Excessive daytime sleepiness due to medical disorders and medications

INTRODUCTION — Some patients have excessive daytime sleepiness (EDS) that is not caused by common disorders such as insufficient sleep, obstructive sleep apnea, or narcolepsy. This may manifest as excessive napping, inappropriate daytime sleep, or even accidents caused by falling asleep while driving or during other activities. In many cases, EDS is due to a treatable medical disorder, and proper diagnosis and treatment offers the possibility of improved daytime sleepiness along with improved medical outcomes.

This topic reviews medical and neurologic disorders associated with problematic sleepiness, beyond primary sleep disorders. An approach to the initial evaluation and management of a patient with EDS is presented separately. The evaluation and management of persistent sleepiness in patients with a known diagnosis of obstructive sleep apnea is also reviewed separately. (See "Approach to the patient with excessive daytime sleepiness" and "Evaluation and management of residual excessive sleepiness in adults with obstructive sleep apnea".)

DEFINITIONS — Excessive daytime sleepiness (EDS) refers to the tendency to fall asleep in inappropriate settings. EDS is separate from mental and physical fatigue, which can be manifested as difficulty or inability initiating activity, reduced capacity maintaining activity, and/or difficulty with concentration and memory. Terms may be used interchangeably by patients, however, and it is not always possible to distinguish them by history alone.

In patients with sleep disorders, fatigue and sleepiness measures are correlated [1]. Clinically, fatigue may be worse after positional change or exercise, but EDS may be briefly improved. A patient with sleepiness may fall asleep when sedentary, but a patient with fatigue may not be able to initiate sleep when at rest.

In the author's experience, sleep disorders often contribute to sleepiness and may also contribute to fatigue. Therefore, efforts to identify and treat underlying sleep disorders are warranted as they may alleviate symptoms regardless of label [2]. (See "Approach to the patient with excessive daytime sleepiness", section on 'Definitions' and "Approach to the adult patient with fatigue".)

INSUFFICIENT SLEEP — Insufficient sleep is the most common and easily overlooked cause of excessive daytime sleepiness (EDS) [3]. In addition to a thorough history, a sleep log (table 1 and table 2) and actigraphy may help document the amount of sleep obtained and can identify factors contributing to poor sleep quality. High-risk groups include:

●Shift workers, who tend to progressively accumulate sleep loss over time (see "Sleep-wake disturbances in shift workers")

●Individuals with behaviorally induced sleep insufficiency due to working multiple jobs, poor sleep hygiene, and family obligations such as caring for children and older family members (see "Insufficient sleep: Definition, epidemiology, and adverse outcomes" and "Insufficient sleep: Evaluation and management")

●Patients with chronic pain (see "Evaluation of chronic non-cancer pain in adults", section on 'Pain severity and impact' and "Pharmacologic management of chronic non-cancer pain in adults")

●Hospitalized patients (see "Poor sleep and insomnia in hospitalized adults" and "Obstructive sleep apnea and other sleep disorders in hospitalized adults")

The adverse effects, evaluation, and management of insufficient sleep are reviewed in detail separately. (See "Insufficient sleep: Definition, epidemiology, and adverse outcomes" and "Insufficient sleep: Evaluation and management".)

NEUROLOGIC DISORDERS — The brain actively generates alertness and sleep, and a variety of neurologic disorders can cause excessive daytime sleepiness (EDS).

Focal central nervous system lesions — Alertness can be impaired by bilateral cortical lesions or midline lesions that damage wake-promoting brainstem regions or their ascending projections to the forebrain. Neuroimaging is unnecessary in most patients with sleepiness, but it should be considered in those with new or unexplained focal neurologic deficits on examination.

●Stroke – Sleepiness and fatigue are common after stroke and may be associated with poor outcomes [4]. One important secondary cause is sleep apnea, which is identified in approximately 60 percent of stroke survivors [5]. Clinical features and questionnaires, such as the Epworth Sleepiness Scale (ESS), lack sensitivity in patients with stroke, and diagnosis requires formal sleep testing with in-laboratory polysomnography or home sleep apnea testing. Treatment of obstructive sleep apnea has the potential to improve stroke rehabilitation outcomes as well as aid in secondary prevention [6]. (See "Sleep-related breathing disorders and stroke".)

EDS is occasionally a direct result of stroke. In such cases, symptoms are typically acute in onset and accompanied by focal neurologic signs. Side effects from medications are another potential cause of sleepiness after acute stroke. Sedating medications have been associated with poor stroke recovery and should be avoided if possible in this setting [7]. (See "Overview of the evaluation of stroke".)

