1. Diabetic Autonomic Neuropathy (DAN)

2. Introduction

3. Epidemi0logy ● Is a serious & a common complication of DM. ● Frequently coexists with other peripheral neuropathies & other diabetic complications or may be isolated. ● Frequently precedes the detection of other complications. ● Prevalence of DAN varies depending on : 1)whether studies have been carried out in the community, clinic, or tertiary referral center. 2)lack of standard accepted definition of DAN & different diagnostic methods. 3)age, sex, duration of DM, type of DM & glycemic control. ● The 5 year mortality rate of diabetics who showed symptoms of DAN & a disrupted HRV in cardiovascular autonomic function tests was 53%, compared to only 15% in diabetics without autonomic dysfunction.

4. Clinical manifestations  Cardiovascular :-  Gastrointestinal:- Resting tachycardia Esophageal dysmotility Orthostatic hypotension Constipation Exercise intolerance Diarrhea Silent myocardial ischemia Fecal incontinence  Genitourinary:-  Metabolic:- Neurogenic bladder Hypoglycemic unawareness Erectile dysfunction Hypoglycemia - associated Retrograde ejaculation autonomic failure Dyspareunia  Sudomotor:-  Pupillary:- Anhydrosis & dry skin Decrease diameter of dark - Heat intolereance adapted pupil

5. Differential Diagnosis (1)Pure autonomic failure (formerly called idiopathic orthostatic hypotension) (2)Multiple system atrophy with autonomic failure (formerly called Shy - Drager syndrome) (3)Addison’s disease & hypopituitarism (4)Hypovolemia (5)Peripheral autonomic neuropathies (e.g amyloid neuropathy, idiopathic autonomic neuropathy) (6)Medications (e.g sympathetic blockers, vasodilators )

6. Pathophysiology Possible pathological mechanisms of diabetic neuropathy : ● Disorders of polyol metabolism ● Disorders of FA metabolism ● Accumulation of glycated proteins ● Endoneural ischemia ● Oxidative stress ● Destruction of nerve growth factors & axonal transport ● Immunological : autoimmune, inflammatory response

7. Aim of the work

8. To study autonomic changes that accompany diabetic neuropathy

9. Materials & Methods

10. The tests were done on 2 groups :  Control group (n=2) : Known healthy subjects  Diabetic neuropathy group (n=2) : Known diabetic patients complicated with peripheral neuropathy

11. Power lab apparatus

12. Sphygmomanometer Bridge amplifier Bio amplifier

13. Pneumotracer ECG leads

14. Disposable syringe Hand grip

15. Lab chart settings

16. Screening (A)Parasympathetic tests :-  HR response to deep breathing :- - The patient breathes deeply for 3 cycles. - Greatest HR difference during each cycle is measured & the differences are averaged. Normal : ≥ 15 BPM Borderline : 11-14 BPM Abnormal : ≤ 10 BPM

17. First cycleSecond cycle Third cycleAverage HR Control 1 96 - 80 = 16 96 - 79 = 1797 - 97 = 18 17 BPM Control 2 89 - 59 = 30 87 - 60 = 2789 - 60 = 29 29 BPM Patient 1 97 - 89 = 8 88 - 79 = 9 97 - 89 = 8 8 BPM (abnormal) Patient 2118 - 90 = 28 135 - 94 = 41139 - 77 = 62 44 BPM

18. HRV with deep respiration (Control)

19. HRV with deep respiration (Patients)

20.  HR response to Valsalva :- - Subject breathes into disposable cardboard mouthpiece attached to sphygmomanometer to keep pressure at 40 mmHg for 15 sec. - Ratio of longest R-R within 20 beats of ending manouvre to shortest R-R during manouvre. - Test is done 3 times & the average ratio is measured. Normal : ≥ 1.21 Abnormal : ≤ 1.20

21. First Valsalva Second Valsalva Third Valsalva Average ratio Control 1 0.88 s/0.56 s = 1.58 0.89 s/0.56 s = 1.6 0.89 s/0.56 s = 1.6 1.59 Control 2 0.78 s/0.35 s = 2.21 0.76 s/0.54 s = 1.40 0.98 s/o.30 s = 3.21 2.27 Patient 1 1.22 s/0.52 s = 2.33 0.84 s/0.52 s = 1.6 1 s/ 0.5 s = 2 1.97 Patient 20.92 s/0.27 s = 3.55 0.63 s/0.17 s = 3.69 1.01 s/0.23 s = 4.44 3.89

