Is Ross syndrome a dysautonomic disorder only? An electrophysiologic and histologic study.

OBJECTIVE: To define the involvement of peripheral nerve fibers in Ross syndrome. METHODS: Mechanical pain perception, tactile and thermal thresholds on hand, foot dorsum, thigh, median nerve orthodromic sensory conduction velocity (SCV) and motor conduction velocity (MCV), sural nerve antidromic SCV, peroneal nerve MCV, H-reflex, F-wave, median, tibial nerve somatosensory evoked potentials (SSEPs), perioral, hand CO(2) laser late (LEPs) and ultralate evoked potentials, sympathetic skin response (SSRs), cardiovascular, Minor sweat, silastic imprint, histamine, photopletysmographic and pupil pilocarpine tests, cutaneous innervation immunohistochemical techniques were studied in 3 patients with Ross syndrome. RESULTS: Quantitative sensory testing showed altered results in patients 1 and 2, and patient 3 had a slight impairment of mechanical pain perception. Nerve conduction, except for a median nerve distal reduction of sensory conduction in patient 1, F-wave and SSEP findings were normal; H-reflex was absent at rest in all patients. Hand LEPs were absent in patient 2, ultralate potentials were absent in patients 1 and 2. Skin biopsy showed a disease duration related reduction of unmyelinated and myelinated sensory fibers and a lack of unmyelinated autonomic fibers in all patients. CONCLUSIONS: Our data suggest that Ross syndrome is a degenerative disorder involving progressive sudomotor fibers, and then epidermal sensory unmyelinated and myelinated fibers.     

Small-fiber involvement in spinobulbar muscular atrophy (Kennedy's disease)

We assessed the involvement of cutaneous innervation in two subjects with a molecularly confirmed diagnosis of spinobulbar muscular atrophy (SBMA) using antidromic nerve conduction studies, quantitative sensory testing, and sweat tests, as well as immunohistochemical techniques and confocal microscopy of glabrous and hairy skin biopsy. Both patients showed a marked reduction in amplitude of sensory action potentials and moderate or severe abnormalities of tactile thresholds and mechanical pain perception. A severe reduction of sweat drops on the Silastic imprint test and a widespread loss of small myelinated and unmyelinated fibers in hairy skin were also observed. Fiber loss involved either somatic or autonomic fibers and did not show any distal-proximal gradient. These results, together with loss of Meissner corpuscles and their large myelinated afferent fibers in glabrous skin, confirmed the extensive involvement of sensory neurons of large and small size and revealed an autonomic skin denervation in SBMA.     

Epidermal nerve fiber density in sensory ganglionopathies: clinical and neurophysiologic correlations.

We assessed the involvement of somatic unmyelinated fibers in sensory ganglionopathies by skin biopsy and quantitative sensory testing (QST). Sixteen patients with ganglionopathy, 16 with axonal neuropathy, and 15 normal controls underwent skin biopsy at the proximal thigh and the distal leg. Intraepidermal nerve fibers (IENF) were immunostained by antiprotein gene product 9.5, and their linear density was quantified under light microscopy. Confocal microscopy studies with double staining of nerve fibers and basement membrane were also performed. Healthy subjects and neuropathy patients showed the typical proximodistal gradient of IENF density; in neuropathies, values were significantly lower at the distal site of the leg, confirming the length-dependent loss of cutaneous innervation. Conversely, ganglionopathy patients with hyperalgesic symptoms did not show any change of IENF density between the proximal thigh and the distal leg. The distinct pattern of epidermal denervation seen in sensory ganglionopathy reflected the degeneration of somatic unmyelinated fibers in a fashion that was not length-dependent, which was consistent with both clinical and neurophysiologic observations and supported the diagnosis.     

