Epilepsy Essentials: Treatment and Outcomes of Functional Seizures—Review of the American Academy of Neurology Functional Seizures Management Guidelines

Functional seizures (FS), previously referred to as psychogenic nonepileptic seizures, are now recognized as functional/dissociative seizures by the International League Against Epilepsy.¹ FS resemble epileptic seizures but lack epileptiform activity on EEG. They are associated with neuropsychiatric comorbidities and stressors, such as impactful life events. Functional neurologic symptoms may manifest as episodes of motor or somatosensory impairment, with or without apparent alterations in awareness, and can substantially affect the performance of activities of daily living.

With increased recognition of FS, the time to reach a diagnosis has decreased. In addition, evidence-based treatments have been developed, and long-term outcomes published.^2–4 Despite these advances, there remains an unmet need to improve the overall quality of life in this patient population. The use of standardized and evidence-based guidelines can reduce diagnostic ambiguity, improve treatment success, and streamline research efforts to improve outcomes.

Comorbid Epilepsy and Psychiatric Conditions

Video EEG (vEEG) is the standard test used to obtain a definitive diagnosis of FS.⁵ A thorough history and event semiology should be elicited from the individual. In addition, witnesses should be sought to describe characteristics of events. Experienced clinicians may observe clinical signs, such as forced eye closure, side-to-side head shaking, and pelvic thrusting,⁶ to further support a suspicion of FS. However, overreliance on historical reporting of these signs may result in underdiagnosis of epileptic seizures, especially when seizures arise from the frontal lobe; Bonini et al⁷ and Gibbs et al⁸ have shown the variance and diversity of clinical features associated with frontal lobe epilepsies.

A common concern of general neurologists managing a broad range of patients is the possibility of missing an underlying diagnosis of epileptic seizures when diagnosing an individual with FS. However, a retrospective chart review study of 460 participants that evaluated proposed criteria for co-occurring FS and epilepsy revealed that 62.6% of people with FS were “unlikely” to have co-occurring epilepsy, whereas only ~11.5% of individuals with FS met a high level of certainty for co-occurring epileptic seizures.⁹ These findings suggest that most individuals with suspected FS have only FS, without concomitant epilepsy.

The American Academy of Neurology (AAN) Guidelines Subcommittee recently published guidelines on the management of FS,¹⁰ providing an evaluation of the current evidence regarding treatment approaches. The guidelines also address diagnostic evaluation. According to the recommendations, clinical history, seizure semiology, and vEEG results should be used to evaluate individuals for co-occurring epilepsy. Epileptic seizures should be treated with appropriate antiseizure medications (ASMs), and the potential risks and benefits of treatment discussed. Clinicians should counsel patients that ASMs lack efficacy in the treatment of FS.¹⁰

Psychological and Pharmacologic interventions

Cognitive behavioral therapy (CBT) and multimodality neurobehavioral therapy (NBT) are well-established interventions used for the treatment of individuals with FS. To date, 3 randomized clinical trials have shown an increased likelihood of freedom from FS at the end of treatment compared with standard medical treatment.^2,11,12 Besides their effectiveness in FS treatment, CBT and NBT have been shown to reduce anxiety and improve quality of life.^3,13,14

CBT emphasizes interactions among thoughts, behaviors, and emotions. Techniques from CBT, including psychoeducation, relaxation training, graduated exposure to avoided situations, and cognitive restructuring, are implemented to improve functioning and reduce symptoms.

NBT is an evidence-based, time-limited, multimodality, integrative psychotherapy that incorporates a biologic-psychologic-social-spiritual formulation, addressing concerns of individuals from a whole-person perspective. NBT techniques include psychoeducation, motivational interviewing, cognitive restructuring, interpersonal communication, mindfulness, and psychodynamic approaches. Along with improvements in clinical outcomes, NBT has been associated with neuroplastic changes in individuals with FS and traumatic brain injury (TBI), including in gray matter,¹⁵ white matter,¹⁶ and functional connectivity,¹⁷ compared with symptomatic controls with TBI without FS.

Other treatment modalities, including mindfulness-based therapies, have shown promising results, with 70% of participants experiencing a 50% reduction in seizure frequency after 12 sessions.¹⁸

Medication studies were also reviewed in the AAN FS Guidelines, including trials of sertraline for the treatment of FS. Medications prescribed for co-occurring psychiatric conditions should be used to treat those comorbidities but should not be used as a primary treatment for FS. Use of benzodiazepines is not recommended for FS treatment due to lack of efficacy, risk of dependence, and potential for iatrogenic harm.¹⁹ The use of ASMs for the treatment of FS is not recommended, unless they are used to treat comorbidities of FS, such as for migraine prophylaxis, specific pain conditions, or bipolar disorder.

Patient Characteristics and Outcomes

FS is most common in young adult women, although the age at onset ranges from childhood to late adulthood.²⁰ Short-term outcomes are generally favorable with studies showing variable rates of event freedom across follow-up periods, most commonly between 12 and 48 months. Outcomes are generally more favorable in children than in adults.²¹ Less is known regarding longer-term outcomes of adequately treated FS beyond 1 year, in part because of low adherence to long-term follow-up.²²

Regarding mortality, a recent large-scale study used electronic medical records to compare mortality rates among participants without seizures, participants with epilepsy, and participants with FS. After adjustment for comorbidities, participants with FS had half the mortality rate of those with epilepsy, but twice the mortality rate of those without seizures.^23,24

Refractory Functional Seizures

Drug-resistant (ie, refractory or intractable) epilepsy is defined as the persistence of seizures despite treatment with ≥2 ASMs at the appropriate dosage and duration. People with ongoing FS may be misdiagnosed with drug-resistant epilepsy when ASMs are ineffective in obtaining event resolution. This phenomenon has been referred to as pseudorefractory epilepsy. In one study reevaluating 122 participants initially diagnosed with drug-resistant epilepsy, 57 were ultimately found to have nonepileptic events,²⁵ further emphasizing the importance of implementing the AAN FS Guidelines into routine clinical practice to prevent misdiagnosis and inappropriate treatment.

Conclusion

The diagnosis and management of FS continue to improve. Still, gaps remain, particularly with respect to long-term outcomes and recurrence across the lifespan. Comorbid epilepsy with FS presents a unique challenge, requiring a thorough evaluation and vEEG to establish definitive diagnoses. Prompt and accurate diagnosis is essential to ensure appropriate treatment while avoiding unnecessary and excessive diagnostic testing and treatment with ASMs in individuals with FS. The recent AAN FS Management Guidelines equip general neurologists, emergency physicians, and primary care providers with evidence-based recommendations for the diagnosis and management of FS.