Accepted Manuscript

Title: Insomnia in people with epilepsy: A review of insomnia

prevalence, risk factors and associations with epilepsy-related
factors

Authors: Philippe Joaquim Oliveira Menezes Macêdo, Pedro

Sudbrack de Oliveira, Nancy Foldvary-Schaefer, Marleide da
Mota Gomes

PII: S0920-1211(16)30412-0
DOI: http://dx.doi.org/doi:10.1016/j.eplepsyres.2017.05.014
Reference: EPIRES 5747

To appear in: Epilepsy Research

Received date: 29-12-2016

Revised date: 18-5-2017
Accepted date: 27-5-2017

Please cite this article as: Macêdo, Philippe Joaquim Oliveira Menezes,
Oliveira, Pedro Sudbrack de, Foldvary-Schaefer, Nancy, Gomes, Marleide da
Mota, Insomnia in people with epilepsy: A review of insomnia prevalence,
risk factors and associations with epilepsy-related factors.Epilepsy Research
http://dx.doi.org/10.1016/j.eplepsyres.2017.05.014

This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.
Insomnia in people with epilepsy: A review of insomnia prevalence, risk factors and associations with epilepsy-related
factors

Philippe Joaquim Oliveira Menezes Macêdo¹, Pedro Sudbrack de Oliveira¹, Nancy Foldvary-Schaefer2, Marleide da Mota
Gomes3.

1. Fellow – Postgraduate Programs, Department of Internal Medicine, Medical School: Federal University of Rio de
Janeiro, Brazil
2. Professor, Sleep Disorders and Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland/OH, United
States of America
3. Associate Professor, Institute of Neurology, Federal University of Rio de Janeiro, Brazil.

Mailing address
Dr. Philippe Joaquim Oliveira Menezes Macêdo: Avenida Venceslau Bráz, nº 95, Institute of Neurology / Federal University
of Rio de Janeiro, Botafogo, Rio de Janeiro/RJ, Brazil. Zip code: 22290-140, E-mail: macedophilippe@outlook.com.

Conflict of interest:
The authors declare no conflicts of interest regarding this paper.
HIGHLIGHTS

 There are few papers evaluating insomnia symptoms or disorders in people with, especially as a
primary outcome.

 Methodological and selection criteria variability hinder an accurate measurement of the real
prevalence of insomnia prevalence, but it is usually higher than the ones found in nonepileptic
subjects.

 Insomnia severity probably increases with seizure severity, and people with epilepsy suffering
from this comorbid sleep disorder usually have greater impairment on quality of life and higher
degree of depressive symptoms.

ABSTRACT
BACKGROUND: Insomnia is a common sleep complaint in the general population, and sleep loss may
be a trigger for epileptic seizures.
OBJECTIVES: To conduct a comprehensive review of the literature of insomnia symptoms and
insomnia disorder, their prevalence and epilepsy-related risk factors in people with epilepsy (PWE).
METHODS: A PUBMED search was performed for articles indexed to June 2016 involving human
subjects, excluding papers in languages other than English, Spanish and Portuguese and case reports.
Eligible studies were those using a clear definition of insomnia and reporting quantitative data
on prevalence rates and risk factors. The search included the following terms: insomnia, sleep
disorder(s), sleep disturbance(s) and sleep-wake in the title and abstract; and epilep* in the title. 425
papers were reviewed and 31 were selected for the final analysis (21 adult and 10 paediatric). Twenty-
one studies used a control group. Two reviewer authors independently extracted all data and a third
author resolved disagreements.
RESULTS: Most studies were hospital-based, cross-sectional and evaluated convenience samples
representing highly select populations. Various insomnia inventories were used. Fourteen assessed
insomnia (10 in adults, four, children), but only five as primary outcome (none in children). Four
evaluated insomnia disorder based on international classification criteria (International Classification of
Sleep Disorders – ICSD-2 – in 3, and DSM-IV-TR, in 1). In adults, insomnia prevalence was 28.9-51%
based on the Insomnia Severity Index ≥15 and 36-74.4% based on DSM-IV-TR or ICSD-2. The
prevalence of insomnia in children was 13.1-31.5% using the Sleep Disturbance Scale for Children and
11% based on ICSD-2 diagnostic criteria. Compared to control groups, PWE usually had higher
frequencies of insomnia symptoms and disorder. Insomnia was associated with greater impairment in
quality of life and higher degree of depressive symptoms in several studies, and was inconsistently
related to female gender, poor seizure control and antiepileptic drug polytherapy. In children, insomnia
was associated with developmental delay, focal epilepsies and poor seizure control.
CONCLUSION: Insomnia symptoms and insomnia disorder are highly prevalent among PWE based on
a limited number of studies with variable inclusion criteria and methodology. Excessive daytime
sleepiness (EDS) was not found to be related to insomnia disorder or symptoms, and the exclusion of
individuals with EDS may explain the higher frequencies of insomnia found in some studies. Additional
investigations are needed given the potential impact of insomnia on seizure control, mood and QOL in
PWE. .

KEYWORDS: insomnia, insomnia severity index, Athens insomnia scale, sleep disorder, sleep
disturbance, epilepsy.
HIGHLIGHTS

 There are few papers evaluating insomnia symptoms or disorders in people with, especially as a
primary outcome.

 Methodological and selection criteria variability hinder an accurate measurement of the real
prevalence of insomnia prevalence, but it is usually higher than the ones found in nonepileptic
subjects.

 Insomnia severity probably increases with seizure severity, and people with epilepsy suffering
from this comorbid sleep disorder usually have greater impairment on quality of life and higher
degree of depressive symptoms.

1. INTRODUCTION

Epilepsy is a brain disorder characterized by an enduring predisposition to generate epileptic seizures with

consequences on neurobiological, cognitive, psychological, and social performance (Fisher et al., 2014). Sleep-wake

complaints are at least twice as common in people with epilepsy (PWE) compared with the general population (Gutter et al.,

2013; Jain et al., 2013; Xu et al., 2006) and comorbid sleep disturbances have been associated with additional impairment in

quality of life (QoL) (de Weerd et al., 2004; Garcia-Morales et al., 2014; Gutter et al., 2013; Piperidou et al., 2008;

Vendrame et al., 2013), worsening seizure control (Batista and Nunes, 2007; Piperidou et al., 2008) and psychiatric

conditions (Vendrame et al., 2013).

Insomnia symptoms and disorders are exceedingly common in the general population with a prevalence of 35-50%

and 12-20%, respectively, sometimes due to comorbid medical or psychiatric conditions, medications or substance use

(Buysse, 2013; Sateia, 2014). Known risk factors include female gender, older age, lower socioeconomic status, comorbid

psychiatric and medical conditions, substance abuse, unemployment, divorce and widowhood (Buysse, 2013). Insomnia is a

known risk factor for the development of depression and anxiety, as well as to impaired QoL and people with insomnia are

at risk for a number of adverse health outcomes including hypertension, diabetes, and cardiovascular events (Buysse, 2013;

Lewis et al., 2014; Sofi et al., 2014; Vgontzas and Fernandez-Mendoza, 2013). Untreated insomnia has an impact in health

care economics, with direct costs (outpatient encounters, drug prescription, cognitive behaviour therapy, procedures) and

indirect costs (lost workplace productivity, higher accident risks) exceeding 100 billion dollars annually in the USA alone

(Ohayon, 2002; Wickwire et al., 2015). Despite this burden and the high costs, insomnia is still undervalued by most health

professionals and patients (Buysse, 2013; Manni and Terzaghi, 2010; Ohayon, 2002).

The relationship between sleep and epilepsy have been explored in previous studies and the existence of a

detrimental effect of sleep deprivation on epileptiform activity is undeniable (Derry and Duncan, 2013; Manni and Terzaghi,

2010). Moreover, sleep disorders are common in PWE, possibly due to the sleep disruption lead by the occurrence of an

epileptic attack or as a consequence of antiepileptic drug therapy (AED) (Manni and Terzaghi, 2010). However, little
research was performed to assess insomnia in epileptic population, therefore prompting a literature review of the prevalence

of insomnia disorder and symptoms in PWE, as well as to identify possible risk factors related to this comorbid sleep

disorder.