QUANTITATIVE SENSORY TESTING AND SWEAT FUNCTION IN FRIEDREICH''S ATAXIA. CORRELATION WITH CUTANEOUS INNERVATION

To evaluate small fiber function in Friedreich's Ataxia (FA), we performed in 7 patients pin-prick, thermal thresholds, and sweat test. All tests were performed in four different sites: hand dorsum, anterior thigh, lateral distal leg, and foot dorsum. The same subjects underwent 3 mm punch skin biopsy from fingertip, anterior thigh, and lateral distal leg. We used a thin needle mounted on a calibrated nylon wire for the pin-prick test, and a Medoc 2001 TSA system for thermal threshold assessment. Sweat test was performed using a silicon mold after stimulation with pilocarpine by iontophoresis.
Skin specimens, cut into 100-μm-thick sections, were double-stained using primary antibodies specific for collagen and nervous fibers and secondary antibodies labeled with Cy3 and Cy5 fluorophores. Tridimensional digitized images were obtained from z-series of 2-μm-thick optical sections acquired with a confocal microscope.
We found in all patients in the more distal sites definite signs of functional impairment of the small fibers. These data correlated with the skin innervation morphological findings that showed, in the same sites, a sensible loss of small fibers regarding both the epidermal free endings and the subepidermal neural plexus. Less severe morphological abnormalities were found in the proximal sites.
The large fiber neuropathy in FA is well documented. Our data show a length-dependent involvement of small fibers in the pathological process.     

IgM deposits on skin nerves in anti-myelin-associated glycoprotein neuropathy

Anti-myelin-associated glycoprotein (anti-MAG) neuropathy is a chronic demyelinating neuropathy with predominant involvement of large sensory fibers and deposits of IgM and complement on sural nerve myelinated fibers. We assessed the presence of IgM deposits on skin myelinated nerve fibers and the involvement of unmyelinated axons in anti-MAG neuropathy. Skin biopsies were performed in 14 patients with anti-MAG neuropathy, in 8 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and in 2 patients with IgM paraproteinemic neuropathy. Biopsies were taken at the proximal thigh in 20 patients, at the distal leg in 21 patients, at the proximal arm in 13 patients, and at the hand or fingertip in 10 patients. We found IgM deposits on dermal myelinated fibers in all anti-MAG neuropathy patients, with a greater prevalence at the distal site of the extremities. Deposits were located throughout the length of the fibers and at the paranodal loops. CIDP and IgM paraproteinemic neuropathies did not show any deposit of IgM. Anti-MAG neuropathy and CIPD patients showed a decrease in epidermal nerve fiber density reflecting an associated axonal loss. In anti-MAG neuropathy, both large- and small-diameter nerve fibers are affected, and specific deposits of IgM are found on skin myelinated nerve fibers.     

Sensory dysfunction in HTLV-I-associated myelopathy/tropical spastic paraparesis. A comprehensive neurophysiological study.

We performed a comprehensive clinical and neurophysiological evaluation of function of the large- and small-caliber afferent pathways in 29 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Sensory symptoms, particularly cutaneous paresthesias, were present in 11 (37.9%) patients. On examination, a mild distal impairment of vibration and sense of position were found in 14 (48.2%) and 5 (17.2%) patients, respectively. Ten (34.4%) patients had distal tactile hypoesthesia and 7 (24.1%) presented pinprick hypoesthesia. Quantitative somatosensory thermotest showed cold hypoesthesia in 58.6% of patients. Nerve conduction studies and electromyography were normal. Tibial somatosensory evoked potentials were abnormal in 88.5% of patients. All of the sensory abnormalities found were restricted to sensations carried by myelinated (A-beta and A-delta) fibers. Unmyelinated C fibers mediating warm sensation and thermal pain appeared unimpaired. Our findings indicate that the sensory dysfunction in HAM/TSP patients is probably due to a lesion restricted to the central nervous system.     

Sensory correlates of pain in peripheral neuropathies

ObjectiveTo characterize sensory threshold alterations in peripheral neuropathies and the relationship between these alterations and the presence of pain.MethodsSeventy-four patients with length-dependent sensory axonal neuropathy were enrolled, including 38 patients with painful neuropathy (complaining of chronic, spontaneous neuropathic pain in the feet) and 36 patients with painless neuropathy. They were compared to 28 age-matched normal controls. A standardized quantitative sensory testing protocol was performed in all individuals to assess large and small fiber function at the foot. Large fibers were assessed by measuring mechanical (pressure and vibration) detection thresholds and small fibers by measuring pain and thermal detection thresholds.ResultsBetween patients with neuropathy and controls, significant differences were found for mechanical and thermal detection thresholds but not for pain thresholds. Patients with painful neuropathy and those with painless neuropathy did not differ regarding mechanical or thermal thresholds, but only by a higher incidence of thermal or dynamic mechanical allodynia in case of painful neuropathy. Pain intensity correlated with the alteration of thermal detection and mechanical pain thresholds.ConclusionsQuantitative sensory testing can support the diagnosis of sensory neuropathy when considering detection threshold measurement. Thermal threshold deterioration was not associated with the occurrence of pain but with its intensity.SignificanceThere is a complex relationship between the loss or functional deficit of large and especially small sensory nerve fibers and the development of pain in peripheral neuropathy.     