●Tumors – Tumors that damage the hypothalamus or midbrain can cause EDS directly by damaging wake-promoting systems or indirectly via secondary hydrocephalus and increased intracranial pressure, which effectively produces bilateral dysfunction of the cortex or midline structures. Tumors in these regions often produce abnormal eye movements, hemiparesis, or pituitary dysfunction, and nearly all of these lesions increase the total daily amount of sleep. Morning headaches can occur with brain tumors, although this pattern is nonspecific and can also be seen with other more common causes of sleepiness, such as obstructive sleep apnea. (See "Overview of the clinical features and diagnosis of brain tumors in adults" and "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)

●Traumatic brain injury – EDS is a prominent symptom after traumatic brain injury, reported by 50 to 80 percent of patients [8-11]. Traumatic brain injury can acutely reduce orexin (hypocretin) levels in the spinal fluid, though levels usually recover later. Severe traumatic brain injury can also injure hypothalamic neurons that produce histamine, a key wake-promoting neurotransmitter. (See "Sleep-wake disorders in patients with traumatic brain injury", section on 'Symptom spectrum'.)

●Multiple sclerosis – Midline structures containing the projecting aminergic and cholinergic systems are particularly vulnerable to damage in patients with multiple sclerosis, and demyelination in these areas as well as inflammation more generally may result in EDS. Antibodies to aquaporin-4 and acute disseminated encephalomyelitis may produce sleepiness through a similar mechanism.

Patients with multiple sclerosis are also at increased risk for a variety of sleep disorders, including restless legs syndrome (RLS) and obstructive sleep apnea, which may contribute to sleepiness. Side effects from medications are another important consideration. One study of 190 patients with multiple sclerosis found that 47 percent used a sedative hypnotic agent, which could have been contributing to fatigue [12]. (See "Manifestations of multiple sclerosis in adults", section on 'Sleep disorders'.)

●Neurosarcoidosis – Sarcoidosis has a predilection for the base of brain and hypothalamus in particular, and involvement of these structures may result in profound sleepiness [13]. Patients with neurologic sarcoidosis usually, but not always, have evidence of systemic disease on chest radiography or computed tomography. Magnetic resonance imaging (MRI) of the brain with gadolinium most commonly demonstrates meningeal and/or parenchymal enhancement in affected areas. (See "Neurologic sarcoidosis".)

Epilepsy — Epilepsy and sleep are highly interrelated. Sleep deprivation or poor sleep quality can precipitate seizures, whereas poor seizure control can disrupt sleep and lead to EDS [14]. One study of 100 patients with epilepsy noted that patients with nocturnal seizure patterns tended to have more daytime sleepiness [15]. Patients with poorly controlled epilepsy are also more likely to be on a variety of antiseizure drugs, many of which induce sleepiness from direct central nervous system effects or indirectly by inducing sleep apnea via relaxation of the upper airway [16]. (See "Comorbidities and complications of epilepsy in adults", section on 'Sleep disorders'.)

Neurodegenerative disorders — A variety of neurodegenerative conditions can induce sleepiness, depending on brain circuitry involved and stage of the disease.

●Parkinson disease is commonly associated with EDS, which may be profound and comparable to that of narcolepsy [17]. The EDS in early Parkinson disease progresses over time [18]. Pathologic studies have demonstrated some loss of the orexin-producing neurons in advanced stages of the disease, although this is probably not the main cause of EDS [19]. Management strategies, including bright light therapy, exercise, and pharmacologic treatments, are reviewed separately. (See "Evaluation and treatment of insomnia, daytime sleepiness, and other sleep disorders in Parkinson disease", section on 'Excessive daytime sleepiness'.)

Other potential causes of sleepiness in patients with Parkinson disease include side effects of medications, disrupted sleep due to poorly controlled rigidity or pain, and comorbid sleep disorders, including sleep-related breathing disorders and periodic limb movements of sleep. (See "Evaluation and treatment of insomnia, daytime sleepiness, and other sleep disorders in Parkinson disease", section on 'Insomnia'.)

●Multiple system atrophy is associated with a similar degree of sleepiness as Parkinson disease. In one study, EDS was reported by 28 percent of patients with multiple system atrophy and correlated with the presence of self-reported sleep-disordered breathing [20]. (See "Multiple system atrophy: Clinical features and diagnosis", section on 'Sleep and breathing disorders'.)

●Dementia with Lewy bodies is associated with EDS as well as rapid eye movement (REM) sleep behavior disorder [21]. (See "Clinical features and diagnosis of dementia with Lewy bodies", section on 'REM sleep behavior disorder'.)

●Alzheimer disease can be associated with circadian rhythm disruption and sleepiness, particularly when there are Parkinsonian features [22]. (See "Sleep-wake disturbances and sleep disorders in patients with dementia", section on 'Excessive daytime sleepiness'.)

●Spinocerebellar ataxia may be associated with profound fatigue and EDS in approximately two-thirds of patients [23]. Patients with spinocerebellar ataxia type 3 (Machado-Joseph disease), the most common of the autosomal-dominant ataxias, also have an increased prevalence of REM sleep behavior disorder, RLS, and insomnia [24,25]. (See "Autosomal dominant spinocerebellar ataxias", section on 'SCA3 (Machado-Joseph disease)'.)