2. METHODS

A PUBMED search was performed to identify publications involving human subjects with epilepsy exploring sleep-

wake disorders and complaints through June 2016 (Figure 1). This search used the terms insomnia, sleep disorder(s), sleep

disturbance(s) and sleep-wake in title and abstract; and epilep (sy,tic), in the title, but not in different languages other than

English, Spanish and Portuguese. Case reports were excluded. Abstracts were reviewed by two investigators (PJOMM and

PSO) for data regarding insomnia symptoms, insomnia disorders and sleep disturbances. Full text analysis was performed

with the purpose of identifying those papers fulfilling standard insomnia disorder diagnostic criteria, using validated

insomnia instruments, such as the Insomnia Severity Index (ISI) and the Athens Insomnia Scale (AIS), and those evaluating

insomnia symptoms.

3. RESULTS

Of 425 studies screened for inclusion, 31 (21 adult, 10 paediatric) fulfilled the inclusion criteria (Tables 1 and 2).

Twenty articles compared outcomes between PWE and controls (Babu et al., 2009; Batista and Nunes, 2007; Chan et al.,

2011; Chen et al., 2011; de Weerd et al., 2004; Gutter et al., 2013; Hoeppner et al., 1984; Im et al., 2016; Ismayilova et al.,

2015; Khatami et al., 2006; Krishnan et al., 2012; Larson et al., 2012; Ng and Bianchi, 2014; Ong et al., 2010; Pizzatto et al.,

2013; Samaitiene et al., 2013; Stores et al., 1998; Wirrell et al., 2005; Yazdi et al., 2013; Zhou et al., 2012), whilst one

compared individuals with refractory and non-refractory epilepsy (Garcia-Morales et al., 2014). Most studies were hospital-

based and cross-sectional, applied sleep questionnaires and evaluated highly selected convenience populations, such as those

without other sleep symptoms/disorders, including excessive daytime sleepiness (EDS) (Chan et al., 2011; Ismayilova et al.,

2015; Khatami et al., 2006; Vendrame et al., 2013; Yang et al., 2016), with higher rates of psychiatric disorders (military

veterans) (Lopez et al., 2013) and with different patterns of seizure control or antiepileptic drug (AED) therapy (Chan et al.,

2011; Cobabe et al., 2015; de Weerd et al., 2004; Gutter et al., 2013; Hoeppner et al., 1984; Im et al., 2016; Krishnan et al.,

2012; Zhou et al., 2012).

In this review, it was noted that studies regarding epilepsy and sleep disturbances frequently lack descriptive and

statistical analysis for specific sleep disorders (such as insomnia, parasomnia and sleep apnea) and rather focus on sleep

complaints and sleep quality more generally. Only five out of the 31 studies focused on insomnia as a primary

endpoint/objective, none in paediatric populations ((Im et al., 2016; Lopez et al., 2013; Quigg et al., 2016; Vendrame et al.,

2013; Yang et al., 2016). Of the 26 remaining studies, two evaluated the presence of insomnia disorder (Ismayilova et al.,
2015; Jain et al., 2013), five applied an insomnia inventory (Cobabe et al., 2015; Garcia-Morales et al., 2014; Piperidou et al.,

2008; Yazdi et al., 2013; Zhou et al., 2012), nine assessed an insomnia subscale of a sleep questionnaire (Batista and Nunes,

2007; Chan et al., 2011; de Weerd et al., 2004; Gutter et al., 2013; Krishnan et al., 2012; Larson et al., 2012; Ong et al., 2010;

Samaitiene et al., 2013; Wirrell et al., 2005) and the rest remarked on the presence of at least one insomnia symptom (Babu et

al., 2009; Chen et al., 2011; Conant et al., 2009; de Almeida et al., 2003; Hoeppner et al., 1984; Khatami et al., 2006;

Komolafe et al., 2015; Pizzatto et al., 2013; Stores et al., 1998).

3.1. Insomnia Classification

4. This review found that the term “insomnia” has been used to refer to both insomnia symptoms and classifiable

disorders, with few including both and differentiating the two (Cobabe et al., 2015; Ismayilova et al., 2015; Quigg et

al., 2016; Yang et al., 2016; Yazdi et al., 2013). Sleep questionnaires were used to assess insomnia symptoms in

both adult and paediatric population and studies commonly explored sleep onset insomnia and sleep maintenance

insomnia. Early morning awakening was directly evaluated in only two studies (Stores et al., 1998; Yazdi et al.,

2013). In adult population studies, insomnia symptoms were commonly evaluated by the ISI or AIS (Cobabe et al.,

2015; Garcia-Morales et al., 2014; Im et al., 2016; Piperidou et al., 2008; Quigg et al., 2016; Stores et al., 1998;

Vendrame et al., 2013; Yang et al., 2016; Yazdi et al., 2013; Zhou et al., 2012) or from an insomnia subscale of

validated sleep questionnaires such as NIMHANS comprehensive sleep disorder questionnaire and Sleep Diagnostic

List (de Weerd et al., 2004; Krishnan et al., 2012), which measured the severity of insomnia symptoms. Other

studies explored the presence or absence of one or more insomnia symptoms (Babu et al., 2009; Chen et al., 2011;

de Almeida et al., 2003; Hoeppner et al., 1984; Khatami et al., 2006; Komolafe et al., 2015; Pizzatto et al., 2013;

Yazdi et al., 2013). In studies assessing paediatric populations, the insomnia subscale of the Sleep Disturbance Scale

for Children was most commonly used (Gutter et al., 2013; Ong et al., 2010; Samaitiene et al., 2013), followed by

the Children Sleep Habits’ Questionnaire (Chan et al., 2011; Larson et al., 2012) and the Sleep Behaviour

Questionnaire (Batista and Nunes, 2007; Wirrell et al., 2005). One study evaluated sleep patterns in subjects with

Angelman syndrome by means of the Behavioral Evaluation of Disorders of Sleep, which only assessed sleep onset

insomnia (Conant et al., 2009). Medical record review (Ng and Bianchi, 2014)was also used.

5. The diagnosis of insomnia disorders was assessed in four papers using the second edition of the International

Classification of Sleep Disorders (ICSD-2) (Jain et al., 2013; Lopez et al., 2013; Yang et al., 2016) or fourth edition

of the Diagnostic and Statistical Manual of Mental Disorders, revised version (DSM-IV-TR) (Ismayilova et al.,

2015). While the ISI and AIS are usually used to measure insomnia symptoms, some papers considered standard

cutoff values for the diagnosis of clinically relevant insomnia (Garcia-Morales et al., 2014; Piperidou et al., 2008;

Quigg et al., 2016; Vendrame et al., 2013; Yazdi et al., 2013). For example, Piperidou et al and Garcia-Morales et al
 studied the occurrence of “insomnia” and “chronic insomnia”, respectively, using standard AIS cutoff score (Garcia-

Morales et al., 2014; Piperidou et al., 2008). Quigg et al., Vendrame et al. and Yazdi et al. used ISI to establish the

presence of clinically relevant insomnia, despite using different cutoff scores values(Quigg et al., 2016; Vendrame

et al., 2013; Yazdi et al., 2013). Moreover, Yang et al. evaluated the reliability of the ISI in epileptic population and

found good agreement between the ICSD-2 criteria and ISI scores, especially those representing the poles of no

insomnia symptoms (< 8) and moderate/severe insomnia (≥ 15) (Yang et al., 2016).

