Epilepsy Therapies Symposium | Do We Really “Outgrow” Seizures?

Abstract

Initiation and maintenance of antiseizure therapy can be relatively straightforward in most patients. Depending on epilepsy type, patients may be more or less likely to enter remission or a resolution of their epilepsy and the International League Against Epilepsy developed clinically guiding definitions in this regard. The mechanisms by which resolution or remission are achieved are poorly understood which complicates clinical decision making and risk estimate for future seizure relapse. The impetus for the maintenance of medical therapy in a seizure-free patient is also age-dependent. In children, one ought to consider the unknown effects of antiseizure medications on the developing brain while family planning, lifestyle, education, or employment are some of the issues that affect the decision making in adults. Patients who enter remission following surgical remediation of their epilepsy represent a distinct category and medication discontinuation is influenced by a number of factors. Another important consideration is comorbidities that often affect medication choices and maintenance. When formulating a management strategy, patient preferences together with careful evaluation and precise and accurate epilepsy diagnosis are key towards guiding medical or surgical management, prognostication for seizure freedom, relapse risk, options for medication discontinuation, and understanding risks and types of comorbidities.

Initiation and maintenance of antiseizure therapy can be relatively straightforward in most patients. Depending on epilepsy type, patients may be more or less likely to enter remission. Yet, medication discontinuation may be wrought with challenges. Is a drug discontinuation appropriate given the seizure or epilepsy type or the patient's circumstances? How does one counsel patients about the risks of seizure recurrence and long-term outcomes? Additionally, in patients with drug-resistant surgically managed epilepsy attainment of seizure freedom and its definition differs from patients without devices. Also, the management of functional events differs from protocols employed in epilepsy seizures. Comorbidities are yet another important consideration affecting medication choices and maintenance. This review aims to discuss these points in order to aid in the practical management of patients with epilepsy (PWE).

Remission in Childhood Epilepsies and Implications for Adulthood

Childhood epilepsy syndromes and their course have recently been redefined by the International League Against Epilepsy (ILAE) in acknowledgment of their heterogeneity and varied response to treatment over time. ¹ They range widely in severity and outcomes, from self-limited epilepsies to severe developmental epileptic encephalopathies. Many self-limited epilepsies were previously thought to be benign yet is now known that mild neuropsychiatric or cognitive comorbidities may coexist. ² Thus, while seizures tend to abate in children with Self-limited Infantile Epilepsy (SeLIE), other sequelae may linger. The ILAE suggests the use of resolved when a person with a specific age-dependent epilepsy syndrome is seizure-free beyond the upper limit of expected age, or a person with epilepsy has had no seizures for 10 years and has not been taking ASM for more than 5 years. The term remission is used when a patient has been seizure-free for 5 years. ³ The mechanisms by which resolution or remission are achieved are poorly understood. It is likely that developmental changes in differential gene expression render initially crucial faulty gene products inessential at a later time point. Another possible mechanism may be the changes in ion channel function during development. For instance, gamma-aminobutyric acid (GABA) changes from facilitating chloride efflux (excitatory) to influx (inhibitory) during the first year of life. ⁴ Many children with self-limited epilepsy will enter eventual remission and resolution and there is a concern about unknown possible adverse effects of antiseizure drugs on the developing brain. These factors prompted research on the impact of delayed treatment. One study evaluated 151 children without symptomatic, myoclonic, or absence epilepsy. Children were not treated until greater than 10 seizures or one episode of status epilepticus. Most (83/113) met the criteria to remain untreated before achieving three or more years of terminal remission. ⁵ Still, most children with epilepsy are treated following their second or third unprovoked seizure. Thus, the timing of antiseizure medication (ASM) withdrawal is a common question. Several key data may inform the decision to taper ASMs. A large meta-analysis of 1769 patients with epilepsy, including 1087 with childhood-onset epilepsy and 19% with self-limited syndrome developed a scoring nomogram for seizure recurrence risk. Those with self-limited syndrome were more likely to undergo a successful medication wean earlier in the epilepsy course. ⁶ While this tool can be applied even in patients lacking specific syndromic diagnosis, high diagnostic precision containing detailed epilepsy characteristics may improve prognostication accuracy. Also, treatment-related factors may influence remission risk in a selected syndrome. For example, ethosuximide seems to be associated with a greater remission rate in childhood absence epilepsy when compared to valproic acid. ⁷ Treatment timing appears to influence remission rates in infantile epileptic spasms syndrome, and using quality improvement methods may enable more rapid first-line therapy use.^8,9 Although childhood epilepsy resolves in nearly 2/3 of children, ¹⁰ comorbid learning disabilities, attention deficit disorder, and behavioral concerns may require prolonged treatment, and providers should evaluate, treat, monitor, and counsel about potential long-term consequences beyond the seizures.