Encephalitis and postinfectious syndromes — Brain inflammation can directly induce sleepiness, which may be mediated by cytokines. Autoimmune or postinfectious central nervous system syndromes can also cause sleepiness, in some cases due to hypothalamic involvement.

●Viral encephalitis can produce severe and diffuse cortical and subcortical injury, thereby causing sleepiness. Encephalitis lethargica, which was associated with profound EDS, may have had a viral etiology. (See "Viral encephalitis in adults".)

●COVID-19 is associated with excessive daytime sleepiness in approximately one-third of patients in both the acute and chronic phases [26,27]. (See "COVID-19: Clinical features" and "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")".)

●Human African trypanosomiasis, or sleepiness sickness, is notable for profound insomnia and increased daytime sleep during the central nervous system phase of protozoal reproduction [28]. Despite increased daytime sleep, total sleep time in 24 hours may not be increased, and such sleep dysregulation reflects a circadian rhythm abnormality [29]. Fever, joint pain, and enlarged lymph nodes typically precede sleep dysregulation. (See "Human African trypanosomiasis: Epidemiology, clinical manifestations, and diagnosis".)

●Postinfectious syndromes associated with pathologic sleepiness may include postinfluenza narcolepsy, which was noted to occur with increased frequency after the H1N1 influenza pandemic in Beijing in 2009 to 2010 and possibly to a lesser degree after H1N1 vaccination in certain countries [30,31]. There is a molecular homology between the orexin system and human leukocyte antigen (HLA)-presented influenza that has been hypothesized to be an autoimmune explanation for postinfluenza narcolepsy [32]. (See "Clinical features and diagnosis of narcolepsy in adults", section on 'Autoimmune hypothesis'.)

●Paraneoplastic limbic encephalitis due to autoantibodies such as anti-Ma2, and anti-Hu is sometimes associated with EDS [33]. In one case series of six patients with anti-Ma2 encephalitis, low cerebrospinal fluid orexin levels were present in four patients with severe sleepiness [34]. Anti-IgLON5 disease is associated with multiple sleep problems, including parasomnias, sleep apnea, insomnia, and EDS, in the context of bulbar complications and movement disorders [33]. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis".)

Neuromuscular disorders — A number of neuromuscular disorders are associated with EDS, independent of sleep-related breathing disorders, which occur with increased frequency in many neuromuscular disorders. Examples include the following:

●Myotonic dystrophy – EDS is a prominent clinical feature of myotonic dystrophy that may persist despite treatment of underlying central and obstructive sleep apnea [35]. Patients with myotonic dystrophy type 1 also can have sleep-onset REM periods, as seen in patients with narcolepsy [36]. Modafinil has been used with some success. (See "Myotonic dystrophy: Etiology, clinical features, and diagnosis", section on 'Sleep disturbance' and "Myotonic dystrophy: Treatment and prognosis", section on 'Excessive daytime sleepiness'.)

●Myasthenia gravis – Myasthenia gravis can be associated with daytime sleepiness, likely through an association with sleep-disordered breathing. In one pilot study, napping led to a 13 percent increase in motor function on a standardized scale, suggesting that sleep may provide therapeutic benefit [37]. (See "Clinical manifestations of myasthenia gravis".)

●Amyotrophic lateral sclerosis (ALS) – Patients with ALS are sleepy for a variety of reasons. Sleep difficulty is often secondary to other problems associated with ALS (eg, dyspnea, dysphagia, mood disorders, inability to change posture during sleep due to weakness). Patients are also at increased risk for sleep-disordered breathing and periodic limb movements of sleep. In a study that included 121 patients with ALS, the prevalence of sleepiness was 26 percent, and ESS scores correlated with global ALS severity scores [38]. (See "Symptom-based management of amyotrophic lateral sclerosis", section on 'Respiratory function management' and "Symptom-based management of amyotrophic lateral sclerosis", section on 'Sleep problems'.)

●Facioscapulohumeral dystrophy (FSHD) – FSHD can cause respiratory complications, and sleep may also be disrupted by pain. In a study of 690 individuals with FSHD, 15 percent had sleepiness defined as an ESS score >10 [39]. (See "Facioscapulohumeral muscular dystrophy", section on 'Clinical features'.)

●Hereditary sensory and autonomic neuropathy type 1E – Patients with sensory and autonomic neuropathy type 1E, caused by mutations in DNMT1, have an increased incidence of a range of sleep disorders, including narcolepsy and REM sleep behavior disorder [40]. (See "Hereditary sensory and autonomic neuropathies", section on 'HSAN1'.)

●Postural tachycardia syndrome – In one study, patients with postural tachycardia syndrome had increased daytime sleepiness compared with controls as assessed by the ESS [41]. (See "Postural tachycardia syndrome".)

Headache — Migraine sufferers may have an increased prevalence of EDS, even when free of headache [42]. In a population-based study, the rate of EDS was approximately twofold higher in patients with migraine compared with non-headache controls (20 versus 9 percent) [43]. This is of particular interest, as many patients with migraine desire sleep to ameliorate symptoms.

