Diabetic Neuropathy

Are You Sure the Patient Has Diabetic Neuropathy?

History: It is important to unveil the presence of risk factors (e.g., poorly controlled hyperglycemia; tall stature; associated dyslipidemia with elevated triglycerides; hypertension; and history of recent falls, which may reflect gait and balance disorders).

Symptoms: May vary due to the type of sensory fibers involved

Peripheral neuropathy

Most common symptoms:

• Pain – most common symptoms that would prompt seeking medical care; intensity may vary from dull to lancinating and disabling; often is worse at night and disrupts sleep

• Dysesthesia – unpleasant sensations of burning, tingling, excessive sensitivity to touch; in same areas as peripheral nerve lesions

• Numbness – feeling as feet of hands are asleep

• Weakness – less common, usually minor; occurs later in the disease process

Anatomic distribution of symptoms and signs is a very important clue: The most distal portion of the longest nerves is affected first. Early symptoms typically involve the tips of the toes and fingers. This proceeds proximally, resulting in a “stocking-glove” pattern of pain and sensory loss.

Autonomic neuropathy

Symptoms of autonomic neuropathy occur, in general, late in the course of the disease and varies based on the form of autonomic neuropathy.

Symptoms associated with orthostatic hypotension:

• Light-headedness

• Weakness

• Faintness

• Dizziness

• Visual impairment

• Syncope on standing

Gastrointestinal (GI) symptoms

Delayed gastric emptying (gastroparesis): not always clinically apparent; the range of symptoms may include:

• Nausea

• Postprandial vomiting

• Bloating

• Loss of appetite

• Early satiety

Esophageal dysfunction:

• Present in up to 20% of diabetic patients, particularly those with known autonomic dysfunction

• Typically intermittent

• Profuse and watery diarrhea

• Typically occurring at night

• Patients with type 1 diabetes mainly

• May alternate with constipation

• Extremely difficult to treat

• History should rule out diarrhea secondary to ingestion of lactose, nonabsorbable hexitols, or medication

The Diabetes Bowel Symptom Questionnaire (DBSQ) has been validated in a diabetic population to quantify gastrointestinal symptoms; however, the predictive value is poor.

Bladder dysfunction:

• Frequency

• Urgency

• Nocturia

• Hesitancy in micturition

• Weak stream

• Dribbling urinary incontinence

• Urine retention

Signs

Diabetic peripheral neuropathy (DPN)

Physical (neurologic) examination:

• Symmetrical distal sensory loss

• Reduced or absent ankle reflexes

Sensory loss is defined in terms of extent and distribution, and involves assessment of:

• Pinprick sensation

• Light touch

• Vibration

• Joint position

A potentially quick, inexpensive, and accurate screening instrument to evaluate high-risk patients in the clinic is the Michigan neuropathy screening instrument (MNSI) and includes assessment for:

• Loss of vibration sense (using a 128-Hz tuning fork) is tested at the big toe. (Image)

• Vibration sensation should be assessed with the big toe unsupported.

• Vibration sensation should be tested bilaterally by placing the tuning fork over the dorsum of the big toe, on the bony prominence of the distal interphalangeal (DIP) joint.

• This is a forced choice examination performed with the patient whose eyes are closed.

In general, the examiner should be able to feel vibration from the hand-held tuning fork for 5 seconds longer on his or her distal forefinger than a normal person can at the big toe (e.g., examiner’s DIP joint of the first finger versus patient’s toe). If the examiner feels vibration for ≥10 seconds on his or her finger, then the vibration is considered decreased.

A trial should be conducted when the tuning fork is not vibrating to be certain that the patient is responding to vibration and not pressure, or some other clue. Vibration is scored as: (1) present if the examiner senses the vibration on his or her finger for <10 seconds, (2) reduced if sensed for ≥10 seconds, or (3) absent (no vibration detected).

Ankle reflexes: should be examined using an appropriate reflex hammer (e.g., Trommer or Queen square).

Ankle reflexes should be elicited in the sitting position with the foot dependent and the patient relaxed. In addition, the foot should be passively positioned and slightly dorsiflexed to obtain optimal stretch of the muscle.

The Achilles tendon should be percussed directly.

If the reflex is obtained, it is graded as present. If the reflex is absent, the patient should be asked to perform the Jendrassik maneuver (i.e., hooking the fingers together and pulling). Reflexes elicited with the Jendrassik maneuver are designated as present with reinforcement. If the reflex is absent, even with the Jendrassik maneuver, the reflex is considered absent.

Foot inspection: for presences of ulcers, small muscle wasting, clawing of the toes, prominent metatarsal heads, dry skin and callus (secondary to sympathetic autonomic dysfunction), prior amputations, and occasionally bony deformity secondary to Charcot neuroarthropathy.

