Studying serum neurofilament light chain levels as a potential new biomarker for small fiber neuropathy.

BACKGROUND AND PURPOSE: Diagnosing small fiber neuropathies can be challenging. To address this issue, whether serum neurofilament light chain (sNfL) could serve as a potential biomarker of damage to epidermal Aδ- and C-fibers was tested. METHODS: Serum NfL levels were assessed in 30 patients diagnosed with small fiber neuropathy and were compared to a control group of 19 healthy individuals. Electrophysiological studies, quantitative sensory testing and quantification of intraepidermal nerve fiber density after skin biopsy were performed in both the proximal and distal leg. RESULTS: Serum NfL levels were not increased in patients with small fiber neuropathy compared to healthy controls (9.1 ± 3.9 and 9.4 ± 3.8, p = 0.83) and did not correlate with intraepidermal nerve fiber density at the lateral calf or lateral thigh or with other parameters of small fiber impairment. CONCLUSION: Serum NfL levels cannot serve as a biomarker for small fiber damage.

[Neuropathic pruritus-Evidence-based treatment recommendations]. / Neuropathischer Pruritus ­ evidenzbasierte Behandlungsempfehlungen.

Neuropathic pruritus is a previously neglected symptom of a wide range of neurological diseases. Peripheral nerve or root compression syndromes, space-occupying lesions of the central nervous system, chronic inflammatory neurological diseases and polyneuropathy can cause neuropathic pruritus. Even when the identification of the underlying neurological disease is successful, a direct causal treatment is not always possible, hence an effective symptomatic treatment remains the only therapeutic option. The purpose of this review article is to present the current literature on various therapeutic agents and options in the treatment of neuropathic pruritus.

Vestibular compensation of otolith graviceptive dysfunction in stroke patients.

BACKGROUND AND PURPOSE: A sensitive and frequent clinical sign of a vestibular tone imbalance is the tilt of the perceived subjective visual vertical (SVV). There are no data yet focusing on lesion location at the cortical level as a factor for predicting compensation from the tilt of the SVV. METHODS: With modern voxelwise lesion behavior mapping analysis, the present study determines whether lesion location in 23 right-hemispheric cortical stroke patients with an otolith dysfunction could predict the compensation of a vestibular tone imbalance in the chronic stage. RESULTS: Our statistical anatomical lesion analysis revealed that lesions of the posterior insular cortex are involved in vestibular otolith compensation. CONCLUSION: The insular cortex appears to be a critical anatomical region for predicting a tilt of the SVV as a chronic disorder in stroke patients.

[Complex regional pain syndrome-An update]. / Komplexes regionales Schmerzsyndrom ­ ein Update.

Complex regional pain syndrome (CRPS) is a pain disorder that develops in the hands or feet after injury. Currently, two types are differentiated, CRPS I without and CRPS II with nerve lesions as well as with either an initially warm or an initially cold subtype, depending on the clinical symptoms. After trauma a certain amount of inflammatory reaction is considered physiological. In acute CRPS this inflammation persists for months and is maintained by diverse inflammatory mediators in peripheral tissue and in blood. This persisting inflammation leads to a sensitization of the nociceptive system, causes somatic cells to proliferate and gives rise to a disrupted endothelial function. The treatment concept aims to antagonize the pathophysiologic components and includes anti-inflammatory and analgetic treatment, mobilization and restoration of the sensorimotor function of the affected limb.

The importance of the insular cortex for vestibular and spatial syndromes.