Frequent yawning is seen during migraine and can also a harbinger of an impending headache [44]. Migraineurs with night-time attacks may represent a subset of patients with more severe and disabling migraine [45]. Basilar migraine can cause sleepiness and even loss of consciousness, possibly through dysfunction of brainstem wake-promoting systems. Some of the chronic prophylactic agents for migraine therapy can also contribute to sleepiness.

Other headache types are similarly associated with daytime sleepiness. One study of 93 patients with secondary headaches of various types found 23 percent had EDS [46].

Neurogenetic disorders — Although neurogenetic disorders are rare when considered individually, collectively they may represent a significant medical cause of EDS. Often these conditions will present in childhood and have associated systemic abnormalities. Examples of disorders associated with sleepiness include:

●Prader-Willi syndrome – Approximately two-thirds of adults with Prader-Willi syndrome report EDS, sometimes with cataplexy-like symptoms [47,48]. Narcolepsy type 1 with classic clinical features and low cerebrospinal fluid orexin levels occurs but is relatively uncommon [48,49]; more commonly, patients have idiopathic hypersomnia, narcolepsy type 2 (narcolepsy without cataplexy), or a mixed hypersomnia phenotype [48]. Obesity is often comorbid, and patients are also at high risk for sleep-related breathing disorders. However, EDS often persists despite adequate treatment of sleep apnea. Some patients may respond to symptomatic treatment with modafinil [48]. (See "Prader-Willi syndrome: Management", section on 'Sleep and respiratory disorders'.)

●Niemann-Pick type C – EDS with or without cataplexy can be seen in patients with Niemann-Pick type C, in association with additional neurologic symptoms (eg, movement disorders, dementia, and eye movement abnormalities) and hepatosplenomegaly. The age of onset and clinical presentation of Niemann-Pick type C are highly variable, and rare patients present in adulthood. Low hypocretin levels in some patients suggest that lysosomal storage abnormalities in the hypothalamus may contribute to the pathogenesis of sleepiness [50]. (See "Overview of Niemann-Pick disease".)

●Moebius syndrome – Moebius syndrome is characterized by congenital facial diplegia and bilateral abducens palsies. Sleepiness in these patients may be related to underlying migrational abnormalities in the brainstem that may affect arousal-promoting pathways. (See "Facial nerve palsy in children", section on 'Congenital facial nerve palsy'.)

●Fragile X syndrome – Fragile X syndrome is an X-linked disorder caused by loss-of-function mutations in the fragile X messenger ribonucleoprotein 1 (FMR1) gene. It is the most common inherited cause of intellectual disability and is often also associated with behavioral abnormalities, including autism spectrum disorder and attentional difficulties [51]. Although X-linked, both males and females can be affected. Dysmorphic features may be present, along with tremor or cerebellar abnormalities. (See "Fragile X syndrome: Clinical features and diagnosis in children and adolescents".)

●Williams syndrome – About one-third of patients with Williams syndrome, also known as Williams-Beuren syndrome, have EDS despite adequate sleep time [52]. Increased sleep fragmentation and movements during sleep have been noted using actigraphy, but this has not yet been explored by polysomnography. Williams syndrome is a multisystem disorder caused by hemizygous deletion of a portion of chromosome 7q, typically recognized by facial dysmorphism ("elfin" facies) and overly friendly personality. (See "Microdeletion syndromes (chromosomes 1 to 11)", section on '7q11.23 deletion syndrome (Williams syndrome)'.)

●Smith-Magenis syndrome – Smith-Magenis syndrome (17p11.2 deletion syndrome) is a condition with facial dysmorphism and high impulsivity that is often associated with significant sleep problems and daytime sleepiness [53]. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '17p11.2 deletion syndrome (Smith-Magenis syndrome)'.)

●Cyclin-dependent kinase-like 5 deficiency disorder – Cyclin-dependent kinase-like 5 deficiency disorder is associated with developmental delay and severe epilepsy. A study of 129 children with this disorder noted that excessive daytime sleepiness was of particular concern to families and had an impact on quality of life [54]. Seizures, sleep disruption, and medication effects may all contribute to somnolence.

MEDICAL CONDITIONS

Cardiovascular disease — A variety of cardiovascular diseases are associated with excessive daytime sleepiness (EDS), often related to comorbid sleep-related breathing disorders. Obstructive sleep apnea is an important consideration, particularly in patients with obesity or metabolic syndrome. Heart failure is associated with an increased prevalence of central sleep apnea and Cheyne-Stokes respiration. (See "Obstructive sleep apnea and cardiovascular disease in adults" and "Sleep-disordered breathing in heart failure".)

Respiratory conditions — Chronic obstructive pulmonary disease may be associated with profound oxygen desaturation despite minimal respiratory events on a polysomnogram. Associated hypoxia and hypercapnia may contribute to cerebral injury and hypersomnolence [55]. Along with EDS, patients may have morning headaches associated with hypercarbia-induced vasodilation, as well as asterixis and myoclonus.

