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RESEARCH PAPER
Year : 2020  |  Volume : 37  |  Issue : 1  |  Page : 4-10

Evaluation of the presence of neuropathy and pruritus in predialysis patients


1 Neurology Clinic, Tunceli Public Hospital, Tunceli, Turkey
2 Neurology Clinic, İstanbul Training and Research Hospital, İstanbul, Turkey
3 Nephrology Clinic, İstanbul Training and Research Hospital, İstanbul, Turkey

Date of Submission19-Jun-2019
Date of Decision10-Oct-2019
Date of Acceptance22-Oct-2019
Date of Web Publication8-May-2020

Correspondence Address:
Cansu Soylemez
Neurology Clinic, Tunceli Public Hospital, Tunceli
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2636-865X.283924

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  Abstract 


Objective: Neuropathy is seen in approximately 70% of patients in the predialysis stage; it is more common in individuals with pruritus, which may be an indicator of neuropathy. The aim of this study was to evaluate the presence of neuropathy and pruritus in the predialysis stage. Methods: The study included 60 patients in the predialysis stage and 30 volunteer controls. Neuropathic symptoms and severity and frequency of itching were recorded. The polyneuropathy (PNP) protocol and sympathetic skin responses (SSRs) were examined. Results: Electromyographic PNP was detected in 28.3% of the patients and pruritus in 36.7%. There was no significant difference in terms of neuropathy and SSR between the groups with and without pruritus (P > 0.05). Body mass index (BMI,P < 0.05) and uric acid levels (P = 0.022) were higher in the group with pruritus. The group in the predialysis stage was divided into two groups according to the stages. There was no difference between the groups in terms of neuropathy and pruritus (P > 0.05), whereas the amplitude and velocity of the median nerve, amplitude and velocity of the tibial nerve, amplitude of the sural nerve, and velocity of the peroneal nerve motor were found to be higher in the control group than in the two groups in the predialysis stage. Furthermore, a prolongation of the distal latency median motor nerve was found in two groups in the predialysis stage compared with the control group (P > 0.05). There was no significant difference between the two groups in terms of the presence of neuropathic symptoms and pruritus (P > 0.05). Conclusion: More than one-third (36.7%) of the patients had pruritus. Increased BMI and uric acid levels showed that it could be important to evaluate the patients in the predialysis stage.

Keywords: Chronic renal failure, neuropathy, predialysis, pruritus


How to cite this article:
Soylemez C, Emre U, Köse S, Tekesin A. Evaluation of the presence of neuropathy and pruritus in predialysis patients. Neurol Sci Neurophysiol 2020;37:4-10

How to cite this URL:
Soylemez C, Emre U, Köse S, Tekesin A. Evaluation of the presence of neuropathy and pruritus in predialysis patients. Neurol Sci Neurophysiol [serial online] 2020 [cited 2020 Oct 20];37:4-10. Available from: http://www.nsnjournal.org/text.asp?2020/37/1/4/283924




  Introduction Top


Chronic renal failure (CRF) is a significant health problem in developed and developing countries and causes a decrease in the quality of life worldwide. It is known that patients with CRF have an increased risk of morbidity due to numerous complications associated with the disease.[1] Peripheral neuropathy (uremic neuropathy) is the most common neurologic complication, affecting 90% of patients undergoing dialysis. Studies have reported that neuropathy is significant in 70% of patients in the predialysis stage.[1],[2]

One of the most important problems affecting the daily life of patients with end-stage kidney disease is pruritus caused by uremia. The pathophysiology of uremic pruritus is still unknown, but its etiology is thought to involve neuropathy.[3] Pruritus in CRF may be a sign of peripheral neuropathy. Neuropathy, a common finding in patients with uremia, changes the perception of peripheral stimuli and creates a sense of itchiness with stimuli that do not cause pruritus under normal conditions.[4] Similarly, the positive results of pregabalin and gabapentin used for the treatment of neuropathic pain in the treatment of pruritus emphasize the importance of neuropathy in the pathophysiology of pruritus.[3]

Although there are many studies on pruritus conducted with patients receiving dialysis treatment, there are few studies on pruritus conducted with patients in the predialysis stage. Taking this as a starting point, the present study aimed to evaluate the presence of neuropathy in patients in the predialysis stage through clinical and electrophysiologic examinations and to determine the frequency of pruritus and its related factors.


