iMedPub Journals

http://journals.imedpub.com

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2014
Vol. 5 No. 1:2 doi: 10.3823/341

Peripheral and central auditory pathways function in patients with type 2 diabetes mellitus
Abstract
This work aimed to investigate peripheral and central hearing function (auditory pathways) in patients with diabetes mellitus (DM). This study included 60 patients with mean age of 39.5713.89 years and duration of illness of 7.375.15 years. We did routine pure tone audiometry (PTA) along with Auditory-Brainstem Response (ABR) at low and high repetition rate frequencies and Event-Related Potentials (ERPs). Fourteen patients (23.33%) had tinnitus and 18 patients (30%) had subjective hearing impairment. PTA reported peripheral auditory neuropathy in 30% (18/60) or (30/120) of ears examined [versus 8.75% (7/80) for control subjects] (P = 0.001). Of them, bilateral sensorineural hearing impairment (SNHI) was reported in (72.22%; n = 13). The latency of wave I was prolonged in 36.67% indicating auditory neuropathy. The latency of wave III and I-III and III-V inter peak latencies (IPLs) were delayed in 46.67% indicating impairment in the cochlear nucleus. The latency of wave V and III-V and I-V IPLs were delayed in 30% without impairment in wave I or III, indicating impairment in the activity in the nuclei of lateral lemniscus. Compared to control subjects, patients had higher hearing threshold at different frequencies (250-8000 Hz) (P = 0.0001), prolonged absolute latencies of waves I, III and V and I-III, III-V and I-V IPLs at 90dBHL low and high repetition frequencies and N100, N200, P200 and P300 components of ERPs (P = 0.0001) and reduced amplitudes of P200 and P300 (P = 0.0001). No signicant differences were identied among different audiologic variables between patients with type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. Patients who were uncontrolled on anti-diabetic medications had prolonged I-V IPLs at 90dBHL low (right: P = 0.025; left: P = 0.041) and high (right: P = 0.047; left: P = 0.036) repetition frequencies and reduced amplitudes

Sherifa A. Hamed1* (M.D.), Mostafa A. Haridi2 (M.D.), Amal M. Elattar3 (M.D.)

1  Department of Neurology and Psychiatry, Assiut University Hospital, Assiut, Egypt. 2 Department of Internal Medicine, Assiut University Hospital, Assiut, Egypt. 3 Department of Audiology, Assiut University Hospital, Assiut, Egypt.

Corresponding author:

 hamed_sherifa@yahoo.com
Sherifa A. Hamed (M.D) Consultant Neurology Professor Department of Neurology and Psychiatry Assiut University Hospital Assiut, Egypt zip code: 71516

Copyright iMedPub

This article is available from: www.jneuro.com

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2014
Vol. 5 No. 1:2 doi: 10.3823/341

of P300 (right: P = 0.050; left: P = 0.052). signicant correlations were identied between many audiologic variables and demographic- clinical- and laboratory- variables In multivariate analysis and after adjustment of other risk factors, there were increase in the odds for latency of wave III (OR 1.90; 95% Cl 1.02 to 3.55, P = 0.044); I-III (OR 2.36; 95% Cl 0.95 to 5.81; P = 0.06) and III-V (OR 2.36; 95% Cl 0.95 to 5.81; P = 0.06) IPLs and amplitude of P300 (OR 2.36; 95% Cl 0.95 to 5.81; P = 0.06) in relationship to the degree hyperglycemia. We conclude that, patients with DM have higher frequency of peripheral and central hearing impairment (i.e. acoustic nerve, auditory pathway throughout the brainstem till the auditory cortex). The degree of hearing impairment was signicantly correlated with glycemic control. This knowledge is important for specialists serving those patients. Key words: Diabetes mellitus, auditory function, Auditory-Brainstem Response, Event Related Potentials.

Introduction
Diabetes mellitus (DM) comprises a group of metabolic disorders and several distinct types that are characterized by abnormalities in carbohydrate metabolism and chronic hyperglycemia. These metabolic disorders are results of complex interaction of genetic, environmental and life style factors [1]. The two main types of DM are type-1 (T1DM) or insulin dependent DM (IDDM) and type-2 (T2DM) or noninsulin dependent DM (NIDDM). T2DM comprises 90% of DM [2]. T2DM is gradual in onset and occurs mainly in the middle age and elderly subjects. T2DM is predominantly due to insulin resistance (IR) with relative insulin deciency or insulin secretion defect [3]. Many organ systems are adversely affected by the metabolic dysregulation associated with DM, particularly with T2DM as the nervous system, heart, retina and kidney [4]. Evidence from several human and animal studies indicated that the prevalence rates of diabetic complications are proportionately related to the magnitude and duration

of antecedent hyperglycemia. Diabetic neuropathy are recognized as the most common nervous system complications caused by DM worldwide [4-10]. Auditory neuropathy or sensorineural hearing impairment (SNHI) has been reported to be one of the common complications of DM. However, its frequency varies between studies and ranges between completely asymptomatic electrophysiological abnormalities to manifest SNHI [11-15]. Central delay in neural conductance along the auditory pathway was also reported with DM and assessed by several means, for example: a) auditory brainstem responses (ABRs) (short- and middle-latencies) which reect auditory pathway function starting from the auditory nerve and throughout the brain stem. While long-latency evoked response or known as Event Related Potentials (ERPs) reects the function within the auditory cortex [16-22]. ABR and ERPs are simple, non-invasive procedures to detect early impairment of auditory pathways even in the absence of specic symptoms. For ABR, wave I and II represent activity in cochlear nerve, wave III in
This article is available from: www.jneuro.com

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2014
Vol. 5 No. 1:2 doi: 10.3823/341

cochlear nucleus, wave V represents activity in nuclei of lateral lemniscus and I-III and I-V interpeak latencies (IPLs) are regarded as auditory conduction time within the brainstem, and b) Transient (TEOAEs) and distortion product (DPOAEs) evoked otoacoustic emissions [23, 24]. Otoacoustic emissions (OAEs) testing permits sensitive assessment of cochlear function from any cause and objective monitoring of dynamic changes in cochlear responsiveness before functional and signicant hearing loss occur. OAEs amplitude indicates the summed activity of outer hair cells (OHCs). Minimal amounts of cochlear damage may cause measurable changes in OAE responses and as scattered OHC loss accumulates, OAE amplitude decreases prior to signicant changes in pure-tone thresholds [25]. Results from animal and human studies indicate that diabetic neuropathy is due to degeneration of nervous system cells as a result of vasculopathy (microangiopathy, macroangiopathy) and direct or indirect effects of hyperglycemia with resultant hypoxia and oxidative stress [26-28]. Thus advances in understanding the spectrum of neurological complications and the physio-pathological mechanisms of damage to the nervous system as a result of DM are highly important in current neurological and therapeutic researches.

medications]. Multivariate analysis was done to determine the relationship between hyperglycemia and cochlear and auditory functions variables after controlling of related confounders.

