Clinical applications of quantitative sensory testing (QST)

Journal of Neurological Sciences 153 (1998) 215–238

Clinical applications of quantitative sensory testing (QST) a

R. Zaslansky , D. Yarnitsky a

a ,b ,

*

Institute of Clinical Neurophysiology, Rambam Medical Center and Technion Medical School, Haifa, Israel 31096 b Department of Neurology, Rambam Medical Center and Technion Medical School, Haifa, Israel 31096

Abstract Quantitative sensory testing (QST) has been used clinically for the last two decades, yielding a substantial number of publications regarding these applications. In this review we tried to amass together the major findings of these publications into one monograph, excluding those dealing with pain. This was done with the aim of assisting clinicians in the better use of QST techniques for the benefit of their patients.  1998 Elsevier Science B.V. Keywords: Quantitative sensory testing; Thermal thresholds; Vibratory thresholds; Neuropathy

Table of Contents 1. Introduction ............................................................................................................................................................................................ 2. Endocrine and metabolic neuropathies ...................................................................................................................................................... 2.1. Diabetes mellitus ............................................................................................................................................................................ 2.2. Uremic polyneuropathy (PNP) ........................................................................................................................................................ 2.3. Vitamin B 12 deficiency ................................................................................................................................................................... 2.4. Liver cirrhosis ................................................................................................................................................................................ 3. Chronic compression–entrapment neuropathies ......................................................................................................................................... 3.1. Carpal tunnel syndrome (CTS) ........................................................................................................................................................ 3.2. Hand–arm vibration syndrome (HAVS) ........................................................................................................................................... 3.3. Lumbrosacral radiculopathy ............................................................................................................................................................ 4. Toxic neuropathies .................................................................................................................................................................................. 4.1. Alcoholic polyneuropathy (PNP) ..................................................................................................................................................... 4.2. Paraneoplastic and chemotherapy-induced neuropathy....................................................................................................................... 4.3. Occupation- and pharmacologic-related toxic neuropathies ................................................................................................................ 4.4. Gulf War syndrome ........................................................................................................................................................................ 5. Infection associated neuropathy ................................................................................................................................................................ 5.1. HIV infection ................................................................................................................................................................................. 5.2. Leprosy infection ........................................................................................................................................................................... 6. Immune-related neuropathies.................................................................................................................................................................... 6.1. Acute inflammatory demyelinating polyradiculoneuropathy [Guillain–Barre syndrome (GBS)]............................................................ 6.2. Systemic lupus erythematosus (SLE) ............................................................................................................................................... 6.3. Sjogren’s syndrome ........................................................................................................................................................................ 7. Hereditary neuropathies and myopathies ................................................................................................................................................... 7.1. Hereditary sensory neuropathy, type I .............................................................................................................................................. 7.2. Hereditary sensory and autonomic neuropathy, type III (Dysautonomia of Riley-Day)......................................................................... 7.3. Myotonic dystrophy........................................................................................................................................................................

216 217 217 220 222 222 222 222 224 225 225 225 226 227 228 228 228 229 229 229 230 230 230 230 230 230

Abbreviations: QST, Quantitative sensory testing; VT, Vibration threshold; NCS, Nerve conduction study; EMG, Electromyography; PNP, Polyneuropathy; IDDM, Insulin-dependent Diabetes mellitus; NIDDM, Noninsulin-dependent Diabetes mellitus. *Corresponding author. Tel.: 1972 4 8542755; fax: 1972 4 8542755; e-mail: [email protected] 0022-510X / 98 / $19.00  1998 Elsevier Science B.V. All rights reserved. PII S0022-510X( 97 )00293-1

216

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

8. Diseases of the central nervous system (CNS) ........................................................................................................................................... 8.1. Cerebrovascular lesions .................................................................................................................................................................. 8.2. Multiple sclerosis (MS) .................................................................................................................................................................. 8.3. Syringomyelia ................................................................................................................................................................................ 8.4. Hereditary spastic paraplegic ........................................................................................................................................................... 9. Trauma ................................................................................................................................................................................................... 9.1. Evaluation of sensory restoration after tissue reconstruction............................................................................................................... 9.2. Burns............................................................................................................................................................................................. 9.3. Whiplash injury.............................................................................................................................................................................. 10. Neurogenic impotence............................................................................................................................................................................ 10.1. Diagnosis of neurogenic impotence by vibration ............................................................................................................................. 10.2. Diagnosis of neurogenic impotence by thermal testing..................................................................................................................... 10.3. Incidence of PNP in impotence ...................................................................................................................................................... 10.4. Conclusions ................................................................................................................................................................................. 11. Itch....................................................................................................................................................................................................... Acknowledgements ...................................................................................................................................................................................... References...................................................................................................................................................................................................

1. Introduction It is now two decades since the publication of the first clinical paper on the use of quantitative sensory testing (QST) techniques (Fruhstrofer et al., 1976), and the field has seen a flurry of subsequent publications. As the reader will note, most clinical situations which affect sensory function have been investigated by means of QST. In most instances, the data is predominantly descriptive, consisting primarily of abnormality rates for various modalities of sensation. Yet, in the major disorders of sensation, such as those associated with Diabetes mellitus, QST research has gone far beyond basic description. Here the use of QST in the clinic is much better defined, including its role in diagnosis, staging, longterm follow-up of the natural history of disease, and determination of treatment efficacy. Data is also available regarding the relative role of QST versus other parameters of neural function, such as electrophysiological and autonomic testing. This review concentrates mainly on QST techniques which measure cutaneous thermal and vibration modalities of sensation. These are the principal modalities of concern in neurological literature. Some reference is made to the measurement of cutaneous pressure threshold by quantified pressure using graded Semmes–Weinstein monofilaments. These QST measures permit evaluation of responses to natural stimuli (heat, vibration, touch) and so assess the complete sensory neural axis, receptor to cortex. Current perception, where the axon is activated directly by electrical current, bypassing the receptors, is another test of sensory function which has been advocated in the last few years (Dinh et al., 1997; Liu et al., 1995). Some major questions regarding this technique are as yet unresolved (Quantitative sensory testing, 1992). Measurement of pain and pain conditions by QST techniques has not been included in this review; this is a complex issue and justifies a review on its own. QST is employed mostly for evaluation of peripheral

231 231 231 231 232 232 232 232 233 233 233 233 234 234 234 234 234

nerve disorders. This may be an outgrowth of the availability and popularity of advanced imaging tools, such as CT and MRI, which are important aids in diagnosis of CNS disorders, but are considerably less useful in diagnosis of peripheral nerve disorders. Testing thermal and vibration modalities enables assessment of the different types of sensory fibres. Vibration stimuli, peripherally, activate large myelinated fibres (A b ) and centrally, the dorsal columns. For the thermal senses, peripherally, cold sensation is mediated by small myelinated fibres (A d ); warm sensation by unmyelinated warm specific C-fibres; heat-pain by small myelinated and unmyelinated nociceptors and cold pain—both types of nociceptors as well as cold fibres. Centrally, all types of thermal stimuli (nonpain and painful) activate the spinoreticulothalamic tracts. Sensory threshold measures are the most commonly employed QST parameter. Being psychophysical responses, QST parameters are very sensitive to different methodological aspects of the test, thus, considerable attention must to paid these details in order to obtain valid and reproducible results. Many studies, particularly when the technique was initially introduced, did not follow strict experimental protocols. As a result, contradictory findings may be encountered in the literature, a trend which is reflected within this review. We have attempted to note and explain incomplete methodology when appropriate. Additional methodological issues, important in threshold determination, include site of testing, pressure of stimulator application, stimulator size and subject training. A common point of criticism is that the test is based on subjective responses. It is clear to every practitioner in the field that QST results are valid only if the patient is cooperative. Provided full cooperation, data collected has been shown reliable over time, and sensitive in diagnosis of a variety of disorders, leaving little doubt that the test is of substantial clinical use. For identification of noncooperating patients, several safeguards and veracity-as-

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

sessment methods have been developed, such as the use of null stimuli (Dyck et al., 1993) and threshold variance (Yarnitsky et al., 1994). A commonly asked question is ‘‘why perform QST when an objective and repeatable test such as NCS is at hand?’’. There are several reasons to do so: (i) small sensory nerve fibres are not detectable by routine electrophysiological techniques used clinically, whereas QST of the thermal modalities is the only clinical test for quantitative assessment of small nerve function; (ii) NCS detects physiological properties of the nerve, often different from the functional properties [e.g. there may be marked slowing of neural conduction in patients with Hereditary Motor Sensory Neuropathy, type I (HMSN I) but these patients may be as yet fully functional], whereas QST evaluates sensory function; (iii) as will be seen in this review, there are many instances in which combining results of the two types of test provides the best sensitivities; (iv) NCS only samples the peripheral nervous system, whereas QST evaluates the whole sensory axis; (v) QST is easier and simpler to perform, and mostly not painful. Also, it does not require highly-trained personnel for testing, and can be readily performed in the field. Thus, it is particularly suited for such purposes as screening and longterm evaluation of sensory function which is acceptable to subjects. We have recently published a review dedicated mostly to methodological aspects of QST (Yarnitsky, 1997) and so here, only a very brief mention of this issue will be made. Several test algorithms are currently employed in QST clinical practice for threshold determination. In the method of ‘limits’, stimuli increase in intensity until sensation occurs, at which moment the patient presses a button. This is a quick performance algorithm but includes a reaction time artifact. The methods of ‘levels’, ‘staircase’, ‘4-2-1’ and similar ones, use fixed stimuli which increase or decrease according to the response given to each stimulus by the subject. The ‘forced-choice’ algorithm uses two time or space epochs, only one of which contains a stimulus. The patient is requested to indicate which epoch contained the stimulus, and after certain criteria for success or failure are met, the stimulus intensity is changed. Statistical considerations regarding normative values and test stability are critical in QST, particularly because of the subjective nature of the test. The existence of stable normative values has helped demonstrate the validity of QST. Although, as with many medical tests there are no sharp diagnostic cut-off criteria, normative values obtained from a sufficiently large normal population, provide the rational basis for quantitative evaluation. The control population should be large enough so that the normative data are generalizable to the population at large, and so that factors such as gender, age and possibly height, can be examined for their influence on the sensory modality being tested. Test stability, which can be evaluated by a number of statistical techniques, (e.g. repeatability, co-efficient of

217

variation) allows the comparison of tests taken at different time points and thus, make QST a valuable method for assessment of time-related changes or therapeutic intervention. The vast majority of QST studies apply to adults, however, thermal testing in children aged 3–7 years old has been demonstrated as feasible, as the children cooperated and the results were reproducible (Hilz et al., 1996). We hope this comprehensive review will assist clinicians in better use of QST techniques for the benefit of their patients, and researchers in advancing somatosensory research, at both basic and applied levels.

2. Endocrine and metabolic neuropathies

2.1. Diabetes mellitus Diabetic neuropathy is the clinical field in which QST has been most commonly applied, covering every aspect of the neuropathy, from diagnosis to therapy. The importance and relevance of QST in this context is mentioned in the San Antonio report sponsored by the American Academy of Neurology and American Diabetic Association (Asbury et al., 1992; Quantitative sensory testing, 1992). The report emphasizes the importance of standardized measures in diabetic neuropathy.

2.1.1. Diagnosis and staging of diabetic polyneuropathy Diabetic polyneuropathy (PNP) comprises several abnormalities, including abnormalities of sensation, thus, the issue of setting minimal criteria for the diagnosis of PNP is critical. In the first of a set of classic papers, sural biopsies were compared to scored symptoms, neurological deficits, sensory thresholds for vibration and cooling, and nerve conduction parameters (Dyck et al., 1993). The authors concluded that abnormality in at least two of the four types of evaluation were an acceptable minimum for diagnosis of PNP. Further experience and the advent of autonomic tests brought about refinement of the initial recommendations in a paper published in 1991 (Dyck et al., 1991). Five types of evaluation were now advocated: scored symptoms, neurological deficits, NCS, QST and quantitative autonomic evaluation. Of the sensory tests, vibration and cooling detection, using the forced choice algorithm, were endorsed. The minimal criteria were changed to abnormality in at least two types of evaluation, one of them being nerve conduction or autonomic tests. Once diagnosed, severity of the PNP can be assessed by one of the following tests: scored symptoms, neurological deficits, abnormalities of NCS or sensory thresholds. QST was suggested as a tool for staging diabetic PNP (Hansson et al., 1991). The authors suggested a set of criteria for assessing severity of diabetic neuropathy based on degree of warm and cold threshold abnormality. They found significant correlation between the thermal abnor-

218

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

malities and the clinical bedside examination of small fibre function and suggested these criteria could be used for longterm assessment of patients. In a very large study, including 6487 diabetics in the UK, a significant correlation was found between VT and the neuropathy disability score (Young et al., 1993).

2.1.2. Prevalence of QST abnormalities in diabetic patients A number of studies present descriptive data regarding the prevalence of sensory abnormalities in diabetes. The frequency of abnormality for different modalities of sensation were determined in 81 diabetic patients (Vinik et al., 1995) employing diagnostic cut-off values which maintained a specificity above 90%: warmth 78%, cold 77%, vibration 88%, touch pressure 77%, current perception at 5 Hz 52%, at 250 Hz 48% and at 2000 Hz 56%. Combining thermal and vibratory tests gave a joint sensitivity of 92–95%, with specificity of 77–86%. The authors consider the combination of thermal and vibratory tests as suitable for screening diabetic patients for neuropathy. In 26 patients with longstanding IDDM, abnormality of VT was found in 77% and of heart rate variability in 92% of patients (Trojaborg et al., 1994a). In 100 diabetic patients, a significant relationship was found between thermal sensitivity and glycosylated haemoglobin; the latter was not associated with vibratory thresholds. Height influenced vibratory but not thermal thresholds (Gadia et al., 1987). VT increased with duration of diabetes as shown in a group of 25 diabetic patients (Christensen, 1969). In a group of 26 diabetics, cold sensation at the lateral malleolus was found to be the most commonly affected modality among the thermal ones (Hilz et al., 1988). These findings were corroborated by another study in which for 40 newly-diagnosed IDDM patients, pathology in cold sensation threshold was the most common (Ziegler et al., 1988a). In a group of 142 IDDM patients, abnormality of thermal sensation was found in 86%, whereas, heat-pain threshold, number of pilocarpine activated sweat glands and amount of sweat secretion, were all abnormal in less than 50% of patients (Navarro et al., 1989). 2.1.3. QST in relation to NCS Sural conduction parameters were compared with QST in 27 symptomatic diabetic patients (Horowitz, 1995). Vibratory sense correlated with sural amplitude, and cold detection threshold correlated with the minimal sural velocity. A significant correlation was found between conduction velocity and motor amplitudes of the median, ulnar and tibial nerves and vibratory thresholds in patients with neuropathy due to diabetes or uremia (Kilma et al., 1991). In 68 DM patients, conduction in the medial plantar (sensory) nerve, thermal, and vibratory senses were measured (Levi et al., 1987). A correlation was found between vibratory and thermal sensation. Many (45%) of the patients with normal sensation, had no conduction re-

sponse, and the absence of conduction response was more prevalent than abnormality of sensory thresholds. It is noted that this nerve is difficult to record from and a response is often not obtained in otherwise normal subjects. Nerve conduction studies were found to be complementary to sensory testing in detection of neuropathy in diabetic patients (Redmond et al., 1992). In 280 patients with IDMM, thermal sensation was more commonly affected than motor or sensory nerve conductions (Navarro and Kennedy, 1991).

