Dementia is characterized by progressive deterioration of memory and cognition (as assessed by mental status and neuropsychologic testing), followed by language dysfunction, hallucinations, other psychotic features, depression, and sleep disturbances. In the advanced stage of the illness, the patient becomes bedridden, mute, and incontinent. Sleep dysfunction with or without abnormal motor activity during sleep is increasingly recognized in patients with irreversible chronic dementing illness. It has been estimated that approximately 10 % of the adult population over the age of 65 years suffer from some kind of dementing illness. The Delphi study in 2005 [111] estimated that there would be 24.3 million people with dementia in the world in 2001, and this was predicted to rise to 81.1 million by 2040. The same panel of experts in a systematic review and metanalysis in 2013 [112] estimated that 35.6 million people lived with dementia worldwide in 2010 with numbers expected to rise to 115.4 million in 2050. However, the Rotterdam study findings published in 2012 [113] provide an optimistic trend that the age-specific dementia incidence has declined between 1990 and 2005 as the population has lived progressively longer, probably as a result of increased use of treatment to minimize vascular risk factors and increased years of education. This observation was reinforced by recent report of robust evidence provided by Satizabal et al. [114] of declining incidence of dementia over three decades in the Framingham Heart Study participants. AD is the most common cause of chronic dementia, accounting for at least 60 % of all cases. Other conditions include DLBD, accounting for at least 15–20 % of the cases; PD with dementia and frontotemporal dementia (FTD) in about 10 %; and corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), multi-infarct or vascular dementia, Huntington’s disease (HD), Creutzfeldt–Jakob disease (CJD), and FFI (described later in the chapter), accounting for the rest of the cases.

Dementia can be classified according to location or according to molecular neurobiologic abnormalities (Box 41.1). In terms of location, dementia is classified into cortical dementia, consisting of AD, FTD, and vascular dementia; subcortical dementia, consisting of PD with dementia, PSP, and HD; and mixed cortical-subcortical dementia, including DLBD, CBD, CJD, and FFI. Most of the degenerative dementing illnesses are proteinopathies due to excessive protein misfolding and intracellular protein aggregation [108]. They are mainly classified into tauopathies, synucleinopathies, prion diseases, and polyglutamine disease. Tau proteins belong to the family of microtubule-associated proteins involved in maintaining the cell shape and serve as tracts for axon transport. The main tauopathies include AD, PSP, CBD, argyrophilic grain disease, Pick’s disease, and FTD with parkinsonism associated with chromosome 17. Alpha-synuclein is a presynaptic protein that helps transport dopamine-laden vessels from the cell body to the synaptic cleft. Synucleinopathies are a group of disorders with abnormal deposition of α-synuclein in the cytoplasm of neurons or glial cells and extracellular deposits of amyloid. The main synucleinopathies include PD, DLBD, and MSA, including Shy–Drager syndrome, striatonigral degeneration, and sporadic olivopontocerebellar atrophy.

Sleep disruption and sleep complaints resulting from sleep-related breathing dysrhythmias have been reported in many patients with cerebral hemispheric stroke. Sleep apnea, snoring, and stroke are intimately related. Sleep apnea may predispose to stroke, and stroke may predispose to sleep apnea. There is increasing evidence based on case-control, epidemiologic, and laboratory studies that snoring and sleep apnea are risk factors for stroke. Confounding variables that are common risk factors for snoring, sleep apnea, and stroke (e.g., hypertension, cardiac disease, age, body mass index [BMI], smoking, and alcohol consumption) should be considered when attempting to establish relationships among snoring, sleep apnea, and stroke. A history of habitual snoring (established through questionnaire studies and interviews with a bed partner or other family members) is a clear risk factor for stroke. There is an increased frequency of sleep apnea in both infratentorial and supratentorial strokes. Sleep apnea may adversely affect the short-term and long-term outcomes in patients with stroke in terms of both morbidity and mortality. It is important to make the diagnosis of sleep apnea in stroke patients, as there is effective treatment for sleep apnea that can decrease the risk of future stroke.

Case-control and epidemiologic studies have established an association between hypertension and habitual snoring [219–222] and between habitual snoring and stroke [223–227]. The prospective study by Koskenvuo et al. [222], adjusting for other risk factors, found that habitual snorers have a significantly increased risk of new stroke or ischemic heart disease. Neau et al. [228] also found a significantly increased adjusted risk of stroke in habitual snorers. Spriggs et al. [229] found that in addition to increasing the risk for stroke, snoring adversely affected the prognosis after a stroke. In a prospective study, Bassetti et al. [230] used PSG to determine the frequency of habitual snoring and sleep apnea in 36 of 59 subjects within 12 days of acute hemispheric stroke or transient ischemic attack (TIA) and in 19 age- and sex-matched controls. Habitual snoring was reported in 58 % of patients with TIA or stroke, in addition to an increased frequency of sleep apnea in patients with TIA and acute stroke.

There is considerable evidence based on several recent large epidemiologic and many case-control studies showing an independent association between obstructive sleep apnea syndrome (OSAS) and stroke. Sleep apnea has been found in up to 72 % of patients with stroke. The pathogenesis is not clearly known, and most likely is multifactorial, involving sympathetic nervous system hyperactivity, activation of inflammatory molecular pathways, endothelial dysfunction, metabolic dysregulation, abnormal coagulation, dyslipidemia, and insulin resistance [231]. There are several well-established risk factors for the development of stroke, including arterial hypertension, cardiac disease, diabetes mellitus, smoking, and dyslipidemia. Although the evidence of association between OSAS and stroke is strong based on mainly cross-sectional, case-control, and some limited longitudinal studies, large-scale collaborative studies including patients with OSA controlled adequately for potential confounders are needed to evaluate the relationship between OSAS and stroke and the potential interactions between different basic mechanisms (Fig. 41.15). The Sleep Heart Health Study [232] is a cross-sectional study including a sample of 6424 individuals who underwent unattended overnight PSG at home. Sleep apnea was significantly associated with the development of stroke, coronary artery disease, and congestive cardiac failure independent of known cardiovascular risk factors.

As part of the Sleep Heart Health Study in a later report, Redline et al. [233] followed 5422 community-based subjects without stroke for a median of 8.7 years and reported in 2010 that 193 developed ischemic stroke with a significant positive association with AHI in men. Stroke risk was estimated to increase by 6 % for each one-unit increase in AHI in men with mild-to-moderate sleep apnea.

A higher prevalence of OSA has also been shown in patients with TIAs compared with controls by Bassetti and Aldrich [234]. Cross-sectional studies, however, cannot make a definite conclusion about the cause-and-effect relationship, and therefore, prospective longitudinal studies are needed. A prospective cohort study of patients admitted for stroke or TIA by Parra et al. [235] demonstrated a higher prevalence of OSA than in the general population. However, this was contradicted in a small case-control study involving 86 patients with TIA matched for age and sex with controls that showed no significant difference in the severity or prevalence of OSAS between the two groups [236]. A study by Wierzbicka et al. [237] involving 43 patients found a high prevalence of sleep apnea in patients with acute stroke and TIA. The authors suggested that overnight screening for SDB should be routinely performed in every patient admitted with stroke or ischemic attack. Grigg-Damberger [238], in a review article, made a similar suggestion and noted that such screening and treatment for OSAS should be incorporated into stroke prevention programs.

In an important observational cohort study, Yaggi et al. [239] performed PSG in 1022 consecutive patients enrolled in the study and verified subsequent events such as strokes and deaths. Proportional hazards analysis was used to determine the independent effect of OSAS on the composite outcome of stroke or death. At baseline, 697 patients (68 %) had a mean AHI of 35 as compared with 2 in controls. After a median follow-up period of 3.4 years, the OSAS syndrome was associated with stroke or death from any cause with a hazard ratio of 2.24. After adjusting for age, sex, smoking habits, alcohol consumption, BMI, and the presence or absence of diabetes mellitus, hyperlipidemia, atrial fibrillation, and hypertension, OSAS retained its statistically significant association with stroke or death with a hazard ratio of 1.97. The authors concluded that OSAS significantly increases the risk of stroke or death from any cause and the increase is independent of other risk factors. Several other studies confirmed an independent association between OSAS and stroke [240–244]. Harbison et al. [240] performed a prospective, uncontrolled observational study at week 2 and a repeat study in 50 patients at weeks 6–9 following stroke-utilizing sleep studies, modified ranking score, Barthel score, Scandinavian Neurological Stroke Scale, and ESS score. They concluded that SDB improved in the first 6–9 weeks following stroke but remained highly prevalent. They made a surprising observation of the presence of SDB in patients with lacunar stroke. Marin et al. [241] did an observational study to compare the incidence of fatal and nonfatal cardiovascular events, including stroke, in simple snorers. They included patients with untreated OSAS, patients treated with CPAP titration, and healthy men recruited from the general population. The subjects were followed up at least once a year for a minimum of 10.1 years, and CPAP adherence was checked with a built-in meter. The study included 264 healthy men, 377 simple snorers, 403 patients with untreated mild-to-moderate OSAS, 235 with untreated severe disease, and 372 with the disease who were treated with CPAP. They found that patients with untreated severe disease had a higher incidence of both fatal cardiovascular events (deaths from myocardial infarction or stroke) and nonfatal cardiovascular events than did untreated patients with mild-to-moderate disease, simple snorers, patients treated with CPAP, and healthy participants. The authors concluded that in men, severe OSAS significantly increased the risk of fatal and nonfatal cardiovascular events and CPAP treatment reduced this risk. Munoz et al. [242]. performed a prospective 6-year longitudinal population-based study in subjects aged 70–100 years. After adjustment for confounding factors, the authors confirmed that patients with severe OSAS at baseline had an increased risk of developing stroke independent of known confounding factors. Artz et al. [243] also demonstrated after a cross-sectional longitudinal analysis of subjects from the general population that there was a strong association between moderate-to-severe SDB and prevalence of stroke independent of the confounding factors. These authors also provided the first prospective evidence that SDB preceded stroke and may contribute to the development of stroke. In a prospective 10-year follow-up study, Sahlin et al. [244] obtained overnight sleep recordings at a mean of 23 days after the onset of stroke in 132 patients. They found that the risk of death was higher among the 23 patients with obstructive apnea (AHI ≥ 15) than controls (AHI < 15), with an adjusted hazard ratio of 1.76 independent of all the confounding factors. There was no difference in mortality between central sleep apnea (CSA) patients and controls.

