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Keywords:

  • Central nervous system;
  • chronic pain;
  • fibromyalgia;
  • hyperalgesia;
  • hyperexcitability

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Studies examining the (hyper)responsiveness of the central nervous system in CFS
  5. How does central sensitisation fit into our overall understanding of CFS?
  6. Implications for clinical practice
  7. Implications for research
  8. Conclusions
  9. Acknowledgements
  10. Address
  11. References

Eur J Clin Invest 2011

Abstract

Background  Central sensitisation entails several top-down and bottom-up mechanisms, all contributing to the hyperresponsiveness of the central nervous system to a variety of inputs. In the late nineties, it was first hypothesised that chronic fatigue syndrome (CFS) is characterised by hypersensitivity of the central nervous system (i.e. central sensitisation). Since then, several studies have examined central sensitisation in patients with CFS. This study provides an overview of such studies.

Materials and Methods  Narrative review.

Results  Various studies showed generalised hyperalgesia in CFS for a variety of sensory stimuli, including electrical stimulation, mechanical pressure, heat and histamine. Various tissues are affected by generalised hyperalgesia: the skin, muscle tissue and the lungs. Generalised hyperalgesia in CFS is augmented, rather than decreased, following various types of stressors like exercise and noxious heat pain. Endogenous inhibition is not activated in response to exercise and activation of diffuse noxious inhibitory controls following noxious heat application to the skin is delayed.

Conclusions  The observation of central sensitisation in CFS is in line with our current understanding of CFS. The presence of central sensitisation in CFS corroborates with the presence of several 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.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Studies examining the (hyper)responsiveness of the central nervous system in CFS
  5. How does central sensitisation fit into our overall understanding of CFS?
  6. Implications for clinical practice
  7. Implications for research
  8. Conclusions
  9. Acknowledgements
  10. Address
  11. References

Defining chronic fatigue syndrome

Chronic fatigue syndrome (CFS) is a relatively common condition characterised by profound disabling fatigue in conjunction with a range of other symptoms. While a variety of case definitions exist, often with varying nomenclatures (reviewed in [1]), the most widely accepted for research purposes remains the 1994 Center for Disease Control and Prevention definition [2]. This relies on the presence of chronic debilitating fatigue of a new onset (not lifelong) and many other symptoms that cannot be explained by any known chronic medical or psychological condition [2]. Hence, the core feature of a CFS diagnosis is the exclusion of any active medical condition (e.g. primary sleep disorders, severe obesity, cancer, hypothyroidism, hepatitis B or C, major depressive disorders with psychotic or melancholic features, bipolar affective disorders, schizophrenia, dementia, alcohol abuse, etc.) [2]. The importance of this feature needs to be stressed because there is evidence that in approximately 40% of patients diagnosed with CFS by community physicians, alternative exclusionary diagnoses can be found after further investigation at specialist CFS clinics [3].

In addition, the fatigue should be unrelated to exertion, is not substantially relieved by rest and should be severely disabling (i.e. causing substantial reductions in activity levels). Finally, four or more of the following symptoms should be present for 6 months or longer: impaired memory or concentration; extreme, prolonged exhaustion and sickness as a result of physical or mental exertion (post-exertional malaise); unrefreshing sleep; muscle pain; pain in multiple joints; headaches of a new kind or greater severity; sore throat and tender lymph nodes (cervical or axillary). Major consequences of the condition are a substantial reduction in patients’ activity level compared with that before the onset of the disease and an abnormal exercise tolerance, characterised by the typical symptom exacerbation and post-exertional malaise after previously well-tolerated exercise levels.

