136 Diabetes Care Volume 40, January 2017

Diabetic Neuropathy: A Position Rodica Pop-Busui,1 Andrew J.M. Boulton,2 Eva L. Feldman,3 Vera Bril,4 Roy Freeman,5 Statement by the American Rayaz A. Malik,6 Jay M. Sosenko,7 and Dan Ziegler8 Diabetes Association

Diabetes Care 2017;40:136–154 | DOI: 10.2337/dc16-2042

Diabetic neuropathies are the most prevalent chronic complications of diabetes. This heterogeneous group of conditions affects different parts of the nervous system and presents with diverse clinical manifestations. The early recognition and appropriate man- agement of neuropathy in the patient with diabetes is important for a number of reasons:

1. Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropathies may be present in patients with diabetes and may be treatable by specific measures. 2. A number of treatment options exist for symptomatic diabetic neuropathy. 3. Up to 50% of diabetic peripheral neuropathies may be asymptomatic. If not recognized and if preventive foot care is not implemented, patients are at risk for injuries to their insensate feet. 4. Recognition and treatment of autonomic neuropathy may improve symptoms,

POSITION STATEMENT reduce sequelae, and improve quality of life.

Among the various forms of diabetic neuropathy, distal symmetric polyneurop- athy (DSPN) and diabetic autonomic neuropathies, particularly cardiovascular au- tonomic neuropathy (CAN), are by far the most studied (1–4). There are several 1 atypical forms of diabetic neuropathy as well (1–4). Patients with prediabetes may Division of Metabolism, Endocrinology & Diabe- – tes, Department of Internal Medicine, University also develop neuropathies that are similar to diabetic neuropathies (5 10). Table 1 of Michigan, Ann Arbor, MI provides a comprehensive classification scheme for the diabetic neuropathies. 2University of Manchester and the Royal Infirmary, Due to a lack of treatments that target the underlying nerve damage, prevention Manchester, U.K. is the key component of diabetes care. Screening for symptoms and signs of diabetic 3Department of Neurology, University of Michigan, neuropathy is also critical in clinical practice, as it may detect the earliest stages of Ann Arbor, MI 4Department of Neurology, University of Toronto, neuropathy, enabling early intervention. Although screening for rarer atypical forms Toronto, Ontario, Canada of diabetic neuropathy may be warranted, DSPN and autonomic neuropathy are the 5Department of Neurology, Harvard Medical most common forms encountered in practice. The strongest available evidence School, Boston, MA regarding treatment pertains to these forms. 6Department of Medicine, Weill Cornell Medicine- Qatar, Doha, Qatar and New York, NY This Position Statement is based on several recent technical reviews, to which the reader 7 – Division of Endocrinology, University of Miami is referred for detailed discussion and relevant references to the literature (3,4,11 16). Miller School of Medicine, Miami, FL 8German Diabetes Center Dusseldorf,¨ Leibniz PREVENTION Center for Diabetes Research at Heinrich Heine Prevention of diabetic neuropathies focuses on glucose control and lifestyle modifica- University, and Department of Endocrinology and Diabetology, Medical Faculty, Heinrich tions. Available evidence pertains only to DSPN and CAN, and most of the large trials Heine University, Dusseldorf,¨ Germany that have evaluated the effect of glucose control on the risk of complications have Corresponding author: Rodica Pop-Busui, rpbusui@ included DSPN and CAN as secondary outcomes or as post hoc analyses rather than as umich.edu. primary outcomes. In addition, in some of these trials, the outcome measures used to This position statement was reviewed and ap- evaluate neuropathy may have limited ability to detect a benefit, if present. proved by the American Diabetes Association Professional Practice Committee in September 2016 and ratified by the American Diabetes As- Recommendations sociation Board of Directors in October 2016. c Optimize glucose control as early as possible to prevent or delay the devel- R.P.-B. and A.J.M.B. served as co-chairs of the opment of distal symmetric polyneuropathy and cardiovascular autonomic writing committee. neuropathy in people with type 1 diabetes. A © 2017 by the American Diabetes Association. c Optimize glucose control to prevent or slow the progression of distal symmet- Readers may use this article as long as the work ric polyneuropathy in people with type 2 diabetes. B is properly cited, the use is educational and not c Consider a multifactorial approach targeting glycemia among other risk factors to for profit, and the work is not altered. More infor- prevent cardiovascular autonomic neuropathy in people with type 2 diabetes. C mation is available at http://www.diabetesjournals .org/content/license. care.diabetesjournals.org Pop-Busui and Associates 137

fi Table 1—Classification for diabetic neuropathies Similar to the ndings in DSPN, the Diabetic neuropathies most robust evidence for CAN preven- A. Diffuse neuropathy tion was reported in type 1 diabetes. DSPN Intensive glucose control designed to c Primarily small-fiber neuropathy achieve near-normal glycemia reduced c Primarily large-fiber neuropathy the risk of incident CAN during the Di- c Mixed small- and large-fiber neuropathy (most common) abetes Control and Complications Trial Autonomic (DCCT) by 45% and by 31% in its follow-up Cardiovascular c Reduced HRV study, the Epidemiology of Diabetes In- c Resting tachycardia terventions and Complications (EDIC) c Orthostatic hypotension study (27). The highly reproducible and c Sudden death (malignant arrhythmia) sensitive testing protocol, the robust Gastrointestinal definitions used for CAN, and the large c Diabetic gastroparesis (gastropathy) sample size in DCCT/EDIC enhance the c Diabetic enteropathy (diarrhea) validity of the results and support the c Colonic hypomotility (constipation) Urogenital rationale for implementing and main- c Diabetic cystopathy (neurogenic bladder) taining tight glucose control as early as c Erectile dysfunction possible in the course of type 1 diabetes. c Female sexual dysfunction In contrast, glycemic control in type 2 Sudomotor dysfunction diabetes has not consistently lowered c Distal hypohydrosis/anhidrosis, the risk of CAN (25). However, a multi- c Gustatory sweating Hypoglycemia unawareness factorial intervention, including a life- Abnormal pupillary function style component, targeting glucose and B. Mononeuropathy (mononeuritis multiplex) (atypical forms) cardiovascular disease risk factors re- Isolated cranial or peripheral nerve (e.g., CN III, ulnar, median, femoral, peroneal) duced the risk of CAN by 60% in people Mononeuritis multiplex (if confluent may resemble polyneuropathy) with type 2 diabetes (28). C. Radiculopathy or polyradiculopathy (atypical forms) Radiculoplexus neuropathy (a.k.a. lumbosacral polyradiculopathy, proximal motor Lifestyle Modifications amyotrophy) Thoracic radiculopathy The best models to date regarding pa- Nondiabetic neuropathies common in diabetes rameters for an evidence-based, inten- Pressure palsies sive lifestyle intervention come from the Chronic inflammatory demyelinating polyneuropathy Diabetes Prevention Program (DPP) Radiculoplexus neuropathy (29), the Steno-2 Study (28), the Italian Acute painful small-fiber neuropathies (treatment-induced) supervised treadmill study (30), and the University of Utah type 2 diabetes study (31). The latter study recently reported nerve fiber regeneration in patients with Glucose Control people with type 2 diabetes develop type 2 diabetes engaged in an exercise Enhanced glucose control in people with DSPN despite adequate glucose control program compared with loss of nerve fi- type 1 diabetes dramatically reduces the (20,25). The presence of multiple comor- bers in those who only followed standard incidence of DSPN (78% relative risk re- bidities, polypharmacy, hypoglycemia, of care. Overall, such an approach focuses – duction) (17 19). In contrast, enhanced and weight gain might have attenuated on either exercise alone (supervised aer- glucose control in people with type 2 di- the effects of glucose control in these obic and/or resistance training) (30,31) or abetes reduces the risk of developing trials and contributed to inconsistent combined dietary modification and exer- – DSPN modestly (5% 9% relative risk re- findings (25). Specific glucose-lowering cise. There is no consensus regarding di- duction) (20,21). In a small trial of Japa- strategies may also contribute to the dis- etary regimens, and although the DPP nese patients with early type 2 diabetes, crepancy. For example, participants, par- used a low-calorie, low-fat diet, others intensive insulin treatment was associ- ticularly men, in the Bypass Angioplasty have championed a Mediterranean diet ated with improvement in selected Revascularization Investigation in Type 2 that is moderately lower in carbohydrate DSPN measures (22), and the Action to Diabetes (BARI 2D) study treated with in- (45%) and higher in fat (35%–40%), with Control Cardiovascular Risk in Diabetes sulin sensitizers had a lower incidence of less than 10% of saturated fat. (ACCORD) trial reported a modest but DSPN over 4 years than those treated Although the DPP (32) and the Impaired significant DSPN risk reduction with with insulin/sulfonylurea (26). This out- Glucose Tolerance Neuropathy (IGTN) the glycemia intervention in individuals come may be a result of less weight gain study (33) reported benefits of lifestyle with type 2 diabetes after 5 years of and less hypoglycemia (26). Last, the fact interventions on measures of CAN and follow-up (21). Yet, no effects are ob- that many patients have had asymptom- DSPN, respectively, these trials did not in- served in other large trials (20,23–25). atic hyperglycemia for many years prior clude subjects with established diabetes. This discrepancy highlights the differ- to the diagnosis of type 2 diabetes may In addition, in the DPP, indices of CAN ences between type 1 and type 2 diabe- also explain the limited benefitinthese improved with the lifestyle intervention tes and emphasizes the point that many patients. and did not change in the other arms (32). 138 Position Statement Diabetes Care Volume 40, January 2017

