Geralyn Spollett, MSN, C-ANP, CDE,1 and Belinda P. Childs, ARNP, MN, CDE, BC-ADM2
1Spollett is an adult nurse practitioner at Yale Diabetes Center, New Haven, CT. 2Childs is a diabetes nurse specialist at Great Plains Diabetes in Wichita, KS.
Diabetic neuropathy is a chronic complication that is among the most costly and disabling of all the complications of diabetes.1 It affects both the peripheral nervous system (sensory and motor) and the autonomic nervous system (ANS). It affects at least 50% of all people with diabetes, yet it is poorly understood. It can have a range of presentations; for example, it may present with obvious symptoms ≥5 years after the diagnosis of type 1 diabetes (T1D), as the initial symptom of previously undiagnosed type 2 diabetes (T2D), or it may be unrecognized and discovered only by careful diagnostic testing. Emerging evidence indicates that neuropathy can be present years before any alteration in glucose levels, at the early stages of diabetes pathogenesis.2 Symptoms of diabetic peripheral neuropathy (DPN) often start with numbness and paresthesia in the toes and feet and can progress to the fingers and hands. Diabetic autonomic neuropathy affects innervation to all of the organs of the body and can cause dysfunction in any body part.3,4
The precise pathogenesis of neuropathy in diabetes is not well understood. Historically, chronic hyperglycemia was seen as the main causative factor increasing oxidative stress, leading to nerve injury.5 Discussion regarding the etiology and pathology of neuropathy is evolving, however, and now is seen as much more complicated. A complex interaction of many variables, including chronic hyperglycemia, insulin deficiency, nerve ischemia, microvascular disease, and nonenzymatic glycation, and other risk factors, such as blood pressure, lipid variables, genetics, and weight, have been suggested as major factors in the development of neuropathy.4,6,7
Neuropathies can be classified by size, function, distribution of innervation, and type of injury. In this chapter, the neuropathies will be classified by function and distribution—the categories being peripheral and autonomic—and then will be separated further into the most common forms seen within each category.
PERIPHERAL NEUROPATHY
In diabetes, the diagnosis of peripheral neuropathy is one of exclusion. A consensus conference defined diabetic neuropathy as the presence of symptoms or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes.8 Many other diseases can cause neuropathic symptoms, and before they can be attributed to diabetes, the clinician must investigate the other possible causes. Chronic inflammatory polyneuropathy, vitamin B12 deficiency, alcoholism, hypothyroidism, heavy metal exposure, and use of isoniazid for tuberculosis prophylaxis all can cause symptoms that can be confused with DPN.9 The differential diagnosis for peripheral neuropathy is given in Table 16.1. It is important to assess the patient for these other causes as some of them are treatable and may improve or resolve the neuropathy.
Table 16.1—Differential Diagnosis of DPN
Metabolic
• Diabetes
• Myedema
• Porphyria
• Uremia
Drugs and Chemicals
• Alcohol
• Chemotherapy drugs
• Nitrofurantoin
• Isoniazid
Neoplastic Disorders
• Lymphoma
Infective or Inflammatory
• Guillain-Barre syndrome
• Lyme disease
Genetic
• Hereditary sensory neuropathy
Source: Adapted from Tesfaye.9
Major risk factors of DPN include diabetes duration, hyperglycemia, and age, followed by prediabetes, hypertension, dyslipidemia, and obesity. Height, smoking, insulin resistance, and hypoinsulinemia pose additional risks. Importantly, hyperglycemia, hypertension, dyslipidemia, obesity, and smoking are modifiable.10
DPN results from widely distributed lesions throughout the peripheral nerves. The deficit is distributed over all sensorimotor nerves and starts in the most distal areas first, usually the toes and feet. DPN usually begins with an early involvement of the long axons in the peripheral nerves, which is the characteristic lesion of neuropathy. Height plays a role because the longer the nerve fiber, the greater its vulnerability to injury.6,11
DPN can manifest in many different forms and classes of DPN usually are grouped into diffuse or focal neuropathies. Diffuse neuropathies include distal symmetric polyneuropathy and autonomic neuropathy. Focal neuropathies involve single or multiple peripheral nerves and are categorized as mononeuropathy, radiculopathy, or entrapment neuropathy.
The most common form of DPN is sensory polyneuropathy,12 which also is known as chronic sensorimotor distal symmetric polyneuropathy. Although the initial symptoms may be absent in some, the typical presentation entails a burning, tingling, or shooting “electrical” pain involving the small-fiber sensory system. Sensory neuropathy symptoms can include increased sensitivity to a stimulus (hyperesthesia) or pain in response to a nonpainful stimulus (allodynia). Others may report only a simple numbness, which is associated with changes in the large-fiber sensory system. The pain or discomfort may fluctuate but usually is worse at night.13
In most cases of sensory polyneuropathy, the patient will present with symmetric pain or discomfort affecting both feet. This form of neuropathy is also called painful diabetic neuropathy (PDN). Over time, or in cases of poorly controlled diabetes, the symptoms will progress, moving from the feet into the legs, and then advancing to the fingers and hands. This commonly is referred to as “stocking and glove” distribution. For many, this is a debilitating problem, interfering with sleep and affecting quality of life.
Assessment
Although symptoms of DPN may be present, other causes of neuropathy should be considered, such as alcohol abuse, vitamin B12 deficiency, thyroid disease, glycemic control, and any inflammatory diseases. Those patients on metformin therapy may be at particular risk for Vitamin B12 deficiency. Screening lab tests may include complete blood count, complete metabolic panel sedimentation rate, A1C, thyroid stimulating hormone, and vitamin B12 level.12
All people with diabetes should be assessed for DPN starting at the diagnosis of T2D and 5 years after the diagnosis of T1D and at least annually thereafter.14 Because up to 50% of DPN may be asymptomatic, people with diabetes should have a foot examination at each office visit. The neurological examination should focus on the lower extremities and always should include an accurate foot inspection for deformities, ulcers, fungal infection, muscle wasting, hair distribution or loss, and the presence or absence of pulses.15 This exam also should include a thorough history of all symptoms (duration, nature of presentation), aggravating and alleviating factors. Proprioception or position sense is important for assessing an individual’s risk of falling. Deep tendon reflexes also may provide additional information on the extent of the neuropathy. Table 16.2 includes several useful sensory tests.
