Peripheral neuropathy has been reported

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1 JOEM Volume 48, Number 6, June CME Available for this Article at ACOEM.org Reduced Epidermal Nerve Density Among Hand-Transmitted Vibration-Exposed Workers Huey-Wen Liang, MD, MSc Sung-Tsang Hsieh, MD, PhD Tsuen-Jen Cheng, MD, ScD Chung-Li Du, MD, PhD Jung-Der Wang, MD, ScD Ming-Fong Chen, MD, PhD Ta-Chen Su, MD, PhD Learning Objectives Compare epidermal nerve density (END), estimated by immunohistochemical staining of skin biopsies from the distal forearm, in ten men exposed occupationally to hand-transmitted vibrations and in age- and gendermatched control subjects. Identify the results of sensory threshold testing and nerve conduction studies, and any correlations found between these or other factors on the one hand and END on the other. Explain the implications of these findings for the development and early diagnosis of hand-arm vibration syndrome. Abstract Objective: The objective of this study was to evaluate ultrastructural changes of epidermal nerve density (END) in workers exposed to hand-transmitted vibration. Methods: Ten male subjects with occupational exposure to hand-transmitted tools for 46.9 hours weekly for an average of 6.5 years were included in this study. We performed a skin biopsy from the forearms and compared the END with 10 age- and gender-matched healthy control subjects. Results: Nine of the 10 subjects had abnormally low END. The END of the exposed workers was significantly lower than the control group ( vs fibers/mm, P 0.005). The difference remained even after one subject with possible undiagnosed diabetes was not included ( vs fibers/mm, P 0.005). The reduction of END did not correlate with the abnormality of nerve conduction studies or quantitative sensory testing. Conclusions: The reduction of END suggested the involvement of small-diameter nerve fibers among this population, and such a histologic change might either be independent or precede changes of large myelinated nerve fibers. ( J Occup Environ Med. 2006;48: ) From the Departments of Physical Medicine and Rehabilitation (Dr Liang), Neurology (Dr Hsieh), Environmental and Occupational Medicine (Drs Cheng, Du, Wang, and Su), and Internal Medicine (Drs Wang, Chen, and Su), National Taiwan University Hospital and National Taiwan University College of Medicine, Taiwan; and the Institute of Occupational Medicine and Industrial Hygiene (Drs Cheng and Wang), College of Public Health, National Taiwan University, Taiwan. Ta-Chen Su has no financial interest related to this article. Address correspondence to: Ta-Chen Su, MD, PhD, Attending Physician, Departments of Internal Medicine, and Environmental and Occupational Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, 7, Chung-Shan South Road, Taipei, Taiwan 100; tachensu@ha.mc.ntu.edu.tw Copyright 2006 by American College of Occupational and Environmental Medicine DOI: /01.jom Peripheral neuropathy has been reported in workers exposed to handtransmitted vibration. 1 3 Numbness, tingling, pain, loss of sensation, reduction of dexterity, and muscular weakness of the hands are common complaints. However, the pathophysiology of vibration-related neuropathy is not well understood. It is suggested to be characterized by a peripheral, diffusely distributed neuropathy with a predominantly sensory impairment. 1 A higher prevalence of entrapment neuropathy (ie, carpal tunnel syndrome) or distal neuropathy was reported among workers using chainsaws, pneumatic hammers, and other vibration-transmitting tools. 1,4 Studies on patients with vibration-induced white fingers showed evident changes, including a decrease in the number of myelinated nerve fibers and thick lamellar fibrosis of the perineurium. 4,5 The correlation between the reduction in motor conduction velocity and ultrastructural changes in the paranodal regions and myelin sheaths have been documented by animal studies. 6 All of the aforementioned findings are supportive of large myelinated nerve fiber involvement among the vibration-exposed population. Meanwhile, rare studies explored the influence of vibration on small unmyelinated nerve fibers. The function of somatic small fibers could be evaluated by quantitative sensory testing (QST), 7 and a few studies found impaired neurophysiological function in vibration-exposed workers Nevertheless, histologic changes of small-diameter nerve fibers have yet not been studied. Epidermal nerve densities (END) are reduced in various

