Diagnostic & Treatment Delay in Temporal Lobe Epilepsy

Epilepsy is a common neurologic disorder affecting 50 million people worldwide.¹ Approximately, one-third of people with epilepsy are estimated to have drug-resistant epilepsy (DRE).² The International League Against Epilepsy (ILAE) defines DRE as failure of adequate trials of 2 tolerated, appropriately chosen and used antiseizure medications (ASMs), whether used as monotherapy or in combination, to achieve sustained seizure freedom.³ Despite the high global burden of epilepsy, there is often a delay in initial diagnosis, even in developed countries.⁴ Moreover, even after initial diagnosis of epilepsy, there are further considerable delays in the identifying DRE, leading to further delay in referral to comprehensive epilepsy centers capable of detailed multidisciplinary evaluation and management. Notably, on average there is a delay of more than 20 years between initial diagnosis and surgical management of people who are failed by optimal use of ASMs.^5,6 We present 2 cases illustrating the course, confounding pitfalls leading to diagnostic delay, and clinical consequences.

In addition, certain nonmotor seizures can be extremely subtle and challenging even for trained neurologists to detect. For example, in the case presented, TS experienced the perception of a cloud coming over her head as a seizure aura. In a multinational retrospective study, the median time to diagnosis was 10 times longer in people with nonmotor seizures compared with motor seizures. Moreover, individuals with nonmotor seizures were prone to experience physical injuries and were at higher risk of motor vehicle accidents.⁷

Case 1 Discussion

This case demonstrates misdiagnosis of epilepsy at initial presentation that resulted in a 10-year treatment delay. Diagnostic delay of epilepsy following initial presentation is common. In a retrospective study of 220 people with suspected new-onset seizures, there was a median delay of 8.7 months and over 50% of participants had more than 5 events before epilepsy was diagnosed.⁴ As can be inferred, individuals with nonconvulsive seizures experience greater delays than those with convulsive seizures. This is in part due to the diversity of presenting symptoms for nonconvulsive seizures. The study also found that individuals with higher socioeconomic disadvantages were at risk for delayed diagnosis.⁶

Seizure Mimics

Misdiagnosis of epilepsy for other neurologic conditions is also known to occur (Box). Instances of visual hallucinations, when combined with headache, blindness, and vomiting are more likely to be diagnosed as migraine despite these symptoms being common in occipital lobe seizures. In a study of individuals with idiopathic occipital epilepsy, 77% were originally misdiagnosed as having migraine.⁸ The majority had postictal headache that was indistinguishable from migraine headache, but differences in epileptic visual hallucinations vs migraine aura were noted. Epileptic hallucinations tended to be colored and circular, occurring repetitively in the same location and tended to be brief on the order of seconds. Migraine aura tended to be achromatic in linear or zigzag patterns, start at the center of the visual field, and expand over minutes toward the periphery.⁹

Acute ischemic stroke and transient ischemic attacks (TIAs) are also known to mimic seizures. In a study of 100 people originally diagnosed with TIA, 13% were found to have seizures as the cause of their transient neurologic symptoms and was the most commonly diagnosed stroke mimic.¹⁰

Todd paralysis, which occurs after focal seizures that generalize on the side contralateral to the seizure, can be misdiagnosed as stroke or TIA, considering they all can present with unilateral hemiplegia.¹¹ Todd paralysis occurs more frequently in older individuals or those with a history of prior stroke, which can further complicate the diagnosis. In this context, appropriate neuroimaging and detailed history collecting should be performed to definitively rule out acute ischemic stroke.^12,13

Psychiatric symptoms, particularly psychic auras can lead to missing a diagnosis of. Interictal, ictal or postictal psychosis can be misdiagnosed as primary psychiatric condition.^14,15

Other common mimics that often present to the emergency department include syncope, metabolic disorders, sleep disorders (eg, narcolepsy with cataplexy), and movement disorders.¹⁶

Avoiding Misdiagnosis of Epilepsy

Avoiding misdiagnosis is important because untreated epilepsy negatively affects patients. A retrospective analysis of claims-based databases including about 60,000 patients found that untreated epilepsy led to a higher incidence of hospitalizations for adverse medical events and increased emergency department visits.¹⁷

