It’s About Time! Timing in Epilepsy Evaluation and Treatment

Abstract

The 2023 American Epilepsy Society Annual Course “It’s About Time” addressed timing in epilepsy evaluation and treatment with respect to health disparity and vulnerable populations and diagnostic, clinical, and epilepsy surgery evaluation. This comprehensive course included topics on gaps in epilepsy care and optimization of behavioral health for patients with epilepsy. The summary details current knowledge in areas of seizure forecasting and epileptogenesis. Intricacies and controversies over timing were discussed for treatment of nonconvulsive seizures and ictal-interictal patterns, acute symptomatic seizures, neuromodulation versus surgery, and epilepsy surgery in status epilepticus. Timing regarding clinical care in autoimmune-associated epilepsy, developmental and epileptic encephalopathy, and dietary therapy were examined. Additionally, salient topics on using novel biomarkers and collaboration with neuropsychological outcomes were also tackled in this all-encompassing lecture series.

Introduction

Timing is a critical factor in medicine and particularly significant in epilepsy care. Clinicians base timing of care or interventions on evidence-based medicine, allowing accurate treatment decisions and improving overall outcomes. The fundamental dichotomy between “treat too soon,” resulting in early unnecessary intervention, and “treat too late,” causing avoidable treatment delays, is essential to deliver precise, individualized care. This review explores this balance and attempts to eliminate tension that may arise when approaching timing in different aspects of epilepsy.

The Big Picture: Time to Fill Fundamental Gaps in Epilepsy Care

Before delving into the timing challenges in specific diagnostic and therapeutic considerations, we acknowledge fundamental imparities that span all epilepsy care. Addressing these gaps is a prerequisite to creating an impact at scale and improving the epilepsy population at large.

1. Disparities on Timing of Treatment and Gaps in Epilepsy Care

Disparities are preventable differences in the burden of disease, injury, violence, or opportunities to achieve optimal health that are experienced by socially disadvantaged populations. There is evidence that in North America minorities with epilepsy may be receiving lower levels of care. ¹ Black and Hispanic people with epilepsy are less likely to have access to specialized care and there is a suggestion that African Americans have lower rates of epilepsy surgery. However, there is an urgent need to increase research about disparities.

Globally, socioeconomic status is an important factor driving epilepsy care. Availability of anti-seizure medications (ASMs) is different across countries based on World Bank income classification. Low-income countries have limited access to basic medications and a low number of child neurologists. This is due to the scarcity of child neurology training programs. ² Projects to support primary care providers and child neurologists working in poor resource regions are important to improve epilepsy care locally.

Significant deficiencies, delays and reduced access to epilepsy care have been identified. These deficits and deficiencies are compounded by historical societal disparities and social determinants of health. Persons with federal insurance, rural dwellers, and persons of color are less likely to see a specialist and less likely to receive timely medical and surgical care. ³ The Institute of Medicine’s report on epilepsy, supported by the American Epilepsy Society and Epilepsy Leadership Council, and the World Health Organization Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders, ⁴ have made recommendations and have set goals to address many of these concerns. Unfortunately, resolution extends beyond the patient, with researchers and providers from underserved populations also facing challenges.

2. Gaps in Behavioral Health in Persons With Epilepsy

Behavioral health encompasses mental health, substance use, life stressors, health behaviors (ie, self-management), and resilience and well-being. Behavioral health concerns are common in persons with epilepsy (PWE) ⁵ ; many PWE rate these concerns as more burdensome than seizures. Studies have shown that addressing behavioral health comorbidities can reduce seizure burden and improve quality of life. Despite this evidence, a majority of PWE with behavioral health concerns continue to have unmet behavioral health needs.

