ASSESSMENT OF SYMPTOMATIC DIABETIC PATIENTS WITH NORMAL NERVE CONDUCTION STUDIES: UTILITY OF CUTANEOUS SILENT PERIODS AND AUTONOMIC

TESTS
PINAR KAHRAMAN KOYTAK, MD, BARIS ISAK, MD, DENIZ BORUCU, MD, KAYIHAN ULUC, MD, TULIN TANRIDAG, MD, and ONDER US, MD Department of Neurology, Marmara University Hospital, Tophanelioglu Cad. 13/15, Istanbul, Turkey Accepted 4 August 2010 ABSTRACT: Established electrophysiological methods have limited clinical utility in the diagnosis of small-fiber neuropathy (SFN). In this study, diabetic patients with clinically diagnosed SFN were evaluated with autonomic tests and cutaneous silent periods (CSPs). Thirty-one diabetic patients with clinically suspected SFN and normal nerve conduction studies were compared with 30 controls. In the upper extremities (UE), the CSP parameters did not differ statistically between the patient and control groups, whereas, in the lower extremities (LE), patients had prolonged CSP latencies (P 0.018) and shortened CSP durations (P < 0.001). The sensitivity of the CSP duration was 32.6%, and the specificity was 96.7%. The expiration-to-inspiration ratios and amplitudes of the sympathetic skin responses in the lower extremities were also reduced. Our findings indicate that the diagnostic utility of CSPs was higher than that of the autonomic tests to support the clinically suspected diagnosis of SFN.
Muscle Nerve 43: 317323, 2011

Small-ber neuropathy (SFN) can be dened as sensory polyneuropathy that predominantly affects small-diameter, thinly myelinated A-delta and unmyelinated C bers.13 Symptoms of SFN can include burning pain affecting the feet, often with allodynia and sometimes with erythromelalgia (red hot and painful skin). Neurologic examination is either normal, or it can show only decreased pinprick and temperature sensation in the distal extremities. Nerve conduction studies (NCS), which reect large-ber function, are typically normal.15 SFN becomes evident during the early phases of glycemic dysregulation.6,7 A frequent cause of SFN is diabetes mellitus.2,8 Although distal symmetric polyneuropathy is the most common type of diabetic neropathy, small bers are often involved early in diabetes, and symptoms related to their dysfunction usually dominate the clinical presentation.2,5
Abbreviations: APB, abductor pollicis brevis muscle; ASP, Autonomic Symptom Profile; CMAP, compound muscle action potential; CSP, cutaneous silent period; DIP, distal interphalangeal; DSP, distal sensory polyneuropathy; E/I ratio, expiration-to-inspiration ratio; EMG, electromyography; HRV, heart rate variability; LE, lower extremities; MN, motor neuron; MP, medial plantar; NCS, nerve conduction studies; NSP, Neuropathy Symptom Profile; QSART, quantitative sudomotor axon reflex test; SFN, small-fiber neuropathy; SNAP, sensory nerve action potential; SP, superficial peroneal; SSR, sympathetic skin response; SU, sural; UE, upper extremities Key words: autonomic tests, cutaneous silent period duration, diabetes mellitus, interneuron, small-fiber neuropathy Correspondence to: P. K. Koytak; e-mail: pinarkahraman@yahoo.com
C V 2011 Wiley Periodicals, Inc.