  Methods Top


The study included 60 patients aged 30–75 years who were not diagnosed as having neuropathy due to CRF by the nephrology outpatient clinic and who were not on neuropathy pain treatment drugs and 30 volunteer controls. The exclusion criteria were as follows: Vitamin B12 deficiency, presence of a hypothyroid, diagnosis of hereditary neuropathy, receiving treatment for cancer, and thus being on drugs that might cause neuropathy and dermatologic disease history in the evaluation of pruritus. All patients underwent detailed neurologic examinations. Age, sex, body mass index (BMI), disease duration, disease stage, and medications were noted. Information was received regarding hypertension (HT), diabetes mellitus (DM), atherosclerotic heart disease (ASHD), rheumatologic disease history, and (if any) additional diseases. Laboratory examinations and glomerular filtration rate (eGFR [chronic kidney disease (CKD)-EPI]), which were routinely performed during admission to the nephrology outpatient clinic, were recorded. The neuropathy symptom score (NSS)[5] was used to obtain data about neuropathy, a visual analog scale (VAS)[6] was used to question the severity of pruritus in patients with pruritus, and the modified itch severity scale (ISS)[7] was used to learn about the charcteristics of pruritus.

All electrophysiologic studies were performed using a Medelec Synergy electromyography (EMG) device. In the polyneuropathy (PNP) protocol, the median and ulnar (sensory and motor) nerves in the left upper extremity, the tibial (motor) and sural (sensory) nerves in the right lower extremity, and the peroneal (motor) nerve in the left lower extremity were examined. Distal motor latencies, sensory and motor conduction velocities, and compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes of all nerves were recorded. To obtain data regarding sensory nerve conduction, the median and ulnar nerves were stimulated from the phalanx II and V, respectively, using the orthodromic technique. The recording electrode was inserted at the wrist in accordance with both nerve traces. To obtain data regarding sural sensory conduction, the recording was performed at the level of the external malleolus; approximately 10–12 cm proximal of the malleolus was stimulated. To obtain data regarding the motor nerve conduction in the upper extremity, stimulation was performed from approximately 7 cm proximal of the recording electrode and the antecubital region for the median nerve, as well as approximately 7 cm proximal of the recording electrode and the elbow alignment for the ulnar nerve.

The sympathetic skin response (SSR) was studied in both hands. The active electrode was placed in the palm, the reference electrode on the back of the hand, and the grounding electrode in the proximal portion of the recording electrode. Electrical stimulation of 0.1 ms and 10–30 mA current was given from the wrist, from the stimulus area of the median nerve. At least three responses were recorded. The SSR was noted as present or absent.

Our study was approved by the İstanbul Training and Research Hospital Hospital (974/2017), Ethics Committee (dated March 31, 2017, decision number: 974), and written informed consent was obtained from all participants.

Statistical analysis

The SPSS 22.0 program was used for statistical analysis. Mean, standard deviation, lowest median, highest median, frequency, and ratio values were used for descriptive statistics of the data. The distribution of the variables was measured using the Kolmogorov–Simirnov test. The Kruskal–Wallis and Mann–Whitney U-tests were used for quantitative independent data analysis. The Chi-square test was used for the analysis of independent qualitative data. The Fisher's exact test was used when Chi-square test conditions were not met.


  Results Top


Of the 60 patients included in the study, 44 (73.3%) were female and 16 (26.7%) were male. The mean age of the study group was 59.6 ± 10.5 years. Of the 30 volunteers included in the control group, 11 were male (37%) and 19 were female (63%). The mean age of the controls was 50.1 ± 7.4 years. The concomitant diseases were HT (86.7%), DM (36.7%), ASHD (11.7%), and rheumatic diseases (8.3%).