Integrated behavioral health care provides a feasible solution for addressing this important clinical practice gap. While epilepsy clinics have wide variability in available resources, a behavioral health screening protocol can be adapted for each setting, provided it considers (1) the targeted population (high risk, new patients), (2) personnel (clinic nurse, behavioral health), (3) method (survey, waiting room), and (4) next steps in care (documentation, positive screen). Clarifying roles and responsibilities and establishing ongoing training models for providers is critical. ⁶

Time Is Brain: Timing in Diagnostic Evaluation, Clinical Care, and Epilepsy Surgery

Early and proper treatment is the mainstay of medicine. Timing in diagnostic evaluation, clinical care, and epilepsy surgery is explored from different aspects in this section. It details critical known aspects of timing prior to seizure formation, including seizure forecasting and epileptogenesis, and examines difficult scenarios in treatment regarding nonconvulsive and ictal-interictal patterns, acute symptomatic seizures (ASyS), epilepsy surgery versus device decisions, and epilepsy surgery with status epilepticus. Broader aspects of epilepsy care that emphasize the significance of timing are summarized, including autoimmune-associated epilepsy, developmental and epileptic encephalopathy, and dietary therapy. Timing in surgical aspects of epilepsy is also addressed in areas involving novel biomarkers and neuropsychological testing. Join me in examining the art of timing for comprehensive epilepsy care.

1. Timing Prior to Seizure Formation

It is time to Predict forecast seizures

The advent of digital EEG and inexpensive computing sparked efforts to predict seizures from EEG. In the 1990s, apparent success predicting seizures was undermined when prediction algorithms did not perform well with novel EEG data due to informational biases used in algorithm training. The 2013 “NeuroVista” study, a prospective trial of seizure prediction in 15 subjects with chronic electrocorticography resuscitated efforts, demonstrating feasibility predicting “high” or “low” risk seizure days. ⁷

Recent studies have shown that seizure risk varies periodically in cycles, ranging from hours to months. This leads to a concept of “seizure forecasting” that emphasizes probabilities of seizure occurrence, rather than prediction when a seizure will begin. Seizure risk cycles are also linked to physiological cycles, for example, EEG spiking rate or heart rate. Tracking seizure cycles and linked physiological markers offer new tools to alert individuals when they are at highest or lowest risk of seizures. ⁸

Before the seizures start: Epileptogenesis and its impact on timing of treatment

Tuberous sclerosis complex

The double-blind placebo controlled PREVeNT trial showed that vigabatrin preventative treatment delayed and reduced the prevalence of infantile spasms (IS) in tuberous sclerosis complex (TSC) infants, similar to EPISTOP results, but this was not the primary driver of the developmental outcomes. ^9,10 There were no added benefits of preventative treatment with vigabatrin in terms of cognitive outcomes at 24 months of age. It confirmed the utility of serial EEGs in identifying the EEG Biomarker as a moderately strong predictor of impending seizures.

The presence of IS remains a notable factor and likely indicates an infant has a significant tuber burden and is at risk for focal seizures and neurodevelopmental delays. This study showed that focal seizures can precede, coexist or follow IS and is the next therapeutic challenge. ⁹ Clinical practice is changing because of TSC prenatal diagnosis, genetic testing, and pediatric neurology referral prior to seizure onset. Rapid recognition and diagnosis of TSC remains central to the care and management of TSC infants, especially those with IS.

Traumatic brain injury

Advances have been made over the past 10 years in understanding traumatic brain injury (TBI) and the pathophysiology of post traumatic epilepsy. However, knowledge gaps remain and only with collaborative efforts will we unravel the pathophysiology and develop new therapeutics and interventions for TBI.

2. Timing in Difficult Clinical or Surgical Scenarios

Timing in critical care: Do we treat nonconvulsive seizures or ictal-interictal patterns?

Therapeutic approaches to patients with nonconvulsive seizures or ictal-interictal continuum (IIC), who are often critically ill, must be individualized.

To treat

Ictal-interictal continuum and electrographic seizures complicate around 30% of hospitalized patients with altered mental status. ¹¹ Studies show a correlation between seizure burden/IIC patterns and poor neurological outcome. ¹² Clinical studies have also found local metabolic distress associated with IIC patterns via FDG-PET, ¹³ oxygen probe, and microdialysis ¹⁴ leading to the metabolic-mismatch hypothesis summarized as seizure/IIC patterns which can outmatch blood supply and oxygenation and lead to secondary brain injury. Although it remains unclear the specific EEG parameters and patient factors that should guide treatment. That is what is the individual patient threshold of seizure or IIC burden at which point more aggressive treatment either via ASMs or IV anesthetics worsens outcomes. A recent study that highlights this uncertainty is the TELSTAR trial. In these post-cardiac arrest patients, it was found that treatment of generalized periodic discharges did not improve outcomes but suggested that treating evolving and rhythmic pattern did. ¹⁵