5.1. Insomnia in adult patients with epilepsy

5.1.1. Prevalence and sociodemographic data

In adults, the prevalence of insomnia disorder or insomnia symptoms widely varied. The prevalence of insomnia

disorder based on international classification criteria (ICSD-2 or DSM-IV-TR) ranged from 36.0% to 74.4% (Ismayilova et

al., 2015; Lopez et al., 2013; Yang et al., 2016). Difficulty in sleep maintenance was the most common insomnia symptom in

PWE (6.9 – 79.0%), followed by difficulty falling asleep (12.9 – 38.1%) (Chen et al., 2011; de Almeida et al., 2003;

Hoeppner et al., 1984; Khatami et al., 2006; Komolafe et al., 2015; Ng and Bianchi, 2014; Pizzatto et al., 2013; Yazdi et al.,

2013). Compared to controls, PWE usually scored higher on insomnia items in most sleep questionnaires (de Weerd et al.,

2004). Krishnan et al. found a 54% prevalence of insomnia symptoms in people with juvenile myoclonic epilepsy versus

24% in controls (Krishnan et al., 2012). Ismayilova et al., Babu et al. and Hoeppner et al. also described higher occurrence of

sleep onset and maintenance insomnia symptoms in PWE than controls (Babu et al., 2009; Hoeppner et al., 1984; Ismayilova

et al., 2015). Others found no significant difference in insomnia symptoms between groups (Khatami et al., 2006; Pizzatto et

al., 2013). The only case-controlled study evaluating insomnia disorder prevalence found a two-fold higher occurrence in

PWE(Ismayilova et al., 2015).

Controlled studies showed that PWE had higher mean scores on insomnia inventories than controls (Im et al., 2016;

Zhou et al., 2012). The prevalence of moderate-to-severe insomnia using the ISI in PWE ranged from 14.5% to 51.0% and

any degree of insomnia symptoms occurred in up to 84.0% of subjects (Cobabe et al., 2015; Im et al., 2016; Quigg et al.,

2016; Vendrame et al., 2013; Yang et al., 2016; Yazdi et al., 2013). As for AIS, Piperidou et al. found that 24.6% of PWE

had a score of six or more in the scale (Piperidou et al., 2008), while Zhou et al showed that epileptic subjects had higher AIS

mean scores at baseline than controls (Zhou et al., 2012).

A higher occurrence of insomnia disorder (or clinical insomnia) was found in women with epilepsy in two studies

(Ismayilova et al., 2015; Vendrame et al., 2013), while Im et al. showed that older age and higher body mass index were

positively related to having an insomnia diagnosis (Im et al., 2016). The remainder of studies did not find a relationship

between insomnia and sex, age or body mass index.

 5.1.2. Epilepsy-related features

A study from 1984 reported a higher occurrence of delayed sleep onset and night awakenings in focal epilepsies

(Hoeppner et al., 1984), but further publications did not reproduce this finding. Higher ISI score was related to shorter

duration of epilepsy in two studies(Quigg et al., 2016; Yang et al., 2016), while insomnia disorder was more common in

patients with nocturnal seizures (Ismayilova et al., 2015), posttraumatic epilepsy (Lopez et al., 2013) and on lamotrigine

therapy (Lopez et al., 2013).

Regarding seizure frequency, this review demonstrated some evidence that patients with poorer seizure control have

higher burden of insomnia than those with a more benign disease (Garcia-Morales et al., 2014; Ismayilova et al., 2015;

Piperidou et al., 2008; Vendrame et al., 2013). For example, Garcia-Morales et al. and Piperidou et al found that insomnia

severity according to AIS was related to poor seizure control, with the first study showing a frequency of insomnia twice

higher in refractory PWE (Garcia-Morales et al., 2014; Piperidou et al., 2008). Ismayilova et al. found that the occurrence of

seizures in the previous two years was an independent risk factor for insomnia in PWE (Ismayilova et al., 2015), while Im et

al. showed that seizure freedom in the previous year was protective against insomnia (Im et al., 2016). In addition, Yang et

al. and Vendrame et al. showed a relationship between insomnia symptom severity using the ISI and AED polytherapy

(Vendrame et al., 2013; Yang et al., 2016). None of the studies assessed epilepsy surgery or other modalities of epilepsy

treatment, such as vagal stimulation or diet.

5.1.3. Comorbid conditions and quality of life

Psychiatric disorder is common in PWE and the occurrence of comorbid sleep disturbance creates an additional

burden in mental health of these patients. For example, Lopez and colleagues found a high occurrence of mood disorders and

psychotic spectrum disorder in military veterans with epilepsy and insomnia disorder. In this study, higher odds of insomnia

were found in subjects with substance abuse and in use of benzodiazepines, antidepressants or antipsychotics, although these

features did not confer an independent risk factor after multivariate analysis (Lopez et al., 2013). Three other studies found a

higher degree of depressive symptoms in insomniacs with epilepsy (Quigg et al., 2016; Vendrame et al., 2013; Yang et al.,

2016), although in one of them this relationship did not persist after multivariate analysis (Yang et al., 2016). On the other

hand, Im et al. did not find a relationship between insomnia symptoms and psychiatric symptomatology (Im et al., 2016).

Comorbid sleep disturbance may be related to insomnia symptoms, such as restless legs syndrome (RLS) complaints

and loud snoring (Khatami et al., 2006). Self-reported insufficient sleep was related to insomnia according to Im et al.(Im et

al., 2016), while Quigg et al. and Yang et al. found higher ISI scores in patients taking sedative-hypnotic medication (Quigg

et al., 2016; Yang et al., 2016). Despite the fact that somnolence is a possible feature of daytime dysfunction in insomnia

disorder, the presence of excessive daytime sleepiness (EDS) is uncommon and raises the probability of comorbid sleep

disorder, such as RLS, obstructive sleep apnea, narcolepsy and parasomnias (Buysse, 2013). Regarding epileptic population,
EDS and ISI scores were positively related in two studies, which did not sustain after multivariate analysis (Quigg et al.,

2016; Yang et al., 2016). Relationship between insomnia and other comorbid medical conditions in PWE were also noted,

such as with chronic pain (Lopez et al., 2013), head trauma (Yang et al., 2016) and asthma/COPD (Yang et al., 2016). The

findings regarding comorbid medical and psychiatric condition are not exclusively of PWE and are commonly cited in the

general population (Budhiraja et al., 2015; Cheatle et al., 2016; Kim et al., 2013; MacFarlane et al., 2014; Ohayon, 2002).

An important finding in this review is the association between sleep complaints and QoL in PWE, which was first

reported by de Weerd et al who found lower mean scores for the mental and physical component summaries in the Short-

Health Survey (SF-36) in patients with sleep complaints (de Weerd et al., 2004). More specifically for insomnia in adults

with epilepsy, Quigg et al, Garcia-Morales et al., Piperidou et al. and Vendrame et al. reported lower scores in most domains

of the Quality of Life in Epilepsy Inventory (QOLIE) (Garcia-Morales et al., 2014; Piperidou et al., 2008; Quigg et al., 2016;

Vendrame et al., 2013).

5.2. Insomnia in paediatric patients with epilepsy

Despite the increase in studies regarding sleep disorders in children with epilepsy over the last decade, none

evaluated insomnia as the primary endpoint and few assessed risk factors and treatment outcomes related to sleep

disturbances. In this review, all paediatric studies explored insomnia among other sleep disturbances (Batista and Nunes,

2007; Chan et al., 2011; Conant et al., 2009; Gutter et al., 2013; Jain et al., 2013; Larson et al., 2012; Ong et al., 2010;

Samaitiene et al., 2013; Stores et al., 1998; Wirrell et al., 2005) and all papers except two included a control group (Conant et

al., 2009; Jain et al., 2013). Insomnia was mainly assessed as a symptom (bedtime resistance, sleep initiation and

maintenance difficulties, sleep anxiety, night arousals and early morning awakening), and only one study assessed the

prevalence of insomnia disorder (Jain et al., 2013).

