1. Diabetic Autonomic Neuropathy
Dr Shahjada Selim
Assistant Professor
Department of Endocrinology
Bangabandhu Sheikh Mujib Medical University, Dhaka

2. Pathogenesis

13. Diagnostic Tests of Cardiovascular Autonomic Neuropathy
Method/Parameters
Resting heart rate
> 100 beats/min is abnormal.
Beat-to-beat heart rate variation *
With the patient at rest and supine (no overnight coffee or hypoglycemic episodes), breathing 6 breaths/min, heart rate monitored by ECG or ANSCORE device, a difference in heart rate of > 15 beats/min is normal and < 10 beats/min is abnormal, R-R inspiration/R-R expiration > 1.17 is abnormal. All indices of HRV are age-dependent.**
Parasympathetic activity

14. Diagnostic Tests of Cardiovascular Autonomic Neuropathy
Method/Parameters
Heart rate response to standing *
During continuous ECG monitoring, the R-R interval is measured at beats 15 and 30 after standing. Normally, a tachycardia is followed by reflex bradycardia. The 30:15 ratio is normally > 1.03.
Sympathetic activity
Heart rate response to Valsalva maneuver *
The subject forcibly exhales into the mouthpiece of a manometer to 40 mmHg for 15 s during ECG monitoring. Healthy subjects develop tachycardia and peripheral vasoconstriction during strain and an overshoot bradycardia and rise in blood pressure with release. The ratio of longest R-R shortest R-R should be > 1.2.
Both parasympathetic and sympathetic activity

15. Systolic blood pressure response to standing
Systolic blood pressure is measured in the supine subject. The patient stands and the systolic blood pressure is measured after 2 min. Normal response is a fall of < 10 mmHg, borderline is a fall of mmHg, and abnormal is a fall of > 30 mmHg with symptoms.
Sympathetic activity
Diastolic blood pressure response to isometric exercise
The subject squeezes a handgrip dynamometer to establish a maximum. Grip is then squeezed at 30% maximum for 5 min. The normal response for diastolic blood pressure is a rise of > 16 mmHg in the other arm.
ECG QT/QTc intervals
The QTc (corrected QT interval on EKG) > 440 ms is abnormal.

16. Spectral analysis
 VLF peak↓ (sympathetic dysfunction)
LF peak ↓  (sympathetic dysfunction)
HF peak  ↓(parasympathetic dysfunction)
LF/HF ratio ↓  (sympathetic imbalance)
Neurovascular flow
Using noninvasive laser Doppler measures of peripheral sympathetic responses to nociception. *
These can now be performed quickly (< 15 min) in the practitioner's office, with a central reference laboratory providing quality control and normative values. VLF, LF, HF = very low-, low-, and high-frequency peaks on spectral analysis. These are now readily available in most cardiologists' practices. **
Lowest normal value of E/I ratio: Age 20-24:1.17; 25-29:1.15; 30-34:1.13; 35-30:1.12; 40-44:1.10; 45-49:1.08; 50-54:1.07; 55-59:1.06; 60-64:1.04; 65-69:1.03; 70-75:1.02 .

17. Heart rate variation test
a surrogate for the diagnosis of DAN of any systems (erectile dysfunction, dizziness, dyspepsia )
it is generally rare to find involvement of any other division of the ANS in the absence of cardiovascular autonomic dysfunction (although it does occur).

23. Screening for and treating diabetic autonomic neuropathy

26. Esophageal enteropathy (disordered peristalsis, abnormal lower esophageal sphincter function)
Gastroparesis diabeticorum (nonobstructive impairment of gastric propulsive activity; brady/tachygastria, pylorospasm)
Diarrhea (impaired motility of the small bowel [bacterial overgrowth syndrome], increased motility and secretory activity [pseudocholeretic diarrhea])

27. Constipation (dysfunction of intrinsic and extrinsic intestinal neurons, decreased or absent gastrocolic reflex)
Fecal incontinence (abnormal internal anal sphincter tone, impaired rectal sensation, abnormal external sphincter)
Gallbladder atony and enlargement

28. Gastroparesis diabeticorum
50 percent of patients with long-standing DM have delayed gastric emptying

29. early satiety, nausea, vomiting, abdominal bloating, epigastric pain, and anorexia.
Episodes of nausea and vomiting may last days to months, or they may occur in cycles.

30. nutrient delivery to the small bowel was interfered  glucose absorption and exogenous insulin administration was disrupted wide swings of glucose levels unexpected postprandial hypoglycemia brittle diabetes  poor sugar control
Tx: tight sugar control, multiple small meals, fat and fiber content↓, prokinetic agents

31. Constipation affecting nearly 60% of diabetic patients
associated with atony of the large bowel and rectum and sometimes with megacolon.
Bouts of constipation may alternate with episodes of diarrhea.

32. Constipation
rule out other causes such as hypothyroidism, side effects of drugs such as amitriptyline or calcium channel blockers, and colonic carcinoma
Anorectal manometry may be used to assess the rectal anal inhibitory reflex
Tx: Sorbitol and lactulose, intermittent use of saline or osmotic laxatives, octreotide

33. Diabetic diarrhea affects 20% of diabetic patients
Increased intestinal motility and secretion caused by diminished sympathetic inhibition
Hypomotility with bacterial overgrowth
Exocrine pancreatic insufficiency
Steatorrhea (fat malabsorption)
Bile-salt malabsorption
Anorectal dysfunction - lowered rectal sensory threshold, weak internal anal sphincter
Concurrent celiac sprue - similar genetic predisposition
Exocrine insufficiency seems to be correlated to early onset of endocrine failure, long-lasting diabetes
mellitus and low body mass index levels. Pancreatology 2003;3:

34. Drug-related diarrhea (metformin and acarbose) and lactose intolerance should be excluded

40. Tx: Glycopyrrolate (antimuscarinic compound) for gustatory sweating

41. Gustatory sweating
Hyperhidrosis associated with eating, may be linked with certain foods, particularly spicy foods and cheeses.
relief by avoiding the inciting food
Glycopyrrolate (antimuscarinic compound) for gustatory sweating

43. Summary A diagnosis by exclusion
Resting tachycardia is an early sign of autonomic neuropathy
Painless MI is particularly common
Orthostatic hypotension is often incorrectly ascribed to hypoglycemia
Erectile dysfunction is a coronary disease marker
Consider less intense glucose control if hypoglycemia unawareness is present
Heart rate variation tests are sensitive detectors for DAN

44. Reference
Diabetic Autonomic Neuropathy Diabetes Care 26:1553–1579, 2003
Diabetic neuropathy: An intensive review Am J Health-Syst Pharm. 2004; 61:160-76
Recent advances in the treatment of diabetic neuropathy Current Opinion in Endocrinology & Diabetes 2006, 13:147–153
REVIEW: Cardiovascular Autonomic Neuropathy Due to Diabetes Mellitus: Clinical Manifestations, Consequences, and Treatment Journal of Clinical Endocrinology and Metabolism - Volume 90, Issue 10 (October 2005)
Diagnosing Diabetic Autonomic Neuropathy from Medscape Diabetes & Endocrinology, Response from Aaron I. Vinik, MD, PhD
Diabetic autonomic neuropathy (DAN) UpToDate on-line

45. Thanks!