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Gao, C.; Pielas, M.; Jiao, F.; Mei, D.; Wang, X.; Kotulska, K.; Jozwiak, S. Treatment Strategies of Epilepsy in Dravet Syndrome. Encyclopedia. Available online: https://encyclopedia.pub/entry/42877 (accessed on 17 April 2024).
Gao C, Pielas M, Jiao F, Mei D, Wang X, Kotulska K, et al. Treatment Strategies of Epilepsy in Dravet Syndrome. Encyclopedia. Available at: https://encyclopedia.pub/entry/42877. Accessed April 17, 2024.
Gao, Chao, Mikolaj Pielas, Fuyong Jiao, Daoqi Mei, Xiaona Wang, Katarzyna Kotulska, Sergiusz Jozwiak. "Treatment Strategies of Epilepsy in Dravet Syndrome" Encyclopedia, https://encyclopedia.pub/entry/42877 (accessed April 17, 2024).
Gao, C., Pielas, M., Jiao, F., Mei, D., Wang, X., Kotulska, K., & Jozwiak, S. (2023, April 07). Treatment Strategies of Epilepsy in Dravet Syndrome. In Encyclopedia. https://encyclopedia.pub/entry/42877
Gao, Chao, et al. "Treatment Strategies of Epilepsy in Dravet Syndrome." Encyclopedia. Web. 07 April, 2023.
Treatment Strategies of Epilepsy in Dravet Syndrome
Edit

Dravet Syndrome (DS) is a developmental epileptic encephalopathy characterized by drug-resistant seizures and other clinical features, including intellectual disability and behavioral, sleep, and gait problems. The pathogenesis is strongly connected to voltage-gated sodium channel dysfunction. The consensus of seizure management in DS consists of a combination of conventional and recently approved drugs such as stiripentol, cannabidiol, and fenfluramine. Despite promising results in randomized clinical trials and extension studies, the prognosis of the developmental outcomes of patients with DS remains unfavorable.

Dravet syndrome epilepsy therapeutic recommendations

1. Introduction and Syndrome Characteristics

Dravet syndrome (DS) is a severe childhood-onset epilepsy syndrome and epileptic encephalopathy (DEE). The first description of the syndrome was made by Charlotte Dravet in 1978 under the name of severe myoclonic epilepsy in infancy; in 1989, the International League Against Epilepsy recognized the disease as a syndrome. The syndrome is considered a rare genetic disease, appearing with an incidence of 1:16,000–1:40,000 [1][2][3][4].
The first symptom of DS is a convulsive seizure appearing in the range of 1 to 18 months, with most of the cases between 4 and 8 months in a previously healthy child. The classic onset is fever-induced, prolonged, and generalized or hemiclonic seizure. The alternating character of unilateral seizures helps to differentiate DS from focal epilepsy. At an early stage, electroencephalographic studies and MRI usually do not reveal pathology [5]. In the course of the disease, patients aged 1 to 5 years develop pharmacoresistant seizures of multiple types, including focal, atypical absences, myoclonic, and atonic. Over time, seizure duration becomes shorter, but their frequency increases.
Interictal EEG evolves to background slowing and focal or generalized epileptiform discharges. Neuroimaging in older children and adults may reveal generalized atrophy or focal abnormalities, including hippocampal sclerosis [6]. Along with drug-resistant epilepsy, intellectual disability, behavioral, language, and sleep disorders, as well as gait abnormalities, are the most common comorbidities observed in patients diagnosed with DS [7][8][9]. Even though adults experience less frequent seizures, with a dominant pattern of nocturnal episodes, their quality of life is severely compromised.
In approximately 80–90% of cases, the syndrome is caused by de novo mutation in the voltage-gated sodium channel gene SCN1A, which results in the haploinsufficiency of Nav1.1, the alpha-1 subunit of the sodium channel. However, mutations in other genes (GABRA1, STXBP1, SCN9A, SCN1B, GABRG2, HCN1, CHD2) have also been described [10][11]. On the contrary, not all SCN1A mutations lead to Dravet Syndrome, but several variants have been found in cases of familial febrile seizures (FS), genetic epilepsy with febrile seizures plus (GEFS+), epilepsy of infancy with migrating focal seizures (EIMFS), or familial hemiplegic migraine type 3 (FHM3) [12][13][14]. The genotype–phenotype model recently published by Brunklaus et al. allows prediction of the development of Dravet Syndrome versus GEFS+ in SCN1A patients [15]. Based on factors such as age at seizure onset and a newly developed SCN1A genetic score, the model assists early recruitment of patients to precision therapies and facilitates family counseling.
Arising opportunities for genetic testing might facilitate early diagnosis, contributing to better developmental outcomes [16][17]. Despite the increasing availability of genetic testing and, therefore, early diagnosis, DS belongs to one of the most difficult epilepsies to manage, with poor neurodevelopmental outcomes. DS causes significant social and financial impacts on caregivers and health services, and moreover, is associated with increased premature mortality risk caused by consequences of status epilepticus and sudden unexpected death in epilepsy (SUDEP) [18][19].