With regard to the clinical importance and relatively high prevalence of SFN, several methods have been applied to assess small-ber function. These methods include quantitative sensory testing,1,5,8,9 tests of sudomotor function,10,11 cardiovagal autonomic testing,4,12 laser evoked potentials,9,13 and skin biopsy.810,14 Unfortunately, most of these methods have limited clinical utility, because they require invasive or time-consuming procedures or specialized, expensive equipment. Autonomic tests that evaluate sympathetic (i.e., sympathetic skin response, or SSR) and parasympathetic functions (i.e., heart rate variability to different provocative maneuvers) are technically easy tests that evaluate the small-ber network.1517 Although they are considered to have lower specicity and sensitivity, they have an advantage of high reproducibility with conventional electromyography (EMG). Another easily applied and readily available electrophysiological method in the evaluation of SFN is the cutaneous silent period (CSP), which consists of a brief suppression of voluntary contraction after strong stimulation of a cutaneous nerve.18 There is signicant evidence that thinly myelinated high-threshold afferents are the essential components of the afferent limb of this nociceptive spinal reex. Normal CSPs have been reported in patients with large-ber neuropathies,1921 who lack sensory nerve action potentials and somatosensory evoked potentials. The CSP is an easy method that has been examined in a number of peripheral neuropathies with small-ber involvement, such as Fabry disease,22 hereditary sensory and autonomic neuropathy,23 human immunodeciency virus (HIV)-related neuropathy,24 and restless leg syndrome.25 The aim of this study was to evaluate the CSP parameters (i.e., latency and duration) and autonomic tests (i.e., SSRs and heart rate variability to deep breathing) in symptomatic diabetic patients with clinically dened distal SFN and normal NCS. In this study we evaluated 31 consecutive diabetic patients (median age 51.9 6 7.0 years) with a clinically suspected diagnosis of SFN and normal NCS.
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Published online 15 February 2011 in Wiley (wileyonlinelibrary.com). DOI 10.1002/mus.21877

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Normative values for CSP and other NCS parameters were obtained from 30 control subjects (median age 49.8 6 7.6 years) without risk factors for neuropathy or abnormalities in their neurological examination.
Controls. Clinical Evaluation. Criteria for the diagnosis of SFN were those of Stewart et al.4 Thus, diabetic patients with the predominant symptom of dysesthesias and either decreased pain and temperature sensation or normal neurologic examination were included. Patients with diminished or absent ankle tendon reexes (with other deep tendon reexes intact) or vibration impairment only at the toes were also included.4,12 Exclusion criteria were: (1) proprioception loss or muscle weakness; (2) any disease other than diabetes that could cause peripheral and/or autonomic neuropathy; (3) presence of radiculopathy or plexopathy; (4) any disease of the central nervous system with pyramidal tract involvement; or (5) skin disorders in the hands or feet that would interfere with CSP and SSR recordings. All patients were fully investigated with routine physical, neurological, and autonomic examinations after being evaluated with the Neuropathy Symptom Prole (NSP) and Autonomic Symptom Prole (ASP).26,27 Vibration sense was assessed by applying a vibrating 128-Hz tuning fork to the dorsum of the hallux and distal interphalangeal joint of the hand (DIP), respectively. The vibration had to be perceived for at least 8 seconds for the hallux and 15 seconds for the DIP. Fine touch was accepted to be normal if a 10-g monolament was felt in least 9 of 10 instances when it was applied to the dorsum of the foot and dorsum of the hand. The study protocol was in accordance with the Helsinki Declaration on Human Rights and was approved by the local ethics committee. All patients and controls gave written informed consent to participate in the study. Electrophysiological Evaluation. The abnormal parameters for electrophysiological evaluation were those that exceeded the range of normal values, as dened by the mean 6 2 standard deviations of amplitudes, conduction velocities, and latencies obtained from the control subjects. Any patient with an NCS parameter that exceeded the limits of 62 SD in at least one nerve was excluded. Nerve Conduction Studies. All electrophysiological data were recorded using an electromyographic (EMG) device (Medelec Synergy EMG; Oxford Instruments Medical, UK). Conventional surface electrode techniques were used for the NCS. Adding uncommon nerves such as medial plantar and/or dorsal sural has been shown to increase the sensitivity of the NCS to diagnose a distal sen318 CSPs and Autonomic Tests in Neuropathy

