Clinical manifestations

Presentation and course

Sleep disorders may be suspected by patient testimony, but confirmation in a sleep laboratory is recommended. Nocturnal polysomnography identifies sleep disruption, as well as abnormal motor behaviors, and daytime multiple latency tests measure daytime sleepiness and provide support for the diagnosis of narcolepsy. Practitioners should be able to distinguish fatigue from excessive daytime sleepiness caused by primary sleep disorders to optimally treat their patients. Sleepiness is the tendency to fall asleep, whereas fatigue is a low level of mental and physical energy.

In a review Caminero and Bartolome claimed that sleep disturbances are more common in multiple sclerosis patients than in the general population and limit these patients' quality of life, concluding that sleep disturbances should be a focal point in any multidisciplinary treatment for multiple sclerosis (16). This concept has also been echoed by Chen and colleagues relative to patients in China (20). The concepts of fatigue and sleepiness are often used interchangeably in multiple sclerosis. Using the Epworth Sleepiness Scale (ESS) for the assessment of daytime sleepiness in patients with multiple sclerosis, sleepiness, as indicated by elevated ESS scores, was less prevalent and less severe than fatigue but was present in a significant proportion of patients with multiple sclerosis (75). Daytime sleepiness in multiple sclerosis patients was frequently associated with comorbid sleep disorders that are often underrecognized and undertreated.

Chronic fatigue is common in multiple sclerosis and may confound the interpretation of sleep disturbances. Patients with multiple sclerosis report difficulty falling asleep, restless sleep, nonrestorative sleep, and early morning awakenings more frequently than control subjects. In a study of 28 consecutive patients with multiple sclerosis, 15 patients (54%) reported sleep-related problems (88). These included difficulties initiating or maintaining sleep, frequent awakenings due to leg spasms, habitual snoring, and nocturia. Three patients showed episodes of nocturnal desaturation, and two had sleep apnea syndrome. MRI of the brain showed abnormalities in 20 of 22 cases studied. Sleep laboratory evaluations in patients with multiple sclerosis revealed early on that sleep disturbance is common in these patients and that its etiology is multifactorial, involving both physical and psychological features (52; 76). In another study of fatigue and sleep disturbances in 30 patients with multiple sclerosis, the authors found a significant correlation between fatigue and disrupted sleep or abnormal sleep cycles (04). Words of caution have been raised by others, suggesting that patients with multiple sclerosis do not often distinguish between fatigue and sleepiness and, therefore, stimulant medication may not be indicated (48). A depressive mood is the main factor influencing quality of life in patients with multiple sclerosis (56). Fatigue is prevalent in multiple sclerosis patients and more than 40% of multiple sclerosis patients complain of fatigue (17). In comparison to controls, multiple sclerosis patients report more fatigue, tiredness, and lack of energy, but not sleepiness (09). Although fatigue is believed to be a primary central process in multiple sclerosis, contributing comorbid factors are sleep disturbance, depression, medication, and deconditioning.

In a systematic review and metaanalyses for the associations between fatigue and 10 sleep variables, results indicated that sleep quality and insomnia were strongly associated with fatigue (08). In contrast, the number of awakenings and sleep duration assessed objectively were not significantly associated with fatigue.

Excessive daytime sleepiness. Excessive somnolence and inappropriate daytime sleep can occur in patients with multiple sclerosis. In some individuals, excessive daytime sleepiness and sleep attacks occur in conjunction with cataplexy, sleep paralysis, and hypnagogic hallucinations leading to a diagnosis of narcolepsy. Excessive somnolence and other narcoleptic symptoms may appear before or after the onset of multiple sclerosis (81), and the age of presentation has varied widely. In some patients, a remitting course of the symptoms of narcolepsy has suggested multiple sclerosis as the cause of the sleep disorder. In older reports, laboratory confirmation of narcolepsy is lacking, or if present, has failed to confirm a diagnosis of narcolepsy (74). In a review of the symptomatic narcolepsies, Autret and colleagues indicated that nine cases of probable or certain multiple sclerosis associated with narcolepsy had been published (06). In a review of 26 patients, Kallweit and colleagues found six patients in their survey and 20 in the literature with an association of multiple sclerosis and narcolepsy (41). The authors identified two types of association: (1) a symptomatic type with multiple sclerosis preceding the onset of narcolepsy and lesions in the hypothalamus in all patients; and (2) a more numerous coexisting type with multiple sclerosis preceding or following the appearance of narcolepsy but no lesions in the hypothalamus. Interestingly, some authors reported a beneficial effect of steroids, immunoglobulins, or natalizumab on narcolepsy symptoms. Kallweit and colleagues suspect that the rarity of published reports indicates underrecognition of the association (41).

In a study of subjective sleep disturbance and excessive daytime sleepiness in patients with multiple sclerosis, the authors correlated subjective sleep questionnaires with results of polysomnography and multiple sleep latency tests (MSLT) (71). They found that subjective sleepiness evaluated with the Epworth Sleepiness Scale and sleep disturbance with the Pittsburgh Sleep Quality Index were not correlated with the results of objective assessments of vigilance (MSLT) and sleep. The authors concluded that although sleep disturbance and excessive daytime sleepiness are frequent among patients with multiple sclerosis, and objective assessment of vigilance and sleep can be challenging.