Quantitative pathology of cutaneous nerve terminal degeneration in the human skin

Pathological diagnosis of neuropathy has traditionally depended on ultrastructural examinations of nerve biopsy specimens, particularly for sensory neuropathies affecting unmyelinated and small-myelinated nociceptive nerves. These sensory nerves terminate in the epidermis of the skin, and the pathology of neuropathy usually begins from nerve terminals. We investigated the feasibility of diagnosing small-fiber sensory neuropathy by evaluating cutaneous innervation. Skin biopsy specimens of 3-mm in diameter were obtained from the distal leg and the distal forearm of 55 healthy controls and 35 patients with sensory neuropathy. In the healthy controls, conventional intraepidermal nerve fiber densities (IENF densities) as measured using the image analysis system in the distal forearm and in the distal leg were correlated (r=0.55, P<0.0001), with significantly higher values in the distal forearm than in the distal leg (17.07+/-6.51 vs 12.92+/-5.33 fibers/mm, P<0.001). Compared to IENF densities of healthy controls, these values of neuropathic patients were significantly reduced in the distal forearm (5.82+/-6.50 fibers/mm, P<0.01) and in the distal leg (2.40+/-2.30, P<0.001). We further explored the possibility of quantifying skin innervation by counting "ocular intraepidermal nerve fiber density" (ocular nerve fiber density) with no aid of an image analysis system. This was based on the fact that the epidermal length on specifically defined sections was very close to the predicted epidermal length of 3 mm, the diameter of skin punches (P=0.14). Ocular nerve fiber densities were significantly correlated with IENF densities as measured by the image analysis system (r=0.99, P<0.0001). Dermal nerve fibers of neuropathic patients either disappeared or became degenerated. These findings were consistent with the notion of early terminal degeneration in neuropathy, and will facilitate quantitative interpretation of epidermal innervation in human neuropathy.     

Sensory involvement in distal myopathy (Welander)

Eleven patients with Welander distal myopathy were subjected to detailed sensory testing including measurements of perception thresholds for vibration and temperature in both hands and feet. The threshold values were compared with normal, age-corrected values and also with data from an age-matched control group consisting of patients with antecedent poliomyelitis with the same degree of paresis.

The screening examination indicated impaired thermal sensibility in all 11 patients and impairment for at least one other sensory modality in 9 patients. In comparison with age-corrected normal values, the measured warm-cold difference limen was abnormal in the feet of 9 patients and the vibratory threshold at least at one test point in 6 patients. When compared with the data from the paretic controls, the thermal abnormality was significant with regard to warm and cold thresholds, the warm-cold difference limen and the heat pain threshold. The vibration threshold abnormality was significant in the feet.

It is concluded that sensibility impairment is present in Welander's myopathy indicating a peripheral sensory neuropathy involving both unmyelinated (C-fibers) and myelinated fibers.     

Chronic ischemic monomelic neuropathy from critical limb ischemia

OBJECTIVE: To describe the peripheral neuropathy resulting from chronic and critical arterial leg ischemia. METHODS: The authors evaluated 19 patients on entry to a gene therapy treatment trial for chronic and critical leg ischemia. Measurements included medical history, examination, neurologic symptom (NSS) and neurologic examination (NES) scores, motor and sensory nerve conduction studies, and quantitative sensory testing. The critically ischemic leg was compared with the less affected contralateral limb. RESULTS: All patients experienced pain from skin ulceration or vascular claudication, but many also had rest pain (58%), numbness (58%), burning (42%), and paresthesias (37%) in the ischemic foot that were consistent with peripheral nerve ischemia. Only three patients (16%) were free of neuropathic symptoms. The most common asymmetric neurologic signs included hypalgesia (74%), toe weakness (64%), hyperesthesia (63%), and pallanesthesia (53%) in the distal leg. NSS and NES were more abnormal in the critically ischemic leg, as were distal motor, total motor, and sensory examination subscores (p < 0.01 for each). Sural sensory potentials were reduced or absent, frequently on both sides. The symptomatic limb had reduced tibial motor amplitudes and increased thermal (cold) sensory thresholds (p < 0.01 for both) whereas the distal latencies, conduction velocities, and vibration thresholds were similar in the two legs. CONCLUSIONS: There is a predominantly sensory neuropathy associated with chronic and critical limb ischemia. Neuropathic symptoms are often obscured by the effects of ischemia on other tissues. The neurophysiologic changes suggest that the underlying pathophysiology is a distal axonopathy affecting nerve fibers of all sizes. Measures of blood flow in the leg correlate with neurologic symptom scores, examination scores, and electrophysiologic testing.     