BACKGROUND AND PURPOSE: The aim of the study was to identify the neuroanatomical correlates and associations of neuropsychological syndromes after acute unilateral right-hemisphere brain lesions. The neuropsychological syndromes considered were orientation in three-dimensional space such as tilts of the subjective visual vertical or of the subjective haptic vertical, pusher syndrome, visual neglect and unawareness of paresis (anosognosia for hemiparesis). These neuropsychological phenomena have been found to occur separately or in different combinations after lesions to the right insular cortex. METHOD: Magnetic resonance imaging scans were obtained from 82 patients with acute right-hemispheric stroke. A lesion-behavior mapping analysis was conducted to specify the neuroanatomical correlates of the above-mentioned neuropsychological syndromes. RESULTS: In all analyses of the individual neuropsychological syndromes the insular cortex was affected. CONCLUSIONS: Thus, the insular cortex is involved in (self-)perception and orientation within a three-dimensional space. Since isolated lesions of the insular cortex did not induce the above neuropsychological phenomena, there have to be other regions involved.

Low mechano-afferent fibers reduce thermal pain but not pain intensity in CRPS.

BACKGROUND: Human hairy (not glabrous skin) is equipped with a subgroup of C-fibers, the C-tactile (CT) fibers. Those do not mediate pain but affective aspects of touch. CT-fiber-activation reduces experimental pain if they are intact. In this pilot study we investigated pain modulating capacities of CT-afferents in CRPS. METHODS: 10 CRPS-patients (mean age 33 years, SEM 3.3) and 11 healthy controls (mean age 43.2 years, SEM 3.9) participated. CT-targeted-touch (brush stroking, velocity: 3 cm/s) was applied on hairy and glabrous skin on the affected and contralateral limb. Patients rated pleasantness of CT-targeted-touch (anchors: 1 "not pleasant"-4 "very pleasant") twice daily on 10 days. Pain intensity (NRS: 0 "no pain" - 10 "worst pain imaginable") was assessed before, 0, 30, 60 and 120 min after each CT-stimulation. To assess sensory changes, quantitative-sensory-testing was performed at the beginning and the end of the trial period. RESULTS: CT-targeted-touch was felt more pleasant on the healthy compared to the affected limb on hairy (p < 0.001) and glabrous skin (p 0.002), independent of allodynia. In contrast to healthy controls patients felt no difference between stimulating glabrous and hairy skin on the affected limb. Thermal pain thresholds increased after CT-stimulation on the affected limb (cold-pain-threshold: p 0.016; heat-pain-threshold: p 0.033). CONCLUSIONS: CT-stimulation normalizes thermal pain thresholds but has no effect on the overall pain in CRPS. Therefore, pain modulating properties of CT-fibers might be too weak to alter chronic pain in CRPS. Moreover, CT-fibers appear to lose their ability to mediate pleasant aspects of touch in CRPS.

[Complex regional pain syndrome-An update]. / Komplexes regionales Schmerzsyndrom ­ ein Update.

Complex regional pain syndrome (CRPS) is a pain disorder that develops in the hands or feet after injury. Currently, two types are differentiated, CRPS I without and CRPS II with nerve lesions as well as with either an initially warm or an initially cold subtype, depending on the clinical symptoms. After trauma a certain amount of inflammatory reaction is considered physiological. In acute CRPS this inflammation persists for months and is maintained by diverse inflammatory mediators in peripheral tissue and in blood. This persisting inflammation leads to a sensitization of the nociceptive system, causes somatic cells to proliferate and gives rise to a disrupted endothelial function. The treatment concept aims to antagonize the pathophysiologic components and includes anti-inflammatory and analgetic treatment, mobilization and restoration of the sensorimotor function of the affected limb.

Cutaneous warmth, but not touch, increases muscle sympathetic nerve activity during a muscle fatigue hand-grip task.

