Priorities for seizure control

Usual degree of seizure control II 7* Akiyama M.

Kobayashi K.

Yoshinaga H.

Ohtsuka Y. A long-term follow-up study of Dravet syndrome up to adulthood. , 8* Genton P.

Velizarova R.

Dravet C. Dravet syndrome: the long-term outcome. , 19* Takayama R.

Fujiwara T.

Shigematsu H.

et al. Long-term course of Dravet syndrome: a study from an epilepsy center in Japan. , 20* Dravet C.

Bureau M.

Guerrini R.

Giraud N.

Roger J. Severe myoclonic epilepsy in infants. Complete seizure control is typically not achievable Strong

Elimination or significant reduction of prolonged convulsive seizures and status epilepticus should represent the highest priority in treatment Strong

Most patients require, on average, three antiepileptic therapies taken consecutively to achieve optimal seizure control Strong

Impact of specific seizure types on development III 10* Ragona F.

Granata T.

Dalla Bernardina B.

et al. Cognitive development in Dravet syndrome: a retrospective, multicenter study of 26 patients. , 37* Ragona F. Cognitive development in children with Dravet syndrome. , 38* Casse-Perrot C.

Wolff M.

Dravet C. Neuropsychological aspects of severe myoclonic epilepsy in infancy. , 39* Wolff M.

Casse-Perrot C.

Dravet C. Severe myoclonic epilepsy of infants (Dravet syndrome): natural history and neuropsychological findings. Both the frequency and duration of convulsive status epilepticus have a large impact on developmental outcome Strong

Both the frequency and duration of prolonged convulsive seizures (5 to 29 minutes) have a moderate to large impact on developmental outcome Strong

Both the frequency and duration of obtundation status epilepticus have a moderate to large impact on developmental outcome Strong

Strategies to reduce seizure triggers

Effective measures IV 40 Wirrell E.C. Treatment of Dravet syndrome. There was no consensus that any particular strategy was effective at preventing seizures in the majority of patients No consensus

The following strategies are effective in at least a modest number of patients:

Allowing the child to nap if tired Strong

Avoidance of overexertion Strong

Avoidance of high ambient temperature Strong

Prophylactic antipyretics with vaccination Strong

Prophylactic antipyretics with illness Strong

Prophylactic benzodiazepines with febrile illness Strong

The following strategies are effective in at least a minority of patients:

Avoidance of flashing lights Strong

Cooling vests Strong

Sunglasses Strong

Avoidance of placing the patient in a bath Strong

The following strategies are not recommended in patients with Dravet syndrome:

Avoiding immunization or selective immunization Strong

Routine use of antibiotics for febrile illnesses Strong

Prophylactic antiepileptic medications

First-line agents III 41* Dressler A.

Trimmel-Schwahofer P.

Reithofer E.

et al. Efficacy and tolerability of the ketogenic diet in Dravet syndrome - Comparison with various standard antiepileptic drug regimen. , 42 Inoue Y.

Ohtsuka Y. S.-S. Group

Long-term safety and efficacy of stiripentol for the treatment of Dravet syndrome: a multicenter, open-label study in Japan. Clobazam and valproic acid are the optimal first-line medications in Dravet syndrome. Treatment should be initiated with one of these agents and the other added if control remains suboptimal Strong

Second-line agents I, stiripentol 13* Wirrell E.C.

Laux L.

Franz D.N.

et al. Stiripentol in Dravet syndrome: results of a retrospective U.S. study. , 42 Inoue Y.

Ohtsuka Y. S.-S. Group

Long-term safety and efficacy of stiripentol for the treatment of Dravet syndrome: a multicenter, open-label study in Japan. , 43 Chiron C.

Marchand M.C.

Tran A.

et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group. , 44* Kassai B.

Chiron C.

Augier S.

et al. Severe myoclonic epilepsy in infancy: a systematic review and a meta-analysis of individual patient data. , 45* Inoue Y.

Ohtsuka Y. Effectiveness of add-on stiripentol to clobazam and valproate in Japanese patients with Dravet syndrome: additional supportive evidence.

III, topiramate 41* Dressler A.

Trimmel-Schwahofer P.

Reithofer E.

et al. Efficacy and tolerability of the ketogenic diet in Dravet syndrome - Comparison with various standard antiepileptic drug regimen. , 46* Coppola G.

Capovilla G.

Montagnini A.

et al. Topiramate as add-on drug in severe myoclonic epilepsy in infancy: an Italian multicenter open trial. , 47* Nieto-Barrera M.

Candau R.

Nieto-Jimenez M.

Correa A.

delPortal L.R.

et al. Topiramate in the treatment of severe myoclonic epilepsy in infancy. , 48* Kroll-Seger J.

Portilla P.

Dulac O.

Chiron C.

et al. Topiramate in the treatment of highly refractory patients with Dravet syndrome. Stiripentol and topiramate are the optimal second-line medications. One of these should be used if seizure control remains poor after use of both first-line therapies Strong

Stiripentol should be used in combination with valproate and clobazam, and there is no evidence to support its use as monotherapy Strong

Later therapeutic options III, levetiracetam 41* Dressler A.