DSPN observed in adult populations (46). and an increased risk of falls. These re- Most common among diabetic neurop- DSPNhasbeenassociatedwithglyce- current minor injuries may further con- athies is chronic DSPN, accounting for mia (14,33–35), height (47) (perhaps tribute to the pathogenesis of CN (58). about 75% of the diabetic neuropathies as a proxy for nerve length), smoking (1,3). A simple definition of DSPN for (48), blood pressure, weight, and lipid Screening and Diagnosis measures (49,50). clinical practice is the presence of symp- Recommendations There is emerging evidence that toms and/or signs of peripheral nerve c All patients should be assessed for fi dysfunction in people with diabetes af- DSPN, especially the painful small- ber distal symmetric polyneuropathy ter the exclusion of other causes. neuropathy subtype, may be present in starting at diagnosis of type 2 di- – Experimental studies suggest a mul- 10% 30% of subjects with impaired glu- abetes and 5 years after the diag- tifactorial pathogenesis of DSPN (Fig. 1), cose tolerance, also known as prediabe- nosis of type 1 diabetes and at – but the causes remain unknown tes (5 10) or metabolic syndrome (51). least annually thereafter. B (34–37). A prevailing view of the patho- DSPN is the most important cause of c Consider screening patients with genesis is that oxidative and inflamma- foot ulceration, and it is also a prereq- prediabetes who have symptoms tory stress may, in the context of uisite in the development of Charcot of peripheral neuropathy. B metabolic dysfunction, damage nerve neuroarthropathy (CN) (52). The reader c Assessment should include a care- cells (34–37). is referred to several other reviews that ful history and either temperature Estimates of the incidence and prev- cover this topic (52,53). Foot ulceration or pinprick sensation (small-fiber alence of DSPN vary greatly (25,38–40), and CN are both recognized as late com- function) and vibration sensation but evidence from several large obser- plications of DSPN (52,54). These late using a 128-Hz tuning fork (large-fiber vational cohorts (41,42) and the DCCT/ complications drive amputation risk function). All patients should have an EDIC (27,43) suggests that DSPN occurs and economic costs of diabetic neurop- annual 10-g monofilament testing to in at least 20% of people with type 1 di- athy and are also predictors of mortality. assess for feet at risk for ulceration abetes after 20 years of disease dura- DSPN is also a major contributor to and amputation. B tion. DSPN may be present in at least falls and fractures (55–57), through c Electrophysiological testing or re- 10%–15% of newly diagnosed patients more advanced small- and large-fiber ferral to a neurologist is rarely with type 2 diabetes (44,45), with rates dysfunction, with loss of sensory, pro- needed for screening, except in increasing to 50% after 10 years of disease prioception, temperature discrimina- situations where the clinical fea- duration (25,26). Rates in youth with tion, and pain, all ultimately leading to tures are atypical, the diagnosis is type 1 and type 2 diabetes approach those unsteadiness, recurrent minor injuries, unclear, or a different etiology is suspected. Atypical features in- clude motor greater than sensory neuropathy, rapid onset, or asym- metrical presentation. B

Patients with type 1 diabetes for 5 or more years and all patients with type 2 diabetes should be assessed annually for DSPN using medical history and simple clinical tests. Up to 50% of pa- tients may experience symptoms of DSPN (Table 2), whereas the rest are asymptomatic. Patients may not volun- teer symptoms but on inquiry may reveal that they are experiencing numbness or other positive symptoms of DSPN. Symptoms vary according to the class of sensory fibers involved. The most common early symptoms are induced by the involvement of small fibers and include pain and dysesthesias (unpleas- ant sensations of burning) (1,4,59,60). Neuropathic pain may be the first symp- Figure 1—Mechanisms of diabetic neuropathy. Factors linked to type 1 diabetes (yellow), type 2 tom that prompts patients to seek med- diabetes (blue), and both (green) cause DNA damage, endoplasmic reticulum stress, mitochon- ical care and is present in up to 25% of drial dysfunction, cellular injury, and irreversible damage. The relative importance of the path- individuals with DSPN (61–63). Charac- ways in this network will vary with cell type, disease profile, and time. ER, endoplasmic reticulum; FFA, free fatty acids; PI3-K, phosphatidylinositol-3 kinase; RNS, reactive nitrogen teristically, the pain is burning, lancinating, species; ROS, reactive oxygen species. Adapted and reprinted from Callaghan et al. (20), with tingling, or shooting (electric shock–like); permission from Elsevier. occurs with paresthesias; presents in care.diabetesjournals.org Pop-Busui and Associates 139

Table 2—Symptoms and signs of DSPN Large myelinated nerve fibers Small myelinated nerve fibers Function Pressure, balance Nociception, protective sensation Symptoms§ Numbness, tingling, poor balance Pain: burning, electric shocks, stabbing Examination Ankle reflexes: reduced/absent Thermal (cold/hot) discrimination: reduced/absent** (clinically diagnostic)** Vibration perception: reduced/absent Pinprick sensation: reduced/absent** 10-g monofilament: reduced/absent Proprioception: reduced/absent §To document the presence of symptoms for diagnosis; **Documented in symmetrical, distal to proximal pattern.

