Understanding, diagnosing, and treating Myalgic encephalomyelitis/chronic fatigue syndrome - State of the art: Report of the 2nd international meeting at the Charité Fatigue Center.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a devastating disease affecting millions of people worldwide. Due to the 2019 pandemic of coronavirus disease (COVID-19), we are facing a significant increase of ME/CFS prevalence. On May 11th to 12th, 2023, the second international ME/CFS conference of the Charité Fatigue Center was held in Berlin, Germany, focusing on pathomechanisms, diagnosis, and treatment. During the two-day conference, more than 100 researchers from various research fields met on-site and over 700 attendees participated online to discuss the state of the art and novel findings in this field. Key topics from the conference included: the role of the immune system, dysfunction of endothelial and autonomic nervous system, and viral reactivation. Furthermore, there were presentations on innovative diagnostic measures and assessments for this complex disease, cutting-edge treatment approaches, and clinical studies. Despite the increased public attention due to the COVID-19 pandemic, the subsequent rise of Long COVID-19 cases, and the rise of funding opportunities to unravel the pathomechanisms underlying ME/CFS, this severe disease remains highly underresearched. Future adequately funded research efforts are needed to further explore the disease etiology and to identify diagnostic markers and targeted therapies.

Complementary and alternative medicine use in narcolepsy.

BACKGROUND: Management of narcolepsy includes behavior strategies and symptomatic pharmacological treatment. In the general population, complementary and alternative medicine (CAM) use is common in Europe (30%), also in chronic neurological disorders (10-20%). The aim of our study was to evaluate frequency and characteristics of CAM use in German narcolepsy patients. METHODS: Demographic, disease-related data frequency and impact of CAM use were assessed in an online survey. Commonly used CAM treatments were predetermined in a questionnaire based on the National Center for Complementary and Alternative Medicine and included the domains: (1) alternative medical systems; (2) biologically based therapies; (3) energy therapies; (4) mind-body interventions, and (5) manipulative and body-based therapies. RESULTS: We analyzed data from 254 questionnaires. Fifteen percent of participants were at the time of survey administration using CAM for narcolepsy, and an additional 18% of participants reported past use. Among the 33% of CAM users, vitamins/trace elements (54%), homoeopathy (48%) and meditation (39%) were used most frequently. 54% of the users described CAM as helpful. CAM users more frequently described having side effects from their previous medication (p = 0.001), and stated more frequently not to comply with pharmacological treatment than non-CAM users (21% vs. 8%; p = 0.024). DISCUSSION: The use of CAM in narcolepsy patients is common. Our results indicate that many patients still feel the need to improve their symptoms, sleepiness and psychological well-being in particular. Frequent medication change, the experience of adverse events and low adherence to physician-recommended medication appears more frequent in CAM users. The impact of CAM however seems to be limited.

Video-based sleep detection using ocular signals under the standard conditions of the maintenance of wakefulness test in patients with sleep disorders.

OBJECTIVE: Excessive sleepiness is a physiological reaction to sleep deficiency but can also be caused by underlying medical conditions. Detecting sleep is essential in preventing accidents and for medical diagnostics. Polysomnography (PSG) is considered the gold standard for the detection of sleep. More convenient video-based methods for detecting sleepiness have recently emerged. APPROACH: The possibility of detecting sleep using video-based ocular signals will be assessed using PSG for reference. Ocular signals and EEG are recorded in parallel under the conditions of the maintenance of wakefulness test (MWT) in 30 patients with sleep disorders. MAIN RESULTS: In detecting sleep, the ocular signal percentage of eyelid closure (PERCLOS) is superior to other ocular signals, resulting in an area under the curve of 0.88. Using a PERCLOS cutoff value of 0.76, sleep is correctly detected with a sensitivity of 89%, a specificity of 76%, the sleep latency is moderately correlated to the reference (rho = 0.66, p < 0.05) and the 95% confidence interval is ±21.1 min. SIGNIFICANCE: Ocular signals can facilitate the detection of sleep under the conditions of the MWT but sleep detection should not solely rely on ocular signals. If PSG recordings are not practicable or if a signal is needed that responds relatively early in the wake/sleep transition, the use of PERCLOS for the detection of sleep is reasonable.