Materials and methods

This is a cross-sectional case-control study. It included 60 patients with DM. The diagnosis of DM was done according to the World Health Organization Expert Committee on DM, Geneva [29]. Diabetics met one or more of the following criteria: 1) had a fasting glucose value greater than 125 mg/dl on two separate occasions; 2) had a 2 hours glucose value greater than 200 mg/dl during a 75 gram oral glucose tolerance test (OGTT); or 3) had a prior diagnosis of DM, and were being treated with hypoglycemic agents and/or diet and exercise. Patients were randomly recruited from the Internal Medicine and Neurology departments of Assiut University Hospital, Assiut, Egypt. Patients were classied according to type of DM into T1DM and T2DM, and the degree of control on anti-diabetic medications into controlled and uncontrolled. Forty age-, sex-, and socioeconomic status- matched subjects were included as healthy controls for comparison. Control subjects were recruited from the general population. Excluded from the study were subjects with: a) previous history of otological or labyrinthine disorders, b) systemic or metabolic diseases associated with hearing loss other than DM and its associated hypercholesterolemia/dyslipidemia, hypertension, insulin resistance and obesity (as renal insufciency, gout, hypothyroidism or active gastrointestinal disease), c) history of hypoglycemic coma or complications of DM (other than peripheral neuropathy) (as nephropathy, retinopathy, etc.) d) clinical evidence of postural hypotension, e) history of stroke or transient ischemic attacks, f) history of head injury, g) reported exposure to unsafe noise, h) previous

Aim of the work

This work aimed to investigate peripheral and central hearing function (auditory pathways) in patients with DM using routine diagnostic audiometry along with Auditory-Brainstem Response (ABR) at low and high repetition rate frequencies and Event-Related Potentials (ERPs). We investigated the relationship between audiologic variables and demographic (age and gender), clinical [type of DM, duration of illness and associated comorbid medical problems (as hypertension and hypercholesterolemia/dyslipidemia) and the degree of control on anti-diabetic
Copyright iMedPub

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2014
Vol. 5 No. 1:2 doi: 10.3823/341

use of ototoxic drugs, i) family history of deafness, and j) use of medication which might be expected to interfere with the functioning of central nervous system (e.g. methyldopa, reserpine, anticonvulsants, antipsychotic and antidepressants). The protocol of this study was in conformity with the local ethics guidelines and informed written consent was obtained from each participant. All study participants underwent a standardized interview questionnaire regarding vascular risk factors.

analyzer Hitachi 911 (Boehinger, Mannheim, USA). Serum uric acid was determined by colorimetric US plus kit, supplied by Roche diagnostics, (GmbH, D-68298 Mannheim, USA).

3) Basic audiolgical evaluation:

All participants underwent basic audiological evaluation which included: a) initial otoscopic examination, b) standard pure tone air and bone conduction audiometry (PTA): which were conducted using dual channel clinical audiometer (Madson OB822, Assens, Denmark). Pure tone audiometric thresholds were measured from 250 to 8000 Hz (250, 500, 1000, 2000, 4000 and 8000 Hz) and pure average thresholds for the right and left ears were obtained, c) speech audiometry: which was done to identify the hearing level at which subjects understood and repeated at least 90% of a set of 10 monosyllables, d) tympanometry: which was done using Middle Ear Analyzer Interacoustics (Az26, Assens, Denmark). Speech audiometry, tympanometry and acoustic reex were done to exclude pathologic conditions of the external or middle ear. Hearing thresholds were determined in decibel hearing level (dB HL). The examined ears were dened as normal if no absolute threshold level > 20 dB was measured over the whole frequency range. Threshold shifts in PTA were considered to be signicant if they showed at least 10 dB change in more than two consecutive frequencies, or if a threshold greater than 20 dB was observed in any audiometric range. Hearing loss was calculated for each ear separately as the amount of threshold shifts above the standard audiometric zero, and the average hearing loss of both ears was calculated. Grading of hearing impairment was adopted according to Northern and Downs [31] into: mild, moderate, moderately severe and severe impairment and are dened as average threshold between 25-40dB, 41-55dB, 56-70dB and 71-90dB respectively.

Methods:
1) Data collection:
Demographic and clinical data were collected as follow: age, gender, type of DM, duration of illness, type of treatment, duration of treatment, degree of control on anti-diabetic medications, systolic blood pressure, diastolic blood pressure, weight, height, body mass index (BMI), degree of obesity. BMI was calculated as follow: BMI [weight (kg)/height (m2)]. Normal was dened if BMI was >20 to <25 kg/m2, over weight if BMI was equal or >25 to <30, obese if BMI was equal or >30 to <35 and morbidly obese if BMI was >35 [30].

2) Specimen collection and analysis:

Venous blood samples were drawn from patients at 8.00 am. Routine hematology tests were done and included: fasting blood glucose (FBG), complete blood count (CBC), renal function, lipogram [serum total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c)] and uric acid. Serum levels of TC, TG, HDL-c and LDL-c were measured by enzymatic colourimetric method using the auto-

This article is available from: www.jneuro.com

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2014
Vol. 5 No. 1:2 doi: 10.3823/341

4) Auditory brainstem response (ABR) recording:

ABR was done by (Nicolet Spirit) OS/2 version 3. ABR was performed using alternating clicks at 0.1 seconds, time window was 10 millisecond and lter settings were 150 Hz-3 kHz. The stimuli were delivered at 90 dBHL with repetition rate of 11.1-51.1 pulse/second. Each response reected an average of 1500 stimuli presentations. The absolute latencies of waves I, III and V and interpeak latencies (IPLs) of I-III, III-V and I-V were recorded from both ears.

