Clinical manifestations

Presentation and course

Insufficient sleep syndrome affects all ages and both sexes.

Patients with sleep insufficiency often report daytime sleepiness that interferes with their activities and functioning. For example, patients with insufficient sleep may inadvertently fall asleep during sedentary activities, such as meetings, reading, watching television or movies, or while driving. Insufficient sleep is associated with an increased risk for motor vehicle accidents by affecting visual search patterns and response times to hazards (46).

The sleep history suggests insufficient sleep by the disparity in reported amount of sleep, often 2 hours or more, when the patient is given the opportunity to sleep ad lib (ie, on a holiday). The excessive daytime sleepiness may become more pronounced in the late afternoon and early evening. Sleepiness usually improves during vacations or holidays. Other symptoms include lack of energy, fatigue, muscle weakness, muscle pain, gastrointestinal disturbances, dry mouth, headache, blurred vision, difficulties with concentration and attention, reduced motivation, irritability, and dysphoria. Any of these symptoms may become the primary focus of the patient and obscure the excessive daytime sleepiness. Importantly, functional and cognitive impairment due to chronic sleep deprivation is often unrecognized by the sufferer.

Prognosis and complications

Complications of insufficient sleep may involve all systems of the body, and important sequelae are listed in Table 1. Recovery from short-term sleep deprivation may occur by restoration of adequate sleep, but long-term sleep deprivation may result in permanent sequelae.

Table 1. Consequences of Insufficient Sleep

Sleepiness associated with insufficient sleep syndrome persists and may get worse without a change in sleep habits. Excessive sleepiness places the subject at increased risk of automobile and industrial accidents, declining job performance, and disrupted social relationships. Sleep deprivation in physicians adversely affects patient care. Impairment of driving abilities due to sleep deprivation is comparable to driving when intoxicated with alcohol and is further exacerbated with concurrent alcohol use. There also are risks associated with excessive caffeine intake or stimulant use that often occurs in patients with insufficient sleep syndrome. Other complications of sleep deprivation include headaches, impaired cognitive functions including language tasks, serial subtraction, memory, attention, and decision making.

In children and adolescents, inadequate sleep impairs attention and concentration and negatively impacts academic performance (11).

A new field of research on bedtime procrastination illuminates a multifaceted phenomenon deeply entrenched in the fabric of modern society. It is defined as the volitional delay of going to bed, without any cause for the delay, resulting in insufficient sleep (20) and has been found to be associated with a myriad of variables, ranging from work obligations to the rigors of parenthood. Studies have demonstrated deficits in self-control and attentional impulsivity. Notably, the insidious allure of smartphone addiction emerges as a potent modulator, exerting its sway over procrastinatory tendencies (16).

Furthermore, psychological stress contributed to further smartphone addiction during the COVID-19 pandemic. In a study by Ma and colleagues, bedtime procrastination predicted the severity of poor sleep quality in children (30).

Anxiety and depression. Chronic insufficient sleep usually results in a more negative mood, with reduced optimism and sociability. Sleep is a potential biomarker for suicidal behavior. A systematic review of literature has revealed a significant association between sleep disturbances and risk of suicide with significant contribution from sleep deprivation-induced neurocognitive deficits, emotional dysregulation, and negative feelings, among other factors (43).

Chronic sleep deprivation is associated with elevated cortisol and decreased testosterone levels. Testosterone is known to enhance the function of the gamma-aminobutyric acid and serotonin systems in the brain. This reduced function provides one possible causal link between two of the most commonly associated psychiatric disorders, depression, and anxiety.

Impairment of brain function. The effects of sleep deprivation on neurocognitive abilities are complex and have been the subject of many studies over the past decade. There is an increasing body of evidence that cognitive complications of sleep deprivation are numerous and are a result of negative effects on the prefrontal cortex and posterior parietal systems. In addition to prefrontal cortex dysfunction, various brain regions involved in verbal working memory have been evaluated and demonstrated vulnerability in the context of sleep deprivation.