Table 16.2—Clinical Sensory Tests for Neuropathy
|
Test |
Instrument |
|
Vibration |
128 Hx tuning fork |
|
Pain (pinprick) |
Neurotips |
|
Pressure |
10 g monofilament |
|
Light touch |
Wisp of cotton |
|
Cold |
Cold tuning fork |
Source: Adapted from Vinik et al.16
According to the American Diabetes Association 2016 Standards of Care, a neurological assessment should include sensitivity to light touch, sensation using a 10 g monofilament, and at least one of the following tests: pinprick, temperature or vibratory sensation.14 These tests are important for assessing protective sensation (see also Chapter 17, Evaluation and Management of the Diabetic Foot). Nerve function tests may include quantitative sensory tests, nerve conduction studies, and electromyography (EMG) or even nerve biopsy. These tests evaluate the evidence of the specific sensory or motor nerve problem, its distribution and severity, and the underlying pathology.17 A negative test does not mean that the patient does not have neuropathy, but rather that the nerve conduction test did not test the nerve fibers that are most associated with that presentation. For example, the EMG procedure does not evaluate c-fiber changes that are associated with small-fiber damage. The rudimentary examination outlined can detect the nerve changes seen in the insensate foot. Patients who do not feel the 10 g monofilament during testing are at high risk for developing foot ulcerations. Some emerging tests for detecting neuropathy include the corneal confocal microscopy, a noninvasive technique that can detect early nerve fiber loss, and the contact heat-evoked potential stimulation that can detect small-fiber dysfunction.10,15
Acute Painful Neuropathy
The main symptoms of acute painful neuropathy, a diffuse small-fiber neuropathy, are pain and paresthesia. These symptoms are worse at night and are found in the feet more often than in the hands. The pain can be intense and is described as a burning, stabbing, or deep aching sensation. Because of the chronic symptoms, anorexia, weight loss, and depression also may be present. This form of neuropathy is more common in men and also can manifest as erectile dysfunction. It often subsides spontaneously, but it also can persist indefinitely and be debilitating, although the latter is rare.5 Health-care professionals should be aware that people who present with longstanding severe hyperglycemia may experience a transient worsening of symptoms of PN with rapid reduction in glucose levels. Patients should be educated that this may occur.
Treatment
Treatment of DPN is based on several approaches: intensive optimal glycemic control and risk factor management, symptomatic pain management,18 and preventive measures. The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive insulin therapy decreases the development and progression of DPN in people with T1D and may even reverse it.19 In addition, the Epidemiology of Diabetes Interventions and Complications study demonstrated a reduced incidence of neuropathy in patients with T1D receiving intensive insulin therapy.20 A recent Cochrane review concluded that more intensive glucose control significantly prevented the development of clinical neuropathy and reduced nerve conduction and vibration threshold abnormalities in T1D. Although not statistically significant, enhanced glucose control in T2D also showed decreased incidence of clinical neuropathy but did significantly reduce nerve conduction and vibration threshold abnormalities.21
Lipid Control
Numerous studies have indicated that hyperlipidemia and hyperglycemia lead to increased oxidative stress and reactive oxygen species,22 and that dyslipidemia may be an independent contributor to DPN. Observational studies suggest that therapy with a statin or fibrate may protect against the development of DPN but randomized clinical trials are necessary.23
Physical Activity
DPN can increase the risk of falls resulting from decreased sensation and poor proprioception. Balance must be assessed and care must be taken to avoid falls. All individuals, particularly those with insensate feet, should engage in balance training exercises, combined with some lower body and core strength training, to lower falls risk. Exercise participation can prevent further loss of muscle strength and flexibility commonly experienced by patients with both small- and large-nerve fiber damage.24 Regular physical activity consisting of aerobic and strengthening exercises has resulted in significant reductions in pain and neuropathic symptoms along with the physical presence of increased intraepidermal nerve fiber branching in a proximal skin biopsy.25
Pain Management
At present there is no consensus regarding a single effective drug for painful neuropathy,18 but pain management may include all forms of analgesics, including acetaminophen, nonsteroidal anti-inflammatory medications, and opioids. Tricyclic antidepressants may help with pain as well as insomnia, a frequent disturbance resulting from increased pain at night. Symptomatic management may include amitriptyline, gabapentin, pregabalin, duloxetine, and tapentadol XR. Gabapentin has been demonstrated to be an effective treatment for PDN, but should be monitored closely because high doses can cause dizziness, lethargy, and supine hypertension. The dosage of gabapentin can vary widely (200–800 mg t.i.d.).
The Standards of Care recommend that either pregabalin or duloxetine be prescribed as the initial pharmacologic treatment. Pregabalin (50–200 mg t.i.d.), duloxetine (60 mg qd), and tapentadol XR (50–250 mg b.i.d) are approved by the U.S. Food and Drug Administration (FDA) for DPN. Opioids have been used but because of issues of dependence should be avoided if possible. Tapentadol XR is a centrally acting opioid analgesic that because of its weak μ-opioid receptor agonist is believed to have less dependence and abuse potential than traditional opioids.26 Efficacy or lack of efficacy of these drugs should be judged after 2–4 weeks of treatment using adequate doses. Care must be taken to assess renal and hepatic health when choosing any of these medications, and cost should be considered (Table 16.3 lists the most commonly used medications.)
Table 16.3—Most Commonly Used Medications
Anticonvulsants
Pregabalin
• Is FDA approved for treatment of DPN pain.
• Binds to and modulates voltage-gated calcium channels.
• Is a more potent regulator of calcium channels than gabapentin (it is this mode of action that may modulate neuropathic pain).
• Has been found to significantly decrease mean pain score in people with painful DPN compared with placebo.
• Main adverse effects include dizziness, somnolence, weight gain, peripheral edema, blurred vision, and constipation.
• It is a controlled (scheduled) drug in the U.S., and, unlike its predecessor gabapentin, there is a possibility it could be habit-forming.
• The maximum approved dose for DPN pain is 300 mg/day in divided doses; stepwise titration is recommended.
Gabapentin
• Has been found to improve pain in people with DPN in several studies.
• Although not FDA approved for the treatment of pain associated with DPN, it is one of the most widely used agents in clinical practice.
• Adverse effects that may require discontinuation of therapy include dizziness, ataxia, somnolence or confusion (especially in older people), headache, nausea, diarrhea, weight gain.
• Dose titration usually starts with 300 mg three times/day, but doses as high as 3,600 mg/day may be required in some patients because of tachyphylaxis.
Serotonin and norepinephrine reuptake inhibitors (SNRIs)
Duloxetine
• It is the second FDA-approved agent for use in painful DPN.
• It is a selective dual SNRI and is relatively balanced in its affinity for reuptake inhibition.
• The spectrum of side effects is superior to the tricyclic agents but less favorable compared with pregabalin.
• Patients frequently experience nausea with initiation of therapy; a slow titration of the drug usually can avoid this common adverse effect.
• Most common adverse effects, besides nausea, are sedation and generalized sleepiness.
• Duloxetine does not usually require dose titration, with most patients requiring 60 mg daily, occasionally 60 mg twice daily.
• May be combined with pregabalin or gabapentin, which usually require lower doses for all.
Venlafaxine
• Venlafaxine has been found to be probably effective in lessening the pain of DPN and is recommended to be considered for treatment.
