Amyotrophic Lateral Sclerosis is a neurodegenerative disease, mostly due to progressive loss of motor neurons, with poor prognosis. Although motor involvement is predominant, other systems may be altered, and, among these, also sleep. The aim of this study is to evaluate sleep in a cohort of patients affected by ALS. We consecutively enrolled 48 patients, whom underwent to clinical and instrumental evaluation, including a full night video-PSG. They were compared to 15 control subjects. Respect to controls, patients had fragmented sleep, with poor sleep efficiency, higher amount of WASO and N1 sleep stage, and lower percentage of N2 and REM sleep stages, despite they perceived a sleep of good quality. Moreover, 33% of patients underwent video-PSG was diagnosed with OSAS, and 14, 28% with nocturnal respiratory insufficiency. Start NIV early is known to raise QOL, prolong life expectancy, and improve compliance to subsequent 24h NIV and tracheal ventilation. Furthermore, sleep of bad quality is a cardiovascular risk factor. In conclusion, in patients with ALS, instrumental assessment of sleep in early stages of the disease should be mandatory.

Congiu P, Tamburrino L, Milioli G, Borghero G, Puligheddu M (2018) Sleep, Sleep Structure and Sleep Disorders in a Cohort of Patients Affected by ALS. Ann Community Med Pract 4(1): 1028.

•    ALS
•    Amyotrophic lateral sclerosis
•    Sleep
•    Sleep disorders
•    Polysomnography

AASM: American Academy of Sleep Medicine; AHI: Apnea-Hypopnea Index; ALS: Amyotrophic Lateral Sclerosis; ALS-FRS: Amyotrophic Lateral Sclerosis-Functional Rating Scale; ALSSS: Amyotrophic Lateral Sclerosis Severity Scale; BQ: Berlin Questionnaire; CBT: Cognitive-Behavior Therapy; ESS: Epworth Sleepiness Scale; FVC: Forced Vital Capacity; FTD: Fronto-Temporal Dementia; IRLSSS: International Restless Legs Syndrome Severity Scale; NIV: Not-Invasive Ventilation; ODI: Oxygen Desaturation Index; OSAS: Obstructive Sleep Apnea Syndrome; PLMS: Periodic Limb Movement during Sleep; PSG: Polysomnography; PSQI: Pittsburgh Sleep Questionnaire Index; QoL: Quality of Life; RBDSQ: REM sleep Behavior Disorder Screening Questionnaire; RLS: Restless Legs Syndrome; SE: Sleep Efficiency; SL: Sleep Latency; TST: Total Sleep Time; WASO: Wakefulness After Sleep Onset

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s Disease or Charcot’s Disease, is an adult-onset progressive and fatal neurodegenerative disease, characterized by progressive loss of cortical, bulbar, and spinal motor neurons with consequent painless paralysis of striatal skeletal muscle, dysphagia, dysarthria and respiratory impairment, up to respiratory failure, that is the most common cause of death in ALS, that usually occurs within 3 years after disease onset. So far there is no effective treatment for ALS, and prognosis is always lethal [1-4].

Although motor involvement in ALS is predominant, other systems may be affected [5], and patients often complaint of disturbed sleep. Fragmented sleep and sleep disorders may be early manifestations of ALS [6-8]. Particular attention has been given mostly to sleep disordered breathing, chronic nocturnal respiratory insufficiency and hypoventilation [9] that commonly anticipates the awake respiratory failure, because of the physiologic vulnerability of respiration during sleep; moreover the role of NIV in increasing survival in ALS patients is well known [6-9].

In fact, almost all patients develop respiratory failure during the course of their illness(10), and Miller and colleagues in a evidence-based review published in 2009 [10] indicated that nocturnal desaturations <90% for 1 cumulative minute is a sensitive indicator of early respiratory insufficiency, and that nocturnal oximetry correlates with survival (mean O2 saturation <93 mmHg is associated with mean survival of 7 months vs 18 months when mean O2 saturation is >93 mmHg), and they recommended to consider nocturnal oximetry to detect hypoventilation. They indicated early intervention with NIV as probably effective in prolonging life expectancy, in slowing the decline of FVC and useful in raise quality of life. Moreover, consideration of starting NIV at the earliest sign of nocturnal hypoventilation or respiratory insufficiency may improve compliance for subsequent diurnal NIV and tracheal ventilation [10].

The aim of this study was to investigate sleep characteristics and any sleep disorder in a cohort of Sardinian patients affected by ALS. Sardinian patients affected by ALS present in a very high percentage, a genetic predisposition to develop the disease that is higher than in other Caucasian population, with exception of Scandinavian. Infact, it has been showed by Borghero et colleagues that Sardinian patients affected by ALS carry a mutation of a ALS-related gene in more than 40% of cases; moreover >10% of Sardinian patients without a known mutation showed a familial positive history of ALS or FTD, indicating the possibility of involvement of other new genes [11,12].