Remission in Surgically Treated Patients With Drug-Resistant Epilepsy

Patients with drug-resistant focal epilepsy face difficult questions when contemplating surgical therapy, such as “will my seizures stop?,” “will I be able to wean off my anti-seizure medications?,” and “what can be done to improve surgery's odds of success?”

Despite an evolving landscape of epilepsy surgery with increasing adoption of Laser Interstitial Thermal Therapy (LITT) and responsive neurostimulation (RNS), ¹¹ there is no unified definition of “remission,” hindering meaningful statements on comparative effectiveness. Success after resective surgery is typically classified as complete seizure-freedom, with 55% rendered immediately seizure-free and never having any seizures up to 12 years posttemporal ¹² or posterior quadrant resection. ¹³ The same occurs in 44% of cases after frontal lobe surgery. ¹⁴ The mantra has therefore been that resections “work” half the time. Conversely, success after neuromodulation is measured by improved seizure-frequency or defined periods of seizure-freedom. Twenty-one percent of patients achieve a 6-month seizure-freedom period by 9 years after RNS implantation, with 35% having > 90% reduction in seizure-frequency. ¹⁵ When resective surgery is held to the same standards, its outcomes are far superior with 92% seizure-free for ≥ 12 months by 9 postoperative years, and 87% having > 90% reduction in seizure-frequency. ¹⁶ The half with “failed surgery” has a 75% reduction in seizure-frequency, ¹⁶ an outcome that significantly improves the quality of life, albeit not as dramatically as complete seizure-freedom. ¹⁷ Remission can be delayed for years after both RNS or resection.^15,16

Balancing the benefits and risks of ASM withdrawal after successful surgery is a challenge for patients, families, and providers. When seizures are controlled after surgery, withdrawing ASMs is attractive in children to avoid delayed brain development and behavioral consequences of long-term potentially unnecessary medications, and in women of childbearing age concerned about ASM teratogenicity. Yet, seizure-free adults who achieved independence after a lifetime of uncontrolled epilepsy, worry about the risks of losing driving privileges or disruptions to their education or career if seizures breakthrough with ASM withdrawal. Evidence to inform decision-making is scarce. The American Academy of Neurology declared in 2021 that there is insufficient evidence that the rate of seizure recurrence with ASM withdrawal following epilepsy surgery after 1 year of seizure freedom versus after 4 years is not significantly different than maintaining patients on ASMs. ¹⁸ The only prospective ASM withdrawal study was neither randomized nor powered for a robust observational design. ¹⁹ Only one observational study ²⁰ included a control arm (continued to take ASMs) finding that seizure control was typically regained after breakthrough seizures that followed complete ASM discontinuation but not those triggered by simply reducing medications. Reducing ASMs at 1 year versus 2 years or later after surgery had similar consequences, a conclusion shared by TimeToStop, ²¹ the one observational study focusing on the pediatric population. There is a clear unmet need for biomarkers that can reliably identify patients at risk for seizure recurrence with ASM withdrawal, and more importantly, those at risk for redeveloping drug-resistance should their seizures recur. Until then, nomograms^6,21–23 predicting individualized risks of seizure breakthrough can inform ASM withdrawal decisions.

The first nomogram in epilepsy was published in 2015. ²⁴ It predicted individualized odds of complete seizure-freedom and Engel I score using six clinical characteristics with modest accuracy (concordance index of 0.6). The later integration of scalp EEG ²⁵ and structural MRI findings ²⁶ improved model performance to a c-index of 0.72, and nomograms to predict naming, ²⁷ memory, ²⁸ and mood ²⁹ decline have been developed (c-index up to 0.81), informing both the odds of benefits and risks with surgery. Machine learning analyzing quantitative MRI measures ³⁰ and network EEG characteristics ³¹ can further enhance model performance. These advances improve outcome prediction. Outcome modification, however, demands a crisp understanding of the mechanisms driving surgical outcomes. Accurate localization is critical for surgical success, and extensive efforts focus on improving it through elegant imaging and electrophysiological analyses. While inaccurate localization likely accounts for uninterrupted epilepsy or early recurrence after surgery, it is unlikely to explain recurrences months or years later. A hypothesis of genetically driven epileptogenesis predisposing some patients for late recurrence is supported by data correlating delayed seizure recurrence with (a) differential gene expression in resected brain tissue from this patient population relative to a seizure-free control, ³² (b) specific single nucleotide polymorphisms in ABCB1 gene in brain tissue, ³³ and (c) potential circulating blood biomarkers (mRNA and miRNA). ³⁴ Further understanding of these mechanisms may identify yet unexplored opportunities to improve surgical outcomes.

