Diabetic autonomic neuropathy

The symptoms of autonomic dysfunction should be elicited carefully during the history and review of systems, particularly since many of these symptoms are potentially treatable. Major clinical manifestations of diabetic autonomic neuropathy include resting Tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastroparesis, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function, “brittle diabetes,” and hypoglycemic autonomic failure.

Cardiovascular autonomic neuropathy is the most studied and clinically important form of diabetic autonomic neuropathy. Cardiac autonomic neuropathy may be indicated by resting Tachycardia (>100 bpm), orthostasis (a fall in systolic blood pressure >20 mmHg upon standing), or other disturbances in autonomic nervous system function involving the skin, pupils, or gastrointestinal and genitourinary systems.

Gastrointestinal disturbances (e.g., esophageal enteropathy, gastroparesis, constipation, diarrhea, fecal incontinence) are common, and any section of the gastrointestinal tract may be affected. Gastroparesis should be suspected in individuals with erratic glucose control. Upper gastrointestinal symptoms should lead to consideration of all possible causes, including autonomic dysfunction. Evaluation of solid-phase gastric emptying using double-isotope scintigraphy may be done if symptoms are suggestive, but test results often correlate poorly with symptoms. Barium studies or referral for endoscopy may be required to rule out structural abnormalities. Constipation is the most common lower gastrointestinal symptom but can alternate with episodes of diarrhea. Endoscopy may be required to rule out other causes. 

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Diabetic autonomic neuropathy is also associated with genitourinary tract disturbances, including bladder and/or sexual dysfunction. Evaluation of bladder dysfunction should be performed for individuals with diabetes who have recurrent urinary tract infections, pyelonephritis, incontinence, or a palpable bladder. In men, diabetic autonomic neuropathy may cause loss of penile erection and/or retrograde ejaculation.

Symptomatic treatments

DPN.

The first step in management of patients with DPN should be to aim for stable and optimal glycemic control. Although controlled trial evidence is lacking, several observational studies suggest that neuropathic symptoms improve not only with optimization of control but also with the avoidance of extreme blood glucose fluctuations. Most patients will require pharmacological treatment for painful symptoms: many agents have efficacy confirmed in published randomized controlled trials, though none are specifically licensed for the management of painful DPN.

Tricyclic drugs.

The usefulness of the tricyclic drugs such as amitriptyline and imipramine has been confirmed in several randomized controlled trials, although they do not have formal FDA approval for this condition. Although cheap and generally efficacious in the management of neuropathic pain, side effects limit their use in many patients. Tricylcic drugs may also exacerbate some autonomic symptoms such as gastroparesis.

Anticonvulsants.

Gabapentin is a commonly prescribed anticonvulsant that has been shown to be efficacious in the treatment of neuropathic pain, although not approved for this condition. It is advisable to start at a small dose and then increase over days to weeks to the dosage that is well tolerated and produces symptomatic relief. The structurally related compound pregabalin is longer acting, has recently been confirmed to be useful in painful diabetic neuropathy in a randomized controlled trial, and is approved for use in this condition. Other anticonvulsant drugs may also be efficacious in the management of neuropathic pain.

Other agents.

The 5-hydroxytryptamine and norepinephrine reuptake inhibitor duloxetine has been approved by the FDA for the treatment of neuropathic pain.
Treatment of autonomic neuropathy

A wide variety of agents are used to treat the symptoms of autonomic neuropathy including metoclopramide for gastroparesis and several medications for bladder and erectile dysfunction. These treatments are frequently used to provide symptomatic relief to patients. Although they do not change the underlying pathology and natural history of the disease process, their use is recommended due to the impact they may have on the quality of life of the patient.

E. Foot care

Recommendations

* Perform a comprehensive foot examination and provide foot self care education annually on patients with diabetes to identify risk factors predictive of ulcers and amputations. (B)
* The foot examination can be accomplished in a primary care setting and should include the use of a monofilament, tuning fork, palpation, and a visual examination. (B)
* A multidisciplinary approach is recommended for individuals with foot ulcers and high-risk feet, especially those with a history of prior ulcer or amputation. (B)
* Refer patients who smoke or with prior lower-extremity complications to foot care specialists for ongoing preventive care and life-long surveillance. (C)
* Initial screening for Peripheral arterial disease (PAD) should include a history for claudication and an assessment of the pedal pulses. Consider obtaining an ankle-brachial index (ABI), as many patients with PAD are asymptomatic. (C)
* Refer patients with significant claudication or a positive ABI for further vascular assessment and consider exercise, medications, and surgical options. (C)

Amputation and foot ulceration are the most common consequences of diabetic neuropathy and major causes of morbidity and disability in people with diabetes. Early recognition and management of independent risk factors can prevent or delay adverse outcomes.

The risk of ulcers or amputations is increased in people who have had diabetes >10 years, are male, have poor glucose control, or have cardiovascular, retinal, or renal complications. The following foot-related risk conditions are associated with an increased risk of amputation:

* Peripheral neuropathy with loss of protective sensation.
* Altered biomechanics (in the presence of neuropathy).
* Evidence of increased pressure (erythema, hemorrhage under a callus).
* Bony deformity.
* Peripheral vascular disease (decreased or absent pedal pulses).
* A history of ulcers or amputation.
* Severe nail pathology.

