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. 2022 May 12;63(7):1761–1777. doi: 10.1111/epi.17274

TABLE 4.

Seizure control endpoints, maintenance therapies, and management of status epilepticus

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 ( physicians : n = 19, 79%; caregivers: n = 9, 56%).
  • Convulsive seizures have a greater impact on quality of life and SUDEP, and thus should be prioritized above nonconvulsive seizures (PHYSICIANS: n = 19, 84%; caregivers: n = 9, 56%).
  • One of the goals of seizure control should be limitation of side effects from ASMs (PHYSICIANS: n = 19, 89%; CAREGIVERS: n = 9, 100%).
  • One of the goals of seizure control should be maximizing quality of life for the patient and their family (PHYSICIANS: n = 19, 100%; CAREGIVERS: n = 9, 89%). 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 ( physicians : n = 19, 74%; caregivers : n = 8, 75%).
  • Prolonged seizures or status epilepticus should lead to review of the home rescue therapy and seizure action plan (PHYSICIANS: n = 19, 100%; CAREGIVERS: n = 9, 89%).
  • Addition of a new therapy should be considered with frequent convulsive seizures (PHYSICIANS: n = 19, 100%; CAREGIVERS: n = 9, 89%).
  • Addition of a new therapy should be considered with frequent nonconvulsive seizures (PHYSICIANS: n = 19, 89%; caregivers : n = 9, 78%).
  • Addition of a new therapy should be considered with emergence of a new seizure type ( physicians : n = 19, 68%; caregivers : n = 9, 78%).
  • A recently approved, new effective therapy for DS should be considered for persons with suboptimal seizure control (PHYSICIANS: n = 19, 95%; caregivers : n = 9, 78%).
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 (PHYSICIANS: n = 19, 100%; caregivers: n = 9, 56% a ).
  • When a newer therapy has been added with improved seizure control, tapering off a less effective one should be considered (PHYSICIANS: n = 19, 100%; CAREGIVERS: n = 8, 88%).
  • 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 (PHYSICIANS: n = 19, 100%; caregivers: n = 9, 56%).
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)?
    1. One ASM only: 8%
    2. Combination of 2 ASMs: 22%
    3. Combination of 3 ASMs: 48%
    4. Combination of 4 ASMs: 21%
    5. Combination of >4 ASMs: 7%
  • What is the role of each of the following medications in persons with DS?
    1. Valproic acid
      • ▪
        Should be used 1st line (PHYSICIANS: n = 18, 83%; CAREGIVERS: n = 9, 100%)
    2. Clobazam:
      • ▪
        Should be used 1st or 2nd line (PHYSICIANS: n = 18, 83%; CAREGIVERS: n = 9, 89%)
    3. Fenfluramine
      • ▪
        Should be used 1st or 2nd line (PHYSICIANS: n = 19, 84%; caregivers : n = 8, 75%)
    4. Stiripentol
      • ▪
        Should be used 1st or 2nd line ( physicians : n = 17, 71%; CAREGIVERS: n = 9, 100%)
    5. Cannabidiol (pharmaceutical grade)
      • ▪
        Should be used 1st or 2nd line (physicians: n = 16, 31%; CAREGIVERS: n = 7, 86%)
      • ▪
        Should be used 1st, 2nd, or 3rd line (PHYSICIANS: n = 16, 81%)
    6. Topiramate
      • ▪
        Should be used 1st, 2nd, or 3rd line (physicians: n = 14, 64%; caregivers : n = 8, 75%)
  • One or two of the currently available medications stand out from the other therapies due to better efficacy and/or improved tolerability ( physicians : n = 19, 74%; caregivers : n = 8, 75%).
    1. Of respondents who responded positively to this question, there was consensus for fenfluramine (PHYSICIANS: n = 14, 93%; CAREGIVERS: n = 6, 83%). However, no other medications received even moderate consensus.
Lamotrigine
  • Lamotrigine should be considered contraindicated in children with DS ( physicians : n = 19, 79%).
  • 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 (PHYSICIANS: n = 19, 100%).
  • In an adult with DS on lamotrigine with good seizure control, tapering off lamotrigine may rarely lead to an exacerbation of seizures (PHYSICIANS: n = 13, 92%).
Non‐pharmaceutical grade medical marijuana
  • Non‐pharmaceutical grade CBD is not recommended for treatment of DS (PHYSICIANS: n = 16, 81%; caregivers: n = 8, 62.5%).
  • 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; physicians: n = 15, 60%).
  • The dose of clobazam should be reduced when stiripentol is added (if the patient is not already on cannabidiol; physicians : n = 17, 76%).
  • The dose of valproic acid should be reduced when stiripentol is added (physicians: n = 17, 41%).
  • When using stiripentol, both clobazam and valproic acid are recommended as cotherapies (PHYSICIANS: n = 17, 82%).
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:
    1. 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 ( physicians : n = 19, 74%).
  • CBC and liver enzymes should be routinely monitored periodically in all patients on valproic acid ( physicians : n = 19, 74%).
Cannabidiol
  • Liver enzymes ± CBC should be routinely monitored in all patients on cannabidiol ( physicians : n = 19, 68%).
Stiripentol
  • Liver enzymes and CBC should be routinely monitored in all patients (physicians: n = 19, 53%).
Dietary therapy
  • Dietary therapy should not be used first line before any ASMs are tried ( physicians : n = 19, 79%; caregivers: n = 8, 38%).
