Neurophysiological evaluation in newly diagnosed Diabetes Mellitus type 1

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1 Cent. Eur. J. Med. 8(4) DOI: /s Central European Journal of Medicine Neurophysiological evaluation in newly diagnosed Diabetes Mellitus type 1 Dragana Matanovic* 1,2, Srdjan Popovic 1,3, Biljana Parapid 4, Ivana Petronic 1,5, Dejan Nikolic 5 Research Article 1 Faculty of Medicine, University of Belgrade, Belgrade, Serbia 2 Clinic for Physical Medicine and Rehabilitation, Clinical Center of Serbia, Belgrade, Serbia 3 Clinic of Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Belgrade, Serbia 4 Cardiology Clinic, Clinical Center of Serbia, Belgrade, Serbia 5 Physical Medicine and Rehabilitation Department, University Children s Hospital, Belgrade, Serbia Received 3 October 2012; Accepted 25 March 2013 Abstract: The aim of the study was to evaluate the effects of hyperglycemia on nerve conduction in patients with newly diagnosed diabetes mellitus type 1, and to investigate the significance of early electrophysiological diagnostics in these patients. The study included 85 newly disclosed patients with type 1 diabetes mellitus, in the first three months after the disease. Nerve conduction velocities (NCV) of further nerves were evaluated: median, peroneal, tibial and sural nerve as well as late responses (F-wave and H-reflex). Metabolic control parameters that were evaluated included: glycemia rate on the day of investigation and HbA1c. All patients had poor metabolic control parameters. We found NCV slowing predominantly in the tibial nerve (in 82.4% of patients). Prolonged F-wave latency was disclosed in 72.9% of patients, while H-reflex was evoked in 27.1% of patients only. The most sensitive parameter in the early neurophysiologic diagnostics was the measurement of F-wave latency. Our study underline the significance of early neurophysiological diagnosis, since hyperglycemia can play an acute role in NCV slowing, despite the absence of clinical symptoms, particularly in the first three months after the diagnosis has been confirmed. Keywords: Neurophysiologic parameters Nerve Conduction Velocity Diabetes Mellitus Polyneuropathy Versita Sp. z o.o 1. Introduction One of the important fields for the study and follow-up of diabetic neuropathy (DN) is subclinical neuropathy that is manifested by the damage of nerve function without clinical signs and symptoms. Recently, the possibility to verifying neuropathic alterations at the time of diabetes mellitus diagnosis, particularly diabetes mellitus type 1 (DM type1) was presented in different studies [1,2]. Previous reports pointed out that acute effects of normalization of blood glucose levels and other metabolic parameters have a direct influence on nerve conduction velocity (NCV), as well as on the nerve structure itself [3]. Hyperglycemia is a significant, but also not the crucial factor, that can lead to blood vessel damage (primarily of capillaries) and hence to the decrease of blood flow in the nerve tissue itself. Studies involving nerve analysis during the biopsy have indicated significant correlation between DN and microvascular abnormalities [4]. Indeed, nerve hypoxia has been mentioned as an important mechanism that could lead to the destruction of the nerve tissue resulting in a decrease of NCV. Most of these studies have been performed on animal models * denikol27@gmail.com 503

2 Neurophysiological evaluation and DM type 1 [5]. In the study by Tesfaye et al. [6], authors have attempted, using fluorescein angiography, to show in vivo the index of blood perfusion of the nerve. They verified a thinned basal membrane on the sural nerve, and occlusion of the epineural arterioles. Pathological changes with various degrees regarding severity can be also found in young diabetics with subclinical forms. Such changes could have a very early onset and therefore it is of great significance to disclose them, using sensitive diagnostic methods, within an appropriate time. This will potentially allow, to a certain degree, to influence these changes by establishing an acute improvement of glycemia and other metabolic parameters. Electrophysiological studies present a non-invasive option and have been previously confirmed as a sensitive method in the evaluation of diabetic polyneuropathies [7]. These methods are more sensitive than known clinical diagnostic tools. Assessment of NCV is a reliable non-invasive method, but histomorphometry of nerve fibers is the most reliable method for the confirmation of neuropathic changes. Veves et al. [8], reported that electrophysiological investigations of lower extremities, particularly in the early stage of DN, are quite reliable, and pointed out their significant correlation with the morphology of nerve fibers [9]. Therefore, the aim of the study was to evaluate the effects of hyperglycemia on nerve conduction in patients with newly diagnosed DM type 1, and to investigate the significance of early electrophysiological diagnostics in these patients. 