Late-Onset Epilepsy

Although epilepsy is often thought of as a pediatric condition, epilepsy occurs across the lifespan. It is somewhat underappreciated that there is a marked increase in the incidence of epilepsy after age 60 (Figure), termed late-onset epilepsy (LOE). Epilepsy at age 75 is twice as prevalent as epilepsy in other periods of adulthood.^1-3 There is a question of whether someone who had epilepsy in childhood but has been in remission for decades might be considered as having new LOE, but typically, onset of LOE is defined as a first seizure or episode of seizure activity. Some data suggest that LOE may be more common among Black people in the US.^4,5 Considering the increase in our aging population, LOE is becoming a major public health issue.

LOE Etiology and Risk Factors

For approximately two-thirds of LOE, a structural cause can be identified, most commonly, cerebrovascular disease (30%-50%),^6,7 neurodegenerative disease (10%-20%), traumatic brain injury (TBI; ≤25%),^8,9 and brain tumors (10%-30%).^10,11 Drug intoxication, drug or alcohol withdrawal, neurologic infections, and autoimmune encephalitis (AE) can also cause seizures in the elderly. For the one-third or more of LOE without a structural cause, termed late-onset unexplained epilepsy (LOUE), occult cerebrovascular disease, prodromal neurodegenerative disease, and sleep apnea have been implicated.^12-14

Cerebrovascular Disease

LOE is common after ischemic and hemorrhagic stroke,¹⁰ and hypertension, even in the absence of stroke, is known to be correlated with the development of LOE.^15,16 A study of people from diverse communities who had LOE showed that having ever smoked, diabetes, and hypertension were risk factors for LOE (Table 1).¹⁷ This study also demonstrated that having the apolipoprotein E ε4 (APOE ε4) allele, which is associated with both cerebrovascular disease and Alzheimer disease (AD), is a risk factor for LOE.¹⁷ Notably, 3 of these 4 risk factors are modifiable and can be addressed with public health measures and preventive care. Further study of this cohort showed that the volume of white matter hyperintensities on MRI—a biomarker for small-vessel cerebrovascular disease—correlated with developing LOE (hazard ratio [HR] 1.27 per age-adjusted SD, 95% CI 1.06–1.54).¹⁸

Neurodegenerative Diseases

Cortical atrophy and the APOE ε4 gene variant are both associated with both LOE and AD,^17,18 and the incidence of LOE in AD is as high as 10% to 20%,¹¹ compared with approximately 1% in the general population over age 65. AD pathology is also considered a cause of LOE in and of itself.¹⁹ Higher rates of LOE are also seen in people with dementia with Lewy bodies (DLB) and frontotemporal dementia.²⁰ A large nested, case-matched study showed a bidirectional relationship between all-cause dementia and epilepsy, demonstrating that having either doubled the risk for the other.²¹

TBI

TBI is a known risk factor for the development of LOE and dementia, including chronic traumatic encephalopathy.^8,9,22 The APOE ε4 allele was associated with increased incidence of posttraumatic epilepsy in 1 study,²³ but not in 3 others.^24-26 The incidence of TBI increases with age and is highest in those over age 80 in the US. With age, falls increase as a cause of TBI.²⁷ A study using a national 5% random sample of 2005 Medicare beneficiaries,²⁸ found that TBI was threefold more common in those with LOE (P<.001).

Brain Tumors

Seizures are the most common presenting symptom of brain tumors and brain metastases, both of which increase in incidence with age. Brain tumor-related epilepsy can also develop later in the course of disease. The pathophysiologic processes by which brain tumors cause seizures have not been fully elucidated; tumor location, tumor burden and rate of growth as well as peritumoral changes in neuro-transmitter homeostasis have been implicated.²⁹

Autoimmune Encephalitis

LOE may also be a manifestation of paraneoplastic/autoimmune antibodies triggering seizures. The availability of tests to screen for these antibodies has improved the detection of AE, and certain seizure semiologies such as facio-brachial dystonic seizures, commonly seen in antiLGI-1 encephalitis, should alert the physician to the possibility of this diagnosis. A retrospective case-matched study of individuals with AE and LOUE found that a high frequency of focal aware seizures was more common in AE (P<.001) as were ictal autonomic manifestations (P=.003).¹²

LOUE

Over one-third of LOE has no structural cause identified.^6,8 There is evidence suggesting that LOUE may be related to cerebrovascular disease, neurodegeneration, and sleep disorders, which are all known to interact with one another.¹³ A case-matched study of adults over age 60 with and without LOUE, showed that those with LOUE had an adjusted 2.3% increase in Framingham Heart Study general cardiovascular disease (FHS-CVD) risk scores.³⁰ LOUE has also been shown to be a risk factor for subsequent stroke or myocardial infarction.³¹ Together, these findings suggest that occult cerebrovascular disease and vascular risk factors may be a cause of LOUE.

