Complex Regional Pain Syndrome and Spreading neuroinflammation and autoimmunity – a model for ME/CFS and fibromyalgia?

Neuroinflammation in ME/CFS and Fibromyalgia

In previous articles I’ve been trying to set out, at some length and based on converging evidence, a proposed model of ME/CFS and a range of other conditions, including fibromyalgia (FMS), in which neuroinflammation may play a central role.

One difficulty in developing a model of ME/CFS in particular is heterogeneity of symptoms and the range of putative triggers. Onset of FMS is often idiopathic.

Complex Regional Pain Syndrome


The pain in chronic regional pain syndrome (CRPS) is intense – even exceeding that found in fibromyalgia

Complex Regional Pain Syndrome 1 (CRPS) (previously known as Reflex Sympathetic Dystrophy or RSD) is a relatively rare but possibly under-diagnosed condition which has been recognized for some 150 years. (It was included by the eminent and influential 19th century neurologist Charcot in the ‘hysteria minor‘ group of disorders.)

Some consider CRPS and fibromyalgia as close cousins, while others seem to want to put some clear blue water between the two based on the more intense pain experienced by CRPS patients (clocking in at a whopping 42 out of 50 on the McGill Pain Scale 2). Regardless, there’s extensive symptom overlap between the two disorders 3 and, by extension, with ME/CFS.

CRPS predominantly affects females (outnumbering men by a factor of four to one), and the most frequent age of onset is in the 40s. But it also occurs in children where it may be associated with Ehlers-Danlos Syndrome, mitochondrial disorders, or nerve entrapment. Most often CRPS develops following a relatively minor injury to a limb (even a needle stick!) associated with obvious nerve damage (CRPS II or causalgia) or without (CRPS I).

What follows is a level of pain that persists long after the injury (or surgery) that is out of proportion to the actual tissue damage and that progresses to a multi-organ systemic illness. No apparent biological basis for the pain has been found.

Reflex sympathetic dystrophy was abandoned as a name as it didn’t properly reflect the disease process, yet the ‘sympathetic’ part is accurate, as activation of the sympathetic nervous system plays a key role in the disorder.

Primary and Systemic Symptoms

The primary symptoms of CRPS are first seen in the affected limbs and include intense burning pain; ‘tropic’, autonomic, vascular sudomotor and endocrine changes affecting skin color and temperature, sweating, hair and nail growth with frequent neurogenic edema and various motor dysfunctions – fixed dystonia (fixed abnormal posture), myoclonic spasms, tremors, paresis (loss of voluntary movement), loss of strength and muscle atrophy.


CRPS differs from FM and ME/CFS in that it produces swelling, color and skin changes and sometimes even deformity in the afflicted limb. Other symptoms and findings, however, are quite similar.

Pain may also spread to other immediately adjacent areas, but can also turn up in areas far from the injury site.

Most intriguing are the systemic co-morbid symptoms that seem not only disproportionate to the initial injury, but at first glance seem completely unrelated and difficult to explain.

These include widespread hyperesthesia and allodynia, deep bone and joint pain, increased levels of pro-inflammatory cytokines suggesting systemic low grade inflammation, cardiac symptoms (chest pain spreading to the arm, neck and jaw, syncope, POTS, and increased heart rate and reduced heart rate variability reflecting generalized autonomic dysfunction) and gastrointestinal (including gastroparesis and reflux) and urological symptoms.

“The current CRPS study demonstrated increased heart rate and reduced heart rate variability. The pathologically reduced cardiac output and exaggerated increase in the total peripheral resistance during orthostatic stress point toward a dysfunction of the autonomic control of the cardiovascular system.”4

Both those statements could have come right out of a chronic fatigue researcher’s playbook.

Cognitive problems are also evident including problems with executive function, naming and memory :

“Significant neuropsychological deficits are present in 65% of patients, with many patients presenting with elements of a dysexecutive syndrome and some patients presenting with global cognitive impairment”5

Needless to say, as with other chronic illnesses – especially those involving pain – depression, anxiety, and symptoms of post-traumatic stress disorder – are common, as is fatigue:

“Almost all severely affected CRPS patients complain of lethargy, tiredness, and weakness.” 6

In one study 69% of patients described “overwhelming fatigue”.

Organic or Psychogenic?


The gender imbalance in CRPS and its many symptoms undoubtedly contributed to its designation as ‘hysteria minor’ despite its overt physical effects

Little wonder then that, since Charcot’s classification of CRPS as “hysteria minor”, these widespread systemic symptoms have often been interpreted and treated as psychogenic or given another euphemism like “medically unexplained”. Indeed, CRPS has also been called the “great imitator” due the overlap with or similarity to other disorders.