Although diagnosis of seizure remains clinical, diagnostic limitations need to be recognized. A single negative EEG can be misleading because only approximately 39% of individuals have epileptiform discharges on EEG after their first unprovoked seizure. The cumulative yield of EEG for finding epileptiform abnormalities increases to 68% after a third EEG, although there is decrease in the increment for each additional EEG.¹⁸ Whenever doubt exists, the patient needs to be referred to a comprehensive epilepsy center for a consultation with an epileptologist. Epilepsy outcome studies have shown that subspecialty care from an epileptologist (rather than a neurologist not specializing in epilepsy) favorably improves seizure control.^19,20

Case 2 Discussion

This case is an example of the considerable diagnostic delay in identification of DRE in people already diagnosed with epilepsy. Delay in identifying DRE leads to delays in referral to a surgical epilepsy center and multidisciplinary epilepsy management. In addition to defining DRE as failure of 2 adequate trials of tolerated and appropriately chosen and used ASM (in combination or as monotherapy), the ILAE defines seizure freedom as the absence of seizures for a minimum of 3 times the longest preintervention interseizure interval (determined from seizures occurring within the past 12 months) or 12 months, whichever is longer.³

Despite this standardized definition, there has not been an appreciable reduction in time to referral to tertiary epilepsy centers.²¹ Notably, in the case presented, there was a 20-year delay between initial diagnosis and referral which is representative of the average length of time cited in multiple studies.⁶ Globally, the treatment gap is similar despite differing socioeconomic contexts. For example, the treatment gap in Australia is 17 years and the treatment gap in India is 18 years.^22,23

Avoiding Delays in Referral

Avoiding delays in DREs is crucial because there are many health consequences associated with undertreated epilepsy including increased risk of sudden unexpected death in epilepsy (SUDEP), psychiatric comorbidities, motor vehicle and other traumatic accidents, and reduced quality of life. Additionally, there is also a substantial economic burden of untreated DRE.^5,18

There are a variety of reasons for delays in identifying DRE and referring individuals to epilepsy centers. In part, this is attributed to a knowledge deficit regarding DRE diagnosis and management amongst general neurologists and primary care providers. In a survey of 84 community neurologists, the majority of participants thought failure of at least 3 ASMs was necessary to diagnose DRE,²⁴ despite earlier literature demonstrating that only a small fraction of individuals will achieve 1 year of seizure freedom after failure of 2 ASMs.²⁵ There were also misconceptions and doubt over the safety and effectiveness of epilepsy surgery in the correct clinical context. For example, 42% of respondents reported there was a less than 70% chance of seizure freedom after temporal lobectomy, which is lower than the rate supported by the literature. Moreover, 31% of respondents also reported witnessing serious complications with epilepsy surgery, despite literature reporting the death rate to be less than 1% and the rate of permanent neurologic deficit to be less than 3%.²⁴ Similarly, a survey of 425 Canadian neurologists found that nearly half of the participating general neurologists failed to correctly define DRE. More than 75% of neurologists in the study reported inadequate access to healthcare resources (eg, long wait times, access to limited resources, and availability) and other patient-related barriers such as apprehension of surgery by the patient or guardian.²⁶ A recent study from Australia surveyed neurologists and individuals with DRE to identify significant factors contributing to the treatment gap. Identified reasons included difficulty of neurologists in identifying DRE, miscommunication between patients and practitioners, long clinic wait times, and lack of patient-centered care.²²

In a retrospective cross-sectional analysis including 115,632 persons with seizures, having a comprehensive epilepsy center within the geographic location of a patient’s residence determined the likelihood of access. Unfortunately, 87% of people with seizures lived outside such an area. However, the study also found that the availability of an epilepsy center did not influence access to specialized epilepsy care for people with private insurance. Only individuals who were uninsured or had public insurance, including Medicaid and Medicare, had excessive gaps in access to specialized care.²⁷ Thus, the barriers and gaps in access to specialized services for epilepsy occur at multiple levels, including referral by the general neurologist and systemic barriers related to insurance coverage.

The ideal treatment goal for epilepsy includes complete seizure freedom and the absence of any side effects.²⁸ Achieving this goal is often daunting in people with DRE. Appropriate and targeted treatment (eg, surgical resection, neuromodulation, a combination of both, and continued ASM therapy) requires a multidisciplinary approach. Prompt referral to comprehensive epilepsy centers allows such detailed evaluation and consideration of a multiplicity of alternative treatment plans.²⁸ A comprehensive epilepsy center (level 3 and 4) has a team of epileptologists, neurosurgeons, neuroradiologists, neuropsychologists, psychiatrists, and social workers. Through a team-based approach, they can provide specialized treatment options and address frequently encountered comorbidities caused by psychologic and social issues.

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