varying combinations; and is typically Assessments should follow the typical Foot Complications worse at night. Neuropathic pain may be DSPN pattern, starting distally (the dor- The simple yet comprehensive clinical accompanied by an exaggerated response sal aspect of the hallux) on both sides exam is principally designed to identify to painful stimuli (hyperalgesia) and pain and move proximally until a sensory those at risk for the late complications evoked by contact, e.g., with socks, shoes, threshold is identified (72). Combining whoneededucationonpreventative and bedclothes (allodynia). Neuropathic at least two examinations will increase foot self-care and regular podiatric pain can lead to interference with daily the sensitivity and specificity of detect- foot care. Recently an even simpler activities, disability, psychosocial impair- ing DSPN, as demonstrated in several ment, and reduced health-related quality cohorts of patients with type 1 and Table 3—Differential diagnosis of of life (64–66). The direct and indirect eco- type 2 diabetes including children and diabetic neuropathies – nomic burden associated with neuro- adolescents (26,46,73 79). Metabolic disease – The diagnosis of DSPN is principally a Thyroid disease (common) pathic pain is substantial (67 69). Renal disease The involvement of large fibers may clinical one (Table 2). A combination of typical symptomatology and symmetrical Systemic disease cause numbness, tingling without pain, Systemic vasculitis and loss of protective sensation. Loss of distal sensory loss or typical signs in the Nonsystemic vasculitis protective sensation indicates the pres- absence of symptoms in a patient with Paraproteinemia (common) ence of DSPN and is a risk factor for di- diabetes is highly suggestive of DSPN Amyloidosis abetic foot ulceration. Patients can also and may not require additional evaluation Infectious initially present with an insensate, numb or referral. As up to half of the patients HIV fi may be asymptomatic, a diagnosis may Hepatitis B foot due to the loss of large bers. Patients Lyme only be made on examination or, in frequently state that their feet feel like Inflammatory some cases, when the patient presents they are wrapped in wool or they are walk- Chronic inflammatory demyelinating ing on thick socks. It is the loss of the “gift with a painless foot ulcer. polyradiculoneuropathy of pain” that permits patients with plantar Clinicians should note that the 10-g Nutritional monofilament test included for the neuropathic ulcers to walk on the lesions, B12* inducing chronicity, frequently complicated annual DSPN screening and diagnosis Postgastroplasty by infection (70). is different than the diagnosis of the Pyridoxine “high-risk foot” for ulceration, a late Thiamine The following clinical tests may be Tocopherol used to assess small- and large-fiber DSPN complication that requires that fi fi Industrial agents, drugs, and metals function distal to proximal (Table 2): four sites ( rst, third, and fth metatarsal heads and plantar surface of distal hallux) Industrial agents Acrylamide fi 1. Small- ber function: pinprick and be tested on each foot (80). Organophosphorous agents temperature sensation Consider excluding neuropathy with Drugs 2. Large-fiber function: vibration per- causes other than diabetes (Table 3) by Alcohol ception, proprioception, 10-g mono- undertaking a family and medication history Amiodarone filament, and ankle reflexes and performing relevant investigations (e.g., Colchicine serum B , folic acid, thyroid function, com- Dapsone 12 Vinka alkaloids A 128-Hz tuning fork can be used for plete blood count, metabolic panel, and a the assessment of vibration perception. Platinum serum protein immunoelectrophoresis) (81). Taxol Assessment of light-touch perception Electrophysiological testing or referral Metals using a 10-g monofilament should include to a neurologist is rarely needed for di- Arsenic evaluation on the dorsal aspect of the agnosis, except in situations where the Mercury great toe bilaterally as previously validated clinical features are atypical, the diagnosis Hereditary by Perkins et al. (71). The 10-g monofila- is unclear, or a different etiology is sus- Hereditary motor, sensory, and ment is a useful clinical tool mainly for pected (2,38,40,80). Atypical features that autonomic neuropathies detecting more advanced neuropathy warrant referral include motor greater than *B12 deficiency is more commonly and identifying patients at increased risk sensory neuropathy, asymmetry of symp- associated with malabsorption rather than nutritional deficiency. of ulceration and amputation (72). toms and signs, and rapid progression. 140 Position Statement Diabetes Care Volume 40, January 2017

foot exam, the “3-minute diabetic foot other agents based on mechanism of ac- c Gabapentin may also be used as exam,” has been proposed (82). This is tion and strength of evidence. Evidence an effective initial approach, taking intended not only for physicians but also levels are assigned based on the strength into account patients’ socioeco- for other health care professionals who of the published clinical evidence for the nomic status, comorbidities, and may only have 15 min for the entire dia- efficacy and safety of the agents for the potential drug interactions. B betes annual review; it requires no equip- treatment of DSPN pain, which should be c Although not approved by the U.S. ment and provides simple advice on considered in clinical decision making. Food and Drug Administration, tri- education on preventative foot self-care. However, a certain degree of publication cyclic antidepressants are also ef- bias should be considered, given that fective for neuropathic pain in Management many negative trials may not have been diabetes but should be used with published (15). Recommendations caution given the higher risk of se- Additional information on dose titra- c Tight glucose control targeting rious side effects. B tion, adverse effects, number needed to near-normal glycemia in patients c Given the high risks of addiction treat, and safety is presented in Table 4. with type 1 diabetes dramatically and other complications, the use reduces the incidence of distal of opioids, including tapentadol symmetric polyneuropathy and is Approved Medications or tramadol, is not recommended Pregabalin and duloxetine have re- recommended for distal symmet- fi as rst- or second-line agents for ceived regulatory approval for the treat- ric polyneuropathy prevention in treating the pain associated with type 1 diabetes. A ment of neuropathic pain in diabetes in DSPN. E the U.S., Europe, and Canada. c In patients with type 2 diabetes a d with more advanced disease and Pregabalin, a calcium channel 2- multiple risk factors and comorbid- No compelling evidence exists in support subunit ligand, is an effective treatment ities, intensive glucose control of glycemic control or lifestyle manage- for neuropathic pain associated with alone is modestly effective in pre- ment as therapies for neuropathic pain in DSPN. It is the most extensively studied venting distal symmetric polyneur- diabetes or prediabetes (33,85), which drug by far in DSPN, with the majority opathy and patient-centered goals leaves only pharmaceutical interventions. of studies being positive regarding should be targeted. B At present, pregabalin and duloxetine the proportion of responders with at least 30%–50% improvement in pain c Lifestyle interventions are recom- have received regulatory approval for the – mended for distal symmetric poly- treatment of neuropathic pain in diabetes (15,86,88 94). There is also some evi- neuropathy prevention in patients by the U.S. Food and Drug Administration dence suggesting a dose response, with a with prediabetes/metabolic syn- (FDA), Health Canada, and the European weaker effect with 300 vs. 600 mg/day drome and type 2 diabetes. B Medicines Agency. The opioid, tapentadol, (88). However, not all trials with pregaba- has regulatory approval in the U.S. and lin have been positive (15,86,95,96), espe- Canada, but the evidence of its use is cially when treating advanced refractory Prevention weaker (15). patients (93). Pregabalin, in contrast to Please refer to PREVENTION on page 136. A large evidence base supports phar- gabapentin (see below), has a linear, Pathogenetic Therapies macological treatment of neuropathic dose-proportional absorption in the thera- Despite the recent major advances in pain in diabetic neuropathy using other peutic dose range (150–600 mg/day) elucidating the pathogenesis of diabetic agents of different classes, as docu- (88). In addition, pregabalin has a more neuropathy, there remains a lack of mented by several recent guidelines rapid onset of action and more limited treatment options that effectively tar- and systematic reviews (15,16,20,86,87). dosage range that requires minimal titra- get the natural history of DSPN (83) or It is important to mention that only a tion. Adverse effects may be more se- reverse DSPN once established. Several fewtrialsthattargetedpaininperipheral vere in older patients (97) and may be pathogenetic pharmacotherapies have neuropathic pain were carried out in DSPN attenuated by lower starting doses and been investigated (36), but evidence alone. However, the results of studies per- more gradual titration. from randomized clinical trials is very formed on peripheral nondiabetic neuro- Duloxetine is a selective norepineph- limited (81,83,84). Advances in DSPN pathic pain or mixed neuropathic pain may rine and serotonin reuptake inhibitor. disease modification need to be con- be applicable to patients with neuropathic Doses of 60 and 120 mg/day showed ef- firmed with further robust evidence pain due to DSPN. ficacy in the treatment of pain associated from clinical trials, together with a bet- Although there are broad general with DSPN in multicenter randomized tri- ter understanding of the mechanisms of agreements among the recommenda- als, although some of these had a rather action of promising treatments (83). tions, there are some inconsistencies that high drop-out rate (15,86,94,96,98–101). are, in part, a consequence of whether the Duloxetine was also suggested to in- Pain Management guidelines are specificforpainfulDSPNor duce improvement in neuropathy-related whether they address neuropathic pain quality of life (100). In longer-term stud- Recommendations due to all causes (15,16,20,86,87). ies, a small increase in A1C was reported c Consider either pregabalin or Below we summarize the available ev- in people with diabetes treated with du- duloxetine as the initial approach idence on the most effective agents for loxetine compared with placebo (102). in the symptomatic treatment for DSPN pain starting with the currently ap- Adverse events may again be more severe neuropathic pain in diabetes. A proved drugs and continuing with the in older people but may be attenuated care.diabetesjournals.org

