Introduction
Anti-seizure medications (ASMs) are the mainstay of management of
epilepsy [1,2]. However, data from cross-sectional studies and
randomized controlled trials have revealed that up to 80% of persons
with epilepsy (PWE) taking ASMs experience an adverse effect [3],
the most common being gastrointestinal disturbances, loss of appetite
and nausea, weight gain, tremor, rash and fatigue/tiredness [4].
Even though these adverse effects (AEs) adversely impact health related
quality of life and reduces patient compliance [1,3,5], it has been
observed that clinicians either under-report or sometimes overlook them
[6].
Since routine screening for AEs in PWE may improve patients’ health
related quality of life, need of a screening tool that can reliably
identify and detect the nature and frequency of AE in PWE on ASMs and
also is easy to administer in a busy clinical setting was identified and
the Liverpool Adverse Events Profile (LAEP) was developed in the 1990s
by Baker et al. to evaluate the most common negative AEs encountered by
the patients that impact patient compliance to prescribed ASMs
[7–12]. LAEP is a validated, epilepsy specific, 19-item
questionnaire which assesses the physical, psychological and cognitive
state of PWE [13] and is one of the widely used scales to detect and
quantify the presence and severity of AEs associated with different ASMs
[7,14,15].
Besides the AEs with ASMs, now it is amply clear that there are multiple
co-morbidities associated with epilepsy in PWE which require
identification and intervention. Depression is one such pathology with
prevalence up to 40%, and PWE need to be evaluated routinely [16].
In this study, using LAEP the adverse effects of ASMs in PWE were
identified and quantified and in order to assess the feasibility of
using LAEP score for predicting depression in PWE, the correlation with
different assessment tools for depression was determined.
- Material and Methods
- Study design: A prospective observational study
- Study Participants: After the Institute Ethics Committee
approval, PWE attending neurology outpatient department (OPD) at All
India Institute of Medical Sciences (AIIMS), New Delhi, India were
included in the study. The inclusion criteria for recruiting the
patients were age ≥ 18years, either gender, meet diagnostic criteria
for epilepsy as per ILAE, and on ASMs. Written informed consent was
obtained; patient and treatment details relevant to the study were
recorded.
- Assessment of adverse effects experienced by PWE: LAEP
screening tool was used for adverse event profiling in enrolled PWE.
LAEP contains 19 items related to both physical and psychological
symptoms. Each item is assessed on a 4-point likert scale where
[1] = never, [2] = seldom, [3] = sometimes and [4] =
often or always, and scores can range from 19 to 76. Higher scores
indicate higher levels of prevalence and severity of adverse
effects. A cut-off point of ≥45 on the LAEP indicates “high
toxicity” whereas <45 indicates “low toxicity” i.e.
mild to moderate adverse effects [3,17,18]. In this study, the
participants were asked all the 19 questions, and their responses
were recorded.
- Assessment of depression in PWE: The instruments used for
the detection of depression in PWE were MINI, NDDI-E, HPHQ-9 and
HAM-D. Permission for using all above tools, where required was duly
taken.
- Correlation between LAEP scores and depression in PWE:Since LAEP contains items pertaining to emotional and psychosomatic
symptoms related to depression, association of the total LEAP score
with co-morbid depression in PWE using other assessment tools was
determined.
- Statistical analysis: Statistical analysis was performed
using STATA statistical software, version 14. The sensitivity,
specificity, likelihood ratio positive and negative, and area under
the curve (AUC) for the ROC curve with its 95% confidence intervals
(CIs) were calculated using MINI as reference standard. The
categorical variables between the group with depression and the
group without depression were compared using the chi-square or the
exact Fisher test, while continuous variables were compared using
the Student’s t test or Mann–Whitney U test. Logistic regression
model was applied to determine the influence of demographic,
epilepsy, and ASM-related factors on LAEP results. Correlation
analysis was also performed between the LAEP score, and depression
scores of other tools. A significance level of p <0.05
(two-tailed) was adopted.
