In particular, sleep-disordered breathing leads not only to daytime sleepiness or fatigue, but also to insomnia and is considered a trigger for parasomnias, epileptic seizures, and a risk factor for cardiovascular disease. Restless legs syndrome is the most common organic cause of insomnia on falling asleep. In addition to the idiopathic form, various secondary causes must be clarified.
In principle, the general practitioner may encounter any form of sleep-wake disorder in his or her practice, although sleep-related respiratory disorders are likely to be by far the most common. In clinical practice, the classification into the four main groups with 1. Shortened sleep (insomnias), 2. prolonged sleep (hypersomnias), 3. disfigured sleep (parasomnias) and 4. shifted sleep (sleep-wake rhythm disorders) proven.
Insomnia is a disorder of falling asleep or sleeping through the night. In this case, psychiatric causes, psychophysiological insomnia or restless legs syndrome must be sought first and foremost. Among the hypersomnias, the sleep apnea syndrome is certainly in the first place, which can usually be reliably clarified by means of respiratory polygraphy or polysomnography. However, it should not be overlooked that frequent sleep apnea syndrome may also be present simultaneously with other causes of daytime sleepiness such as sleep deficiency syndrome, depression, or together with neurological diseases or even in combination with narcolepsy. Parasomnias include quite different complex or simple behaviors during sleep. The most important of these are somnambulism, epileptic seizures, panic attacks, or REM sleep behavior disorder. However, in general practice, crampi nocturni or twitches to fall asleep are also a common complaint. Among the sleep-wake rhythm disorders , the shift worker syndrome is certainly the most important, along with the delayed sleep-wake rhythm in adolescents or the advanced sleep-wake rhythm in the elderly.
Because all of these sleep-disrupting factors negatively influence each other, it is of great importance to diagnose and treat all of them at the same time, if possible.
The physiological sleep
Healthy, adult persons usually need between 7 and 9 hours of sleep per day, although there are large individual differences between short and long sleepers. In young adults, sleep stage II takes up the bulk, about half, of sleep, REM sleep about 25%, deep sleep about 15%, and transitional sleep stage I about 10%. However, there are large differences depending on age, in that newborns and toddlers have a much greater proportion of REM.
Sleep pressure, which is subjectively manifested by daytime sleepiness, is controlled on the one hand by a “homeostatic component” and on the other hand by a “circadian mechanism”. The homeostatic component (= process S) describes the increasing sleepiness with the duration of wakefulness. The circadian mechanism (= process C) describes the internal clock with an average cycle duration of approx. 24.2 hours. Recent research results have shown that the whole brain does not necessarily have to be in the same state, but that at times certain parts of the brain can be awake while other areas are asleep (concept of regional sleep).
Sleep-wake disorders
Terminology: Patients with sleep-wake disorders will present very different subjective complaints to the treating physician, which must first be clarified in their exact meaning. In the case of insomnia, it must be clarified whether it is a falling asleep disorder, a sleeping through disorder, or early waking (the last hour?). The concept of fatigue should be differentiated into fatigue proper, which is also understood as lack of energy or adynamia without the tendency to fall asleep, and increases during physical work, versus daytime sleepiness, which leads to falling asleep in passive situations and is alleviated during physical activities. The Epworth score offers itself as a well-suited questionnaire, with a score of >10 indicating sleepiness. The term hypersomnia should be used to describe a prolonged need for sleep of more than 11 hours per 24-hour day. The English term fatigue is used very differently in the literature, including synonymously with sleepiness, which is not the case with the German term Ermüdbarkeit or Erschöpfbarkeit. We understand by it the subjective feeling of a pronounced decrease in performance during a certain physical or mental work, which is well known as a characteristic of chronic fatigue syndrome (= CFS).
Classification: The total of approximately 80 named “sleep-wake disorders” from the ICSD 3 (= International Classification of Sleep Disorders, Version 3, 2014) can be classified into the following four main groups for clinical purposes:
- Insomnias: decreased sleep
- Hypersomnias: increased sleep
- Parasomnias: disfigured sleep
- Sleep-wake cycle disorders: shifted sleep
Insomnias: In the case of insomnia, a distinction must be made between problems falling asleep and staying asleep and “premature awakening”, because these subtypes indicate different causes, the latter, for example, depression. Because of the therapeutic consequences, it is also important to differentiate between acute or chronic (>3 months) insomnia. “Non-restorative sleep,” which is characterized by either daytime sleepiness or daytime sleepiness, is now classified as hypersomnia.