5.2.1. Prevalence and sociodemographic data

Jain et al. evaluated insomnia according the ICSD-2 criteria and included polysomnography to exclude other sleep

disorders, reporting a prevalence of approximately 11% (Jain et al., 2013). The frequency of pathological cutoff score on the

Sleep Disturbance Scale for Children in children with epilepsy ranged from 13.1% to 31.5%, which were usually higher than

the ones found in controls (Gutter et al., 2013; Ong et al., 2010; Samaitiene et al., 2013). Chan et al. and Larson et al. found

more parental-reported sleep complaints related to bedtime resistance, sleep onset delay, night awakenings and sleep anxiety,

based on the Children´s Sleep Habits Questionnaire in epileptic subjects than controls (Chan et al., 2011; Larson et al., 2012).

A Brazilian study evaluated two populations of children with and without epilepsy and found that younger children (2-6

years) had more difficulty falling asleep and night awakenings than normal subjects, while older ones (7-14 years) had worse

sleep habits (Batista and Nunes, 2007). Apart from bedtime resistance, Wirrel et al. found that children with epilepsy have
significantly higher scores on the Sleep Behaviour Questionnaire than their healthy siblings, which included the assessment

of sleep latency and sleep fragmentation (Wirrell et al., 2005). Increased rates of other sleep complaints, such as sleep-

disordered breathing, parasomnias and daytime sleepiness were also found in three studies, suggesting that insomnia

complaints are part of the clinical presentation of other primary sleep disorders (Gutter et al., 2013; Ong et al., 2010; Wirrell

et al., 2005).

In our review, no relationship was found between insomnia and sociodemographic data except for one study that

described more bedtime resistance in younger epileptic children (Chan et al., 2011).

5.2.2. Epilepsy-related features

A higher frequency of bedtime resistance and delayed sleep onset was found in children with focal epilepsies based

in two studies (Batista and Nunes, 2007; Conant et al., 2009), while other studies related insomnia complaints with nocturnal

seizures (Batista and Nunes, 2007) and valproate therapy (Chan et al., 2011). Regarding seizure control, Batista et al. and

Wirrel et al. found that insomnia symptoms were more common in children with refractory epilepsy (Batista and Nunes,

2007; Wirrell et al., 2005), while Samaitiene et al. found longer sleep latencies in children experiencing seizures in the

previous six months (Samaitiene et al., 2013). Batista et al also described higher frequency of night awakenings in patients

undergoing AED polytherapy (Batista and Nunes, 2007). As for insomnia disorder, Jain et al. exhibited a relationship with

focal seizures and AED monotherapy (Jain et al., 2013). Despite the efficacy of ketogenic diet and epilepsy surgery in

controlling the frequency of epileptic attacks in paediatric population, none of the studies evaluated the impact of epilepsy

surgery on insomnia-related outcomes, therefore requiring more thorough research.

5.2.3. Comorbid conditions and quality of life

Insomnia symptoms were more common in children with epilepsy that also presented developmental delay (Bazil,

2003; Chan et al., 2011; Conant et al., 2009; Jain et al., 2013; Wirrell et al., 2005) and decreased number of sleep hours

(Gutter et al., 2013). The presence of bedtime resistance and night awakening raised the odds of parental report of room

sharing and co-sleeping in one study, which suggests an additional concern over the epileptic child (Larson et al., 2012).

Despite the relationship between epilepsy and sleep disturbances in children, no study addressed the association between

insomnia disorder or symptoms and psychosocial dysfunction or QoL.

6. DISCUSSION
 Studies in adults with epilepsy show that the frequency of insomnia varied widely and was usually higher than those

found in nonepileptic subjects (Chen et al., 2011; de Weerd et al., 2004; Hoeppner et al., 1984; Im et al., 2016; Ismayilova et

al., 2015; Khatami et al., 2006; Krishnan et al., 2012; Pizzatto et al., 2013; Yazdi et al., 2013; Zhou et al., 2012). Most papers

defined insomnia symptomatically and measures of insomnia severity were broadly used, such as insomnia inventories

(Cobabe et al., 2015; Garcia-Morales et al., 2014; Im et al., 2016; Piperidou et al., 2008; Quigg et al., 2016; Vendrame et al.,

2013; Yang et al., 2016; Yazdi et al., 2013; Zhou et al., 2012) and insomnia subscales of sleep questionnaires (Chan et al.,

2011; de Weerd et al., 2004; Gutter et al., 2013; Krishnan et al., 2012; Larson et al., 2012; Ong et al., 2010; Samaitiene et al.,

2013). However, insomnia disorders were assessed in only four studies (Ismayilova et al., 2015; Jain et al., 2013; Lopez et

al., 2013; Yang et al., 2016) and remain poorly elucidated in PWE.

The wide ranges of point prevalence of insomnia reported using the same definition is notable. The frequency of

mild to severe insomnia based on the ISI was as low as 17.7% and as high as 84% in PWE (Cobabe et al., 2015; Quigg et al.,

2016; Vendrame et al., 2013; Yang et al., 2016; Yazdi et al., 2013). Methodological variability probably accounts for most of

the discrepancy, however, epilepsy type and severity and AED burden likely contribute. Difficulty in sleep maintenance

remains the most common insomnia symptom, occurring in up to 79% of epileptic adults (Chen et al., 2011; de Almeida et

al., 2003; Hoeppner et al., 1984; Khatami et al., 2006; Komolafe et al., 2015; Ng and Bianchi, 2014; Pizzatto et al., 2013;

Yazdi et al., 2013). The prevalence of insomnia disorder (ICSD-2 or DSM-IV-TR) ranged from 36.0 to 74.4% (Ismayilova et

al., 2015; Lopez et al., 2013; Yang et al., 2016). In general, the frequency of both insomnia symptoms and disorder in adults

with epilepsy is higher than the general population (Buysse, 2013; Ohayon, 2002).

Insomnia may be related to female gender, older age, higher body mass index, head trauma and asthma/COPD,

although the veracity of these associations remains unclear due to methodological and population variability (Im et al., 2016;

Ismayilova et al., 2015; Vendrame et al., 2013; Yang et al., 2016). Similar to studies in the general population, PWE and

comorbid insomnia do not exhibit higher odds of EDS, especially as independent risk factors (Babu et al., 2009; Cobabe et

al., 2015; de Weerd et al., 2004; Garcia-Morales et al., 2014; Hoeppner et al., 1984; Im et al., 2016; Ismayilova et al., 2015;

Khatami et al., 2006; Komolafe et al., 2015; Krishnan et al., 2012; Lopez et al., 2013; Ng and Bianchi, 2014; Piperidou et al.,

2008; Quigg et al., 2016; Vendrame et al., 2013; Yang et al., 2016; Yazdi et al., 2013). PWE can manifest EDS not only in

the context of comorbid sleep disorder, but also due to the deleterious effect of nocturnal seizures on sleep architecture or by

the sedation caused by AEDs which warrants further investigation(Derry and Duncan, 2013; Manni and Terzaghi, 2010).

An important aim of this analysis was to identify epilepsy-related factors associated with insomnia. We observed a

number of characteristics associated with insomnia symptoms and/or disorders including posttraumatic epilepsy (Lopez et

al., 2013), focal epilepsy (Hoeppner et al., 1984), nocturnal seizures (Ismayilova et al., 2015), refractory epilepsy (Garcia-

Morales et al., 2014; Hoeppner et al., 1984; Piperidou et al., 2008) and AED polytherapy (Vendrame et al., 2013; Yang et

al., 2016) in both adult and paediatric populations. Studies that found relationship between insomnia and refractory seizures
did not exhibit a relationship between insomnia and AED polytherapy and vice versa, although patients with refractory

epilepsy are more likely to be on at least two AEDs (Garcia-Morales et al., 2014; Piperidou et al., 2008; Vendrame et al.,

2013; Yang et al., 2016). In fact, AEDs may influence sleep architecture and may lead to sleep disturbances (Manni and

Terzaghi, 2010), which probably increases with raising dosage or number of AEDs. While AEDs such as lamotrigine and

felbamate are known to produce insomnia in clinical practice (Sadler, 1999), this review failed to identify studies exploring

specific AEDs with exception of one that showed that lamotrigine was independently related to insomnia disorder in military

veterans with epilepsy (Lopez et al., 2013). Finally, this review also exposed the lack of research regarding the impact of

epilepsy treatment on the development of insomnia and other sleep disorders, not only for AEDs but also for other treatment

modalities, such as epilepsy surgery, vagal stimulation and ketogenic diet.

