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Reviews/Commentaries/ADA Statements REVIEW ARTICLE

Diabetic Neuropathies: Update on Definitions, Diagnostic Criteria, Estimation of Severity, and Treatments

1 2 SOLOMON TESFAYE, MD, FRCP RAYAZ A. MALIK, MD important risk covariate (5,7). This vari- 2 8 ANDREW J.M. BOULTON, MD VINCENZA SPALLONE, MD, PHD ety has been shown to be stabilized, per- 3 9 PETER J. DYCK, MD AARON VINIK, MD, PHD 4 10 haps even improved, by rigorous ROY FREEMAN, MD LUCIANO BERNARDI, MD 5 11 glycemic control. This MICHAEL HOROWITZ, MD, PHD PAUL VALENSI, MD 6 has been shown to be statistically associ- PETER KEMPLER, MD, PHD ON BEHALF OF THE TORONTO DIABETIC 7 ated with retinopathy and nephropathy GIUSEPPE LAURIA, MD NEUROPATHY EXPERT GROUP* (1,6). Autonomic dysfunction and neuro- pathic may develop over time. The atypical DPNs are different from Preceding the joint meeting of the 19th annual Diabetic Neuropathy Study Group of the Euro- DSPN in several important features, i.e., pean Association for the Study of (NEURODIAB) and the 8th International Symposium onset, course, manifestations, associa- on Diabetic Neuropathy in Toronto, Canada, 13–18 October 2009, expert panels were convened tions, and perhaps putative mechanisms to provide updates on classification, definitions, diagnostic criteria, and treatments of diabetic peripheral neuropathies (DPNs), , painful DPNs, and structural alter- (3,4,9). They appear to be intercurrent ations in DPNs. varieties, developing at any time during the course of a patient’s diabetes (3,9). Diabetes Care 33:2285–2293, 2010 Onset of symptoms may be acute, sub- acute, or chronic, but the course is usually CLASSIFICATION AND ies can be further classified into at least monophasic or fluctuating over time. Pain DEFINITION OF DIABETIC two major subgroups seems compelling and autonomic symptoms are typical fea- NEUROPATHIES — The neuropa- (3,4). The typical DPN is a chronic, sym- tures (3,9) and altered immunity has been thies developing in patients with diabetes metrical, length-dependent sensorimotor suggested. Studies have suggested that are known to be heterogenous by their polyneuropathy (DSPN) and is thought to impaired fasting or impaired glu- symptoms, pattern of neurologic involve- be the most common variety (1). It devel- cose tolerance (IGT) is more common in ment, course, risk covariates, pathologic ops on (or with) a background of long- chronic idiopathic axonal polyneurop- alterations, and underlying mechanisms standing , associated athy, but other studies do not support this (1,2). Thomas (3) and Boulton et al. (4) metabolic derangements (increased view (3,10). separated these into generalized and fo- polyol flux, accumulation of advanced cal/multifocal varieties (e.g., multiple glycation end products, oxidative stress, Diabetic sensorimotor polyneuropathy mononeuropathy, lumbosacral, thoracic, and lipid alterations among other meta- Case definition. The 1988 San Antonio and cervical radiculoplexus neuropa- bolic abnormalities) and cardiovascular Conference on Diabetic Neuropathy (11), thies) (3,4). It is known that similar pat- risk factors (5–7). Alterations of mi- Boulton et al. (4), and the American Acad- terns of neuropathy occur in patients crovessels, similar to those observed in di- emy of Neurology (AAN), American As- without diabetes (2). Moreover, diabetic abetic retinopathy and nephropathy, sociation of Electrodiagnostic Medicine patients can develop chronic inflamma- appear to be associated with the patho- (AAEM), and American Academy of Phys- tory demyelinating polyradiculopathy. logic alterations of (8). Total hy- ical Medicine and Rehabilitation The evidence that generalized variet- perglycemic exposure is perhaps the most (AAPM&R) (12) have proposed criteria ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● for diabetic neuropathies. From the 1Diabetes Research Unit, Sheffield Teaching Hospitals, Sheffield, U.K.; the 2Department of Med- We propose separate definitions for icine, University of Manchester, Manchester, U.K.; the 3Department of Neurology, Mayo Clinic, Rochester typical DPN (DSPN) and atypical DPNs. Minnesota; the 4Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; DSPN is a symmetrical, length-dependent 5 6 the Department of Medicine, University of Adelaide, Adelaide, Australia; the I Department of Medicine, sensorimotor polyneuropathy attributable Semmelweis University, Budapest, Hungary; the 7Neuromuscular Unit, Istituto Di Ricovero e Cura a Carattere Scientifico Foundation, “Carlo Besta” Neurological Institute, Milan, Italy; the 8Depart- to metabolic and microvessel alterations ment of Internal Medicine, University of Tor Vergata, Rome, Italy; the 9Strelitz Diabetes Research Insti- as a result of chronic hyperglycemia ex- tutes, Eastern Virginia