We consecutively enrolled 48 patients affected by ALS (15females, 33 males; mean age 62, 44 years, 11,21 SD), referred to Sleep Disorders Center – University of Cagliari. Diagnosis of definite or probable ALS was made according to the EL-Escorial WFN revised criteria(13,14) at the ALS outpatient service – AOU of Cagliari.

Exclusion criteria were: age < 18 years, pregnancy, patients who denied consent, and severity of the disease as to prevent 1 night in the sleep lab room. All selected patients were eligible to be included in the study. The study was approved by ethical committee (approval no. 2013/3205), and all patients provided the informed consent. Each subject underwent to clinical and instrumental examination.

Clinical evaluation

All patients underwent a thorough history, and a complete general and neurological examination. Functional impairment was evaluated with ALS-Functional Rating Scale (ALS-FRS) [15,16] and with ALSSS (ALS severity scale) [17]. Moreover they answered to specific sleep questionnaire, namely Epworth Sleepiness Scale (ESS) [18,19], Berlin Questionnaire (BQ) [20,21] for risk of OSAS [22], Pittsburgh Sleep Quality Index (PSQI) [23,24], REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) [25], and in cases of Restless Legs Syndrome (RLS) [26-29], they answered to International Restless Legs Syndrome Study Group Scale (IRLSSS) questionnaire [30]. Control group consisted of 15 healthy age-matched subjects (7 women and 8 men, mean age 60.4 yrs, 10.35 S.D.), without any complaints of sleep, medical and neurological disturbances or disorders.

Instrumental evaluation

All subjects underwent a full-night video-polysomnography (video-PSG), carried out in a standard sound-attenuated sleep laboratory, according to AASM scoring manual [31]. For recording parameters and details see Puligheddu et al. [32], Sleep stages were blindly scored following standard criteria [31,33] by two clinical neurophysiologists expert in sleep medicine (GM and PC).

Statistical analysis

For statistical analysis Prism 7 for Mac OS X - GraphPad softawere was used. For comparison of data between patients and controls Student’s t test was used for data with Gaussian distribution, Mann-Withney test was used for data without normal distribution. Gaussian distribution of data was evaluated by means of D’Agostino & Pearson Normality test. Correlation between sleep scoring parameters and ALS-FRS score was evaluated by calculating the Pearson correlation coefficient (Pearson’s r). Differences were considered significant when p value were <0.05.

Clinical evaluation

Age and sex of the two groups were not statistically different. Clinical parameters of patients are specified in Table 1. Patients affected by ALS had an average ALS-FRS score of 33.61 ± 8.42, and an average ALSSS score of 30.48 ± 5.43. Mean age at disease onset was 59 years ± 12.40, and mean duration of the disease at time of evaluation was 3.78 years ± 5.34. Five patients had a bulbar type at disease onset; six patients had generalized type at disease onset, while the others had spinal form of ALS at disease onset. Average ESS was below threshold for excessive daytime sleepiness (5.39 ± 3.68), average PSQI was low(8.61 ± 4.43) indicating that patients perceived a good quality sleep, average RBDSQ was 3.98 ± 2.80.Two patients were suspected to have RBD, based on RBDSQ. Two patients, both females, received diagnosis of RLS. None of the patients had cognitive impairment as showed by a comprehensive test battery.

Instrumental evaluation

Sleep parameters for two groups are reported in Table 2. Two patients did not perform video-PSG, despite signed consent, and four patients had a TST<4h, time necessary for reliable cardio respiratory assessment during sleep.

Respect to control subjects, ALS patients showed fragmented sleep with poor sleep efficiency (p<0.0001), increased sleep latency (p=0.0012), reduction of TST (p=0.0025), increased WASO (p=0.0005) and N1 stage of NREM sleep (p<0.0001), and reduced percentage of N2 stage of NREM sleep (p<0.0001) and of REM sleep stage (p=0.0039). One patient had no REM sleep, nine patients had a percentage of REM sleep < 10% of TST, and among these in three it was lower than 4% of TST. There were no statistical differences in percentage of N3 sleep stage between patients and controls. Figure 1 shows three hypnograms with curve of SpO2 of three patients.

Assessment of correlation between sleep scoring parameters, namely TST, SL, SE, WASO%, N1%, N2%, N3%, and REM%, and ALS-FRS score showed a statistically significant positive association between ALS-FRS and percentage of N2 and N3, as the r coefficient was > 0.3 for both N2% and for N3% (respectively p=0.177 and p=0.011). These results indicate that the higher the ALS-FRS score, the higher the percentage of N2 and N3 stages, thus the percentage of both N2 and N3 sleep stages were less in ALS patients with the most severe illness (Table 3 and Figure 2).