The Psychomotor Vigilance Test Compared to a Divided Attention Steering Simulation in Patients with Moderate or Severe Obstructive Sleep Apnea.

BACKGROUND: Sleepiness at the wheel affects 10% to 15% of drivers and is one major cause of death on highways with one-third of fatal accidents. Obstructive sleep apnea (OSA) is one of the most common sleep disorders leading to sleepiness at the wheel. The aim of this study was to compare the psychomotor vigilance test reaction time (PVT RT) in OSA patients and controls (morning and afternoon) with the results of a divided attention steering simulator (DASS). A second purpose was to compare these results with the mean sleep latencies in the multiple sleep latency test (MSLT), the Epworth Sleepiness Scale (ESS) values and a neurocognitive test (test of attentional performance, TAP). PATIENTS AND METHODS: Thirty eight OSA patients and 16 age and sex matched healthy controls were investigated by ESS, PVT, TAP, MSLT, and DASS (response time, failed responses, lane deviation, and off-road-events). RESULTS: With increasing age, the performance in the DASS decreased. There was no correlation between the DASS and the results of the MSLT and ESS. The controls showed a significantly faster DASS response time in the morning compared to OSA patients (median 2.1 versus 3.0; p=0.044) and fewer off-road events (9 versus 37; p=0.042). We found a moderate correlation between the PVT RT and all parameters of the DASS, as well as the TAP "alertness" subtest. CONCLUSION: The increase of PVT RT as well as the decreased tonic alertness in the TAP in untreated OSA patients correlated with an impairment of simulated driving performance. The PVT and the TAP are both suitable diagnostic tools for measuring impaired driving ability in OSA patients. The MSLT did not correlate with the simulated driving performance. We recommend investigation of a longer version of the PVT in order to increase its sensitivity.

Comparison of the Oxford Sleep Resistance Test and the Multiple Sleep Latency Test.

OBJECTIVE: The Oxford Sleep Resistance Test (OSLER) consists of four tests over 40 min conducted in a dark and quiet room. If a dim light flashes the patient has to briefly depress a button and then press it again immediately, which indicates that the patient resists sleep. The Maintenance of Wakefulness test (MWT) is another test to assess the ability to maintain wakefulness. Previous studies found a good correlation between the sleep latencies measured with the Osler and the MWT. The most widely used Multiple Sleep Latency Test (MSLT) measures the propensity to fall asleep and not the inability to stay awake. Up to this date there have been no studies comparing the Osler and the MSLT, which is the aim of the study presented here. APPROACH: After a night of polysomnography we investigated the sleep latencies the following day with the Osler and the MSLT in 43 patients suffering from moderate or severe obstructive sleep apnea (OSA) (33 men and 10 women; median age 59 years; median apnea hypopnea index 30.5 per hour sleep). We analysed the correlation between these two tests and between values in the Epworth Sleepiness Scale (ESS) and the Karolinska Sleepiness Scale (KSS) and these two tests. MAIN RESULTS: We did not find a correlation between the Osler and the MSLT nor between these two tests and the questionnaires (ESS, KSS). The only significant correlation was found between the mean MSLT latency and the sleep onset latency in the polysomnography the night before. Seven patients stayed awake during the Osler and showed a decreased mean sleep latency in the MSLT. SIGNIFICANCE: The Osler, the MSLT and the questionnaires measure different objective and subjective aspects of sleepiness. In untreated OSA patients an increased propensity to fall asleep was not automatically associated with the inability to stay awake.

Contactless recording of sleep apnea and periodic leg movements by nocturnal 3-D-video and subsequent visual perceptive computing.

Contactless measurements during the night by a 3-D-camera are less time-consuming in comparison to polysomnography because they do not require sophisticated wiring. However, it is not clear what might be the diagnostic benefit and accuracy of this technology. We investigated 59 persons simultaneously by polysomnography and 3-D-camera and visual perceptive computing (19 patients with restless legs syndrome (RLS), 21 patients with obstructive sleep apnea (OSA), and 19 healthy volunteers). There was a significant correlation between the apnea hypopnea index (AHI) measured by polysomnography and respiratory events measured with the 3-D-camera in OSA patients (r = 0.823; p < 0.001). The receiver operating characteristic curve yielded a sensitivity of 90% for OSA with a specificity of 71.4%. In RLS patients 72.8% of leg movements confirmed by polysomnography could be detected by 3-D-video and a significant moderate correlation was found between PLM measured by polysomnography and by the 3-D-camera (RLS: r = 0.654; p = 0.004). In total, 95.4% of the sleep epochs were correctly classified by the machine learning approach, but only 32.5% of awake epochs. Further studies should investigate, if this technique might be an alternative to home sleep testing in persons with an increased pre-test probability for OSA.