Several early studies [245–247] evaluated the role of CPAP in the treatment of patients with OSAS and found significant protection against new vascular events after ischemic stroke. Bassetti et al. [247] found a beneficial effect of CPAP in a small percentage of patients. In contrast, after a randomized controlled trial of CPAP in patients with stroke with an AHI of 30 or more, Hsu et al. [248] found no benefit from CPAP treatment. These authors advocated that CPAP treatment should be used for patients with stroke only if there are symptoms of SDB. Similar to the findings of Bassetti et al. [247], Palombani and Guilleminault [249] found that the majority of stroke patients with OSAS rejected CPAP treatment, and they suggested that better education and support of patients and families, and special training sessions, will be needed to improve adherence in such patients.

Obstructive sleep apnea is the most common form of SDB in stroke victims, and the prevalence in stroke patients exceeds the figure quoted for the general population [218, 236, 250–266]. Bassetti et al. [254] suggested that the presence of OSA should be suspected in men and elderly patients with diabetes mellitus and nighttime onset of TIA or stroke. The increased prevalence of OSAS in patients with TIA and stroke suggests that OSAS does not commonly precede but rather follows the onset of cerebrovascular events [255, 256]. It is notable that acute stroke may aggravate preexisting SDB or even may cause it de novo [255]. Improvement of SDB often occurs in the recovery phase after stroke [254, 256].

Mansukhani et al. [260] from Mayo Clinic in a prospective cohort study included 174 consecutive patients with acute ischemic stroke. Using Berlin Sleep Questionnaire, they identified 105 patients (60.4 %) with a high risk for OSA and seven patients (4 %) with a previous diagnosis of OSA. They found that those with a previous diagnosis of OSA were more likely to die within the first month after stroke and had worse functional outcome. Such comorbid OSA and stroke causing poor functional outcome [252, 257, 261] and increased poststroke mortality [231, 234] had been observed by earlier investigators.

In an important meta-analysis of 29 articles (2343 patients), Johnson and Johnson [262] observed that the percentage of stroke and TIA patients with OSA is up to 72 % (with an AHI of 5 or more) and up to 63 % (with an AHI of 10 or more), and the type of apnea is primarily obstructive (only 7 % had central apnea). They also made the following important observations: Comorbid OSA and stroke are more common in men than women and in older than younger subjects; nocturia may be a predictor and recurrent stroke may be an indicator.

In a recent review of stroke and sleep apnea, Davis et al. [263] cautioned that we may be neglecting a modifiable stroke risk factor. They provide evidence that sleep apnea is an important but under-recognized risk factor for incident and recurrent stroke which may adversely affect stroke recovery and that CPAP titration improves functional outcome after stroke. The authors further state that several preliminary randomized trials of CPAP therapy after stroke suggest diagnosing OSA in stroke patients may be best accomplished with portable devices, but these are less sensitive and specific for the diagnosis of OSA than a formal in-laboratory polysomnography (PSG). Many preliminary randomized trials of CPAP therapy for SDB in stroke patients have shown improvement in stroke scales, motor recovery, symptoms of sleepiness, and depression, but some randomized trials have shown no difference in outcome [249]. Despite inconsistencies, Davis et al. [263] made the following important conclusions regarding CPAP therapy for sleep apnea in stroke: Increased CPAP adherence improves stroke recovery, but adherence remains a problem because of advancing age, severity of stroke causing facial paralysis, dysphasia, and impaired cognition [249, 254, 263–267]. However, better selection, patient education, and early CPAP treatment during hospitalization or as soon as the patient can tolerate may improve increasing adherence and treatment benefit.

In addition to OSA, patients with stroke may have central sleep apnea (CSA), including central periodic breathing and CSB Figure (Fig. 41.16) [268–272]. CSA and CSB may persist in 6–29 % of stroke patients and may adversely affect the recovery [252]. Nopmaneejumrusler et al. [272] suggested that in patients with stroke, CSA and Cheyne–Stokes respirations are associated with hypocapnia and occult left ventricular systolic dysfunction but are not related to the location or type of stroke. Hermann et al. [271] found central periodic breathing during sleep in 3 of 31 patients with first-ever stroke in the absence of cardiopulmonary dysfunction. They assessed the patients using PSG, MRI of the brain, and echocardiography. They concluded that central periodic breathing during sleep may be present in strokes involving the autonomic (insular) and volitional (cingulate and thalamus) respiratory networks and that breathing improved in all patients during stroke recovery. Bonnin-Vilaplana et al. [268] described CSB in patients with first-ever lacunar stroke. In a recent retrospective analysis of adaptive servoventilation (ASV) treatment for persistent CSA in postacute ischemic stroke patients without concomitant congestive cardiac failure, Brill et al. [269] observed that ASV was well tolerated and clinically effective in these patients.

Some studies have addressed circadian variations of stroke onset. In a study of 53 stroke patients, Kapen et al. [273] confirmed their previous reports of prevalence for the onset of stroke in the morning during a 6-hour period after awakening from sleep. This is similar to the peak incidence in the morning hours for myocardial infarction and sudden cardiac death. All of these conditions may be aggravated by a combination of circadian increase of corticosteroids and catecholamines, increased blood pressure and heart rate in the morning, and increased platelet “aggregability.” (Normal subjects exhibit increased platelet aggregability in the early morning [274]. In several other studies, the incidence of stroke was highest during sleep at night [275] or during early morning hours after awakening from nocturnal sleep [276, 277]. In order to investigate circadian variations in situations at stroke onset, Omama et al. [278] analyzed 12,957 cases of first-ever stroke onset diagnosed from the Iowa Stroke Registry between 1991 and 1996 by CT or MRI of the brain. They noted that patients who had cerebral infarctions showed a bimodal pattern with a higher peak in the morning and a lower peak in the afternoon, whereas intracerebral hemorrhage and subarachnoid hemorrhage patients had the same bimodal pattern but with a lower peak in the morning and a higher peak in the afternoon. The authors concluded that sleep tends to promote ischemic stroke and suppresses hemorrhagic stroke. Another study from Japan [279] found that intracerebral hemorrhage during the sleep period may be more detrimental compared with the intracerebral hemorrhage during awake periods, causing larger hematoma and higher mortality rates.

Freund [296] should probably be credited with the first report of patients with hypersomnolence following paramedian thalamic strokes. Thalamic stroke may cause ipsilateral loss of sleep spindles [297], and bilateral paramedian thalamic infarcts may be associated with hypersomnia [298, 299]. Bassetti et al. [299] evaluated 12 patients with MRI-proven isolated paramedian thalamic stroke and hypersomnia. The patients were evenly divided between groups of severe and mild hypersomnia. Nocturnal PSG findings included increased stage 1 NREM sleep, reduced stage 2 NREM sleep, and a reduced number of sleep spindles. Bassetti et al. [299], however, found intact REM sleep as well as circadian, ultradian, and homeostatic sleep regulation in their patients. The authors concluded that hypersomnia after paramedian thalamic stroke is accompanied by deficient arousal during the day and insufficient spindling and slow-wave sleep production at night. Their observation supported the hypothesis of a dual role of the paramedian thalamus for the maintenance of sleep-wake regulation.