sory polyneuropathy (DSP).28,29 In all patients and controls, motor conduction was studied in bilateral posterior tibial and common peroneal nerves, and sensory conduction was studied in bilateral sural (SU), supercial peroneal (SP), and medial plantar (MP) nerves. In the upper extremities, median and ulnar motor and sensory, and radial sensory nerve conductions were studied unilaterally. In subjects with carpal tunnel syndrome, the contralateral extremity was evaluated. Except for the MP nerve, all sensory nerves were studied antidromically. Amplitudes, latencies, and nerve conduction velocity parameters were determined for motor and sensory nerves. The latency of the sensory nerve action potential (SNAP) was measured to the onset of the rst negative deection, and it was used to calculate the conduction velocity. The amplitudes of the SNAP and compound muscle action potential (CMAP) were measured from baseline to the peak of the negative deection of the potential. Filter settings were 5 Hz to 10 kHz for motor studies and 20 Hz to 2 kHz for sensory studies. F-Waves. Minimal F-wave latencies and persistence were recorded from the posterior tibial (abductor hallucis longus), peroneal (extensor digitorum brevis muscle), and ulnar (adductor digiti minimi muscle) nerves. Subjects were asked to relax, and no facilitation technique was used. Twenty supramaximal stimuli were applied at a frequency of 1 Hz. Filter settings were 2 Hz to 3 kHz, sensitivity was 100 lV/division, and total sweep time was 50 ms for upper extremities (UE) and 100 ms for lower extremities (LE). Heart Rate Variability to Deep Breathing (Expiration-to-Inspiration Ratio). The expiration-to-inspiration (E/I) ratio has been suggested to be sufcient for evaluation of cardiac autonomic neuropathy.30 All subjects were asked to avoid excessive physical exercise, ingestion of drinks with caffeine, and to stop taking anticholinergic, sympathomimetic medications, or a- or b-blocker drugs for 24 hours prior to testing. Two stainless-steel disk electrodes were placed on the dorsum of the hands, one as an active electrode and the other as the reference. Filters were set at 20100 Hz, sensitivity was 100 lV, and the sweep speed was 2 s. Subjects were asked to take eight consecutive deep breaths, each with 5 s of inspiration and 5 s of expiration, while QRS complexes were recorded. After a 5-min rest, the procedure was repeated. The longest RR interval measured on the oscilloscope was divided by the shortest to obtain the E/I ratio. Sympathetic Skin Responses. The room temperature was stabilized at 23 C, and the skin temperature of the individuals was stabilized at 32 C. Filters were set at 0.2100 Hz, sensitivity was 500 lV,
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FIGURE 1. CSP recordings from APB muscles of a control subject (A) and a patient (B). CSP recordings from TA muscles of a control (C) and a patient (D). For diabetic patients, the cutaneous silent period (CSP) latency was prolonged and CSP duration was shortened in tibialis anterior (TA) recordings when compared with controls. CSP latency and duration in abductor pollicis brevis (APB) recordings did not show a significant difference between patients and controls.

