Correlation of Neuropathy with Corneal Sensitivity and Lacrimal Gland Secretion in Type 2 Diabetes Mellitus Patient

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1 ORIGINAL ARTICLE Correlation of with Corneal Sensitivity and Lacrimal Gland Secretion in Tye 2 Diabetes Mellitus Patient Andreas Nuho FL*, Imam Subekti**, Dasnan Ismail***, Ratna Sitomul**** ABSTRACT Aim: to evaluate correlation between blood glucose control, corneal sensitivity and lacrimal secretion in tye 2 DM with eriheral neuroathy Methods: a cross sectional study has been conducted in 20 tye DM with eriheral neuroathy and 20 without eriheral neuroathy at the Deartment of Internal Medicine and Ohthalmology, Citomangunkusumo Hosital, Faculty of Medicine University of Indonesia, from August through November All subject underwent a comrehensive medical examination, including esthesiometer Semmes-Weinstein 10 g, HbA1c, test, and corneal sensitivity measurements. Results: the mean corneal sensitivity was significantly lower in diabetic atients with neuroathy (= 0.000). HbA1c was related to corneal sensitivity (=0.016) Conclusion: in tye 2 DM with eriheral neuroathy, corneal sensitivity was demonstrated to be significantly decrease, all of which seems to be due to the status of blood glucose control. Key words: eriheral neuroathy, lacrimal secretion, corneal sensitivity. *Deartment of Internal Medicine,Faculty of Medicine of The University of Indonesia-Dr.Cito Mangunkusumo National Central General Hosital, Jakarta, **Division of Endocrinology-Metabolism, ***Division of Cardiology, Deartment of Internal Medicine,Faculty of Medicine of The University of Indonesia-Dr.Cito Mangunkusumo National Central General Hosital, Jakarta,, ****Division of Infecton and Immunology, Deartement of Ohthalmology, Faculty of Medicine of The University of Indonesia-Dr.Cito Mangunkusumo National Central General Hosital, Jakarta. INTRODUCTION Diabetes mellitus (DM) is a metabolic disease, which is characterized by hyerglycemia due to defect on insulin secretion, insulin function, or both. In 1995, DM revalence at adolescence grou was about 7,4%, and it is estimated to increase u to 9% in In Indonesia the revalence of DM in 190 was 1,5% - 2,3% in oulation over 15 years old. And, in Manado the revalence was 6,1%. The survey of Deartment of Health 190 reveals that DM occuied the 1 th rank disease. And it is estimated that there will be 7 million of diabetics atient in ,3 Wasadji 4 found that DM cases was increasing from 1,7% to 5,6% between 192 and 1993 in Jakarta. In 195, Bahar 5 reorted was that the revalence of eriheral neuroathy was 5% while autonomic arasymathic neuroathy was 11,9%. By using 10 g monofilament Suryotono 6 found 53,1% neuroathy in DM atient with diabetic foot ulcer while it was only 9.7% in those without diabetic ulcer. By using electromyograhy, Yuson 7 found 2,3% neuroathy cases in diabetic atient, without neuroatic symtom. On 2000, Atlas of Diabetes, it is estimated about 125 million Indonesian eole aged over 20 years old. With assumtion of DM revalence of about 4,6%, there will be 5,6 million eole of diabetic atient, and this number will increase in 2020 u to,2 million atients. It will lead to a big roblem, articularly in the management of DM comlications. Hyerglycemia may cause chronic microvascular comlication such as on kidney and eyes, and macrovascular comlication on coronary, foot and brain blood vessel, as well as neurological defect. 9,10 The most founded neurological defect is symmetric distal sensory olyneuroathy The symtoms of neuroathy usually aear after 9-10 years of DM. Indeed, Pirart found about 12% neuroathy cases in recent diabetic atient. The most founded symtoms are numbness, 130