2. Material and Methods 2.1. Study group The study involved 85 patients with diagnosed DM type 1. There were 57 male and 28 female patients. Mean age of participants was 26.12±2.71 years. They were included in electrophysiological examination within the first three months (70-90 days) after DM type 1 diagnosis. Prior to inclusion in the study, eligible participants were informed about the study protocol and informed consent was obtained. The study was conducted in accordance with the Declaration of Helsinki. Before the electrophysiological examination, presence of subjective neurological findings (numbness and different degrees of paresthesias in legs) as well as clinical neurological findings (different forms of polineuropathies that were diagnosed by Board Certified Neurologist) were assessed as well. All patients were evaluated for metabolic control parameters: glycemia rate on the day of investigation and HbA1c levels. For diagnosis of DM we followed the recommendations of American Diabetes Association and for HbA1c values set to be 6.5% [10]. According to recommendations for DM type 1 definition criteria, further parameters were evaluated: levels of urine C-peptide < 20 μg/day, levels of fasting serum C-peptide < 0.5 μg/ml, or levels of serum C- peptide < 1.0 μg/ml after loading and insulin therapy necessity during one year after established diagnosis [11]. The exclusion criteria were patients with DM type 1, who were not newly diagnosed and patients with other types of neuropathies: B12 vitamin deficiency induced neuropathy, alcoholic, uremic neuropathy and others. Further neurophysiologic parameters were assessed: motor conduction velocity (MCV) for the peroneal, tibial and median nerves, and sensory conduction velocity (SCV) for the sural nerve, as well as late response latency (F-wave and H-reflex in the tibial nerve) Study methods The study was carried out using stimulation technique by percutaneous electrodes and results were recorded by surface electrodes. Patients were placed in supine position and examination was done when patients were relaxed in room temperature between o C. To establish conduction velocity in evaluated nerves, intercatodal distance between two stimulative percutaneous electrodes was divided by the difference value (ms) that was generated by subtracting distal latency from proximal latency. F-waves and H-reflexes were evaluated as supplement parameters, since they provide information about conduction over an entire nerve including proximal portions [12,13]. Although temperature of extremities influence the NCV and amplitude, in particular, lower temperatures decrease NCV and increases amplitude, prior examination, extremities were warmed up to a surface temperature between o C [14] Statistical analysis To present frequencies of subjective neurological findings, neuropathies and subjects with prolonged latencies of evaluated electrodiagnostic parameters we used whole numbers and percents. Mean values with standard deviation (SD) were used to represent metabolic control parameters, as well as prolonged electrodiagnostic parameters that were evaluated. Chi squared test (χ 2 ) was used to assess statistical difference in frequencies between; subjective and clinical (neuropathies) neurological findings, as well difference in frequencies of DTL and MCV between peroneal and tibial nerve and difference in frequencies of MCV between peroneal and sural nerve, as well as between tibial and sural nerve, and 504

3 D. Matanovic et al. prolonged F-wave latency and H-reflex. Student s t test was used to assess presence of statistical difference in glycemic rate values between the time of diagnosis and evaluation time. Statistical significance was set to p< Results Mean duration of illness from the time of diagnosis until neurophysiologic evaluation was 43.13±5.02 days. Body mass index (BMI) of evaluated patients was 20.28±2.6kg/m 2. For all patients insulin therapy was initiated with mean dosage of 0.523±0.02 U/kg/day. Table 1 presents general and metabolic parameters in patients that were included in the treatment. Subjective neurological findings were significantly more frequent than clinical neurological findings in the form of neuropathies (χ 2 =55.51; p<0.01) (Table 1). Sensomotoric neuropathy was more frequent than dominant sensory neuropathy but without statistical significance (p>0.05). Mean glycemia values on the day of the evaluation were 9.09±4.27mmol/l (range 4.2 to 21.5mmol/l). These values of glycemia did not significantly differ from the values at the time of diagnosis (t=1.97; p>0.05) (Table 1). Table 2 shows frequencies of prolonged electrophysiological parameters. There was no significant difference in the frequency of prolonged DTL for peroneal and tibial nerve (χ 2 =3.53; p>0.05), while there was a significant increase in the number of participants with prolonged MCV for tibial nerve compared with those who had prolonged MCV for peroneal nerve (χ 2 =48.32; p<0.01) (Table 