Exosome microRNA signatures in patients with complex regional pain syndrome undergoing plasma exchange.

BACKGROUND: Therapeutic plasma exchange (PE) or plasmapheresis is an extracorporeal procedure employed to treat immunological disorders. Exosomes, nanosized vesicles of endosomal origin, mediate intercellular communication by transferring cargo proteins and nucleic acids and regulate many pathophysiological processes. Exosomal miRNAs are potential biomarkers due to their stability and dysregulation in diseases including complex regional pain syndrome (CRPS), a chronic pain disorder with persistent inflammation. A previous study showed that a subset of CRPS patients responded to PE. METHODS: As a proof-of-concept, we investigated the PE-induced exosomal miRNA changes in six CRPS patients. Plasma cytokine levels were measured by HPLC and correlated with miRNA expression. Luciferase assay following co-transfection of HEK293 cells with target 3'UTR constructs and miRNA mimics was used to evaluate miRNA mediated gene regulation of target mRNA. Transient transfection of THP-1 cells with miRNA mimics followed by estimation of target gene and protein expression was used to validate the findings. RESULTS: Comparison of miRNAs in exosomes from the serum of three responders and three poor-responders showed that 17 miRNAs differed significantly before and after therapy. Of these, poor responders had lower exosomal hsa-miR-338-5p. We show that miR-338-5p can bind to the interleukin 6 (IL-6) 3' untranslated region and can regulate IL-6 mRNA and protein levels in vitro. PE resulted in a significant reduction of IL-6 in CRPS patients. CONCLUSIONS: We propose that lower pretreatment levels of miR-338-5p in poor responders are linked to IL-6 levels and inflammation in CRPS. Our data suggests the feasibility of exploring exosomal miRNAs as a strategy in patient stratification for maximizing therapeutic outcome of PE.

Plasma Exchange Therapy in Patients with Complex Regional Pain Syndrome.

BACKGROUND: Complex regional pain syndrome (CRPS) is a severe chronic pain condition that most often develops following trauma. Some investigators have postulated CRPS to be a post-traumatic neuralgia associated with distal degeneration of small-diameter peripheral axons. Intravenous immunoglobulin treatment (IVIG) has been shown to be efficacious in the treatment of painful polyneuropathies. Some CRPS patients have been reported to respond to IVIG. Based on a recent hypothesis proposing an autoimmune etiology for CRPS, we decided to offer plasma exchange therapy (PE) to CRPS patients with a clinical presentation suggestive of a small fiber neuropathy. OBJECTIVES: To evaluate the efficacy of PE in a group of CRPS patients with a clinical presentation suggestive of a small fiber neuropathy that were either non-responders or poor responders to their current treatment. STUDY DESIGN: This is a retrospective case series study of CRPS patients that met the Budapest diagnostic criteria for CRPS and received PE as treatment for their illness between September 2012 and June 2014. Approval for this review was granted by the Drexel University Institutional Review Board. SETTING: Drexel University College of Medicine pain clinic METHODS: Thirty-three CRPS patients that received PE treatment were retrospectively studied. The workup for these patients consisted of a complete medical and pain evaluation, the completion of the short-form McGill questionnaire, quantitative sensory testing (QST), and skin punch biopsy. The PE protocol was as follows: all patients had a series of PE therapies (range 5 to 11 with a mean of 7.2) performed over a 2 to 3 week period. Following the PE series, the patients had a pain evaluation and completed the short-form McGill questionnaire. Patients that responded to PE were offered maintenance therapy consisting of either weekly PE or other immune modulating agents. In these patients, their pain was evaluated during the maintenance phase. RESULTS: Thirty of the 33 patients demonstrated significant (P < 0.01) median pain reduction of 64% following the initial series of PE. Three patients demonstrated no improvement. Twenty-four patients are receiving maintenance therapy, the pain reduction in these patients following the initial PE series has been maintained with either weekly PE (n = 15), oral immune modulating agents (n = 8), or IVIG (n = 1). The remaining 6 patients are not receiving maintenance therapy and their pain has returned to pre-treatment levels. In addition, this study suggests that patients with the greatest loss of small fibers and the greatest temperature sensory deficits are most likey to benefit from PE therapy. LIMITATIONS: The major limitation of this study is its retrospective nature which includes non-randomization, non-blinding, and an uncontrolled design. CONCLUSIONS: This study shows that PE is effective in a subset of patients with severe long-standing CRPS and that the reduction in pain following the initial series of PE treatments can be maintained on a weekly PE schedule, IVIG, or with other immune modulating drugs. Large, randomized, placebo controlled studies may be required to confirm and expand these results. Such studies may lead to new therapies for this severe life-altering condition.

Acute loss of spatial navigational skills in a case of a right posterior hippocampus stroke.

The ability to accurately navigate within an environment (known or new) is not fully understood but involves a number of highly complicated cognitive process related to both central and peripheral nervous system structures and neuronal networks. We describe a patient who developed loss of his spatial navigational skills associated with an acute ischemic right posterior hippocampal lesion. Neuropsychological assessment displayed clear evidence of impaired visuospatial/visuoconstructional abilities with relative preservation of many other cognitive functions involving orientation, language, and verbal memory. The underlying anatomy responsible for the navigational impairment seen in our patient could be due to impairment in the function of the right hippocampus to form, store, and retrieve new 'cognitive/spatial maps'. To our knowledge this is one of the few documented cases demonstrating impaired navigational abilities with a relatively discrete right-sided, posterior hippocampal lesion.

Kinesigenic dyskinesia in a case of voltage-gated potassium channel-complex protein antibody encephalitis.

OBJECTIVE: To describe the first case (to our knowledge) of voltage-gated potassium channel-complex protein antibody encephalitis with kinesigenic dyskinesia and cramp-fasciculation syndrome. DESIGN: Case report. SETTING: Hospitalized care. PATIENT: A 38-year-old man with a history of bronchial asthma, eczema, vitiligo, and immune complex mesangiopathic glomerulonephritis presented with abnormal movements. MAIN OUTCOME MEASURES: Clinical examination, magnetic resonance imaging, single-photon emission computed tomography, electromyography and nerve conduction studies, video-electroencephalographic monitoring, plasmapheresis exchange therapy, and intravenous immunoglobulin administration. RESULTS: Clinical examination revealed paroxysmal kinesigenic dyskinesia and fasciculations. Magnetic resonance imaging of the brain revealed a left caudate and left putamen increased signal lesion on T2-weighted and fluid-attenuated inversion recovery sequences as well as increased flow in the same region on single-photon emission computed tomographic scans. Electromyography and nerve conduction studies revealed significant afterdischarges, cramp potentials, and continuous motor activity. The video-electroencephalographic monitoring revealed no epileptiform discharges. The patient dramatically improved after 5 plasmapheresis exchange treatments and a course of intravenous immunoglobulin at 2 gm/kg over 5 divided doses. CONCLUSION: To our knowledge, this is the first report of paroxysmal kinesigenic dyskinesia with voltage-gated potassium channel-complex protein antibody encephalitis associated with the cramp fasciculation syndrome.