Diagnostic Considerations for New-Onset Epilepsy in Older Adults

In the United States, increases in the number and proportion of older adults have led to new challenges for clinicians. Successes in public health and disease management have led to longer lifespans and increasing numbers of older adults, with a projected 83.7 million people older than 65 years by 2050.¹ Older adults, defined in this review as people age ≥60 years, are at increased risk of neurologic disorders, including epilepsy.^2-5 Of neurologic disorders affecting this group, epilepsy ranks as the third most common behind stroke and dementia, both of which are risk factors for the development of epilepsy.⁵ Epilepsy is associated with increased morbidity and mortality, particularly for older individuals.⁴ Thus, early recognition and accurate diagnosis by health care providers are important for the older adult with epilepsy.

Epidemiology

The bimodal nature of the incidence of epilepsy has long been recognized, with an initial peak in infancy followed by a nadir in young adulthood, with progressive increased incidence with age thereafter (Figure).^6,7 Illustrating this trend, one study identified an epilepsy incidence of 25.8 per 100,000 for people age 60 to 74 years and 101.1 per 100,000 for those age 75 to 89 years.⁸ Epilepsy incidence is nearly 60% higher in developing countries than in industrialized countries.⁶ In the United States, >550,000 older adults have epilepsy, with 50,000 older adults diagnosed with epilepsy each year.⁹ It is estimated that up to 1.5% of people age ≥75 years have epilepsy, with a prevalence in nursing home residents of nearly 8%.^10,11 Older adults with epilepsy have significantly increased risk of overall mortality and status epilepticus.^4,12

Etiologies

The development of epilepsy in older adults can often be attributed to neurologic disorders common in this population. However, in approximately half of these individuals, no cause is identified.^3,4 Among older individuals with epilepsy and an identified etiology, nearly 50% of cases are secondary to cerebrovascular disease, with the majority due to ischemic stroke.^2,4 However, strokes with greatest risk for development of subsequent epilepsy are hemorrhagic, large volume, cortical, recurrent, and those which present with acute symptomatic seizures.^2,13 There is a reciprocal relationship between cerebrovascular injury and epilepsy: the risk of stroke triples for individuals who develop epilepsy late in life, and the risk of epilepsy increases 20-fold in the first year after a stroke.^2,14 Dementia is estimated to be the causative factor in 20% of cases of epilepsy in older adults, with ~10 times the risk of development of epilepsy in individuals with Alzheimer disease or dementia with Lewy bodies.^2-4 A bidirectional relationship has also been found between epilepsy and dementia, such that individuals with either condition are 2 to 10 times more likely to develop the other.¹⁵ Autoimmune or paraneoplastic antibody-mediated etiologies are increasingly recognized in people with epilepsy, including in older adults.

Clinical Aspects

Older adults are at increased risk for acute symptomatic seizures and epilepsy.⁴ Acute symptomatic seizures occur in close temporal association with an acute central nervous system insult and include seizures within 1 week of a stroke, traumatic brain injury, anoxic encephalopathy, or intracranial surgical procedure; at first identification of a subdural hematoma; in the setting of an active central nervous system infection; during an active phase of multiple sclerosis or other autoimmune disease; in the presence of severe metabolic derangements (noted within 24 hours); induced by drug and alcohol intoxication or withdrawal; or induced by exposure to well-known epileptogenic drugs.

Acute symptomatic seizures differ from epilepsy in that they do not lead to an enduring predisposition to recurrent unprovoked seizures and carry a prognosis distinct from epilepsy.¹⁶ In general, treatment or resolution of the underlying cause results in resolution of seizures and low risk of recurrence, although some individuals ultimately may develop recurrent unprovoked seizures and meet criteria for a diagnosis of epilepsy. Reports indicate that up to half of all acute symptomatic seizures in older people are related to cerebrovascular disease, with other common etiologies including traumatic brain injury, toxic or metabolic causes, and infections.¹⁷

In contrast to acute symptomatic seizures, epilepsy is a disorder characterized by an enduring predisposition to recurrent, unprovoked seizures.¹⁸ Epilepsy is commonly diagnosed clinically; diagnostic testing and evaluation are typically supportive in nature and low sensitivity. The International League Against Epilepsy guidelines state that a diagnosis of epilepsy may be reached if any of the following criteria are met:¹⁸

• ≥2 unprovoked seizures >24 hours apart
• 1 unprovoked seizure and a risk of seizure recurrence of ≥60% over the next 10 years
• Diagnosis of an epilepsy syndrome

Epileptic seizures may be symptomatic (related to a known underlying central nervous system abnormality) or idiopathic. Older adults are at increased risk of structural abnormalities including strokes, tumors, falls, and dementia, each of which increases risk for the development of epilepsy.¹⁹ New-onset epilepsy in the older adult is typically focal onset, although generalized epilepsy may rarely present later in adulthood and onset has been reported in individuals up to 75 years of age.^19,20