5) Event-Related Potentials (ERPs) testing:

ERPs testing was done on a separate day. It takes at least one and half hour to administer (as repetition of testing was needed to assure accuracy). ERPs are series of scalp waves that are extracted from the electroencephalogram (EEG) by time domain analysis and averaging of EEG activity following multiple stimulus repetitions. They were elicited with an auditory discrimination task paradigm by presenting a series of binaural 1.000 Hz (standard) versus 2,000 Hz (target) tones at 70 dB with a 10 millisecond rise/fall and 40 millisecond plateau time. Tones were presented at a rate of 1.1 per second, with target tones occurring randomly with a 0.2 probability. Subjects were sitting with their eyes closed and were instructed to mentally count the number of the target but not the frequent tones, and then asked to report the number of target tones counted at the end of each run. Potentials were recorded from scalp electrodes placed at Cz and were referred to linked ears. Filter settings were 0.5 and 70 Hz. Responses to 30 target and 120 non-target tones were obtained in each trial. Separate averages for target and non-target tones were obtained. Before recording, subjects were familiarized with the two tones and instructed to press a button when they heard target tones. The obtained ERPs were subdivided into early or sensory-evoked
Copyright iMedPub

components (e.g. P100, N100, P200, N200), which emerge within the rst 100-200 millisecond after stimulus onset and basically reect stimulus detection and auditory evoked brainstem potentials, and later or cognitive-related components (e.g. P300). Latencies of each event-related component (N100, P200, N200 and P300) were measured. P300 latency was measured as the major positive peak after N200, within a range of 250-500 milliseconds. The amplitudes of N200 and P300 were measured as peak to peak from the negative component just before the wave to the maximum positive peak of the wave. P300 is believed to index stimulus signicance and the amount of attention allocated to the eliciting stimulus event, being maximal to task-relevant or attended stimuli and being absent or small to task-irrelevant or unattended stimuli [32].

Statistical analysis
Calculations were performed using SPSS, version 12.0. Data were presented as mean SD (standard deviation). Independent two-sided Students t test was used for comparison between groups. Pearsons r was used to assess correlations. Multivari ate analysis was done by stepwise forward logistic regression based on the probability ratios. The dependent variable was audiologic variables. Variables that showed signicant association with audiologic variables in the simple linear regression analysis (i.e. p<0.05) were used as independent variables for multiple logistic regression analysis. Multivariate odds ratio (OR) for risk factors and 95% condence interval (CI) were calculated. For all tests, p<0.05 was considered statistically signicant.

Results
This study included 60 patients with DM (T1DM = 16, T2DM = 44; male = 21; females = 39), with mean age of 39.5713.89 years and duration of

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2014
Vol. 5 No. 1:2 doi: 10.3823/341

illness of 7.375.15 years. Nearly 48.33% of the patients were uncontrolled on anti-diabetic treatment. Demographic and clinical characteristics of the studied group were shown in Tables 1. Fourteen patients (23.33%) had tinnitus and 18 patients (30%) had subjective hearing impairment (unilateral = 6 or 33.33%; bilateral = 12 or 66.67%). PTA re-

ported peripheral auditory neuropathy or SNHI in 30% of patients (18/60) [T1DM = 5 (31.25% or 5/16); T2DM = 13 (29.55% or 13/44)] or (30/120) of ears examined [versus 8.75% (7/80) for control subjects] (P = 0.001). Bilateral SNHI was reported in (72.22%; n = 13). Mild, moderate and severe SNHI was identied in 40% (12/30), 33.33% (10/30)

Table 1. Demographic, clinical and laboratory characteristics of the studied groups.

Demographic and Clinical characteristics Male/female Age; years Duration of illness; years Type of DM Type 1 DM Type 2 DM Type of treatment Oral hypoglycemic Insulin and oral hypoglycemic Duration of treatment; years Degree of control on treatment Controlled Uncontrolled Degree of obesity; # (%) normal Overweight Obese Morbidly obese BMI; kg/m2 Blood Pressure; mmHg Systolic blood pressure Diastolic blood pressure Number of patients with hypertension Fasting blood sugar; mmol/l Lipid prole TC; mg/dl LDL-c; mg/dl TG; mg/dl HDL-c; mg/dl Number of patients with dyslipidemia Patients (n = 60) 21/39 20-55 (39.5713.89) 1-25 (7.375.15) 16 (26.67%) 44 (73.33%) 38 (63.33%) 22 (36.67%) 1-25 (7.275.11) 31 (51.67%) 29 (48.33%) 37 (61.67%) 12 (20.00%) 8 (13.33%) 3 (5.00%) 17.0-40.0 (27.295.25) 70-140 (121.8413.02) 65-110 (77.049.01) 32 (56.14%) 3-26 (11.325.41) 135.00-295.00 190.0043.39 41.00-196.00 100.0231.88 42.00-450.00 187.60109.34 23.00-79.00 45.0413.24 37 (64.91%) 18 (45.00%) 12 (30.00%) 6 (15.00%) 4 (10.00%) 15.20-53.50 (29.336.75) 100.00-130.00 (120.00.00) 60.00-85.00 (80.00.00) 0 3.10-5.40 (4.300.71) 124.00-195.00 168.107.10 170.00-270.00 115.3025.40 49.00-128.00 92.108.20 35.00-48.00 43.901.20 0 Control subjects (n = 40) 12/28 20-50 (30.257.40) P-value 0.380 -

0.564 0.456 0.760 0.0001

0.052 0.289 0.007 0.750

This article is available from: www.jneuro.com

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2014
Vol. 5 No. 1:2 doi: 10.3823/341

Kidney function tests Urea; mmol/l Creatinine; mol/l Uric acid; mg/dl

0.90-8.00 4.111.08 37.80-130.00 66.5922.60 3.991.71

3.00-7.00 4.400.30 45.00-110.00 74.705.00 4.610.99

0.850 0.855 0.670

Data are expressed as mean SD; number (%). TC, total cholesterol; TG, triglycerides; LDL-c, low density lipoprotein cholesterol; HDL-c, high density lipoprotein cholesterol.

