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Indications for additional oxygen treatment
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High-flow nasal cannula oxygen therapy for chronic ventilatory failure
Long-term domiciliary use of high-flow oxygen therapy as an alternative to NIV and
supplemental oxygen is being investigated. Feasibility studies have shown home
high-flow nasal oxygen/air use is possible in COPD patients post-exacerbation,
but the results of long-term randomised trials are awaited. A further discussion on
palliation and advance directives in end-stage disease is included in chapter 13.5 of
this Handbook.
Further reading
• Abdo WF, et al. (2012). Oxygen-induced hypercapnia in COPD: myths and facts. Crit Care;
16: 323.
• Criner GJ, et al. (2022). Feasibility of using daily home high-flow nasal therapy in COPD patients
following a recent COPD hospitalization. Chronic Obstr Pulm Dis; 9: 4–14.
• Jacobs SS, et al. (2020). Home oxygen therapy for adults with chronic lung disease. An
ocial American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med; 202:
e121–e141.
• Kaul S, et al. (2006). The eect of entrainment site and inspiratory pressure on the delivery of
oxygen therapy during non-invasive mechanical ventilation (NIMV) in acute COPD patients.
Eur Respir Rev; 15: 190–191.
• O’Driscoll BR, et al. (2017). British Thoracic Society guideline for oxygen use in adults in
healthcare and emergency settings. BMJ Open Respir Res; 4: e000170.
• Thys F, et al. (2002). Determinants of F
two-level positive pressure ventilation. Eur Respir J; 19: 653–657.
with oxygen supplementation during noninvasive
i,O2
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Palliation and advance
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directives in end-stage
disease
Anita K. Simonds
Palliative medicine aims to identify and ameliorate symptoms, improve quality of
life and wellbeing and support patients with severe acute or chronic disease, and
their caregivers. This is not just limited to the end-of-life phase (last 6–12 months
of life), as patients with neuromuscular conditions may require symptom palliation
intermittently for much of their life; those with COPD for may do so for several years
during the advanced phase; and a focused approach is required for individuals with
rapidly progressive disease such as motor neurone disease (MND)/amyotropic lateral
sclerosis (ALS). While breathlessness is common in chronic respiratory disorders,
symptoms such as fatigue, muscle cramps, upper airway secretions, joint pain,
anxiety and depression may be equally troublesome or dominate, depending on the
underlying condition and stage of the natural history.
Key points
• Symptom palliation is not limited to the end-of-life phase, and is
compatible with active interventions such as ICU admission and invasive
ventilation.
• Palliative medicine should be part of a multidisciplinary approach. Respiratory
support/sleep teams must learn from palliative care colleagues, apply
knowledge in the interests of patients, and share care where possible.
• An advance care plan should be developed collaboratively in all patients with
alveolar hypoventilation receiving NIV or long-term oxygen therapy due to
chronic neuromuscular or chronic pulmonary disease.
• Advance care plans include advance directives on treatment refusal, which
may be binding in some jurisdictions. The plan should also cover a range of
care preferences – such as ICU admission, cardiopulmonary resuscitation and
preferred place of death.
• Patients/proxies should be provided with accurate, up-to-date information to
aid decision-making.
• Support should always be oered to caregiver(s) as well as the patient.
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MND/ALS
While ventilatory support extends survival in MND/ALS and may reduce breathless
and symptoms due to nocturnal hypoventilation, survival is related to nature of onset,
FVC and symptom score at diagnosis. Bulbar-onset patients may have more rapid
progression, and unsurprisingly those with a lower FVC and higher symptom score
at diagnosis have a worse prognosis. A symptom-focused approach to deal with
problems such as drooling, muscle cramps and mood swings is very helpful. Decisionmaking including the timing of initiation of NIV, consideration of tracheostomy
ventilation for disease progression, psychosocial aspects and advance care plans
are discussed herein, and elsewhere in this Handbook. Care delivered at home by
an outreach team combined with telemonitoring can be very eective, and reduces
stressful hospital visits.