Other potential causes of EDS in patients with respiratory disease include chronic cough, which may fragment nocturnal sleep, and systemic inflammation.

Systemic inflammation — Inflammatory cytokines (eg, interleukin-1-beta, interleukin-6, tumor necrosis factor alpha) and prostaglandins are well-known sleep-promoting factors [56,57]. Any chronic infection or inflammatory condition may result in sleepiness, possibly due to these inflammatory mediators. Some of the more common examples are rheumatologic disease and cancer.

●Rheumatologic disorders – Fatigue and EDS related to profound inflammation are prominent symptoms in many patients with rheumatologic disorders. Joint pain and reduced physical activity may also contribute to sleep disruption and subsequent EDS, although in some cases active pain may increase arousal and counteract daytime sleepiness [58].

●Malignancy – EDS is commonly seen in patients with malignancy [59,60]. Contributing factors may include the direct effects of cytokines produced in response to the cancer, cytokine release associated with tumor lysis syndrome, side effects from chemotherapy or radiation, and the presence of metastatic disease in the brain [61,62]. In a study of 16 patients with malignancy who underwent a multiple sleep latency test, the mean sleep latency was less than eight minutes in 69 percent [63].

Hematologic disorders — Hematologic disorders can produce sleepiness by way of associated sleep disorders.

●Iron deficiency – Iron deficiency is often associated with restless legs syndrome (RLS) and periodic limb movements of sleep, which may interfere with sleep and result in EDS. A study of 744 older adult patients noted excessive daytime sleepiness defined by an Epworth Sleepiness Scale (ESS) score >10 in 24 percent [64]. Reductions in gray matter iron stores [65] may also contribute directly to a reduction in projecting alertness system function. Cerebral iron stores may be considerably lower than what is detected by peripheral blood measures, and even patients with a "low normal" ferritin (eg, ≤75 to 100 ng/mL) may improve with iron supplementation. Comorbid depression is also important to recognize and treat, as mood symptoms may be interpreted as sleepiness. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults".)

●Hemochromatosis – Patients with hemochromatosis may have EDS related to iron overload and subsequent hepatic dysfunction (see 'Metabolic encephalopathy' below). Endocrine dysfunction as a result of iron deposition in the pituitary is another potential cause of sleepiness. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

●Sickle cell disease – Obstructive sleep apnea and other forms of sleep-disordered breathing occur with increased frequency in patients with sickle cell disease [66]. In addition to producing EDS, sleep apnea may also increase the frequency of acute pain episodes and chronic cardiopulmonary disease. (See "Overview of the pulmonary complications of sickle cell disease", section on 'Sleep-disordered breathing'.)

●Primary immune thrombocytopenia – In a study of 653 patients with primary immune thrombocytopenia, fatigue and/or sleepiness were reported by 20 to 40 percent of patients and correlated with low platelet count, treatment with steroids, bleeding symptoms, and the presence of other comorbid conditions [67]. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis".)

Metabolic encephalopathy — Metabolic abnormalities due to organ dysfunction can result in sleepiness ranging from mild symptoms to profound encephalopathy with obtundation and coma.

●Hepatic dysfunction – Sleep-wake disturbances, including both insomnia and EDS, are common initial manifestations of hepatic encephalopathy that may precede other neurologic symptoms and signs in patients with liver dysfunction and/or portosystemic shunting. In patients with more severe sleepiness, attentional difficulties, psychomotor slowing, and associated movement disorders such as asterixis will often be present. Most patients with hepatic encephalopathy have advanced chronic liver disease and physical stigmata of hepatic dysfunction. (See "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis".)

Chronic liver disease can also be associated with EDS, even in the absence of hepatic encephalopathy. In a study of 48 women with primary biliary cirrhosis and normal liver synthetic function, more than half of patients had significant daytime sleepiness (ESS score >10) [68]. Compared with healthy controls, these patients also had twice as much daytime sleep as measured by actigraphy [68]. A study of 192 patients with metabolic dysfunction-associated steatotic liver disease noted that an ESS score >10 was a predictor of reduced health-related quality of life in a diverse population [69].

●Renal failure – EDS is common in patients with renal failure and may arise from multiple factors. Patients with end-stage renal disease are at increased risk for sleep apnea, which can be worsened by fluid overload [70]. RLS and periodic limb movements affect up to 50 percent of patients on hemodialysis. Other potential contributing factors include insomnia, poor sleep quality, and side effects from medications. Elevated metabolites may also play a role [71]. (See "Sleep disorders in end-stage kidney disease".)

●Endocrine disorders – A variety of endocrine disorders, including diabetes, clinical and subclinical hypothyroidism, pituitary adenomas, and Addison's disease, can be associated with EDS [72,73]. In patients with diabetes, episodes of severe hypoglycemia may increase the likelihood of daytime sleepiness [74]. Polycystic ovarian syndrome is also associated with EDS as well as an increased incidence of sleep-disordered breathing [75].