Table 2. Results of Pure Tone Audiometry (PTA) thresholds, Auditory-brainstem response (ABR) at 90 dB HL with low and high repetition rate frequencies and Event-Related Potentials (ERPs) components.
Patients Right Left Right Controls Left PTA 14.383.34 18.172.34 16.334.36 18.834.99 22.083.79 25.176.49 14.821.49 17.883.97 17.003.65 19.722.07 24.505.91 25.505.49 10.513.80 6.621.56 9.052.67 8.193.25 12.814.57 11.002.27 ABR 11.031.50 7.063.10 8.992.87 7.191.15 11.912.57 10.001.47 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001

Audiologic variables Frequency [Hz] 250 500 1000 2000 4000 8000 ABR at 90dBHL low repetition: Wave latencies: I III V Interpeak latencies: I-III III-V I-V ABR at 90dBHL high repetition: Wave latencies: I III V Interpeak latencies: I-III III-V I-V

P1-value

P2-value

1.950.19 3.890.27 5.980.27 2.960.24 1.950.25 4.020.41

1.950.27 3.820.20 5.970.29 2.990.25 1.900.25 3.970.32

1.240.18 3.040.62 5.290.74 1.980.21 1.240.23 3.090.39

1.800.15 3.040.74 5.060.61 2.080.21 1.290.23 3.090.62

0.0001 0.0001 0.0001 0.0001 0.0001 0.0001

0.0001 0.0001 0.0001 0.0001 0.0001 0.0001

1.820.27 3.930.48 6.130.35 2.970.23 2.110.22 4.880.31

1.920.28 4.000.49 6.010.62 2.750.35 2.800.26 4.140.31

1.280.18 3.020.14 5.300.42 2.040.25 1.070.35 3.070.60

1.250.11 3.050.13 5.050.24 2.030.18 2.000.16 3.130.13

0.0001 0.0001 0.0001 0.0001 0.0001 0.0001

0.0001 0.0001 0.0001 0.0001 0.0001 0.0001

Copyright iMedPub

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2014
Vol. 5 No. 1:2 doi: 10.3823/341

ERPs N100 latency (msec) N200 latency (msec) P200 latency (msec) P200 amplitude (mv) P300 latency (msec) P300 amplitude (mv) 128.3138.60 246.0845.71 177.5631.57 6.824.11 343.5933.67 8.114.24 129.8434.30 244.4966.60 182.6428.66 7.033.21 346.3832.82 8.434.03 112.1825.71 242.1229.33 162.4124.51 9.113.67 325.1223.96 9.962.72 112.0025.08 231.8819.92 169.9426.66 9.103.45 311.9430.75 10.912.27 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001

Data are expressed as mean SD. P1- and P2-values: signicance versus controls subjects (right and left sides) respectively.

and 26.67% (8/30) of ears involved, respectively. The latency of wave I was prolonged in 36.67% (n = 22) of patients with DM indicating impairment of auditory or acoustic nerve transmission till the level of cochlear nucleus. The latency of wave III and I-III and III-V IPLs were delayed in 46.67% (n = 28) of patients with DM (without impairment in wave I or V) indicating impairment in the cochlear nucleus. The latency of wave V and III-V and I-V IPLs were delayed in 30% (n = 18) with DM without impairment in wave I or III, indicating impairment in activity in the nuclei of lateral lemniscus. Table 2 showed results of PTA thresholds, ABR at 90 dB HL with low and high repetition rate frequencies and ERPs components. Compared to control subjects, patients with DM had higher hearing threshold at different frequencies (250-8000 Hz) (P = 0.0001 for all), prolonged absolute latencies of waves I, III and V and I-III, III-V and I-V IPLs at 90dBHL low and high repetition frequencies of ABR and N100, N200, P200 and P300 components of ERPs (P = 0.0001 for all) and reduced amplitudes of P200 and P300 components of ERPs (P = 0.0001 for all). Table 3 and 4: showed results of PTA thresholds, ABR at 90 dB HL with low and high repetition rate frequencies and ERPs components according to the type of DM and the degree of control on anti-diabetic drugs. No signicant differences were identied among different audiologic variables between patients with

T1DM and T2DM. Patients who were uncontrolled on anti-diabetic medications had prolonged I-V IPLs at 90dBHL low (right: P = 0.025; left: P = 0.041) and high (right: P = 0.047; left: P = 0.036) repetition frequencies and reduced amplitudes of P300 (right: P = 0.050; left: P = 0.052). Correlations between audiologic variables and demographic, clinical and the degree of control on anti-diabetic medications showed signicant associations between: 1) age at presentation and latency of wave III at low repetition rate frequencies (r = 0.335, P = 0.035) and P300 latency (r = 0.401, P = 0.005), 2) duration of DM and latency of wave V at low repetition rate frequencies (r = 0.358, P = 0.023), 3) systolic blood pressure and hearing threshold at 8000 Hz (r = 0.383, P = 0.007) and latency of wave III at high repetition rate frequencies (r = 0.372, P = 0.018), 4) diastolic blood pressure and hearing threshold at 4000 Hz (r = 0.393, P = 0.005); latency of wave III (r = 0.354, P = 0.023), 5) TC level and latency of wave III (r = 359, P = 0.023), III-V IPLs at low repetition rate frequencies (r = 0.324, P = 0.042) and P300 latency (r = 455, P = 0.001); LDL-c level and hearing threshold at 8000 Hz (r = 0.341, P = 0.016); TG level and hearing threshold at 4000 Hz (r = 0.302, P = 0.035) and IIIV (r = 0.388, P = 0.013), I-V (r = 0.353, P = 0.027) IPLs at low repetition rate frequencies and latency

This article is available from: www.jneuro.com

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2014
Vol. 5 No. 1:2 doi: 10.3823/341