and the sweep speed was 10 s. Six-millimeter stainless-steel disk electrodes were used for recordings. Recording electrodes were placed on palmar and dorsal surfaces of both hands and plantar and dorsal surfaces of both feet. Electrodes on palmar and plantar surfaces were the active electrode, and electrodes on the dorsal surfaces were the reference electrode. For the palmar SSRs, electrical stimuli were applied to the left median nerve at the wrist and for the plantar SSRs the left posterior tibial nerve was stimulated behind the medial malleolus. Stimulation intensity was 25 mA, and the duration was 0.2 ms. Stimuli were given randomly at a minimum of 3060-s intervals to avoid habituation. The latency was dened as the interval from the stimulus artifact to the rst deection from baseline. The amplitude was measured from the beginning of the negative deection to the highest peak of the negative potential.15 Cutaneous Silent Period Evaluation. The CSP was recorded from left upper and lower extremities. Filters were set at 50-Hz to 5-kHz, sweep speed was 250 ms, and sensitivity was 100 lV. The CSPs of the UE were evoked by using a bar stimulator xed on the index nger, and were recorded using a bar electrode over the contracting abductor pollicis brevis (APB) muscle. During steady submaximal (50% of the maximal contraction) thumb abduction, 10 consecutive painful electrical stimuli of 25-mA intensity and 1-ms duration were applied to the index nger. EMG activity
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was displayed on the oscilloscope screen and also played over a loudspeaker to provide visual and auditory feedback to the subject and examiner, in order to monitor the steadiness of contraction. The CSPs of the LE were obtained in a similar manner, with the recording electrode over the belly of the tibialis anterior muscle and the stimulating electrode behind the lateral malleolus. During steady submaximal dorsiexion, the sural nerve was stimulated with the same intensity and duration as in the UE. To eliminate the inuence of a decreased number of motor units due to entrapment neuropathy, CSPs were recorded from the contralateral LE in the patients with a peroneal CMAP amplitude of <2 mV. The individual traces of CSPs were superimposed on the monitor display. The beginning and end of the CSPs were identied by visual inspection of the abrupt cessation of the EMG activity and its return in the superimposed traces. Although the beginning was measured as CSP latency, the time interval between the beginning and the end-point was dened as the CSP duration (Fig. 1). We evaluated the latency and duration of the CSP because these variables are less dependent on the background of the contraction.
Statistics. Statistical analysis was performed using SPSS for Windows, version 11.5 (SPSS, Inc., Chicago, Illinois). Data are expressed as mean 6 MUSCLE & NERVE March 2011 319

Table 1A. Demographics of patients and control subjects. Demographic data Female/male Age (years) Height (cm) Weight (kg) Body mass index (kg/m2) Patients 24/7 51.9 6 7.0 160.0 6 6.4 74.2 6 12.0 28.9 6 4.4 Controls 23/7 49.8 6 7.6 163.7 6 8.4 73.6 6 13.8 27.4 6 4.5 P 0.944 0.267 0.099 0.866 0.188

standard deviation, unless stated otherwise. Normal distributions of the data were determined by the ShapiroWilk normality test. Depending on the distribution of data, either raw data or logarithmic transformations were used. Comparison between two groups was performed by Students t-test or MannWhitney U-test. Categorical variables were compared using the chi-square test. For correlation analysis, Pearsons and Spearmans rank correlation coefcients were used. The statistical signicance limit was accepted at P < 0.05.
RESULTS Demographics. The mean age of patients was 51.9 6 7.0 years and that of the control subjects was 49.8 6 7.6 years. There were no age or gender differences between groups. The height and body mass indices of patients and controls did not differ (Table 1A). Clinical Characteristics. One patient had type 1 diabetes mellitus, and all others were type 2. The mean duration of diabetes was 68.2 months (range 1216 months), and mean glycated hemoglobin was 6.7 6 0.7% in the patient group. Paresthesias and/or dysesthesias were the chief complaints in all patients. The mean duration of neuropathic symptoms was 25.1 months (range 184 months). Neurological examination revealed impaired pain and temperature sensation in 15 patients (48.4%). Two patients (6.5%) had impaired vibration sensation at the toes, but intact vibration sensation at the ankles. Deep tendon reexes were elicited in all patients, but ankle reexes were diminished in 6 patients (19.4%). None of the patients had proprioceptive or motor decits. The clinical characteristics of the patients are summarized in Table 1B. Many patients with predominantly small-ber neuropathy have mild, often subclinical large-ber involvement; a practical working denition allows the presence of mild large-ber dysfunction.4 Therefore, we did not exclude the patients with distally located, mild, subclinical sensory ndings related to myelinated sensory axons. There is no consensus in the literature regarding the amount 320 CSPs and Autonomic Tests in Neuropathy