In one study of 44 patients with multiple sclerosis, 19 (43.2%) had fatigue and sleepiness, 15 (34%) had only fatigue, and 10 (22.7%) had neither fatigue nor sleepiness (25). Central hypersomnia was found in 10 (53%) patients with fatigue and sleepiness, in two (13%) patients with fatigue only, and in three (30%) patients with neither fatigue nor sleepiness. Patients with central hypersomnia were younger and sleepier than those without hypersomnia, but they had similar levels of fatigue, disability, depression, cognitive performance, and frequencies of the human leukocyte antigen DQB1*0602 genotype. The authors concluded that central hypersomnias are frequent in multiple sclerosis when fatigue and sleepiness are present and that screening patients with polysomnography is recommended.

Restless legs syndrome. In a prospective study of 156 patients with multiple sclerosis, the authors found that 51 subjects (32.7%) (mean age 43.8 +/- 12.8) met the criteria for restless legs syndrome (59). In a small group (8.5%), restless legs syndrome preceded clinical multiple sclerosis onset, whereas in the remaining cases restless legs syndrome was followed by or occurred simultaneously with the clinical onset of multiple sclerosis. No significant differences were found in multiple sclerosis duration, gender, and sleep habits between both groups of multiple sclerosis patients. The primary progressive course of multiple sclerosis was more represented in the restless legs syndrome group and had a higher disability score (Expanded Disability Status Scale score). The authors concluded that restless legs syndrome is a common finding in multiples sclerosis patients and should be considered among the symptomatic restless legs syndrome forms. Furthermore, restless legs syndrome was also associated with higher disability. In another study with MRI technology, mean diffusivity and fractional anisotropy histograms metrics of the normal-appearing tissues of the brain and cervical cord were assessed in patients with multiple sclerosis with and without restless legs syndrome. Cervical cord average fractional anisotropy was significantly reduced in multiple sclerosis patients with restless legs syndrome compared to those without. This form of restless legs syndrome should be considered as symptomatic. The authors concluded that higher disability and cervical cord damage represent a significant risk factor for restless legs syndrome in multiple sclerosis patients (60). Further corroboration came in the study by Minar and colleagues concluding that risk of restless legs syndrome/Willis-Ekbom disease in multiple sclerosis increases with presence of lesions in spinal cord (67).

In a cross-sectional study of 65,544 women (aged 41 to 58 years) free of diabetes, arthritis, and pregnancy, who were participating in the Nurses' Health Study 2 cohort, the authors found that among women with multiple sclerosis, the prevalence of restless legs syndrome and severe restless legs syndrome (15+ times/month) was 15.5% and 9.9% in 2005, respectively, relative to 6.4% and 2.6% among women without multiple sclerosis (53). After adjustments for confounders, women with multiple sclerosis had a higher likelihood of having restless legs syndrome (odds ratio [OR] = 2.72, 95% confidence interval [CI] 1.89-3.93), severe restless legs syndrome (OR = 4.12, 95% CI 2.65-6.42), and daily daytime sleepiness (OR = 2.11, 95% CI 1.31-3.42) compared with women without multiple sclerosis.

Periodic limb movements (PLMS). In one study, patients with multiple sclerosis without restless legs syndrome and multiple sclerosis with restless legs syndrome presented increased sleep latency, increased percentage of sleep stage N1, and reduced total sleep time compared to healthy controls and idiopathic restless legs syndrome (31). The periodic limb movements index was higher in multiple sclerosis without restless legs syndrome than in healthy controls (p = 0.035). The authors concluded that multiple sclerosis is a risk factor for periodic limb movements, lowering sleep quality.

Insomnia. In a study of 206 multiple sclerosis patients, 22.3% fulfilled criteria for chronic insomnia disorder (CID). Insomnia of sleep initiation was observed in 11.7%, maintenance insomnia in 11.2%, and terminal insomnia in 10.2%. Chronic insomnia disorder was more frequent in female patients, those with nocturnal symptoms, those with medical comorbidities, and those with higher levels of anxiety, depression and fatigue. Female sex, medical comorbidities, anxiety, and fatigue were identified as independent factors of chronic insomnia disorder. Chronic insomnia disorder patients had a significantly lower self-reported quality of life (99).

REM sleep behavior disorder. In one case report, REM sleep behavior disorder was the heralding manifestation of multiple sclerosis; the patient had MRI hyperintensities in the pons and in a periventricular location (73). In another case report, a 51-year-old woman developed nocturnal manifestations suggestive of REM sleep behavior disorder following an acute attack of multiple sclerosis. The patient had no recall of dreams associated with bizarre nocturnal behavior. However, the polysomnogram showed REM sleep without atonia. MRI of the brain showed increased T2 signal in the dorsal pons suggestive of demyelination. The nocturnal events responded to the administration of clonazepam at bedtime (90).