CFS pathophysiology and psychology

In spite of decades of international research efforts, the exact aetiology and pathophysiology of CFS remains unknown. Many physiological systems have been studied in people with CFS, and several dysfunctions have been reported. Although no single dysfunction turned out to be a hallmark of the illness, our understanding of CFS has increased substantially. The onset of CFS is often sudden and precipitated by an infectious episode [4,5], but in some patients, onset is more insidious and can be preceded by negative, stressful life events [6,7]. The latter may explain the malfunctioning of the short-term (autonomic nervous system) and long-term (hypothalamus–pituitary–adrenal axis) stress response systems. Indeed, patients with CFS have many autonomic manifestations [8–10], and the hypothalamus–pituitary–adrenal axis is characterised by mild hypocortisolism, a blunted adrenocorticotropin response to stressors and enhanced negative feedback [11,12]. Some patients with CFS show evidence for infectious agents in their blood [13–15], which is in line with numerous reports of altered immune functioning [16–18]. In addition, a body of scientific literature provides evidence of a variety of perpetuating psychological factors [19–22]. Accordingly, on present albeit incomplete evidence, we can hypothesise that both pathophysiological and psychological factors have a role to play in the development or maintenance of CFS. These factors may be mutually reinforcing, as in most illnesses, although there is no consensus as yet on the direction of the association; suggested mechanisms are as yet based on observed associations rather than causation or linkage.

The mechanism of central sensitisation

Central sensitisation is defined as an augmentation of responsiveness of central neurons to input from unimodal and polymodal receptors [23]. As indicated in its name, central sensitisation is anatomically located primarily in the central nervous system. Central sensitisation entails several top-down and bottom-up mechanisms, all contributing to the hyperresponsiveness of the central nervous system to a variety of inputs. The following top-down mechanisms take part of central sensitisation: altered sensory processing in the brain [24], malfunctioning of descending inhibitory mechanisms like diffuse noxious inhibitory control (DNIC) [25], increased activity of descending facilitatory pathways and temporal summation of sensory stimuli or wind-up [24,26]. The altered sensory processing in the brain is best illustrated by the overactive pain neuromatrix as seen in case of central sensitisation: increased activity is present in brain areas known to be involved in acute pain sensations like the insula, anterior cingulate cortex and the prefrontal cortex, but not in the primary or secondary somatosensory cortex [27]. An overactive pain neuromatrix entails brain activity in regions not involved in acute pain sensations as well: various brain stem nuclei, dorsolateral frontal cortex and the parietal associated cortex [27]. Long-term potentiation of neuronal synapses in the anterior cingulate cortex [28] and decreased gamma-aminobutyric acid (GABA)-neurotransmission [29] represent two other mechanisms contributing to the overactive brain neuromatrix and hence the altered sensory processing in the brain.

Besides top-down mechanisms, bottom-up mechanisms take part in central sensitisation as well. For example, peripheral injury and other kind of stressors like infections trigger the release of the pro-inflammatory cytokines and consequent activation of spinal cord glia with cyclooxygenase-2 and prostaglandin E2 expression in the central nervous system [30–33]. For comprehensive reviews on central sensitisation, the interested readers are referred to the following papers: [34–37].

The outcome of the processes involved in central sensitisation is an increased responsiveness to a variety of stimuli including mechanical pressure, chemical substances, light, sound, cold, heat and electricity. The increased sensitivity to variable stimuli results in a decreased load tolerance. Hence, the clinical picture of central sensitisation resembles those seen in cases with CFS. Although clinical guidelines for the recognition and assessment of central sensitisation in pain patients have been provided [38], an international consensus definition or clinical criteria for central sensitisation are essentially lacking. Central sensitisation has been observed to occur in a wide variety of chronic ‘unexplained’ disorders, including chronic whiplash-associated disorders [39,40], temporomandibular disorders [41], chronic low back pain [42], fibromyalgia [34], chronic tension-type headache [43,44] and migraine [45,46] among others.

Central sensitisation in CFS?

Many people with CFS feel most comfortable attributing their illness to a disorder of the central nervous system, and this seems to be rational given the cluster of symptoms that occur in the illness, although direct evidence is still scarce. Symptoms like fatigue, nonrefreshing 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. In the past 20 years, it has been hypothesised that CFS is characterised by hypersensitivity of the central nervous system (i.e. central sensitisation) [47,48]. Since then, several studies have examined central sensitisation in patients with CFS. This study provides an overview of such studies, showing that evidence for central sensitisation in patients with CFS is cumulating. In addition, it is explained how central sensitisation fits into our current understanding of CFS (e.g. hypothalamus–pituitary–adrenal axis, immune system and psychological dysfunctions).

Studies examining the (hyper)responsiveness of the central nervous system in CFS

  1. Top of page
  2. Abstract
  3. Introduction
  4. Studies examining the (hyper)responsiveness of the central nervous system in CFS
  5. How does central sensitisation fit into our overall understanding of CFS?
  6. Implications for clinical practice
  7. Implications for research
  8. Conclusions
  9. Acknowledgements
  10. Address
  11. References

A major characteristic of central sensitisation represents the increased responsiveness to a variety of somatosensory stimuli (Table 1).

