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. 2021 Dec 10;16(12):e0261386. doi: 10.1371/journal.pone.0261386

Sleep quality and associated factors among adult patients with epilepsy attending follow-up care at referral hospitals in Amhara region, Ethiopia

Sintayehu Simie Tsega 1,*, Birhaneselassie Gebeyehu Yazew 1, Kennean Mekonnen 2
Editor: Hamidreza Karimi-Sari3
PMCID: PMC8664217  PMID: 34890425

Abstract

Background

Globally, epilepsy is the commonest neurological disorder in adults. It has significant health and economic consequences to the affected individuals and the family. There is ample evidence that epileptic patients are at increased risk of poor sleep quality than the general population. However, there is limited evidence on sleep quality among epileptic patients and associated factors in Ethiopia. Therefore, this study investigated the prevalence of poor sleep quality and associated factors among adult patients with epilepsy.

Method

Institutional based cross-sectional study was conducted among adult epileptic patients attending follow-up care at referral hospitals in the Amhara region. A total of 575 epileptic patients were recruited using a stratified systematic random sampling technique. An interviewer-administered semi-structured questionnaire and record review were used for data collection. To assess sleep quality the pretested Pittsburgh Sleep Quality Index (PSQI) tool was used. A binary logistic regression model was used to assess factors associated with poor sleep quality. Variables with a p-value less than 0.2 in the bivariable binary logistic regression analysis were considered for the multivariable binary logistic regression analysis. In the multivariable binary logistic regression analysis, the Adjusted Odds Ratio (AOR) with the 95% Confidence Interval (CI) were reported to declare the statistical significance and strength of association. Model fitness was assessed using the Hosmer-Lemeshow test and was adequate (p>0.05). Multicollinearity of the independent variables was assessed using the Variance Inflation Factor (VIF) and the mean VIF was less than 10.

Results

A total of 565 participants were enrolled in the study with a response rate of 98.3%. The prevalence of poor sleep quality among adult epileptic patients was 68.8% [95% CI: 64.8%, 72.5%]. In the multivariable binary logistic regression, being unable to read and write [AOR = 3.16, 95%CI: 1.53, 6.51], taking polytherapy treatment [AOR = 2.10, 95% CI: 1.37, 3.21], poor medication adherence [AOR = 2.53, 95%CI: 1.02, 6.23] and having poor support [AOR = 2.72, 95%CI: 1.53, 4.82] and moderate social support [AOR = 1.89, 95%CI: 1.05, 3.41] were significantly associated with higher odds of poor sleep quality.

Conclusion and recommendation

Poor sleep quality is a major public health concern in Ethiopia. The patient’s level of education, number of medication use, medication adherence, and social support were found significant predictors of poor sleep quality. These findings highlight improving medication adherence and social support are effective strategies to improve the sleep quality of epileptic patients. Besides, it is better to give special emphasis to those epileptic patients with a low level of education and taking polytherapy to enhance sleep quality.

Background

Epilepsy is a neurological disorder attributed to the disruption of brain electrical activity characterized by abnormal body movement and sensory disturbances [1]. It is the most common form of chronic neurological disease affecting more than 50 million people worldwide, of whom, 80% were living in Low-and Middle-Income Countries (LMICs) [2]. The vast majority (70%) of new-onset of epilepsy occur in adults [3]. Epilepsy imposes huge physical, emotional and economic consequences [4, 5].

Sleep is a natural reversible sleep-wake cycle and physiological process that is characterized by perceptual disengagement [6]. Sleep quality is measured by how long and how healthy an individual sleeps, it also contains how problematic it is for an individual to fall asleep and how many times a person wakes up throughout the night [7, 8]. Based on the 2017 result of the National Sleep Foundation (NSF) in the United States of America (USA), good sleep quality is indicated by sleeping more time while in bed (at least 85% of the total time), falling asleep within 30 minutes or less, waking up not more than once per night, and being awake for 20 minutes or less after initially falling asleep [9].

Poor sleep quality impairs the quality of life, cognitive function, and emotion of epileptic individuals [10]. Adults with epilepsy experience poorer sleep quality than their peer healthy counterparts, owing to the nocturnal seizures, which results in marked decrements in quality of life [11]. Likewise, poor sleep is a serious health problem in the contemporary world and the burden commonly observed among epileptic patients that could activate seizures [1216]. Further, it can induce various adverse outcomes among epilepsy patients, including excessive daytime sleepiness and cognitive impairment [17]. Poor sleep quality is also related to daytime dysfunction and depression and negatively impacts the quality of life [18].

Sleep quality influences physical, intellectual, and emotional health, and good quality of sleep is an essential element for epileptic patients but is highly overlooked [6]. Its deprivation weakens physical function, lowers productivity, and can cause a mental health problem [19].

Previous studies identified several factors which have a significant association with poor sleep quality among adult epileptic patients, of them, taking more than one antiepileptic drug and poor medication adherence was the strongest risk factor for poor sleep quality [20, 21]. Currently, in developing countries including Ethiopia, the prevalence of epilepsy has been increased dramatically over time [22]. Different authors showed that epileptic patients are at increased risk of comorbidities, of which poor sleep quality is the commonest. Poor sleep quality in epileptic patients makes clinical management more complicated. Therefore, understanding the magnitude and associated factors of poor sleep quality could help to enhance the anti-epileptic treatment outcomes. There is a dearth of information on the prevalence and associated factors of sleep quality among adult Epileptic patients in the study area.

Despite poor sleep quality among epileptic patients having significant physical, mental, and economic consequences, there is limited evidence on the prevalence of poor sleep quality and associated factors among epileptic patients in Ethiopia. Though there are studies reported in Ethiopia [23, 24], these findings cannot be generalized to the current study area as there is huge socio-economic difference such as level of education, wealth, health care access, and health information between them. Besides, we incorporated important predictors such as perceived stigma which is identified as a proximal predictor of sleep quality among epileptic patients. Therefore, this study aimed to investigate the prevalence and associated factors of poor sleep quality among epileptic patients who had follow-up care at referral hospitals in the Amhara region. The findings of the study would give a spotlight to mental health experts, clinicians, and other stakeholders to design a strategy to mitigate the problem and the associated consequences. Moreover, the results of this study would provide information for healthcare providers, caregivers; zonal and regional health administrative to give attention to adult Epileptic patients to optimize and improve the quality of life through improving on service quality primarily on sleep quality.