It holds that appellation in common with lupus, fibromyalgia and even sometimes chronic fatigue syndrome.

All now seems to be about to change. There is growing evidence, summarized in the following paper, that CRPS is a neuroinflammatory disorder and that it may be of autoimmune origin, with the result that the CRPS/RSD community is now discussing the likelihood of another name change.

Neuroinflammation, Neuroautoimmunity, and the Comorbidities of Complex Regional Pain Syndrome 7 – Mark S. Cooper and Vincent P. Clark

This intriguing paper sets out a model which, based on emerging evidence, attempts to explain the mechanisms by which a local peripheral injury can result, in a small minority of patients, in a widespread chronic multi-system condition. The key mechanism they propose is called spreading neuroinflammation.


As in ME/CFS and FM, a stressor, in this case often a small injury, can result in devastating changes for some. ‘Neuroinflammatory spreading’ could explain why…

Given that CRPS is a condition for which a neuroinflammatory process has been proposed and, unlike in ME/CFS or FMS, the initial trigger in many cases is unambiguous, CRPS may provide a more constrained environment in which to explore a potential neuroinflammatory model of other complex multi-system syndromes including ME/CFS and FMS.

It’s worth repeating that a) it often takes only a small injury to trigger this devastating disorder, and b) as occurs with post-viral ME/CFS or trauma induced fibromyalgia, only a minority of people develop it, and c) the symptoms of CRPS are quite distinct from the original trauma.

This is a complex paper, which I can only hope to skim over. For those of you interested, the full paper is well worth reading. I’ve attached a list of references and some related resources below.

Spreading Neuroinflammation and Neuroinflammatory Tracks

Experimental evidence supports the notion of spreading neuroinflammation where inflammation spreads from the initial injury site throughout the nervous system, either towards the periphery or to higher level regions.

Peripheral trauma or injury results in activated microglia at first order neurons. In a minority of patients, neuroinflammation migrates trans-synaptically to second order synapses at higher levels of the nervous system including the thalamus (an area of the brain involved in sensory perception, motor functions, sleep and alertness).


Inflammatory spreading through the nervous system appears to cause both central sensitivity, and affect some of the same cognitive processes that are disturbed in ME/CFS…

In CRPS, it appears that a complex interaction of activated microglia, astroglia and NMDA (N-methyl-D-aspartate or glutamate) receptors in the spinal cord results in “wind-up” (a nerve process that exacerbates pain), central sensitization, loss of inhibitory tone, excessive sensory gain (pain signals are amplified) and reduced sensory gating.

First, an injury in the periphery (body) activates first order nociceptive (pain sensing) neurons to release the signaling cytokine CCL21, which then triggers secondary neuroinflammation in the thalamus, creating a ‘central generator of neuropathic pain’.

Neuroinflammation or neuroinflammatory tracks that spread through the nervous system alter neurotransmission and coding, causing higher order functional changes in the nervous system including, perhaps, deficits in higher level brain tasks such as executive functioning.

It’s important to note that these neuroinflammatory tracks may not necessarily result in easily detected structural changes to the nervous system (e.g. demyelination of nerves or gross structural changes to the brain). Functional or dynamic lesions that may also contribute to the pathology may be undetectable using neuroimaging technologies such as traditional MRI scans.

“Spreading neuroinflammation provides a non-psychogenic etiology to plausibly explain the progression and chronicity of certain disease states, as well as the migration of symptoms to different portions of the body. This mechanistic concept of spreading neuroinflammation within the CNS needs to be incorporated into differential diagnosis of neurological and neuropsychiatric disorders, as well as into the standard use of the Diagnostic and Statistical Manual for Mental Disorders (DSM). This would substantially advance the recognition and diagnosis of neuroinflammatory-mediated functional disorders within the biomedical community.”

Spreading neuroinflammation in ME/CFS and FMS?

Spreading neuroinflammation provides a mechanism by which a discrete peripheral injury can set up a chain of physiological and functional changes to the peripheral and central nervous system that results in a widespread, chronic systemic illness.

However, few ME/CFS patients report similar physical trauma around the time of onset, but a substantial proportion report onset following a viral illness. A neurotropic virus (one with an affinity for infecting neurons) is one possibility as long as the virus can cross the blood brain barrier. (One example is the Japanese Encephalitis virus, which causes neuroinflammation of the central nervous system, but no such similar virus has been found consistently in ME/CFS patients.)