2 Vol 36 Number 3 July-Setember 2004 Correlation of with Corneal Sensitivity weakness and losing of ain sensation. 16,17 Chronic hyerglycemia also cause neurological defect in the eyes. The cornea is innervated by sensory nerves, i.e. first branch of the fifth cranial (Trigeminus) nerve. 1 Defect on this nerve causes lower corneal sensitivity and imaired secretion of lacrimal gland resulting in lowering of blinking reflex. That will increase the risk of corneal ulcer. 19 In , Rahmadhani 20 reorted that 6,5% of corneal ulcer cases were accomanied by DM. Regarding the ohtalmologic comlication of diabetic atient, we should are interested in evaluating the cornea and secretion of lacrimal glands in diabetic atient, esecially on those who have develoed eriheral neuroathy. Positive Exclude from study TYPE 2 DM PATIENT Evaluation of Exclusion Criteria Positive Negative Examine Periheral with S-W10 g Monofilament Negative Examine the HbA1c Level METHODS The data was collected at the Deartment of Internal Medicine, Division of Endocrinology and Metabolism and at the Deartment of Ohthalmology Division of Infection and Immunology Faculty of Medicine University of Indonesia / Cito Mangunkusumo Hosital Jakarta from August through November The data was collected by consecutive random samling method, then inclusion and exclusion criteria and comlete exlanation about the study were imlemented. Comrehensive history, hysical examination, and also HbA1c examination by ELISA method were conducted. The eriheral neuroathy examination was done by monofilament 10 g Semmes-Weinstein on the first digit of left and right foot. The examination of vibration sensation was done by 12 Hz tuning fork. The examination of autonomic heart function was done by SRR5 GSM AHM utility. Corneal neuroathy was examined by Cochet-Bonnet esthesiometer. Lacrimal gland secretion was examined by Test. The samle needed was 40 DM atients, 20 atients with eriheral neuroathy and 20 atients without eriheral neuroathy resectively, by ower of 0%, 0.05 significance, and correlation coefficient of Data was exressed in text, table and grahic form. The obtained data was rocessed with comuterization. The univariate analysis was alied: to calculate mean and standard deviation (SD), bivariate analysis: to observe correlation within 2 variable by Chi square test. And multivariate analysis was used to calculate correlation of some variables with eriheral neuroathy incident by using logistic regression. P value of 0.05 was token as limit of significance. RESULTS Examine Sensation Vibration with 12 HZ Tuning Fork Autonomic Function with SRR5 Examine Corneal Sensitivity with Cochet-bonet Estensiometer Lacrimal Gland Secretion with Test Figure 1. The Flow Chart Study Subjects of this study were divided into 2 grous, i.e. the grou with eriheral neuroathy, and the grou without eriheral neuroathy. Each grou consists of 20 subjects. In neuroathy grou, the duration of disease ranged from 1 27 years with the mean of 10.6 years. In the grou without neuroathy, the duration of DM ranged from 1 21 years with mean value of.1 years. The age of subjects in neuroathy grou ranged from years with mean value of 59.0 years while in the grou without neuroathy ranged from years, with mean value of 57.1 years. Both grou were socio-demograhically equal and statistically has no significant difference. Socio Demograhic Characteristic Table 1 sohows that most of the atients aged between years. There was more female in the grou without neuroathy. Clinical Characteristic On table 2 we could observe the mean value of HbA1c level in neuroathy grou was significantly higher than the grou without neuroathy. Corneal sensitivity of both grou have been decreased, but it was significantly lower in the grou with eriheral neuroathy. Most of DM tie 2 atients have 131