Methods

Study design, period, and setting

An institutional-based cross-sectional study was conducted among adult epileptic patients attending follow-up care at referral hospitals in the Amhara region from March 23 to April 23, 2021. Amhara region, the second-most populous region in the Federal Democratic Republic of Ethiopia. There are a total of eight Referral Hospitals, of these five are found in the Northwestern part of the region, namely; Debre Markos, Debre Tabor, University of Gondar comprehensive specialized Referral Hospital, Tibebegion Comprehensive Referral Hospital, and Felegehiwot Comprehensive Referral hospital, whereas Dessie referral hospital and Woldia Referral hospitals are eastern Amhara and Debrebirahan referral hospital in southern Amhara. Among those, four referral hospitals were selected randomly by using a simple random sampling method, those hospitals are Felegehiwot referral hospital, a tertiary hospital found in Bahir Dar which is the capital city of the Amhara National Regional State, located approximately 565 km northwest of Addis Ababa, Debre Markos referral hospital placed at Debre Markos town, 256 km from Bahir-Dar, the capital of Amhara Regional State and located 300 km from Addis Ababa, the capital city of Ethiopia, Dessie referral hospital found at Dessie town 480 km from Bahir Dar, the capital city of Amhara regional state and located 401 km away from Addis Ababa, the capital city of Ethiopia and Debretabor comprehensive specialized referral hospital.

Source and study population

Adult epileptic patients attending follow-up care at referral hospitals in the Amhara region were the source of the population whereas adult epileptic patients who were attending follow-up care during the data collection period at selected referral hospitals in the Amhara region were the study population. Patients with epilepsy having at least one month of follow-up at selected referral hospitals were included in the study but those who were severely ill and unable to respond were excluded from the study.

Sample size determination and sampling technique

The sample size was determined by using a single population proportion formula for the first objective considering the following assumptions (Z = 1.96, d = 0.05, and P = 65.4%) [25]. For secondary objectives i.e. for factors associated with poor sleep quality, the sample size was calculated for factors like sex and number of therapy using Epi-Info version 7 statistical software. Finally, the sample size we obtained from the first objective was the largest and taken as our final sample. By using the design effect as 1.5 and adding a 10% non-response rate, the final estimated sample size was 575. Eight referral hospitals are giving epilepsy follow-up services in Amhara Region. The study was conducted on those four randomly selected Referral Hospitals of epilepsy follow-up care and therefore there are an averagely of 1361 epilepsy patients during the data collection period. Then from them, 575 participants were proportionally allocated to each selected referral hospital and those participants were interviewed by systematic random sampling technique considering every two individuals. To avoid recycling of data’s special marks were used in the chart and supported by verbal confirmation whether to participate or not in the previous four weeks. The sampling interval value was determined by dividing the total adult epilepsy clients who have a follow-up at referral hospitals in the Amhara region (n = 1361) by the sample size, 1361/575. The first individual was selected using a lottery method.

Measurements and data collection technique

Data were collected by five BSc nurses. In addition to the principal investigator, two supervisors were responsible for monitoring the data collection process and the data was collected through face-to-face interviews and medical chart review for the one-month duration. Sleep quality was assessed by using the Pittsburgh Sleep Quality Index, a Self-report questioner containing 19 items assessing seven components of sleep over the past month: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, daytime dysfunction, and use of sleep medications. Each component is scored (range 0–3). A total global PSQI score ranges from 0 to 21 (26) classifying a global score of ≥ 5 as poor sleep quality [26]. We used Cronbach’s alpha to assess the internal consistency of a set of scale or test items. The value varies between 0 and 1 and that a higher value indicates a higher internal consistency. The general rule of thumb is that a Cronbach’s alpha of 0.70 and above is good, 0. 80 and above is better, and 0. 90 and above is best. It is computed by correlating the score for each scale item with the total score for each observation, and then comparing that of the variance for all individual item scores [27];

α=(KK1)(1i=0kyi2/x2)

Where;

K refers to the number of the scale item

δyi2 refers to the variance with the item i

δ2x refers to the variance associated with the observed total scores

In this study, the internal consistency was found Cronbach’s alpha α = 0.86.

The Hospital Anxiety and Depression Scale (HADS) was confirmed its validity and reliability among Ethiopian HIV-positive subjects with Cronbach’s alpha (0.87) [28]. It is a brief and internationally used self-rating scale with 14 items (seven items for each). In this study Cronbach’s alpha was for HADS-A was (0.92), HADS-D (0.90), and for both anxiety and depression (HADS) was 0.95.

Perceived stigma was assessed by the Kilifi Stigma Scale of Epilepsy, which was developed and validated in Kilifi, Kenya, with high internal consistency, Cronbach’s α of 0.91. It is a three-point Likert scoring system scored as “not at all” (0), “sometimes” (1), and “always” (2). It has fifteen items and a total score was calculated by the addition of all item scores. The score above the median value of the data showed the presence of perceived/felt stigma [29, 30]. In this study, its Cronbach’s alpha was 0.95.

Medication adherence level was evaluated by using the ten-item Medication Adherence Rating Scale (MARS). It includes questions asking adherence and drug attitude, and the total score is the sum of these questions which is supposed to assess adherence in better quality [31]. In this study Crobanch alpha = 0.79. Social support was assessed by the Oslo-3 items social support scale (Oslo SSS), which has three items with a Likert scale [32]. Its Cronbach’s alpha was done (0.94). Sleep Hygiene Index (SHI), assesses the practice of sleep hygiene behaviors. It has 13-item each item is rated on a five-point scale ranging from 0 (never) to 4 (always). An overall score varies from 0 to 52 [33]. Cronbach’s alpha was done (0.94).