The light touch examination can be also easily performed in the office; however, note the differences in the examination technique for evaluation.

Loss of light touch (using 10-g monofilament) is tested at the dorsal aspects of both big toes. (Image) For this examination, it is important that the patient’s foot be supported (i.e., allowing the sole of the foot to rest on a flat, warm surface). The filament should initially be prestressed (4 to 6 perpendicular applications to the dorsum of the examiner’s first finger). The filament is then applied to the dorsum of the big toe midway between the nail fold and the DIP joint.

The toe should not be held directly. The filament is applied perpendicularly and briefly (<1 second), with an even pressure. When the filament bends, the force of 10 g has been applied. The patient, whose eyes are closed, should be asked to respond yes if he or she feels the filament. Eight correct responses out of 10 applications is considered normal; 1 to 7 correct responses indicates reduced sensation; no correct answers translates into absent sensation.

• Painless injuries may be apparent on examination. (Image)

• These often occur over pressure points on the foot, most commonly over the metatarsal heads. Infection commonly complicates the situation, followed by gangrene if vascular dysfunction is present.

• Involvement of large sensory fibers only is rare and may manifest with gait ataxia especially at night or when the patient walks with closed eyes.

• In patients with severe DPN, motor involvement may become clinically apparent with weakness of toe dorsiflexion and of intrinsic hand muscles.

Autonomic neuropathy

Cardiovascular autonomic neuropathy:

• Absence of heart rate variation with deep breathing is easy to measure at the bedside and could reveal early signs of cardiovascular autonomic neuropathy.

• Resting tachycardia with a fixed heart rate are characteristic late findings in diabetic patients with vagal impairment.

• Resting heart rates of 90 to 100 bpm and occasional heart rate increments up to 130 bpm occur.

• Measurement of supine and standing blood pressure (BP) is needed to diagnose orthostatic hypotension.

Urogenital: Bladder dysfunction may ultimately result in urinary retention with evidence of an enlarged bladder on abdominal examination.

Key laboratory and other evaluations

DPN:

Consensus statements from the American Diabetes Association, American Neurological Association, and most recently the Toronto consensus on diabetic neuropathies reviewed the research, definitions, diagnostic criteria, and estimation of severity of DPN.

Clinical Pearl: In clinical practice, DPN remains a clinical diagnosis and equipment requiring an electrical power source is rarely needed in the assessment of peripheral nerve function.

The diagnosis and classification of DPN for research and clinical trials should be based on at least one standardized measure from each of the following categories:

• Clinical symptoms

• Clinical examination

• Electrophysiologic testing

• Quantitative sensory testing (QST)

• Autonomic testing

• Skin biopsy and assessment of intraepidermal nerve fiber density (IENFD)

• Clinical symptoms and examination: were discussed amply above

Instruments: A number of simplified composite scores of symptoms have been developed such as:

• The neuropathy symptom score (NSS)

• The neuropathy symptom profile (NSP)

• The Michigan neuropathy screening instrument (MNSI) symptoms questionnaire

• The Toronto neuropathy instrument

In general all can be administered in a few minutes and score typical symptoms with additional weighting for nocturnal exacerbation.

Quality of life has increasingly been emphasized as an important factor in the natural history of neuropathic symptomatology. Specific instruments have been developed and validated for use in diabetic neuropathy, such as:

• NeuroQol

• The Norfolk quality of life questionnaire-diabetic neuropathy (QOL-DN)

Electrophysiology (EMG):

Nerve conduction tests and EMG are objective, noninvasive, and highly reliable measures that do not rely on a patient’s response. However, the tests only measure large fiber afferent and motor nerve function and are therefore of limited use in the evaluation of painful diabetic neuropathy.

Although electrophysiologic assessment can help to diagnose the presence of neural dysfunction, it cannot determine the cause; there is no test available that confirms diabetes as the cause of the neuropathy.

Clinical Pearl: In clinical practice, electrophysiological tests (nerve conduction tests and EMG) and specialized neurology evaluation are needed only in situations where the clinical features are atypical (such as asymmetric symptoms and signs, or weakness)

Quantitative sensory testing (QST):

• Assesses the patient’s ability to detect a number of sensory stimuli directly quantifying the degree of sensory loss from the most vulnerable site—the foot.

• It must be remembered that QST results are a function of the patient’s concentration and cooperation.

• An abnormal finding does not necessarily indicate peripheral neuropathy; the abnormality may lie anywhere in the afferent neural pathway.

• QST varies in complexity: the simpler instruments can be used in day to day clinical practice, whereas the more sophisticated instruments, usually requiring more expensive equipment and an external power source, are commonly used for more detailed assessment and for follow-up assessments in clinical trials.