Structural changes in human hippocampal subfields resulting from sleep deprivation play a role in determining vulnerability to impairment of memory and are also associated with the quality of NREM slow-wave oscillations during recovery sleep; they also play a role in determining the extent of memory restoration (41). These findings may serve as a predictive biomarker of susceptibility to memory impairment and recovery from sleep deprivation in professions where memory function is critical and insufficient sleep is prevalent. A double-blind, placebo-controlled randomized study to determine the impact of sleep restriction (reduction of 1 hour of habitual sleep duration) on cognitive performance showed impairment of a test of working memory but no effect on tests of sustained attention or decision making (42). Sleep deprivation causes impairment of cognitive flexibility, ie, feedback is less effective in driving behavior modification under changing circumstances (22).

Sleep deprivation may affect the performance in professions requiring intact cognitive function. There has been considerable concern about the performance of overworked and sleep-deprived residents in university hospitals. A study has shown that sleep-deprived surgeons' technical skills are between 11.9% and 32% negatively impacted in a standardized simulated environment, which is likely to have clinical implications for patient safety (50).

Structural and biochemical changes in the brain. Several experimental studies in rats have shown that sleep deprivation causes structural changes in the central nervous system. Sleep-deprived basal forebrain—one of the brain’s main wakefulness centers—experiences an increased release of nitric oxide leading to a buildup of adenosine, a nucleoside that can also affect neural function. Sleep deprivation increases heat shock protein expression in mice. In experiments on mice, extended wakefulness results in reduced sirtuin type 3 (SirT3) activity and, ultimately, degeneration of locus ceruleus neurons (51). Prolonged wakefulness is a metabolic stressor to locus ceruleus neurons leading to failure of adaptive mitochondrial metabolic responses mediated by SirT3, which coordinates mitochondrial energy production and redox homeostasis.

Animal studies have indicated that sleep is essential for maintenance of integrity of cell membranes and myelin in the brain, which are susceptible to sleep deprivation. A diffusion tensor imaging study of normal human volunteers showed that sleep deprivation was associated with widespread decreases in fractional anisotropy that indicate reductions in axial diffusivity, mainly including bilateral frontotemporal and parieto-occipital white matter, the corpus callosum, the thalamus, and the brain stem (14). The findings of this study are consistent with the view that microstructural changes occur in the white matter of the adult human brain over hours to days of sleep deprivation. Permeability of the blood-brain barrier is increased in rats subjected to sleep loss of long duration and is restored following sleep recovery. An ultrastructural study in rats has shown that chronic sleep loss disrupts interendothelial junctions that leads to blood-brain barrier hyperpermeability in the hippocampus (23). The authors of the study suggest that this is because expression of claudin-5, which regulates blood-brain barrier permeability by modifying brain microvascular endothelial cells, is decreased after chronic sleep loss as compared to intact animals.

Diffusion tensor imaging has been applied to the study of diseases characterized by cognitive instability, which is amplified by sleep deprivation and measured by number of lapses on the psychomotor vigilance test (52). There was a considerable inter-individual variation of cognitive instability in response to sleep deprivation, which was associated with differences in white matter integrity.

Cardiovascular effects. Research in the cardiac effects of sleep deprivation has shown that both acute total and short-term partial sleep deprivation results in elevated high-sensitivity C-reactive protein concentrations, a biomarker of inflammation that has been shown to be predictive of cardiovascular morbidity. A review of clinical trials has shown that sleep deprivation can induce autonomic nervous dysfunction, hypertension, arrhythmia, oxidative stress, endothelial dysfunction, inflammation, and metabolic disorder in patients with coronary heart disease (39). Furthermore, sleep insufficiency positively associates with systolic blood pressure or diastolic blood pressure fluctuations (01).

Effects on the reproductive system. Results of a randomized study on Chinese men showed that sleep deprivation with late bedtime was associated with impaired sperm health in the study cohort, partly through increase of antisperm antibody production in the semen (29).