Variables and data analysis

The dependent variable was the quality of sleep (poor/good) and the independent variables were Socio-demographic factors (age, sex, marital status, occupational status, level of income, and educational status), Clinically related factors (drug adherence, duration of treatment, seizure type, frequency of seizure, number of medication taken, and comorbidity), Behavioral factors(substance use (alcohol, chat, cigarette, illicit drugs) or other substances) and psychosocial factors(anxiety, sleep hygiene, depression, perceived stigma, and social support). Data were coded and entered to Epi data version 4.6 statistical software and then exported to STATA version 14 statistical software. For analysis Chi-square assumption was checked for categorical variables to check the presence of statistically significant association with sleep quality and to screen them for the binary logistic regression model. The prevalence of poor sleep quality with the 95% Confidence Interval (CI) was reported. For the associated factors, a binary logistic regression model was fitted. Both bi-variable and multi-variable binary logistic regression analyses were done, and variables with a p-value ≤ 0.2 in the bi-variable binary logistic regression analysis were considered for the multivariable analysis. In the multivariable binary logistic regression analysis, the Adjusted Odds Ratio (AOR) with the 95% CI was reported to declare the statistical significance and strength of association between poor sleep quality and the independent variables. The model fitness was assessed by the Hosmer-Lemeshow test (0.31). Multicollinearity of the independent variables was assessed by using Variance Inflation Factor (VIF) and the mean VIF was 2.64.

Ethical consideration

The study was approved by the Research Ethical Review Committee of the school of nursing, College Medicine, and Health Sciences on behalf of the University of Gondar review board S/n/164/2013. A formal letter indicating the approval was obtained and submitted to Amhara Referral Hospitals’ administrative. Oral informed consent was obtained from each participant and personal identification like name and medical registration numbers were not used to maintain confidentiality.

Results

Socio-demographic characteristics of the study participants

A total of 565 participants were enrolled in the study, with a 98.3% response rate. Among the study participants more than half (53.27%) were females, 301(53.27%) were married, 165(29.20%) attended secondary school and 306(54.16%) were orthodox religion followers. The median (±IQR) age of participants was 35 ±14 years. The median average family monthly income was 1500 ±1000 ETB (Table 1).

Table 1. Socio-demographic characteristics of adult patients with epilepsy attending follow-up care at referral hospitals in Amhara region, Ethiopia, 2021 (n = 565).

Variable Category Frequency (n) Percent (%)
Sex Male 264 46.73
Female 301 53.27
Age (in years) 18–24 73 12.92
25–34 195 31.51
35–44 172 30.44
≥45 125 22.12
Marital status Married 268 47.43
Single 198 35.04
Divorced 68 12.04
Widowed 31 5.49
Educational status Unable to read and write 138 24.42
Primary school 162 28.67
Secondary school 165 29.20
College and above 100 17.70
Occupational status Farmer 80 14.16
Government employee 84 14.87
Housewife 110 19.47
Merchant 80 14.16
Self-employee 128 22.65
Student 83 14.69
Religion Orthodox 306 54.16
Muslim 153 27.08
Protestant 91 16.11
Others* 15 2.65
Residence Urban 292 51.68
Rural 273 48.32
Average family monthly income(ETB) ≤1000 255 45.13
>1000 310 54.87

** Other* = Catholic, joeva, Adventist.

Clinical characteristics of the participants

Among study participants, more than two-thirds (61.06%) were used polytherapy anti-epileptic medication, 323(57.17) were used phenytoin, 366(64.78%) had one up to two seizure frequencies per month and 384(67.96%) of adult epileptic patients had good medication adherence (Table 2).

Table 2. Clinical characteristics of adult patients with epilepsy attending follow-up care at referral hospitals in Amhara region, Ethiopia, 2021 (n = 565).

Variable Category Frequency(n) Percent (%)
Therapy One 220 38.94
Two and above 345 61.06
Medication type Carbamazepine Yes 200 35.40
No 365 64.60
Phenobarbital Yes 311 55.04
No 254 44.96
Phenytoin Yes 323 57.17
No 242 42.83
Sodium valproate Yes 99 17.52
No 466 82.48
Other medication Yes 16 2.83
No 549 97.17
Duration of treatment in years <5 480 84.96
6–10 78 13.80
≥11 7 1.24
Comorbidity Yes 20 3.54
No 545 96.46
Seizure frequency/ month 0 50 8.85
1–2 366 64.78
≥3 149 26.37
Seizure type Focal 13 2.30
Generalized 552 97.70
Drug adherence Good 384 67.96
Poor 181 32.04

Other medication = Chlorothiazide and Hydrochlorothiazide.

Behavioral and psychosocial characteristics of the study participants

Among study participants, more than one-third (36.46%) of epileptic patients had poor social support and 42.65% had strong social support. Regarding perceived stigma, about 47.43% were felt perceived stigma (Table 3).

Table 3. Behavioral and psychological characteristics of adult patients with epilepsy attending follow up care at referral hospitals in Amhara region, Ethiopia, 2021 (n = 565).

Variables Category Frequency(n) Percent (%)
Substance use
Alcohol drinking Yes 82 14.51
No 483 85.49
Chat chewing Yes 6 1.06
No 559 98.94
Cigarette smoking Yes 8 1.42
No 557 98.58
Anxiety no 285 50.44
yes 280 49.56
Depression No 292 51.68
yes 273 48.32
Perceived stigma No 297 52.57
yes 268 47.43
Sleep hygiene Poor 276 48.85
Good 289 51.15

Pittsburgh Sleep Quality Index (PSQI) subscale score

Among study participants, 227(40.18%) rated their overall sleep quality as fairly good. About 133(23.54%) of the study participants slept 85% and above of their time spent in bed. The participants went to bed on average at 8:00 pm and wakeup at 7:00 Am. moreover, the meantime for sleep was 9:00hrs (Table 4).

Table 4. The Pittsburgh Sleep Quality Index (PSQI) subscale scores among adult epileptic patients attending follow-up care at referral hospitals in Amhara region, Ethiopia, 2021.