Sleep disordered breathing. Polysomnographic data from a cross-sectional study of 48 patients with multiple sclerosis were compared with those of sleep laboratory-referred patients without multiple sclerosis matched for age, gender, and body mass index, and with a separate group of 48 randomly selected, referred patients (11). The authors found that the mean AHI was higher among patients with multiple sclerosis than among control groups (p=0.0011 and 0.0118, respectively). Those with evidence of brainstem involvement showed particularly strong differences in AHI (p=0.0060 and 0.0016). The authors concluded that the data suggest a predisposition for obstructive sleep apnea and accompanying central apneas among patients with multiple sclerosis, particularly among those with brainstem involvement.

On the other hand, in a cross-sectional, observational, instrumental study, 67 multiple sclerosis patients (men/women: 20/47; mean age: 50.6 ± 8.2 years) underwent polysomnography and maintenance of wakefulness test (84). Findings were compared to 67 age-, sex-, BMI-matched healthy controls. The authors found that the frequency of sleep-related breathing disorder was comparable in multiple sclerosis patients and healthy controls. The authors concluded that the study failed to provide evidence of an association between multiple sclerosis-specific symptoms such as fatigue, sleepiness, depression, and central or obstructive apneas, even in the presence of brainstem lesions.

Cognitive deficits in multiple sclerosis. The majority of multiple sclerosis patients suffer from impairments in cognition such as processing speed, working memory, learning, executive function, visuospatial processing, and language dysfunction (02). Undiagnosed and untreated sleep apnea could explain some of the cognitive dysfunction in multiple sclerosis and is a modifiable factor. Intermittent hypoxia and sleep degrade neurocognitive function in the general population, and likely have a similar effect in patients with multiple sclerosis. In fact, sleep apnea causes some of the same neuroimaging and neuropathological abnormalities in the periventricular region that are seen in patients with multiple sclerosis (23). To this effect, a common differential diagnosis of MR images in patients with subcortical white matter intensities has to be made between multiple sclerosis and small vessel disease. In one study of 38 adults with clinically definite multiple sclerosis in-center polysomnographic studies showed that the oxygen desaturation index and minimum oxygen saturation were significantly associated with performance on multiple Minimal Assessment of Cognitive Function in Multiple Sclerosis measures, as well as working memory, processing speed, and attention (10). Apnea severity measures accounted for between 12% and 23% of the variance in cognitive test performance. Polysomnographic measures of sleep fragmentation, as reflected by the total arousal index, and total sleep time explained 18% and 27% of the variance in performance. The author concluded that in patients with multiple sclerosis, obstructive sleep apnea and sleep disturbance are significantly associated with diminished visual memory, verbal memory, executive function, attention, processing speed, and working memory, suggesting that if sleep disorders degrade cognitive functions, effective treatment could offer new opportunities to improve cognitive functioning in patients with multiple sclerosis (58).

Yawning. Repetitive yawning can be a symptom of multiple sclerosis, and yawning may provide symptom relief in patients with multiple sclerosis. One survey showed that more than one in three patients reported that their multiple sclerosis symptoms improved following a yawn, and of those experiencing relief, nearly half reported that it lasted for several minutes or longer (34). Yawning has been related to thermoregulation. Other authors have confirmed that yawning is increased in multiple sclerosis (28).

Neuromyelitis optica spectrum disorder. A review of the literature on sleep quality in neuromyelitis optica spectrum disorder (NMOSD) revealed abundant problems with sleep (29). The authors performed a literature search and found 13 studies with 1401 individuals with neuromyelitis optica spectrum disorder that included at least one measure of sleep quality. Pittsburgh Sleep Quality Index (PSQI) scores of individuals from four studies were compared with data from control subjects. The results showed that approximately 70% of individuals with neuromyelitis optica spectrum disorder can be classified as poor sleepers. Decreased sleep quality was significantly associated with decreased quality of life and increased anxiety, depression, and disability status. Sleep disturbances in neuromyelitis optica spectrum disorder were similar in severity to those in multiple sclerosis. The authors concluded that sleep disturbances are a major contributor to neuromyelitis optica spectrum disorder burden and may arise from the disruption of sleep circuitry, in addition to physical and psychological complications.

COVID-19 pandemia. During the COVID-19 outbreak, worse quality of sleep was noticed in relapsing-remitting multiple sclerosis patients than in healthy individuals (87). High levels of sleep disturbance and fatigue in relapsing-remitting multiple sclerosis patients correlated with worse quality of life, female gender, lower educational level, and partner status. The authors concluded that fatigue and quality of sleep in this patient population should be monitored during pandemic states.

Prognosis and complications

The number of nocturnal awakenings and number of daytime naps are increased in multiple sclerosis. Frequent causes of awakening are bladder problems, muscle spasms, anxiety, depression, and periodic limb movements.