The mean duration of CRF in the patients was 6.7 ± 6.3 years (the most recent being recently diagnosed and the longest being diagnosed 34 years ago). According to the eGFR (CKD-EPI), six patients (10%) were at Stage I, eight patients (13.3%) were at Stage II, 16 patients (26.7%) were at Stage IIIa, 14 patients (23.3%) were at Stage IIIb, 15 patients (25%) were at Stage IV, and one patient (1.7%) was at Stage V.

In the NSS, the mean total NSS (T-NSS) was 1.7 ± 1.5 (range, 0–5). There were no patients with motor symptoms in the NSS evaluation. Forty patients (66.7%) had positive sensory symptoms, 26 (43.3%) had autonomic symptoms, and 17 (28.3%) had negative sensory symptoms.

PNP was found in 17 patients (28.3%), which was sensory type in 76.5% of patients and sensory-motor axonal type in the remaining patients; 58.8% of patients with PNP had diabetes. SSRs were obtained in 53 patients (83.3%) on the right and left hands. Pruritus was observed in 22 (36.7%) patients. The mean VAS score of the patients was 2.0 ± 3.3. The mean score of the modified ISS was 1.6 ± 3.2 (range, 0–16) [Table 1].
Table 1: Electromyography abnormalities and distribution of pruritus findings in patients with predialysis

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No significant difference was found between the groups with and without pruritus in terms of age and sex (P > 0.05). Furthermore, no significant differences were found in terms of the stages of the disease and the concomitant diseases (P < 0.05 and P > 0.05, respectively). BMI (P < 0.05) and uric acid levels (P = 0.022) were significantly higher in the group with pruritus. No significant differences were found between the groups with and without pruritus in terms of T-NSS score, NSS-motor symptoms, NSS-positive sensory symptoms, NSS-negative sensory symptoms, presence of NSS autonomic symptoms, and presence of PNP with T-NSS score (P > 0.05) [Table 2].
Table 2: Neuropathic complaints and electromyography abnormalities with and without itching

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The patients in Stages I, II, and IIIa were classified as Group I, and the patients in Stages IIIb, IV, and V were classified as Group II. Then, both groups were compared with the control group.

The mean age of the volunteers in the control group was lower than the mean age of the patient group (P < 0.05). There was no significant difference between Group I and Group II in terms of mean age (P > 0.05). Similarly, there was no difference in terms of sex distribution among Group I, Group II, and the control group (P > 0.05).

Left median nerve CMAP, left median nerve motor velocity, left median nerve SNAP, right tibial nerve CMAP, right tibial nerve velocity, right sural nerve amplitude, and left peroneal nerve motor velocity were significantly higher in the control group than in Group I and Group II (P < 0.05) [Table 3]. In Group I and Group II, left median nerve motor distal latency was significantly longer than in the control group (P < 0.05).
Table 3: The distribution of electromyography parameters in patient and control groups

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No significant differences were found between Group I and Group II in terms of VAS scores, pruritus rates, and pruritus severity scores (P > 0.05). Similarly, there were no significant differences between the two groups in terms of T-NSS scores, NSS-motor symptoms, NSS-positive sensory symptoms, NSS-negative sensory symptoms, and NSS autonomic symptoms (P > 0.05). No significant correlation was found between the two groups in terms of the presence of PNP [Table 4].
Table 4: Distribution of neuropathic complaints and electromyography abnormalities among patient groups