2 550 Reduced Epidermal Nerve Density Among Hand Arm Vibration Syndrome Liang et al types of small-fiber neuropathies, including diabetes mellitus, amyloidosis, toxins, and inherited sensory and autonomic neuropathies. 11,12 In patients with peripheral neuropathies, epidermal innervation is correlated with the elevation of thermal thresholds for warm sensation. 13 No previous research has been performed to evaluate the changes of END among vibration-exposed workers. We performed skin biopsy over the forearms of a group of vibrationexposed subjects and compared their END with those of age- and gendermatched healthy control subjects. The study aimed to provide more pathoanatomic evidence of vibration-related neuropathy. Materials and Methods Subjects The patients were recruited from the clinic of occupational medicine at the National Taiwan University in Taipei, Taiwan. They came for the determination of occupation-related hand arm vibration syndrome (HAVS) for workers compensation. All of the participants were males with an average age of 42.3 years. Demographic data and occupational history was obtained from all subjects on their initial visit (Table 1). All of the subjects reported bilateral hand numbness, tingling, and paresthesia of approximately 2 years duration after the initiation of construction work. The symptoms were described as occasional initially, which then progressed and were aggravated after working with vibration-exposing tasks. All of their symptoms were classified as either 2 SN or 3 SN based on the Stockholm revised vibration syndrome classification system. 14 A series of tests were performed, including nerve conduction studies, blood tests, and quantitative sensory tests. The blood tests included biochemistry examinations (fasting blood glucose, hemoglobulin A1C, lipid profile, vitamin B12, and folic acid), infectious disease studies (hepatitis C, human immunosuppressive virus [HIV], Venereal Disease Research Laboratory test [VDRL]) and immunologic profile (rheumatoid factor, antinuclear antibody, cryoprotein). Age- and gender-matched control subjects were randomly selected from the database of the Department of Neurology. 13 The normal control subjects were recruited from a previously described cohort, including those visiting the National Taiwan University Hospital, Taipei, Taiwan for a physical checkup. The evaluation included detailed questionnaires and neurologic examinations to identify any neurologic disorder or clinical neuropathy. Examinations consisted of laboratory tests (complete blood count, fasting plasma glucose, hemoglobin A1C, liver and renal functions, serum protein electrophoresis, antinuclear antibody, and vitamin B12 level), nerve conduction studies, and quantitative sensory testing. Ten controls with an average age of 43.1 years were selected. There was no habitual alcohol drinking or smoking in the control group. All of them had normal nerve conduction studies (NCS) and quantitative sensory tests and no occupational exposure to handtransmitted vibration. All of the patients signed informed consent to undergo skin biopsy for the quantification of epidermal innervation. Work History A detailed work history regarding occupational exposure to vibratory tools was obtained from a questionnaire. A picture album of vibration tools was assembled to assist tool recognition while taking work exposure history. The patients were former construction workers of the underground railway system and were all responsible for the operation of rock-cracking and drilling machines. We also consulted the Institute of Occupational Safety and Health, Council of Labor Affairs, Executive Yuan, Taiwan to confirm the models of the vibration tools (Hitachi, Mammer Martillo, PH-65A and H 41SC). We determined the extent of vibration exposure as much as possible, TABLE 1 Demographic, Electrophysiological, and Skin Biopsy Findings in Vibration-Exposed Subjects Case No. Age (yr) Duration Exposure (yr) Duration Removal (yr) Alcohol Consumption (g) END (fibers/mm) Sensory Threshold Warm Cold Vibratory NCS (abn) abn abn abn N l9.13 (N) abn abn abn N (abn) abn abn abn N (abn) N N N N (abn) abn N N Bilateral CTS (abn) abn N abn N (abn) abn N abn N (abn) abn abn abn PN (abn) abn abn abn Bilateral CTS (abn) ND ND ND N ND indicates not done; N, normal (normal sensory threshold or normal nerve conduction studies); abn, abnormal, ie, elevated sensory threshold or reduced END; NCS, nerve conduction study; CTS, carpal tunnel syndrome; PN, polyneuropathy.