Clinical vignette

A 43-year-old woman was referred to the Sleep Center with complaints of sleepwalking at night. The patient was a smoker and had smoked during nocturnal events, causing burns in her bed covers. There was a history of multiple sclerosis, confirmed with MRI images of the brain and spinal cord, dating back 2 years, and chronic fatigue. Multiple sclerosis had affected motor power on the left side. In addition, she was being treated for migraines, depression, asthma, and hypothyroidism. The medication regimen included baclofen, clonazepam, aripiprazole, bupropion, pregabalin, topiramate, citalopram, hydrocodone, buspirone, tamsulosin, cetirizine, and fingolimod. The examination showed morbid obesity and moderate left hemiparesis. An overnight polysomnogram showed paroxysmal arousals in non-REM sleep characterized by suddenly sitting up in bed. The apnea-hypopnea index was seven events per hour of sleep, the arousal index was 13 per hour, and oxygen saturation levels were essentially within normal limits. A subsequent CPAP protocol study showed a pressure requirement of 9 cm of H20. Despite compliance with CPAP, nocturnal events continued. A 5-day computer-assisted digital video EEG monitoring study conducted in the Epilepsy Monitoring Unit showed presence of intermittent frontocentral theta slow waves consistent with encephalopathy, but no epileptiform activity. Sleepwalking events failed to occur during the study. The final diagnoses were sleep apnea and non-REM parasomnia of unknown origin in the setting of multiple sclerosis.

Comment. As is commonly observed in patients with multiple sclerosis, sleep-related conditions diagnosed in this patient, such as sleep apnea and non-REM parasomnia, were likely multifactorial, including principally obesity and adverse medication effects in the context of structural brain lesions. Sleep apnea was well controlled with CPAP, thus, eliminating a possible triggering factor for parasomnias and a source of daytime fatigue. Seizures were ruled out with appropriate testing. Should the patient continue presenting nocturnal wandering episodes, a bed alarm will be prescribed.

Biological basis

Glymphatic system and multiple sclerosis. The glymphatic system utilizes end-feet Aquaporin 4 channels within perivascular astrocytes, causing cerebrospinal fluid to flow into the perivascular space (97). This system is a pathway providing nutrients and waste disposal of the brain parenchyma, including products of metabolic activity, such as amyloid-beta. The glymphatic system is selectively active during slow-wave sleep, and its activity is affected by both sleep dysfunction and deprivation. Dysfunction of the glymphatic system has been proposed as a potential driver of neurodegeneration and of metabolic injury to the brain in both multiple sclerosis subjects and demyelination animal models. In a retrospective cross-sectional study on human multiple sclerosis patients, the diffusion tensor imaging along the perivascular space index was found to be significantly lower in multiple sclerosis patients compared to healthy controls, with progressive multiple sclerosis patients exhibiting lower values than relapsing-remitting multiple sclerosis patients (18). The results of this study indicate that impaired glymphatic function may lead to the accumulation of neuroinflammatory and neurotoxic factors, resulting in progressive demyelination and neuronal loss.

Etiology and pathogenesis

The etiology of both multiple sclerosis and narcolepsy remains partially unknown. The susceptibility to multiple sclerosis is coded by genes within or close to the human leukocyte antigen DR-DQ subregion (37). Patients with narcolepsy exhibit the highest known association between the human leukocyte antigen DR2 and DQw1 antigens and a disease entity, estimated at 95% or above. This coincidence of genetic susceptibility between multiple sclerosis and narcolepsy has led some authors to postulate a common immunogenetic etiology. Fogdell and colleagues have postulated that the human leukocyte antigen Dw2 haplotype in patients with multiple sclerosis and narcolepsy extends to the DRB5 locus (32). According to another study, the HLA-DQB1*06:02 allele alone was not sufficient to cause multiple sclerosis patients to develop narcolepsy (57).

Based on the remitting course of sleep attacks exhibited by some patients with multiple sclerosis, the hypothesis has been advanced that multiple sclerosis may cause symptomatic narcolepsy (07). Castaigne and Escourolle observed midbrain plaques in the hypothalamic periventricular region of a patient with bouts of sleep and multiple sclerosis (19). Later, Auer and colleagues reported plaques of multiple sclerosis in the medulla oblongata of two patients who died in their sleep (05). The lesions incompletely involved the medullary reticular formation controlling automatic breathing leading the authors to hypothesize that the patients died as a result of sleep apnea. Neuropathologic lesions in patients with multiple sclerosis and narcolepsy are an often cited but rarely observed occurrence as estimated by literature reports. The coincidence of multiple sclerosis and narcolepsy type 1 was noted in one family (72). The association between multiple sclerosis and sleep disturbance is higher than expected, and other pathogenetic mechanisms have been investigated. Early on it was found that patients with multiple sclerosis engage in more daytime napping than control subjects (53% vs. 21% of controls) (52), indicating bladder problems with nocturnal and early morning awakenings as common causes of sleep alteration. Two cases of intractable hiccups and sleep apnea syndrome with lesions detected by MRI in the tegmentum of the medulla point to a pathogenetic correlation between anatomic location and clinical manifestations (33). The authors indicate that development of intractable hiccups should suggest the associated presence of sleep apnea syndrome.