Metabolic syndrome. Several epidemiologic studies show an association between sleep duration of less than 6 hours nightly and obesity and diabetes. Sleep restriction decreases glucose tolerance and insulin sensitivity without adequate compensation in beta cell function. Sleep deprivation has also been shown to reduce leptin and increase ghrelin levels, hormones that increase hunger and appetite (26). Even a relatively brief period of mild sleep deprivation (one and half hours of sleep loss per night over 3 weeks) can lead to changes in insulin sensitivity and body weight (38). Furthermore, sleep deprivation may alter the content of the foods we choose to eat. In a study, 11 subjects increased their consumption of calories from snacks, choosing foods with higher carbohydrate content when sleep deprived to 5.5 hours nightly, as compared to when sleeping 8.5 hours per night (33). A small study looking at cerebral functional MRI showed that subjects who were sleep deprived to 5 hours had a greater increase in brain activity in areas associated with reward when exposed to food stimuli as compared to when they were well rested (45).

Immune system, inflammation, and infection. Systemic infections have been induced in animal models by sleep deprivation. The impact of sleep deprivation on the immune response in humans has been shown to have important consequences. Sleep deprivation has been shown to decrease antibody production following influenza vaccination. In a small study, sleep deprivation dampened the normal circadian T-cell function and regulation, which occurs over a 24-hour period (08). A prospective observational study involving over 50,000 nurses showed that sleeping less than 5 hours per night was associated with a 1.39 relative risk of developing pneumonia (35).

Genetic factors in susceptibility to effects of sleep deprivation. Although sleep duration can be influenced by environmental factors and chronotype, human familial sleep disorders indicate that there is a strong genetic modulation of sleep. Studies on identical and fraternal twins have shown that resiliency and vulnerability to sleep loss are highly heritable (27). There is an ongoing search for genes related to vulnerability phenotype, but none has been identified that can explain the different responses to sleep deprivation. Individual differences in energy balance responses to sleep restriction indicate these responses are phenotypic, with behavioral, physiological, and genetic differences underlying these responses. High-density genome-wide association studies for sleep duration in European populations have identified an intronic variant in the ABCC9 gene that explains approximately 5% of the variation in sleep duration (02). ABCC9 encodes an ATP-sensitive potassium channel subunit (SUR2), which serves as a sensor of intracellular energy metabolism.

Identification of biomarkers, including genetic polymorphisms related to orexin signaling, are important for predicting an individual’s vulnerability to overeating and gaining weight when sleep deprived as they will be an important factor in the management of these problems (44).

Sleep deprivation and the epigenome. Although neuronal effects of sleep deprivation start at the DNA and RNA level resulting in dysregulation of cognitive functions, the epigenome plays an important role in regulating gene expression in this context (15). One example is that sleep deprivation disrupts the cyclic adenosine 3′,5′-monophosphate (cAMP) pathway and CREB (cAMP response element-binding) protein, which mediates histone deacetylase inhibitors, a common epigenetic mechanism.

Effect of insufficient sleep on circadian rhythms. Sleep homeostasis, circadian rhythmicity, and metabolism are interrelated. In mice, sleep restriction leads to approximately an 80% reduction in circadian transcripts in the brain and severe disruption of the liver transcriptome, whereas in humans, sleep restriction leads to a 1.9% reduction in circadian transcripts in whole blood (05). Despite significant reduction in the circadian regulation of transcription in peripheral tissues, rhythms within the suprachiasmatic nucleus are not disrupted. Molecular pathways associated with these disruptions point to molecular mechanisms underlying established adverse effects of sleep deprivation.

Increased risk of cancer due to disruption of circadian rhythms and insufficient sleep. Epidemiologic studies suggest increased risk for breast cancer in night- and rotating-shift female workers, which may be due to several interconnected mechanisms resulting from shift work, such as suppression of melatonin by exposure to light at night, impairment of the immune system due to sleep-deprivation, and metabolic changes with generation of proinflammatory reactive oxygen species (18). This topic, however, is controversial. A large prospective study in Sweden found no association between insufficient sleep and risk of prostate cancer (31).

