History

Fact Explanation
Cardiovascular symptoms: exercise intolerance, fatigue, sustained heart rate, syncope, dizziness, light headedness, balance problems [1] Cardiovascular neuropathy is a result of damage to vagal and sympathetic nerves. [2] The pathogenesis is complex and involves a cascade of pathways activated by hyperglycaemia resulting in neuronal ischaemia and cellular death [3]
Gastrointestinal symptoms: dysphagia, diarrhea, constipation, loss of bowel control [4] Dysphagia occurs due to reduced contraction amplitudes of the tubular esophagus [2] Diabetic diarrhea is a result of increased or uncoordinated transit time in the small intestine, bacterial overgrowth, or increased intestinal secretions. [2] Constipation occurs due to decreased transit time in the large intestine. Loss of bowel control is due to reduced threshold of conscious rectal sensation,decreased resting anal sphincter pressure.[2]
Genitourinary symptoms: loss of bladder control, urinary tract infection, urinary frequency or dribbling, erectile dysfunction, loss of libido, dyspareunia, vaginal dryness [4] Loss of bladder control occurs by the Inability to sense a full bladder and detrusor muscle hypoactivity.These conditions can progress to overflow incontinence and urinary tract infections.Hyperglycemia alone also can cause increased urine production and incontinence. loss of libido,dyspareunia,vaginal dryness is a result of pelvic plexus neuropathy [2] Erectile dysfunction in diabetes is multifactorial, including neuropathy,hypogonadism, vascular disease, metabolic control and psychogenic factors. Diabetic men have impaired neurogenic and endothelium mediated relaxation of penile smooth muscles [5]
Sudomotor symptoms: pruritus, dry skin, limb hair loss,anhidrosis,heat intolerance,gustatory sweating [4] Dry skin,hair loss- Poor peripheral circulation (neuronal input to the peripheral vasculature is decreased or absent) [2] Gustatory sweating-Loss of autonomic supply to auriculotemporal nerve. [6]
Endocrine symptoms: hypoglycemic unawareness [4] Impaired catecholamine release prevents the warning signs of hypoglcemia. counterregulatory response hypoglycemia is reduced due to autonomic dysfunction [2]
Eyes: diplopia [2] Loss of autonomic supply to ocular muscles.[2]
Dizziness while standing up from seated position [4] This is due to orthostatic hypotension (i.e. a decrease in systolic blood pressure of ≥20 mm Hg or diastolic blood pressure of ≥10 mm Hg when standing up. Vasomotor neuropathy frequently causes orthostatic hypotension by affecting the splanchnic and peripheral vascular beds.[2]
Poor diabetic control , long duration of diabetes, History of hypertension, dyslipidemia [7] Risk factors for the development of diabetic autonomic neuropathy as damage to the nerves will be increased with time due to longer exposure to hyperglycemia. The risk is also high in patients who are having other comorbidities which has macrovascular events such as hypertension and dyslipidemia [7]
References
  1. VINIK A. I., MASER R. E., MITCHELL B. D., FREEMAN R.. Diabetic Autonomic Neuropathy. Diabetes Care [online] 2003 May, 26(5):1553-1579 [viewed 13 May 2014] Available from: http://care.diabetesjournals.org/content/26/5/1553.full
  2. VINIK A I., ERBAS T., Recognizing and treating diabetic autonomic neuropathy. Cleveland clinic journal of medicine [online] November 2001, volume 68 number 11 [viewed 13 May 2014] Available from: http://www.ccjm.org/content/68/11/928.full.pdf
  3. DIMITROPOULOS G, TAHRANI AA, STEVENS MJ. Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes [online] 2014 Feb 15, 5(1):17-39 [viewed 09 September 2014] Available from: doi:10.4239/wjd.v5.i1.17
  4. ARING A M., JONES D E., FALKO J M., Evaluation and Prevention of Diabetic Neuropathy. American Family Physician [online] June 2005, 71(11):2123-2128 [viewed 13 May 2014]. Available from: http://www.aafp.org/afp/2005/0601/p2123.html#afp20050601p2123-t1
  5. PENSON D. F., WESSELLS H.. Erectile Dysfunction in Diabetic Patients. Diabetes Spectrum [online] 2004 October, 17(4):225-230 [viewed 10 September 2014] Available from: doi:10.2337/diaspect.17.4.225
  6. BRONSHVAG M M., Spectrum of gustatory sweating with especial reference to its presence in diabetics with autonomic neuropathy. The American Journal of Clinical Nutrition [online] February 1978, page 307-309 [viewed 13 May 2014] Available from: http://ajcn.nutrition.org/content/31/2/307.full.pdf
  7. BOULTON A. J.M., VINIK A. I., AREZZO J. C., BRIL V., FELDMAN E. L., FREEMAN R., MALIK R. A., MASER R. E., SOSENKO J. M., ZIEGLER D.. Diabetic Neuropathies: A statement by the American Diabetes Association. Diabetes Care [online] 2005 April, 28(4):956-962 [viewed 10 September 2014] Available from: doi:10.2337/diacare.28.4.956

