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A systematic review of adults with Dravet syndrome

  • Arunan Selvarajah
    Affiliations
    Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada

    Adult Epilepsy Genetics Program, Division of Neurology, Krembil Research Institute, Toronto Western Hospital, Toronto, Canada
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  • Quratulain Zulfiqar-Ali
    Affiliations
    Adult Epilepsy Genetics Program, Division of Neurology, Krembil Research Institute, Toronto Western Hospital, Toronto, Canada
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  • Paula Marques
    Affiliations
    Adult Epilepsy Genetics Program, Division of Neurology, Krembil Research Institute, Toronto Western Hospital, Toronto, Canada

    Division of Neurology, Department of Medicine, University of Toronto, ON, Canada
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  • Marlene Rong
    Affiliations
    Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada

    Adult Epilepsy Genetics Program, Division of Neurology, Krembil Research Institute, Toronto Western Hospital, Toronto, Canada
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  • Danielle M. Andrade
    Correspondence
    Corresponding author at: Department of Neurology, University of Toronto, Toronto Western Hospital, 5W-445, 399 Bathurst St., Toronto, ON, M5T 2S8, Canada.
    Affiliations
    Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada

    Adult Epilepsy Genetics Program, Division of Neurology, Krembil Research Institute, Toronto Western Hospital, Toronto, Canada

    Division of Neurology, Department of Medicine, University of Toronto, ON, Canada

    Krembil Neurosciences Institute, University Health Network, Toronto, ON, Canada
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Open ArchivePublished:February 22, 2021DOI:https://doi.org/10.1016/j.seizure.2021.02.025

      Highlights

      • Systematic review reveals lopsided lack of studies in adults compared to children.
      • Adults tend to decrease in seizure frequency as they age.
      • Parkinsonian features with exception to resting tremors are observed in adults.
      • Diagnosis of Dravet Syndrome differs in adults versus in children.

      Abstract

      Dravet Syndrome (DS) is a rare and severe infantile-onset epileptic encephalopathy. DS research focuses mainly on children. We did a systematic review, completed on January 18th, 2021, examining the number of clinical DS studies. We show that there are 208 studies on children exclusively, 28 studies on adults exclusively, and 116 studies involving adults and children combined. This 7:1 ratio of children to adult studies exclusively shows the dearth of research that addresses long-term natural history of DS into adulthood.
      Through this systematic review, we examine the most up-to-date information in DS adults as it pertains to seizures, electroencephalogram, imaging, treatment, motor abnormalities, cognitive and social behavior outcomes, cardiac abnormalities, sleep disturbances, diagnosis in adults, and mortality.
      Overall, the frequency of seizures increases in the first decade of life and then myoclonic, atypical absences and focal seizures with impaired awareness tend to decrease in frequency or even disappear in adulthood. Adults tend to have a notable reduction in status epilepticus, especially after 30 years of age. Parkinsonian features were seen in patients as young as 19 years old and are more severe in older patients, suggesting a progression of the parkinsonian symptoms. In adulthood, patients continue to present with behavior problems, associated with a lower health-related quality of life. The leading reported cause of death in DS adults is Sudden Unexpected Death in Epilepsy (SUDEP).
      Further studies in older adults are needed to understand the long-term outcomes of patients with DS.

      Keywords

      1. Introduction

      Dravet Syndrome (DS), previously known as “severe myoclonic epilepsy of infancy (SMEI)”, was first described by Charlotte Dravet in 1978 [
      • Dravet C.
      Les epilepsies graves de l’enfant.
      ]. DS is a rare, early-onset, treatment-resistant, epileptic encephalopathy that presents in the first or second year of life [
      • Dravet C.
      • Oguni H.
      Dravet syndrome (severe myoclonic epilepsy in infancy).
      ]. The reported incidence is between 1 in 15,000–1 in 41,000 [
      • Wu Y.W.
      • et al.
      Incidence of dravet syndrome in a US population.
      ,
      • Bayat A.
      • Hjalgrim H.
      • Møller R.S.
      The incidence of SCN1A-related Dravet syndrome in Denmark is 1:22,000: a population-based study from 2004 to 2009.
      ,
      • Brunklaus A.
      • Ellis R.
      • Reavey E.
      • Forbes G.H.
      • Zuberi S.M.
      Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome.
      ]. In the late 1980s and early 1990s, variability was noticed amongst the myoclonic seizures, where they were absent in some patients. These patients were classified as having borderline SMEI, known as SMEIB. Given the fact that this condition is not restricted to infancy, the disease was re-named as Dravet syndrome [
      • Dravet C.
      The core Dravet syndrome phenotype.
      ]. In 2001, SCN1A pathogenic variants were identified as the main cause of DS [
      • Claes L.
      • et al.
      De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy.
      ]. DS was later classified as an epileptic encephalopathy by the International League Against Epilepsy (ILAE) [
      Commission on classification and terminology of the international league against epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes.
      ].
      Although DS is well-studied in the pediatric population, there is very little information regarding Dravet syndrome in adulthood [
      • Genton P.
      • Velizarova R.
      • Dravet
      • Dravet C.
      Syndrome: the long-term outcome.
      ,
      • Jansen F.E.
      • et al.
      Severe myoclonic epilepsy of infancy (Dravet syndrome): recognition and diagnosis in adults.
      ,
      • Rilstone J.J.
      • Coelho F.M.
      • Minassian B.A.
      • Andrade D.M.
      Dravet syndrome: seizure control and gait in adults with different SCN1A mutations.
      ,
      • Akiyama M.
      • Kobayashi K.
      • Yoshinaga H.
      • Ohtsuka Y.
      A long-term follow-up study of Dravet syndrome up to adulthood.
      ]. We performed a systematic review of the DS literature. Here we will discuss the most up-to-date information on etiology, seizures, electroencephalogram (EEG), imaging, treatment, motor abnormalities, cognitive and social behavior outcomes, diagnosis in adults and mortality in adults with DS.

      2. Methods

      Due to the limited literature on DS adults and children, our objective was to identify the number of DS clinical studies or reports through a systematic review. Two independent reviewers (AS and MR) performed the initial screening of the studies based on the titles and abstracts on PubMed and Medline. After the removal of duplicate manuscripts and irrelevant studies, full-text screenings were carried out for eligible articles. A third independent reviewer (QZA) reviewed discrepancies between the first two reviewers. The search terms on PubMed include (("dravet"[Title/Abstract]) NOT (mouse)) OR (("severe myoclonic epilepsy in infancy"[Title/Abstract]) NOT (mouse)). The search term on Medline was “dravet”, and we checked off “human” and “English language” in our search.
      The studies were further categorized into adults exclusively, children exclusively, and adults & children combined. Adults are defined as individuals that were 18 years or older. The category “adults & children” was defined as a study that included a combination of adults and children.