Medical School, Norfolk, Virginia; the 10Clinica Medica 1, Universita’ di Pavia, posure (diabetes) and cardiovascular risk Pavia, Italy; and the 11Service d’Endocrinologie-Diabe´tologie-Nutrition, Hoˆpital Jean Verdier, Assistance covariates. An abnormality of con- Publique-Hoˆpitaux de Paris, Universite´ Paris Nord, Center for Research in Human Nutrition, Ile-de- duction tests, which is frequently subclin- France, Bondy, France. Corresponding author: Solomon Tesfaye, [email protected]. ical, appears to be the first objective Received 8 July 2010 and accepted 20 July 2010. quantitative indication of the condition. *A complete list of the members of the Toronto Diabetic Neuropathy Expert Group is provided in The occurrences of APPENDIX. and nephropathy in a given patient DOI: 10.2337/dc10-1303 © 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly strengthen the case that the polyneurop- cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. athy is attributable to diabetes. Other org/licenses/by-nc-nd/3.0/ for details. causes of sensorimotor polyneuropathy care.diabetesjournals.org DIABETES CARE, VOLUME 33, NUMBER 10, OCTOBER 2010 2285 Update on diabetic neuropathies need to be excluded. For epidemiologic Definitions of minimal criteria for in the peripheral somatosensory system in surveys or controlled clinical trials of typical DPN people with diabetes.” The prevalence of DSPN, we advocate the use of nerve con- 1. Possible DSPN. The presence of NP in the diabetic population is difficult duction (NC) testing as an early and reli- symptoms or signs of DSPN may include to estimate as definitions have varied able indicator of the occurrence of this the following: symptoms–decreased sen- enormously among studies; however, it is neuropathy. To be reliable the test must sation, positive neuropathic sensory crudely estimated that between 3 and be done rigorously using appropriate ref- symptoms (e.g., “asleep numbness,” 25% of patients might experience NP erence values corrected for applicable prickling or stabbing, burning or aching (17). Similarly, there are limited data on variables. Volunteered or elicited symp- pain) predominantly in the toes, feet, or the natural history of painful DPN with toms and signs and other clinical neuro- legs; or signs–symmetric decrease of dis- some studies suggesting that painful physiologic abnormalities are also needed tal sensation or unequivocally decreased symptoms improve with the worsening of to characterize the symptoms, signs, and or absent ankle reflexes. the sensory loss and others reporting no overall severity of the polyneuropathy. 2. Probable DSPN. The presence of a appreciable occurrence of remissions Recent studies emphasize the importance combination of symptoms and signs of (17). of the proficiency of the clinical neuro- neuropathy include any two or more of In practice, the diagnosis of painful logic assessment (13,14). Atypical DPNs the following: neuropathic symptoms, DPN is a clinical one, which relies on the have been less well characterized and decreased distal sensation, or unequivo- patient’s description of pain. The symp- cally decreased or absent ankle reflexes. toms are distal, symmetrical, often associ- studied. 3. Confirmed DSPN. The presence of an ated with nocturnal exacerbations, and Estimating severity. Estimating the se- abnormality of NC and a symptom or commonly described as prickling, deep verity of DSPN has not received the atten- symptoms or a sign or signs of neuropa- aching, sharp, like an electric shock, and tion it deserves. For a given patient with thy confirm DSPN. If NC is normal, a val- burning (13) with hyperalgesia and fre- diabetes, it is not sufficient to simply idated measure of small fiber neuropathy quently allodynia upon examination (17). identify patients as having or not having (SFN) (with class 1 evidence) may be The symptoms are usually associated with DSPN—severity also needs to be ascer- used. the clinical signs of peripheral neuropa- tained. We suggest a reliable objective To assess for the severity of DSPN, thy, although occasionally in acute pain- and quantitative measure (i.e., NC abnor- several approaches can be recommended: ful DPN, the symptoms may occur in the mality) as the minimal criteria for the di- the graded approach outlined above, var- absence of signs. A number of simple nu- agnosis of DSPN. When NC values have ious continuous measures of sum scores meric rating scales can be used to assess not been assessed, it is not possible to pro- of neurologic signs, symptoms or nerve the frequency and severity of painful vide a confirmed diagnosis of DSPN— test scores, scores of function of acts of symptoms (18), and other causes of NP only a possible or probable diagnosis. daily living or of predetermined tasks or must be excluded. The severity of pain