Purpose of Review
In amyotrophic lateral sclerosis (ALS), sleep disruption is frequently present and substantially adds to disease burden. This review aims to summarize current knowledge on causes, ...pathophysiology, and treatment of sleep disturbances in ALS.
Recent Findings
Motor neuron degeneration and muscle weakness may lead to muscle cramps, pain, spasticity, immobilization, restless legs, sleep-disordered breathing, and difficulties to clear secretions. Furthermore, existential fears and depression may promote insomnia. Sleep-disordered breathing, and nocturnal hypoventilation in particular, requires ventilatory support which meaningfully prolongs survival and improves health-related quality of life albeit respiratory failure is inevitable. Early indication for non-invasive ventilation can be achieved by inclusion of capnometry in diagnostic sleep studies.
Summary
Sleep disruption is extremely common in ALS and may arise from different etiologies. The absence of causative therapeutic options for ALS underlines the importance of symptomatic and palliative treatment strategies that acknowledge sleep-related complaints.
Neuromuscular disorders (NMDs) encompass a highly diverse group of conditions that affect the skeletal muscles, peripheral nervous system, or motor endplate. Depending on the underlying disease, ...common characteristics include progressive muscle weakness and sensory disturbances, both of which can contribute to sleep disruption. Disorders of sleep are extremely frequent in NMDs and substantially co-determine overall morbidity, quality of life, and survival. As many NMDs currently lack a cure, supportive therapy is mandatory and includes appropriate management of sleep-related symptoms. Specific sleep disorders that may arise in NMDs include insomnia due to pain or leg muscle cramps, restless legs syndrome, and sleep-disordered breathing, notably obstructive sleep apnea and hypoventilation. This review article aims to comprehensively outline the clinical spectrum of sleep disorders and sleep properties associated with NMDs.
Chronic low‐grade inflammation, in particular increased concentrations of proinflammatory cytokines such as interleukin (IL)‐6 in the circulation, is observed with increasing age, but it is also as a ...consequence of various medical and psychological conditions, as well as life‐style choices. Since molecules such as IL‐6 have pleiotropic effects, consequences are wide ranging. This short review summarizes the evidence showing how IL‐6 elevations in the context of inflammatory disease affect the organism, with a focus on sleep‐related symptoms and fatigue; and conversely, how alterations in sleep duration and quality stimulate increased concentrations of IL‐6 in the circulation. Research showing that acute as well as chronic psychological stress also increase concentrations of IL‐6 supports the notion of a close link between an organism's response to physiological and psychological perturbations. The findings summarized here further underscore the particular importance of IL‐6 as a messenger molecule that connects peripheral regulatory processes with the CNS.
In numerous neuromuscular disorders (NMDs), respiratory muscle weakness is present, and acute or chronic respiratory failure may evolve. Very often, respiratory involvement substantially adds to the ...burden of disease, impairs quality of life, or reduces life expectancy. This article summarizes new aspects of both diagnosis and management of respiratory muscle weakness in patients with NMDs.
Drugs like deflazacort, ataluren, eteplirsen, and nusinersen are now approved treatments for Duchenne Muscular Dystrophy and Spinal Muscular Atrophy, and others are on their way in NMDs. Although observing how innovative drugs will change the natural history of these diseases, including respiratory function over time, adequate symptomatic treatment remains meaningful and is strongly recommended. Physicians should systematically take respiratory involvement into account to improve patients' quality of life and prognosis.
First, it is outlined in which subtypes of NMD respiratory muscle dysfunction is particularly relevant. Second, new developments regarding diagnostic procedures, including respiratory muscle strength testing, spirometry, and sleep studies, are covered. Third, this article gives an overview on current concepts of ventilatory support and management of secretions in patients with NMD.
Objective
Weight loss has been identified as a negative prognostic factor in amyotrophic lateral sclerosis, but there is no evidence regarding whether a high‐caloric diet increases survival. ...Therefore, we sought to evaluate the efficacy of a high‐caloric fatty diet (HCFD) for increasing survival.
Methods
A 1:1 randomized, placebo‐controlled, parallel‐group, double‐blinded trial (LIPCAL‐ALS study) was conducted between February 2015 and September 2018. Patients were followed up at 3, 6, 9, 12, 15, and 18 months after randomization. The study was performed at 12 sites of the clinical and scientific network of German motor neuron disease centers (ALS/MND‐NET). Eligible patients were randomly assigned (1:1) to receive either HCFD (405kcal/day, 100% fat) or placebo in addition to riluzole (100mg/day). The primary endpoint was survival time, defined as time to death or time to study cutoff date.
Results
Two hundred one patients (80 female, 121 male, age = 62.4 ± 10.8 years) were included. The confirmatory analysis of the primary outcome survival showed a survival probability of 0.39 (95% confidence interval CI = 0.27–0.51) in the placebo group and 0.37 (95% CI = 0.25–0.49) in the HCFD group, both after 28 months (point in time of the last event). The hazard ratio was 0.97, 1‐sided 97.5% CI = −∞ to 1.44, p = 0.44.
Interpretation
The results provide no evidence for a life‐prolonging effect of HCFD for the whole amyotrophic lateral sclerosis population. However, post hoc analysis revealed a significant survival benefit for the subgroup of fast‐progressing patients. ANN NEUROL 2020;87:206–216
Objective
In amyotrophic lateral sclerosis (ALS), respiratory muscle involvement and sleep-disordered breathing relate to worse prognosis. The present study investigated whether respiratory outcomes ...on first-ever sleep studies predict survival in patients with ALS, specifically taking into account subsequent initiation of non-invasive ventilation (NIV).
Methods
From patients with ALS, baseline sleep study records, transcutaneous capnometry, early morning blood gas analysis, survival data and clinical disease characteristics were retrospectively analyzed. Patients were stratified according to whether enduring NIV was consecutively established (“NIV(+)”) or not (“NIV(–)”).
Results
Among the study cohort (
n
= 158, 72 female, 51 with bulbar onset ALS, 105 deceased) sleep-disordered breathing was present at baseline evaluation in 97 patients. Early morning base excess (EMBE) > 2 mmol/l predicted nocturnal hypercapnia. Ninety-five patients were NIV(+) and 63 were NIV(–). Survival from baseline sleep studies was significantly reduced in NIV(–) but not in NIV(+) patients with nocturnal CO
2
tension ≥ 50 mmHg, apnea hypopnea index ≥ 5/h, and EMBE > 2 mmol/l. Hazard ratio for EMBE > 2 mmol/l was increased in NIV(–) patients only, and EMBE independently predicted survival in both NIV(–) and NIV(+) patients. Furthermore, EMBE on baseline sleep studies was the only predictor for survival from symptom onset, and hazard ratio for shorter survival was markedly higher in the NIV(–) than the NIV(+) group (2.85,
p
= 0.005, vs. 1.71,
p
= 0.042).
Interpretation: In patients with ALS, EMBE > 2 mmol/l predicts nocturnal hypercapnia and shorter survival. Negative effects of sleep-disordered breathing on survival are statistically abolished by sustained NIV.
Reference values derived from existing diaphragm ultrasound protocols are inconsistent, and the association between sonographic measures of diaphragm function and volitional tests of respiratory ...muscle strength is still ambiguous.
To propose a standardized and comprehensive protocol for diaphragm ultrasound in order to determine lower limits of normal (LLN) for both diaphragm excursion and thickness in healthy subjects and to explore the association between volitional tests of respiratory muscle strength and diaphragm ultrasound parameters.
Seventy healthy adult subjects (25 men, 45 women; age 34 ± 13 years) underwent spirometric lung function testing, determination of maximal inspiratory and expiratory pressure along with ultrasound evaluation of diaphragm excursion and thickness during tidal breathing, deep breathing, and maximum voluntary sniff. Excursion data were collected for amplitude and velocity of diaphragm displacement. Diaphragm thickness was measured in the zone of apposition at total lung capacity (TLC) and functional residual capacity (FRC). All participants underwent invasive measurement of transdiaphragmatic pressure (Pdi) during different voluntary breathing maneuvers.
Ultrasound data were successfully obtained in all participants (procedure duration 12 ± 3 min). LLNs (defined as the 5th percentile) for diaphragm excursion were as follows: (a) during tidal breathing: 1.2 cm (males; M) and 1.2 cm (females; F) for amplitude, and 0.8 cm/s (M) and 0.8 cm/s (F) for velocity, (b) during maximum voluntary sniff: 2.0 cm (M) and 1.5 cm (F) for amplitude, and 6.7 (M) cm/s and 5.2 cm/s (F) for velocity, and (c) at TLC: 7.9 cm (M) and 6.4 cm (F) for amplitude. LLN for diaphragm thickness was 0.17 cm (M) and 0.15 cm (F) at FRC, and 0.46 cm (M) and 0.35 cm (F) at TLC. Values for males were consistently higher than for females, independent of age. LLN for diaphragmatic thickening ratio was 2.2 with no difference between genders. LLN for invasively measured Pdi during different breathing maneuvers are presented. Voluntary Pdi showed only weak correlation with both diaphragm excursion velocity and amplitude during forced inspiration.
Diaphragm ultrasound is an easy-to-perform and reproducible diagnostic tool for noninvasive assessment of diaphragm excursion and thickness. It supplements but does not replace respiratory muscle strength testing.
Abstract Charcot-Marie-Tooth (CMT) neuropathies belong to the most common neurogenetic disorders. To date, mutations in more than 40 genes are known to be able to cause CMT. This genetic ...heterogeneity is a challenge for genetic diagnostics. Data on frequencies of mutations in CMT genes from large patient cohorts are needed to develop strategies for efficient genetic testing. In this study we have analysed patient histories, electrophysiological and genetic testing data in our cohort of 776 patients. In electrophysiologically demyelinating CMT, PMP22 duplication was the most common genetic cause, followed by mutations in GJB1 and MPZ . In axonal CMT, GJB1 was the most commonly affected gene, followed by MFN2 and MPZ . In CMT1, the clearance rate was 66%, in CMT2 it was 35%. Overall, the genetic clearance rate in our patient cohort was 58%. We found a higher rate of genetic diagnosis in patients seen in our neuromuscular center compared to out-of-clinic patients whose DNA was tested in our laboratory. This study provides further data on frequencies of CMT genes and subtypes and points to the importance of a thorough clinical and electrophysiological work-up for the direction of genetic testing.
Introduction
Spinal and bulbar muscular atrophy (SBMA) is a progressive, X-linked lower motor neuron disorder exclusively affecting men. Since knowledge on sleep disorders in SBMA is scarce compared ...to other motoneuron diseases, this retrospective case-control study aimed to investigate sleep and sleep-related breathing in patients with SBMA.
Methods
In 23 non-ventilated patients with SBMA (median age 52 years), clinical disease characteristics, forced vital capacity and diagnostic polysomnographies were retrospectively evaluated. In 16 patients, overnight transcutaneous capnometry was available. Twenty-three male control subjects with chronic insomnia were matched for age and body mass index.
Results
In patients with SBMA obstructive sleep apnoea (OSA, apnoea-hypopnoea index/AHI > 5/h) was more frequent than in control subjects (14/23 or 61% vs. 6/23 or 26%,
p
= 0.02), and median AHI was significantly higher in patients (9.0/h vs. 3.4/h,
p
< 0.01). Among SBMA patients, the AHI was not related to age or body mass index. Alveolar hypoventilation as reflected by nocturnal hypercapnia was found in 3/16 patients. Rapid eye movement (REM) sleep without atonia was present in 44% of SBMA patients but only in 4% of controls (
p
< 0.01). During REM and non-REM sleep, no behavioural abnormalities were observed in either group. Periodic limb movements in sleep (index > 15/h) were frequent in SBMA patients but rarely disrupted sleep.
Conclusions
In patients with SBMA, sleep-disordered breathing may comprise both OSA and nocturnal hypoventilation. REM sleep without atonia may also be found, but its clinical significance remains unclear. In patients complaining of sleep-related symptoms, cardiorespiratory polysomnography and transcutaneous capnometry are recommended.
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