      3. Results

      We performed a general literature search in July 2020, and updated with a systematic review up until January 2021. A combined search from PubMed and Medline identified 1108 unique manuscripts and after the intial screening, 317 irrelevant and non-english manuscripts were excluded. Full-text screenings of 791 articles were performed, and 439 articles were excluded with reasons: 65 were animal models, 116 on genetic mechanisms only, and 258 combined reviews and commentaries. The remaining 352 eligible articles were classified into the three groups, as depicted in Fig. 1. There were 28 articles with adults exclusively in the literature. In comparison with the child studies, there is a 1:7 ratio of adult to children studies exclusively.
      Fig. 1
      Fig. 1Process of study selection for inclusion of the systematic review.
      The papers reviewed usually combine several aspects of Dravet syndrome (seizures types, EEG charactristics, medications, comorbidities, etc). In addition, it is not clear which patients were reported in several studies by the same authors. Finally, some children from older studies may have become adults and reported again by the same authors. Therefore, we opted to report the combined findings in patients that are 18 years of age and older.

      3.1 Etiology

      Seventy to 80 % of DS patients have SCN1A gene pathogenic variants. These are split into: truncating (40–50 %), missense (40 %), and deletions involving a few exons or the entire gene in 2–3 %. The few remaining are splice site mutations [
      • Marini C.
      • et al.
      The genetics of Dravet syndrome.
      ,
      • Connolly M.B.
      Dravet syndrome: diagnosis and long-term course.
      ]. Individuals that do not test positive for SCN1A pathogenic variants may have smaller SCN1A exon deletions or chromosomal rearrangements. These changes may be discovered using techniques such as multiplex ligation-dependent probe amplification (MPLA) or comparative genome hybridization (CGH) [
      • Marini C.
      • et al.
      The genetics of Dravet syndrome.
      ,
      • Connolly M.B.
      Dravet syndrome: diagnosis and long-term course.
      ]. Not all SCN1A pathogenic variants cause DS, some will cause a much milder phenotype like GEFS+, while others can cause a more severe phenotype [
      • Claes L.
      • et al.
      De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy.
      ,
      • Scheffer I.E.
      N. R. SCN1A-related phenotypes: Epilepsy and beyond.
      ]. A proposed pathophysiological mechanism for Dravet Syndrome is the “interneuron hypothesis”, where pathogenic variants in SCN1A result in dysfunctional interneurons GABAergic inhibition, ultimately leading to excessive neuronal excitation.14,16] SCN1A encodes a sodium channel protein called Nav1.1. This sodium channel is found in low levels in neonates. In early development, Nav1.1 expression increases and Nav1.3 decreases, however in DS individuals the expression of normal Nav1.1 does not increase to physiologic levels [
      • Connolly M.B.
      Dravet syndrome: diagnosis and long-term course.
      ,
      • Yamakawa K.
      Molecular and cellular basis: insights from experimental models of Dravet syndrome.
      ]. SCN1A is expressed in several regions, including the cortex, hippocampus, basal ganglia, cerebellum, and peripheral nerves [
      • Lukk M.
      • et al.
      A global map of human gene expression.
      ]. Given the widespread distribution of the Nav1.1 protein, it is not surprising that DS patients have several symptoms such as sleep, appetite, balance and motor disturbances, in addition to intractable seizures [
      • Villas N.
      • Meskis M.A.
      • Goodliffe S.
      Dravet syndrome: characteristics, comorbidities, and caregiver concerns.
      ].
      Clearly, the etiology of DS does not change when a patient becomes older. Interestingly, some children with a DS phenotype harboring pathogenic variants in genes other than SCN1A, could manifest an adult phenotype that is different from that of adults with DS and pathogenic SCN1A variants. Thus suggesting that some genes can mimic DS in childhood, but the natural history of their disease might be different.
      Mutations in PCDH19, GABRA1, GABRG2, SCN1B, SCN2A, SCN8A, SCN9A, STXBPI, HCN1, KCN2A and CHD2 have been reported to have phenotypes that may mimic as Dravet syndrome [
      • Marini C.
      • et al.
      The genetics of Dravet syndrome.
      ,
      • Connolly M.B.
      Dravet syndrome: diagnosis and long-term course.
      ,
      • Steel D.
      • Symonds J.D.
      • Zuberi S.M.
      • Brunklaus A.
      Dravet syndrome and its mimics: beyond SCN1A.
      ,
      • De Jonghe P.
      Molecular genetics of Dravet syndrome.
      ]. However, as more patients are being described, it is possible to observe some differences between patients with SCN1A and other genes, especially as these patients grow older. For instance, girls with PCDH19 tend to have clusters of febrile seizures, but when they become adults they have a higher chance of developing schizophrenia [
      • Vlaskamp D.R.M.
      • et al.
      Schizophrenia is a later-onset feature of PCDH19 girls clustering epilepsy.
      ]. Patients with SCN8A tend to respond better to sodium channel inhibitor drugs, while SCN1A DS patients then to have more seizures and worse intellectual outcome if exposed to this class of drugs.