Not to treat

Inconsistent evidence links seizures or certain patterns to markers of neuronal injury and overall outcomes. However, no clinical trials have demonstrated an unequivocal association of indiscriminate suppression of electrographic hyperexcitable patterns with improvement in outcomes to date. Reasons for this lack of definitive evidence in favor of treating such patterns are manifold. Nonconvulsive seizures and patterns falling on the IIC can be refractory, often requiring escalation to anti-seizure polypharmacy which can lead to significant compounding of side effects and negative impact on outcomes, particularly if escalated to therapeutic coma with anesthetics. ¹⁶ Moreover, the underlying mechanism driving hyperexcitability must be considered, such as inflammation, drug-effect, ischemia-triggered, all of which are less responsive to ASMs than interventions that directly target such mechanisms. ¹⁷

Acute symptomatic seizures: Discontinue or continue treatment?

The current concept of ASyS as “seizures that occur in close temporal relationship with an acute CNS insult” is a troubled one. The first problem is heterogeneity, as the current definition brings together provoked seizures with virtually no recurrence risk and high-risk situations, such as stroke, brain trauma or infections under one umbrella concept. The second problem is timing: What is “close temporal relationship”? One week for acute posttraumatic seizures, 1 or 2 weeks for acute post-stroke seizures, and how long for post-inflammatory or post-infectious etiology? There is currently neither a clear concept nor solid data for these time frames. The third problem is the clinically relevant issue of treatment.

Discontinue treatment

There is consensus and good evidence that early treatment with ASM can reduce recurrence of ASyS, but there is no evidence that long-term ASM treatment can reduce the risk of epilepsy. ¹⁸ Moreover, prolonged treatment with ASM interferes significantly with neurorecovery and significantly worsens neurorehabilitation outcomes. ¹⁹ Therefore, ASM should be withdrawn as soon as possible and patients with a higher risk of unprovoked seizures should be monitored closely. Clinical trials of antiepileptogenesis are ongoing and they may represent the dawn of a new era. ²⁰

Continue treatment

Reducing seizure recurrence risk by addressing the underlying cause is appealing. Yet some etiologies may not be entirely reversible, with gliosis and hemosiderin deposition potentially persisting. After an ASyS, there is a significant risk of subsequent seizures, ²¹ especially within 1 month after ASyS, potentially increasing rehospitalization during the crucial neurorecovery period. Initiation and continuation of ASM in unprovoked seizure patients lowers recurrence over 2 years, particularly for those with multiple seizures at presentation. ²² This aligns with electrographic ASyS, where single electrographic seizures are rare on continuous EEG monitoring. Moreover, ASyS is associated with a significantly higher risk of 30-day mortality compared to first unprovoked seizures. ²¹ Patients exhibiting specific EEG findings associated with high seizure risk ²³ might benefit from post-hospitalization ASM management. Studies on prolonged ASMs and patient-related outcomes measures (PROM) typically involved all but not exclusively ASyS patients, used older ASMs, and omitted EEG stratification. ²⁴ However, recent research focusing exclusively on ASyS patients using newer ASMs indicates no differences in PROM when continuing ASM posthospital discharge. ²⁵

Neuromodulate or resect: Which comes first?

Over the past 2 decades, there has been significant evolution in surgical options for patients with drug-resistant epilepsy. Standardized resections and disconnections have developed into nuanced, individualized resections often guided by invasive intracranial recordings. In recent times, there has been a shift toward minimally invasive ablative strategies. The evolution of neuromodulation has been similarly dramatic with a progression from vagal nerve stimulation (VNS) to thalamic deep brain stimulation (DBS) and most recently responsive neurostimulation (RNS). The proliferation of choices in the surgeon’s toolkit inevitably sparks debate on the optimal sequencing of treatment strategies. Such decisions hinge on considerations encompassing the patient’s aspirations and surgical experience and expertise at a particular center.

There are scenarios where resection emerges as the optimal first choice, instances where neuromodulation stands as the best initial option, and situations marked by genuine equipoise, where surgical expertise and the ability to provide state of the art interventions should dictate decision-making.