PSQI subscale         Category Frequency (n) Percent
sleep latency (C2) <15mints+not during the past month 222 39.29
16–30 mints+ less than once a week 226 40.00
31-60min+ once or twice a week 71 12.57
>60 mints + three or more times a week 46 8.14
Sleep duration (C3) >7hrs 477 84.42
6–7 hrs 70 12.39
5–6 hrs 11 1.95
<5 hrs 7 1.24
Habitual sleep efficiency (C4) ≥85% 133 23.54
75%-84% 5 0.88
65%-74% 35 6.19
<65% 392 69.38
Sleep disturbance (C5) None 90 15.93
1–9 389 68.85
10–18 58 10.27
19–27 28 4.96
Medication use for sleep (C6) Not during the last month 510 90.27
less than once a week 28 4.96
once or twice a week 23 4.07
≥3 times a week 4 0.71
Daytime dysfunction (C7) No problem 314 55.58
Slight problem(1-2/week) 119 21.06
Moderate problem>2/week) 110 19.47
Big problem >3/week 22 3.89
Global sleep quality Median IQR
6 4

**Key: IQR- Inter Quartile Range, PSQI-Pittsburgh Sleep Quality Index, and C-component.

The most frequent reason for the difficulty in maintaining sleep was pain 334(59.12%) followed by midnight wake up or early morning in 273 patients (48.32%), to use the bathroom in 191 patients (33.81%), unable to fall asleep within 30 minutes in 188 patients (32.27%), having bad dreams in 139 patients (26.60%), coughing in 128 patients (22.65%), feeling of too hot in 121 patients (21.42%), having difficulty of breathing in 119 patients (21.06%), felling of too cold in 114 patients (20.18%) and others (for taking medication and for praying) in 29 patients (4.24%). In this study, the prevalence of poor sleep quality among adult epileptic patients was found to be 68.8% (95%CI; 64.8%, 72.5%). The prevalence of poor sleep quality among adult epileptic patients taking polytherapy treatment was 76.8% (95%CI; 72.0%, 80.1%) whereas monotherapy treatment was 56.4% (95%CI; 49.7%, 62.8%).

Factors associated with poor sleep quality

In the multivariable binary logistic regression analysis, educational status, number of medications, social support, and medication adherence were significantly associated with poor sleep quality. An epileptic patient who was unable to read and write had 3.16 times (AOR = 3.16, 95%CI: (1.53, 6.51)) higher odds of poor sleep quality as compared to those who attained college and above. The odds of poor sleep quality among patients who took more than one anti-epileptic drug were 2.10 times (AOR = 2.10, 95%CI: (1.37, 3.21)) higher than those who took one anti-epileptic drug. Epileptic patients who had poor medication adherence were 2.53 times (AOR = 2.53, 95%CI: (1.02, 6.23)) higher odds of poor sleep quality compared to those who had good medication adherence. Epileptic patients who had poor social support had 2.72 times (AOR = 2.72, 95%CI: (1.53, 4.82)) and those who had moderate social support had 1.89 times (AOR = 1.89, 95%CI: (1.05, 3.41)) higher odds of poor sleep quality compared to those who have strong social support (Table 5).

Table 5. Factors associated with poor sleep quality among adult epileptic patients attending follow-up care at referral hospitals in Amhara region, Ethiopia, 2021.

Variable Category       Sleep quality COR(95%CI) AOR(95%CI) P-value
Poor (%) Good (%)
Sex Female 222(73.75) 79(26.25) 1.63(1.14,2.34) 1.26(0.83,1.92) 0.28
Male 167(63.26) 97(36.74) 1.00 1.00
Age in years 18–24 41(56.16) 32(43.84) 1.00 1.00
25–34 134(68.72) 61(31.28) 1.71(0.99,2.98) 1.51(0.82,2.79) 0.18
35–44 123(71.51) 49(28.49) 1.96(1.11,3.46) 1.31(0.69,2.49) 0.40
≥45 91(72.80) 34(27.20) 2.09(1.14,3.83) 0.81(0.39,1.68) 0.57
Educational status Unable to read and write 121(87.68) 17(12.32) 4.18(2.18,8.00) 3.16(1.53,6.51) ** 0.002
Primary school 92(56.79) 70(43.21) 0.77(0.46,1.29) 0.57(0.32,1.01) 0.06
Secondary school 113(68.48) 52(31.52) 1.28(0.76,2.15) 1.02(0.55,1.86) 0.96
College and above 63(63.00) 37(37.00) 1.00 1.00
Average monthly income(ETB) ≤1000 191(74.90) 64(25.10) 1.69(1.17,2.43) 1.30(0.84,2.01) 0.23
>1000 198(63.87) 112(36.13) 1.00 1.00
Therapy Two and above 265(76.81) 80(23.19) 2.56(1.78,3.69) 2.10(1.37,3.21) ** 0.001
One 124(56.36) 96(43.64) 1.00 1.00
Seizure frequency per month 0 32(64.00) 18(36.00) 1.00 1.00
1–2 234(63.93) 132(36.07) 0.99(0.54,1.84) 0.95(0.46,1.95) 0.89
≥3 123(82.55) 26(17.45 2.66(1.30,5.44) 0.64(0.21,1.98) 0.44
Substance use Yes 82(85.42) 14(14.58) 3.09(1.69,5.62) 1.07(0.49,2.34) 0.85
No 307(65.46) 162(34.54) 1.00 1.00
Anxiety Yes 210(75.00) 70(25.00) 1.78(1.24,2.55) 0.64(0.27,1.47) 0.29
No 179(62.81) 106(37.19 1.00 1.00
Depression Yes 209(76.56) 64(23.44) 2.03(1.41,2.93) 1.94(0.83,4.55) 0.12
No 180(61.64) 112(38.36) 1.00 1.00
Perceived stigma Yes 197(73.51) 71(26.49) 1.52(1.06,2.18) 0.73(0.35,1.51) 0.39
No 192(64.65) 105(35.35) 1.00 1.00
Drug adherence poor 154(85.08) 27(14.92) 3.62(2.29,5.71) 2.53(1.02,6.23) * 0.04
good 235(61.20) 149(38.80) 1.00 1.00
Social support poor 169(82.04) 37(17.96) 3.96(2.56,6.14) 2.72(1.53,4.82) ** 0.001
moderate 91(77.12) 27(22.88) 2.93(1.78,4.82) 1.89(1.05,3.41) * 0.03
strong 129(53.53) 112(46.47) 1.00 1.00
Sleep hygiene poor 208(75.36) 68(24.64) 1.82(1.27,2.62) 1.14(0.67,1.94) 0.62
good 181(62.63) 108(37.37) 1.00 1.00

*p-value<0.05,

**p-value<0.01 COR = Crude Odds Ratio, AOR = Adjusted Odds Ratio and CI = confidence interval. Model fitness: Hosmer Lemeshow Goodness of fittest; P value was 0.31.