      3.2 Seizures

      Dravet Syndrome patients experience a multitude of seizure types over their lifetime. Seizure onset is between 1–18 months, with generalized clonic-tonic seizures (GCTS) or hemiconvulsive seizures often seen initially. They are usually triggered by hyperthermia (fever, hot baths, etc.) and can be very prolonged, sometimes leading to status epilepticus. Myoclonic seizures usually are seen by age of 2 years [
      • Dravet C.
      The core Dravet syndrome phenotype.
      ,
      Commission on classification and terminology of the international league against epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes.
      ]. Children also develop obtundation status, focal seizures with impaired awareness (FSIA), and atypical absences seizures (AAS), usually after 2 years of age. Typical absences and infantile spasms are not characteristic of DS. Overall, the frequency of seizures increases in the first decade of life and then it may plateau or even decrease during adolescence and into adulthood [
      • Dravet C.
      The core Dravet syndrome phenotype.
      ,
      • Genton P.
      • Velizarova R.
      • Dravet
      • Dravet C.
      Syndrome: the long-term outcome.
      ,
      • Jansen F.E.
      • et al.
      Severe myoclonic epilepsy of infancy (Dravet syndrome): recognition and diagnosis in adults.
      ,
      • Rilstone J.J.
      • Coelho F.M.
      • Minassian B.A.
      • Andrade D.M.
      Dravet syndrome: seizure control and gait in adults with different SCN1A mutations.
      ,
      • Akiyama M.
      • Kobayashi K.
      • Yoshinaga H.
      • Ohtsuka Y.
      A long-term follow-up study of Dravet syndrome up to adulthood.
      ,
      • Takayama R.
      • et al.
      Long-term course of Dravet syndrome: a study from an epilepsy center in Japan.
      ]. Myoclonic, atypical absences and FSIA tend to decrease further in frequency or even disappear in adulthood [
      • Jansen F.E.
      • et al.
      Severe myoclonic epilepsy of infancy (Dravet syndrome): recognition and diagnosis in adults.
      ,
      • Jansen F.E.
      • et al.
      Severe myoclonic epilepsy of infancy (Dravet syndrome): recognition and diagnosis in adults.
      ,
      • Rilstone J.J.
      • Coelho F.M.
      • Minassian B.A.
      • Andrade D.M.
      Dravet syndrome: seizure control and gait in adults with different SCN1A mutations.
      ,
      • Akiyama M.
      • Kobayashi K.
      • Yoshinaga H.
      • Ohtsuka Y.
      A long-term follow-up study of Dravet syndrome up to adulthood.
      ,
      • Takayama R.
      • et al.
      Long-term course of Dravet syndrome: a study from an epilepsy center in Japan.
      ,
      • Fasano A.
      • Borlot F.
      • Lang A.E.
      • Andrade D.M.
      Antecollis and levodopa-responsive parkinsonism are late features of dravet syndrome.
      ]. The important differences between adults and children with DS are nocturnal seizures and status epilepticus episodes. Convulsive seizures have a tendency to become more restricted to periods of sleep in adults, termed nocturnal convulsive seizures, although they may also happen during daytime naps. This type of seizure may have a generalized or focal (most frequently frontal) onset [
      • Genton P.
      • Velizarova R.
      • Dravet
      • Dravet C.
      Syndrome: the long-term outcome.
      ,
      • Akiyama M.
      • Kobayashi K.
      • Yoshinaga H.
      • Ohtsuka Y.
      A long-term follow-up study of Dravet syndrome up to adulthood.
      ,
      • Cheah C.S.
      • et al.
      Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome.
      ,
      • Takayama R.
      • et al.
      Long-term course of Dravet syndrome: a study from an epilepsy center in Japan.
      ]. Nocturnal seizures were reported by Akiyama et al. in 19/31 (61 %) of adults with DS [
      • Akiyama M.
      • Kobayashi K.
      • Yoshinaga H.
      • Ohtsuka Y.
      A long-term follow-up study of Dravet syndrome up to adulthood.
      ]. Other studies in adults did not report the frequency of the different types of seizures. Status epilepticus occurs at a greater frequency in children from birth to five years of age, in comparison to adults. Adults seem to have a notable reduction in status epilepticus, especially after 30 years of age [
      • Genton P.
      • Velizarova R.
      • Dravet
      • Dravet C.
      Syndrome: the long-term outcome.
      ,
      • Rilstone J.J.
      • Coelho F.M.
      • Minassian B.A.
      • Andrade D.M.
      Dravet syndrome: seizure control and gait in adults with different SCN1A mutations.
      ,
      • Takayama R.
      • et al.
      Long-term course of Dravet syndrome: a study from an epilepsy center in Japan.
      ]. Table 1 displays the types of seizures reported in 6 adult studies.
      Table 1Breakdown of frequency and types of seizures amongst Dravet Syndrome adults.
      Type of Seizures
      StudyNumber of patients (n)Average age (years) and rangeSeizure-free (n)FS (n)MS (n)AAS (n)GCS /GTCS (n)Focal (n)SE (n)
      Akiyama et al, 201031Average:24.45/31 (16 %)9/31 (29 %)2/31 (6%)N/A26/31 (84 %)N/A3/31 (10 %)
      Range: 18−43
      Darra et al, 201950Average: 2910/50 (20 %)12/40 (30 %)8/50 (16 %)3/50 (6%)37/50 (74 %)9/50 (18 %)2/50 (4%)
      Range: 18−50
      Genton et al, 201124Average: NR2/24 (8%)12/24 (50 %)1/24 (4%)6/24 (25 %)21/24 (88 %)1/24 (4%)1/24 (4%)
      Range 20−50
      Jansen et al, 200614Average: 260/14 (0%)N/A2/14 (14 %)N/A14/14 (100 %)N/AN/A
      Range:18−47
      Rilstone et al, 201210Average:28.22/10 (20 %)N/A2/10 (20 %)2/10 (20 %)8/10 (80 %)3/10 (30 %)1/10 (10 %)
      Range: 18−47
      Takayama et al, 201464Average: NR5/64 (8%)N/A5/64 (8%)1/64 (2%)59/64 (92 %)N/A0/64 (0%)
      Range 19−45
      Abbreviations: NR: Not Recorded; N/A: Not available; FS: Febrile Seizures; MS: Myoclonic Seizures; AAS: Atypical Absence Seizures; GCS: Generalized Clonic Seizures; GTCS: Generalized Tonic-Clonic Seizures; SE: Status Epilepticus.