In homeostasis, somatosensory C fibre afferents are hypothesised to mediate input to the brain about interactions with external stimuli and sympathetic efference provides the output that regulates bodily functions. We aimed to test this hypothesis and whether different types of innocuous somatosensory input have differential effects. Healthy volunteers performed a muscle fatigue (hand-grip) task to exhaustion, which produces increased muscle sympathetic nerve activity (MSNA), as measured through microneurography. Participants completed the muscle fatigue task without concurrent cutaneous sensory stimulation (control) or we applied skin warming (heat pack) as a C fibre stimulation, slow brush stroking as C and Aß fibre stimulation, or vibration as Aß fibre stimulation, to the participant's forearm. We also measured heart rate, the duration of the hand-grip task, and ratings of pain at the end of the task. Concurrent skin warming showed increased MSNA compared to the other conditions. Tactile stimuli (brushing, vibration) were not significantly different to the control (no intervention) condition. Warming increased the pain from the muscle contraction, whereas the tactile stimuli did not. We interpret the effect of warming on MSNA as providing relevant afferent information during muscle contraction, which needed to be counteracted via vasoconstriction to maintain homeostasis. Brushing and vibration were less homeostatically relevant stimuli for the muscle contraction and hence had no significant effect. The findings add sensory specificity to our current understanding of homeostatic regulation through somatosensory afferent and sympathetic efferent pathways.

Ambient Air Pollution Increases the Risk of Cerebrovascular and Neuropsychiatric Disorders through Induction of Inflammation and Oxidative Stress.

Exposure to ambient air pollution is a well-established determinant of health and disease. The Lancet Commission on pollution and health concludes that air pollution is the leading environmental cause of global disease and premature death. Indeed, there is a growing body of evidence that links air pollution not only to adverse cardiorespiratory effects but also to increased risk of cerebrovascular and neuropsychiatric disorders. Despite being a relatively new area of investigation, overall, there is mounting recent evidence showing that exposure to multiple air pollutants, in particular to fine particles, may affect the central nervous system (CNS) and brain health, thereby contributing to increased risk of stroke, dementia, Parkinson's disease, cognitive dysfunction, neurodevelopmental disorders, depression and other related conditions. The underlying molecular mechanisms of susceptibility and disease remain largely elusive. However, emerging evidence suggests inflammation and oxidative stress to be crucial factors in the pathogenesis of air pollution-induced disorders, driven by the enhanced production of proinflammatory mediators and reactive oxygen species in response to exposure to various air pollutants. From a public health perspective, mitigation measures are urgent to reduce the burden of disease and premature mortality from ambient air pollution.

Complex regional pain syndrome: a focus on the autonomic nervous system.

PURPOSE: Although autonomic features are part of the diagnostic criteria for complex regional pain syndrome (CRPS), the role of the autonomic nervous system in CRPS pathophysiology has been downplayed in recent years. The purpose of this review is to redress this imbalance. METHODS: We focus in this review on the contribution of the autonomic nervous system to CRPS pathophysiology. In particular, we discuss regional sympathetic and systemic autonomic disturbances in CRPS and the mechanisms which may underlie them, and consider links between these mechanisms, immune disturbances and pain. RESULTS: The focused literature research revealed that immune reactions, alterations in receptor populations (e.g., upregulation of adrenoceptors and reduced cutaneous nerve fiber density) and central changes in autonomic drive seem to contribute to regional and systemic disturbances in sympathetic activity and to sympathetically maintained pain in CRPS. CONCLUSIONS: We conclude that alterations in the sympathetic nervous system contribute to CRPS pathology. Understanding these alterations may be an important step towards providing appropriate treatments for CRPS.

Neuropeptide regulation of adaptive immunity in the tibia fracture model of complex regional pain syndrome.