Discussion

Poor sleep quality is a serious health problem for adult patients with Epilepsy in low-and middle-income countries including Ethiopia. This study found that the prevalence of poor sleep quality among adult Epileptic patients was 68.8%. This finding was in line with studies conducted in Ethiopia, Addis Ababa 65.4% [25], United States of America 72% [34], and Brazil 67.3% [26]. However, it was higher than studies reported in Taiwan 50% [20], Korea 41.1 [35], Spain 53.6% [36], India 48% [37], Turkey 42.7% and Southeast Asia 33% [8]. Possible reasons for the difference may be due to the use of different screening tools and cutoff points.

Besides, the discrepancy may be due to exclusion and inclusion criteria of the study participants (comorbidity, medications known to affect sleep, night work, shift work, and Patients who received phenobarbital) were excluded in the study conducted in Taiwan [20]. Patients having comorbidity, night workers, shift workers were excluded whereas patients having been followed for epilepsy for at least two years were the Inclusion criteria in a study conducted in Turkey [38]. In a study conducted in Korea, epilepsy patients’ ages greater than or equal to 20 years were included [35].

In a study done in Karnataka, India patients with comorbid diseases or medications known to affect sleep, other than Valproic acid, and those with substance abuse of any degree were excluded [37].

The finding from this study was lower than a study conducted in Nigeria [39]. The variation may be due to measurement tool difference (Epworth sleepiness score tool was used in a study conducted in Nigeria whereas the PSQI tool was used in this study).

In the current study, associations were observed between poor sleep quality and different independent variables. The odds of developing poor sleep quality among patients who are unable to read and write were nearly three times as compared to those who attended college and above.

The possible justification may be due to the lesser knowledge they may have about seizure-triggering factors and seizure management as well as they may not easily understand instructions given from health professionals and this may result in poor medication adherence, poor seizure control which may result in poor sleep quality. Moreover, it might be also due to fewer employment opportunities because people who are unable to read and write are less likely to have different job offers and less chance of employment by both governmental and non-governmental organizations which may result in stress and turn compromise their sleep quality.

The odds of developing poor sleep quality among patients who took more than one drug were more than two times more likely to develop poor sleep quality as compared to those who took one anti-epileptic drug. This finding is supported by studies conducted in Addis Ababa, Ethiopia Taiwan, India, and Delhi India [20, 25, 40, 41]. The possible reason may be due to that the use of polytherapy anti-epileptic drugs may raise undesirable effects and drug-drug interactions result in poor sleep quality. Even though a few pieces of literature have suggested that in epilepsy, more than one AED in general required in medication-resistant cases, and the higher the number of AEDs needed, the higher is the degree of severity of pharmaco-resistance. therefore the tight relation between poor sleep quality and AED polytherapy suggests that poor sleep quality may arise as a result of the disease itself, or it may be secondary to the effects of medications [34]. Besides this, patients who had Polytherapy medication treatment might have un-affordability issues which result in stress, poor medication adherence, and poor sleep quality.

Epileptic patients who had poor medication adherence to their AED were nearly three times more likely to develop poor sleep quality as compared to their counterparts. This finding was supported by study findings conducted in Addis Ababa, Ethiopia [25], Taiwan [20], India [41], and Brazil [42]. The possible justification might be that epileptic patients with poor medication adherence to their antiepileptic drug could result in increased seizure frequency, hospital admissions, increased health care cost, and worse clinical outcomes that may contribute patients to having poor sleep quality. Moreover, patients who had poor adherence to their AED may lead to reduced seizure control, decreased work productivity, and seizure-related job loss, stress, and poor sleep quality.

Epileptic patients who had poor Social support were nearly three times and moderate social support were nearly two times more likely to have poor sleep quality as compared to participants who have strong social support. This finding was supported by a study conducted in Southeast Asia [8].

The possible justification might be due to the sense of being not loved and socially lonely can contribute to providing that an uncomfortable environment that hinders the capability to cope with the disease condition results in poor sleep quality.

Moreover, this might be due to persons who had poor social support cannot have the ability to avoid negative feelings in their personal life, not being able to concentrate on their daily activities and they cannot make their life meaningful which may end with poor sleep quality. Furthermore, epileptic patients who have poor social support can contribute to greater perceived stress and hopelessness, they also go through stressful conditions and which consequences in poor sleep quality. Strong social support is believed to endorse good sleep quality by providing a safe context in which close family or friends care for sleepers’ enemies or other threats [43].

Limitation of the study

The study may be prone to recall bias as it assesses sleep conditions before a month. Due to the cross-sectional nature of the study, we are unable to draw the cause-effect relationships of poor sleep quality and the predictors.

Conclusion

The finding of this study showed that more than two–thirds of the study participants had poor sleep quality at referral hospitals in the Amhara region. Unable to read and write, polytherapy treatment, poor medication adherence, and having poor and moderate social support, were factors that increase the occurrence of poor sleep quality. Therefore, to improve the sleep quality of epileptic patients the health care provider should give special emphasis to those who took multidrug, poorly adhered, or who are unable to read and write through social integration [44].

Supporting information

S1 Dataset

(DTA)

Acknowledgments

We would like to thank study participants, data collectors, and supervisors for their unreserved contribution during data collection. Also, we would like to forward our gratitude to Amhara region Referral Hospital administrators, heads of the chronic outpatient department, and health care providers for their valuable support during data collection.

Abbreviations

AEDs

Anti-Epileptic Drugs

AOR

Adjusted Odds Ratio

MARs

Medication Adherence Rating scale

CI

Confidence Interval

HADS-A

Hospital Anxiety, and Depression Scale-anxiety component

HADS-D

Hospital Anxiety, and Depression Scale-depression component

OSS-3

Oslo-3 items social support scale

PSQI

Pittsburgh Sleep Quality Index and SHI: Sleep Hygiene Index

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The University of Gondar College of Medicine and Health sciences was the funding source for this study. It was funding for data collection and we acknowledge it.

