At the 1-month gastroenterology clinic visit, she reported a marked improvement in her leg and bowel symptoms. LDN was continued long term. At the 3-month sleep medicine clinic visit, interrogation of the sleep apnea device over 90 days revealed 82% use >4 hours with 6 hours average use per night. At a 16-month gastroenterology clinic visit, she returned with reports of 1 month of bloating, fatigue, and episodic minor attacks of pain in the arms and nose in cold weather. Inadequate treatment of sleep apnea was suspected because the patient revealed she would often have nightmares, and in the morning, she would find her BiPAP device on the floor. There was mild diffuse abdominal tenderness. Complete remission of CRPS was noted in her right leg (Fig. 2). LDN was continued, and 3 therapies were added: (1) rifaximin (1650 mg/d for 1 month) to retreat SIBO; (2) erythromycin (50 mg/night long term, which acts as motilin-like hormone to stimulate the small intestinal migrating motor complex, which reduces SIBO relapse)20; and (3) clonazepam (1 mg/night) to reduce nightmares and reduce the urge to remove the BiPAP device. At the 6-month sleep medicine clinic visit, interrogation of the BiPAP device over 30 days documented improvement to 100% use >4 hours with >7 hours average use per night. Multiple communications over the following 9 months revealed that there had been rapid and sustained remission of all CRPS pain, bowel symptoms, and fatigue.
In this case, remission of CRPS was attained by directing therapy toward SIBO, OSA, and potential increased microglia activity. We theorize that cytokine production including tumor necrosis factor produced by SIBO21 and OSA22 may act as stimuli for ongoing CRPS symptoms. Experimental therapy of unregulated inflammation and microglia activation using LDN has been reported in pain disorders including 2 cases of CRPS.11,20
Systemic pain disorders have been reported in association with SIBO, and thus, this inflammatory state may also play an additional role in CRPS in a patient who has the appropriate phenotypic risk and/or had one of the classic initial inciting triggering events (as was seen in this patient). Pain disorders associated with SIBO include IBS with diarrhea predominance (IBS-d), fibromyalgia, restless legs syndrome, interstitial cystitis, and chronic prostatitis.21 Finally, inflammation and immune disorders in general have been observed to be present in 95% of the 38 highly associated causes, disorders, and triggering factors for secondary restless legs syndrome.23
There is a known relationship of CRPS and the gastrointestinal tract. Dysbiosis (alterations of the microbiome) and increased intestinal permeability (which is present in SIBO) have been reported in CRPS, and these 2 conditions also cause chronic systemic inflammation.24–26 IBS is common in CRPS although the relationship has hitherto not been elucidated.27 In multiple studies, SIBO was found to be present in up to 50% of IBS-d patients.21 Treatment of both SIBO and IBS with rifaximin, a nonabsorbed, gut-directed antibiotic, has been extensively studied, and use of rifaximin for IBS-d was approved by the U.S. Food and Drug Administration in May 2015.28 Increased levels of substance P are present in IBS-d and are more pronounced in women.29 This observation might have significance because there is a bidirectional gut–brain connection between the microbiome and substance P.30 This neuropeptide is thought to play a role in CRPS,31,32 and women are also more prone to have CRPS as previously noted. Finally, SIBO may also play a role in CRPS by means of lipopolysaccharide translocation through SIBO-induced increased intestinal permeability, which then could activate microglia activity.33
Ehlers-Danlos syndrome is a dominant inherited systemic disorder, and the incidence may be as high as 2% of the population.19 This syndrome is commonly missed in childhood, and adults may present with a unique set of problems that may leave physicians confounded as seen in our patient and her kindred. Thus, published reports of concomitant CRPS and Ehlers-Danlos syndrome are far rare.20,34 The authors of a case series with 4 patients proposed that Ehlers-Danlos syndrome contributed to CRPS via stretch injury to the nerves traversing hypermobile joints, increased fragility of nerve connective tissue, and/or nerve trauma from more frequent surgery.34 Subsequently, both syndromes have been subsequently concurrently diagnosed in approximately 25% of 1 of the author’s pain management practice.
Three alternative mechanisms whereby Ehlers-Danlos syndrome contributes to CRPS are proposed. Ehlers-Danlos syndrome causes OSA owing to connective tissue laxity,35 and thus, subsequent chronic hypoxia-induced inflammation22 may contribute to CRPS activation. This mechanism appeared to play a role in our patient because complete remission of all CRPS symptoms was not attained until sleep apnea therapy was completely optimized. Gastrointestinal symptoms are common in both CRPS and Ehlers-Danlos syndrome.27,36 In Ehlers-Danlos syndrome, SIBO and small intestinal motility changes have been reported: dilated small intestinal diameter, small bowel diverticulosis, small intestinal motility disorders, and loose connective tissue in the mesentery that allows for drooping of the small intestine to create a relative blind loop.37–40 Defective collagen synthesis, α-actin deficiency, and autonomic dysfunction are potential explanations for abnormal motility in Ehlers-Danlos syndrome.41,42 SIBO may be common in CRPS because Goebel et al.25 demonstrated that increased intestinal permeability was common in CRPS. A recent case report using long-term cephalosporin to keep CRPS in remission supports the idea that manipulation of the microbiome may play a role in CRPS therapy.43 Thus, inflammation from SIBO caused by Ehlers-Danlos syndrome may contribute to CPRS activation. Finally, the severity of CRPS may be enhanced in patients with Ehlers-Danlos syndrome owing to central hypersensitivity.44
In our patient, LDN was administered to attenuate microglia activation by blocking Toll-like receptors 2 and 4.11,20 In addition, LDN causes rebound met-enkephelin production, which then regulates systemic inflammation by regulating T- and B-cell lymphocyte response, and cytokine production, which may be important in CRPS.11 This is now the third reported case in which LDN has demonstrated improvement in CRPS symptoms.20 Subsequently, 1 of the authors has used this therapy frequently in his practice and has observed therapeutic benefit in patients with CRPS. Administration of LDN as off-label use for pain control is experimental.
The limitations of this report include that CRPS symptoms might have gone into spontaneous remission although most patients experience symptoms for many years.6,7 The unremitting nature of this patient’s symptoms and the rapid response to each course of therapy argue against this concern. Multimodality therapy was administered so it is unknown how much each contributed to remission of CRPS symptoms. However, a multimodality approach by pain management physicians is commonplace in CRPS.1
Physicians may not be familiar with the SIBO link to IBS, and thus, gastrointestinal symptoms may be dismissed as unrelated problems in the patient with CRPS. OSA may go unrecognized because sleep disturbance is common in CRPS and is often blamed on pain. An epidemiological study of the prevalence of Ehlers-Danlos syndrome, SIBO, and OSA is required to further understand the roles that these conditions may play in CRPS. It is possible that undiagnosed Ehlers-Danlos syndrome in patients with CRPS could also explain some cases of familial CRPS. We theorize that recognition and treatment of underlying causes of inflammation are likely to be important future modalities in CRPS.
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