Table 1.   Overview of the various sensory stimuli to which patients with chronic fatigue syndrome (CFS) have been tested
Referencen (CFS + controls)Sensory stimulusMethod of administrationAnatomical locationResponse in CFS vs. healthy controls
Vecchiet et al. [52]21 + 20Electrical stimulationElectrical device with 2 surface and 2 needle electrodesTrapezius, deltoid and quadriceps muscle and overlying subcutis and skinLower pain threshold at all sites in muscle tissue; no difference in skin and subcutis
Vecchiet et al. [53]21 + 30Electrical stimulationElectrical device with 2 surface and 2 needle electrodesTrapezius, deltoid and quadriceps muscle and overlying subcutis and skinLower pain threshold at all sites in muscle tissue; no difference in skin and subcutis
Meeus et al. [51]30 + 30Mechanical pressureManual pressure algometerBilaterally at seven nonspecific sites on both trunk and extremities, including asymptomatic sidesGeneralised hyperalgesia: lower pressure pain thresholds at symptomatic and asymptomatic sides
Ullrich et al. [57]15 + 15Cold pressor testImmersion in cold bathNondominant handNo difference in cold pain threshold
     No difference in cold pain tolerance
Meeus et al. [25]31 + 31Noxious hot water (46 °C)Immersion in hot bathDominant armIncreased pain perception
     Delayed activation of diffuse noxious inhibitory controls
Nijs et al. [17]137 + 27HistamineAerosol inhalationBronchiHyperresponsiveness: increased bronchoconstriction
Whiteside et al. [60]5 + 5Mechanical pressurePressure algometerSkin web between thumb and index fingerDecrease in pain threshold following exercise
Meeus et al. [61]26 + 31 + 21 with chronic low back painMechanical pressurePressure algometerHand, back, arm and calfDecrease in pain threshold following exercise
Van Oosterwijck et al. [62]22 + 22Mechanical pressurePressure algometerHand, calf and backDecrease in pain threshold following exercise
Geisser et al. [93]36 (mixed CFS and fibromyalgia)Mechanical pressurePressure dolorimetryThumbnail, lateral epicondyleLower pain thresholds & tolerance associated with higher clinical pain
  Noxious heatContact thermodeVolar forearmHeat pain unrelated to clinical pain

Evidence for widespread hyperalgesia

A method that has been used often to detect central sensitisation in various chronic unexplained disorders is the examination of generalised, widespread hyperalgesia. By measuring pain thresholds on both symptomatic and asymptomatic or remote places in patients and healthy controls, widespread hyperalgesia or secondary hyperalgesia can be detected. Lower pressure pain thresholds at symptomatic areas may represent primary hyperalgesia because of sensitised nociceptors within injured peripheral musculoskeletal structures, but when lower pressure pain thresholds are detected at asymptomatic places as well, then central sensitisation must be present [49,50]. Indeed, findings of numerous areas of hyperalgesia in sites outside and remote to the symptomatic site, together with a nonsegmental general decrease in pain thresholds, may infer a generalised hyperexcitability of central nociceptive pathways [49]. A case–control study identified lower pressure pain thresholds for all tested areas in CFS patients compared with healthy controls, even at pain-free locations [51]. Depression, hypervigilance or catastrophising did not confound the observed differences. The secondary hyperalgesia and the widespread appearance of the pain in the absence of real tissue damage support the hypothesis regarding deregulated central nociceptive mechanisms in CFS.

Two studies compared the pain thresholds to electrical stimulation of muscle tissue, skin and subcutis between patients with CFS and healthy controls [52,53]. No difference in electrical pain thresholds of the skin and subcutis were observed, but much lower electrical pain threshold at all sites in the muscle tissue were found in the CFS group (i.e. trapezius, deltoid and quadriceps muscle) [52,53]. Again, these data point towards generalised hyperalgesia in patients with CFS.

