Gender differences in quality of life and psychiatric comorbidities among persons with juvenile myoclonic epilepsy: A single-center cross-sectional study

INTRODUCTION

Juvenile myoclonic epilepsy (JME) is the most common idiopathic generalized/genetic epilepsy syndrome. Gender differences are known in clinical presentation, with a well-identified female predilection.^[1] Gender differences are also known to impact seizure-related prognosis. Female patients with JME with absence seizures and stress-related precipitants tend to have the highest prevalence of drug refractoriness.^[2] The female gender may also be associated with several negative disease-based outcomes.^[3] Women with JME have a higher prevalence of absence seizures,^[4] later response to antiseizure medications (ASMs), and worse seizure control. Electroencephalographic (EEG) changes have also been reported, with women having more prolonged EEG epileptiform discharge runs and eye closure sensitivity.^[3]

Gender-specific psychosocial outcomes are known for epilepsy in general. Women with epilepsy display more anxiety, lower employment, and greater divorce rates compared to men with epilepsy.^[5] Persons with JME may suffer from poorer social cognition, disadvantageous social traits including cognitive impulsivity,^[6] and unfavorable social outcomes.^[7] Poorer quality of life (QoL) may be associated with the presence of psychiatric comorbidities.^[8] Comorbid psychiatric disorders occur in 37–51% of persons with JME, and are known to negatively impact QoL.^[9-13] Moreover, nearly 35% of JME may be refractory, with psychiatric comorbidities being one of the variables that may contribute to refractoriness.^[14] Most studies on QoL and psychiatric comorbidities in JME do not address gender differences. This is an important issue for several reasons: Women in the reproductive age group with JME are generally not prescribed valproate,^[5,15] which is the drug of choice and is associated with better disease-based outcomes. Instead, levetiracetam and benzodiazepines are preferred for women. Levetiracetam itself may contribute to psychiatric and behavioral issues in 10–15% of adult patients, occasionally leading to discontinuation of the drug.^[16]

Recognizing this gap in the literature, we aimed to study gender-based differences in QoL and psychiatric comorbidities among persons with JME.

MATERIALS AND METHODS

RESULTS

We enrolled 50 patients with JME. Eighteen (36%) were male and 32 (64%) were female patients [Table 1]. The median age of males at study enrollment was 23.5 (range 15–38) years. The median age of females was 22 (16–48) years. The median age at onset in males was 15 (11–19) years and in females was 15.5 (12–22) years. The median duration of illness was 9 (2–37) years among males and 7 (0.5–26) years among females. Most patients had a combination of myoclonic seizures and GTCS. 30% (n = 6) of male patients had 1–2 GTCS/year, 30% had more frequent and 30% had less frequent GTCS. 12.5% of female patients had 1–2 GTCS/year. The remainder had not had GTCS after the onset of the disease. Only one patient provided a history of absence seizures. Among males, 50% were on monotherapy (valproate or levetiracetam), whereas 65.6% (21/32) of female patients were on monotherapy with levetiracetam. Suboptimal seizure control was observed in 65.6% of females and 50% of males (P = 0.2790).

The median QOLIE-31-P score among males was 68.31 (37.13–91.82) and for females was 66.9 (31.7–99.1) [Table 2]. The median overall QoL score for males was 65 (25–87.5), which qualified as “fair” QoL. For females, the median overall QoL score was 62.5 (10–87.5) which also qualified as “fair” QoL. No significant difference was noted between genders in QoL (P = 0.723).

Among males, 55.5% (10/18) suffered from psychiatric comorbidity [Table 3]. Of these, two had mild depression and eight had anxiety (7 had mild and 1 had moderate anxiety. Among female patients, 34.4% had comorbid psychiatric issues; 6 had anxiety (4 had mild and 2 had moderate anxiety) and 5 had depression (mild). No significant difference was noted between genders in terms of psychiatric comorbidities (P = 0.9136). No association could be determined between QoL and features such as the presence of psychiatric comorbidities, age at onset, epilepsy duration, seizure control monotherapy/polytherapy, or sociodemographic features (age, gender, educational status, socio-economic status, religion, occupation, and marital status). No association could be determined between the presence of psychiatric comorbidities and features such as age at onset, epilepsy duration, monotherapy/polytherapy, or sociodemographic features (age, gender, educational status, socio-economic status, religion, occupation, and marital status).

Subgroup analysis of QOLIE-AD-48 was conducted among patients below 17 years of age (one male, three females). For the male patient, the score was 54.9 and the average score for females was 61.5.

DISCUSSION

In this cross-sectional study, no significant gender differences in persons with JME in terms of QoL and psychiatric comorbidities were observed. This is the first study to examine gender-related concerns in persons with JME in terms of psychiatric comorbidities and QoL.