In contrast, Guilleminault et al. [300] reported three patients with pseudohypersomnia and presleep behavior with bilateral paramedian thalamic lesions. These authors used long-term monitoring with an infrared video camera and polygraphic study to document that their patients did not develop the normal NREM cycling during the day; rather, the EEG indicated a mixture of low-amplitude theta and alpha frequency waves during the day, with “sleep-like behavior.” The patients exhibited the behavioral aspects of sleep during the day, suggesting to Guilleminault et al. [300] that these subjects did not present hypersomnia but a “de-arousal” and were left in the transition between wakefulness and sleep. These authors [300] cited a report by Catsman-Berrevoets and von Harskamp [301] of a similar patient with compulsive presleep behavior and apathy due to bilateral thalamic stroke who responded to bromocriptine. There are a few other scattered cases reported of hypersomnolence following bilateral paramedian thalamic infarct [302–306]. Scammell et al. [307] described a narcolepsy-like syndrome with low CSF hypocretin-1 in a 23-year-old man after diencephalic stroke following the removal of a craniopharyngioma. Similar syndrome has been described by Castaigne et al. [298] after paramedian thalamic and midbrain infarcts.

Brain stem glioma with automatic respiratory failure was mentioned by Plum [13]. Ito et al. [342] described two children with brain stem gliomas and sleep apnea. Brain stem tumor may cause disorganization of the tonic and phasic events of REM sleep, as described in a patient whose pontine tumor caused a marked decrease in the atonia of REM sleep [343]. Lee et al. [344] reported a 74-year-old woman with recurrent acoustic neuroma at the cerebellopontine angle presenting as central alveolar hypoventilation. The patient had shallow breathing during sleep and had hypersomnolence during the daytime. Arterial blood gases showed increased Paco ₂ and decreased partial pressure of arterial oxygen (Pao ₂). Tumor resection eliminated hypersomnolence and respiratory failure. A patient seen by the senior author with a medullary tumor that caused severe hypoventilation during sleep required tracheostomy (unpublished observation). The central apneic episodes in the same patient became prolonged when the tracheostomy tube was occluded.

Sleep disturbances are very common in MS and may be seen in over 50 % of patients [398–454]. Surprisingly, there is a lack of adequate evaluation and characterization of such dysfunction in a systematic manner using subjective and objective measures in MS patients. Most MS patients suffer from an unexplained fatigue (see Chap. 42). An important reason for such fatigue may be an unsuspected sleep disorder, such as SDB or insufficient nocturnal sleep. Sleep disturbances in MS may include insomnia, hypersomnia, SDB, narcolepsy, restless legs syndrome (RLS)-PLMS, and RBD [398–454]. We do not know whether such sleep disturbances have an adverse impact on the natural history of MS (Fig. 41.18). Also, we have insufficient knowledge about the effects of treatment of MS with immunomodulating therapies on sleep-wake disturbances (see further on). It is not known whether sleep-wake disorder is related to the severity of the illness as there have not been adequate studies in a large number of MS patients complaining of sleep-wake disorder correlating with Kurtzke’s expanded disability scale score.

In individuals with MS, a demyelinating plaque may involve the hypnogenic and respiratory neurons in the brain stem, giving rise to sleep disturbance and SRBDs. A few such cases have been described in MS patients. An unusual patient, a 38-year-old man who had a clinical diagnosis of acute demyelinating lesion in the cervicomedullary junction, was described by Newsom Davis [398]. The patient had an autonomous breathing pattern, but he could neither take a voluntary breath nor stop breathing, thus illustrating the apparent independence of the mechanisms controlling metabolic and behavioral respiratory control systems. A patient reported by Rizvi et al. [399], whose brain stem dysfunction was consistent with MS, became apneic when asleep but was able to breathe when awake. His hypercapnic and hypoxic ventilatory responses were normal. Boor and associates [400] described a 40-year-old patient with paralysis of automatic respiration. During relaxation, the patient had recurrent apnea, but the breathing was stable when the patient was alert. The discovery at postmortem examination of a large, demyelinating lesion in the central medulla involving the medullary respiratory neurons explained the respiratory failure.

There are other reports of SDB [401–407] in MS, including failure of automatic respiration (Ondine’s curse) [408] with sudden respiratory arrest and nocturnal death, CSA, hypoventilation, and paroxysmal hyperventilation. It is important to consider such a possibility when patients complain of EDS, fatigue, and disturbed sleep associated with snoring. Figures 41.19 and 41.20 show a sample of the hypnogram and overnight PSG recording from a 51-year-old woman with a history of MS showing frequent obstructive, mixed, and central apneas and hypopneas during both NREM and REM sleep associated with mild-to-moderate oxygen desaturation and frequent arousals, as well as REM sleep dysregulation with longer REM sleep in the early part of the night.

In addition to sleep-related breathing abnormalities, other sleep difficulties have been commonly reported in MS patients, including insomnia and EDS [401, 402, 431–435, 440, 441]. Insomnia is the most common sleep problem in MS with an overall prevalence of more than 40 %. Tachibana et al. [431] evaluated 28 consecutive patients with MS, 15 of whom had sleep problems that included difficulty initiating sleep, frequent awakenings, difficulty maintaining sleep, habitual snoring, and nocturia. All-night oximetric study showed sleep-related O₂ desaturation in three patients, two of whom had sleep apnea on PSG investigations. The authors concluded that sleep disturbance in MS is common but poorly recognized. Ferini-Strambi et al. [401] performed PSG studies in 25 MS patients and compared the results with 25 age- and sex-matched controls. They found reduced sleep efficiency with increased awakenings during sleep and an excess of PLMS in patients as compared with the controls. The cross-sectional study of Veauthier et al. [404] quoted 25 % prevalence of insomnia in MS patients, but most other studies in MS did not consider standardized diagnostic criteria confounding a methodological limitation. Sleep disturbance causing repeated arousals and sleep fragmentation is thought to be a contributing factor for MS-related fatigue [402, 436] (see also Chap. 42). An important cause of insomnia in MS is comorbid depression, which has a high prevalence (up to 50 %); it is important to recognize depression as treatment may improve sleep dysfunction and quality of life [417–419, 428, 430, 443–446, 454].

RLS-PLMS has a high prevalence in MS patients and in the general population [420, 435]. RLS-PLMS is an important cause of insomnia in these patients. Manconi et al. [435] studied 156 MS patients using a structured questionnaire and assessing the ESS; about one-third of their subjects satisfied the criteria for RLS. These authors noted that the primary progressive form of MS was more representative of the RLS group, which showed a higher ESS score than those without RLS. In a later multicenter Italian REMS study, Manconi et al. [447] reported that the prevalence of RLS was 19 % in MS and 4.2 % in controls. They identified the following risk factors: older age, longer duration, primary progressive MS form, higher disability, and the presence of leg jerks at sleep onset.

A recent meta-analysis by Schurks and Bussfeld [420] covering 24 studies estimated fourfold higher risk of RLS in MS patients than in those without MS. Manconi and collaborators [421] based on diffusion tensor MRI study suggested that cervical cord damage was a significant risk factor for RLS in MS which agrees with previous suggestion by Hartmann et al. [422]. A disconnection between brain stem and spinal cord due to interruption of ascending or descending pathways from the cervical spinal cord may be provided as an explanation for RLS in these patients [409].

Most patients with MS suffer from an unexplained fatigue (see also Chap. 42). In the studies by Attarian et al. [436], Kaynak et al. [402], and others [415], there is a significant correlation between fatigue and disrupted sleep with sleep fragmentation, alteration of sleep macrostructure and microstructure, poor quality of life, and depression.

Hypersomnolence with low CSF hypocretin-1 levels in primary and secondary narcolepsy [423–425, 438, 449, 450–453] and RBD [439] have also been observed in some MS patients. Plazzi et al. [439] described a 25-year-old woman with MS who presented with RBD as an initial presentation of MS, and this subsequently resolved after treatment with adrenocorticotrophic hormone. No MRI documentation, however, of brain lesions was provided. More recently, Tippmann-Peikert et al. [426] reported a 51-year-old woman with acute MS and RBD showing a large MS plaque (MRI T2 signal) in the dorsal pons similar to the lesion site causing RBD-like behavior in cats. One study [427] estimated prevalence of RBD in MS as 1.4 %.

Treatment of MS with immunomodulating therapies such as interferon and methylprednisolone may cause sleep disturbances in the form of hypersomnolence, increasing fatigue, insomnia, and depression [454, 456]. The newer medications such as glatiramer acetate (Copaxone) or mitoxantrone (Novantrone) have not been found to cause sleep disturbance in MS, but adequate studies have not been undertaken. Insomnia, however, has been reported with laquinimod treatment in MS patients [457]. No specific information is available for natalizumab and fingolimod [409]. There is a report [458] showing that compared with oral baclofen, intrathecal infusion to treat severe spasticity in MS patients improved sleep continuity without affecting respiratory function.

Merlino et al. [440] studied 120 MS patients to assess the prevalence of sleep dysfunction in MS and to evaluate various factors affecting sleep quality and quality-of-life indicators. These authors found poor sleep in 47.5 % of the patients and concluded that poor sleep is an independent predictor of impaired quality of life, directing our attention to assessment and treatment of sleep dysfunction in MS patients to improve the quality of life. They also confirmed significantly higher mean Kurtzke MS disability scores among poor sleepers than among good sleepers, supporting an earlier report by Lobentanz et al. [446] but contradicting other reports [431, 432, 439] showing no correlation with these scores.