Cutaneous thermal thresholds in patients with painful burning feet.

Small nerve fibre sensory function was assessed by psychophysical estimates of cutaneous thermal thresholds in 30 patients who presented with the symptoms of painful burning feet. Thresholds were abnormal in 12 and normal in 18 patients although symptoms in the two groups were very similar. Various hypotheses for the mechanism of pain in small fibre neuropathy have been proposed previously and these are discussed, but the cause of symptoms in patients with normal thresholds, is unknown. The possibility exists that these patients have a neuropathic disorder which affects only those unmyelinated fibres involved with pain.     

Skin biopsy and quantitative sensory testing do not predict response to lidocaine patch in painful neuropathies

Predictors of response to neuropathic pain treatment in patients with painful distal sensory neuropathies are lacking. The 5% lidocaine patch is believed to exert its effects on neuropathic pain via a local stabilizing effect on cutaneous sensory afferents. As such, it provides a model to assess whether the status of epidermal innervation as determined by skin biopsy or quantitative sensory testing (QST) of small- and large-diameter sensory afferents might serve as predictors of response to topical, locally active treatment. In this study we assessed associations between epidermal nerve fiber (ENF) densities, sensory nerve conduction studies (NCS), QST, and response to a 5% lidocaine patch in patients with painful distal sensory neuropathies. We observed no association between distal leg epidermal and subepidermal innervation and response to the lidocaine patch. Several patients with complete loss of distal leg ENF showed a response to the lidocaine patch. Similarly we observed no consistent association between treatment response and QST for vibration, cooling, warm, heat-pain, and cold-pain thresholds, or distal sensory NCS. Thus, distal-leg skin biopsy, QST, and sensory NCS cannot be used to identify patients with painful polyneuropathy likely to respond to a lidocaine patch in clinical practice. Further studies are required to clarify precisely the mechanism and site of action of the lidocaine patch in patients with peripheral neuropathic pain.     

The extent of small fibre sensory neuropathy in diabetics with plantar foot ulceration.

Thresholds for cutaneous warming and cooling stimuli were measured in 20 diabetics with neuropathic foot ulcers. All patients had a profound disturbance of sensory perception in the ulcerated foot with complete loss of perception of warming; thresholds for vibration and cooling were highly abnormal in all but two patients. Measurements of thermal threshold were made on both feet in 10 patients: warming was lost bilaterally in all, and cooling was bilaterally absent in six. There was no clear pattern of sensory loss in those diabetics with unilateral foot ulceration to suggest that sensory impairment was the determining factor for the development of a plantar ulcer. Measurements of thermal thresholds were made at additional sites in 13 patients and although the most marked abnormalities of sensation were always found in the feet, in some severe neuropaths, abnormal thresholds on the hand and even the face were demonstrated. Thresholds for warming were invariably more abnormal than thresholds for cooling. The diabetics with neuropathic ulceration in this study all had severe generalised peripheral nerve disease involving large myelinated as well as both small myelinated and unmyelinated sensory fibres. The quantitative evidence on the distribution of sensory loss for thermal sensations supports the hypothesis that the neuropathic process affecting the small myelinated and unmyelinated fibres is length dependent.     

Loss of sensory function in patients with idiopathic hand dystonia

Former studies suggest an additional involvement of the sensory nervous system, beside the involuntary contractions of antagonist muscles, in idiopathic hand dystonia. We studied contact heat‐evoked potentials and quantitative sensory testing (QST) in 10 patients suffering from idiopathic hand dystonia and 10 age‐matched healthy controls. Cortical potentials recorded from the vertex (Pz) after contact heat stimulation of the volar forearm and the dorsum of the hand at a temperature of 51°C showed significantly reduced A‐δ‐amplitudes. Numerical pain ratings on the affected side in comparison to the unaffected side and to healthy controls were significantly reduced. QST results showed an impairment of the thermal detection thresholds, the mechanical pain sensitivity and the mechanical pain threshold at the affected body side of the patients. Our results suggest a loss of distinct sensory functions of the affected hand in comparison with the contralateral hand and to matched healthy subjects in patients suffering from idiopathic hand dystonia. For the first time, an extended loss of sensory function could be shown in patients suffering from idiopathic hand dystonia. © 2010 Movement Disorder Society.     