Table 4—Treatment for pain associated with DSPN (15,16,20,86,87) Dose NNT range 30–50% Common adverse Major adverse Drug class Agent Initial Effective improvement** events events Anticonvulsants Pregabalin* (15,86,88–94) 25–75 mg, 1–33/day 300–600 mg/day 3.3–8.3 c Somnolence c Angioedema c Dizziness c Hepatotoxicity c Peripheral edema c Rhabdomyolysis c Headache c Suicidal thoughts and behavior c Ataxia c Seizures after rapid discontinuation c Fatigue c Thrombocytopenia c Xerostomia c Weight gain Gabapentin (15,86,96,105–111) 100–300 mg, 1–33/day 900–3,600 mg/day 3.3–7.2 c Somnolence c Stevens-Johnson syndrome c Dizziness c Suicidal thoughts and behavior c Ataxia c Seizures after rapid discontinuation c Fatigue Antidepressants Serotonin-norepinephrine Duloxetine* (15,86,94,96,98–101) 20–30 mg/day 60–120 mg/day 3.8–11 c Nausea c Stevens-Johnson syndrome reuptake inhibitors c Somnolence c Hepatotoxicity c Dizziness c Hypertensive crisis c Constipation c Gastrointestinal hemorrhage c Dyspepsia c Delirium c Diarrhea c Myocardial infarction c Xerostomia c Cardiac arrhythmias c Anorexia c Glaucoma c Headache c Suicidal thoughts and behavior c Diaphoresis c Shift to mania in patients with c Insomnia bipolar disorder c Fatigue c Seizures c Decreased libido c Severe hyponatremia c Fragility bone fractures c Serotonin syndrome c Neuroleptic malignant syndrome c Venlafaxine (15,16,20,86,87,126,127) 37.5 mg/day 75–225 mg/day 5.2–8.4 c Nausea Same as duloxetine c Somnolence

c Dizziness 141 Associates and Pop-Busui c Constipation c Dyspepsia c Diarrhea c Xerostomia c Anorexia Continued on p. 142 4 oiinStatement Position 142

Table 4—Continued Dose NNT range 30–50% Common adverse Major adverse Drug class Agent Initial Effective improvement** events events c Headache c Diaphoresis c Insomnia c Fatigue c Decreased libido Tricyclic antidepressants Amitriptyline (16,110,112–116) 10–25 mg/day 25–100 mg/day 2.1–4.2 c Xerostomia c Delirium c Somnolence c Cardiac arrhythmias c Fatigue c Conduction abnormalities c Headache c Myocardial infarction c Dizziness c Heart failure exacerbation c Insomnia c Stroke c Orthostatic hypotension c Seizures c Anorexia c Hepatotoxicity c Nausea c Bone marrow suppression c Urinary retention c Suicidal thoughts and behavior c Constipation c Shift to mania in bipolar disorder c Blurred vision c Neuroleptic malignant syndrome c Accommodation c Serotonin syndrome c Disturbance c Severe hyponatremia c Mydriasis c Fragility bone fractures c Weight gain Desipramine (113,118–121,122) c Same as above c Same as above Nortriptyline c Same as above c Same as above (15,16,86,87,113,114,120,121,123) Opioids Tramadol (15,16,86,87,109,130) 50 mg, 1–23/day 210 mg/day 3.1–6.4 c Somnolence c Confusion c Nausea c Seizures c Vomiting c Cardiac arrhythmias c Constipation c Hypertension ibtsCare Diabetes c Light-headedness c Hypersensitivity reactions c Dizziness c Stevens-Johnson syndrome c Headache Tapentadol* (103,104,135) Immediate release: Immediate-release: day 1: N/A c Somnolence c Respiratory depression – c c 50 100 mg, 700 mg; after day 1, Nausea Serotonin syndrome 2017 January 40, Volume 4–63/day 60 mg/day Extended release: Extended release: c Vomiting c Seizures 50 mg, 23/day 50 mg, 23/day c Constipation c Hypertension c Dizziness c Neonatal opioid withdrawal syndrome NNT, number needed to treat. *FDA approved. **FDA considers 30–50% improvement to be significant. care.diabetesjournals.org Pop-Busui and Associates 143

with lower doses and progressive titra- antidepressant effect (112). A recent Co- (131). Although tramadol has a lower tions of duloxetine. chrane Review questioned the quality of potential for abuse compared with other Tapentadol extended release is a evidence on amitriptyline by raising con- opioids, given these safety concerns, it novel centrally acting opioid analgesic cerns for bias given the small sample size is not recommended for use as first- or that exerts its analgesic effects through in most and concluded that in fact there second-line agent. both m-opioid receptor agonism and is no clear evidence for a beneficial effect Controlled-release oxycodone im- noradrenaline reuptake inhibition. for amitriptyline on DSPN pain, especially proved pain scores in two single-center Extended-release tapentadol was ap- when balanced against spectrum of side trials in patients with painful diabetic proved by the FDA for the treatment effects (117). However, there was no neuropathy, one of which had a small of neuropathic pain associated with good evidence of a lack of effect either sample size (132,133). It may provide diabetes based on data from two multi- (117). additional analgesia for patients on a2-d center randomized withdrawal, placebo- The secondary amines, nortriptyline ligand treatment (134). As with all opioids, controlled phase 3 trials (103,104). However, and desipramine, have a less trouble- it is not recommended for use as first-, both used an enriched design and there- some side effect profile than the tertiary second-, or third-line agent. fore are not generalizable, and a recent amines, amitriptyline and imipramine, Warnings on All Opioids systematic review and meta-analysis by although fewer randomized controlled Despite the demonstrated effectiveness the International Association for the trials were performed with these agents, of opioids in the treatment of neuro- Study of Pain Special Interest Group on and the potential for bias was high given pathic pain (15,132,134,135), there is a Neuropathic Pain (NeuPSIG) found the the small size (113,118–123). The use of high risk of addiction, abuse, sedation, evidence of the effectiveness of tapenta- these agents is preferable, particularly in and other complications and psychoso- dol in reducing neuropathic pain incon- – older and side effect prone patients cial issues even with short-term opioid clusive (15). Therefore, given the high – (113,118 121). use. For these reasons, opioids are not risk for addiction and safety concerns Several studies have suggested that recommended in the treatment of pain- compared with the relatively modest there is an increased risk of myocardial ful DSPN before failure of other agents pain reduction, the use of tapentadol ischemia and arrhythmogenesis associ- that do not have these associated con- extended release is not recommended ated with tricyclic agents (124,125). Because cerns (136–138). as first- or second-line treatment. of concerns of possible cardiotoxicity, tricy- Although add-on therapy with strong Anticonvulsants clic antidepressants should be used with opioids may be required in some pa- Gabapentin, like pregabalin, also binds caution in patients with known or suspected tients who do not respond to all other the calcium channel a2-d subunit and cardiac disease. combinations, referral to specialized pain has shown efficacy in a number of clin- Venlafaxine, a selective norepineph- clinics is recommended in these cases to ical trials for treating the pain associated rine and serotonin reuptake inhibitor, avoid risks. with DSPN (15,86,96,105–111). How- in doses between 150 and 225 mg/day Additional Considerations for Pain ever, not all painful DSPN studies, has shown some effectiveness in the treatment of painful DSPN (126,127). Management some of which are unpublished, have Combination therapy, including combi- Both venlafaxine and duloxetine (see been positive (15,107). nations with opioids, may provide effec- Given its pharmacokinetic profile, above) inhibit the reuptake of serotonin tive treatment for diabetic neuropathic gabapentin requires gradual titration and norepinephrine without the musca- pain at lower doses (94,139). A detailed and doses up to 1,800–3,600 mg are gen- rinic, histaminic, and adrenergic side ef- approach for pain management is amply erally needed to be clinically effective fects that accompany the use of the covered in other literature (15,109), (96,105–107). Adverse effects may be tricyclic agents (98–100,102). However, and a simple algorithm for clinical prac- more severe in older patients (97). the level of evidence for pain reduction tice use is shown in Fig. 2. associated with DSPN is higher with du- Monoamine Reuptake Inhibitors loxetine (see above). Venlafaxine may The monoamine reuptake inhibitorsd Treatment of Foot Complications tricyclic antidepressants, selective serotonin lower the seizure threshold, and gradual Detailed treatment of foot ulceration reuptake inhibitors, and norepinephrine tapering is recommended to avoid the and CN is beyond the scope of this state- and serotonin reuptake inhibitorsd emergence of adverse events upon dis- ment, and the reader is referred to a increase synaptic monoamine levels and continuation (126,127). relevant review (54). Effective off-loading directly influence the activity of the de- Opioid and Atypical Opioid Analgesics that prevents patients with plantar neu- scending neurons. Tramadol is a centrally acting analgesic ropathic ulcers to walk on the lesions is Amitriptyline, although not FDA ap- with pain relief mediated by a weak the key to successful management proved, is the most used of the tricyclic m-opioid receptor agonist activity and (52,54). Off-loading, usually with casting, agents. Many previous guidelines rec- inhibition of norepinephrine and seroto- and careful follow-up and repeated in- ommend the medication as a first-line nin reuptake (128,129). It is an effective vestigations are also key components treatment based on few randomized, agent in the treatment of painful dia- for the management of CN (52,54). On- blinded, placebo-controlled clinical tri- betic peripheral neuropathy compared going education and regular podiatry fol- als that reported significant improvement with placebo as demonstrated by two low-up can reduce the incidence of foot in neuropathic pain (110,112–116). The large multicenter trials (129,130), and complications in those found to be at effectiveness appeared unrelated to the it appears to have long-term effects “high risk.” Early intervention for foot 144 Position Statement Diabetes Care Volume 40, January 2017