Delayed diffuse noxious inhibitory controls

One study evaluated the efficacy of ‘DNIC’ in patients with CFS [25]. DNIC rely on painful conditioning stimulation of one part of the body to inhibit pain in another part [54], to remove the ‘noise’ and to focus on relevant stimuli. DNIC includes the mechanism of spatial summation of pain [55], which depends on the number of central neurons recruited [56] and thus the stimulated area. As the stimulated area increases, inhibitory interactions should take place between nociceptive afferent inputs within this area. For example, progressive immersion of the hand and arm in hot water causes nociceptive input from the hand (= conditioning stimulus) to inhibit nociceptive input from the arm [55]. In the study of DNIC in CFS, the dominant arm of the patients and healthy controls was immersed in noxious hot water (46 °C), generating hyperalgesia (i.e. increased pain perception) and delayed activation of DNIC in the CFS group [25]. In patients with CFS, DNIC react slower to spatial summation of thermal noxious stimuli, supporting the view that central sensitisation is inherent to CFS.

Another study compared pain threshold and tolerance levels for cold pain between 15 monozygotic twins with CFS and their cotwins without CFS [57]. Even though pain threshold, pain tolerance and all cold pressor pain ratings differed substantially between patients and controls, the results failed to show statistically significant differences [57]. Although the use of monozygotic twins for a case control design should be acknowledged as an important study strength, the study findings appear to be underpowered. The authors themselves indicate that the small sample size requires further research [57]. Still, at current, it remains unclear whether the sensitivity to thermal noxious stimuli in patients with CFS is limited to heat or not.

Dysfunction of endogenous inhibition during exercise

In normal circumstances, pain thresholds increase during physical activity because of the release of endogenous opioids, growth factors [58] and other strong inhibitory mechanisms (‘descending inhibition’) orchestrated by the central nervous system [59]. In a pilot study of five CFS patients and five healthy controls, Whiteside et al. [60] showed for the first time that patients with CFS have a dysfunction of endogenous nociceptive inhibition during exercise: the CFS group showed a decrease in pain threshold following exercise. These findings were confirmed in two larger studies [61,62], one of which compared CFS patients with healthy sedentary controls and chronic low back pain patients [61]. The lack of endogenous inhibition during exercise was only present in the CFS group, not in the chronic low back pain group [61]. Taken together, these studies show that patients with CFS have a lack of descending inhibition during exercise. This finding has been replicated using different modes of exercise [62]. The lack of endogenous inhibition during exercise accounts in part for the post-exertional malaise experienced by CFS patients [62].

Nitric oxide plays a complex role in nociceptive processing [59]. Although evidence exists regarding the beneficial effects of the release of small amounts of nitric oxide during inhibition of nociceptive pathways [63], excessive amounts of nitric oxide are able to reduce nociceptive inhibitory activity of the central nervous system, leading to central sensitisation of dorsal horn neurones [64]. Excessive amounts of nitric oxide have been documented in patients with CFS [65] but refuted by others [66]. Importantly, nitric oxide levels do not change following exercise and are unrelated to the lack of endogenous inhibition during exercise in CFS [61].

Real-time quantitative polymerase chain reaction (PCR) was used to study gene expression in leucocytes prior to and following submaximal exercise in 19 patients with CFS and 16 healthy control subjects [67]. At rest, no differences in gene expression were observed. In response to exercise, marked differences in gene expression occurred between the two groups. In the CFS group, the mRNA increased for genes that can detect increases in muscle produced metabolites, genes important for sympathetic nervous system processes and immune function genes [67]. No such changes occurred in the control group. Among the CFS patients, the observed increases in gene expression were correlated with self-reported symptoms of fatigue and pain [67]. These study findings point towards increased muscle sensitivity following exercise in CFS, in a way that even resting levels of metabolites could activate sensory fatigue afferents [67]. Hence, these findings contribute to the evidence in favour of central sensitisation in CFS and are in line with the dysfunctional endogenous inhibition during exercise as seen in CFS.

Brain studies

Dysfunctional descending inhibitory action is one of the major characteristics of central sensitisation. The brain stem is crucial for normal descending inhibitory action. Hence, the studies showing hypoperfusion [68] and hypometabolism [69] of the brainstem in patients with CFS are in line with the central sensitisation hypothesis.