BACKGROUND: Both dysfunctional neuropeptide signaling and immune system activation are characteristic of complex regional pain syndrome (CRPS). Unknown is whether substance P (SP) or calcitonin gene-related peptide (CGRP) support autoantibody production and, consequently, nociceptive sensitization. METHODS: These experiments involved the use of a well-characterized tibia fracture model of CRPS. Mice deficient in SP expression (Tac1-/-) and CGRP signaling (RAMP1-/-) were used to probe the neuropeptide dependence of post-fracture sensitization and antibody production. The deposition of IgM in the spinal cord, sciatic nerves, and skin was followed using Western blotting, as was expression of the CRPS-related autoantigen cytokeratin 16 (Krt16). Passive serum transfer to B-cell-deficient muMT mice was used to assess the production of functional autoantibodies in CRPS model mice. The use of immunohistochemistry allowed us to assess neuropeptide-containing fiber distribution and Langerhans cell abundance in mouse and human CRPS patient skin, while Langerhans cell-deficient mice were used to assess the functional contributions of these cells. RESULTS: Functional SP and CGRP signaling were required both for the full development of nociceptive sensitization after fracture and the deposition of IgM in skin and neural tissues. Furthermore, the passive transfer of serum from wildtype but not neuropeptide-deficient mice to fractured muMT mice caused enhanced allodynia and postural unweighting. Langerhans cells were increased in number in the skin of fracture mice and CRPS patients, and those increases in mice were reduced in neuropeptide signaling-deficient animals. Unexpectedly, Langerhans cell-deficient mice showed normal nociceptive sensitization after fracture. However, the increased expression of Krt16 after tibia fracture was not seen in neuropeptide-deficient mice. CONCLUSIONS: Collectively, these data support the hypothesis that neuropeptide signaling in the fracture limb of mice is required for autoantigenic IgM production and nociceptive sensitization. The mechanism may be related to neuropeptide-supported autoantigen expression.

Progression of transthyretin (TTR) amyloidosis in donors and recipients after domino liver transplantation-a prospective single-center cohort study.

Liver transplantation (LT) is the first-line therapy in patients with transthyretin (TTR) amyloidosis and progressive familial amyloid polyneuropathy (FAP). Explanted organs from these patients can be used for domino liver transplantation (DLT). After DLT, de novo amyloidosis may develop in domino recipients (DR). Data were collected prospectively in a transplant database. Electroneurography by nerve conduction velocity (NCV), quantitative sensory testing, heart rate variability (HRV), sympathetic skin response, orthostatic reaction (tilt table test), transthoracic echocardiography, cardiac MRI and organ biopsy results were evaluated. The cohort included 24 FAP- (11 Val30Met, 13 nonVal30Met) and 23 DR-patients. DR symptoms referred to post-DLT only, while those of FAP patients were both pre- and post-transplantation. Symptoms of TTR-amyloidosis in Val30Met and Non-Val30Met patients pre- and post-LT were similarly distributed. Biopsy-proven de novo amyloidosis occurred in 4/23 DR after a mean observation of 10 years. Analysis for manifestations of amyloidosis only included patients with available 5-year follow-up data (n = 13 FAP, n = 12 DR). Compared to Val30Met FAP patients pre-LT, Val30Met DR patients had better NCV (P = 0.04) and HRV (P = 0.015). In the Non-Val30Met group no differences were found between DR and FAP patients pre-LT. TTR-amyloidosis symptoms showed no differences in FAP patients pre- and 5 years post-LT, irrespective of Val30Met status. In DR patients, de novo amyloidosis occurred earlier than expected. Therefore, recipients for DLT need to be carefully selected and followed.

Molecular signature of complex regional pain syndrome (CRPS) and its analysis.

INTRODUCTION: Complex Regional Pain Syndrome (CRPS) is a rare, but often disabling pain disease. Biomarkers are lacking, but several inflammatory substances have been associated with the pathophysiology. This review outlines the current knowledge with respect to target biomolecules and the analytical tools available to measure them. Areas covered: Targets include cytokines, neuropeptides and resolvins; analysis strategies are thus needed for different classes of substances such as proteins, peptides, lipids and small molecules. Traditional methods like immunoassays are of importance next to state-of-the art high-resolution mass spectrometry techniques and 'omics' approaches. Expert commentary: Future biomarker studies need larger cohorts, which improve subgrouping of patients due to their presumed pathophysiology, and highly standardized workflows from sampling to analysis.

Low threshold unmyelinated mechanoafferents can modulate pain.

