6.0 BRIEF RESUME OF THE INTENDED WORK

ANNEXURE-I

6.1 NEED FOR STUDY :

Diabetes Mellitus is a common metabolic disorder with alarmingly increasing worldwide incidence. It has risen over the past two decades from an estimated 30 million cases in 1985 to177 million in 2000, and is estimated to cross a global estimate of 360 million individuals by 2030.

India leads the world today with the largest number of diabetics in any given country. In the 1970s, the prevalence of diabetes among urban Indians was reported to be 2.1 per cent and this has now risen to 12.1 per cent.

Diabetes was previously known to man for centuries but yet fully understood. Though, in 1922, insulin was introduced, as one of the prime therapies in control of diabetes mellitus, it was disappointing that the complications were increasingly observed in surviving patients.

Autonomic neuropathy is one which is often a disabling complication of Diabetes Mellitus. Failure to recognize the symptoms in a Diabetic, as due to autonomic neuropathy, may lead to a lot of unnecessary investigations and, sometimes, to wasteful treatment, such as testosterone in sexual impotence. Disorder of the Autonomic nervous system is being increasingly recognized in Diabetes Mellitus but the extent of abnormality in various organ systems is yet to be determined. Their interpretations have been aided over the years by the development of simple non-invasive test of cardiovascular reflex functions, though a more detailed analysis needs sophisticated equipments, such as a tilt table, a pulse transducer and tests like Light Reflex Pupillography (LRP), whichevaluate the pupil autonomic functions. These simple tests can detect even the earliest evidences of Autonomic Neuropathy.

Yet we must recall that autonomic neuropathy in Diabetes can be associated with substantial morbidity and mortality, however insidious the onset may be. In fact, sudden death due to a cardiac arrest and silent myocardial infarction in Diabetes Mellitus has been attributed to Cardiac Autonomic Dysfunction.

Similarly, impotence in Diabetes has been a very common symptom, though less commonly reported, and may have significant psychological effects.

Depending on the methods of assessment, the prevalence of Autonomic Neuropathy in Diabetics ranges from 10-100%. Thus, this study of Autonomic Manifestations in Diabetes Mellitus is of great significance.

ANNEXURE-II

6.2 REVIEW OF LITERATURE:

Diabetes has been known to man since centuries before Christ. Shushrutha, in 5th century B.C., described it as “`Madhumeha’-urine resembling honey”. According to Papyrus Ebers, Diabetes was known to 3500 years ago, in the days of Moses. Celsus was the first among those who gave a good clinical description of Diabetes. Areatus was the first to name it `Diabetes’ (meaning `to run through’), in the second century A.D.

Clinical features delineating autonomic neuropathy were first described in detail by Jordan in 1936 and Rundle in 1945. During 1950s and 1960s, physiologists devised a variety of techniques to ascertain the pattern of autonomic nervous involvement. The methods were cumbersome, unpleasant for the patient and highly prone for errors, due to lack of patient compliance. After 1960, simple non-invasive tests were devised, and it soon became apparent that autonomic involvement was not only more common than previously thought, but also it can be detected objectively before it manifested clinically.

Noronha J.L., Bhandarkar S.D., Shenoy P.N., Retnam V.J., 19811conducted a study to determine the frequency and pattern of autonomic neuropathy in Diabetic patients, in which a selective group of 33 well-controlled diabetics (27 men and 6 women), who had had the disease for at least 5 years were investigated for the presence and pattern of autonomic neuropathy (31 were Non-Insulin Dependant Diabetes Mellitus and 2 were Insulin Dependant Diabetes Mellitus)

Of them, 17 patients had one or more symptoms, of which 9 patients complained of nocturnal polyuria, 8 had impotence, 7 had postural giddiness, and only 2 had constipation.

R.C.Gupta , M.D. Chittora, et al, 1995,2 conducted a study on 50 patients of Diabetes Mellitus (both IDDM and NIDDM) with typical symptoms, signs and positive bed side tests of autonomic neuropathy. All of the patients were followed for three months during which strict metabolic control was achieved by routine treatment with oral hypoglycemic agents and/or insulin, simply by change in their previous treatment dosages and better attention to diet and physical activity.

22% patients showed significant improvement in symptoms of autonomic neuropathy, 42% showed partial improvement and 36% did not show any improvement.