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Decision Letter 0

Hamidreza Karimi-Sari

11 Oct 2021

PONE-D-21-26585Sleep quality and associated factors among adult patients with epilepsy attending follow-up care at Referral Hospitals in Amhara Region, EthiopiaPLOS ONE

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Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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**********

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Reviewer #2: Yes

**********

5. Review Comments to the Author

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Reviewer #1: The authors have used multiple questionnaires and logistic regression to assess sleep quality in the Amhara Region, Ethiopia. The authors have found that medical adherence, social support, education level and anti-epileptic drug load are significant predictors for sleep quality.

Major points:

1. The language and punctuation throughout the manuscript needs attention. There are many instances where errors make it difficult to interpret the authors meaning. Some examples of the errors are listed below (please note that the errors listed are from the first page but there are many more errors on that first page and throughout the entire manuscript than are listed here):

- Correct neurologic to neurological in the abstract

- Line 52: capitalize first letter at the beginning of the sentence.

- Line 55: incorrect placement of commas

- Line 59: I believe the authors might mean ‘measured’ or ‘gauged’ rather than manifested

- Line 65: replace ‘later’ with ‘after’

- Line 67: poor should be poorer

2. I found the discussion of Cronbach’s alpha confusing and unclear. How was it actually being used and how was it being calculated. Please include the formula for how Cronbach’s alpha is calculated in the paper and explain more clearly how it is being used. For example: Cronbach alpha was calculated for each questionnaire to determine internal consistency, meaning that each question was assessing the same concept. It would also be useful to describe that the value varies between 0 and 1 and that a higher value indicates a higher internal consistency. What is the cut-off value for the questionnaire to be considered ‘valid and reliable’?

3. Sleep comorbidities? Were patients with sleep comorbidities included in this study? If so, please look at how those patients might be influencing the results and include a thorough discussion as to how this might bias your results.

Minor points:

4. Line 239: I assume the patients wakeup at 7AM not PM on average?

5. How does 8pm bedtime compare to healthy individuals in the region? Is that an earlier bedtime than normal?

6. Please separate the discussion of each questionnaire in the methods section into individual paragraphs. It is confusing having some paragraphs discuss one questionnaire and others discuss multiple unrelated questionnaires.

7. Please make sure you are clear for each questionnaire as to how the questions are scored (what range of numbers) and whether a higher/lower score indicates better/worse sleep hygiene (for example).

8. Is the high prevalence of pain causing wake up thought to be related to their epilepsy or is this consistent with the healthy population from the region?

9. Was the ability to read and write associated with medication adherence? Seems with the data at hand you could actually test the theory you are putting forward on lines 295-296.

10. Spelling mistake in title of final figure

Reviewer #2: Important paper that seeks to relate the quality of sleep with sociodemographic, clinical, behavioral and psychosocial factors in patients with epilepsy. Here are suggestions for modification:

In the abstract and in line 87, replace "literature" by "authors" because it is the latter who suggest or show something. There is no need in the summary and discussion to represent the confidence interval. In line 42, replace "common" with important, great presence, any term that stands out more than common.

In the introduction, line 58, improve sleep description. It is not "started" by a circadian cycle but has circadian rhythmicity. Furthermore, the correct one is the phase of wakefulness and not the period. Nor would I say that the quality of sleep "manifests" itself and the term "slumbering" is not very common in the literature.

In line 66, is cited multitude of sequelae, I would like to see this paragraph more developed. The same applies for the consequences of poor sleep quality, on line 71.

I suggest paying attention to some parts of the work regarding the writing of English. For example, the paragraph in line 74 is a science communication text and not a text for a scientific journal at the PLOS ONE level. It should not be abandoned but rewritten with greater scientific rigor. There are also several small grammar errors throughout the text that a review by an English language specialist can be helpful.

In line 83, complete the study description reasoning. On line 91, remove "As to our search of the literature"

I didn't understand the justification in lines 93, 94, 95. Elaborate this part better. On line 96, "Would be able" gets too vague. Need to be more assertive.

In the results, in Table 1: Why age groups are not homogeneous: 18-24; 25-31; 32-38; 39-45; and > 45. I suggest using 5 groups.

In the body of the text, provide more details on the results shown in table 1, 2. Table 2 can be joined with table 3. Rethink the need to include figure 1, or include the other factors that are associated with poor sleep quality, "Being incapable of reading and writing", "undergoing polytherapy", "having poor medication adherence" and "having poor and moderate social support". In table 4, it is not clear "<15mints + not during the last month" (?). Describe in the caption what IQR means. I see no need for Figure 2 unless the results are discussed in the later section.

Remove the subheadings "Subjective sleep quality rate (component one)", "Sleep disturbance (component five)" and "Sleep quality prevalence" Provide a more detailed and joint description of all PSQI results.

Discussion

Do not repeat in line 272 what the objectives of the study are. Add the first paragraphs and remove any mention of standard deviations, confidence intervals, for example (95% CI; 64.8%, 72.5%) because we are in the discussion part and not the results part.

The last paragraph reflects my criticism of the need to revise English. I understood what the authors mean but the text can improve a lot. It is necessary to discuss with references about the outcome of pain (component five). In the conclusions, cite what was said in the summary of the work about how to improve the quality of sleep in these patients.

**********

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Reviewer #1: No

Reviewer #2: Yes: Leandro Lourenção Duarte

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PLoS One. 2021 Dec 10;16(12):e0261386. doi: 10.1371/journal.pone.0261386.r002

Author response to Decision Letter 0


16 Nov 2021

Point by point response for editors/reviewers comments

PLOS ONE Journal

Manuscript title: Sleep quality and associated factors among adult patients with epilepsy attending follow-up care at Referral Hospitals in Amhara Region, Ethiopia

Manuscript ID: PONE-D-21-26585

Dear editor/reviewer.

Dear all,

We would like to thank you for this constructive, building, and improvable comments on this manuscript that would improve the content of the manuscript. We considered each comment and clarification questions of editors and reviewers on the manuscript thoroughly. Our point-by-point responses for each comment and question are described in detail on the following pages. Further, the details of changes were shown by track changes in the supplementary document attached.