Trimmel-Schwahofer P.

Reithofer E.

et al. Efficacy and tolerability of the ketogenic diet in Dravet syndrome - Comparison with various standard antiepileptic drug regimen. , 49* Striano P.

Coppola A.

Pezzella M.

et al. An open-label trial of levetiracetam in severe myoclonic epilepsy of infancy.

IV, bromides, 45* Inoue Y.

Ohtsuka Y. Effectiveness of add-on stiripentol to clobazam and valproate in Japanese patients with Dravet syndrome: additional supportive evidence. , 50* Tanabe T.

Awaya Y.

Matsuishi T.

et al. Management of and prophylaxis against status epilepticus in children with severe myoclonic epilepsy in infancy (SMEI; Dravet syndrome)–a nationwide questionnaire survey in Japan. , 51* Oguni H.

Hayashi K.

Oguni M.

et al. Treatment of severe myoclonic epilepsy in infants with bromide and its borderline variant. , 52* Lotte J.

Haberlandt E.

Neubauer B.

Staudt M.

Kluger G.J. Bromide in patients with SCN1A-mutations manifesting as Dravet syndrome. 53 Mueller A.

Boor R.

Coppola G.

et al. Low long-term efficacy and tolerability of add-on rufinamide in patients with Dravet syndrome.

NA, others In patients with suboptimal response to first- and second-line therapies:

Clonazepam, levetiracetam, and zonisamide are moderately effective Strong

Ethosuximide (for atypical absences) and phenobarbital may be effective Moderate

No consensus regarding efficacy of rufinamide, acetazolamide, or bromides No consensus

Exacerbating therapies II 14* Ceulemans B. Overall management of patients with Dravet syndrome. , 18* Xu X.

Zhang Y.

Sun H.

et al. Early clinical features and diagnosis of Dravet syndrome in 138 Chinese patients with SCN1A mutations. , 54* Guerrini R.

Dravet C.

Genton P.

Belmonte A.

Kaminska A.

Dulac O. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. , 55* Thanh T.N.

Chiron C.

Dellatolas G.

et al. , 56 Chipaux M.

Villeneuve N.

Sabouraud P.

et al. Unusual consequences of status epilepticus in Dravet syndrome. Carbamazepine, oxcarbazepine, lamotrigine, phenytoin, and vigabatrin often exacerbate seizures and should be avoided Strong

Dietary therapies

Efficacy and impact on development II 41* Dressler A.

Trimmel-Schwahofer P.

Reithofer E.

et al. Efficacy and tolerability of the ketogenic diet in Dravet syndrome - Comparison with various standard antiepileptic drug regimen. , 57* Caraballo R.H. Nonpharmacologic treatments of Dravet syndrome: focus on the ketogenic diet. , 58* Laux L.

Blackford R. The ketogenic diet in Dravet syndrome. , 59* Kang H.C.

Kim Y.J.

Kim D.W.

Kim H.D. Efficacy and safety of the ketogenic diet for intractable childhood epilepsy: Korean multicentric experience. , 60* Nabbout R.

Copioli C.

Chipaux M.

et al. Ketogenic diet also benefits Dravet syndrome patients receiving stiripentol: a prospective pilot study. The ketogenic diet is moderately effective for seizure control and could be considered second line in patients with suboptimal response to clobazam and valproic acid Strong

Dietary therapies have a positive impact on cognition and behavior in most patients Moderate

Diet variations NA The traditional ketogenic diet ∗ ∗ Standard of care for all persons with epilepsy, not unique to Dravet syndrome.

Is the best dietary option for young children aged less than six years Moderate

Is a good option for children aged 7-12 years Moderate

While the traditional diet could also be used in teens and adults, other diet options may be preferable Strong

Modified Atkins diet ∗ ∗ Standard of care for all persons with epilepsy, not unique to Dravet syndrome.

Is the best dietary option for teens and adults and a reasonable option for children aged 2-12 years Moderate

Low-glycemic-index diet

No consensus regarding the use of a low-glycemic-index diet in Dravet syndrome No consensus

Surgical therapies

Efficacy versus risk NA Before considering any surgery, including vagus nerve stimulation, patients must be evaluated at a comprehensive epilepsy center with extensive expertise in Dravet syndrome to ensure other therapies have been maximized Strong

Vagus nerve stimulation III 41* Dressler A.

Trimmel-Schwahofer P.

Reithofer E.

et al. Efficacy and tolerability of the ketogenic diet in Dravet syndrome - Comparison with various standard antiepileptic drug regimen. , 57* Caraballo R.H. Nonpharmacologic treatments of Dravet syndrome: focus on the ketogenic diet. , 61* Zamponi N.

Passamonti C.

Cappanera S.

Petrelli C. Clinical course of young patients with Dravet syndrome after vagal nerve stimulation. , 62* Rossignol E.

Lortie A.

Thomas T.

et al. Vagus nerve stimulation in pediatric epileptic syndromes. , 63* Shahwan A.

Bailey C.

Maxiner W.