Since the severity of DSPN is a combina- of disability. Irrespective of which ap- can be reliably assessed by the visual an- tion of neuropathy symptoms, signs, neu- proach is used, it is necessary to ensure alog scale, which is the oldest and best rophysiologic test abnormalities, and good performance of evaluations with validated measure, or the numerical rat- other dysfunctions and impairments, the monitoring proficiency. ing scale, e.g., the 11-point Likert scale sum scores of various measures of neuro- 4. Subclinical DSPN. The presence of (0 ϭ no pain, 10 ϭ worst possible pain), logic signs, symptoms, neurophysiologic no signs or symptoms of neuropathy are which has been most widely used in neu- test abnormalities, or scores of function of confirmed with abnormal NCs or a vali- ropathic pain studies. A number of vali- activities of daily living may provide an dated measure of SFN (with class 1 dated scales and questionnaires including indication of the severity (13). evidence). the Symptoms Inven- An alternative approach to estimating We recommend that definitions 1, 2, tory, Brief Pain Inventory, Neuropathic severity is to indicate severity by grades. or 3 be used for clinical practice and def- Pain Questionnaire, and McGill Pain Dyck (15) described the stages of severity: initions 3 or 4 be used for research Questionnaire, may be used (18). Quality no abnormality of NC, e.g., studies. of life (QoL) improvement should also be ؍ Grade 0 ● ⌺ 5 NC normal deviates Ͻ95th percen- assessed, preferably using a validated tile or another suitable NC criterion Atypical DPNs neuropathy-specific scale such as Neuro- Before further classification of these poly- Qol or the Norfolk Quality of Life Scale abnormality of NC, e.g., ⌺ ؍ Grade 1a ● neuropathies, setting the minimal criteria (19). Outcomes must be measured using 5 NC normal deviates Ն95th percentile for diagnosis and estimating severity and patient-reported improvement in scales without symptoms or signs further characterizing of epidemiologic for pain and QoL as measured on vali- ؍ ● Grade 1b NC abnormality of stage 1a and mechanistic studies are needed. The dated instruments. External observers plus neurologic signs typical of DSPN issue of painful, autonomic, and nerve can play no part in the assessment of the but without neuropathy symptoms morphologic abnormalities are discussed subjects’ responses to new therapies for -NC abnormality of stage 1a in subsequent sections. NP; thus, measures such as the “physi ؍ Grade 2a ● with or without signs (but if present, cian’s global impression of response” are Ͻ2b) and with typical neuropathic PAINFUL DPN — A definition of pe- not valid. symptoms ripheral neuropathic pain (NP) in diabe- For clinical trials of putative new -NC abnormality of stage tes, adapted from a definition recently therapies for painful DPN, rigorous pa ؍ Grade 2b ● 1a, a moderate degree of weakness (i.e., proposed by the International Association tient selection with the use of NP scales 50%) of ankle dorsiflexion with or for the Study of Pain (16), is “pain arising and outcome measures are indicated. In- without neuropathy symptoms. as a direct consequence of abnormalities clusion criteria for such trials would nor-

2286 DIABETES CARE, VOLUME 33, NUMBER 10, OCTOBER 2010 care.diabetesjournals.org Tesfaye and Associates mally include NP associated with DPN for the autonomic in the set- function are based on the time-domain Ͼ6 months duration, mean weekly pain ting of diabetes or metabolic derange- rate (HR) response to deep breath- score of between 4 and 10 on an 11-point ments of pre-diabetes after the exclusion ing, a Valsalva maneuver, and postural numerical rating scale, exclusion of pain of other causes. DAN may affect cardio- change. Of these tests, HR to deep breath- not associated with DPN, mononeuropa- vascular, gastrointestinal (GI), and uro- ing has the greatest specificity (ϳ80%). thies or proximal neuropathies, non- genital systems, and sudomotor function. Cardiovascular sympathetic function is neuropathic chronic pain, and central It may result in signs and symptoms or assessed by measuring the BP response to pain. may be subclinically detectable by spe- orthostatic change and a Valsalva maneu- Pharmacological management of cific tests. ver. The performance of these tests should painful DPN almost exclusively consists be standardized, and the influence of con- of symptomatic therapies (those that im- Cardiovascular autonomic founding variables such as , prove symptoms of painful DPN without neuropathy hydration, and antecedent activity should an effect on underlying causes or natural Epidemiology. Cardiovascular auto- be minimized. Age normative values history) (20). The antioxidant ␣-lipoic nomic neuropathy (CAN) is defined as should be used. The combination of car- acid