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Dravet syndrome: Management and prognosis

Dravet syndrome: Management and prognosis
Literature review current through: Jan 2024.
This topic last updated: Nov 08, 2022.

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. Pathogenic variants in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene are identified in 70 to 80 percent of patients with 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 use of benzodiazepines with illness, but it 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 a traditional 50 Hz screen [2]. Emotional stress and other recognized triggering factors should also be avoided when possible.

Vaccinations

Recommended vaccinations – Patients with DS should receive all standard vaccinations as appropriate for age and region, including annual influenza and coronavirus disease 2019 (COVID-19) vaccinations [3]. (See "Standard immunizations for children and adolescents: Overview" and "Standard immunizations for nonpregnant adults" and "COVID-19: Vaccines".)

Observational data in children with DS indicate that vaccinations before or after disease onset do not affect clinical or intellectual outcomes [4-7]. Available data suggest that the COVID-19 vaccination is generally well tolerated in older children and adults with DS. In a study of 120 individuals with DS (age 12 years and older; median age 19.5 years), increased seizures following COVID-19 vaccination were reported by 13 percent, and none developed status epilepticus [8]. No side effects of the vaccination were reported by 50 percent.

Postvaccination seizures – Postvaccination 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 [4]. 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.

As in healthy children, the risk of postvaccination seizure likely varies according to the type of vaccine and the age of the child; the risk may be highest in association with the measles, mumps, and rubella (MMR) vaccine [4]. Postvaccination seizures may also be seen in patients who do not develop fever, implicating an immune-mediated mechanism [9]. (See "Clinical features and evaluation of febrile seizures", section on 'Immunization'.)

ANTISEIZURE THERAPY

Goals of therapy — The goals of treatment are to reduce both the length and number of seizures (especially convulsive seizures), prevent status epilepticus, limit adverse effects of antiseizure medications, promote better neurocognitive development, and improve quality of life.

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.

Options for antiseizure therapy — Maintenance antiseizure therapies for DS as ranked by a 2022 international consensus panel were as follows [3]:

Valproate: first line

Clobazam, fenfluramine, and stiripentol: second line

Cannabidiol (pharmaceutical): third line

Topiramate and the ketogenic diet: fourth line

However, the separation between these categories is not universally agreed upon. Some experts include clobazam, fenfluramine, or stiripentol as first line [3]. Others have argued 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 [10].

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

Initial therapy

Our approach — 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. 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.

There is some debate as to the timing of antiseizure medication initiation, especially since it might be difficult to determine if the patient will develop DS, generalized epilepsy with febrile seizures plus (GEFS+), or another condition after just the first seizures. Genetic testing may help in the decision to start antiseizure medication early if an SCN1A pathogenic variant previously associated with DS cases is found. It might be more difficult to make a decision when the SCN1A variant is not clearly linked to DS or the variant has uncertain significance. A prediction model (The SCN1A Epilepsy Prediction Model) incorporating age of seizure onset and an SCN1A-specific genetic score was developed to calculate the probability of developing DS versus GEFS+ in these cases [11].

In practice, the optimization of treatment of infants and young children with DS requires considerable expertise and also depends, at least in part, upon local resources.

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 [3,12].

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

Adverse 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 [13]. (See "Seizures and epilepsy in children: Initial treatment and monitoring", section on 'Teratogenicity'.)

Efficacy – 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 [12]. 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 [14].

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 initial therapy — The approach to patients with poor seizure control or intolerance to first-line therapy with valproate is individualized but generally includes trials of second-, third-, and/or fourth-line antiseizure therapies. (See 'Options for antiseizure therapy' above.)

