Auto-antibodies against the paranodal proteins neurofascin-155 and contactin-1 have recently been described in patients with chronic inflammatory demyelinating polyradiculoneuropathy and are associated with a distinct clinical phenotype and response to treatment. Contactin-associated protein 1 (Caspr, encoded by CNTNAP1) is a paranodal protein that is attached to neurofascin-155 and contactin-1 (CNTN1) but has not yet been identified as a sole antigen in patients with inflammatory neuropathies. In the present study, we screened a cohort of 35 patients with chronic inflammatory demyelinating polyradiculoneuropathy (age range 20-80, 10 female, 25 male) and 22 patients with Guillain-Barré syndrome (age range 17-86, eight female, 14 male) for autoantibodies against paranodal antigens. We identified two patients, one with chronic inflammatory demyelinating polyradiculoneuropathy and one with Guillain-Barré syndrome, with autoantibodies against Caspr by binding assays using Caspr transfected human embryonic kidney cells and murine teased fibres. IgG3 was the predominant autoantibody subclass in the patient with Guillain-Barré syndrome, IgG4 was predominant in the patient with chronic inflammatory demyelinating polyradiculoneuropathy. Accordingly, complement deposition after binding to HEK293 cells was detectable in the patient with IgG3 autoantibodies only, not in the patient with IgG4. Severe disruption of the paranodal and nodal architecture was detectable in teased fibres of the sural nerve biopsy and in dermal myelinated fibres, supporting the notion of the paranodes being the site of pathology. Deposition of IgG at the paranodes was detected in teased fibre preparations of the sural nerve, further supporting the pathogenicity of anti-Caspr autoantibodies. Pain was one of the predominant findings in both patients, possibly reflected by binding of patients' IgG to TRPV1 immunoreactive dorsal root ganglia neurons. Our results demonstrate that the paranodal protein Caspr constitutes a new antigen that leads to autoantibody generation as part of the novel entity of neuropathies associated with autoantibodies against paranodal proteins.
In addition to A-beta fibres the human hairy skin has unmyelinated (C) fibres responsive to light touch. Previous functional magnetic resonance imaging (fMRI) studies in a subject with a neuronopathy who specifically lacks A-beta afferents indicated that tactile C afferents (CT) activate insular cortex, whereas no response was seen in somatosensory areas 1 and 2. Psychophysical tests suggested that CT afferents give rise to an inconsistent perception of weak and pleasant touch. By examining two neuronopathy subjects as well as control subjects we have now demonstrated that CT stimulation can elicit a sympathetic skin response. Further, the neuronopathy subjects' ability to localize stimuli which activate CT afferents was very poor but above chance level. The findings support the interpretation that the CT system is well suited to underpin affective rather than discriminative functions of tactile sensations.
Botulinum toxin A (BoNT/A) has been used therapeutically to treat muscular hypercontractions and sudomotor hyperactivity. There is increasing evidence that BoNT/A might also have analgesic properties, in particular in headache. In the present investigation we tested the often cited hypothesis that BoNT/A-induced analgesia can be attributed to inhibition of neuropeptide release from nociceptive nerve fibers. In 15 healthy volunteers BoNT/A (5, 10, 20 mouse units BOTOX) or saline (contralateral side) was injected intracutaneously on the volar forearm. On day zero, the day of injection, no further tests were performed. We repeatedly elicited pain, mechanical hyperalgesia and neurogenic flare by transcutaneous electrical stimulation simultaneously on the BoNT/A and saline treated side on day 1, 2, 3, 7 and 14 after injection. Before each session, sweating and local anhidrosis was assessed by iodine starch staining.BoNT/A suppressed sweating as early as from the second day after injection (p < 0.001). The size of electrically induced flare was smaller on the BoNT/A treated arm (BoNT/A side: 21.46 cm(2) +/- 3.58, saline side 24.80 +/- 3.46, p < 0.005) and BoNT/A reduced electrically-induced pain by about 10 % (p < 0.001). However, hyperalgesia to pin-prick and allodynia after electrical stimulation were unchanged. In conclusion our results indicate that peripheral neuropeptide release is attenuated by BoNT/A. In contrast, the analgesic effect of BoNT/A was very limited. Therefore we assume that other than neuropeptide mechanisms must be important for BoNT/A induced pain relief in clinical pain syndromes.
Background Vestibular paroxysmia (VP) is defined as neurovascular compression (NVC) syndrome of the eighth cranial nerve (N.VIII). The aim was to assess the sensitivity and specificity of MRI and the significance of audiovestibular testing in the diagnosis of VP. Methods 20 VP patients and, for control, 20 subjects with trigeminal neuralgia (TN) were included and underwent MRI (constructive interference in steady-state, time-of-flight MR angiography) for detection of a NVC between N.VIII and vessels. All VP patients received detailed audiovestibular testing. Results A NVC of N.VIII could be detected in all VP patients rendering a sensitivity of 100% and a specificity of 65% for the diagnosis of VP by MRI. Distance between brain stem and compressing vessels varied between 0.0 and 10.2
OBJECTIVE -Pathophysiology explaining pain in diabetic neuropathy (DN) is still unknown.RESEARCH DESIGN AND METHODS -Thirty patients with peripheral DN (17 men and 13 women; mean age 52.4 Ϯ 2.5 years) were investigated. Fifteen patients had neuropathic pain, and 15 patients were free of pain. Patients were followed over 2 years and examined at the beginning and thereafter every 6 months. Clinical severity and painfulness of the DN were assessed by the neuropathy impairment score and visual analog scales (VASs). Cold and warm perception thresholds as well as heat pain thresholds were obtained for evaluation of A␦-and C-fibers. Nerve conduction velocities (NCVs) and vibratory thresholds were recorded for analysis of thickly myelinated fibers. Moreover, for assessment of cardiac vagal function, heart rate variability (HRV) was evaluated. In order to reduce day-to-day variability of pain, mean values of the five time points over 2 years were calculated and used for further analysis. Data were compared with an age-and sex-matched control group of healthy volunteers.RESULTS -There were significant differences regarding electrophysiological studies, HRV and quantitative sensory testing (QST) between patients and healthy control subjects (P Ͻ 0.001). Generally, patients with neuropathic pain were indistinguishable from pain-free patients. In the pain group, however, VAS pain ratings were correlated to the impairment of small-fiber function (cold detection thresholds, P ϭ 0.02; warm detection thresholds, P ϭ 0.056).CONCLUSIONS -Intensity of pain in painful DN seems to depend on small nerve fiber damage and deafferentation. Diabetes Care 27:2386 -2391, 2004D iabetic neuropathy (DN) is the most frequent neuropathy in western countries and affects ϳ60% of all diabetic patients (1). About 13% of patients with DN report neuropathic pain (2), which includes spontaneous pain such as burning feet or dysesthesia (3). Unfortunately, there are no predictors for the development of pain as a symptom of DN. The intensity of pain may vary substantially within days or weeks. There are mood, seasonal, social, and daily activity influences that modify pain intensity or pain-coping strategies (4). This variability complicates the quantification of clinical neuropathic pain. The detailed mechanisms leading to neuropathic pain are not specific for DN and may even vary between patients. The most important mechanisms are the accumulation of sodium channels on injured axons (5), sympatho-afferent coupling (6), disinhibition of nociception (7), and peripheral or central sensitization (8). However, the predominant pathophysiology in painful DN is unknown (9).Tests to analyze nerve function in DN include assessment of sensory and motor nerve conduction velocity (NCV), quantitative sensory testing (QST) for different afferent fiber classes (10), analysis of heart rate variability (HRV) for vagal function, and sudomotor axon reflexes for peripheral sympathetic fibers (11). Histological data can be obtained from nerve or skin biopsies (12). However, ...
Slow brushing stimuli - optimal for activation of C-tactile fibres - can reduce pain from cutaneous heating. No such effect was seen with fast brushing or vibration. These observations indicate the role of C-tactile fibres in pain modulation.
Our results indicate that warm and cold complex regional pain syndromes (CRPS) are associated with different clinical findings, beyond skin temperature changes. This might have implications for the understanding of CRPS pathophysiology.
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