Clinical manifestations in older individuals with epilepsy differ from those in younger adults. This may be related to localization differences, as seizures in older adults are more likely to be extratemporal (particularly frontal) than temporal onset.²¹ This localization difference may in part be secondary to the fact that epilepsy in older adults is more likely to be remotely symptomatic, particularly poststroke.¹² However, temporal lobe epilepsy is also common, especially after a history of infectious or paraneoplastic encephalitis. In older adults, auras and automatisms may be less prominent, and events are more often described as confusion or dizziness.^4,12 Postictal confusion can last considerably longer (days to weeks) in older compared with younger individuals (minutes or hours).¹² Both focal and generalized motor seizures are less prevalent in older adults,²² which can make diagnosis more challenging.^12,23 Status epilepticus is more common in older individuals, including generalized convulsive status epilepticus.^4,12

Differential Diagnosis

Epilepsy can be a particularly challenging diagnosis in the older adult. One study of older adults with epilepsy identified an average diagnostic delay of >2 years from symptom onset, with only 37% of individuals admitted to the epilepsy monitoring unit (EMU) correctly diagnosed at initial evaluation.²⁴ Numerous potential barriers exist that may affect clinicians’ ability to formulate an appropriate differential diagnosis, including limitations in individual history, differences in clinical manifestations, and medical comorbidities.⁴ A detailed history is vital for accurate diagnosis, and older individuals may be unable to provide critical information due to underlying dementia, stroke, or other communication difficulties. Older adults often live alone or in care facilities where adequate monitoring is unavailable. Furthermore, people in care facilities often have numerous caretakers who may be unaware of individuals’ medical histories or neurologic baseline status, so transient events may not be well documented or reported to providers.

Among individuals who are aware of episodes, older adults are more likely to report nonspecific symptoms including dizziness, memory loss, and abnormal head sensations as their typical semiology.^4,19 Medical comorbidities may affect clinicians’ ability to diagnose epilepsy accurately, as other conditions can manifest similarly to seizures. Providers may misattribute transient neurologic symptoms from seizures to disorders in other organ systems rather than pursuing an appropriate workup and diagnostic evaluation for epilepsy. In contrast, some providers may overdiagnose transient episodes as epileptic, putting individuals at risk for treatment-related complications. Previous studies of older individuals admitted to an EMU for diagnostic testing identified that the majority of these individuals who did not have epilepsy were treated with antiseizure medication before testing was performed.^25,26

The differential diagnosis for seizures in older adults is broad and includes primary neurologic and non-neurologic causes (see Table). Among primary neurologic etiologies, transient ischemic attack and stroke should be considered in any individual with acute onset of focal neurologic deficit, particularly in individuals with cardiovascular risk factors. Complex migraines (including hemiplegic migraine) may present with focal neurologic deficits or transient symptoms, often including positive visual or sensory phenomena with confusion in addition to typical headaches. Movement disorders increase in prevalence with age and tremors, tics, myoclonus, and dystonia may present as recurrent, uncontrollable stereotyped episodes in older adults. Individuals with cerebral amyloid angiopathy may experience amyloid spells or transient focal neurologic episodes, which may present with limb shaking, paresthesias, movements, and decreased responsiveness lasting minutes, sometimes in clusters.²⁷ Transient global amnesia typically presents as a single isolated incident of anterograde amnesia lasting several hours.⁴ Sleep disorders, including rapid eye movement (REM) sleep behavior disorder, narcolepsy, hypnic jerks, and other parasomnias are commonly mistaken for seizure disorders.^4,28 REM sleep behavior disorder is common among older adults, with episodes of abnormally disinhibited muscle tone during REM sleep, during which individuals may exhibit violent movements, yelling, or other activity which can be mistaken for frontal lobe epilepsy. This is commonly associated with sedative or antipsychotic medication use, but is also seen in individuals with movement disorders including Parkinson disease and Lewy body dementia. Hypnic jerks are transient benign peripheral myoclonus movements that occur during sleep–wake transition and may be confused for cortical (epileptic) myoclonus.⁴ Older individuals with Alzheimer disease or other cognitive disorders may experience delirium and transient disorientation and confusion, which may be difficult to distinguish from seizures.