Many report the onset of symptoms following common viral infections such as mononucleosis, and the Dubbo studies suggest that a small minority will develop ME/CFS following a variety of common infections, just as only a few develop CRPS following trauma.

Two speculative hypotheses suggest possible “hit and run” scenarios. In one, a sensory ganglia or paraganglia infection of the vagus nerve establishes a self-perpetuating activation of glial cells leading to ongoing sickness behavior 8. In the other, as demonstrated in an animal model, a common respiratory infection (a modified form of the H1N1 flu virus) can establish spreading neuroinflammation in glial cells contained in the olfactory bulb, which is anatomically close to key brain regions. The authors propose that repeated such encounters with common viruses might explain neurodegenerative conditions such as Alzheimer’s. 9

In contrast, estimates for precipitating factors in FMS vary from around 70% being idiopathic to up to 50% reporting onset following physical trauma.


Given that there is a clearly identified trigger, why then do only a small proportion of patients go on to develop CRPS? CRPS literature suggests that some people do appear to have a predisposition to developing conditions such as CRPS. (Given the history of the condition in the medical community it would be little surprise if these predispositions were presented as psychological or personality-based).

The gender bias (like ME/CFS and FMS), though, is suggestive of many autoimmune diseases, and some autoimmune diseases cause similar widespread systemic symptoms (Sjogren’s Syndrome), and autoantibodies to neurotransmitters can result in muscle pain, stiffness and dystonia (Stiff Person Syndrome).


Adrenergic receptor issues have shown up in both CRPS and chronic fatigue syndrome

An autoimmune contribution to CRPS now appears likely given recent findings that 90% of an adult CRPS cohort had autoantibodies (agonistic, therefore upregulating) to either the beta(2)-adrenergic receptor (β2AR) or the muscarinic acetylcholine receptor (M2R). Fifty percent of the cohort had autoantibodies to both. 10

The actions and distribution of these receptors closely match CRPS symptoms: β2AR or M2R receptors are found in the cerebellum, reticular formation, motor cortex, and thalamus in the brain, in the sympathetic and parasympathetic nervous system, the heart, the pyramidal motor pathway to skeletal muscles, in peripheral nerves, and in astrocytes and microglia.

Interestingly Alan Light’s team 11 recently found a threefold upregulation of gene expression for the adrenergic alpha2a receptor in ME/CFS patients following exercise. In addition, several studies have found autoantibodies to muscarinic acetylcholine receptors in ME/CFS 12, 13 and Sjogren’s Syndrome 14. Evidence for autoimmunity in FMS is scant but fibromyalgia does appear to occur co-morbidly in autoimmune diseases such as lupus, rheumatoid arthritis and autoimmune thyroid disease 15.

Peripheral injury can lead to a transient disruption of the blood/spinal cord and/or blood/brain barrier. In a CRPS patient with a peripheral nerve injury, circulating autoantibodies may infiltrate into the parenchyma (microglia and astrocytes) of the affected nerve causing a neuroautoimmune response as the immune system reacts to autoantibodies that bind to neuronal and glial cells. Autoimmune attack of peripheral nerves may then trigger spreading neuroinflammation in the spinal cord leading to the systemic co-morbid symptoms seen in CPRS.

Thus autoimmunity might sustain and exacerbate the spreading mechanism of neuroinflammation described above.

Small fiber neuropathy provides an intriguing potential link between FMS, CRPS and autoimmunity. Objective evidence of small fiber neuropathy has been found in FMS patients, most recently by the pain researcher Anne Louise Oaklander 16. Dr. Oaklander also studies CRPS patients and has found that those (Type I) patients, previously presumed not to have a nerve injury, actually have small fiber neuropathy 17. Could these previously undetected microscopic lesions be sufficient to trigger the infiltration of autoantibodies into the central nervous system either through the breakdown of the blood brain barrier by pro-inflammatory cytokines or via peripheral glial cells?

nerve damage

Small fiber neuropathy has been found in CRPS/FM and ME/CFS patients. This image shows two highly degraded nerves; i.e., a neuropathy,

This model therefore provides a mechanism whereby peripheral inflammation (potentially exacerbated by autoantibodies to either the β2AR or M2R receptors) can propagate from the peripheral injury site to higher levels of the nervous system, resulting in hyperexcitability and eventually impacting higher cognitive functions (avoiding the blood brain barrier issue by propagating via the parenchyma of the central nervous system).