COPD and chronic lung disease
As well as optimising control of COPD according to guidelines, opiates may reduce
breathlessness in advanced disease. For the management of breathlessness or
chronic pain in patients with ventilatory failure using NIV, the dose of opiate should
not be reduced because of concerns about carbon dioxide retention; instead
ventilatory settings should be adjusted so this does not occur. These interventions
and nonpharmaceutical measures are covered in the Further reading.
Inherited neuromuscular disorders: new features
The natural history of some inherited neuromuscular disorders has changed
significantly over the past few decades. Prior to the use of ventilatory support,
infants with spinal muscular atrophy (SMA)1 died before the age of 24 months; the
mean age of survival in Duchenne muscular dystrophy (DMD) was in the late teens;
and many children with congenital myopathies and muscular dystrophies did not
survive childhood. Now, ventilatory support extends survival by decades in some
conditions, but new complications may arise. For example, older DMD patients
may develop autonomic bowel problems, renal and bladder calculi, cardiac failure,
dysrhythmias and large-joint pain and contractures. These all require specific
management and care.
Furthermore, new therapies such as the oligonucleotides in SMA, and gene therapy
and gene editing in DMD, SMA and congenital myopathies, may alter the natural
history significantly. Short- and long-term responses to these therapies are associated
with uncertainty for the individual and their family, and in many cases symptom
palliation can be combined with an active approach such as intensive care unit (ICU)
admission, invasive ventilation and resuscitation if agreed with patient and family,
and a good outcome is expected.
Advance care planning/advance directives
Advance directives or ‘advanced decisions to refuse treatment’ are part of an advance
care plan. This communication exercise should occur as a result of discussion
between the patient, family, caregivers and medical team. The anticipatory plan
should encompass the individual’s preferences, goals and priorities of care, such as
whether they wish to be admitted to the ICU, have tracheostomy ventilation or a
gastrostomy, undergo cardiopulmonary resuscitation, and where they would prefer
to die. The collaborative process ideally occurs at the patient’s pace, and when
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done well improves outcomes for patients and families, and should ensure that the
patient is not subject to unwanted interventions. Advance directives are oen used
to refuse treatment, but advance care planning is just as important in those who
wish to receive full interventions including resuscitation and ICU admission/invasive
ventilation.
The course of many chronic lung conditions is dicult to predict, as aer chronic
deterioration, the person may die of a sudden acute exacerbation, and the patient’s
views may change over time. However, the discussion should begin with any patient
starting long-term oxygen therapy or NIV, focusing on understanding expectations
for the future and autonomy and allowing the patient to play a full role in decisionmaking. Mental capacity is required for advance care decisions and requires the
individual to understand the benefits and disadvantages of taking up treatments,
or not, and the ability to weigh this information in the balance. In some countries
a legal document (power of attorney) can be used to enable the patient to appoint
one or more people (proxies) to make decisions on their behalf, should they lose
the capacity to do so.
Palliative care in long-term NIV users
As chronic pulmonary disease and neuromuscular conditions progress, patients can
become increasingly dependent on NIV. This may require adaptation of settings and
interfaces, taking into account that patients may become less able to don or do these,
or operate the ventilator unaided. The support plan should cover risk management and
include a back-up ventilator and battery power for those with more than nocturnal
ventilator dependence. With increasing bulbar involvement, NIV management may
be problematical and tracheostomy ventilation can be considered, but is not suitable
for all. The pros and cons should be carefully explained: the patient’s wishes, home
and family circumstances, carer training and care package availability/financing are
important factors (chapter 13.2 of this Handbook).
Psychosocial support
Psychological and social support should be available as part of the multidisciplinary
team approach. Pinto et al. (2021) showed that emotional distress was common in
MND/ALS patients and related to deterioration in physical function, and the concept
of the loss of a future. Changes in symptoms, feeling unsupported by the healthcare
team and poor communication add to the distress. Experiencing support from others,
finding of hope and exerting control were all positive features. Depression and anxiety
are common in advanced COPD patients and personalised approaches to treat these
not only improve mental health, but also reduce hospital admissions.