In a normal population up to 30% suffer from sleep disorders and in about 10% these are so severe that sleeping pills are taken. Women are affected more often than men. The doctor must primarily look for depression and anxiety disorders. However, internal or neurological diseases with pain, gastroesophageal reflux, extrapyramidal movement disorders, dementia development, hyperthyroidism, or various medications and addictive substances can also disrupt sleep.
If no current cause can be found, it is often a so-called psychophysiological, also called learned insomnia, the cause of which may lie far back in time. Although the original cause of the insomnia, such as a crying child, great worry, or illness, has since disappeared, the sleep disorder persists like a bad habit. The therapy is based on behavioral therapy, which includes couch restriction as the most important element and can be supported by a temporary use of sleep-inducing antidepressants. To put it simply, the affected person is only allowed to lie down for as long as the desired sleep should last per 24 hours, and this regardless of whether or not there is also waking time in the lying down position. This measure may cause increased fatigue or sleepiness during the first 8 weeks, which is often difficult to tolerate without the help of a therapist.
An important organic cause of severe sleep disorders is Restless Legs Syndrome (RLS), which is so pronounced in about 3% of a normal population that drug treatment becomes necessary. The diagnosis can be made relatively easily on the basis of five essential criteria: (1.) Unpleasant sensations mostly of the legs, less frequently also of the arms, which force to get up and walk around. (2.) Symptoms are more severe in the evening or at night, (3.) especially in a sitting or lying position, which (4.) clearly improve with activity and (5.) relevantly affect quality of life.
After RLS diagnosis, a distinction must be made between a secondary (co-morbid) form and the idiopathic form. In the idiopathic form, the suspected dopamine deficiency in the central nervous system alone is sufficient for the manifestation of clinical symptoms. In the secondary form, symptoms do not become clinically manifest until a secondary disease, such as iron deficiency, renal insufficiency, or polyneuropathy, is added. It is also of great importance to look for unfavorable stimulants (coffee, alcohol, chocolate) or contraindicated medications (neuroleptics, antiemetics, certain antidepressants). An iron deficiency in need of substitution is already assumed at low normal ferritin levels <75 µg/L, which is related to the severely impaired iron transport through the blood-brain barrier.
If no causative treatment is possible, symptomatic therapy with dopamine agonists (pramipexole, ropinirole, rotigotine) or antiepileptic drugs (gabapentin, pregabalin, rivotril) remains. Codeine or opiates must occasionally be used as 3rd-line agents. The choice of drug is mainly based on the co-morbidities and side effects of the drugs. Dopamine-containing agents should be avoided in cases of addiction, while the mentioned antiepileptic drugs are not used, in cases of obesity, untreated sleep apnea, COPD or risk of falls. Patients must be informed in advance about any side effects. Because of the high risk of so-called augmentation, a paradoxical worsening of RLS as a side effect of short-acting dopaminergic agents, L-dopa is no longer used as a first-choice agent.
Hypersomnias: Daytime sleepiness can have many different causes. The most common cause is probably a banal sleep deficit, which should be clarified by a test period of sufficient sleep. A sleep duration of 8-9 hours on weekends or vacations cannot be shortened by more than about one hour during the week. If sleep is shortened to a greater extent over several nights, increasing daytime sleepiness and correspondingly impaired performance must be expected. After 24 hours without sleep, the performance of a healthy person drops to the level as under 0.8 per mille alcohol, which is known to be incompatible with driving.
The time of sleep cannot be shifted arbitrarily either, because the “inner clock” leads to a very superficial, non-restorative sleep when the time of bed changes constantly. One then speaks of a “lack of sleep hygiene”.
After excluding social causes of sleepiness, pathological causes will have to be clarified. First of all, during the clinical examination and in the laboratory, various internal causes are searched for, such as severe cardio-pulmonary diseases, chronic infections, hypothyroidism, anemia, iron deficiency, etc., but also neurological diseases such as Parkinson’s disease or multiple sclerosis, which cannot be discussed in detail here.
Within the sleep-wake disorders with daytime sleepiness, sleep-related breathing disorders are far in the forefront numerically, which are further subdivided into obstructive (OSAS) and central apnea syndromes (CSAS) including Cheyne-Stokes breathing patterns, and sleep-related hypoventilation and hypoxemia syndromes. These disease groups are addressed here only in the context of differential diagnostic considerations for nonpneumologic causes of daytime sleepiness/sleepiness.