give rise to symptoms of anxiety (143). Two research tools that can be used to assess quality of life that are neuropathy specificaretheNeuro- QoL (Quality of Life in Neurological Dis- orders) (144) and QOL-DN (Norfolk Quality of Life-Diabetic Neuropathy) instruments (145).

DIABETIC AUTONOMIC NEUROPATHIES Autonomic neuropathies affect the auto- nomic neurons (parasympathetic, sympa- thetic, or both) and are associated with a variety of site-specificsymptoms.The symptoms and signs of autonomic dys- function should be elicited carefully dur- ing the medical history and physical examination. Major clinical manifesta- tions of diabetic autonomic neuropathy include hypoglycemia unawareness, rest- Figure 2—Algorithm for management of the patient with pain because of DSPN. AE, adverse ing tachycardia, orthostatic hypotension, events.*Pregabalin is FDA approved for painful DSPN, whereas gabapentin is not. Pharmaco- gastroparesis, constipation, diarrhea, fe- kinetic profile, spectrum of AEs, drug interactions, comorbidities, and costs to be considered cal incontinence, erectile dysfunction, in selecting the agent of choice. **Duloxetine is FDA approved for painful DSPN, whereas neurogenic bladder, and sudomotor dys- venlafaxine is not. Pharmacokinetic profile, spectrum of AEs, drug interactions, comorbidities, and costs to be considered in selecting the agent of choice. #None is FDA approved for painful function with either increased or de- DSPN. Spectrum of AEs, drug interactions, and comorbidities need be considered if selecting creased sweating. these agents. Although CAN is the most studied and clinically relevant of the diabetic auto- lesions and CN or suspected CN can slow clinical practice to evaluate risk of falls nomic neuropathies, gastrointestinal, or reverse progression. in patients at risk (55,58). genitourinary, and sudomotor dysfunc- tion should be considered in the optimal Fall Prevention care of patients with diabetes. Psychosocial Factors Recommendation Recommendations CAN c Tests assessing gait and balance Although CAN prevalence is very low in c Consider treatment with duloxe- may be considered in people with tine, pregabalin, and gabapentin to newly diagnosed patients with type 1 distal symmetric polyneuropathy improve quality of life in patients diabetes (146), CAN prevalence in- to evaluate the risk of falls. E with neuropathic pain. C creases substantially with diabetes du- ration (13,25), and prevalence rates of c Assess the effects of distal symmet- at least 30% were observed in the DSPN may also compromise balance in ric polyneuropathy on quality of life DCCT/EDIC cohort after 20 years of di- daily activities (58). For instance, pro- to improve adherence and response abetes duration (27,147). In type 2 di- gressive loss of proprioception (dimin- to neuropathic pain treatment. E abetes, the prevalence of CAN also ished sensation) and later weakness, increases with diabetes duration and superimposed on age-related functional Assessing the effects of DSPN on a pa- may be present in up to 60% of patients impairments, lead to imbalance and un- tient’s quality of life is emerging as a with type 2 diabetes after 15 years steadiness in gait, with increased like- component of patient care and may (13,148,149). CAN may affect youth, es- lihood of a fall (55,58). A decline in play an important part in the adher- pecially young women and those with cognitive function, polypharmacy, and ence and the response to therapies elevated A1C levels, with prevalence neuropathic pain may further contribute. in patients with neuropathic pain rates of at least 20% reported in youth In addition, treatment of neuropathic (140). Some studies report an improve- with type 1 or type 2 diabetes (150). In pain often requires dosages and drug ment in quality of life in people with addition, CAN is present in patients with combinations that may further increase painful DSPN treated with duloxetine impaired glucose tolerance, insulin the fall risk due to cognitive impair- (100), pregabalin (141), and gabapentin resistance, or metabolic syndrome ment, drowsiness, dizziness, blurred vi- (106,142). A longitudinal study has (10,32,151). sion, and gait disturbances (97,109). shown that DSPN is a risk factor for de- A timely diagnosis of CAN may have Older patients are the most susceptible pression and the strongest symptom important clinical implications, as CAN is (97,109). Therefore, tests assessing gait associated with depression was un- an independent risk factor for cardio- and balance may be considered in steadiness. Pain with DSPN may also vascular mortality, arrhythmia, silent care.diabetesjournals.org Pop-Busui and Associates 145

ischemia, any major cardiovascular and many other risk factors, including c Consider assessing symptoms and event, and myocardial dysfunction use of various classes of medication signs of cardiovascular autonomic (152–157). Data from two large cardio- use (154). neuropathy in patients with hypo- vascular outcomes trials that included It was also suggested that intensifi- glycemia unawareness. C 31,531 patients with stable heart dis- cation of glucose and blood pressure ease and/or diabetes followed for a me- management may increase the risk of dian of 5 years reported that heart rate, a cardiovascular event in people with The most common symptoms of CAN an indirect measure of CAN, analyzed as signs of CAN (161–165). Similarly, emerg- occur upon standing and include light- either categorical (baseline heart rate ing evidence demonstrates an associa- headedness, weakness, palpitations, faint- .70 vs. #70 bpm) or across heart rate tion between CAN and glucose variability, ness, and syncope (13,169,170) (Table 5). quintile, was independently associated especially in the hypoglycemic range The patient should be asked about these with significant increases in cardiovas- (150,164). symptoms when a medical history is taken cular disease (CVD) events and all-cause In addition, CAN independently predicts in the office, although the correlation of death (158). CAN may also be associated the progression of diabetic nephropathy symptoms with overall autonomic deficits with hemodynamic instability or cardio- and chronic kidney disease in diabetes is weak (149,171). However, these symp- respiratory arrest (159). CAN was the (13,166–168). toms may occur quite late in the disease strongest risk factor for mortality in a course (25,27,147,149). It may be appropri- large cohort of patients with type 1 di- Screening and Diagnosis atetoscreenpatientswithhypoglycemia abetes participating in the EURODIAB unawareness, as this may be associated Recommendations Prospective Cohort Study (160), and a with CAN (81). c Symptoms and signs of autonomic meta-analysis of several trials reported neuropathy should be assessed in In its early stages, CAN may be com- higher mortality risk with worse mea- patients with microvascular and pletely asymptomatic and detected only sures of CAN (152). neuropathic complications. E by decreased heart rate variability (HRV) Conclusive evidence that supports with deep breathing (13,169,170). Test- c In the presence of symptoms or fi CAN as an independent predictor of signs of cardiovascular autonomic ingHRVmaybedoneintheof ce by fi mortality was con rmed in more than neuropathy, tests excluding other either 1) taking an electrocardiogram re- 8,000 participants with type 2 diabetes comorbidities or drug effects/ cording as a patient begins to rise from a in the ACCORD trial (154). Hazard ratios interactions that could mimic car- seated position or 2) taking an electro- – for all-cause and CVD mortality in those diovascular autonomic neuropa- cardiogram recording during 1 2minof with CAN were as high as 2.14 after ad- thy should be performed. E deep breathing with calculation of HRV justing for all traditional CVD risk factors (11,81,170).