Additionally, LOUE tends to localize predominantly to the left temporal lobe and is associated with higher rates of medial lobe atrophy.³⁰ Considering that this is where accumulation of neurotoxic proteins in neurodegenerative diseases and dementia is first seen,^32,33 LOUE could reflect prodromal dementia/neurodegenerative disease. This is further supported by seizure being a known first presentation of AD,^34,35 and that persons with LOUE have low AΒ⁴² and elevated phosphorylated tau cerebrospinal fluid (CSF) levels, indicative of underlying AD pathology.³⁶

Sleep apnea increases epilepsy risk 1.5 times and, conversely, obstructive sleep apnea occurs at higher frequency in people with LOUE compared with the general population.^37,38

LOE Diagnosis

In people over age 60 with LOE, there tend to be fewer convulsions, more confusion, and longer recovery times. Thus, as with all neurologic conditions, a careful history is needed, and as with all seizure disorders a reliable observer of seizure episodes can be the key to diagnosis.

Focal seizures, which are more common in LOE, may mimic confusional states, transient ischemic attacks (TIAs), or fluctuations seen in dementia, but with seizures, there is a paroxysmal and stereotyped pattern to the events. The postictal state lasts longer in LOE, which can help differentiate a seizure from an episode of syncope. Focal seizures, however, are more difficult to recognize than generalized tonic-clonic seizures (GTCs), which may result in delayed diagnosis.³⁹ GTCs can be mimicked by several conditions that are more common with aging (eg, cardiac arrest or arrhythmias, syncope, or falls) and it is critical to rule these out when a person presents with a first seizure episode.

Neuroimaging should be done to evaluate for structural causes including brain tumors, prior strokes, small vessel cerebrovascular disease, or atrophy patterns suggestive of AD and other neurodegenerative diseases. It is important to use a seizure-protocol MRI scan with appropriate sequences. There should also be a search for cortical microhemorrhages as possible epileptogenic foci. Particular attention to the temporal lobe and any signs of cortical atrophy is warranted. Repeat MRI should at times be considered to rule out the interval development of a structural lesion such as a tumor.

EEG may help to confirm the diagnosis and localize seizure foci, and temporal lobe epilepsy is seen more often in LOE and especially in LOUE.³⁰ People over age 60, however, also have more benign variants that can be misinterpreted as epileptiform or have subclinical epileptiform discharges without a history of seizures. For example, in people with AD, a study of 24-hour ambulatory EEG showed that 20% had epileptiform discharges but had never had a seizure.⁴⁰ It is essential to capture sleep because it is the most common state when epileptiform discharges arise, as a result, ambulatory EEGs ranging from 1 to 3 days can have a higher yield as compared to 30-minute EEGs. If there is a concern about unusual nocturnal behaviors, a sleep study with a full set of EEG electrodes can be beneficial to rule out obstructive sleep apnea or rapid eye movement (REM) sleep behavior disorder (RBD).⁴⁰

Cardiac enzymes and ECG should be ordered to rule out arrythmias or myocardial ischemia. If suspicion for an arrhythmia is high, at-home cardiac monitoring may help to further rule out any paroxysmal cardiac events. Screening for potentially causative new medications or withdrawal from alcohol or other substances is warranted for acute seizures. Plasma and even CSF antibody studies should be obtained if there is any suspicion of AE; clues include the presence of hyponatremia, a high burden of seizures, rapid memory loss, new onset psychiatric symptoms or movement disorders, and specific MRI features.⁴¹

When no structural cause is found and LOUE is diagnosed, it is essential to continue evaluating patients for potential causes that may not have been apparent initially or that may develop over time. To develop a better understanding of seizure semiology, family members and care partners can be asked to take videos (usually with their phones) of the seizure episodes. As discussed, repeat neuroimaging and lab studies may be needed.

A trial of antiseizure medications (ASMs) may be helpful when all other potential causes have been ruled out, and there is still diagnostic uncertainty. A response to ASMs would confirm the diagnosis of epilepsy. The key to trials of ASMs is to reach a therapeutic dose with slow titration. Once a therapeutic dose is reached, the duration of ASM treatment is based on whether symptoms respond to treatment, provided the ASM is taken for a period long enough that a seizure would be expected. As discussed in the next section, studies suggest that most LOUE is responsive to pharmacotherapy,³⁰ so if seizures do not respond, that is reason to continue looking for a cause of seizures (AE for example) or alternative diagnoses.