Disturbance of thermal homeostasis. Short-term, ie, less than or equal to four nights, sleep deprivation can disturb thermal homeostasis, which affects autonomic and behavioral thermoeffectors during acute exposure to low and high ambient temperatures (25). This may be a predisposing factor for the development of thermal injuries.

Sleep deprivation and neurologic disorders. The MedLink article on insomnia describes sleep disorders that occur in various neurologic disorders. The impact of sleep deprivation in several neurologic disorders has been reviewed (07). Important findings are summarized in a Table 2.

Table 2. Effect of Sleep Deprivation on Neurologic Disorders Disease

Clinical vignette

A 27-year-old, right-handed woman presented to the sleep center outpatient clinic for initial evaluation of her longstanding excessive daytime sleepiness. For the past 7 years, the patient had been excessively sleepy during the day, falling asleep in sedentary situations. Specifically, she reported falling asleep when grading her students’ papers (she used to fall asleep in class when she was a student herself), in traffic at red lights, when talking to people, and when watching television. She stated that her sleepiness worsened after she began working two jobs several years ago. On weekdays, she usually went to bed around 11:30 PM to midnight and got up at 5:30 AM, sleeping a solid 5.5 hours. On weekends, she usually went to bed around 4 AM and slept until noon or 1 PM. When she slept in longer, she felt more refreshed, but was still sleepy and tended to fall asleep, although less frequently, during sedentary situations. She did not take any scheduled naps. She rarely drank caffeinated beverages. She drank alcohol every other weekend. She denied smoking or using recreational drugs. She denied snoring, gasping for air, choking spells, or being told she stops breathing when asleep. She denied cataplexy or hypnagogic hallucinations. On occasion, however, she endorsed the presence of sleep paralysis. She did not have any restless leg symptoms or insomnia.

Past medical history. Noncontributory.

Medications. Fexofenadine hydrochloride and fluticasone propionate.

Social history. She was a teacher and a part-time bartender. She was single and lived with her boyfriend. She did not smoke or abuse alcohol or drugs. She only used alcohol in social situations.

Family history. This was significant for excessive daytime sleepiness in an aunt whom she thought may have had obstructive sleep apnea.

Review of systems. Negative for any psychiatric problems.

Neurologic examination. Completely normal.

Actigraphy confirmed the patient’s clinical history, showing an average sleep time of 5.5 hours at night during weekdays and 8 to 9 hours during the weekends.

After actigraphy was done, she went on her summer break and increased her daily sleep significantly. Her symptoms resolved over 10 days. No further evaluation was needed.

Biological basis

Etiology and pathogenesis

Insufficient sleep syndrome results when an individual fails to obtain sufficient to maintain normal alertness throughout the day (03). By far, the most common cause of excessive daytime sleepiness in modern society is chronic sleep deprivation. Twenty-four-hour availability of smartphones, email, shopping, and stock market information on the Internet, as well as 24-hour news networks and television programming, encourage wakefulness at the expense of sleep. More and more businesses, including fast food restaurants, remain open 24 hours a day and unwittingly contribute to their clients’ sleep deprivation. Demands of schools, extracurricular activities, and technology use have increased the incidence of insufficient sleep syndrome among children and adolescents (47).

Sufficient sleep is not measured in absolute hours obtained; rather, it is measured in terms of the amount of sleep that individuals need to maintain alertness relative to the amount of sleep they get. The amount of sleep needed is genetically determined and can vary by individual. Some individuals require 9 hours of sleep per night to maintain normal wakefulness, and if they receive 7 hours, they may become sleepy during the day. Average total sleep time for adults is seven and a half to 8 hours, and epidemiological studies indicate that most adults require 7 to 8 hours of sleep to maintain good health. Sleeping less than 6 hours per night is associated with excessive daytime sleepiness (21). Sleep deprivation is cumulative so that after several nights of moderate sleep restriction, deficits in cognitive performance are equivalent to fewer nights of total sleep deprivation.