3 JOEM Volume 48, Number 6, June even after the subjects had left their jobs for a period of time. With the pictures of the vibration tools and the packing inserts of these machines, as well as the detailed questionnaire of working time and duration, we confirmed the vibration-related work exposure time and duration for each worker. The records of their working history were confirmed by the construction company to ensure their respective job content and duration. Nerve Conduction Studies and Quantitative Sensory Testing Nerve conduction studies were conducted with a Nicolet Viking IV Electromyographer (Madison, WI) following standardized methods. The nerves studied included the bilateral median, ulnar, tibial peroneal, and sural nerves. Quantitative sensory testing was performed with a Thermal Sensory Analyzer and Vibratory Sensory Analyzer (Medoc Advanced Medical System, Minneapolis, MN) to measure sensory thresholds of warm, cold, and vibratory sensations by the procedures described in prior reports. 15,16 The stimulator was applied to the skin of the thumb and index finger for thermal stimuli and to the index knuckle for vibratory stimuli. The examiner explained these procedures to the subjects, and the subjects underwent several trials to become familiar with the test. The examination was in a quiet room at a room temperature of 21 to 24 C with skin temperatures between 31 and 34 C. The reference temperature of the examination was set at 32 C, and the temperature went up (warm stimuli) or went down (cold stimuli) according to the default algorithms. Skin Biopsy and Immunohistochemistry Skin biopsy was performed by punches of 3 mm in diameter over the extensor side of the distal forearm 5 cm above the middle point of the line connecting the radial styloid process and the ulnar styloid process, after local anesthesia with 2% lidocaine. 13 The wounds were covered with sterile gauze and healed well after 7 to 10 days. Skin tissues were fixed with 4% paraformaldehyde in 0.1 M phosphatebuffered saline (PB), ph 7.4, for 48 hours. After thorough rinsing in PB, the samples were cryoprotected with 30% sucrose in PB overnight. Sections at 50 m perpendicular to the dermis were cut on a sliding microtome (Microm 440E; Microm, Germany) and sections from each tissue were labeled sequentially and stored with antifreeze (30% ethylene glycol in PB) at 20 C and then treated with 0.5% Triton X-100 in 0.5 M Tris buffer, ph 7.6 (Tris) for 30 minutes and processed for immunostaining. These were quenched with 1% H 2 O 2, blocked with 5% normal goat serum in 0.5% nonfat dry milk/tris, and incubated with rabbit antiserum to protein gene product (PGP) 9.5 (Ultra- Clone, U.K.; diluted 1:1000 in 1% normal serum/tris) at 4 C for 16 to 24 hours. After rinsing in Tris, sections were incubated with bio-tinylated goat antirabbit immunoglobulin G at room temperature for 1 hour followed by incubation with the avidin biotin complex (Vector, Burlingame, CA) for another hour. The reaction product was demonstrated with chromogen SG (Vector) and counterstained with eosin (Sigma, St. Louis, MO). Quantification of Epidermal Innervation Epidermal innervation was quantified following established protocols with the slides all coded and the readers blinded. 17 PGP 9.5-immunoreactive nerve fibers in the epidermis of each section were counted at a magnification of 40 with an Olympus B 40 microscope (Tokyo, Japan) through the depth of the entire section. Each individual nerve fiber with branching points inside the epidermis was counted as one. For epidermal fibers with branching points in the dermis, each individual nerve fiber was counted separately. The length of the each section was measured using Image-Pro PLUS software (Media Cybernetics, Silver Spring, MD). Each tissue was sectioned into 48 to 50 sections and labeled sequentially. The epidermal nerve fiber densities of the stained sections were defined as the IENF density of that tissue specimen and expressed as fibers/mm. The cutoff point of the END for subjects less than 60 years of age was fibers/mm according to the normative values from our laboratory. Statistical