Diabetic neuropathy affects the peripheral sensory and motor nerves as well as the autonomic nervous system while diabetic autonomic neuropathy (DAN) involves all organ systems [1] but manifests initially in the longer nerves such as the vagus nerve. Although DAN is known to occur at any time in patients with type 1 and type 2 diabetes, it typically develops in patients with long-standing diabetes with poor blood glucose control. Subclinical DAN, however, can appear within a year of detecting type 2 diabetes and up to 2 years after the diagnosis of type 1 diabetes [2]. The prevalence of DAN varies amongst published studies [3] depending upon the measures used to assess the condition.

The overt clinical manifestations due to autonomic dysfunction and microvascular complications can occur concurrently but without a specific pattern [4] and can be classified according to the involved organ system as follows:

• Cardiovascular autonomic neuropathy (CAN) features: fatigue, syncope, dizziness, tachycardia at rest, poor tolerance to exercise, orthostatic hypotension, asymptomatic myocardial ischemia
• Gastrointestinal (GI) symptoms are common and include esophageal dysfunction, dysphagia, gastroparesis with bloating, nausea, vomiting, diarrhea, constipation and loss of bowel control
• Genitourinary manifestations can be a loss of bladder control (neurogenic bladder), urinary tract infection, increased urinary frequency or dribbling, loss of libido, erectile dysfunction, dyspareunia, vaginal dryness, and anorgasmia.
• Sudomotor (sweat gland system) features are anhidrosis, pruritus, dry skin, limb alopecia, calluses, heat intolerance, gustatory sweating
• Endocrine organ system is represented by a lack of awareness about hypoglycemia
• Ophthalmic complications: pupillary dysfunction, Argyll-Robertson pupil, difficulty driving at night
• Psychological manifestations include anxiety, depression, sleep disorders and cognitive changes.

• Hypothermia

  Changes in the body's ability to regulate temperature may make you more prone to body chilling (hypothermia) or heat-related illness, such as heatstroke or heat exhaustion. [cigna.com]

• Pallor

  Face Pallor. Reduced or absent sweating. Vision Blurring of vision. Tunnel vision. Light sensitivity. Difficulty focusing. Reduced lacrimation. Gradual reduction of pupillary size. [patient.info]

  There was pallor present in the palpebral conjunctiva, nails, and the palms. On extraoral examination hypertelorism, exophthalmos, depressed nasal bridge, broad face, and a prognathic mandible were noted. [hindawi.com]

• Nausea

  Insular source location was associated with HRV assessments (all P 0.02), and the shift (expressed in mm) correlated negatively with physical health (P 0.001) and positively with nausea (P 0.03) and postprandial fullness (P 0.03). [ncbi.nlm.nih.gov]

  Digestive problems: Eating smaller meals more frequently or taking soups/semi-solid foods are known to relieve symptoms of bloating, nausea, and other conditions. Medications could be used to manage nausea, constipation, and diarrhea. [dovemed.com]

  This can result in symptoms such as abdominal bloating, nausea, heartburn and unpredictable changes in blood glucose levels. [diabetes.co.uk]

• Diarrhea

  […] the hypotension and diarrhea and led to better blood glucose control. [ncbi.nlm.nih.gov]

  Diarrhea can occur when the nerves that control the small intestine are damaged. The diarrhea occurs most often at night. Constipation is another common result of damage to nerves in the intestines. Sometimes, the stomach is affected. [diabetes.org]

• Constipation

  Autonomic neuropathy was assessed by the presence of symptoms like dysphagia, abdominal fullness, nausea, vomiting, diarrhea /- nocturnal, faecal incontinence or constipation, dysuria, urinary incontinence, the gustatory sweating, impotence etc. and were [ncbi.nlm.nih.gov]

  Add fluid and fiber to your diet to prevent bloating and constipation. Laxatives can help with constipation, and other medicines can treat diarrhea and belly pain. Sleep with the head of your bed raised to prevent heartburn. [webmd.com]

• Vomiting

  Autonomic neuropathy was assessed by the presence of symptoms like dysphagia, abdominal fullness, nausea, vomiting, diarrhea /- nocturnal, faecal incontinence or constipation, dysuria, urinary incontinence, the gustatory sweating, impotence etc. and were [ncbi.nlm.nih.gov]

  It loses the ability to move food through the digestive system, causing vomiting and bloating. This condition, called gastroparesis, can change how fast the body absorbs food. It can make it hard to match insulin doses to food portions. [diabetes.org]