2.1.4. Methodology Several papers focus on the methodology of QST employing healthy controls and diabetic patients. Spatial two alternative forced choice was employed in DM patients for detection of thermal sensation abnormality (Arezzo et al., 1986). Sensitivity of the methods of limits and forced choice for identification of abnormality in thermal thresholds in 33 diabetic patients was compared (Claus et al., 1990). No difference in sensitivity between the two methods were found, yet the authors found that forced choice took 6 times longer to perform than the method of limits. Equal sensitivities for the methods of limits and forced choice were found in another study (Levi et al., 1989). Another major issue related to the methodology is reproducibility. Although mostly studied in normals, several publications have focused on diabetic patients. Intersession coefficients of variation were calculated for 132 patients (Valensi et al., 1993), 35.3% found for vibration at medial melleolus, 41% for vibration at great toe, 64.5% for warm and 116.6% for cold thresholds at the foot. The extremely high coefficients for warmth and cold indicate large intersession differences rendering these threshold measurements clinically unusable. The authors give a detailed analysis of the variation for inter-institutional and inter-observer components. Coefficients of variation of 16–19% were found for vibration in the foot in 313 diabetics (Armstrong et al., 1991). A Pearson correlation coefficient of 0.81 for vibration between two sessions was found in 60 diabetic patients, very similar to the coefficient found in normals (Bertelsmann et al., 1986). A ‘warmth sensitivity index,’ the range between warmth sensory threshold and heat-pain threshold, was suggested as a sensitive tool for detection of neuropathy in diabetics with no clinical evidence of neuropathy (Jensen et al., 1991). 2.1.5. Natural history of diabetic neuropathy by QST parameters Two-hundred and one well-established NIDDM patients were followed for 2 years (Sosenko et al., 1993). The increase in thermal and vibratory thresholds during this period was significant between baseline and first year, and between first and second years. For example, warm sensory thresholds increased from 2.68C (median value) at

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

baseline, to 38C after one year, and 3.48C after two years. Similarly, cold thresholds were 1.98C, 2.38C and 2.78C, respectively. In contrast, in 71 newly-diagnosed NIDDM patients, only a slight deterioration was measured in VT at the feet, over five years (Hillson et al., 1984). Multiple regression analysis of the wide range of individual changes in the VT showed that mean fasting levels and age were amongst a number of significantly associated factors. Hyperglycemia had a significant effect on the VT over the 5 years in that an increase of 1 mmol / l in mean fasting glucose had an effect equivalent to an extra 5 years of age. These findings increase the weight of evidence pointing to the importance of restoring blood glucose in diabetics to as near to normal as is feasible.

2.1.6. QST and follow-up of diabetic complications Diversity is found regarding which sensory parameters are useful in identification of patients at risk for diabetic foot ulcer. The diversity reflects the different etiologies of diabetic PNP (mainly small or large fibre or mixed) and lack of uniformity amongst the subject populations. Furthermore, QST would not be sensitive to the vascular element in ulcers. In general, vibratory and pressureperception thresholds were found to be useful for identification of patients at risk. In a group of 20 patients, all with ulcerated feet, thermal and vibratory testing indicated widespread severe loss of both large and small fibres (Ali et al., 1989). The authors compared sensation in ulcerated vs. nonulcerated feet, and were unable to find any difference. Had a difference been found, one might interpret the sensory dysfunction as a pathophysiological factor in ulcer development. In contrast, in another study, sensation of 314 patients, of whom 91 had an ulcer during or prior to the study, was compared to patients without ulcers (Sosenko et al., 1990). Those with ulcers had significantly higher pressure perception thresholds at the hallux. Vibratory and thermal sensations were less sensitive in identification of ulceration. Thus, the authors suggest foot pressure threshold as a good measure for identification of patients at risk. VT was highly associated with ulcers in a study including 86 diabetic patients with ulcers and 49 without, whereas, ankle pressure index was associated with ulceration to a limited degree (Boulton et al., 1986). VT testing was suggested by these authors as the best tool for identification of patients at risk. This conclusion is shared by findings of another study in which 11 diabetic patients without PNP, 27 with PNP but no ulceration, and 23 with PNP and ulcers were tested by vibration (Le Quesne et al., 1990). The authors found that warm threshold detection was useful for detection of both minor and severe sensory abnormalities. However, it was a poor parameter for marking progress. On the other hand, VT testing was found useful in detecting abnormality and good for follow-up. QST (vibratory and thermal) parameters and autonomic tests (heart beat variation at paced breathing) demonstrated the pres-

219

ence of advanced autonomic and somatosensory neuropathy in nearly all patients with peripheral disease and foot ulcers, compared to those without (Guy et al., 1985; Hoeldtke et al., 1994). QST was found not to be useful for identifying patients with painful neuropathies in two studies. In 30 patients with painful PNP, only 40% had abnormal sensory function of small fibres (Smith et al., 1991). In 38 diabetics with no PNP, 32 with PNP but no pain and 52 with PNP and pain, no differences were found between the groups for VT, thermal discrimination, current perception thresholds, autonomic tests and NCS (Veves et al., 1994). It is noted that although pain was studied, pain thresholds or perception magnitude above threshold level were not measured. However, in a third study large and small fibre functions (vibration and thermal sensation) in the feet were worse in diabetics with painful neuropathy compared to those with nonpainful neuropathy (Ziegler et al., 1988b).

2.1.7. QST for therapy assessment The effects of continuous subcutaneous insulin infusion on painful diabetic neuropathy were assessed in 15 IDDM patients every 3 months over a 12 month period (Bertelsmann et al., 1987). PNP was assessed by a pain score, sensory clinical examination, NCS, autonomic function, thermal and vibratory thresholds of the foot. The only parameters to change were a significant reduction in thermal scores which paralleled a decrease in pain scores. The authors regard these findings as suggesting that sensory small fibres are more sensitive to changes in blood glucose levels than autonomic or large fibres. This confirms the importance of thermal sensation quantification in longitudinal studies of patients with diabetic neuropathy. One-hundred and eleven patients participated in a multicenter study which compared the effect of g-linolenic acid (at 480 mg / day) and placebo on the course of mild diabetic neuropathy over 1 year (Keen et al., 1993). The effects of the drug on the neuropathy were assessed by 16 parameters including NCS, cold and warm thresholds and clinical examination of leg and hand sensation. Of the 16 parameters tested, 13 were significantly different after 1 year. Sex, age, type of diabetes did not influence the results but the treatment was more effective in patients whose starting level of HbA1 was #10% compared to a starting level of .10%. The authors conclude that g-linolenic acid may prevent deterioration and in some cases reverse the neuropathy. The effect of treatment with the aldose reductase inhibitor, Ponalrestat, was studied in 30 diabetic patients (IDDM and NIDDM) with established peripheral and autonomic neuropathy (Gill et al., 1990). Sixteen weeks of randomly-assigned active or placebo treatment followed an initial 4 week placebo run-in phase. Parameters employed for assessment of neuropathy included VT, autonomic measures and scoring of symptoms. Mean VT of the Ponalrestat-treated group, compared to the placebo-treated

220

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

group, significantly improved over the 4 foot sites examined. The other indices of neuropathy indicated only a trend towards improvement. The authors concluded that Ponalrestat improves some of the clinical features of diabetic neuropathy, and suggested that the drug favors large fibres, thus explaining the improvement in vibration sensibility. The effects of combined pancreas and kidney transplantation on neuropathy were evaluated in 26 IDDM patients with end-stage nephropathy, 9 of whom were available for testing after the transplantation (Trojaborg et al., 1994b). Before transplantation, all patients had clinical signs and symptoms consistent with peripheral neuropathy. VT was abnormal in the feet of 89% and in the hand of 11% patients. Warm and cold thresholds were abnormal in 89% patients. The average follow-up after surgery was 41 months. In 6 patients with functioning combined transplants, improvement was detected in clinical and electrophysiological parameters. Of these patients, VT decreased in 1 patient and increased in another. Cold sensation thresholds in the feet decreased in 2 patients and remained unchanged in 4 others. Improvement in some autonomic functions was detected in 2 patients. Quality of life for those patients with a successful combined transplant was better that of those without. In this small sample of patients, QST was not found to be a sensitive tool for detection of improvement. Substantial effort has been made in recent years in the use of neurotrophins for therapy of diabetic PNP. Thermal thresholds including heat-pain and C-fibre derived axon reflex vasodilatation, but not autonomic tests were found to correlate with decreased levels of NGF and neuropeptides in skin biopsies in 17 IDDM patients with early diabetic PNP (Anand et al., 1996). The authors propose that a decrease in endogenous NGF influences the development of diabetic PNP. Thus, early and prolonged treatment with NFG may protect against development of the condition.

2.1.8. Conclusions QST techniques are now well established for assessment of diabetic neuropathy in diagnosis, staging and follow-up of natural history. Drug studies, a few of which are cited above, are a major field for application of QST. The sensory parameters affected by therapy are varied, probably reflecting that different classes of fibres affected by the different therapies. Methodological issues such as sensitivity of various methods in detection of neuropathy have been tested specifically for diabetics, some studies have found high sensitivities for both vibratory and thermal tests. Prediction of feet ‘at risk’ for ulceration by QST is demonstrated yet agreement is lacking as to which QST parameter is best suited to detection and follow-up. The technique may be sensitive for identification of painful vs. nonpainful PNP. As diabetic PNP can affect either large or small fibres, or both, complete sensory assessment requires the use of both thermal and vibratory testing.

2.2. Uremic polyneuropathy ( PNP) Uremic PNP is a mixed sensory-motor disease, predominantly affecting the distal parts of the lower limbs earlier and more severely than the upper limbs. Since the proliferation of haemodialysis and transplantation technology, advanced neuropathy is less frequent amongst uremic patients. However, subclinical or mild cases of neuropathy can be found in approximately 50% of these patients (Schaumburg et al., 1992). Thus, for detection of these cases, QST may be more desirable that NCS because of the need for frequent and longterm examinations over the course of dialysis. The characteristic large fibre involvement of the lower limbs in early stages suggests the utility of VT at the feet. The early clinical features of sensory disturbances, including painful tingling and electric feelings, indicate that examination of small fibre function by thermal testing at the feet, may also be useful.

2.2.1. Diagnosis of uremic polyneuropathy Both vibratory and thermal thresholds have indeed been found to be a useful tool in assessment of uremic PNP. VT was measured at the pulp of thumb, big toe and medial malleolus in 97 patients with chronic renal failure (13–73 years) and 85 healthy subjects (21–65 years) (Nielsen, 1972). In controls, VT correlated exponentially with age. The rate of elevation was faster on the lower compared to the upper extremity and faster in males compared to females. In patients, the average deviation from the normal mean VT, adjusted for age and sex, was significantly elevated for both upper and lower extremities. Male patients were more significantly affected than females. In females, no correlation was found between kidney function and / or age; in males, VT deteriorated significantly with advancing kidney failure and for comparable degree of kidney failure, VT was more affected in old compared to young patients. VT was more affected on lower vs. upper extremity and distal vs. proximal test sites. The degree of VT impairment was roughly correlated with severity of clinical neuropathy. Peroneal motor conduction velocity correlated with VT, whereas median conduction parameters did not. Sensitivity of NCS was found to be 82% compared to 32% for VT and 27% for clinical signs with specificities of 96; 80 and 87% respectively. The author concludes that despite the low sensitivity and high specificity of VT, it provides a quantitative measure, readily applicable for bedside examination which may prove to be of particular value in longitudinal studies. The sensitivity of quantitative vibratory testing and scaled tuning fork at the malleoli, clinical examination and NCS were assessed in 40 end-stage uremic (19–79 years) and 35 alcoholic patients (22–61 years) (Hilz et al., 1995). Quantitative vibratory testing was markedly more sensitive than the tuning fork—the former revealed pathology in 53.3%, and the latter only in 8%. Quantitative vibratory testing improved the sensitivity of the examining protocol

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

for PNP by 1.44, as it increased the number of patients diagnosed as having neuropathy (26 rather than 18 patients). Despite NCS and VT testing nerve fibres of a similar calibre, correlation between the two tests was low, indicating the methods are not interchangeable, yet vibratory testing can be used to complement NCS. Neuropathy was evaluated in 64 nondiabetic, chronic renal failure patients, treated with maintenance dialysis (22–75 years) (Lindblom and Tegner, 1985). Thermal sensation was measured at the hand and foot using the method of limits. Clinical signs of neuropathy were found in 65% of patients. When NCS data was included the prevalence rose to 83%. In 15% of patients the first sign of neuropathy was a pathological NCS, whereas in 15% of patients, abnormal thermal sensitivity was the first sign of neuropathy. VT at the foot was abnormal in 36%. Thermal sensations at the foot were abnormal in 30% of patients, while in the hands they were normal. Due to a large range of normality for heat-pain threshold, they were not found to be useful for diagnosis. Factors such as (i) lack of a significant relationship between measures of large (VT and NCV) and small fibres and, (ii) thermal abnormality often being the first sign of neuropathy, lead the authors to suggest that in uremic PNP, small fibre neuropathy may be a separate entity from the large fibre neuropathy in analogy to the small fibre neuropathy of Diabetes mellitus. Sensation was studied in 36 patients with end-stage renal failure (18–72 years) (Yosipovitch et al., 1995a). The outstanding abnormality was a high percentage of sensation of warmth or heat in response to low temperature stimuli given to the feet. This phenomena of ‘paradoxical heat sensation’ was found in 42% of patients, which is beyond the normal prevalence of nearly 10%. A positive relation to cold hypaesthesia, suggests that disinhibition may be a possible mechanism, probably reflecting a process of progressive PNP. Paradoxical sensation was also positively related to high serum creatinine levels. As such it may serve as an indicator of advanced renal failure or insufficient dialysis. PNP, based on at least two parameters in the clinical examination or QST (thermal or vibration) were found in 39% of patients. In 11% patients, paradoxical sensation was the only pathology. Heat-pain thresholds were abnormal in only one patient. In contrast, one study (Angus-Leppan and Burke, 1992) did not find thermal testing to be a useful diagnostic tool. Thermal sensation was abnormal in 30% of 20 end-stage renal failure patients compared to NCS abnormalities in 80% of patients. However, testing was performed at the forearm, which is probably an inappropriate site in light of the etiology of PNP.

2.2.2. QST for assessment of therapy VT was measured in 15 nondiabetic patients with endstage renal failure receiving maintenance haemodialysis for 1 to almost 8 years (average 4 years) (Daniel et al., 1977). VT was tested at the ulnar styloids and lateral malleolus

221

before dialysis, on average 10.2 times. In 128 normals, VT in the feet were higher than hands, and no gender difference was found. VT was higher in patients compared to controls at the initial stages of treatment. Threshold readings decreased the longer patients were dialyzed, approximating those of controls. Parameters of clinical signs of neuropathy, VT and NCS were compared in 73 patients with chronic renal failure, treated by a low protein diet (LPD), of whom, at a later stage, 65 were transferred to haemodialysis (Tegner and Lindholm, 1985a). During the LPD, foot VT correlated significantly with the clinical grading of neuropathy better than did NCS parameters. During haemodialysis, NCS parameters were better correlated with the clinical grading than VT. The authors attribute the different responses to different pathophysiological mechanisms operating during conservative treatment (LPD) or haemodialysis. Longterm fluctuations of the clinical signs were best assessed by motor nerve conduction of the median nerve and VT of the foot. The single most useful test was VT of the foot as it correlated with the clinical grading of the neuropathy during both types of treatment. In a retrospective analysis to assess whether haemodialysis or continuous ambulatory peritoneal dialysis (CAPD) is preferable with respect to uremic neuropathy, 22 male, nondiabetic, uremic patients treated with haemodialysis and 21 treated with CAPD were followed for 9–50 months (Tegner and Lindholm, 1985b). Clinical signs worsened in the HD patients but not in the CAPD patients; motor NCVs decreased in both groups; VT increased markedly in the CAPD patients but not in the HD patients. The overall differences between HD or CAPD were not of sufficient magnitude to prefer one form of treatment over the other.