Treatment

With approximately two-thirds of LOE having identifiable causes, treatment is often focused on the underlying cause with ASMs also used. For LOUE, the remaining third, treatment with ASMs is successful in up to 92% of cases.³⁰ The choice of ASM is based on tolerability and safety, prioritizing ASMs that do not interact with antihypertensives, blood thinners, or statins (Table 2).^42-45 ASMs that can be used at low doses with few drug-drug interactions include levetiracetam, lamotrigine, and gabapentin.

Patients should be counseled that side effects of levetiracetam include sedation, fatigue, sleep disturbance, irritability, mood disorders, and other psychiatric effects.⁴⁶ If there is an excellent response to levetiravcetam but neuropsychiatric side effects are intolerable, a switch to brivaracetam can be tried or to another ASM. With lamotrigine, there is a risk of rash, gait instability, and falls, making slow titration to a therapeutic dose particularly important.⁴⁷ Gabapentin can also cause fatigue or be sedating, and the 3-times daily dosing can markedly lower adherence to treatment in this age group. In the presence of renal insufficiency, gabapentin can be used twice a day instead.⁴⁸ Extended-release options for ASMs generally have better tolerability but can sometimes be more costly.

Lacosamide may as an alternative with attention to potential cardiac side effects such as PR prolongation.⁴⁹ Enzyme-inducing ASMs (eg, phenytoin, carbamazepine, oxcarbazepine or phenobarbital) should be avoided because of the potential for drug-drug interactions; these may also carry higher risk of cardiac side effects and are known to increase risk of osteoporosis.⁵⁰ Valproic acid can be particularly helpful in patients who need an ASM and mood stabilizer but has a number of side effects (see Table 1).

Mood disorders and cognitive dysfunction are more common in epilepsy than in the general population and increase with aging as does sleep apnea.¹³ Screening for these comorbid conditions should be part of caring for any person with LOE. Screening for depression and anxiety can be done easily with tools such as the Patient Health Questionnaire-9 (PHQ-9), Geriatric Depression Scale (GDS), and the Generalized Anxiety Disorder-7 (GAD-7) scales. If mood disorders are found, lamotrigine may be the preferred ASM,⁴⁷ and referrals to psychiatry should be made depending on symptom severity. If psychiatric care is difficult to access, however, neurologists and primary care specialists may safely prescribe antidepressant medications to people over age 65 while avoiding medications that can lower seizure threshold such as buproprion.

To screen for cognitive dysfunction, the Mini-Mental State Examination (MMSE) or Montreal Cognitive Assessment (MoCA) are brief and easily administered. A positive screen for cognitive disorders warrants referral for neuropsychologic evaluation, when available, and referral to a cognitive disorder specialist.

A careful sleep history can screen for the presence of sleep disorders and should query not only difficulty sleeping at night but also whether excessive daytime sleepiness is present. If sleep difficulties are found, referral for a sleep study is judicious.

Counseling patients about the importance of sleep—whether sleep difficulties are present or not—and not overusing alcohol is also wise because poor sleep and alcohol consumption are 2 factors known to exacerbate seizures. A healthy diet, exercise, and staying cognitively and socially active can also be recommended to promote both cardiac and neurologic health.⁵¹

Lastly, anyone caring for people with LOE should understand that these individuals have higher risks of stroke, dementia, and sleep apnea, and monitor patients closely for these conditions and address vascular risk factors. Patients and care partners can be counseled and educated about these risks and how to recognize them. Similarly, people over age 65 with AD can be counseled about their increased risk of seizure and educated to recognize seizures and provide seizure first aid if needed.

Summary

The incidence of epilepsy increases markedly after age 60, and the prevalence of LOE at age 75 is twice that of other stages of adulthood. Although LOE most often has structural causes, up to 30% has an unidentifiable cause. LOUE may be the harbinger of occult cerebrovascular disease; prodromal dementia; sleep apnea; or unidentified brain cancer, metastases, or paraneoplastic disease. LOE should be kept in the differential diagnosis for any paroxysmal event in people over age 60, and, when no cause is identified, repeat evaluations for potential causes are warranted. Treatment with nonenzyme-inducing ASMs is recommended and usually successful but should be started at a low dose and slowly uptitrated to therapeutic levels. People with LOE are at higher risk of mood disorders, cognitive dysfunction and dementia, cerebrovascular disease including stroke, and sleep apnea; periodic screening for these comorbidities is also recommended.