PWE are at higher risk of developing psychiatric disturbances, especially mood disorders and psychosis, and it is

estimated that one-third will experience a mental illness during their lifetime (Kanner, 2016). This relationship is

bidirectional, as psychiatric disorders may precede the onset of epilepsy and the occurrence of seizures may induce

psychological and behavioral problems having neurobiological, psychosocial or pharmacological underpinnings (Bragatti et

al., 2011). This review identified three studies reporting higher prevalence of mood disorders and depressive symptoms

among PWE with insomnia symptoms (Lopez et al., 2013; Quigg et al., 2016; Vendrame et al., 2013). However, due to their

cross-sectional design, it was not possible to determine the direction of the effect.

The most consistent evidence of the burden of insomnia in PWE is the associated impairment in QoL (Garcia-

Morales et al., 2014; Lopez et al., 2013; Piperidou et al., 2008; Quigg et al., 2016; Vendrame et al., 2013; Yang et al., 2016).

The stigma of epilepsy and negative impact of seizures and AEDs on QoL have been extensively reported (Hopker et al.,

2017; Thomas and Nair, 2011; Wo et al., 2016). These negative effects include poor self-esteem, academic and occupational

underachievement, low marriage rates and seizure-induced physical and mental consequences (Shetty et al., 2011).

Investigations of QoL in epilepsy rarely include objective sleep measures, which need to be better assessed in future studies.

Another finding of this review is the paucity of investigations assessing insomnia in children with epilepsy. Sleep

disturbances not only affect seizure control and QoL, but increase the risk of behavioral problems in this population (Chan et

al., 2011; Gutter et al., 2013; Stores et al., 1998). While insomnia symptoms were usually more common in epileptic children

than healthy controls (Batista and Nunes, 2007; Chan et al., 2011; Gutter et al., 2013; Larson et al., 2012; Ong et al., 2010;

Samaitiene et al., 2013; Stores et al., 1998; Wirrell et al., 2005), only one study addressed insomnia disorders (Jain et al.,

2013) which was within the range of school-aged children and adolescents (Ozgun et al., 2016), and none were prospective

with insomnia as the primary outcome. Insomnia symptoms were related to poor seizure control (Batista and Nunes, 2007;

Wirrell et al., 2005), focal epilepsies (Batista and Nunes, 2007; Conant et al., 2009) nocturnal seizures (Batista and Nunes,

2007) and valproate therapy (Chan et al., 2011), while insomnia disorder was more likely to have focal seizures and on AED

monotherapy (Jain et al., 2013). Developmental delay was related to bedtime resistance and children with bedtime difficulties
and night awakenings were more likely to co-sleep or share a room with their parents when compared to their healthy

siblings (Batista and Nunes, 2007; Chan et al., 2011; Conant et al., 2009; Jain et al., 2013; Larson et al., 2012). Higher

frequency of co-sleeping and room sharing in epileptic children could be explained by parental concern over their sick

children, especially relating to nocturnal seizures. Although some studies evaluated QoL in epileptic children with sleep

disturbances, none assessed the direct effect of insomnia.

It is important to highlight some limitations regarding this review. PUBMED search for the keywords “epilepsy”

and “epileptic” were restricted to the title and the extension to the abstract or the inclusion of diseases manifested as or

related to epilepsy could have add more papers and data (Dravet syndrome, Lennox-Gastaut syndrome and tuberous

sclerosis, for example). Due to methodological heterogeneity among studies, we opted for a descriptive analysis of the data

and the performance of a systematic analysis (such as meta-analysis) could have clarified some interactions between

insomnia and seizure control, psychiatric comorbidity or quality of life.

7. CONCLUSIONS

Interest in the complex, reciprocal relationships between sleep and epilepsy has risen dramatically in recent years,

but many questions remain. This is the first review of insomnia in PWE and it highlights the need for more research given the

high prevalence of insomnia symptoms in PWE and the potential impact of insomnia on epilepsy-related outcomes.

Methodological variability played an important role in this uncertainty, as those related to insomnia definition, population

selection criteria, and highly selected samples may explain the high rates of insomnia disorder and symptoms in this review,

especially those excluding individuals with comorbid sleep disorders that are usually related with sleepiness. Nonetheless,

most studies demonstrate that PWE have higher frequency of insomnia (especially symptoms) than nonepileptic subjects and

that insomnia severity may increase with seizure severity. Likewise, insomnia creates additional impairment on QoL and

raises the frequency of psychiatric disturbance in epileptic population, especially depression. Consequently, further research

on the prevalence of insomnia in more representative or community-based populations using standard definitions are needed,

besides studies focusing on the interaction between epilepsy treatment (politherapy, specific AEDs, ketogenic diet, epilepsy

surgery) and the development of insomnia, as well as the impact of insomnia treatment on seizure control, psychiatric

comorbidity and QoL.

REFERENCES

Babu, C.S., Satishchandra, P., Sinha, S., Subbakrishna, D.K., 2009. Co-morbidities in people living with epilepsy: hospital
based case-control study from a resource-poor setting. Epilepsy research 86, 146-152.

Batista, B.H., Nunes, M.L., 2007. Evaluation of sleep habits in children with epilepsy. Epilepsy Behav 11, 60-64.

Bazil, C.W., 2003. Epilepsy and sleep disturbance. Epilepsy Behav 4 Suppl 2, S39-45.
Bragatti , J.A., Torres, C.M., Isolan, G.R., Bianchin, M.M., 2011. Psychiatric Comorbidities of Epilepsy: A Review. J Neurol
Neurophysiol S2.

Budhiraja, R., Siddiqi, T.A., Quan, S.F., 2015. Sleep disorders in chronic obstructive pulmonary disease: etiology, impact,
and management. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep
Medicine 11, 259-270.

Buysse, D.J., 2013. Insomnia. Jama 309, 706-716.

Chan, B., Cheong, E.Y., Ng, S.F., Chan, Y.C., Lee, Q.U., Chan, K.Y., 2011. Evaluation of sleep disturbances in children
with epilepsy: a questionnaire-based case-control study. Epilepsy Behav 21, 437-440.

Cheatle, M.D., Foster, S., Pinkett, A., Lesneski, M., Qu, D., Dhingra, L., 2016. Assessing and Managing Sleep Disturbance
in Patients with Chronic Pain. Anesthesiology clinics 34, 379-393.

Chen, N.C., Tsai, M.H., Chang, C.C., Lu, C.H., Chang, W.N., Lai, S.L., Tseng, Y.L., Chuang, Y.C., 2011. Sleep quality and
daytime sleepiness in patients with epilepsy. Acta Neurol Taiwan 20, 249-256.

Cobabe, M.M., Sessler, D.I., Nowacki, A.S., O'Rourke, C., Andrews, N., Foldvary-Schaefer, N., 2015. Impact of sleep
duration on seizure frequency in adults with epilepsy: a sleep diary study. Epilepsy Behav 43, 143-148.

Conant, K.D., Thibert, R.L., Thiele, E.A., 2009. Epilepsy and the sleep-wake patterns found in Angelman syndrome.
Epilepsia 50, 2497-2500.

de Almeida, C.A., Lins, O.G., Lins, S.G., Laurentino, S., Valenca, M.M., 2003. [Sleep disorders in temporal lobe epilepsy].
Arq Neuropsiquiatr 61, 979-987.

de Weerd, A., de Haas, S., Otte, A., Trenite, D.K., van Erp, G., Cohen, A., de Kam, M., van Gerven, J., 2004. Subjective
sleep disturbance in patients with partial epilepsy: a questionnaire-based study on prevalence and impact on quality of life.
Epilepsia 45, 1397-1404.