2.2.3. QST for further understanding of uremic puritis Since C-fibres transmit pain, thermal sensation, itch and sympathetic innervation to sweat glands, correlations between these functions were sought after in an attempt to further understand uremic puritis (Yosipovitch et al., 1995b). Abnormal thresholds for warmth sensation in the foot were found in 35% and in 20% for the hand in 40 patients with end-stage renal failure due to primary renal disease. None of the patients had abnormal thresholds for heat-pain. No correlation was found between thermal and pain sensations, sweat deficiency and pruritus, indicating that pain and itch are possibly transmitted by distinct subgroups of neurons. Alternatively, the same neural pathways may serve both itch and pain, but heat-pain threshold may not be sufficiently sensitive to detect minor alterations in nociceptor function. 2.2.4. Conclusions Despite the low sensitivity of VT, it is regarded by many authors as an important test for assessment of neuropathy in uremia as it correlates with the clinical grading, also

222

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

being a quantitative measure, it is easy to perform, noninvasive, suitable for longitudinal studies and complementary to the ‘gold-standard’ NCS. Several studies have shown that thermal sensation may be the first abnormality to manifest itself, but the incidence of thermal abnormality is relatively low. Heat-pain thresholds were not found to be a sensitive parameter for detection of neuropathy in these patients.

2.3. Vitamin B12 deficiency Central and peripheral nerves may be affected by vitamin B12 deficiency. The initial symptoms include paresthesias, the most consistent sign that follows is loss of vibration sense. VT was tested in 42 post-gastrectomy patients with marginally low serum vitamin B12 values (,200 pg / ml) and heterogeneous symptomatology which suggested that some were affected by only myelopathy, while others were in the early stages of combined systems disease (myelopathy and peripheral neuropathy) (Roos, 1977). VT at the pulp of the index finger, hallux, and medial malleolus were significantly elevated compared to controls. Forty patients were given treatment with vitamin B12 injections, but only 25 remained fully compliant throughout the follow-up of 6–12 months. In the 25 compliant patients, and therefore adequately treated, VT at the foot dropped significantly towards normal levels although they remained above those of the healthy controls. There was a corresponding marked improvement in peripheral neuropathic symptoms. No such improvements were seen in the noncompliant group, of whom four showed symptom progression, nor in the myelopathy-only group.

2.4. Liver cirrhosis PNP in liver disease is most frequently associated with cirrhosis and alcoholism. In 100 patients with liver cirrhosis, 38 of whom had an alcoholic aetiology, alcoholism and severe cirrhosis were associated with vibratory abnormalities, whereas, only alcoholism was associated with thermal abnormalities (Gentile et al., 1993).

3. Chronic compression–entrapment neuropathies

3.1. Carpal tunnel syndrome ( CTS) CTS is the most common compression neuropathy observed in clinical practice, ranking second only to back injury in frequency and in Worker’s Compensation claims (Grant et al., 1992). NCS is considered the ‘gold standard’ for diagnosis of CTS. Use of QST in diagnosis of CTS would be desirable, particularly as a mass screening method. Due to the involvement of large fibres in CTS, VT would be expected to reveal abnormalities. Although some

reports give relatively high sensitivity of VT in detection of CTS, more so following provocation, the usefulness of VT for this purpose is limited. Thermal testing, has been employed in a small number of studies and found, as expected, to be of little diagnostic value.

3.1.1. Prevalence of QST abnormalities in CTS Several studies regard VT as useful in evaluation of CTS. For example, the incidence of impairment for different sensory modalities was studied in fingers 2, 3 and 5, in 33 hands of 22 patients with symptoms of CTS for a mean duration of 1 year (Borg and Lindblom, 1988). Abnormality for vibration, tactile pulses and monofilaments occurred equally in 52% of patients; two point discrimination was abnormal in 30% and graphesthesia in 24%; thresholds for warm and cold stimuli were abnormal in 15% of hands. In 82% of hands, at least one elevated perception threshold was found in digits 2 and / or 3, indicating that impairment of sensibility can be demonstrated in a majority of CTS patients if more than one test is applied. Thresholds of the 5 th finger were significantly elevated in half of the CTS hands, substantially lowering the specificity, and thus, usefulness of this testing procedure. In a similar study, VT was tested in fingers 2 and 5, in 28 hands (17 patients) who were diagnosed by NCS as having idiopathic CTS (Imai et al., 1990). While VT in the 2 nd finger was higher in patients than controls, 36% also had abnormal VT of the 5 th finger. Pathology of some of the patients may be related to exposure to occupational cumulative repetitive mechanical stimuli at the wrist. In contrast, a study which does not regard QST as beneficial for evaluating CTS, measured VT and temperature sensations in 28 hands (23 patients) with symptomatic, EMGconfirmed CTS (Merchut et al., 1990). No difference was found between patients and controls, and sensory abnormality limited to the index finger was only found in 11% of hands. No clear relationship was found between the QST findings and NCS abnormalities. The unexpected finding of abnormal VT in the 5 th finger in CTS patients, common to several studies, is disturbing. This could reflect either a methodological fault in the testing procedure or presence of subclinical ulnar or generalized neuropathy. The latter possibility does not reconcile with absence of NCS abnormalities in the ulnar nerve in most of these patients. This finding cautions against the use of the 5 th finger as intra-patient control. 3.1.2. Thermal testing in CTS The diagnostic value of thermal threshold measurements in CTS was evaluated in 24 patients with clinical and electrophysiological evidence of CTS (Goadsby and Burke, 1994). While warmth and cold thresholds were significantly elevated in patients compared to controls for both the 2 nd and 5 th fingers, the incidence of abnormality was low (25% and 17% for the 2 nd digit, 17% and 13% for

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

the 5 th digit for warmth and cold, respectively). Findings suggest little diagnostic value. Thermal sensory thresholds correlated with magnitude of spontaneous pain in 23 CTS patients (Lang et al., 1995). Significant correlations were found between pain intensity and motor distal latency, motor amplitude and heat-pain thresholds. The authors also found that thresholds for warmth, cold and heat-pain were higher in CTS subjects compared to controls.

3.1.3. Vibratory testing for screening CTS The ability of NCS and vibration to screen for CTS in an industrial setting was evaluated (Grant et al., 1992). VT was measured for 3 rd and 5 th fingers using the forcedchoice method, in 47 controls, 63 manufacturing plant workers with and without symptoms and 22 NCS-diagnosed CTS patients. VT for the 3 rd finger was highest in the last group, yet they were significantly high only in those hands in which registered motor nerve conduction time was more than 3SDs above the control group mean. No difference was found between fingers 3 and 5. Specificity was 47% and 59% for nerve conduction and vibration, respectively. The high false-negative rates associated with the vibratory test, limits its usefulness in screening for CTS. Motor nerve conduction time was more sensitive for screening of CTS than was vibration. In contrast to the above findings, vibratory testing is advocated as a useful screening tool as it allows for cost-effective, noninvasive screening for cumulative trauma in the work place (Jetzer, 1991). In this study, VT in subjects with CTS confirmed by EMG, recent surgery or sensory and motor symptoms were significantly different compared to controls. 3.1.4. Vibratory testing after provocation Improving sensitivity of VT testing for diagnosis of CTS was attempted by combining it with a test which provokes sensory symptoms (Borg and Lindblom, 1986). During 16 min of continuous wrist flexion VT increased by 2–8 times the values at rest in fingers 2 or 3 in all CTS hands in 24 symptomatic hands, half of which had abnormal NCS. In a large group of workers (n5144) (Gerr et al., 1995), 57 symptomatic hands with NCS evidence for CTS, 58 symptomatic hands with normal NCS and 123 control hands were evaluated. While no difference in VT were found between the 2 nd and 5 th fingers before flexion, it became significant after flexion. At specificities of 70 and 80% the best sensitivity amongst the vibration outcomes before wrist flexion were 35 and 28% whereas after wrist flexion the sensitivities were 61 and 57%. The two papers suggest VT measurement during flexion is a diagnostic test with high sensitivity and specificity. 3.1.5. The ‘ vibrogram’ Screening for VT at several frequencies might give a more comprehensive picture on the sensory function than

223

testing at a single frequency. Thus, similar to the audiogram, a ‘vibrogram’ for stimulation frequencies of 8– 500 Hz was developed (Lundborg et al., 1986). In control subjects, the vibrogram had a typical age-dependent shape which differed characteristically compared to patients with confirmed CTS. The vibrogram had sensitivity of 77% compared to symptoms; 76% compared to two-point discrimination, and 83% compared to NCS. The vibrogram was abnormal in 54% of patients with an intact NCS. Use of the vibrogram in screening for CTS was evaluated in 167 industrial workers (Werner et al., 1995). Vibrometry did not differentiate those individuals with from those without CTS. The use of multiple frequencies did not improve the screening compared to testing at 120 or 125 Hz. This was supported by the relatively low correlation between VT and the NCS measures. It seems that the vibrogram has only a limited role in detection of CTS.

3.1.6. Longterm variations in VT readings Daily variations of VT were assessed in 2 women with CTS and 2 women without it, by daily VT recordings over a 3-month period (White et al., 1994). A marked day to day variation was registered, explained in part by fluid retention along the menstrual cycle. The authors conclude that VT recordings are analogous to blood pressure recordings which require continuous readings over a prolonged period of time to provide an accurate understanding of a subjects’ condition. 3.1.7. VT for evaluation of carpal tunnel release Threshold (vibration and Semmes–Weinstein monofilaments) and innervation density tests (static or moving 2-point discrimination) were compared for assessment of sensibility in CTS in 23 hands of 20 patients before and 6 weeks after carpal tunnel release (Szabo et al., 1984). The threshold tests were found to reflect nerve function more sensitively. 3.1.8. Conclusions There is no clear evidence for the utility of VT in the diagnosis of CTS. The main drawbacks are low sensitivity compared to NCS, and low specificity expressed in finding abnormalities in territories outside those of the median nerve, e.g. the ulnar. The nonuniformity across studies may be due to seemingly minor technical details such as pressure of probe application, probe size, specific algorithm used, and nonuniform selection criteria of patients all which have an effect on results. Until new evidence is collected, it seems that the recommendation of the American Academy of Neurology from 1993 (Practice parameter for carpal tunnel syndrome, 1993) still holds. Accordingly, for CTS ‘‘...the benefits of sensory quantification, including vibrometry and current perception thresholds have not as yet been fully established’’.

224

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

3.2. Hand–arm vibration syndrome ( HAVS) The pathologies which may result from exposure to chronic vibration are varied and depend on whether the individual experiences whole body vibration or a more local insult such as hand–arm vibration (Gupta and McCabe, 1993). The latter resulted in a syndrome known since 1911, and originally named for its first chronicled symptom, ‘vibration white finger’ (VWF). This syndrome was renamed ‘Hand–Arm Vibration Syndrome’ (HAVS) in 1985 by international agreement in recognition of its wider effects (Taylor, 1986). Although improved designs for vibratory tools and restrictions on their operating times have led to a worldwide reduction in reported cases of hand–arm vibration syndrome, the disease prevalence estimate of 50% (range 6% to 100%) of exposed workers (Stromberg et al., 1996; Taylor, 1986) would suggest a prevalence of 1 200 000 persons in the United States alone (Cherniack, 1990). The syndrome has three distinct symptom groups: (i) sensory symptoms; (ii) sensory and vasospastic symptoms, and; (iii) vasospastic symptoms (classic white finger), affecting respectively 50%, 30% and 20% of patients (Stromberg et al., 1996). Understanding of the seriousness of the condition has been delayed by the fact that digital blanching is its most visually prominent (Ekenvall et al., 1987) but not most prevalent or serious symptom. Reduced manual dexterity has emerged as the most common and perhaps most debilitating feature of the disease (Bigli and Pelmear, 1993; Ekenvall et al., 1987). Therapy is principally by prevention–cessation of exposure, avoidance of cold and smoking, and empirical medical therapy with sympatholytics, nifedipine, ketanserine, clonidin, captopril, and prostanoids (Palmer and Collin, 1993; Taylor, 1986); recovery may not be complete even after 5 years (Nasu and Ishida, 1986). Treatment is further vexed by the similarity in presentation and etiology to carpal tunnel syndrome for which, unlike HAVS, there is a surgical remedy (Pelmear and Taylor, 1994). The now standard Stockholm staging system of this disease is based on separate vascular and sensorineural evaluations of the condition (Gemne et al., 1987; Lundborg, 1994). As with CTS, vibratory testing has been refined by testing a range of frequencies (Lundborg et al., 1986). VT has now been added to the list of objective tests for HAVS (Taylor, 1993). However, the weight of published evidence suggests that at this stage, QST is not sensitive enough for clinical application, although, it has statistical validity for group studies.

3.2.1. Diagnosis of HAVS VT tested after release of sphygmomanometric occlusion (to enhance vascular symptoms) of the arm in 149 forest workers failed to discriminate on an individual basis between subjects with and without symptoms of HAVS.

However it did distinguish a subpopulation of patients with decreased hand grip force (Aatola et al., 1990). Sensation was assessed in 48 dentists using high-speed rotating hand pieces for over 10 years, 10 of whom had tingling and numbness of hands, especially the dominant (drill-holding) one (Ekenvall et al., 1990). VT was elevated in the symptomatic, long-exposure group when tested in the dominant hand at the 2 nd (exposed) and 5 th (nonexposed) fingers. The effect on vibration perception was especially noted at low frequencies (8–16 Hz); for testing over a range (8–500 Hz). The similar findings for the exposed 2 nd finger and unexposed 5 th finger devalueates VT in this context. In contrast to the studies above which did not find vibratory or thermal testing useful in HAVS, a number of studies do. Yet, many caution that larger groups of subjects must be studied before the proper tests are selected and that norms data of subjects exposed to vibration is necessary before application of these tests for screening is possible. In 48 vibration-exposed shipyard workers, divided into 2 groups—severely and mildly symptomatic, of the QST modalities used strength dynamemetry and VT discriminated between the groups while NCS did not do so (Cherniack et al., 1990). In a follow-up of 672 chain saw operators over 10 years, disturbances in VT (at 125 Hz) were persistent (Futatsuka et al., 1990). For 19 underground gold mine drillers and 16 gold mill workers as controls (Narini et al., 1993). Symptoms of numbness, pain and weakness were reported in 63% subjects, while 84% reported vascular symptoms. Higher VT, higher incidence of positive provocation tests and higher cutaneous pressure thresholds were found in the exposed as compared to the control group. Vibrogram was obtained for vibration exposed 77 workers and 77 controls (Virokannas, 1992). Thresholds were significantly higher in exposed workers at all six frequencies. A dose–response relationship was found between length of exposure and extent of threshold disturbance. Alcohol consumption (at 125 Hz) and the presence of carpal tunnel syndrome (at 250 Hz) were also associated with significantly increased thresholds, however, vascular symptoms were not correlated with VT. On the basis of the VT elevations in exposed workers, the authors regard testing of VT as a useful measure for assessing the sensory aspects of HAVS. Sensory testing using vibration and thermal perception in 70 grinder operators was compared with the results of the same procedures in 72 nonexposed controls; perception thresholds were reported to differ significantly between the groups (Ho and Yu, 1986). A small study of 10 dental technicians, who are typically exposed to high-frequency (up to 40 kHz) vibratory stimuli revealed elevated vibration, warmth and cold perception thresholds in most and significant differences compared to

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

10 controls (Hjortsberg et al., 1989). NCS parameters showed no differences between the groups. The authors propose that high-frequency vibration should interfere with function of the distal nerve endings and receptors, thus, QST is more appropriate than NCS which by-passes the receptors. QST and NCS were undertaken in 55 symptomatic exposed patients, graded on a scale by (Brammer and Pyykko, 1987; Ekenvall et al., 1989). The majority of patients had abnormalities on all three test modalities with thermal thresholds showing the earliest signs of disturbance followed by VT and NCS changes. The degree of QST / NCS abnormality correlated with the severity of the grading. The authors suggest that these tests may indeed be sufficiently sensitive for diagnosis of vibration syndrome on an individual basis although clearly, the number of subjects in each category was small.

