Are there sleep-specific phenotypes in patients with chronic fatigue syndrome?
By Dr. Jason G. Ellis
Chronic fatigue syndrome (CFS), as defined by the international consensus definition, is a condition characterised by profound fatigue, of definite onset, which has persisted for at least 6 months, and causes substantial disruption to the individual’s daily functioning. In addition to fatigue, at least four other key symptoms are required to fulfil diagnostic criteria, including muscle and joint pain, headache, cognitive dysfunction and unrefreshing sleep. Thus defined, CFS affects between 0.23% and 2.6% of the adult population. There are several theories as to the pathogenesis of CFS. However, it is most likely that the development and maintenance of CFS are multifactorial. Predisposing factors include a general propensity to both emotional and physical distress, a history of abuse, being more than usually physically active and being perfectionist. Precipitating events include viruses such as glandular fever and major life events.9 ,10 Several factors appear to be involved in the maintenance of symptoms. Physiologically, evidence suggests dysregulation of the hypothalamic pituitary adrenal (HPA) axis, increased cytokine production and HPA responsiveness to cytokines, hypersensitivity in the central nervous system (ie, central sensitisation) and autonomic dysfunction. Two studies also highlight the importance of illness beliefs and behaviours. Individuals who adopt all or nothing coping styles in response to symptoms (ie, push on through until they crash out) and attribute broad ranges of everyday symptoms to their illness are more likely to develop CFS postvirally. In sum, research suggests that in CFS multiple processes in distinct domains, such as physiology, illness beliefs, inconsistent activity, sleep disturbance, medical uncertainty and lack of guidance, can interact to maintain or exacerbate symptoms.
As aforementioned, unrefreshing sleep is one key diagnostic characteristic of CFS.1 It is also one of the most common symptom complaints,20 ,21 with 87–95% of patients reporting sleep difficulties (Gotts ZM, unpublished PhD thesis) that do not improve over the course of the illness.22 Where the purpose of sleep is the subject of intense debate, its importance to human health and well-being is undeniable. Examinations of individuals deprived of or restricted from sleep consistently demonstrate deteriorations in mood, cognition and performance.23 The purpose of each different sleep stage is also unclear, although it is generally agreed that the lighter stages of sleep (stage 1 sleep and stage 2 sleep) afford transitions between wakefulness and sleep and then between slow wave sleep (SWS) and Rapid Eye Movement sleep (REM). SWS and REM are believed to confer recuperative, restorative and learning properties for the individual (eg, the secretion of growth hormone, consolidation of memory).24 ,25 Therefore, the proportion of each sleep stage and timing of entry into each sleep stage, SWS and REM in particular, are important for the long-term maintenance of human physical and mental health.
Symptoms such as unrefreshing sleep may not only be markers of CFS; they may also serve to maintain it. For instance, there may be reciprocal links between sleep quality, sleep-wake regulation and fatigue. There is evidence of this. For instance, studies have shown that adopting activity and sleep management strategies improves HPA axis functioning as measured by cortisol levels.26 This suggests that further investigation of sleep disturbance of CFS is of more than academic importance but may highlight new avenues for intervention. From a clinical perspective, it is also important to study sleep more thoroughly in CFS as it may highlight some areas of diagnostic ambiguity. For instance, previous studies have shown that sleep disorders (notably obstructive-sleep apnoea) are occasionally identified during polysomnographic (PSG) assessments with CFS patient cohorts.27–30
Although over 30 PSG studies on individuals with CFS exist, conclusive statements about the type of sleep abnormalities in this population are difficult. Few studies report a full characterisation of both sleep continuity (the timing, efficiency and amount of sleep obtained) and sleep architecture (amount of each sleep or wake stage and the timing of transitions to each sleep stage), with some studies providing no PSG data at all.27 ,31–35 Moreover, reporting practices differ widely, making interpretation and comparisons difficult (eg, studies report the percentage of each sleep and wake stage as an index of Sleep Period Time, Total Sleep Time (TST) or even Time in Bed),29 ,30 ,36–43 while others report the number of minutes spent in each stage.44–48 What can be concluded from previous PSG studies is that, in each study, deviations from ‘normal sleep’ exist, but there is no consistent pattern. For example, where two studies44 ,45 report poor sleep efficiencies and ‘normal range’ REM latencies, others36 ,37 ,45 found ‘normal range’ sleep efficiencies and short REM latencies and yet others still report a normal sleep efficiency and a long-REM latency (REML)41 or poor sleep efficiency and long-REM latencies.48 Moreover, the picture remains unclear after controlling for the severity of patients’ self-reported sleep complaints.49 ,50 Although differences in protocol, definitional criteria and reporting criteria may, to some extent, explain these differences, an alternative explanation is that sleep difficulties in individuals with CFS are not homogeneous and various sleep phenotypes exist in this population.