●Toxin exposure – Industrial toxins or organic solvents such as cyclohexane [76] can be associated with encephalopathy as well as sleep disruption and sleepiness [77]. Organic solvents in particular can damage white matter tracts, possibly including those that contribute to ascending wakefulness drive. An occupational history may help identify exposure to these agents.

●Rare metabolic disorders – Rare metabolic disorders should be considered as a cause of otherwise unexplained EDS, especially in children and when there is a family history. Ornithine transcarbamylase deficiency and mitochondrial disorders may be associated with intermittent encephalopathy with sleepiness as well as intermittent symptoms in multiple organ systems. Hearing loss and short stature are classic clues for a mitochondrial abnormality, and a maternal inheritance pattern may be identified. Screening can be initiated with lactate and pyruvate levels as well as amino acid levels and urine organic acid profiles in selected patients. (See "Inborn errors of metabolism: Identifying the specific disorder".)

Peptic ulcer disease and reflux — In a study of over 2500 adults with a range of medical disorders and no suspicion for sleep apnea or narcolepsy, peptic ulcer disease was the most common medical disorder associated with sleepiness, with 50 percent of patients reporting significant daytime sleepiness [42].

Gastroesophageal reflux can cause arousals from sleep that may not be evident on routine polysomnography that does not include esophageal pH measurements [78]. In patients with daytime reflux symptoms and sleepiness that is otherwise unexplained, dietary manipulation, sleeping in the left lateral decubitus position with the head of the bed slightly raised, and a trial of an acid-reducing agent may help clarify the diagnosis.

Vitamin deficiencies — In severe cases, vitamin B12 deficiency can be associated with white matter lesions and subsequent EDS. Precipitation of severe symptoms in previously borderline B12 deficiency has been noted with exposure to nitrous oxide. Limited data suggest that vitamin B12 also has effects on circadian rhythms, including one study demonstrating enhanced vigilance after adding B12 to circadian phototherapy in 28 patients with Alzheimer disease [79].

Vitamin D deficiency occurs with increased frequency in multiple sclerosis and sleep apnea [80]. Whether vitamin D deficiency is implicated in EDS is unclear, and the relationship may be confounded by reduced light exposure and physical activity.

Pregnancy — Pregnant women are nearly twice as likely as controls to report EDS [81]. Sleep is often disrupted during pregnancy, with multiple contributors including hormonal changes, back pain and other physical discomforts, sleep-disordered breathing [82], and RLS. Sleep disruption may persist postpartum, independent of care of the newborn. (See "Obstructive sleep apnea in pregnancy" and "Restless legs syndrome during pregnancy and lactation".)

MEDICATIONS — A variety of medications and substances can cause sleepiness directly or indirectly through aggravation of sleep disorders. In general, medications that cause sleepiness should be given at night, when possible, to minimize daytime effects.

Sleep aids and opioids — Sleep aids are widely prescribed and may be unnecessary in many patients. Daytime sleepiness in patients taking sleep aids can often be addressed by reducing or eliminating sedative agents, focusing on behavioral therapies, and effectively treating any underlying sleep disorders or medical conditions.

●Benzodiazepines and nonbenzodiazepine benzodiazepine receptor agonists ("Z-drug" hypnotics) induce sleepiness by enhancing gamma-aminobutyric acid (GABA)-ergic signaling. As with all drugs, the possibility of bioaccumulation due to reduced metabolism or elimination in the setting of hepatic dysfunction should be considered, particularly in older adults and women. (See "Pharmacotherapy for insomnia in adults", section on 'Benzodiazepine receptor agonists'.)

●Barbiturates and opioids may suppress alertness as well as impair respiration in sleep. Combining of these drugs with other sedatives can produce dangerous synergistic effects. (See "Sleep-disordered breathing in patients chronically using opioids", section on 'Effects of opioids on sleep and respiration'.)

●Over-the-counter agents associated with sleepiness include antihistamines, which directly antagonize wake-promoting histamine signaling, and some natural health products, such as valerian, melatonin, and kava. Contamination by unknown harmful substances should also be considered as a cause of sleepiness in patients taking poorly regulated health products.

Medications used for neurologic and psychiatric disorders

●Many antiseizure drugs have direct sedating effects [83]. Serum drug levels may be useful to rule out excess drug accumulation when sleepiness is prominent. Serum ammonia should be checked in patients with excessive sleepiness on valproic acid, as toxicity can cause encephalopathy via hyperammonemia in the absence of other liver function abnormalities. Carnitine supplementation can reduce ammonia levels in this setting. (See "Valproic acid poisoning", section on 'Carnitine supplementation'.)

Some antiseizure drugs may relax airway muscles and precipitate obstructive sleep apnea or sleep-related breathing disorders, leading indirectly to daytime sleepiness. (See "Comorbidities and complications of epilepsy in adults", section on 'Sleep disorders'.)

●Antipsychotics are often sedating and can aggravate restless legs syndrome (RLS) and periodic limb movements of sleep. Among atypical antipsychotics, quetiapine may be the most likely to cause EDS [84].