BACKGROUND: Human, hairy skin contains a subgroup of C-fibers, the C-low threshold mechanoreceptive afferents ((C-LTMR) C-tactile or C-touch (CT) fibers) that are linked with the signaling of affective aspects of human touch. Recent studies suggest an involvement of these afferents in the modulation of pain in healthy volunteers. Small fiber neuropathy (SFN) is associated with a damage of C-fibers. Therefore, an impairment of C-LTMRs can be assumed. We aimed to elaborate a possible role of CT-afferents in pain modulation by investigating healthy volunteers and SFN-patients. METHODS: Experiment I: 20 SFN-patients (12 women, median age 52.0 years) and 20 healthy controls (14 women, median age 43.0 years) participated in this prospective fMRI and psychophysical study. Heat-pain (HP), CT-targeted touch (slow brushing) and HP combined with CT-targeted touch were applied in randomized order to the left shank in a block design. The participants rated pain intensity on a visual analogue scale. Experiment II: We investigated a possible impact of pain intensity on CT induced pain modulation (10 healthy participants). The intensity of HP stimulation was chosen to induce pain intensity 50/100 (NRS). HP stimulation was applied with and without CT-targeted touch. RESULTS: Experiment I: CT-stimulation was sufficient to reduce heat pain in healthy participants (p = 0.016), but not in SFN-patients. HP induced pain intensity was significantly higher (32,2 vs 52,6) in SFN-patients. During HP, bold responses in pain associated areas were observed in both groups. Additional CT-stimulation elicited no significant difference of bold responses compared to HP. Experiment II: In healthy volunteers, we reproduced a significant reduction of HP intensity by CT-stimulation (p = 0.038). CONCLUSIONS: CT input seems to be sufficient to modulate pain, independent of intensity of the pain stimulus. As a prerequisite, the CT fibers have to be intact as in healthy volunteers. If CT fibers are impaired - as in SFN -, CT-targeted touch does not modulate pain intensity. The location of CT-induced pain modulation might be attributed to the level of the dorsal horn since the cortical activation pattern of heat pain with and without CT-targeted touch did not differ in healthy subjects and in SFN-patients.

Association of Neglect-Like Symptoms with Anxiety, Somatization, and Depersonalization in Complex Regional Pain Syndrome.

Background: Many patients with complex regional pain syndrome (CRPS) report some foreignness of the affected limb, which is referred to as "neglect-like symptoms" (NLS). Despite similarities of the NLS reports to symptoms of body image disturbances in mental disorders, no study has been conducted to examine such associations. Methods: We investigated 50 patients with CRPS and 45 pain control patients (N = 27, chronic limb pain; N = 18, migraine headache). NLS, anxiety, depression, depersonalization, and somatization were assessed using validated questionnaires. Results: Seventy-two percent of the CRPS patients reported at least one NLS vs 29.6% and 33.3% in the two patient control groups. In limb pain controls, NLS correlated with pain intensity. In CRPS patients, NLS correlated with anxiety (rho = 0.658, P < 0.001), somatization (rho = 0.616, P < 0.001), depersonalization (rho = 0.634, P < 0.001), and pain catastrophizing (rho = 0.456, P < 0.01), but not with intensity of pain, duration of pain, or pain disability. Conclusions: In CRPS patients, NLS could be a result of somatization, depression, anxiety, and depersonalization, but probably not of pain. Whether these associations are causative must be clarified in longitudinal psychological studies.

[Neurological or interdisciplinary outpatient pain treatment: comparison of treatment success and satisfaction]. / Neurologische oder interdisziplinäre Schmerzambulanz: Vergleich des Behandlungserfolges und der Zufriedenheit.

