Diagnosis and Management of Dravet Syndrome

Other seizure types: frequency and age at presentation

• Myoclonic seizures
  • Seen in 50–90% of cases
  • Typically begin between 1 and 3 years of age, but all physicians and 4/5 caregivers who responded indicated they may be seen in the first year of life.
• Absence seizures
  • No consensus on whether these are seen in majority of cases or not (physicians or caregivers).
  • Typically begin between 1 and 5 years of age, but 53% of physicians and 1/3 caregivers who responded indicated they could begin in the first year of life.
• Focal impaired awareness seizures
  • Seen in more than half of cases
  • Typically, onset is between 1 and 5 years, but 57% of physicians and 1/3 caregivers indicated they could begin in the first year of life.
• Atonic seizures
  • Seen in fewer than half of cases
  • Typically, onset is between ages 1 and 5 years, but 8% of physicians and 1/3 caregivers indicated they could begin in the first year of life.
• Tonic seizures
  • Seen in fewer than half of cases; seen in more than half of cases
  • No consensus for typical age at onset (physicians or caregivers), and only 7% of physicians but 4/4 caregivers indicated they could begin in the first year of life.
• Nonconvulsive (obtundation) status epilepticus
  • Seen in 10%–49% of cases
  • Usually starts in the first decade of life, but only 29% of physicians and 0/2 caregivers indicated this could begin in the first year of life.

Persistence of seizure types into adulthood

• Myoclonic seizures:
  • Persist in fewer than half of cases into adulthood
• Absence seizures:
  • Persist in fewer than half of cases into adulthood
• Atonic seizures:
  • Persist in fewer than half of cases into adulthood
• Tonic seizures:
  • Persist in fewer than half of cases into adulthood
  • Persist in more than half of cases into adulthood
• Brief (<5 min) generalized tonic–clonic seizures:
  • Persist in more than half of cases into adulthood
• Focal impaired awareness seizures:
  • No consensus (physicians or caregivers)
• Brief (<5 min) focal motor seizures:
  • No consensus (physicians)
  • Persist in fewer than half of cases into adulthood
• Prolonged (5–29 min) convulsive seizures
  • Persist in fewer than half of cases into adulthood
• Convulsive status epilepticus (≥30 min):
  • Persists in fewer than half of cases into adulthood
• Nonconvulsive status epilepticus:
  • Persists in fewer than half of cases into adulthood

Genetic testing

• Provided the cost of an epilepsy gene panel is similar to SCN1A targeted testing, an epilepsy gene panel is the preferred genetic study for young children with suspected DS
• SCN1A pathogenic variants are detected in >85% of DS patients

Neuroimaging

• Brain MRI is typically normal at diagnosis
• With time, variable degrees of cortical atrophy may be seen on MRI; however, this may not be recognized, as serial MRI is typically not performed in persons with DS
• Hippocampal sclerosis may develop over time in a minority of cases

EEG

• With the exception of postictal slowing, the EEG background is typically normal prior to 12 months of age
• In persons 5 years and older, background slowing is present in most cases
• Interictal discharges are seen in fewer than half of cases before 12 months of age
• Interictal discharges are seen in most cases by 5 years of age
• Interictal discharges may be focal, multifocal, and/or generalized
• Up to half of persons with DS show a photoparoxysmal response on EEG at some point over their disease course. This finding may be age dependent and abate with time
• Recorded seizures are often “falsely generalized,” meaning that changes may appear bilateral on EEG early in a seizure that is clinically focal, or may appear bilateral at onset and then become and remain asymmetric
• Recorded seizures may be “unstable,” meaning that the epileptiform discharge changes topographically, moving from one brain region to another during the same seizure
• A minority of adolescents with DS may develop bifrontal spike-and-slow-wave with generalized polyspikes in sleep, which correlate with axial tonic seizures