administered intravenously is the the impairment of autonomic control of diovascular autonomic tests with sudo- only pathogenetic treatment that has effi- the cardiovascular system. The preva- motor function tests may allow a more cacy confirmed from several randomized lence of CAN varies widely from 2.5 to accurate diagnosis of DAN (36). controlled trials and confirmation in a 50%. Factors that influence the preva- Diabetic patients with features of car- meta-analysis (level A evidence [12]) lence of CAN include the diagnostic cri- diac autonomic dysfunction such as un- (21). Although spinal cord stimulation teria used, patient age, and the duration of explained tachycardia, orthostatic might be useful in refractory painful DPN diabetes (29,30). Additional clinical cor- hypotension, and poor exercise tolerance, (22), insufficient evidence exists for any relates and predictors of CAN include or with other symptoms of autonomic nonpharmacological therapies. glycemic control, presence of DPN, ne- dysfunction should be evaluated for the Level A evidence exists to support the phropathy and retinopathy, blood pres- presence of CAN. Screening for CAN use of tricyclic (e.g., am- sure (BP) levels, obesity, smoking, and should be performed at the diagnosis itriptyline), the gabapen- cholesterol and triglycerides levels of and 5 years after tin and , and the serotonin and (30,31). Intervention studies have docu- the diagnosis of , particu- norepinephrine reuptake inhibitor dulox- mented the protective effect of glycemic larly in patients at greater risk of CAN due etine (20,23–26). There is also random- control in type 1 diabetes (32) and a mul- to a history of poor glycemic control, ized controlled trial (RCT) evidence for tifactorial strategy aimed at lifestyle cardiovascular risk factors, DPN, and the use of opiates such as and change with pharmacological correction macro- and microangiopathic diabetic in painful DPN (20,23). There is of hyperglycemia, , dyslipi- complications. no evidence available to support the use demia, and microalbuminuria (33). Diagnostic criteria and staging of of the (27). Preliminary ev- CAN is significantly associated with CAN are still being debated. We suggest idence shows promise for topical treat- overall mortality (34) and in some—but that the presence of one abnormal cardio- ment using a 5% lignocaine plaster not all—studies with morbidity such as vagal test identifies possible or early CAN applied to the most painful area (28), silent myocardial ischemia, coronary ar- (29); at least two abnormal HR tests are although larger RCTs are required. First- tery , stroke, required for a definite or confirmed diag- line therapies for painful DPN are a tricy- progression, and perioperative morbid- nosis of CAN (30); and orthostatic hypo- clic , , ity. Some pathogenetic mechanisms may tension (asymptomatic or symptomatic), pregabalin, or , taking into ac- link CAN to cardiovascular dysfunction in addition to HR test abnormalities, iden- count patient comorbidities and cost and diabetic complications (34). Thus, tify a condition of severe or advanced (20,23). Combinations of first-line thera- CAN assessment may be used for cardio- CAN (31). Progressive stages of CAN are pies may be considered if there is pain, vascular risk stratification in patients with associated with an increasingly worse despite a change in first-line mono- and without established cardiovascular prognosis (34). therapy (20,23). If pain is still inade- disease; as a marker for patients requiring Assessment of potential consequences quately controlled, opiods such as more intensive monitoring during the of CAN. Attenuation (nondipping) or tramadol and oxycodone may be added in perioperative period and other physiolog- loss of BP nocturnal fall (reverse dipping) a combination treatment (20,23). A num- ical stresses; and as an indicator for more on ambulatory BP monitoring have been ber of areas relating to painful DPN war- intensive pharmacotherapeutic and life- associated with CAN and attributed to the rant further investigation including style management of comorbid disruption of the circadian variation in population-based prevalence and natural conditions. sympathovagal activity (37). In diabetic history studies, trials using active com- CAN assessment. Cardiovascular reflex patients, nondipping or reverse dipping parators rather than , assessment tests are the gold standard in clinical au- are independent predictors of cardiovas- of combination therapies in addition to tonomic testing. These tests have good cular events and the progression of dia- placebo, and longer-term studies of the sensitivity, specificity, and reproducibil- betic nephropathy. Ambulatory BP efficacy and durability of treatments of ity and are noninvasive, safe, well- monitoring may be useful in patients with painful DPN (23). standardized, and easily performed (35). CAN to detect nondipping and to address However, a Valsalva maneuver must not 24-h BP control (Table 1). DIABETIC AUTONOMIC be performed in patients with prolifera- QT prolongation is an independent NEUROPATHY — Diabetic auto- tive retinopathy. The most widely used predictor of mortality in diabetic patients nomic neuropathy (DAN) is a disorder of tests assessing cardiac parasympathetic and is weakly associated with CAN (38) care.diabetesjournals.org DIABETES CARE, VOLUME 33, NUMBER 10, OCTOBER 2010 2287 Update on diabetic neuropathies