Examination

Fact Explanation
Resting tachycardia [1] Damage to the autonomic nerve fibers that innervate the heart and blood vessels [1] Occurs at a relatively early stage of the disease. Heart rate of 90-130 beats per minute can be observed and is associated with a reduction in parasympathetic tone followed by increased sympathetic activity as the disease progresses [2]
Pupillary: Pupillomotor function impairment, Argyll-Robertson pupil [1] Loss of autonomic supply to ocular muscles [1]
Orthostatic hypotension [3] Reduction in systolic blood pressure by > 20 mmHg or in diastolic blood pressure by > 10 mmHg 2 min following postural change from supine to standing. occurs as a result of the impairment of the sympathetic response to postural change secondary to poor norepinephrine response and abnormalities in the baro-receptor sensitivity [2]
Abnormal circadian pattern of blood pressure [3] Correlate with postural hypotension due to cardiovascular autonomic neuropathy. blood pressure rises during the night and falls in the early morning [1]
References
  1. VINIK A I., ERBAS T., Recognizing and treating diabetic autonomic neuropathy. Cleveland clinic journal of medicine [online] November 2001, volume 68 number 11 [viewed 13 May 2014] Available from: http://www.ccjm.org/content/68/11/928.full.pdf
  2. DIMITROPOULOS G, TAHRANI AA, STEVENS MJ. Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes [online] 2014 Feb 15, 5(1):17-39 [viewed 09 September 2014] Available from: doi:10.4239/wjd.v5.i1.17
  3. VINIK A. I., MASER R. E., MITCHELL B. D., FREEMAN R.. Diabetic Autonomic Neuropathy. Diabetes Care [online] 2003 May, 26(5):1553-1579 [viewed 13 May 2014] Available from: http://care.diabetesjournals.org/content/26/5/1553.full

Differential Diagnoses

Fact Explanation
Pure autonomic failure [1] Signs and symptoms of decreased sympathetic and parasympathetic functions occur.More specifically, symptoms include orthostatic hypotension,gastroparesis,urinary retention,decreased sweating,ophthalmologic manifestations and failure of either erection or ejaculation [1]
Multiple system atrophy [1] Autonomic manifestations are similar.Neurologic features may also be present such as, Pyramidal or cerebellar abnormalities, Variable parkinsonian findings [1]
Pheochromocytoma [2] Signs and symptoms of increased sympathetic activity occur [2]
Hypopituitarism [2] Signs and symptoms of autonomic impairment occurs. Depends on which hormone is deficient. eg: Insufficient levels of growth hormone-weakness, low blood sugar levels and reduced exercise tolerance [2]
Complications from vasodilators (nitrates, calcium channel blockers, hydralazine) [2] Causes erectile dysfunction [2]
Complications from sympathetic blockers (methyldopa, clonidine, prazosin, guanethidine, phenothiazine, tricyclic antidepressants) [2] Causes autonomic instability [2]
Other causes of diarrhea, constipation, and gastrointestinal dysfunction [2] Important to rule out. Eg-Drug related diarrhea (due to metformin,acarbose) [2]
References
  1. GURME M., Idiopathic Orthostatic Hypotension and other Autonomic Failure Syndromes. Medscape [online] March 2014, [viewed 13 May 2014] Available from: http://emedicine.medscape.com/article/1154266-overview
  2. VINIK A I., ERBAS T., Recognizing and treating diabetic autonomic neuropathy. Cleveland clinic journal of medicine [online] November 2001, volume 68 number 11 [viewed 13 May 2014] Available from: http://www.ccjm.org/content/68/11/928.full.pdf