      3.3 Electroencephalogram (EEGs)

      EEG features change with age, and can be examined ictally and interictally. Most interictal EEG recordings are normal during first year of life. From the second year onwards, generalized spike-wave or polyspike-wave, focal or multifocal epileptiform discharges are seen in approximately half of the children and in 75 % of adolescents and adults [
      • Connolly M.B.
      Dravet syndrome: diagnosis and long-term course.
      ,
      • Lee H.F.
      • Chi C.S.
      • Tsai C.R.
      • Chen C.H.
      • Wang C.C.
      Electroencephalographic features of patients with SCN1A-positive dravet syndrome.
      ]. Lee et al. performed EEGs in 37 patients, including 6 adults aged between 18–26 years old. [25] The interictal EEG readings for 3/6 (50 %) were normal, and the other 3/6 (50 %) had slow background. Only 2/6 adult patients (33 %) had ictal EEG recordings (induced by hot water bath during the EEG). One of these 2 adult patients had myoclonic seizures, evolving into AAS, and ultimately to GTCS. Her EEG showed generalized spike and waves. The other adult patient had a GTCS but the EEG recording was obscured by muscle artifact, from the beginning [
      • Lee H.F.
      • Chi C.S.
      • Tsai C.R.
      • Chen C.H.
      • Wang C.C.
      Electroencephalographic features of patients with SCN1A-positive dravet syndrome.
      ]. Genton et al., reported 8/24 (33 %) adult patients having normal background activity, and 11/24 (46 %) having slow and disorganized activity [
      • Genton P.
      • Velizarova R.
      • Dravet
      • Dravet C.
      Syndrome: the long-term outcome.
      ]. Other paroxysmal epileptiform abnormalities reported in adults were: multifocal in 11/24 (46 %), generalized in 6/24 (25 %) and focal in 7/24 (28 %). Takayama and colleagues reported 49/64 adult patients having epileptiform discharges: 43/49 (88 %) had focal spike and sharp waves, 5/49 (10 %) had diffuse discharges, and 1/49 (2%) had focal spike and sharp waves, and diffuse discharges [
      • Takayama R.
      • et al.
      Long-term course of Dravet syndrome: a study from an epilepsy center in Japan.
      ]. Overall, there are two adult studies exclusively, three adult and child studies exclusively, and six child studies exclusively that describe EEG features. There are several review papers discussing EEG features in children as well.

      3.4 MRI

      There is currently no studies on adults exclusively describing MRI features. However, there are four studies in children exclusively, and one study describing both adult and children. Despite the small number of imaging studies in DS of any age, most of reported findings are normal [
      • Brunklaus A.
      • Ellis R.
      • Reavey E.
      • Forbes G.H.
      • Zuberi S.M.
      Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome.
      ,
      • Haginoya K.
      • et al.
      [18 F]fluorodeoxyglucose-positron emission tomography study of genetically confirmed patients with Dravet syndrome.
      ,
      • Wirrell E.C.
      Treatment of Dravet syndrome.
      ,
      • Mancardi M.
      • et al.
      Brain MRI Findings in severe myoclonic epilepsy in infancy and genotype-phenotype correlations *, † † †Pasquale Striano, †Maria.
      ]. Some patients however have hippocampal sclerosis. A case study examining two children with DS and SCN1A mutations showed that both had mesial temporal sclerosis (MTS) [
      • Tiefes A.M.
      • et al.
      Mesial temporal sclerosis in SCN1A-Related epilepsy: two long-term EEG case studies.
      ]. Another child study reported 4/20 (20 %) of patients with DS and definite MTS, and 2/20 (10 %) with DS and possible MTS or abnormal mesial temporal structures [
      • Van Poppel K.
      • et al.
      Mesial temporal sclerosis in a cohort of children with SCN1A gene mutation.
      ]. Another interesting study includes six DS children with malformations of cortical development (MCDs), three of whom have focal cortical dysplasia (FCD) [
      • Barba C.
      • et al.
      Co-occurring malformations of cortical development and SCN1A gene mutations.
      ]. A 21 year-old adult showed cortical brain atrophy [
      • Striano P.
      • et al.
      Brain MRI findings in severe myoclonic epilepsy in infancy and Genotype?PHenotype correlations.
      ]. Generally, children and most adults have normal MRIs, however some adults may experience mild generalized atrophy and hippocampal sclerosis.