• Dose should be progressively titrated, selecting the minimum effective dose to mitigate side effects.
• Most common adverse effects include nausea, sedation, dizziness, and generalized sleepiness.
Tricyclic antidepressants (TCAs)
• Act by blocking neuronal reuptake of norepinephrine and serotonin, thereby potentiating the inhibitory effect of these neurotransmitters in nociceptive pathways.
• Amitriptyline, imipramine, and desipramine have all been found, in small RCTs, to relieve pain better than placebo in patients with DPN.
• Additional support for the efficacy of TCAs was provided by a meta-analysis of 21 clinical trials.
• Adverse effects are common and sometime troublesome with TCAs and may lead to treatment withdrawal.
• In clinical trials of TCAs, ~20% of participants withdrew because of intolerable adverse effects, such as severe sedation, confusion, and anticholinergic adverse effects. Suicidal ideation also was described.
• Side effects are particularly problematic in older patients, in whom it is advisable to start at low dosages nightly.
• The most commonly used TCAs may be ranked in order from most to least associated with anticholinergic effects as follows: amitriptyline, imipramine, nortriptyline, and desipramine.
Opioid analgesics
Tapentadol XR has a dual mode of action, activates the μ-opioid receptor and inhibits the repute of norepinephrine, similar to tramadol, but differs in that it has a weak uptake of serotonin and is significantly more potent. It is useful for people who do not respond well to more commonly used opioids as a result of genetic factors preventing metabolism of CYP3A4 and CYP2D6. It is a weak-moderate opioid with a potency greater than tramadol but less than morphine.
• They are considered second-line approaches.
• Suppress pain by activating µ-receptors, which are present on the pre- and postsynaptic membranes of primary afferent nerve fibers, second-order neurons in the dorsal horn of the spinal cord, and neurons in pain-relevant supraspinal centers.
• May be considered either in combination with existing therapies or for use alone.
• Are used commonly for DPN pain, but have significant adverse effects with long-term use.
• Dependence may occur.
• Oxycodone has been found to be superior to placebo in the treatment of DPN pain.
• Tramadol (a weak opioid that acts through low-affinity binding to micro-opioid receptors and weak inhibition of norepinephrine and serotonin reuptake) also has been found to be effective in treatment of pain in DPN. It is often good treatment for breakthrough or refractory pain.
Topical capsaicin cream
• May be used in combination with other therapies or alone for pain that is refractory.
• Stimulates the release and subsequent depletion of substance P from sensory nerve fibers.
• A few small studies have demonstrated the effectiveness of capsaicin cream in control of pain and improvement in daily activities.
• Poor adherence is common because of the need for frequent applications, an initial exacerbation of symptoms, and frequent burning and redness at the application site.
Transcutaneous electrical nerve stimulation (TENS) or acupuncture
• May be added on to existing therapy or used alone in refractory cases.
• Uncontrolled studies of TENS and of acupuncture have been reported to decrease pain in patients with DPN.
• A report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology, based on a review of the literature up to April 2009, concluded that TENS may have some effectiveness for reducing pain caused by diabetic peripheral neuropathy, but there is no evidence for confirmed efficacy in well-designed randomized trials.
The main treatment goal is the titration of medication to achieve efficacy with as few side effects as possible. Topical agents, such as capsaicin, a derivative of hot peppers, have been shown to be effective by releasing substance P from local nerve endings.27
Evidence also shows that α-lipoic acid and α-linoleic acid can improve the sensory symptoms of diabetic polyneuropathy, primarily by ability to inhibit oxidation. α-Lipoic acid is a potent antioxidant and can be given both orally and intravenously. It has been used effectively in Germany for years and has been shown in international randomized controlled trials to effectively treat DPN.27,28 α-Linoleic acid is a fatty acid found in evening primrose oil and also has been used to treat diabetic neuropathy. α-Linoleic acid may improve problems with nerve membrane structure, impulse conduction, and nerve blood flow at doses of 360–480 mg/day.29 Although both of these acids have demonstrated benefit in relieving the painful symptoms of diabetic neuropathy, further investigation is needed. For chronic unrelieved pain, referral to a pain management team may be appropriate.
Neuropathic Foot Ulcer
A large part of assessing and treating DPN is aimed not only at symptom relief but also protection of the skin and prevention of injury. Trauma and damage to the foot can occur in distal symmetrical polyneuropathy because of the loss of sensitivity to pain, decreased proprioception, loss of muscle, foot deformities, and vascular changes. Because of the loss of feeling in the foot and repetitive trauma, ulceration can occur. The metatarsal heads are the most common sites, but ulcers can form in other areas of pressure. In the absence of pain, calluses form over the metatarsal areas and become thickened. The overlying skin breaks down, ulceration occurs, and the foot may become infected. Treatment should be prophylactic and include foot care education and identification of abnormal foot shape and improper weight bearing. Once ulcers do occur, however, treatment includes ensuring appropriate shoe fit and mechanical measures to reduce (or eliminate) improper weight bearing. Debridement may be necessary to remove excess callus, and antibiotics will be needed if infection is present.
Charcot’s Joint
Neuropathic arthropathy, or Charcot’s joint, also occurs with impaired pain recognition and proprioception but without motor loss. The foot appears swollen and red, with a flattened arch, and usually is painless and warm. The gait becomes abnormal, and repeated trauma occurs as a result. X-ray examination may reveal multiple fractures, osteopenia, bone lysis, and osteomyelitis. The pulses often are strong and bounding, but these pulses are due to the shunting of blood and may lead to more problems, such as excessive bone resorption and fractures. A podiatric or orthopedic referral is always necessary for the management of Charcot’s joint and should be initiated as soon as possible to reduce foot disfiguration. Any symptoms of a red and hot foot in individuals with diabetes should be referred for X-ray and assessment of Charcot’s joint.
Treatment
Early diagnosis and management is imperative to prevent further deterioration. Treatment consists of reducing or eliminating weight bearing and preventing further structural damage. Antibiotics are needed if cellulitis or osteomyelitis is present. As in the treatment of neuropathic ulcers, proper shoes and mechanical devices will be necessary because the shape of the foot is usually grossly abnormal.7,10,11
Proximal Motor Neuropathy
Proximal motor neuropathy, or diabetic amyotrophy, affects a single or multiple peripheral nerves. It usually presents with severe aching pain and burning and is followed by severe muscle atrophy in the limb girdle, weight loss, weakness and wasting of lower-extremity muscles, and pain in the thigh muscles, lumbar regions, or perineal regions. This syndrome is uncommon (0.8% among U.S. individuals with diabetes, although higher in T2D) and usually occurs in older adults. The onset is usually acute, with complete or partial recovery occurring within 12–24 months in most patients.30
Cranial Neuropathies
Cranial neuropathies occur frequently, usually in older adults. The onset is abrupt and asymmetrical; and it may be either painful or painless. The third cranial nerve is the most commonly affected. Symptoms often have a rapid onset and may include diplopia, decreased pupil size.
