Original Article
Prevalence of neuropathy in patients with impaired glucose tolerance using various electrophysiological tests Meena A Kannan, Sailaja Sarva, Rukmini Mridula Kandadai, Vishnupriya Rao Paturi1, Sheik Afshan Jabeen, Rupam Borgohain Departments of Neurology and 1Endocrinology, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, Andhra Pradesh, India
Abstract Background: Neuropathy is often an associated feature woth long-standing type II diabetes mellitus. Neuropathy may occur even in subjects with impaired glucose tolerance. Objective: To study the prevalence of neuropathy using different electrophysiological techniques in subjects with impaired glucose tolerance (IGT) and no other identifiable cause of neuropathy. Materials and Methods: The study was conducted on 30 age-matched controls and 58 subjects with impaired oral glucose tolerance test (OGTT) attending diabetic awareness. Prediabetes was defined using World Health Organization (WHO) criteria. All subjects had normal glycosylated hemoglobin HbA (1c), vitamin B12 levels, and thyroid function. Neuropathy was evaluated by nerve conduction studies (NCS) performed on one upper and both lower limbs, dorsal sural nerve, medial and lateral planter nerve conductions using conventional techniques. Neuropathy was also evaluated by autononic function tests, and quantitative sensory testing (QST). The subjects were followed up for 4 years. Results: Out of 58 subjects, 19 (32.8%) had neuropathy. Nerve conduction studies showed evidence of neuropathy in 14 (24.13%) subjects, autonomic neuropathy was detected in 8 (13.8%), and QST was found to be abnormal in 16 (27.6%) subjects. Twenty subjects (34.5%) developed diabetes mellitus in the follow-up period. Conclusions: Neuropathy was detected in 32.8% subjects with IGT. Small fiber neuropathy was most common. Of all the three parameters studied, QST was found to be most sensitive technique for the detection of neuropathy. Assessment of medial plantar and dorsal sural NCS increases the sensitivity in the detection of neuropathy.
Address for correspondence: Dr. A. K. Meena, Department of Neurology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad-500 082, Telangana, Andhra Pradesh, India. E‑mail: [email protected] Received : 09-12-2014 Review completed : 10-12-2014 Accepted : 16-12-2014
Key words: Impaired glucose tolerance, nerve conduction studies, neuropathy,
prediabetes, quantitative sensory testing
Introduction Diabetes mellitus (DM) and the associated disease outcomes are a cause for concern worldwide. The current Access this article online Quick Response Code:
Website: www.neurologyindia.com PMID: *** DOI: 10.4103/0028-3886.149393
656
global prevalence of DM for all ages has been estimated at 2.8% and is projected to be 4.4 percent by 2030.[1] The need of the hour is to identify and treat the risk factors that may prevent the onset of DM and minimize morbidity. DM is often associated with peripheral neuropathy (PN) an important cause of foot ulceration, and amputation. Currently, there is a growing focus on the study of early diabetic neuropathy. The Diabetes Control and Complications Trial (DCCT) demonstrated that improved glycemic control can slow the progression of neuropathy.[2] Recent observational studies suggest an association between impaired glucose tolerance (IGT) and neuropathy. These studies have suggested a Neurology India | Nov-Dec 2014 | Vol 62 | Issue 6
Kannan, et al.: Impaired glucose tolerance and neuropathy
predominance of involvement of small nerve fibers in the neuropathy of IGT.[3,4] It has been shown that IGT is an indicator of pre‑diabetes. Prediabetes is a condition in which blood glucose levels are higher than normal, but not high enough to be diagnosed as type 2 DM. Pre‑diabetes is a known risk factor for overt diabetes and its macrovascular complications. Although neuropathy is an extensively studied complication in patients with DM; however, the neuropathy risk in pre‑diabetes has not been well characterized. The potential link between pre‑diabetes and neuropathy has been recognized based on clinical observation that many patients with idiopathic neuropathy share phenotypic characteristics of diabetes, such as obesity, hypertension, and dyslipidemia, without having overt diabetes. This led several investigtors to examine the prevalence of pre‑diabetes using OGTT. The prevelance of neuropathy in these patients was between 40% and 50%, These observations suggest that a substantial proportion of subjects with IGT exhibit PN and/or neuropathic pain.[5] But, whether neuropathy already exists in the pre‑diabetic stage with IGT is not clear. With this background, this present study was undertaken to determine the prevalence of neuropathy in patients with pre‑diabetes with IGT using different electrophysiological techniques who had no other identifiable cause of neuropathy.