Rarely, patients will be controlled on one or two antiseizure medications in the first years of disease. Addition of a third antiseizure medication is often associated with more adverse effects. As such, if the last addition was effective in controlling seizures, one of the medications with the least perceived benefit might be tapered. Valproic acid and fenfluramine are rated as therapies with good tolerability. Improved alertness and/or behavior are observed with ketogenic diet, fenfluramine, and cannabidiol (pharmaceutical). Polypharmacy can introduce substantial cognitive issues, which the ketogenic diet can avoid. When to combine medications or move to other treatments is more of an art than a science, at least at this point.

Clobazam — Clobazam is our preferred 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 is approved for patients with Lennox-Gastaut syndrome.

Dose – For patients two years of age or older and ≤30 kg body weight, clobazam may be started at 5 mg per day in one dose, typically given at bedtime [34]. The dose may be increased in intervals no shorter than every seven days to a maximum total dose of 20 mg per day; doses >5 mg should be given in divided doses twice daily. For patients >30 kg body weight, clobazam may be started at 10 mg in two divided doses and increased in intervals no shorter than every seven days to a maximum total dose of 40 mg per day.

When used with stiripentol, clobazam levels typically increase 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.

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

Efficacy – 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 [12,17,18].

Stiripentol — Stiripentol is generally considered a second-line medication for DS, although some experts rank it as first line [3]. Stiripentol should be used in combination with valproate and clobazam, as there is no evidence to support its use as monotherapy.

Stiripentol is an allosteric modulator of the gamma-aminobutyric acid A (GABA-A) receptor with direct activating effects [19]. The drug is available for clinical use in Canada, Europe, and Japan under an orphan drug designation. Stiripentol is approved by the US Food and Drug Administration (FDA) for the treatment of seizures associated with DS in patients who are six months of age and older, weigh 7 kg or more, and are taking clobazam [20]. Notably, stiripentol has limited availability and is restricted in many countries [21,22].

Dose – 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 [23], although some children may require up to 100 mg/kg per day.

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 [24]. Another study suggested that stiripentol-naïve adults may tolerate even lower doses (15 to 25 mg/kg per day) [25]. This study also showed that some adults on concomitant stiripentol and valproate developed a hyperammonemic encephalopathy, which could be managed with carnitine supplementation in some of them.

Adverse effects – The most common adverse effects of stiripentol are somnolence, decreased appetite, agitation, ataxia, weight loss, hypotonia, nausea, tremor, dysarthria, and insomnia. 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) [26].

Note that stiripentol inhibits cytochrome P450 enzymes, thereby increasing blood levels of some antiseizure medications, especially clobazam, valproate, and fenfluramine [27]. 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 [28].

Comprehensive information on drug-drug interactions can be determined using the Lexicomp drug interactions tool.

EfficacyStiripentol has been evaluated in two multicenter, placebo-controlled randomized trials in patients with DS [29-31]. In the first trial, 42 patients with DS who were randomly assigned to receive either stiripentol (50 mg/kg per day) or placebo as add-on therapy to clobazam and valproate [29]. 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 (nine versus zero). 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 [29]. Unpublished data from a second trial of similar design in 22 patients with DS have been reported in abstract form [30] and as part of a patient-level meta-analysis [32]. 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 [17,18,26,33,34], as well as reductions in seizure length, frequency of status epilepticus, frequency of hospitalizations, and frequency of rescue medication use [35]. Long-term follow-up data suggest that the benefit of stiripentol persists into adulthood [24].

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 [26]. The median number of antiseizure medications tried before stiripentol was seven, and over one-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.

Fenfluramine — The antiobesity drug fenfluramine is generally considered a second-line antiseizure medication for DS, although some experts rank it as first line [3]. Fenfluramine, which was withdrawn from the market in 2001 due to an association with cardiac valve injury and pulmonary hypertension [36], was approved by the FDA in June 2020 for the treatment of seizures associated with DS in patients age two years and older [37]. It is not clear how fenfluramine may control seizures. One possible mechanism is via modulation of N-methyl-D-aspartate receptor (NMDAR)-mediated excitation [38], and another is through serotonergic effects.

DoseFenfluramine 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 [39]. 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 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.