Technology to Detect Driver Sleepiness.

This article reports on sleepiness, drowsiness, tiredness, and fatigue. An assessment of sleepiness can be done with electroencephalograms, electrooculograms, and electromyograms in validated tests, such as the multiple sleep latency test and the maintenance of wakefulness test. These 2 tests serve as references for quantitative assessment of daytime sleepiness and drowsiness. Correlates for sleepiness, such as reaction time tests, can be used but are less reliable. Questionnaires are self-administered and popular measures for perceived sleepiness. Driver drowsiness assessment is an important part of sleep laboratory testing, because European Union regulations require assessments due to risk of accidents in patients with sleep disorders.

Comparison of Apnea Detection Using Oronasal Thermal Airflow Sensor, Nasal Pressure Transducer, Respiratory Inductance Plethysmography and Tracheal Sound Sensor.

STUDY OBJECTIVES: Evaluation of apnea detection using a tracheal sound (TS) sensor during sleep in patients with obstructive sleep apnea. METHODS: Polysomnographic recordings of 32 patients (25 male, mean age 66.7 ± 15.3 years, and mean body mass index 30.1 ± 4.5 kg/m2) were analyzed to compare the detection of apneas by four different methods of airflow signals: oronasal thermal airflow sensor (thermistor), nasal pressure transducer (NP), respiratory inductance plethysmography (RIPsum) and TS. The four used signals were scored randomly and independently from each other according to American Academy of Sleep Medicine rules. Results of apnea detection using NP, RIPsum and TS signals were compared to those obtained by thermistor as a reference signal. RESULTS: The number of apneas detected by the thermistor was 4,167. The number of apneas detected using the NP was 5,416 (+29.97%), using the RIPsum was 2,959 (-29.71%) and using the TS was 5,019 (+20.45%). The kappa statistics (95% confidence interval) were 0.72 (0.71 to 0.74) for TS, 0.69 (0.67 to 0.70) for NP, and 0.57 (0.55 to 0.59) for RIPsum. The sensitivity/specificity (%) with respect to the thermistor were 99.23/69.27, 64.07/93.06 and 96.06/76.07 for the NP, RIPsum and TS respectively. CONCLUSIONS: With the sensor placed properly on the suprasternal notch, tracheal sounds could help detecting apneas that are underscored by the RIPsum and identify apneas that may be overscored by the NP sensor due to mouth breathing. In the absence of thermistor, TS sensors can be used for apnea detection. CLINICAL TRIAL REGISTRATION: Registry: German Clinical Trials Register (DRKS), Title: Using the tracheal sound probe of the polygraph CID102 to detect and differentiate obstructive, central, and mixed sleep apneas in patients with sleep disordered breathing, Identifier: DRKS00012795, URL: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00012795.

Apnea and hypopnea characterization using esophageal pressure, respiratory inductance plethysmography, and suprasternal pressure: a comparative study.