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  Discussion Top


Peripheral neuropathy in CRF has been reported in 15%–85% of the various studies, and it is a common cause of severe disability.[8] Studies have reported a decrease in sensory and motor nerve conduction velocities and a decrease in sensory response amplitudes in the preclinical period.[9] In our study, EMG analysis showed PNP in 28.3% of the patients. PNP was mostly sensory axonal type (76.5%) and the rest had sensory-motor axonal type. Similar to previous studies, we found a significant difference in some parameters of nerve conduction in our patients compared with the control group. Jasti et al. compared the clinical and electrophysiological parameters of peripheral neuropathy in predialysis patients according to the severity of renal failure, and the prevalence of peripheral neuropathy was found to be higher in the group with severe renal failure. Again, ulnar nerve SNAP, median nerve SNAP, median motor nerve CMAP, and velocity were the parameters that differentiated severe renal failure from mild-to-moderate renal failure.[9] In our study, there was no significant difference in the comparison between stages and an abnormality in nerve conduction compared with the normal population. Left median nerve CMAP, left median nerve motor velocity, left median nerve SNAP, right tibial nerve CMAP, right tibial nerve velocity, right sural nerve amplitude, and left peroneal nerve motor velocity were significantly lower than, and prolongation of the distal latency median motor nerve was found in the two groups compared with the control group in our study. Jasti et al. reported that neuropathy was more frequent in the diabetic group.[9] As is known, DM is one of the most frequent metabolic causes inducing neuropathy. In our study, 58.8% of the patients with neuropathy were diabetic. This was one of the factors limiting the study.

The pathophysiology of pruritus, which is common in patients with CRF and affects daily life negatively, is not clear, just like peripheral neuropathy.[3],[8] Many hypotheses, especially neuropathic hypotheses, have been proposed.[3] A study conducted with 402 patients in the predialysis stage by Solak et al.[10] reported pruritus in 18.9% of patients, and another study conducted with 200 patients receiving both predialysis and hemodialysis treatment by Khanna et al.[11] reported pruritus in 36% of patients. Similar to that finding, in the present study, we found that 36.7% of 60 patients in the predialysis stage had pruritus.

In the literature, the relationship between pruritus and neuropathy is generally compared in patients undergoing dialysis, and it has been found statitiscally significant. To the best of this author's knowledge, no study has been conducted to examine pruritus and neuropathy in patients in the predialysis stage. In the present study, it was found that the frequency of electromyographically evidenced PNP was 27.3% in patients with pruritus and 28.9% in patients without pruritus. We observed no significant statistical difference between pruritus and neuropathy. In their study on pruritus and paresthesia, Zakrzewska-Pniewska and Jedras found a significant relationship.[12] The fact that 72.7% of thee patients with pruritus had a high rate of positive sensory symptoms in the present study may suggest that pruritus is associated with the presence of symptoms, regardless of the presence of neuropathy evidenced by EMG.

The frequency of PNP has been reported in varying rates in the literature. Aggarwal et al.[1] and Krishnan et al.[13] reported higher rates of neuropathy. In both studies, T-NSS scores higher than 2 (although it cannot be displayed electromyographically) were evaluated as symptomatic neuropathy. In our study, the lower neuropathy rate can be linked with the presence of neuropathy only through EMG evaluation. In the present study, 66.7% of the patients had positive sensory symptoms, 43.3% had autonomic symptoms, and 28.3% had negative sensory symptoms. Similarly, in a study conducted with 40 patients receiving hemodialysis treatment, Solak et al. reported that although neuropathic symptoms were present in all patients, 77.5% of the patients showed EMG changes consistent with peripheral neuropathy evidenced by EMG.[3] Besides, the high rates of neuropathic symptoms in patients compared with the frequency of neuropathy may be attributed to small fiber neuropathy, which we could not be detected electromyographically. Sensory symptoms such as hot–cold intolerance, numbness, burning, freezing, and pain, and symptoms of autonomic dysfunction in patients with uremia show that small fiber neuropathy should be considered as a clinical entity in patients with CRF. It has recently been suggested that axonal depolarization in patients with uremia might be induced by a change in the function of the Na/K pump and that the inhibition of the Na/K pump by uremic neurotoxins might induce changes in nerve conduction by membrane depolarization.[1] In the present study, we found that some electrophysiologic parameters were lower in the patient groups compared with the control group. Significant changes in the nerve conduction in some parameters compared with the control group suggest that the processes that cause neuropathy may be related to changes in cellular extensibility at the electrophysiologic level. This draws attention to the importance of electrophysiologic examinations in asymptomatic patients.