Table 1—Cardiovascular autonomic tests and suggested indications for their use

Clinical diagnosis Research End point in clinical trials HR cardiovascular tests Yes Yes Yes test Yes Yes No (low sensitivity) QT interval Yes (additional information and risk Yes No (low sensitivity) stratification) ABPM for dipping status Yes (risk stratification) Yes No (low sensitivity) HRV time- and frequency- Yes (early additional information Yes Yes domain indices and risk stratification) BRS measures No (offers early additional Yes Yes information and risk stratification but low availability) Scintigraphic studies No (low availability and limited Yes Yes standardization) MNSA No (low availability and limited Yes Possible (used in lifestyle intervention data in CAN) trials in obesity) Catecholamine assessment No (low availability) Yes Possible (used in lifestyle intervention trials in obesity) ABPM, ambulatory BP monitoring; HRV, ; MNSA, muscle sympathetic nerve activity.

(Table 1). The pathogenesis of QT pro- muscle. The technique is invasive and longitudinal studies to clarify the natural longation is multifactorial and correlates time-consuming. Whole-body sympa- history of CAN in diabetes and pre- include female sex, nephropathy, coro- thetic activity is most accurately assessed diabetes, to evaluate the impact of phar- nary heart disease, glycemic control, sys- by measurements of plasma concentra- macologic and lifestyle interventions tolic BP, physical activity, and BMI. tions of noradrenaline and adrenaline. targeting CAN, and to determine the ef- CAN testing for clinical trials and re- Assessment of cardiac vagal barore- fect of CAN on clinical outcomes; 2) the search. The time-domain HR tests and flex sensitivity (BRS) combines informa- refinement and standardization of re- the BP response to postural change have tion derived from both HR and BP in search measures to permit more wide- the reproducibility necessary for clinical response to pharmacological or spontane- spread use; and 3) the need for studies of trials. These tests were used as end points ous BP perturbations. Cardiac vagal BRS combined cardiovascular autonomic and in the Diabetes Control and Complica- is a well-established prognostic index in other autonomic measures to improve di- tions Trial/Epidemiology of Diabetes In- the general and diabetic populations (39) agnosis and outcome assessment. terventions and Complications Study and is frequently used in research studies (DCCT/EDIC) and other clinical trials. (Table 1). Cardiac sympathetic BRS can GI autonomic neuropathy Frequency-domain indexes obtained be measured with simultaneous record- GI motor, sensory, and secretory func- by applying spectral analysis to HR vari- ings of muscle sympathetic nerve activity. tions are modulated by the interaction of ability of short (5–7 min) and longer Scintigraphic studies with radio la- the autonomic (sympathetic and para- (24-h) electrocardiogram recordings pro- beled noradrenaline analogues allow sympathetic) and enteric nervous systems vide a measure of sympathetic and para- a direct semi-quantitative ([123I]- with underlying rhythmicity generated by sympathetic modulation of HR. HR the interstitial cells of Cajal located within metaiodobenzylguanidine [MIBG] and spectral power in the high-frequency re- the smooth muscle. Evaluation of GI au- single photon emission computed tomog- gion is a measure of parasympathetic tonomic function is difficult in humans, raphy) and quantitative assessment modulation, while spectral power in the 11 and the diagnosis of GI autonomic neu- low-frequency region provides a measure ([ C]-hydroxyephedrine [HED] and ropathy is often one of exclusion. While of both sympathetic and parasympathetic positron emission tomography) of cardiac irreversible autonomic neuropathy has modulation. The low-frequency BP vari- sympathetic integrity. Scintigraphic ab- been regarded as the cause of disordered ability may provide a measure of sympa- normalities are associated with CAN but gut motility in diabetes, recent evidence thetic modulation. To correctly assess the may also be present in patients with nor- indicates a heterogeneous picture with a significance of the different