The authors suggest that autoimmunity may be a predisposing factor and may develop in conjunction with a wide range of environmental or psychological stressors:

“The key concept here is that the development of autoimmunity to specific neuroautoantigens may be the initiating event for many cases of CRPS. Psychological stressors, physical trauma, infectious agents, and/or genetic susceptibility could all play a role in the breakdown of self-tolerance, and the onset of an autoimmune response. This set of etiological linkages fits well with documented clinical experience with CRPS (Mitchell 1872; Birklein et al. 2000). Psychological stressors and immunologic priming have been linked to the enhanced activation of microglia to nervous system injury (Frank et al. 2007; Hains et al. 2010).”

A note of caution, though: While the authors stress potential environmental triggers for autoimmunity, Professor Jonathan Edwards (who pioneered the use of B-cell depleting Rituximab in the treatment of autoimmune rheumatoid arthritis and who is advising on a UK trial of Rituximab in ME/CFS) has stated in discussions on Phoenix Rising that the development of autoimmunity is essentially a random event generated entirely by the immune system’s “accidental” production of antibodies that bind to “self” cells. From this perspective, environmental triggers may be innocent bystanders in the development of autoimmunity but, as with damage to peripheral nerves in CRPS, may provide the opportunity for the autoantibodies to enter the nervous system causing systemic disease.

CRPS Treatments

Current treatments for CRPS appear to be aimed at symptomatic relief and/or attempting to prevent further progression of the condition. Amongst these are a familiar collection of drug and non-drug therapies targeted at pain, neuropathic pain, and neuroinflammation.

Physiotherapy and psychotherapy are commonly used, while more invasive/radical treatments such as surgical sympathectomy and spinal cord stimulation have been tried

On- and off-label drugs include NSAIDS and corticosteroids which appear to be of little use once the condition has become chronic. Others (Neurontin, Lyrica, Cymbalta, Savella, Baclofen and Ketamine) work to either boost the inhibitory neurotransmitter GABA or block excitatory glutamate NMDA receptors – the balance between the two having been long implicated in chronic pain, movement disorders, and neuroinflammation generally. Ibudoblast, the antibiotic Minocycline, and Low Dose Naltrexone may attenuate activated glia 18, which, as discussed above, are clearly implicated in neuroinflammation in CRPS. In contrast, long term use of opioids may increase glial cell activation.

With immune activation implicated in CRPS, intravenous immunoglobulin (IVIG) treatment (antibodies extracted from healthy donors that may be helpful in some disorders of the immune system) has shown some efficacy in a small trial.

If autoimmunity does underlie CRPS, then previous treatment approaches are only addressing the symptoms and not the root cause. However, as the autoimmune findings are fairly recent (2011 in the case of the findings discussed above) B cell depletion therapy using agents such as Rituximab have not been tried in CRPS.

Reference 19 provides a more complete overview of treatment options and contraindications.

A (posthumous) Apology from M Charcot?

Has Charcot’s inclusion of CRPS within the hysteria minor disorders led to unnecessary skepticism and sub-optimal treatment from the medical profession over many decades? Possibly, but perhaps his students (including Freud) and the psychiatrist who claimed that Charcot knew “almost nothing about major psychiatric illness” 20 should have paid more attention to all of his writings before invoking ‘psychogenic’, ‘somatization’ or ‘conversion disorders’.


An era focused on psychological explanations passed over Charcot’s belief that undiagnosed lesions also played a role.

While Charcot may have dabbled in psychology and hypnotism, he was first and foremost a neurologist and to quote the main paper under discussion here:

In the 1880s, Charcot first hypothesized that hysteria was generated by non-structural lesions in the nervous system (Harris 2005). He postulated that these lesions were likely to be biochemical or physiological in character. In describing a case study, during a lecture on hysteria, Charcot (1885) stated: “We have here unquestionably one of those lesions which escape our present means of anatomical investigation, and which, for want of a better term, we designate dynamic or functional lesions.”

Charcot’s conception of disorders such as CRPS was clearly that they were due to physiological “lesions” that were not detectable by the then-current neurological means for investigation that depended on visible structural changes.

Or, in a nutshell, absence of evidence does not mean evidence of absence.

Perhaps now medical science and technology has advanced enough to detect microscopic structural lesions plus functional and temporal dysregulation of the nervous system of the type described here as “neuroinflammatory tracks” relegating “psychogenic” explanations of conditions such as CRPS and other “medically unexplained” symptoms to the past. 21

Could ME/CFS and FMS share a similar neuroinflammatory and possibly autoimmune etiology that, to date, has largely evaded investigators?