of large-ber dysfunction that can coexist and still allow the diagnosis of small-ber neuropathy. The NSP results indicate that the most common symptoms were tingling, cramps, numbness, and burning in 24 (77.4%), 20 (64.5%), 16 (51.6%), and 16 (51.6%) patients, respectively. Twenty-nine of 31 patients (94.5%) reported at least one autonomic symptom on the ASP. Most autonomic symptoms were mild; orthostatic dizziness (67.7%), postprandial (45.1%), vasomotor (38.7%), and urinary (38.7%) symptoms were the most prominent.
Nerve Conduction Studies. NCS and F Waves. All patients enrolled in the study had normal NCS compared with the normative data obtained from controls. Patients and control subjects had no signicant differences in motor NCS, sensory NCS, or F-wave parameters (P > 0.05). Heart Rate Variability to Deep Breathing (E/I Ratio). The mean E/I ratio of patients (1.25 6 0.11) was signicantly lower than that of controls (1.35 6 0.17) (P 0.047). When the normal limits were calculated from the logarithmically transformed data of controls, only 2 patients (6.5%) were found to have abnormal heart rate variability (HRV) (Table 2). Sympathetic Skin Responses. SSRs were elicited in all subjects. The SSR latencies were prolonged in patients compared with controls, but the difference was not statistically signicant. There was no signicant difference in palmar SSR amplitudes between groups, whereas the plantar SSR amplitudes were signicantly lower in patients than in the control group (Table 2). It is notable, however, that only 2 patients had abnormal SSR amplitudes by the criterion of <2 standard deviations under the mean of normal controls. Thus, this abnormality dened abnormality in only 2 patients. Cutaneous Silent Period. In the UE, the latencies and durations of the cutaneous silent periods did not differ signicantly between patients and controls (P > 0.05). However, patients had signicantly prolonged CSP latencies (P 0.018) and

Table 1B. Clinical characteristics of the patients. n (%) Insulin Oral antidiabetic drugs Family history of diabetes Decreased pain and temperature sensation Impaired proprioception Impaired vibration sensation Diminished ankle reflex Absent ankle reflex Motor deficit MUSCLE & NERVE 7 21 19 15 0 2 6 0 0 (22.6%) (67.7%) (61.3%) (48.4%) (0%) (6.5%) (19.4%) (0%) (0%)

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Table 2. Expiration-to-inspiration ratios and the sympathetic skin response parameters in patients and control subjects. Autonomic parameters E/I ratio UE SSR latency (ms) UE SSR amplitude (mV) LE SSR latency (ms) LE SSR amplitude (mV) Patients (mean 6 SD) 1.25 1.40 2.85 2.17 1.14 6 6 6 6 6 0.11 0.11 1.26 0.21 0.53 Controls (mean 6 SD) 1.35 1.36 2.93 2.10 1.62 6 6 6 6 6 0,17 0.14 1.23 0.22 0.74 P 0.047 0.192 0.799 0.171 0.005

E/I, expiration-to-inspiration ratio; SSR, sympathetic skin response; UE, upper extremities; LE, lower extremities.

shortened CSP durations (P < 0.001) in the LE, when compared with controls (Table 3). The upper limit of CSP latency and lower limit of CSP duration were found to be 115.9 ms and 31.5 ms, respectively, on the basis of the calculation of limits in control subjects. According to these values, 4 (12.9%) patients had abnormal CSP latency and 10 (32.3%) patients had abnormal CSP duration. Therefore, the sensitivity of the CSP duration in the LE was 32.3%, and the specicity was 96.7% for dening diabetic patients with small-ber neuropathy. Patients were further divided into two subgroups (by means of CSP durations shorter and longer than 31.5 ms) for evaluation on the basis of differences in clinical characteristics (i.e., demographics and neurological examination ndings) and other electrophysiological ndings (i.e., sensory and motor NCS, F-wave parameters, and autonomic tests). Also, correlation analyses were used to nd any possible association between the CSP parameters and the autonomic function tests. There was no difference between the subgroups and no correlation between the CSP parameters and the SSR latencies, SSR amplitudes, and E/I ratios.
DISCUSSION