Derry, C.P., Duncan, S., 2013. Sleep and epilepsy. Epilepsy Behav 26, 394-404.

Fisher, R.S., Acevedo, C., Arzimanoglou, A., Bogacz, A., Cross, J.H., Elger, C.E., Engel, J., Jr., Forsgren, L., French, J.A.,
Glynn, M., Hesdorffer, D.C., Lee, B.I., Mathern, G.W., Moshe, S.L., Perucca, E., Scheffer, I.E., Tomson, T., Watanabe, M.,
Wiebe, S., 2014. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 55, 475-482.

Garcia-Morales, I., Gil-Nagel, A., de Rosendo, J., Torres-Falcon, A., 2014. [Sleep disorders and quality of life in refractory
partial epilepsy: results of the SLEEP study]. Rev Neurol 58, 152-160.

Gutter, T., Brouwer, O.F., de Weerd, A.W., 2013. Subjective sleep disturbances in children with partial epilepsy and their
effects on quality of life. Epilepsy Behav 28, 481-488.

Hoeppner, J.B., Garron, D.C., Cartwright, R.D., 1984. Self-reported sleep disorder symptoms in epilepsy. Epilepsia 25, 434-
437.

Hopker, C.D., Berberian, A.P., Massi, G., Willig, M.H., Tonocchi, R., 2017. The individual with epilepsy: perceptions about
the disease and implications on quality of life. CoDAS 29, e20150236.
Im, H.J., Park, S.H., Baek, S.H., Chu, M.K., Yang, K.I., Kim, W.J., Yun, C.H., 2016. Associations of impaired sleep quality,
insomnia, and sleepiness with epilepsy: A questionnaire-based case-control study. Epilepsy Behav 57, 55-59.

Ismayilova, V., Demir, A.U., Tezer, F.I., 2015. Subjective sleep disturbance in epilepsy patients at an outpatient clinic: A
questionnaire-based study on prevalence. Epilepsy research 115, 119-125.

Jain, S.V., Simakajornboon, N., Glauser, T.A., 2013. Provider practices impact adequate diagnosis of sleep disorders in
children with epilepsy. J Child Neurol 28, 589-595.

Kanner, A.M., 2016. Psychiatric comorbidities in epilepsy: Should they be considered in the classification of epileptic
disorders? Epilepsy & Behavior 64, 306-308.

Khatami, R., Zutter, D., Siegel, A., Mathis, J., Donati, F., Bassetti, C.L., 2006. Sleep-wake habits and disorders in a series of
100 adult epilepsy patients--a prospective study. Seizure 15, 299-306.

Kim, W.H., Kim, B.S., Kim, S.K., Chang, S.M., Lee, D.W., Cho, M.J., Bae, J.N., 2013. Prevalence of insomnia and
associated factors in a community sample of elderly individuals in South Korea. International psychogeriatrics 25, 1729-
1737.

Komolafe, M.A., Sunmonu, T.A., Ogunrin, O.A., Disu, J.O., Ezeala, B.A., Abubakar, S.A., Iwuoso, E., 2015. Sleep
disturbances among patients with epilepsy in Nigeria. Ann Afr Med 14, 103-108.

Krishnan, P., Sinha, S., Taly, A.B., Ramachandraiah, C.T., Rao, S., Satishchandra, P., 2012. Sleep disturbances in juvenile
myoclonic epilepsy: a sleep questionnaire-based study. Epilepsy Behav 23, 305-309.

Larson, A.M., Ryther, R.C., Jennesson, M., Geffrey, A.L., Bruno, P.L., Anagnos, C.J., Shoeb, A.H., Thibert, R.L., Thiele,
E.A., 2012. Impact of pediatric epilepsy on sleep patterns and behaviors in children and parents. Epilepsia 53, 1162-1169.

Lewis, P.E., Emasealu, O.V., Rohrbeck, P., Hu, Z., 2014. Risk of type II diabetes and hypertension associated with chronic
insomnia among active component, U.S. Armed Forces, 1998-2013. Msmr 21, 6-13.

Lopez, M.R., Cheng, J.Y., Kanner, A.M., Carvalho, D.Z., Diamond, J.A., Wallace, D.M., 2013. Insomnia symptoms in South
Florida military veterans with epilepsy. Epilepsy Behav 27, 159-164.

MacFarlane, J., Morin, C.M., Montplaisir, J., 2014. Hypnotics in insomnia: the experience of zolpidem. Clinical therapeutics
36, 1676-1701.

Manni, R., Terzaghi, M., 2010. Comorbidity between epilepsy and sleep disorders. Epilepsy research 90, 171-177.

Ng, M.C., Bianchi, M.T., 2014. Sleep misperception in persons with epilepsy. Epilepsy Behav 36, 9-11.

Ohayon, M.M., 2002. Epidemiology of insomnia: what we know and what we still need to learn. Sleep medicine reviews 6,
97-111.

Ong, L.C., Yang, W.W., Wong, S.W., alSiddiq, F., Khu, Y.S., 2010. Sleep habits and disturbances in Malaysian children
with epilepsy. J Paediatr Child Health 46, 80-84.
Ozgun, N., Sonmez, F.M., Topbas, M., Can, G., Goker, Z., 2016. Insomnia, parasomnia, and predisposing factors in Turkish
school children. Pediatrics international : official journal of the Japan Pediatric Society 58, 1014-1022.

Piperidou, C., Karlovasitou, A., Triantafyllou, N., Terzoudi, A., Constantinidis, T., Vadikolias, K., Heliopoulos, I.,
Vassilopoulos, D., Balogiannis, S., 2008. Influence of sleep disturbance on quality of life of patients with epilepsy. Seizure
17, 588-594.

Pizzatto, R., Lin, K., Watanabe, N., Campiolo, G., Bicalho, M.A., Guarnieri, R., Claudino, R., Walz, R., Sukys-Claudino, L.,
2013. Excessive sleepiness and sleep patterns in patients with epilepsy: a case-control study. Epilepsy Behav 29, 63-66.

Quigg, M., Gharai, S., Ruland, J., Schroeder, C., Hodges, M., Ingersoll, K.S., Thorndike, F.P., Yan, G., Ritterband, L.M.,
2016. Insomnia in epilepsy is associated with continuing seizures and worse quality of life. Epilepsy research 122, 91-96.

Sadler, M., 1999. Lamotrigine associated with insomnia. Epilepsia 40, 322-325.

Samaitiene, R., Norkuniene, J., Tumiene, B., Grikiniene, J., 2013. Sleep and behavioral problems in rolandic epilepsy.
Pediatr Neurol 48, 115-122.

Sateia, M.J., 2014. International classification of sleep disorders-third edition: highlights and modifications. Chest 146, 1387-
1394.

Shetty, P.H., Naik, R.K., Saroja, A., Punith, K., 2011. Quality of life in patients with epilepsy in India. Journal of
neurosciences in rural practice 2, 33-38.

Sofi, F., Cesari, F., Casini, A., Macchi, C., Abbate, R., Gensini, G.F., 2014. Insomnia and risk of cardiovascular disease: a
meta-analysis. Eur J Prev Cardiol 21, 57-64.

Stores, G., Wiggs, L., Campling, G., 1998. Sleep disorders and their relationship to psychological disturbance in children
with epilepsy. Child Care Health Dev 24, 5-19.

Thomas, S.V., Nair, A., 2011. Confronting the stigma of epilepsy. Annals of Indian Academy of Neurology 14, 158-163.