      3.5 Treatment

      Seizures in DS are usually resistant to antiepileptic drugs (AEDs) and most other forms of treatment, including ketogenic diet and neurostimulation [
      • Wirrell E.C.
      • et al.
      Optimizing the diagnosis and management of dravet syndrome: recommendations from a north american consensus panel.
      ,
      • Cross J.H.
      • et al.
      Dravet syndrome: treatment options and management of prolonged seizures.
      ,
      • Knupp K.G.
      • Wirrell E.C.
      Treatment strategies for dravet syndrome.
      ]. At the time this review was completed (January 2021), the first line drugs to treat DS seizures include valproic acid and clobazam. If this strategy is not effective, stiripentol is used with valproic acid and/or clobazam [
      • Wirrell E.C.
      • et al.
      Optimizing the diagnosis and management of dravet syndrome: recommendations from a north american consensus panel.
      ,
      • Cross J.H.
      • et al.
      Dravet syndrome: treatment options and management of prolonged seizures.
      ,
      • Wallace A.
      • Wirrell E.
      • Kenney-Jung D.L.
      Pharmacotherapy for dravet syndrome.
      ]. Stiripentol inactivates CYP2C19 and when used with clobazam, clobazam levels increase by two-fold (and its active metabolite norclobazam levels increases five-fold) [
      • Inoue Y.
      • et al.
      Stiripentol open study in Japanese patients with Dravet syndrome.
      ,
      • Nickels K.C.
      • Wirrell E.C.
      Stiripentol in the management of epilepsy.
      ]. In adult patients, stiripentol has shown to be effective in reducing generalized clonic-tonic and focal seizures [
      • Balestrini S.
      • Sisodiya S.M.
      Audit of use of stiripentol in adults with Dravet syndrome.
      ,
      • Chiron C.
      • et al.
      Do children with Dravet syndrome continue to benefit from stiripentol for long through adulthood?.
      ,
      • Myers K.A.
      • Lightfoot P.
      • Patil S.G.
      • Cross J.H.
      • Scheffer I.E.
      Stiripentol efficacy and safety in Dravet syndrome: a 12-year observational study.
      ]. However, it may be difficult to attain the same levels as in children, mainly due to side effects [
      • Chiron C.
      • et al.
      Do children with Dravet syndrome continue to benefit from stiripentol for long through adulthood?.
      ]. A recent study in adults with DS shows hyperammonemia in patients who started stiripentol in adulthood. Treatment with carnitine helped reduce ammonia levels as well as side effects (attributed by parents to stiripentol, although they could be related to the increase in valproate caused by stiripentol) in this population [
      • Zulfiqar Ali Q.
      • et al.
      Starting stiripentol in adults with Dravet syndrome? Watch for ammonia and carnitine.
      ]. Topiramate and ketogenic diet are also second line therapy alternatives [
      • Wirrell E.C.
      • et al.
      Optimizing the diagnosis and management of dravet syndrome: recommendations from a north american consensus panel.
      ,
      • Cross J.H.
      • et al.
      Dravet syndrome: treatment options and management of prolonged seizures.
      ].
      Third line therapies includes the use of levetiracetam, clonazepam, zonisamide, ethoxusimide (for absence seizures), phenobarbital and neuromodulation [
      • Wirrell E.C.
      • et al.
      Optimizing the diagnosis and management of dravet syndrome: recommendations from a north american consensus panel.
      ]. Recently, cannabidiol has been approved to treat DS, and several studies have shown efficacy in decreasing seizures in children up to age 18 years [
      • Devinsky O.
      • et al.
      Trial of cannabidiol for drug-resistant seizures in the dravet syndrome.
      ,
      • Laux L.C.
      • et al.
      Long-term safety and efficacy of cannabidiol in children and adults with treatmentresistant Lennox-Gastaut syndrome or Dravet syndrome: expanded access program results.
      ]. A couple of phase 3 randomized control trials of fenfluramine studies have shown a significant decrease in mean monthly convulsive seizure frequency (MCSF) in children and young adults aged 18 years that were taking fenfluramine in stiripentol-inclusive AED regimens [
      • Nabbout R.
      • et al.
      Fenfluramine for treatment-resistant seizures in patients with dravet syndrome receiving stiripentol-inclusive regimens: a randomized clinical trial.
      ,
      • Sullivan J.
      • et al.
      Fenfluramine HCl (Fintepla ®) provides long‐term clinically meaningful reduction in seizure frequency: analysis of an ongoing open‐label extension study.
      ]. Other fenfluramine trials also observed a significant reduction in MCSF in children and young adults. These studies showed a higher dose of fenfluramine extended the amount of days without a seizure, relative to a smaller dose [
      • Bishop K.I.
      • Isquith P.K.
      • Gioia G.
      Profound reduction in seizure frequency (≥75%) leads to improved everyday executive function: analysis from a phase 3 study of ZX008 (Fenfluramine HCl) in Children/Young adults with dravet syndrome.
      ,
      • Dlugos D.J.
      • French J.A.
      • Lock M.
      • Farfel G.M.
      • Haney D.M.G.
      Fenfluramine in Dravet Syndrome: Re-analysis of Study 1 Using Time-to-Event to Measure Treatment Effect.
      ,
      • Lagae L.
      • et al.
      Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial.
      ,
      • Specchio N.
      • et al.
      Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a real‐world study.
      ]. Fenfluramine has just been approved by FDA for use in patients with DS. It is yet unclear if CBD and fenfluramine will be considered first line drugs [
      • Wirrell E.C.
      • Nabbout R.
      Recent advances in the drug treatment of dravet syndrome.
      ]. So far, their use has primarily been as an add-on drug in patients that are already on valproate, clobazam plus/minus also stiripentol. They have not yet been used as monotherapies. Sodium channel inhibitor drugs can aggravate seizures (both duration and frequency) and should be avoided [
      • Guerrini R.
      • et al.
      Lamotrigine and seizure aggravation in severe myoclonic epilepsy.
      ]. Unfortunately, several adults who had not been diagnosed with Dravet syndrome during childhood are still treated with sodium channel blockers [
      • Andrade D.M.
      • et al.
      Epilepsy: transition from pediatric to adult care. Recommendations of the Ontario epilepsy implementation task force.
      ,
      • Nabbout R.
      • et al.
      ].
      A meta-analyis examining the efficacy of ketogenic diet in DS by Wang YQ et al. displayed a combined efficacy rate for ≥50 % seizure reduction was 63 % at 3, 6 and 12 month checkpoints in 167 combined DS children [
      • Wang Y.Q.
      • Fang Z.X.
      • Zhang Y.W.
      • Xie L.L.
      • Jiang L.
      Efficacy of the ketogenic diet in patients with Dravet syndrome: a meta-analysis.
      ]. Another study of 20 children also reported ≥50 % seizure reduction in 80 % of them [
      • Yan N.
      • et al.
      Prospective study of the efficacy of a ketogenic diet in 20 patients with Dravet syndrome.
      ]. On the other hand, the literature lacks information on the impact of the ketogenic diet on the efficicacy of seizure reduction for DS adults.
      Neuromodulation through deep brain stimulation (DBS) or vagus nerve stimulation (VNS) have shown a decrease in seizure frequency. In a DBS study conducted by Andrade and colleagues, DBS was implanted in two adults ages 19 years (anterior nucleus of the thalamus) and 34 years (centro-median nucleus of the thalamus), respectively [
      • Andrade D.M.
      • Hamani C.
      • Lozano A.M.
      • Wennberg R.A.
      Dravet syndrome and deep brain stimulation: seizure control after 10 years of treatment.
      ]. The 19-year old patient showed immediate improvement with a 90 % reduction in seizure frequency. However the 34-year old did not have any benefits for the first several years after implantation. The target was changed to the anterior nucleus of the thalamus in the second patient, but her seizures did not improve. After several more years and changes in medications, her seizures finally abated. The age at initiation of DBS treatment and type of seizures may be related to efficacy. Also the type of seizures and location of implanted electrodes, and finally, ageing may have helped in seizure control in the second patient [
      • Andrade D.M.
      • Hamani C.
      • Lozano A.M.
      • Wennberg R.A.
      Dravet syndrome and deep brain stimulation: seizure control after 10 years of treatment.
      ].
      In DS children, there are many studies that display a efficacy of ≥ 50 % seizure reduction with a VNS implant [
      • Orosz I.
      • et al.
      Vagus nerve stimulation for drug-resistant epilepsy: a European long-term study up to 24 months in 347 children.
      ,
      • Dibué-Adjei M.
      • Fischer I.
      • Steiger H.J.
      • Kamp M.A.
      Efficacy of adjunctive vagus nerve stimulation in patients with Dravet syndrome: a meta-analysis of 68 patients.
      ,
      • Fulton S.P.
      • Van Poppel K.
      • Mcgregor A.L.
      • Mudigoudar B.
      • Wheless J.W.
      Vagus nerve stimulation in intractable epilepsy associated with SCN1A gene abnormalities.
      ]. A meta-analysis on the efficacy of VNS on 68 DS patients (13 studies) was reported by Dibué-Adjei et al. [
      • Dibué-Adjei M.
      • Fischer I.
      • Steiger H.J.
      • Kamp M.A.
      Efficacy of adjunctive vagus nerve stimulation in patients with Dravet syndrome: a meta-analysis of 68 patients.
      ] and showed an average of 55.2 % seizure reduction in these patients. In another study of adults and children, Fulton et al. reported on three DS adults with VNS implants: a 24 year-old female became seizure-free 8 years after the implant, a 22 year-old female had 78 % reduction in GTCS 9 years after the implant, and a 19 year-old female had nonspecific seizure improvement 10 years after the implant [
      • Fulton S.P.
      • Van Poppel K.
      • Mcgregor A.L.
      • Mudigoudar B.
      • Wheless J.W.
      Vagus nerve stimulation in intractable epilepsy associated with SCN1A gene abnormalities.
      ]. Zamponi et al. studied two patients, a 10-year old and 25-year old that were treated with vagus nerve stimulator (VNS) and followed up 9 and 6 years respectively, both had reduced seizure frequency into adulthood [
      • Zamponi N.
      • Passamonti C.
      • Cappanera S.
      • Petrelli C.
      Clinical course of young patients with Dravet syndrome after vagal nerve stimulation.
      ]. The younger patient did not have any cognitive or motor benefits, however did show a clinically important difference in adaptive behaviour. The older patient did not see benefits from a cognitive and motor perspective.