3.2.2. Conclusions Both group screening and the diagnosis of individuals with HAVS are still heavily dependent upon patient reportage of clinical symptoms and detailed exposure history. Although there is an increasing and recognised role of altered VT as an objective test for HAVS in groups at risk, the application of QST to the diagnosis of individual cases remains problematic because of the considerable overlap of results of disabled and symptom-free subjects. Thus, it is suggested that the test be used to supplement other diagnostic techniques. A number of studies show that thermal sensation is impaired in subjects subjected to vibration injury. 3.3. Lumbrosacral radiculopathy Lumbrosacral radiculopathy is characterized by disturbances in sensibility due compression of spinal root nerves. The ‘gold standard’ for diagnosis is painful and involved EMG testing. Thermal testing and VT may show some promise as an alternative diagnostic test, but clinical application awaits more formal investigation. C-fibre sensibility was tested by thresholds for warmth and heat-pain sensation on the foot, ipsi- and contralaterally to the nerve root compression, in 9 subjects (2344 years) with chronic lumbosacral radiculopathy (L5 or S1), diagnosed by CT (Strian et al., 1991). While in 19 controls, there was no difference between sides or between the adjacent dermatomes L5 and S1, in the patients, warmth thresholds were increased in the ipsilateral dermatome and normal in the contralateral dermatome. Heat-pain thresholds were near normal ipsilaterally but clearly decreased contralaterally. The authors suggest that the modalities for heat-pain and warmth are affected differently in longterm lumbrosacral nerve root compression. Warmth-mediating fibres are compressed but the effect is restricted to the affected side. The differential heat-pain response may be explained by a weakening of the spinal pain inhibitory

225

system. On the ipsilateral side, the compression lead to a combination of decreased inhibitory control by large fibres and nociceptive activity in small fibres leading to the negligible increase in pain threshold. On the contralateral side, the large fibre compression resulted in loss of inhibition and sensitization, expressed by the decreased pain threshold. VT at the hallux and little toe were measured in a group of patients with lumbrosacral radiculopathy (M. Kligman, personal communication). In patients suspected of feigning symptoms for the purpose of secondary gain, VT was elevated with large variance, while in patients whose symptoms were considered as indicating organic disease, VT was also high, but the variance was small. This pattern is similar to that found for thermal senses in normals intentionally feigning sensory abnormality compared to patients with sensory impairment due to diabetic PNP (Yarnitsky et al., 1994).

4. Toxic neuropathies

4.1. Alcoholic polyneuropathy ( PNP) Alcoholism is a very common etiologic factor for PNP. Sural nerve biopsies from patients with alcoholic neuropathy indicate that both large and small diameter fibres are damaged to the same extent (Tredici and Minazzi, 1975). Thus, both vibratory and thermal testing would be expected to be useful in the detection of peripheral neuropathy in these subjects. VT was tested in 100 male alcoholic subjects and 52 controls who had no other etiologic factors for PNP (Sosenko et al., 1991). Subjects had been drinking for 11–13 years and were receiving vitamin supplements. Tests were performed on the foot. VT of the alcoholics were significantly higher compared to controls, regardless of age and drinking duration. Height and body mass index were not influential. Subjects with signs of hypesthesia in any part of the body either alone or together with paresthesia had significantly higher VT compared to controls. The same was true for asymptomatic subjects. Indicating that vibration was also sensitive to patients with subclinical neuropathy. Fifty chronic alcoholics were examined for evidence of PNP (Hilz et al., 1994). All subjects had a history of alcohol abuse for more than 7 years, daily alcohol consumption exceeding 100 grams and a positive Munich Alcoholism Test. Six thermal-sensation parameters were tested behind the internal melleolus, using the method of limits. Thresholds for cold sensation were raised in 62% of patients; warmth sensation in 24%; heat-pain in 22%; 12% and 10% of patients were hypoesthetic to heat and cold pain, respectively; paradoxical sensation of warmth to low temperature stimuli was found in 10% of patients.

226

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

4.1.1. Conclusion Both vibratory and thermal testing has been found useful in the detection of peripheral neuropathy in subjects with ethanol abuse. 4.2. Paraneoplastic and chemotherapy-induced neuropathy Peripheral neuropathy is common in patients with malignancy, due to many possible factors—disturbances of metabolic or endocrine origin, nutritional deficiency, infection, chemotherapy or as a paraneoplastic phenomena. Chemotherapy-induced neuropathy may be particularly severe in some treatments for some individuals. Particularly for those patients who achieve remission, quality of life may be severely affected by a preventable neuropathy. As a consequence, continuous follow-up and dose adjustment are called for. QST is ideally suited for these purposes.

4.2.1. Prevalence of QST abnormalities in cancer patients VT in the index finger of 171 neurologically asymptomatic cancer patients, uncovered subclinical neuropathy in 12.3% of patients (Lipton et al., 1987). The threshold elevation could not be ascribed to known and identifiable risk factors for neuropathy. The authors concluded that the sensory abnormalities in this group of cancer patients seemed to be directly associated with the neoplasm. The same team later (Lipton et al., 1991) evaluated both large and small fibre function in the toe and nondominant index finger of 29 cancer patients. VT was elevated in the toes of 43% of patients, higher in the second study than in the first, probably reflecting that the feet are a more sensitive measurement site than hands. Thermal thresholds were elevated at the feet in 43% of patients. No such effect was apparent in the fingers. The authors conclude that large and small fibre dysfunction is common in cancer patients. As the majority of patients with abnormal thermal thresholds did not have abnormal VT, the authors suggest that these phenomena may be independent. 4.2.2. Evaluation of chemotherapy-induced neuropathy 4.2.2.1. Vincristine. Neurotoxicity is the known doselimiting side effect of vincristine. The peripheral neuropathy attributed to vincristine is a mixed sensorimotor one which may progress to ataxia and impairment of hand function. The neurotoxicity is dose dependent and believed to be reversible after cessation of treatment (Postma et al., 1993). The potentially longterm effects of vincristine on the peripheral nervous system were investigated in 40 patients with non Hodgkin’s Lymphoma who had been treated up to a cumulative dose of 12 mg of the drug over 18–24 weeks (Postma et al., 1993). The evaluations were per-

formed 4 to 77 months (median 34 months) after the last vincristine treatment. Based on a questionnaire, post-vincristine patients were grouped as asymptomatic (n513), transiently symptomatic (n514), and persistently symptomatic (n513). Based on the neurological examination, eight of 13 ‘asymptomatic’ patients had abnormal findings, while 10 had abnormalities in either vibratory or thermal threshold perception at the foot. Of 14 patients classified as ‘transiently symptomatic’, 8 had abnormal findings detected by neurological examination and the same number had abnormal vibratory or thermal responses. All of the 13 persistently-symptomatic patients had pathological sensory testing results according to all testing modalities employed. The authors believe their findings from the QST to be ‘sensitive but rather unspecific’.

4.2.2.2. Cisplatin. A major side-effect of cisplatin treatment is a dose-dependent, sensory neuropathy affecting 40–100% of patients. Sural nerve biopsies have shown a decrease in the number of thick, myelinated fibres. Elevated VT was found to be an early sign of cisplatin neurotoxicity, detected 6 weeks to 2 months earlier than clinical signs and symptoms, which became apparent after a cumulative cisplatin dose of 450 mg / m 2 (Elderson et al., 1989) or in conjunction with clinical signs after a cumulative dose of 455686 mg / m 2 (Thompson et al., 1984). Measurement in the feet and hands was of similar sensitivity and appeared at the same time, thus, measurements can be restricted to either extremity. Thermal thresholds did not change during the treatment period (Elderson et al., 1989). According to the authors, VT measurement is a valuable assessment tool for assessment of cisplatin neurotoxicity Thirty patients treated with six cycles of cisplatin, vinblastine and bleomycin, were examined for longterm effects of neurotoxicity, 4–8 years after treatment. Subjective symptoms were found in 37%, signs in 73%, VT was elevated in 80% and warm sensation thresholds were elevated in 33% of patients (Hansen et al., 1989). According to the authors, the neurotoxic damage after this type of treatment is likely to be irreversible. 4.2.2.3. Docetaxel ( Taxotere). Docetaxel is a semisynthetic toxoid used against a wide variety of solid tumors, typically in advanced nonsmall cell lung carcinoma and as second line in metastatic breast cancer. The drug was observed to have induced a predominantly sensory neuropathy in 49% of 41 patients given 100 mg / m 2 per cycle and cumulative doses of 150–1100 mg / m 2 (Hilknes et al., 1996). The neuropathy was evaluated by a clinical sumscore for symptoms and signs and by measurement of VT at the dorsum of the hand. Although the severity of sensory impairment was dose-dependent according to neurological examination, the authors did not find a relationship between vibratory results and the severity of docetaxelinduced neuropathy. The authors conclude that vibratory

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

testing is not a reliable tool for monitoring docetaxelinduced neuropathy. The associated pain reported by a relatively high number of patients suggests that this may be a neuropathy in which small nerve fibres are differentially damaged. Eleven percent of 186 patients who received docetaxel at a dose of 100 mg / m 2 per cycle with cumulative doses from 50–720 mg / m 2 developed symptoms and signs indicative of peripheral neuropathy but that only 2 of these had sensory abnormalities detected by current perception thresholds (CPTs) measured at the lateral aspects of the distal second finger and the hallux (New et al., 1996). A subgroup of 13 patients underwent NCS which detected neurological impairment in 10.

4.2.2.4. Docetaxel and cisplatin-combination chemotherapy. Neurotoxicity in 21 cancer patients treated with a combination of docetaxel (135–350 mg / m 2 ) and cisplatin (75–100 mg / m 2 ) was evaluated (Chaudhry et al., 1994). Patient symptoms indicated the presence of neuropathy in 76% of patients, neurological examination in 95%, NCS in 95%, H-reflex latency in 81%, VT at the halluces bilaterally were elevated in 81%, tip of the index finger in 52%. The elevated VT correlated with the cumulative taxol dose for both feet and hand but not with cumulative cisplatin dose. 4.2.3. Conclusions Vibratory and thermal stimuli can be used for quantification of sensory damage in cancer patients. As with other toxic neuropathies, testing has been found to be most sensitive when performed at the feet. In the case of vincristin toxicity, vibration and thermal testing was found to be sensitive but unspecific. In the case of cisplatin neurotoxicity, vibration but not thermal testing was useful. QST testing was not as useful in detecting neuropathy when docetaxel was given on its own yet, when given in combination with cisplatin, vibratory testing adequately indicated nerve pathology. 4.3. Occupation- and pharmacologic-related toxic neuropathies Screening tests to be used for preemployment or periodic monitoring, or for evaluation of a toxicant which is identified but no clinical disease is apparent should ideally, be rapidly administered, require relatively inexpensive and portable equipment suitable for field settings and be nonthreatening so as to be acceptable to subjects (Moody et al., 1986). Three tools are regarded as fulfilling these requirements: (i) screening questionnaires; (ii) neurological examination; and (iii) quantitative vibratory and thermal testing. NCS is often no more sensitive or reproducible than the clinical neurological examination in screening for the evaluation of subclinical neurotoxicity.

227

4.3.1. Industrial /organic solvents Ninety workers (19–59 years), exposed to industrial solvents for 1–44 years (mean 19.6 years), were screened by VT (Halonen et al., 1986). Fifteen subjects with abnormally high or increased bilateral responses in the feet (n58) or hands (n57) underwent NCS to determine the degree of suspected PNP. These were abnormal for most subjects with increased VT in the feet, whereas, normal for all subjects with increased VT in the hands. No correlation was found between duration of exposure and VT, thus, time of exposure may not be the determining factor in the neuropathy or possibly the increased VT may be due to other factors than the solvents considered. Forty-one workers (20–60 years) exposed to acrylamide at concentrations of 0.2–1.58 mg / m 3 for 0.5–8 years were tested by vibration at 120 Hz (Deng et al., 1993). The testing procedure was a combination of 2-alternativeForced Choice and Limits at index finger and great toe. VT was increased in 59% of the workers compared to agematched normals. Testing by tuning fork revealed decreased sensation in 37% of workers. Four-hundred thirty seven workers (16–72 years), exposed to organic solvents (e.g. thinners–xylene and toluene) for 1 month to 38 years were tested by VT (125 Hz) at the medial malleolus (Aratani et al., 1993). VT was abnormally high in 13% of 437 workers. VT correlated significantly with age and job experience but not with urinary metabolites. The test took 3 min, making this a suitable method for screening large populations. VT of solvent–exposed commercial painters (n528) was compared to nonexposed workers (Demers et al., 1991). Painters had higher VT in the four extremities compared to controls. Ninety-nine metal degreasers were examined for association between longterm exposure to degreasing solvents, mainly tricholoroethylene, and the outcome of a clinical neurological examination, focusing on a number of factors which included VT (Rasmussen et al., 1993). VT was associated with solvent exposure but multivariate analysis showed that age explained most of the increase. The authors say the findings of previous studies, e.g. Demers et al. (1991) who found significantly higher thresholds in solvent exposed subjects are limited since they employed comparative statistics which do not provide sufficient control for confounding factors, such as age. 4.3.2. Conclusions Although thermal testing for screening for occupational neurotoxicity has been advocated, we have not found published studies in which the technique has been applied. One possible reason may be that suitable portable testing equipment for the field was not readily available. On the other hand, VT testing is commonly applied, yet, there are contradictory findings regarding test results such as whether time of exposure to industrial solvents correlates with VT. Most authors find the technique useful in

228

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

screening large populations for sensory abnormalities or for selecting subjects for further laboratory investigation, yet the currently found sensitivity for detecting neurotoxicity is low. Emphasis is made that further additional field studies are required so that the sensitivity, reproducibility and standardized test procedures can be more rigorously determined.