Vendrame, M., Yang, B., Jackson, S., Auerbach, S.H., 2013. Insomnia and epilepsy: a questionnaire-based study. Journal of
clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine 9, 141-146.

Vgontzas, A.N., Fernandez-Mendoza, J., 2013. Objective measures are useful in subtyping chronic insomnia. Sleep 36, 1125-
1126.

Wickwire, E.M., Shaya, F.T., Scharf, S.M., 2015. Health economics of insomnia treatments: The return on investment for a
good night's sleep. Sleep medicine reviews 30, 72-82.

Wirrell, E., Blackman, M., Barlow, K., Mah, J., Hamiwka, L., 2005. Sleep disturbances in children with epilepsy compared
with their nearest-aged siblings. Dev Med Child Neurol 47, 754-759.

Wo, M.C., Lim, K.S., Choo, W.Y., Tan, C.T., 2016. Factors affecting the employability in people with epilepsy. Epilepsy
research 128, 6-11.
Xu, X., Brandenburg, N.A., McDermott, A.M., Bazil, C.W., 2006. Sleep disturbances reported by refractory partial-onset
epilepsy patients receiving polytherapy. Epilepsia 47, 1176-1183.

Yang, K.I., Grigg-Damberger, M., Andrews, N., O'Rourke, C., Bena, J., Foldvary-Schaefer, N., 2016. Severity of self-
reported insomnia in adults with epilepsy is related to comorbid medical disorders and depressive symptoms. Epilepsy Behav
60, 27-32.

Yazdi, Z., Sadeghniiat-Haghighi, K., Naimian, S., Zohal, M.A., Ghaniri, M., 2013. Prevalence of Sleep Disorders and their
Effects on Sleep Quality in Epileptic Patients. Basic Clin Neurosci 4, 36-41.

Zhou, J.Y., Tang, X.D., Huang, L.L., Zhong, Z.Q., Lei, F., Zhou, D., 2012. The acute effects of levetiracetam on nocturnal
sleep and daytime sleepiness in patients with partial epilepsy. J Clin Neurosci 19, 956-960.
Figure 1. Study assessment diagram
 Table 1. Studies addressing insomnia disorder or symptoms in adult populations
Relationship with
Study design and
Insomnia definition Prevalence epilepsy-related Associated factors
population
factors
ISI >15:
As disorder and symptoms. (+) Decreased total
Yang et al., 2016, USA ICSD-2: 74.4%.
0 Insomnia according ICSD-2. ISI >15 sleep time, head
Cross-sectional ISI 08-14: 36.7%.
1 Insomnia inventory (+) Polytherapy. trauma, sedative-
90 adults PWE. ISI >15: 28.9%.
Insomnia Severity Index hypnotics and
asthma/COPD.
Quigg et al., 2016,
Higher ISI score
USA
0 Insomnia Inventory ISI (>08): 51%. (–) Seizure freedom Higher ISI score
Cross-sectional
2 Insomnia Severity Index ISI (>10): 43%. in the last four weeks (+) impaired QoL.
207 adults PWE.

Im et al., 2016, Korea ISI >15

ISI >15
Cross-sectional, with (+) Short duration of
0 Insomnia Inventory PWE vs Control Subjects (+) Older age, higher
control group epilepsy
3 Insomnia Severity Index ISI (>15): 14.5% vs 4.6%. BMI and insufficient
180 adults PWE (–) Seizure freedom
sleep
2836 healthy subjects. for ≥ 1 year
Ismayilova et al.,
2015, Turkey
Insomnia disorder
Cross-sectional, with As disorder PWE vs Control subjects
(+) Nocturnal Insomnia disorder
0 control group DSM-IV-TR criteria Insomnia disorder: 36% vs 15%.
seizures. (+) Female gender
4 208 adults PWE As symptoms SOI: 24% vs 20%.
(+) Seizures in the and higher BMI
212 healthy subjects. SOI and SMI SMI: 12% vs 6%.
previous 2 years.

Komolafe et al, 2015,

Nigeria As symptoms. Insomnia: 19.3%
0
Multi center, cross- SOI and SMI SOI: 12.9% ---------------------- ---------------------
5
sectional Insomnia (SOI or SMI) SMI: 6.5%
124 adults PWE.
Cobabe et al, 2015,
0 USA Insomnia Inventory.
ISI ≥08: 50% ---------------------- ---------------------
6 Cross-sectional Insomnia severity index
44 adults PWE
0 García-Morales et al,, Insomnia Inventory Refractory vs non-refractory AIS > 6 in PWE: AIS > 6 in PWE:
7 2014, Spain Athems Insomnia Scale. AIS > 6: 38% vs 17%. (+) Refractory (+) Impaired QoL.
Multi center, Cross- epilepsy
sectional, with control
group
264 refractory PWE
(focal).
237 non-refractory
PWE (focal)
Ng et al., 2014, USA
Cross-sectional, with
control group Unclear definition.
0 64 PWE. Insomnia (checked in a list of PWE
---------------------- ---------------------
8 50 Insomniacs without reasons for PSG or from sleep Insomnia: 36%.
OSA questionnaire data)
50 OSA patients
without insomnia
Lopez et al., 2013,
Insomnia disorder
USA Insomnia disorder
0 As disorder. (+) Posttraumatic
Cross-sectional ICSD-2: 40% (+) mood disorders,
9 ICSD-2 criteria. epilepsy, lamotrigine
165 military veterans psychotic disorders.
therapy.
with epilepsy.
Insomnia disorder
Vendrame et al., 2013,
(+) Female gender,
1 USA Insomnia Inventory ISI 08-14: 33 Insomnia disorder
depression
0 Cross sectional Insomnia Severity Index ISI >15: 51% (+) Polytherapy
symptoms and
152 adults PWE.
impaired QoL.
Pizzatto et al., 2013,
Brazil
1 Cross-sectional, with As symptoms. PWE vs Control Subjects
-------------------------- -------------------------
1 control group SOI SOI: 30.7%.* vs 23.5%.*
140 PWE
85 control subjects.
Yazdi et al., 2012, Iran PWE vs control subjects
Insomnia Inventory
Cross-sectional, with ISI ≥08*: 17.7% vs 14.5%.
1 Insomnia Severity Index
control group SOI*: 38.1%* vs 40.1%. ---------------------- ---------------------
2 As symptoms.
152 adults PWE SMI: 58.6% vs 33.5%.
SOI and SMI and EMA
152 healthy subjects. EMA*: 28.3%* vs 24.3%.
Chen et al., 2011,
Taiwan
PWE vs Control subjects
1 Cross-sectional, with As symptoms.
SOI: 17% vs 7% ---------------------- ---------------------
3 control group SOI and SMI
SMI: 57% vs 20%
100 PWE
30 healthy volunteers
Krishnan et al., 2011,
India
Cross-sectional, with Insomnia subscale of sleep
1 control group questionnaire. PWE vs Control subjects
---------------------- ---------------------
4 50 patients with NIMHANS comprehensive Insomnia subscale: 54% vs 24%
juvenile myoclonic sleep questionnaire.
epilepsy
50 healthy subjects.
 Zhou et al, 2011,
China
PWE vs Control subjects
1 Prospective, with Insomnia Inventory
AIS mean score was higher in ---------------------- ---------------------
5 control group Athems Insomnia Scale.
PWE than control subjects.
11 PWE
10 controls.