Development

• Development is usually normal prior to 18 months of age, although subtle delays may be appreciated prior to that time in a minority of cases
• Subtle delays are typically evident between 18 and 36 months.
• Intellectual disability (developmental quotient < 70) is present in most children aged 3 year and older).
• Degree of intellectual disability worsens with time, with most young adults having moderate to severe intellectual disability.
• Most children exhibit stagnation (lack of or slower progression) as opposed to true regression (loss of skills)
• Encephalopathy and regression can occur following a bout of prolonged febrile status epilepticus in a minority of cases
• Social skills are better preserved than communication skills
• The following factors are correlated with poor developmental outcome:
  • Younger age at onset of DS
  • Greater number of convulsive status epilepticus (>30 min) episodes
  • Greater duration of longest convulsive status epilepticus event
  • Longer use of contraindicated medications (i.e., sodium channel blockers including lamotrigine) in early life
  • Delay in use of optimal therapies
  • Appearance of absence and/or myoclonic seizures in the first year of life
  • Appearance of tonic seizures
  • Higher frequency of interictal discharges on EEG if the first year of life
  • Early motor delay
  • Greater number or longer episodes of nonconvulsive status epilepticus
  • Specific types of SCN1A variants

Attention problems, autism, and behavior problems

• Attention problems are present in most school-aged children and teens with DS
• Stimulant medications are safe to use in persons with DS with significant attention problems
• Stimulant medications are effective in persons with DS with significant attention problems.
• Internalizing behaviors (depression, anxiety) are seen in a minority of preschool children but become more common with age and are present in more than half of adults.
• Externalizing behaviors (aggression, impulsivity) are seen in more than half of persons at the following ages:
  • Preschool children
  • School-aged children
  • Teens
  • Adults
• Prevalence of autistic features in children with DS:
  • Preschool children: physicians: n = 18, 72% stated prevalence of autistic features was <50%; CAREGIVERS: n = 9, 89% stated prevalence of autistic features was >50%.
  • School-aged children: physicians: n = 19, 68% stated prevalence of autistic features was <50%; CAREGIVERS, n = 8, 100% said prevalence of autistic features was >50%.
• Children with DS are at risk of autism spectrum disorder and concerns may be more apparent to parents/caregivers than neurology providers. Providers should query families for these concerns at regular follow-up visits.
• Less than half of preschool and school-aged children with DS have undergone a formal evaluation for autism
• Current resources limit the number of at-risk children who undergo formal evaluation for autism, leading to probable underdiagnosis of autism in DS

Gait problems and parkinsonian features

• Gait abnormalities including ataxia or crouch gait are noted in approximately half of school-aged (age 6–11 years) children with DS.
• Gait abnormalities are seen in the majority of teens and young adults with DS.
• Parkinsonian features including bradykinesia, rigidity, parkinsonian gait (stooped, stiff, unsteady), and postural instability are seen in a majority of adults with DS; however, resting tremor is typically absent
• Therapies prescribed for gait disorders:
• Physiotherapy and/or occupational therapy prescribed by 12/18 physicians and used by 6/8 caregivers. Median benefit reported by physicians was 5 and by caregivers was 6, on a scale of 1–9, where 1 is no benefit and 9 is marked benefit.
• Sinemet (physicians: only 6 had ever tried Sinemet and only 4 treated more than 5 patients. Of physicians who had tried Sinemet, median reported benefit was 5 on a scale of 1–9).

Speech

• Most/all children with DS should be routinely referred for speech assessment and therapy.
• Speech therapy is at least moderately beneficial for teens and adults with DS (physicians: n = 15, median score of 6 on a scale of 1–9; caregivers: n = 9, median score of 7 on a scale of 1–9).

Sleep problems

• Sleep problems are seen in a majority of persons with DS and can include increased nocturnal wakening, snoring, insomnia, and/or excessive daytime somnolence
• Questions regarding sleep should be routinely asked as part of continuing care of a person with DS
• A formal sleep study should be considered if a clinical history of a possible sleep disorder is obtained.
• Attention to sleep hygiene is important in managing sleep problems associated with DS
• Melatonin may be considered for persons with difficulty with initiating and maintaining sleep, but there are limited data on its efficacy
• Benefits of melatonin for sleep:
• 18 physicians had experience using melatonin, median efficacy = 6.5 of 9 on a scale of 1–9, where 1 is no benefit and 9 is highly effective.
• 6 caregivers had experience with melatonin, median efficacy = 6.5 of 9.
• Benefits of clonidine for sleep:
• 7 physicians had experience using clonidine, median efficacy = 7 of 9.
• 3 caregivers had experience using clonidine, median efficacy = 6 of 9.