Frequent OSAS is not always about overweight men who have been snoring loudly for many years. The diagnostic difficulty lies in differentiating banal snoring from “Upper Airway Resistance Syndrome” to actual OSAS on the one hand, and at the same time correctly classifying the disease value between a physiological fatigue or sleepiness to a pathological extent of sleepiness. OSAS is diagnosed when both an apnea-hypopnea index (AHI) >5/h and subjective distress in the form of daytime sleepiness or fatigue or nocturnal dyspnea, breathing pauses observed by others, insomnia or secondary diseases such as arterial hypertension, heart failure, atrial fibrillation or type 2 diabetes mellitus are present.
If the clinic is typical and the pre-test probability is correspondingly high, further diagnosis by means of respiratory polygraphy (rPG) is reasonable; if the presentation is less typical and the differential diagnosis (DD) is correspondingly broader, polysomnography (PSG) should be preferred and, depending on the clinic, a multiple sleep latency test (MSLT) and/or actigraphy should also be planned. With rPG and even more with oximetry alone, OSAS with a clearly abnormal finding can be detected, but a normal result can never exclude OSAS with certainty because of the lower sensitivity compared to PSG!
The AHI correlates only very poorly with the extent of daytime sleepiness, which is why this value cannot be used to assess fitness to drive. Women with OSA occasionally complain even more of insomnia than daytime sleepiness. To avoid missing symptom-poor patients, dry mouth, nocturnal thirst, nocturia, and early morning headache should also be asked about. OSAS, as a common cause of arterial hypertension, should not be missed, especially if blood pressure levels are difficult to adjust. Cardiovascular sequelae correlate more with time in hypoxia than with AHI. OSA is also considered a triggering moment for non-REM and REM parasomnias including sleep-related eating disorders and nocturnal epileptic seizures. Because of the strong mutual interactions between sleep-disordered breathing and all other psychosocial and pathological sleep disorders, it is essential to look for all sleep-disrupting factors and, if possible, to treat all of them as well.
PAP therapy is considered the method of first choice, although the indication also still depends on any cardiovascular risk factors and on the occupational activity of the affected person. Fine-tuning of PAP parameters requires a high degree of patience, knowledge and persistence from the patient, but also from the treating physician, which cannot be delegated to non-medical staff alone. Unfortunately, despite well-functioning PAP therapy, residual daytime sleepiness (RES) persists in a relevant percentage. Before PAP treatment is judged to have failed, polysomnography should be derived while on therapy, because AHI values are rarely ever not correctly mapped by the PAP device, especially if central sleep apnea has developed while on PAP therapy (treatment-emergent CSA, formerly called complex sleep apnea). If the polysomnographic control reveals a perfect PAP function, it is necessary to revisit the whole range of DD of daytime sleepiness from sleep insufficiency to narcolepsy to non-organic hypersomnia due to depression.
It is not so rare that polysomnographic review will demonstrate satisfactory adjustment of PAP therapy, but at the same time objectify an elevated index (>15/h) of periodic leg movements during sleep (PLMS). The question then arises here whether these PLMS could be the cause of daytime sleepiness/sleepiness, which is classified as Periodic Leg Movement Disorder (PLMD). Despite this logical-sounding construct, the causal relationship should not be considered certain and therefore, when treating PLMS with a dopamine agonist, one should pay attention to whether daytime sleepiness/sleepiness actually improves. If this is not the case, careful consideration should be given to continuing treatment for years, with the risk that augmentation may develop later. In questionable cases, long-term therapy with non-dopaminergic agents could be a compromise.
At the end of a long, possibly unsuccessful diagnostic process, the difficult DD between narcolepsy (with or without cataplexy), idiopathic hypersomnia and non-organic hypersomnia is not uncommon. ICSD 3 are counted among the “Central Disorders of Hypersomnolence” and must also still be distinguished from Chronic Fatigue Syndrome (CFS) .
Narcolepsy: Narcolepsy often begins in adolescence with extreme daytime sleepiness and involuntary attacks of falling asleep during inactive and later even during active situations. Sleepiness hits adolescents at a particularly problematic period in their lives during puberty, at school, or during apprenticeship, with potentially serious negative consequences on their psychosocial development and on their professional careers.