Given the cardinal role of serotonergic neurotransmitter system in descending inhibitory action, a positron emission tomography assessed the involvement of serotonin in CFS [70]. There is evidence for a deregulated serotonergic neurotransmission in the rostral anterior cingulate of CFS patients, in a pattern that is consistent with altered pain processing [70]. More specifically, the density of serotonin transporters was significantly reduced in the rostral subdivision of the anterior cingulate (involved in the processing of emotional information) of CFS patients vs. healthy controls. In line with this is a study using positron emission tomography to show decreased 5-hydroxytryptamine 1A (5-HT1A) receptor number or affinity in patients with CFS [71].

Substance P, a peptide involved in the neurotransmission of pain from the periphery to the central nervous system, is typically elevated (about three times) in the cerebrospinal fluid, but not in the plasma, of patients with fibromyalgia [72]. Substance P levels are not upregulated in the cerebrospinal fluid of CFS patients [72]. However, the study reporting normal substance P levels in CFS excluded all patients fulfilling the diagnostic criteria for fibromyalgia [72]. This implies that the findings are restricted to CFS patients without chronic widespread pain, which is a minority of the CFS population [73,74]. Studies examining substance P levels in the cerebrospinal fluid of CFS patients with and without chronic widespread pain/fibromyalgia are warranted.

Other findings

Using a histamine bronchoprovocation test, the respiratory system of patients with CFS has been shown to be hyperreactive [17]. Bronchial hyperresponsiveness was present in 73 of 137 patients [17]. Even though some evidence for immune activation (more cytotoxic T cells) in relation to bronchial hyperresponsiveness was provided, the high prevalence of bronchial hyperresponsiveness can be viewed as another piece of evidence in support of central sensitisation in at least a large subset of the CFS population [17]. Still, this finding requires replication.

How does central sensitisation fit into our overall understanding of CFS?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Studies examining the (hyper)responsiveness of the central nervous system in CFS
  5. How does central sensitisation fit into our overall understanding of CFS?
  6. Implications for clinical practice
  7. Implications for research
  8. Conclusions
  9. Acknowledgements
  10. Address
  11. References

Central sensitisation can explain many, if not all, CFS symptoms. Central sensitisation accords with much of what is already known about CFS i.e. the presence of infectious agents and immune dysfunctions; the impaired hypothalamus–pituitary–adrenal axis; and the role of several psychological factors in the maintenance and development of the illness, as discussed later.

Cognitive emotional sensitisation

Facilitatory pathways from the brainstem have been identified. Forebrain centres are capable of exerting powerful influences on various nuclei of the brainstem, including the nuclei identified as the origin of the descending facilitatory pathway [75]. The activity in descending pathways is not constant but can be modulated, for example by the level of vigilance, attention and stress [76]. This has been referred to as ‘cognitive emotional sensitisation’ and can be a target for therapies [77]. Hence, forebrain products such as cognitions, emotions, attention, and motivation have influence on the clinical pain experience [75]. Catastrophising [21], problems with acceptance [22] and activity-avoidance [19] have been identified as factors perpetuating factors for CFS. These psychological factors may inhibit descending pathways in the central nervous system, resulting in sensitisation of dorsal horn spinal cord neurons [75]. Hence, cognitive and emotional factors could be contributing to and possibly sustaining the mechanism of central sensitisation in CFS. This notion is supported by the fact that cognitive behavioural therapy – a form of psychotherapy used to treat a variety of psychological impairments, but also used as a therapeutic adjunct for symptom management and coping in illnesses such as cardiac, cancer, diabetes and chronic pain – has been shown to be effective for the treatment of CFS [78–80]. Indeed, part of the effects observed with of cognitive behavioural therapy for CFS may be explained by its action on cognitive emotional sensitisation. Reducing the impact of perpetuating cognitive and emotional factors in patients with CFS might lead to desensitisation, as has been shown in patients with fibromyalgia [81].

Connections between immune dysfunction and central sensitisation

Infection triggers the release of the pro-inflammatory cytokine interleukin-1β, which is known to play a major role in inducing cyclooxygenase-2 (COX-2) and prostaglandin E2 expression in the central nervous system [30,31]. Upregulation of COX-2 and prostaglandin E2 sensitises peripheral nerve terminals. Peripheral infections activate spinal cord glia (both microglia and astrocytes), which in turn enhance the pain response by releasing nitric oxide and proinflammatory cytokines [32,33]. These dynamic immune-to-brain communication pathways might, at least in part, explain a variety of psychological and physiological symptoms (the ‘sickness response’) seen in patients with CFS.

