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8 Diagnosis and Management of OSA Comorbid with Insomnia (COMISA) 109
Fig. 8.2 The connection between symptoms and clinical elements linked to obstructive sleep apnea
and insomnia. With permission from: Faith and colleagues.
https://doi.org/10.5664/jcsm.27772
8.2 Prevalence of COMISA
Research addressing COMISA has been conducted in two different ways—firstly,
looking for the insomnia among subjects with OSA and secondly, assessment of
OSA among subjects with chronic insomnia. This research has shown that preva-
lence of insomnia among subjects with OSA is higher than the prevalence of OSA
among subjects with insomnia (Zhang et al. 2019). Moreover, there is paucity of
studies that have assessed OSA among subjects with chronic insomnia. This could
be related to the fact that insomnia is still not considered as an indication for
polysomnography, unless patients show some prominent symptoms suggestive of
comorbid sleep disorders (Schutte-Rodin et al. 2008; Riemann et al. 2017).
Results of the research in this area have been confounded by varying definitions
of insomnia and difference in methods to define OSA (Zhang et al.
2019). Studies
have used different clinical criteria (Diagnostic and Statistical Manual versus Inter-
national Classification of Sleep Disorders), validated questionnaires and scales, viz,
insomnia severity index to define insomnia (Sweetman et al. 2019a; Zhang et al.
2019; Ong and Crawford 2013). In some of the studies, diagnostic criteria for
insomnia were relaxed to presence of at least one nighttime symptom while in
others, daytime impact of nighttime symptoms was considered mandatory to diag-
nose insomnia (Ong and Crawford
2013). Studies following former criteria for the
diagnosis of insomnia showed greater prevalence of insomnia compa red to those
following latter criteria (Ong and Crawford
2013).
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110 R. Gupta and L. K. Saini
Table 8.1 Differences in patient characteristics based upon primary complaint (Ong and Crawford
2013)
1. Primary complaint insomnia having COMISA compared to pure OSA
Subjects more likely to:
• Female
• Have dysfunctional beliefs about sleep
• Have restless legs syndrome
• Lesser alcohol use
2. Primary complaint OSA having COMISA compared to No-OSA
Subjects more likely to:
• Male
• Older
• Higher body mass index
• Nighttime and daytime symptoms of OSA
Similar to the definition of insomnia, different definitions were used to define
OSA across literature, for example, apnea-hypopnea index greater than 5 or
15 which were scored using either polysomnography or polygraphy (Sweetman
et al.
2019a; Zhang et al. 2019). Most of the studies are cross-sectional in nature
and thus can underestimate the true prevalence as insomnia may follow a relapsing
remitting pattern (Ong and Crawford
2013). Many of the studies have also excluded
diagnosed cases of OSA from the study, further reducing the prevalence (Ong and
Crawford 2013). These factors have resulted in heterogeneity in the results of
various studies. Studies also show different characteristics based on primary com-
plaint (Table
8.1).
8.2.1 Prevalence of Insomnia Among Subjects with OSA
Around one third of patients with OSA also suffer from comorbid insomnia;
however, it varies between 6% and 84% across different studies (Zhang et al.
2019; Ong and Crawford 2013). A recent study used the international classification
of sleep disorders 3rd edition (ICSD-3) criteria for the diagnosis of insomnia and
reported that 29% subjects with OSA report comorbid insomnia, predominantly
difficulty in maintenance of sleep and falling asleep in half of them (Stelzer et al.
2021). Insomnia in patients with OSA can be predicted by presence of female
gender, age greater than 60 years, tobacco use, presence of daytime sleepiness,
symptoms of depression, and anxiety (Stelzer et al.
2021; Cho et al. 2018 ). These
factors further highlight the role of neurodegeneration (including areas regulating
sleep-wake cycle), hypothalamo-pituitary-adrenal (HPA) axis and cortical arousal
for the occurrence of insomnia among OSA patients (Stelzer et al.
2021).
Most of the patients report difficulty in maintaining the sleep while initial and
terminal insomnia are less prevalent (Zhang et al.
2019; Lichstein et al. 2013). It
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could be related to frequent awakenings (micro-arousals as well as complete
arousals) associated with episodes of apnea, sympathetic stimulation, and activation
of HPA axis, latter two being implicated in pathogenesis of insomnia (discussed in
Sect.
8.5 in detail).
8 Diagnosis and Management of OSA Comorbid with Insomnia (COMISA) 111
Interestingly, prevalence of insomnia
among patients with OSA differs across
geographical regions. A recent review and metanalysis reported that pooled preva-
lence of insomnia among patients with OSA was higher in European and American
regions compared to the Western Pacific region (Fig.
8.3) (Zhang et al. 2019).
Authors explained that these differences could be related to difference in the
population included in the studies. Studies from Western Pacific region
included younger participants, had fewer women and with lower body mass index
compared to other two regions. However, in this metanalysis—age, body mass
index, as well as severity of OSA as measured by apnea-hypopnea index (AHI)
were not associated with insomnia (Zhang et al.
2019). Insomnia disorder and early
and middle phenotypes of insomnia are more common among females compared to
males having OSA (Zhang et al.
2019). This meta-analysis further reported that
criteria used to diagno se insomnia varied across studies and could have been a
source of heterogeneity.
8.2.1.1 Risk Factors for Insomnia Among OSA
Older age (60 years or more) and use of tobacco are risk factors for insomnia among
subjects having OSA (Stelzer et al. 2021). Most of these patients report initial and
sleep-maintenance insomnia (Stelzer et al.
2021). Severity of OSA was lower in this
group, but there was no difference observed between genders with regards to
prevalence of insomnia (Stelzer et al. 2021).
8.2.2 Prevalence of OSA Among Subjects with Insomnia
Occult OSA is common among veterans. Among the veterans (mean age 72 years),
nearly 50% subjects with insomnia were found to have comorbid OSA (defined as
AHI ≥ 15); however, the prevalence ranges between 7% and 69% across studies
(Ong and Crawford 2013; Kinugawa et al, 2012; Hein, et al, 2017; Fung et al. 2013).
None of the nighttime symptoms of OSA, but only history of excessive daytime
sleepiness was found to correlate with the diagnosis of OSA (Fung et al. 2013
).
Patients having comorbid OSA had higher body mass index and shorter mean sleep
onset latency on multiple sleep latency test and are usually older (Hein et al,
2017; Kinugawa et al. 2012). However, body mass index did not fall in “obese”
range among these patients (Kinugawa et al. 2012). Thus, elderly persons suffering
from insomnia and daytime sleepiness should be screened for presence of comorbid
OSA, even when they are not obese.
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112 R. Gupta and L. K. Saini
Fig. 8.3 The prevalence of insomnia among patients with OSA was higher in European and American regions compared to the Western Pacific region
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8 Diagnosis and Management of OSA Comorbid with Insomnia (COMISA) 113
8.2.2.1 Risk Factors for OSA Among Patients with Insomnia
To find out the OSA among patients with insomnia, it is important to find out the risk
factors associated with it. In general, regular, loud snoring and witnessed pauses in
breath are considered as signs of OSA. However, among veterans having primary
diagnosis of insomnia, these signs appear inadequate to raise the suspicion. For
example, Fung et al. reported that these signs could not identify patients with OSA,
while excessive daytime sleepiness appeared to be a reliable indicator (Fung et al.
2013). On the other hand, during middle age, subjects having OSA were more likely
to be male, older than 50 years, obese, had history of snoring, had metabolic
syndrome, raised C-reactive protein, reported dif ficulty in maintenance of sleep
and excessive daytime sleepiness (Hein et al.
2017). There are two possibilities for
these findings . First, patients with obvious nighttime symptoms of OSA attracts
attention early and hence, do not remain untreated (Fung et al.
2013). On the other
hand, excessive daytime sleepiness may remain unnoticed for a long time and hence
it indicated occult OSA in both middle-aged and veterans (Fung et al. 2013; Hein
et al. 2017). Secondly, symptoms profile varies according to the age. Lower prev-
alence of nighttime symptoms among elderly could be explained by shorter and
fragmented sleep that does not allow nighttime symptoms of OSA to get noticed
(Fung et al.
2013).
8.3 Objective Measures of Sleep in COMISA
Subjects with pure insomnia and COMISA show shorter total sleep time, greater
percentage of wake after sleep onset, poorer sleep efficiency compared to subjects
having OSA and normal controls (Choi et al.
2016, 2018). These parameters do not
appear unexpected considering the pathophysiology of insomnia. However, percent-
age of light sleep (N1) and arousal index was significantly greater in OSA group
compared to pure insomnia and COMISA (Choi et al. 2016). Interestingly, while
respiratory events related arousal dominated in OSA group, most of arousals in other
two groups were spontaneous (Choi et al. 2016). Thus, despite having greater time
spent in lighter sleep and higher arousal index, patients with OSA do not report
insomnia. Other studies did not find these differences and reported that sleep-
architecture, arousal index, periodic limb movement index, and oxygen saturation
were comparable between OSA subjects with and without insomnia (Stelzer et al.
2021; Cho et al. 2018; Lichstein et al. 2013). These findings suggest that insomnia is
an independent disorder and its presence leads to misperception of sleep as wake-
fulness despite having comparable sleep macro-architecture (Choi et al. 2016).
Misperception of sleep also follows a gradient and it is greatest among patients
with insomnia compared to patients having OSA or COMI SA (Choi et al.
2016;
Bianchi et al. 2013). In other words, presence of OSA reduces the difference
between subjective and objective sleep (Bianchi et al. 2013). Interestingly, mismatch
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between objective and perceived sleep is not related to the proportion of N1 sleep or
number of nocturnal awakenings (Bianchi et al. 2013).
114 R. Gupta and L. K. Saini
Insomnia in patients with OSA is not
a byproduct of OSA for several reasons.
Proportion of patients with initial and sleep maintenance insomnia are similar across
groups. Time spent is wake after sleep onset is also comparable across groups.
Lastly, severity of respiratory parameters , namely, respiratory disturbance index,
minimum oxygen desaturation, respiratory event-related arousal index are also
comparable between OSA and COMISA (Lichstein et al. 2013).
Taken together, evidence suggests that patients with COMISA form a different
subgroup where two disorders are comorbid and warrants independent treatment.
8.4 Need for Identification of COMISA
Patients with COMISA suffer from two disorders and this combination is likely to
produce greater disability and poorer quality of lif e among them compared to
patients with either disorders. This has been confirmed in clinical investigations
where subjects with COMISA were found to have poorer scores on physical and
social domains compared to subjects with pure OSA (Cho et al.
2018; Tasbakan
et al. 2018). On the other hand, compared to pure OSA and insomnia, presence of
both the disorders together among patients with COMISA do not have addictive
effects on cardiovascular risk, which is contrary to the theoretic possibility, as
reported by Luyster et al. (
2014). They also reported that prevalence of diabetes,
hypertension, and dyslipidemia was also comparable between OSA and COMISA
(Luyster et al.
2014). Diameter of brachial artery was also comparable between these
two groups (OSA vs COMISA), though it was greater than pure insomnia and
control groups (Luyster et al. 2014). These findings suggest that OSA is main culprit
for the cardiovascular and metabolic changes in these patients with little, if at all,
contribution from insomnia. However, further research is required whereby a num-
ber of factors related to insomnia, for example, chronicity of insomnia, duration of
sleep in a day among patients with insomnia (insomnia with objective short sleep
assessed longitudinally) are required before refuting absence of additive effect
(Luyster et al.
2014).
Two studies have assessed the effect of gender on quality of life among patients
with COMISA. One study showed that perception of quality of life was dependent
upon gender as women with COMISA report poorer quality of life in all domains
than men (Tasbakan et al. 2018). However, another study reported opposite findings
with men having COMISA had greater fatigue and poorer quality of life compared to
opposite gender (Lee et al.
2014). Thus, the available evidence indicates towards
poorer quali ty of life among patients with COMISA, however, further research is
required in this area.
Besides affecting quality of life, longitudinal data suggest that comorbid insom-
nia adversely affects adherence to positive airway pressure (PAP) therapy resulting
lesser daily use and lesser nights with PAP use greater than 4 h (Ong and Crawford
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Table 8.2 Why should
COMISA be addressed? (Ong
and Crawford ; Cho et al.
; Ong and Crisostomo
; Luyster et al. ;
Jeon et al.
)2021
20102013
2018
2013
Patients with COMISA are at increased risk for
• Reduced vigilance
• Depression
• Sleepiness
• Poor quality of life
• Functional impairment
• Chronic pain
• Hypertension
• Coronary artery disease
• Congestive heart failure
• Diabetes mellitus
• Metabolic syndrome
• Stroke
• Work absenteeism
• Poor adherence to positive airway pressure therapy
• Accidents: Motor vehicle and industrial
2013; Wallace et al. 2018). However, contradictory results have been shown in
another study which reported that presence of insomnia does not affect adherence to
PAP (Cho et al. 2018). Thus, this area is open for further research. Concomitant
occurrence of insomnia and OSA increase risk for psychiatric and other medical
disorders as well (Table
8.2).
8 Diagnosis and Management of OSA Comorbid with Insomnia (COMISA) 115
Pathophysiologically, O occurrence of metabolic, cardiovascular, and cerebro-
vascular morbidities could be ascribed to pathophysiology of insomnia as well OSA
that includes recurrent hypoxemia, formation of reactive oxygen species and other
free radicals, sympathetic surge, and hypercortisolemia due to activation of HPA
axis (Gupta and Knapp 2014).