• Vibration perception

• Is indicative of myelinated fiber function

• The vibration perception threshold increases with age in nondiabetic individuals and also tends to be higher in the lower extremities

• As well as being useful in clinical practice, the vibration perception threshold has been used in clinical research and epidemiologic studies

• It can be evaluated with simple pocket-sized disposable devices, such as the tuning fork or the Vibratip, or with more complex and expensive devices such as Vibratron II, neurothesiometer, or CASE IV.

Clinical Pearl: Evaluation with the 128-Hz tuning fork described above is the easiest, least expensive, and usually sufficient to assess vibration perception in daily clinical practice.

Other evaluations

Skin biopsy and corneal confocal microscopy:

• Immunohistochemical quantification of intraepidermal nerve fibers using punch skin biopsies has increasingly been used to quantify small fiber neuropathies in diabetes and in prediabetic states, such as impaired glucose tolerance.

• Lifestyle interventions, including diet and exercise, have been shown to improve not only symptoms of neuropathy but also objective measures including intraepidermal nerve fiber density.

• Corneal confocal microscopy (CCM) represents a novel reiterative in vivo clinical examination technique that is capable of imaging corneal nerve fibers in a noninvasive technique.

• Currently, these techniques are used in research only.

Autonomic testing

Cardiovascular autonomic neuropathy (CAN):

Several diagnostic approaches with varying degrees of complexity are available to diagnose CAN in practice or research.

These include:

• Heartburn

• Dysphagia for solids

Diarrhea:

Although GI symptoms are common in diabetes, these are often due to factors other than autonomic dysfunction.

• Cardiovascular reflex testing (CART)

• Heart rate variability

• 24-hour blood pressure profiles

• Orthostatic hypotension

• Baroreflex sensitivity

• Cardiac sympathetic imaging

• Microneurography or occlusion plethysmography

CART can be used in clinical practice and are described below. All the rest of the evaluations are used for research only, and have been amply described elsewhere.

CART assesses the cardiovascular autonomic function using provocative physiologic maneuvers and include:

Changes in R-R interval with deep breathing, a measure of sinus arrhythmia during quiet respiration reflecting primarily parasympathetic function

• The R-R response to standing, inducing reflex tachycardia followed by bradycardia which is jointly vagal and baroreflex-mediated

• The Valsalva ratio which evaluates cardiovagal function in response to a standardized increase in intrathoracic pressure (Valsalva maneuver)

• Orthostatic hypotension

• BP response to a Valsalva maneuver and sustained isometric muscular strain, which is now used in clinical research only

• Although no test is clearly superior, the deep breathing test is the most widely used test due to its high reproducibility, approximately 80% specificity, and ease of use.

Gastrointestinal autonomic neuropathy (gastroparesis)

Gastric emptying studies:

Gastric emptying can be affected by many factors, including medications, smoking, and blood glucose concentrations, and standardization of testing is important. A barium meal and/or upper endoscopy studies are always recommended to rule out mucosal lesions or obstruction.

Scintigraphy:

Still regarded as the ‘gold standard’ technique for measurement of gastric emptying. It also helps to assess the intragastric distribution of a meal, frequently abnormal in diabetic patients.

Standardization of the technique between centers is very important and recent “consensus” guidelines recommend a low-fat, egg white meal labeled with 99mTc sulfur colloid and consumed with jam and toast as a sandwich, along with a glass of water. The limitations of scintigraphy are exposure to a modest dose of radiation, the relative expense, and the need for specialist centers.

Breath tests:

• Use nonradioactive 13 C-acetate or octanoic acid as a label

• Are safe and inexpensive

• Results correlate well with scintigraphy results

Ultrasonography is a noninvasive diagnostic method and 2- and-3-dimensional ultrasound have been validated for measuring the emptying of liquids and semisolids.

Magnetic resonance imaging has been used to measure gastric emptying and motility with excellent reproductivity, but its use is limited to research purposes. Surface electrogastrography to detect abnormalities in gastric pacemaking.

Erectile dysfunction

Clinical evaluation

A comprehensive interview is a key diagnostic procedure for assessing erectile dysfunction and includes information on:

• Sexual and medical history

• Drug use for associated comorbidities (tranquillizers, antidepressants, antihypertensives)

• Psychological and organic factors

• Distinguish it from other forms of sexual difficulty, such as penile curvature or premature ejaculation.

Clinical Pearl: The use of validated questionnaires, such as the International Index of Erectile Function (IIEF) and the Sexual Encounter Profile (SEP), is the most appropriate method to characterize frequency and severity of erectile dysfunction (ED) symptoms.

Laboratory

• Routine laboratory tests include: Hb A1c, fasting blood glucose, and lipid profile.

• Measurements for bio-available testosterone is recommended in patients who do not respond to phosphodiesterase type 5 (PDE-5) inhibitors to rule out primary or hypogonadotropic hypogonadism.