The aim of this study was to compare the satisfaction and success of treatment for pain patients who were interdisciplinary (anaesthesiological, psychosomatic, neurological, orthopedic) treated or underwent neurological care alone. Methods We selected 183 patients who were treated in our neurological clinic and in our interdisciplinary pain management center (IST). Of these, 142 patients having polyneuropathy, headache or muskuloskelettal pain were included in the final analysis. 39 patients (27.5 %) were treated in the IST and 103 patients were treated exclusively by a neurologist. These patients were asked to complete a questionnaire, and were queried about the satisfaction and pain parameters. Results The neurological and multidisciplinary pain treatment led to a similar improvement in pain (p < 0.001). This effect was independent of the underlying disease. The interdisciplinary outpatient treatment resulted not primarily in an increased patient satisfaction. Conclusions The reduction of pain and patient satisfaction of neurological outpatient pain treatment were comparable with those of a multidisciplinary outpatient therapy. The only significant advantage of the interdisciplinary treatment was lower hospitalization rate after therapy. This result cannot evaluate the efficiency of inpatient or day hospital pain management, but suggests that in many cases a neurological outpatient pain therapy is sufficient, so that neurological outpatient care should be promoted.

Local anaesthetic sympathetic blockade for complex regional pain syndrome.

BACKGROUND: This review is an update of a previously published review in the Cochrane Database of Systematic Reviews, 2005, Issue 4 (and last updated in the Cochrane Database of Systematic Reviews, 2013 issue 8), on local anaesthetic blockade (LASB) of the sympathetic chain to treat people with complex regional pain syndrome (CRPS). OBJECTIVES: To assess the efficacy of LASB for the treatment of pain in CRPS and to evaluate the incidence of adverse effects of the procedure. SEARCH METHODS: For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 9), MEDLINE (Ovid), EMBASE (Ovid), LILACS (Birme), conference abstracts of the World Congresses of the International Association for the Study of Pain, and various clinical trial registers up to September 2015. We also searched bibliographies from retrieved articles for additional studies. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) that evaluated the effect of sympathetic blockade with local anaesthetics in children or adults with CRPS compared to placebo, no treatment, or alternative treatments. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The outcomes of interest were reduction in pain intensity, the proportion who achieved moderate or substantial pain relief, the duration of pain relief, and the presence of adverse effects in each treatment arm. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created a 'Summary of findings' table. MAIN RESULTS: We included an additional four studies (N = 154) in this update. For this update, we excluded studies that did not follow up patients for more than 48 hours. As a result, we excluded four studies from the previous review in this update. Overall we included 12 studies (N = 461), all of which we judged to be at high or unclear risk of bias. Overall, the quality of evidence was low to very low, downgraded due to limitations, inconsistency, imprecision, indirectness, or a combination of these.Two small studies compared LASB to placebo/sham (N = 32). They did not demonstrate significant short-term benefit for LASB for pain intensity (moderate quality evidence).One small study (N = 36) at high risk of bias compared thoracic sympathetic block with corticosteroid and local anaesthetic versus injection of the same agents into the subcutaneous space, reporting statistically significant and clinically important differences in pain intensity at one-year follow-up but not at short term follow-up (very low quality evidence).Of two studies that investigated LASB as an addition to rehabilitation treatment, the only study that reported pain outcomes demonstrated no additional benefit from LASB (very low quality evidence).Eight small randomised studies compared sympathetic blockade to various other active interventions. Most studies found no difference in pain outcomes between sympathetic block versus other active treatments (low to very low quality evidence).One small study compared ultrasound-guided LASB with non-guided LASB and found no clinically important difference in pain outcomes (very low quality evidence).Six studies reported adverse events, all with minor effects reported. AUTHORS' CONCLUSIONS: This update's results are similar to the previous versions of this systematic review, and the main conclusions are unchanged. There remains a scarcity of published evidence and a lack of high quality evidence to support or refute the use of local anaesthetic sympathetic blockade for CRPS. From the existing evidence, it is not possible to draw firm conclusions regarding the efficacy or safety of this intervention, but the limited data available do not suggest that LASB is effective for reducing pain in CRPS.