4.3.3. Ethylene oxide ( EO) EO is commonly used to sterilized heat-sensitive products used by hospital patients and personnel. Ethylene chlorohydrin (EC), a by-product, is considered highly toxic. Chronic exposure to EO is associated with PNP. Twelve surgical nurses and technicians with 5 months exposure to high levels of EO and EC and symptoms of exposure were examined (Brashear et al., 1996). Clinical examination revealed signs of neuropathy in 75% subjects; light touch was impaired in the median and ulnar distribution of the hand using Semmes–Weinstein monofilaments in 91% subjects; VT was elevated in 44%; NCS was abnormal in 36%; biopsy in the most severely affected patient revealed signs of axonal injury. The monofilaments and VT provided objective evidence of sensory impairment in these patients. 4.3.4. Pyridoxine (vitamin B6 ) toxicity Pyridoxine (vitamin B 6 ) is routinely given as adjunct therapy for tuberculosis and as part of multiple vitamin therapy. High levels of B 6 may result in PNP. Low and high doses of pyridoxine (1 to 3 g / d, respectively) were administered orally to 5 healthy volunteers (Berger et al., 1992). Subjects underwent periodic neurological clinical examinations and laboratory tests which consisted of serum pyridoxal phosphate levels, NCS, VT and thermal testing. The onset of sensory symptoms and QST abnormalities coincided in both low and high-dose subjects, except one in whom thermal thresholds became abnormal without clinical symptoms. Abnormalities in NCS lagged behind the QST changes in 3 / 4 subjects. A cardinal finding of this study is that QST measurements proved to be a sensitive laboratory measure of sensory dysfunction in pyridoxine toxicity. Furthermore, finding small fibre dysfunction challenges the commonly held notion that pyrodoxine affects large fibres preferentially. Monitoring by QST proved to be a powerful and confirmatory measure of sensory dysfunction which may have gone undetected had only NCS been utilized. 4.4. Gulf War syndrome Many veterans returning from the Gulf War exhibited a number of pathological signs which are thought to be related to chemotoxic or biological warfare exposure. Some of the signs indicate damage to both the peripheral and central nervous systems. The controversial nature of the illness, including early doubt as to whether such a

syndrome exists, has lead to employment of every possible diagnostic methodology, including QST. Because of the mysterious nature of the disease, the role of QST is not yet determined. QST of the foot consisting of heat, cold and vibratory thresholds were part of an extensive neurological evaluation of 14 Gulf War veterans and 13 controls matched for factors such as age, sex, handiness (Jamal et al., 1996). Of the quantitative tests only cold thresholds were abnormal. The clinical relevance of this findings is not clear to the authors. Epidemiological analysis and laboratory studies support the hypothesis that chronic symptoms in many Gulf War veterans are due to a chemical injury to the nervous system (Haley et al., 1997). Three factor analysis-derived syndromes were identified: (i) ‘impaired cognition’ (n55 veterans), (ii) ‘confusion ataxia’ (n513 veterans); and (iii) ‘arthro-myo-neuropathy’ (n55 veterans) which may be separate or variants of a single syndrome. Assessment of the peripheral system by extensive neurophysiological testing included QST of warm, cold and vibratory sensations of the upper and lower extremities. Of the five veterans with the third syndrome, all had abnormal cold and vibratory sensation in either upper or lower extremities. The authors suggest that a subset of veterans with Gulf War-related illnesses appear to have contracted a subtle neurologic injury or illness in the war. For a more definite interpretation of the results a larger sample of subjects and control veterans is needed.

5. Infection associated neuropathy

5.1. HIV infection Peripheral neuropathy occurs in 15–50% of patients infected with HIV and includes a number of neuropathies the most common being distal symmetrical painful PNP (DSP), occurring in approximately one-third of HIV patients and pathologically evident in almost all cases at time of autopsy (Gulenvich et al., 1992; Simpson and Tagliati, 1994; Winer et al., 1992). QST has been applied in patients with DSP, specifically in the detection of incipient (preclinical) neuropathy and in the assessment of treatment-related neurotoxicity.

5.1.1. Identification of AIDS-related neuropathy Thresholds for warm and cold sensation at the foot were the diagnostic test most frequently abnormal and were detectable even in the absence of NCS abnormalities in 80 seropositive HIV patients and 28 seronegative controls who were followed for 1–3 years. Thresholds for warm sensation were more frequently abnormal than those for cold (Winer et al., 1992). VT was studied in 179 seropositive HIV patients [28 with acquired immunodeficiency syndrome (AIDS) or

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

AIDS-related syndrome (ARC) and 151 asymptomatic] and 32 HIV-seronegative controls (Gulenvich et al., 1992), none of which had clinical neuropathy. The prevalence of abnormal VT results was comparable with abnormal NCS, yet, both abnormalities coexisted in only about half the patients. Detectable peripheral nerve damage, as assessed by VT, appeared to have occurred mainly after progression to AIDS /ARC.

5.1.2. Assessment of drug toxicity In 52 patients with AIDS or ARC receiving different doses of the antiviral agent 29,39-dideoxycytidine (ddC) and who subsequently developed a primarily sensory, dose-dependent distal axonopathy (Berger et al., 1993; Schaumburg et al., 1990), VT was the single most sensitive indicator of subclinical neuropathy, although at the time of maximal symptoms, VT showed abnormality in 100% and NCS in 80%. VT demonstrated subclinical neuropathy in less than 10% of 76 asymptomatic or mildly symptomatic HIV patients receiving a potent antiretroviral nucleoside, zidovudine (ZDV, at doses of 800–1200 mg daily for a median of 52 weeks) or placebo (Bozzette et al., 1991). The authors conclude that VT is of low sensitivity for this type of neuropathy. NCS was not conducted in this study. The sensory symptoms of pain and hyperesthesia in these patients indicate that small fibres are involved in ZDV neuropathy. It is therefore, possible that thermal testing would have been more sensitive in revealing nerve dysfunction in these patients. 5.1.3. Conclusions The devastating disorders of the nervous system which complicate HIV infections are likely to increase in prevalence as more effective therapies for HIV and its attendant opportunistic infections are treated. Prompt recognition and follow-up of these neuropathies could improve the quality of life in these patients. VT was good as was NCS in identifying incipient DPN in seropositive HIV patients while, thermal sensation was more sensitive than NCS. Vibration testing was more sensitive than NCS in detection of drug-related subclinical neuropathy due to ddC, but once the neuropathy was clinically evident, both vibration and NCS were equally sensitive. VT was less sensitive than symptoms for detecting ZDV neuropathy. 5.2. Leprosy infection The mainly tropical and subtropical bacillary infection of nerves by Mycobacterium leprae which results in leprosy is annually diagnosed in somewhat more than 100 000 persons. The disease is endemic in the world’s poorer areas (e.g. India, Indonesia, Mayanmar) making field testing for earlier diagnosis the goal of many studies of leprosy and its associated sensory impairments. Lesser

229

endemic foci include parts of South America and those of Florida, Texas and Louisiana which border on the Gulf of Mexico. Invasion by the bacilli may or may not be progressive from cutaneous to subcutaeous nerves resulting in characteristic patches of superficial sensory loss. There is disagreement as to which sensory modality – small or large fibre mediated – is first to become impaired. As early detection of nerve damage is essential for prevention of disability, there have been several initiatives in applying QST for the quantification of the sensory loss. Attempts are being made at quantification of sensory loss in leprosy (Brown et al., 1996; Klenerman and Hammond, 1988; Singh et al., 1985; Srinivasan and Stumpe, 1989; Tutakne et al., 1985). Emphasis is placed on development of equipment which is suitable for field testing. Although altered temperature and vibration thresholds appear to be of use as indicators of leprotic sensory losses, nonuniform and unconventional testing techniques has made evaluation of some results difficult. In the meantime, the diagnosis of leprosy will continue to rest, as it traditionally has, upon recognition of the characteristic lesions and, where possible, more expensive biopsy and immunological testing.

6. Immune-related neuropathies

6.1. Acute inflammatory demyelinating polyradiculoneuropathy [ Guillain–Barre syndrome ( GBS)] Guillain–Barre syndrome (GBS) is characterised by infection of large and small myelinated fibres. Therefore, disturbances in vibratory and cold sensation may be expected, suggesting a role for VT and testing of cold sensation. Twenty-two patients with Guillain–Barre syndrome, average age of 49 (range 17–49), were tested by NCS and thermal testing at onset of the disease and again at the peak of neurological manifestations (Thomaides et al., 1992). Subjects were retested 6 and 12 months after onset. Clinically, signs of sensory involvement were minimal. Thermal testing showed that 68% of patients had at least 1 abnormal thermal threshold at the initial sensation testing session. At the peak of neurological disability, cold sensation at the ankle and wrist were abnormal in 73% of the patients and heat thresholds at the ankle and wrist were abnormal in 55% and 50% of patients, respectively. At 6 and 12 months, NCS and clinical parameters returned to normal, yet, improvement in thermal responses was minimal. Comprehensive neurophysiological examination of 3 patients with Miller–Fischer syndrome, a variant of GBS, initially revealed that thermal and vibratory testing were abnormal without obvious clinical sensory signs but subsequently returned to normal, following clinical recovery

230

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

(Jamal and Ballantyne, 1988). QST was useful in revealing subclinical sensory dysfunction in these patients.

6.1.1. Conclusions The finding that cold sensation was more frequently abnormal than heat sensation is in line with the demyelination process characteristic of GBS. Demyelination affects the small myelinated fibres conveying information about cold stimuli. Both studies found abnormal warmth sensation. Since warmth is mediated by unmyelinated fibres, this modality would be expected to remain unaffected. A possible explanation is that the inflammatory process within the nerve may have affected these fibres as well. Thus, in GBS, thermal testing of both cold and warmth modalities, may have a role during the acute phase of the disease and during follow-up in revealing what is often subclinical sensory involvement. Vibratory testing of large fibres, as performed in the second study, is called for. 6.2. Systemic lupus erythematosus ( SLE) Neurological involvement in SLE is common, with CNS manifestations predominating; those of the peripheral nervous system seem to be less prevalent and less well characterised. Reported frequencies of peripheral neuropathy range from 3–18% (Omdal et al., 1991). Thirty-four SLE patients and 34 healthy, age and sex matched controls were tested by standardised symptom scores, NCS and VT (Omdal et al., 1993, 1991). VT for the index finger of patients was significantly higher compared to controls. VT for the toe was not different compared to controls.

6.3. Sjogren’ s syndrome Sensory PNP rather than CNS involvement predomi¨ nates when Sjogren’s syndrome is complicated by neurologic involvement. Abnormal thermal testing results verified small fibre neuropathy in one patient with Sjogren’s syndrome; NCS was normal (Denislic et al., 1995).

7. Hereditary neuropathies and myopathies

7.1. Hereditary sensory neuropathy, type I A case of hereditary sensory neuropathy resembling Dyck’s Hereditary Sensory Neuropathy Type I is described (O’Brien et al., 1980). Sensory testing revealed intact responses to thermal stimuli, yet, there was marked impairment in pain sensation in the feet up to mid thigh and from the wrist to elbow. Stimuli at 08C or 458C or 708C elicited a temperature response but not pain.

7.2. Hereditary sensory and autonomic neuropathy, type III ( Dysautonomia of Riley-Day) Familial dysautonomia is a recessively inherited disorder seen predominantly in Jewish infants and children. Nerve biopsy reveals diminution of small myelinated and unmyelinated fibres leading to impairment or loss of pain and temperature sensation, rendering QST appropriate for quantification of sensation in the disease. Twenty subjects with Familial dysautonomia were tested at 6 different body sites for warmth, cold sensation, heatpain (a selection of patients) and vibratory thresholds using the method of limits (Max Hilz, personal communication). The findings include a patchy distribution of temperature perception with the feet being less frequently impaired than the hands and areas of fairly normal perception, e.g. in the neck. Cold and warm perceptions were equally affected. A large repertoire of sensory abnormalities were found including abnormally high warmth, cold perception and heat-pain thresholds; incomplete perception (for repeated stimuli some stimuli were perceived, others not); paradoxical sensations; dysesthesia, paresthesia. Vibratory thresholds were significantly more frequently abnormal than NCS. The pattern of sensory impairment found is not typical of a dying back process nor is it typical of the PNP seen in diabetics as it varied strongly from one patient to another and in different parts of the body in the same patient. Results indicate that in these patients, small fibres are present in some areas of the body whereas, missing in others. Contrary to other neuropathies, the pattern of impairment cannot be predicted.

7.3. Myotonic dystrophy The hypothesis that myotonic dystrophy is a pure myotonic disorder is being increasingly challenged by clinical and electrophysiological findings of neuropathic components in the disease (Jamal et al., 1986). QST was used, amongst other tests, to evaluate the extent of neuropathic disturbance in 24 patients (15–63 years) with 0.2–22 years duration of clinical symptoms of myotonic dystrophy (Jamal et al., 1986). Subjective sensory symptoms were reported by 54% of the patients. Thermal thresholds were abnormal in 83% of patients; more at the ankle (79%) than wrist (50%). Heat sensation was more frequently abnormal than cold sensation. Vibratory sensation was abnormal at the foot in 21% of patients. No correlation was found between age or duration of symptoms and the other neurophysiological parameters. The authors conclude that myotonic dystrophy is not a pure myopathy, as there is significant dysfunction in both peripheral motor and large and small sensory nerve fibres. Caution should be exercised in interpretation and application of these findings as they have not been duplicated, to the best of our knowledge.

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

231

8. Diseases of the central nervous system (CNS)

8.2. Multiple sclerosis ( MS)

Sensory symptoms are common in diseases of the CNS such as stroke, multiple sclerosis and syringomyelia yet, in this type of patient, sensory symptoms have generally evoked less interest than disturbances of motor function. Even without presence of central pain, sensory symptoms can be disturbing and affect the functioning of these patients. QST may be relevant in the assessment of patients with central dysfunction as it affords a more precise means for quantification of sensation than the ordinary bedside techniques and specifically for this type of patient can be used to monitor the functioning of the two major ascending somatosensory pathways. Tests for vibration and tactile sensibility can be used to assess the dorsal column medial lemniscal pathway and those testing thermal sensation and pain can be used to assess the spinothalamic tract. When QST is carried out on patients with brain lesions, particular care should be paid to check that the patient is alert and understands the procedures (Boivie, 1993).

Complete loss of sensation is rare in MS patients, but clinical findings such as hemianesthesia to pain or disturbances in vibratory sense, indicate that QST may have a role in sensory evaluation of these patients. Thresholds for sensation of warmth were abnormal in 6 feet and 8 hands of 16 patients with probable or definite MS (Hansen et al., 1996). The incidence of paradoxical heat sensation, report of warmth in response to low temperature stimuli, was high in these patients. Vibration sensibility was more severely affected than thermal modalities in MS patients with no central pain (n517, duration 19 years, range 442 years), whereas, temperature sensibility was more affected in patients with MS and central pain (n529, duration 16 years, range 2–41 years) (Boivie, 1993). Seventy-six percent of patients from both groups had an abnormal threshold for either vibration, touch, temperature, heat-pain and / or cold pain. Patients showed considerable covariation in vibratory and tactile disturbances. In 12 patients with definite MS, 75% had an abnormal QST (VT in 48%, thermal thresholds in 17%), especially at the toe (Merchut and Gruener, 1993). Vibratory abnormalities coincided with clinical sensory deficits, and the correlation was poorer for thermal thresholds. Although SEP, commonly used for detection of sensory deficits in MS, showed greater sensitivity than the QST, the authors advocate use of QST methods for follow up of sensory changes in MS patients as the tests are easy to perform and cause less discomfort to patients. In 33 patients (23–59 years old) with definite MS (mean disease duration 5.5 years) vibratory thresholds at the toe were abnormal in 68% of patients (Heijenbrok et al., 1992). No relation was found between these thresholds and severity of disease. Thermal thresholds were elevated less frequently (30% of patients) and only in patients with severe disease. A number of subjects with abnormal thresholds (vibratory and thermal) denied presence of sensory symptoms, indicating that subclinical lesions may be detected by QST in MS patients.

