Researchers Work to Better Predict Worse Cognitive Outcomes in Dravet

Ana Pena, PhD avatar

by Ana Pena, PhD |

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Researchers have identified two significant factors that can help predict cognitive outcomes in Dravet syndrome patients: Longer  treatment with antiepileptics that block sodium channelsand being younger when the first afebrile seizure occurs.

The study “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” was published in the journal Epilepsia.

Very little is known about the factors that can predict or influence progression or severity of Dravet syndrome. The types and timing of seizures experienced by individuals with Dravet may change over time and the severity of developmental delays varies.

Accurately predicting outcomes for those with mutations in the sodium channel SCN1A — the genetic cause of most Dravet syndrome cases — is still not possible, making it essential to identify more accurate biomarkers to improve prognosis of this disease.

To find clinical features that can help predict the evolution of seizures into Dravet syndrome and  outcomes, researchers investigated the influence of so-called contraindicated medications — antiepileptics that act as sodium channel blockers — on cognitive decline of Dravet patients.

These types of antiepileptics act by reducing sodium entry inside neurons, decreasing the nerve cells’ excitability.

Although there have been reports showing that sodium channel blockers can aggravate the number and severity of seizures in patients with Dravet, the effects of taking these medications never have been validated in a large sample of patients. Despite that, a large segment of patients with Dravet syndrome — between 21 and 100 percent — continue to be prescribed these medicines, often before they even obtain a diagnosis of Dravet.

The Dutch researchers designed a retrospective study comparing potential predictors of clinical outcome between individuals with SCN1A mutations who developed Dravet syndrome and those with SCN1A mutations that did not.

A total of 164 participants were included; they all had confirmed disease-causing SCN1A mutations and were referred to the University Medical Center Utrecht in the Netherlands.

Participants were categorized into two groups: 116 patients with Dravet syndrome and 48 patients with non–Dravet syndrome, including patients with generalized epilepsy with febrile seizure plus (GEFS+) or febrile seizures.

Cognitive function at the time of inclusion was evaluated by a team of expert physicians, based on intelligence and developmental quotients, performance at school, communication and adaptive behavior.

For each patient, the total number of months of use of sodium channel blockers was determined. The list included lamotrigine, phenytoin, carbamazepine oxcarbazepine and vigabatrin.

Nearly half (45%) of Dravet syndrome patients had a cognitive impairment considered “severe or profound,” which was in striking contrast with almost all non-Dravet patients who had normal cognitive capacities (90%).

The large majority of patients with Dravet had taken sodium channel blockers (86%) for a median cumulative duration of 11 months, during the first five years after seizures started.

Several differences were significantly associated with Dravet syndrome patients, compared to the non-Dravet group: Younger age of seizure onset (median 5 versus 12 months); higher frequency of secondary types of seizures before the first year of age (59% versus 6%), and; increased chances of having been admitted to an intensive care unit (47% versus 12%).

From all factors, the best predictor of Dravet syndrome development was the age of the first afebrile seizure, particularly if it occurred within the first two years of life.

Ninety-five percent of Dravet patients had their first afebrile seizure before the age of 2, compared to 29 percent of non-Dravet patients. In fact, a considerable proportion of non-Dravet patients (36%) had never had an afebrile seizure, a circumstance never observed in studies of Dravet patients. 

Age at the first afebrile seizure was shown to be a better predictor than age at seizure onset, which previously had been considered the most relevant factor associated with Dravet syndrome.

Also, most Dravet patients carried SCN1A gene mutations resulting in incomplete or strongly altered SCN1A protein, whereas non-Dravet contained point mutations were less likely to trigger severe defects in the SCN1A protein.

Overall, the analysis indicated that the best predictors of the worse cognitive outcomes were age at first observation of developmental delay, age at first afebrile seizure, and duration of treatment with sodium channel blockers.

The longer this type of medication was used, the higher the probability of a worse cognitive outcome and more severe cognitive decline in the first five years after disease started.

Researchers cautioned that although the use of contraindicated medication is not the sole responsibility for cognitive decline in Dravet patients, it is still an important factor to consider.

“We specifically observed the largest effect of CIM [contraindicated medication] use in the second year of disease, indicating that the developing brain might be particularly sensitive to CIM during this time frame. This finding emphasizes the importance of an early diagnosis and correct clinical management as soon as possible in the disease course,” researchers wrote.

Moreover, prospective studies, looking at adults with Dravet should be undertaken to understand if continued treatment with sodium channel blockers results in continued cognitive deterioration.

“We furthermore identified age at first afebrile seizure as an important predictor for evolution of seizures into Dravet syndrome, as well as for the severity of Dravet syndrome, which can be used to counsel parents of young patients with SCN1A-related seizures,” the researchers concluded.