●Anticholinergic agents are often prescribed for pain syndromes and can induce somnolence. Most tricyclic antidepressants have anticholinergic features.

●Antidepressants can have alerting or sedative characteristics, depending on the specific drug and the individual [85]. Patients with daytime sleepiness may do best with an alerting antidepressant taken in the morning. (See "Unipolar major depression in adults: Choosing initial treatment", section on 'Side effects'.)

●Dopaminergic drugs and direct dopaminergic agonists are associated with hypersomnolence, particularly at higher doses and in patients with Parkinson disease [86].

Medications used for other conditions — Many other common medications may produce sleepiness, especially in the setting of underlying organ dysfunction, multiple medical comorbidities, or advanced age.

●Nonsteroidal anti-inflammatory drugs such as aspirin and ibuprofen taken during the daytime can produce mild daytime sleepiness, possibly via interference with prostaglandin production [87].

●Antimicrobials such as penicillin and metronidazole may have direct central nervous system effects. A causal relationship can be difficult to determine in the context of illness and organ failure, which may also contribute to somnolence [88].

●Antispasmodics often have anticholinergic properties associated with sleepiness.

●Antiarrhythmic agents can induce sleepiness. Digoxin in particular has a relatively narrow therapeutic window, and drug interactions and changes in renal function can increase serum levels and lead to toxicity. (See "Treatment with digoxin: Initial dosing, monitoring, and dose modification".)

●Alpha-2 agonists such as clonidine and alpha-1 antagonists such as prazosin can be sedating.

●Beta-blockers have been associated with sleep disruption and consequent daytime sleepiness as well as impairments in mood.

●Diuretic medications may cause nocturia, thereby disrupting sleep and producing daytime sleepiness.

Substance abuse — Toxicology screens for drugs of abuse should be considered in patients with unexplained sleepiness, particularly when symptoms are acute. Alcohol, marijuana, and opioids are some of the more common substances associated with excessive sleepiness.

●Alcohol, marijuana, and opioid intoxication syndromes are commonly associated with excessive sleepiness. Alcohol is acutely sedating, and chronic use can also produce daytime sleepiness by fragmenting sleep. Marijuana can produce abnormalities on the multiple sleep latency test (MSLT) that are compatible with narcolepsy [89]. Opioids can induce chronic daytime sleepiness [90], independent of their effects on breathing patterns and apneas during sleep. (See "Insomnia in patients with a substance use disorder", section on 'Clinical features' and "Sleep-disordered breathing in patients chronically using opioids".)

●Gamma hydroxybutyrate (GHB) intoxication should be considered in cases of profound coma that resolves in several hours with no apparent abnormality on toxicology screen. GHB has a short half-life and is not detected on routine toxicology screens. Definitive confirmation requires gas chromatography/mass spectrometry analysis. (See "Gamma hydroxybutyrate (GHB) intoxication".)

●Withdrawal of stimulating substances may trigger hypersomnolence. Cocaine and amphetamine withdrawal can produce sleepiness and even sleep-onset rapid eye movement (REM) periods (SOREMPs) on an MSLT. Caffeine withdrawal may also be associated with sleepiness and headache. Many commonly used over-the-counter products contain significant amounts of caffeine, and this should be considered in a detailed medication and substance use history.

EVALUATION AND MANAGEMENT — There is no single effective treatment for sleepiness related to medical disorders. Efforts should be made to address the underlying medical disorder and maximize symptomatic management.

While most of the medical disorders reviewed above will be apparent by history, physical examination, and basic blood work (see "Approach to the patient with excessive daytime sleepiness", section on 'Initial evaluation'), additional tests may be warranted in selected patients. Examples include lactate and pyruvate for suspected mitochondrial disorders, serum ammonia to rule out hyperammonemia, endocrine testing, and an erythrocyte sedimentation rate. A history of restless legs or periodic limb movements during sleep should prompt measurement of serum ferritin, B12, and creatinine. Blood and urine toxicology screens should be considered when there are few clues to the source of symptoms or in the presence of drug-seeking behaviors. Magnetic resonance imaging (MRI) of the brain with contrast may be indicated when there are focal neurologic signs or suspicion for an inflammatory neurologic process. (See 'Neurologic disorders' above and 'Medical conditions' above and 'Substance abuse' above.)

Recognition and treatment of comorbid sleep and circadian rhythm disorders are paramount (table 3). In particular, obstructive sleep apnea is common, frequently undiagnosed, and often inadequately treated due to poor adherence to positive airway pressure therapy. Polysomnography or home sleep apnea testing is required to make a diagnosis of sleep apnea and to confirm adequate response to therapy. The role of polysomnography, the multiple sleep latency test (MSLT), and other additional testing in the initial evaluation of sleepiness is reviewed separately. (See "Approach to the patient with excessive daytime sleepiness", section on 'Testing'.)