8.1. Cerebrovascular lesions Sensation was assessed clinically and by thresholds for cold, warmth and heat-pain sensation in patients (n539) with a first-ever stroke and presenting with lacunar syndromes (pure motor, sensory-motor or pure sensory) and MRI findings compatible with occlusion of a single artery (Samuelsson et al., 1994). Thermal sensations were measured bilaterally at the cheek, hand and leg. Patients with pure sensory and sensory-motor stroke involvement, had significant thermal hypaesthesia on the affected side for all modalities and test areas. In 5 / 9 patients thermal testing indicated a complete syndrome whereas, clinical testing indicated only a partial syndrome. Thus, the authors caution against distinguishing between partial and complete syndromes on the basis of clinical examination alone. Patients with pure motor stroke, exhibited hypaesthesia for cold sensation in the hand and leg and heat-pain in the hand. Thermal perception generally improved during the first year after stroke onset except for post-stroke pain in 3 patients. Thalamic infarcts predominated amongst patients with the most pronounced thermal abnormalities.

8.1.1. Conclusions In some patients with pure sensory and sensory-motor stroke involvement, thermal testing was more sensitive than the sensory clinical examination in revealing the extent of sensory impairment. In patients with pure motor stroke, thermal testing revealed subclinical sensory impairment. Testing at the hand can probably serve for most screening procedures as abnormalities were most pronounced at this location.

8.2.1. Conclusions Vibratory and thermal testing can be used to quantify sensory abnormalities in MS patients. The prevalence of reported vibration and thermal abnormalities differs, yet, vibration is more frequently abnormal, except for the case in MS patients with central pain, where as expected the opposite was found. Vibratory and thermal tests are less sensitive than SEP, but they are easier to perform, less time consuming and less disturbing for patients. Paradoxical heat sensation is highly prevalent amongst MS patients. 8.3. Syringomyelia Syringomyelia (from the Greek syrinx, ‘pipe’ or ‘tube’)

232

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

is a chronic progressive degenerative disorder of the spinal chord. The precise clinical picture depends upon the crosssectional and longitudinal extent of the syrinx. The cardinal symptoms caused by extension of the syrinx into the anterior spinal commissure thus, injuring the spinothalamic tracts, are loss of pain and thermal sense with preservation of touch, over the neck, shoulders and arms. Thermal and pain thresholds can be used for evaluation of sensibility. In 9 patients with syringomyelia identified by MRI and CT, temperature sensibility was lost or severely abnormal (Boivie, 1993). In eight, sensation to heat and cold pain was severely reduced or absent. In 5 patients with symptoms at the upper extremities, the abnormalities were not symmetrically distributed and normal or almost normal sensibility was found in one hand. This indicates that the lesion was located mainly on one side. Vibratory and touch sensation in four patients was severely reduced, indicating the syrinx may have enlarged and caused major damage including much of the gray matter and zone where the dorsal root fibres enter the cord.

8.4. Hereditary spastic paraplegic Hereditary spastic paraplegia may be combined with other neurologic abnormalities, one of which may be PNP. QST techniques were employed to quantify sensory deficit in 23 patients (20–73 years) from 14 families with hereditary spastic paraplegia (Schady and Sheard, 1990). In 30% of patients, thermal, heat-pain, vibratory and tactile thresholds were significantly raised in patients compared to controls. Sensation was more severely impaired in the feet than the hands. The authors suggest that QST was more sensitive in some cases than the standard electrophysiological tests since all patients had a least one elevated sensory threshold whereas, 60% of patients had abnormal NCS and / or somatosensory evoked potentials. The authors conclude that although the clinical picture in hereditary spastic paraplegia is dominated by a spastic paresis, subclinical sensory impairment is common and this may reflect involvement of both the peripheral and central nervous systems.

9. Trauma

most clinicians do not have regular experience with them (McAllister, 1994). The utility of nominal scale tests of tactile sensibility was compared with that of QST for the longterm (mean 8.3 years) assessment of sensibility in 58 patients who sustained nerve injury in the upper limb and were treated by primary microsurgical nerve suture within 24 h (McAllister, 1994). The nominal scale tests were found to discriminate poorly between denervated and control sides as the tests were almost always positive, but the quantitative tests discriminated well. The latter included static and moving 2-point discrimination, detection of ridge (measures discriminative tactile sensibility), cold and warmth sensation, VT and cutaneous pressure threshold. Consequently, the author suggests that these tests may be the most useful in distinguishing between the quality of sensory outcome deriving from different types of nerve injury and different reconstructive techniques. Thermal and vibratory testing in these patients revealed that tactile sensibility remained abnormal and thermal sensibility recovered but thresholds remained abnormally raised. Heat-induced pain threshold appeared to recover to normal but the ability to distinguish between normal thermal sensation and thermally-induced pain was reduced. Accordingly, recovery of normal sensibility after nerve injury is not possible, though in the best results and when only a limited area is affected, sensory deficit may be minor. Several other studies evaluated sensation after reconstruction of different types of tissue. The majority of techniques used in these studies were not quantitative and so are beyond the scope of this paper. Yet, studies such as the ones outlined below, open the path for application of QST techniques in this field. Prospective assessment of sensation was carried out in innervated vs. noninnervated forearm flaps used for intraoral reconstruction in patients undergoing partial glossectomy and resection of the associated floor of the mouth for squamous cell carcinoma (Boyd et al., 1994). Sensibility was tested in patients with extensive palmar thumb pulp and soft tissue loss treated by staged transfer of radial nerve innervated flap tissues from the dorsum on the index finger (Walker et al., 1986). The quality of sensation associated with preservation of the posterior branch of the great auricular nerve was compared to sacrifice of the nerve during routine parotid surgery (Brown and Ord, 1989).

9.1. Evaluation of sensory restoration after tissue reconstruction

9.2. Burns

A wide variety of clinical measures of sensory performance have been described and recommended for use in hand surgery, QST techniques are amongst them (McAllister, 1994). Compared to nominal scales, QST is advantageous in being quantifiable and strong statistical methodology can be applied for analysis of results. Yet, since QST techniques have only recently been introduced in the field,

In injury to the skin surface, receptors for touch and nerve endings for thermal sensation are damaged or destroyed. QST which examines function from the receptor could thus, be usefully employed in determining remaining function and recovery. Sensory loss after full-thickness injury burns requiring skin grafting procedures was quantified in 16 patients and

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

in 42 controls (Ward and Tuckett, 1991). Patients were evaluated at a mean of 16 months (range 1–42 months) after injury. Probes for eliciting different types of stimuli were controlled by computer. Of the parameters tested, touch and vibration were significantly raised on the burned sites compared to controls and also compared to nonburned sites in patients. Vibration thresholds were significantly higher on nonburned sites in burns patients compared to control subjects. Since the noninjured sites were distant from the burn, the deficits were probably not caused by direct injury. The authors conclude that sensory function is reduced in patients after burns and they discuss alternative mechanisms which may have caused these changes.

9.3. Whiplash injury Although the pathology of whiplash injury is not known, the possibility that central trigeminal structures in the brainstem and upper spinal cord are damaged in whiplash injury has been raised. As there are few objective neurological findings of trigeminal sensory deficits in patients after whiplash injury, the authors (Knibestol et al., 1990) suggest applying QST techniques to demonstrate sensory disturbances in this condition. Thirty patients with whiplash injury were tested bilaterally by VT over the first and third divisions of the trigeminal nerve and for thermal thresholds over the three divisions of the trigeminal nerve. Of these, 16 patients had chronic and disabling symptoms and 14 were asymptomatic six months or more after trauma. Clinical examination revealed no pathology in the patients. Both vibratory and thermal thresholds were significantly higher in the patients with chronic symptoms compared to asymptomatic and normals. This indicates, according to the authors, that in patients with chronic symptoms after whiplash injury there is damage to the central trigeminal pathway in the upper spinal cord segments and the ponto-medullary levels of the brainstem. The symmetry of sensory abnormalities and very high thermal and vibratory threshold elevations without concomitant clinical correlates for the chronic patients are difficult to reconcile with. The results of this study await replication.

10. Neurogenic impotence Penile erection is a complex physiological response initiated by mechanical and reflexogenic stimulation of the genital organs. Intact penile sensory input is important for sexual function (Bemelmans et al., 1995). Attempts have been made to apply vibratory and thermal testing for evaluation of neurogenic impotence.

10.1. Diagnosis of neurogenic impotence by vibration VT and dorsal nerve evoked potentials (DNSEP) were

233

obtained from 137 patients with organic impotence and 118 controls (Goldstein, 1988). VT was abnormal in 72% of the patients, and 47% of patients with abnormal VT, had abnormal DNSEPs. The author suggests that as VT is noninvasive and impairment was found in a large number of patients who had no obvious preexisting neuropathology, the technique can be used for screening of all impotence patients. The opposite conclusion is presented in a study in which neuro-urophysiological tests were compared with VT in 31 unselected patients with erectile dysfunction, 9 of whom had Diabetes mellitus (Bemelmans et al., 1995). The neurophysiological investigation consisted of tibial and pudendal SEP, bulbocavernosus reflex latency, and VT at penis and ankle. While coefficient of replication reliability for VT 0.99, no relationship was found between penile VT measurements and penile neurophysiological tests. The authors conclude that VT measurements cannot be used for evaluation of penile innervation and cannot replace the currently used neurophysiological tests.

10.2. Diagnosis of neurogenic impotence by thermal testing In two studies, thermal thresholds were recorded in patients with impotence of diabetic and other etiologies. Measurement of thermal thresholds samples small fibre function, and is expected to be a more direct means for evaluation of neurogenic impotence than the large fibre related tests of VT, SEP and bulbocavernous reflex. Yet, clinical application of the thermal results is hampered due to missing data on responses of diabetics with normal potency. Thermal sensation was measured at the wrist and penile shaft in 50 impotent patients including 27 diabetics and 8 after pelvic trauma and 30 controls (Robinson et al., 1987). Autonomic cardiovascular testing revealed that 11% of subjects had definite and 59% had early signs of autonomic neuropathy. Thermal testing at the penis, revealed severe impairment in 63%, impairment in 30% and normal response in 7%. The authors regard thermal testing as showing abnormality at an earlier stage than autonomic cardiovascular tests, and as a useful test for neurogenicity in diabetic impotence. For pelvic trauma patients, autonomic tests were normal, while thermal tests were abnormal at the penis in 87.5% patients. In another study, 33 men were assessed for erectile dysfunction, of whom 15 were clinically considered neurogenic, of these 14 were diabetic. All diabetic subjects had abnormal thresholds for heat sensation and 64% had abnormal thresholds for cold at the feet, the electrophysiological measure of the bulbocavernosus reflex, was normal in 5 / 9 patients. Subjects with nonneuropathic erectile dysfunction had thermal thresholds within the normal range, including 5 diabetics, whose dysfunction was attributed to a variety of conditions. Of the tests

234

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

conducted, thermal responses were highly specific to those patients whose impotence was of a neurogenic background and it was better in detecting abnormality than the bulbocavernosus reflex (Fowler et al., 1988). Data from normal subjects regarding penile thermal thresholds is lacking. Consequently, upper normal thresholds and repeatability values of cold and warm on the dorsal aspect of the penile shaft were measured in 35 healthy volunteers. Thresholds were tested by the method of limits and levels (Yarnitsky et al., 1996). According to the authors, despite having tested a small number of subjects, repeatabilities, bias and threshold values were consistent and comparable to those previously described to measurements for the hand and foot. This indicates that the penile values obtained are reliable.

10.3. Incidence of PNP in impotence Evaluation of 341 consecutive impotent patients, of which 106 were diabetic included NCS, thermal testing and VT (Vardi et al., 1996). Criteria for diagnosis of PNP followed recommendations by (Dyck et al., 1985) requiring the presence of at least two abnormalities to establish pathology. Accordingly, PNP was present in 19% of all patients, in 38% of the diabetics and 10% of the nondiabetics.

10.4. Conclusions Penile vibration perception is advocated for evaluation of peripheral and central components of the dorsal nerve afferent pathway in impotent patients, yet, the role of VT measurement in diagnosis of neurogenic impotence is not clear. The technique is advocated by some authors but according to others, vibratory testing of penile glands innervation cannot replace the currently used neurophysiological tests; vibratory testing is not applicable in the penile glands as it contains little if any vibration receptors but mainly nerve free endings. Thermal testing at the penile shaft or feet in subjects with neurogenic impotence has been shown to be sensitive compared to autonomic cardiovascular tests or electrophysiological measures. As studies evaluating specificity for this modality are lacking, its value in clinical diagnosis remains open.

11. Itch A model of histamine-induced itch was employed to quantify the effects of a high-potency topical corticosteroid, clobetasol propionate and menthol for alleviation of pain and itch in normals (Yosipovitch et al., 1996a,b). Thermal sensation and pain thresholds on the volar aspect of the arm were evaluated by the method of limits before and after induction of itch and of the medication. The only changes in thermal sensation were: elevated warm sensory

threshold after histamine, and elevated cold sensory threshold after topical alcohol. Local skin temperature change, subsequent to histamine and alcohol could possibly explain the threshold changes.

Acknowledgements We thank Drs Ari Dale and Elliot Sprecher for their help and most useful comments.

References Aatola, S., Farkkila, M., Pyykko, I., Korhonen, O., Starck, J., 1990. Vibration perception threshold of forest worker’s finger during temporary obstructed blood circulation. Int. Arch. Occup. Environ. Health. 62 (6), 451–453. Ali, Z., Carroll, M., Robertson, K.P., Fowler, C.J., 1989. The extent of small fibre sensory neuropathy in diabetics with plantar foot ulceration. J. Neurol. Neurosurg. Psychiatry. 52 (1), 94–98. Anand, P., Terenghi, G., Warner, G., Kopelman, P., Williams-Chestnut, R.E., Sinicropi, D.V., 1996. The role of endogenous nerve growth factor in human diabetic neuropathy. Nature Med. 2 (6), 703–707. Angus-Leppan, H., Burke, D., 1992. The function of large and small nerve fibres in renal failure. Muscle Nerve 15 (3), 288–294. Aratani, J., Suzuki, H., Hashimoto, K., 1993. Measurement of vibratoy perception threshold (VPT) in workers exposed to organic solvents. Env. Res. 61, 357–361. Arezzo, J.C., Schaumburg, H.H., Laudadio, C., 1986. Thermal sensitivity tester. Device for quantitative assessment of thermal sense in diabetic neuropathy. Diabetes 35 (5), 590–592. Armstrong, F.M., Bradbury, J.E., Ellis, S.H. et al., 1991. A study of peripheral diabetic neuropathy. The application of age-related reference values. Diabet. Med. 8, 595–599. Asbury, A. et al., 1992. Proceedings of a consensus development conference on standardized measures in diabetic neuropathy. Neurology 42, 1823–1839. Bemelmans, B.L., Hendrikx, L.B., Koldewijn, E.L., Lemmens, W.A., Debruyne, F.M., Meuleman, E.J., 1995. Comparison of biothesiometry and neurourophysiological investigations for the clinical evaluation of patients with erectile dysfunction. J. Urol. 153 (5), 1483–1486. Berger, A.R., Arezzo, J.C., Schaumburg, H.H. et al., 1993. 29,39-Dideoxycytidine (ddC) toxic neuropathy: A study of 52 patients. Neurology 43, 358–362. Berger, A.R., Schaumburg, H.H., Schroeder, C., Apfel, S., Reynolds, R., 1992. Dose response, coasting, and differential fibre vulnerability in human toxic neuropathy: a prospective study of pyridoxine neurotoxicity. Neurology 42 (7), 1367–1370. Bertelsmann, F.W., Heimans, J.J., Van Rooy, J.C.G.M., Dankmeijer, H.F., van der Veen, E.A., 1987. Peripheral nerve function in patients with painful diabetic neuropathy treated with continuous subcutaneous insulin infusion. J. Neurol. Neurosurg. Psychiatry 50, 1337–1341. Bertelsmann, F.W., Heimans, J.J., van Rooy, J.C., Heine, R.J., van der Veen, E.A., 1986. Reproducibility of vibratory perception thresholds in patients with diabetic neuropathy. Diabetes Res. 3 (9), 463–646. Bigli, C., Pelmear, P.L., 1993. Hand–arm vibration syndrome: A guide to medical impairment assessment. JOM 35 (9), 936–942. Boivie, J., 1993. Sensory abnormalities in patients with central nervous system lesions as shown by quantitative sensory tests. In: Boivie, J., Hansson, P., Lindblom, U. (Eds.). Touch, Temperature, and Pain in Health and Disease: Mechanisms and Assessments. Progress in Pain Research and Management, vol 3, IASP Press, Seattle. pp. 179–192. Borg, K., Lindblom, U., 1988. Diagnostic value of quantitative sensory