Table 5—Symptoms and signs associated with diabetic autonomic neuropathy CAN Gastrointestinal Urogenital Sudomotor Resting tachycardia Gastroparesis (Gastropathy) Bladder dysfunction Dry skin Abnormal blood pressure regulation c Nausea c Frequency c Anhidrosis c Nondipping c Bloating c Urgency c Gustatory c Reverse dipping c Loss of appetite c Nocturia sweating c Early satiety c Hesitancy c Postprandial vomiting c Weak stream c Brittle diabetes c Dribbling c Urinary incontinence c Urinary retention Orthostatic hypotension (all with standing) Esophageal dysfunction Male sexual dysfunction c Light-headedness c Heartburn c Erectile dysfunction c Weakness c Dysphagia for solids c Decreased libido c Faintness c Abnormal ejaculation c Visual impairment c Syncope Orthostatic tachycardia or bradycardia Diabetic diarrhea Female sexual dysfunction and chronotropic incompetence c Profuse and watery diarrhea c Decreased sexual desire (all with standing) c Fecal incontinence c Increasedpainduringintercourse c Light-headedness c May alternate with constipation c Decreased sexual arousal c Weakness c Inadequate lubrication c Faintness c Dizziness c Visual impairment c Syncope Exercise intolerance Constipation c May alternate with explosive diarrhea 146 Position Statement Diabetes Care Volume 40, January 2017

In more advanced cases, patients may or when the diagnosis of CAN is likely, c Consider a multifactorial approach present with resting tachycardia (.100 clinicians may not need to perform addi- targeting glycemia among other bpm) and exercise intolerance (13,170). tional tests given costs and burden. risk factors to prevent cardiovas- Advanced disease may also be associated Exclusion of other comorbidities or cular autonomic neuropathy in with orthostatic hypotension (a fall in sys- drug effects/interactions that may present people with type 2 diabetes. C tolic or diastolic blood pressure by with the symptoms or signs of CAN and c Consider lifestyle modifications to .20 mmHg or .10 mmHg, respectively, that mimic CAN may be needed (81,174) improve cardiovascular autonomic upon standing without an appropriate in- (Table 6). In addition, polypharmacy may neuropathy in patients with predia- crease in heart rate) (172). Orthostatic also directly or indirectly impact CAN. betes. C hypotension is usually easy to document in the office. In most cases of CAN, there Treatment is no compensatory increase in the heart Prevention. Please refer to PREVENTION on As with DSPN, multiple other therapies tar- rate, despite hypotension (173). page 136. geting various pathogenetic mechanisms The diagnosis includes documentation Recommendations have failed to reverse established CAN. of symptoms (Table 5) and signs of CAN, c Optimize glucose control as early CAN treatment is generally focused on alle- which include impaired HRV, higher rest- as possible to prevent or delay the viating symptoms and should be targeted fi ing heart rate, and presence of ortho- development of cardiovascular to the speci c clinical manifestation. static hypotension. In a symptomatic autonomic neuropathy in people Symptomatic Treatment of Orthostatic patient presenting with resting tachycar- with type 1 diabetes. A Hypotension. Treatment for orthostatic dia, with a history of poor glucose control, hypotension is challenging and usually

Table 6—Diagnostic algorithm for CAN Symptoms Signs/diagnostic tests Differential workup Resting tachycardia Palpitations Clinical exam: resting heart c Anemia Could be asymptomatic rate .100 bpm c Hypothyroidism c Fever c CVD (atrial fibrillation, flutter, other) c Dehydration c Adrenal insufficiency c Medications c Sympathomimetic agents (asthma) c Over-the-counter cold agents containing ephedrine or pseudoephedrine c Dietary supplements (e.g., ephedra alkaloids) c Smoking, alcohol, caffeine c Recreational drugs (cocaine, amphetamines, methamphetamine, mephedrone) Orthostatic hypotension Light-headedness Clinical exam: a reduction of .20 mmHg in c Adrenal insufficiency Weakness the systolic blood pressure or .10 mmHg c Intravascular volume depletion Faintness in diastolic blood pressure c Blood loss/acute anemia Visual impairment c Dehydration Syncope c Pregnancy/postpartum c CVD c Arrhythmias c Heart failure c Myocarditis c Pericarditis c Valvular heart disease c Alcohol c Medication c Antiadrenergics c Antianginals c Antiarrhythmics c Anticholinergics c Diuretics c ACE inhibitors/angiotensin receptor blocker c Narcotics c Neuroleptics c Sedatives care.diabetesjournals.org Pop-Busui and Associates 147

involves both pharmacological and non- Screening and Diagnosis gold standard is the measurement of pharmacological interventions. Physical gastric emptying with scintigraphy of di- Recommendations activity and exercise should be encour- gestible solids at 15-min intervals for 4 h c Evaluate for gastroparesis in peo- after food intake; the use of 13C-octanoic aged to avoid deconditioning, which is ple with diabetic neuropathy, ret- acid breath test is emerging as a viable known to exacerbate orthostatic into- inopathy, and/or nephropathy by fl alternative (12,179). Optimization of lerance. Volume repletion with uids assessing for symptoms of unex- glucose levels prior to scanning is and salt is central to the management of pected glycemic variability, early fl needed (182,186–188) to avoid false- orthostatic hypotension. Low-dose u- satiety, bloating, nausea, and fi positive results. drocortisone may be bene cial in sup- vomiting. C plementing volume repletion in some c Exclusion of other causes docu- Treatment patients, although there are growing con- mented to alter gastric emptying, cerns on risk of supine hypertension. such as use of opioids or glucagon- Recommendation As neurogenic orthostatic hypoten- like peptide 1 receptor agonists c Consider short-term metoclopra- sion is in large part a consequence of and organic gastric outlet obstruction, mide in the treatment of diabetic the failure of norepinephrine release is needed before performing special- gastroparesis. E from sympathetic neurons, the adminis- ized testing for gastroparesis. C tration of sympathomimetic medications c To test for gastroparesis, either mea- Treatment for diabetic gastroparesis is central to the care of patients whose sure gastric emptying with scintigra- may be very challenging. Dietary changes symptoms are not controlled with other phy of digestible solids at 15-min may be useful, such as eating multiple measures (173). Midodrine, a peripheral, intervals for 4 h after food intake a 13 small meals and decreasing dietary fat selective, direct 1-adrenoreceptor ago- or use a C-octanoic acid breath and fiber intake. Withdrawing drugs with nist, is an FDA-approved drug for the treat- test. B ment of orthostatic hypotension (175). effects on gastrointestinal motility, such Midodrine should be titrated gradually to as opioids, anticholinergics, tricyclic efficacy. It should be used only when pa- Gastroparesis may manifest with a antidepressants, glucagon-like peptide tients intend to be upright or seated to broad spectrum of symptoms and signs 1 receptor agonists, pramlintide, and minimize supine hypertension (173). Re- (12,177,179,181). As part of a medical possibly dipeptidyl peptidase 4 inhibi- cently, droxidopa was approved by the history, providers are encouraged to tors, may also improve intestinal motility FDA for the treatment of neurogenic or- document symptoms of gastroparesis, (180,191). In cases of severe gastropare- thostatic hypotension but not specifically such as early satiety, fullness, bloating, sis, pharmacological interventions are for patients with orthostatic hypotension nausea, vomiting, dyspepsia, and ab- needed. Only metoclopramide, a proki- due to diabetes (176). dominal pain. However, gastroparesis netic agent, is approved by the FDA for may be clinically silent in the majority the treatment of gastroparesis. How- of cases, and symptoms do not neces- ever, the level of evidence regarding Gastrointestinal Neuropathies fi sarily correspond with severity of gas- the bene ts of metoclopramide for the Gastrointestinal neuropathies may involve troparesis and are poorly associated management of gastroparesis is weak, any portion of the gastrointestinal tract with abnormal gastric emptying (184,185). and given the risk for serious adverse with manifestations including esophageal effects (extrapyramidal symptoms, such Symptoms such as anorexia, nausea, dysmotility, gastroparesis (delayed gastric as acute dystonic reactions; drug- vomiting, and dyspepsia are nonspecific emptying), constipation, diarrhea, and fe- induced parkinsonism; akathisia; and and resemble many other conditions cal incontinence. The prevalence data on tardive dyskinesia), its use in the treat- (186) and may just be associated with gastroparesis are limited, as most reports ment of gastroparesis beyond 5 days is the presence of diabetes (181). Impor- were from selected case series rather than no longer recommended by the FDA and larger populations, and there was inconsis- tantly, hyperglycemia, hypoglycemia, the European Medicines Agency. It tency in the outcome measures used and acute changes in blood glucose are should be reserved for severe cases (177). In the only community-based study, welldocumentedtoaltergastricemptying that are unresponsive to other therapies the cumulative incidence of gastroparesis (182,187,188), as are some medications, (191). over 10 years was higher in type 1 diabetes especially opioids, other pain manage- (5%) than in type 2 diabetes (1%) and in ment agents, and glucagon-like pep- Urogenital Neuropathies control subjects (1%) (178). tide 1 receptor agonists (189,190). Diabetic autonomic neuropathy may Gastroparesis may directly affect gly- Therefore, all these factors known to also cause genitourinary disturbances, cemic management (e.g., insulin dose or affect gastric emptying should always including sexual dysfunction and blad- other antidiabetes agents) and may be a be considered before a firm diagnosis is der dysfunction. In men, diabetic auto- cause of glucose variability and unex- established. nomic neuropathy may cause erectile plained hypoglycemia due to the disso- Exclusion of organic causes of gastric dysfunction (ED) and/or retrograde ciation between food absorption and outlet obstruction or peptic ulcer dis- ejaculation. ED is three times more com- the pharmacokinetic profiles of insulin ease (with esophagogastroduodenoscopy mon in men with diabetes than those and other agents (12,179–182). Gastro- or a barium study of the stomach) is without the disease (192–194). Sexual paresis is mainly found in patients with needed before considering specialized dysfunctionisalsomorecommonin long-standing diabetes (183). testing for gastroparesis. The diagnostic women with diabetes (195–199). 148 Position Statement Diabetes Care Volume 40, January 2017