Analysis Epidermal nerve densities were expressed as the mean standard deviation for both the vibrationexposed and normal control groups. The results were compared using the Mann-Whitney test. The differences of the END between subjects with normal or abnormal QST and NCS were also compared with the Mann- Whitney test. SPSS for Windows (version 10.0; SPSS, Chicago, IL) was used for all of the statistical analysis. Any difference with a P value less than 0.05 was considered statistically significant. Results Their mean work hours were 46.9 hours per week, whereas the average exposure duration was years (range, 3 15 years). They had been removed from their jobs for an average of years (range, 2 8 years). None of these studies was positive for immunologic profile, HIV, or VDRL. One case had positive hepatitis C antibody, whereas another case had abnormally elevated hemoglobin A1C (6.5% in case no. 1). None were taking hypoglycemic agents or diagnosed with diabetes mellitus. Their vitamin B12 and folic acid levels are all within normal limits. Sensory Threshold and Nerve Conduction Studies Table 1 showed the results of the sensory threshold testing of nine subjects. All but one (88.9%) of the subjects had abnormally elevated thermal

4 552 Reduced Epidermal Nerve Density Among Hand Arm Vibration Syndrome Liang et al threshold to warm sensation. The proportion of abnormal sensory threshold testing for cold and vibratory sensation was 55.6% and 77.8%, respectively. Three subjects had abnormal nerve conduction results. Two fulfilled the criteria of bilateral carpal tunnel syndrome, whereas another was compatible with polyneuropathy. Case no. 5 had a moderately severe degree of carpal tunnel syndrome over the right side and a mild degree over the left side. 18 Case no. 9 had a moderately severe degree of bilateral carpal tunnel syndrome. Table 2 showed no correlation among abnormal END, NCS, and sensory threshold tests by Spearman correlation analysis. There was no significant difference of END between subjects with normal and abnormal sensory threshold and nerve conduction studies by Mann-Whitney test, although the subjects with abnormal nerve conduction studies had a trend of lower mean END compared with those with normal results ( vs fiber/mm, P 0.138). TABLE 2 Correlation of Between Normal or Abnormal Epidermal Nerve Density (END), Nerve Conduction Studies (NCS) and Sensory Threshold, Analyzed by Spearman s Correlation Coefficient END NCS Warm Threshold Cold Threshold NCS r P Warm threshold r r P P Cold threshold r r r P P P Vibratory threshold r r r r P P P P Fig. 1. Skin biopsy results of case no. 1. The skin was immunostained with an antiserum against protein gene product 9.5 (PGP 9.5) and then counterstained with eosin. PGP 9.5 immunoreactivities are present in dermal nerve bundles (arrow). A single epidermal nerve (arrowhead in set) originates from subepidermal nerve plexuses and passes through keratinocytes of the epidermis. The abundance of epidermal nerve requires quantification. Pathology of Cutaneous Innervation Figure 1 shows the results of the skin biopsy of case no. 1. The skin was immunostained with an antiserum against protein gene product 9.5 (PGP 9.5) and then counterstained with eosin. As shown in the illustration, PGP 9.5 immunoreactivities are present in dermal nerve bundles. Single epidermal nerves that originate from the subepidermal nerve plexuses pass through keratinocytes of the epidermis. The END values of vibrationexposed subjects were significantly lower than those of age- and gendermatched control subjects ( vs fibers/mm, P 0.005) (Fig. 2). Nine of 10 workers had abnormally reduced END according to the normative data with a cutoff point of fibers/mm for those aged less than 60 years (Table 1). To rule out the influence of potential diabetes, one case with abnormally elevated hemoglobulin A1C was excluded during a repeat analysis. The END of the vibration-exposed subjects was still significantly lower than that of controls ( vs fibers/mm, P 0.005). The daily alcohol consumption was not correlated with the END and the result was insignificant (Pearson s correlation coefficient was 0.26, P 0.47). Discussion The major finding in this study is the significant reduction of forearm END in 10 workers who had been exposed to hand-transmitted vibration as compared with those of ageand gender-matched normal control subjects. This study is also the first to document the use of END in the diagnosis of sensory neuropathy in suspected HAVS. Exposure to hand-transmitted vibration has been reported to induce peripheral neuropathy. 