Harvey A.S. Vagus nerve stimulation for refractory epilepsy in children: More to VNS than seizure frequency reduction. , 64* Bremer A.

Lossius M.I.

Nakken K.O. Dravet syndrome–considerable delay in making the diagnosis. , 65* Orosz I.

McCormick D.

Zamponi N.

et al. Vagus nerve stimulation for drug-resistant epilepsy: a European long-term study up to 24 months in 347 children. , 66 Dlouhy B.J.

Miller B.

Jeong A.

Bertrand M.E.

Limbrick Jr., D.D.

Smyth M.D. Palliative epilepsy surgery in Dravet syndrome-case series and review of the literature. Vagus nerve stimulation can be considered but only after failure of both first- (clobazam and valproic acid) and second-line (stiripentol, topiramate, and ketogenic diet) treatments Moderate

Vagus nerve stimulation has a minimal to moderate impact on seizure reduction but is generally less efficacious than the ketogenic diet Strong

No consensus was reached regarding the efficacy of the magnet to prevent prolonged seizures No consensus

Vagus nerve stimulation does not significantly benefit development or behavior in most patients Moderate

Temporal lobectomy NA Resective epilepsy surgery, including temporal lobectomy, should not be performed in patients with Dravet syndrome Strong

Corpus callosotomy III 66 Dlouhy B.J.

Miller B.

Jeong A.

Bertrand M.E.

Limbrick Jr., D.D.

Smyth M.D. Palliative epilepsy surgery in Dravet syndrome-case series and review of the literature. Callosotomy may be considered in a patient with intractable drop seizures but only after failure of clobazam, valproate, stiripentol, topiramate, levetiracetam, and the ketogenic diet Moderate

The benefit of corpus callosotomy in Dravet syndrome is unclear, and the potential risk/benefit ratio must be carefully considered, disclosed to and discussed with the family before surgery Strong

Rescue medication for home use

Need for home rescue medication II 36 Camfield P.

Camfield C.

Nolan K. Helping families cope with the devastation of Dravet syndrome. All patients need both a home rescue medication and seizure protocol, which can be carried out at their local hospital Strong

Optimal rescue therapies for age NA For children ≤6 years ∗ ∗ Standard of care for all persons with epilepsy, not unique to Dravet syndrome.

Rectal diazepam Strong

Buccal/nasal midazolam Strong

For children aged 7-12 years and teens/adults ∗ ∗ Standard of care for all persons with epilepsy, not unique to Dravet syndrome.

Buccal/nasal midazolam Strong

Parameters for administration of rescue medication NA At a minimum, rescue medication should be given within 3 to 5 minutes of onset of a convulsive seizure in all age groups ∗ ∗ Standard of care for all persons with epilepsy, not unique to Dravet syndrome. Strong

However, in those with a recent history of convulsive seizures that are typically prolonged, rescue medication should be given at the time of convulsive seizure onset Strong

A second full dose of rescue medication should be given 5 to 10 minutes after the initial dose in patients of all ages who continue to convulse ∗ ∗ Standard of care for all persons with epilepsy, not unique to Dravet syndrome. Strong

For brief convulsive seizures that are clustering, rescue medications should be administered ∗ ∗ Standard of care for all persons with epilepsy, not unique to Dravet syndrome. Strong

For clusters of nonconvulsive seizures, no consensus was reached regarding use of rescue medication No consensus

Management of status epilepticus

Recommended first-line agents III 50 Tanabe T.

Awaya Y.

Matsuishi T.

et al. Management of and prophylaxis against status epilepticus in children with severe myoclonic epilepsy in infancy (SMEI; Dravet syndrome)–a nationwide questionnaire survey in Japan. Intravenous benzodiazepines should be the first medication administered if a patient presents to hospital with an ongoing seizure, and a second dose of benzodiazepine should be given if the seizure persists, particularly if the patient did not receive a home dose of rescue medication ∗ ∗ Standard of care for all persons with epilepsy, not unique to Dravet syndrome. Strong

Recommended therapies if convulsive seizure persists after intravenous benzodiazepine III 50 Tanabe T.

Awaya Y.

Matsuishi T.

et al. Management of and prophylaxis against status epilepticus in children with severe myoclonic epilepsy in infancy (SMEI; Dravet syndrome)–a nationwide questionnaire survey in Japan. If the patient continues to convulse despite intravenous benzodiazepine, a valproic acid load is an appropriate next option Strong

There was no consensus regarding other abortive therapies in the management of convulsive status epilepticus No consensus

Use of alternative therapies

Medical marijuana III 67* Porter B.E.

Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. , 68 Press C.A.

Knupp K.G.

Chapman K.E. Parental reporting of response to oral cannabis extract for treatment of refractory epilepsy. , 69 Devinsky O.

Marsh E.

Friedman D.

et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Medical marijuana is moderately effective for Dravet syndrome † † Based on only nine respondents—the remainder indicated they had insufficient experience using this agent for Dravet syndrome to comment on efficacy. Strong

There was no consensus regarding the specific type of medical marijuana recommended No consensus