• ED tests may be useful in patients who do not respond to PDE-5 inhibitors; the tests include evaluations of nocturnal penile tumescence, penile Doppler ultrasound, bulbo-cavernosus reflex, dorsal sensory nerve conduction of the penis, amplitude and latency of penile sympathetic skin response, pudendal nerve somatosensory evoked potentials, assessment of PGE1 effect on erection, psychological evaluation, and urodynamic studies.

Clinical Pearl: Complex ED tests are rarely needed in clinical practice.

Bladder dysfunction

Clinical evaluation

The severity of lower urinary tract symptoms (LUTS) can be assessed by comprehensive interview to include specific questions about urinary symptoms, ideally using a validated questionnaire for incontinence and lower urinary tract symptoms.

The American Urological Association symptom index (AUASI) is a standardized, seven-item questionnaire that quantifies the presence and frequency of the following lower urinary tract symptoms: nocturia, frequency, urgency, weak urinary stream, intermittency, straining, and the sensation of incomplete emptying. Scores on the index range from 0 to 35, with widely accepted cut points of 0 to 7, 8 to 19, and 20 to 35 designated as none/mild, moderate, and severe LUTS, respectively.

Assessments of perineal sensation, sphincter tone, and the bulbocavernosus reflex may identify peripheral neuropathy consistent with diabetes. Complete urogynecologic examination is needed to exclude pelvic organ prolapse or other pelvic disorders.

Laboratory

Since diabetic patients are at increased risk of bacterial cystitis, microscopic urinanalysis and a culture are essential in assessing patients complaining of LUTS.

Urodynamic testing

Detailed assessment of bladder function with urodynamic studies is indicated only if initial management is unsuccessful, or if there is doubt about the diagnosis. This may include cystometry, uroflow, simultaneous pressure/flow studies, sphincter electromyography, urethral pressure profilometry with evaluation of leak-point pressure, measurement of peak urinary flow rate, and postvoid residual volume (PVR).

Clinical Pearl: Basic laboratory tests for all cases include:

• Hb A1c and possibly an oral glucose tolerance test (OGTT) to confirm diabetes or impaired glucose tolerance

• Thyroid-stimulating hormone (TSH) test to rule out thyroid dysfunction

• Vitamin B12 and folate to exclude dysfunction

• Serum creatinine, blood urea nitrogen (BUN), and epidermal growth factor receptor (EGFR) to exclude chronic kidney disease

• Lipid profiles may reveal the metabolic syndrome dyslipidemia

What Else Could the Patient Have?

Cyanocobalamin deficiency

Suspect if:

• Poor nutrition

• Malabsorption

• Alcoholism

• Certain drugs (e.g., trimethoprim, methotrexate, phenytoin)

• Pernicious anemia/atrophic gastritis

• Infection with Helicobacter pylori

• Patients are more likely to be older (>65 years)

Laboratory to rule out:

• CBC: Macrocytic anemia

• Reduced serum folate/vitamin B₁₂ level

Uremia

Other causes for end-stage renal disease (ESRD) may be present such as:

• Systemic lupus erythematosus

• Polycystic kidney disease

• Chronic idiopathic glomerulopathies

• Amyloidosis

• Severe hypertension

Laboratory: Abnormal BUN, creatinine, glomular filtration rate (GFR) consistent with ESRD

• Chronic alcoholism

• Wernicke encephalopathy

• Positive history of daily intake

• Signs of malnutrition

• Korsakoff amnestic syndrome

Laboratory: abnormal liver function tests, thiamine deficiency, anemia

Drug-induced neuropathy

Positive drug history for known drugs to be a risk for development of neuropathy, such as:

• Antivirals: stavudine, didanosine, lamivudine, ritonavir, zalcitabine

• Antibacterials

• Antineoplastic: thalidomide, platinum agents

• Immunosuppressants

• Cardiovascular: amiodarone

Heavy metal poisoning

• Peripheral neuropathy due to an axonal degeneration, primarily affecting motor nerves

• Most frequently manifests with extensor weakness (or wrist/ankle drop)

• Abdominal pain (“lead colic”), constipation, joint pains, muscle aches, headache, anorexia, decreased libido, difficulty concentrating and deficits in short-term memory, anemia, nephropathy, and other symptoms and signs in various combinations.

Laboratory: Abnormally high blood levels of lead or other metals.

Chronic inflammatory demyelinating neuropathy (CIPD)

• Severe, predominantly motor neuropathy

• Progressive in nature

• Features progress despite optimal glycemic control

Tests to differentiate:

• Nerve biopsies: increased numbers of macrophages.

• Nerve conduction studies are recommended and show a combination of slowed conduction velocities, prolonged distal latencies, prolonged F-wave latencies, and conduction block in one or more nerves.