Response to reviewers’ comment

Reviewer#1

1. The language and punctuation throughout the manuscript needs attention. There are many instances where errors make it difficult to interpret the authors meaning. Some examples of the errors are listed below (please note that the errors listed are from the first page but there are many more errors on that first page and throughout the entire manuscript than are listed here)

-Correct neurologic to neurological in the abstract

- Line 52: capitalize first letter at the beginning of the sentence.

- Line 55: incorrect placement of commas

- Line 59: I believe the authors might mean ‘measured’ or ‘gauged’ rather than manifested

- Line 65: replace ‘later’ with ‘after’

- Line 67: poor should be poorer

Authors’ response: Thank you for reviewer for the comments. We have addressed all the comments. We had extensively edited the entire manuscript for grammatical errors, sentence structure and typographical errors with the help of language experts at the University. (See the revised manuscript)

2. I found the discussion of Cronbach’s alpha confusing and unclear. How was it actually being used and how was it being calculated. Please include the formula for how Cronbach’s alpha is calculated in the paper and explain more clearly how it is being used. For example: Cronbach’s alpha was calculated for each questionnaire to determine internal consistency, meaning that each question was assessing the same concept. It would also be useful to describe that the value varies between 0 and 1 and that a higher value indicates a higher internal consistency. What is the cut-off value for the questionnaire to be considered ‘valid and reliable’?

Authors’ response: Thank you reviewer for the comments. As you said we assessed Cronbach’s alpha to assess the internal consistency, it is ranged from 0 to 1. Literatures suggested that as general rule that α of 0.6 – 0.7 indicates an acceptable level of reliability, and 0.8 and above is considered as a very good level of internal consistency. For further we have included the formula to calculate Cronbach’s alpha and some statement about it. If you need further justification we are ready to provide it. (See the Method section, Page 5-6, line 153-163)

3. Sleep comorbidities? Were patients with sleep comorbidities included in this study? If so, please look at how those patients might be influencing the results and include a thorough discussion as to how this might bias your results.

Authors’ response: Thank you reviewer for the comments. As you said sleep comorbidities like underlying medical conditions which may have association with sleep quality might influence our findings. And therefore, we considered underlying comorbidity other than epilepsy as independent variable and considered in the analysis. We planned to consider this variable during analysis to control its confounding effect on others, but unfortunately this variable did not fulfill the chi-square assumption /in the bivariable binary logistic regression analysis and we did not considered in the multivariable binary logistic regression analysis. That is why we did not discuss this in the discussion section. (See the revised manuscript)

Minor points

4. Line 239: I assume the patients’ wakeup at 7AM not PM on average?

Authors’ response: Thank you reviewer for the comments. It was editorial error and we have addressed the comment. (See the revised manuscript)

5. How does 8pm bedtime compare to healthy individuals in the region? Is that an earlier bedtime than normal?

Authors’ response: Thank you reviewer for the comment. We have asked this question to compute the component habitual sleep efficiency (PSQI) (Component 4: Habitual sleep efficiency Component 4 (total # of hours asleep) / (total # of hours in bed) x 100 (>85%=0, 75%-84%=1, 65%-74%=2, <65%=3). Simultaneously, we have reported average bedtime, relatively which is usual time in case of Ethiopia. Therefore, if our response does not convince you we are ready to remove this sentence in the manuscript as it is not standalone variable in this study.

6. Please separate the discussion of each questionnaire in the methods section into individual paragraphs. It is confusing having some paragraphs discuss one questionnaire and others discuss multiple unrelated questionnaires.

Authors’ response: Thank you reviewer for the comment. We accept it and use separate paragraph for each questionnaire. (See Method section, line 146-182, and page 5-6)

7. Please make sure you are clear for each questionnaire as to how the questions are scored (what range of numbers) and whether a higher/lower score indicates better/worse sleep hygiene (for example).

Authors’ response: Thank you for the comments. We have computed each scores based on the tools recommendation and we make sure that we have checked the scores are correct. (See the revised manuscript)

8. Is the high prevalence of pain causing wake up thought to be related to their epilepsy or is this consistent with the healthy population from the region?

Authors’ response: Thank you reviewer for the comment. To compute Component 5, there is one question about sleep disturbance and cause of disturbance. One of the option was pain and the high prevalence of pain causing wake up was high and we believe that this pain is related to epilepsy and its associated morbidity than the healthy population. (See Revised manuscript)

9. Was the ability to read and write associated with medication adherence? Seems with the data at hand you could actually test the theory you are putting forward on lines 295-296.

Authors’ response: Thank you reviewer for the comment. We gave this possible explanation for why those who were unable to read and write had higher odds of poor sleep quality than who attained college and above based on our knowledge. As per your suggestion we have checked whether there was significant association between education and adherence using chi-square and odds ratio based on the cells in cross tabulation, which indicated that there was no significant association between them and we remove that statement in the discussion section. (See the revised manuscript)

10. Spelling mistake in title of final figure

Authors’ response: Thank you reviewer for the comment. We have modified it. (See the revised manuscript)

Reviewer#2

1. In the abstract and in line 87, replace "literature" by "authors" because it is the latter who suggest or show something. There is no need in the summary and discussion to represent the confidence interval. In line 42, replace "common" with important, great presence, any term that stands out more than common.

Authors’ response: Thank you for the comments, we have addressed all the comments. (See the revised manuscript)

2. In the introduction, line 58, improve sleep description. It is not "started" by a circadian cycle but has circadian rhythmicity. Furthermore, the correct one is the phase of wakefulness and not the period. Nor would I say that the quality of sleep "manifests" itself and the term "slumbering" is not very common in the literature.

Authors’ response: Thank you reviewer for the comment. We rephrase it and use the most appropriate definitions of sleep quality. (See the revised manuscript)

3. In line 66, is cited multitude of sequelae, I would like to see this paragraph more developed. The same applies for the consequences of poor sleep quality, on line 71.

Authors’ response: Thank you reviewer for the comments. We have addressed it. (See the revised manuscript)

4. I suggest paying attention to some parts of the work regarding the writing of English. For example, the paragraph in line 74 is a science communication text and not a text for a scientific journal at the PLOS ONE level. It should not be abandoned but rewritten with greater scientific rigor. There are also several small grammar errors throughout the text that a review by an English language specialist can be helpful.