Absent innervation of skin and sweat glands in congenital insensitivity to pain with anhidrosis.

OBJECTIVES: A case of a 10-year-old girl with congenital insensitivity to pain with anhidrosis (CIPA) is reported. METHODS AND RESULTS: Parents referred several hyperpyretic episodes without sweating occurring since birth, and insensitivity to pain, noticed when the child was 2 years old. Her body had many bruises and scars, bone fractures and signs of self-mutilation. Neurological examination was normal except for insensitivity to pain. Her IQ was 52. Electrical and tactile sensory nerve conduction velocities were normal. The patient was unable to detect thermal stimuli. Histamine injection evoked a wheal but not a flare; pilocarpine by iontophoresis did not induce sweat. Microneurography showed neural activity from A-beta sensory fibers while nociceptive and skin sympathetic C fiber nerve activity was absent. No small myelinated fibers and very rare unmyelinated fibers were found in the sural nerve. Immunohistochemistry showed a lack of nerve fibers in the epidermis and only few hypotrophic and uninnervated sweat glands in the dermis. CONCLUSIONS: The lack of innervation of the skin (C and A-delta fibers) appears to be the morphological basis of insensitivity to pain and anhidrosis, and is consistent with the loss of unmyelinated and small myelinated fibers in the sural nerve biopsy.     

Functional interactions between tumor and peripheral nerve: changes in excitability and morphology of primary afferent fibers in a murine model of cancer pain

We used a murine model to investigate functional interactions between tumors and peripheral nerves that may contribute to pain associated with cancer. Implantation of fibrosarcoma cells in and around the calcaneus bone produced mechanical hyperalgesia of the ipsilateral paw. Electrophysiological recordings from primary afferent fibers in control and hyperalgesic mice with tumor revealed the development of spontaneous activity (0.2-3.4 Hz) in 34% of cutaneous C-fibers adjacent to the tumor (9-17 d after implantation). C-fibers in tumor-bearing mice exhibited a mean decrease in heat threshold of 3.5 +/− 0.10 °C. We also examined innervation of the skin overlying the tumor. Epidermal nerve fibers (ENFs) were immunostained for protein gene product 9.5, imaged using confocal microscopy, and analyzed in terms of number of fibers per millimeter of epidermal length and branching (number of nodes per fiber). Divergent morphological changes were linked to tumor progression. Although branching of ENFs increased significantly relative to control values, in later stages (16-24 d after implantation) of tumor growth a sharp decrease in the number of ENFs was observed. This decay of epidermal innervation of skin over the tumor coincided temporally with gradual loss of electrophysiological activity in tumor-bearing mice. The development of spontaneous activity and sensitization to heat in C-fibers and increased innervation of cutaneous structures within the first 2 weeks of tumor growth suggest activation and sensitization of a proportion of C-fibers. The decrease in the number of ENFs observed in later stages of tumor development implicates neuropathic involvement in this model of cancer pain.     

Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies

OBJECTIVE: To study intraepidermal nerve fiber (IENF) density in distal leg skin biopsies, sural nerve morphometry, electrophysiology, and clinical features in patients with peripheral neuropathies. METHODS: We studied 26 patients with neuropathic complaints who had undergone clinical evaluation, nerve conduction studies, distal leg skin biopsy, and sural nerve biopsy. We quantified densities of IENF and of myelinated and unmyelinated fibers in the sural nerve. Associations among skin and sural nerve morphometric measures and sensory nerve action potential (SNAP) amplitudes were examined nonparametrically. Morphometric measures were examined with respect to diagnostic category of neuropathy. RESULTS: IENF density correlated with the densities of sural nerve total myelinated (r = 0.57, p = 0.0011), small myelinated (r = 0.53, p = 0.0029), and large myelinated fibers (r = 0.49, p = 0.0054). There was a trend toward an association between IENF and sural nerve unmyelinated fiber densities (r = 0.32, p = 0.054). Sural SNAP amplitude and large myelinated fiber densities were highly correlated (r = 0.87, p < 0.0001). IENF density and sural nerve small fiber measures were concordant in 73% of patients. Reduced IENF density was the only indicator of small fiber depletion in 23% of cases. It was usually normal in acquired demyelinating neuropathies and where clinical suspicion for neuropathy was low. CONCLUSIONS: Distal leg Intraepidermal nerve (IENF) density may be more sensitive than sural nerve biopsy in identifying small fiber sensory neuropathies. Assessments of IENF density and large fiber measures on biopsy and electrophysiology are both useful for characterizing sensory and sensorimotor neuropathies.     

