Epilepsy is a fairly prevalent condition marked by recurrent seizures, which arise from disruptions in the electrical activity of cortical neurons. Recent estimates indicate that epilepsy contributes to 1% of the global disease burden and ranks as the fourth most common neurological disorder, impacting individuals across all age groups.(1,2) Cognitive function refers to advanced brain activities, including the ability to adapt behavior, solve problems, retain information, and maintain focus.(3) Various factors can affect the cognitive and behavioral consequences of epilepsy.(4) Antiepileptic drugs (AEDs) may share a common mechanism for managing seizures and cognitive issues by reducing the likelihood of excessive neuronal firing, thereby decreasing seizure frequency. Other mechanisms may also play a role.(5)

Typically, antiepileptic drug treatment is initiated when a patient experiences more than one unprovoked seizure within a year. The cognitive adverse effects (CAE) associated with AED monotherapy are generally mild, provided that the blood levels of the anticonvulsants remain within the therapeutic range. In contrast, polypharmacy tends to have a more pronounced negative impact on cognitive function compared to monotherapy, regardless of the specific AEDs used. The neuropsychological functions that are often negatively affected by antiepileptic medications include psychomotor speed, attention, memory, mood, and language, with issues such as dysphasia and anomia being common. Patients typically report a more favorable cognitive profile for newer antiepileptic drugs compared to older ones. However, topiramate, a relatively new medication, stands out as it is linked to significant cognitive, behavioral, and psychiatric side effects. When topiramate is introduced as an adjunctive treatment for individuals with refractory epilepsy, it has been associated with notable declines in verbal IQ, verbal fluency, and verbal learning.(6–8)

Cognitive impairments in individuals with epilepsy are typically addressed indirectly through effective seizure management, which may include early surgical intervention, the selection of anti-epileptic medications with favorable cognitive profiles, and the treatment of associated conditions like depression.(9) The positive impact of anti-epileptic drugs in controlling seizures can sometimes counterbalance their negative cognitive side effects. However, direct interventions aimed at cognitive deficits related to epilepsy, such as vagal nerve stimulation, cholinergic replacement therapies, and stimulants, have limited supporting evidence and are not generally recommended in clinical settings.(10)

Memory rehabilitation techniques may offer more effective direct treatment options for individuals experiencing significant cognitive challenges.(11) The impact of anti-epileptic drugs on cognitive function within the Indian population remains under-researched. Therefore, we aim to investigate how these medications affect cognitive parameters across various epileptic conditions in a South Indian cohort.

Our study primarily seeks to compare cognitive impairments in epilepsy patients treated with both newer and traditional anti-epileptic drugs. Additionally, we will examine how the duration of anti-epileptic therapy influences cognitive function, as well as the effects of mono-therapy versus poly-therapy on cognition in these patients. Furthermore, we will assess which cognitive domains are most commonly impacted by anti-epileptic drugs. Further research is necessary to thoroughly understand the comparative effects of new anti-epileptic drugs relative to older ones.

This research was a cross-sectional observational study aimed at assessing the point prevalence of adverse cognitive effects associated with antiepileptic treatment. No follow-up of the patients was conducted. The study took place over an 8-month period during November 2022 and July 2023 at the Neurology department of the Government General Hospital, a tertiary care teaching hospital, Vijayawada, Andhra Pradesh. The materials utilized for the study included a checklist for eligibility verification, an Informed Consent Form available in English and Telugu, a Data Collection Form, and the Folstein Mini-Mental State Examination Scale (MMSE)(12) in English and Telugu. Approval for the protocol was obtained from the Institutional Ethics Committee.

The inclusion criteria encompassed all adult patients with a history of epilepsy who had been undergoing treatment for a minimum of one month. Exclusion criteria included individuals under 18 years of age, those with an educational level below 10th grade, pregnant and lactating women, patients with mental disabilities, as well as those who are deaf, mute, or blind. Additionally, individuals who had experienced a stroke or were in a coma, those with traumatic brain injuries, Alzheimer’s or Parkinson’s disease, intracranial space-occupying lesions, acutely ill patients, and geriatric patients aged 60 years and older were also excluded.