References and some Resources

1. Complex regional pain syndrome

Wikipedia http://en.wikipedia.org/wiki/Complex_regional_pain_syndrome


American RSD Hope – http://www.rsdhope.org/mcgill-pain-index—where-is-crps-pain-ranked.html

3. Development of a Symptoms Questionnaire for Complex Regional Pain Syndrome and Potentially Related Illnesses: The Trauma Related Neuronal Dysfunction Symptoms Inventory

Susan Collins, MSc, Jacobus J. van Hilten, MD, PhD, Johan Marinus, PhD, Wouter W. Zuurmond, MD, PhD, Jaap J. de Lange, MD, PhD, Roberto S. Perez, PhD


4. Heart Rate Variability in Complex Regional Pain Syndrome during Rest and Mental and Orthostatic


Astrid J. Terkelsen, M.D., Ph.D, Henning Mølgaard, M.D., Ph.D., John Hansen, M.Sc.EE, Ph.D.,

Nanna B. Finnerup, M.D., Ph.D., Karsten Krøner, M.D., Troels S. Jensen, M.D., Ph.D.


5. Neuropsychological deficits associated with Complex Regional Pain Syndrome


6. Systemic Complications of Complex Regional Pain Syndrome

Robert J Swartzman


7. Neuroinflammation, Neuroautoimmunity, and the Co-Morbidities of Complex Regional Pain Syndrome

Mark S. Cooper and Vincent P. Clark


8. Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis.

VanElzakker MB.


9. Neuroinflammation Resulting from Covert Brain Invasion by Common Viruses—a Potential Role in Local and Global Neurodegeneration

Jeannine A. Majde, Ph.D.


10. Autoimmunity against the β2 adrenergic receptor and muscarinic-2 receptor in complex regional pain syndrome.

Kohr D, Singh P, Tschernatsch M, Kaps M, Pouokam E, Diener M, Kummer W, Birklein F, Vincent A, Goebel A, Wallukat G, Blaes F.


11. Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression

Jacob D. Meyera, Alan R. Light, Sanjay K. Shuklad, Derek Clevidence, Steven Yale, Aaron J. Stegner & Dane B. Cook


12. Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome.

Tanaka S, Kuratsune H, Hidaka Y, Hakariya Y, Tatsumi KI, Takano T, Kanakura Y, Amino N.


13. Reduction of [11C](+)3-MPB Binding in Brain of Chronic Fatigue Syndrome with Serum Autoantibody against Muscarinic Cholinergic Receptor

Shigeyuki Yamamoto, Yasuomi Ouchi, Daisaku Nakatsuka, Tsuyoshi Tahara, Kei Mizuno, Seiki Tajima, Hirotaka Onoe, Etsuji Yoshikawa, Hideo Tsukada, Masao Iwase, Kouzi Yamaguti, Hirohiko Kuratsune, Yasuyoshi Watanabe


14. Clinical associations of autoantibodies to human muscarinic acetylcholine receptor 3213–228 in primary Sjögren’s syndrome

L. Kovács, I. Marczinovits, A. György, G. K. Tóth , L. Dorgai, J. Pál , J. Molnár and G. Pokorny


15. Fibromyalgia and Autoimmune Disease : The Pain Behind Autoimmunity

Dan Buskila, MD, Piercarlo Sarzi-Puttini, MD.


16. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia.

Oaklander AL, Herzog ZD, Downs HM, Klein MM.


17. Is reflex sympathetic dystrophy/complex regional pain syndrome type I a small-fiber neuropathy?

Oaklander AL, Fields HL.


18. Treatment of Complex Regional Pain Syndrome (CRPS) Using Low Dose Naltrexone (LDN)

Pradeep Chopra and Mark S. Cooper


19. Complex Regional Pain Syndrome or Reflex Sympathetic Dystrophy

Updates on Treatment

Pradeep Chopra MD


20. Jean-Martin Charcot



21. Rethinking the Psychogenic Model of Complex Regional Pain Syndrome.

Renee J Hill, Pradeep Chopra, Toni Richard



Complex regional pain syndrome

NHS Choices


Complex Regional Pain Syndrome Fact Sheet

National Institute of Neurological Disorders and Stroke


Reflex Sympathetic Dystrophy Syndrome Association – http://www.rsds.org/2/what_is_rsd_crps/

Complex Regional Pain Syndrome – Practical Pain Management.com



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