Neuromodulate first

The impact of neuromodulation in clinical care is relevant since it is the ideal epilepsy surgery: it is non-lesional, reversible, and modifiable. It is minimally invasive and improves neurologic function. Neuromodulation is the electric stimulation of a neural target that is used to stop abnormal epileptic activity. Currently, the question is which target and parameters to choose. All stimulation sites either block seizure propagation (used for primary generalized seizures, multiple epileptic foci) or block seizure generation; this option needs to have a precise focus location (hippocampal stimulation, primary motor cortex or supplementary motor cortex foci). Studies suggest that electrical neuromodulation works by stopping after-discharge development and increasing its threshold in kindled rats. Stopping seizure generation takes up to 6 months to show maximum seizure reduction. While hippocampal focus stimulation takes 1 to 3 months to show its major impact, motor cortex seizures focus has a 1-week period. Patients show improvement of their neurological development and quality of life scales.

Resect first

The prevailing evidence base, therapeutic efficacy, and economic implications, all strongly favor the use of resective or ablative techniques wherever possible.

Is there a time for surgery with status epilepticus?

The high morbidity and mortality of super refractory status epilepticus (SRSE) highlights the need for effective treatment options. When resective surgery is an option in this setting, the benefits clearly outweigh the risks in most instances. The etiology and the type of surgery in 35 pediatric cases from 3 series showed a pattern similar to other pediatric series with chronic epilepsy; resective surgery stopped SRSE in all patients. ²⁶ The etiology in adult series, on the contrary, was heterogenous and was different from other adult series with chronic epilepsy. ²⁷ Semiology, preexisting deficits, video EEG, and MRI serve as the major tools guiding surgery; nearly all patients had intraoperative electrocorticogram during surgery further guiding the surgical strategy. Neuromodulation methods, such as VNS, RNS, and DBS are viable options in the setting of status epilepticus, with a cautious acknowledgment of the complexity in interpreting outcomes in the current literature. ²⁸

3. Timing in Broader Aspects of Epilepsy Care

Autoimmune-associated epilepsy and seizures: Tips for avoiding delays

Timeliness of diagnosis and treatment is essential in certain autoimmune encephalitides, in which seizures are common. Delays can result in chronic epilepsy and other neurologic deficits. The autoimmune-associated seizure disorders most likely to respond to immunotherapy are those due to antibodies targeting cell surface or synaptic epitopes (eg, LGI1, NMDAR encephalitis). Those due to cytotoxic T-cell mediated inflammation (eg, Rasmussen, paraneoplastic) are less responsive.

Unique clinical features may aid diagnosis. These include brevity (<20 seconds) and high frequency (multiple daily) seizures, and faciobrachial dystonic seizures in LGI1, and psychosis, temporal and extratemporal seizures, dysautonomia, dyskinesias in NMDAR. EEG may be normal in LGI1, and often shows generalized rhythmic delta in NMDAR. ²⁹

Causes for delay include failure to recognize clinical features, omitting CSF, misdiagnosis (eg, anxiety, functional, psychosis, cerebrovascular), normal EEG and MRI, poor neurology access, and rarity. ³⁰

Developmental and epileptic encephalopathy: Timing of treatment to deliver the greatest cognitive and behavioral impact

In epileptic encephalopathies, the epileptiform activity itself contributes to the severe cognitive and behavioral impairment beyond what is expected from the underlying etiology. The resolution of the epileptiform activity will improve the cognitive and behavioral concerns. However, especially as knowledge of genetic epilepsies grew, it became increasingly clear that the underlying pathology was often just as important as the epileptiform activity for developmental and behavioral outcomes. In 2016/2017, the International League Against Epilepsy (ILAE) suggested new terminology, developmental and epileptic encephalopathies (DEEs), to address these situations. ³¹ Many genetic epilepsies, such as Dravet syndrome, are examples of DEEs.

For DEEs, to maximize cognitive and behavioral outcomes, both the seizures and underlying pathology should be addressed immediately when possible. Example of DEEs in which treatment is available for the underlying pathology include pyridoxine dependent seizures and Glut-1-deficiency. For Dravet syndrome, no approved disease modifying therapy exists. However, gene and gene regulation studies are being examined as possible future treatment for Dravet syndrome as well as other genetic epilepsies.