regions, res- mal cardiovascular autonomic tests (40). range of fixed pathology and reversible piration should be measured or con- No standardized methodology or norma- functional abnormalities (41). Acute hy- trolled breathing performed. These tive values exist, and available data on re- perglycemia slows gastric emptying (GE), methods, which need standardization, producibility are limited. Scintigraphic while -induced ac- have been widely used in research and as studies are appropriate to explore the ef- celerates it. end points in clinical trials. fects of sympathetic dysfunction on car- Clinical features. Disordered GI motil- Sympathetic outflow, at rest and in diac metabolism and function and are ity may be associated with GI symptoms, response to various physiological pertur- useful in assessing cardiac sympathetic impaired oral drug absorption, poor gly- bations, can be measured directly via mi- function in research studies. cemic control, malnutrition, abnormal croelectrodes inserted into a fascicle of a Issues for future research. Research is- postprandial regulation of BP, poor QoL, distal sympathetic nerve to the skin or sues include: 1) the need for multivariate and a high rate of hospitalization. The re-

2288 DIABETES CARE, VOLUME 33, NUMBER 10, OCTOBER 2010 care.diabetesjournals.org Tesfaye and Associates lationships with symptoms and CAN are appealing options, at least as a screening evaluated and managed in all patients relatively weak (42). Esophageal transit is tool. They are safe, easy to perform, inex- with ED and cardiovascular disease. Al- delayed in ϳ50% of patients with long- pensive, and correlate well with scintigra- though ED is a part of autonomic dys- standing diabetes and may be associated phy. Ultrasonography (two-dimensional function, ED prevalence in patients with with regurgitation, dysphagia, and a pro- and three-dimensional) is noninvasive DAN and the prevalence of DAN among pensity for pill-induced esophageal ero- and two-dimensional ultrasound has patients with ED have not been analyzed sions and strictures. affects been validated for measuring emptying of in large epidemiological studies. ϳ40% of patients with longstanding dia- liquids and semi-solids. However, obesity betes. Symptoms are variable and more and abdominal gas, together with the ne- Bladder dysfunction common in patients with worse chronic cessity for an experienced operator, have Bladder complications can be due to an glycemic control and psychological limited its widespread use. Surface elec- alteration of the detrusor smooth muscle, disorders (43). trogastrography, used to detect abdomi- neuronal dysfunction, and urothelial dys- The rate of GE is a major determi- nal gastric slow-wave activity, should be function. Estimates of the prevalence of nant of postprandial blood glucose regarded as a research tool. A barium bladder dysfunction are 43 to 87% of type changes. In insulin-treated patients, nu- meal has no role in quantifying GE. 1 diabetic patients and 25% of type 2 trient delivery needs to be matched to In the investigation of “diabetic diar- diabetic patients. Diabetes duration is the action of the exogenous insulin, and rhea” celiac disease, exocrine pancreatic significantly associated with severe incon- delayed GE is a cause of otherwise un- insufficiency and small intestinal bacterial tinence. The correlation between diabetic explained hypoglycemia (44). overgrowth must be excluded. Tests of cystopathy and Postprandial hypotension occurs fre- anorectal motor and sensory function are ranges from 75 to 100%. quently in diabetes, and its magnitude is well developed for clinical use. Common symptoms include dysuria, related directly to GE rate. The prevalence frequency, urgency, nocturia, and incom- of disordered small and large intestinal plete bladder emptying. Other symptoms and anorectal motility is high. The prevalence of erectile dysfunction include infrequent voiding, poor stream, may result from rapid or slow transit, (ED) among diabetic men varies from 35 hesitancy in initiating micturition, recur- which is complicated by bacterial over- to 90%, depending mainly on the various rent cystitis, and stress and urgency uri- growth and/or disordered secretion. Con- methods applied (46). Neuropathy is one nary incontinence. Since urological stipation frequently occurs. Fecal of the leading causes of ED, along with conditions such as benign prostatic hy- incontinence is not uncommon and is re- glycation of elastic fibers, peripheral vas- pertrophy in men or gynecological disor- lated to reduced and unstable internal culopathy, endothelial dysfunction, psy- ders in women may share the same anal sphincter tone and impaired rectal chological factors, drugs, and hormonal symptoms, these causes must be excluded compliance and sensation. changes (47). ED seems to be associated by appropriate testing. Assessment. Studies of GI autonomic with a higher rate of abnormal sensory Diagnosis should use a validated neuropathy, whether performed for clin- and autonomic tests. ED is a predictor of questionnaire for lower urinary tract ical, epidemiological, or research pur- cardiovascular events and is associated symptoms (LUTS). The type of bladder poses, may potentially be focused on GI with silent myocardial ischemia in type 2 dysfunction is most readily characterized symptoms, QoL, GI motility/transit, gly- diabetes (48). Alteration of QoL and de- with complete urodynamic testing. Mea- cemic control, and/or postprandial BP. A pressive symptoms seem to precede ED. surement of peak urinary flow rate and number of instruments are available to In clinical trials, ED was more severe and postvoid residual volume (PVR) should quantify GI symptoms, including the Di- more resistant to treatment in diabetic be considered in diabetic patients with abetes Bowel Symptom Questionnaire. than in nondiabetic individuals. LUTS when diagnosis remains doubtful Objective GE measurement is advocated Key diagnostic procedures of ED in- (50). PVR is ideally measured by portable for the diagnosis of gastroparesis. Evalua- clude comprehensive patient history (sex- ultrasound (51). Urodynamic findings in- tion of solid emptying is probably more ual, medical, drugs, alcohol, tobacco, and clude impaired bladder sensation, in- sensitive than that of low-nutrient liquid psychosocial). The use of validated ques- creased cystometric capacity, decreased or semi-solid meals. Medications that may tionnaires, such as the International In- (or sometimes unexplained increased) influence GE should ideally be with- dex of Erectile Function and the Sexual detrusor contractility, and increased PVR drawn, glycemia should ideally be Ͻ10 Encounter Profile, is the most appropriate (52). Microscopic urinalysis and culture mmol/l throughout the test, and other method to characterize the frequency and are essential in assessing patients com- causes of gastroparesis must be excluded. severity of ED symptoms. Other explora- plaining of LUTS. Bladder dysfunction Failure to demonstrate delayed GE does tions, including evaluation of nocturnal has not been assessed up to now in epide- not necessarily imply that symptoms are penile tumescence, penile Doppler ultra- miological and longitudinal studies or in not due to “diabetic gastropathy,” but it sound, sacral response, bulbo-cavernosus RCTs. does help guide drug therapy. Scintigra- reflex, dorsal sensory nerve conduction of phy is still regarded as the gold standard the penis, amplitude and latency of penile technique for GE measurement. Stan- sympathetic skin response, and pudendal Sudomotor dysfunction dardization of the meal technique has nerve somatosensory-evoked potentials Sweat glands are innervated by the sudo- been improved by the recommendation (49), may be useful in patients who do not motor, postganglionic, unmyelinated of a low-fat, egg white meal labeled with respond to phosphodiesterase (PDE)-5 cholinergic sympathetic C-fibers. Sudo- technetium-99 (99mTc) sulfur colloid inhibitors. Due to the potential risks of motor dysfunction may result in dryness (45). Breath tests using nonradioactive 13 adverse or unanticipated drug interac- of foot skin and has been associated with C-acetate or -octanoic acid as a label are tions, cardiac risk factors should be foot ulceration (53). Assessment of sudo- care.diabetesjournals.org DIABETES CARE, VOLUME 33, NUMBER 10, OCTOBER 2010 2289 Update on diabetic neuropathies motor dysfunction contributes to the de- pure SFN (59), a cut-off IENF density of (63), was more prominent in painful neu- tection of autonomic dysfunction in DPN. Յ8.8/mm at the ankle was associated ropathy (63), and improved 6 months The quantitative sudomotor axon re- with a sensitivity of 77.2% and a specific- after combined / trans- flex test (QSART) is capable of detecting ity of 79.6%. In a study of 210 patients plantation (67). Its quantification may distal small fiber polyneuropathy with a with SFN (60), which included 65 dia- be a surrogate marker of diabetic sensitivity of Ͼ75% (54). QSART may be betic patients, the Z-scores and 5th per- neuropathy. considered the reference method for the centile provided the highest specificity detection of sudomotor dysfunction and (98 and 95%, respectively) but the lowest Nerve axon reflex/flare response is used for clinical and research purposes. sensitivity (31 and 35%, respectively) Stimulation of C-nociceptive fibers by Other available techniques for assessment compared with the receiver operating acetylcholine iontophoresis induces vaso- of sudomotor function include the ther- characteristic analysis (specificity 64%, dilation, which can be