Among non-neurologic causes, cardiovascular disorders including cardiac arrhythmias, hypotension, or convulsive syncope may result in transient loss of consciousness with abnormal movements and may be mistaken for seizures by even experienced clinicians. Metabolic and toxic disturbances including hypoglycemia, hyponatremia, hypercalcemia, renal or hepatic failure, and other electrolyte abnormalities can present with altered mental status and transient generalized or focal neurologic symptoms, which may be mistaken for seizures. Severe toxic and metabolic derangements may cause seizures, although these typically represent acute symptomatic seizures. Polypharmacy and medication toxicity can also result in transient symptoms including dizziness, unresponsiveness, and confusion. Some older adults experience psychogenic nonepileptic seizures or psychogenic nonepileptic episodes, which are functional symptoms that can manifest as recurrent, transient episodes resembling epileptic seizures.

Diagnostic Evaluation

In older individuals presenting with transient neurologic symptoms, diagnosis is often challenging, and it is important to consider seizures and epilepsy in the differential diagnosis. In individuals with high clinical suspicion for epilepsy the clinician may determine that the individual meets criteria for a clinical diagnosis without waiting for subsequent testing and recommend immediate treatment. However, additional workup is recommended for individuals in whom the diagnosis remains unclear to clarify etiology, risk of recurrence, and treatment.

In general, all older adults with suspected new-onset seizures or epilepsy should receive neuroimaging with contrast-enhanced MRI of the brain.²⁹ In individuals unable to undergo MRI (eg, resource-limited settings, MRI-incompatible pacemakers), alternative neuroimaging with brain CT may be pursued. However, CT is less sensitive in identifying small, potentially epileptogenic neuroanatomic abnormalities, so MRI should be obtained if possible.²⁹ Individuals with suspected infectious, inflammatory, neoplastic, paraneoplastic, or hemorrhagic causes should undergo lumbar puncture with cerebrospinal fluid analysis.²⁹ Autoimmune epilepsy is an increasingly recognized etiology for new-onset epilepsy in adults, particularly rapidly medically refractory epilepsy. Such individuals should be assessed using the Antibody Prevalence in Epilepsy and Encephalopathy (APE2) score to help delineate individuals who may be at high risk for autoimmune causes. In such cases, serum and CSF analysis for autoimmune antibodies is recommended.³⁰

EEG is an important tool that measures and records brain electrical activity and is considered one of the primary diagnostic evaluations for individuals with possible seizures. The sensitivity of routine EEG testing is notably low, with diagnostic yield in older adults estimated at 26%.²⁶ Sensitivity may improve if EEG testing is obtained within 48 hours of a seizure, in a sleep-deprived state, or performed serially.^29,31 Prolonged EEG monitoring can further assist in diagnosis and may be pursued in both inpatient (EMU) or outpatient (ambulatory EEG) settings. During EMU admissions, providers are able to monitor individuals on EEG with video, capture or provoke episodes in a hospital setting, and clarify diagnosis of epilepsy and nonepileptic events. This allows providers to reduce or discontinue seizure medication safely and reduce the risk for complications related to seizures and seizure provocation. Older adults may be underreferred for EMU evaluation: one study identified that only ~3% of all adult EMU admissions were individuals age >60 years.²² Ambulatory EEGs allow for prolonged EEG monitoring in the home setting and may be performed with or without video. Because ambulatory EEGs are obtained in the individual’s home setting, complications that are associated with inpatient hospitalization can be avoided including delirium, iatrogenic medication errors, and deep venous thrombosis. Furthermore, ambulatory EEG testing is estimated to cost up to 65% less than a single day of an inpatient EMU admission.³² One recent study of ambulatory EEG testing identified 37% diagnostic yield, with 21% of studies resulting in change in management.³²

Older adults with transient episodes that may be cardiac in nature or with known cardiovascular risk factors should undergo cardiovascular evaluation, which may include an electrocardiogram, Holter monitoring, echocardiogram, or consultation with a cardiologist. Polysomnography should be considered in individuals with nocturnal episodes and possible sleep disorders. Tilt table testing may be indicated in individuals with suspected autonomic dysfunction. Laboratory evaluation during episodes may be diagnostic in the case of hyperglycemia or other metabolic etiologies. Providers should review medication lists in detail and assess whether new medications or dosing correlate to symptom onset. Although not generally diagnostic, family, nurses, or care facility staff may be able to provide video of recurrent, unexplained episodes for review, which may be helpful in clarifying potential semiology and symptoms of which older individuals may not be aware or able to report.¹⁹

At times, definitive diagnosis may prove elusive and the provider may need to discuss risks and benefits of empiric treatment, including potential diagnostic benefit.

Conclusions

As the population ages, the number of older adults with epilepsy is rising. This disorder is often misdiagnosed in older individuals and is associated with increased morbidity and mortality rates, with potential dramatic reductions in quality of life. Accurate diagnosis of seizures and epilepsy in older individuals can be challenging, considering limitations in clinical history, medical comorbidities, and nonspecific clinical manifestations. Neuroimaging and EEG testing, including ambulatory EEG, are important tools in the evaluation of older adults with potential seizure disorders.