Issues on Diagnosing, Managing Dravet Syndrome Reaches Consensus

Issues on Diagnosing, Managing Dravet Syndrome Reaches Consensus

An international panel of physicians and caregivers with expertise in Dravet syndrome is recommending genetic testing in children ages 2 to 15 months who develop normally but have a prolonged seizure after fever or vaccination.

Among several consensus statements, the panel also recommended a number of currently available therapies for first- or second-line maintenance therapies to control seizures caused by Dravet.

the study,”The International Consensus on Diagnosis and Management of Dravet Syndrome,” was published in epilepsy.

Dravet syndrome is a type of epilepsy marked by prolonged seizures that begin in the first year of life. Up to 90% of cases are caused by variants of the SCN1A gene that leads to a deficiency in a protein channel that transports sodium, which is essential for generating electrical signals in nerves and muscles.

Consensus among healthcare providers on diagnosing and managing Dravet was established before the approval of three Dravet-specific treatments: Epidiolex (cannabidiol), Fintepla (fenfluramine), and Diacomit (stiripentol). Other disease-modifying therapies (DMTs) are in development.

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Researchers at the Mayo Clinic in Minnesota, in collaboration with the Dravet Syndrome Foundation, convened a worldwide panel of 31 physicians and caregivers with recognized expertise in Dravet to establish a new disease management consensus within the context of the therapeutic advances. Panel members rated the consensus statements.

Genetics testing

There was a strong consensus in favor of genetic testing for developmentally normal children, ages 2–15 months, who have a single prolonged hemiclonic seizure (one side of the body) or focal/generalized seizures with unknown cause after a fever or vaccination. There was a moderate consensus for genetic testing for other types of seizures.

In those with recurrent seizures of unknown origin, there was a strong consensus for genetic testing in children, ages 2–15 months, with focal/generalized seizures with or without fever, and in children 6–15 months with recurrent brief hemiclonic seizures without fever . A moderate consensus was established for infants 2–15 months with recurrent but brief hemiclonic seizures, with or without fever.

A strong consensus was also reached for SCN1A variants causing more than 85% of cases, for an initial brain MRI to show normal findings, and that an electroencephalogram (EEG) — a measure of brain electrical activity — is often normal before one year of age, but shows altered activity in most cases by age 5.

Development is considered normal before 18 months of age. However, that subtle developmental delays may be seen before that time reached a strong consensus among physicians, but a moderate agreement among caregivers. That intellectual disability is present by age 3 and becomes more apparent with time reached a strong consensus with all panel members.

Problems with attention being present in most children by school age also reached a strong consensus, as well as depression and anxiety being more prevalent with increasing age and present in most adult patients.

There was disagreement between caregivers and physicians regarding autistic features, with a strong consensus among caregivers that such features are present in most children. Physicians said most patients lacked autistic characteristics.

That difficulties with gait are seen in half of the school-aged children and most teens and young adults, and may resemble features of Parkinson’s disease in adulthood, reached a strong consensus among panelists as did sleep problems occurring in most persons. The best treatment for these problems were less clear, however.

A strong consensus was reached that families of those with Dravet must be counseled about the significant risk of sudden death in epilepsy at the time of diagnosis. The effectiveness of devices to detect seizures was rated 7 by caregivers and 6 by physicians on a scale of 1 to 9.

Split consensus on vaccines

Physicians reached a strong consensus regarding routine childhood vaccines, as well as COVID vaccination, whereas caregivers achieved a moderate agreement. A moderate consensus was attained for the annual influenza vaccine among all panelists, and medications to reduce vaccine-associated fever reached a strong consensus.

The panel identified the need for a knowledgeable adult provider when transitioning care to an adult caregiver, the importance of clear communication between pediatric and adult care providers, family education, and a comprehensive transition assessment document prepared by the pediatric provider.

Maximizing quality of life was an important goal of seizure control for patients and families along with limiting side effects from medications. Physicians had a strong consensus that controlling convulsive seizures should be a priority over nonconvulsive episodes because of their impact on quality of life. There was no consensus with caregivers. All panel members agreed that new therapies should be considered.

As an appropriate first-line treatment, the anticonvulsant medication Depacon (valproic acid) attained a strong consensus and Klonopin (clobazam) may be considered a first or second antiseizure medication. Other first-line therapies included Diacomit (physicians: moderate, caregivers: strong) and Fintepla (physicians: strong, caregivers: moderate).

Epidiolex as a first- or second-line treatment achieved a strong consensus among physicians only. There was strong consensus from physicians, but no consensus from caregivers against the use of non-pharmaceutical grade cannabidiol.

A moderate consensus was reached for the classic ketogenic diet for children 6 and younger, but a firm agreement for the modified Atkins diet for teens and adults.

There was a strong consensus that vagus nerve stimulation resulted in a less than 50% reduction in seizures, and should be tried after Depacon, Klonopin, Diacomit, and the ketogenic diet.

Consensus on DMTs

There was a universal consensus on recommending a safe DMT that provided greater seizure control than current therapies that reduce cognitive impairment and other comorbidities. In starting these DMTs as soon as possible, there was a moderate agreement among physicians but not with caregivers.

If the DMT was better than current therapies at reducing seizures, but not comorbidities, there was still consensus for a recommendation, which was strong with physicians and moderate with caregivers. There was no agreement about first-line use in these cases.

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In contrast, if a DMT improved cognition and co-existing conditions, but not seizures, there was still a consensus to recommend this therapy among physicians, while moderate with caregivers. Starting such medication as soon as possible reached an agreement among physicians only.

An agreement was achieved that the current frequency of seizures or degree of intellectual disability in children should impact the decision to prescribe DMTs. Moreover, if a DMT was effective and safe in clinical trials enrolling younger patients, there was a moderate consensus with physicians, but not with caregivers, to consider them for those too old for the trial.

Lastly, there was agreement across the panel that all people with Dravet need rescue medication at home.

“We believe that this International [Dravet syndrome] Consensus, informed by both experienced global caregivers and MD voices, provides a strong overview of the impact of [Dravet syndrome]therapeutic goals and optimal management strategies taking into account the recent therapeutic advances and evolving DMTs,” the researchers wrote.

“We hope these results will impact clinical practice by identifying who to screen and how to manage seizures and comorbidities to improve outcomes in persons with Dravet syndrome,” they said.

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