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Michael Polydefkis, M.D. M.H.S. Kathy Burks, C.R.N.P.
02-10-2011
- Diabetic autonomic neuropathy (DAN) is a common, underappreciated complication of diabetes with significant negative impact on survival and quality of life.
- Involvement of autonomic nerves in diabetes follows a length-dependent pattern. The longest autonomic nerve - the vegus nerve is the first affected, and provides 75% of parasympathetic tone, with a broad range of effects.
- Prevalence estimates of DAN depend on the criteria used and population studied. In general, rates increase with the degree of testing performed.
- In one population-based study, visceral autonomic neuropathy, based upon symptoms, had prevalence of 5.5% (Dyck). In contrast, another community-based study reported prevalence of DAN, as defined by abnormal heart rate variability (HRV) tests, of 16.7% (Ziegler). Cardiovascular autonomic neuropathy, defined as abnormal results in more than two of six autonomic function tests, among 1171 diabetic patients across 22 European diabetic centers was 25.3% for DMI and 34.3% DM2 (Zeigler).
- Patients with DAN are at increased risk of cardiovascular (CV) events and death. The usual diurnal variation in myocardial infarction (MI) is reversed in DAN patients , with less frequent MI in morning, more in the evening hours.
- Patients with DAN affecting cardovascular system (C-DAN) have a 5X increased mortality rate at 5 years compared to subjects without cardiovascularDAN. (Valensi)
- Diagnosis of DAN is based upon the organ system affected.
- Most prominent clinical autonomic signs and symptoms in diabetes include the pupil, sweat glands, genitourinary system, gastrointestinal tract system, adrenal medullary system, and the cardiovascular system.
- C-DAN causes abnormal heart rate (HR) control as well as abnormal central and peripheral vascular tone. Often presents as increased resting HR due to preferential loss of vagal parasympathetic tone, but increased HR variability, with reduced cardiac ejection fraction, systolic dysfunction and decreased diastolic filling, may be the earliest indicators of C-DAN. With progression, HR can become fixed due to loss of both sympathetic and parasympathetic function. Orthostatic hypotension, (a fall in systolic BP > 30 mmHg upon standing) is also common, attributed to loss of sympathetic innervation of splanchnic vasomotor fibers and reduced peripheral resistance. C-DAN diagnosis may require tilt-table or heart rate variability testing, in an EMG and/or cardiac clinical laboratory.
- Sudomotor dysfunction: anhidrosis of the extremities, sometimes accompanied by compensatory hyperhidrosis in the trunk. With progression, diffuse anhydrosis. Gustatory sweating-- abnormal sweating over the face, head, neck, shoulders, and chest after eating-- can also be seen.
- Formal diagnosis of sudomotor dysfunction: detailed assessment of sweat production either through quantitative sweat axon reflex test (sweat production in response to the iontophoresis of acetylcholine), or a thermoregulatory sweat test (assessing territories of sweat production through the application of moisture sensitive powder. Subjects lie in a controlled sauna chamber and sweat production is detected by the powder changing color when it contacts moisture).
- Gastrointestinal (GI) symptoms: common, often reflecting GI autonomic neuropathy. Upper GI: heartburn, dysphagia for solids, early satiety, anorexia, nausea, vomiting, epigastric discomfort, and bloating. Lower GI: diarrhea and constipation. GI symptoms reflect both the vagal nerve (responsible for esophageal and gastric motility) and intrinsic enteric neurons. Often impossible to distinguish between the two and diagnosis relies largely on motility studies such as esophageal scintigraphy and gastric emptying studies. Pathologically, abnormalities in gastric mucosal innervation. Delayed gastric emptying can be lead to bezoars in stomach that also interfere with nutrient delivery to the small bowel and cause unstable diabetes. Diabetic diarrhea is typically profuse, watery, lasting hours or days and frequently alternates with constipation.
- GU System: Most commonly erectile dysfunction (ED) and neurogenic bladder.
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ED in diabetes is multifactorial, including neuropathy, vascular disease, metabolic control, nutrition, endocrine disorders, psychogenic factors, and medications. Parasympathetic dysfunction of the penis results in reduced relaxation of the corpus cavernosa and reduced blood flow.
- Neurogenic bladder is easily diagnosed by a postvoid residual volume of >150 mL, and is a risk for urinary infections (UTIs). More than two >2 UTIs in a year suggests possible neurogenic bladder. The bladder is innervated by sympathetic, parasympathetic, and somatic nerves and the earliest signs of dysfunction in diabetes are related to impaired bladder sensation producing an elevated micturition reflex threshold.