An immune attack on anti-aquaporin 4 (anti-AQP4), which is highly expressed in the hypothalamic periventricular regions, may be partially responsible for hypothalamic lesions and hypocretin deficiency in patients with narcolepsy and excessive daytime sleepiness associated with an autoimmune demyelinating disorder. A study showed that in seven patients with multiple sclerosis who were exhibiting excessive daytime sleepiness there were bilateral and symmetrical hypothalamic lesions associated with marked or moderate hypocretin deficiency (43). Four of these patients met the ICSD-2 criteria for narcolepsy. Three patients, including two patients with narcolepsy, were seropositive for anti-AQP4 antibody and diagnosed as having neuromyelitis optica.

There is suggestive evidence that patients with an autoimmune disorder are at higher risk of a second autoimmune disease. In a study of the comorbid immunopathological diseases associated with narcolepsy in 156 patients, 26 (16.6%) had one or more associated immunopathological diseases, such as multiple sclerosis, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, psoriasis, Crohn disease, ulcerative colitis, autoimmune thyroid disease, Peyronie disease, and idiopathic recurrent facial palsy (61). The results suggest that the prevalence of comorbid immunopathological diseases is high. Cataplexy is significantly more severe in patients with narcolepsy plus immunopathological diseases.

Fatigue in multiple sclerosis has been defined as reversible motor and cognitive impairment with reduced motivation, desire to rest, and low level of mental and physical energy. It can appear spontaneously or be brought on by mental or physical activity, humidity, acute infection, or food ingestion. It is relieved by daytime sleep or rest without sleep. It can occur at any time but is usually worse in the afternoon (66). An investigation of sleep apnea, fatigue, and excessive daytime sleepiness in patients with multiple sclerosis showed that fatigue and daytime sleepiness in multiple sclerosis cannot be explained by nocturnal apneas or oxygen desaturation (100). Another study with actigraphy and multiple sleep latency tests failed to reveal a circadian disturbance in patients with multiple sclerosis (89). Other authors have pointed out that multiple sclerosis causes sleep fragmentation in both macro and microstructure of sleep (45). In the view of these authors, fatigue in multiple sclerosis could be partially explained by disruption of sleep microstructure, poor subjective sleep quality, and depression. The concept of a multifactorial cause has gathered strength. Correlates of general and physical fatigue are disease-related, behavioral, and psychosocial factors, whereas correlates of mental fatigue are psychosocial factors (91). Potentially modifiable factors account for a considerable portion of fatigue. Other authors (98) have found substantially normal sleep-wake and body core temperature rhythmicity in patients with multiple sclerosis and fatigue, concluding that subjective fatigue and abnormal sleep and body core temperature rhythmicity can be independent manifestations in multiple sclerosis patients. In any case, sleep disturbance may be an important factor contributing to fatigue in multiple sclerosis and is associated with treatable symptoms including pain and nocturia (86). Veauthier and colleagues investigated the relationship between fatigue and sleep disorders in patients with multiple sclerosis (96; 95). The authors studied 66 multiple sclerosis patients with overnight polysomnography. Using a cut-off point of 45 in the Modified Fatigue Impact Scale (MFIS), the cohort was stratified into a fatigued multiple sclerosis subgroup (n=26) and a nonfatigued multiple sclerosis subgroup (n=40). They found that 96% of the fatigued group was suffering from a specific sleep disorder, as opposed to 60% of the nonfatigued patients (p=0.001). Sleep-related breathing disorders were more frequent in the fatigued patients (27%) than in the nonfatigued patients (2.5%). The results suggested that suffering from a sleep disorder was associated with an increased risk of fatigue in multiple sclerosis (odds ratio: 18.5; 95% CI 1.6-208; p=0.018) and concluded that there is a clear and significant relationship between fatigue and sleep disorders. Hypnotic use is highly prevalent among multiple sclerosis patients, and carryover effects from hypnotic agents, in particular over-the-counter diphenhydramine-containing products, could contribute to daytime fatigue (13). In one study of 76 patients including nocturnal polysomnography, 69.7% had higher fatigue scores using the modified fatigue impact scale when there was presence of restless legs syndrome (p = 0.005) and periodic limb movements (p = 0.014) (79). Excessive daytime sleepiness, total sleep time, sleep efficiency, respiratory disturbances, and percentage of time spent in the different sleep stages (N1, N2, N3, and rapid eye movement) were not associated with fatigue. The authors concluded that multiple sclerosis patients with a diagnosis of restless legs syndrome had significantly higher global fatigue scores compared to those without restless legs syndrome.

Reports suggest that hypocretin-1 level may be reduced in CSF in patients with multiple sclerosis, hypersomnia, and hypothalamic lesions verified by MRI (44). In patients with attacks of multiple sclerosis without sleepiness and no hypothalamic lesions shown on MRI, hypocretin analysis in CSF showed that the hypocretin system was intact (47). Cerebrospinal fluid orexin A was decreased in CNS inflammatory diseases other than multiple sclerosis (21), where it showed a trend toward reduction but did not correlate significantly with measures of fatigue and hypersomnolence. Melatonin is a neurohormone mainly produced by the pineal gland following a circadian rhythm. It not only regulates the wake-sleep rhythm but also exerts antinociceptive, antidepressant, anxiolytic, and immunomodulating properties. There is evidence that melatonin secretion is dysregulated in multiple sclerosis patients, suggesting that melatonin could be a potential target for therapeutic intervention (83). Clinical trials of melatonin supplementation in multiple sclerosis patients are underway.