The primary nding of this study is that the CSP and autonomic parameters are affected in the LE of diabetic patients with signs and symptoms of distal small-ber polyneuropathy but normal conventional NCS. The diagnostic utility of the CSP was superior to the autonomic tests in these patients to conrm the clinically suspected diagnosis of distal small-ber polyneuropathy. In the UE, there was no signicant difference in CSP parameters between patient and control

groups, whereas patients had signicantly prolonged CSP latencies and shortened CSP durations in the LE when compared with controls. The E/I ratios and the amplitudes of SSR in the LE were also signicantly lower in patients than in controls, but they were insufcient to dene individual abnormality. Diabetic SFN is difcult to demonstrate clinically because of the lack of objective methods to conrm the clinically suspected diagnosis. Complaints and neurological examination ndings still constitute the mainstay of the SFN diagnosis. However, as routine NCS can only demonstrate largeber function, a variety of methods have been investigated to document small-ber dysfunction.4,9,11,12,14 In an evidence-based review published in 2009,10 specic tests, such as the quantitative sudomotor axon reex test (QSART), were found to be valuable in documenting small-ber loss with a high degree of sensitivity, making the test useful to conrm the diagnosis of small-ber polyneuropathy (Level C). Also, skin biopsy was found to be very useful in determining intraepidermal nerve ber density and documenting smallber loss (Level C).10 In addition, laser Doppler are31 and corneal confocal microscopy32,33 are relatively novel techniques that can detect early small-ber damage noninvasively. Studies have shown that corneal confocal microscopy is highly informative to quantify small-ber changes and stratify the severity of somatic neuropathy in the early phases of glycemic dysregulation.32 However, these methods cannot yet be applied in most medical centers due to the lack of specialized equipment and staff. As a result, simpler methods that utilize standard EMG equipment, which is readily available in most neurology clinics, would allow

Table 3. Comparison of the CSP parameters. CSP parameters UE CSP latency (ms) UE CSP duration (ms) LE CSP latency (ms) LE CSP duration (ms) Patients (mean 6 SD) 67.24 57.01 101.58 39.26 6 6 6 6 12.71 11.31 14.52 12.40 Controls (mean 6 SD) 61.39 59.33 93.46 62.32 6 6 6 6 10.92 7.28 11.24 15.41 P 0.059 0.347 0.018 0.001

CSP, cutaneous silent period; UE, upper extremities; LE, lower extremities.