1 3 The sites of nerve impairment may be located in the receptor organs of the skin, in the nerve fibers at a distant or proximal level, or in the nerve cell bodies. 19 Some studies have documented the higher risk of entrapment neuropathies (ie, carpal tunnel syndrome) among workers using chainsaws, pneumatic hammers, and other vibration-transmitting tools. 1,2,4 Furthermore, nerve impairments of the other segments of the upper extremities and lower extremities have been found by other

5 JOEM Volume 48, Number 6, June Fig. 2. Comparison of epidermal nerve density (END) between the study subjects and the control group. The means are indicated by the bar lines. studies. 1,3,20,21 It has, therefore, been suggested that vibration-exposed neuropathy is characterized by diffuse and multifocal impairment. 1 The involvement of large myelinated nerve fibers has likewise been revealed by both neurophysiological function testing (ie, nerve conduction study) and histologic studies. 1,3,6,21 Studies on patients with vibrationinduced white fingers revealed evident changes, including a decrease in the number of myelinated nerve fibers and thick lamellar fibrosis of the perineurium. 4,5 Moreover, the studies by Ho and Chang showed histologic changes of the paranodal regions, myelin sheath, and Schmidt- Lanterman incisures in animal studies. 6,22 Meanwhile, the influence of vibration on small unmyelinated nerve fibers has not been adequately studied yet. Previous studies noted that patients of vibration-induced white fingers had a higher proportion of impaired QST, which evaluate the neurophysiological function of somatic small fibers QST is suitable for screening in the field because it is generally easy to perform and is usually not associated with significant pain. 8 It is also effective in documenting dysfunction in patients with small-fiber neuropathy but with normal NCS. 23 However, it is criticized for the inherent shortage of multiple covariates and test methodologies. Lack of normative values, standardized methods, or a gold standard for the presence of sensory neuropathy may obscure the clinical application. 8 Unlike those of large myelinated nerve fibers, histologic changes related to small fibers are rarely studied among vibration-exposed workers. Epidermal nerve densities had been used to evaluate various types of small-fiber neuropathies. 12,13,15 Previous studies had found a more global involvement among various kinds of neuropathies since the improvement of investigation tools on small-diameter nerve fibers. 12,15,24 By using different neural markers, including PGP 9.5, which is particularly abundant in small-diameter nerves, skin innervation could be quantified by immunocytochemistry. Our results showed a significant reduction of END over the forearms among vibration-exposed subjects and confirm a wider involvement of vibration-induced neuropathy. It is not surprising to find a poor correlation between NCS and END because of the different sizes of nerves evaluated. A much higher proportion of abnormal END than NCS also imply that the involvement of small fibers might be independent or precede changes of the large myelinated nerve fiber in vibration-induced neuropathies. However, further studies are warranted to prove this hypothesis. Moreover, we could not find a correlation between END and QST. It is not consistent with previous studies that showed a correlation between END and the elevation of thermal thresholds for warm sensation in patients with peripheral neuropathies. 