• Lumbar tap: high cerebrospinal fluid (CSF) protein

Sarcoidosis

Various clinical signs:

• Fever

• Skin signs (e.g., erythema nodosum)

• Joint and/or eye lesions

Tests to differentiate:

• Chest imaging may show bilateral hilar lymphadenopathy and pulmonary reticular opacities

• Biopsies of accessible lesions are diagnostic

Management and Treatment of the Disease

DPN

• Pathogenetic or disease-modifying therapies – those that might alter (slow) the progressive loss of nerve function that characterizes the natural history of neuropathy

• Only demonstrated method available is tight glycemic control

The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy of type I diabetes reduced the incidence of neuropathy by 60% over a 5-year period in patients who did not have neuropathy at baseline. Observational follow-up of the DCCT cohort, epidemiology of diabetes interventions and complications (EDIC) at years 13 and 14, showed that 25% and 35%, respectively, of the former intensive and conventional treatment groups had confirmed clinical neuropathy, demonstrating the long-term persistent beneficial effects of intensive glucose control in type 1 diabetes.

There is some evidence for a reduction in risk of DN with optimal blood glucose control in people with type 2 diabetes, but it is not as strong of evidence as that for type 1 diabetes. When treating painful neuropathy, maintaining stable blood glucose levels may provide symptom relief.

Symptomatic relief

Treatment for pain

Pregabalin:

• Approved for treatment of DN pain in some countries.

• 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 DN compared with placebo.

• Has similar adverse effects to duloxetine, although patients do not frequently experience nausea.

• Is a controlled (scheduled) drug in the U.S., and, unlike its predecessor gabapentin, there is a possibility it could be habit-forming.

Gabapentin:

• Has been found to improve pain in people with DN in several studies.

• Although not approved for the treatment of pain associated with peripheral neuropathy in some countries, is widely used.

• May have adverse effects that require discontinuation of therapy. These include unsteadiness, somnolence or confusion (especially in older people), headache, nausea, and diarrhea.

Duloxetine:

• Is approved in some countries for use in painful DN.

• Clinical studies have found it safe and effective in the management of painful DN.

• Is a selective dual serotonin-norepinephrine reuptake inhibitor, and is relatively balanced in its affinity for reuptake inhibition.

• Patients frequently experience nausea with initiation of therapy; a slow titration of the drug can usually avoid this common adverse effect.

• Most common adverse effects, besides nausea: sedation and generalized sleepiness .

• Pregabalin or gabapentin may be combined with duloxetine if necessary. Few direct head-to-head comparisons have been conducted between drugs for the treatment of DN pain.

Antidepressants

These may be used in people not tolerating or able to take any of the first-line agents. They may be used alone or sometimes in combination with pregabalin or gabapentin.

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 randomized controlled trials to relieve pain better than placebo in patients with DN.

• Additional support for the efficacy of TCAs was provided by a meta-analysis of 21 clinical trials.

• Adverse effects are common with TCAs and may lead to treatment withdrawal. In clinical trials of TCAs, approximately 20% of participants withdrew because of intolerable adverse effects, such as sedation, confusion, and anticholinergic adverse effects.

• The most commonly used TCAs may be ranked in order from most to least associated anticholinergic effects as follows: amitriptyline, imipramine, nortriptyline, and desipramine.

Selective serotonin-reuptake inhibitors (SSRIs):

• Paroxetine has been found to reduce symptoms significantly.

• Fluoxetine was effective only in patients who were depressed.

• Sertraline was shown to lead to a reduction in pain from DN in a small open-label study of 8 patients, but a placebo-controlled study has not yet been conducted.

Opioid analgesics:

• May be considered either in combination with existing therapies or for use alone.

• Have recently started to be used again as a treatment for neuropathic pain.

• Are commonly used, but have significant adverse effects with long-term use.

• Dependence is common and serious.

• Suppress pain by activating mu-receptors, which are present on the presynaptic 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.

• Tapentadol is a centrally acting opioid analgesic that is a mu opioid receptor agonist as well as a noradrenaline reuptake inhibitor. The extended release form has been approved by the Food and Drug Administration for the treatment of diabetic neuropathic pain.

• Because of the high risk for addiction and safety concerns while only providing modest pain relief, extended release tapentadol is not recommended as a first or second line therapy in most patients.

• Oxycodone has been found to be superior to placebo in the treatment of DN 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 DN.

• Tramadol is often good treatment for breakthrough or refractory pain.

Carbamazepine:

• Has been found to be associated with modest improvement in pain in DN compared with placebo.

• May be tried, but in selected cases only, due to serious side effects and risks that outweigh the modest benefit.