3). The MCV of median nerve were within the physiological limits, with mean velocity of 54.43±4.86 m/s (Table 4). In 24/85 (28.2%) patients, we were unable to register sensory conduction velocity (SCV) in the sural nerve. There was a significant increase in participants with prolonged MCV for tibial nerve versus those with prolonged SCV for sural nerve (χ 2 =50.35; p<0.01), while no significant difference in the proportion of prolonged MCV for peroneal nerve and prolonged SCV for sural nerve was noticed (χ 2 =0.03; p>0.05) (Table 3). We found no significant differences in frequencies between genders for tibial and peroneal nerve concerning prolonged DTL and prolonged MCV (Table 5). A similar pattern applies for prolonged SCV of sural nerve regarding frequencies between genders (Table 5). Measuring late response latencies (F-wave and H- reflex) in the tibial nerve indicated that prolonged latency of F-wave was registered in 72.9% of patients, while H-reflex was evoked in only 27.1% of patients (Table 2). Prolonged latency of F-wave was significantly more frequent than H-reflex in DM type 1 patients (χ 2 =35.79; p<0.01). Table 1. Presentation of general and metabolic parameters in evaluated population General parameters N=85 Positive N (%) Subjective neurological findings 73 (85.9) Clinical neurological findings 25 (29.4) Dominant sensory neuropathy 24 (28.2) Sensomotoric neuropathy 35 (41.2) Metabolic parameters Mean values Glycemia (mmol/l) 10.20±2.96 HbA1c (%) 9.04±4.14 Table 2. Distribution of prolonged electrophysiological parameters Electrophysiological parameters Tibial nerve Sural nerve Peroneal nerve Prolonged DTL N (%) 40 (47.1) Prolonged MCV N (%) 70 (82.4) Total Males Females Total Males Females Total Males Females N=85 N=57 N=28 N=85 N=57 N=28 N=85 N=57 N=28 28 (49.1) 46 (80.7) 12 (42.9) 24 (85.7) Prolonged SCV N (%) (28.2) Prolonged F-wave latency (%) (32.9) (29.4) 16 (28.1) 8 (28.7) 62 (72.9) - - H-reflex (%) 23 (27.1) (33.3) 17 (29.8) (32.1) 8 (28.6) DTL-Distal terminal latency; MCV-Motor conductive velocity; SCV-Sensory conduction velocity 505

4 Neurophysiological evaluation and DM type 1 Table 3. Differences in frequencies of patients with prolonged evaluated electrophysiological parameters Electrophysiological parameters χ 2 test values Peroneal/Tibial Nerve Tibial/Sural Nerve Prolonged DTL/Prolonged DTL Prolonged MCV/Prolonged MCV 48.32* - - Prolonged MCV/Prolonged SCV * 0.03 DTL-Distal terminal latency; MCV-Motor conductive velocity; SCV- Sensory conduction velocity; *p<0.01 Peroneal/Sural Nerve Table 4. Mean values of evaluated electrophysiological parameters Electrophysiological parameters Tibial nerve Sural nerve Peroneal nerve Total Total Total N=85 N=85 N=85 Prolonged DTL (Mean value; m/s) Prolonged MCV (Mean value; m/s) Prolonged SCV (Mean value; m/s) 7.76± ± ± ± ± DTL-Distal terminal latency; MCV-Motor conductive velocity; SCV-Sensory conduction velocity Table 5. Statistical interpretation of patients with prolonged evaluated electrophysiological parameters due to the gender χ 2 test values male/female 4. Discussion Sural nerve Peroneal nerve Prolonged DTL N (%) Prolonged MCV N (%) Prolonged SCV N (%) DTL-Distal terminal latency; MCV-Motor conductive velocity; SCV- Sensory conduction velocity Tibial nerve Previously, it was noticed that almost two thirds of patients with DM type 1 develop diabetic neuropathy [4]. Frequent positive subjective neurological complaints in this study, versus clinical neurological findings, indicate the importance of evaluation of possible nerve damage in early stages of disease by NCV. Among evaluated metabolic parameters, we registered elevated mean rates, particularly for HbA1c (9.04±4.14%), which may indicate a prolonged period of subclinical form of diabetes. These findings correlate with significantly increased subjective neurological complaints. It should be noticed that we did not register MCV in one patient, for whom it was suspected that there is an association of the underlying disease and neurologic disorder. From the results of this study, prolonged MCV latencies were significantly frequent for tibial nerve versus MCV latencies for peroneal nerve and SCV latencies for sural nerve, indicating more sensitivity of tibial nerve to the fluctuations of metabolic parameters in patients with DM type 1. Prolonged latency of F-wave was significantly more frequent than onset of H-reflex in patients with DM type 1. Previously it was noticed that the best indicator of neuropathic changes in general is F-wave, particularly its prolonged latency [15]. Such findings correlate with the results from our study indicating that almost three quarters of evaluated patients were with prolonged latency for F-wave. It is assumed as well that it is sufficient to determine minimal F-wave latency, while measuring segmental MCV is not always necessary. Electrophysiological investigation enabled us to register neuropathic changes, mostly of acute character, in 68/85 (80%) of patients. Giving the fact that subjective neurological findings were more frequent than clinical neurological findings, it could be pointed out that our results are in accordance with the data of other authors [16], who have indicated that neurophysiologic parameters are more sensitive than a classical clinical neurological examination. Furthermore, our study showed that the lower extremities were predominantly involved. In the phase of insulin-dependent diabetes disclosure, MCV findings of the median nerve were within the physiological limits. 506