Hypothalamus–pituitary–adrenal axis dysfunction and central sensitisation

Cortisol and corticotropin-releasing factor, two crucial players in the hypothalamus–pituitary–adrenal axis, are both involved in pain sensitivity [82,83]. The deficient hypothalamus–pituitary–adrenal axis functioning in patients with CFS, characterised by mild hypocortisolism, a blunted adrenocorticotropin response to stressors and an enhanced negative feedback of the hypothalamus–pituitary–adrenal axis [11,12], might foster pathological immune activation. The latter implies the release of pro-inflammatory cytokines [83] like interleukin-1β, provoking hypersensitivity of the central nervous system and the so-called ‘sickness response’ [84]. In addition, cortisol has strong (pain) inhibitory capacity, which suggests that hypocortisolism in CFS might contribute to (pain) hypersensitivity. Finally, corticotropin-releasing factor not only results in the release of adrenocorticotropine hormone (ACTH) but also triggers the release of β-endorphins.

Implications for clinical practice

  1. Top of page
  2. Abstract
  3. Introduction
  4. Studies examining the (hyper)responsiveness of the central nervous system in CFS
  5. How does central sensitisation fit into our overall understanding of CFS?
  6. Implications for clinical practice
  7. Implications for research
  8. Conclusions
  9. Acknowledgements
  10. Address
  11. References

The finding that central sensitisation is present in a large proportion of CFS patients calls for treatment strategies that desensitise the central nervous system. First, cognitive behavioural therapy could be employed to addresses the cognitive emotional aspect of central sensitisation. Hence, a comprehensive treatment of central sensitisation should include cognitive behavioural therapy. This notion is in line with the current evidence-based practice guidelines for the management of CFS [85]. Second, various centrally acting drugs have been shown to target mechanisms involved in central sensitisation in animals that theoretically desensitise the central nervous system in humans. These include acetaminophen, serotonin reuptake inhibitor drugs, selective and balanced serotonin and norepinephrine reuptake inhibitor drugs, the serotonin precursor tryptophan, opioids, NMDA-receptor antagonists and calcium channel a2δ ligands [reviewed in 86]. However, the applicability of such drugs for CFS will rely on the outcome of future causation and effectiveness studies. Likewise, various noninvasive treatment options for desensitising the central nervous system in patients with central sensitisation have been proposed, based on the premise that they are capable of activating descending nociceptive inhibition. These include transcranial magnetic stimulation [87,88] and transcutaneous electric nerve stimulation [89–91].

It is unlikely that a single drug or nonpharmacological intervention like cognitive behavioural therapy will be identified as capable of treating a complex mechanism as central sensitisation in CFS patients. Therefore, it is advocated to apply an individually tailored approach when combining different treatment options for treating central sensitisation in patients with CFS. All together, these treatment options should aim at activating descending inhibitory pathways together with decreasing descending facilitatory pathways, rather than targeting peripheral causes of fatigue and pain. For example, one might search for pharmacological options to address the lack of endogenous inhibition during exercise as seen in CFS, prior to commencing a graded exercise, or patient-directed pacing programme. This might overcome the side effects of such exercise interventions in these patients and might even help to reduce the extent of post-exertional malaise seen in some patients.

When identifying patients who will benefit most likely from such a desensitisation-approach, it is important to search for patients in which the clinical picture is dominated by central sensitisation. Such patients can be identified clinically by questioning the patient regarding hypersensitivity to bright light, sound, smell, hot or cold sensations, pressure, touch and mechanical loading [38]. Widespread hyperalgesia can be recognised by palpating for muscle tone at various anatomical locations [38]. Ideally, such signs of central hyperexcitability will cease once the patient recovers.