• The risk of carbamazepine-associated leukopenia and pancytopenia mandates that patients have a complete blood count (CBC) after the first month of therapy, and then have monthly CBCs for 3 months.

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 .

• Multiple studies have demonstrated the effectiveness of capsaicin cream in control of pain and improvement in daily activities.

• Poor adherence is common, due to 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 usually quite refractory cases.

• In a controlled study, TENS more effective than sham treatment in reducing pain in patients with DN.

• Uncontrolled studies of TENS and of acupuncture have been reported to decrease pain in >75% of patients with DN.

Autonomic neuropathy

The only proven pathogenic therapy is glucose control, mainly in type 1 diabetes mellitus (T1DM).

Cardiovascular autonomic neuropathy (CAN):

Glucose control

As with DPN, intensive control of hyperglycemia early in the course of type 1 diabetes was shown to prevent or reverse CAN compared with conventional treatment, as demonstrated by the DCCT. During EDIC follow-up, although CAN progressed substantially in both former DCCT intensive and conventional treatment groups, the prevalence and incidence of CAN in EDIC remained significantly lower in the former intensive group than in the former conventional group. Treatment group differences in the mean Hb A_1c level during DCCT and EDIC explained virtually all of the beneficial effects of intensive versus conventional therapy on risk of incident CAN, supporting the idea that intensive treatment of T1DM should be initiated as early as safely possible.

In type 2 diabetes the effects of glycemic control are less conclusive. The VA Cooperative Study and the Veterans Affairs Diabetes Trial (VADT) demonstrated no difference in the prevalence of autonomic neuropathy in T2D patients with tight glycemic control compared with those without tight control.

Multiple risk factor intervention

In the STENO 2 trial, an intensive multifactorial cardiovascular risk intervention targeting glucose, blood pressure, lipids, smoking, and other lifestyle factors reduced the progression or the development of CAN among T2DM patients. In the Diabetes Prevention Program, indices of CAN improved most in the lifestyle modification arm compared with the metformin or placebo arm.

Therapies targeting pathogenetic pathways

Several phase II randomized controlled trials have shown favorable effects on heart rate variability (HRV) indices using the antioxidant alpha-lipoic acid, vitamin E, and C-peptide. However, others showed negative or inconclusive effects.

An increase in HRV has been also described—with some controversy—in diabetic patients with angiotensin converting enzyme inhibitors, angiotensin II type 1 receptor blockers, cardioselective beta-blockers without intrinsic sympathomimetic activity (e.g., metoprolol, nebivolol, bisoprolol), digoxin, and verapamil. Some have proposed the use of cardioselective beta-blockers to treat resting tachycardia associated with CAN, but to date there is no clear evidence on their efficacy in diabetic CAN.

Symptomatic treatment

Symptomatic treatment of autonomic neuropathy

Orthostatic hypotension

Lifestyle and supportive measures:

• Avoid sudden changes in body posture to the head-up position

• Avoid medications that aggravate hypotension (i.e., tricyclic antidepressants, phenothiazines, diuretics)

• Eat small, frequent meals

• Elevate the head of the bed 18 inches at night

• Use a compressible garment over the legs and abdomen

• Use physical counter maneuvers, such as leg crossing, squatting, and muscle pumping

• Increase fluid and salt intake if not contraindicated

Pharmacologic therapy

Midodrine:

• A peripheral-selective direct alpha-1-adrenoreceptor agonist

• Several double-blind, placebo-controlled studies have documented its efficacy in the treatment of orthostatic hypotension

• The only FDA-approved agent for the treatment of orthostatic hypotension

• Doses of 2.5 to 10 mg, three to four times/day, are usually recommended

• First dose to be taken before arising

• Avoid taking several hours before planned recumbent position

• Main adverse effects include: piloerection, pruritus, paresthesia, supine hypertension, urinary retention

Fludrocortisone:

• A synthetic mineralocorticoid, with a long duration of action, which induces plasma expansion

• It may also enhance the sensitivity of blood vessels to circulating catecholamines

• The effects are not immediate, occur over a 1- to 2-week period

• Treatment usually begins with 0.05 mg at bedtime, and may be titrated gradually to a maximum of 0.2 mg/day. Higher doses are associated with higher risk for side effects.

• Main adverse advents include supine hypertension, hypokalemia, hypomagnesemia, congestive heart failure, peripheral edema

• May cause fluid overload in patients with congestive heart failure

Erythropoietin:

• May improve standing blood pressure in patients with orthostatic hypotension

• Possible mechanisms of action include increase in red cell mass and central blood volume; correction of the normochromic normocytic anemia that frequently accompanies diabetic autonomic neuropathy; and a direct or indirect neurohumoral effect on the vascular wall and vascular tone regulation, mediated via nitric oxide pathway

• It can be administered in diabetic patients with orthostatic hypotension and hemoglobin levels under 11 g/dl

• Doses between 25 and 75 U/kg subcutaneously or intravenously three times/week until the hemoglobin reaches target of 12 g/dl followed by lower maintenance doses

• Risk of serious cardiovascular events should be considered

Somatostatin analogues:

• May attenuate the postprandial BP fall, and reduce orthostatic hypotension in patients with autonomic failure

• Mechanisms of action include a local effect on splanchnic vasculature by inhibiting the release of vasoactive GI peptides, enhanced cardiac output, and an increase in forearm and splanchnic vascular resistance

• Usually 25 to 200 mcg/day octreotide are given subcutaneously in divided doses every 8 hours

• Long-acting depot preparation may be used, 20 to 30 mg intramuscularly once monthly

• Adverse events include severe hypertension

Caffeine citrate:

• A methylxanthine with well-established pressor effect, primarily due to blockade of vasodilating adenosine receptors

• May improve orthostatic hypotension and attenuate postprandial hypotension

• Recommended dose 100 to 250 mg orally three times daily dose expressed as anhydrous caffeine

• May be taken as tablets or caffeinated beverage

• Tachyphylaxis occurs with continuing use of caffeine.

Gastroparesis

Dietary changes:

• Eating multiple small meals

• Decreasing dietary fat and fiber

Drug therapy (prokinetic agents)

Metoclopramide:

• Has antiemetic properties, stimulates acetylcholine release in the myenteric plexus, and is a dopamine antagonist

• Possible adverse effects include extrapyramidal symptoms, such as acute dystonic reactions (drug-induced parkinsonism, akathisia; tardive dyskinesia), galactorrhea, amenorrhea, gynecomastia, and hyperprolactinemia

Domperidone (not FDA approved in the U.S.):

• Peripheral dopamine receptor antagonist

• Acts as a prokinetic agent, increasing the number and/or the intensity of gastric contractions, and improves symptoms in patients with diabetic gastroparesis

• Stimulates both liquid- and solid-phase gastric emptying

• Major benefit results from its antiemetic properties and, to a lesser extent, its motor stimulatory actions

• A systematic review of all studies using oral domperidone for the treatment of diabetic gastroparesis demonstrated improvement in gastric emptying and the efficacy of domperidone in treating gastroparesis

• Role has become controversial, due to safety concerns, and it has never been approved for marketing by the FDA in the U.S.

Erythromycin:

• Effective in accelerating gastric emptying

• Believed to act by stimulating motilin receptors in the gut

• May be used orally or intravenously

Onabotulinumtoxin A (formerly known as botulinum toxin type A):

• Reserved for severe diabetic gastroparesis refractory to dietary changes and the use of high-dose prokinetic agents

Other nonpharmacologic methods

Gastric pacing (stimulation):

• Short-term studies of gastric pacing in humans have demonstrated that it is possible to entrain gastric slow waves and normalize myoelectrical activity with pacing

• Uses high-frequency, low-amplitude signals that do not alter gastric myoelectrical or muscular activity

• Improvements in nausea and vomiting with gastric stimulation in people with gastroparesis have been reported

Surgery:

• Persistent vomiting may require a surgical approach.

• Placement of a feeding jejunostomy to bypass an atonic stomach has been advocated, based on clinical practice.

• Radical surgery, consisting of resection of a large portion of the stomach, with performance of a Roux-en-Y loop was successful in a small series of patients.

Diabetic diarrhea

Drug therapy

Broad spectrum antibiotics:

• Metronidazole 500 mg every 6 hours for 3 weeks; or 750 mg every 8 hours for 3 weeks

• Ampicillin or tetracycline 250 mg every 6 to 8 hours for 14 days

• Amoxicillin/clavulanate 875 mg twice daily for 14 days (dose refers to the amoxicillin component)

Cholestyramine:

• Chelates bile salts

• Used if the hydrogen breath test is normal, or if patients fail an empiric trial of broad-spectrum antibiotics

Octreotide:

• Accelerates gastric emptying, inhibits small bowel transit, reduces ileocolonic bolus transfers, inhibits postprandial colonic tonic response, and increases colonic phasic pressure activity in healthy volunteers

• May be used if other methods have not helped

Erectile dysfunction

Drug therapy

Phosphodiesterase-5 (PDE-5) inhibitors:

• Preferred therapy for erectile dysfunction

• Several agents approved (sildenafil, tadalafil, vardenafil)

• Efficacy demonstrated in randomized placebo-controlled clinical trials

• In general well tolerated

• Headaches and flushing are most frequent adverse event reported; other adverse effects reported in a descending order of frequency may include upper respiratory tract complaints, flulike syndromes, dyspepsia, myalgias, abnormal vision, and back pain

Nonpharmacologic approaches

Intracavernosal injections:

• Success rate is high, with nearly 90% of patients achieving erection

Other therapies:

• Vacuum devices

• Rigid penile implants

• Inflatable prostheses for the treatment of erectile dysfunction

All have mild to modest benefits

• Bethanechol, a parasympathomimetic agent, may be helpful.