Babu et al., 2009,

India
As symptoms.
1 Cross sectional with PWE vs Control subjects
Insomnia (SOI or SMI or ---------------------- ---------------------
6 control group Insomnia: 6.9% vs 0.4%.
EMA)
250 adults PWE
250 control subjects
Piperidou et al., 2008,
Greece AIS ≥ 6
1 Insomnia Inventory AIS ≥ 6
Multi center, cross- AIS ≥ 6: 24.6%. (+) Higher seizure
7 Athems Insomnia Scale. (+) Impaired QOL.
sectional frequency.
124 adults PWE

SOI
Khatami et al., 2006,
(+) Restless legs
Switzerland
PWE vs Control subjects symptoms.
1 Cross-sectional, with As symptoms.
SOI*: 34% vs 28%. ---------------------- SMI
8 control group SOI and SMI
SMI*: 52% vs 38% (+) Restless legs
100 adults PWE.
symptoms and loud
90 healthy controls.
snoring.

de Weerd et al., 2004,

Netherlands
Multi center,
Insomnia subscale of sleep PWE vs Control subjects
1 Community based, Sleep disturbances
questionnaire. Mean score of insomnia ----------------------
9 cross-sectional, with (+) impaired QoL.
Sleep Diagnostic List. subscale was higher in PWE
control group
486 PWE (partial)
492 healthy controls.
de Almeida et al.,
2 2003, Brazil As symptoms. SOI: 26%
---------------------- ---------------------
0 Cross-sectional SOI and SMI SMI: 79%
39 PWE.
Hoeppner et al., 1984, Delayed sleep onset
USA (+) partial seizures.
PWE vs Control subjects
Cross-sectional, with Night awakenings
2 As symptoms. SOI: 26.6% vs 17.4%.
control group (+) partial seizures ---------------------
1 SOI and SMI SMI: 46.6% vs 21.7%
30 adult PWE and frequent seizures
23 non-epileptic (daily, weekly and
volunteers. monthly)
(+) positive relationship / (–) negative relationship.
* No statistical difference between control subjects and PWE.
AIS: Athems Insomnia Scale / COPD: chronic obstructive pulmonary disease / DSM-IV-TR: Diagnostic and Statistical Manual of
Mental Disorders, 4th edition, revised / EMA: early morning awakening / ICSD-2: International Classification of Sleep Disorders,
2nd edition / ISI: Insomnia Severity Index / OSA: obstructive sleep apnea / PWE: people with epilepsy / QoL: quality of life / SMI:
Sleep maintenance insomnia / SOI: Sleep onset insomnia / SMI: sleep maintenance insomnia
 Table 2. Studies addressing insomnia disorder or symptoms in paediatric populations
Relationship with
Study design and
Insomnia definition Prevalence epilepsy-related Associated factors
population
factors
Gutter et al., 2013, Delayed sleep onset
Insomnia subscale of sleep
Netherlands (+) Decreased
questionnaire. PWE vs Control subjects
0 Cross-sectional, with number of sleep
SDSC – pathological cutoff SDSC: 26.15% vs 6.02%. ---------------------------
1 control group hours
As symptoms DSO: 27.69% vs 15.06%.
130 PWE Sleep disturbances
Delayed Sleep Onset (DSO)
161 control subjects. (+) impaired QoL.
PWE
Samaitienė et al., SDSC: 13.1%
2012, Lithuania Insomnia subscale of sleep Control subjects
Longer sleep latency
0 Cross-sectional, with questionnaire. SDSC: no report
(+) Seizures in the --------------------------
2 control group SDSC – pathological cutoff Sleep latency
previous six months.
61 PWE (rolandic) Sleep latency PWE had statistical longer
25 control subjects. sleep latency than control
subjects
Larson et al., 2012, Insomnia subscale of sleep Bedtime resistance
PWE vs Control subjects
USA questionnaire. (+) Co-sleeping and
Mean scores on sleep onset
Community based CSHQ - higher scores represent room sharing..
0 delay, bedtime resistance
Cross-sectional, with more sleep disturbances. --------------------------- Night wakings
3 and night wakings
control group Sleep Onset Delay – Mean score (+) Co-sleeping,
subscores were higher in
105 PWE Bedtime resistance – Mean score room sharing and
PWE.
79 control subjects. Night wakings – Mean score developmental delay.
Jain et al., 2012, USA
Insomnia disorder Insomnia disorder
0 Cross-sectional As disorder.
Insomnia disorder: 11%. (+) Focal epilepsies (+) Developmental
4 108 PWE evaluated in ICSD-2 criteria
and monotherapy. delay.
sleep clinics.
 Insomnia subscale of sleep
Chan et al.,, 2011, PWE vs Control subjects
questionnaire.
Hong Kong Mean scores on sleep onset Bedtime resistance
CSHQ - higher scores represent Night wakings
0 Cross-sectional, with delay, bedtime resistance (+) Developmental
more sleep disturbances. (+) Sodium valproate
5 control group and night wakings delay.
Sleep Onset Delay – Mean score therapy.
63 PWE subscores were higher in (–) Older age.
Bedtime resistance – Mean score
169 control subjects. PWE.
Night wakings – Mean score

Ong et al., 2010,

Insomnia subscale of sleep
Malaysia
questionnaire. PWE
0 Cross-sectional, with
SDSC – pathological cutoff SDSC: 31.5% vs 4.3%. --------------------------- --------------------------
6 control group
As symptoms DSO: 32.6% vs 7.6%
92 PWE
Delayed Sleep Onset
92 control subjects.
Conant et al., 2009,
USA 50.5% had trouble with
Community based, sleep initiation and, of Trouble with sleep
0 As symptoms
cross-sectional those, 82% had epilepsy. initiation --------------------------
7 Trouble with sleep initiation.
290 patients with PWE had also decreased (+) Focal seizures
Angelman syndrome. need for sleep.

Bedtime Resistance
and, Delayed Sleep
Compared to controls, Onset
As symptoms.
CWE had higher (+) Nocturnal seizures Night awakenings
Children aging 02–06 years-old
frequency of bedtime and focal seizures (+) Developmental
(C02-06)
resistance, delayed sleep without secondary delay.
Batista & Nunes, Sleep Habits Inventory
onset and night awakening. generalization.
2007, Brazil
Night awakenings
Cross-sectional, with
0 (+) Refractory epilepsy
control group
8 and polytherapy.
121 PWE
121 control subjects
Compared to control
Higher scores on SBQ
As symptoms. subjects, CWE had higher Higher scores on
(+) Nocturnal seizures,
Children aging 07–14 years-old scores on SBQ. There was SBQ
generalized seizures,
(C07-14) no specific comparison (+) Developmental
poor seizure control
Sleep Behaviour Questionnaire between the groups about delay.
and polytherapy
insomnia symptoms.

Insomnia subscale of sleep

Wirrell et al., 2005, PWE vs Control subjects Sleep fragmentation
questionnaire.
Canada Compared to controls, (+) Mental
Sleep Behaviour Questionnaire – Sleep latency and
Cross-sectional, with CWE had higher retardation.
0 higher scores represents higher sleep fragmentation
control group frequency of bedtime Sleep disturbances
9 sleep disturbance (+) Refractory
55 PWE difficulties and sleep (+) Behavioral
Sleep latency – Mean score epilepsy.
55 control subjects. fragmentation, as well as problems and
Bedtime difficulties – Mean score
increased sleep latency. impaired QoL.
Sleep fragmentation – Mean score
Stores et al., 1998,
United Kingdom PWE vs Control subjects Poor sleep quality’s
As symptoms.
Cross-sectional, with Compared to control cluster
1 Wake up more than twice per
control group subjects, CWE had higher -------------------------- (+) disturbed daytime
0 night (score)
79 PWE. scores on questions related behaviour.
Early Morning awakening (score)
73 control subjects. to insomnia symptoms.

(+) positive relationship / (–) negative relationship.

* No statistical difference between control subjects and PWE.
BEDS: Behavioral Evaluation of Disorders of Sleep / BR: Bedtime resistance / C02-06: Children aging 02-06 years old / C07-14:
Children aging 07-14 years old / CSHQ: Children´s Sleep Habits Questionnaire / CWE: children with epilepsy / DSO: Delayed
sleep onset / ICSD-2: International Classification of Sleep Disorders, 2nd edition / NW: Night wakings / PWE: People with epilepsy
/ SBQ: Sleep Behaviour Questionnaire / SDSC: Sleep Disturbance Scale for Children