Autonomic dysfunction

• Routine cardiac testing is not required for persons with DS
• There is no consistent therapy that is effective for dysautonomia

SUDEP

• Persons with DS have a significant risk of SUDEP. Families must be made aware of this potential risk at diagnosis
• Risk of SUDEP will be at least mildly to moderately reduced due to recently approved seizure medications that have shown improved efficacy for DS
• Use of monitoring devices for seizures:
• 68% of physicians did not routinely recommend the use of seizure monitoring devices for their patients with DS, but 74% would support a family's request for such a device.
• 31% of physicians reported that >50% of their patients used a seizure monitoring device.
• 67% of caregivers reported that >50% of persons with DS used a seizure monitoring device.
• Effectiveness of monitoring devices for seizure detection was rated by physicians (n = 15) as 6 (IQR = 5–7) and by caregivers (n = 8) as 7 (IQR = 6–9) on a scale of 1–9, where 1 is ineffective and 9 is highly effective.
• There was no consensus among physicians or caregivers that any particular monitoring device was more efficacious than another.

Vaccinations

• Persons with DS should receive all routine vaccinations
• Persons with DS should receive an annual influenza vaccination
• Routine use of antipyretic medication around vaccinations should be considered to reduce likelihood of seizures
• Routine use of additional antiseizure medication (such as benzodiazepines) around vaccinations should be considered to reduce the likelihood of seizures (physicians: n = 19, 53%; caregivers: n = 9, 67% that this should NOT be done).
• Persons with DS who are eligible should receive the COVID-19 vaccination

Transition of care to adult neurology

• The following factors are key to successful transition to adult care for persons with DS:
• Identifying a competent adult provider who understands DS
• Clear communication between the pediatric and adult neurology providers around the time of transition
• Education of the family with a focus on progressive transition that occurs over a prolonged period, rather than a single transfer of care
• Creation of a detailed transition document by the pediatric provider that summarizes the subject's medical course, comorbidities, and social supports, which is given to the adult provider
• The following factors are significant barriers in successful transition to adult care for persons with DS:
• Lack of adult providers with expertise in DS
• Reluctance of families to transition as they are very bonded to their pediatric team
• Lack of appropriate infrastructure in the adult setting to provide holistic care to a young adult with DS
• Limited involvement and/or inclusion of parents/caregivers in care decisions once transition to an adult provider has occurred

Goals for seizure control

• In DS, it is appropriate to accept infrequent, brief convulsive seizures with the main goal focused on avoiding prolonged convulsive seizures and status epilepticus
• Convulsive seizures have a greater impact on quality of life and SUDEP, and thus should be prioritized above nonconvulsive seizures
• One of the goals of seizure control should be limitation of side effects from ASMs.
• One of the goals of seizure control should be maximizing quality of life for the patient and their family. The definition of seizure control varies with age (physicians: n = 19, 58%; caregivers: n = 9, 78% state it is NOT dependent on age).

Factors that should prompt consideration of a new therapy

• Prolonged seizures or status epilepticus should lead to a review of current maintenance therapies. A new maintenance therapy could be added, but the potential for benefit and risk of adverse effects must be considered. Addition of a therapy with higher documented efficacy may be reasonable; however, adding a therapy with limited efficacy, in someone who has already trialed the more effective therapies, may not be indicated
• Prolonged seizures or status epilepticus should lead to review of the home rescue therapy and seizure action plan
• Addition of a new therapy should be considered with frequent convulsive seizures
• Addition of a new therapy should be considered with frequent nonconvulsive seizures
• Addition of a new therapy should be considered with emergence of a new seizure type
• A recently approved, new effective therapy for DS should be considered for persons with suboptimal seizure control

Factors that should prompt consideration of tapering off medication, other than intolerable side effects

• A therapy that does not result in improved seizure control despite achieving maximum tolerated dose should be strongly considered for tapering
• When a newer therapy has been added with improved seizure control, tapering off a less effective one should be considered
• In a person with DS who is on several antiseizure therapies and who has achieved a prolonged period of seizure control, it is appropriate to consider tapering off one of the therapies deemed to be either least effective or associated with more significant side effects