NIV withdrawal in end-stage disease
If it is the patient’s settled wish, NIV withdrawal is ethically permissible as an
expression of autonomy in many countries, if the patient is at the end of life and
the burden of the disease and treatment outweighs any benefit. Most experience
has been gained in NIV withdrawal in patients with end-stage MND/ALS. This can
be done in hospital, a hospice or at home according to the patient’s wishes. It is
very important that the decision is discussed and agreed with the partner, family
and all members of the team. Normally, aer starting an opiate subcutaneous
infusion (combined with antiemetic and a sedative such as midazolam) to control
symptoms, the NIV interface is removed when the patient is fully unconscious and
the eyelash reflex is lost. The infusion should be carefully titrated to maintain control
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of symptoms and the patient’s comfort until they die, the cause of death being their
underlying disease.
Caregiver support and bereavement care
The importance of caregiver support cannot be overstated, as the burden to caregivers/
family members is frequently underappreciated. Many experience isolation, financial
hardship due to the impact on their employment, and mood changes. Family carers
face a change to their anticipated future, and an alteration of their role, e.g. from
partner to carer. Support groups and networks can be very valuable for both carers
and patients, and carers should always be asked about symptoms and mood, and how
they are coping. Communication with family members/caregivers aer the death of
the patient is almost always helpful, if done thoughtfully, and is an important way of
learning how we can do better in future.
Further reading
• Curtis JR (2008). Palliative and end-of-life care for patients with severe COPD. Eur Respir J; 32:
796–803.
• Faull C (2018). End-of-life care and non-invasive ventilation. In: Elliott M, et al., eds. Non-
Invasive Ventilation and Weaning, Principles and Practice. 2nd Edn. Boston, CRC Press; pp.
571–581.
• Faull C, et al. (2016). Withdrawal of ventilation at the request of a patient with motor neurone
disease. Guidance for professionals. BMJ Supp Palliat Care 6: 144–146.
• Halpin DMG (2018). Palliative care for people with COPD: eective but underused. Eur Respir J;
51: 1702645.
• Pinto A, et al. (2021). Emotional distress and well-being among people with motor neurone
disease (MND) and their family caregivers: a qualitative interview study. BMJ Open; 11:
e044724.
• Pyszora A, et al. (2022). Non-pharmacological management in palliative care for patients with
advanced COPD. Front Cardiovasc Med; 9: 907664.
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Identifying which patients
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to refer for further
investigation
Luigi Ferini-Strambi, Francesca Casoni and Maria Paola Mogavero
Classification and epidemiology of nonrespiratory sleep disorders
According to the third edition of the ICSD (ICSD-3), sleep disorders can be divided
into six dierent categories: insomnia, hypersomnia, parasomnia, sleep-related
movement disorders, sleep breathing disorders and circadian rhythm disorders. Many
of these disorders have a high prevalence in the general population and, among
sleep breathing disorders, OSA is the most frequent, with a prevalence of 9–38%.
Nonrespiratory sleep disorders include the other five categories: insomnia, with a
prevalence of 6–33%; hypersomnia, with a prevalence ranging from 0.5% to 1.6%;
parasomnias, among which REM sleep behavioural disorder (RBD) has a prevalence
of 3–10%; sleep-related movement disorders, such as restless legs syndrome (RLS),
with a prevalence of 5.5–11.6% in Europe and North America and 1–7.5% in Asia,
and periodic limb movements during sleep (PLMS), the prevalence of which is up to
30% in the general population; and finally, circadian rhythm disorders, which have a
prevalence of 3–10%. A summary list is given in table 1.
Focusing on nonrespiratory sleep disorders, according to ICSD-3 criteria, chronic
insomnia is a sleep disorder characterised by diculty in falling asleep or in maintaining
sleep or by early awakening, with a negative impact on daily performance, which may
Key points
• Nonrespiratory sleep disorders represent a wide range of disorders. Some
of these have a high prevalence in the general population, with a negative
impact on the health of those aected.
• A broad knowledge of these disorders and an accurate diagnostic framework,
both clinical and instrumental, are essential for a targeted and timely treatment
of these pathologies, reducing the risk of complications and comorbidities.
• For the purposes of a correct diagnosis, a broad and in-depth knowledge of
the many laboratory investigations (as well as the parametric scales used in
sleep) available to the clinician for the study of sleep disorders is necessary,
since the phenotypic pictures are oen varied, complex and interconnected.