3 Andreas Nuho,etal Acta Med Indones-Indones J Intern Med decreasing vibration sensation and abnormal autonomic reflex. Generally, the of both grou decreased. Table 1. Grou Demograhic Characteristic Table 2. Grou Clinical Characteristic Correlation Between Corneal Sensitivity and Periheral On table 3 we could observe that generally the eyes corneal sensitivity of both grou has been decreased. The grou with eriheral neuroathy has lower corneal sensitivity than the grou without neuroathy and statistically there was significant difference ( <0.05). Correlation Between Test and Periheral On table 4, the mean value of Schimer test in eriheral neuroathy grou was lower than the grou without neuroathy, but statistically there was no significant difference in both grous. 132 Age years years years Sex Male Female Education Low Intermediate High Occuation Emloyed Unemloyed Mean value of DM eriod (years) Mean value of HbA1c Level (%) Vibration Sensation Decrease Autonomic Reflex Abnormal Cornea Sensitivitity Decrease Test Decrease ( n = 20 ) Neuroath y (n=20) Tye 2 DM Without (n=20) 10,6,1 0,296 7,4 6,5 0, (5%) 3 (15%) 13 (65%) 7 (35%) 20 (100%) 0 20 (100%) 0 n= subject amount = significance Tye 2 DM Without ( n = 20 ) (0%) 4 (20%) 12 (60%) (40%) 15 (75%) 5 (25%) 20 (100%) 0 0,335 0,500 0, ,100 1,000 1,000 0,047 Table 3. Correlation Between Corneal Sensitivity and Periheral in tye 2 DM Corneal Sensitivity tye 2 DM Without n Mean SD n Mean SD 20 33,3 6, ,0 4, 0,000 n = subject amount, SD = Standard Deviation, = significance Table 4. Correlation Between Periheral Test in tye 2 DM Right Left Correlation HbA1c Level and Corneal Sensitivity On table 5, we could observe the correlation (R=0.3) between HbA1c and corneal sensitivity, which was statistically significant ( = 0.016). The correlation attern was negative. Correlation Between Test and Autonomic Reflex Table 6, showed that the test result has been decreased in all the atients and there was significant correlation between test and autonomic neuroathy. Table 6. Correlation between Test and Autonomic Reflex in tye 2 DM Right Test Left Test tye 2 DM Without n Mean SD n Mean SD 20 5,4 2,7 20 6,5 1,4 0, , 2,5 20 6,4 1,1 0,65 n = Subject amount, SD = standard deviation, = significance Table 5. Correlation between HbA1c Level and Corneal Sensitivity in tye 2 DM tye 2 DM R a Sloe All ( n = 37 ) 0,3 50,39-1,91 0,016 n = amount, R = coefficient correlation, = significance a = interset Abnormal Autonomic Reflex n Mean SD n Mean SD 25 6, 1,7 15 4,5 2,2 0, , 1,5 15 4,0 2,0 0,002 n = amount SD = standard deviation = significance P

4 Vol 36 Number 3 July-Setember 2004 Correlation of with Corneal Sensitivity DISCUSSION This study is a comarative cross sectional study. Indeendent variable was only valued once, hence we may not observe the effect of that indeendent variable to eriheral neuroathy incident. Limitation of this study was that it did not use examination of nerve conduction velocity to evaluate eriheral neuroathy, which may detect neuroathy u to 100%. Monofilament may be used to evaluate eriheral neuroathy because it has sensitivity and secificity value of 95 and 2% resectively. 22 The test was not an exact examination to evaluate lacrimal gland secretion, but this examination was clinically simle and inexensive so that grossly we may use it to evaluate lacrimal gland secretion. Prevalence of DM neuroathy of children is about 2% which will be increase in keeing with the DM eriod. Pirart reorted that neuroathy cases has been increased from 12% to 50%, Palumbo et al reorted 4% to 15%, after 20 and 25 years. 21 In Cito Mangunkusumo Hosital, Jakarta, Asril Bahar in 195 reorted that diabetic neuroathy incidence was about 7.02 SD 5.5 years. Partanen et al 15 found the mean of neuroathy comlication was 10 years. In this study, we found mean DM eriod of neuroathy grou was 10.6 years and in the grou without neuroathy tehre was.1 years. The correlation between DM eriod and neuroathy was statistically not significant. This was due to the subject of study hard to recisely redict when he has DM, hence it was hard to redict how long was the DM eriod. These fact was suorted by Pirart who found neuroathy comlication in 12% of recent DM atients. This study found that mean value of HbA1c level in eriheral neuroathy grou was significantly higher than the grou without neuroathy. The effect of blood glucose control on the develoment of DM comlication has been studied by The United Kingdom Prosective Diabetes Study (UKPDS) 23 It suorted the hyerglycemia