22. HR response to Valsalva (Control)

23. HR response to Valsalva (Patients)

24.  HR response to standing :- 30 : 15 ratio Longest R-R at 30th beat & Shortest R-R at 15th beat Normal : ≥ 1.04 Borderline : 1.01-1.04 Abnormal : ≤ 1.00 Shortest R-R Longest R-R 30 : 15 ratio Control 1 0.05 s 0.26 s 5.57 Control 2 0.272 s 0.89 s 3.27 Patient 1 0.24 s 0.3 s 1.24 Patient 2 0.35 s 1.28 s 3.67

25. B)Sympathetic tests :-  BP response to standing :- Normal : ≤ 10 mmHg Borderline : 11-20 mmHg Abnormal : ≥ 30 mmHg Lying Standing (after 1 min) Difference in systolic BP Control 1 120 / 80 zero Control 2 120 / 75 130 / 80 10 Patient 1 140 / 90 zero Patient 2 100 / 70 88 / 70 12 (Borderline)

26. Response to standing (Control)

27. Response to standing (Patients)

28.  BP response to sustained handgrip :- - Maintaining handgrip at 30% of max. voluntary pressure for up to 5 min. - Systolic BP is recorded every min. - Stop if rise reaches normal level. If not, record just before handgrip release at 5 min. Normal : ≥ 16 mmHg Borderline : 11-15 mmHg Abnormal : ≤ 10 mmHg

29. Before 1 min 2 min 3 min 4 min 5 min Control 1 120 / 80 130 / 90 130 / 96 136 / 98 Control 2 130 / 90 140 / 90 144 / 100 146 / 100 Patient 1 140 / 100 142 / 108 150 / 100 140 / 110 140 / 106 140 / 106 (abnormal) Patient 2 100 / 80 110 / 90 114 / 90 116 / 90

30. Hand grip (Control + patients)

31. Discussion

32. ► The tests described are based on the responses of HR & BP to variety of stimuli. ► The first 3 tests reflect cardiac parasympathetic integrity. While the last 2 tests start to give abnormal results with more severe sympathetic nerve damage. ► While each test may be used individually, all 5 should be performed when possible, so giving fuller information about the state of the autonomic nervous system. ► These tests are valid as specific markers of autonomic neuropathy if the following has been carefully ruled out & taken into consideration : 1-End-organ failure & other concomitant illness 2-Drug use (including anti-depressants, over-the-counter antihistaminics & cough, cold preparations, diuretics & aspirin) 3-Life style issues (such as exercise, smoking & caffeine intake) 4-Age

33. Grading Normal : All tests normal or 1 borderline Mildly abnormal : One of the 3 HR tests abnormal or 2 borderline Definitely abnormal : ≥ 2 of the HR tests abnormal Severely abnormal : ≥ 2 of the HR tests abnormal plus one or both of the BP tests abnormal, or both borderline EWING DJ, CLARKE BF (1982):Diagnosis and management of diabetic autonomic neuropathy. BRITISH MEDICAL JOURNAL; 285 2 OCTOBER :916-18.

34. ► By studying the results of the control group & the diabetic neuropathy group, we found that : - HRV with deep respiration was below the normal level in patient 1 while it was normal in patient 2. -There was no abnormality detected in results of Valsalva test & HR response to standing in both patients. -The result of BP response to sustained handgrip was below the normal level in patient 1. -Results of BP response to standing test in patient 2 was borderline. -To conclude, patient 1 has both sympathetic & parasympathetic affection. On the other hand patient 2 is normal, yet the sympathetic system starts to be affected.

35. ►The natural history of autonomic damage in diabetic patients is becoming clearer, with parasympathetic damage occurring earlier. Ewing DJ, Campbell IW, Clarke BF (1981): Heart rate changes in diabetes Mellitus. Lancet;i:183-6. However, this isn’t always the fact, sometimes the sympathetic system may be affected earlier than parasympathetic system. (http://care.diabetesjournals.org/content/26/5/1553.full)http://care.diabetesjournals.org/content/26/5/1553.full

36. Thank you