Epidemiology

The prevalence of sleep disorders in multiple sclerosis, according to a study conducted in 100 multiple sclerosis patients in Spain, was 36% (01). In this study, depression was the only variable independently related with the presence of sleep disorders in multiple sclerosis patients.

In the Italian multicenter study of symptomatic restless legs syndrome and multiple sclerosis, restless legs syndrome was significantly associated with multiple sclerosis (prevalence in multiple sclerosis was 19% vs. 4.2% in control subjects) and was especially prominent in patients with severe pyramidal and sensory disability (38). The authors concluded that the results support the notion that inflammatory damage caused by multiple sclerosis may induce a secondary form of restless legs syndrome. Restless legs syndrome had a significant impact on sleep quality in patients with multiple sclerosis and should be considered in the differential diagnosis in cases of insomnia unresponsive to treatment with hypnotic drugs. In another study in China, 695 patients were randomly selected from a cohort of patients with multiple sclerosis and matched with similar age- and sex- healthy controls (n = 603). Using a face-to-face interview questionnaire, the authors found a significantly higher prevalence of restless legs syndrome among patients with multiple sclerosis compared to healthy controls (odds ratio [OR], 3.8; P <  0.001). Older multiple sclerosis age at onset and a longer multiple sclerosis duration were identified as risk factors. Patients with both multiple sclerosis and restless legs syndrome were more likely to suffer from sleep complaints compared to patients with multiple sclerosis without restless legs syndrome. The authors concluded that restless legs syndrome was significantly associated with multiple sclerosis, affecting negatively the quality of sleep (55). A word of caution has been voiced by authors who have found that multiple sclerosis patients have a high false-positive rate of restless legs syndrome diagnosis using a standardized questionnaire, which may be largely attributable to multiple sclerosis-related sensorimotor symptoms (65). The same authors suggest that the periodic leg movements during wakefulness (PLMW) index on overnight polysomnography (PSG) may be useful in identifying true-positive restless legs syndrome patients.

In a study of 120 patients with multiple sclerosis (64), the authors found that 47.5% of patients were poor sleepers, constituting an independent predictor of quality of life. The authors concluded that patients with multiple sclerosis who are poor sleepers should receive immediate assessment and treatment, in consideration that in addition to specific sleep disturbances, other clinical conditions such as pain, depression, and urinary incontinence can disrupt nocturnal sleep.

In a cross-sectional study of 11,400 individuals who identified themselves as having multiple sclerosis, questions were asked using standard validated questionnaires related to primary sleep disorders, sleepiness, fatigue severity, and sleep patterns (15). The authors found that among the completed surveys, 898 (37.8%) screened positive for obstructive sleep apnea, 746 (31.6%) for moderate to severe insomnia, and 866 (36.8%) for restless legs syndrome. In contrast, only 4%, 11%, and 12% of the cohort reported being diagnosed with obstructive sleep apnea, insomnia, and restless legs syndrome, respectively. Based on the Epworth Sleepiness Scale, excessive daytime sleepiness was noted in 30% of respondents, and more than 60% of the respondents reported an abnormal level of fatigue based on the Fatigue Severity Scale. The authors concluded that the vast majority of sleep disorders were undiagnosed in patients with multiple sclerosis and that greater attention to sleep problems in this population is warranted.

Other authors have confirmed the high prevalence of obstructive sleep apnea in patients with multiple sclerosis (12). In a study where 195 multiple sclerosis patients completed a questionnaire comprised of items regarding obstructive sleep apnea diagnosis, sleep quality and quantity, and daytime symptoms, the authors found 41 patients (21%) who carried a formal diagnosis of obstructive sleep apnea. The authors concluded that sleep disturbances, in particular obstructive sleep apnea, may be highly prevalent yet underrecognized contributors to fatigue in patients with multiple sclerosis.

Prevention

Sleep disturbance in multiple sclerosis is multifactorial, involving physical and emotional features (52). Bladder problems, spasticity, depression (52), and periodic limb movements (76) may cause or contribute to sleep disturbance in multiple sclerosis. The human leukocyte antigen DR2 histocompatibility antigen underlies both multiple sclerosis and narcolepsy, providing strong support for a common inheritance (102).

Differential diagnosis

Narcolepsy type 1 and narcolepsy type 2 should be distinguished from other sleep disturbances in patients with multiple sclerosis. Fatigue is a common symptom in multiple sclerosis that may be confused with or contribute to disordered sleep. A variety of underlying physical and emotional factors (bladder problems, spasticity, muscle spasms, periodic leg movements, depression, and anxiety) that converge to disturb nocturnal sleep in patients with multiple sclerosis should be considered. Excessive daytime somnolence in multiple sclerosis may be secondary to nocturnal disruption and nonrestorative sleep, likely amenable to proper management.