theory which causes microvascular comlication, and they found that by controlling the blood glucose (HbA1c level less than 7%) the develoment of comlication such as nehroathy, retinoathy and neuroathy will decrease. Other study that has been conducted by The Diabetes Control and Comlications Trial (DCCT) 24 in DM tye 1 atients, found that by controlling the blood glucose, it will decrease the risk of DM comlication. This study was not aimed to find the effect of HbA1c to neuroathy comlication because this study was cross sectional. But this study revealed that HbA1c level in eriheral neuroathy grou was higher than the grou without eriheral neuroathy. Generally we found that the correlation between eriheral neuroathy and corneal sensitivity of this study has been decreased in both grous. In eriheral neuroathy grou, all of its subjects (100%) have low corneal sensitivity, while in the grou without eriheral neuroathy 75% of atients have low corneal sensitivity. The mean value of corneal sensitivity in eriheral neuroathy grou was significantly lower than the grou without eriheral neuroathy. Dogru et all 25 found the mean value of corneal sensitivity in DM atient with eriheral neuroathy and without eriheral neuroathy. The decreased corneal sensitivity in DM atient was art of eriheral oly-neuroathy. Study of diabetics rats found morhological changes in their corneal nerve cells. Rosenberg et all 26 found decreased corneal nerve fibres in diabetics atient, while their corneal sensitivity decreased only in the grou of severe neuroathy. This result was different from Dogru et al articularly in the grou without neuroathy. This difference may be due to different examination method of eriheral neuroathy. Dogru et al used the examination of nerve conduction velocity, hence it may detect nerve disorder at early stage. As known, the corneal nerve fibres is 400 times more momerous than the feet nerves. Although the decrease on nerve conduction in feet, the corneal nerve disorder has not observed yet. The effect of DM on lacrimal gland secretion was studied by Moss et al 27 who found correlation between DM and dry eye syndrome. Dry eye is disorder that occured on eye ball s surface because of decrease lacrimal gland secreation or increase evaoration of tear film. In this study there was decreased lacrimal gland secretion in both grous. The mean value of test in eriheral neuroathy grou was lower than the grou without neuroathy. The result of statistic test revealed no significant difference. Dogru et al found test result in the grou with and without eriheral neuroathy. Martin Gobbels 2 found lower lacrimal gland secretion in diabetics atient than normal control, the same results has also been reorted by Saito et al. 29 There are multifactorial causes of decreased lacrimal gland secretion such as autoimmune disease, inflamation, trauma and diabetes mellitus. The results of this study differ from that of Dogru s et al. It may be due to other factors such as smoking, coffee, and multivitamin usage which did not excluded from this study. 133

5 Andreas Nuho,etal Acta Med Indones-Indones J Intern Med In addition, hormonal factor such as decreased estrogen hormon in menoause female can also affect the lacrimal gland secretion. Most of subjects in this study were female above 50 years-old, so there was osibility of menoause. This was suorted by Susiyanti 30 in the Deartment of Ohthalmology Faculty of Medicine, Cito Mangunkusumo Hosital who found that the severity of dry eye will increase along with the eriod of amnorrhoea ost menoause. There was negative correlation between HbA1c level and corneal sensitivity of blood glucose effect to corneal sensitivity in this study, which revealed every 1 ercent raise in HbA1c level will decrease 1.9 mm corneal sensitivity, and it was statistically significant. The result of animal exeriment found that high blood glucose decreased mioinositol concentration and increased sorbitol level on Schwan cell and axon that resulting damage corneal nerve