Optimal timing and delivery of dietary therapy in epilepsy

Ketogenic diet therapy (KDT) should be considered when patients are diagnosed with drug-resistant epilepsy, but potential surgical candidates should be offered appropriate evaluation. ^32,33 For certain epilepsy syndromes, KDT initiation should be considered even earlier. Interested patients should receive counselling on expectations and barriers to treatment and nutritional assessment that includes anthropometric measures and diet intake history. The classic ketogenic diet is recommended in children under 2 years of age and the modified Atkins diet is often selected in adolescents and adults. However, the specific KDT chosen, and method of initiation should be individualized to each patient. While initiation and monitoring of KDT has typically been in person, recent studies suggest virtual platforms as a viable option. Discontinue KDT using a gradual taper after 3 months if unsuccessful. For cases with benefit, KDT is discontinued at 2 years in most children, but duration is dependent on treatment response in adults.

4. Time—The Modifiable Factor in Epilepsy Surgery

The treatment aim for epilepsy patients is to achieve seizure freedom as soon as possible and with minimum side effects or functional deficit. In selected patients with medically intractable epilepsy, we know epilepsy surgery can be safe and effective. In this context timing matters as:

Short epilepsy duration is associated with improved seizure outcome and quality of life after epilepsy surgery

Mortality rates are highest in patients with uncontrolled seizures

Despite clear practice parameters, survey studies suggest presurgical evaluation may take 12 to 20 years from seizure onset. The main barriers identified are (1) gaps in knowledge, (2) inadequate social support, and (3) inadequate resources and waiting times. Time to presurgical evaluation is the main modifiable factor that may change the overall outcome in medically intractable epilepsy patients. We must continue to investigate and address the barriers and establish facilitators to achieve seizure freedom as soon as possible. ³⁴ Collaborative processes, such as those described below, can assist in creating better timing and more complete care for our patients.

Is it time to utilize novel epilepsy biomarkers?

Neurosurgical intervention is the best available treatment for patients with drug-resistant epilepsy. For these patients, surgical planning requires noninvasive and invasive biomarkers that delineate the epileptogenic zone. Electric and magnetic source imaging play fundamental roles in the presurgical evaluation of these patients since they can obviate the need for invasive procedures or, in more complex clinical cases, can optimize their planning. ³⁵ Yet, these methods are currently underutilized since they are performed in only a few tertiary epilepsy centers on a regular basis. When they provide inconclusive findings, a brain network is responsible for the generation of seizures instead of a focal epileptiform focus. Functional connectivity applied to noninvasive as well as invasive electrophysiological recordings can map this network and identify pathological hubs that facilitate the spread of epileptiform activity. ³⁶ Surgical resection of these hubs may lead patients who suffer from drug-resistant epilepsy to seizure freedom.

Neuropsych outcomes: Time for collaborative standardization

Pediatric epilepsy surgery is underutilized despite ILAE guidance to consider options once drug-resistant epilepsy is evident. Barriers include provider and patient/caregiver factors as well as health disparities. ³⁷ Short-term (1-2 years) neuropsychological outcomes following surgery demonstrate no major changes at a group level; ³⁸ however, long-term outcomes (4+ years) demonstrate significant improvement related to stopping ongoing seizures and cessation of ASMs. ³⁹ There is individual variability in neuropsychological outcomes following surgery and understanding the minority (<20%) of patients that have significant declines with specific cognitive skills (rarely a global decline) as well as the ∼20% that have meaningful improvement is important. Challenges include amassing the sample sizes needed which takes years at a single institution when techniques change and when looking at subsets of patients. To achieve the Epilepsy Benchmark of creating personalized prediction tools, multicenter systematic prospective data collection is needed. These efforts are underway including the Pediatric Epilepsy Research Consortium Surgery Workgroup. ⁴⁰

Conclusion

Timing may be everything in epilepsy evaluation and treatment. The areas detailed in this summary provide evidence-based guidelines on the significance of timing regarding different aspects of epilepsy management. Disparities, health inequity, and behavioral health for patients with epilepsy are areas where growth is critical. Vital aspects of timing in diagnostic evaluation, clinical care, and surgical care are confronted and challenged. The delicate, but necessary, decision-making balance in timing involving epilepsy is instrumental for execution of exemplary care. In summary, timing is a critical and often modifiable factor in epilepsy evaluation and treatment and should be carefully considered and optimized in all circumstances for the goal of achieving excellence in epilepsy.