Limited data exist on QoL and its determinants in JME. In a retrospective study among 33 patients with JME (21 females) who were followed for more than 20 years, early and long-term seizure freedom was associated with better QoL (odds ratio 2.25).^[21] The presence of more severe epilepsy, side effects from ASMs, the presence of depression, and sleep disruptions negatively impacted QoL. Another study, which assessed 30 patients with JME, explored the impact of psychiatric comorbidities on QoL, using the QoL in Epilepsy Inventory-89 (QOLIE-89). JME patients who had mood disorders scored lower on the attention/concentration subscale and negatively affected QoL.^[9] In another large study from India with 165 patients with JME, the presence of psychiatric comorbidities was associated with a lower overall QOLIE-31 score (55.84 ± 13.07 vs. 68.70 ± 11.23, P < 0.001) and lower social function score (80.95 ± 19.22 vs. 91.09 ± 14.74, P < 0.001).^[10] Similar to the latter study, most persons with JME in our study had “fair” QoL, although we did not observe a correlation between the presence of psychiatric comorbidity or seizure control. Gender-stratified QoL has not been explored in these studies.

In terms of psychiatric comorbidities, the burden in JME is substantial. The prevalence of psychiatric comorbidities ranges from 37% to 51%.^[11-13] In a study from India, 46.6% of persons with JME had psychiatric disorders.^[10] In this study, females constituted 38.6% of the cohort. Similar to our study, 16.3% of the patients in this study had depressive disorder, and 30.3% had anxiety, which is similar to our cohort (28% had anxiety overall). This is also similar to another study by de Araujo Filho and Yacubian.^[22] However, the proportion of male patients with JME was much higher (44%) in our study compared to female patients, which trended toward statistical significance. This is an interesting finding that urges assessment in larger studies.

The profile of psychiatric comorbidities among persons with JME has also been observed to differ among those who harbor anxiety compared to those who have comorbid depression. In a study by Somayajula et al., depression was more prevalent among older persons (above 35 years of age) with JME, and a strong correlation was observed between marriage and depression.^[10] We did not observe such a difference, which may be due to the small number of patients who were married in our cohort, and the younger age group. Only one patient in each of the groups based on gender was above the age of 35 years.

Only one patient provided a history of absence seizures, suggesting that this seizure type was likely to be underrecognized in our cohort. As per historical cohorts, 20–40% of patients with JME have absence seizures.

Expectedly, a significantly higher proportion of male patients were on valproate treatment compared to female patients in our cohort. Valproate has well-established dose-dependent teratogenic effects and is avoided in women of childbearing potential.^[23] However, valproate has better efficacy in JME compared to alternative drugs. This is also reflected in our observation that a higher proportion of women in our cohort continued to have seizures compared to men, although this difference was not statistically significant. Lamotrigine (<325 mg/day) may also be used as an alternative drug in this subgroup,^[24] but it was highly underutilized in our cohort. This could partly be because levetiracetam, valproate, phenytoin, and clobazam are provided by our institute, whereas lamotrigine is not available, explaining the bias in prescription from our center. Of the 25% of women who were on valproate from our center, only two had completed the family. These observations indicate the challenges of managing JME among patients of childbearing potential. A prescription of valproate in this population should be at the lowest possible dose and after an informed discussion with the patient regarding risks and benefits.^[23]

The implication of gender on seizure-related prognosis remains uncertain, with conflicting reports in the literature. In a meta-analysis by Stevelink et al., gender was not a determinant of refractoriness in JME.^[14] Even long-term prognosis in terms of seizure control and freedom may not differ between male and female patients.^[25] Our study did not find a significant difference in terms of seizure control among male and female patients with JME.

The strengths of this study were a comprehensive assessment of psychiatric comorbidities, first by the M.I.N.I screening questionnaire and then confirmation based on DSM-5 criteria. A detailed QoL assessment was performed using QOLIE-31-P and QOLIE-48-AD scores. This is the first study to assess gender differences in QoL and psychiatric comorbidities in JME.

The limitations include a small number of patients enrolled, which was mainly due to the study being conducted during the COVID-19 pandemic, which restricted recruitment. We did not assess the relationship between seizure-related outcomes and QoL in terms of gender, which is also an interesting question to consider.

CONCLUSION

Persons with JME do not have gender-stratified differences in terms of psychiatric comorbidities and QoL despite differences in exposure to ASMs and other gender-related factors. Both female and male persons with JME should be screened for psychiatric comorbidities, specifically anxiety, and depression, and also assessed for differences in neuropsychological profiles and determinants of such differences, if any. Studies with a larger number of patients are required to assess determinants of QoL among persons with JME.