cells. Dogru et al who found lower corneal sensitivity in DM atient with bad metabolic control comared to good metabolic control. Seifart 31 in his study found that higher level of HbA1c will increase the risk of dry eye develoment, the same thing was found by Palmoski 32 Examination of vibration sensation is usualy used to evaluate neuroathy in nerve fibres with large diameter. In diabetics atient, neuroathy may occured in small or large nerve but usually found in both combination. of small nerve usually recede the large. In this study we found 17 subjects (5%) of eriheral neuroathy grou with decrease vibration sensation while in the grou without eriheral neuroathy there was 16 subjects (0%), but statistically there was no significant difference. Sorman 33 found that vibration sensation has better sensitivity to detect eriheral neuroathy than monofilament. This difference because neuroathy may occur in large or small nerves. We need further study to determine the tye of nerve involved in neuroathy. Autonomic neuroathy is art of diabetic neuroathy. Prevalence of autonomic neuroathy range from 17 40%. In diabetic atient with eriheral neuroathy there was 50% cases accomanied by asymtomatic autonomic neuroathy. Mortality rate of autonomic neuroathy ranged from 15-40%. Cardiovascular reflex was used to detect autonomic neuroathy. This study found 13 subjects (65%) in eriheral neuroathy grou with abnormal autonomic reflex while in the grou without neuroathy there was 12 subjects (60%). These revealed that autonomic neuroathy has been occured in eriheral neuroathy grou and the grou without neuroathy, but it was statistically has no significant difference. Sundvisk 34 found that autonomic neuroathy has strong correlation with eriheral neuroathy in diabetic atients. In the grou of tye 2 DM atients with or without autonomic neuroathy, mean value of their test was decreased. There was significant difference of that decrease in both grous. Andersen 35 found that there is no significant difference of lacrimal gland secretion in diabetic atient with and without autonomic neuroathy. Different result of these studies ossibly because of abnomal autonomic neuroathy classification in this study was combining intermediate and abnormal grou, so that the abnormal amount is greater than normal and it affected the statistical count. CONCLUSION Corneal sensitivity in tye 2 DM atient with eriheral neuroathy was lower and has significant difference comared to diabetic atient without eriheral neuroathy. Lacrimal gland secretion in tye 2 DM atient with eriheral neuroathy has no significant difference comared to diabetic atient without eriheral neuroathy. There was significant correlation between blood glucose control (HbA1c) and corneal neuroathy incidence. We need to evaluate the corneal sensitivity of tye 2 DM atient with eriheral neuroathy There should be well blood glucose control (HbA1c) in tye 2 DM atient to reduce the incidence of corneal neuroathy. REFERENCES 1. American Diabetes Association: screening for tye 2 diabetes (osition statement). Diabetes Care; 26 (sul 1): Suyono S. Masalah diabetes di Indonesia. Buku ajar ilmu enyakit dalam. Dalam: Noer S, ed. Jakarta: Balai Penerbit FKUI; Wasadji S. Diabetes mellitus, mekanisme dasar dan engelolaannya yang rasional. Penatalaksanaan diabetes mellitus teradu. Dalam: Soegondo S,ed. Jakarta: Aksara Buana; Wasadji S, Soegondo S, Rochamah, Suyono S, Suartondo, Sukaton U. Dietary attern of diabetics in an urban oulation in Indonesia. JAFES 192; 2(2): Bahar A. Neuroati autonom diabetik diagnosis dini dan revalensinya di unit enyakit dalam RSCM Jakarta. Bagian Ilmu Penyakit Dalam FKUI/RSUPN CM. Jakarta 195 [Tesis]. 6. Suryotono T. Peran neuroati ada ulkus diabetik ada asien DMTTI rawat ina RS Cito Mangunkusumo Jakarta. Bagian Ilmu Penyakit Dalam FKUI/RSUPN CM. Jakarta 1997 [Tesis]. 7. Yulson. Gambaran elektroneurografi ada dm tie II tana keluhan neuroati di RSCM. Bagian Saraf FKUI/RSUPN CM. 134

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