  […] syncope, dizziness, tachycardia at rest, poor tolerance to exercise, orthostatic hypotension, asymptomatic myocardial ischemia Gastrointestinal (GI) symptoms are common and include esophageal dysfunction, dysphagia, gastroparesis with bloating, nausea, vomiting [symptoma.com]

  Symptoms are wide-ranging, the ADA says, and can include: • Indigestion or heartburn • Nausea, vomiting undigested food or bloating • Diarrhea or constipation • Blood glucose levels are suddenly difficult to predict • Bladder control problems • Frequent [diabeteshealth.com]

• Fecal Incontinence

  Digestive system Damage to the nerves of your digestive system can cause symptoms such as the following: bloating, fullness, and nausea constipation diarrhea, especially at night diarrhea alternating with constipation fecal incontinence problems swallowing [niddk.nih.gov]

  esophageal enteropathy, gastroparesis, constipation, diarrhea, and fecal incontinence) are common, and any section of the GI tract may be affected. Gastroparesis should be suspected in individuals with erratic glucose control. [ncbi.nlm.nih.gov]

  incontinence Genitourinary Erectile dysfunction Retrograde ejaculation Cystopathy Neurogenic bladder Sweating disturbances Areas of symmetrical anhydrosis Gustatory sweating Metabolic Hypoglycemia unawareness Hypoglycemia unresponsiveness Pupillary Decreased [medscape.com]

  incontinence Female Sexual Dysfunction : Decreased sexual desire, Increased pain during intercourse, Decreased sexual arousal, Inadequate lubrication Abnormal blood pressure regulation : Non-dipping, Reverse dipping Constipation Orthostatic Hypotension [diapedia.org]

• Hypotension

  Patients with postural hypotension have intermittent symptoms over the years but rarely become severely disabled. They have a poorer prognosis than patients with symptomatic autonomic neuropathy without postural hypotension. [ncbi.nlm.nih.gov]

• Orthostatic Hypotension

  First-line treatments include midodrine for orthostatic hypotension, prokinetic drugs for gastroparesis, broad-spectrum antibiotics for diabetic diarrhea, and sildenafil for erectile dysfunction. [ncbi.nlm.nih.gov]

  The proposed causes of orthostatic hypotension include damaged sympathetic vasoconstrictor fibres, and impaired baroreceptor function. 1 Few papers have described the treatment of diabetic orthostatic hypotension with β -blockers. 2 Combined β 1 and β [nature.com]

  People with orthostatic hypotension are advised to avoid sitting up or standing up suddenly; wear compression stockings; avoid medications that aggravate orthostatic hypotension, such as tricyclic antidepressants; eat small, frequent meals; and drink [diabetesselfmanagement.com]

  Whether a patient develops symptoms of orthostatic hypotension depends on cerebral autoregulation, a process whereby cerebral perfusion remains unchanged in the face of changing systemic BP. [mayoclinic.pure.elsevier.com]

  Orthostatic hypotension with a decrease in systolic blood pressure of more than 30 mm Hg on standing up is noted in DAN. [symptoma.com]

• Tachycardia

  Cardiac autonomic neuropathy (CAN) has been linked to resting tachycardia, postural hypotension, orthostatic bradycardia and orthostatic tachycardia (POTTS), exercise intolerance, decreased hypoxia-induced respiratory drive, loss of baroreceptor sensitivity [ncbi.nlm.nih.gov]

  Physical examination is likely to indicate variability in heart rate (resting tachycardia followed by bradycardia and later a fixed heart rate). [symptoma.com]

  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. [medscape.com]

  Symptoms and Signs Resting tachycardia due to parasympathetic damage is one of the most typical signs of CAN. [touchendocrinology.com]

• Exertional Chest Pain

  In the ECGs of diabetic patients with exertional chest pain, a prolonged anginal perceptual threshold (ie, the time from onset of 0.1 mV ST depression to the onset of angina pectoris during exercise) was associated with the presence of CAN.29 Hence, patients [ahajournals.org]

• Pupillary Abnormality

  The incidence and severity of pupillary abnormalities did not differ between patients with and without CAN or PN. [ncbi.nlm.nih.gov]

  The evaluation of pupillary abnormalities, hypoglycemia unawareness and unresponsiveness, neurovascular dysfunction, and sweating disturbances are for the most part done only in research laboratories, require specialized equipment and familiarity with [medscape.com]

