Axon reflex flare and quantitative sudomotor axon reflex contribute in the diagnosis of small fiber neuropathy.

INTRODUCTION: Objective diagnosis of small fiber impairment is difficult. METHODS: We used the quantitative sudomotor axon reflex test (QSART) and axon-reflex-flare-test in the foot and thigh of 46 patients with peripheral neuropathy to assess C-fiber function in addition to conventional neurography and thermal threshold testing. RESULTS: In all patients, small fiber impairment was suspected because of abnormal warmth detection thresholds (76% of all tested) and/or pain in the feet. A total of 83% had reduced axon-reflex flare areas and 17% lower QSART scores. Patients with pure small fiber neuropathy had higher rates of reduced flare areas (87.5%) and sweating rates (25.5%). There was no difference between patients with and without pain regarding thermotesting and axon-reflex testing. CONCLUSIONS: Both axon-reflex tests are helpful to identify objectively patients with small fiber impairment. Afferent and efferent C-fiber classes can be impaired differently. These tests detect small fiber impairment, but they cannot differentiate between painful and nonpainful neuropathy.

Thoracoscopic sympathectomy at the T2 or T3 level facilitates bradykinin-induced protein extravasation in human forearm skin.

BACKGROUND: The endogenous peptide bradykinin (BK) is an inflammatory mediator that induces nociceptor activation and sensitization as well as protein extravasation and vasodilation. OBJECTIVE: To test the hypothesis if sympathectomy affects BK-induced inflammation in humans. METHODS: Dermal microdialysis was employed on the volar forearm in 10 patients (21-41 years) with regional hyperhidrosis before and three months after preganglionic endoscopic transthoracic sympathetic clipping (ETSC) at the T2 or T3 level and in 10 healthy volunteers (22-36 years). After 60 minutes perfusion with Ringer's solution microdialysis fibers were perfused with BK 10(-7) M and 10(-5) M for 30 minutes followed by 30 minutes Ringer's solution again. To assess protein extravasation dialysate protein content was measured photometrically and Laser-Doppler imaging was used to quantify axonreflex vasodilation. RESULTS: Baseline flux values after ETSC were higher as compared with controls and preoperative values (anova, Bonferroni post hoc test, P < 0.05), but neither BK 10(-7) M nor 10(-5) M led to significant vasodilation. Baseline dialysate protein did not significantly differ between groups. BK 10(-5) M induced protein extravasation while BK 10(-7) M was ineffective, and BK 10(-5) M induced protein extravasation was significantly enhanced after ETSC (P < 0.001). CONCLUSIONS: Forearm skin perfusion is increased after ETSC on the T2 or T3 level indicating decreased sympathetic activity while BK-induced protein extravasation was increased. These results show that preganglionic sympathectomy does not diminish bradykinin-induced protein extravasation as found for postganglionic sympathectomy in rats.

Guillain-Barré syndrome as leading manifestation of graft-versus-host disease in an allogeneic bone marrow transplanted patient.

Guillain-Barré Syndrome (GBS) is the most frequent cause of neuromuscular paralysis in industrialized countries and usually occurs after respiratory and gastrointestinal infections. However, in rare cases GBS is associated with Graft-versus-Host Disease (GvHD). In the present case we report on a female allogeneic bone marrow transplanted patient who developed GBS as a leading manifestation of GvHD subsequent to discontinuation of her immunosuppressive medication with cyclosporine. In contrast to former case reports both IVIg and plasma exchange failed while resumption of immunosuppressive medication improved the condition of the patient clearly.

C-fiber axon reflex flare size correlates with epidermal nerve fiber density in human skin biopsies.

The size of the neurogenic axon reflex flare (ARFS) has been proposed to serve as a non-invasive measure of C-fiber neuropathies. This idea is based on the observation that ARFS is often reduced in patients with small-fiber neuropathies. In this study, we compared ARFS and electrically evoked axon reflex sweating with intraepidermal nerve fiber density (IENF) in patients with peripheral neuropathy in order to validate these methods against an objective standard method of diagnosing small-fiber neuropathy. ARFS was significantly correlated with IENF, while axon reflex sweating was not correlated to IENF. We conclude that measurement of ARFS is a potential objective non-invasive diagnostic tool for analysis of C-fiber function in patients with small-fiber neuropathies.

Effective immunosuppressant therapy with cyclophosphamide and corticosteroids in paraneoplastic cerebellar degeneration.

