Abstract
Vary-O’Neal A, Miranzadeh S, Husein N, Holroyd-Leduc J, Sajobi TT, Wiebe S, Deacon C, Tellez-Zenteno JF, Josephson CB, Keezer MR. Neurology. 2023;100(11):e1135-e1147. doi:10.1212/WNL.0000000000201701. PMID: 36535780. Frailty is an important aspect of biological aging, referring to the increased vulnerability of individuals with frailty to physical and psychological stressors. While older adults with epilepsy are an important and distinct clinical group, there are no data on frailty in this population. We hypothesize that frailty will correlate with the seizure frequency and especially the tolerability of anti-seizure medications (ASMs) in older adults with epilepsy. We recruited individuals aged 60 years or older with active epilepsy from 4 Canadian hospital centers. We reported the seizure frequency in the 3 months preceding the interview, while ASM tolerability was quantified using the Liverpool Adverse Events Profile (LAEP). We applied 3 measures of frailty: grip strength as a measure of physical frailty, 1 self-reported score (Edmonton frail score [EFS]), and 1 scale completed by a healthcare professional (clinical frailty scale [CFS]). We also administered standardized questionnaires measuring levels of anxiety, depression, functional disability, and quality of life and obtained relevant clinical and demographic data. Forty-three women and 43 men aged 60-93 years were recruited, 87% of whom had focal epilepsy, with an average frequency of 3.4 seizures per month. Multiple linear regression and zero-inflated negative binomial regression models showed that EFS and CFS scores were associated with decreased ASM tolerability, each point increase leading to 1.83 (95% CI: 0.67-4.30) and 2.49 (95% CI: 1.27-2.39) point increases on the LAEP scale, respectively. Neither the EFS and CFS scores nor grip strength were significantly associated with seizure frequency. The EFS was moderately correlated with depression, anxiety, quality of life, and functional disability, demonstrating the best construct validity among the 3 tested measures of frailty. The EFS was significantly, both statistically and clinically, associated with ASM tolerability. It also showed multiple advantages in performance while assessing for frailty in older adults with epilepsy, when compared with the 2 other measures of frailty that we tested. Future studies must focus on what role the EFS during epilepsy diagnosis may play in ASM selection among older adults with epilepsy.Background and Objective:
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Commentary
We unconsciously carry a mental construct that conjures up a person’s image based on their demographical details, especially age. Rarely do we become aware of it. Meeting a new patient in the clinic whose actual physicality is starkly different and worse than the unconscious, age-based mental image can be such rare instance. Not just the age-inappropriate wrinkles or graying hair but their demeanor, body language, slowed movements, examination findings, and even lab tests crystallize the wide gap between our expectations and reality. Combined, these features communicate a gestalt of the “frailty” phenomenon. Frailty is an age-related clinical condition characterized by an increased susceptibility to sudden, disproportionate functional decline following stressor events, typically in the setting of physiological capacity deterioration of several organ systems. 1 Frailty is multidimensional and includes nutrition, mobility, physical activity, strength, endurance, balance, cognition, senses, mood, and social domains. 2 In daily lives, frailty highlights people aging at different rates, and in health care, universally associated with worse medical and surgical outcomes. 3
Frailty and its impact on epilepsy burden and management remain largely unexplored. The manuscript by Vary-O’Neal et al is the first major venture in systematically analyzing frailty and its impact on older adults with epilepsy. 4 Their goal was to investigate frailty’s association with seizure control (frequency in preceding 3 months) and anti-seizure medication (ASM) tolerability (based on Liverpool adverse event profile [LAEP]; tolerance decreases with an increase in LAEP scores). Additionally, they sought to compare three measures of frailty, chosen based on the simplicity of administration, and find one that best captures the frailty in older adults with epilepsy and has robust construct validity. These measures included Edmonton frail scale (EFS; self-reported questionnaire), the clinical frailty scale (CFS; completed by a clinician based on the participant’s physical condition and overall demeanor), and grip strength (a measure of physical strength recorded by hand dynamometer). They included 86 older adults with epilepsy (60-93 years; 50% women; 87% with focal epilepsy) taking at least one ASM who agreed to participate at 4 Canadian epilepsy centers. These patients were dichotomized into “frail” and “robust” based on scores on each frailty measure. Anti-seizure medication tolerability inversely correlates with frailty (not on grip strength) after adjusting for age, sex, and comorbidity burden. For every one-point increase in EFS and CFS, LAEP increased on average by 1.83 points (95% CI: 1.27-2.39) and 2.49 points (95% CI: 0.67-4.30), respectively. In contrast, frailty was not associated with seizure control.