13 Although the subjects had been removed from their vibration-exposed jobs for an average of 5 years, the reduction of END remained significant. A previous report suggested that the symptoms of HAVS might persist for a few years and that the sensorineural abnormalities seem to be more resistant than vascular disorders to improvement or recovery after stoppage of the use of vibrating tools Kurozawa et al followed up 99 male workers and found that the blanching of fingers persisted even after many years of vibration exposure in workers with initially advanced stages. 26 Our study implied that the loss and decrease in number of epidermal small fibers also remained after cessation of vibration exposure. Some medical conditions are associated with a reduction of ENDs, including diabetes mellitus, amyloidosis, toxins, HIV infection, and alcoholism. 11,12 We collected medical history and symptoms to determine possible coexisting causes of small-fiber neuropathy. The first confounding factor is abnormal plasma glucose level, which was found in one of our subjects (hemoglobulin A1C: 6.5%). He denied any history or medication for hyperglycemia. The reduction of END remained after we removed this subject from analysis and the influence of diabetics was not likely. The other confounding factor is a high percentage of alcohol consumption. Small-fiber loss was found among subjects with painful alcoholic polyneuropathy with normal thiamine

6 554 Reduced Epidermal Nerve Density Among Hand Arm Vibration Syndrome Liang et al status. 12 The clinical symptoms included painful sensation and some degree of muscular atrophy and weakness, which was not found in our subjects. No other report could clarify the influence of alcohol consumption on the END. We correlated daily alcohol consumption with the END and found no significant correlation. Therefore, alcohol consumption could not explain the decreased END in our cases, although some potential effect could still not be totally ruled out. In a cohort study in the United Kingdom, disability in HAVS was largely related to a sensorineural component of the Stockholm workshop scale rather than the vascular scale, and early identification of the impaired sensorineural component was also suggested for the prevention of further disability. 28 Sensorineural tests have been valuable in assessing subjects with medicolegal compensation claims for HAVS in the United Kingdom. 29 However, the consensus report in the American Academy of Neurology indicates that QST should not be the sole criteria used in diagnosing the structural pathology of either a peripheral or central nervous system origin. 7 Thus, a diagnostic dilemma in HAVS is still debatable before a truly objective test can be developed. 29 It seems that measurement of END can provide more information, but the problems of a relatively wide range of normative value and the influence of other confounding factors should be studied before clinical application is feasible. There are some limitations in this study. The exposure dosage of handtransmitted vibrations in our cases could not be quantified and a dose response relationship could not be explored. However, the information related to the vibration exposure from both the workers and their company could be confirmed. The consistent findings in impaired QST and decreased END also support the sensory neuropathy of HAVS in our cases. In conclusion, we applied skin biopsy with PGP 9.5 immunohistochemistry as an investigation tool to evaluate the END for hand-transmitted vibration-exposed subjects and found a significant reduction as compared with healthy control groups. We suggest the involvement of smalldiameter nerve fibers among this population and such a histologic change might be independent or precede changes of large myelinated nerve fibers. This study also indicates the possible use of END in the diagnosis of sensory neuropathies in patients with suspected HAVS. References 1. Bovenzi M, Giannini F, Rossi S. Vibration-induced multifocal neuropathy in forestry workers: electrophysiological findings in relation to vibration exposure and finger circulation. Int Arch Occup Environ Health. 2000;73: Nilsson T, Hagberg M, Burstrom L, et al. Impaired nerve conduction in the carpal tunnel of platers and truck assemblers exposed to hand arm vibration. Scand J Work Environ Health. 