Presence of OSA among subjects with insomnia does not affect effectiveness of
cognitive behavi
or therapy for insomnia (CBTi) (Ong and Crawford
2013;
Sweetman et al.
2017). In other words, magnitude of improvement in symptoms of
insomnia is comparable between patients with COMISA and insomnia following
CBTi (Sweetman et al. 2017). Thus, CBTi before institution of PAP therapy among
patients with COMISA can not only improve insomnia, but also improve adherence
to PAP therapy.
8.5 Pathogenesis of COMISA
Though exact mecha nism leading to COMISA is not clear, however, certain theo-
retical models have been proposed (Ong and Crawford 2013). These models are
based on cross -sectional as well and longitudinal studies. Longitudinal studies,
nonetheless, challenge the models proposed based on cross-sectional studies (Ong
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and Crawford 2013). For the sake of understanding, these models are discussed here
(Fig.
8.4).
116 R. Gupta and L. K. Saini
Fig. 8.4 Pathophysiological mechanism involved in OSA as well as insomnia may precipitate each
other and can work in feed forward manner to develop COMISA
8.5.1 OSA Leading to Insomnia
A numbe r of factors are considered to be instrumental in occurrence of insomnia
among patients having OSA. First, it is a well-known fact that respiratory events
occurring during OSA may lead to micro-arousals. Sleep deprivation occurring
because of these micro-arousals actives stress pathway, whi ch in turn, may lead to
insomnia (Ong and Crawford 2013). Respiratory events also cause sympathetic
surge at the termination, whi ch can facilitate hyperarousal leading to insomnia
(Ong and Crawford
2013) (Fig.
8.5
). Thirdly, a number of patients are not able to
tolerate either mask or the pressure of PAP and thus remains awake or experience
disturbed sleep. When sleep disturbances continue for a long time, through the
kindling mechanisms insomnia becomes chronic and severe. Fourth, it is possible
that patients having untreated OSA remains in the state of sleep-debt and thus do not
experience insomnia. When sleep-debt improves after treatment of OSA, insomnia
gets unmasked (Ong and Crawford
2013). Lastly, OSA is usually associated with
nocturnal polyuria which compels the person to wake up repeatedly. Repeated
awakenings may lead to behavioral changes that include extension of bedtime, use
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8 Diagnosis and Management of OSA Comorbid with Insomnia (COMISA) 117
Fig. 8.5 An epoch showing that respiratory events can also lead to a sympathetic surge at the termination, facilitating hyperarousal and leading to insomnia
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of stimulants like caffeine during the day, which in trun facilitate insomnia through
psychophysiological model (Janssen et al. 2019). However, data from cross-
sectional as well as longitudinal studies do not provide any confirmatory evidence
that any of these hypotheses is better than the others. (Ong and Crawford
2013).
118 R. Gupta and L. K. Saini
.
8.5.2 Insomnia Leads to OSA
Though never investigated properly, some of the studies suggest that insomnia alters
the tone of muscles of upper airway leading to precipitation of OSA (Ong and
Crawford 2013). Persons with low arousal threshold wake u p from the sleep is close
association with a respiratory event. Recurrent awakenings and subsequent sleep
reduce the wakefulness stimulus and, predispose to unstable breathing through
ventilatory control mechanisms (Janssen et al.
2019). These changes predispose to
OSA. However, further research is required to validate this hypothesis.
8.5.3 Feed Forward Mechanisms to COMISA
Sections 8.5.1 and 8.5.2 clearly state that insomnia and OSA may increase occur-
rence of each other through multiple mechanisms.
8.6 How to Screen and Diagnose COMISA?
Insomnia is difficult to be diagnosed in the presence of other sleep disorders
including OSA (Ong and Crawford
2013). It needs to be remembered that overlap
of symptoms between OSA and insomnia may have a positive influence in the
diagnosis of either disorders before and after treatment of both the disorders
(Sweetman et al.
2019a) (see Fig. 8.2). In other words, overlap of symptoms may
spuriously enhance the chances of diagnosis of insomnia among patients with OSA
(Sweetman et al. 2019a). Thus, care must be taken while diagnosing insomnia
among subjects wi th OSA. Moreover, care should also be taken to differentiate
insomnia symptoms from insomnia disorder as symptoms appears to have greater
prevalence compared to disorder in general population (Mallon et al. 2014).
A number of screening instruments are available to screen and diagnose insom-
nia. Commonly used questionnaires include insomnia severity index and Athens
insomnia scale (Bastien et al.
2001; Soldatos et al. 2000). However, insomnia
severity index can overestimate insomnia among patients having OSA (Wallace
and Wohlgemuth 2019). Other instruments have not been validated in this
population.
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