Table 3. Results of Pure Tone Audiometry (PTA) thresholds, Auditory-brainstem response (ABR) at 90 dB HL with low and high repetition rate frequencies and Event-Related Potentials (ERPs) components according to the type of diabetes mellitus.
Audiologic variables Frequency [Hz] 250 500 1000 2000 4000 8000 13.442.18 18.752.02 15.631.82 17.811.99 21.884.16 30.317.96 17.132.66 19.382.81 16.881.88 18.942.61 23.754.91 32.198.76 16.131.92 19.521.96 17.421.54 19.841.89 24.032.41 23.232.74 14.842.07 17.331.87 17.581.76 20.002.50 23.872.58 22.262.59 T1DM Right Left Right T2DM Left P1value PTA 0.304 0.009 0.067 0.002 0.172 0.100 ABR 0.347 0.072 0.022 0.009 0.098 0.071 0.727 0.019 0.007 0.0001 0.011 0.036 0.774 0.194 0.011 0.001 0.071 0.333 0.360 0.787 0.456 0.465 0.657 0.411 0.502 0.550 0.785 0.770 0.980 0.291 P2value P3value P4value P5value P6value

ABR at 90dBHL low repetition: Wave latencies: I III V Interpeak latencies: I-III III-V I-V ABR at 90dBHL high repetition: Wave latencies: I III V Interpeak latencies: I-III III-V I-V

1.960.18 3.790.27 5.820.24

1.950.22 3.830.27 5.950.26

1.250.21 3.200.28 5.270.29

1.250.29 3.010.16 5.250.26

0.0001 0.0001 0.0001

0.0001 0.001 0.0001

0.0001 0.0001 0.0001

0.0001 0.001 0.0001

0.944 0.993 0.570

0.965 0.777 0.232

2.830.20 2.830.31 4.360.26

2.720.21 1.980.21 3.940.32

2.050.27 1.220.23 3.280.48

2.080.30 1.090.27 3.040.32

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.800 0.356 0.526

0.649 0.297 0.452

2.830.22 3.950.63 6.970.43

2.920.28 4.090.33 5.741.25

1.850.33 3.200.49 6.140.35

1.900.26 3.030.23 5.080.29

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.823 0.448 0.812

0.249 0.629 0.419

2.970.20 2.880.18 4.810.24

2.700.46 2.010.17 4.800.41

2.160.24 2.080.23 4.250.35

2.120.35 1.230.31 4.130.27

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.952 0.737 0.615

0.646 0.853 0.823

Copyright iMedPub

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2014
Vol. 5 No. 1:2 doi: 10.3823/341

ERPs N100 latency (msec) N200 latency (msec) P200 latency (msec) P200 amplitude (mv) P300 latency (msec) P300 amplitude (mv) 116.8138.60 130.0031.64 136.8342.53 131.4835.60 0.0001 0.0001 0.0001 0.0001 0.101 0.886

245.4419.07 230.6965.47 246.3461.13 249.9776.39 0.0001

0.0001

0.0001

0.0001

0.942

0.379

175.8826.15 182.5633.39 190.1740.03 184.4824.94 0.0001

0.0001

0.0001

0.0001

0.156

0.842

7.411.38

6.040.79

6.810.69

6.340.46

0.0001

0.0001

0.0001

0.0001

0.704

0.747

347.2827.37 343.3925.35 344.1034.62 348.4035.05 0.0001

0.0001

0.0001

0.0001

0.737

0.585

8.981.01

8.401.03

8.480.79

8.420.75

0.0001

0.0001

0.0001

0.0001

0.696

0.989

Data are expressed as mean SD. T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus. P1- and P2-values: T1DM versus controls (right and left sides) respectively. P3- and P4-values: T2DM versus controls (right and left sides) respectively. P5- and P6-values: T1DM versus T2DM (right and left sides) respectively.

of wave III at high repetition rate frequencies (r = 0.442, P = 0.004); HDL-c level and hearing threshold at 250 Hz (r = -0.327, P = 0.022) and latency of wave III at low (r = -0.357, P = 0.024) and high (r = -0.478, P = 0.002) repetition rate frequencies and P300 latency (r = -0.393, P = 0.006), and 6) blood sugar level and hearing threshold at 4000 Hz (r = 0.302, P = 0.035) and 8000 Hz (r = 350, P = 0.007), latency of wave III (r = 399, P = 0.011), wave V (r = 0.445, P = 0.005), I-III (r = 0.456, P = 0.004), III-V (r = 0.321, P = 0.044) and I-V (r = 0.355, P = 0.003) IPLs at low repetition rate frequencies, I-III (r = 0.543, P = 0.001) and III-V (r = 0.456, P = 0.002) IPLs at high repetition rate frequencies; and latency

(r = 0.467, P = 0.002) and amplitude (r = -0.530, P = 0.001) of P300. In multivariate analysis and after adjustment of other risk factors, there were increase in the odds for latency of wave III (OR 1.90; 95% Cl 1.02 to 3.55, P = 0.044); I-III (OR 2.36; 95% Cl 0.95 to 5.81; P = 0.06) and III-V (OR 2.36; 95% Cl 0.95 to 5.81; P = 0.06) IPLs and amplitude of P300 (OR 2.36; 95% Cl 0.95 to 5.81; P = 0.06) in relationship to the degree hyperglycemia. Although it is not our aim, 38 patients (63.33%) had bilateral sensory/sensorimotor peripheral neuropathy and all also had peripheral (n = 18) and/or central (n = 20) auditory neuropathy.
This article is available from: www.jneuro.com

10

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2014
Vol. 5 No. 1:2 doi: 10.3823/341

Table 4.  Results of Pure Tone Audiometry (PTA) thresholds, Auditory-brainstem response (ABR) at 90 dB HL with low and high repetition rate frequencies and Event-Related Potentials (ERPs) components according to the degree of control on anti-diabetic drugs.
Audiologic variables Frequency [Hz] 250 500 1000 2000 4000 8000 16.582.59 20.002.29 17.371.96 21.321.91 22.112.71 23.953.23 17.633.23 17.892.79 19.212.33 21.052.77 25.003.44 22.633.30 14.261.80 18.701.97 16.301.55 17.782.04 24.443.15 27.595.14 14.221.69 17.881.86 16.111.59 18.812.60 23.703.28 28.525.49 Controlled patients Right Left Uncontrolled patients Right Left P1value PTA 0.686 0.006 0.014 0.0001 0.036 0.009 ABR 0.357 0.174 0.007 0.005 0.061 0.171 0.023 0.138 0.142 0.042 0.002 0.001 0.307 0.507 0.338 0.061 0.106 0.026 0.468 0.671 0.670 0.212 0.576 0.552 0.358 0.998 0.280 0.559 0.786 0.363 P2value P3value P4value P5value P6value