All individuals with diabetes should receive an annual foot examination to identify high-risk foot conditions. This examination should include assessment of protective sensation, foot structure and biomechanics, vascular status, and skin integrity. People with one or more high-risk foot condition should be evaluated more frequently for the development of additional risk factors. People with neuropathy should have a visual inspection of their feet at every visit with a health care professional. Evaluation of neurological status in the low-risk foot should include a quantitative somatosensory threshold test, using the Semmes-Weinstein 5.07 (10-g) monofilament. The skin should be assessed for integrity, especially between the toes and under the metatarsal heads. The presence of erythema, warmth, or callus formation may indicate areas of tissue damage with impending breakdown. Bony deformities, limitation in joint mobility, and problems with gait and balance should be assessed.

People with neuropathy or evidence of increased plantar pressure may be adequately managed with well-fitted walking shoes or athletic shoes. Patients should be educated on the implications of sensory loss and the ways to substitute other sensory modalities (hand palpation, visual inspection) for surveillance of early problems. People with evidence of increased plantar pressure (e.g., erythema, warmth, callus, or measured pressure) should use footwear that cushions and redistributes the pressure. Callus can be debrided with a scalpel by a foot care specialist or other health professional with experience and training in foot care. People with bony deformities (e.g., hammertoes, prominent metatarsal heads, or bunions) may need extra-wide shoes or depth shoes. People with extreme bony deformities (e.g., Charcot foot) that cannot be accommodated with commercial therapeutic footwear may need custom-molded shoes.

Initial screening for PAD should include a history for claudication and an assessment of the pedal pulses. Consider obtaining an ABI, as many patients with PAD are asymptomatic. Refer patients with significant or a positive ABI for further vascular assessment and consider exercise, medications, and surgical options.

Patients with diabetes and high-risk foot conditions should be educated regarding their risk factors and appropriate management. Patients at risk should understand the implications of the loss of protective sensation, the importance of foot monitoring on a daily basis, the proper care of the foot, including nail and skin care, and the selection of appropriate footwear. The patient??ôs understanding of these issues and their physical ability to conduct proper foot surveillance and care should be assessed. Patients with visual difficulties, physical constraints preventing movement, or cognitive problems that impair their ability to assess the condition of the foot and to institute appropriate responses will need other people, such as family members, to assist in their care. Patients at low risk may benefit from education on foot care and footwear.

For a detailed review of the evidence and further discussion, see the ADA??ôs technical review and position statement in this subject.
Problems involving the feet, especially ulcers and wound care, may require care by a podiatrist, orthopedic surgeon, or rehabilitation specialist experienced in the management of individuals with diabetes. For a complete discussion on wound care, see the ADA??ôs consensus statement on diabetic foot wound care.

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AMERICAN DIABETES ASSOCIATION
DIABETES CARE, VOLUME 27, SUPPLEMENT 1, JANUARY 2004

References
1.  Bode BW (Ed.): Medical Management of Type 1 Diabetes. 4th ed. Alexandria, VA, American Diabetes Association, 2004
2.  Zimmerman BR (Ed.): Medical Management of Type 2 Diabetes. 4th ed. Alexandria, VA, American Diabetes Association, 1998
3.  Kilingensmith G (Ed.): Intensive Diabetes Management.  3rd ed.  Alexandria, VA, American Diabetes Association, 2003
4.  The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183-1197, 1997
4a.World Health Organization:  Diabetes Mellitus: Report of a WHO Study Group. Geneva, World Health Org., 1985 (Tech. Rep. Ser., no. 727)
5.  The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 26:3160 - 3167, 2003
6.  Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaaniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344:1343-1350, 2001
7.  Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, Hu ZX, Lin J, Xiao JZ, Cao HB, Liu PA, Jiang XG, Jiang YY, Wang JP, Zheng H, Zhang H, Bennett PH, Howard BV: Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the DaQing IGT and Diabetes Study. Diabetes Care 20:537- 544, 1997
8.  The Diabetes Prevention Program Research Group:  Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393- 403, 2002
9.  Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M: Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomized trial. Lancet 359:2072-2077, 2002
10.  Sjostrom L, et al: XENDOS ( Xenical in the prevention of diabetes in obese subjects):  a landmark study.  Poster presented at the International Congress on Obesity (ICO), San Paulo, Brazil, 2002
11.  Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz, Hodis HN, Azen SP: Preservation of pancreatic β-cell function and prevention of type 2 diabetes by pharmacological trewatment of insulin resistance in high-risk hispanic women. Diabetes 51:2796 -2803, 2002
12.  Engelgau ME, Narayan KMV, Herman WH:  Screening for type 2 diabetes (Technical Review).  Diabetes Care 23:1563-1580, 2000 [erratum appears in Diabetes Care 23:1868 -1869, 2000]
13.  American Diabetes Association: Type 2 diabetes in children and adolescents (Consensus Statement).  Diabetes Care 23:381-389, 2000
14.  American Diabetes Association: Gestational diabetes mellitus (Position Statement). Diabetes Care 27 (Suppl. 1):S88 - S90, 2004
15.  The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. N Engl J Med 329: 977-986, 1993
16.  The UK Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352: 837- 853, 1998
17.  The UK Prospective Diabetes Study Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854 -865, 1998

May 27, 10 • Diabetes mellitus