Earlier Is Not Always Better: Outcomes When Epilepsy Occurs in Early Life Versus Adolescence.

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Commentary

As Child Neurologists, we often remind trainees that children, even adolescents, are not simply “small adults.” Pediatric patients have their own diseases, comorbidities, and outcomes. However, it is also important to remind ourselves that not all pediatric patients are the same, either. Infants and toddlers are not simply “smaller children.” Developmental outcomes, pharmacoresistance, and mortality vary greatly between children with epilepsy onset during adolescence compared to onset early in life. Two recently published articles remind us of this point.

Epilepsy, both focal and generalized, can occur at any time during childhood. Alsfouk et al recently examined the outcomes of teenagers with newly diagnosed epilepsy and came to the overall conclusion that these patients were likely to have good seizure control, good responsiveness to medication, low risk of sudden unexpected death in epilepsy or other seizure-related mortality, but were also at high risk for seizure relapse after treatment withdrawal. However, when Berg and colleagues reviewed outcomes of early life (onset < age 3 years) epilepsy, the results were remarkably different. Pharmacoresistance was common, mortality was higher, and it was concluded that early onset epilepsy, especially onset within the first year of life, is a high-risk situation until proven otherwise.

How can 2 studies on pediatric epilepsy outcomes arrive at such vastly different conclusions? Can age alone really be that much of a determining factor? If the same children had the same epilepsy, but onset occurred later, would the outcome be better? The answer is a simple “yes”…and “no.” In reality, the issue is far more complicated than just the immaturity of the pediatric brain. The differences are most likely due to a combination of factors, including electroclinical syndrome, etiology, as well as the effects of continuing seizures and medication on developing networks.

Electroclinical syndrome classification can be helpful in guiding physicians toward preferred treatments and recommended evaluations, as well as counseling families on expected outcomes and comorbidities. Syndromes with onset in adolescence include the generalized genetic epilepsy syndromes (juvenile myoclonic epilepsy, juvenile absence epilepsy, and epilepsy with generalized tonic-clonic seizures alone). These syndromes are well-characterized, with approximately 2/3 of patients enjoying seizure freedom, but less than 20% being able to remain seizure-free when medications were discontinued.[1] Indeed, 53% of Alsfouk’s cohort was classified as one of these 3 syndromes, with 72% of the patients with generalized epilepsy enjoying long-term seizure freedom. However, only 30% of all patients, focal or generalized, were able to remain seizure-free after withdrawing medications. By comparison, electroclinical syndromes that present in the first year of life include epileptic encephalopathies such as West syndrome, Ohtahara syndrome, Dravet syndrome, epilepsy of infancy with migrating focal seizures, myoclonic encephalopathy in nonprogressive disorders, and myoclonic epilepsy in infancy.[2] Like the generalized genetic epilepsy syndromes, these syndromes are also well-characterized, with the majority demonstrating high risk of medical intractability.[3] As expected, 35% of the infants in Berg’s study met criteria for pharmacoresistance within the year after epilepsy diagnosis, compared to 9% Alsfouk’s teenagers.

Etiology is also an important determining factor in epilepsy outcome. Abnormal neuroimaging is an independent risk factor for intractable epilepsy that occurs early and is enduring, as well as decreased remission.[3-5] In Alsfouk’s study of adolescents, epilepsy etiology was classified as structural in 12%. By comparison, structural etiology has been identified in up to 35% to 40% of children with early onset epilepsy.[2,3,6] Genetic variants are also an important etiological factor to consider. While genetic variants can cause epilepsy of variable clinical severity, they are also associated with early onset epilepsy and epileptic encephalopathies, such as Dravet and West syndromes.[2,6,7] Genetic testing in children with epilepsy onset prior to age 3 years has revealed pathogenic variants in up to 40%.[6]

Finally, we must consider how continuing seizures and chronic medication use affect growing and developing brains. When children with epilepsy onset prior to age 3 years underwent formal neuropsychometric testing, age at epilepsy onset was found to be the single most reliable predictor of developmental outcome, with earlier age of onset being associated with lower developmental quotient.[8] There was no correlation between developmental outcome and underlying pathology, suggesting the developmental decline was related to the epilepsy and seizures, rather than the underlying cause.[8] Continued seizures as a cause of development decline is supported by the observation by Berg that lower full scale IQ (FSIQ < 80) was correlated with younger age of epilepsy onset only in the children with ongoing seizures due to pharmacoresistance.[9] In addition, children who undergo surgical resection for epilepsy demonstrate improvements in neuropsychological functioning, even though one would expect some degree cognitive decline following a resection.[10] Furthermore, while continued seizures can have a detrimental effect, and the use of antiseizure medications (ASMs) are an essential part of treating seizures, these medications are not benign. Boshuisen has demonstrated that withdrawing ASMs after epilepsy surgery was associated with increased IQ, even when controlled for confounders, such as age at epilepsy surgery and preoperative IQ score.[11]

In summary, there are significant differences in epilepsy outcomes and comorbidities, depending on age of onset due to multiple factors. Does this mean we take a defeatist’s approach to early onset epilepsies and accept the likelihood of pharmacoresistance and developmental disabilities? No! Does this mean we view adolescent onset epilepsy as “easy” and “uncomplicated?” Certainly not! It is important to recognize these populations as different, understand the epilepsy syndromes that occur in these age groups, so that we can apply this information to use the best treatments possible, screen for known comorbidities, and provide appropriate counseling to patients and families.