ABR at 90dBHL low repetition: Wave latencies: I III V Interpeak latencies: I-III III-V I-V ABR at 90dBHL high repetition: Wave latencies: I III V Interpeak latencies: I-III III-V I-V

1.970.19 3.830.17 5.800.32

1.980.25 3.770.19 5.920.26

1.250.21 3.010.31 5.170.25

1.240.29 3.240.19 5.020.26

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.841 0.678 0.727

0.663 0.225 0.260

2.910.19 1.980.20 4.900.56

2.940.29 1.860.31 4.820.37

2.100.27 1.210.28 4.270.32

2.120.27 1.360.21 4.460.27

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.241 0.339 0.025

0.423 0.232 0.041

1.930.36 3.990.55 6.170.31

1.940.31 4.070.19 5.820.98

1.290.26 3.160.52 6.130.42

1.230.26 3.030.30 5.030.31

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.236 0.468 0.732

0.927 0.596 0.267

2.180.29 2.070.16 4.870.38

2.110.40 1.940.35 4.880.30

2.140.18 2.100.26 4.140.29

2.170.38 1.230.21 4.040.22

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.0001 0.0001 0.0001

0.635 0.642 0.050

0.706 0.406 0.052

Copyright iMedPub

11

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2014
Vol. 5 No. 1:2 doi: 10.3823/341

ERPs N100 latency (msec) N200 latency (msec) P200 latency (msec) P200 amplitude (mv) P300 latency (msec) P300 amplitude (mv) 121.2946.77 129.2433.53 134.5937.63 133.4434.46 0.0001 0.0001 0.0001 0.0001 0.331 0.842

250.8235.43 218.8425.60 242.8858.61 257.5238.61 0.0001

0.0001

0.0001

0.0001

0.578

0.223

181.3537.16 181.8225.05 187.3036.56 187.3027.77 0.0001

0.0001

0.0001

0.0001

0.607

0.533

8.27345

7.893.68

9.184.36

8.433.99

0.0001

0.0001

0.0001

0.0001

0.447

0.280

342.4420.40 338.4435.07 347.6734.22 352.0535.22 0.0001

0.0001

0.0001

0.0001

0.593

0.091

5.662.42

5.232.02

8.025.13

6.692.83

0.0001

0.0001

0.0001

0.0001

0.047

0.036

Data are expressed as mean SD. P1- and P2-values: controlled patients versus controls (right and left sides) respectively. P3- and P4-values: uncontrolled patients versus controls (right and left sides) respectively. P5- and P6-values: controlled versus uncontrolled patients (right and left sides) respectively.

Discussion
The results of this study indicate the followings: 1) patients with DM had higher frequency of peripheral hearing impairment. 2) Patients with DM had higher frequency of central hearing impairment. 3) Vascular compromise with reduced blood ow to the cochlea and/or direct effect of hyperglycemia has been suggested as possible etiologies of auditory dysfunction in patients with DM. FIRST, the ndings indicate that DM is associated with high frequency of auditory neuropathy. Nearly 30% of patients with DM had higher hearing thresholds indicating peripheral auditory neuropathy or SDHI which appeared at different frequencies (2508000 Hz) [11-14] particularly high frequencies and

regardless the type of DM (T1DM versus T2DM) and the degree of control on anti-diabetic medications. This is also supported by the nding that 36.67% had prolonged absolute latency of wave I of ABR (which indicate impairment of auditory or acoustic nerve transmission till the level of cochlear nucleus) [16, 17, 19-22]. Studies evaluated the frequency and distribution of risk factors among populations with idiopathic sensorineural hearing loss revealed that DM is among the frequent vascular metabolic risk factors (Latent: 63.8%, manifest diabetes: 6.6%) followed by hyperuricemia (35.9%) and hyperlipoproteinemia (24.2%) [33]. SECOND, the results of this study conrmed that patients with DM reported a higher frequency of central impairment of auditory pathways as eviThis article is available from: www.jneuro.com

12

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2014
Vol. 5 No. 1:2 doi: 10.3823/341

denced by prolongation of wave III and I-III, III-V and I-V IPLs indicating delayed transmission at the level of brainstem [19-22]. We also reported abnormalities in P300 component of ERPs (a long-latency auditory evoked response) in the form of delayed latencies (indicating demyelination) and reduced amplitudes (indicating axonapathy and degeneration) which further conrm central involvement of auditory pathway (i.e. auditory cortex) [18]. THIRD, the possibilities that vascular compromise with reduced blood ow to the cochlea and/or direct effect of hyperglycemia as a possible etiology of auditory dysfunction in our patients, are highly suggested, as evidenced by the following: 1) It is well known that the cochlea is a vascular region provided with terminal capillary bed. The high metabolic demands of the inner ear and the inherited properties of the cochlea making it unable to form collateral vessels that could restore blood ow in the ischemic regions resulting in high sensitivity to minimal blood ow reduction [34] and appearance of clinical manifestations even before evidence of macrovascular complication [35]. In support, SNHI was observed at higher frequencies (2000-8000 Hz) [23, 24]. High frequency loss has been found to be related to outer hair cells (OHCs) degeneration along base-to-apex gradient or mainly in the basal turns of the cochlea that follows reduced function of the stria vascularis, a highly vascular epithelium [36]. This is commonly attributed to atherosclerosisrelated microcirculatory disturbances of the cochlear vasculature [14, 35]. DM might decrease the function of the stria vascularis and OHCs loss in a similar manner involved in other related metabolic vascular diseases as hyperchlosterolemia/dyslipidemia [9, 26, 28] and hyperuricemia [37]. 2) We reported that 63.33% had bilateral sensory/sensorimotor peripheral neuropathy and all also had peripheral and/or central auditory neuropathy. Vascular compromise of the vasa nervorum (which are small arteries that provide blood supply to peripheral nerves) has been suggested as the pathologic lesion responsible for
Copyright iMedPub

SNHI with DM. In support, the absence in signicant difference in hearing impairment regardless of type and duration of DM but the correlation with the blood sugar level is in support to the notion that the degree of hyperglycemia is the main cause of hearing impairment with DM. In fact, studies indicated that diabetic neuropathy is a dynamic process, both degeneration and regeneration occurs simultaneously [26-28], however a shift of the balance between degeneration and regeneration toward more degeneration may occur overtime [27]. Impairment of regenerative capacity of nervous system cells may occur as a result of hyperglycemia, reduction of nerve blood ow and hypoxia, impairment of cellular scavenging activity against oxidative stress [38], abnormal fatty acid metabolism [9, 27], ATPase activity, depletion of myoinositol [39], increase in platelet aggregation [40] and loss of growth factor systems [41, 42]. Despite the importance of the results of this study, there are some limitations which include: 1) relatively small number of patients, and 2) due to the cross-sectional design of this study; the temporal relation between appearances of auditory dysfunction in patients with DM is unknown.