  By using sophisticated electronic gadgetary, Smith et a1 [22] found pupillary abnormalities in all the diabetics they studied. The contribution of such changes to the visual difficulties in the diabetics needs to be assessed. [jpgmonline.com]

  Diabetes Care 2006, 29: 1300–1306. 10.2337/dc05-2470 View Article Google Scholar Smith S, Dewhirst R: A simple diagnostic test for pupillary abnormality in diabetic autonomic neuropathy. [biomedical-engineering-online.biomedcentral.com]

• Decreased Sweating

  Decreased sweating may be evident on examination. For example, on a very warm day if the socks are very dry this likely represents decreased sweating. 4. [americanautonomicsociety.org]

  If you experience excessive sweating, your doctor may prescribe a medication that decreases sweating, such as glycopyrrolate (Ribinul, Robinul Forte) or clonidine (Catapres). [diabetesdaily.com]

  sweating in the feet or increased sweating in the hands, nausea or bloating after eating, persistent diarrhea or constipation, or leaking of urine. [clinicaltrials.gov]

  Sweat glands If you have too much sweating, your doctor may suggest avoiding too much heat or humidity a prescription antiperspirant or medicine to decrease sweating surgery to cut the nerves in the sweat glands or to remove sweat glands Hypoglycemia [niddk.nih.gov]

• Increased Sweating

  sweating in the hands, nausea or bloating after eating, persistent diarrhea or constipation, or leaking of urine. [clinicaltrials.gov]

• Circumoral Paresthesia

  paresthesia, and headache, may occur on changes from a supine to an erect position and may be caused by postural tachycardia syndrome (POTS), inappropriate sinus tachycardia, neurocardiogenic syncope, or abnormalities in baroreceptor function. [ahajournals.org]

• Peripheral Neuropathy

  The patients were also tested for glycemic control and presence of peripheral neuropathy. [ncbi.nlm.nih.gov]

• Dysautonomia

  The ANSiscope computes a percentage of dysautonomia from a recording of 571 RR intervals recordings for patients at rest in supine position. They are then classified as having healthy(H)/early(E)/late(L)/ advanced(A) or most advanced(MA) DAN. [endocrine-abstracts.org]

  Pathophysiology Cardiovascular autonomic neuropathy (CAN) is the most frequent complication of diabetes and one of the major components of diabetic dysautonomia. [touchendocrinology.com]

  Dysautonomia Foundation, Inc. FD Now Faces and Voices of FD - an educational video on FD from the Dysautonomia Foundation, Inc. [dysautonomiainternational.org]

  Signs and causes of autonomic neuropathy The primary cause of autonomic neuropathy is diabetes, but there are other causes as well, including: Familial dysautonomia Idiopathic orthostatic hypotension Multiple system atrophy with autonomic failure Parkinson [belmarrahealth.com]

• Retrograde Ejaculation

  In men, DAN may cause loss of penile erection and/or retrograde ejaculation. [ncbi.nlm.nih.gov]

  The surgical correction of retrograde ejaculation. J Urol 1975; 114(6):888–890. PubMed Google Scholar 63. Ramadan AE, el-Demiry MI. Surgical correction of post-operative retrograde ejaculation. Br J Urol 1985; 57(4):458–461. [link.springer.com]

  ejaculation Cystopathy Neurogenic bladder Sweating disturbances Areas of symmetrical anhydrosis Gustatory sweating Metabolic Hypoglycemia unawareness Hypoglycemia unresponsiveness Pupillary Decreased diameter of dark-adapted pupil Argyll-Robertson-type [medscape.com]

• Urinary Retention

  Gastrointestinal Urogenital Impaired Rate Variability Gastroparesis : Nausea, Bloating, Loss of appetite, Early satiety, Postprandial vomiting Bladder dysfunction : Frequency, Urgency, Nocturia, Hesitancy, Weak stream, Dribbling, Urinary incontinence, Urinary [diapedia.org]

  Signs and symptoms[edit] The signs and symptoms of autonomic neuropathy include the following:[citation needed] Urinary bladder conditions: bladder incontinence or urinary retention Gastrointestinal tract: dysphagia, abdominal pain, nausea, vomiting, [en.wikipedia.org]

  retention) but unlike peripheral autonomic neuropathies have extrapyramidal dysfunction (akinesia, tremor, rigidity). [patient.info]