Hypoventilation syndrome in bulbar poliomyelitis was first documented quantitatively by Sarnoff et al. [459]. They described four patients who could breathe voluntarily on command but hypoventilated during periods of sleep and quiescence. The authors described irregular rate and rhythm of respiration, incoordination of the muscles of respiration, and hypoventilation resulting from decreased sensitivity of the respiratory center to Paco ₂ as a result of direct involvement of the respiratory center by the poliomyelitis virus. Two of their patients benefited from electrophrenic respiration.

An extensive report on the clinical and physiologic findings in 20 of 250 poliomyelitis patients with central respiratory disturbances was given by Plum and Swanson [16]. These patients’ respiratory disturbances could not be explained by involvement of the spinal motor neurons or airway obstruction. In acute bulbar poliomyelitis, the disordered breathing progressed through three successive stages. Stage I was characterized by disorder of respiratory rhythm during sleep, when breathing became irregular in rate and depth with periods of apnea ranging from 4 to 12 s. During stage II, normal breathing required increasing effort and concentration, and strong auditory or painful stimuli were necessary to maintain respiratory rhythmicity. At this stage, the patients had impaired chemosensitivity of the central respiratory centers as evidenced by a reduction in ventilation and carbon dioxide retention after O₂ inhalation. Sleep exacerbated the breathing difficulty, and there were longer periods of apnea. The respiratory homeostasis was lost entirely in stage III, and there was no ventilatory responsiveness to reflex, chemical, or other neuronal stimuli. The respiratory pattern was chaotic, with varying periods of apnea. The patients required ventilatory support to maintain respiratory homeostasis. Severe inflammatory changes and small areas of necrosis in the ventrolateral reticular formation of the medulla were noted in two patients on neuropathologic examination.

The breathing abnormalities in this series rarely lasted more than 2 weeks, but two patients had sleep-related irregular respiration that persisted many months after acute poliomyelitis. These two patients also demonstrated impaired hypercapnic ventilatory response and hypoventilation during administration of 100 % O₂. The physiologic abnormalities suggested severe and permanent dysfunction of the medullary respiratory neurons. In several convalescent spinal poliomyelitis patients, the authors also observed subnormal ventilatory response to carbon dioxide with reduction of maximum breathing capacity or vital capacity to less than 50 % of predicted normal values. These findings implied that peripheral mechanisms that cause restriction of chest movements may also contribute to impaired ventilatory response to carbon dioxide.

Post-polio syndrome is manifested clinically by increasing weakness or wasting of the previously affected muscles and by involvement of previously unaffected regions of the body, fatigue, aches and pains, and sometimes symptoms secondary to sleep-related hypoventilation, such as EDS and tiredness [460, 461]. The exact mechanism of post-polio syndrome is not known. Some of the symptoms (e.g., EDS and fatigue) could result from sleep-related hypoventilation or apnea and sleep disturbances [462]. Thus, it is important to be aware of sleep apnea in such patients. This syndrome has been described in patients who had poliomyelitis decades earlier. Guilleminault and Motta [463] reported on five such men who had a history of bulbar poliomyelitis 16 years earlier. All had EDS, and PSG study documented numerous episodes of apneas, which were predominantly central but also mixed and upper airway obstructive types associated with O₂ desaturation. Their longest apneas were seen during REM sleep. It is important to know that these patients resemble those with primary sleep apnea syndrome. Presumably, the lesions in these cases involved the medullary respiratory neurons, and thus, central lesions were responsible for all three types of apneas. The patients’ symptoms improved and daytime somnolence decreased after ventilatory assistance at night.

Steljes et al. [462] performed PSG examinations on 13 post-polio patients, 5 of whom used rocking beds for ventilatory assistance and 8 of whom had no ventilatory assistance. Patients who required ventilatory assistance demonstrated severe sleep disturbances with decreased total sleep time, reduced sleep efficiency, and decreased percentages of stage 2 NREM sleep, slow-wave sleep, and REM sleep, but increased awakenings and percentage of stage 1 NREM sleep. Respiratory abnormalities in these patients consisted of hypoventilation, apneas, and hypopneas associated with significant O₂ desaturation. These patients did not respond to CPAP treatment with the rocking bed, but they showed improvement in sleep structure and respiratory function after mechanical ventilation via nasal mask. Five of the eight patients who required no ventilatory assistance also showed impairment of sleep architecture similar to the other group, but the findings were less severe. All but one patient from the second group had obstructive or mixed apneas, which were treated successfully with nasal CPAP. One patient with mixed apnea and marked hypoventilation improved after treatment with nasal ventilation by mask.

Polysomnographic and pulmonary function studies by Bye et al. [464] and Ellis et al. [465] documented respiratory failure and sleep hypoxemia, particularly during REM sleep, in patients with post-polio respiratory muscle weakness. Sleep studies by Ellis’ group [465] under controlled conditions without respiratory support showed repeated arousals with disruption and fragmentation of the REM-NREM cycle. In a retrospective review of medical records from 108 consecutive patients with post-polio syndrome and sleep disturbances encountered during an 11-year period at the Mayo Clinic, Hsu and Staats [466] reported PSG findings from 35 patients fulfilling the inclusion criteria. All patients had hypersomnolence as the most common presenting symptom, and the authors identified three patterns of sleep disturbances: OSA, hypoventilation, and a combination of both. They concluded that SDB is a late sequela of poliomyelitis. Dean et al. [467] from the National Institutes of Health reported the PSG findings in 10 patients with clinical signs of post-polio syndrome. They noted disruption of sleep architecture due to sleep apnea (both central and obstructive), which was more frequent in patients with bulbar involvement who had more central than obstructive apneas. Bruno [468] reported abnormal movements during sleep studies (e.g., random myoclonus, brief ballistic and slow grasping movements, and PLMS) in seven poliomyelitis survivors. A physiologic study to understand the sequence of events during REM sleep in 13 patients with post-polio syndrome by Siegel et al. [469] from the National Institutes of Health measured latencies to the onset of the first occurrence of muscle tone reduction, the first sawtooth waves, and the first REMs in 13 patients with post-polio syndrome. The latencies for the entire group were longer than those of the normal volunteers, and the latencies for the bulbar group were significantly longer than those for the nonbulbar group of post-polio patients. The authors concluded that prolongation of these latencies may be due to prolonged recruitment time for neurons in the pontine tegmentum as a result of damage from the poliomyelitis virus in the past.

In a more recent report, Marin et al. [470] observed 10 fulfilling the diagnostic criteria for RLS/WED (2 men, 8 women; mean age of 42.5 years) among 35 post-polio patients in the outpatient clinics. They noted a concomitant occurrence of both RLS and post-polio patients suggesting a possible common underlying mechanism for both conditions. This is a small sample without controls, and epidemiologic studies including larger samples are needed to confirm this relationship. Silva et al. [471] in a brief report described some nonspecific sleep architectural changes, increased PLMS, and apnea-hypopnea index in overnight polysomnographic studies obtained from 60 randomly selected post-polio patients. The authors concluded these abnormalities reflected a dysfunction of the surviving motor neurons in the brain stem. There have been no new advances in the management of post-polio patients [472].

Some patients with syringobulbia-myelia may have alveolar hypoventilation and sleep-related apneas or irregular breathing and stridor. Haponik et al. [473] described such a case. The patient was a 35-year-old woman whose polygraphic examination showed 370 upper airway obstructive apneas lasting 10–170 s associated with hypoxemia during 7 h of NREM stages 1 and 2 sleep. The patient died 9 months after the onset of the illness, and neuropathologic examination disclosed a syrinx that extended from the lower third of the medulla to the upper thoracic spinal cord. Nogues et al. [474] studied 30 patients with syringomyelia, including 17 with syringobulbia, using overnight PSG and pulmonary function tests that also included hypercapnic ventilatory response; they found SDB (central, mixed, and obstructive apneas) in 1 of 13 patients with syringomyelia and 13 of 17 patients with syringobulbia. Impaired hypercapnic ventilatory response was noted in patients with syringobulbia. They found that symptoms of dysphagia and dysphonia rather than the size of the cavity on MRI or muscle weakness were predictive of SDB. These authors [475] also reported PLMS during NREM stages 1 and 2 in 16 of 26 patients with syringomyelia and periodic limb movements in wakefulness in three of these patients. The EMG latency delay between the upper and lower limb muscles suggested conduction along slowly conducting propriospinal pathways, indicating spinal cord hyperexcitability similar to the propriospinal propagation of PLMS in some RLS patients [476]. An occasional report [477] of postural tachycardia syndrome (see later) in syringomyelia and cardiovascular autonomic [478] impairment associated with sleep apnea in syringomyelia and syringobulbia suggest involvement of brain stem and spinal autonomic neurons. In a recent review published in 2012, Massimi et al. [479] stated that in the last three decades, only 41 cases of abrupt onset of syringomyelia associated with Chiari malformation type 1, respiratory failure (29 %), and cardiac autonomic dysfunction have been reported.

Cohn and Kuida [480] and White et al. [481] described alveolar hypoventilation, CSA, EDS, and subnormal hypercapnic ventilatory response after western equine encephalitis. The respiratory center was thought to have been damaged by the virus. Iranzo et al. [482] reported six patients with nonparaneoplastic limbic encephalitis associated with antibodies to voltage-gated potassium channels. Five of these patients had RBD associated with the onset of limbic encephalitis and in three of these immunosuppression resulted in the resolution of RBD in parallel with remission of the limbic syndrome. The authors suggested that RBD may be seen in the setting of voltage-gated potassium channel antibody-associated limbic encephalitis, which may be related to an autoimmune-mediated mechanism.

Sleep dysfunction, including total insomnia, NREM and REM parasomnia, has been described in many other types of autoimmune (antibody-mediated) encephalopathies [483–485] (e.g., anti-NMDA-receptor encephalitis and several limbic encephalitis subtypes). Distinctive clinical features including sleep disorders along with neuroimaging and electrophysiologic findings may indicate specific antibody-mediated encephalitis. A novel encephalopathy (a tauopathy) associated with cell surface autoimmunity (IgLON5) causing a novel NREM and REM parasomnia (RBD) with OSA has been recently described [486].

Arnold–Chiari malformation, particularly types I and II, may cause SDB, predominately CSA but also upper airway OSA, and central hypoventilation, including sudden respiratory arrest during sleep or postoperatively [487–489]. A repeat PSG in 6 of 12 patients out of 16 consecutive patients with Arnold Chiari malformation type I showed a decrease in the central apnea index following decompression surgery [490]. In a study by Sergio et al. [491] reporting 103 patients with Arnold–Chiari malformation (36 with type I and 67 with type II), a video-PSG study showed RBD in 23 and SDB in 65 (predominantly with CSA syndrome in 61 of the 65 patients). More recently, PSG documented a high prevalence of sleep apnea (both central and obstructive) in 16 children with Chiari type II [492] and eight out of 22 children with Chiari type I [493] malformations who showed significant improvement of central apneas after surgical decompression. Figures 41.21 and 41.22 show a hypnogram and a 120-second excerpt from a PSG recording from a 52-year-old man with Arnold–Chiari malformation type I. The hypnogram findings suggest REM sleep-related hypoventilation, and the PSG tracing shows obstructive apneas and hypopneas.

In spinal cord disorders, sleep disturbances occur as a result of sleep-related respiratory dysrhythmias causing sleep apneas, hypopneas, or hypoventilation associated with hypoxemia and repeated arousals. The voluntary or behavioral respiratory control system descends via the corticospinal tracts, and the metabolic or automatic respiratory control system descends via the reticulospinal tracts; the two systems are integrated in the spinal cord (see also Chap. 11). The behavioral system is located in the dorsolateral quadrant of the cervical spinal cord [13, 14] and the automatic respiratory system in the ventrolateral quadrant. These two systems control the final common respiratory pathways of the spinal respiratory motor neurons, which send impulses along the phrenic and intercostal nerves to the main respiratory muscles. The anterior horn cells in the third, fourth, and fifth cervical spinal cord segments give rise to phrenic nerves, and the intercostal nerves originate from the ventral rami from the anterior horn cells in the thoracic spinal cord. It is known that transection of either the dorsolateral or the ventrolateral quadrant of the spinal cord may independently affect the voluntary and the automatic respiratory control systems [79]. Most reports, however, refer to transection of the ventrolateral tracts giving rise to dysfunction of the metabolic respiratory control system. Direct involvement of the lower motor respiratory pathways, either in the anterior horn or in the phrenic and intercostal nerves, may also give rise to respiratory dysfunction. Three patterns of respiratory dysfunction have been summarized by Krieger and Rosomoff [494]: (1) efferent motor impairment (e.g., phrenic nerve paralysis causing diaphragmatic weakness) associated with reduced vital capacity, (2) impaired hypercapnic ventilatory response without significant chest wall or diaphragmatic weakness and with normal vital capacity, and (3) a mixture of these two abnormalities. The lesions that cause such dysfunction in the spinal cord may include spinal surgery, spinal trauma, amyotrophic lateral sclerosis (ALS), syringomyelia, cervical spinal cord tumor, and cervical myelitis (demyelinating or nonspecific myelitis).

Several cases of sleep apnea have been described after spinal surgery [494–496]. Krieger and Rosomoff [495] also described sleep apnea after high cervical cordotomy. These authors observed respiratory dysfunction within 24–48 h of bilateral percutaneous cervical cordotomy in 10 patients [494]. Although the authors concluded that the ascending reticular fibers in the ventrolateral segment of the spinal cord that relay afferent impulses to the medullary respiratory center had been damaged in their patients, it is most likely that selective damage to the descending automatic respiratory control fibers in the ventrolateral quadrant of the spinal cord was the lesion responsible. In two other patients, Krieger and Rosomoff [495] described sleep apnea that required assisted ventilation at night for several days after anterior spinal surgery at C3-4 interspace. Lahuerta et al. [496] performed high cervical cord percutaneous cordotomy for pain management in 12 patients, all of whom died during sleep postoperatively, presumably from respiratory dysrhythmia. These patients had lesions involving the anterolateral funiculus in the C2 segment, where respiratory fibers are intermingled with ascending pain fibers. Thus, these reports clearly document Ondine’s curse as a sequela of high cervical spinal cord lesions.

OSA has been described in patients with cervical spine fractures [497] or high spinal cord injury [498, 499]. Guilleminault [500] described eight victims of neck trauma who showed sleep apnea, hypoxemia, and EDS and suggested that mild compression of the lower medulla and upper cervical spinal cord might cause respiratory disturbances during sleep after severe whiplash injury or odontoid fractures. In another report, Stockhammer et al. [501] documented sleep apnea syndrome in 55 % men and 20 % of women in a series of 50 randomly selected patients with tetraplegia resulting from spinal cord injuries. The authors concluded that the incidence of sleep apnea syndrome is high in tetraplegia, especially in older men with large neck circumference and long-standing spinal cord injuries. More recent reports also emphasized a high prevalence of sleep dysfunction and sleep-disordered breathing (SDB) [502–506] in spinal cord injury. Sleep complaints are frequent in spinal cord injury patients and may include difficulty in falling asleep, repeated awakening, impaired sleep quality, increasing use of sleeping medication, snoring, and daytime napping [503, 507]. Proserpio et al. [502] in a prospective observational study evaluated 35 patients with spinal cord injury (15 tetraplegics and 20 paraplegics) within the first year after injury. They noted OSA in nine (25.7 %) and PLMS in 10 (28.6 %) patients. In their patients, the frequency of OSA was higher in tetraplegics than paraplegics, similar to high prevalence of SDB in tetraplegics reported previously by Berlowitz et al. [508]. Another important observation in this study is the high prevalence of OSA after cervical cord injury. Finally, the absence of daytime sleepiness related to OSA in their patients is in line with similar previous observation [505] and that noted in heart failure patients with SDB [507].

There are a few scattered reports of PLMS associated with paraplegia due to spinal cord injury or other spinal cord lesions [509–512]. The authors of these papers concluded that the PLMS resulted from disinhibition of the spinal locomotor generator. It should be noted that the question of the spinal cord as the generator for PLMS remains highly speculative and controversial. In a recent preliminary neurophysiologic study in a subgroup of spinal cord injury patients, Ferri et al. [513] observed a cerebral and autonomic response to leg movements in 45 % of patients with acute spinal cord injury suggesting the potential presence of surviving spinal or extraspinal connections.

Respiratory failure is defined as an inability of the lungs to effectively exchange gas and maintain normal acid-base balance as a result of failure of the respiratory system anywhere from the medullary respiratory controllers to the chest bellows and the lungs, including the upper airways. As a result of this failure, there is reduction in Pao ₂ and increased Paco ₂. A Pao ₂ of less than 60 mm Hg and a Paco ₂ of more than 45 mm Hg at sea levels are commonly considered criteria for respiratory failure. Most neuromuscular disorders cause ventilatory failure, which is defined as inadequate alveolar ventilation with reduced tidal volume causing low Pao ₂ and high Paco ₂.

Respiratory failure in neuromuscular disorders begins during sleep, followed by gradual or relentless progression unless interrupted by ventilatory support at night. A variety of physiologic changes occur in the central control of breathing and in the respiratory muscles during sleep (see Chap. 11) that are responsible for initiating respiratory failure in sleep in patients with neuromuscular disorders. Additionally, there may be a comorbid upper airway obstruction not related to neuromuscular disorders. However, in many of these patients, the upper airway muscles are also affected, causing upper airway OSA. The accessory muscles of respiration maintain breathing during NREM sleep in patients with weakness of the diaphragm, the main muscle of ventilation; however, during REM sleep, there is hypotonia or atonia of these accessory muscles, and ventilation then depends exclusively on the diaphragm. Therefore, in patients with diaphragmatic weakness, ventilation is severely affected during REM sleep, causing REM hypoventilation. This is the first stage of respiratory failure in neuromuscular disorders (Fig. 41.24). As the disease advances to the second stage, the accessory muscles of respiration are affected severely, thus causing ventilatory disturbance during NREM sleep [513, 520]. In the final stage (stage 3) of neuromuscular disorders, ventilation is affected even during the daytime, causing altered blood gases (e.g., hypoxemia and hypercapnia) during wakefulness. Stage 2 of respiratory failure may be related to either progression of the neuromuscular disorder or superimposed intercurrent infection (e.g., pneumonia), or both.

Several authors aimed at identifying daytime predictors of SDB and nocturnal hypoventilation and its onset [521–523]. These authors concluded that progressive ventilatory restriction in neuromuscular diseases correlates with respiratory muscle weakness and can be predicted from daytime lung and respiratory muscle function. Inspiratory vital capacity (IVC) and maximum inspiratory muscle pressure (PI_max) are the two important predictors of the onset of respiratory failure [521, 522]. IVC of less than 60 % and PI_max of less than 4.5 kPa predicted onset of REM hypoventilation, IVC of less than 40 % and PI_max of less than 4.0 kPa predicted both REM and NREM hypoventilation, and IVC of less than 25 % and PI_max of less than 3.5 kPa predicted daytime respiratory failure. However, Lyall et al. [523] and Morgan et al. [524] suggested that the noninvasive maximal sniff pressure measurement is more sensitive than vital capacity and static maximal inspiratory muscle pressure in patients with ALS and in assessing the risk of ventilatory failure. Carratu et al. [525] in a later preliminary study in 31 ALS patients confirmed that maximal sniff nasal inspiratory pressure (SNIP) lower than 60 CMH₂0 may be an early predictor of SDB in ALS. It has also been suggested that a significant fall of vital capacity from the erect to the supine position (70 % or less of the predicted value) indicates the presence of diaphragmatic weakness [526–528]. A fluoroscopy will confirm the weak movement of the dome of the diaphragm during inspiration. A serial blood gas determination is important in detecting impending respiratory failure. It should be remembered that a normal daytime Pao ₂ and Paco ₂ does not exclude REM-related hypoventilation.

In patients with weak respiratory muscles, regardless of cause, the waking breathing difficulties may worsen during sleep. While patients are awake, both voluntary and metabolic respiratory controls are intact and central respiratory neurons increase the rate of firing or recruit additional respiratory neurons to maintain ventilation adequately to drive weak respiratory muscles [91]. During sleep, however, voluntary control is absent and respiration is dependent entirely on the metabolic control system. Respiratory neurons are thus vulnerable during sleep, aggravating the ventilatory problems and causing more severe hypoventilation and even apneas and hypopneas. Functional impairment of the sensitivity of the central respiratory neurons, causing decreased metabolic respiratory control, may also give rise to apnea-hypopnea during both REM and NREM sleep. Oropharyngeal (upper airway) muscle weakness coupled with REM-related hypotonia or atonia of the muscles may contribute to possible upper airway OSA.

In summary, breathing disorders causing sleep-related hypoventilation in neuromuscular disorders may be related to the following factors:

All these factors may lead to ventilatory failure in neuromuscular disorders initially at night in the early stage. As a result of alveolar hypoventilation and ventilation-perfusion mismatching, hypoxemia and hypercapnia occur, giving rise to chronic respiratory failure even during the daytime at an advanced stage of the illness (Fig. 41.24).

The initial approach to clinical diagnosis of acute respiratory failure, as may occur in patients with acute inflammatory demyelinating polyradiculoneuropathies (e.g., Guillain–Barré syndrome) or myasthenic crisis, is quite obvious. Patients may have irregular, rapid, shallow, or periodic breathing, intermittent cessation of breathing, and cyanosis. However, recurrent hypoventilation in neuromuscular disorders may present insidiously and may initially remain asymptomatic [514, 515, 529–531]. A high index of clinical suspicion is needed. Clinical clues include the presence of EDS, nocturnal restlessness, frequent unexplained arousals, daytime fatigue, shortness of breath, orthopnea (breathlessness in supine position), morning headache, intellectual deterioration and failure to thrive and declining school performance in children. Signs of impending cor pulmonale include insomnia, morning lethargy, headache, and unexplained leg edema. Patients with neuromuscular disorders manifesting these clinical features should be investigated to uncover nocturnal hypoventilation in order to prevent adverse consequences of chronic respiratory failure, such as congestive cardiac failure and cardiac arrhythmia. Special attention during physical examination should be paid to uncover bulbar and respiratory muscle weakness, use of accessory muscles of respiration, and paradoxical breathing. Neuromuscular disorders causing SDB, respiratory failure, and sleep disturbance include ALS or motor neuron disease, primary muscle diseases, acute and chronic inflammatory demyelinating polyneuropathies, hereditary sensorimotor neuropathy, phrenic neuropathy, and neuromuscular junctional disorders (Fig. 41.23).

Amyotrophic lateral sclerosis is the most common degenerative disease of the motor neurons in adults, affecting the spinal cord, brain stem, motor cortex, and corticospinal tracts. It is characterized by a progressive degeneration of both upper and lower motor neurons manifesting as a varying combination of lower motor neuron (e.g., muscle weakness, wasting, fasciculation, dysarthria, and dysphagia) and upper motor neuron (e.g., spasticity, hyper-reflexia, and extensor plantar response) signs. The readers are referred to the revised El Escorial and Awaji criteria for diagnosing ALS [532]. ALS can cause profound sleep disturbances associated with EDS as a result of repeated arousals and sleep fragmentation due to nocturnal hypoventilation, recurrent episodes of sleep apnea, hypopnea, hypoxemia, and hypercapnia. Insomnia related to other factors, such as decreased mobility, muscle cramps, anxiety, and difficulty in swallowing, may be present in some patients. SDB in ALS may result from weakness of the upper airway, diaphragmatic, and intercostal muscles due to involvement of the bulbar, phrenic, and intercostal motor neurons. In addition, degeneration of central respiratory neurons may occur, causing central and upper airway OSAs. Generally, respiratory failure in ALS occurs late, but occasionally this may be a presenting feature requiring mechanical ventilation [529, 533]. Diaphragmatic weakness resulting from the degeneration of phrenic neurons is noted frequently in ALS and is mainly responsible for nocturnal hypoventilation, initially during REM sleep [514, 515]. Newsom Davis’ group [534] described eight patients with diaphragmatic paralysis resulting from a variety of motor disorders. One of their patients had Kugelberg–Welander syndrome. The following features may be helpful in the diagnosis of diaphragmatic paralysis:

Sleep-related respiratory dysrhythmia is a common complication of ALS causing central and obstructive sleep apneas, sleep hypoventilation, and respiratory failure associated with daytime hypersomnolence [514, 515, 535–538]. Overnight polygraphic recording documenting both central and upper airway obstructive apneas (Fig. 41.25) associated with severe oxygen desaturation, and alveolar hypoventilation taken from a PSG tracing of one of our (SC) ALS patients is shown here.

Ferguson et al. [535] studied 18 ALS patients with mild-to-severe bulbar muscle involvement and 10 age-matched control subjects. Most patients complained of difficulty initiating and maintaining sleep. All patients and controls had overnight PSG study, and 13 ALS patients had a second night of PSG study. ALS patients had more arousals and stage changes per hour, more stage 1 NREM sleep, and shorter total sleep time than controls. ALS patients had mild SDB with greater AHI than controls. It is notable that SDB was similar in ALS patients with or without respiratory muscle weakness. The SDB consisted of REM-related nonobstructive and central apneas. In an early study, Minz et al. [536] described PSG findings in 12 ALS patients, six men and six women. Four patients had both central and obstructive apneas. Sleep structure was normal in eight, but the others had frequent awakenings.

Howard et al. [537] described 14 patients with motor neuron disease associated with respiratory dysfunction. Eleven received respiratory support, including CPAP and intermittent positive pressure ventilation (IPPV) at night with considerable benefit. In a recent report, Lo Coco et al. [538] studied 100 consecutive ALS patients and 100 age- and sex-matched control subjects using PSQ and ESS as well as overnight PSG in 12 patients and the ALS Functional Rating Scale—Review (ALSFRS-R) in all patients. Fifty-nine percent of patients and 36 % of controls had sleep disturbances. The most common nighttime sleep complaints by patients with ALS included nocturia (54 %), sleep fragmentation (48 %), and nocturnal leg cramps (45 %). PSG showed decreased sleep efficiency and fragmented sleep architecture. These authors demonstrated that ALS patients had significant impairment of quality of sleep which correlated with the severity of illness (reduced ALSFRS-R score), daytime somnolence, ESS score, and depression. This is an important study challenging the clinicians to be aware of sleep-wake problems in ALS patients, because timely intervention could lead to better quality of life for these patients.

There have been several reports focusing on the role of noninvasive IPPV at night on the quality of life and the prognosis (see later in the Sect. “Treatment of Sleep and Respiratory Dysfunction Secondary to Neurologic Disorders”).

The most common type of muscular dystrophy (nonmyotonic) associated with respiratory dysrhythmia-related sleep dysfunction is Duchenne’s muscular dystrophy (DMD) and its variant, Becker muscular dystrophy (BMD). DMD is an x-linked recessive disorder with mutation of the dystrophin gene causing sarcolemmal membrane instability. Dystrophin is absent in DMD but is reduced in BMD. DMD is a relentlessly progressive disorder of muscle weakness, involving initially the pelvifemoral muscles resulting in an inability to stand and walk with confinement to a wheel chair within a few years. Respiratory failure with repeated awakenings at night and EDS occur in the late stage of the disease associated with alveolar hypoventilation and obstructive sleep apnea (OSA). Hypoventilation results from respiratory muscle weakness and scoliosis with restrictive pulmonary deficit, whereas OSA is secondary to upper airway muscle weakness.

Sleep-related respiratory dysrhythmias (both obstructive and central apneas) accompanied by O₂ desaturation and daytime hypersomnolence have been described in many patients with Duchenne’s muscular dystrophy [517, 566–571]. Although respiratory failure is most commonly noted in Duchenne’s muscular dystrophy, sometimes it also occurs in the more advanced stages of Becker’s, limb-girdle, and facioscapulohumeral muscular dystrophies [514, 515, 517].

Smith and associates [567] described 14 patients with Duchenne’s muscular dystrophy who had sleep apneas or hypopneas associated with marked O₂ desaturation. These authors stated that the severity of SDB in Duchenne’s muscular dystrophy could not reliably be ascertained from daytime pulmonary function studies and asserted that sleep studies are essential.

Howard et al. [568] described nocturnal hypoventilation and respiratory failure in 84 patients with primary muscle disorders that included Duchenne’s, Becker’s, limb-girdle, and facioscapulohumeral muscular dystrophies; adult-onset acid maltase deficiency; myotonic dystrophy; polymyositis; congenital myopathies; and rigid spine syndrome. All patients needed ventilatory support in the form of negative or positive pressure ventilation or tracheostomy.

Khan and Heckmatt [569] studied 21 patients aged 13–23 years with Duchenne’s muscular dystrophy and 12 age-matched controls using 2 consecutive nights of PSG. They noted apneas, 60 % of which were obstructive in nature, with hypoxemia in 12 patients. The respiratory care of patients with Duchenne’s muscular dystrophy has been summarized in a consensus statement developed by the American Thoracic Society [534].

In a more recent study, Polat et al. [572] studied 35 children (12 with DMD and 23 controls) using PSG and they noted sleep-wake-related symptoms in 50 % of their patients. In an earlier study [517], similar symptoms were seen in up to 42 % and OSA in 16.6 %. These authors concluded that being wheelchair-bound or having scoliosis did not predict SDB, and so these patients should be investigated with PSG recording because if DMD patients are found to have SDB, treatment with nocturnal noninvasive positive pressure ventilation will improve the quality of life and longevity. In one of the largest studies [573] of 32 children with DMD by Suresh et al., OSA was noted in 31 % and these authors also recommended PSG for wheelchair-bound patients. They noted a bimodal presentation with OSA occurring in the first decade, whereas hypoventilation was seen more commonly in the second decade.

SDB including hypoventilation and OSA has been described in limb-girdle muscular dystrophy [574–576] (several subtypes are described based on distinct molecular abnormalities) and facioscapulohumeral muscular dystrophy [577, 578], the third most common form of muscular dystrophy after DMD and myotonic dystrophy, but not in a systematic manner.

Khan et al. [579] described eight children 6–13 years of age with congenital myopathy, congenital muscular dystrophy, and rigid spine syndromes with respiratory failure. PSG documented nocturnal hypoxemia and severe hypoventilation. Sleep disturbances included repeated awakenings. Sleep complaints and sleep-related periodic respiratory dysrhythmias are also common in other congenital myopathies such as nemaline rod myopathy, centrotubular and central core disease, merosin deficiency myopathy, and congenital muscular dystrophy [579–584]. Most of these present in childhood, but sometimes there is delayed presentation in adulthood [579–581] (see further on).

Dystrophica myotonica, or myotonic dystrophy type 1 (DM1), is an adult-onset, dominantly inherited muscular dystrophy associated with myotonia. DM1 is a multisystem disorder due to a trinucleotide expansion mutation (CTG sequence) on the DMPK gene on chromosome 19, frontal baldness, cataract, endocrinopathy, and neuropsychologic deficit. Benaim and Worster-Drought [585] were most probably the first to describe alveolar hypoventilation in myotonic dystrophy. Alveolar hypoventilation associated with hypoxemia, as well as impaired hypercapnic and hypoxic ventilatory responses, may be present in both the early and the late stages of the illness. Several authors [517, 586–590] performed polygraphic studies that showed central, mixed, and upper airway obstructive sleep apneas, and sleep-onset REM was noted in some patients. The latter finding may have been due to sleep deprivation secondary to sleep-related respiratory disturbances. Two fundamental mechanisms account for the SDB in this illness: (1) weakness and myotonia of the respiratory and upper airway muscles and (2) an inherited abnormality of the central control of ventilation, most likely related to a common generalized membrane abnormality of the muscles and other tissues, including brain stem neurons that regulate breathing and sleep [587–591].

Sleep studies by Bye et al. [464] in four patients with myotonic dystrophy showed REM sleep-related O₂ desaturation and sleep disorganization. Several other authors have described alveolar hypoventilation, daytime somnolence, and periodic breathing in patients with myotonic dystrophy in single case reports and small and large series [517, 587–604].

Begin et al. [599] found a high prevalence of chronic alveolar hypoventilation in a series of 134 patients with myotonic dystrophy. The authors suggested that the central ventilatory control mechanism is abnormal in myotonic dystrophy patients, contributing to chronic alveolar hypoventilation. These authors concluded that the chronic alveolar hypoventilation resulted from a combination of inspiratory muscle weakness and loading. In addition, the presence of EDS suggested reduced central ventilatory drive or sleep apnea in these patients. The clinicopathologic study by Ono et al. [602] of one patient with myotonic dystrophy, alveolar hypoventilation, and hypersomnia supported the hypothesis postulated by Begin et al. [599]. On postmortem examination of this patient, Ono et al. [602] observed significant neuronal loss and gliosis in the midbrain and pontine raphe, as well as the pontomedullary reticular formation.

Park and Radtke [601] reviewed seven patients with myotonic dystrophy referred to their sleep disorder center. All patients had PSG. Five patients were subsequently given an MSLT. Each of the five who had an MSLT showed the evidence of moderate hypersomnia. Three of these five patients had two sleep-onset REM episodes, only one of whom showed the evidence of sleep apnea in the overnight PSG study. Human leukocyte antigen (HLA) typing was negative for DQW2, but DQW1 was present in two patients. The authors reviewed the literature available (they published their own paper in 1995) and found 86 patients, including their seven patients, with myotonic dystrophy who also had hypersomnolence. Ten percent of the reported patients with hypersomnolence had documented alveolar hypoventilation. Respiratory center hypoexcitability or myotonic muscle weakness is thought to be responsible for alveolar hypoventilation. Correction of hypoventilation does not always lead to improvement of EDS [597, 601]. SDB events were noted in 57 % of the reported patients with EDS, and both central and obstructive sleep apneas were observed. The presence of sleep-onset REMs in these patients supported the hypothesis of a primary CNS abnormality as the cause of EDS [601]. EDS in myotonic dystrophy patients often occurs in the absence of sleep apnea [600, 601]. EDS in their patients [601] responded to methylphenidate treatment. Martinez-Rodriguez et al. [603] measured CSF hypocretin-1 levels in six patients with myotonic dystrophy type 1 complaining of excessive daytime sleepiness who were HLA-DQB1*0602 negative and found to have significantly lower hypocretin-1 levels compared to the control values. The authors concluded that the dysfunction of the hypothalamic hypocretin system may be responsible for hypersomnia in myotonic dystrophy type 1. However, other authors [604, 605] did not find low CSF hypocretin levels in DM1 patients.

In summary, SDB including OSA and nocturnal hypoventilation, EDS, and REM sleep dysregulation are frequently noted in DM1 patients. There is reasonable explanation for the mechanism of sleep-related breathing disorder as stated above. However, an explanation for REM sleep dysregulation and EDS is not always obvious. In a case-control study including 40 DM1 patients and 40 controls, Yu et al. [590] observed EDS in 80 % of patients (ESS score was more than 10 in 31.4 %, and MSLT mean latency was less than 8 min in 12.5 %) and one SOREM in the majority of the patients, whereas two or more SOREMs were seen in about one-third of the patients. These authors also found higher REM density in patients than in controls. REM sleep dysregulation with two or more SOREMs or increased REM density in DM1 patients was also noted by Park et al. [601], Martinez-Rodriguez and coinvestigators [603], and Gibbs et al. [606]. It has been suggested that EDS and REM sleep dysregulation in DM1 patients are not necessarily related to SDB but may be due to an intrinsic CNS dysfunction involving sleep-wake-regulating neurons [590, 593, 600, 601, 604, 607].

Sleep disturbances have also been reported in proximal myotonic myopathy (PROMM), also known as myotonic dystrophy type 2 (DM2). PROMM is an autosomal dominant multisystem disorder caused by a CCTG repeat expansion in intron 1 of the zinc finger protein 9 gene (ZNF9), which is differentiated from myotonic dystrophy type 1 by the absence of a chromosome 19 CTG trinucleotide repeat that is associated with type 1 [608, 609].

DM2 has many overlapping clinical features with DM1 such as cataracts, myotonia, cardiomyopathy, autosomal dominant inheritance, diffuse muscle aches and pains, and insulin resistance, but differs from DMI in more proximal distribution of muscle weakness, later onset of the illness, slower progression, and genetic testing. Sleep disturbances including SDB and hypersomnolence have been described in many DMI patients (see above), but a description of sleep problems has been characteristically absent in DM2 until recently. In a brief report, the senior author described sleep disturbances in two sisters, aged 51 and 53, with PROMM [610, 611]. The patients had difficulty initiating sleep, EDS, snoring, frequent awakenings, and movements during sleep. Overnight PSG study showed decreased sleep efficiency, increased number of arousals, and sleep architecture abnormalities. One patient had absent REM sleep, and the other patient had dissociated REM sleep characterized by phasic REM bursts associated with EEG patterns showing sleep spindles and alpha intrusions. These sleep abnormalities in PROMM suggested involvement of the REM-NREM-generating neurons as part of a multisystem membrane disorder. Subsequently, our (SC) group reported more patients with DM2 showing SDB [612] and one with REM behavior disorder [613]. Many other investigators in case series and scattered case reports of DM2 reported a variety of sleep dysfunction including SDB, PLMS, EDS, RLS, and insomnia [614–618]. However, no systematic study involving a large number of DM2 patients with longitudinal follow-up is available. The MRI findings of white matter hyperintensity in T₂-weighted images in six patients from three families with PROMM described by Hund et al. [619] suggested brain involvement in PROMM, but the relationship between the sleep disturbances and the MRI abnormalities remains to be determined.

Alveolar hypoventilation has been described in several cases of mild-to-moderate myopathy associated with adult-onset acid maltase deficiency, a variant of glycogen storage disease, also known as Pompe disease. Pompe disease (or glycogen storage disease type II) is an autosomal recessive, serious, and often fatal disorder of glycogen metabolism. It is due to mutations in the acid alpha-glucosidase (GAA) gene, absence of which causes cardiorespiratory failure in the first year, whereas reduced GAA activity gives rise to progressive respiratory failure later in life [620, 621]. The disease may present in the early stage with diaphragmatic weakness causing hypoventilation, initially during REM sleep and later causing respiratory failure even during the daytime. Presence of macroglossia and significant tongue weakness should direct attention to upper airway dysfunction causing OSA. It is important to make the correct diagnosis early by performing electromyographic (EMG), biochemical, histochemical, or morphological examination of muscle biopsy samples, determination of low GAA activity in skin fibroblasts or blood samples, respiratory function, and genetic testing as specific treatment is now available. The Federal Drug Administration (FDA) in the USA and the European Authority recently approved alglucosidase alfa (recombinant human GAA, Myozyme, Genzyme Corporation, Cambridge, MA, USA) as enzyme replacement therapy (ERT) for the treatment of Pompe disease (biweekly intravenous infusion of 20 mg/kg body weight) [620, 621]. Subsequent clinical data suggest that ERT delays progression of symptoms, but many patients will require additional ventilator support, especially during sleep [620].

Bye et al. [464] described REM sleep-related hypoxemia and sleep disorganization in acid maltase deficiency. An adult patient with acid maltase deficiency with severe OSA and respiratory failure was reported by Margolis et al. [622]. Despite ventilatory support, the patient died. At postmortem examination, profound muscle replacement by fibrofatty tissue was noted in the tongue and diaphragm. The authors suggested that severe tongue weakness due to fatty metamorphosis associated with macroglossia contributed to the upper airway obstruction in this patient. The brain was not examined at the autopsy.

Riley et al. [566] described alveolar hypoventilation in two patients with congenital myopathies (one with nemaline myopathy and the other with a myopathy of uncertain type). The patients’ ventilatory response to carbon dioxide was absent, and the authors suggested that the alveolar hypoventilation may have been due to a primary defect in the central chemoreceptor control of breathing. Their other suggestion was that the sensory stimuli from skeletal muscle receptors (e.g., muscle spindles) may have played a role in the blunted hypercapnic ventilatory response by altering afferent input to the CNS. There are other reports of sleep hypoventilation in congenital myopathy [464, 579, 622– 624].

Obstructive sleep apnea with sleep-related hypoxemia and sleep disturbances have also been described in patients with polymyositis [464, 517, 568, 625] including inclusion body myositis [626] and mitochondrial encephalomyopathy [627–630].

Myasthenia gravis, myasthenic syndrome, botulism, and tick paralysis are several neuromuscular junction disorders characterized by easy fatigability of the muscles, including the bulbar and other respiratory muscles, owing to failure of neuromuscular junctional transmission of the nerve impulses. The most important of these conditions is myasthenia gravis, an autoimmune disease characterized by a reduction in the number of functional acetylcholine receptors in the postjunctional region. Acute respiratory failure is often a dreaded complication of myasthenia gravis, and patients need immediate assisted ventilation for life support [91, 514, 515]. The respiratory failure, moreover, may be mild during wakefulness but may deteriorate considerably during sleep.

An important study by Quera-Salva et al. [631] reported the pulmonary function and PSG studies of 16 women and 4 men whose mean age was 40 years and who were diagnosed and treated for myasthenia gravis. Polysomnographic findings included moderately disturbed nocturnal sleep with an increase in stage 1 NREM and decreased slow-wave and REM sleep. Eleven patients had an RDI of 5 or higher. They had central, obstructive, and mixed apneas and hypopneas accompanied by decreased O₂ saturation. All patients with REM sleep-related apneas or hypopneas had disturbed nocturnal sleep with a sensation of breathlessness. Twelve patients had insufficient sleep owing to awakening in the middle of the night and early morning hours with a sensation of breathlessness. Four of the 12 patients also had daytime hypersomnolence. The authors suggested that those patients of advancing age, moderately increased BMI, abnormal pulmonary function results, and daytime abnormal blood gas concentrations are at particular risk for SDB. Since this report, there have been a few other reports of SDB in patients with myasthenia gravis [632–635].

Manni et al. [632] studied breathing patterns during sleep in 14 patients with mild generalized myasthenia gravis. Polysomnographic study documented infrequent central apneas, mainly during REM sleep, in five patients associated with O₂ desaturation. Putman and Wise [633] described a 54-year-old woman with myasthenia gravis and episodes of shortness of breath, which were more severe at night. The flow-volume loops suggested extrathoracic airway obstruction. They also surveyed a total of 61 myasthenia gravis patients referred to their pulmonary function laboratory during 42 months. They found a pattern of extrathoracic upper airway obstruction in 7 of the 12 patients who had flow-volume loops. Nicolle et al. [634] randomly selected 100 patients with myasthenia gravis out of 400 patients from their database. They found a prevalence of OSA of 36 % based on PSG study in 50 patients compared to an expected prevalence of 15–20 % of the general population. The prevalence of OSAS (those with daytime sleepiness) was 11 % compared to 3 % in the general population. The authors suggested that it is important to inquire about OSA symptoms in myasthenia gravis patients for adequate management of fatigue in these patients. Prudlo et al. [635] investigated sleep and breathing in 19 myasthenia gravis patients utilizing two consecutive overnight PSG studies. These authors found clinically relevant SDB in terms of OSA (defined as an RDI of > 0/h) in only four patients, who had also a few central apneas. The authors failed to confirm the high occurrence of central respiratory events during sleep and also failed to find a causal relationship between medically stable myasthenia gravis and OSA. Thus, some investigators observed more central than obstructive apneas [632], whereas others noted predominantly obstructive apneas. The final answer remains to be determined. Some investigators [636] reported a high prevalence of patient-reported sleep disturbance which was correlated with disease severity, while some other researchers [637] reported a high prevalence of RLS in MG compared with controls.

Fernandes Oliveira and coinvestigators [638] made a meta-analysis of 17 cross-sectional observational or clinical studies assessing the quality of sleep in MG patients published between 1970 and 2014. They found that the literature is limited and the evidence for sleep dysfunction in MG is inconclusive because some studies reported poor sleep quality, EDS, RLS, and SDB in patients with MG, whereas others did not report such associations. The authors recommended further research to investigate sleep dysfunction in MG.

Myasthenic syndrome, or Lambert–Eaton syndrome, is a disorder of the neuromuscular junction in the presynaptic region and is often a paraneoplastic manifestation, mostly of oat cell carcinoma of the lungs. Patients complain of muscle weakness and fatigue involving the limbs accompanied by decreased or absent muscle stretch reflexes and characteristic electrodiagnostic findings that differentiate this from myasthenia gravis. Very few data exist on SDB and sleep dysfunction in Lambert–Eaton myasthenic syndrome.

Botulism caused by Clostridium botulinum and tick paralysis caused by the female wood tick Dermacentor andersonii may also cause neuromuscular junctional transmission defects, which are due to released toxin, and may cause respiratory failure and sleep dysfunction, but adequate studies have not been performed.