The cause of sleepiness in insufficient sleep syndrome is a voluntary restriction of daily sleep time below the individual's specific biological sleep requirements.

Long working hours and shift work increase the risk for insufficient sleep syndrome. Night-shift workers sleep at least 8 hours less each week than do day workers -- an amount equaling the loss of an entire night of sleep every week. A metaanalysis of literature has concluded that health and safety consequences of shift work are like insufficient sleep syndrome, and they are likely to share common mechanisms, but further research is required to determine whether insufficient sleep is the cause of adverse health effects associated with shift work (24).

Studies of healthy normal sleepers have shown that a reduction of sleep time by as little as 2 hours per night produces increased daytime sleepiness as measured by the multiple sleep latency test and that the daytime sleepiness accumulates over successive nights of restricted sleep. Most patients with insufficient sleep syndrome are healthy, normal sleepers who chronically deprive themselves of an adequate daily amount of sleep for professional or personal purposes. The extended sleep times these patients report getting on weekends are not sufficient for full recovery (36).

A study found that cognitive impairment caused by sleep loss varies considerably among individuals and resembles the effect of alcohol intoxication; molecular brain imaging showed that ethanol induces an upregulation of cerebral A1 adenosine receptors with increase up to 26% like in sleep deprivation (13). Therefore, targeting the brain’s adenosine system might enable discovery of countermeasures against cognitive impairment induced by both sleep deprivation and alcohol intoxication.

The essential feature of insufficient sleep syndrome is that the patient is biologically normal; thus, the syndrome should be considered a behavioral one. No pathological process disturbs the patient's ability to initiate or maintain sleep and to remain normally alert during the day following a night of adequate amount of sleep for that person.

Sleep deprivation modulates the gain control and synaptic gating in orexin neurons, which tune them to strong wake-promoting excitatory signals, while dampening weak synaptic inputs to allow transition to sleep in the absence of such strong signals (10).

Biomarkers of insufficient sleep. Biomarkers may be indicators of various disturbances in the human body that may be either causes or effects of insufficient sleep. They may offer insight into pathomechanisms and form the basis of diagnostic tests and help in monitoring the effect of management.

A machine-learning approach using panels of 6 to72 mRNA biomarkers showed that accuracy of classifying acute sleep loss was 92%, but only 57% for classifying chronic sleep insufficiency, and there was little overlap with biomarkers for circadian phase (28).

A crossover laboratory study on humans undergoing experimental insufficient sleep identified 65 metabolomic biomarkers, of which the most important ones involved ATP binding cassette transporters in lipid homeostasis, phospholipid metabolic process, plasma lipoprotein remodeling, and sphingolipid metabolism (12). These biomarkers require further development and validation to advance our understanding of the ill effects of insufficient sleep, improve diagnosis of sleep disorders, and identify targets for interventions to counteract the negative health consequences of insufficient sleep.

Epidemiology

In fact, in the United States, 34.9% of children from infancy to 17 years old sleep less than recommended for their age (49). In adults, 37% of people aged between 20 to 39 years old, 40.3% of those aged between 40 and 59 years old, and 32% of those 60 years or older sleep less than 7 hours per night (04).

Prevention

Education regarding the inevitable consequences of restricted sleep and the cumulative effects of such restriction may reduce the occurrence of insufficient sleep syndrome. Although the relation between sleep time and daytime sleepiness seems obvious to most people, socioeconomic circumstances of individuals can lead to a chronic restriction of sleep time and denial of the obvious cause of the symptoms. Individuals at risk include those working two or more jobs, those who report to work extremely early, or those with extensive work and homecare responsibilities. As mentioned above, children and adolescents are becoming more and more at risk for developing insufficient sleep syndrome. It is, therefore, important that health care providers of individuals in this age group inquire about their sleep hygiene and counsel patients and families about age-appropriate sleep needs.