      3.6 Motor abnormalities

      3.6.1 Gait

      In 2012, two studies showed that adult DS patients developed “crouch” gait, defined as having a hip flexion and a knee flexion during their standing posture [
      • Rilstone J.J.
      • Coelho F.M.
      • Minassian B.A.
      • Andrade D.M.
      Dravet syndrome: seizure control and gait in adults with different SCN1A mutations.
      ,
      • Rodda J.M.
      • Scheffer I.E.
      • McMahon J.M.
      • Berkovic S.F.
      • Graham H.K.
      Progressive gait deterioration in adolescents with Dravet syndrome.
      ]. The one study correlating SCN1A variants and gait, crouch gait was only found in patients that had missense mutations in the pore-forming region or nonsense mutations leading to premature protein truncation. Other gait abnormalities were later described in adults with DS: small steps, high variability, wide base and en bloc turns [
      • Fasano A.
      • Borlot F.
      • Lang A.E.
      • Andrade D.M.
      Antecollis and levodopa-responsive parkinsonism are late features of dravet syndrome.
      ]. The largest survey in DS conducted by the Dravet Syndrome Foundation noted that 45/51 individuals of 16–25 years of age reported gait disturbances and 33/48 experienced ataxia. It was also noted that 4/4 patients older than 26 years of age reported gait disturbances, and 1/4 experienced ataxia [
      • Villas N.
      • Meskis M.A.
      • Goodliffe S.
      Dravet syndrome: characteristics, comorbidities, and caregiver concerns.
      ].

      3.6.2 Parkinsonian features

      We studied DS patients using a (modified) Unified Parkinson’s Disease Rating Scale (mUPDRS) [
      • Fasano A.
      • Borlot F.
      • Lang A.E.
      • Andrade D.M.
      Antecollis and levodopa-responsive parkinsonism are late features of dravet syndrome.
      ]. Parkinsonian features were seen in patients as young as 19 years old. However, they appear to be more severe in older patients, suggesting a progression of the parkinsonian symptoms. The parkinsonian features observed include: bradykinesia, rigidity, parkinsonian gait with small steps, en bloc turning, postural instability, dysarthria, antecollis, camptocormia, and even hoarding behavior [
      • Fasano A.
      • Borlot F.
      • Lang A.E.
      • Andrade D.M.
      Antecollis and levodopa-responsive parkinsonism are late features of dravet syndrome.
      ,
      • Aljaafari D.
      • Fasano A.
      • Nascimento F.A.
      • Lang A.E.
      • Andrade D.M.
      Adult motor phenotype differentiates Dravet syndrome from Lennox-Gastaut syndrome and links SCN1A to early onset parkinsonian features.
      ]. The resting tremor, which is typical in Parkinson’s disease, is not present in DS patients. DS patients often have action tremor, which can be attributed to valproate. Antipsychotic drugs can induce parkinsonian features, but the adult DS patients from this study have not been exposed to antipsychotic drugs. It is unclear if DS patients have classic Parkinson’s disease with typical neuropathologic findings. In order to determine if the parkinsonian features were due to the SCN1A abnormalities or the large amounts of AEDs DS patients received since a young age, adult patients with DS were compared to adult patients with Lennox-Gastaut syndrome (LGS). That study showed that antecollis and parkinsonian gait were distinctly more common in Dravet syndrome patients than patients in the LGS adult population, suggesting that the SCN1A variant is more likely than AEDs to be the cause of parkinsonian symptoms [
      • Aljaafari D.
      • Fasano A.
      • Nascimento F.A.
      • Lang A.E.
      • Andrade D.M.
      Adult motor phenotype differentiates Dravet syndrome from Lennox-Gastaut syndrome and links SCN1A to early onset parkinsonian features.
      ]. In a study conducted by Turner et al., they assessed dysarthria using the Frenchay Dysarthria Assessment 2nd ed (FDA-2), with a score of 7 or below equivalent to <1% of the normative sample. Of the 4 cooperating DS adults: 2/4 scored <7 for lips rounding and retraction, tongue elevation, protrusion, and lateral movements; 1/4 was able to smile but did not show tongue elevation, protrusion and lateral movements; 1/4 scored >7 for all tasks. Overall, they found a trend of more severe dysarthria in DS adults than in children [
      • Turner S.J.
      • et al.
      Dysarthria and broader motor speech deficits in Dravet syndrome.
      ].