Bell’s palsy (seventh nerve) can cause facial pain, drooping eyelid, and lacrimation. This occurs with more frequency and prognosis for recovery may be worse in patients with diabetes. Treatment is usually conservative. Symptoms will subside, but it can take ≥6–8 weeks.11,17
Practical Point
Decreased pupil size may cause problems for individuals when entering a poorly lighted area or driving at night because pupils cannot dilate and adjust to darkness. Preventive education is necessary to avoid accidents or falls. Findings should be documented in the physical examination notes.
Practical Point
Take a detailed history and ask about the occurrence of unusual sweating, usually over the face and upper body during or after eating. Patients sometimes misinterpret these symptoms as hypoglycemic or hyperglycemic reactions and may treat them inappropriately.
Radiculopathy
Radiculopathy is a sensory neuropathy (intercostal or truncal) with a dermatomal pain and loss of cutaneous sensation. A single sensory nerve root is affected and is almost always unilateral and asymmetrical, with either hyperesthesia or paresthesia. This syndrome may be mistaken for acute abdominal crisis, herniated disc, herpes zoster, or spinal cord compression. Radiculopathies cause the most morbidity with low back pain and weakness. When the thoracic spine is affected, pain and dysesthesias may occur along the trunk, chest, and abdominal wall.31 Spontaneous remission usually occurs within 3–6 months, and pain management will be necessary during that time.7,18
Entrapment Neuropathies
Entrapment neuropathies (mononeuropathy/multiplex) are isolated peripheral nerve palsies that can cause focal nerve damage at common entrapment sites such as the wrist and palm, upper arm and elbow, or thigh. The risk of developing carpal tunnel syndrome is twice as common in individuals with diabetes. Diagnosis is made by electrodiagnostic studies. Treatment may be conservative, such as immobilization with a splint, or surgical, which is often minor in nature. Untreated entrapment injuries, however, often lead to muscle atrophy of the hand and permanent disability.
AUTONOMIC NEUROPATHY
Autonomic neuropathy is a serious form of neuropathy that often goes unrecognized because of its slow onset and confusing symptoms. In patients with DPN, up to 50% may have asymptomatic autonomic neuropathy.11Types of autonomic neuropathy include cardiovascular, gastrointestinal, genitourinary, and sudomotor (see Table 16.4). Autonomic control for each organ system usually is divided between opposing sympathetic and parasympathetic systems. Usually, the parasympathetic nerve fibers are affected first, and within 5 years, sympathetic nervous system dysfunction appears. The ANS is a complex entity that consists of a reflex arc made up of a sensor, afferent nerve, central nervous system (CNS), component efferent nerve, nerve ending, and effector organ. Because autonomic control of each organ is divided between opposing parasympathetic and sympathetic innervation, a symptom such as tachycardia could be attributed to either a decrease in sympathetic function or an increase in parasympathetic function.17
The development of autonomic neuropathy often is considered ominous because the mortality rate over a 3- to 5-year period is as high as 50–60%.11,17 Although the involvement of the ANS is often diffuse, symptoms often are confined to a single organ system.17 The organ systems most often affected by autonomic neuropathy are the cardiovascular system, gastrointestinal tract, genitourinary system, sweat glands, adrenal medulla, and ocular pupil.30
Table 16.4 Symptoms for Cardiovascular, Gastrointestinal, and Urogenital Autonomic Neuropathies
Practical Point
In the assessment for autonomic neuropathy affecting the genitourinary system identify voiding pattern, frequency of urinary tract infections, difficulty starting urinary stream, and presence or absence of bladder fullness. Obtain urinalysis if there is any suspicion of a urinary tract infection. Palpate and percuss the suprapubic area.
Abnormal Pupillary Function
Decreased parasympathetic tone produces a smaller-than-normal pupil. This can be diagnosed during a routine eye examination or with the aid of a measuring device called a pupilometer. No specific treatment is needed.18
Sudomotor Dysfunction
Autonomic neuropathy affects the sweat glands through the involvement of the C-fiber, which assists in the regulation of microvascular blood flow (MBF). Sudomotor dysfunction causes dry skin and itching and can affect quality of life. It also can cause anhidrosis, impairing thermoregulation and leading to heat intolerance, as well as hyperhydrosis. These symptoms adversely affect skin quality and structure, foot ulcerations, and edema. Because dry cracked feet and hands can act as a portal to infection, and hyperhidrosis of the feet can promote tinea pedis and other fungal infections, care must be taken to prevent these problems through excellent hygiene and observance of foot care guidelines (see Chapter 17, Evaluation and Management of the Diabetic Foot).
Because the skin is an accessible organ for assessing MBF and endothelial function and correlates to systemic measurements of endothelial function and myocardial microcirculation, the evaluation of sudomotor function is valuable to clinician. Testing procedures are complex, however, and require a specialist. Some methods, such as laser Doppler and its variations, are still under study and have shown advantages and disadvantages.32
The recommendations for the treatment of dry feet requires the same attentive care as that directed in all foot care guidelines: daily examination, excellent foot hygiene, use of a good moisturizer, and protective and sturdy footwear to avoid foot ulcerations.
Gustatory Sweating
Abnormal profuse sweating that occurs when eating certain foods, particularly cheese or foods that are spicy, is thought to be of no risk, but it can be both bothersome and perplexing. It frequently is not recognized by health-care professionals as a diabetes-related neuropathy. The diaphoresis may be attributed mistakenly to hypoglycemia, particularly if the patient has gastroparesis and does not digest foods well. Unlike hypoglycemia, however, gustatory sweating is limited to the face and upper body. Anticholinergic drugs may alleviate symptoms, although this may require a high dose, which can produce unwanted side effects.18
Bladder Dysfunction
There is a high correlation of bladder cystopathy and peripheral neuropathy with an estimate of ≥75%.32 It affects both men and women. In general, urinary incontinence affects nearly 50% of women, but women with diabetes are more likely to experience severe and symptomatic urinary incontinence. In men, urinary tract symptoms frequently are attributed to benign prostatic hyperplasia (BPH), but cystopathy from diabetes and BPH often coexist. Urodynamic studies identified impaired first sensation for urination, increased capacity to hold urine, detrusor muscle under activity, or overactivity, high post-void residual urine volume, and bladder outlet obstruction.33
A sensory abnormality of the detrusor muscle, the muscle that contracts to squeeze out urine while urinating, is one of the earliest autonomic symptoms to occur and results in impaired bladder sensation. Neuronal and urothelial dysfunction also are present. A decreased sensation of bladder fullness and decreased urinary frequency can lead to urinary tract infections (UTIs). The parasympathetic involvement leads to decreased bladder contractions, causing individuals to have to strain to urinate. Incomplete bladder emptying causes residual urine in the bladder that contributes to increased or chronic UTI.32 Urinary incontinence also may develop.17,31 In some patients, overactive bladder—caused by both central and peripheral neuropathy—not only affects quality of life but also can add a confusing symptom in the assessment for UTIs.