The effect of differential and complete nerve block on experimental muscle pain in humans.

We have attempted to examine the nerve fiber population mediating experimentally induced muscle pain in humans. Two established methods induced muscle pain: continuous, intramuscular, electrical stimulation and intramuscular infusion of hypertonic saline. A progressive nerve block was achieved by a combination of compression nerve block and intravenous regional anesthesia. Regular tests of muscle pain intensity were performed during the blocking period of 60 min. At the same time, the blocking of thick and thin afferents was monitored by assessment of proprioception and cutaneous touch, pin-prick, pressure pain, and heat-detection thresholds. Electrically induced muscle pain was inhibited (P < 0.0001) in parallel with proprioception, touch, and pin-prick, which were mediated by thick and thin myelinated nerve fibers. Saline-induced muscle pain was inhibited (P < 0.002) synchronously with heat detection and pressure pain, which are mediated by unmyelinated nerve fibers. Based on the present psychophysical experiments, it is suggested that: (1) myelinated afferents mediated mainly electrically induced muscle pain, and (2) unmyelinated afferents mediated mainly saline-induced muscle pain.     

Intraepidermal nerve fibre density, quantitative sensory testing and nerve conduction studies in a patient material with symptoms and signs of sensory polyneuropathy

Small diameter nerve fibre (SDNF) neuropathy is an axonal sensory neuropathy affecting unmyelinated (C) and thin myelinated (A-delta) fibres. We have evaluated 75 patients with symptoms and signs suggesting SDNF dysfunction with or without symptoms and signs of co-existing large diameter nerve fibre involvement. The patients were examined clinically and underwent skin biopsy, quantitative sensory testing (QST) and nerve conduction studies (NCS). The purpose of this study was to compare the relationship between the different methods and in particular measurements of thermal thresholds and intraepidermal nerve fibre (IENF) density in the same site of the distal leg. The main subdivision of the patient material was made according to the overall NCS pattern. Patients with normal NCS (38) had 6.4 +/- 3.8 and patients with abnormal NCS (37) had 4.4 +/- 3.4 IENF per mm (P = 0.02). Limen (difference between warm and cold perception thresholds) was significantly higher (more abnormal) in those with abnormal than in those with normal NCS (22.1 +/- 9.1 vs. 13.4 +/- 5.6, P < 0.0001). Cold perception threshold was more abnormal (P < 0.0001) than warm perception threshold (P = 0.002). Correlation between IENF and QST was statistically significant only when NCS was abnormal, and thus dependent of a more severe neuropathic process in SDNFs.     

Potential c-fiber damage in Wilson's disease

OBJECTIVES: To find out about potential involvement of the peripheral and autonomic nervous system in Wilson's disease (WD). MATERIAL AND METHODS: Seventeen patients with laboratory proven WD were examined with quantitative sensory testing (QST) (thermal, pain and vibratory sensation), pupillometric evaluation and electrophysiological testing of basal ganglia motor function [frequency of most rapid alternating movements (MRAM), reaction time (RT), contraction time (CT)]. Results were compared with those obtained in 20 healthy controls. RESULTS: After correction for multiple comparisons, patients with WD showed significantly higher thresholds for warm sensation [sural and peroneal nerve, thermal sensory limen (TSL), unpaired t-test]. Individual results were pathological in eight (peroneal) and nine (sural nerve) patients, respectively. Pupil function was not altered. Patients with WD showed significant slowing of MRAM and prolongation of RT and CT. There was no significant correlation between RT and QST results. CONCLUSIONS: These findings are compatible with a potential involvement of unmyelinated warm-specific C fibers in WD, independent from predominant basal ganglia motor dysfunction.