Ensuring adequate sleep time is essential for all patients with daytime sleepiness. In cases of uncertainty, actigraphy may be a useful adjunct to sleep logs to help quantify sleep and detect unrecognized circadian and sleep disorders. (See "Insufficient sleep: Evaluation and management".)

Elimination of sedating medications is helpful if possible. Timing of medications can be adjusted to get maximal sedative effects at night. Stimulating medications should be taken in the daytime. (See 'Medications' above.)

Behavioral strategies include more light exposure in the daytime, which can improve alertness. Physical activity or even position changes (eg, standing instead of sitting) can also increase alertness during monotonous tasks or situations.

If sleepiness persists despite optimal treatment of the underlying medical disorder, then a wake-promoting medication can be considered [91,92]. There are no established pharmacologic therapies for symptomatic management of sleepiness in this setting. Wake-promoting agents (eg, modafinil, armodafinil) or stimulants (eg, methylphenidate) might be expected to have some benefit based on experience in patients with central disorders of hypersomnolence such as narcolepsy (see "Treatment of narcolepsy in adults", section on 'Approach to pharmacotherapy'), but direct data are very limited in patients with sleepiness due to a medical or neurologic disorder. Specific patient groups in which these drugs have been studied, sometimes with mixed results, include the following:

●Multiple sclerosis (see "Symptom management of multiple sclerosis in adults", section on 'Fatigue')

●Parkinson disease (see "Evaluation and treatment of insomnia, daytime sleepiness, and other sleep disorders in Parkinson disease", section on 'Wake-promoting agents')

●Traumatic brain injury (see "Sleep-wake disorders in patients with traumatic brain injury", section on 'Excessive daytime sleepiness')

●Cancer-related fatigue (see "Cancer-related fatigue: Treatment", section on 'Psychostimulants and other wakefulness agents')

In the author's experience, a trial of modafinil may be worthwhile in patients with persistent excessive daytime sleepiness, preferably confirmed objectively on an MSLT. Such objective physiologic measures are helpful to track medication response. Other sleep disorders should be ruled out and appropriate behavioral strategies implemented. Stimulant medications are typically reserved for more refractory symptoms. Pitolisant and solriamfetol may also be considered based on experience in sleep apnea as adjunctive therapy [93,94]. (See "Evaluation and management of residual excessive sleepiness in adults with obstructive sleep apnea", section on 'Treatment'.)

Potential side effects and cost often factor into decisions, and safety of certain medications may vary based on underlying organ dysfunction and concurrent medications such as warfarin or hormonal contraception, which might pose problems in terms of drug interactions. A typical starting dose of modafinil is 100 mg in the morning; a second dose of 100 mg at noon can be added if necessary. A reduced starting dose is advised in older adults.

Regardless of the underlying cause, patients with daytime sleepiness should be warned about the risks of drowsy driving and educated about prevention and risk modification. (See "Drowsy driving: Risks, evaluation, and management", section on 'Prevention and countermeasures'.)

SUMMARY

●Insufficient sleep – Insufficient sleep is perhaps the most common and easily overlooked cause of excessive daytime sleepiness (EDS) in patients with medical illness. High-risk groups include shift workers, patients with competing family responsibilities, patients with chronic pain, and hospitalized patients. (See 'Insufficient sleep' above.)

●Neurologic disorders – Neurologic disorders can manifest with EDS due to involvement of the cortex bilaterally or midline structures that are critical for maintaining alertness. Other neurologic disorders are associated with an increased risk of primary sleep disorders such as sleep apnea and periodic limb movement disorder. (See 'Neurologic disorders' above.)

●Medical conditions – A wide range of chronic medical illnesses are associated with sleepiness, which may be mediated by inflammatory cytokines, endocrine dysfunction, metabolic encephalopathy, or comorbid sleep disorders. (See 'Medical conditions' above.)

●Medication side effects – Side effects of medications are an important cause of EDS in patients with chronic illness. Such patients are often at increased risk for sedative side effects due to polypharmacy, organ dysfunction, and advanced age. (See 'Medications' above.)

●Evaluation and management – There is no single effective treatment for EDS related to medical disorders, and management requires a stepwise approach.

•Ensuring adequate sleep time is essential for all patients. Comorbid sleep disorders should be diagnosed and treated. In particular, obstructive sleep apnea is common, frequently undiagnosed, and often inadequately treated due to poor adherence to positive airway pressure therapy. Essential medications with sedative properties should be given at night, when possible, and alerting medications given in the morning. (See 'Evaluation and management' above.)

•The role of wake-promoting agents or stimulants in patients with persistent sleepiness is uncertain. Existing data are limited, and small studies in selected patient groups (eg, multiple sclerosis, Parkinson disease, cancer) have had mixed results. (See 'Evaluation and management' above.)

●Safety and driving – Regardless of the underlying cause, patients with EDS should be warned about the risks of drowsy driving and educated about prevention and risk modification. (See "Drowsy driving: Risks, evaluation, and management", section on 'Prevention and countermeasures'.)