One of the study’s biggest achievements is in finding a clear winner among the 3 frailty scales tested. Edmonton frail score has the best convergent validity due to its significantly moderate correlation with depression, anxiety, quality of life, and functional disability scores. Additionally, it identifies the highest proportion of frail older individuals with epilepsy and finds them to significantly differ from robust individuals on all LAEP domains of ASM tolerability. In addition, it takes a multidimensional approach to frailty, mirroring our evolved understating of the condition. 5 Developed in Canada, EFS enquires about participants’ subjective sense of health, social support, help needed with activities of daily living, and feelings of sadness or depression. Differences in socioeconomic, ethnic, and cultural background can influence such domains. Hence, to a skeptic, the EFS scale performing best when tested in Canadian epilepsy centers may come as no surprise. A quick literature review allays those concerns. Edmonton frail score is validated in other countries, including Turkey, Thailand, Brazil, and various medical and surgical populations. 6 -8
A literature search reveals less than half-dozen articles investigating frailty’s role in people with epilepsy's (PWE's) health. One study found that worsening frailty was associated with an increased rate of nonhome discharge and mortality after epilepsy surgery on univariable analysis. 9 Surgical outcomes and complications in well-selected older adults, including septuagenarians, is comparable to their younger counterparts. 10,11 However, a recent survey of Canadian geriatricians, neurologists, and epileptologists revealed that almost all of them refrained from referring frail older adults for epilepsy surgery. 12 Another UK primary care database study found that in people with late-onset epilepsy, dementia, and worsening frailty were associated with higher mortality. 13 These studies replicate frailty’s well-established deleterious effect on health outcomes and emphasize the urgency for deepening our understanding of its impact on the health of PWE. 3
Aging is typically a risk factor for adverse health outcomes in the general population. However, it lacks sensitivity and specificity to aid individual decision-making, motivating the cliché “age is just a number!”. Frailty, in contrast, is dynamic, giving rise to “good” and “bad” days, which can potentially be prevented and is reversible. 14 The cross-sectional study by Vary-O’Neal et al is not designed to capture the longitudinal frailty changes while aging with epilepsy. Living with epilepsy may potentially hasten frailty compared to peers because several factors driving frailty are commonly noted in PWE. These include restricted mobility and active lifestyle, increased risk of injuries, social stigmatization or isolation, and psychiatric comorbidities. Frailty is not limited to older adults, and 6 frailty parameters had a ≥20% prevalence in community-dwelling middle-aged adults (50-65 years old). 15 These include low activity, exhaustion, living alone, balance impairment, weakness, and executive dysfunction, which are not uncommon in PWE. Therefore, we need studies to map out the natural history of frailty among PWE starting at ages younger than 60. The generalizability of the current study’s findings to all older adults is slightly hampered by its exclusion of individuals with major cognitive deficits and lacking data on patients who declined participation.
A widely recognized rule of thumb in managing ASMs among older adults with epilepsy is to start low and go slow. Most ASMs have comparable seizure control efficacy, this management principle emphasizes enhancing tolerability. The current study provides strong evidence that even after adjusting for age, sex, and comorbidities, frailty in older adults remains a major driver of poor ASM tolerability. In more concrete terms, the study shows that a one to two-point increase in EFS can push an individual LAEP item from “never” to close to being “sometimes” and “always,” respectively, which would warrant a change of the ASM. The increased vulnerability to ASM’s adverse effects among frail older adults likely stems from pharmacokinetic and pharmacodynamics changes deteriorating more rapidly than expected of their age.
The authors did not find frailty to be associated with the patient’s age or the duration of epilepsy on any of the 3 measures. However, EFS shows a trend for frail individuals having an earlier onset of epilepsy (31.5 vs 41 years mean onset age; P = .078). Larger sample sizes in future studies may solidify this association, which could be clinically significant given the almost 10 years difference between the 2 groups and the potential preventability of frailty. 14 Additionally, this trend underscores the possible acceleration of frailty among PWE secondary to the disadvantages faced by them. Anti-seizure medication type (enzyme-inducing vs nonenzyme-inducing) and number were not associated with frail and robust subgroups in the study. Up to two-thirds of older adults receive enzyme-inducing ASMs, 16 which negatively impact bone- and cardiovascular health. It is conceivable that within an individual with epilepsy, a combination of epilepsy factors, chiefly age of onset, seizure control, and ASM use, may have a bidirectional relationship with frailty, thereby blurring a clear cause-and-effect relationship. It may explain frailty’s lack of association with ASM tolerability in older adults with first-time seizures. 17 As we delve deeper into the role of frailty in PWE, the study conducted by Vary-O’Neal et al will serve as a foundational piece of research.
