Objective sleep measures in chronic fatigue syndrome patients: A systematic review and meta-analysis

Abstract

Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report disrupted and unrefreshing sleep in association with worsened fatigue symptoms. However, the nature and magnitude of sleep architecture alteration in ME/CFS is not known, with studies using objective sleep measures in ME/CFS generating contradictory results. The current manuscript aimed to review and meta-analyse of case-control studies with objective sleep measures in ME/CSF. A search was conducted in PubMed, Scopus, Medline, Google Scholar, and Psychoinfo databases. After review, 24 studies were included in the meta-analysis, including 20 studies with 801 adults (ME/CFS = 426; controls = 375), and 4 studies with 477 adolescents (ME/CFS = 242; controls = 235), who underwent objective measurement of sleep. Adult ME/CFS patients spend longer time in bed, longer sleep onset latency, longer awake time after sleep onset, reduced sleep efficiency, decreased stage 2 sleep, more Stage 3, and longer rapid eye movement sleep latency. However, adolescent ME/CFS patients had longer time in bed, longer total sleep time, longer sleep onset latency, and reduced sleep efficiency. The meta-analysis results demonstrate that sleep is altered in ME/CFS, with changes seeming to differ between adolescent and adults, and suggesting sympathetic and parasympathetic nervous system alterations in ME/CFS.

Keywords: Actigraphy watch; Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); Objective measurements; Polysomnography (PSG); Sleep; Systematic review.

Fig. 1.

Flow diagram of the systematic review Legend: ME/CFS: Chronic Fatigue Syndrome.

Fig. 2.

Total time in bed (min) differences between ME/CFS and healthy controls. (A) Fourteen studies reported the differences in adults, showing that ME/CFS patients spent 26.63 minutes longer total time in bed than controls, with no significant differences in the PSG studies, and with 77.21 min longer time spent in bed reported by actigraphy watches. (B) Two studies reported the differences in adolescents with ME/CFS patients as compared to healthy controls, showing the adolescents have 72.04 minutes longer time in bed than, with considerable heterogeneity between the studies. The size of the green squares represents the study weight into the observed meta-analysis results.

Fig. 3.

Total sleep time (min) differences between ME/CFS and healthy controls. (A) Nineteen studies reported the differences in adults showing that adult ME/CFS patients have no differences in total time with only 0.52 minutes less total sleep time than controls, with a considerable heterogeneity between the studies. However, when subdivide the studies based on modalities used to measure sleep, ME/CFS showed a non-significant 8.41 min less total sleep time when using PSG but demonstrated 45.96 min more total sleep time when using Actigraphy. (B) Four studies reported the differences in adolescents showing that ME/CFS adolescent patients had 54.6 min longer total sleep time than, with a considerable heterogeneity between the studies. The size of the green squares represents the study weight into the observed meta-analysis results.

Fig. 4.

Sleep latency (min) differences between ME/CFS and healthy controls. (A) Seventeen studies reported the differences in adults with overall difference showing that ME/CFS patients took 7.19 min longer to fall to sleep than controls and with a considerable heterogeneity between the studies. (B) Three studies reported non-significant differences in adolescents with overall difference showing ME/CFS patients to have a trend of 27.61 minutes longer time to fall to sleep, with a considerable heterogeneity between the studies. The size of the green squares represents the study weight into the observed meta-analysis results.

Fig. 5.

Sleep efficiency (%) differences between ME/CFS and healthy controls. (A) Eighteen studies reported the differences in adults with overall difference showing that ME/CFS patients had 4.5% less sleep efficiency with a moderate heterogeneity between the studies. Studies that used PSG showed less the sleep efficiency in ME/CFS patients of 4.81%, while studies that used Actigraphy reported reduce sleep efficiency in ME/CFS patients of 3.24%. (B) Two studies reported non-significant differences in adolescents with overall difference showing ME/CFS patients had 4.5% less sleep efficiency when compared to controls, with a considerable heterogeneity between the studies. The size of the green squares represents the study weight into the observed meta-analysis results.

Fig. 6:

Once the blood brain barrier (BBB) allows the infiltration of peripheral pro-inflammatory cytokines to pass through to the brain actively or passively, some pro-inflammatory cytokines play dual-roles as sleep regulators leading to the sleep disturbances. These pro-inflammatory cytokines initiate a positive feedback mechanism that upregulates the activation of microglia resulting in increased pro-inflammatory cytokine production and increased BBB leakage. Furthermore, the unregulated cytokine release could increase the microglial activation and priming causing a chronic pro-inflammatory microenvironment including astrocytes, hypoxia, reactive oxygen species (ROS), elevated cytokine levels, and microglial activation. These chronic proinflammatory environments could cause the alteration of the chemoreceptors in the afferent vagus nerve that has synaptic connection to the nucleus of the solitary tract (NTS) of dorsal brainstem. This causes alteration of the sympathetic and parasympathetic nervous system which could lead to disruption of the sleep, along with other symptoms of ME/CFS.