The aim of the study was to determine whether specific sleep phenotypes existed in patients with CFS. A large consecutive series of patients, meeting the criteria for CFS, underwent a single night of polysomnography to determine the presence or absence of distinct sleep phenotypes. The first finding, over 30% of individuals meeting diagnostic criteria for CFS, also demonstrated that a Primary Sleep Disorder (PSD; sleep apnoea or PLMD) is important and underscores the need to assess for PSDs in CFS populations. As the recommended treatment strategies for some PSDs differ considerably from those for CFS (eg, Continuous Positive Airway Pressure for apnoea vs sleep management strategies in CFS), it is important to direct the individual to, or adjunct, appropriate care pathways as soon as possible. This finding also questions the ability to differentiate fatigue associated with sleep apnoea or PLMD from that associated with CFS. Here, family members and/or carers may be helpful for diagnosis sensitivity as they are likely to be aware of nocturnal breathing disturbances (ie, heavy snoring, gasping or pauses in breathing).
The overall PSG results (after excluding sleep apnoea and PLMD) confirm objective sleep difficulties in patients with CFS. When the percentages of each sleep stage in ‘normal’ adult sleepers (ie, <5% wake, between 2% and 5% stage 1, between 45% and 55% stage 2, between 13% and 23% SWS and between 20% and 25% REM52) are compared with those in the present sample, it is seen that this group falls outside the range for all these variables. The present sample is spending more time awake and in the lighter stages of sleep (stages 1 and 2 sleep), and less time in the deeper sleep stages of sleep (ie, stage 2 sleep and SWS) and in REM. Further, using the quantitative benchmarks of sleep disturbance outlined by Edinger et al,53 it can be seen that where sleep efficiency and SLs appear to be on the cusp of ‘normal’ sleep in the present sample (85% sleep efficiency is considered normal and SL of >30 denotes a sleep problem), WASO appears to be almost twice as long as is considered problematic (>30 min tends to denote a sleep problem). Together, these findings indicate that sleep is an objectively verifiable problem for patients with CFS that should be addressed clinically.
The cluster analysis identified, at saturation, four sleep phenotypes. The dendrogram identified two groups partially related (ie, groups 1 and 4) and two that were largely independent (ie, groups 2 and 3). This configuration was confirmed by ANOVA showing statistically significant differences in sleep continuity and architecture variables between the groups. That said, where statistical significance and relative characterisation (eg, highest in variable WX and Y and lowest in variable Z) are important in understanding between-group differences, the more salient question is whether these four groups are clinically relevant in terms of specific sleep treatments in patients with CFS. The use of different pharmacological agents (benzodiazepines, z-hypnotics or stimulants) or therapeutic interventions (ie, Cognitive Behavioural Therapy for Insomnia or behavioural modification strategies) has been shown to have differential effects on specific aspects of sleep continuity and architecture. For example, zolpidem appears to have a better impact on the number of awakenings and perceived quality of sleep compared with nitrazepam, and lormetazapam appears to be better in reducing SLs than zoplicone.54 As such, tailoring treatment options to the sleep problems presenting in this population is likely to be more effective (table 3).