Investigations - for Diagnosis

Fact Explanation
Heart rate response to standing and to the Valsalva maneuver [1] Heart rate response to standing- The R-R interval is measured at beats 15 and 30 after the patient stands A 30:15 ratio of less than 1.03 is abnormal Heart rate response to Valsalva maneuver- The patient forcibly exhales into the mouthpiece of a manometer, exerting a pressure of 40 mm Hg for 15 seconds A ratio of longest to shortest R-R interval of less than 1.2 is abnormal [2]
Tests of blood pressure control [2] Systolic blood pressure response to standing- Systolic blood pressure is measured when the patient is lying down and 2 minutes after the patient stands A fall of more than 30 mm Hg is abnormal A fall of 10 to 29 mm Hg is borderline Diastolic blood pressure response to isometric exercise- The patient squeezes a handgrip dynamometer to establish his or her maximum.The patient then squeezes the grip at 30% maximum for 5 minutes.A rise of less than 16 mm Hg in the contralateral arm is abnormal [2]
Gastroduodenoscopy [2] To exclude pyloric or other mechanical obstruction( in assessing the gastrointestinal autonomic function) [2]
Anorectal manometry [2] To exclude other causes for constipation ( to evaluate sphincter tone) [2]
Assessment of renal functions and cystometry [2] To exclude other causes of bladder dysfunction [2]
Penile-brachial pressure index [3] Penile blood flow can be measured by Doppler flow studies of the dorsal penile arteries, and the ratio is Penile-brachial pressure index. low value indicates vascular disease
Hormonal evaluation (luteinizing hormone, testosterone, free testosterone, prolactin) [3] To exclude other causes of erectile dysfunction. [3]
References
  1. ROWAIYE OO, JANKOWSKA EA, PONIKOWSKA B. Baroreceptor sensitivity and diabetes mellitus. Cardiol J [online] 2013, 20(5):453-63 [viewed 10 September 2014] Available from: doi:10.5603/CJ.2013.0130
  2. VINIK A. I., MASER R. E., MITCHELL B. D., FREEMAN R.. Diabetic Autonomic Neuropathy. Diabetes Care [online] 2003 May, 26(5):1553-1579 [viewed 13 May 2014] Available from: http://care.diabetesjournals.org/content/26/5/1553.full
  3. PENSON D. F., WESSELLS H.. Erectile Dysfunction in Diabetic Patients. Diabetes Spectrum [online] 2004 October, 17(4):225-230 [viewed 10 September 2014] Available from: doi:10.2337/diaspect.17.4.225

Investigations - Fitness for Management

Fact Explanation
Lipid profile [1] Important to assess other co morbidities in order to prevent cardiovascular adverse events. targets - LDL-Cholesterol <100 mg/dL, HDL-Cholesterol >50 mg/dL, and triglycerides <150 mg/dL [2]
References
  1. VINIK A I., ERBAS T., Recognizing and treating diabetic autonomic neuropathy. Cleveland clinic journal of medicine [online] November 2001, volume 68 number 11 [viewed 13 May 2014] Available from: http://www.ccjm.org/content/68/11/928.full.pdf
  2. BUSE J. B., GINSBERG H. N., BAKRIS G. L., CLARK N. G., COSTA F., ECKEL R., FONSECA V., GERSTEIN H. C., GRUNDY S., NESTO R. W., PIGNONE M. P., PLUTZKY J., PORTE D., REDBERG R., STITZEL K. F., STONE N. J.. Primary Prevention of Cardiovascular Diseases in People With Diabetes Mellitus: A Scientific Statement From the American Heart Association and the American Diabetes Association. Circulation [online] 2006 December, 115(1):114-126 [viewed 10 September 2014] Available from: doi:10.1161/CIRCULATIONAHA.106.179294