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identication and early intervention in these patients. Besides distal somatic nerves, autonomic bers are also affected in SFN. Autonomic testing is suggested in distal SFN (Level C).10 Novak et al. investigated the degree and severity of autonomic impairment in patients with painful feet, and reported that cholinergic and skin vasomotor bers were preferentially involved, sparing systemic adrenergic bers.34 In another study, it was proposed that HRV and SSR be used in combination in the assessment of autonomic function in peripheral neuropathies.17 In our study, these two autonomic function tests were applied to demonstrate small-ber dysfunction. HRV to deep breathing is easy to perform and is a reliable test of cardiovagal function.10,15 It has been reported to detect the presence of diabetic polyneuropathy with nearly the same sensitivity as NCS.35 However, its sensitivity in detection of pure SFN shows great variability on the basis of different protocols and calculations to quantify HRV. The E/I ratio is one of the simplest and most commonly used calculations.16 In our study, the mean of E/I ratio in diabetic patients with pure SFN was found to be signicantly lower when compared with control subjects. However, it was not sensitive enough to determine abnormality in patients. The SSR is a simple test used to assess peripheral sympathetic cholinergic (sudomotor) functions.15 Levy and colleagues evaluated SSR parameters in diabetic patients and reported SSR as an objective, quantitative, and reproducible test in diabetic polyneuropathy.36 In our study, the SSR parameters were signicantly reduced in the LE, but they were not sufcient to distinguish patients from controls. The relatively lower sensitivity of autonomic tests in our study could be attributed to the small sample size of the patients. Among the electrophysiological parameters assessed in this study, the most diagnostic was the CSP. It is a spinal inhibitory reex characterized by transient cessation of voluntary EMG activity after painful stimulation of a cutaneous sensory nerve.18,19 The afferent limb of the CSP is considered to be mediated mostly by small-diameter slowly conducting A-delta bers (and possibly, to a lesser extent, large bers).18 Although the CSP can be obtained with high reproducibility, its complex pathway with interference of peripheral and supraspinal structures,3740 prolongation in several entrapment neuropathies,38,39 or dissociation of the data yielded with the advanced techniques, such as laser evoked potentials,13 has made clinicians reluctant to use it. The reduction of CSP duration despite the relatively normal sensory afferent branch (due to the
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normal autonomic tests and sensory NCS) and the normal efferent branch (normal motor NCS and F-waves with full persistence) made us consider that the responsible site for deterioration in CSP parameters should also be localized at the spinal level, possibly at the interneuron level for the early phase of diabetes. The oligo- or polysynaptic interneuron segment serves not only as a bridge between the sensory afferent bers and alpha motor neurons (MNs), but also as a modulator for inhibition of MNs.40 Deterioration of conduction would delay silencing of MNs (i.e., prolonged latency of CSP) and disinhibition of MNs would allow recruitment in response to corticomotoneuronal drive (i.e., reduction in duration of CSP). Dysfunction of inhibition of the interneurons that are responsible for silencing of MNs matches totally with the model that was proposed by Leis and colleagues.40 Prolongation of CSP duration in peripheral entrapment syndromes was attributed to preservation of A-delta bers, probably due to their less vulnerable small diameters or oversensitization.38,39 However, those hypothetical mechanisms have not been proven. In earlier phases of the neuropathic process, prolongation of CSP duration could be attributed to involvement of other interneuronal networks in the spinal cord. Hence, we suggest that CSP parameters should be evaluated in patients in earlier phases of glycemic intolerance, particularly impaired glucose tolerance or impaired fasting glucose. The LE predominance for deterioration in CSP parameters could be due to preferential involvement of distal sensory nerves in the LE in the early stages of polyneuropathies.41 The sensitivity and specity of CSP duration in the LE of our patients were comparable even with results of skin biopsy, which is considered to have high diagnostic accuracy for SFN.10,42 Herrmann and colleagues assessed the MP SNAPs and skin biopsy in patients with suspected distal sensory neuropathy but normal NCS. Similar to our ndings for CSP sensitivity, skin biopsy was unequivocally abnormal in almost one third of the patients with normal MP SNAPs in subgroup analyses of patients.42 There are several weaknesses in our study. First, correlation of results with advanced techniques, such as skin biopsy and laser evoked potentials, or advanced autonomic tests, such as power spectral analysis of heart rate or QSART, would have added more sensitivity. The relatively small sample size was another limitation of this study. In conclusion, the CSP seems to be promising in the assessment of early diabetic small-ber neuropathy, and therefore it may be useful for routine electrophysiological assessment. The CSP is an
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easy, reproducible, and noninvasive electrophysiological technique. Although painful stimuli are required to evoke the CSP, it is well tolerated. The evaluation of CSP parameters in the lower extremities may make time-consuming and troublesome procedures of advanced techniques, such as skin biopsy, unnecessary and allow clinicians to detect polyneuropathy in patients with normal NCS in the early phases of glucose intolerance. Despite its advantages, validation via further comparison with existing autonomic ancillary tests and development of clearer normal values are still required. Also, involvement of the interneuronal network in the spinal cord should be considered for further studies in the early stages of polyneuropathy.
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CSPs and Autonomic Tests in Neuropathy

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