Implications for research

  1. Top of page
  2. Abstract
  3. Introduction
  4. Studies examining the (hyper)responsiveness of the central nervous system in CFS
  5. How does central sensitisation fit into our overall understanding of CFS?
  6. Implications for clinical practice
  7. Implications for research
  8. Conclusions
  9. Acknowledgements
  10. Address
  11. References

Studies examining the (combined) effects of treatment strategies aiming at desensitising the central nervous system in patients with CFS are currently unavailable. In general, little is known about the effect of pharmacotherapy and other treatment strategies on the mechanism of central sensitisation in humans. Therefore, future work should examine the effects of various (combined) treatment strategies on central sensitisation in patients with CFS. This can be accomplished by including outcome measures like temporal summation [24], spatial summation (or diffuse noxious inhibitory control) [25] or the nociceptive flexion reflex threshold [81] in conjunction with clinical outcomes (e.g. fatigue and pain severity and variability, quality of life) in future randomised (cross-over) clinical trials. Likewise, causation studies of all the treatment options proposed earlier are required. Indeed, centrally acting drugs might lead to side effects, especially in case of generalised hypersensitivity.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Studies examining the (hyper)responsiveness of the central nervous system in CFS
  5. How does central sensitisation fit into our overall understanding of CFS?
  6. Implications for clinical practice
  7. Implications for research
  8. Conclusions
  9. Acknowledgements
  10. Address
  11. References

Mounting evidence supporting a role for central sensitisation in at least a large subset of the CFS population is currently available. Central sensitisation accords with much of what is already known about CFS.

However, the majority of the studies examining central hyperexcitability in CFS come from our group and hence require replication in other settings. Further study in this area is required. In addition, the studies showing delayed DNIC [25] and generalised hyperalgesia [51] in CFS, and two of three studies that found dysfunctional endogenous inhibition in response to exercise in CFS [61,62] used the presence of chronic pain as an inclusion criteria. Hence, some of the findings summarised here apply to CFS patients with chronic pain solely.

On the other hand, nearly all studies examining the mechanism of central sensitisation in CFS point in the same direction. This is important for an illness with a long history of disagreement between scientists and conflicting data across studies. A change in thinking towards studying and treating CFS as a central sensitisation disorder appears warranted. Others have indicated previously that CFS research should transfer its focal point to the central nervous system [92].

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Studies examining the (hyper)responsiveness of the central nervous system in CFS
  5. How does central sensitisation fit into our overall understanding of CFS?
  6. Implications for clinical practice
  7. Implications for research
  8. Conclusions
  9. Acknowledgements
  10. Address
  11. References

Kelly Ickmans is a research fellow of ME Research UK, a national charity funding biomedical research into Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Mira Meeus is a postdoctoral research fellow of the Research Foundation Flanders (FWO). Jessica Van Oosterwijck is a research fellow of the Vrije Universiteit Brussel (OZR1596).

Address

  1. Top of page
  2. Abstract
  3. Introduction
  4. Studies examining the (hyper)responsiveness of the central nervous system in CFS
  5. How does central sensitisation fit into our overall understanding of CFS?
  6. Implications for clinical practice
  7. Implications for research
  8. Conclusions
  9. Acknowledgements
  10. Address
  11. References

Department of Human Physiology, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel (VUB), Pleinlaan 2, Brussel, Belgium (J. Nijs, M. Meeus, J. Van Oosterwijck, K. Ickmans); Division of Musculoskeletal Physiotherapy, Department of Health Care Sciences, Artesis University College Antwerp, Van Aertselaerstraat 31, B-2170 Merksem, Antwerp, Belgium (J. Nijs, M. Meeus, J. Van Oosterwijck, K. Ickmans); Department of Physical Medicine and Physiotherapy, University Hospital Brussels (UZB), Laarbeeklaan 101, B-1090 Jette, Brussels, Belgium (J. Nijs, J. Van Oosterwijck, K. Ickmans); Reference centre for chronic fatigue syndrome, Department of Internal Medicine, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Edegem, Antwerp, Belgium (G. Moorkens); Multidisciplinary Pain Center (PCT), University Hospital Antwerp (UZA), Wilrijkstraat 10, B-2650 Edegem, Antwerp, Belgium (G. Hans); Department of Immunology, Allergy and Rheumatology, University of Antwerp (UA), Wilrijkstraat 10, B-2650 Edegem, Antwerp, Belgium (L. S. De Clerck).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Studies examining the (hyper)responsiveness of the central nervous system in CFS
  5. How does central sensitisation fit into our overall understanding of CFS?
  6. Implications for clinical practice
  7. Implications for research
  8. Conclusions
  9. Acknowledgements
  10. Address
  11. References