Patients attending the outpatient clinic of hospital for a review of their antiepileptic therapy were screened using a checklist to determine their eligibility for the study. Each participant provided informed consent to take part in the study, after which they were interviewed using a structured data collection form that recorded demographic information, disease specifics, and medication details. Both male and female patients were included in the study. The cognitive assessment was conducted utilizing the MMSE tool, a neuropsychological test administered to all enrolled patients, with their scores recorded. The data collected from the study were input into SPSS for analysis. IBM SPSS Statistics 21 and Graph Pad Prism version 7.03 were employed for data analysis. Statistical evaluation of the results was performed using t-tests and one-way ANOVA.

A total of 145 patients were screened according to the inclusion and exclusion criteria, 100 were deemed eligible and subsequently enrolled. Baseline demographic details and MMSE scores were showed in Table 1. Nearly 90% of patients were age between 18 to 50 years. Male population contributes 56% and female 44%. Slightly higher patients were received poly-therapy (53%) and mono-therapy (47%). Patients who received mono-therapy, three-fourths (76.6%) of the patients on conventional antiepileptic drugs and only one-forth (23.4%) of the patients were on  newer antiepileptic drugs. Approximately 80% of patients received combination of two conventional AED compared to combination of newer AED and one CAED and one NAED. A total of 53% of patients were taking AEDs either mono-therapy or poly-therapy between 4 to 8 years and only 5 patients received more than 10 years of AED as drug therapy. MMSE scores showed significant differences in mono-therapy versus poly-therapy (25.34±4.32 and 20.45±3.84, P<0.001) CAED+CAED poly-therapy versus other different poly-therapies (18.28±2.10, P<0.001) and duration of drug therapy whoever taken more than 10 years of AED (17.09±2.59, P<0.001)

Table 1: Baseline demographic details and MMSE scores

AED: Anti-epileptic drugs; CAED: Conventional AED; NAED: Newer AED; MMSE: Folstein Mini-Mental State Examination Scale; SD: Standard deviation; * indicates P<0.001 in comparison with other groups

Variation of MMSE scores with respect to duration of mono-therapy were showed in Table 2. Patients who received more than 10 years of single conventional AED were showed less MMSE score as compared to other categories of duration of drug therapy (20.04±2.37, P<0.001) whereas patients who treated with single newer AED doesn’t show any significant difference among different duration of mono-therapy

Table 2: Variation of MMSE scores with respect to duration of mono-therapy

AED: Anti-epileptic drugs; CAED: Conventional AED; NAED: Newer AED; MMSE: Folstein Mini-Mental State Examination Scale; SD: Standard deviation; * indicates P<0.001 in comparison with other groups

Variation of MMSE scores with respect to duration of poly-therapy was showed in Table 3. MMSE scores were compared among different poly-therapies such as two different drugs of CAED and two different drugs of NAED and one CAED and one NAED. Patients who received CAED+CAED for a period of more than 10 years has showed lower MMSE scores and showed significant difference (16.05±1.52, P<0.001). Patients who received NAED+NAED and CAED+NAED not showed any significant difference with respect to duration of poly-therapy

Table 3: Variation of MMSE scores with respect to duration of poly-therapy

AED: Anti-epileptic drugs; CAED: Conventional AED; NAED: Newer AED; MMSE: Folstein Mini-Mental State Examination Scale; SD: Standard deviation; * indicates P<0.001 in comparison with other groups

Effect of mono-therapy and poly-therapy on cognitive domain scores were showed in Figure 1. Statistically significant differences in the means for orientation and language & visuo-spatial skills. The mean scores of registration, attention & calculation and memory were comparable in both groups of mono-therapy and poly-therapy. Orientation cognitive domain has highest domain score and memory cognitive domain has lowest domain score

Figure 1: Effect of mono-therapy and poly-therapy on cognitive domain scores 

Among 100 patients diagnosed with epilepsy, 36 (76.6%) were treated with conventional antiepileptic drugs (CAED), while 11 (23.4%) were on newer antiepileptic drugs (NAED) as monotherapy. Additionally, 42 (79.3%) patients were undergoing classical polytherapy, 7 (13.2%) were receiving newer polytherapy, and 4 (7.5%) were treated with a combination of both classical and newer antiepileptic drugs in a polytherapy regimen.