Conclusions
Patients with DM have higher frequency of peripheral and central hearing impairment (i.e. acoustic nerve, auditory pathway throughout the brainstem till the auditory cortex). The degree of hearing impairment was signicantly correlated with glycemic control. This knowledge is important for specialists serving those patients and thus frequent evaluation by audiometric tests in DM patients is recommended for controlling hearing disorders by therapeutic and rehabilitation procedures. Future related researches are also important and have to include the following: a) longitudinal studies that prospectively

13

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2014
Vol. 5 No. 1:2 doi: 10.3823/341

assess the relation of the disease process over time on auditory functioning of patients with DM, and b) randomized clinical trials that prospectively compare auditory function in response to different treatment modalities including anti-diabetic medications, vasodilator, antioxidants versus a control group of DM patients.

Abbreviations
DM, diabetes mellitus; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; IR, insulin resistance; BMI, body mass index; PTA, pure tone audiometry; CHI, conductive hearing impairment; SNHI, sensorineural hearing impairment; ABR, AuditoryBrainstem Response; ERPs, Event Related Potentials; TC, total cholesterol; TG, triglycerides; LDL-c, low density lipoprotein cholesterol; HDL-c, high density lipoprotein cholesterol.

Conict of interests
We declare that this work has no conict of interests. There is no involvement of sponsor for this work design, data collection, analysis, interpretation, drafting, nor the decision to submit this paper for publication. All are authors responsibility.

14

This article is available from: www.jneuro.com

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2014
Vol. 5 No. 1:2 doi: 10.3823/341

References
1. Sacks, DB. Carbohydrates in Tietz Textbook of clinical chemistry (5th ed) Burtis. Acral and Ashwood Edward. W.B. Sounders comp. Philadelphia 2001, 427-461. 2. Bonow, RO., Gheorghiade, M. The diabetes epidemic: a national and global crisis, Am J Med. 2004; 116 (suppl. 5A): 2S-10S. 3. Kasuga, M. Insulin resistance and pancreatic beta cell failure. J Clin Invest. 2006; 116 (7): 1756-1760. 4. Troni, W., Carta, Q., Cantello, R., Caselle, M.T., Rainero, I. Peripheral nerve function and metabolic control in diabetes mellitus. Ann Neurol. 1984; 16 (2):178-183. 5. Dyck, PJ., Kratz, KM., Karnes, JL., Litchy, WJ., Klein, R., Pach, JM., Wilson, DM., OBrien, PC., Melton, LJ. 3rd., Service, FJ. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology 1993; 43 (4): 817-824. 6. Biessels, GJ., Cristino, NA., Rutten, GJ., Hamers, FP., Erkelens, DW., Gispen, WH. Neurophysiological changes in the central and peripheral nervous system of streptozotocin-diabetic rats. Course of development and effects of insulin treatment. Brain 1999; 122 (Pt. 3): 757-768. 7. Hilz, MJ., Marthol, H., Neundorfer, B. Diabetic somatic polyneuropathy. Pathogenesis, clinical manifestations and therapeutic concepts. Fortschritte Der Neurologie-Psychiatrie 2000; 68 (6): 278-288. 8. Ryan, CM., Geckle, MO., Orchard, TJ. Cognitive efciency declines over time in adults with type 1 diabetes: Effects of micro. a n d macrovascular complications. Diabetologia 2003; 46 (7): 940-948. 9. El-kossi, AE., Abdellah, MM., Rashad, AM., Hamed, SA. The Effectiveness of Evening Primrose in Glycemic Control and Improvement of Nerve Structure and Function in Diabetic Rats. J Clin Exper Invest 2011; 2 (2): 133-150. 10. Hamed, SA., Abd Elaal, RF., Mohamad, KA., Youssef, AH., Abdou, MA. Neuropsychological, Neurophysiological and Laboratory Markers of Direct Brain Injury in Type 2 Diabetes Mellitus. Journal of Neurology and Neuroscience 2012; 3 (1): 2. 11. Friedman, SA., Schulman, RH., Weiss, S. Hearing and diabetic neuropathy. Arch Intern Med. 1975; 135 (4): 573-576. 12. Kurien, M., Thomas, K., Bhanu, TS. Hearing thresholds in patients with diabetes mellitus. J Laryngol Otol. 1989; 103 (2):164-168. 13. Schmolke, B., Hormann, K. Vascular risk factors of sudden deafness and its incidence in the normal population. A retrospective study. HNO 1990; 38 (1): 440-405. 14. Daz de Len-Morales, LV., Juregui-Renaud, K., Garay-Sevilla, ME., Hernndez-Prado, J., Malacara-Hernndez, JM. Auditory impairment in patients with type 2 diabetes mellitus. Arch Med Res. 2005; 36 (5): 507-510. 15. Hong, BN., Kang, TH. Auditory neuropathy in streptozotocin-induced diabetic mouse. Neurosci Lett 2008; 431 (3): 268-272. 16. Martini, A., Comacchio, F., Fedele, D., Crepaldi, G., Sala, O. Auditory brainstem evoked responses in the clinical evaluation and follow-up of insulin-dependent diabetic subjects. Acta Otolaryngol. 1987; 103 (5-6): 620-627. 17. Pozzessere, G., Rizzo, PA., Valle, E., Mollica, MA., Sanarelli, L., Morano, S., Pietravalle, P., Di Mario, U., Morocutti, C. A longitudinal study of multimodal evoked potentials in diabetes mellitus. Diabetes Res. 1989; 10 (1): 17-20.