Differential diagnosis

Confusing conditions

Insufficient sleep syndrome is differentiated from narcolepsy based on the absence of the accessory signs and symptoms of narcolepsy, from other sleep disorders of excessive sleepiness (ie, sleep apnea syndrome or periodic limb movement disorder based on a polysomnogram showing normal sleep), from insomnia based on absence of difficulty initiating or maintaining sleep, from idiopathic hypersomnia based on shortened habitual sleep times, and from mood disorders based on the normal psychological screening. The differentiation from idiopathic hypersomnia can be a diagnostic challenge because both entities are associated with high sleep efficiency, difficulty on waking in the morning, and reduced latency on the multiple sleep latency test. Idiopathic hypersomnia, however, does not respond to trials of increased amount of sleep at night. The diagnosis should not be made when the sleep environment is not conducive to sleep or when the patient's sleep schedule has been acutely restricted due to work or school deadlines, is irregular, or periodically shifts due to changes in the patient's work schedule. In addition, it should not be made when the patient also has an insomnia complaint. In other conditions presenting with excessive daytime somnolence, such as environmental sleep disorder and posttraumatic hypersomnia, the clinical history is important in establishing the correct diagnosis (03).

A neuropsychological study has shown that the effect of insufficient sleep at baseline can make a non-injured athlete look like a concussed athlete with sufficient sleep because of cognitive underperformance, which would skew post-concussion comparisons (37). Therefore, there may need to be consideration of prior night's sleep when determining whether a baseline can be used as a valid comparison.

Diagnostic workup

Evaluation of suspected insufficient sleep should be done with a thorough sleep history and physical exam. Other comorbidities should be ruled out. Common mimics of sleep deprivation, such as insomnia, restless legs syndrome, and obstructive sleep apnea, need to be ruled out. Medical or psychiatric comorbidities or medications and drugs that interfere with sleep need to be identified.

If the diagnosis is still unclear based on history alone, sleep diaries or actigraphy can be helpful. Lately, wearable sleep trackers have become useful.

Polysomnography or multiple sleep latency tests are not indicated for insufficient sleep but are indicated if another sleep disorder, such as obstructive sleep apnea, is suspected.

Management

Management of insufficient sleep syndrome requires a complete evaluation that establishes the presence of excessive daytime sleepiness and rules out the various biological causes of sleepiness. Having reached an accurate diagnosis, the patient can be educated about the reason for excessive sleepiness and instructed on sleep extension.

There are currently no medications approved or recommended for the treatment of sleep deprivation. The treatment is sleep extension. When sleep deprivation is caused by another disorder, treatment of the disorder is recommended.

Sleep deprivation as a therapeutic measure for depression. It is worth mentioning that since the 19070s, sleep deprivation has been used for treatment of depression. An fMRI study demonstrated that sleep deprivation reduced functional connectivity between the posterior cingulate cortex and the bilateral anterior cingulate cortex, but enhanced connectivity between the dorsal nexus and the distinct areas in the right dorsolateral prefrontal cortex (09). Although the onset of the therapeutic effect of sleep deprivation is rapid, the duration of action is short-lived. A systematic review of clinical studies combining sleep deprivation with repetitive transcranial stimulation indicates some augmentation of antidepressant effect, but more studies are needed to confirm this (48). A metaanalysis of sleep deprivation in the treatment of bipolar depression found an overall response rate of almost 50%, especially when used with medication, and should guide the future management approaches (17).

Special considerations

Geriatric. Sleep architecture changes with aging. Delta-wave sleep decrease, and the proportion of time spent in lighter sleep increases; this results in increased sleep disruptions. The elderly are more susceptible to effects of sleep deprivation.

Pregnancy

Up to 15% of women report insufficient sleep during pregnancy (34). Insufficient sleep and short sleep duration during pregnancy greatly increase the risk for preterm birth, gestational hyperglycemia, and depression symptoms (32; 34; 19).