urination urgency, weak urinary stream) of nerve entrapment. Nerve entrap- Recommendations and is linked to the presence of diabetic ments may require surgical decompres- c Consider screening men with other neuropathy in both men and women sion. The improvement in symptom forms of diabetic neuropathy annu- (12,206). Female sexual dysfunction oc- severity and functional status score is ally for erectile dysfunction with sim- curs more frequently in women with di- no different between patients with ple questions about a patient’s libido abetes than in those without diabetes and without diabetes (213). and ability to reach and maintain an (196,207) and presents as decreased erection. C sexual desire, increased pain during in- Diabetic Radiculoplexus Neuropathy c Consider screening patients with Diabetic radiculoplexus neuropathy, tercourse, decreased sexual arousal, other forms of diabetic neuropathy a.k.a. diabetic amyotrophy or diabetic and inadequate lubrication. for lower urinary tract symptoms polyradiculoneuropathy, typically involves Evaluation of bladder function should and female sexual dysfunction in the lumbosacral plexus (214–216). The be performed for individuals with diabe- the presence of recurrent urinary complication occurs mostly in men with tes who have recurrent urinary tract in- tract infections using targeted ques- type 2 diabetes. People with the condi- fections, pyelonephritis, incontinence, tioning regarding symptoms, such tion routinely present with extreme uni- or a palpable bladder. The medical his- as nocturia, pain during intercourse, lateral thigh pain and weight loss, tory should include simple questions to and others. E followed by motor weakness. Electro- unveil symptoms of lower urinary tract physiological assessment is required to symptoms and female sexual dysfunc- ED document the extent of disease and tion (196,207,208). ED may be a consequence of autonomic alternative etiologies, including degen- neuropathy, as autonomic neurotrans- Sudomotor Dysfunction erative disc disease or neoplastic, infec- mission controls the cavernosal and de- Sudomotor dysfunction may manifest as tious, and inflammatory spinal disease trusor smooth muscle tone and function dry skin, anhidrosis, or heat intolerance (215,216). The disorder is usually self- (200). The etiology, however, is multi- (209,210). A rare form of sudomotor limiting, and patients improve over factorial, and clinicians should also eval- dysfunction is gustatory sweating that time with medical management and uate other vascular risk factors such as comprises excessive sweating limited physical therapy (214,215). There is hypertension, hyperlipidemia, obesity, exclusively to the head and neck region presently no evidence from randomized endothelial dysfunction, smoking, CVD, triggered by food consumption or, in trials to support any recommendation concomitant medication, and psycho- some cases, the smell of food. Originally on the use of any immunotherapy treat- genic factors (12). There is evidence of described as being solely due to auto- ment in this condition (217). associations between ED and other di- nomic neuropathy, gustatory sweating Treatment-Induced Neuropathy abetes complications, including CAN is also described in patients with dia- – Treatment-induced neuropathy in diabe- (201 203). betic nephropathy on dialysis (211). A diagnosis should be made after es- tes (also referred to as insulin neuritis) is Onthebasisoftheavailableevi- fi tablishing the signs and symptoms of ED considered a rare iatrogenic small- ber dence, the routine screening for sudo- neuropathy caused by an abrupt im- and after excluding alternate causes. Cli- motor dysfunction in clinical practice nicians should consider performing hor- provement in glycemic control in the set- is not recommended at this time. The ting of chronic hyperglycemia, especially monal evaluation (luteinizing hormone, fi ef cacy of the topical antimuscarinic in patients with very poor glucose control testosterone, free testosterone, pro- agent glycopyrrolate in the treatment (218). The prevalence and risk factors of lactin) to rule out hypogonadism. In fi of gustatory sweating was con rmed this disorder are not known but are cur- addition, a variety of medications and in a randomized controlled trial, and rently under study. organic causes should be excluded (12). daily application attenuates this compli- Glucose control was associated with a cation in most patients for at least 24 h NEUROPATHY END POINTS FOR lower incidence of erectile dysfunction (212). RESEARCH AND CLINICAL TRIALS in men with type 1 diabetes (204,205). There are currently no approved disease- Evidence is less strong for type 2 diabe- ATYPICAL NEUROPATHIES modifying therapies for DSPN, CAN, or tes. Control of other risk factors such as Mononeuropathies other forms of diabetic neuropathy, hypertension and hyperlipidemia may Mononeuropathies occur more com- and multiple clinical trials for these also improve the condition (12). Pharma- monly in patients with diabetes than conditions have failed. Important con- cological treatment includes phosphodi- in those without diabetes (1) and can tributing factors include a lack of agree- fi esterase type 5 inhibitors as rst-line occur as a result of involvement of the ment and uniformity in the use of the therapy and transurethral prostaglan- median, ulnar, radial, and common pe- most sensitive DSPN measures that cap- dins, intracavernosal injections, vacuum roneal nerves (213). Cranial neuropa- ture the natural history of the disease devices, and penile prosthesis in more thies present acutely and are rare; and detect repair in the specific nerve advanced cases. primarily involve cranial nerves III, IV, fiber populations, as well as the inclusion Lower Urinary Tract Symptoms and Female VI, and VII; and usually resolve sponta- of appropriate patient populations. Sexual Dysfunction neously over several months (213). Thus, a valid and careful diagnosis for Lower urinary tract symptoms manifest Electrophysiological studies are most DSPN in clinical research is critical for as urinary incontinence and bladder dys- helpful in identifying nerve conduction correctly identifying the appropriate function (nocturia, frequent urination, slowing or conduction block at the site patient population targeted for either a care.diabetesjournals.org Pop-Busui and Associates 149