Asymptomatic UTIs can occur. Periodic urinalysis is indicated to detect UTI. Also, symptoms of fever and rapid deterioration of blood glucose control may indicate UTIs even in the absence of dysuria.
Tests of bladder function include postvoiding intravenous pyelogram, postvoiding catheterization, cystometry, sphincter EMG, uroflometry, urethral pressure profile, and an electrophysiological test of bladder innervation.11,17 A postvoiding residual of >150 mL is diagnostic of abnormal bladder function. Suprapubic dullness to percussion over the bladder area can detect a fully asymptomatic neurogenic bladder.
Treatment
Treatment should be aimed at reducing the number of UTIs. Instructing individuals to urinate at least every 3–4 h, even in the absence of a feeling of bladder fullness, will help to reduce the number of UTIs. Medications such as bethanechol may help. If bladder emptying becomes difficult, self-catheterization may be necessary.17 Frequent straight catheterization, as much as three times per day, may be necessary to address the problem. Patient education on proper technique for self-catheterization is essential to diminish the risk for UTI.
Erectile Dysfunction
Erectile dysfunction (ED), or impotence, is a frequent and disturbing symptom and may affect at least 50% of all men with diabetes. It is defined as the consistent inability to achieve or maintain an erection that permits intercourse. ED also is characterized by the absence of erections during sleep and early morning. It can be the earliest symptom of autonomic neuropathy.17,34 The occurrence of ED is an indicator of advancing cardiovascular disease and, as such, should prompt a thorough cardiac examination or referral to a cardiologist.35
There is no difference in the incidence of ED between patients with T1D and those with T2D when matched for age.36 The sympathetic nerves mediate both orgasm and ejaculation. The parasympathetic nerves control erectile function. Impotence caused by autonomic neuropathy progresses gradually but may be permanent within 2 years. Changes in the vasculature of the penis may play a role in sexual dysfunction and will need to be evaluated as well.11
Practical Point
Discuss or initiate discussion of ED to determine whether the condition exists. Often, reluctance on the part of the patient to discuss ED will result in this condition going untreated. It is important to consider psychological factors as a cause. Questions about ability to experience nighttime or early morning erections may help differentiate between organic and psychogenic ED. Vardenafil and sildenafil may not be used if a patient is using a nitrate (e.g., nitroglycerin).
Diagnosis
Diagnosis of ED is made by a detailed sexual history, including rapidity of onset of symptoms and time of day of occurrences. An assessment should include history of sexual desire, orgasms, and erectile and ejaculatory function. Psychological sexual satisfaction is as important to assess as physical capabilities. Other possible adverse effects of drug therapy (e.g., some antihypertensives, antidepressants, tranquilizers), diseases (e.g., prostate, peripheral vascular), psychological problems, and other physical conditions (e.g., smoking, alcohol) must be explored before diagnosing ED as caused by autonomic neuropathy.
Testosterone replacement for those men with low levels is recommended and different formulations are available. The transdermal formulation has been studied in men with diabetes and was shown to be effective. Safety concerns should be addressed when this hormone is used in elderly men, and hematologic, cardiovascular, breast, and prostatic assessments need to be done before this treatment is initiated.37
Practical Point
Careful history taking is essential in selecting the most appropriate therapy for ED. It is important to consider psychological factors as underlying or contributing to the problem. Counseling by a skilled mental health professional may be a necessary component in the treatment plan.
Testing
Tests include nocturnal penile tumescence monitoring, which is used to differentiate between organic and psychogenic impotence. Other tests such as nerve conduction, vascular ultrasonography, pressure, and circumference measurements also may be used to obtain a diagnosis.17
Treatment
The options for treating ED can be divided into three categories: 1) oral, intraurethral, and injected medications; 2) mechanical devices; and 3) surgical interventions.38
Men prefer oral medications because of the ease of use. In using these medications, men have a precoital, coital, and postcoital experience that replicates pre-ED intercourse. Oral medications are usually taken ~0.5–1 h before intercourse (vardenafil, sildenafil, or tadalafil). The exception to this dosing schedule is the longer-acting tadalafil. The medications all work by inhibiting phosphodiesterase type 5 (PDE-5), which allows for an increase in vasodilation and blood flow, resulting in penile rigidity. The cascade of chemical changes that lead to an erection is initiated during foreplay; therefore, the PDE-5 inhibitors are effective only once sexual stimulation occurs. After ejaculation, the penis relaxes into its refractory phase. Most common side effects include flushing, headache, dyspepsia, and nasal congestion. High-fat-content meals eaten before the use of these drugs tend to slow the reaction time. Both vardenafil and sildenafil remain active in the system for ~4 h, and tadalafil at the 20-mg dose can remain active for up to 36 h. The FDA has now approved use of a 2.5 mg or 5 mg daily dose of tadalafil. Patients should not take the shorter-acting PDE-5 inhibitors more than once in a 24-h period. These drugs should not be prescribed for patients taking nitrate medications as serious cardiovascular side effects, such as hypotension, can occur.38
Practical Point
Assess heart rate for tachycardia, blood pressure orthostatic measurements (lying, sitting, and standing), and history of symptoms of lightheadedness, weakness, fatigue, visual blurring, and neck pain. A thorough list of all antihypertensive medications taken and changes in therapy should be noted, especially if new symptoms develop.
Alprostadil, a vasodilator used for ED, can be injected into the corpus of the penis or can be used in pellet form placed by applicator into the urethral opening. The drug is used to increase penile blood flow. As an injected medication, it is considered the gold standard by urologists. If an erection cannot be achieved through the injection of alprostadil, then there is little chance of restoring erectile function by any other medications. The duration of the erection is from 0.5 h to 2 h.
Recently, intraurethral alprostadil has been the drug of choice for ED treatment in those who cannot use PDE-5 inhibitors.39 Its use is contraindicated when intercourse is for the purpose of conception. Vaginal burning during intercourse can occur with the pellet form of alprostadil. The most severe side effect, priapism (defined as a painful, continuing, unwanted erection), is considered a medical emergency.
Alprostadil injections should not be used more than three times per week, with at least 24 h between uses. In pellet form, it should not be used more than twice in a 24-h period.
The first dose of injected alprostadil usually is administered in the physician’s office to evaluate the drug’s effect and titrate dose accordingly. The patient must learn the proper technique and site for drug administration at home.