Nocturia refers to the need to pass urine several times overnight. The authors assembled a group of experts to develop practical approaches for assessing and treating nocturia in neurologic disease, including multiple sclerosis, as reported in the article by van Merode and colleagues (93).

Diagnostic workup

Diagnostic criteria for multiple sclerosis serve to identify patients with this condition, whereas polysomnography and multiple sleep latency testing are required to distinguish narcolepsy from other causes of excessive daytime sleepiness. MRI of the brain can exceptionally reveal a plaque of demyelination in the hypothalamic area, as observed in a patient with multiple sclerosis exacerbation who developed acute hypersomnia and had undetectable hypocretin in CSF (39). Nocturnal polysomnography identifies sleep disruption and daytime multiple latency tests measure daytime sleepiness in patients with multiple sclerosis. Narcolepsy is diagnosed when REM sleep with short-onset REM sleep latency (SOREMP) appears in two or more segments of the multiple sleep latency test and the mean onset of daytime sleep demonstrates a latency of eight minutes or less in at least four segments; SOREMP in the nocturnal polysomnogram may substitute for one REM sleep segment during daytime testing (03). Human leukocyte antigen typing demonstrates DR2 positivity in 50% to 60% of multiple sclerosis patients (26). Tools such as the Fatigue Impact Scale and the Fatigue Severity Scale can be used to help clinicians and researchers measure fatigue. The Symptom Management Model can be used to guide healthcare practitioners in the assessment and treatment of fatigue (40).

In a meta-analysis of 13 polysomnographic articles aimed to explore polysomnographically-measured sleep differences between multiple sclerosis and healthy controls, the authors found significant differences (103). Studies revealed reductions in N2 and sleep efficiency, and increases in wake time after sleep onset, periodic limb movement index, and periodic limb movement arousal index in multiple sclerosis patients compared with controls. Although meta-regression analyses showed that some of the heterogeneity was explained by age and daytime sleepiness of multiple sclerosis patients, the authors concluded that polysomnographic abnormalities are present in patients with multiple sclerosis and that a comprehensive polysomnographic assessment of sleep changes in these patients is desirable.

Management

Poor sleep is common in patients with multiple sclerosis, representing an independent predictor of quality of life. Patients with multiple sclerosis who are poor sleepers should receive prompt assessment and treatment. Antidepressant medication has been suggested for the treatment of sleep disorders in multiple sclerosis. Also, amantadine has been proposed for the alleviation of chronic fatigue (76; 49; 101). REM sleep behavior disorder in a patient with multiple sclerosis responded to the administration of clonazepam 0.25 mg at bedtime (90). The safety and efficacy of modafinil was assessed in a single-blind, pilot study involving 72 patients with multiple sclerosis. The results suggested that 200 mg/day of modafinil significantly improved fatigue and was well tolerated by patients (78). However, a double-blind, placebo-controlled, parallel group study of modafinil, up to 400 mg/day, in 115 patients with multiple sclerosis showed no improvement of fatigue. The primary outcome variable was the change of the Modified Fatigue Impact Scale (85). Modafinil had a substantial placebo effect on outcomes such as fatigue, excessive sleepiness, and depression in patients with multiple sclerosis and did not provide any benefit greater than placebo according to a review (50). Similar results were obtained by Möller and colleagues in a study of 121 patients with multiple sclerosis receiving modafinil 200 mg daily (69). The study failed to support modafinil as an effective treatment for fatigue in multiple sclerosis. However, modafinil may be useful when multiple sclerosis fatigue is associated with sleepiness (54). Emerging research indicates that melatonin supplementation may have therapeutic benefits in multiple sclerosis (MS) due to its involvement in anti-inflammatory mechanisms, oxidative stress reduction, and modulation of the gut microbiota (68). Furthermore, melatonin has been linked to the seasonal relapse rate in patients with multiple sclerosis. Melatonin supplementation in individuals with multiple sclerosis may improve quality of life with lower doses. On the other hand, according to Morsali and colleagues, there are insufficient data to support the regular melatonin prescription in multiple sclerosis (70). Few studies, the diversity of the dosage, route, and duration of melatonin administration, and the diversity of assessment tests are limiting factors that lead to unconvincing findings.

In a pilot study, 11 individuals with multiple sclerosis and symptoms of insomnia residing in nine different states participated in six weekly cognitive behavioral therapy (CBT-i) sessions with a trained CBT-i provider via live video (92). The authors assessed insomnia severity, sleep quality, and fatigue severity before and after treatment, as well as other secondary parameters. They concluded that tele-CBTi is feasible and has outcome measures that are similar to those of in-person CBT-i treatment. The final take was that tele-CBTi may increase access to insomnia treatment in individuals with multiple sclerosis.