specific intervention or for prognostic 5. Smith AG, Singleton JR. Diabetic neuropathy. 18. Diabetes Control and Complications Re- implications. Continuum (Minneap Minn) 2012;18:60–84 search Group Effect of intensive diabetes treat- The use of validated clinical instru- 6. Singleton JR, Smith AG, Bromberg MB. ment on nerve conduction in the Diabetes Increased prevalence of impaired glucose toler- Control and Complications Trial. Ann Neurol ments such as the Michigan Neuropathy ance in patients with painful sensory neuropa- 1995;38:869–880 Screening Instrument (MNSI) (most thy. Diabetes Care 2001;24:1448–1453 19. Linn T, Ortac K, Laube H, Federlin K. Inten- widely used in large cohorts of pa- 7. Asghar O, Petropoulos IN, Alam U, et al. Cor- sive therapy in adult insulin-dependent diabe- tients with type 1 and type 2 diabetes) neal confocal microscopy detects neuropathy in tes mellitus is associated with improved insulin (21,26,27,46,74,75), the modified Tor- subjects with impaired glucose tolerance. Dia- sensitivity and reserve: a randomized, con- betes Care 2014;37:2643–2646 trolled, prospective study over 5 years in onto Clinical Neuropathy Scale (mTCNS) 8. Bongaerts BW, Rathmann W, Heier M, et al. newly diagnosed patients. Metabolism 1996; (73), the Utah Early Neuropathy Scale Older subjects with diabetes and prediabetes 45:1508–1513 (UENS) (77), or the Neuropathy Disabil- are frequently unaware of having distal senso- 20. Callaghan BC, Cheng HT, Stables CL, Smith ity Score (NDS) (44) are recommended. rimotor polyneuropathy: the KORA F4 study. AL, Feldman EL. Diabetic neuropathy: clinical – These may be combined with electro- Diabetes Care 2013;36:1141 1146 manifestations and current treatments. Lancet 9. Im S, Kim SR, Park JH, Kim YS, Park GY. As- Neurol 2012;11:521–534 physiology; measures of small-fiber sessment of the medial dorsal cutaneous, dorsal 21. Ismail-Beigi F, Craven T, Banerji MA, et al.; damage and repair, such as intraepider- sural, and medial plantar nerves in impaired ACCORD trial group. Effect of intensive treat- mal nerve fiber density (219–221) or glucose tolerance and diabetic patients with ment of hyperglycaemia on microvascular out- corneal confocal microscopy (222); and normal sural and superficial peroneal nerve re- comes in type 2 diabetes: an analysis of the – objective measures of patient function sponses. Diabetes Care 2012;35:834 839 ACCORD randomised trial. Lancet 2010;376: 10. Ziegler D, Rathmann W, Dickhaus T, 419–430 in the design of DSPN trials. Meisinger C, Mielck A; KORA Study Group. Prev- 22. Ohkubo Y, Kishikawa H, Araki E, et al. Inten- The recommended CAN measures for alence of polyneuropathy in pre-diabetes and sive insulin therapy prevents the progression of clinical trials targeting either a specific diabetes is associated with abdominal obesity diabetic microvascular complications in Japa- intervention or for prognostic implica- and macroangiopathy: the MONICA/KORA nese patients with non-insulin-dependent dia- Augsburg Surveys S2 and S3. Diabetes Care tions include 1) standardized cardiovas- betes mellitus: a randomized prospective 6-year 2008;31:464–469 study. Diabetes Res Clin Pract 1995;28:103–117 cular autonomic reflex tests that are 11. Bernardi L, Spallone V, Stevens M, et al.; 23. Charles M, Ejskjaer N, Witte DR, Borch- simple, sensitive, specific, reproducible, Toronto Consensus Panel on Diabetic Neuropa- Johnsen K, Lauritzen T, Sandbaek A. Prevalence and assess the changes in the R-R inter- thy. Investigation methods for cardiac auto- of neuropathy and peripheral arterial disease val on electrocardiogram recordings in nomic function in human research studies. and the impact of treatment in people with Diabetes Metab Res Rev 2011;27:639–653 response to simple clinical maneuvers screen-detected type 2 diabetes: the ADDITION- 12. Kempler P, Amarenco G, Freeman R, et al.; Denmark study. Diabetes Care 2011;34:2244– (deep breathing, Valsalva, and standing) Toronto Consensus Panel on Diabetic Neuropa- 2249 (13,81,191,223); 2) indices of HRV (see thy. Gastrointestinal autonomic neuropathy, 24. Charles M, Fleischer J, Witte DR, et al. above) (11,151,169); and 3)resting erectile-, bladder- and sudomotor dysfunction Impact of early detection and treatment of heart rate and QTc (154,156,157). 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Sudoscan, a noninvasive 154 Position Statement Diabetes Care Volume 40, January 2017

tool for detecting diabetic small fiber neuropa- 216. Laughlin RS, Dyck PJ. Electrodiagnostic diagnosis of small fiber neuropathy. Report of a thy and autonomic dysfunction. Diabetes Tech- testing in lumbosacral plexopathies. Phys Med joint task force of the European Federation of nol Ther 2013;15:948–953 Rehabil Clin N Am 2013;24:93–105 Neurological Societies and the Peripheral Nerve 211. Shaw JE, Parker R, Hollis S, Gokal R, 217. Chan YC, Lo YL, Chan ES. Immunotherapy Society. Eur J Neurol 2010;17:903–912,e944– Boulton AJ. Gustatory sweating in diabetes mel- for diabetic amyotrophy. Cochrane Database e909 litus. Diabet Med 1996;13:1033–1037 Syst Rev 2012;6:CD006521 222. Chen X, Graham J, Dabbah MA, et al. 212. Shaw JE, Abbott CA, Tindle K, Hollis S, Boulton 218. Gibbons CH, Freeman R. Treatment-induced Small nerve fiber quantification in the diagno- AJ. A randomised controlled trial of topical glyco- neuropathy of diabetes: an acute, iatrogenic com- sis of diabetic sensorimotor polyneuropathy: pyrrolate, the first specific treatment for diabetic plication of diabetes. Brain 2015;138:43–52 comparing corneal confocal microscopy with gustatory sweating. Diabetologia 1997;40:299–301 219. Lauria G, Bakkers M, Schmitz C, et al. Intra- intraepidermal nerve fiber density. Diabetes 213. Smith BE. Focal and entrapment neuropa- epidermal nerve fiber density at the distal leg: a Care 2015;38:1138–1144 thies. Handb Clin Neurol 2014;126:31–43 worldwide normative reference study. J Pe- 223. Low PA, Denq JC, Opfer-Gehrking TL, 214. Dyck PJ, Windebank AJ. Diabetic and non- ripher Nerv Syst 2010;15:202–207 Dyck PJ, O’Brien PC, Slezak JM. Effect of age and diabetic lumbosacral radiculoplexus neuropa- 220. Lauria G, Devigili G. Skin biopsy as a diag- gender on sudomotor and cardiovagal func- thies: new insights into pathophysiology and nostic tool in peripheral neuropathy. Nat Clin tion and blood pressure response to tilt in treatment. Muscle Nerve 2002;25:477–491 Pract Neurol 2007;3:546–557 normal subjects. Muscle Nerve 1997;20:1561– 215. Massie R, Mauermann ML, Staff NP, et al. 221. Lauria G, Hsieh ST, Johansson O, et al.; Eu- 1568 Diabetic cervical radiculoplexus neuropathy: a ropean Federation of Neurological Societies; 224. Pop-Busui R. What do we know and we do distinct syndrome expanding the spectrum of Peripheral Nerve Society. European Federation not know about cardiovascular autonomic neu- diabetic radiculoplexus neuropathies. Brain of Neurological Societies/Peripheral Nerve Soci- ropathy in diabetes. J Cardiovasc Transl Res 2012;135:3074–3088 ety guideline on the use of skin biopsy in the 2012;5:463–478