OBJECTIVES: To determine if recording of suprasternal pressure (SSP) can classify apneas and hypopneas as reliably as respiratory inductance plethysmography (RIP) belts and to compare the two methods to classification with esophageal pressure (Pes), the reference method for assessing respiratory effort. METHODS: In addition to polysomnographic recordings that included Pes, SSP was recorded. Recordings from 32 patients (25 males, mean age 66.7 ± 15.3 years, and mean BMI 30.1 ± 4.5 kg/m2) were used to compare the classification of detected apneas and hypopneas by three methods of respiratory effort evaluation (Pes, RIP belts, and SSP). Signals were analyzed randomly and independently from each other. All recordings were analyzed according to AASM guidelines. RESULTS: Using Pes as a reference for apnea characterization, the Cohen kappa (κ) was 0.93 for SSP and 0.87 for the RIP. The sensitivity/specificity of SSP was 97.0%/96.9% for obstructive, 93.9%/98.3% for central, and 94.9%/97.9% for mixed apneas. The sensitivity/specificity of the RIP was 97.4%/91.9% for obstructive, 87.5%/97.9% for central, and 85.6%/96.6% for mixed apneas. For hypopnea characterization using the Pes as a reference, κ was 0.92 for SSP and 0.86 for the RIP. The sensitivity/specificity of SSP was 99.7%/97.6% for obstructive and 97.6%/99.7% for central. The sensitivity/specificity of the RIP was 99.8%/81.1% for obstructive and 81.1%/99.8% for central. CONCLUSIONS: These results confirm the excellent agreement in the detection of respiratory effort between SSP, RIP belts, and Pes signals. Thus, we conclude that apnea and hypopnea characterization in adults with SSP is a reliable method.

The first night effect in multiple sclerosis patients undergoing home-based polysomnography.

BACKGROUND: The first night effect (FNE) is a polysomnography (PSG) habituation effect in the first of several consecutive in-laboratory PSGs (I-PSGs). The FNE is caused by the discomfort provoked by electrodes and cables and the exposure to an unfamiliar environment. A reverse FNE (RFNE) with an improved sleep in the first night is characteristic of insomnia, presumably because the video PSG in the sleep laboratory leads to a decrease in the negatively toned cognitive activity. Therefore, two or more I-PSGs are required for an accurate diagnosis. Although the FNE is well documented in I-PSG, little is known about the FNE and the RFNE in home-based PSGs (H-PSGs). METHODS: This is a retrospective analysis of a recently published cross-sectional study using H-PSG. Sixty-three consecutive patients suffering from multiple sclerosis (MS) were investigated by two consecutive H-PSGs without video. The differences between the first and second H-PSGs were analyzed. The patients were classified into four subgroups: no sleep disorder, insomnia, sleep-related breathing disorders (SRBDs), and periodic limb movement disorder or restless legs syndrome (PLMD/RLS). RESULTS: MS patients suffering from insomnia showed no RFNE. MS patients with SRBD or PLMD/RLS showed no reduced sleep efficiency but significantly less slow wave sleep. Furthermore, SRBD patients showed significantly less non-rapid eye movement (NREM) sleep, and PLMD/RLS patients were significantly awake longer in the first night after sleep onset (increased wake-after-sleep-onset time) and showed a higher rapid eye movement (REM) latency. CONCLUSION: SRBD and PLMD/RLS patients showed a significant FNE. Two consecutive H-PSGs are required in these patients to obtain a precise hypnogram even in the ambulatory field. In MS patients suffering from insomnia, no RFNE was found, and in insomnia patients one H-PSG seems to be sufficient.

The Berlin Treatment Algorithm: recommendations for tailored innovative therapeutic strategies for multiple sclerosis-related fatigue.

More than 80% of multiple sclerosis (MS) patients suffer from fatigue. Despite this, there are few therapeutic options and evidence-based pharmacological treatments are lacking. The associated societal burden is substantial (MS fatigue is a major reason for part-time employment or early retirement), and at least one out of four MS patients view fatigue as the most burdensome symptom of their disease. The mechanisms underlying MS-related fatigue are poorly understood, and objective criteria for distinguishing and evaluating levels of fatigue and tiredness have not yet been developed. A further complication is that both symptoms may also be unspecific indicators of many other diseases (including depression, sleep disorders, anemia, renal failure, liver diseases, chronic obstructive pulmonary disease, drug side effects, recent MS relapses, infections, nocturia, cancer, thyroid hypofunction, lack of physical exercise). This paper reviews current treatment options of MS-related fatigue in order to establish an individualized therapeutic strategy that factors in existing comorbid disorders. To ensure that such a strategy can also be easily and widely implemented, a comprehensive approach is needed, which ideally takes into account all other possible causes and which is moreover cost efficient. Using a diagnostic interview, depressive disorders, sleep disorders and side effects of the medication should be identified and addressed. All MS patients suffering from fatigue should fill out the Modified Fatigue Impact Scale, Epworth Sleepiness Scale, the Beck Depression Inventory (or a similar depression scale), and the Pittsburgh Sleep Quality Index (or the Insomnia Severity Index). In some patients, polygraphic or polysomnographic investigations should be performed. The treatment of underlying sleep disorders, drug therapy with alfacalcidol or fampridine, exercise therapy, and cognitive behavioral therapy-based interventions may be effective against MS-related fatigue. The objectives of this article are to identify the reasons for fatigue in patients suffering from multiple sclerosis and to introduce individually tailored treatment approaches. Moreover, this paper focuses on current knowledge about MS-related fatigue in relation to brain atrophy and lesions, cognition, disease course, and other findings in an attempt to identify future research directions.