A distinction is made between narcolepsy type 1, in which cataplexies also occur, and type 2, in which cataplexies are (still) absent. Cataplexies are sudden muscle paralyses, e.g. in the face (brief inability to speak), head or knees, each triggered by an emotion, such as laughter or anger. Patients also report hypnagogic hallucinations and sleep paralysis. The most common form of hypnagogic hallucination is probably the so-called feeling of presence, with the strong impression that there is a stranger in the bedroom. The first sleep paralyses, when the affected person cannot move at all before falling asleep or after waking up, occasionally trigger fears of death. Paradoxically, although narcolepsy patients fall asleep quickly in the evening, they often suffer from sleep-through insomnia. The cause of narcolepsy type 1 has been identified as a hypocretin deficiency in the brain, which can be diagnosed in cerebrospinal fluid. Together with the long known association to the HLA-DQB1*0602 haplotype, it is suspected that due to a genetic predisposition an immune process destroys the hypocretin-forming cells in the hypothalamus.
To confirm the diagnosis, the Multiple Sleep Latency Test (MSLT) is available in addition to HLA and hypocretin determination, especially in type 2, in which a particularly short mean sleep latency (<8 minutes) and early REM periods are searched for in >2 of 5 MSLT runs (SOREM). However, the sleep physician must not under any circumstances overlook the fact that a short latency to fall asleep with >2 SOREMs is by no means pathognomonic for narcolepsy, because the same constellation can also be present in the case of inadequate sleep hygiene or in the case of non-organic hypersomnia in the context of depression.
Stimulants (modafinil, methylphenidate, amphetamines, pitolisant) for daytime sleepiness and gamma hydroxybutyrate (GHB) or antidepressants for cataplexy treatment are available for symptomatic therapy. GHB is also very suitable for the treatment of sleep-through insomnia.
In the very rare idiopathic hypersomnia, a positive family history and a somewhat different type of sleepiness are often found, with a markedly prolonged sleep requirement of >11 hours per 24 hours and sleep drunkenness in the morning after awakening. Often such patients need several alarm clocks. Cataplexies do not occur, while sleep paralysis or hypnagogic hallucinations are less common than in narcolepsy. In the MSLT, a short latency to fall asleep is also found, but typically no clustered SOREMs. Symptomatic therapy with stimulants is analogous to the treatment of daytime sleepiness in narcolepsy.
The relatively frequent non-organic hypersomnia occurs in combination with various psychiatric diseases and can persist for a long time as a residual state in partially remitted depression as a particularly therapy-resistant symptom, which is not even interpreted as such by the patient (and possibly also by the physician) in view of the normalized mood. In such patients, daytime sleepiness is often found in combination with disturbed nighttime sleep including. Early waking and clinophilia (the tendency to stay in bed after waking). Antidepressants from the group of norepinephrine or dopamine reuptake inhibitors are often used therapeutically.
Chronic fatigue syndrome (CFS) is characterized by not only mental but also physical exhaustibility during usual daily activities such as climbing stairs, cooking, etc. In these patients, often neither a clear physical nor a clear psychiatric disease can be diagnosed. Therapeutically, an adapted “build-up training” is carried out here, if necessary combined with psychotherapy and administration of drive-increasing antidepressants. If the cause of daytime sleepiness or fatigue remains unclear despite extensive investigations, one should not shy away from an honest “diagnosis” of excessive daytime sleepiness of unexplained aetiology.
Assessment of fitness to drive in the case of daytime sleepiness
It is part of the physician’s duty of care to make every patient with daytime sleepiness individually aware of the risk of microsleep, including the legal consequences (withdrawal of identification, fine, and insurance recourse), and of his or her own responsibility, including the effective measures to take in the event of emerging drowsiness at the wheel (pull over, drink coffee, and turn on a power nap).
Patients who have caused a microsleep accident or occupational sleepers should be referred to an accredited sleep center for evaluation. Patients with daytime sleepiness who wish to apply for a driver’s license or who have to undergo periodic checks by the medical officers of the Road Traffic Authority (level 1-4 doctors) should be examined beforehand and ideally be able to present a certificate of a successful multiple wakefulness test (MWT) to the medical officer.
Parasomnias
Parasomnias are complex motor manifestations that occur only during sleep. Sleepwalking (somnambulism) belongs to the awakening disorders together with Pavor nocturnus (night terrors) and confusional aw akening. Patients usually “wake up” abruptly from deep sleep in the first half of the night, but not all brain areas are equally awake. The brain areas responsible for consciousness, rational action, and memory are not “awake,” which is why sleepwalkers can move irrationally and later remember the event vaguely at best. Dreams can sometimes be remembered in this process, but usually also inaccurately and less vividly than in REM sleep behavior disorder. Risk factors include any factor that leads to deeper sleep, such as a sleep deficit the previous night, fever, or sleep medications. On the other hand, any arousal stimuli during deep sleep are also considered triggering moments, such as external disturbing factors, alcohol, urinary urgency and especially psychological stress. Specific forms of sleepwalking include eating at night (Sleep Related Eating Disorder), sexual assault toward a partner (Sexsomnia) , and driving a car (Sleep Driving) or committing criminal acts while asleep.