Paraneoplastic cerebellar degeneration (PCD) is a rare immune mediated phenomenon often associated with cancer of the ovarian. Hitherto, tumor dissection is the mainstay in therapy while immunomodulatory treatment regimes often fail. Here we report on an 86 year old female patient who developed a severe pancerebellar syndrome. Clinical course, onconeural (anti-Yo) antibodies and detection of ovarian cancer suggest the assumption of PCD as the most probable diagnosis. We initiated a high-dose course of corticosteroids followed by a single dose of cyclophosphamide (600 mg/day). Surprisingly patient's condition improved and stabilized within days subsequent to cyclophosphamide application. This case demonstrates the benefit of immunosuppressive therapy in an anti-Yo positive patient with severe PCD secondary to an ovarian cancer.

Severe spinal cord ischemia subsequent to fibrocartilaginous embolism.

Fibrocartilaginous embolism is a rare cause of spinal cord ischemia. Here we report the case of a young previously healthy man who noted sudden thoracic spinal belt-like pain after intensive physical effort. Following a free interval he developed paraplegia, complete sensory loss below Th(4) and inability to voluntarily purge bladder and bowel. Neuroimaging exposed an intramedullary longitudinal hyperintense signal from C(6) down to the conus in T2-weighted images, intersomatic disc collapses and vertebral body infarctions (C(5-7)/Th(8-10)). Other plausible diagnosis, e.g. spinal contusion, cord compression or acute onset transverse myelitis were excluded. Altogether, clinical presentation, neuroimaging and lack of evidence of other plausible diagnosis suggest fibrocartilaginous embolism as the most probable diagnosis.

www.tnt-radiology.de: Teach and be taught radiology: implementation of a web-based training program based on user preferences as determined by survery.

RATIONALE AND OBJECTIVES: To create a Web-based training program addressing the needs of a large, heterogeneous audience of users. MATERIALS AND METHODS: We defined our target group as consisting of medical professionals who teach radiology, or who, by their own perception, would benefit from improving their radiologic image interpretation skills. We interviewed 483 members of this group, eliciting their preferences with regard to layout, interactivity, contents, and other categories (11 in total). Considering majority preferences as recommendations and using the help of a special interest group of medical students, we assembled 500 teaching cases over a 1-year period into an interactive training program and made it available on the World Wide Web. RESULTS: Important preferences expressed by majorities of interviewees were: high levels of interactivity, clear layout, intuitive usability, short page load times, permissibility of saving content locally, cost-free access, consideration of user input in the site development. To our knowledge, our web program TNT-Radiology, accessible at , is the first to implement all of these recommendations simultaneously. CONCLUSIONS: We have created a Web-based program usable for teaching and learning radiologic image interpretation that meets the needs of a heterogeneous target audience to an unprecedented extent.

Thermal thresholds predict painfulness of diabetic neuropathies.

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 +/- 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 Adelta- 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 < 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 = 0.02; warm detection thresholds, P = 0.056). CONCLUSIONS: Intensity of pain in painful DN seems to depend on small nerve fiber damage and deafferentation.

Chemically and electrically induced sweating and flare reaction.

Both thin afferent (nociceptors) and efferent (sympathetic sudomotor) nerve fibers can be activated electrically and chemically, resulting in neurogenic erythema and sweating. These reactions have been used before to assess the impairment of sympathetic and nociceptor fibers in humans. In this study, electrically induced sweating and erythema were assessed simultaneously in the foot dorsum and thigh, and were compared to chemically induced activation. Reproducible intensity-response relations (stimulation intensities 0-30 mA, 1 Hz) were obtained from 32 subjects. The steepest increase of the sweat response was induced at lower intensities as compared to that of the erythema (18.3 mA vs. 25.7 mA, p<0.01) and reached a plateau for intensities above 25 mA, suggesting lower electrical thresholds for sudomotor fibers. Maximum flare areas induced electrically with 30 mA were smaller than those evoked chemically (flare size: 4.5 cm2 vs. 10.6 cm2). In contrast, the electrically evoked sweating rate was higher than that evoked chemically (acetylcholine, or ACh; sweating rate 0.31 vs. 0.21 microl/cm2/min, p<0.01), which might be attributed to an increased effectiveness of synchronized discharge in sympathetic fibers upon electrical stimulation.

Assessing function and pathology in familial dysautonomia: assessment of temperature perception, sweating and cutaneous innervation.

This study was performed to assess cutaneous nerve fibre loss in conjunction with temperature and sweating dysfunction in familial dysautonomia (FD). In ten FD patients, we determined warm and cold thresholds at the calf and shoulder, and sweating in response to acetylcholine iontophoresis over the calf and forearm. Punch skin biopsies from calf and back were immunostained and imaged to assess nerve fibre density and neuropeptide content. Mean temperature thresholds and baseline sweat rate were elevated in the patients, while total sweat volume and response time did not differ from controls. The average density of epidermal nerve fibres was greatly diminished in the calf and back. There was also severe nerve loss from the subepidermal neural plexus (SNP) and deep dermis. The few sweat glands present within the biopsies had had reduced innervation density. Substance P immunoreactive (-ir) and calcitonin gene related peptide-ir (CGRP-ir) were virtually absent, but vasoactive intestinal peptide-ir (VIP-ir) nerves were present in the SNP. Empty Schwann cell sheaths were observed. Temperature perception was more impaired than sweating. Epidermal nerve fibre density was found to be profoundly reduced in FD. Decreased SP and CGRP-ir nerves suggest that the FD gene mutation causes secondary neurotransmitter depletions. Empty Schwann cell sheaths and VIP-ir nerves suggest active denervation and regeneration.

Catecholamine release in human skin--a microdialysis study.

Dermal microdialysis might be a promising tool to investigate properties of sympathetic neurons in the skin as investigation of peripheral noradrenergic neurons in humans usually relies on highly variable vasoconstrictor reflexes or on indirect measurements like skin temperature recordings. To evaluate this technique, 21 experiments were performed in 15 healthy subjects with four intracutaneous microdialysis fibers (diameter, 200 microm; cutoff, 5 kDa) at hands or feet. After 60 min, saline perfusion tyramine at concentrations of 0.195 to 200 microg/ml was applied for 15 min followed by a 15-min saline perfusion again. Catecholamine concentrations were detected through high-performance liquid chromatography with electrochemical detection. Control experiments were performed in human skin homogenates with and without tyramine incubation. In vivo, norepinephrine (NE) concentration increased from 36.3 +/- 10.2 pg/ml to 84.4 +/- 18.4 pg/ml (P < 0.001) during stimulation with tyramine, dialysate dopamine (DA) concentration increased from 105.2 +/- 36.5 pg/ml to 7162.4 +/- 3972.4 pg/ml (P < 0.001). Both tyramine-induced NE and DA release were dose-dependent (NE: r = 0.438, P < 0.05; DA: r = 0.894, P < 0.001). In skin homogenates, tyramine incubation led to a significant increase of DA concentrations (387.0 +/- 34.8 pg/ml, controls: 13.2 +/- 2.4 pg/ml; P < 0.05), while NE and epinephrine levels remained unchanged. In conclusion, our experiments show that dermal microdialysis is capable of locally measuring catecholamines in human skin. This offers the opportunity to investigate the function of the peripheral sympathetic nervous system. Additional to non-enzymatic oxidation, DA increase probably reflects metabolic degradation of tyramine by non-neuronal pathways and therefore does not reflect local sympathetic innervation.

Electrically stimulated axon reflexes are diminished in diabetic small fiber neuropathies.

Axon reflex mediated flare depends on the density and the function of cutaneous C-fibers and may be impaired in diabetic neuropathy. We induced neurogenic axon reflex flare by intracutaneous electrical stimulation and analyzed size and intensity of the flare on the dorsum of the foot and ventral thigh with laser Doppler imaging (LDI). We investigated 12 diabetic subjects with small fiber neuropathies (SFNs), 5 diabetic subjects without neuropathy (NO-Ns), and 14 healthy control subjects. Five of the normal subjects were reassessed after 12 months. In comparing patients with SFN to control subjects, we found that SFN flare size but not the intensity of vasodilation (flux) was reduced on the feet (P < 0.001) and thighs (P < 0.007). Furthermore, electrical thresholds for flare induction were increased (thighs P < 0.001 and feet P < 0.03). In NO-Ns, flare size at the feet (P < 0.02) and flux at both sites (thighs P < 0.001 and feet P < 0.002) were even increased. Test/retest evaluation of our method revealed a good correlation (r = 0.83, P < 0.004). Intracutaneous electrical stimulation of C-fibers and scanning the flare with LDI is a sensitive tool to reliably detect small fiber impairment in diabetic SFN subjects and even increased neuropeptide release in NO-Ns.