Authors’ response: Thank you for the comments. We extensively modified the entire manuscript with the help of language experts. (See the revised manuscript)

5. In line 83, complete the study description reasoning. On line 91, remove "As to our search of the literature"

Authors’ response: Thank you reviewer for the comment. We have modified it. (See the revised manuscript)

6. I didn't understand the justification in lines 93, 94, 95. Elaborate this part better. On line 96, "Would be able" gets too vague. Need to be more assertive.

Authors’ response: Thank you reviewer for the comments. We have rewrote it. (See the revised manuscript)

7. In the results, in Table 1: Why age groups are not homogeneous: 18-24; 25-31; 32-38; 39-45; and > 45. I suggest using 5 groups.

Authors’ response: Thank you reviewer for the suggestions but we have categorizing the variable age based on previous literature and scientific evidence that is why the category is not homogeneous. Therefore, we keep it as it is.

8. In the body of the text, provide more details on the results shown in table 1, 2. Table 2 can be joined with table 3. Rethink the need to include figure 1, or include the other factors that are associated with poor sleep quality, "Being incapable of reading and writing", "undergoing polytherapy", "having poor medication adherence" and "having poor and moderate social support".

Authors’ response: Thank you reviewer for comments. The tables and figure have different information and we prefer it to present separately. (See the revised manuscript)

9. In table 4, it is not clear "<15mints + not during the last month" (?).

Authors’ response: Thank you for the comments, in the PSQI questionnaire tool component two was assessed as question #2 (after recoding was done ) sum with question #5a Score meaning that #2 Score (<15min (0), 16-30min (1), 31-60 min (2), >60min (3))+ #5a Score (if sum is equal 0=0; 1-2=1; 3-4=2; 5-6=3).

10. Describe in the caption what IQR means. I see no need for Figure 2 unless the results are discussed in the later section.

Authors’ response: Thank you for the comments, we have addressed all the comments. (See the revised manuscript)

11. Remove the subheadings "Subjective sleep quality rate (component one)", "Sleep disturbance (component five)" and "Sleep quality prevalence" Provide a more detailed and joint description of all PSQI results.

Authors’ response: Thank you for the comments, we have addressed all the comments. (See the revised manuscript)

12. Do not repeat in line 272 what the objectives of the study are. Add the first paragraphs and remove any mention of standard deviations, confidence intervals, for example (95% CI; 64.8%, 72.5%) because we are in the discussion part and not the results part.

Authors’ response: Thank you for the comments, we have addressed all the comments. (See the revised manuscript)

13. The last paragraph reflects my criticism of the need to revise English. I understood what the authors mean but the text can improve a lot. It is necessary to discuss with references about the outcome of pain (component five). In the conclusions, cite what was said in the summary of the work about how to improve the quality of sleep in these patients.

Authors’ response: Thank you reviewer for the concerns. We used pain as one item to compute component five but not considered as a separate variable, then we aggregate the seven components to generate sleep quality global score. Then, based on the score we computed we categorized as poor or good. Therefore, we have not discuss about pain as it was not our objective/was not our independent variables. If these does not convince you we are ready to discuss about it, if it does not make our document lose its focus. (See the revised manuscript)

Attachment

Submitted filename: Point by point response.docx

Decision Letter 1

Hamidreza Karimi-Sari

25 Nov 2021

PONE-D-21-26585R1Sleep quality and associated factors among adult patients with epilepsy attending follow-up care at Referral Hospitals in Amhara Region, EthiopiaPLOS ONE

Dear Dr. Simie,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

ACADEMIC EDITOR:I appreciate the authors' work to revise their manuscript. This version of manuscript is significantly improved compared to the last version. I have another minor comment which should be addressed before being published. The figure one is not necessary. So, please remove this figure. Instead, you can mention the frequency and frequency percent of these reasons in the text. For example: The most frequent reason for the difficulty in maintaining sleep was pain in XX participant (59.12%), followed by midnight wakeup in XX patients (48.32%),...

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PLoS One. 2021 Dec 10;16(12):e0261386. doi: 10.1371/journal.pone.0261386.r004

Author response to Decision Letter 1


26 Nov 2021

Point by point response for editors/reviewers comments

PLOS ONE Journal

Manuscript title: Sleep quality and associated factors among adult patients with epilepsy attending follow-up care at Referral Hospitals in Amhara Region, Ethiopia

Manuscript ID: PONE-D-21-26585R1

Dear editor/reviewer.

Dear all,

We would like to thank you for the constructive, building, and improvable comments on this manuscript that would improve the content of the manuscript. We considered each comment and clarification question of editors and reviewers on the manuscript thoroughly. Our point-by-point responses for each comment and question are described in detail on the following pages. Further, the details of changes were shown by track changes in the supplementary document attached.

Response to Editors comment

1. I appreciate the authors' work to revise their manuscript. This version of manuscript is significantly improved compared to the last version. I have another minor comment which should be addressed before being published. The figure one is not necessary. So, please remove this figure. Instead, you can mention the frequency and frequency percent of these reasons in the text. For example: The most frequent reason for the difficulty in maintaining sleep was pain in XX participant (59.12%), followed by midnight wakeup in XX patients (48.32%),...

Authors’ response: Thank you for the comments. As per your suggestion, we have removed Figure 1 and we wrote the frequencies with the corresponding percentage in text format. (See the revised manuscript)

Attachment

Submitted filename: Authors response.docx

Decision Letter 2

Hamidreza Karimi-Sari

1 Dec 2021

Sleep quality and associated factors among adult patients with epilepsy attending follow-up care at Referral Hospitals in Amhara Region, Ethiopia

PONE-D-21-26585R2

Dear Dr. Simie,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Hamidreza Karimi-Sari, MD

Academic Editor

PLOS ONE

Acceptance letter

Hamidreza Karimi-Sari

3 Dec 2021

PONE-D-21-26585R2

Sleep quality and associated factors among adult patients with epilepsy attending follow-up care at Referral Hospitals in Amhara Region, Ethiopia

Dear Dr. Simie Tsega:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Hamidreza Karimi-Sari

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Dataset

    (DTA)

    Attachment

    Submitted filename: Point by point response.docx

    Attachment

    Submitted filename: Authors response.docx

    Data Availability Statement

    All relevant data are within the paper and its Supporting Information files.


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