Adverse effects – While generally well tolerated, adverse effects of fenfluramine in these trials included fatigue, lethargy, somnolence, diarrhea, loss of appetite, pyrexia, and loss of weight [21,40]. 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 [41]. In the United States, fenfluramine will be available only through a risk evaluation and mitigation strategy (REMS) program [39]. 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.

Efficacy – The FDA approval was based upon the findings of two trials [21,40]. The potential benefit of fenfluramine is illustrated by a 14-week trial that randomly assigned 119 patients (mean age nine years) in a 1:1:1 ratio to fenfluramine 0.7 mg/kg per day, fenfluramine 0.2 mg/kg per day, or placebo [21]. 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 [40]. Patients were randomly assigned to fenfluramine (0.4 mg/kg per day, maximum of 17 mg per day) or to placebo. a clinically meaningful (≥50 percent) reduction in seizure frequency was achieved for 54 percent of patients in the fenfluramine group, compared with 5 percent in the placebo group. An open-label extension study showed that fenfluramine treatment was associated with a sustained reduction in convulsive seizures 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 [42,43].

Cannabidiol — Cannabidiol (pharmaceutical) is approved by the FDA for the treatment of seizures associated with DS, Lennox-Gastaut syndrome, and tuberous sclerosis complex in patients ≥1 year of age [44]. 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 [45]. 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.

DoseCannabidiol (pharmaceutical) is an oral solution (100 mg/mL) [46]. 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 [47]. 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.

Adverse effects – 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 [46]. 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 [48]. 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.

Efficacy – Preliminary support for the efficacy in DS of cannabidiol (pharmaceutical) was provided by an open-label trial of patients with intractable epilepsy that included 32 patients with DS [49]. 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 per day) or placebo in addition to standard antiseizure medication treatment [22]. 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.

In a long-term open-label extension trial of patients with DS, 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 [50]. Additional studies are required to assess whether tetrahydrocannabinol (THC)-containing cannabidiol preparations are safe and effective in this population of patients [51].

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

DoseTopiramate 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.

Adverse effects – Adverse effects of topiramate were observed in approximately 15 percent of patients, most commonly anorexia, weight loss, behavioral disturbances, emotional and language regression, and renal stones [52-56].

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'.)

Efficacy – In small observational studies in patients with DS, topiramate was associated with ≥50 percent reduction in seizures in 50 to 85 percent of patients, including 16 to 18 percent who remained seizure free for approximately one year [52-56].

Ketogenic dietary therapy — The ketogenic diet is a viable option for motivated patients, families, and caregivers with access to an experienced multidisciplinary team. A 2022 international consensus on DS suggests that dietary therapy should be considered after failure of three or four antiseizure medications [3]. (See "Ketogenic dietary therapies for the treatment of epilepsy".)

Administration – Provision of the ketogenic dietary therapy requires supervision by an experienced dietitian and neurologist, ideally in the context of a multidisciplinary program with additional endocrinology, psychology, and social work support. (See "Ketogenic dietary therapies for the treatment of epilepsy", section on 'Implementation'.)

Use of dietary therapies should be reviewed in older patients who will be transitioned to an adult epilepsy program. Although dietary therapy clinics are somewhat common in pediatric centers, they are far less common in adult epilepsy programs [57].

Adverse effects – 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 'Adverse effects' and "Ketogenic dietary therapies for the treatment of epilepsy", section on 'Contraindications'.)

Efficacy – 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 [18,58-61]. Some studies have also suggested improvement in behavior and cognition [59,61] as well as in EEG features [58,60]. Overall, the efficacy of the diet compares favorably with other options (eg, additional drugs, vagus nerve stimulation) in patients with poorly controlled seizures [18].

Less restrictive ketogenic 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'.)

Other options

LevetiracetamLevetiracetam 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 SCN1A pathogenic variant) were treated with levetiracetam for an initial five- to six-week titration period and then a 12-week evaluation phase [62]. 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 [18,63].