  • Dietary therapy should be considered after failure of 1–2 ASMs (physicians: n = 19, 42%; caregivers: n = 9, 56%).
  • Dietary therapy should be considered after failure of 3–4 ASMs (PHYSICIANS: n = 19, 84%; CAREGIVERS: n = 7, 86%).
  • In infants aged <2 years, the classical ketogenic diet is the recommended option ( physicians : n = 15, 73%).
  • In children 2–6 years, the classical ketogenic diet is the recommended option ( physicians : n = 16, 75%).
  • In school‐aged children, the classical ketogenic diet (physicians: n = 16, 56%) or modified Atkins diet are the recommended options (physicians: n = 16, 56%).
  • In adolescents, the modified Atkins diet is the recommended option (PHYSICIANS: n = 15, 87%).
  • In adults, the modified Atkins diet is the recommended option (physicians b : n = 9, 89%).
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:
    1. Valproate (PHYSICIANS: n = 19, 100%)
    2. Clobazam (PHYSICIANS: n = 19, 100%)
    3. Fenfluramine ( physicians : n = 13, 77%)
    4. Stiripentol (PHYSICIANS: n = 13, 92%)
    5. Topiramate ( physicians : n = 13, 77%)
    6. Cannabidiol, pharmaceutical grade ( physicians : n = 13, 77%)
    7. Ketogenic diet, if feasible for the family (PHYSICIANS: n = 19, 84%)
  • Vagus nerve stimulation in persons with DS usually leads to a <50% reduction in seizure frequency (PHYSICIANS: n = 12, 100%; CAREGIVERS: n = 5, 100%).
  • 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 ( physicians : n= 14, 79%).
    1. 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. 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 (PHYSICIANS: n = 13, 92%).
    1. 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 (PHYSICIANS: n = 18, 100%; CAREGIVERS: n = 9, 100%):
    1. Would use as early as possible ( physicians : n = 18, 72%; caregivers: n = 9, 44%)
    2. Would use at some point before trying a 3rd ASM (PHYSICIANS: n = 18, 89%; CAREGIVERS: n = 9, 89%)
  • 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 (PHYSICIANS: n = 18, 83%; caregivers : n = 8, 75%):
    1. Would use as early as possible (physicians: n = 15, 47%; caregivers: n = 6, 50%)
    2. Would use at some point before trying a 3rd ASM ( physicians : n = 15, 67%; CAREGIVERS: n = 6, 100%)
  • 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 (PHYSICIANS: n = 18, 89%; caregivers : n = 8, 75%):
    1. Would use as early as possible ( physicians : n = 16, 69%; caregivers: n = 6, 17%)
    2. Would use at some point before trying a 3rd ASM (PHYSICIANS: n = 16, 88%; caregivers : n = 6, 67%)
  • 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 ( physicians : n = 17, 71%; caregivers: n = 8, 50%).
  • In a preschool or early school‐aged child, current seizure frequency would not impact the decision to recommend disease‐modifying treatment (PHYSICIANS: n = 12, 83%; CAREGIVERS: n = 6, 100%).
  • In a preschool or early school‐aged child, degree of intellectual disability would not impact the decision to recommend these therapies (PHYSICIANS: n = 12, 83%; caregivers : n = 6, 67%). If both gene therapy and antisense oligonucleotides were safe and effective, gene therapy is the preferred option, as only one treatment is needed (PHYSICIANS: n = 10, 80%; caregivers b : n = 2, 50%).
Seizure emergencies
  • All persons with DS should have a home rescue medication (PHYSICIANS: n = 19, 100%; CAREGIVERS: n = 10, 100%).
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:
    1. IV valproic acid load (assuming the child is not already on maintenance valproate with high therapeutic levels; physicians: n = 19, 63%)
    2. IV phenytoin or fosphenytoin load (physicians: N = 19, 47%)
    3. IV levetiracetam load (physicians: n = 19, 37%)
  • 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:
    1. IV midazolam infusion ( physicians : n = 19, 79%)
    2. IV phenobarbital load (PHYSICIANS: n = 19, 89%)
    3. IV lacosamide load (PHYSICIANS: n = 19, 100%)
  • 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:
    1. IV valproic acid load (assuming the child is not already on maintenance valproate with high therapeutic levels; PHYSICIANS: n = 19, 95%)
    2. IV levetiracetam load (PHYSICIANS: n = 19, 84%)
    3. IV phenytoin or fosphenytoin load (physicians: n = 19, 63%)
    4. IV midazolam infusion (physicians : n = 19, 58%)
    5. IV phenobarbital load (physicians: n = 19, 53%)
  • Phenytoin or fosphenytoin are NOT considered contraindicated when used as acute treatment for prolonged seizures in DS (PHYSICIANS: n = 19, 89%).

Bold and all‐capital text indicates Strong consensus; bold and italic text indicates Moderate consensus; nonbold and italic text indicates no consensus.

Abbreviations: ASM, antiseizure medication; CBC, complete blood count; CBD, cannabidiol; DS, Dravet syndrome; IQR, interquartile range; IV, intravenous; SUDEP, sudden unexpected death in epilepsy; THC, tetrahydrocannabinol.

a

3/9 caregivers who did not agree commented that certain ASMs may lead to improvement in comorbidities, and that alone may be reason to continue them even if seizures are not improved.

b

Consensus was not determined for statements where >50% of the group did not provide a response.