Materials and Methods The study was conducted in the department of Neurology, at our institute and the study cohort included 58 subjects. We adhered to the good clinical practice guidelines of Helsinki declaration. The protocol was approved by the hospital ethics committee and informed consent was taken from all the subjects. The study subjects were referred from a diabetes health camp conducted at the department of Endocrinology. These subjects were diagnosed to have prediabetes as for the World Health Organization (WHO) criteria.[6] Age‑matched subjects with normal GTT were the controls. The subjects were followed for a 4‑year period for development of diabetes. The subjects were considered prediabetic if the fasting plasma glucose was less than 126 mg/dl and the 2‑hour oral glucose tolerance test (OGTT) was between 140–200 mg/dl. Other inclusion were: Normal glycosylated hemoglobin (HbA1c), normal vitamin B12 levels and thyroid function. Serum antinuclear antibodies (ANA) were negative in all of the patients. Individuals who had non‑healing skin sores or any foot deformities, history of exposure to agents such as heavy metals, anti‑tuberculosis drugs, cancer drugs, opioid drugs were excluded from the study. Individuals who Neurology India | Nov-Dec 2014 | Vol 62 | Issue 6
were fasting or had a light breakfast were also excluded from the study. Also, anti‑hypertensive medication if any was administered to study participants after the tests were performed. A detailed clinical examination was done by a neuromuscular expert using neuropathy total symptom score (NTSS).[7] All patients were clinically normal. Complete clinical neurological assessment was done on all these patients by a neuromuscular specialist. Subjects who had symptoms of neuropathy were excluded from the study. None of the patients included in the study had neurological deficit. Medtronic Keypoint machine (Denmark) was used for nerve condiction studies (NCS) using surface electrodes with >45‑min acclimatization (room temperature 22–24°C). Examinations were performed as per the established clinical practice. Conventional NCS were done in one upper and both lower limbs: Median, ulnar, bilateral common peroneal, posterior tibial, sural nerves, dorsal sural nerves, and medial and lateral plantar nerves. Neuropathy was considered when abnormal NCS were present in ≥2 nerves.[8] NCS was considered abnormal if there was reduction of Compound Muscle Action Potential / Sensory Nerve Action Potential (CMAP/ SNAP) amplitudes, reduction in conduction velocity, increased distal latencies more than 2 standard deviations. Tests for evaluation of autonomic function tests (AFT) were: Heart rate response to deep breathing (HRDB), valsalva maneuver, standing (30:15 ratio), blood pressure response to standing and sympathetic skin response (SSR). Abnormality in ≥2 tests were considered as abnormal AFT.[9] Quantitative sensory testing (QST) was performed by Computer Assisted Sensory Examination System IV (CASE IV–WR Medical). QST was performed at the dorsal surface of great toe. Vibration detection threshold (VDT) was estimated at maximum allowed stimulation of 576.60 µm and tested at 4, 2, and 1 stepping algorithm with null stimuli.[10] Thresholds ≥95th percentile for age were taken as abnormal. Cooling detection threshold (CDT) was evaluated at the dorsal surface of the foot. The maximum allowed stimulation was 9oC for 10 sec. with starting temperature of 30oC and ramp rate of 4.0oC. at 4, 2, and 1 stepping algorithm with null stimuli. Heat pain threshold (HPT) was evaluated at the dorsal surface of the foot. Maximum stimulation was fixed at 45oC for 10 sec., with baseline skin temperature of 34oC, measured on scale of 1 to 10 where one was considered as the least discomfort or pain and 10 as most severe pain. It was assessed by testing with non‑repeating ascending stepping algorithms with null stimuli.[11] 657
Kannan, et al.: Impaired glucose tolerance and neuropathy
The significance of the variables were calculated using Chi square test (P 30 is a risk factor for prediabetes and DM. However, prediabetes is seen in non‑obese individuals (BMI < 30 kg/m2).[28,29] In our study, 96.6% had BMI < 30. Low HDL cholesterol has been found to be a risk factor for developing neuropathy as described previously.[30] It can be inferred from this study that QST can be a more useful technique than NCS as it may allow earlier diagnosis of neuropathy in IGT. But, QST tests are dependent on subjective responses and therefore have a high interobserver variability and poor reproducibility. It is, therefore, suggested to combine QST with NCS and with patient’s symptoms to arrive at a diagnosis. This study can be further extended to a larger sample size. Also, skin biopsy can be included as a measure of neuropathy. The study demonstrated that a considerable proportion of subjects with IGT exhibit subclinical, asymptomatic PN especially of small fibers. Dorsal sural nerve conduction and medial plantar nerve conduction study should be included in the protocol. Family history of diabetes may predispose to prediabetes neuropathy. Subjects with dyslipidemia and BMI
