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Identifying patients to refer for further investigation
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of the causes of EDS is therefore one of the most complex challenges and requires
investigations at several levels, such as metabolic, neuroimaging and biochemical,
in addition to the most commonly used sleep medicine assessments, such as PSG,
actigraphy, 24-h EEG and vigilance tests (MSLT or MWT).
In recent years, the evidence of the association of RBD with neurodegeneration
processes, especially alpha-synucleinopathies, has been continuously growing and
several published papers have shown that some neurophysiological characteristics
can underline prodromal stages or early neurodegeneration. Thus, video-PSG is
mandatory when REM sleep parasomnia is suspected. This assessment has also been
recently included in the diagnostic criteria of various neurogenerative diseases, such
as Lewy body dementia or multisystem atrophy. Neurodegenerative processes can
also be associated with circadian rhythm disturbances (with a total subversion of the
sleep–wake cycle), EDS and insomnia. In these cases, it may be very important to use
actigraphy and a sleep diary for the diagnosis and therapy monitoring.
Conclusion
In consideration of the data available, the importance of assessing sleep disorders
and accurately classifying them into their correct diagnostic category appears to be
fundamental in order to provide patients with a targeted therapeutic intervention
and reduce the risks of complications, comorbidities, resistance to treatment and
health costs.
Further reading
• Antelmi E, et al. (2021). REM sleep behavior disorder: mimics and variants. Sleep Med Rev; 60:
101515.
• Bruni O, et al. (2022). Chronic insomnia of early childhood: phenotypes and pathophysiology.
Neurosci Biobehav Rev; 137: 104653.
• Dauvilliers Y, et al. (2018). REM sleep behaviour disorder. Nat Rev Dis Primers; 4: 19.
• DelRosso LM, et al. (2021). Restless legs syndrome in children and adolescents. Child Adolesc
Psychiatr Clin N Am; 30: 143–157.
• Ferini-Strambi L, et al. (2021). Insomnia disorder: clinical and research challenges for the 21st
century. Eur J Neurol; 28: 2156–2167.
• Ferri R, et al. (2022). Leg movements during sleep in children treated with serotonergic
antidepressants. Sleep; 45: zsab236.
• Figorilli M, et al. (2021). Neurophysiological aspects of REM sleep behavior disorder (RBD):
a narrative review. Brain Sci; 11: 1588.
• Kim JH, et al. (2018). Circadian rhythm sleep–wake disorders in older adults. Sleep Med Clin;
13: 39–50.
• Meira E Cruz M, et al. (2023). Comorbid insomnia and sleep apnea in children: a preliminary
explorative study. J Sleep Res; 32: e13705.
• Ragnoli B, et al. (2021). Comorbid insomnia and obstructive sleep apnea (COMISA): current
concepts of patient management. Int J Environ Res Public Health; 18: 9248.
• Riemann D, et al. (2017). European guideline for the diagnosis and treatment of insomnia.
J Sleep Res; 26: 675–700.
• Schipper MH, et al. (2020). Sleep-related leg movements in obstructive sleep apnea:
definitions, determinants, and clinical consequences. Sleep Med; 75: 131–140.
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Identifying patients to refer for further investigation
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• Somma A, et al. (2018). Interview-based ratings of DSM-IV Axis II/DSM-5 Section II
Personality Disorder symptoms in consecutively admitted insomnia patients: a comparison
study with consecutively admitted psychotherapy patients matched on age and gender.
Compr Psychiatry; 87: 100–106.
• Stefani A, et al. (2019). Clinical neurophysiology of REM parasomnias. Handb Clin Neurol; 161:
381–396.
• Zucconi M, et al. (2021). Classification of sleep disorders. In: Bassetti C, et al., eds. Sleep
Medicine Textbook. 2nd Edn. Regensburg, European Sleep Research Society; pp. 151–166.
315ERS Handbook: Respiratory Sleep Medicine
Insomnia
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Luigi Ferini-Strambi, Marco Sforza and Andrea Galbiati
Chronic insomnia: definition, diagnosis and pathophysiology
Insomnia disorder is one of the most frequent mental disorders and the most frequent
sleep disorder encountered in clinical practice, as between 11.3% and 58.2% of
the population meets the diagnostic criteria. Insomnia disorder is characterised by
diculties initiating and maintaining sleep and or/waking up too early, resulting
in dissatisfaction with sleep and significant daytime impairments such as fatigue,
cognitive impairment, impaired social and occupational performance and irritability.
Importantly, in accordance with the latest diagnostic manual, chronic insomnia
disorder is defined by temporal specifiers, i.e. the disturbance occurs at least three
times per week for ≥3 months (diagnostic criteria are presented in table 1).
Although former diagnostic classifications recognised two main subtypes of insomnia
disorder – namely primary and secondary insomnia disorder (i.e. when insomnia
symptoms are better explained by a coincident psychiatric, medical or substance
use/abuse disorder) – recent nosology (ICSD-3 and the Diagnostic and Statistical
Manual of Mental Disorders 5th edition) removed this distinction in favour of a more
comprehensive category, since well-founded conclusions about the association or
direction of causality between insomnia and comorbid conditions are oen not reliable.
Indeed, insomnia disorder occurs frequently in association with other conditions, in
particular mental disorders, but can also precede the onset of psychopathology. As
an example, a recent meta-analysis of longitudinal studies reported that insomnia
disorder increases the risk of the development of mental pathologies, in particular
depression, anxiety, alcohol abuse and psychosis. Moreover, insomnia disorder can
persist despite an eective treatment of the comorbid condition, or can aggravate the
symptoms of the comorbid condition.
Key points
• Insomnia disorder is the most frequent sleep disorder in clinical practice.
• Diagnosis of insomnia disorder is performed solely based on the patient’s
subjective report.
• CBT-I is the first-choice treatment.
• COMISA oen limits adherence to interventions for both disorders.
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Table 1. Diagnostic criteria for chronic insomnia disorder according to ICSD-3
A The patient reports, or the patient’s parent or caregiver observes, one or more of the
following:
Diculty initiating sleep
Diculty maintaining sleep
Waking up earlier than desired
Resistance to going to bed on appropriate schedule
Diculty sleeping without parent or caregiver intervention
B The patient reports, or the patient’s parent or caregiver observes, one or more of the
following related to the night-time sleep diculty:
Fatigue/malaise
Attention, concentration or memory impairment
Impaired social, family, occupational or academic performance
Mood disturbance/irritability
Daytime sleepiness
Behavioural problems (e.g. hyperactivity, impulsivity, aggression)
Reduced motivation/energy/initiative
Proneness for errors/accidents
Concerns about or dissatisfaction with sleep
C The reported sleep/wake complaints cannot be explained purely by inadequate
opportunity (i.e. enough time is allotted for sleep) or inadequate circumstances
(i.e. the environment is safe, dark, quiet and comfortable) for sleep
D The sleep disturbance and associated daytime symptoms occur at least three times
per week
E The sleep disturbance and associated daytime symptoms have been present for
≥3 months
F The sleep/wake diculty is not better explained by another sleep disorder
Criteria A–F must be met.
Although the pathophysiology of the disorder is still unknown, the model of
hyperarousal is able to account for dierent features or the disorder. Indeed, this
model describes and conceptualises insomnia disorder outside the night-time view: it
conceives insomnia as a 24-h disorder characterised by increased autonomic, cortical
and cognitive arousal resulting in a psychophysiological asset incompatible with
sleep drive. Some of the literature investigates genetic predisposition to insomnia
disorder. Although some findings reported an association between sleep disturbance
and alterations of circadian clock genes, as well as neurotransmitter function genes
related to sleep–wake regulation, recent findings have suggested an overlap between
insomnia disorder and depression, stress and anxiety disorders, rather than with other
sleep disorders or clock-related genes.
As reported in table 1, diagnosis of insomnia disorder is performed solely based on the
patient’s subjective report, in particular through information obtained by use of sleep
diaries. In fact, PSG recordings can be used to rule out the presence of other sleep
disorders or to investigate the presence of sleep misperception (i.e. the tendency of
some patients with insomnia disorder to underestimate the duration of sleep period),
but not for diagnostic purposes. The same applies to actigraphic evaluation, which can
be used for a reliable long-term objective assessment (7–14 days), but without clear
indications for diagnosis of insomnia disorder. Nevertheless, some considerations
can be made. A meta-analysis investigating PSG alterations in insomnia disorder
reported that these patients displayed a disruption of sleep continuity (as expressed
by waking aer sleep onset and sleep eciency), an increased sleep-onset latency
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and a significant reduction of slow wave sleep (SWS) and REM sleep in comparison to
good sleepers. Moreover, increased activity of fast frequencies can be observed at EEG
level and this is probably associated with the phenomenon of sleep misperception, i.e.
the tendency of patients with insomnia disorder to underestimate the sleep period,
overestimating wakefulness. Another remarkable anomaly related to insomnia disorder
regards SWS and its homeostatic function. Indeed, it has been reported that insomnia
disorder patients show 1) lower increase in or rebound SWS aer sleep deprivation and
decreased SWS pressure; 2) reduced δ-sleep EEG power; and 3) longer SWS latencies.
Yet another anomaly in insomnia disorder concerns REM sleep: patients show an
increased instability of REM sleep, characterised by frequent arousals in comparison
to good sleepers. Importantly, given the strong involvement of REM sleep in emotional
processing and the overnight dissipation of emotional distress, this instability may
also represent the bridge between insomnia and psychopathology, in particular
depression and anxiety disorders. Finally, although there is no strict cut-o in term of
hours spent asleep to distinguish patients with insomnia disorder from good sleepers,
a classification of patients based on total sleep time has been proposed. According
to this view, patients with insomnia disorder characterised by short sleep duration,
objectively documented with a total sleep time <6 h, had higher risk of hypertension,
impaired heart rate variability, diabetes, neurocognitive impairment and mortality in
comparison to patients with insomnia disorder with normal sleep duration (≥6 h);
the latter are characterised by more ‘psychological’ features, including an anxiousruminative profile, sleep misperception and are more likely to remit.
Treatment
Following the European guidelines for the diagnosis and treatment of insomnia, the
first-choice treatment for insomnia disorder is represented by cognitive behavioural
therapy for insomnia (CBT-I). Specifically, randomised controlled trials have
demonstrated that CBT-I is more ecacious than pharmacotherapy in the long term.
CBT-I is a multimodal approach, usually applied by an expert clinician in four to eight
face-to-face or group sessions, comprising the following.
• Psycho-education on sleep hygiene, which includes ‘sleep hygiene rules’ about
health practices (e.g. clockwatching, physical exercise, substance use) and
environmental factors (e.g. light, noise, temperature) able to promote or disrupt
sleep. Furthermore, psychoeducation includes basic information about normal
sleep and age-related changes in sleep patterns.
• Behavioural interventions (e.g. stimulus control and sleep restriction); sleep
restriction therapy (SRT) is a method designed to reduce the time spent in bed by
the patients to the actual amount of sleep that is recorded in diaries. The aim is to
improve sleep consolidation and constrain its occurrence to a pre-defined timeline.
Stimulus control therapy is a set of instructions aimed to restore the bedroom–
sleep association with the purpose of re-consolidating the sleep–wake schedule: 1)
go to bed only when sleepy; 2) get out of bed when unable to sleep; 3) use the bed/
bedroom only for sleep and sex (i.e. no reading, no watching television); 4) arise at
the same time every morning; 5) do not nap during the day.
• Relaxation therapy includes clinical procedures aimed at reducing somatic tension
(e.g. progressive muscle relaxation, autogenic training) or intrusive thoughts at
bedtime (e.g. imagery training, meditation).
• Cognitive techniques aim to identify, challenge and modify dysfunctional beliefs
regarding sleep, insomnia and its consequences, including methods to reduce or
prevent excessive monitoring and worrying.
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Several reviews and meta-analyses have been focused on CBT-I ecacy. The literature
suggests that CBT-I is eective in primary and comorbid insomnia, with results at
least as eective as pharmacotherapy in the short term. Face-to-face treatments
and treatments of at least four sessions seem to be more eective than self-help
interventions or face-to-face interventions with fewer sessions. In addition, controlled
studies investigating CBT-I long-term ecacy reported clear evidence for long-lasting
eects. Indeed, the American College of Physicians has recommended CBT-I as the
initial treatment for all adults with chronic insomnia. Notably, since the access to
CBT-I is oen restricted due to the limited number of professionals who are trained
for this intervention, digital CBT-I represents a valid option.
Moreover, there are several pharmacological options for the treatment of insomnia
disorder. These include benzodiazepines and benzodiazepine receptor agonists, ant idepressants, antipsychotics, antihistamines, phytotherapeutic substances, melatonin
and orexin receptor antagonists. Although several of them are ecacious in the short
term, long-term eects are questionable and severely limited by side-eects. Indeed,
pharmacotherapy is not considered the best therapeutic approach.
Comorbid insomnia and sleep apnoea
Insomnia and insomnia symptoms are commonly observed in patients with OSA.
Among insomnia patients, 29–67% fulfil the diagnostic criteria for OSA, and 39–58%
of OSA patients report insomnia symptoms. Comorbid insomnia and sleep apnoea
(COMISA) patients have significant daytime impairments and reduced quality of
life compared to those with OSA or insomnia disorder alone. COMISA treatment
represents a challenge for clinicians, since the condition oen limits adherence to
interventions for both disorders. Guidelines suggest that clinicians whose primary
focus is on the treatment of patients with insomnia disorder screen for underlying
OSA, and in case of comorbidity, patients may require targeted treatments for each
disorder, specifically CBT-I and CPAP therapy.
CPAP represents the gold standard for OSA treatment, since its ecacy in reducing
the frequency of respiratory events during sleep, sleep fragmentation, sleepiness,
in improving daytime functioning and in reducing the occurrence of CVDs has been
extensively demonstrated. Unfortunately, its ecacy is severely undermined by poor
adherence. Between 30% and 80% of OSA patients can be classified as nonadherent
(i.e. CPAP usage for <4 h per night), hindering the expected improvement in levels of
sleepiness and daily functioning. Although CBT-I in these patients can be considered a
valuable option, improve CPAP adherence in addition, some concerns have been raised
about SRT. Remarkably, COMISA patients treated with CBT-I should be monitored
carefully for the risk associated with excessive levels of sleepiness, in particular during
the first week of the therapy when SRT is typically delivered. Remarkably, despite the
complexity of the COMISA condition, these therapeutic options seem to be eective
in these patients.
Further reading
• American Academy of Sleep Medicine (AASM) (2014). The International Classification of Sleep
Disorders (ICSD-3). 3rd Edn. Darien, AASM.
• American Psychiatric Association (APA) (2013). American Psychiatric Association: Diagnostic
and Statistical Manual of Mental Disorders (DSM-5). 5th Edn. Arlington, APA.
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Insomnia
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• Baglioni C, et al. (2014). Sleep changes in the disorder of insomnia: a meta-analysis of
polysomnographic studies. Sleep Med Rev; 18: 195–213.
• Hammerschlag AR, et al. (2017). Genome-wide association analysis of insomnia complaints
identifies risk genes and genetic overlap with psychiatric and metabolic traits. Nat Genet; 49:
1584–1592.
• Hertenstein E, et al. (2019). Insomnia as a predictor of mental disorders: a systematic review
and meta-analysis. Sleep Med Rev; 43: 96–105.
• Jansen PR, et al. (2019). Genome-wide analysis of insomnia in 1,331,010 individuals identifies
new risk loci and functional pathways. Nat Genet; 51: 394–403.
• Mignot E, et al. (2022). Safety and ecacy of daridorexant in patients with insomnia disorder:
results from two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials.
Lancet Neurol; 21: 125–139.
• Mitchell MD, et al. (2012). Comparative eectiveness of cognitive behavioral therapy for
insomnia: a systematic review. BMC Fam Pract; 13: 40.
• Morin CM, et al. (2020). Incidence, persistence, and remission rates of insomnia over 5 years.
JAMA Netw Open; 3: e2018782.
• Pigeon WR, et al. (2006). Sleep homeostasis in primary insomnia. Sleep Med Rev; 10: 247–254.
• Qaseem A, et al. (2016). Management of chronic insomnia disorder in adults: a clinical practice
guideline from the American College of Physicians. Ann Intern Med; 165: 125–133.
• Riemann D, et al. (2015). The neurobiology, investigation, and treatment of chronic insomnia.
Lancet Neurol; 14: 547–558.
• Riemann D, et al. (2017). European guideline for the diagnosis and treatment of insomnia.
J Sleep Res; 26: 675–700.
• Rios P, et al. (2019). Comparative eectiveness and safety of pharmacological and non-
pharmacological interventions for insomnia: an overview of reviews. Syst Rev; 8: 281.
• Sweetman A, et al. (2019). Co-morbid insomnia and sleep apnea (COMISA): prevalence,
consequences, methodological considerations, and recent randomized controlled trials. Brain
Sci; 9: 371.
• Vgontzas AN, et al. (2013). Insomnia with objective short sleep duration: the most biologically
severe phenotype of the disorder. Sleep Med Rev; 17: 241–254.
• Wittchen HU, et al. (2011). The size and burden of mental disorders and other disorders of the
brain in Europe 2010. Eur Neuropsychopharmacol; 21: 655–679.
• Zhang Y, et al. (2019). Worldwide and regional prevalence rates of co-occurrence of insomnia
and insomnia symptoms with obstructive sleep apnea: a systematic review and meta-analysis.
Sleep Med Rev; 45: 195–213.
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Restless legs syndrome
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Ambra Stefani and Ulf Kallweit
Diagnosis of restless legs syndrome
Restless legs syndrome (RLS) is a neurological sensorimotor disorder characterised by
unpleasant sensations, mainly in the lower limbs, accompanied by the urge to move.
Symptoms worsen at rest and in the evening, and are relieved by movement. RLS
aects 5–13% of the general population in Europe and the USA. Symptoms lead to
delayed sleep onset, poor sleep quality, psychological distress and impaired healthrelated quality of life.
RLS diagnosis is clinical. All five essential diagnostic criteria from the International RLS
Study Group (IRLSSG) must be met: 1) an urge to move the legs, usually but not always
accompanied by or felt to be caused by uncomfortable and unpleasant sensations in
the legs; 2) the urge to move the legs and any accompanying unpleasant sensations
begin or worsen during periods of rest or inactivity such as lying down or sitting; 3)
the urge to move the legs and any accompanying unpleasant sensations are partially
or totally relieved by movement, such as walking or stretching, at least as long as the
activity continues; 4) the urge to move the legs and any accompanying unpleasant
sensations during rest or inactivity only occur or are worse in the evening or night than
during the day; 5) the occurrences of the above features are not solely accounted for as
symptoms primary to another medical or behavioural condition (e.g. myalgia, venous
stasis, leg oedema, arthritis, leg cramps, positional discomfort, habitual foot tapping).
Mimics must be excluded, but the same disorders able to mimic RLS symptoms may
be present as comorbid disease. Thus, presence of RLS mimics per se does not exclude
RLS. People with sleep-related breathing disorders frequently have comorbidities
Key points
• RLS is a common neurological sensorimotor disorder characterised by an urge
to move the limbs and unpleasant sensations, worsened by rest and improved
by movement, with a circadian rhythmicity.
• Genetic factors, dopamine dysfunction, brain iron deficiency, glutamatergic
and adenosine dysregulation, and hypoxia play a role in RLS pathogenesis.
• Management includes prevention of augmentation. Exacerbating factors
should be eliminated. α2δ ligands should be considered as initial treatment.
Other options include dopaminergic drugs and (in some cases) opioids.
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Restless legs syndrome
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representing potential RLS mimics. Not only exclusion of mimics but also recognition
of comorbidities is essential to optimise RLS management and improve patients’
quality of life.
Periodic leg movements during sleep
The neurophysiological hallmark of RLS is periodic leg movements during sleep
(PLMS), present in >80% of RLS patients. PLMS are not needed for RLS diagnosis
and are present in several other sleep and neurological disorders (e.g. sleep-related
breathing disorders, narcolepsy, REM sleep behaviour disorder, movement disorders,
multiple sclerosis) and in healthy subjects. Although some studies have suggested an
association between PLMS and cardiovascular risk, the clinical relevance of PLMS is
still unclear. Thus, PLMS treatment in people without RLS is not recommended.
RLS pathophysiology
RLS is a multifactorial disease, with genetic and environmental factors interacting in
triggering disease manifestation and influencing the clinical phenotype. A positive
family history is present in up to 60% of people with RLS, with 23 common genetic risk
variants in 22 genomic loci described to date. Pathogenetic mechanisms underlying
RLS include brain iron deficiency, dopaminergic, glutamatergic and adenosine
dysregulation, and hypoxia.
Brain iron deficiency
Although RLS prevalence is high among individuals with insucient iron availability,
most people with RLS have brain iron deficiency but normal systemic iron.
Dopaminergic dysregulation
Dysregulation of the dopaminergic system in people with RLS is supported by
symptom improvement with dopaminergic treatment, and by the development of
augmentation as a paradoxical response to the same drugs. This is due to a presynaptic hyperdopaminergic state and a post-synaptic receptor downregulation in
people with RLS, with consequent relative dopamine deficit in the evening and at
night (due to circadian changes in dopamine levels), as shown in figure 1.
Glutamatergic and adenosine dysregulation
Involvement of glutamatergic and adenosine systems in RLS is supported by positive
eects on symptoms of drugs acting on these neurotransmitters. Moreover, basal
glutamate levels in the thalamus are increased in people with RLS compared to controls.
Hypoxia
A role of hypoxia in RLS pathogenesis is indicated by higher RLS prevalence in
populations living at high altitude and in people with lung diseases associated with
hypoxia (including OSA), as well as by the findings of peripheral hypoxia, peripheral
muscular microvascular abnormalities and upregulation of the vascular endothelial
growth factor in the leg skeletal muscle in people with RLS.
Management of RLS
Current guidelines for RLS treatment and prevention of augmentation are provided by
the IRLSSG. Augmentation is a paradoxical response to RLS dopaminergic treatment,
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Restless legs syndrome
Dopamine
RLS later part of the
b) RLS late evening/
c)Physiologicala)
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night/daytime
Figure 1. Pre- and post-synaptic dopaminergic state: a) in physiological conditions; b and c)
in people with RLS, b) in the later part of the night and during the daytime, and c) in the late
evening and early part of the night. Due to circadian changes in dopamine levels, the nadir
is reached in the early part of the night, whereas in the later part of the night dopaminergic
activity starts to increase and reaches the highest levels in the early part of the day. Note that, for
simplification, decreased dopamine receptor D2/3 (D2/3R) activity is represented as decreased
D2/3R quantity, but could also be due to decreased sensitivity or anity.
early part of the night
D2/3R
characterised by earlier onset of symptoms, shorter latency to the onset of symptoms
at rest, worsening of symptom severity, reduced duration of treatment eect and
involvement of previously unaected body parts.
Drug treatment should be started only when symptoms are bothersome, and
exacerbating factors should first be eliminated (e.g. through iron supplementation
when indicated). As prevention of augmentation is key in RLS management, α2δ
ligands (i.e. gabapentin/pregabalin, which bind with high anity to α2δ subunits of
voltage-gated calcium channels) should be considered as initial treatment. The most
common side-eects of these include dizziness, sedation and weight gain. If electing to
start treatment with dopaminergics, long-acting drugs should be preferred, with daily
dosage as low as possible, in any case not exceeding maximal dosage recommended
for RLS. Possible side-eects of dopaminergics include confusion, low BP, compulsive
behaviours or sleep attacks.
Treatment of augmentation is complex. An algorithm by the IRLSSG includes
(depending, for example, on augmentation severity) changes in dose of the
dopaminergic drugs, switching to long-acting dopamine agonists, α2δ ligands or
opioids, cross-titration and wash-out strategies.
Specific guidelines are available for particular conditions like pregnancy and lactation
and iron supplementation in children.
323ERS Handbook: Respiratory Sleep Medicine
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