- Clinical symptoms of autonomic neuropathy DAN generally do not occur until long after the onset of diabetes. Subclinical autonomic dysfunction, however, can occur within a year of diagnosis in type 2 diabetes (T2DM) and within 2 years in type 1 diabetes (T1DM).
- Symptoms of DAN are based upon the organ system involved.
- C-DAN symptoms typically include dizziness, weakness, fatigue and visual blurring. Symptoms of more advanced C-DAN include postural hypotension, exercise intolerance, asymptomatic cardiac ischemia, and intraoperative cardiovascular lability. C-DAN also confers an increased risk of death due to MI.
- Sudomotor dysfunction symptoms are typically subtle, including heat intolerance and central hyperhydrosis. Lack of sweat production in the feet is believed to predispose patients to ulcer formation.
- GI diabetic autonomic symptoms (GI-DAN) classified into upper and lower GI involvement. Upper GI include heartburn, dysphagia for solids, early satiety, anorexia, nausea, vomiting, epigastric discomfort, and bloating, while lower GI involvement causes alternating diarrhea and constipation.
- GU diabetic autonomic symptoms consist of ED and neurogenic bladder. Symptoms of the latter are variable and include hesitancy in micturition, weak stream, and dribbling. Ultimately, incomplete bladder emptying, bladder overdistension, and urine retention predispose patients to UTIs.
- C-DAN: Intensive glycemic and multifactorial treatment slows C-DAN (Gaede) and there is evidence that pharmaceutical grade alpha-lipoic acid (not available in the US) slows the progression. Discontinue medications that can produce/aggravate orthostasis.Can treat orthostasis with mineralocorticoids (such as ; 9-å-fluorohydrocortisone, initiated at 0.1 mg/day and increased, as needed to 0.5 mg daily.) and peripherally activing sympathomimetics (such as midodrine, dose titrated from 2.5 mg to 10 mg three times a day.). Unfortunately, symptoms generally do not respond until fluid retention and edema develop.
- Sudomotor dysfunction: anticholinergic agents such as trihexyphenidyl, propantheline, or scopolamine, although efficacy limited by other anticholinergic effects, such as dry mouth, urinary retention, and constipation. Glycopyrolate is successful in some patients with gustatory sweating. Intracutaneous injection of botulinum toxin type A is useful as a focal treatment.
- GI-DAN 4-6 small meals per day and reduction of dietary fat content also helpful. Prokinetic agents for gastroparesis include metoclopramide, domperidone , erythromycin, and levosulpiride. The severe and intermittent nature of diabetic diarrhea makes treatment and assessment difficult and best done in a GI clinic.
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ED: withdrawal of offending medications coupled with psychological counseling, medical treatment, or surgery. Medical treatment includes guanine monophosphate type-5 phosphodiesterase inhibitors that enhance blood flow to the corpora cavernosae with sexual stimulation. Other therapies include the injection of vasoactive substances such as papaverine, phentolamine, and prostaglandin E1 into the corpus cavernosum, transurethral delivery of vasoactive agents, and mechanical devices such asvacuum erection device or constricting rings. Penile prosthetic implants available if these therapies fail or are not tolerated by the patient.
- Neurogenic bladder: instructed patient to palpate bladder and, if they are unable to initiate micturition when bladder is full, use Crede's maneuver to start flow of urine every 4 hours. Parasympathomimetics such as bethanechol (10 to 30 mg three times a day) sometimes partially helps. Extended sphincter relaxation can be achieved with a alpha1-blocker, such as doxazosin. Clean intermittent self-catheterization may also be necessary.
- Regular follow up of patients with DAN to assess symptoms and effects of the medications.
- ADA consensus statement suggests that screening for DAN should be instituted at diagnosis for T2DM and 5 years after diagnosis T1DM. Screening typically consists of a history and an examination for signs of autonomic dysfunction focusing on HR variability, including expiration-to-inspiration ratio and in response to Valsalva and standing. Repeat screening annually; if positive, appropriate diagnostic tests and symptomatic treatments should be instituted.
- Autonomic symptoms that produce disability or that affect QOL do occur.
- Systematic, annual review of autonomic symptoms is critical to diagnosis.
- Treatment is generally best reserved for specialized clinics.
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