Prevalence of neuropathy in patients with impaired glucose tolerance using various electrophysiological tests Meena A Kannan, Sailaja Sarva, Rukmini Mridula Kandadai, Vishnupriya Rao Paturi1, Sheik Afshan Jabeen, Rupam Borgohain Departments of Neurology and 1Endocrinology, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, Andhra Pradesh, India
Abstract Background: Neuropathy is often an associated feature woth long-standing type II diabetes mellitus. Neuropathy may occur even in subjects with impaired glucose tolerance. Objective: To study the prevalence of neuropathy using different electrophysiological techniques in subjects with impaired glucose tolerance (IGT) and no other identifiable cause of neuropathy. Materials and Methods: The study was conducted on 30 age-matched controls and 58 subjects with impaired oral glucose tolerance test (OGTT) attending diabetic awareness. Prediabetes was defined using World Health Organization (WHO) criteria. All subjects had normal glycosylated hemoglobin HbA (1c), vitamin B12 levels, and thyroid function. Neuropathy was evaluated by nerve conduction studies (NCS) performed on one upper and both lower limbs, dorsal sural nerve, medial and lateral planter nerve conductions using conventional techniques. Neuropathy was also evaluated by autononic function tests, and quantitative sensory testing (QST). The subjects were followed up for 4 years. Results: Out of 58 subjects, 19 (32.8%) had neuropathy. Nerve conduction studies showed evidence of neuropathy in 14 (24.13%) subjects, autonomic neuropathy was detected in 8 (13.8%), and QST was found to be abnormal in 16 (27.6%) subjects. Twenty subjects (34.5%) developed diabetes mellitus in the follow-up period. Conclusions: Neuropathy was detected in 32.8% subjects with IGT. Small fiber neuropathy was most common. Of all the three parameters studied, QST was found to be most sensitive technique for the detection of neuropathy. Assessment of medial plantar and dorsal sural NCS increases the sensitivity in the detection of neuropathy.
Address for correspondence: Dr. A. K. Meena, Department of Neurology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad-500 082, Telangana, Andhra Pradesh, India. E‑mail: [email protected] Received : 09-12-2014 Review completed : 10-12-2014 Accepted : 16-12-2014
Key words: Impaired glucose tolerance, nerve conduction studies, neuropathy,
prediabetes, quantitative sensory testing
Introduction Diabetes mellitus (DM) and the associated disease outcomes are a cause for concern worldwide. The current Access this article online Quick Response Code:
Website: www.neurologyindia.com PMID: *** DOI: 10.4103/0028-3886.149393
656
global prevalence of DM for all ages has been estimated at 2.8% and is projected to be 4.4 percent by 2030.[1] The need of the hour is to identify and treat the risk factors that may prevent the onset of DM and minimize morbidity. DM is often associated with peripheral neuropathy (PN) an important cause of foot ulceration, and amputation. Currently, there is a growing focus on the study of early diabetic neuropathy. The Diabetes Control and Complications Trial (DCCT) demonstrated that improved glycemic control can slow the progression of neuropathy.[2] Recent observational studies suggest an association between impaired glucose tolerance (IGT) and neuropathy. These studies have suggested a Neurology India | Nov-Dec 2014 | Vol 62 | Issue 6
Kannan, et al.: Impaired glucose tolerance and neuropathy
predominance of involvement of small nerve fibers in the neuropathy of IGT.[3,4] It has been shown that IGT is an indicator of pre‑diabetes. Prediabetes is a condition in which blood glucose levels are higher than normal, but not high enough to be diagnosed as type 2 DM. Pre‑diabetes is a known risk factor for overt diabetes and its macrovascular complications. Although neuropathy is an extensively studied complication in patients with DM; however, the neuropathy risk in pre‑diabetes has not been well characterized. The potential link between pre‑diabetes and neuropathy has been recognized based on clinical observation that many patients with idiopathic neuropathy share phenotypic characteristics of diabetes, such as obesity, hypertension, and dyslipidemia, without having overt diabetes. This led several investigtors to examine the prevalence of pre‑diabetes using OGTT. The prevelance of neuropathy in these patients was between 40% and 50%, These observations suggest that a substantial proportion of subjects with IGT exhibit PN and/or neuropathic pain.[5] But, whether neuropathy already exists in the pre‑diabetic stage with IGT is not clear. With this background, this present study was undertaken to determine the prevalence of neuropathy in patients with pre‑diabetes with IGT using different electrophysiological techniques who had no other identifiable cause of neuropathy.