Moreover, patients had higher AHI (apnea-hypopnea index) and ODI (Oxygen desaturation index) and they spent more sleep time with SpO2 below 90% respect to controls, which were previously selected with AHI and ODI <5 and mean SpO2 higher than 90%.Five patients were diagnosed with moderate to severe OSAS (11,9%), and 9 with mild OSAS (21,4%). Mean AHI of OSAS patients was (17.34 ± 12.27); mean AHI of all patients was 7.83 ± 10.6).REM-related events were predominant. Average value of mean SpO2 during TST was 94.32% ± 3.17%), mean minimum SpO2 during TST was 84.92% ± 7.29%), and six patients (14, 28%) were diagnosed with nocturnal respiratory failure.

Based on the clinical and polysomnographic diagnosis, the appropriate treatment and follow-up were set. In particular, patients diagnosed with OSAS and/or nocturnal hypoventilation/ respiratory insufficiency were immediately evaluated by pneumologist in order to start the nocturnal NIV, with the aim to raise QOL, prolong life expectancy, and increase compliance to an eventual future diurnal NIV.

How concern PLMS, although they have been previously reported to be increased in ALS patients [34-36], in a previous work [32], in which we performed a much more detailed analysis of motor activity during sleep [37-39], we did not find any differences between a population of ALS patients and control subjects. We concluded that the association between RLS, PLMS and ALS might be due to the most frequent emergence of RLS/PLMS and also of ALS in advanced age [40-42], and the discrepancy in findings might be due to the different methods of detecting PLMS [32].

Table 1: Clinical parameters of ALS patients (n=48; 15 females, 33 males).

Table 2: Sleep scoring parameters of ALS patients and control subjects.

Table 3: Correlation between sleep scoring parameters and severity of disease based on ALS-FRS score, by means of Pearson’s correlation].

Sleep in patients affected by ALS may be affected by many disorders, such as immobility, nocturnal cramps, excessive salivation with ineffective cough, circadian rhythm alterations, nocturnal hypoxia and hypoventilation [6]. Moreover also sleep disorders may affects sleep in these patients, namely RLS [40], PLMS [34-36,41] and RBD [41-44], that, as we discussed in a previous paper [32], may be a casual association due to the most frequent emergence of all these disorders in advanced age.

Results of this study confirm that sleep in patients affected by ALS is altered, with deeply disrupted sleep structure, characterized by lower TST, and SE, and higher SL, increased percentage of N1 sleep stage and of WASO, and reduced percentage of N2 and REM sleep stages. We could hypothesize that reduction up to absence of REM sleep may be a “protective” central mechanism against phasic desaturation and hypoventilation, as also shown by Arnulf [34]. Moreover, we could speculate that impairment of sleep structure, with reduction of SE, and increase of N1 sleep stage and of WASO, observed since the earliest stages of the disease, may be due to several factors, including sleep breathing disorders. On the other hand, the reduction of percentage of N3, that well-correlates with the severity of the illness, make us speculate that in advanced stages of disease neuro degeneration may involve also structures responsible for regulation of sleep.

Despite this marked alteration of sleep structure with poor sleep efficiency, high sleep fragmentation and increased amount of WASO, sleep is not subjectively perceived as altered as it really is by patients. The discrepancy between perceived sleep quality and objective alteration of sleep structure might be attributed to a possible preclinical cognitive disorder. Furthermore the mutual relationship between sleep and cognitive functions in neurodegenerative disorders like Parkinson’s disease and Alzheimer Disease is well-recognized [6], instead this interconnection has not been described yet in patients affected by ALS, but it is well-recognized that cognitive impairment in ALS is a negative prognostic factor [45].

Moreover, sleep disorders are associated to daytime impairment, excessive daytime sleepiness, easy fatigue, and in these patients, affected by a neurodegenerative disease characterized by exhaustion of motor system, they may exacerbate day and night symptoms, leading to a further reduction in physical strength, and worsening quality of life.

Moreover, sleep disorders, typically sleep breathing disorders, but also sleep fragmentation, and insomnia, especially when associated with reduction of sleep duration [46], represent an independent risk factor for cardiovascular mortality, mostly when sleep reduction and sleep fragmentation are strongly associated [47], as we have observed in our cohort of subjects affected by ALS. Thus, treating sleep fragmentation by using sleep hygiene, cognitive-behavioral (CBT) protocol for insomnia, and eventually any antidepressants with sedative effects (e.g. trazodone, mirtazapine), that improve rapidly sleep quality [48,49], might be helpful in ameliorate SE, with consequent reduction of fatigue and diurnal sleepiness.

Therefore, sleep is often altered in patients affected by ALS, even in early stage of disease, and it worsens with progression of the illness; thus, evaluation of sleep in patients affected by ALS should be mandatory in diagnostic iter, in order to early identify and adequately treat any sleep disorders, especially sleep breathing disorders and early nocturnal hypoventilation, with the final aim of raise quality of life, and eventually prolong life expectancy

Funding: This research was supported by the Regional Council of Sardinia Grant (2015) (M. Puligheddu, P. Congiu) and by Fondazione Banco di Sardegna (2016) (M. Puligheddu, P. Congiu).

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