In a study conducted by Khanna et al., who compared skin findings in patients receiving hemodialysis treatment and those in the predialysis stage, it was found that pruritus increased with the severity of the disease and was found to be unrelated to the duration of the disease.[11] In the present study, contrary to our expectations, we found no statistically significant differences between Group I and Group II. A similar finding was reported in the study of Solak et al.[10] This suggests that the presence of multiple skin conditions such as xerosis and the presence of multiple etiologies may affect pruritus, regardless of the stages.

Studies on the underlying mechanisms in patients with CRF-associated pruritus have reported different demographic characteristics and laboratory findings. Although several studies have reported a relationship between males and pruritus,[14] most studies observed no significant relationship between pruritus and the patient's age, sex, and type of underlying kidney disease.[15] Many major studies found pruritus to be correlated with chronic diseases, smoking, increased BMI, increased white blood cells, low hemoglobin, and serum albumin levels,[10],[15],[16] whereas some studies found no significant differences in serum creatinine, urea, uric acid, and hematocrit values.[15] In the present study, there was no significant difference in many parameters, but the uric acid level was significantly higher in the group with pruritus.

Prignano et al. reported that pruritus was more severe in overweight patients with psoriasis and linked this with the increase in folds due to weight, increased body temperature, and the possibility that sweating could aggravate pruritus.[17] Most studies conducted with patients with CRF-associated pruritus reported no significant correlation between BMI and pruritus, whereas, in the present study, we found a more pronounced increase in BMI in the group with pruritus. This suggests that the anatomic tendency in overweight patients may cause an increase in pruritus.

In the present study, autonomic symptoms were observed in 40.3% of the patients; this rate was 50% in the group with pruritus. SSR reflects sudomotor activity and is associated with sweat gland activation through the cholinergic system. Cholinergic dysfunction in uremic pruritus may cause SSR abnormalities.[18] Studies with patients receiving dialysis treatment have correlated the abnormality of SSR amplitude with dysautonomia.[12] Considering the frequency of autonomic neuropathy in our study, SSR was taken from most of the patients. Although the absence of SSR is considered pathological, there was no significant correlation between the presence of autonomic symptoms and SSR. We cannot comment on whether there was a change in these parameters because the amplitude and latencies of SSR were not taken into consideration in the present study for technical reasons, which is one of its limitations.

Studies found that the RR interval in patients with uremia was abnormal.[12],[19] The RR interval in addition to erythrocyte sedimentation rate in these patients may provide more objective results in autonomic system evaluations.


  Conclusion Top


Although the presence of neuropathy was not significantly greater in patients in the predialysis stage in our study, the frequent neuropathic symptoms and abnormalities in nerve conduction compared with the normal patient group suggest that small fiber neuropathy or urea levels may be affected at the cellular level. The relationship between pruritus and increased BMI and uric acid level found in 36.7% of the patients may be important in elucidating the possible mechanism of pruritus in patients in the predialysis stage. It may also highlight the positive effects of the prevention of weight gain and low uric acid levels on the quality of life of patients.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.



Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Aggarwal HK, Sood S, Jain D, Kaverappa V, Yadav S Evaluation of spectrum of peripheral neuropathy in predialysis patients with chronic kidney disease. Ren Fail 2013;35:1323-9.  Back to cited text no. 1
    
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Arnold R, Issar T, Krishnan AV, Pussell BA. Neurological complications in chronic kidney disease. M Cardiovasc Dis 2016;5.  Back to cited text no. 2
    
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Solak Y, Bıyık Z, Atalay H, Gaıpov A, Guney F, Turk S, et al. Pregabalin versus gabapentin in the treatment of neuropathic pruritus in maintenance haemodialysis patients Nephrology 2012;17:710-7.  Back to cited text no. 3
    
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Binder A, Koroschetz J, Baron R. Disease mechanisms in neuropathic itch. Nat Clin Pract Neurol 2008;4:329-37.  Back to cited text no. 4
    