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238 testing (QST) in carpal tunnel syndrome. Acta Neurol. Scand. 78 (6), 537–541. Borg, K., Lindblom, U., 1986. Increase of vibration threshold during wrist flexion in patients with carpal tunnel syndrome. Pain 26 (2), 211–219. Boulton, A.J., Kubrusly, D.B., Bowker, J.H. et al., 1986. Impaired vibratory perception and diabetic foot ulceration. Diabet. Med. 3 (4), 335–337. Boyd, B., Mulholland, S., Gullane, P. et al., 1994. Reinnervated lateral antebrachial cutaneous neurosome flaps in oral reconstruction: Are we making sense? Plastic Reconstr. Surg. 93 (7), 1350–1359. Bozzette, S.A., Santangelo, J., Villasana, D. et al., 1991. Peripheral nerve function in persons with asymptomatic or minimally symptomatic HIV disease: Absence of zidovudine neurotoxicity. J. Acquired Immune Defic. Syndr. 4, 851–855. Brammer, A.J., Pyykko, I., 1987. Vibration-induced neuropathy. Detection by nerve conduction measurements. Scand. J. Work. Environ. Health. 13 (4), 317–322. Brashear, A., Unverzagt, F.W., Farber, M.O., Bonnin, J.M., Garcia, J.G.N., Grober, E., 1996. Ethylene oxide neurotoxicity: A cluster of 12 nurses with peripheral and central nervous system toxicity. Neurology 46, 992–998. Brown, J.S., Ord, R.A., 1989. Preserving the great auricular nerve in parotid surgery. Brit. J. Oral and Maxiofacial Surg. 27, 459–466. Brown, T.R., Kovindha, A., Wathanadilokkol, U., Piefer, A., Smith, T., Kraft, G.H., 1996. Leprosy neuropathy: correlation of clinical and electrophysiological tests. Indian J. Lepr. 68 (1), 1–14. Chaudhry, V., Rowinsky, E.K., Sartorius, S.E., Donehower, R.C., Cornblath, D.R., 1994. Peripheral neuropathy from Taxol and Cisplatin combination chemotherapy: clinical and electrophysiological studies. Ann. Neurol. 35, 304–311. Cherniack, M.G., Letz, R., Gerr, F., Brammer, A., Pace, P., 1990. Detailed clinical assessment of neurological function in symptomatic shipyard workers. Br. J. Ind. Med. 47 (8), 566–572. Cherniack, M.G., 1990. Raynaud’s phenomenon of occupational origin. Arch. Intern. Med. 150 (3), 519–522. Christensen, N.J., 1969. Vibratory perception and blood flow in the feet of diabetics. Acta Med. Scand. 185 (6), 553–559. Claus, D., Hilz, M.J., Neundorfer, B., 1990. Thermal discrimination thresholds: a comparison of different methods. Acta Neurol. Scand. 81 (6), 533–540. Daniel, C.R., Bower, J.D., Pearson, J.E., Holbert, R.D., 1977. Vibrometry and uremic peripheral neuropathy. South Med. J 70 (11), 1311–1313. Demers, R.Y., Markell, B.L., Wabeke, R., 1991. Peripheral vibratory sense deficits in solvent-exposed painters. J. Occup. Med. 33 (10), 1051– 1054. Deng, H., He, F., Zhang, S., Calleman, C.J., Costa, L.G., 1993. Quantitative measurements of vibration threshold in healthy adults and acrylamide workers. Int. Arch. Occup. Environ. Health 65, 53–56. Denislic, M., Meh, D., Popovic, M., Kos-Golja, M., 1995. Small nerve ¨ fibre dysfunction in a patient with Sjogren’s syndrome. Scan. J. Rheumatol. 24, 257–259. Dinh, S., Marroquin, E., Raj, P., 1997. Neuroselective quantification of allodynia by current perception threshold evaluation in RSD patients. Regional Anesthesia 22 (2S), 44. Dyck P.J., Karnes, J., O’Brien, P.C., Zimmerman, I.R. Detection thresholds of cutaneous sensation in humans. In: Dyck, P.D. (Ed.), Peripheral Neuropathy. W.B. Saunders Co. 3rd Edition, 1993. pp. 706–728. Dyck, P.J., Kratz, K.M., Lehman, K.A. et al., 1991. The Rochester Diabetic Neuropathy Study: Design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests. Neurology 41, 799–807. Dyck, P.J., Karnes, J.L., Daube, J., O’Brien, P.C., Service, F.J., 1985. Clinical and neuropathological criteria for the diagnosis and staging of diabetic polyneuropathy. Brain 108, 861–880. Ekenvall, L., Nilsson, B.Y., Falconer, C., 1990. Sensory perception in the hands of dentists. Scand. J. Work Environ. Health 16 (5), 334–339.

235

Ekenvall, L., Gemne, G., Tegner, R., 1989. Correspondence between neurological symptoms and outcome of quantitative sensory testing in the hand–arm vibration syndrome. Br. J. Ind. Med. 46 (8), 570–574. Ekenvall, L., Lindblad, L.E., Bevegard, S., Etzell, B.M., 1987. High vascular tone but no obliterative lesions in vibration white fingers. Am. J. Ind. Med. 12 (1), 47–54. Elderson, A., Gerritsen van der Hoop, R., Haanstra, W., Neijt, J.P., Gispen, W.H., Jennekens, F.G.I., 1989. Vibration perception and thermoception as quantitative measurements in the monitoring of cisplatin-induced neurotoxicity. J. Neurol. Sci. 93, 167–174. Fowler, C.J., Ali, Z., Kirby, R.S., Pryor, J.P., 1988. The value of testing for unmyelinated fibre, sensory neuropathy in diabetic impotence. Br. J. Urol. 61 (1), 63–67. Fruhstrofer, H., Lindblom, U., Schmidt, W.C., 1976. Method for quantitative estimation of thermal thresholds in patients. J. Neurol. Neurosurg. Psychiatry 39, 1071–1075. Futatsuka, M., Inaoka, N., Ueno, T., 1990. Validity of function tests on the upper extremities in establishing a prognosis in vibration syndrome. Ind. Health 28 (2), 41–52. Gadia, M.T., Natori, N., Ramos, L.B., Ayyar, D.R., Skyler, J.S., Sosenko, J.M., 1987. Influence of height on quantitative sensory, nerve-conduction, and clinical indices of diabetic peripheral neuropathy. Diabetes Care 10 (5), 613–616. Gemne, G., Pyykko, I., Taylor, W., Pelmear, P.L., 1987. 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 13 (4), 275– 278. Gentile, S., Marmo, R., Orlando, C., Peduto, A., Montella, F., Coltorti, M., 1993. Alterations of vibratory and thermal peripheral sensitivity in liver cirrhosis. Ital. J. Gastroenterol. 25 (6), 307–313. Gerr, F., Letz, R., Harris-Abbott, D., Hopkins, L.C., 1995. Sensitivity and specificity of vibrometry for detection of carpal tunnel syndrome. J. Occup. Environ. Med. 37 (9), 1108–1115. Gill, J.S., Williams, G., Ghatei, M.A., Hetreed, A.H., Mather, H.M., Bloom, S.R., 1990. Effect of the aldose reductase inhibitor, Ponalrestat, on diabetic neuropathy. Diabete and Metabolisme (Paris) 16, 296–302. Goadsby, P.J., Burke, D., 1994. Deficits in the function of small and large afferent fibres in confirmed cases of carpal tunnel syndrome. Muscle Nerve 17 (6), 614–622. Goldstein, I., 1988. Evaluation of penile nerves. In: Tanagho, E.A., Leu, T.F., McClure, R.D. (Eds.), Contemporary Management of Impotence and Infertility. Williams and Wilkins, USA. 1988, pp: 70–83. Grant, K.A., Congleton, J.J., Koppa, R.J., Lessard, C.S., Huchingson, R.D., 1992. Use of motor nerve conduction testing and vibration sensitivity testing as screening tools for carpal tunnel syndrome in industry. J. Hand Surg. 17A, 71–76. Gulenvich, S.J., Kalmijn, J.A., Thal, L.J. et al., 1992. Sensory testing in human immunodeficiency virus type 1-infected men. Arch. Neurol. 49, 1281–1284. Gupta, A., McCabe, S.J., 1993. Vibration white finger . Hand Clin. 9 (2), 325–337. Guy, R.J., Clark, C.A., Malcolm, P.N., Watkins, P.J., 1985. Evaluation of thermal and vibration sensation in diabetic neuropathy. Diabetologia 28 (3), 131–137. Haley, R.W., Hom, J., Roland, P.S. et al., 1997. Evaluation of neurologic function in Gulf War veterans. J. Am. Med. Assoc. 277 (3), 223–230. Halonen, P., Halonen, J.-P., Lang, H.A., Karskela, V., 1986. Vibratory perception thresholds in shipyard workers exposed to solvents. Acta Neurol. Scand. 73, 561–565. Hansen, C., Hopf, H.C., Treede, R.D., 1996. Paradoxical heat sensation in patients with multiple sclerosis—Evidence for a supraspinal integration of temperature sensation. Brain 119, 1729–1736. Hansen, S.W., Helweg-Larsen, S., Trojaborg, W., 1989. Longterm neurotoxicity in patients treated with cisplatin, vinblastine and bleomycin for metastatic germ cell cancer. J. Clin. Oncol. 7 (10), 1457–1461.

236

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

Hansson, P., Lindblom, U., Lindstrom, P., 1991. Graded assessment and classification of impaired temperature sensibility in patients with diabetic polyneuropathy. J. Neurol. Neurosurg. Psychiatry 54 (6), 527–530. Heijenbrok, M.W., Anema, J.R., Faes, T.J., Bertelsmann, F.W., Heimans, J.J., Polman, C.H., 1992. Quantitative measurement of vibratory sense and temperature sense in patients with multiple sclerosis. Electromyogr. Clin. Neurophysiol. 32 (7–8), 385–388. Hilknes, P.H.E., Verweij, J., Stoter, G., Vecht, C.J., Van putten, W.L.J., Van Den Bent, M.J., 1996. Peripheral neurotoxicity induced by docetaxel. Neurology 46, 104–108. Hillson, R.M., Hockaday, T.D.R., Newton, D.J., 1984. Hyperglycemia is one correlate of deterioration in vibration sense during the 5 years after diagnosis of Type 2 (noninsulin-dependent) diabetes. Diabetologia 26, 122–126. Hilz, M., Glorius, S.E., Schweibold, G., Neuner, I., Stemper, B., Axelrod, F.B., 1996. Quantitative thermal perception testing in preschool children. Muscle and Nerve 19, 381–383. Hilz, M.J., Zimmermann, P., Rosl, G. et al., 1995. Vibrameter testing facilitates the diagnosis of uremic and alcoholic polyneuropathy. Acta Neurol. Scand. 92, 486–490. Hilz, M.J., Claus, D., Neundorfer, B., Zimmermann, P., Beric, A., 1994. Is heat hypoalgesia a useful parameter in quantitative thermal testing of alcoholic polyneuropathy? Muscle Nerve 17 (12), 1456–1460. Hilz, M.J., Claus, D., Neundorfer, B., 1988. Early diagnosis of diabetic small fibre neuropathy by disturbed cold perception. J. Diabet. Complications 2 (1), 38–43. Hjortsberg, U., Rosen, I., Orbaek, P., Lundborg, G., Balogh, I., 1989. Finger receptor dysfunction in dental technicians exposed to highfrequency vibration. Scand. J. Work Environ. Health 15 (5), 339–344. Ho, S.T., Yu, H.S., 1986. A study of neurophysiological measurements and various function tests on workers occupationally exposed to vibration. Int. Arch. Occup. Environ. Health 58 (4), 259–268. Hoeldtke, R.D., Davis, K.M., Hshieh, P.B., Gaspar, S.R., Dworkin, G.E., 1994. Are there two types of diabetic foot ulcers? J. Diabet. Complications 8 (2), 117–125. Horowitz, S.H., 1995. Correlation of near-nerve sural conduction and quantified sensory testing in patients with diabetic neuropathy. Muscle Nerve 18 (10), 1202–1204. Imai, T., Matsumoto, H., Minami, R., 1990. Asymptomatic ulnar neuropathy in carpal tunnel syndrome. Arch. Phys. Med. Rehabil. 71 (12), 992–994. Jamal, G.A., Hansen, S., Apartopoulos, F., Peden, A., 1996. The ‘Gulf War syndrome’. Is there evidence of dysfunction in the nervous system? J. Neurol. Neurosurg. Psychiatry 60 (4), 449–451. Jamal, G.A., Ballantyne, J.P., 1988. The localization of the lesion in patients with acute ophthalmoplegia, ataxia and areflexia (Miller Fisher syndrome). A serial multimodal neurophysiological study. Brain 111 (Pt 1), 95–114. Jamal, G.A., Weir, A.I., Hansen, S., Ballantyne, J.P., 1986. Myotonic dystrophy: A reassessment by conventional and more recently introduced neurophysiological techniques. Brain 109, 1279–1296. Jensen, T.S., Bach, F.W., Kastrup, J., Dejgaard, A., Brennum, J., 1991. Vibratory and thermal thresholds in diabetics with and without clinical neuropathy Acta. Neurol. Scand. 84 (4), 326–333. Jetzer, T.C., 1991. Use of vibration testing in the early evaluation of workers with carpal tunnel syndrome. J. Occup. Med. 33 (2), 117– 120. Keen, H., Payan, J., Allawi, J. et al., 1993. Treatment of diabetic neuropathy with g-linolenic acid. Diabetes Care 16 (1), 8–15. Klenerman, P., Hammond, C., 1988. Vibration sensation in leprosy patches. Int. J. Lepr. Other Mycobact. Dis. 56 (3), 466–468. Klima, R.R., Weigand, A.H., DeLisa, J.A., 1991. Nerve conduction studies and vibration perception thresholds in diabetic and uremic neuropathy. Am. J. Phys. Med. Rehabil. 70 (2), 86–90. Knibestol, M., Hildingsson, C., Toolanen, G., 1990. Trigeminal sensory impairment after soft-tissue injury of the cervical spine. A quantitative