- Results
- Liverpool Adverse Events Profile and clinico-demographic
characteristics: Three hundred and nine PWE (51.5% females)
attending the neurology OPD at AIIMS, New Delhi between July 2018 –
March 2020, meeting eligibility criteria were enrolled in the study,
and underwent neuropsychiatric evaluation. The age of the
participants ranged from 18–75 years, mean age 28.8±9.1 years. Two
hundred and nine PWE had a diagnosis of generalized seizures and 100
PWE had focal seizures. A total of 236 subjects had had seizures
within 2 years and 73 subjects were seizure free ≥ 2 years (Table
1).
Among the PWE, 38.2% were on monotherapy and rest were on polytherapy.
Among monotherapy, most PWE were on Levetiracetam (62 out of 118).
Clobazam was the most commonly used ASM in polytherapy (153 out of 191)
followed by levetiracetam (115 out of 191). In polytherapy, while 89 PWE
received two ASMs, 59 received three ASMs, 35 received four ASMs, 07
received five ASMS, and 01 PWE received seven ASMs.
Table 2 gives the mean score, medians, and frequency response of each
item of the LAEP. The mean LAEP scores in PWE were 28.2 ± 6.2 and ranged
from 19 to 49. There was no significant difference in LAEP scores based
on demographic variables. Expectedly, the exceptions were number of ASMs
as polytherapy was more likely to be related with higher LAEP scores
(Table 1).
Adverse event profiling using LAEP: The most common AE were
feeling of anger/ aggression (92.9%), nervousness and/or agitation
(72.7%), memory problems (67.6%), tiredness (62.5%), headache
(54.7%), restlessness (43.6%), hair loss (43.4%), depression (43%)
and disturbed sleep (39.2%) (Figure 1). Only 16 PWE (5PWE on
monotherapy and 11 on Polytherapy) had LAEP score ≥ 45 i.e. had high
toxicity.
ASMs and LAEP scores: The frequency of common AEs varied
among different ASMs. Feeling of anger/ aggression was more present in
CBZ> LEV> SV> PHT, nervousness
and/or agitation in CBZ> SV>
LEV> PHT, memory problems in PHT>
CBZ> LEV> SV, tiredness in LEV>
PHT> CBZ> SV, depression in
PHT> CBZ> LEV> SV, headache in
PHT> LEV> CBZ> PHT, hair loss
in LEV=CBZ> SV> PHT, and disturbed sleep in
PHT> CBZ> SV> LEV. However, LEV
polytherapy was significantly associated with three AEs - tiredness
(p=0.007), difficulty in concentrating (p=0.008), and depression
(p=0.043).
Per se phenytoin was associated with highest LEAP score (n= 6, 28.7 ±
9.8), followed by carbamazepine (n=17, 27.8 ± 5.3), levetiracetam (n=62,
26.7 ± 5.8), and sodium valproate (n=27, 25.8 ± 5.3), but the difference
was not statistically significant. In addition, there was no significant
difference in LAEP score when the daily dose range of prescribed ASMs
was compared (carbamazepine - <800mg vs. ≥800mg, 27.8±6.9 vs.
23±0; phenytoin- 100mg vs. >100mg, 25± 1.7 vs. 32.3 ±
14.01; sodium valproate- <1000mg vs. ≥ 1000mg, 26.1 ± 6.03 vs.
25.1 ± 3.8), except in case of levetiracetam where PWE on ≥1500mg had
higher LAEP score than PWE on <1500mg (p= 0.0525) (Table 3).
In Levetiracetam group on ≥1500mg, there were significantly increased
complaints of adverse events i.e. difficulty in concentrating (p=
0.0097), dizziness (p= 0.0478), and depression (p= 0.0116).
Polytherapy was associated with higher LAEP score as compared to
monotherapy and the difference was statistically significant (p=0.0013)
(Table 1). There was a statistically significant difference between PWE
on monotherapy or polytherapy for certain specific items on LAEP namely
headache (p= 0.045), shaky hands (p= 0.003) and memory problems (p=
0.000), where as adverse events related to mood and behaviour were
restlessness (p=0.043), feeling of anger and aggression to others
(p=0.036), nervousness or agitation (p=0.002) and depression (p= 0.000)
(Table 4).
In polytherapy combinations, the most commonly prescribed ASMs were
levetiracetam and clobazam. The LAEP score increased with addition of an
ASM, and was higher when either of the ASMs levetiracetam,
carbamazepine, phenytoin and sodium valproate were prescribed with three
or more ASMs (Table 5).
Prevalence of depression in PWE: Using the different tools,
the percentage of PWE detected positive for depression were 38.8,
39.8, 43 and 43.4 with MINI, NDDI-E, HAM-D and PHQ-9 respectively. In
case of LAEP, as per the 17th item of scale i.e.
depression, 57% reported no depression, 22.3% rarely had depression,
17.2% experienced it sometimes, and 3.6% always or often reported
depression. PWE with depression had significantly (p<0.0001)
higher LAEP score than PWE without depression (Table 1).
ROC curve for detecting depression in PWE: The frequency of
responses of each item of LAEP is given in table 2. ROC analysis
revealed that at a cut-off score of ≥28, the LAEP had a sensitivity of
88.33%, a specificity of 83.60%, and an area under the curve (AUC)
of 0.932 (95% confidence interval [CI] = 0.905–0.959; standard
error [SE] = 0.014) (Table 6, Figure 2).
All the adverse events in LAEP had significant association with
depression irrespective of nature i.e. whether adverse events were
related to CNS (neurological) or non-CNS (cosmetic or gastrointestinal)
or psychiatric (mood and behaviour).
Correlations between LAEP and depression scores: A
statistically significant, strong positive correlation of LAEP score
with depression scores as assessed by different screening instruments
was observed (Table 7). Subjects with higher LAEP score had more
severe depression.
Discussion:
Upto 88 percent of PWE using ASMs have at least one AE, which has a
significant detrimental impact on their quality of life and treatment
adherence, resulting in treatment failure and seizure recurrence
[1,10,19]. It is apparent that early detection of PWE at high risk
of adverse event burden might help avoid treatment failures. Apart from
this, psychiatric co-morbidities can potentially have a negative
influence on seizure control [20]. It is evident that the treatment
of epilepsy cannot be limited to the achievement of seizure-freedom
alone, managing related co-morbidities particularly depression is
important [21]. While clinicians can use any depression assessment
instrument, such as the MINI, NDDI-E, HAM-D, or PHQ-9 to identify
psychiatric co-morbidities, it may not be feasible for an
epileptologist/ neurologist to routinely evaluate each and every PWE for
depression and ASM related AEs using different tools. A quick inventory
that can screen PWE at risk of depression as well as the AEs of ASMs
without unnecessarily increasing the burden to clinicians may be useful
and save time and resources.
The LAEP is a commonly used screening tool that quantifies subjective
symptoms reported by patients. According to many studies, LAEP screens a
greater percentage of adverse events than spontaneous reporting
[11,17,22]. According to Carreno et al (2008), ASM-related AE was
found in 34% of PWE when assessed by spontaneous reporting and 66%
when assessed using a checklist [22]. Another study reported that
the prevalence of adverse events identified by a validated screening
approach was nearly three times that of an unstructured interview
[11,23]. Thus LAEP score needs to be obtained for assessing
prevalence of AEs in PWE.
In earlier studies, a wide variation in mean LAEP scores in PWE on ASMs
has been reported, ranging from 27 to 43 [24]. In this study, a
comparatively lower mean LAEP score was observed i.e. 28.15±6.24,
inspite of the fact that study was carried out in a tertiary care
setting. The reason for lower score in this study is not clear.
