Detecting And Treating Patients With Diabetic Autonomic Neuropathy

By Damieon Brown, DPM and Javier La Fontaine, DPM

Autonomic neuropathy may significantly affect the quality of life of patients with diabetes. Unfortunately, despite the common prevalence of this condition in this population, autonomic neuropathy is one of the least understood and recognized complications of diabetes. Not only is there a cloudy picture in regard to the pathogenesis of the condition, there are various clinical manifestations with no degree of consistency in which they may occur. With this in mind, let’s take a closer look at this potentially serious complication among people with diabetes. Autonomic neuropathy generally involves the entire autonomic nervous system and is marked by dysfunction of one or more organ systems. One may notice clinical manifestations of autonomic neuropathy among patients with longstanding diabetes and in those with less acute dysfunction that occurs within one to two years of being diagnosed with diabetes. The pathogenesis of autonomic neuropathy includes theories of metabolic insult to the nerve fibers, neurovascular insufficiency, autoimmune damage and neurohormonal growth factor deficiency. The direct neuronal damage is the result of increased glycemic activation leading to sorbitol accumulation. Some researchers also believe the activation of protein kinase C may be the contributing cause of vasoconstriction and reduction in neuronal blood flow. The combination of increased oxidative stress and increased free radical production may also cause vascular endothelial damage and reduce the bioavailability of nitric oxide.1 A Closer Look At Clinical Manifestations Clinical manifestations of autonomic neuropathy tend to occur simultaneously but not consistently in the same pattern. These patients tend to have cardiovascular, gastrointestinal, gastrourinary, metabolic, sudomotor and pupillary problems.1 Cardiovascular autonomic neuropathy (CAN) has been one of the commonly overlooked complications among patients with diabetes.2 This tends to result from damage to the autonomic nerve fibers that innervate the heart and blood vessels, and cause abnormalities in heart rate and vascular dynamics. CAN may be marked by clinical manifestations such as exercise intolerance, orthostatic hypotension and silent myocardial ischemia. Exercise intolerance in regard to autonomic dysfunction has been shown to have marked effects on decreased heart rate and blood pressure in those with CAN. Orthostatic hypotension usually occurs in the diabetic population due to damage of the efferent sympathetic fibers that are part of the splanchnic vasculature. If patients with diabetes start to complain of symptoms such as lightheadedness, dizziness, fatigue, weakness, blurry vision and neck pain, proceed with further workup in order to differentiate CAN from any other cause associated with these symptoms. Myocardial ischemia is an entity that is not clearly understood. Previous studies suggest that this is caused by damage to the myocardial sensory afferent fibers in the autonomic nerve. If these patients experience chest pain in any location along with confusion, unexplained fatigue, edema, nausea, hemoptysis and vomiting, one should have a high index of suspicion for a silent heart attack. How Does This Relate To The Diabetic Foot? The autonomic nervous system controls microvascular skin flow.3 In the diabetic population, the rhythmic contraction of small vessels such as arterioles, venules and small arteries is affected. Loss of control of these vessels will increase blood flow in the absence of large vessel peripheral arterial occlusive disease. This is also a consequence of increased arteriovenous shunting and results in a warm foot with distended dorsal foot veins.4 According to Low, et. al., this physiological problem may lead to diabetic neuropathy as well.5 This problem resembles premature aging. The clinical pedal manifestations of autonomic neuropathy are dry skin, loss of sweating, distended veins and fissuring, which may lead to ulcerations, infection and gangrene.6 It has been documented in the literature that autonomic neuropathy may increase osteoclastic activity, resulting in reduced bone density. Young, et. al., found reduced bone density in the lower limbs of 17 patients with Charcot in comparison to 10 neuropathic control subjects.7 Therefore, Charcot arthropathy may reflect the severity of autonomic neuropathy. Nerve function involves large nerve fibers and small nerve fibers. Tests such as vibration, proprioception and loss of protective sensation, deep tendon reflexes, muscle strength, two-point discrimination and pinprick are good indicators of large fiber neuropathy.2 These patients present with symptoms such as lacinating pain, radiating pain, heaviness or numbness in the feet and legs. Clinically, one may note wasting of the intrinsic muscle of the foot with cheiroarthropathy or ankle equinus. Nerve conduction velocity is rarely indicated for diagnosing diabetic neuropathy and is primarily a large fiber test. Small fiber nerve functions account for perception of heat, cold and pain sensation. Signs and symptoms of small fiber neuropathy include burning, cold feet, a feeling of being on “pins and needles” and hyperalgesia. Unfortunately, a practical diagnostic test for small fiber neuropathy does not exist yet. Several tests are described in the literature. The quantitative sudomotor axon reflex test (QSART) machine enables one to measure the sweating function of the foot. However, the variability of the test is not well understood. Although autonomic neuropathy is considered a small fiber neuropathy, it is imperative to identify these patients with autonomic neuropathy by questioning specific signs and symptoms that they may experience. Asking the patient about symptoms such as gastroparesis, incontinence, sexual dysfunction and dizziness with change in position (postural hypotension) may help facilitate an appropriate and timely diagnosis. How Autonomic Neuropathy Can Adversely Affect Wound Healing Hyperglycemia is the most important risk factor when it comes to the pathogenesis of diabetic microvascular disease or “functional microcirculation.” Although it is not well understood, changes in hydrostatic pressure at the level of capillaries will lead to increased permeability of plasma proteins leading to endothelial dysfunction and loss of autoregulation. One of the theories that may explain the effect of functional microcirculation in wound healing is the loss of control of the arteriovenous shunting caused by autonomic neuropathy (small fiber neuropathy), specifically the c-fibers. This process will lead to oxygenation of the venous blood and shunting of blood away from the skin, which leads to tissue hypoxia. Case Study: Trying To Heal A Stubborn Puncture Wound A 56-year-old Hispanic female presented to our institution three weeks after experiencing a puncture wound to her left hallux. She noted a throbbing pain and increased swelling in this area two days prior to her visit. The patient did not seek professional help until her emergency room visit. Her past medical history includes NIDDM for eight years, hypertension, hyperlipidemia, coronary artery disease, myocardial infarction in 1995, nephropathy and retinopathy. Her current medications include metformin, glipizide, enalapril and Toprol XL. She had smoked for 40 years but quit in 1995. She denied any alcohol consumption. Upon a physical examination, we found that the obese patient had a palpable dorsalis pedis pulse but a barely palpable posterior tibial pulse in both feet. Her capillary filling time was less than three seconds. She also demonstrated a loss of protective sensation to 10 sites in both feet. We noted dry, xerotic skin in the lower extremities and no pedal hair. Her puncture wound was on the plantar aspect of her left hallux with erythema extending through the first interspace and a full thickness dry eschar in the lateral aspect of the hallux. A laboratory evaluation was within normal limits. Radiographs revealed no foreign body nor signs of osteomyelitis. Since there were concerns about her blood flow status, we ordered non-invasive studies. Significant findings included a left ABI of .91, a TBI of .43 and biphasic waveforms to the anterior tibial artery and posterior tibial artery. Transcutaneous oximetry at the midfoot level demonstrated a response from 1 to 23 mmHg to 100 percent oxygen challenge for 10 minutes. Vascular surgery recommended that the patient should heal. We first performed an open partial first ray amputation, which demonstrated a local abscess at the first interspace with a significant soft tissue loss. However, five days after the surgery, the wound did not progress. After again consulting the vascular team, we performed an angiogram. The angiogram revealed iliac disease and 60 percent stenosis of the anterior tibial and posterior tibial artery of the left lower extremity. The vascular team decided to stent the lesion in the iliac artery and monitor the wound. Five days later, the wound still demonstrated no improvement. At this point, the vascular team decided to perform an angioplasty at the level of the anterior tibial artery and posterior tibial artery. Again, the team performed transcutaneous oximetry, which demonstrated an increase from 33 to 54 mmHg at the midfoot level. Arterial Doppler waveforms improved to a triphasic signal. The vascular surgery team said they had achieved optimal blood flow. The team continued appropriate local wound care with the patient on an outpatient basis. One month later, the patient was readmitted to the hospital for a non-healing wound with cellulitis. However, when the team employed hyperbaric oxygen therapy, they were able to heal the patient’s wound. This case demonstrates the fact that this patient had a minimal peripheral arterial occlusive disease. Even after the improvement of blood flow after interventional angioplasties, the patient still needed adjunctive therapy, specifically hyperbaric oxygen therapy, to achieve complete healing. It demonstrates that tissue hypoxia was the etiology in this problem wound, not diminished blood flow. Final Notes Dysfunction from autonomic neuropathy can be a complicating factor in the diabetic population. Identifying the patient with diabetic autonomic neuropathy will help clinicians assess the spectrum of the disease and subsequently place this patient in the “at risk” category, knowing that he or she could be at risk for ulcerations, gangrene or Charcot arthropathy. Dr. La Fontaine is an Assistant Professor in the Department of Orthopedics/Podiatry at the University of Texas Health Science Center. Dr. Brown is a first-year resident in the aforementioned department at the University of Texas Health Science Center. Dr. Steinberg (pictured) is an Assistant Professor in the Department of Orthopaedics/Podiatry Service at the University of Texas Health Science Center.