The most important therapeutic measures consist in securing the bedroom with locking windows and doors, locking away dangerous objects, poisons and especially the car keys. Medications such as clonazepam are mainly used for nights when sufferers stay in a strange place, such as a hotel.
A very similar disorder in the second half of the night from REM sleep is REM sleep behavior disorder. Affected are especially older men, who behave aggressively by acting out their fight-emphasized dreams, so to speak. In contrast to REM sleep in healthy subjects, when the axial muscles are completely paralyzed at the spinal cord level, comparable to a handbrake, in these patients the spinal muscle paralysis is defective, with a corresponding lack of braking effect on motor dream activity. According to recent studies, REM sleep behavior disorder is considered a risk factor for developing into Parkinson’s disease or dementia.
During light sleep, a whole series of “parasomnias” occur, which today are classified together with RLS as sleep-related movement disorders, such as “talking in sleep,” rhythmic falling asleep stereotypies such as head and body rolling or banging, foot tremor (leg banging), calf cramps, twitching to fall asleep, and teeth grinding.
The crampi nocturni can occasionally be very painful and, if they occur frequently, can also lead to relevant suffering. Diagnosis is usually straightforward, only rarely DD presents difficulties in differentiation from atypical restless legs symptoms. However, the treatment is anything but simple. The commonly known therapy with magnesium has actually never been scientifically proven. The best effect was obtained by systematic stretching of the affected muscles before bedtime. Some effect was demonstrated with treatment with gabapentin, and in smaller series, a beneficial effect was found with vitamin B complex, calcium blockers (verapamil), or circulatory stimulants (naftidrofuryl).
Independent of the sleep stage, epileptic seizures and enuresis nocturna may occur. Among epileptic seizures, so-called frontal lobe seizures occur particularly frequently during sleep, which today are called “sleep-related hypermotor epilepsy” (SHE) and DD must always be distinguished from parasomnias or nocturnal panic attacks.
Sleep-wake cycle disorders
Best known, in addition to shift worker sleep problems , is the difficulty falling asleep during “jet-lag,” which is more common during trips east than the problem of getting up during trips west. The reason for this is the “internal clock”, which for most people has a cycle of just over 24 hours. Younger people up to the age of about 30 can still adapt relatively flexibly to changing working hours, but from this age onwards rapid adaptation to changing working hours becomes increasingly difficult. A well known problem in adolescents between 15 and 25 years of age is the syndrome of sleep phase delayed (“sleep phase delayed syndrome”). These mostly young patients have a great tendency to go to bed very late and to get up around noon. The cause lies not only in social behavior, but also in a physiological shift of the internal clock backwards. If behavioral therapy measures – best supported by psychotherapeutic coaching – are not sufficient to remedy the sleep problems, a therapy trial with melatonin in the evening and bright light in the morning (>10,000 lux) can be used to facilitate falling asleep earlier.
The opposite effect can be observed in older people who go to bed much too early and then complain when they wake up at night or wake up too early in the morning (Sleep Phase Advanced Syndrome). In these patients, it is necessary to use activation therapies in the evening under better light conditions to delay the time to fall asleep.
Take-Home Messages
- Simplified, sleep-wake disorders can be divided into 4 groups for clinical concerns, where sleep is decreased, increased, disfigured, or postponed.
- There are many interactions between the different sleep-wake disorders, which is why all causes should be diagnosed and treated if possible.
- In particular, sleep-disordered breathing causes not only daytime sleepiness or fatigue, but also insomnia, and is considered to trigger parasomnias, epileptic seizures, and to be a risk factor for diabetes, arterial hypertension, and cardiovascular disease.
- Assessing fitness to drive is part of a physician’s duty of care in any patient with daytime sleepiness.
- Restless legs syndrome is the most common organic cause of insomnia of falling asleep. In addition to the idiopathic form, various secondary causes, especially iron deficiency, must be clarified.
Bibliography with the author
HAUSARZT PRAXIS 2020; 15(4): 11-16