Materials and Methods The study was conducted in the department of Neurology, at our institute and the study cohort included 58 subjects. We adhered to the good clinical practice guidelines of Helsinki declaration. The protocol was approved by the hospital ethics committee and informed consent was taken from all the subjects. The study subjects were referred from a diabetes health camp conducted at the department of Endocrinology. These subjects were diagnosed to have prediabetes as for the World Health Organization (WHO) criteria.[6] Age‑matched subjects with normal GTT were the controls. The subjects were followed for a 4‑year period for development of diabetes. The subjects were considered prediabetic if the fasting plasma glucose was less than 126 mg/dl and the 2‑hour oral glucose tolerance test (OGTT) was between 140–200 mg/dl. Other inclusion were: Normal glycosylated hemoglobin (HbA1c), normal vitamin B12 levels and thyroid function. Serum antinuclear antibodies (ANA) were negative in all of the patients. Individuals who had non‑healing skin sores or any foot deformities, history of exposure to agents such as heavy metals, anti‑tuberculosis drugs, cancer drugs, opioid drugs were excluded from the study. Individuals who Neurology India | Nov-Dec 2014 | Vol 62 | Issue 6
were fasting or had a light breakfast were also excluded from the study. Also, anti‑hypertensive medication if any was administered to study participants after the tests were performed. A detailed clinical examination was done by a neuromuscular expert using neuropathy total symptom score (NTSS).[7] All patients were clinically normal. Complete clinical neurological assessment was done on all these patients by a neuromuscular specialist. Subjects who had symptoms of neuropathy were excluded from the study. None of the patients included in the study had neurological deficit. Medtronic Keypoint machine (Denmark) was used for nerve condiction studies (NCS) using surface electrodes with >45‑min acclimatization (room temperature 22–24°C). Examinations were performed as per the established clinical practice. Conventional NCS were done in one upper and both lower limbs: Median, ulnar, bilateral common peroneal, posterior tibial, sural nerves, dorsal sural nerves, and medial and lateral plantar nerves. Neuropathy was considered when abnormal NCS were present in ≥2 nerves.[8] NCS was considered abnormal if there was reduction of Compound Muscle Action Potential / Sensory Nerve Action Potential (CMAP/ SNAP) amplitudes, reduction in conduction velocity, increased distal latencies more than 2 standard deviations. Tests for evaluation of autonomic function tests (AFT) were: Heart rate response to deep breathing (HRDB), valsalva maneuver, standing (30:15 ratio), blood pressure response to standing and sympathetic skin response (SSR). Abnormality in ≥2 tests were considered as abnormal AFT.[9] Quantitative sensory testing (QST) was performed by Computer Assisted Sensory Examination System IV (CASE IV–WR Medical). QST was performed at the dorsal surface of great toe. Vibration detection threshold (VDT) was estimated at maximum allowed stimulation of 576.60 µm and tested at 4, 2, and 1 stepping algorithm with null stimuli.[10] Thresholds ≥95th percentile for age were taken as abnormal. Cooling detection threshold (CDT) was evaluated at the dorsal surface of the foot. The maximum allowed stimulation was 9oC for 10 sec. with starting temperature of 30oC and ramp rate of 4.0oC. at 4, 2, and 1 stepping algorithm with null stimuli. Heat pain threshold (HPT) was evaluated at the dorsal surface of the foot. Maximum stimulation was fixed at 45oC for 10 sec., with baseline skin temperature of 34oC, measured on scale of 1 to 10 where one was considered as the least discomfort or pain and 10 as most severe pain. It was assessed by testing with non‑repeating ascending stepping algorithms with null stimuli.[11] 657
Kannan, et al.: Impaired glucose tolerance and neuropathy
The significance of the variables were calculated using Chi square test (P 30 is a risk factor for prediabetes and DM. However, prediabetes is seen in non‑obese individuals (BMI < 30 kg/m2).[28,29] In our study, 96.6% had BMI < 30. Low HDL cholesterol has been found to be a risk factor for developing neuropathy as described previously.[30] It can be inferred from this study that QST can be a more useful technique than NCS as it may allow earlier diagnosis of neuropathy in IGT. But, QST tests are dependent on subjective responses and therefore have a high interobserver variability and poor reproducibility. It is, therefore, suggested to combine QST with NCS and with patient’s symptoms to arrive at a diagnosis. This study can be further extended to a larger sample size. Also, skin biopsy can be included as a measure of neuropathy. The study demonstrated that a considerable proportion of subjects with IGT exhibit subclinical, asymptomatic PN especially of small fibers. Dorsal sural nerve conduction and medial plantar nerve conduction study should be included in the protocol. Family history of diabetes may predispose to prediabetes neuropathy. Subjects with dyslipidemia and BMI