Subjective sleep complaints indicate objective sleep problems in psychosomatic patients: a prospective polysomnographic study.

OBJECTIVE: To elucidate the relationship between subjective complaints and polysomnographical parameters in psychosomatic patients. METHOD: A convenience sample of patients from a psychosomatic inpatient unit were classified according to the Pittsburgh Sleep Quality Index (PSQI) as very poor sleepers (PSQI >10, n=80) and good sleepers (PSQI <6, n=19). They then underwent a polysomnography and in the morning rated their previous night's sleep using a published protocol (Deutschen Gesellschaft für Schlafforschung und Schlafmedizin morning protocol [MP]). RESULTS: In the polysomnography, significant differences were found between very poor and good sleepers according to the PSQI with respect to sleep efficiency and time awake after sleep onset. When comparing objective PSG and subjective MP, the polysomnographical sleep onset latency was significantly positively correlated with the corresponding parameters of the MP: the subjective sleep onset latency in minutes and the subjective evaluation of sleep onset latency (very short, short, normal, long, very long) were positively correlated with the sleep latency measured by polysomnography. The polysomnographical time awake after sleep onset (in minutes) was positively correlated with the subjective time awake after sleep onset (in minutes), evaluation of time awake after sleep onset (seldom, normal often), and subjective restfulness. The polysomnographical total sleep time (TST) was positively correlated with the subjective TST. Conversely, the polysomnographical TST was negatively correlated with the evaluation of TST (high polysomnographical TST was correlated with the subjective evaluation of having slept short or normal and vice versa). The polysomnographical sleep efficiency was positively correlated with subjective feeling of current well-being in the morning and subjective TST and negatively with subjective restfulness, subjective sleep onset latency, subjective evaluation of sleep onset latency, and evaluation of time awake after sleep onset. CONCLUSION: The data suggest that, in general, patients selected from the extremes of reported very poor sleepers and good sleepers have different amounts of sleep when measured in the laboratory, and that in general, the amount and timing of sleep in the laboratory are quite well perceived and reported by these groups. The data came from psychosomatic patients and suggest that even in this patient group, respective sleep complaints are more than just the expression of general somatization or lamenting.

Poor Sleep in Multiple Sclerosis Correlates with Beck Depression Inventory Values, but Not with Polysomnographic Data.

Objectives. Pittsburgh Sleep Quality Index (PSQI) values correlate with depression, but studies investigating the relationship between PSQI values and polysomnographic (PSG) data showed inconsistent findings. Methods. Sixty-five consecutive patients with multiple sclerosis (MS) were retrospectively classified as "good sleepers" (GS) (PSQI ≤ 5) and "poor sleepers" (PS) (PSQI > 5). The PSG data and the values of the Visual Analog Scale (VAS) of fatigue, Modified Fatigue Impact Scale (MFIS), Fatigue Severity Scale (FSS), Epworth Sleepiness Scale (ESS), and the Beck Depression Inventory (BDI) were compared. Results. No significant differences were found either for PSG data or for ESS, MFIS, and FSS values; but PS showed significantly increased BDI and VAS values. Conclusions. Poor sleep is associated with increased depression and fatigue scale values.

Periodic limb movements during REM sleep in multiple sclerosis: a previously undescribed entity.

BACKGROUND: There are few studies describing periodic limb movement syndrome (PLMS) in rapid eye movement (REM) sleep in patients with narcolepsy, restless legs syndrome, REM sleep behavior disorder, and spinal cord injury, and to a lesser extent, in insomnia patients and healthy controls, but no published cases in multiple sclerosis (MS). The aim of this study was to investigate PLMS in REM sleep in MS and to analyze whether it is associated with age, sex, disability, and laboratory findings. METHODS: From a study of MS patients originally published in 2011, we retrospectively analyzed periodic limb movements (PLMs) during REM sleep by classifying patients into two subgroups: PLM during REM sleep greater than or equal to ten per hour of REM sleep (n=7) vs less than ten per hour of REM sleep (n=59). A univariate analysis between PLM and disability, age, sex, laboratory findings, and polysomnographic data was performed. RESULTS: MS patients with more than ten PLMs per hour of REM sleep showed a significantly higher disability measured by the Kurtzke expanded disability status scale (EDSS) (P=0.023). The presence of more than ten PLMs per hour of REM sleep was associated with a greater likelihood of disability (odds ratio 22.1; 95% confidence interval 3.5-139.7; P<0.0001), whereas there were no differences in laboratory and other polysomnographic findings. CONCLUSION: PLMs during REM sleep were not described in MS earlier, and they are associated with disability measured by the EDSS.

Sleep Disorders Reduce Health-Related Quality of Life in Multiple Sclerosis (Nottingham Health Profile Data in Patients with Multiple Sclerosis).

Quality of Life (QoL) is decreased in multiple sclerosis (MS), but studies about the impact of sleep disorders (SD) on health-related quality of Life (HRQoL) are lacking. From our original cohort, a cross-sectional polysomnographic (PSG) study in consecutive MS patients, we retrospectively analysed the previously unpublished data of the Nottingham Health Profile (NHP). Those MS patients suffering from sleep disorders (n = 49) showed significantly lower HRQoL compared to MS patients without sleep disorders (n = 17). Subsequently, we classified the patients into four subgroups: insomnia (n = 17), restless-legs syndrome, periodic limb movement disorder and SD due to leg pain (n = 24), obstructive sleep apnea (n = 8) and patients without sleep disorder (n = 17). OSA and insomnia patients showed significantly higher NHP values and decreased HRQoL not only for the sleep subscale but also for the "energy" and "emotional" area of the NHP. In addition, OSA patients also showed increased NHP values in the "physical abilities" area. Interestingly, we did not find a correlation between the objective PSG parameters and the subjective sleep items of the NHP. However, this study demonstrates that sleep disorders can reduce HRQoL in MS patients and should be considered as an important confounder in all studies investigating HRQoL in MS.

Sleep disorders in multiple sclerosis. Review.

Sleep disorders are common in patients with multiple sclerosis (MS) and play a crucial role in health and quality of life; however, they are often overlooked. The most important sleep disorders in this context are as follows: insomnia, restless legs syndrome, periodic limb movement disorders, and sleep-related breathing disorders (SRBD). It is unclear if MS-related processes (lesions, brain atrophy) can cause symptomatic forms of sleep apnea. MS-related narcolepsy-like symptoms are described in the literature and, in some cases, have resolved with methylprednisolone pulse therapy. Similarly, REM sleep behavior disorder (RBD) is very rare in MS, but it can be an initial sign of MS where cortisone therapy may be helpful and can be taken into account in this specific context. Independent diagnosis and treatment is required for all of the abovementioned conditions. Treating physicians and neurologists should be aware of these comorbidities and initiate specific therapy. Highly fatigued or sleepy MS patients should have polysomnography in order not to overlook these diagnoses.

Sleep disorders in multiple sclerosis and their relationship to fatigue.

Treatment of multiple sclerosis (MS)-related fatigue is still a challenging task, given that no proven therapies exist and its mechanisms are not known. Our review highlights the relationship between MS-related fatigue and sleep disorders (SD). Although many studies suggest a higher overall prevalence of SD in MS, there are no valid and robust data to confirm this hypothesis until now except for restless legs syndrome (RLS): the prevalence of RLS in MS patients-especially in those with severe pyramidal and sensory disability-seems to be four times higher than in controls subjects. RLS is sometimes difficult to distinguish from spasticity and in case of doubt, probatory dopaminergic therapy or polysomnographic (PSG) investigations may be helpful. Nocturia may impact MS-related fatigue and should be considered. The treatment of underlying SD led to an improvement of MS-related fatigue. From a scientific point of view, SD should be examined in all studies investigating MS-related fatigue and be considered as a relevant confounder.