Maintenance ASMs

• What is the maximal number of ASMs that are reasonable to use together in a person with DS? Physicians: median = 3, IQR = 3–4; caregivers: median 3, IQR = 3–4.
• How many of your current patients are presently treated with the following number of ASMs (physicians only)?
  • One ASM only: 8%
  • Combination of 2 ASMs: 22%
  • Combination of 3 ASMs: 48%
  • Combination of 4 ASMs: 21%
  • Combination of >4 ASMs: 7%
• What is the role of each of the following medications in persons with DS?
  • Valproic acid
    • ▪Should be used 1st line
  • Clobazam:
    • ▪Should be used 1st or 2nd line
  • Fenfluramine
    • ▪Should be used 1st or 2nd line
  • Stiripentol
    • ▪Should be used 1st or 2nd line
  • Cannabidiol (pharmaceutical grade)
    • ▪Should be used 1st or 2nd line
    • ▪Should be used 1st, 2nd, or 3rd line
  • Topiramate
    • ▪Should be used 1st, 2nd, or 3rd line
• One or two of the currently available medications stand out from the other therapies due to better efficacy and/or improved tolerability
  • Of respondents who responded positively to this question, there was consensus for fenfluramine. However, no other medications received even moderate consensus.

Lamotrigine

• Lamotrigine should be considered contraindicated in children with DS
• Lamotrigine may have a very limited role in adults with refractory seizures due to DS, but should not be used until all appropriate 1st, 2nd, and 3rd line agents have been trialed. If started, careful observation is needed to ensure it is not exacerbating seizures.
• In an adult with DS on lamotrigine with good seizure control, tapering off lamotrigine may rarely lead to an exacerbation of seizures

Non-pharmaceutical grade medical marijuana

• Non-pharmaceutical grade CBD is not recommended for treatment of DS
• Only 16% of physicians and 37% of caregivers indicated they had experience using low-dose THC, but all stated they did not see improved benefit with THC.

Drug–drug interactions

• The dose of clobazam should be reduced when cannabidiol is added (if the patient is not already on stiripentol
• The dose of clobazam should be reduced when stiripentol is added (if the patient is not already on cannabidiol
• The dose of valproic acid should be reduced when stiripentol is added
• When using stiripentol, both clobazam and valproic acid are recommended as cotherapies

Fenfluramine

• How much of a concern is cardiac valvulopathy or pulmonary hypertension with fenfluramine (scored from 1–9, where 1 = no concern and 9 = extreme concern)? Physicians: median score = 3/9, IQR = 2–5; caregivers: median score = 3/9, IQR = 2–7.
• Serotonin syndrome:
  • Fenfluramine could be used with caution in combination with a serotonergic agent (physiciansb: n = 7, 71%). However, only 2 physicians had combined fenfluramine with a serotonergic agent; neither had noted symptoms of serotonin syndrome.

Medications that impact appetite

• Topiramate was identified by 63% of physicians and 50% of caregivers as a medication that most impacts appetite.
• Stiripentol was identified by 58% of physicians and 67% of caregivers as a medication that most impacts appetite.
• Fenfluramine was identified by 47% of physicians and 50% of caregivers as a medication that most impacts appetite.
• Pharmaceutical-grade CBD was identified by 37% of physicians and 17% of caregivers as a medication that most impacts appetite.
• Valproic acid was identified by 21% of physicians and 33% of caregivers as a medication that most impacts appetite.

Bloodwork monitoring while on ASMs

Valproic acid

• Patients on valproic acid do not need routine drug levels drawn. However, valproic acid levels should be strongly considered in the presence of poor seizure control or with possible dose-dependent side effects
• CBC and liver enzymes should be routinely monitored periodically in all patients on valproic acid

Cannabidiol

• Liver enzymes ± CBC should be routinely monitored in all patients on cannabidiol