M.Lakhotia, P.K.D. Shah, R.Vyas, S.S. Jain, 1997,3studied 50 Diabetic patients (38 NIDDM and 12 IDDM) and 10 healthy age matched controls, after they were subjected to 7 standardized autonomic reflex tests. Based on the scoring criteria for severity of Dysautonomia, 8 of the IDDM and 24 of the NIDDM patients had Dysautonomia, with one-third of the total study group having Grade 4 Autonomic Dysfunction.

They also revealed that the severity of Autonomic dysfunction was directly related to the duration of disease in NIDDM, whereas in IDDM, this relation was not seen.

Harrison’s Principles of Internal Medicine, 17th edition, 4 states that the earliest autonomic abnormality, typically asymptomatic, consists of vagal disturbances, which can be detected as reduced heart rate variation with deep breathing, and loss of distal sudomotor functions. Autonomic dysfunctionsmay lengthen QT interval thus increasing the risk of sudden death due to cardiac arrhythmias. Typical signs and symptoms of hypoglycemia may fail to appear because of damage to sympathetic innervations.

Symptomatic visceral autonomic neuropathy had a prevalence of 5.5% in a population-based study of Diabetic patients in Rochester, Minnesota.5

In a Community-based Population study of Diabetic Neuropathy in Oxford, England, 5 the prevalence of Autonomic Neuropathy as defined by one or more abnormal Heart Rate Variability (HRV) test results was 16.7%.

In a further study, Ziegler and colleagues5evaluated the prevalence of cardiac autonomic neuropathy1171 diabetic patients randomly recruited from 22 diabetes centers in Germany, Austria and Switzerland, The study found that 25.3% of patients with Type 1 Diabetes and 34.3% of patients with Type 2 Diabetes had abnormal in more than two of six autonomic function tests.

A.Goel, Ruchika Agarwal, et al, 2004, 7aimed to study, in 75 Diabetic adults, the importance of simple bedside tests (Ewing’s methodology) in recognizing Cardiac Autonomic Neuropathy. It was concluded that Ewing’s Battery of tests are simple bedside, feasible, accurate and essential component of the comprehensive Diabetic care yet the symptoms alone are inadequate in diagnosing Autonomic Neuropathy.

J.M.Pappachan, J.Sebastian, et al,8 conducted a study on the prevalence of Cardiac Autonomic Neuropathy (CAN) and its relationship to corrected QT interval, among 100 diabetic patients (both Type 1 and Type 2), assessed by the 5 autonomic function tests by Ewing’s methodology. This study revealed the prevalence to be 60%, with the univariate analysis showing a significant association between CAN and Prolonged corrected QT interval (OR 5.55s).

Mathias Dutsch, Harold Marthol, et al, 2004, 9 tested whether Light Reflex Pupillography (LRP) demonstrates autonomic papillary dysfunction in Diabetics independently from Cardiac Autonomic Neuropathy (CAN) and Peripheral Neuropathy in 36 Type 2 Diabetes Mellitus and 36 controls. 28 (77.8%) patients had abnormal pupillography results but only 20 patients (56%) had signs of Peripheral Neuropathy or CAN, and in 9 Patients with Peripheral Neuropathy, only Pupillography identified autonomic neuropathy. Thus, LRP demonstrates sympathetic and parasympathetic pupillary dysfunction independently from Peripheral Neuropathy or CAN, and thus, refines the diagnosis of Autonomic Neuropathy in Type 2 Diabetes Mellitus.

Harold Marthol, Udo Zikheili, et al, 2007, 10studied 13 patients with early stage Type 2 Diabetes Mellitus by continuously recording the R-R interval, mean blood pressure and mean middle cerebral blood flow at rest, mainly to assess the contribution of cerebral autoregulation to orthostatic intolerance, in diabetic patients with dysautonomia.

The study revealed a constant and intact cerebral blood flow, in spite of earlier and greater impairment of peripheral vasomotor control, thus maintaining cerebral blood flow constant and protecting patients from symptoms of syncope.

D. Chowdary, N. Patel, Update Article on Approach to case of Autonomic Neuropathy, 11 states that Diabetes Mellitus is the most important cause of autonomic neuropathy. Autonomic features, which involve the cardiovascular, gastrointestinal, urogenital, sudomotor and pupillomotor systems, occur in varying combinations, of which, Orthostatic Hypotension is often the first, recognized and most disabling symptom.