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Dyck PJ. Detection, characterization, and staging of polyneuropathy: Assessed in diabetics. Muscle Nerve 1988;11:21-32.  Back to cited text no. 5
    
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Reich A, Heisig M, Phan NQ, Taneda K, Takamori K, Takeuchi S, et al. Visual Analogue Scale: Evaluation of the instrument for the assessment of pruritus. Acta Derm Venereol 2012;92:497-501.  Back to cited text no. 6
    
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Majeski C, Johnson JA, Davison SN, Lauzon CJ. Itch severity scale: A self-report instrument for the measurement of pruritus severity. Br J Dermatol 2007;156:667-73.  Back to cited text no. 7
    
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Gupta P, Gupta R. Severity of chronic kidney disease associated pruritus clinically related to symptomatic pheripheral neuropathy in patients of end stage renal disease on maintenance hemodialysis: Our experience. JK Sci 2016;18:150-4.  Back to cited text no. 8
    
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Jasti DB, Mallipeddi S, Apparao A, Vengamma B, Sivakumar V, Kolli S. A clinical and electrophysiological study of peripheral neuropathies in predialysis chronic kidney disease patients and relation of severity of peripheral neuropathy with degree of renal failure. J Neurosci Rural Pract 2017;8:516-24.  Back to cited text no. 9
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10.
Solak B, Açıkkgöz SB, Sipahi S, Erdem T. Epidemiology and determinants of pruritus in pre-dialysis chronic kidney disease patients. Int Urol Nephrol 2016;48:585-91.  Back to cited text no. 10
    
11.
Khanna D, Singal A, Kalra OP. Comparison of cutaneous manifestations in chronic kidney disease with or without dialysis. Postgrad Med J 2010;86:641-7.  Back to cited text no. 11
    
12.
Zakrzewska-Pniewska B, Jedras M. Is pruritus in chronic uremic patients related to peripheral somatic and autonomic neuropathy? Study by R-R interval variation test (RRIV) and by sympathetic skin response (SSR). Neurophysiol Clin 2001;31:181-93.  Back to cited text no. 12
    
13.
Krishnan AV, Phoon RK, Pussell BA, Charlesworth JA, Bostock H, Kiernan MC, et al. Altered motor nerve excitability in end-stage kidney disease. Brain 2005;28:2164-74.  Back to cited text no. 13
    
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Kimata N, Fuller DS, Saito A, Akizawa T, Fukuhara S, Pisoni RL, et al. Pruritus in hemodialysis patients: Results from the Japanese dialysis outcomes and practice patterns study (JDOPPS). Hemodial Int 2014;18:657-67.  Back to cited text no. 14
    
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Shirazian S, Aina O, Park Y, Chowdhury N, Leger K, Hou L, et al. Chronic kidney disease-associated pruritus: Impact on quality of life and current management challenges. Int J Nephrol Renovasc Dis 2017;10:11-26.  Back to cited text no. 15
    
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Ramakrishnan K, Bond TC, Claxton A, Sood VC, Kootsikas M, Agnese W, et al. Clinical characteristics and outcomes of end-stage renal disease patients with self-reported pruritus symptoms. Int J Nephrol Renovasc Dis 2013;7:1-12.  Back to cited text no. 16
    
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Prignano F, Ricceri F, Pescitelli L, Lotti T. Itch in psoriasis: Epidemiology, clinical aspects and treatment options. Clin Cosmet Investig Dermatol 2009;2:9-13.  Back to cited text no. 17
    
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Polat A, Korkmaz S, Özlece Köse H. Assessment of sympathetic skin response to acne vulgaris. Med Sci 2017;6:668-70.  Back to cited text no. 18
    
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Wang SJ, Liao KK, Liou HH, Lee SS, Tsai CP, Lin KP. Sympathetic skin response and R-R interval variation in chronic uremic patients. Muscle Nerve 1994;17:411-8.  Back to cited text no. 19
    



 
 
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