Foundational Work in Absence Epilepsy: Laying the Groundwork and Establishing the Gold-Standard

Commentary

Absence seizures are notoriously challenging for both medical providers and families/caregivers to identify based on visual features alone and persons with epilepsy (PWE) very rarely take note when a brief absence has occurred.^1,2 While the hallmark seizure of childhood absence epilepsy (CAE) associated with generalized 3-Hz spike and wave discharges on electroencephalogram (EEG), they can be seen in other generalized childhood epilepsy syndromes such as myoclonic absence epilepsy, juvenile absence epilepsy, and juvenile myoclonic epilepsy and often as atypical absence in Lennox-Gastaut syndrome. When there are other findings, such as myoclonus, clonic movements, automatisms, postural change, and autonomic features, absence seizures may be more readily suspected, however, given the usual brief duration, oftentimes subtle features, and the challenge of distinguishing absence seizures versus focal seizures with impaired consciousness or absence seizures from episodes of inattention or zoning out, video-EEG has remained the gold standard for diagnosis and classification of absence seizures.^1,3

The National Institute of Neurological Disorders and Stroke (NINDS) was established in 1950 and in its 75-year history has funded critical epilepsy research, which has laid the foundation of our understanding of absence epilepsy, prognostic features, and established the gold-standards for diagnosis and treatment of absence seizures. J. Kiffin Penry's tenure as Chief of the Epilepsy Branch, and subsequent NINDS-funded work, helped shape modern epilepsy care. Penry and colleagues set the stage for the modern use of video EEG monitoring,^3,4 which has remained critical for identification and quantification of absence seizures.

In their 1975 study, Penry et al. performed EEG recordings with simultaneous video monitoring in 48 patients, aged 4 to 24 years, recording 374 absence seizures. ³ Patients were included if they had demonstrated absence seizures witnessed by one of the authors and were not excluded on the basis of intelligence quotient, the co-occurrence of other seizure types, nor use of antiseizure medications. Only seizures with clinical accompaniment were included with clinical criteria based on prior classification by Gastaut as either simple or complex: 1. Mild clonic component; 2. Increased postural tone; 3. Reduction/loss of postural tone; 4. Automatisms; 5. Autonomic features; 6. Mixed features. ⁵ Their findings included that most patients had seizures 10 s or less in duration (85%), automatisms were commonly seen (88%) including being present in every seizure in 23% (11 patients), and mild clonic movements were seen in 71% of those studied (n = 34). Simple absences were seen in only 9.4% of the seizures. Individual patients tended to have seizures of similar duration and clinical features/classification (P < .01 and P < .02, respectively). This seminal work provided clear clinical classification of absence seizures and highlighted the necessity of simultaneous video and EEG recordings for true seizure classification, findings which carry forward to how we make clinical and electroclinical diagnosis of absence seizures today.

Another key NINDS-funded study by Sato, Dreifuss, and Penry focused on prognostic factors in absence epilepsy through a longitudinal, long-term prospective follow-up study. ⁶ Forty-eight patients were followed for an average of 6.9 years (5.8-8 years), with age at study onset of 5.3 to 24.3 years, with ultimately 27 patients becoming seizure free. In patients with only absence seizures, 78.3% (n = 18) of 23 patients were seizure-free compared to 31.8% (n = 7) of 22 patients had both absence and generalized tonic-clonic (GTC) seizures (P < .001). While not statistically significant, a shorter duration of epilepsy was more likely to be associated with seizure cessation, while subsequent onset of GTCs was more likely to be associated with continued seizures, regardless of age of onset of absence or GTC seizures. Other notable findings were that those with a normal neurologic examination were statistically more likely to outgrow absence seizures. EEG findings demonstrated that having an initial normal background for age, compared to diffuse slowing, was more likely to be associated with subsequent cessation of seizures (all types), being statistically significant for absence seizures cessation. On multivariate analysis, absent history of GTCs, IQ ≥ 90, and negative family history were significant factors for cessation of all seizure types, while IQ ≥ 90 and normal EEG background were significant factors for cessation of absence seizures. For those with 2 or 3 factors, approximately 90% were seizure-free at follow-up, compared to those without any significant factors who all continued to have seizures. For absence seizures, 87.5% (n = 14) with both and 72% (n = 18) with 1 factor were seizure-free, compared to only 1 patient without any significant factors. This work highlighted both long-term outcomes of absence epilepsy and prognostic factors associated with long-term seizure freedom, which continue to be relevant in day-to-day clinical decision-making and prognostication.

When it comes to treatment of absence seizures, the study of ethosuximide, valproic acid, and lamotrigine in CAE by Glauser and colleagues for the Childhood Absence Epilepsy Study Group sets the standard for care for children with CAE. ⁷ In this double-blind randomized controlled study, the efficacy, tolerability, and neuropsychological effects of ethosuximide, valproic acid, and lamotrigine were studied in newly diagnosed absence epilepsy with the primary outcome being seizure freedom (absence of treatment failure) after 16 weeks of treatment. This prospective trial, conducted at 32 U.S. sites, included 453 children, with a median age of 7 years 5 months, randomly assigned to 1 of 3 treatment arms. Treatment failure was defined as the presence of clinical or electrographic seizures in subjects receiving the highest allowable or maximally tolerated dose, with a week 20 visit for those with subsequent dose escalation. Connor's Continuous Performance Test was performed as well as pharmacokinetic analyses for those without seizures at weeks 16 or 20. Those without seizures continued to receive medication for an additional 2 years in a double-blind manner. At week 16 or 20, 209 children (47%) were free from treatment failure, with those on either ethosuximide or valproic acid with higher freedom from failure rates (53% and 50%, respectively) compared to lamotrigine (29%). Lack of seizure control in 24% and intolerable side effects and 22% were the most common reasons for treatment failure, with the lamotrigine group making up the majority of those with ongoing seizures. Regarding neuropsychological evaluation, Confidence Index results from the Connor's Continuous Performance Test in 316 subjects demonstrated that the valproic acid group had significantly worse scores at the week 16 and 20 visits than those in the ethosuximide and lamotrigine groups (P < .001 for both comparisons). In a subsequent analysis, the authors evaluated outcomes of the double-blind study at 12 months. ⁸ Their findings were similar to the previous study, with 12-month freedom-from-failure rates of 45% and 44% for ethosuximide and valproic acid, respectively, compared to lamotrigine (21%), with two-thirds of treatment failures due to lack of seizure control seen in patients in the lamotrigine group. Of the 115 subjects who discontinued the study due to adverse effects, 42% were in the valproic acid group, and performance (Confidence Index) continued to be worse in the valproic acid group compared to the other 2 treatments. This study provided strong evidence for the treatment of CAE demonstrating that ethosuximide is the treatment of choice over lamotrigine due to efficacy and over valproic acid due to side effects.

As has been demonstrated, the support of the NINDS in advancing epilepsy care has been immeasurable. These funded works have laid the foundation for how we evaluate and treat absence seizures and how we can provide as clear prognostication as possible for persons with absence epilepsy and their families. Without these pivotal studies and the strong support of the NINDS, how we care for PWE would be very different today.