Dysautonomia results from a failure of the Autonomic nervous system to compensate for the acute decrease in venous return that occurs with upright posture. This compensatory failure is attributed to a failure of the baroreceptors to detect a drop in the blood pressure or a derangement in the afferent limb of the Autonomic Nervous System to respond to the decrease in the blood pressure. Alternatively or concomitantly, the failure of the peripheral circulation to respond to a drop in blood pressure is attributed to a reduction in the end-organ responsiveness to circulating vasoconstrictors. Severe Dysautonomia results in a dramatic drop in Blood pressure and syncope. 6

Non-invasive, well-validated clinical tests of autonomic functions are of immense value to diagnose the presence and to demonstrate the distribution of autonomic failure in Diabetes Mellitus

ANNEXURE-III

6.3Objectives and Background of the Study:

  1. To observe the presenting manifestations of autonomic dysfunction in Diabetes Mellitus.
  2. Objective assessment of the autonomic dysfunction in relation to cardiovascular involvement.
  3. To evaluate influencing factors like duration of Diabetes, glycemic status and complications on occurrence and frequency of autonomic neuropathy.

7. MATERIALS AND METHODS:

ANNEXURE-IV

7.1 SOURCE OF DATA:

The data will be collected from Diabetic patients, admitted to Department of Medicine at SriAdichunchungiriHospital and ResearchCenter, B.G.Nagara.

ANNEXURE-V A

7.3 Does the study require any investigations or interventions to be conducted on patients or other animals, if so, please describe briefly:

Investigations:

  1. Blood routine (Haemoglobin, Total count, Differential count, ESR)
  2. Urine routine
  3. Fasting Blood Sugar
  4. Post-prandial Blood Sugar
  5. Glycosylated Haemoglogin (%)
  6. Blood Urea
  7. Serum Creatinine
  8. Electrocardiogram

7.4 Has Ethical Clearance been obtained from your institution in case of 7.3

YES

ANNEXURE-V

7.2 METHOD OF COLLECTION OF DATA:

Section of patients: the study will be conducted on 50 patients, who were admitted with Diabetes Mellitus of duration of minimum 5 years, in the Department of Medicine, at SriAdichunchungiriHospital and Research Centre, B.G.Nagara.

Duration of Study:18 months

Sample size: The sample size includes 50 patients with Diabetes Mellitus, {Type 1 (IDDM) and Type 2(NIDDM) patients included}, with duration of minimum of 5 years, selected by simple random method.

Inclusion criteria:

Criteria for diagnosis of Diabetes4 12 14 15 16:

  1. Symptoms of Diabetes (polyuria, polydipsia, polyphagia,excessivefatigue, weight loss, blurred vision, growth impairment) with Random Blood Glucose (venous blood) concentration of more than 200 mg/dl.

OR

  1. A fasting (of more than 8 hours) blood glucose levels of more than 126 mg/dl.

OR

  1. Two-hour Post-prandial blood glucose levels of more than 200 mg/dl.

The etiology of Diabetes in an individual can usually be assigned on the basis of clinical criteria. Individuals with type 1 DM4 tends to have the following characteristics:

  • Onset of diabetes prior to age 30
  • Lean body habitus.
  • Requirement of insulin as the initial therapy.
  • Propensity to develop ketoacidosis
  • An increased risk of other autoimmune disorders such as autoimmune thyroid diseases, pernicious anemia and vitiligo.4

The study shall include Diabetics, diagnosed, as above, of duration of minimum period of 5 years.

Exclusion Criteria: Patients with:-

  • Severe Anemia
  • Congestive Cardiac Failure
  • Uncontrolled Diabetes
  • Gross Nutritional Deficiency
  • Chronic alcoholism.
  • Exposure to lead, Neurotoxic drugs ( like INH) and drugs affect in the autonomic function
  • Renal Failure
  • On Anti-hypertensive medication
  • Chronic obstructive lung disease
  • Central or peripheral neuropathies due to cause other than Diabetes
  • Liver Diseases
  • Cardiac arrhythmias

Were excluded from the study.