Antiseizure Medication Discontinuation in Psychogenic Nonepileptic Event

Psychogenic nonepileptic events (PNEEs) are classified as a Functional Neurological Symptom Disorder in the DSM-5, ³⁵ and defined as a disease of abrupt paroxysmal change in behavior, consciousness, motor or sensation activity. The defining feature being that clinical semiology has no electrophysiological correlation with electroencephalogram (EEG) monitoring and is not an epilepsy syndrome. The incidence of this disease is reported to be 1.4 to 4.9 in 100 000 per year, with a prevalence of 2 to 33 in 100 000 with a female predominance. ³⁶ While not an epilepsy syndrome, these patients account for 5% to 10% of patients seen in epilepsy clinics and 20% to 40% of those evaluated in the epilepsy monitoring units (EMU). ³⁶ Common features of PNEE include a history of traumatic brain injury, depression, anxiety, and sexual or physical abuse or neglect. Antecedent trauma is identified in up to 80% of cases, although this is not required for the PNEE diagnosis.^36,37 Accurate diagnosis has an impact on prognosis and it is commonly delayed.^37,38 Features of PNEE include prolonged events that are nonstereotyped, variable, and fluctuating with out-of-phase or asynchronized, clonic activity and commonly with side-to-side movements, pelvic thrusting, and closed eyes during events. ³⁷ Urinary incontinence, occurrence out of sleep and injuries are less frequent although a reported lifetime prevalence of injury is estimated at around 24%. ³⁹ It is important to approach the evaluation of this disease critically and rule out alternative diagnoses with specific attention to frontal lobe epilepsy. ³⁷ Experienced physicians are reported to have low error rates in diagnosing PNEE based on the clinical semiology and EEG evaluation. ⁴⁰ ILEA Task Force has recommended video-EEG monitoring for documentation and classification of these events and induction techniques may aid in event capture. ³⁷ When communicating this diagnosis to the patient, it is recommended to use clear language that states this is an established diagnosis, alternative testing is not indicated, multidisciplinary care including mental health treatment is recommended and resolution of symptoms is achievable. ⁴¹ Resolution of events is variable with rates ranging from 17% to 80%. Predictors of response include shorter time to diagnosis while poor response is often seen in comorbid depression, personality disorder, and substance abuse. ⁴² In a prospective study of 99 EMU-documented PNEE patients, 25% had resolution at the time of diagnosis. ⁴³ Those with a resolution of events may still report low quality of life and high distress, and those with continued events often report confusion and lack of understanding of the diagnosis. ⁴⁴ Diagnostic delay leads to higher exposure to ASMs leading to side effects and inaccurate care in emergency room settings. ³⁸ Higher rates of remission are reported in those who discontinue ASMs at the time of diagnosis or while in the EMU.^45,46 Patients with dual diagnosis of epilepsy and PNEE represent a unique challenge. If PNEE can be confidently differentiated, patients are often able to decrease ASM burden and achieve improvement in PNEE. ⁴⁷ An initial randomized control trial of cognitive behavior therapy from the NEST-T Consortium, showed a significant reduction in monthly PNEE events in 59% of patients receiving a combination of CBT and sertraline versus 51% and 27% of cases receiving respectively CBT or sertraline alone and in 39% of subjects in the treatment-as-usual arm. ⁴⁸ Although this reduction was not seen in a larger randomized controlled study, the investigators report several secondary outcomes including less bothersome events, improved functioning, and treatment satisfaction. ⁴⁹ In summary, about 50% of PNEE patients with accurate diagnosis and early ASM discontinuation will achieve event remission. We need further research on effective interventions for those with continued events.

Seizure Recurrence and Long-Term Outcome After Discontinuation of Medications

Although withdrawal of ASMs following a period of seizure freedom is frequently performed, the long-term outcomes are less well understood. ASM withdrawal is common in the pediatric population, but there is more apprehension among adult patients because of the consequences of seizure recurrence. Most data regarding seizure freedom following ASM withdrawal are limited to 4 to 5 years and suggest one-third of patients will have seizure recurrence within that time. Long-term follow-up data, for example, more than 10 years, are uncommon and lack a control group for comparison. These series suggest a risk of late seizure recurrence of about 4% after 5 years. Of concern is also the possibility of not regaining seizure control following recurrence after ASM withdrawal. In several series, ∼ 20% of patients did not regain control of their epilepsy with the resumption of medications. In some surgical series, the probability of regaining control was reported as low as 45% to 63%. However, controlled studies did not show a difference in seizure control following recurrence in ASM withdrawn versus control patients, but the data was limited to 5 years. With the advent of electronic records, longer and more accurate long-term seizure information is needed to assess long-term outcomes following ASM withdrawal. In addition, patients withdrawn from ASMs need an enduring record of their seizures and a continuity of care should recurrence occur. In all, withdrawal of ASMs following seizure control may be successful and continued seizure freedom beyond 5 years is a strong predictor for ongoing seizure freedom.

