adults with DS. Evidence consists of a series of 12 adults with DS (age range 23 to 43 years) with prominent parkinsonism, of whom two received a trial of levodopa/carbidopa [75]. Both patients showed sustained improvement in slowness and rigidity over 16 weeks with no measurable toxicity.

Behavioral issues — Impairments in social skills, executive function, and attention are common in children with DS. In our experience, hyperactivity tends to resolve in adulthood. (See "Dravet syndrome: Genetics, clinical features, and diagnosis", section on 'Behavioral disturbances' and "Dravet syndrome: Genetics, clinical features, and diagnosis", section on 'Cognitive impairment'.)

Nonpharmacologic strategies that may be of benefit include psychotherapy, family counseling, caregiver education, and rehabilitation services (eg, speech therapy, physical and occupational therapy). Neurocognitive evaluations are useful before a child reaches school age to help guide these interventions and assess progress over time.

When pharmacologic treatment is necessary, first-generation antipsychotics should be avoided due to risk of extrapyramidal side effects, which may be increased in patients with DS who often have parkinsonism at baseline [75]. There are no definitive contraindications to the newer psychiatric drugs. Potential drug interactions between psychiatric and antiseizure medications should not be overlooked [33].

Sleep problems — Sleep problems are frequent complaints of caregivers of patients with Dravet syndrome; these include frequent awakenings (due to seizures or not associated with visible seizures) and insomnia [76,77]. In one report that surveyed 76 parents, a large majority (93 percent) monitored their children sleep, either by sleeping in the same room or through the use of monitoring devices [76,77].

PROGNOSIS — Patients with DS have an increased risk of premature mortality, although some patients live well into adulthood. The most common causes of death appear to be sudden unexpected death in epilepsy (SUDEP) and status epilepticus.

A study conducted by the International Dravet syndrome Epilepsy Action League (IDEA League) included 833 patients with DS in their membership database [78]. Within this cohort, 31 patients (3.7 percent) were known to have died between 2000 and 2010. The mean age of death was 4.6 years (range 10 months to 17 years). Nineteen of the 31 deaths were due to SUDEP (61 percent), 10 due to status epilepticus (32 percent), 1 due to accident, and 1 due to ketoacidosis. A smaller study that included 100 patients with DS estimated a SUDEP risk of 9.3 per 1000 person-years [79], a rate similar to if not higher than that observed in adults with drug-resistant epilepsy. (See "Sudden unexpected death in epilepsy", section on 'Incidence'.)

A separate retrospective multicenter study of 623 patients with DS estimated a DS-attributable mortality rate of 10 percent [80]. The median age of death was 6 years and 8 months, ranging from 13 months to 25 years. SUDEP accounted for 53 percent of the deaths, status epilepticus for 36 percent, and drowning for 10 percent [80].

As in the broader epilepsy population, disclosure of SUDEP risk is an important part of patient, family, and caregiver counseling. SUDEP risk factors, potential causes, and prevention strategies are discussed in detail separately. (See "Sudden unexpected death in epilepsy".)

The average life expectancy of patients with DS has not been well characterized. In small series of adults with DS, the age of surviving patients ranges from 18 to 66 years [81-84]. Of note, individuals born before the mid-1970s, when DS was first described, could be alive and misdiagnosed as other conditions such as cerebral palsy, Lennox-Gastaut syndrome, or vaccine encephalopathy.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in children".)

SUMMARY AND RECOMMENDATIONS

●Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy, is a rare epilepsy syndrome characterized by refractory epilepsy with multiple different seizure types and poor neurodevelopmental outcomes. DS is classified as a genetic epilepsy syndrome and as a developmental and epileptic encephalopathy. (See "Dravet syndrome: Genetics, clinical features, and diagnosis".)

●The goals of treatment are to reduce both the length and number of seizures and prevent status epilepticus, limit adverse effects of antiseizure medications, and improve quality of life. Pharmacologic therapy is the mainstay of treatment, but the ketogenic diet and neuromodulation techniques are viable options in selected patients.

●Seizure triggers, including increased body temperature, flashing lights, and visual patterns, should be avoided as best as possible. (See 'Avoidance of seizure triggers' above.)

●Vaccinations should not be withheld from children with DS. Although patients with DS are at increased risk for post-vaccination febrile (or afebrile) seizures, evidence suggests that immunizations before or after disease onset do not affect clinical and intellectual outcomes. (See 'Vaccine-associated seizures' above.)

●The most commonly used antiseizure medications in patients with DS are valproate, clobazam, topiramate, stiripentol (where available), levetiracetam, and bromides. Among these, we suggest valproate and clobazam as first-line therapies in most patients (Grade 2C). As in other patients with epilepsy, antiseizure medication therapy is approached in a stepwise manner, maximizing one drug before adding a second, with close monitoring for clinical response and toxicity. (See 'Initial therapy' above and 'Patients who fail first two drugs' above.)

●Both cannabidiol (pharmaceutical) and fenfluramine are approved in the United States for the treatment of seizures associated with DS. Further study is needed to better define their efficacy and long-term safety in patients with DS. (See 'Cannabidiol' above and 'Fenfluramine' above.)

●We suggest avoiding carbamazepine and its analogs (oxcarbazepine and eslicarbazepine), lamotrigine, and phenytoin for seizure prevention in patients with DS due to their potential to worsen seizure control (Grade 2C). (See 'Drugs to avoid' above.)

●All patients with DS should be provided with a seizure action plan to be shared with school and other caretakers. (See 'Seizure action plan' above.)

●Ketogenic diet and neuromodulation (vagus nerve stimulation [VNS], deep brain stimulation [DBS]) should be considered in patients whose seizures cannot be controlled with antiseizure medications. (See 'Ketogenic diet' above and 'Surgical therapies' above.)

●Motor impairment and skeletal deformities are managed with physical and occupational therapy as well as orthopedics referral when appropriate. Adults with parkinsonism may benefit from a trial of levodopa/carbidopa, although further confirmatory studies are needed. (See 'Motor impairment' above.)

●Patients with DS are at increased risk for premature mortality due to sudden unexpected death in epilepsy (SUDEP) and status epilepticus (SE), but some patients live well into adulthood. (See 'Prognosis' above.)