Method of Study:

The selected 50 Diabetic patients will be questioned about the presence of symptoms reported to be related to autonomic neuropathy, viz. postural giddiness, nocturnal polyuria, disturbances of bladder sphincter, constipation, diarrhea, impotence and bouts of localized sweating.

Selected patients will be subjected to a detailed clinical examination and an optic fundus examination. Then the following test will be performed to assess the autonomic functions of these patients:-

  1. Tests reflecting Parasympathetic functions:
  2. Heart rate variation during deep breathing.
  3. Heart rate response to Valsalva Maneuver
  4. Immediate Heart rate response to Standing.

2. Tests reflecting Sympathetic functions:

a. Blood pressure response to standing.

b. Blood pressure response to sustained handgrip.

3. Corrected QT-interval in the electrocardiogram, to assess cardiac autonomic neuropathy features.

Based on the variations in the above tests, the Autonomic Manifestations in Diabetics shall be ascertained, and further analyzed.

ANNEXURE-VI

8.LIST OF REFERENCES

  1. Noronha J.L., BhandarkarS.D., Shenoy P.N., Retnam V.J.Autonomic Neuropathy in Diabetes Mellitus, J Postgrad Med 1981; 27: 1-6
  2. R.C.Gupta, M.D. Chittora, A. Jain, A study of Autonomic Neuropathy in Diabetes Mellitus in relation to its metabolic control, JAPI 1995,vol. 43, no.7
  3. M, Lakhotia, P.K.D. Shah, R.Vyas, S.S. Jain, A. Yadav, M.K.Parihar, Clinical Dysautonomia in Diabetes Mellitus- A Study with Seven Autonomic Reflex Function Tests, JAPI 1997, vol. 45, no.4
  4. Harrison’s Principles of Internal Medicine, Autonomic Neuropathy in Diabetes Mellitus, Chapter 338, 17th edition, pg.2289-2293.
  5. Vivian A. Fonseca, Clinical Diabetes: Translating Research into practice, Chapter 11, Pages 145- 146
  6. Luther. T. Clark, Cardiovascular Diseases and Diabetes, Pages 117-118
  7. A.Goel. Ruchika Agarwal, S.Singla, K.K. Lakhani, D.T. Sonigra, S.B. Agarwal, A clinical study on Autonomic nervous system manifestations in Diabetes mellitus.
  8. J.M.Pappachan, J.Sebastian, B.C. Bino, et al, Cardiac Autonomic Neuropathy in Diabetes Mellitus: prevalence, risk factors and utility of Corrected QT interval in the ECG for its Diagnosis, Kottayam Medical College, South India. Melaka Manipal Medical College, Malaysia.
  9. Matthias Dutsch, Harald Marthol, Georg Michelson, Bernhard Neundorfer, Max Josef Hilz, Pupillography refines the diagnosis of Diabetic Autonomic Neuropathy,Journal of the Neurological Sciences, 15th July 2004, vol.222, issue 1, pages 75-81.
  10. Harald Marthol, Udo Zikeli, Clive Martin Brown, Marcin Tutaj, Max Josef Hilz, Cardiovascular and Cerebrovascular responses to lower body negative pressure in Type 2 Diabetic patients, Journal of the Neurological Sciences, 31st January 2007, vol.252, issue 2, pages 99-105.
  11. D. Chowdary, N. Patel, Update article on Approach to a case of Autonomic Peripheral Neuropathy
  12. A P I Textbook of Medicine, Diagnosis of Diabetes Mellitus, 8th edition, vol. 2, pages 1049-1051
  13. Pradeepa. R, Mohan .V, The changing scenario of the diabetes: Epidemic Implications for India, Indian Journal of Medical Research, Oct 2002
  14. Who consultation group. Defination, diagnosis, and classification of Diabetes mellitus and its complication, 2nd edition part 1: Diagnosis and classification of Diabetes Mellitus WHO/NCD/NCS/99. Geneva: World Health Organization, 1999: 1-59
  15. American Diabetes Association
    Standards of medical care in diabetes—2007
    Diabetes Care 2007; 30(Suppl 1), S4-S41
  16. Gabir M.M., Hanson R.L., Dabela D. et al. The 1997 American Diabetic Association and 1999 World Health Organization criteria for Hyperglycemia in the diagnosis and prediction of Diabetes. Diabetes Care 2000; 23;1108-1112