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In this issue of the Journal of Internal Medicine, Lewis and colleagues [1] provide compelling data for a novel subgroup within the chronic fatigue syndrome (CFS) population. They show that approximately 13% (24/179) of CFS patients have postural orthostatic tachycardia syndrome (POTS), a form of dysautonomia implying that when patients change their body position from supine to upright, their heart rate will increase abnormally (tachycardia). POTS is associated with several symptoms often seen in CFS patients: fatigue, lightheadedness, dizziness, neurocognitive deficits and exercise intolerance. Importantly, this was a confirmatory study of a previously published pilot study that found a prevalence rate for POTS of 29% in a smaller sample (n = 63) of CFS patients [2]. Another significant finding is the differences in fatigue severity, depressive thoughts and daytime hypersomnolence between CFS patients with and without POTS, providing evidence for the clinical importance of POTS in CFS.

The identification of a clinical important subgroup in the CFS population is an important step for patients suffering from this underestimated illness and for carers treating these patients. The idea of subgrouping in relation to autonomic findings in people with CFS dates back to 1999 [3]. The study by Lewis et al. [1] confirms these initial ideas, and opens the path for clinical and scientific innovations. The next step would be to validate these findings in other settings and different countries, preferentially in population-based studies. Studies examining whether these findings are independent from gender are warranted as well: women and men recruit their sympathetic nervous system differently for short-term responses to stressful stimuli like experimental pain [4].

Furthermore, indications for autonomic dysfunctions are present in different case definitions of CFS. Hence, the Canadian case definition [5] assigns the presence of autonomic symptoms as one of the major criteria to define CFS. In that regard, studies examining the presence of POTS in patients fulfilling different diagnostic criteria are important as well in subgrouping the CFS population. Likewise, the exact role of deconditioning in relation to POTS in CFS requires in-depth study. Although deconditioning is etiologically unrelated to CFS, recent data point to an association between POTS and deconditioning [6], and this finding requires testing in the CFS population. Orthostatic stress impairs neurocognitive capabilities in patients with CFS [7], which stresses the importance of further examining the interactions between POTS (treatment) and neurocognitive capabilities and neurocognitive symptoms in people with CFS.

In addition, longitudinal studies examining the temporal stability and natural course of POTS in CFS are warranted, as well as treatment studies that aim at testing potential strategies for ‘correcting’ POTS in patients with CFS. In line with this view, the Newcastle group previously conducted a placebo-controlled trial of home orthostatic tilt training in CFS patients [8]. They found reductions in orthostatic intolerance that were maintained at 6 months follow-up [8]. However, the same study revealed that the treatment did not improve fatigue levels, which questions the clinical importance of the treatment effects. Hence, further work in this area is warranted. Given the association between POTS and deconditioning observed in non-CFS patients with CFS [6], exercise therapy might be a treatment option worthwhile investigating.

How does POTS fits into our current understanding of CFS? POTS is associated with less effective autoregulation of cerebral blood flow during orthostatic challenge [9], and there is consistent evidence for decreased cerebral blood flow in patients with CFS [10, 11]. Cerebral autoregulation aims to maintain a stable and adequate cerebral blood flow. Autonomic effects are prominent in dynamic cerebral autoregulation, whereas vasomotor effects dominate static or steady-state cerebral autoregulation. An impaired cerebral blood flow might be due to previously observed blood flow abnormalities in CFS, like prolonged acetylcholine-induced vasodilatation in the microcirculation [12]. In line with this, autonomic dysfunction may explain POTS and related cerebral blood flow impairment in CFS. Indeed, cumulating evidence supports autonomic dysfunction in CFS [13-15]. Less effective autoregulation of cerebral blood flow in CFS might account for POTS-related symptoms lightheadedness, dizziness and neurocognitive deficits as typically reported by many CFS sufferers. However, a recent study refutes the link between neurocognitive performance and decreased cerebral blood flow in young patients with CFS [11].

Impaired autoregulation of cerebral blood flow might even account for exercise intolerance in CFS: a lack of endogenous analgesia in response to exercise has been shown repeatedly in patients with CFS and it partly explains symptom flares following exercise (i.e. postexertional malaise) [16-19]. Sufficient cerebral blood flow to the brain is cardinal for the increased brain activity required for activating brain-orchestrated endogenous analgesia during exercise. Several brain areas co-work to orchestrate endogenous analgesia during exercise, including the brainstem, thalamus and the prefrontal cortex [19]. Hence, if the autonomic nervous system is unable to sufficiently increase cerebral blood flow during exercise, this in turn might lead to an inability to activate brain-orchestrated endogenous analgesia during exercise in patients with CFS. This view is supported by a near-infrared spectroscopy study that revealed an impaired prefrontal cortex oxygenation during incremental maximal exercise in CFS patients [20].

Taken together, the study by Lewis and colleagues [1] further supports the notion of CFS being a central nervous system disorder. This view is supported by numerous studies evidencing autonomic nervous system malfunctioning in CFS; Professor Newton's group has contributed substantially to this development [13-15]. Many people with CFS feel most comfortable attributing their illness to a disorder of the central nervous system, and this opinion seems to be rational given the cluster of symptoms that occur in the illness. Symptoms like fatigue, non-refreshing sleep, concentration difficulties, impairments in short-term memory, sensitivity to variable stimuli like bright light and chemicals, a decreased load tolerance and widespread pain are suggestive of central nervous system involvement.

Another feature of CFS that indicates central nervous system involvement is hyperexcitability of the central nervous system. Several studies have been conducted to examine the presence of hyperexcitability of the central nervous system (i.e. central sensitization) in CFS, and all studies point in the same direction. Indeed, studies showed generalized hyperalgesia in CFS for a variety of sensory stimuli and in various tissues, including the skin, muscle tissue and the lungs (reviewed in [21]). Importantly, the observation of central sensitization in CFS is in line with our current understanding of CFS: it corroborates with psychological influences on the illness, the presence of infectious agents and immune dysfunctions and the dysfunctional hypothalamus pituitary adrenal-axis as seen in these severely debilitated patients [21]. Other important scientific observations suggestive of CFS being a central nervous system disorder includes decreased grey matter volume in the brain [22, 23], evidence for brainstem dysfunction (white matter changes [24], hypoperfusion [25] and hypometabolism [26]) in a manner that is consistent with autonomic nervous system dysfunction [24] and dysfunctional endogenous analgesia [21], deregulated serotonergic neurotransmission in the rostral anterior cingulate [27], and the deficient hypothalamus pituitary adrenal-axis functioning [28, 29].

In conclusion, Lewis et al. [1] have provided solid evidence for POTS being a clinically important subgroup in the CFS population. Further research in this area is warranted, especially for examining the natural course of POTS in CFS patients, and for identifying effective treatment strategies for treating POTS in CFS patients. The finding of POTS in some CFS patients is in line with the body of evidence pointing towards CFS being a central nervous system disorder.

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