Investigations - Followup

Fact Explanation
Test for heart-rate variability-Check the response to Valsalva maneuver [1] Depends on the symptoms and signs. Monitor every year for response to treatment [1]
Measure blood pressure standing and supine [2] Monitor response to treatment of postural hypotension - reduction in systolic blood pressure by > 20 mmHg or in diastolic blood pressure by > 10 mmHg 2 min following postural change from supine to standing [2]
upper-GI endoscopy or barium series [3] Monitor response to treatment of gastrointestinal dysfunction [1] to rule out structural or mucosal abnormalities of the GI tract [3]
Cystometrogram [1] Bladder sensation and upper urinary tract dilation can be assessed with cystometry and voiding cystometrogram [1]
Sweat test [4] used to evaluate the integrity of central and peripheral sympathetic sudomotor pathways from the central nervous system to the cutaneous sweat glands. Asymmetric sweat patterns and anhidrotic areas are noted in autonomic failure [4]
References
  1. VINIK A I., ERBAS T., Recognizing and treating diabetic autonomic neuropathy. Cleveland clinic journal of medicine [online] November 2001, volume 68 number 11 [viewed 13 May 2014] Available from: http://www.ccjm.org/content/68/11/928.full.pdf
  2. DIMITROPOULOS G, TAHRANI AA, STEVENS MJ. Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes [online] 2014 Feb 15, 5(1):17-39 [viewed 10 September 2014] Available from: doi:10.4239/wjd.v5.i1.17
  3. VINIK A. I., MASER R. E., MITCHELL B. D., FREEMAN R.. Diabetic Autonomic Neuropathy. Diabetes Care [online] 2003 May, 26(5):1553-1579 [viewed 10 September 2014] Available from: doi:10.2337/diacare.26.5.1553
  4. ILLIGENS BM, GIBBONS CH. Sweat testing to evaluate autonomic function Clin Auton Res [online] 2009 Apr, 19(2):79-87 [viewed 10 September 2014] Available from: doi:10.1007/s10286-008-0506-8

Investigations - Screening/Staging

Fact Explanation
Test for heart-rate variability [1] Screening depends on the symptoms and signs. Check the response to Valsalva maneuver,response to standing If negative: repeat yearly If positive: apply appropriate diagnostic tests, treat symptoms [1]
urine culture [2] Bladder dysfunction can cause recurrent urinary tract infection, pyelonephritis [2]
Ultra sound scan abdomen [2] Postvoid ultrasound to assess residual volume and upper-urinary tract dilation [2]
Cystometrogram [2] Cystometry and voiding cystometrogram to measure bladder sensation and volume pressure changes associated with bladder filling with known volumes of water and voiding [2]
References
  1. VINIK A I., ERBAS T., Recognizing and treating diabetic autonomic neuropathy. Cleveland clinic journal of medicine [online] November 2001, volume 68 number 11 [viewed 13 May 2014] Available from: http://www.ccjm.org/content/68/11/928.full.pdf
  2. VINIK A. I., MASER R. E., MITCHELL B. D., FREEMAN R.. Diabetic Autonomic Neuropathy. Diabetes Care [online] 2003 May, 26(5):1553-1579 [viewed 13 May 2014] Available from: http://care.diabetesjournals.org/content/26/5/1553.full

Management - General Measures

Fact Explanation
Tight glycemic control [1] Reduces the prevalence of autonomic dysfunction and slows the deterioration of R-R variation. [2]
Physical activity [3] at least 150 minutes of moderate-intensity aerobic physical activity or at least 90 minutes of vigorous aerobic exercise per week is recommended in order to reduce cardiovascular adverse events. The physical activity should be distributed over at least 3 days per week, with no more than 2 consecutive inactive days. [3]
References
  1. VINIK A. I., MASER R. E., MITCHELL B. D., FREEMAN R.. Diabetic Autonomic Neuropathy. Diabetes Care [online] 2003 May, 26(5):1553-1579 [viewed 13 May 2014] Available from: http://care.diabetesjournals.org/content/26/5/1553.full
  2. VINIK A I., ERBAS T., Recognizing and treating diabetic autonomic neuropathy. Cleveland clinic journal of medicine [online] November 2001, volume 68 number 11 [viewed 13 May 2014] Available from: http://www.ccjm.org/content/68/11/928.full.pdf
  3. BUSE J. B., GINSBERG H. N., BAKRIS G. L., CLARK N. G., COSTA F., ECKEL R., FONSECA V., GERSTEIN H. C., GRUNDY S., NESTO R. W., PIGNONE M. P., PLUTZKY J., PORTE D., REDBERG R., STITZEL K. F., STONE N. J.. Primary Prevention of Cardiovascular Diseases in People With Diabetes Mellitus: A Scientific Statement From the American Heart Association and the American Diabetes Association. Circulation [online] 2006 December, 115(1):114-126 [viewed 10 September 2014] Available from: doi:10.1161/CIRCULATIONAHA.106.179294