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'.)

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 [64,65]. Side effects are usually mild and include somnolence, decreased appetite, and skin rash.

Neuromodulation techniques – These are potential options in patients with DS, although the available data are limited and somewhat mixed:

Vagus nerve stimulation (VNS) – 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 three months, 6 percent at 6 months, and 31 percent at 12 months [66]. Five of eight patients experienced some reduction in seizure burden (33 to 61 percent) at 12 months [66]. 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 [67]. 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 six months; 25 (5 out of 20) at 12 months; and 38.5 percent (5 out of 13) at 24 months [68].

Deep brain stimulation (DBS) – 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 [69,70]. It is therefore not yet possible to draw conclusions on the effectiveness of DBS in these patients.

Surgery – Patients with DS are not usually candidates for resective epilepsy surgery based on the multifocal and generalized nature of disorder [67].

Drugs to avoid — Sodium channel-blocking antiseizure medications such as carbamazepine and its analogs (oxcarbazepine and eslicarbazepine), lamotrigine, and phenytoin may aggravate seizures in patients with DS and should generally be avoided for maintenance therapy [71-76]. In addition, use of these drugs for patients with DS may be associated with worse cognitive outcomes [77]. Phenytoin has also been reported to trigger paroxysmal movement disorders in some patients [75,76]. However, phenytoin and fosphenytoin may be used as emergency treatment to abort status epilepticus in patients with DS. (See 'Status epilepticus' below.)

Rare patients do seem to benefit from sodium channel-blocking drugs, and seizures may even worsen when these drugs are removed [78].

SEIZURE EMERGENCIES

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 [79]. 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 5 to 10 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)'.)

Status epilepticus — Status epilepticus is common in patients with DS and should be expected. A seizure action plan (see 'Seizure action plan' above) should be in place to reduce the risk of developing status epilepticus. If the seizures do not abate, management of status epilepticus in patients with DS is similar to management in patients without DS. (See "Management of convulsive status epilepticus in children" and "Convulsive status epilepticus in adults: Management".)

Although phenytoin is a sodium channel blocker and therefore is not recommended as maintenance antiseizure therapy in DS, phenytoin or fosphenytoin can be used as acute treatment for prolonged seizures in DS [3]. Clinical experience and expert opinion suggest that phenytoin/fosphenytoin is helpful in the emergency treatment of seizures and status epilepticus in patients with DS [3,57,80].

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 [81]. Both patients showed sustained improvement in slowness and rigidity over 16 weeks with no measurable toxicity.

Developmental delay — Developmental delay or stagnation is a core feature of DS. Children should be referred for 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.

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, and caregiver education. 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 [81]. There are no definitive contraindications to the newer psychiatric drugs. Potential drug interactions between psychiatric and antiseizure medications should not be overlooked [35].

Sleep problems — Sleep problems are frequent complaints of caregivers of patients with DS; these include frequent awakenings (due to seizures or not associated with visible seizures) and insomnia [82,83]. In one report that surveyed 76 parents, a large majority (93 percent) monitored their children's sleep, either by sleeping in the same room or through the use of monitoring devices [82,83].

Counseling to improve sleep hygiene may be helpful (table 5A-B); the utility of melatonin is unclear given limited data [3]. (See "Assessment of sleep disorders in children" and "Behavioral sleep problems in children".)

TRANSITION TO ADULT CARE — DS begins in early childhood and persists throughout adulthood [57]. The majority of patients with DS have lifelong refractory seizures as well as moderate to severe cognitive impairment. The indications and contraindications for antiseizure treatments differ from those of most other epilepsy syndromes. In addition, patients with DS have multiple comorbidities requiring intensive multidisciplinary care.

