Diabetic AutonomicNeuropathy

(DAN)

Introduction

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 .

Clinical manifestationsCardiovascular :- Gastrointestinal:- Resting tachycardia Esophageal dysmotility Orthostatic hypotension Constipation Exercise intolerance Diarrhea Silent myocardial ischemia Fecal incontinenceGenitourinary:- 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

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 )

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

Aim of the work

To study autonomic changes that accompany diabetic neuropathy

Materials & Methods

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

Power lab apparatus

SphygmomanometerBridge amplifier

Bio amplifier

Pneumotracer

ECG leads

Disposable syringe

Hand grip

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

First cycle

Second cycle

Third cycle

Average HR

Control 1

96 - 80 = 16

96 - 79 = 17

97 - 97 = 18

17 BPM

Control 2

89 - 59 = 30

87 - 60 = 27

89 - 60 = 29

29 BPM

Patient 1

97 - 89 = 8

88 - 79 = 9

97 - 89 = 8

8 BPM (abnormal)

Patient 2

118 - 90 = 28

135 - 94 = 41

139 - 77 = 62

44 BPM

HRV with deep respiration (Control)

HRV with deep respiration (Patients)

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

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 2

0.92 s/0.27 s = 3.55

0.63 s/0.17 s = 3.69

1.01 s/0.23 s = 4.44

3.89

HR response to Valsalva (Control)

HR response to Valsalva (Patients)

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

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 / 80 120 / 80 zero

Control 2 120 / 75 130 / 80 10

Patient 1 140 / 90 140 / 90 zero

Patient 2 100 / 70 88 / 70 12 (Borderline)

Response to standing (Control)

Response to standing (Patients)

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

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

Hand grip (Control + patients)

Discussion

► 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

GradingNormal : 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.

► 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 .

►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)

Thank you