References 1. Vinik AI, Maser RE, Mitchell BD, Freeman R: Diabetic Autonomic Neuropathy. Diabetes Care, Vol. 26(5), 1553-1579, May 2003. 2. Tananberg RJ, Schumer MP, Greene DA, Pfeifer MA: The Diabetic Foot. Mosby 6th ED., 33-64, Philadelphia 2001. 3. Armstrong DJ, Lavery LA, Harkless LB: Treatment-based classification system for assessment and care of diabetic feet. JAPMA 86: 311-316, 1996. 4. Boulton AJM, Scarpello JHB, Ward JD: Venous oxygenation in the diabetic neuropathic foot: Evidence of arteriovenous shunting? Diabetologia 22:6-8, 1982. 5. Low PA, Nickander KK, Tritschler HJ: The roles of oxidative stress and antioxidant treatment in experimental diabetic neuropathy. Diabetes 46 (Suppl. 2): S38-S42, 1997. 6. Gries A, Cameron NE, Low PA, Ziegler D: Textbook of diabetic neuropathy. P55, 297, Thieme, New York, 2003. 7. Young MJ, Marshall A, Adams JE et. al.: Osteopenia, Neurological dysfunction, and the development of Charcot Neuroarthropathy. Diabetes Care, Vol. 18(1), 34-38, January, 1995.


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