Dravet Study Links Early Use of Sodium Channel Blockers, Worse Cognitive Function

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Sodium channel blockers

Long-term use of sodium channel blockers in the first five years of disease has been linked to poorer cognitive function in Dravet syndrome patients.

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.

Mutations in the SCN1A gene are the main underlying cause of Dravet syndrome. This gene provides instructions for making one part (the alpha subunit) of a sodium channel. These channels, primarily found in the brain, control the flow of sodium ions into cells.

Variants in SCN1A can result in variable disease severities and other disease phenotypes, including genetic epilepsy with febrile seizures plus (GEFS+) syndrome and febrile seizures.

A large phenotypic variability exists among Dravet syndrome patients: Some are severely disabled and experience ongoing seizures; others live more independent lives.

“Parents often experience great uncertainty about the prognosis of their children when a pathogenic SCN1A variant is found early in life, because accurate prediction of the consequences of an SCN1A variant is still not possible, and different SCN1A‐related phenotypes may be indistinguishable at their first presentation,” the authors wrote.

There is a critical need to identify more accurate disease predictors.

The team analyzed 164 Dutch participants with mutations in the SCN1A gene. Of these, 116 were diagnosed with Dravet syndrome (with a median age of 14), and 48 with non-Dravet syndrome (a median age of 22). The goal was to identify clinical symptoms that could help predict the evolution of seizures and cognitive outcomes for Dravet syndrome specifically.

In 104 Dravet syndrome patients, seizure onset was at least five years prior to cognitive assessment.

Non-Dravet syndrome patients were diagnosed with either GEFS+ or with febrile seizures.

The team evaluated the effects of contraindicated medication on cognitive function of Dravet syndrome patients when administered in the first five years of disease.

Not all common antiepileptic medicines are suitable for Dravet syndrome patients, and some should be avoided because they can make the symptoms worse.

Contraindicated medication evaluated included sodium channel blockers lamotrigine (brand name Lamictal), phenytoin (brand name Dilantin, among others), carbamazepine (Tegretol), oxcarbazepine (Trileptal) and vigabatrin (Sabril).

Additional clinical parameters evaluated included age for seizure onset; first signs of developmental delay and first afebrile seizure; whether the patient had ever been admitted to an ICU; and the type of secondary seizures.

Cognitive function was evaluated at the moment of enrollment as a five-point scale: A score of 1 meant no intellectual disability, and 5 meant severe intellectual disability. Forty-five percent of Dravet syndrome patients scored a 5, while the majority of non-Dravet patients (90%) scored a 1.

The results showed that longer treatment with contraindicated medication (CIM) during the first five years after seizure onset was significantly associated with a worse cognitive outcome at the time of inclusion, including lower intelligence and developmental scores.

Predicators of worse cognitive outcomes included the duration of contraindicated medication use, the age at first observation of developmental delay, and the age at first afebrile seizure. The latter was the most accurate predictor for the evolution of seizures in all Dravet syndrome patients.

“[O]ur data suggest that a longer use [of contraindicated medicine] in the first 5 years of disease can have negative effects on cognitive outcome in Dravet syndrome. An early diagnosis is essential to avoid these drugs,” researchers said.

These results confirm other studies in which sodium channel blockers such as lamotrigine and carbamazepine were linked to more frequent or severe seizures in Dravet syndrome patients. They also support how early diagnosis and appropriate treatments can improve long-term cognitive outcomes.

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