1994;20: Sakakibara H, Hirata M, Hashiguchi T, et al. Affected segments of the median nerve detected by fractionated nerve conduction measurement in vibration-induced neuropathy. Ind Health. 1998;36: Takeuchi T, Futatsuka M, Imanishi H, et al. Pathological changes observed in the finger biopsy of patients with vibrationinduced white finger. Scand J Work Environ Health. 1986;12: Takeuchi T, Motohiro T, HImanishi H. Ultrastructural changes in peripheral nerves of the fingers of three vibrationexposed persons with Raynaud s phenomenon. Scand J Work Environ Health. 1988;14: Chang KY, Ho ST, Yu HS. Vibration induced neurophysiological and electron microscopical changes in rat peripheral nerves. Occup Environ Med. 1994;51: Yarnisky D. Quantitative sensory testing. Muscle Nerve. 1997;20: Lundstrom R. Neurological diagnosis aspects of quantitative sensory testing methodology in relation to hand arm vibration syndrome. Int Arch Occup Environ Health. 2002;75: Ekenvall L, Gemne G, Tegner R. Correspondence between neurological symptoms and outcome of quantitative sensory testing in the hand arm vibration syndrome. Br J Ind Med. 1989;46: Nharada N, Matsumoto T. A study of various function tests on the upper extremities for vibration syndrome. Am Ind Hyg Assoc J. 1981;42: Lacomis D. Small-fiber neuropathy. Muscle Nerve. 2002;26: Koike H, Mori K, Misu KMH, et al. Painful alcoholic polyneuropathy with predominant small-fiber loss and normal thiamine status. Neurology. 2001;56: Pan CL, Yuki N, Koga M, et al. Degeneration of nociceptive nerve terminals in human peripheral neuropathy. Neuroreport. 2001;12: Gemne G, Pyykko I, Taylor W, et al. The Stockholm Workshop scale for the classification of cold-induced Raynaud s phenomenon in the hand arm vibration syndrome (revision of the Taylor-Pelmear scale). Scand J Work Environ Health. 1987;13: Pan CL, Tseng TJ, Lin YH, et al. Cutaneous innervation in Guillain-Barre syndrome: pathology and clinical correlations. Brain. 2003;126: Yarnitsky D, Ochoa JL. Warm and cold specific somatosensory system. Psychophysical thresholds, reaction times and peripheral conduction velocities. Brain. 1991;114: Chiang HY, Huang IT, Chen WP, et al. Regional difference in epidermal thinning after skin denervation. Exp Neurol. 1998;154: Bland JDP. A neurophysiological grading scale for carpal tunnel syndrome. Muscle Nerve. 2000;23: Lundborg G, Dahlin LB, Hansson H, et al. Vibration exposure and peripheral nerve fiber damage. J Hand Surg [Am]. 1990;15: Hirata M, Sakakibara H, Yamada S, et al. Medial plantar nerve conduction velocities among patients with vibration syndrome due to chain-saw work. Int Arch Occup Environ Health. 1999;72: Ho ST, Yu HS. A study of neurophysiological measurements and various function tests on workers occupationally exposed to vibration. Int Arch Occup Environ Health. 1986;58: Ho ST, Yu HS. Ultrastructural changes of the peripheral nerve induced by vibration: an experimental study. Br J Ind Med. 1989; 46: Magda P, Latov N, Renard MV, et al. Quantitative sensory testing: high sensitivity in small fiber neuropathy with normal NCS/EMG. J Peripher Nerv Syst. 2002;7: Ko MH, Chen WP, Lin-Shiau SY, et al. Age-dependent acrylamide neurotoxicity in mice: morphology, physiology, and function. Exp Neurol. 1999;158:37 46.

7 JOEM Volume 48, Number 6, June Koskimies K, Pyykko I, Starck J, et al. Vibration syndrome among Finnish forest workers between 1972 and Int Arch Occup Environ Health. 1992;64: Kurozawa Y, Nasu Y, Hosoda T, et al. Long-term follow-up study on patients with vibration-induced white finger (VWF). J Occup Environ Med. 2002;44: Bovenzi M, Franzinelli A, Scattoni L, et al. Hand-arm vibration syndrome among travertine workers: a follow up study. Occup Environ Med. 1994;51: Mason HJ, Poole K, Elms J. Upper limb disability in HAVS cases how does it related to the neurosensory or vascular elements of HAVS? Occup Med (Lond). 2005;55: McGeoch KL, Lawson IJ, Burke F, et al. Use of sensorineural tests in a large volume of medico-legal compensation claims for HAVS. Occup Med (Lond). 2004;54: