Genetic Testing in Epilepsy Helps Inform Patient Management

A genetic diagnosis of epilepsy frequently led to changes in clinical management and improved outcomes in patients of all ages, a retrospective cross-sectional study showed.

Changes in clinical management followed a genetic diagnosis for half (208 of 418), typically within 3 months of clinicians' receipt of the result (81.7%), reported researchers led by Dianalee McKnight, PhD, of Invitae, the San Francisco laboratory that performed the genetic testing.

These changes included the addition of a new medication (21.7%), initiation of medication (14.2%), referral of a patient to a specialist (13.4%), vigilance for subclinical or extra-neurological disease features (12.8%), and discontinuing a medication (11.7%).

Of 167 patients with follow-up clinical information available a mean 584 days after diagnosis, three-quarters had positive outcomes reported in the JAMA Neurology paper, including reduction or elimination of seizures (64.7%), decreased severity of other clinical signs (22.2%) and reduced medication adverse effects (6.6%).

"Our findings address a longstanding question about the clinical benefits of genetic testing for epilepsy," McKnight and coauthors of the ELEVIATE Consortium suggested, noting the current paucity of genetic testing recommendations for individuals with epilepsy.

"The data from our study suggest the development of recommendations related to the use of genetic testing in the clinical evaluation of all individuals with epilepsy to potentially guide clinical decision-making, improve patient outcomes, and save health care dollars," they wrote.

Genetic etiologies account for seizures in up to 40% of children and 23% of adults with epilepsy, the group wrote. Previous studies suggested that genetic diagnosis helps guide clinical treatment for anywhere from 20% to 60% of patients.

In an accompanying editorial, Joseph E. Sullivan, MD, of the University of California San Francisco, wrote: "We are on the brink of a new era of epilepsy treatment that goes beyond symptom management by simply trying to reduce seizures with antiseizure medications based on semiology and rather aspire to have a more targeted treatment approach based on underlying mechanisms that will only be possible with a precise genetic characterization regardless of age."

The study included 418 patients from infancy to 52 years of age (53.8% female) who had been referred for multigene panel testing between 2016 and 2020 through the Invitae commercial genetic testing laboratory. Median age at the time of testing was 4 years with an interquartile range of 1-10 years. About 90% presented with seizure onset and were clinically diagnosed in infancy.

"Even if testing has not been done early, it should never be considered too late," Sullivan noted.

While only 12 adults were included in the study, 29% of them had a reduction in seizures when a clinical change was made, which "highlights the importance of confirming a genetic etiology in patients of any age," Sullivan wrote. He urged more testing in larger cohorts of patients and clinicians to provide as much detailed clinical phenotype and outcome data as possible.

McKnight and colleagues assessed clinical management changes after a genetic diagnosis, defined by at least one pathogenic or likely pathogenic (P/LP) variant in autosomal dominant and X-linked diseases or two P/LP variants in autosomal recessive diseases. Subsequent patient outcomes were reported by healthcare professionals on case report forms at a mean 1.6 years after testing (range 27-1,673 days).

A small proportion of patients had worsening of outcomes such as a decline in their condition (12.0%), increased seizure frequency (3.6%), and adverse medication effects (1.8%).

In 178 patients (43%), clinical management remained unchanged. Reasons given included that the patient's current management plan already reflected recommendations associated with the test result (48.3%), that the test finding did not inform clinical management at that time (25.2%), and that it may be used prognostically to inform future treatment decisions (19.1%).

"Strikingly, these reasons account for more than 90% of patients without changes to their clinical management, suggesting that the genetic diagnoses were still informative," authors noted. They pointed out that "beyond informing diagnoses and improving clinical management, genetic testing can clarify diagnostic uncertainty."

In U.K. data, first-line use has been shown to decrease time to diagnosis by 98% and decrease health care costs by 70%. "Well-controlled seizures result in reduced average annual overall health care costs for all types of seizures ($23,238 in 2007 to $13,839 in 2009) and improved quality of life compared with uncontrolled seizures," McKnight's group noted, citing previous studies.

Limitations noted by authors included possible ascertainment bias and limited follow-up data on for some patients due to the time between genetic testing and case report form completion.

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