Interestingly, LAEP scores were also not found to be influenced by
demographic variables like gender, age, seizure control, and epilepsy
type. In many studies LAEP score increased with female gender, older
age, higher seizure frequency, uncontrolled generalized seizures, etc
[1,14,19]. In case of ASMs, PWE on carbamazepine were reported to
have the highest LAEP score in some studies [13], however in this
study, phenytoin use was associated with the highest LAEP score followed
by Carbamazepine. A recent study has also reported that PWE using
oxcarbazepine had a higher score of LAEP [14]. Kowski et al (2016)
reported significant association of levetiracetam with anger/aggression,
nervousness/agitation, and depression [19]. In our study, LEV
polytherapy was significantly associated with tiredness, difficulty in
concentrating, and depression. Feeling of anger/ aggression and
nervousness and/or agitation were reported more with CBZ; depression,
headache, disturbed sleep, and memory problems were more frequent in
PHT; tiredness in LEV, and hair loss both in LEV and CBZ. While other
studies have also reported that the incidence rate of AEs increase, with
increased dosages of ASMs [25]. However, there was no significant
difference in LAEP score when the daily dose range of prescribed ASMs
was compared except in levetiracetam where PWE on ≥1500mg had higher
LAEP score than PWE on <1500mg. Levetiracetam ≥1500mg group
was significantly associated with adverse events i.e. difficulty in
concentrating, dizziness, and depression.
Higher seizure frequency, symptomatic epilepsy, drug resistance, ASM
polytherapy, younger age at epilepsy onset, female gender, and
depression are all shown to be related with a higher burden of AEs of
ASM [1,14,19]. The current study found that PWE on polytherapy and
those having depression had significantly higher LAEP score, however no
significant association was observed with gender, age, seizure control
and type of seizures. Our observation that polytherapy causes more
adverse effects than monotherapy was consistent with the results
documented by previous studies [13,26]. Andrew et al (2012) reported
that tiredness, memory problems and difficulty concentrating were the
most common AEs and were consistently higher in polytherapy than in
monotherapy [13]. It has been observed that ASMs have a 30-40%
incidence of adverse side effects, and this rate increases to 50-60% if
PWE takes two or more drugs at the same time [27,28]. A consistently
higher score of LAEP was reported in PWE with depression. Mula (2009)
has also reported that as compared to PWE without depression, PWE with
depression are more likely to experience adverse effects of ASMs
[29].
Some studies have reported positive correlation of the total LEAP score
with depression [15]. This is presumed to be because the LAEP
contains items pertaining to emotional and psychosomatic symptoms
related to depression, and it is suggested that LAEP may be useful for
screening major depression [15,30]. However, these workers contended
that the use of the LAEP scale along with depression assessment tool may
be necessary due to the fact that some AEs of ASMs are readily assessed
through routine screening (rash, weight gain/loss), others are difficult
to observe, and some of the AEs of ASMs resemble with somatic symptoms
of depression such as difficulty in concentrating, fatigue and sleep
disorders [15,18]. We validated LAEP using MINI as reference
standard, and it was seen that at a cut-off of ≥ 28 LAEP can screen PWE
positive for co-morbid depression as well as monitor the AEs of ASMs.
Kwon & Park (2018) suggested a cut-off of >40 (sensitivity
80%; specificity 80%) could detect major depression disorder [15].
However, with a cut-off of ≥ 28 (sensitivity 88.3%; specificity 83.6%)
of LAEP, even minimal or mild depression will not be overlooked. It is
suggested that PWE with a LAEP score of more than 28 be referred for
psychiatric evaluation and subsequent investigation with diagnostic
tools of depression such as MINI, SCID, etc.
The limitation of the study was its cross-sectional design. This study
was carried out in a tertiary care center, where the majority of the
patients have refractory or drug resistant epilepsy and therefore, the
results might not be representative of PWE in the general population.
Conclusion:
The systematic use of LAEP in epilepsy clinics may enhance
identification and quantification of ASM adverse effects, as well as
lead prescription adjustments to decrease toxicity or adverse effects,
and improve patients’ health status. Use of LAEP will also help in
recognizing PWE who are more likely to become depressed, and thus can be
referred to psychiatry for further clinical assessment and management.