2. Limitation of Provoking Factors

Prompt, adequate treatment and reduction of seizure-provoking factors are key to minimizing the risk of status epilepticus and providing proper long-term management. Fever and hyperthermia are notable triggers in children and adults with DS [5]; therefore, avoiding high ambient temperatures, reduction of contact with sick persons, early use of antipyretics, and physical cooling methods are strongly recommended. Many patients are prone to seizures during exhaustion, and overexcitement is reported to be a common trigger, therefore, avoiding situations such as crowded, noisy assemblies helps to reduce the frequency of seizures [20]. Photosensitivity and visual patterns should also be considered triggering factors [21]. Vaccines are also known to be a seizure-precipitating factor with or without vaccine-associated fever [22]. Due to the COVID-19 pandemic, several SARS-CoV-2 vaccines have been approved recently. Although some case reports in the literature reveal neurological complications after COVID-19 vaccines, two surveys conducted in the UK and worldwide suggest that SARS-CoV-2 vaccines are well-tolerated in the DS population. [23][24].

3. Contraindicated Medications

It is broadly acknowledged that sodium channel blockers (e.g., carbamazepine, oxcarbazepine, lamotrigine, and phenytoin) may aggravate seizures in patients with Dravet syndrome and worsen cognitive outcomes [25]. This effect was initially described by Guerrini et al. [26]. Other anti-seizure medications such as vigabatrin, rufinamide, and phenobarbital may also exacerbate seizures in some patients with DS [25][27]. However, it has been reported that some patients may benefit from these agents, particularly lamotrigine, with observed exacerbation when weaning [28]. Thus, careful consideration must be given before therapeutic approaches with patients already taking sodium-channel blockers.

4. Acute Treatment

Prompt and efficient treatment, in cases of prolonged seizures and status epilepticus, prevents secondary brain damage and minimizes the mortality rate in DS. Administration of benzodiazepine compounds in both inpatients and outpatients remains the first line of acute treatment. In hospital settings, the intravenous route is preferred; otherwise, depending on availability, benzodiazepines might be administered via an intranasal, buccal, or intramuscular route with comparable efficacy [29][30]. Another promising route of administering alprazolam via a Staccato breath-actuated device has emerged in recent years [31]. While the usage of second-line agents such as phenytoin and phenobarbital is debatable, intravenous ganaxolone might be beneficial [32].

5. Chronic Management

Therapeutic approaches in DS have undergone tremendous changes in the last few years and are currently heading to more personalized treatment. The drugs which were recently approved for the treatment of the syndrome include stiripentol, fenfluramine, and cannabidiol.

5.1. Stiripentol (STP)

Stiripentol received orphan drug status in the European Union in 2001, and in 2007, the EMA granted conditional marketing authorization, followed by approval by Japan and Canada in 2012 and the United States in 2018.
The drug inhibits the synaptosomal uptake of GABA and acts as an allosteric modulator of the GABAa receptor [33][34]. Stiripentol inhibits CYP450 isoenzymes, which leads to an increase in the concentration of other anti-seizure medications, including clobazam [35][36].
As an add-on therapy to VPA and CLB, stiripentol was demonstrated to reduce seizure frequency in two randomized, placebo-controlled trials [37][38]. Responders, which counted for participants with >50% reduction in the frequency of clonic or tonic-clonic seizures during the second month of the double-blind period compared to baseline, were 71% on the stiripentol arm and 5% on placebo. The second study showed similar results (67% of responders on stiripentol vs. 9% on placebo). The most common adverse events (stiripentol vs. placebo) included somnolence (67% vs. 23%), decreased appetite (46% vs. 10%), decreased weight (27% vs. 6%), agitation (27% vs. 16%), and hypotonia (18% vs. 13%). Neutropenia has been reported in some cases and was reversible by dosage reduction [39]. Long-term efficacy and safety of stiripentol were later determined in several observational studies, including patients with a wide age range, including adults [40][41][42][43].