To facilitate the transition from pediatric to adult care, a two-page transition guide was developed by the members of the medical advisory board of the Dravet Syndrome Foundation and is freely available for downloading [57]:

Dravet Syndrome Transition Guide page 1

Dravet Syndrome Transition Guide page 2

PROGNOSIS

Severe and persistent impairments — DS is a developmental and epileptic encephalopathy characterized by refractory epilepsy, neurodevelopmental delay, neurologic disability, and cognitive and motor system dysfunction persisting into adulthood [84]. These aspects of DS are reviewed separately. (See "Dravet syndrome: Genetics, clinical features, and diagnosis", section on 'Clinical features and EEG findings'.)

Premature mortality — 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 [85].

A study conducted by the International Dravet syndrome Epilepsy Action League (IDEA League) included 833 patients with DS in their membership database [86]. 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), one due to accident, and one due to ketoacidosis. A smaller study that included 100 patients with DS estimated a SUDEP risk of 9.3 per 1000 person-years [87], 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 [88]. The median age of death was six years and eight 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 [88].

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 ranged from 18 to 66 years [89-92]. 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

Description – Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy characterized by refractory epilepsy with multiple different seizure types and poor neurodevelopmental outcomes. (See "Dravet syndrome: Genetics, clinical features, and diagnosis".)

Avoidance of seizure triggers – 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 – Vaccinations should not be withheld from children and adults with DS. Although patients with DS are at increased risk for postvaccination febrile (or afebrile) seizures, evidence suggests that vaccinations before or after disease onset do not affect clinical and intellectual outcomes. (See 'Vaccinations' above.)

Goals of antiseizure therapy – The main goals are to reduce both the length and number of seizures (especially convulsive seizures, which can be associated with sudden unexpected death in epilepsy [SUDEP]), prevent status epilepticus, limit adverse effects of antiseizure medications, and improve quality of life. Complete control of routine seizures is rarely achieved. (See 'Goals of therapy' above.)

Initial antiseizure therapy – For patients with DS, we suggest valproate as initial antiseizure therapy (Grade 2C). Most patients with DS require two or more drugs to achieve reasonable seizure control. (See 'Initial therapy' above.)

Failure of initial therapyClobazam is our preferred add-on therapy in patients with DS if seizures remain poorly controlled despite adequate valproate dosing and serum levels. Most patients with DS can be assessed for response by history and clinical seizure frequency; shortening of prolonged seizures and avoidance of status epilepticus are important goals. Drug resistance is a well-recognized feature of seizures in DS, and antiseizure therapies have overall limited efficacy. The approach to patients with poor seizure control or intolerance to first-line therapy is individualized but generally includes trials of second- through fourth-line therapies such as clobazam, fenfluramine, stiripentol, cannabidiol (pharmaceutical), topiramate, and/or ketogenic diet. (See 'Assessment of response' above and 'Patients who fail initial therapy' above.)

Medications to avoidCarbamazepine and its analogs (oxcarbazepine and eslicarbazepine), lamotrigine, and phenytoin should not be used for seizure prevention in patients with DS due to their potential to worsen seizure control. (See 'Drugs to avoid' above.)

Seizure emergencies

All patients with DS should be provided with a seizure action plan, including the use of rescue benzodiazepines, to be shared with school and other caregivers. (See 'Seizure action plan' above.)

Status epilepticus is common in patients with DS; management is similar to patients without DS. (See "Management of convulsive status epilepticus in children" and "Convulsive status epilepticus in adults: Management".)

Comorbidities

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. (See 'Motor impairment' above.)

Children with DS should be referred for speech, physical, and occupational therapy.

Behavioral problems may benefit from psychotherapy, family counseling, and caregiver education. First-generation antipsychotics should be avoided.

Prognosis – DS is characterized by refractory epilepsy, neurodevelopmental delay, neurologic disability, and cognitive and motor system dysfunction persisting into adulthood. Patients with DS are at increased risk for premature mortality due to SUDEP and status epilepticus (SE), but some patients live well into adulthood. (See 'Prognosis' above.)

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Topic 108722 Version 24.0

References

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