Mechanical vacuum devices and surgically implanted penile prostheses are methods of treatment, but recently they have been used less often because oral medications are more easily used and are noninvasive.6,17 The vacuum device uses negative pressure to draw blood into the penis. A ring then is placed at the base of the penis to retain the engorgement of the cavernosa. Patients using this device can achieve satisfactory erections ~75% of the time.36,40 It is cumbersome and very mechanical, however, and many men find it psychologically unappealing.
Penile implants have improved markedly over the past few years, and the mechanical failures formerly associated with their use have been reduced. Various forms of implants range from semirigid to inflatable devices using saline reservoirs.41 The selection of which device is best for the patient should be made under the guidance of a urology surgeon. Infections resulting from the surgically implanted device are still of concern for men with diabetes.
Female Sexual Dysfunction
The incidence of sexual dysfunction in women with diabetes is as high as 30%, and the symptoms usually are decreased vaginal lubrication, vaginal wall atrophy, loss of orgasm, and dyspareunia (painful intercourse).37 The sympathetic nervous system mediates orgasm, whereas the parasympathetic system affects vaginal lubrication.17
It is more difficult to diagnose female sexual dysfunction related to neuropathy because the symptoms can be due to hormonal changes of menopause as well as psychological distress. The assessment must explore topics that can be difficult for the patient to discuss. The nurse will need to approach the subject in a sensitive and professional manner. Taking a careful history regarding painful intercourse, problems achieving orgasm, vaginal dryness, libido, and partner issues will help to determine treatment.42 Treatment may include the use of vaginal lubricants or estrogen creams.
Cardiac Autonomic Neuropathy
The prevalence of cardiac autonomic neuropathy (CAN) is thought to ~ 20%.36 Because specific evaluation for CAN usually is not done as part of the annual screening process, the estimation of prevalence may be lower than actuality. Although rare, CAN has been documented in adolescents and is exacerbated during puberty. It is seen most often in children and adolescents with diabetes of long duration with poor glycemic control.43
The most frequent symptoms of CAN are resting tachycardia and postural hypotension. Other notable symptoms include exercise intolerance, painless myocardial infarction (due to cardiac denervation), and heat intolerance. Increased heart rate is due to vagal cardiac neuropathy and may cause tachycardia to be at a fixed rate. Postural hypotension can be caused by a disturbance in the baroreceptors, which normally control blood pressure during a change in position. Symptoms may be lightheadedness and syncope on position change or extended standing. Sudden death may occur. Cardiac arrest may occur in people with severe CAN, with the greatest risk occurring during surgery. Parasympathetic cardiac dysfunction is seen first, followed by sympathetic dysfunction.17,44 The increased frequency of sudden death in patients with CAN might be attributed to cardiac arrhythmias, silent cardiac ischemia, sleep apnea, and abnormal response to hypoxia.6
Treatment includes careful management of hypertension medications and steps to improve glycemic control. In treating postural hypotension, wearing elastic support stockings, increasing salt intake, and elevating the head of the bed during sleep have been helpful. Drug therapy may include fludrocortisone, sympathomimetics (e.g., clonidine), and pressor agents.
Screening Tests for CAN
• Resting heart rate: >100 bpm, but over time may decrease to 80–100 bpm
• Beat-to-beat heart rate variation: measures variability of heart rate
• Valsalva maneuver: measures heart rate and peripheral vasoconstriction during strain
•Heart rate response to standing: measures heart rate (tachycardia at beat 15 is normal and bradycardia at beat 30 is normal)
• Systolic blood pressure response to standing: abnormal when blood pressure falls >30 mmHg within the first 2 min of standing
• Diastolic blood pressure rise with sustained exercise: using a hand-gripped meter, the diastolic blood pressure should rise
• QT interval on electrocardiogram: measured according to a normal standard
Gastropathy
Neuropathy of the gastrointestinal (GI) tract may involve any portion of the system from the esophagus to the rectum. The prevalence of gastroparesis in T1D and T2D ranges from 9% to 75%. Because studies with higher prevalence did not control for comorbidities or medication use, other experts estimate the prevalence to be ~25%.36 Delayed gastric emptying, or gastroparesis, can lead to abnormal absorption of glucose and oral medications. The undigested food may remain in the stomach for hours after a meal.17 The result is suboptimal glucose control, with hyperglycemia or hypoglycemia depending on the time and amount of food retention. Constipation is the most common lower gastrointestinal symptom but can alternate with episodes of diarrhea.
Practical Point
The gastrointestinal system can be the site of various autonomic neuropathies. Difficulty swallowing, poor gastric motility with delayed gastric emptying, constipation, and diarrhea may be gastrointestinal symptoms associated with diabetic gastropathy. Patients are often unaware of the underlying association with diabetes.
Practical Point
Asking specific questions to reveal the extent of gastrointestinal distress is essential to the diagnosis of gastropathy. Topics to discuss to obtain pertinent information include changes in appetite, difficulty swallowing, feelings of fullness, unexplained nausea or vomiting, bloating, heartburn, abdominal cramping or pain, weight loss or gain, and diarrhea or constipation patterns. Because widely fluctuating blood glucose levels may reveal gastropathy, a careful review of recent glucose control is essential, especially if it has deteriorated without apparent cause.
Testing
Evaluation of gastric emptying should be done if symptoms are present. Barium studies are no longer used. Referral for endoscopy may be required to rule out other causes. If gastric emptying studies are needed, the general consensus is that blood glucose should be under reasonable control and as close to euglycemia as possible on the day of the study. It is recommended that serum glucose be measured before the study and noted in the report. If the blood glucose is >275 mg/dL on the morning of the test, the glucose should be lowered with insulin to <275 mg/dL or the study should be rescheduled for another day.45 Some centers administer insulin to lower the blood glucose to <180 mg/dL before the study.
Treatment
Treatment of this condition is aimed at controlling the potentially debilitating symptoms and improving glycemic control.46 Episodes of hyperglycemia can delay gastric emptying; conversely, hypoglycemia will increase it. Symptoms of gastropathy include heartburn or dysphagia, gastric esophageal reflux, early satiety, delayed gastric emptying and feelings of fullness, nausea or vomiting, constipation, diarrhea or incontinence of stool, and anorexia.
The treatment of diabetes gastropathy includes improving gastric emptying if necessary, as well as improving symptoms. Treatment may include exercise, smoking cessation, dietary management with small frequent meals, use of medications that promote gastric emptying, excellent management of blood glucose, liquid feedings (which are emptied more easily from the stomach), and avoidance of fatty foods and fiber. A nutritional assessment and counseling with a dietitian to include a calorie count and dietary adjustments may be necessary to ensure adequate intake.47 The following drugs have been shown to be useful as antiemetics and increase action on the smooth muscle to increase the rate of gastric emptying of both solids and liquids: metoclopramide, erythromycin, and domperidone (not available in the U.S.).46,47 Metoclopramide must be used with caution, and any person prescribed this drug must be assessed for tardive dyskinesthia.