5.2. Fenfluramine (FFA)

Fenfluramine (Fintepla) was approved by the FDA and EMA in 2020 for the treatment of seizures in Dravet Syndrome. The drug was first used in the 1970s as an anorectic agent for patients with obesity, but it was withdrawn from the market in 1997 due to pulmonary hypertension and cardiac valvulopathy cases when used in high dosages [44].
The mechanism of action of fenfluramine is not fully elucidated. It has a high affinity for 5HT2A and 5HT2C receptors modulating the serotonergic pathway, but an additional effect on the sigma 1 receptor is also described [45][46][47].
Two prospective, double-blind, placebo-controlled trials demonstrated the efficacy and safety of fenfluramine in treating Dravet Syndrome [48][49]. In the first study, FFA was compared at two dosages (0.7 mg/kg/day and 0.2 mg/kg/day) with a placebo; patients on STP were not included. At both dosages, the effect, defined as mean monthly convulsive seizure frequency reduction (MCSF), was significantly higher in comparison to the placebo group (70% and 41%, respectively, versus 7.5%). In the second study, patients using 0.4 mg/kg/day fenfluramine as an add-on therapy to stiripentol attained a 54% reduction in monthly convulsive seizure frequency versus 5% with placebo. The responders’ rate for profound reduction (75% and more in MCSF) were 50% and 23% for higher and lower doses of FFA without STP, respectively, and 35% in the population study using STP. The most common adverse effects reported were decreased appetite, weight loss, diarrhea, fatigue, and somnolence. A cardiac follow-up did not reveal valvular heart disease or pulmonary hypertension. Therapy with FFA was also linked with prolonged seizure-free time intervals and provided a significantly higher number of seizure-free days [50]. Subsequent open-label extension studies and data from an access program confirmed the efficacy and safety of FFA in DS patients [51][52].

5.3. Cannabidiol (CBD)

Although the effect of CBD on seizure reduction is not fully understood and is not specific to DS, Epidiolex/Epidyolex (a pure plant-derived CBD) was approved in 2018 in the United States and in 2019 in Europe for use in DS therapy as a reliable and quality-standardized product. CBD has also been approved as an adjunctive therapy in Lennox–Gastaut Syndrome (LGS) and tuberous sclerosis complex. The efficacy of cannabidiol was at first described in an open-label, prospective study of childhood-onset epilepsy of different etiology. Among patients included in the study, those diagnosed with Dravet Syndrome achieved a higher response than other subgroups, with a reduction of 69.2% and 46.7%, respectively, for the frequency of tonic and tonic-clonic seizures [53].
Due to the positive effect of the study, two randomized placebo-controlled trials (GWPCARE1 and GWPCARE2) were conducted to measure the efficacy of Epidiolex titrated to 20 mg/kg/day in seizure frequency reduction specifically in Dravet Syndrome [54][55]. They documented a significantly higher reduction of seizure frequency in the CBD group in comparison to the placebo group (39% vs. 13% in the total treatment period and 41% vs. 16% in the maintenance period). In the GWPCARE2 trial, two dosages (10 mg/kg/day and 20 mg/kg/day) were compared with placebo. The reported reduction from baseline was 48.7% and 45.6%, respectively. In both studies, patients treated with clobazam achieved higher reduction, probably due to an increased concentration of both compounds [56]. The most common adverse effects were similar in both studies and included somnolence, loss of appetite, and diarrhea [52][53]. Clinical practice and open-label extension studies have recently published evidence of CBD’s good tolerance and effectiveness [57][58][59][60].
Although several RCTs have proven the efficacy of stiripentol, fenfluramine, and cannabidiol, no comparison studies have been conducted. Due to new drugs being registered, but a lack of comparison studies, there was a strong need for therapeutical guidelines in DS [61][62]. In 2022, a multinational consensus based on the Delphi method was developed [63]; according to the consensus, valproic acid remains the first-line agent. Stiripentol, fenfluramine, and clobazam in different combinations should be added to VPA. Cannabidiol, with a lower efficacy in DS, remains behind the drugs mentioned. Ketogenic diets tend to not only reduce seizures but also improve cognitive outcomes [64].

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