• Overflow Incontinence

  These conditions can progress to overflow incontinence and urinary tract infections. Hyperglycemia alone also can cause increased urine production and incontinence. [aafp.org]

  Finally, overflow incontinence occurs because of denervation of the external and internal sphincter (129,130). The somatic pudendal nerve innervates the external sphincter, whereas the sympathetic hypogastric nerves innervate the internal sphincter. [care.diabetesjournals.org]

• Bladder Distention

  A grossly overdistended bladder should be drained by catheter to improve contractility, and the patient should be instructed to void by the clock rather than waiting for the sensation of bladder distention. [care.diabetesjournals.org]

The diagnosis of DAN focuses on symptoms linked to a specific organ system. The patient history will elicit symptoms of DAN, review history of diabetes management, family history of diabetes, medication history and exclude other etiologies of neuropathy like alcoholism, vitamin B12 deficiency, malignancy and autoimmune diseases. Physical examination is likely to indicate variability in heart rate (resting tachycardia followed by bradycardia and later a fixed heart rate). Examination of the skin may reveal areas of alopecia with changes in the skin and nails and callus formation. There may also be erythematous "peritrophic" intertriginous areas between the toes. Neurological examination is essential to evaluate the ability for mental arithmetics which can be diminished in DAN. An ophthalmic evaluation is also required to detect effects of DAN on the eyes.

Laboratory tests include complete blood count, fasting and post-meal blood glucose levels, hemoglobin A1c levels as well as lipid profile, serum blood urea nitrogen and serum creatinine (to exclude concomitant diabetic nephropathy). Serial blood glucose testing may be required to monitor DAN.

Since the cardiovascular system is most commonly affected with life-threatening problems and as several tests are available to evaluate it, DAN is tested first. Five noninvasive tests for DAN include the Valsalva maneuver, the response of heart rate to deep breathing and standing; and blood pressure response to standing and sustained handgrip [5]. Orthostatic hypotension with a decrease in systolic blood pressure of more than 30 mm Hg on standing up is noted in DAN. An electrocardiogram (ECG) may show prolonged corrected QT interval and QT dispersion indicating an imbalance between the sympathetic innervation on the two sides of the heart [6]. Power spectral analysis of short R-R intervals or a 24 hour ECG is a sensitive and early test for identification of DAN [7] [8]. Exercise stress test is likely to reveal limited or decreased tolerance while echocardiography may show decreased cardiac ejection fraction with systolic dysfunction and poor diastolic filling [9].

Gastric scintigraphy can be employed to evaluate gastric emptying although its results do not correlate with the symptom severity in DAN patients. Other imaging tests are usually not helpful in the diagnosis of DAN.

• Ketonuria

  He was underweight, had ketonuria, and such muscle loss that he was unable to sit unaided. Insulin treatment was started. He developed severe symptomatic postural hypotension. [ncbi.nlm.nih.gov]

• Prolongation of Corrected QT Interval

  A relationship between CAN and prolongation of corrected QT interval is well demonstrated, and this substantiates the risk of cardiac arrhythmia and sudden death.21,22 More precisely, CAN alters the heart rate dependence of ventricular repolarisation [touchendocrinology.com]

• Torsades De Pointes

  de pointes, as in long QT syndrome. [ahajournals.org]

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2. Pfeifer MA, Weinberg CR, Cook DL, et al. Autonomic neural dysfunction in recently diagnosed diabetic subjects. Diabetes Care 1984;7:447-453
3. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care. 2003;26:1553–79.
4. Ewing DJ. Cardiac autonomic neuropathy. In Diabetes and Heart Disease. Jarret RJ, Ed. Elsevier, Amsterdam, the Netherlands. 1984; 99–132
5. Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care 1985;8:491-498
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7. Freeman R, Saul P, Roberts M, Berger RD, Broadbridge C, Cohen R. Spectral analysis of heart rate in diabetic autonomic neuropathy. Arch Neurol 1991;48:185-190
8. Risk M, Bril V, Broadbridge C, Cohen A. Heart rate variability measurement in diabetic neuropathy: review of methods. Diabetes Technol Ther 2001;3:63-76
9. Kahn J, Zola B, Juni J, Vinik AI. Decreased exercise heart rate in diabetic subjects with cardiac autonomic neuropathy. Diabetes Care 1986;9:389-394