Gastric pacing also has been used in severe gastroparesis. Patients with gastroparesis often have depression. Antidepressants and psychotherapy often are successful and are important adjuncts to conventional therapy.
Impaired Hypoglycemic Awareness and Hypoglycemia Unawareness
The response to hypoglycemia in people treated with insulin is mediated by the ANS. Impaired hypoglycemic awareness and hypoglycemia unawareness result in the inability of the person to recognize and treat hypoglycemia, with potential for injury or harm. The counterregulatory response consists of an increase in glucose production from the liver, a decrease in peripheral glucose uptake, and the secretion of glucagon and epinephrine. In individuals with T1D, the glucagon response to low blood glucose deteriorates 1–5 years after diagnosis. Epinephrine responses also may decrease as the duration of the disease increases. The combined absence of glucagon and epinephrine responses decreases counterregulation. The usual signs and symptoms of hypoglycemia (tremulousness, sweating, and tachycardia) may be absent but can include confusion, lethargy, amnesia, mental irritability, and seizures.6,17
Impaired hypoglycemic awareness and hypoglycemic unawareness can occur as a result of tight blood glucose control or frequent episodes of hypoglycemia. It may be necessary to adjust targets for glycemia to improve hypoglycemia unawareness. Research suggests that preventing all hypoglycemia for ~3 weeks will allow the individual to regain their hypoglycemia awareness.48 Hypoglycemia awareness training programs may aid people with this complication. (Blood glucose awareness training is described in Chapter 19, Behavioral Strategies for Improving Self-Management.)
Practical Point
Individuals with hypoglycemia unawareness may have difficulty achieving glycemic control, and more frequent blood glucose monitoring is warranted. People with hypoglycemia unawareness in high-risk situations, such as driving, should consider monitoring their blood glucose before the activity and regularly during the activity. Continuous glucose monitoring (CGM) may be a useful adjunctive therapy for those with hypoglycemia unawareness as it allows them to observe glucose trends and respond proactively to avoid hypoglycemia. This technology does not replace capillary blood glucose monitoring in that the CGM results can lag ≥10 min in reporting the actual glucose reading.
Helping the individual recognize subtle symptoms that may indicate hypoglycemia and prompt a glucose check, such as tingling around the mouth or a decreased ability to concentrate, is a critical component of patient education. Carrying glucose-monitoring equipment and portable hypoglycemia treatments, such as glucose gel, juice boxes, or glucose tablets, at all times is essential for safe management of this problem.
SUMMARY
Neuropathy is a common chronic disorder in diabetes and is both complex and difficult to understand. It is often the nurse who performs the initial assessment, and by knowing the questions to ask and in seeking further information, quality care can be achieved for the patient. The symptoms of neuropathy, both peripheral and autonomic, present the patient with significant challenges in daily living as well as diabetes self-care management. The role of the nurse as a member of an interdisciplinary team of dietitians, nurse practitioners, and physician specialists is to assist the patient in learning the components of self-care necessary to reduce symptoms and prevent disease progression. This may involve pain management for peripheral neuropathy, changes in diet for gastroparesis, self-catheterization for bladder dysfunction, or use of a home blood pressure monitoring kit for orthostatic hypotension. An understanding of the complexity of the various neuropathies is important in caring for and educating individuals with these conditions.
REFERENCES
1. Peltier A, Groutman SA, Callaghan BC. Painful diabetic neuropathy. BMJ 2014;348:1799
2. Lee CC, Perkins BA, Kayaniyil S, Harris SB, Retnakaran R, Gerstein HC, Zinman B, Hanley AJ. Peripheral neuropathy and nerve dysfunction in individuals at high risk for type 2 diabetes: the PROMISE cohort. Diabetes Care 2015;38:793–800
3. Vinik AI. Diagnosing diabetic autonomic neuropathy. MedScape. 2004. Available from http://www.medscape.com/viewarticle/473205. Accessed 4 January 2005
4. Bailes BK. Diabetes mellitus and its chronic complications. AORN J 2002;76:266–276, 278–282
5. Ziegler D, Sohr C, Nourooz-Zadeh J. Oxidative stress and antioxidant defense in relation to the severity of diabetic polyneuropathy and cardiovascular autonomic neuropathy. Diabetes Care 2004;26:2178–2183
6. Freeman R. The nervous system and diabetes. In Joslin’s Diabetes Mellitus. 14th ed. Kahn CR, Weir GC, King GL, Jacobson AM, Moses AC, Smith RJ, Eds. Philadelphia, Lippincott Williams & Wilkins, 2005, p. 951–964
7. Pop-Busui R, Stevens M. Autonomic neuropathy in diabetes. In Therapy for Diabetes Mellitus and Related Disorders. 6th ed. Umpierrez G, Ed. Alexandria, VA, American Diabetes Association, 2014, p. 834–863
8. American Diabetes Association, American Academy of Neurology. Consensus statement: report and recommendations of the San Antonio conference on diabetic neuropathy. Diabetes Care 1988;11:592–597
9. Tesfaye S. Clinical features of peripheral and autonomic neuropathies. In Diabetic Neuropathy. Tesfaye S, Boulton A, Eds. New York, Oxford University Press, 2009, p. 17–27
10. Papanas N, Ziegler D. Corneal confocal microscopy: recent progress in the evaluation of diabetic neuropathy. J Diabetes Invest 2015;6:381–389. doi:10.1111/jdi.12335
11. Boulton AJM, Vinik AI, Arezzo JC, Bril V, Feldman EL, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 2005;28:956–962
12. Hovaguimian A. The diagnosis and treatment of diabetic neuropathy for the non-neurologist. Pract Diabetes 2012;31:8–12
13. Fowler MJ. Microvascular and macrovascular complications of diabetes. Clin Diabetes 2011;29:116–122
14. American Diabetes Association. Standards of medical care in diabetes—2016. Clinical recommendations. Diabetes Care 2016;39(Suppl. 1):S72–S80