When Seizures Remit but Comorbidities Remain

Epilepsy is more than just seizures and often features comorbidities before, during, and after active disease, which imposes a significant burden on patients and families. ⁵⁰ “Comorbidity” is a distinct additional clinical entity that exists during the clinical course of a patient's index disease. ⁵¹ It includes a heterogeneous group of conditions, such as cognitive, behavioral, and systemic, and the exact relational mechanism between them remains obscure. ⁵² Comorbidities can arise due to epilepsy, due to an unfortunate co-occurrence of two conditions, or result in a bidirectional relationship. The underlying mechanism of comorbidities in patients with epilepsy is related to a combination of shared biological mechanisms, substantial overlap in their genetic risk, or shared underlying etiologies. ⁵³ Genetic factors may lead to abnormal excitability and disrupted synaptic plasticity in early neurodevelopment, leading to the evolution of epilepsy and other comorbidities throughout the lifespan. ⁵⁴ Comorbidities have been grouped into categories according to the underlying pathophysiological mechanisms, including causative, reciprocal, mutual, resultant, and coincidental. ⁵¹ Psychiatric comorbidity exhibits a reciprocal or bidirectional relationship with epilepsy. For example, a psychiatric disease is associated with a higher risk of pharmaco-resistance and may worsen outcomes following anterior temporal lobectomy.^55,56

Resultant comorbidities occur as a consequence of epileptic seizures, antiseizure treatment, interictal epileptiform discharges, and epilepsy surgery. ⁵¹ Caplan et al have reported an increased incidence of psychiatric diagnoses in patients with Childhood Absence Epilepsy (CAE) and noted that CAE may affect linguistic ability, executive function, and social competence, especially in the setting of longer duration of disease, uncontrolled seizures and antiseizure treatment. ⁵⁷ Psychiatric comorbidities are strongly associated with worse long-term quality of life parameters in childhood-onset epilepsy; thus, even if seizures are remitted, screening and treatment for these and other conditions ought to be a part of comprehensive epilepsy care. ⁵⁸ A study evaluating cognitive dysfunction in Juvenile Myoclonic Epilepsy noted impairments in neuropsychological testing extending beyond attention and executive function and observed that there was a positive correlation between the duration of epilepsy and cognitive decline. ⁵⁹

Monjauze et al ⁶⁰ performed language assessment in subjects aged 6 to 35 years affected by active or remitted self-limited epilepsy with centrotemporal spikes (SeLECTS) and identified moderate to severe language impairments, especially in expressive grammar and literacy skills. These language deficits persisted despite EEG normalization. On the contrary, Kavros et al ⁶¹ evaluated children with SeLECTS and found impaired attention systems related to active centrotemporal spikes. Interestingly, the impairments seemed to resolve upon EEG normalization. Psychiatric conditions can have a more significant impact on QOL than epilepsy itself. Screening programs like the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) are essential for early identification and management of depression, which is frequently undetected and undertreated in people with epilepsy. Other comorbid psychiatric disorders, such as ADHD, can also contribute to worse cognitive performance and benefit from pharmacotherapy. ⁶²

In conclusion, careful evaluation and precise and accurate epilepsy diagnosis are key towards guiding medical or surgical management, prognostication for seizure freedom, relapse risk, options for medication discontinuation, and understanding risks and types of comorbidities. In the medical management of epilepsies, the old principle of aiming for seizure freedom with a minimum number of effective drugs holds true. This approach remains the most effective in minimizing side effects and improving the quality of life. While some comorbidities are unavoidable due to shared biological mechanisms, it is important to consider resultant comorbidities when contemplating management strategies. When medical therapy fails, epilepsy surgery ought to be discussed early to avoid adverse consequences of uncontrolled epilepsy on cognition, quality of life, and risk of early mortality. Surgery is often curative for epilepsy and alleviates comorbidities, behavioral disorders, and psychological functioning. ⁶³ While interventions can alleviate comorbidities, they do not mitigate the underlying pathophysiology. Hence, there is a drive to utilize a “genomic-first” approach to identify etiology and pathological mechanisms for both epilepsy and associated conditions. ²³ A better understanding of the shared pathologic mechanisms is likely to yield novel biomarkers, precision medication, or disease-modifying agents to improve outcomes.