The results of an open trial revealed that medical treatment of sleep disorders may improve multiple sclerosis-related fatigue when patients adhere to treatment recommendations (94). A similar conclusion was reached in a controlled, nonrandomized clinical treatment study of 62 multiple sclerosis patients (22). Subjects completed standardized questionnaires including the Fatigue Severity Scale (FSS), Multidimensional Fatigue Inventory (MFI), Epworth Sleepiness Scale (ESS), and Pittsburgh Sleep Quality Index (PSQI), and underwent polysomnography (PSG). FSS and MFI general and mental fatigue scores improved significantly from baseline to follow-up in treated patients (p< 0.03), but not in nontreated patients. ESS and PSQI scores also improved significantly in treated subjects (p< 0.001). Adjusted multivariate analyses confirmed significant effects of sleep disorder treatment on FSS (-0.87, p=0.005), MFI general fatigue score (p=0.034), ESS (p=0.042), and PSQI (p=0.023). The authors concluded that treatment of sleep disorders can improve fatigue and other clinical outcomes in multiple sclerosis.

In one study, CPAP therapy was associated with a significant reduction of Fatigue Severity Scale scores (5.8 ± 0.5 vs. 4.8 ± 0.6, P = 0.04) in patients with multiple sclerosis and obstructive sleep apnea, but the scores remained pathological (≥4.0) in all patients (42). The authors concluded that an investigation should be considered in daily medical practice in multiple sclerosis patients with severe fatigue obstructive sleep apnea because sleep-related respiratory disturbance is high, and CPAP therapy reduces fatigue severity. In another study, among patients with multiple sclerosis, obstructive sleep apnea and sleep disturbance were significantly associated with diminished visual memory, verbal memory, executive function, attention, processing speed, and working memory (10). The authors concluded that effective treatment of sleep apnea could offer new opportunities to improve cognitive functioning in patients with multiple sclerosis.

In a randomized, double-blind trial, 49 multiple sclerosis patients with fatigue, poor subjective sleep quality, and mild to moderate obstructive sleep apnea were treated with fixed or sham CPAP for six months (46). The authors found that in nonsevere sleep apnea patients, CPAP did not significantly improve fatigue at six months, but in secondary analyses, there was a significant reduction in somnolence with CPAP applications at three months.

In another study, participants were offered treatment with CPAP and participation in an open label study (62). Twenty-eight of 34 (82%) completers participated in this study for a mean of 2.7 years, and 16 (57%) patients were treated with CPAP (mean use 5.4 ± 1.0 h/night. The following scales were used: Fatigue Scale for Motor and Cognitive Functions (p = 0.008, p = 0.012), Pittsburgh Sleep Quality Index (p = 0.016), Center of Epidemiological Studies-Depression Scale (p = 0.05), and Multiple Sclerosis Quality of Life-54 (MSQOL-54) physical and mental component scores (p = 0.012, p = 0.023). There were no improvements in Epworth Sleepiness Scale. The authors concluded that long-term CPAP use was associated with improved fatigue and physical quality of life in multiple sclerosis patients with obstructive sleep apnea-hypopnea.

Three patients with multiple sclerosis and moderate to severe complaints of bruxism in the two weeks following multiple sclerosis attacks responded favorably to botulinum toxin (Btx) injections applied to masseter and temporalis muscles. None of the three patients had a diagnosis of bruxism prior to the multiple sclerosis attack. All three patients presented with morning headaches and jaw pain or tightness (82).

Few studies have specifically addressed the impact of drugs on the sleep of multiple sclerosis patients. Interferon-beta and some symptomatic medications may affect sleep contributing to fatigue, depression, and poor quality of life (51); natalizumab and cannabinoids may improve sleep (14). In one study patients underwent PSG and MSLT before their first natalizumab infusion and after their seventh (80). The Modified Fatigue Impact Scale, Fatigue Severity Scale (FSS), Epworth Sleepiness Scale (ESS), and visual analogue scale for fatigue (VAS-F) were completed at the first, fourth, and seventh natalizumab infusions. Cognitive tests and the Hospital Anxiety and Depression Scale were performed at the first and seventh infusions. Treatment with natalizumab was associated with improvements in fatigue, sleepiness, and mood, but changes in objective measures of sleep were not significant.

Twenty-three participants with multiple sclerosis and significant fatigue were enrolled in one study (63). All participants underwent overnight polysomnography to assess for possible obstructive sleep apnea and cognitive tests. Cognitive and fatigue measures were repeated in those subsequently treated for obstructive sleep apnea and in a control group. Seven participants (30%) were diagnosed with obstructive sleep apnea (AHI> 5/hr). Verbal learning at follow-up assessment had improved significantly in those treated for obstructive sleep apnea, compared with the untreated control group. The study suggests a favorable outcome in verbal learning in people with multiple sclerosis when co-morbid obstructive sleep apnea is treated.

In a retrospective medical record review of 141 patients with multiple sclerosis, patients experienced significant symptom improvement after initiation of medical cannabis administration (77). There was alleviation of pain (72% of patients) and spasticity (48% of patients), and improvement in sleep (40% of patients). In many patients, medical cannabis was well tolerated.