      3.7 Cognitive behaviour and social outcomes

      Intellectual disability (ID) is a well-known comorbidity of DS, but it is still unclear as to what extent ID is the result of a significant damage caused by seizures in a developing brain, the use of contraindicated medications such as sodium channel inhibitors, the abnormal levels of Nav1.1 protein or a combination of these factors. Normal cognitive development is observed until the age range of 1–4 years. In this time frame, abnormal cognitive development is clinically recognized, and leads to moderate or severe intellectual disability [
      • Ragona F.
      • et al.
      Dravet syndrome: early clinical manifestations and cognitive outcome in 37 Italian patients.
      ,
      • Wolff M.
      • Cassé-Perrot C.
      • Dravet C.
      Severe myoclonic epilepsy of infants (Dravet syndrome): natural history and neuropsychological findings.
      ]. In adults with intellectual disability, detecting a decline in cognitive function can be challenging. Parents and caregivers of adults with DS often complain that patients can no longer perform motor or cognitively as they used to [
      • Villas N.
      • Meskis M.A.
      • Goodliffe S.
      Dravet syndrome: characteristics, comorbidities, and caregiver concerns.
      ].
      In 2019, a study conducted by Darra et al. showed 70.5 % of 22 adolescents with “complete forms” (i.e., myoclonic phenotype) had moderate or severe ID, whereas the same level of ID was seen in more than 80 % of the 35 adults with the complete phenotype. They also noted that the most cognitive impairment was observed in DS adults with the most persisting seizures [
      • Darra F.
      • et al.
      Dravet syndrome: early electroclinical findings and long-term outcome in adolescents and adults.
      ].
      Another study showed that the longer the use of contraindicated medications in the first 5 years of disease, the worse the cognitive outcome in these patients [
      • De Lange I.M.
      • et al.
      Influence of contraindicated medication use on cognitive outcome in Dravet syndrome and age at first afebrile seizure as a clinical predictor in SCN1A-related seizure phenotypes.
      ]. In a study examining 45 patients conducted by Brown et al., they displayed a negative trend in cross-sectional analyses of cognitive, and behavior functioning versus age [
      • Brown A.
      • et al.
      Cognitive, behavioral, and social functioning in children and adults with Dravet syndrome.
      ]. They were also able to show that social problems and autism are common in the DS population. Another 2019 study with 85 DS patients aged between 2 and 44 years revealed on average 56.5 % patients had behavior problems, and 62.3 % had abnormal attention problems [
      • Sinoo C.
      • et al.
      Behavior problems and health-related quality of life in Dravet syndrome.
      ]. Furthermore, behavior issues were a strong predictor of a lower health-related quality of life (HRQoL).

      3.8 Cardiac abnormalities

      An emerging topic in DS are cardiac abnormalities. There is currently no studies exclusively in adults, however there are two child studies and a study with adults and children combined. One child study showed that DS children had significantly different cardiac electrical and autonomic function values compared to age-matched healthy controls [
      • Lyu S.Y.
      • et al.
      Longitudinal change of cardiac electrical and autonomic function and potential risk factors in children with dravet syndrome.
      ]. The other child study showed that DS patients have an abnormal regulation of heart rate [
      • Delogu A.B.
      • et al.
      Electrical and autonomic cardiac function in patients with Dravet syndrome.
      ]. They also showed an imbalance of cardiac autonomic function primarily with an adrenergic tone, that may lead to increased risk for tachyarrhythmias. The study with adults and children was not able to identify major arrythmias, which could explain high SUDEP rates [
      • Shmuely S.
      • et al.
      Cardiac arrhythmias in Dravet syndrome: an observational multicenter study.
      ]. However, peri-ictal QTc-lengthening was more common in DS compared to age-matched epilepsy controls.

      3.9 Sleep disturbances

      Sleep disturbances have been reported in DS patients [
      • Van Nuland A.
      • et al.
      Sleep in Dravet syndrome: a parent-driven survey.
      ,
      • Schoonjans A.S.
      • De Keersmaecker S.
      • Van Bouwel M.
      • Ceulemans B.
      More daytime sleepiness and worse quality of sleep in patients with Dravet Syndrome compared to other epilepsy patients.
      ]. There are no adult exclusive studies, however there are three adult and child combined studies, and three child exclusive studies on sleep disturbances. A randomized control trial of melatonin for DS adults and children did not increase the total sleep, however provided some clinical benefits [
      • Myers K.A.
      • et al.
      Randomized controlled trial of melatonin for sleep disturbance in dravet syndrome: the DREAMS study.
      ]. Another study in DS adults and children showed in comparison to other epilepsies, DS have more night waking problems, reflective in their parent-reported poor quality of sleep [
      • Schoonjans A.S.
      • De Keersmaecker S.
      • Van Bouwel M.
      • Ceulemans B.
      More daytime sleepiness and worse quality of sleep in patients with Dravet Syndrome compared to other epilepsy patients.
      . The final study combining adult and child DS patients saw individuals older than 20 years of age on average had issues initiating and maintaining sleep [
      • Licheni S.H.
      • Mcmahon J.M.
      • Schneider A.L.
      • Davey M.J.
      • Scheffer I.E.
      Sleep problems in Dravet syndrome: a modifiable comorbidity.
      ]. Overall, children studies primarily reported the sleep disturbances and underdiagnosis of nocturnal GTCS [
      • Van Nuland A.
      • et al.
      Sleep in Dravet syndrome: a parent-driven survey.
      ,
      • Dhamija R.
      • Erickson M.K.
      • St Louis E.K.
      • Wirrell E.
      • Kotagal S.
      Sleep abnormalities in children with dravet syndrome.
      ].

      3.10 Diagnosing adults with Dravet syndrome

      It is important to recognize the differences in diagnosis of children and adults. Differential diagnosis largely relies on distinct phases of DS. The accurate diagnosis of DS after the first few febrile seizures can be extremely challenging. It is equally difficult to diagnose adults that may no longer display the typical myoclonic seizures, especially if their pediatric seizure history was not captured in detail. Often, parents do not remember details of the first seizures or even if they were febrile or not. It is important to remember that genetic diagnosis was not easily obtained when our adult patients were children. Furthermore, adult neurologists do not routinely ask for or are not comfortable interpreting genetic test results.
      Depending on the timing of accurate diagnosis, prolonged treatment with CIMs such as sodium channel inhibitors have shown to be detrimental [
      • De Lange I.M.
      • et al.
      Influence of contraindicated medication use on cognitive outcome in Dravet syndrome and age at first afebrile seizure as a clinical predictor in SCN1A-related seizure phenotypes.
      ]. As a result, adults who were not diagnosed during childhood, have often received CIMs for long periods of time prior to accurate diagnosis, leading to less favorable cognitive and social outcomes [
      • De Lange I.M.
      • et al.
      Influence of contraindicated medication use on cognitive outcome in Dravet syndrome and age at first afebrile seizure as a clinical predictor in SCN1A-related seizure phenotypes.
      ]. This may also represent the gap in DS adult research, as these patients are not diagnosed properly, have early unfavourable outcomes, or did not transition appropriately from pediatric care to adult care [
      • Andrade D.M.
      • et al.
      Epilepsy: transition from pediatric to adult care. Recommendations of the Ontario epilepsy implementation task force.
      ,
      • Borlot F.
      • et al.
      Epilepsy transition: challenges of caring for adults with childhood-onset seizures.
      ]. Another contributing factor to the absence of research in adults with DS is that many adult neurologists have indicated lack of training to care for adults with severe forms of pediatric-onset epilepsy, especially when associated with ID and autism [
      • Borlot F.
      • et al.
      Epilepsy transition: challenges of caring for adults with childhood-onset seizures.
      ,
      • Camfield P.R.
      • et al.
      Conference Proceedings how can transition to adult care be best orchestrated for adolescents with epilepsy?.
      ].