18. Pozzessere, G., Valle, E., de Crignis, S., Cordischi, VM., Fattapposta, F., Rizzo, PA., Pietravalle, P., Cristina, G., Morano, S., di Mario, U. Abnormalities of cognitive functions in IDDM revealed by P300 eventrelated potential analysis. Comparison with short-latency evoked potentials and psychometric tests. Diabetes 1991; 40 (8): 952-928. 19. Nakamura, Y., Takahashi, M., Kitaguti, M., Imaoka, H., Kono, N., Tarui, S. Abnormal brainstem evoked potentials in diabetes mellitus. Evoked potential testings and magnetic resonance imaging. Electromyogr Clin Neurophysiol 1991; 31 (4): 243-249. 20. Al-Azzawi, LM., Mirza, KB. The usefulness of the brainstem auditory evoked potential in the early diagnosis of cranial nerve neuropathy associated with diabetes mellitus. Electromyogr Clin Neurophysiol 2004; 44 (7): 387-394. 21. Durmus, C., Yetiser, S., Durmus, O. Auditory brainstem evoked responses in insulin-dependent (ID) and non-insulin-dependent (NID) diabetic subjects with normal hearing. Intern J Audiol. 2004; 43 (1): 2933. 22. Gupta, R., Aslam, M., Hasan, S., Siddiqi, S. Type -2 diabetes mellitus and auditory brainstem responses-a hospital based study. Ind J Endocrinol Metab. 2010; 14 (1): 9-11. 23. Prieve, BA., Gorga, MP., Schmidt, A., Neely, S., Peters, J., Schultes, L., Jesteadt, W. Analysis of transient-evoked otoacoustic emissions in normal-hearing and hearing-impaired ears. J Acoust Soc Am. 1993; 93 (6): 3308-3319. 24. Hussain, DM., Gorga, MP., Neely, ST., Keefe, DH., Peters, J. Transient evoked otoacoustic emissions in patients with normal hearing and in patients with hearing loss. Ear Hear 1998; 19 (6): 434-449. 25. Kemp, DT. Otoacoustic emissions, traveling waves and cochlear mechanisms. Hear Res. 1986; 22: 95-104. 26. Cameron, NE., Cotter, MA. Metabolic and vascular factors in the pathogenesis of diabetic neuropathy. Diabetes 1997; 46 (Suppl. 2): S3137. 27. Apfel, SC. Nerve regeneration in diabetic neuropathy. Diabetes Obes Metab. 1999; 1 (1): 3-11. 28. Ravussin, E., Smith, SR. Increased fat intake, impaired fat oxidation, and failure of fat cell proliferation result in ectopic fat storage, insulin resistance, and type 2 diabetes mellitus. Ann N Y Acad Sci. 2002; 967: 363-378. 29. WHO Expert Committee on Biological Standardization. Thirty-fth report. World Health Organ Tech Rep Ser. 1985; 725: 1-140. 30. Niewoehner, CB. Endocrine pathophysiology. Fence Ceek Publ., Madison, 1998. 31. Northern, JL., Downs, MP. Hearing and hearing loss in children. In: Butter, J. (Ed.). Hearing in children. Baltimore: Williams and Wikins, 1991, pp. 1-31. 32. Polich, J. P300 clinical utility and control of variability. J Clin Neurophysiol 1998; 15 (1): 14-33. 33. Wilke, H., Grossgerge, H., Haubold, E., Kahlke, W., Frahm, H., Regler, B. Frequency and distribution of risk factors in hearing loss. Fortschr Med. 1977; 95 (28): 1757-1764. 34. Einer, H., Tengborn, L., Axelsson, A., Edstrm, S. Sudden sensorineural hearing loss and hemostatic mechanisms. Arch Otolaryngol Head Neck Surg. 1994; 120 (5): 526-540. 35. Lalanne, MC., Doutremepuich, C., Boj, F., Traissac, L., Quichaud, F. Some hemostatic and hemorheological disorders in auditory and vestibular impairments. Thromb Res. 1992; 66 (6): 787-791.

Copyright iMedPub

15

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2014
Vol. 5 No. 1:2 doi: 10.3823/341

36. Marcucci, R., Alessandrello Liotta, A., Cellai, AP., Rogolino, A., Berloco, P., Leprini, E., Pagnini, P., Abbate, R., Prisco, D. Cardiovascular and thrombophilic risk factors for idiopathic sudden sensorineural hearing loss. J Thromb Haem 2005; 3 (5): 929-934. 37. Hamed, SA., Elattar, AM. Auditory Involvement in Hyperuricemia: Otoacoustic Emissions Analysis. Am J Otolaryng 2010; 31 (3): 154-161. 38. Khler, W., Kuklinski, B., Rhlmann, C., Pltz, C. Diabetes mellitus . a free radical-associated disease. Results of adjuvant antioxidant supplementation. Z Gesamte Inn Med. 1993; 48 (5): 223-232. 39. Greene, DA., Lattimer, SA. Action of sorbinil in diabetic peripheral nerve. Relationship of polyol (sorbitol) pathway inhibition to a myoinositolmediated defect in sodium-potassium ATPase activity. Diabetes 1984; 33 (8): 712-716.

4 0. Stevens, EJ., Carrington, AL., Tomlinson, DR. Prostacyclin release in experimental diabetes: Effects of evening primrose oil. Prostaglandins Leukot Essent Fatty Acids 1993; 49 (3): 699-706. 41. Chiarelli, F., Santilli, F., Mohn, A. Role of growth factors in the development of diabetic complications. Horm Res. 2000; 53 (2): 53-67. 42. Hamed, SA. Cerebrolysin in Treatment of Acquired Peripheral Nervous System Diseases: A clinical experience. Neural Regen Res. 2011; 6 (18): 1415-20.

Comment on this article:

http://medicalia.org/ Where Doctors exchange clinical experiences, review their cases and share clinical knowledge. You can also access lots of medical publications for free. Join Now!

Publish with iMedPub http://www.imedpub.com

Journal of Neurology and Neuroscience (JNeuro.com) is a hybrid, peer-reviewed journal that considers articles concerned with any aspect of clinical neurosciences such as neurology, psychiatry and neurosurgery, as well as basic research on neuroscience where neurologists and neuroscientists publish together.

Submit your manuscript here:

http://www.jneuro.com

16

This article is available from: www.jneuro.com