Stiripentol

• Liver enzymes and CBC should be routinely monitored in all patients

Dietary therapy

• Dietary therapy should not be used first line before any ASMs are tried
• Dietary therapy should be considered after failure of 1–2 ASMs
• Dietary therapy should be considered after failure of 3–4 ASMs
• In infants aged <2 years, the classical ketogenic diet is the recommended option
• In children 2–6 years, the classical ketogenic diet is the recommended option
• In school-aged children, the classical ketogenic diet or modified Atkins diet are the recommended options
• In adolescents, the modified Atkins diet is the recommended option
• In adults, the modified Atkins diet is the recommended option

Vagus nerve stimulation and epilepsy surgery

• For families willing to consider vagus nerve stimulation and where resources are available to place that device, the following therapies should be tried prior to placing that device:
  • Valproate
  • Clobazam
  • Fenfluramine
  • Stiripentol
  • Topiramate
  • Cannabidiol, pharmaceutical grade
  • Ketogenic diet, if feasible for the family
• Vagus nerve stimulation in persons with DS usually leads to a <50% reduction in seizure frequency
• How beneficial is the magnet at stopping seizures in persons with DS (scored from 1–9, where 1 is not effective and 9 is highly effective)? Physicians: median score = 3.5; caregivers: median score = 6.

Other epilepsy surgical procedures

• There is no role for corpus callosotomy in DS.
  • 2 physicians were aware of a total of 3 persons who had undergone callosotomy for atonic seizures. Of these, 2 had improvement in atonic seizure frequency (1 only transiently).
  • 2 caregivers were aware of 2 persons who had undergone callosotomy. One was reported to have reduced atonic seizures, whereas the other did not benefit.
• There is no role for temporal lobectomy in DS.
  • 7 physicians were aware of a total of 16 patients who had undergone temporal lobectomy. Only one was reported to have a mild reduction in seizures, whereas the rest did not benefit.

Disease-modifying therapies

Assuming a disease-modifying therapy was proven to be safe, there were no barriers to access, and cost was not prohibitive:

• A disease-modifying therapy is recommended if it leads to greater reduction in seizures than the current best therapy AND has an impact on reducing cognitive and other comorbidities
  • Would use as early as possible
  • Would use at some point before trying a 3rd ASM
• A disease-modifying therapy is recommended if it leads to greater reduction in seizures than the current best therapy, even if it has NO impact on comorbidities
  • Would use as early as possible
  • Would use at some point before trying a 3rd ASM
• A disease-modifying therapy is recommended if it has an impact on reducing cognitive and other comorbidities, even if it has NO greater impact on seizures than the current best therapy
  • Would use as early as possible
  • Would use at some point before trying a 3rd ASM
• If studies of disease-modifying therapy in infants and preschool children showed an impact on both seizures and comorbidities, but studies had not been performed in older persons with DS, such therapies should be considered for use in older children and adults with moderate to severe intellectual disability
• In a preschool or early school-aged child, current seizure frequency would not impact the decision to recommend disease-modifying treatment
• In a preschool or early school-aged child, degree of intellectual disability would not impact the decision to recommend these therapies
• If both gene therapy and antisense oligonucleotides were safe and effective, gene therapy is the preferred option, as only one treatment is neede

Seizure emergencies

• All persons with DS should have a home rescue medication

Status epilepticus (physicians only)

• In a patient with DS presenting with a prolonged convulsive seizure that has not responded to 2 appropriate doses of benzodiazepines, the optimal next option is:
  • IV valproic acid load (assuming the child is not already on maintenance valproate with high therapeutic levels;
  • IV phenytoin or fosphenytoin load
  • IV levetiracetam load
• In a patient with DS presenting with a prolonged convulsive seizure that has not responded to 2 appropriate doses of benzodiazepines, the following are NOT recommended as the optimal next option:
  • IV midazolam infusion
  • IV phenobarbital load
  • IV lacosamide load
• In a patient with DS presenting with a prolonged convulsive seizure that has not responded to 2 appropriate doses of benzodiazepines, the following agents are appropriate to use either first or second line as acute treatment:
  • IV valproic acid load (assuming the child is not already on maintenance valproate with high therapeutic levels;
  • IV levetiracetam load
  • IV phenytoin or fosphenytoin load
  • IV midazolam infusion
  • IV phenobarbital load
• Phenytoin or fosphenytoin are NOT considered contraindicated when used as acute treatment for prolonged seizures in DS