      3.11 Mortality

      There are 23 papers describing deaths in DS children exclusively, 3 papers exclusively on adults, and 5 papers in adults and children combined. Dravet Syndrome is highly correlated with premature mortality, as it can occur at any age. In comparison to adult studies, children studies report more deaths, as adult studies primarily discuss survivors. The list of causes of death include Sudden Unexpected Death in Epilepsy (SUDEP), status epilepticus (SE), drowning or accident, and fatal infection [
      • Shmuely S.
      • Sisodiya S.M.
      • Gunning W.B.
      • Sander J.W.
      • Thijs R.D.
      Mortality in dravet syndrome: a review.
      ]. There is limited information regarding adult deaths such as Genton et al., where 5/24 (21 %) adults between 20−50 years of age died: 3/24 (13 %) due to SUDEP; 1/24 (4%) due to status epilepticus; and 1/24 (4%) due to an unknown reason [
      • Genton P.
      • Velizarova R.
      • Dravet
      • Dravet C.
      Syndrome: the long-term outcome.
      ]. Cooper and colleagues assessed moratlity in 17 patients (2 adults, 15 children): both adults (aged 18 and 19) and 8/15 (53 %) children deaths were by SUDEP; 4/15(27 %) children died due to SE; and 3/15 (20 %) were unknown [
      • Cooper M.S.
      • et al.
      Mortality in Dravet syndrome.
      ]. Sakauchi and colleagues conducted a questionnaire in Japan to study death-related causes where 6/59 deaths happened in adults: 4 out of 6 adults died due to SUDEP and 2/6 drowned [
      • Sakauchi M.
      • et al.
      Mortality in Dravet syndrome: search for risk factors in Japanese patients.
      ]. Takayama et al. reported two DS adult deaths: one due to drowning and one febrile-illness related sudden death [
      • Takayama R.
      • et al.
      Long-term course of Dravet syndrome: a study from an epilepsy center in Japan.
      ]. Overall from these studies, SUDEP is the primary cause of death in adults. Though less common, SE, pneumonia/infection and drowning are also causes of death in these individuals. Comparatively however, the literature on DS premature death is more common in childhood.

      4. Advances and future research

      Current treatments of DS have aimed mostly at seizure control. However, in general there are no clear improvement observed in the motor and cognitive domains, mortality, social and cognitive outcomes with the traditional DS therapy. Just recently, drug trials for DS have included other measures in addition to seizures. For instance, within one year of fenfluramine treatment in patients aged 2–18 years, the patients that had a greater decrease in seizure frequency showed greater improvement in overall executive function [
      • Bishop K.I.
      • Isquith P.K.
      • Gioia G.
      Profound reduction in seizure frequency (≥75%) leads to improved everyday executive function: analysis from a phase 3 study of ZX008 (Fenfluramine HCl) in Children/Young adults with dravet syndrome.
      ]. This study did not show improvement in motor function. Although cognitive, social and behavioral outcomes are not examined thus far in CBD human trials, a DS mouse model has recently shown improvements in social behavior and cognition, and reduced anxiety-like and depression-like behaviours [
      • Patra P.H.
      • et al.
      Cannabidiol improves survival and behavioural co-morbidities of Dravet syndrome in mice background and purpose: dravet syndrome is a severe, genetic form of paediatric.
      ]. CBD did not affect motor function in these mice.
      A potential novel therapy that can address all the comorbidities is to replenish the Nav1.1 proteins that are lost due to SCN1A pathogenic variants. These methods include antisense oligonucleotide (ASO) technology and adeno-associated viral (AAV) vector-based approach.
      Initial gene therapy studies used ASO technology in a DS mouse model to increase SCN1A mRNA expression and consequently Nav1.1 protein levels. A single dose ultimately prevented generalized seizures and SUDEP in 79/80 (99 %) [
      • Han Z.
      • Chrisiansen A.
      • Aznarez I.
      • Liau G.
      • Chen C.
      • Anumonwo C.
      • et al.
      I. L. TANGO – Targeted Augmentation of Nuclear Gene Output for the Treatment of Dravet Syndrome.
      ]. Another study displayed an upregulation of SCN1A mRNA expression and Nav1.1 levels that also used ASO technology in vitro and in vivo (mouse and non-human primate models) [
      • Hsiao J.
      • et al.
      Upregulation of haploinsufficient gene expression in the brain by targeting a long non-coding RNA improves seizure phenotype in a model of dravet syndrome.
      ]. Other studies include a GABA-selective AAV vector that incorporates highly conserved human regulatory sequences, constricting expression to GABA interneurons in SCN1A haplosufficient mice [
      • Young A.N.
      • Tanenhaus A.
      • Chen M.
      • et al.
      A GABA-selective AAV vector-based approach to up-regulate endogenous Scn1a expression reverses key phenotypes in a mouse model of Dravet syndrome.
      ,
      • Miller I.
      • Dlugos D.
      • Segal E.
      • et al.
      From gene replacement to gene regulation: developing a disease-modifying AAV gene therapy vector for SCN1A–positive (SCN1A+) pediatric epilepsy.
      ]. They also successfully upregulated SCN1A expression using an engineered transcription factor, ultimately reversing multiple phenotypic characteristics. Another AAV study targeted increases in the multifunctional B1 sodium channel auxiliary subunit (AAV-NaVB1) to increase NavB1 in SCN1A haplosufficient mice [
      • Niibori Y.
      • Lee S.J.
      • Minassian B.A.
      • Hampson D.R.
      Sexually divergent mortality and partial phenotypic rescue after gene therapy in a mouse model of dravet syndrome.
      ]. The observed males had normalization of motor activity and improved in tests examining anxiety, fear, learning and memory. At the time of this writing, ASO clinical trials have already started, and the AAV vector approach is advancing towards clinical trial development.
      In conclusion, there is very limited information on adults with Dravet Syndrome. This review highlights the few studies on adults regarding seizure, motor, cognitive outcomes, premature death as well as challenges in diagnosis and treatment of adults with DS. There is not enough studies to determine the lifespan of this population, in part due to the fact that many older adults witih DS were not properly diagnosed, most studies focus only on children or young adults, and some patients with DS may be lost to follow up, especially as their parents age and die. Closing this gap in long-term outcomes research may ultimately improve the quality of life of adults with Dravet syndrome.

      Declaration of Competing Interest

      None.

      Acknowledgement

      DMA has received research grants from Dravet Syndrome Foundation .

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