5 D. Matanovic et al. These results are comparable to the previous observations, which stress that hyperglycemia plays a major role in lowering of MCV, particularly in the lower extremities [16-18], while the findings concerning the median nerve are, at this stage, mostly within the physiological limits. Numerous studies documented that there is a correlation between the elevated HbA1c values and late complications [4,19,20], among them neuropathy [4,21]. This type of correlation can also be seen in our study. According to Liu et al., it is more appropriate to make a comparison of glycosylated hemoglobin than glycemic values, because such findings can indicate metabolic regulation over longer periods, regardless of the time of day, patient s activities and food intake [22-26]. HbA1c values can be regarded as one of the best biochemical parameters that correlate with the registered lowered values of MCV [4,27]. Recently it has been shown that polyneuropathy can be registered even in children, including the neuropathy of sural nerve, when diagnosing DM type 1 [28]. Electrophysiological investigations present sensitive, noninvasive procedures in the diagnostics and follow-up of DM complications. In our study, such investigations indicate the possibility of detection of a larger number of patients with neuropathic disorders instead of performing clinical neurological examinations alone. Such diagnostics are significant in the detection of subclinical forms, when changes are still mostly reversible and when a rapid and good metabolic control can still influence the patient s improvement. Additionally, it should be stressed that subjective neurological findings can be utilized to disclose subclinical diabetic neuropathy. 5. Conclusion Our results underline the significance of early neurophysiological diagnosis particularly in the evaluation of newly diagnosed DM type 1 patients. We have shown that hyperglycemia could play, to the certain degree, an acute role in the slowing of NCV despite the absence of clinical symptoms. Therefore, it is necessary to follow the development and course of diabetic neuropathy from the early beginning and over a longer period of time. Such diagnostics should be included into an obligatory patient s check-up. 6. Statement of Conflict of Interest Authors declare no conflict of interest. References [1] Li Z., Hu X., Tang N., Significance of nueroelectrophysiological tests in the early diagnosis of sub-clinical neuropathay with diabetes mellitus, J. Huazhong Univ. Sci. Technolog. Med. Sci., 2006,26, [2] Karsidag S., Morali S., Sargin M., Salman S., Karsidag K., Us O., The electrophysiological findings of subclinical neuropathy in patients with recently diagnosed type 1 diabetes mellitus, Diabetes Res. Clin. Pract., 2005, 67, [3] Riiniama P., Souminen K., Tolonen U., Jantti V., Knip M., Tapanainem P., Peripheral nerve functions in increasingly impaired during puberty in adolescents with type 1 diabetes, Diabetes Care, 2001, 24, [4] Charles M., Soedamah-Muthu S.S., Tesfaye S., Fuller J.H., Arezzo J.C., Chaturvedi N., et al., Low peripheral nerve conduction velocities and amplitudes are strongly related to diabetic microvascular complications in type 1 diabetes: the EURODIAB Prospective Complications Study, Diabetes Care, 2010, 33, [5] Wright R.A., Nukada H., Vascular and metabolic factors in the pathogenesis of experimental diabetic neuropathy in mature rats, Brain, 1994, 117(Pt 6), [6] Tesfaye S., Hariss J., Jakubowski J.J., Mody C., Wilson R.M., Rennie I.G., et al., Impaired blood flow and arterio-venous shunting in human diabetic neuropathy: a novel technique of nerve photography and fluorescein angiography, Diabetologia, 1993, 36, [7] Perkins B.A., Ngo M., Bril V., Symmetry of nerve conduction studies in different stage of diabetic polyneuropathy, Muscle Nerve, 2002, 25, [8] Veves A., Malik R.A., Lye R.H., Masson E.A., Sharma A.K., Schady W., et al., The relationship between sural nerve morphometric findings and measures of peripheral nerve function in mild diabetic neuropathy, Diabetic Medicine, 1991, 8, [9] Malik R.A., Tesfaye S., Thompson S.D., Veves A., Sharma A.K., Boulton A.J., et al., Endoneural localization of microvascular damage in human diabetic neuropathy, Diabetologia, 1993, 36, [10] American Diabetes Association., Diagnosis and classification of diabetes mellitus, Diabetes Care, 2010, 33, S62 S69 507

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