Management - Specific Treatments

Fact Explanation
Treatment of cardiac autonomic neuropathy [1] Beta-blockers s that are cardioselective (eg:atenolol, metoprolol, acebutolol)- Opposing the sympathetic stimulus, and thereby restore the parasympathetic-sympathetic balance. ACE inhibitors-Increase heart-rate variation and decrease mortality in patients with mild microalbuminuria. [1]
Treatment of orthostatic hypotension [1] Non pharmacological- Wear supportive stockings to increase venous return, Cautioned to get out of bed slowly, To avoid hot baths, To take their insulin injections while lying down, perform physical counter-manoeuvres (leg crossing, stooping and squatting), increase fluid and salt intake. 9-fluorohydrocortisone and supplementary salt- May benefit for some patients with orthostatic hypotension.But not effective until edema settles,therefore carries a rick of heart failure. [2] Clonidine- An alpha-2 agonist, can treat a deficiency of alpha-2 adrenergic receptor in patients with orthostatic hypotension. [1] Somatostatin and somatostatin analogues (octreotide) inhibit the release of vasoactive peptides from the GI tract and thus increase splanchnic vasoconstriction, leading to increase in mean blood pressure [2]
Treatment of sudomotor autonomic neuropathy [1] Emolients-Softens skin and prevents dryness [1]
Treatment of gastrointestinal dysfunction [1] Treatment of gastropariesis should include: Non pharmacological-Advise to eat multiple small meals (4–6 per day) and to reduce the fat content of their diet to less than 40 g/day. [1] Prokinetic agents such as metoclopramide,domperidone,erythromycin, and levosulpirid. [1] Treatment of diabetic diarrhea 1)Fluid and electrolyte balance 2)Antidiarrheal agents (eg, loperamide and diphenoxylate) - can reduce the number of stools, but they may also be associated with toxic megacolon [1] 3)Bacterial overgrowth due to stasis of the bowel may contribute to diarrhea, in which case broad-spectrum antibiotics (e.g., tetracycline and metronidazole) are useful. [3]
Treatment of genitourinary tract dysfunction [1] Treating erectile dysfunction 1)Cease taking medications known to cause erectile dysfunction 2) Phosphodiesterase Type 5 Inhibitors - Sildenafil (Viagra) : work by potentiating the effect of nitric oxide in the penis 3)Vacuum Erection Devices [4] Treating female sexual dysfunction- Application of vaginal lubricants, including topical estrogen creams [1] Treating bladder dysfunction- 1)Patients are asked to palpate for their bladder and empty it when it is full 2) Alpha-1 blocker- sphincter relaxation [1]
Treatment of hypoglycemic unawareness and unresponsiveness [1] Intensive glycemic control therapy- Using very small boluses of long-acting insulin is recommended [1]
References
  1. VINIK A I., ERBAS T., Recognizing and treating diabetic autonomic neuropathy. Cleveland clinic journal of medicine [online] November 2001, volume 68 number 11 [viewed 13 May 2014] Available from: http://www.ccjm.org/content/68/11/928.full.pdf
  2. DIMITROPOULOS G, TAHRANI AA, STEVENS MJ. Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes [online] 2014 Feb 15, 5(1):17-39 [viewed 10 September 2014] Available from: doi:10.4239/wjd.v5.i1.17
  3. VINIK A. I., MASER R. E., MITCHELL B. D., FREEMAN R.. Diabetic Autonomic Neuropathy. Diabetes Care [online] 2003 May, 26(5):1553-1579 [viewed 10 September 2014] Available from: doi:10.2337/diacare.26.5.1553
  4. PENSON D. F., WESSELLS H.. Erectile Dysfunction in Diabetic Patients. Diabetes Spectrum [online] 2004 October, 17(4):225-230 [viewed 10 September 2014] Available from: doi:10.2337/diaspect.17.4.225