15. Vinik AI, Casellini CM. Guidelines in the management of diabetic nerve pain: clinical utility of pregabalin. Diabetes Metab Syndr Obes 2013;6:57–78. doi:10.2147/DMSO.S24825
16. Vinik AI, Nevoret ML, Casellini C, Parsons H. Diabetic Neuropathy (review). Endocrinol Metab Clin North Am 2013; 42:747–787
17. Greene DA, Feldman EL, Stevens MJ, Sima AAF, Albers JW, Pfeifer MA. Diabetic neuropathy. In Ellenberg and Rifkin’s Diabetes Mellitus. 5th ed. Porte D, Sherwin RS, Eds. Stamford, CT, Appleton and Lange, 1997, p. 1009–1074
18. Javed S, Petropoulos IN, Alam U, Malik RA. Treatment of painful diabetic neuropathy. Ther Adv Chronic Dis 2015;6:15–28
19. Nathan DM, Cagliero E. Fuel metabolism. In Endocrinology and Metabolism. 4th ed. Felig P, Frohman LA, Eds. New York, McGraw-Hill, 2001, p. 827–927
20. Albers JW, Herman WH, Pop-Busui R, Feldman EL, Martin CL, Cleary PA, et al. Effects of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Diabetes Care 2010;33:1090–1096
21. Callaghan BC, Little AA, Feldman EL, Hughes RA. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev 2012;6:CD007543. doi:10.1002/14651858.CD007543.pub2
22. Karunakaran U, Park K-G. A systematic review of oxidative stress and safety of antioxidants in diabetes: focus on islets and their defense. Diabetes Metab J 2013;37:106–112
23. Davis TM, Yeap, BB, Davis WA, Bruce DG. Lipid lowering therapy and peripheral sensory neuropathy in type 2 diabetes: The Fremantle diabetes study. Diabetologia 2008;51:562–566
24. Colberg SR, Vinik AI. Exercising with peripheral or autonomic neuropathy: what health care providers and diabetic patients need to know. Phys Sportsmed 2014;42:15–22
25. Kluding PM, Pasnoor M, Singh R, et al. The effect of exercise on neuropathic symptoms, nerve function, and cutaneous innervation in people with diabetic peripheral neuropathy. J Diabetes Complic 2012;26:424–429
26. Cohen K, Shinkazh N, Frank J, Israel I, Fellner C. Pharmacological treatment of diabetic peripheral neuropathy. Pharm Therap 2015;40:372–388
27. Ziegler D, Reljanovic M, Mehnert H, Gries FA. Alpha lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials. Exp Clin Endocrinol Diabetes 1999;107:421–430
28. SYDNEY Trial Authors. The sensory symptoms of diabetic polyneuropathy are improved with a-lipoic acid: the SYDNEY trial. Diabetes Care 2003;26:770–776
29. Shane-McWhorter L. Complementary and Alternative Medicine (CAM) Supplement Use in People with Diabetes: A Clinician’s Guide. Alexandria, VA, American Diabetes Association, 2007
30. Kedlaya D. Diabetic lumbosacral plexopathy. Medscape. 2016. Available from http://emedicine.medscape.com/article/1935459-medication#showall. Accessed 7 November 2014
31. Deli G, Bosnyak E, Pusch G, Komoly S, Feher G. Diabetic neuropathies: diagnosis and management. Neuroendocrinology 2013;98:267–280. doi:10.4093/dmj.2013.37.2.106
32. Kempler P, Amarenco G, Freeman R, Frontoni S, Horowitz M, Stevens M, Low P, Pop-Busui R, Tahrani AA, Tesfaye S, Varkonyi T, Zieglar D, Valensi P; on behalf of The Toronto Consensus Panel on Diabetic Neuropathy. Management strategies for gastrointestinal, erectile, bladder and sudomotor dysfunction in patients with diabetes. Diabetes Metab Res Rev 2011;27:665–677
33. Bansal R, Agrawal MM, Modi M, Mandal AK, Singh SK. Urodynamic profile of diabetic patients with lower urinary tract symptoms: association of diabetic cystopathy with autonomic and peripheral neuropathy. Urology2011;77:699–705
34. Munarriz R, Traish A, Goldstein I. Erectile dysfunction in diabetes. In Joslin’s Diabetes Mellitus. 14th ed. Kahn CR, Weir GC, King GL, Jacobson AM, Moses AC, Smith RJ, Eds. Philadelphia, Lippincott Williams & Wilkins, 2005, p. 999–1013
35. Pop-Busui R, Hotaling J, Braffett BH, Cleary PA, Dunn RL, Martin CL, Jacobson AM, Wessells H, Sarma AV; DCCT/EDIC Research Group. Cardiovascular autonomic neuropathy, erectile dysfunction and lower urinary tract symptoms in men with type 1 diabetes: Findings from the DCCT/EDIC. J Urol 2015;193:2045–2051
36. Snow KJ, Guay A. Erectile dysfunction in diabetes mellitus. In Medical Management of Diabetes Mellitus. Leahy JL, Clark NG, Cefalu WT, Eds. New York, Marcel Dekker, 2000, p. 427–442
37. Kizilay F, Gali HE, Serefoglu EC. Diabetes and sexuality. Sex Med Rev 2016;5:45–51
38. Kamenov ZA. A comprehensive review of erectile dysfunction in men with diabetes. Exp Clin Endocrine Diabetes 2015;123:141–158
39. Dinsmore W, Lopes TM, Potempa AJ, Piha J, Costa P. Intraurethral alprostadil in the management of erectile dysfunction: a reappraisal of the clinical evidence. Clin Pract 2014;11:3-15
40. Hellstrom WJG, Montague DK, Moncada I, Carson C, Minhas S, Faria G, Krishnamurti S. Implants, mechanical devices and vascular surgery for erectile dysfunction. J Sex Med 2010;7:501–523
41. Thorve VS, Kshirsagar AD, Vyawahare NS, Joshi VS, Ingale KG, Mohite RJ. Diabetes-induced erectile dysfunction: epidemiology, pathophysiology and management. J Diabetes Compl 2011;25:129–136
42. Phillips A, Phillips S. Recognizing female sexual dysfunction as an essential aspect of effective diabetes care. Apple Nurs Res 2015;28:235–238
43. Tang M, Donaghue KC, Cho YH, Craig ME. Autonomic neuropathy in young people with type 1 diabetes: a systemic review. Pediatric Diabetes 2013;14:239–243
44. Unger RH, Foster DW. Diabetes mellitus. In Williams Textbook of Endocrinology. 9th ed. Wilson JD, Foster DW, Kronenberg HM, Larsen PR, Eds. Philadelphia, W.B. Saunders, 1998, p. 973–1060
45. Abell TL, Camilleri M, Donohoe K, Hasler W L, Lin H, et al. Consensus recommendations for gastric emptying scintigraphy: joint report of the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. J Nucl Med Tech 2008;36:44–54
46. Bernstein G. The diabetic stomach: management strategies for clinicians and patients. Diabetes Spect 2000;13:11–15
47. Mashimo H, Goyal RK. Effects of diabetes mellitus on the digestive system. In Joslin’s Diabetes Mellitus. 14th ed. Kahn CR, Weir GC, King GL, Jacobson GC, Moses AC, Smith RJ, Eds. Philadelphia, Lippincott Williams & Wilkins, 2005, p. 1070–1086
48. Cryer PE, Childs B. Negotiating the barrier to hypoglycemia in diabetes. Diabetes Spect 2002;15:20–27