The study revealed that socio-demographic factors influenced cognitive function within this patient group. Although the mean Mini-Mental State Examination (MMSE) scores did not show statistically significant differences across the three age groups analyzed, the findings align with previous research. Earlier studies indicated that while age may not directly correlate with the occurrence of cognitive adverse effects (CAEs), it likely influences the manifestation of cognitive challenges. A complicating factor in assessing age-related effects is the variation in assessment tools used across different age demographics.(7)

The type of treatment administered was found to significantly affect cognitive function, with patients on polytherapy exhibiting lower mean MMSE scores compared to those on monotherapy. Supporting literature has corroborated these findings, with one study noting that polytherapy with antiepileptic drugs is linked to poorer cognitive outcomes.(13) Another investigation reported that the mean MMSE score for patients on monotherapy (27.13) was superior to that of those on polytherapy (26.38), although the difference was not statistically significant.(14)

Furthermore, the impact of CAED polytherapy versus NAED polytherapy on cognitive function demonstrated a statistically significant difference among patients. The mean MMSE score for those on CAED polytherapy was lower when compared to those on NAED polytherapy and those receiving a combination of CAED and NAED. Previous studies have also supported these observations, indicating that, in general, newer antiepileptic drugs may have different cognitive effects. The findings indicate that, overall, new antiepileptic drugs (AEDs) exhibit little to no adverse cognitive effects. In studies comparing newer AEDs (NAEDs) with conventional AEDs (CAEDs), there was a noticeable preference for NAEDs.(15) Consequently, our results advocate for the use of NAED polytherapy over other treatment options to enhance cognitive functioning in patients. Additionally, the duration of AED use significantly influences cognitive performance, with patients on AEDs for over ten years showing a marked decline in their mean Mini-Mental State Examination (MMSE) scores compared to those on shorter regimens.

Research findings of Aldenkamp AP et al., has indicated that cognitive side effects can reflect the long-term consequences of AED therapy, suggesting that prolonged treatment may exacerbate these effects, thereby affecting daily functioning in patients with refractory epilepsy.(16) Therefore, it is essential to assess the cognitive impact of newer medications, as this could open new avenues in clinical practice for treating patients without inducing cognitive deficits.

When examining the effects of AED monotherapy (both CAED and NAED) and the duration of treatment on MMSE scores, no statistically significant differences were observed. The mean MMSE scores across these groups were similar, indicating that cognitive functioning is similarly impacted by both types of mono-therapy, which is a novel finding from our study. However, when analyzing the effects of AED polytherapy (both CAED and NAED) in relation to treatment duration on MMSE scores, we found statistically significant differences. Our research revealed the lowest mean MMSE scores among patients on CAED combinations for more than ten years. Furthermore, we compared five cognitive domains—orientation, registration, attention and calculation, memory, and language and visuospatial skills—between patients on monotherapy and polytherapy, discovering statistically significant differences in the means for orientation and language and visuospatial skills. The mean scores of registration, attention & calculation and memory were comparable in both groups of mono-therapy and poly-therapy, formed a new finding in our study. A study conducted by Vijaykumar et al., reported the similar findings.(17)

Both positive and negative cognitive effects has been observed with both conventional and newer antiepileptic drugs. The present study concluded that impairment of cognition was comparable in both the gender. Patients who received poly-therepy with CAEDs had more cognitive impairment as compared to NAEDs and combination of CAED and NAED poly-therapy. In addition to that, patients who are on mono-therapy with CAED and mono-therapy with NAED was comparable and no significant difference between the groups. Moreover, patients who were on more than 10 years of AED therapy either with mono-therapy or poly-therapy had lower MMSE scores which indicates greater impairment of cognition. In the present study, various cognitive domains were assessed and we found that patients who received poly-therapy with AEDs has significant affected by the orientation and language & visuo-spatial skills. However, the cognitive domains were not affected and not showed significant difference between mono-therapy with CAED and mono-therapy with NAED. 

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this research paper.

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