• Bladder training, such as scheduled voiding, may be used particularly for urge incontinence.

• The Crede maneuver

What’s the Evidence?/References

Tesfaye, S, Boulton, AJ, Dyck, PJ. “Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments.”. Diabetes Care. vol. 33. 2010. pp. 2285-93. (This is the summary paper of the NIH Consensus Statement on Diabetic Neuropathies held in Toronto in 2009.)

Spallone, V, Ziegler, D, Freeman, R. “Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management.”. Diabetes Metab Res Rev. vol. 27. 2011. pp. 639-53. (This is the main paper from The Cardiovascular Autonomic Neuropathy (CAN) Subcommittee of the Toronto Diabetic Neuropathy Expert Group worked to update the guidelines on CAN, with regard to epidemiology, clinical impact, diagnosis, clinical usefulness of CAN testing, and management.)

Kempler, P, Amarenco, G, Freeman, R. “Gastrointestinal autonomic neuropathy, erectile-, bladder- and sudomotor dysfunction in patients with diabetes mellitus: clinical impact, assessment, diagnosis, and management.”. Diabetes Metab Res Rev. vol. 27. 2011. pp. 665-77. (This is the summary of the other Autonomic Neuropathies Subcommittee of the Toronto Diabetic Neuropathy Expert Group that updated the guidelines with regard to epidemiology, clinical impact, diagnosis, clinical usefulness of various testing, and current evidence regarding treatment and management.)

Pop-Busui, R. “What do we know and we do not know about cardiovascular autonomic neuropathy in diabetes. Invited review.”. J Cardiovasc Transl Res,. vol. 5. 2012. pp. 463-78. (A more recent review with more clinical implications of the cardiovascular autonomic neuropathy.)

Diabetes Care.. vol. 40. 2017. pp. S93-98.

Tesfaye, S, Chaturvedi, N, Eaton, SE. “Vascular risk factors and diabetic neuropathy.”. N Engl J Med. vol. 352. 2005. pp. 341-50.

Lauria, G, Hsieh, ST, Johansson, O. “European Federation of Neurological Societies/Peripheral Nerve Society guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society.”. Eur J Neurol. vol. 17. 2010. pp. 903-12.

Tavakoli, M, Quattrini, C, Abbott, C. “Corneal confocal microscopy: a novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy.”. Diabetes Care. vol. 33. 2010. pp. 1792-7.

Feldman, EL, Stevens, MJ, Thomas, PK. “A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy.”. Diabetes Care. vol. 17. 1994. pp. 1281-9.

N Engl J Med. vol. 329. 1993. pp. 977-86.

“Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial.”. Ann Neurol. vol. 38. 1995. pp. 869-80.

“The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT).”. Diabetologia. vol. 41. 1998. pp. 416-23.

Albers, JW, Herman, WH, Pop-Busui, R. “Effect 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. vol. 33. 2010. pp. 1090-6.

Pop-Busui, R, Low, P, Waberski, B. “Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC).”. Circulation. vol. 119. 2009. pp. 2886-93.

Bril, V, England, JD, Franklin, GM. “Evidence-based guideline: treatment of painful diabetic neuropathy—report of the American Association of Neuromuscular and Electrodiagnostic Medicine, the American Academy of Neurology, and the American Academy of Physical Medicine & Rehabilitation. American Academy of Neurology; American Association of Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation.”. Muscle Nerve. vol. 43. 2011. pp. 910-7.

Quilici, S, Chancellor, J, Löthgren, M. “Meta-analysis of duloxetine vs. pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain.”. BMC Neurol. vol. 9. 2009. pp. 6

Dworkin, RH, O’Connor, AB, Backonja, M. “Pharmacologic management of neuropathic pain: evidence-based recommendations.”. Pain. vol. 132. 2007. pp. 237-5.

Finnerup, NB, Attal, N, Haroutounian, S. “Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis.”. Lancet Neurol. vol. 14. 2015. pp. 162-173.

Schwartz, S, Etropolski, M, Shapiro, DY. “Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo- controlled trial.”. Curr Med Res Opin. vol. 27. 2011. pp. 151-162.

Vinik, AI, Shapiro, DY, Rauschkolb, C. “A randomized withdrawal, placebo-controlled study evaluating the efficacy and tolerability of tapentadol extended release in patients with chronic painful diabetic peripheral neuropathy.”. Diabetes Care. vol. 37. 2014. pp. 2302-2309.

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