evaluation of cutaneous thresholds for vibration and temperature. Acta Neurol. Scand. 82 (4), 271–276. Lang, E., Claus, D., Neundorfer, B., Handwerker, H.O., 1995. Parameters of thick and thin nerve-fibre functions as predictors of pain in carpal tunnel syndrome. Pain 60, 295–302. Le Quesne, P.M., Fowler, C.J., Parkhouse, N., 1990. Peripheral neuropathy profile in various groups of diabetics. J. Neurol. Neurosurg. Psychiatry. 53, 558–563. Levi, D., Abraham, R., Reid, G., 1989. A comparison of two methods for measuring thermal thresholds in diabetic neuropathy. J. Neurol. Neurosurg. Psychiatry 52, 1072–1077. Levi, D.M., Abraham, R.R., Abraham, R.M., 1987. Small- and large-fibre involvement in early diabetic neuropathy: A study with the medial plantar response and sensory thresholds. Diabetes Care 10 (4), 441– 447. Lindblom, U., Tegner, R., 1985. Thermal sensitivity in uremic neuropathy. Acta Neurol. Scand. 71 (4), 290–2904. Lipton, R.B., Galer, B.S., Dutcher, J.P. et al., 1991. Large and small fibre type sensory dysfunction in patients with cancer. J. Neurol. Neurosurg. Psychiatry 54 (8), 706–709. Lipton, R.B., Galer, B.S., Dutcher, J.P. et al., 1987. Quantitative sensory testing demonstrates that subclinical sensory neuropathy is prevalent in patients with cancer. Arch. Neurol. 44 (9), 944–946. Liu, S., Kopacz, K.J., Carpenter, R.L., 1995. Quantitative assessment of differential sensory nerve block after lidocaine spinal anesthesia. Anesthesiology 82 (1), 60–63. Lundborg, G., 1994. Pain, nerve dysfunction and fatigue in a vibrationexposed population. Qual. Life Res. 3 (Suppl 1), S39–S42. Lundborg, G., Lie-Stenstrom, A.K., Sollerman, C., Stromberg, T., Pyykko, I., 1986. Digital vibrogram: a new diagnostic tool for sensory testing in compression neuropathy. J. Hand Surg. (Am.) 11 (5), 693–699. McAllister, R.M., 1994. Recovery of sensibility in the hand after nerve injuries. In: Boivie, J., Hansson, P., Lindblom, U. Touch, Temperature and Pain in Health and Disease: Mechanisms and Assessments. Progress in Pain Research and Management, vol. 3, IASP Press, Seattle. pp. 163–178. Merchut, M.P., Gruener, G., 1993. Quantitative sensory threshold testing in patients with multiple sclerosis. Electromyogr. Clin. Neurophysiol. 33 (2), 119–124. Merchut, M.P., Kelly, M.A., Toleikis, S.C., 1990. Quantitative sensory thresholds in carpal tunnel syndrome. Electromyogr. Clin. Neurophysiol. 30 (2), 119–124. Moody, L., Arezzo, J., Otto, D., 1986. Screening occupational populations for asymptomatic or early peripheral neuropathy. J. Occup. Med. 28 (10), 975–986. Narini, P.P., Novak, C.B., Mackinnon, S.E., Coulson-Roos, C., 1993. Occupational exposure to hand vibration in northern Ontario gold miners. J. Hand Surg. (Am.) 18 (6), 1051–1058. Nasu, Y., Ishida, K., 1986. Follow-up study of patients with vibration syndrome in Japan. Scand. J. Work Environ Health 12 (4), 313–319. Navarro, X., Kennedy, W.R., 1991. Evaluation of thermal and pain sensitivity in type I diabetic patients. J. Neurol. Neurosurg. Psychiatry 54 (1), 60–64. Navarro, X., Kennedy, W.R., Fries, T.J., 1989. Small nerve fibre dysfunction in diabetic neuropathy. Muscle Nerve 12 (6), 498–507. New, P.Z., Jackson, C.E., Rinaldi, D., Burris, H., Barohn, R.J., 1996. Peripheral neuropathy secondary to docetaxel (Taxotere). Neurology 46 (1), 108–111. Nielsen, V.K., 1972. The peripheral nerve function in chronic renal failure. IV. An analysis of the vibratory perception threshold. Acta Med. Scand. 191, 287–296. O’Brien, B., Jackson, R., Tang-Wai, R., Lewis, A.J., Atack, E.A., 1980. Hereditary sensory neuropathy: A case with pain and temperature dissociation. Can. J. Neurol. Sci. 7 (1), 73–76. Omdal, R., Mellgren, S.I., Husby, G., Salvesen, R., Henriksen, O.A., Torbergsen, T., 1993. A controlled study of peripheral neuropathy in systemic lupus erythematosus. Acta Neurol. Scan. 88, 41–46.

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238 Omdal, R., Henriksen, O.A., Mellgren, S.I., Husby, G., 1991. Peripheral neuropathy in systemic lupus erythematosus. Neurology 41, 808–811. Palmer, R.A., Collin, J., 1993. Vibration white finger. Br. J. Surg. 80 (6), 705–709. Pelmear, P.L., Taylor, W., 1994. Carpal tunnel syndrome and hand–arm vibration syndrome. A diagnostic enigma. Arch. Neurol. 51 (4), 416–420. Postma, T.J., Benard, B.A., Huijgens, P.C., Ossenkoppele, G.J., Heimans, J.J., 1993. Longterm effects of vincristine on the peripheral nervous system. J. Neurooncol. 15 (1), 23–27. Practice parameter for carpal tunnel syndrome, 1993. (Summary statement) Neurology 43, 2406–2409. Quantitative sensory testing, 1992. Diabetes Care 15 (3), 1092–1094. Rasmussen, K., Arlien-Soborg, P., Sabroe, S., 1993. Clinical neurological findings among metal degreasers exposed to chlorinated solvents. Acta Neurol. Scand. 87, 200–204. Redmond, J.M., McKenna, M.J., Feingold, M., Ahmad, B.K., 1992. Sensory testing versus nerve conduction velocity in diabetic polyneuropathy. Muscle Nerve 15 (12), 1334–1339. Robinson, L.Q., Woodcock, J.P., Stephenson, T.P., 1987. Results of investigation of impotence in patients with overt or probable neuropathy. Br. J. Urol. 60 (6), 583–587. Roos, D., 1977. The vibration perception threshold in gastrectomized patients with low serum B 12 . A clinical and biothesiometric follow-up after intensive B 12 therapy. Acta Neurol. Scand. 56 (6), 551–562. Samuelsson, M., Samuelsson, L., Lindell, D., 1994. Sensory symptoms and signs and results of quantitative sensory thermal testing in patients with lacunar infarct syndromes. Stroke 25 (11), 2165–2170. Schady, W., Sheard, A., 1990. A quantitative study of sensory function in hereditary spastic paraplegia. Brain 113, 709–720. Schaumburg, H.H., Berger, A.R., Thomas, P.K. Disorders of Peripheral Nerves, 2nd ed. F.A. Davis, 1992. pp: 157–159. Schaumburg, H.H., Arezzo, J.C., Berger, A.R., Skowron, G., Bozzette, S., Soo, W., 1990. Dideoxycytidine (ddC) neuropathy in human immunodeficiency virus infections: A report of 52 patients. Neurology 40 (Suppl 1), 1133. Simpson, D.M., Tagliati, M., 1994. Neurologic manifestations of AIDS. Ann. Intern. Med. 121, 769–785. Singh, G., Tutakne, M.A., Tiwari, V.D., Dutta, R.K., 1985. Quantification of thermal sensory loss in follow up of progress in leprosy. Indian J. Lepr. 57 (4), 790–795. Smith, S.J., Ali, Z., Fowler, C.J., 1991. Cutaneous thermal thresholds in patients with painful burning feet. J. Neurol. Neurosurg. Psychiatry 54 (10), 877–881. Sosenko, J.M., Kato, M., Soto, R., Bild, D.E., 1993. A prospective study of sensory function in patients with type 2 diabetes. Diabet. Med. 10 (2), 110–114. Sosenko, J.M., Soto, R., Aronson, J., Kato, M., Caralis, P.V., Ayyar, D.R., 1991. The prevalence and extent of vibration sensitivity impairment in men with chronic ethanol abuse. J. Stud. Alcohol 52 (4), 374–376. Sosenko, J.M., Kato, M., Soto, R., Bild, D.E., 1990. Comparison of quantitative sensory threshold measures for their association with foot ulceration in diabetic patients. Diabetes care 13 (10), 1057–1061. Srinivasan, H., Stumpe, B., 1989. Leprosy diagnosis: a device for testing the thermal sensibility of skin lesions in the field. Bull. World Health Organ. 67 (6), 635–641. Strian, F., Lautenbacher, S., Karlbauer, G., Galfe, G., 1991. Disturbances of C-fibre-mediated sensibility in lumbosacral disc disease. J. Neurol. Neurosurg. Psych. 54, 1013–1014. Stromberg, T., Dahlin, L.B., Lundborg, G., 1996. Hand problems in 100 vibration-exposed symptomatic male workers. J. Hand Surg. (Br.) 21 (3), 315–319. Szabo, R.M., Gelberman, S., Richard, H., Dimick, M.P., 1984. Sensibility testing in patients with carpal tunnel syndrome. J. Bone and Joint Surg. 66A (1), 60–64. Taylor, J.S., 1986. Vibration syndrome: a missed diagnosis. Occup. Med. 1 (2), 259–272.

237

Taylor, W., 1993. The hand–arm vibration syndrome–diagnosis, assessment and objective tests: a review. J. R. Soc. Med. 86 (2), 101–103. Tegner, R., Lindholm, B., 1985. Vibratory perception threshold compared with nerve conduction velocity in the evaluation of uremic neuropathy. Acta Neurol. Scand. 71 (4), 284–289. Tegner, R., Lindholm, B., 1985. Uremic polyneuropathy: Different effects of haemodialysis and continuous anbulatory peritoneal dialysis. Acta Med. Scand. 218, 409–416. Thomaides, T.N., Kerezoudi, E.P., Zoukos, Y., Chaudhuri, K.R., 1992. Thermal thresholds and motor sensory conduction measurements in Guillain–Barre Syndrome:12-month follow-up study. Eur. Neurol. 32, 274–280. Thompson, S.W., Davis, L.E., Kornefeld, M., Hilgers, R.D., Standefer, J.C., 1984. Cisplatin neuropathy. Clinical, electrophysiological, morphologic and toxicology studies. Cancer 54, 1269–1275. Tredici, G., Minazzi, M., 1975. Alcoholic neuropathy, an electronmicroscopic study. J. Neurol. Sci. 25, 333–346. Trojaborg, W., Smith, T., Jakobsen, J., Rasmussen, K., 1994. Cardiorespiratory reflexes, vibratory and thermal thresholds, sensory and motor conduction in diabetic patients with end-stage nephropathy. Acta Neurol. Scand. 90 (1), 1–4. Trojaborg, W., Smith, T., Jakobsen, J., Rasmussen, K., 1994. Effect of pancreas and kidney transplantation on the neuropathic profile in insulin-dependent diabetics with end-stage nephropathy. Acta Neurol. Scand. 90 (1), 5–9. Tutakne, M.A., Tiwari, V.D., Chakrabarty, N., Gupta, C.M., 1985. Quantification of thermal sensory perception in leprosy (A preliminary report). Indian J. Leprosy 57 (2), 360–363. Valensi, P., Attali, J.R., Gagant, S., 1993. Reproducibility of parameters for assessment of diabetic neuropathy. The French group for research and study of diabetic neuropathy. Diabet. Med. 10 (10), 933–939. Vardi, Y., Sprecher, E., Kanter, Y., Livne, P.M., Hemli, J.A., Yarnitsky, D., 1996. Polyneuropathy in impotence. Int. J. Impot. Res. 8, 65–68. Veves, A., Young, M.J., Manes, C., Boulton, A.J., 1994. Differences in peripheral and autonomic nerve function measurements in painful and painless neuropathy. A clinical study. Diabetes Care 17 (10), 1200– 1202. Vinik, A.I., Suwanwalaikorn, S., Stansberry, K.B., Holland, M.T., McNitt, P.M., Colen, L.E., 1995. Quantitative measurement of cutaneous perception in diabetic neuropathy (see comments). Muscle Nerve 18 (6), 574–584. Virokannas, H., 1992. Vibration perception thresholds in workers exposed to vibration. Int. Arch. Occup. Environ. Health 64 (5), 377–382. Walker, M.A., Hurley, C.B., May, J.W., 1986. Radial nerve cross-finger flap differential nerve contribution in thumb reconstruction. J. Hand Surg. 11A, 881–887. Ward, R.S., Tuckett, R.P., 1991. Quantitative threshold changes in cutaneous sensation of patients with burns. J. Burn Care Rehabil. 12 (6), 569–575. Werner, R.A., Franzblau, A., Johnston, E., 1995. Comparison of multiple frequency vibrometry testing and sensory nerve conduction measures in screening for carpal tunnel syndrome in an industrial setting. Am. J. Phys. Med. Rehabil. 74 (2), 101–106. White, K.M., Congleton, J.J., Huchingson, R.D., Koppa, R.J., Pendleton, O.J., 1994. Vibrometry testing for carpal tunnel syndrome: a longitudinal study of daily variations. Arch Phys. Med. Rehabil. 75 (1), 25–28. Winer, J.B., Bang, B., Clarck, J.R. et al., 1992. A study of neuropathy in HIV infection. Quarterly J. Med. 83 (302), 473–488. Yarnitsky, D., 1997. Quantitative sensory testing. Muscle and Nerve 20, 198–204. Yarnitsky, D., Sprecher, E., Vardi, Y., 1996. Penile thermal sensation. J. Urology 156, 391–393. Yarnitsky, D., Sprecher, E., Tamir, A., Zaslansky, R., Hemli, J.A., 1994. Variance of sensory threshold measurements: discrimination of feigners from trustworthy performers. J. Neurol. Sci. 125, 186–189. Yosipovitch, G., Szolar, C., Hui, X.Y., Maibach, H., 1996. High-potency

238

R. Zaslansky, D. Yarnitsky / Journal of Neurological Sciences 153 (1998) 215 – 238

topical corticosteroid rapidly decreases histamine-induced itch but not thermal sensation and pain in human beings. J. Am. Acad. Dermatol. 35 (1), 118–120. Yosipovitch, G., Szolar, C., Ying Hui, X., Maibach, H., 1996. Effect of topically applied menthol on thermal, pain and itch sensations and biophysical properties of the skin. Arch. Dermatol. Res. 288, 245–248. Yosipovitch, G., Reis, J., Tur, E., Sprecher, E., Yarnitsky, D., Boner, G., 1995. Sweat secretion, stratum corneum hydration, small nerve function and pruritus in patients with advanced chronic renal failure. Br. J. Dermatol. 133 (4), 561–564. Yosipovitch, G., Yarnitsky, D., Mermelstein, V. et al., 1995. Paradoxical heat sensation in uremic polyneuropathy. Muscle Nerve 18 (7), 768– 771.

Young, M.J., Boulton, A.J.M., Macleod, A.F., Williams, D.R.R., Sonksen, P.H., 1993. A multicenter study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia 36, 150–154. Ziegler, D., Mayer, P., Gries, F.A., 1988. Evaluation of thermal, pain, and vibration sensation thresholds in newly diagnosed type 1 diabetic patients. J. Neurol. Neurosurg. Psychiatry 51 (11), 1420–1424. Ziegler, D., Mayer, P., Wiefels, K., Gries, F.A., 1988. Assessment of small and large fibre function in longterm type 1 (insulin-dependent) diabetic patients with and without painful neuropathy. Pain 34 (1), 1–10.