• The treatment and prevention of sleep disorders is an important factor
for the prevention of medical, psychiatric, inflammatory, metabolic and
neurodegenerative diseases.
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Table 1. Classification of nonrespiratory sleep disorders
Insomnia
Chronic insomnia
Short-term insomnia
Other insomnia
Central disorders of hypersomnolence
IH
Narcolepsy type 1
Narcolepsy type 2
Kleine–Levin syndrome
Insucient sleep syndrome
Parasomnia and parasomnia overlap disorders
NREM sleep
Confusional arousals
Sleep terrors
Sleepwalking
Sleep-related eating disorder
REM sleep
RBD
Sleep-related movement disorders
RLS
Periodic limb movement disorder
Sleep bruxism
Restless sleep disorder
Circadian rhythm sleep–wake disorders
Advanced sleep–wake phase disorder
Delayed sleep–wake phase disorder
Irregular sleep–wake rhythm disorder
Jet lag disorder
Shi work disorder
Adapted from the ICSD-3.
manifest itself with fatigue, EDS or diculty concentrating and paying attention, for
at least three times a week and for a duration of 3 months, not attributable to other
sleep disorders or medical or pharmacological conditions. Insomnia in early childhood
can manifest itself with dierent phenotypes, which can translate into dierent
pharmacological approaches: insomnia with motor restlessness; insomnia without
diculty falling asleep but characterised by long-lasting early morning awakenings;
insomnia with multiple nocturnal awakenings and diculty falling asleep; and,
importantly, insomnia with normal or reduced sleep duration.
The ICSD-3 criteria define hypersomnias as disorders characterised mainly by EDS,
manifesting as an inability to remain alert and awake during the main periods of
wakefulness during the day, with incoercible sleep or involuntary bouts of drowsiness
or sleep. According to the classification, they are distinguished as narcolepsy type 1
and type 2 (NT1 and NT2), idiopathic hypersomnia (IH), Kleine–Levin syndrome and
insucient sleep syndrome; the latter is the most frequent cause of EDS. Moreover,
there are hypersomnias secondary to psychiatric conditions or associated with other
sleep disorders or medical or iatrogenic conditions.
Circadian rhythm disorders are a category of sleep disorders characterised by a chronic
misalignment between the endogenous circadian rhythm and the desired or required
rhythm of the surrounding environment or of social/work programmes. These
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disorders can cause symptoms of insomnia, EDS or both, with possible impairment
of the cognitive, social, educational and work spheres, or possible negative impact
on other important functions. This category includes advanced sleep–wake phase
disorder, delayed sleep–wake phase disorder, irregular sleep–wake rhythm disorder,
jet lag disorder and shi work disorder (in the case of shi workers).
The ICSD-3 defines parasomnia as undesirable physical events or experiences that
occur during entry into sleep, during sleep at night, or during awakening. These
disorders are classified according to the sleep phase during which they occur: NREM
sleep-related parasomnias, REM sleep-related parasomnias and other parasomnias
(such as sleep-related hallucinations and nocturnal enuresis). NREM sleep-related
parasomnias include confusional arousals, sleep terrors, sleepwalking and sleeprelated eating disorder. Conversely, RBD is a parasomnia linked to REM sleep. However,
some patients meet the diagnostic criteria for both NREM and REM sleep parasomnia,
and are diagnosed as having parasomnia overlap disorder.
According to the ICSD-3 criteria, sleep-related movement disorders are characterised
by simple, usually stereotyped, movements that disturb nocturnal sleep or its onset.
The main ones are RLS, periodic limb movement disorder (PLMD) and nocturnal
bruxism. Restless sleep disorder is a recently identified childhood disorder that has
been proposed for inclusion into this category.
Diagnostic approach to nonrespiratory sleep disorders
An accurate physiological, hypnological, family, work and pharmacological
anamnesis are fundamental for evaluating the patient and for establishing which
further laboratory and instrumental investigations are needed for the diagnostic
definition and treatment. The diagnosis of some of these disorders is essentially
clinical (diagnosis makes use of anamnestic data), for example for insomnia
(diagnosed according to the ICSD-3 criteria and symptoms previously described)
and RLS. RLS is defined by the diagnostic criteria as an urgent need to move the
legs, oen but not always accompanied or perceived as a result of unpleasant
sensations in the legs, with symptoms that begin or worsen during periods of rest
or inactivity, only in the evening or at night, which is partially or totally eliminated
with movement and not attributable to another medical condition (myalgia, venous
stasis, arthritis, oedema or leg cramps). Although such clinical diagnosis may be
possible, even in these cases it is common in practice to order PSG or actigraphy
studies to exclude that these diseases are due to or associated with other sleep
disorders whose diagnosis requires instrumental investigations, such as sleeprelated breathing or movement disorders. For example, PLMD is characterised by
episodes of repetitive, highly stereotyped, limb movements that occur during sleep
(PLMS) with a frequency of >15 events·h−1 (in children >5 events·h−1) associated
with a clinical sleep disturbance or a complaint of daytime fatigue. The most recent
international criteria for scoring PLMS define them as limb movements included in
regular and non-interrupted sequences of at least four events with onset-to-onset
intermovement intervals of 10–90 s.
The studies required depend on the type of sleep disorder that is suspected,
considering that some of them need PSG for their diagnosis, based on the ICSD-3
criteria or for dierential diagnosis. As an example, video-PSG in the case of
parasomnia is mandatory in order to exclude seizures during sleep. Video-PSG is
necessary for diagnostic purposes both for NREM parasomnias, during which it will
be possible to document non-paroxysmal motor events during deep sleep stages,
and for RBD, in which the loss of physiological atonia will be observed during REM
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sleep (as well as the possible concomitant presence of motor events, generally large
and oen violent, in this stage of sleep, due to the fact that the patient mimics the
dream content).
Sometimes (as in the case of hypersomnia) the use of vigilance tests, such as the
MSLT, is also mandatory, while the maintenance of wakefulness test (MWT) is useful
for an objective evaluation of EDS. According to the ICSD-3, NT1 is characterised
by persistent EDS (>3 months) with uncontrollable sleep bouts (‘sleep attacks’
and naps lasting up to 15–20 min, during which patients oen report a dream),
hypnagogic and hypnopompic hallucinations, sleep paralysis and cataplexy (sudden
and usually brief loss of muscle tone, with preserved consciousness, most oen
induced by emotions, indicating an intrusion of REM sleep atonia in wakefulness).
For the diagnosis in adults, the mean sleep latency (MSL) at the MSLT should be
<8 min, with the occurrence of at least two sleep-onset REM periods (SOREMPs)
during the test or at least one SOREMP at the MSLT and another recorded in the
previous night PSG, and dosage of orexin in the cerebrospinal fluid (CSF) should
be <110 pg·mL−1. According to the ICSD-3 criteria, NT2 is characterised by EDS
for at least 3 months, absence of cataplexy, an average sleep latency at MSLT of
<8 min and at least two SOREMPs at MSLT and/or PSG, and CSF orexin levels of
>110 pg·mL−1. Following the ICSD-3 criteria, IH also manifests itself with EDS
demonstrated by an average sleep latency at MSLT <8 min, but will show fewer
than two SOREMPs at MSLT and/or PSG, provided that other possible causes of EDS
are carefully excluded.
24-h EEG monitoring is a valid tool for the study of hypersomnia or EDS, insomnia
and circadian changes. For circadian changes, actigraphic monitoring for 2 weeks is
important (in any case it should not be carried out for <1 week and should include the
weekend), because it shows the patient’s sleep–wake cycle and therefore the dierent
types of circadian rhythm disturbances. For example, in the delayed or early phase
disorders, actigraphic monitoring allows observation of whether there is a lag of ≥2 h
with respect to a physiological sleep–wake cycle, allowing an accurate diagnosis. In
addition, this tool is very useful for documenting chronic sleep deprivation (the most
common cause of EDS).
Actigraphy, PSG and 24-h EEG monitoring are very useful for treatment monitoring
as well as for diagnosis. There are also other investigations that must be requested
to exclude secondary forms of the diseases, such as neuroimaging (brain MRI,
brain positron emission tomography (PET) or dopamine active transporter (DAT)
scan), EEG, EMG and blood or CSF chemistry tests, depending on the diagnostic
hypothesis.
A sleep diary carefully compiled by the patient is needed in order to obtain a reliable
actigraphic assessment of total sleep time and wakefulness aer sleep onset. The sleep
diary is another very useful tool both in the diagnostic framework and for treatment
monitoring; however, it is a subjective evaluation method, which should therefore be
associated with actigraphic monitoring. In the sleep diary, the patient is required to
indicate any therapy taken, their habits such as consumption of beverages containing
alcohol, caeine or other stimulating substances, with relative time of intake, and,
for each monitored day, bedtime, estimated sleep latency, number and duration of
perceived nocturnal awakenings, final awakening time and time spent in bed, total
time of perceived sleep, eventual naps and their duration as well as the times at which
they occur, and, finally, the perceived quality of sleep. Quite oen, other scales, such
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as the ESS, can be associated with the sleep diary, as can sleep quality scales such as
the Pittsburgh Sleep Quality Index and the Morningness–Eveningness Questionnaire
for the assessment of chronotype.
Oen, nonrespiratory sleep disorders can be comorbid with other pathologies and
influence the evolution of a clinical picture, represent a risk factor for multiple morbid
conditions or prevent their onset. There are in fact many complex pictures in clinical
practice, which the clinician should consider in order to direct the patient towards
the most appropriate diagnostic investigations and the correct therapeutic approach.
Nonrespiratory sleep disorders comorbid with other sleep disorders
Very oen, in clinical practice, multiple sleep disturbances can occur at the same time.
For example, the association between OSAS and insomnia can be mentioned here,
constituting a recently proposed clinical entity labelled COMISA (comorbid insomnia
and sleep apnoea), whose prevalence is estimated at between 40% and 60% in the
general adult population, and 16% in a recent study conducted in paediatric age
groups. This disorder oen represents a morbid condition in patients with insomnia,
possibly causing drug resistance. For this reason, it is essential to investigate the
dierent phenotypes of insomnia and, in these cases, although the diagnosis of
insomnia is clinical, to study the patient features also by PSG.
Other situations in which instrumental investigations in patients with insomnia are
required are those in which this may actually be related to sleep-related movement
disorders, such as RLS or PLMS, for a dierential diagnosis with circadian rhythm
disorders, and when a parasomnia can be suspected. In these cases, further
instrumental investigations such as PSG, video-PSG or actigraphy may be needed.
Sometimes a respiratory disorder during nocturnal sleep can mimic or trigger clinical
events that simulate a parasomnia, such as RBD, in which case video-PSG is essential
to make a correct diagnosis. Additionally, parasomnias also undergo dierential
diagnosis with some types of epilepsy. In other instances, respiratory events during
sleep can be associated with periodic movements of the lower limbs and PSG is
important to define the most appropriate treatment approach (the treatment of
respiratory events in fact may sometimes be beneficial for the motor events, without
necessarily requiring drug therapy).
Nonrespiratory sleep disorders comorbid with other pathological conditions
Chronic sleep deprivation and insomnia are frequently associated with psychiatric
problems, with a bidirectional relationship. Moreover, sleep-related movement
disorders, such as RLS or PLMS, can also be associated with psychiatric disorders,
both depressive disorders and attention deficit hyperactivity disorder (ADHD). Some
antidepressant compounds, especially selective serotonin reuptake inhibitors, are
associated with the onset of RLS or PLMS. In these conditions, knowledge of sleep
disorders is therefore of great importance in order to avoid the risk of complications
and resistance to drug treatment, or even a worsening of the clinical picture.
EDS, a very frequent symptom in patients with sleep-related respiratory disorders,
can be found in various metabolic, endocrinological or iatrogenic conditions (which
must therefore be excluded, in the context of dierential diagnostics). It can be found
in all nonrespiratory sleep disorders (due to alterations in the sleep–wake cycle,
poor sleep hygiene, sleep deprivation or its fragmentation) and is the key symptom
in hypersomnia (some of which, such as narcolepsy or Kleine–Levin syndrome, may
cause dierential diagnosis problems with psychiatric disorders). The definition
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