quantitatively mea- moregulatory sweat test, silastic imprint sensitivity 78%). Thus, the diagnostic sured and serve as a measure of small fiber method, the indicator plaster method yield of skin biopsy may depend on the function (68). This technique correlates (55), and the quantitative direct and indi- reference and cut-off values selected and with other measurements of small fiber rect reflex test (QDIRT) (56). Compara- the definition of SFN. IENF density cor- function and may be considered for the tive studies of the sensitivity and relates inversely with both cold and heat diagnosis of SFN in diabetic patients. The specificity of these diagnostic techniques detection thresholds (61). laser Doppler imaging flare test evaluates are necessary. Sudomotor function has The AAN, AAEM, and AAPM&R pro- 44°C heat-induced and is re- not yet been assessed in epidemiological vide a level C recommendation for the use duced in subjects with IGT and type 2 and longitudinal studies or in RCTs. of skin biopsy to diagnose DSPN, partic- diabetic patients with and without neu- ularly SFN (36). The European Federa- ropathy (69). Further studies are required EMERGING MARKERS OF tion of the Neurological Societies and the to validate these tests as diagnostic tools DPN: FOCUS ON SMALL Peripheral Nerve Society revised guide- or as outcome measures in clinical trials. FIBERS — It was proposed earlier in lines on the use of skin biopsy in the di- this article that if NC is normal, a vali- agnosis of SFN and have concluded that Definition of SFN dated measure (with class 1 evidence) of IENF density is a reliable and efficient In diabetic patients, we propose to grade SFN may be used. We have therefore as- technique to confirm the clinical diagno- SFN as follows: 1) possible: the presence sessed the validity of established and sis of SFN with a level A recommendation of length-dependent symptoms and/or emerging measures of SFN and propose a (58). The presence of diffuse IENF swell- clinical signs of small fiber damage; 2) definition. ings, especially if large, may predict a de- probable: the presence of length- cline in IENF density (58) dependent symptoms, clinical signs of Nerve biopsy DPN. IENF density is significantly re- small fiber damage, and normal sural NC Nerve biopsy detects unmyelinated fiber duced in patients with normal NC, sug- study; and 3) definite: the presence of damage while myelinated nerve fiber gesting early damage to small nerve fibers length-dependent symptoms, clinical morphology is still normal in patients (62,63), and there is an inverse correla- signs of small fiber damage, normal sural with early DPN (57). However, nerve bi- tion with the Neurological Disability NC study, and altered IENF density at the opsy is an invasive and highly specialized Score (63). Additionally, IENF density is ankle and/or abnormal quantitative sen- procedure that requires electron- lower in diabetic patients with painful— sory testing thermal thresholds at the foot. microscopy and cannot be advocated for compared with painless—early neuropa- At present, it is not possible to suggest routine use. thy (64). A 1-year diet and exercise criteria to define the severity of SFN in intervention program for patients with DPN. Skin biopsy SFN and IGT led to increased IENF den- Skin punch biopsy, a minimally invasive sity (65). These data suggest that IENF CONCLUSIONS — Diabetic poly- procedure, allows morphometric quanti- loss is an early feature of diabetes, neuropathy is one of the most common fication of intraepidermal nerve fibers progresses with increasing neuropathic long-term complications of diabetes af- (IENF) most commonly expressed as the severity, and may repair with early fecting ϳ50% of all diabetic people. This number of IENF per length of section intervention. review by an international panel of ex- (IENF/mm). Intra- and inter-observer Sudomotor innervations. Recently, a perts examines recent literature regarding variability for the assessment of IENF skin biopsy study has shown a correlation diagnostic criteria for DPN, painful DPN, density is good, declines with age, is lower between nerve fiber density, and autonomic neuropathy and makes di- in males than in females, and is not influ- neuropathic symptoms, neurological def- agnostic recommendations in the context enced by weight or height (58). The blis- icits, and sweat production in diabetic of clinical practice and research. The re- ter technique is a less invasive procedure patients (66). view also discusses emerging markers of that assesses innervation of the epidermis DPN. Finally, the diagnostic criteria for alone and shows good agreement with Corneal confocal microscopy DPN are likely to evolve with develop- punch biopsy (58). Corneal confocal microscopy is a nonin- ments in the field, and there is clearly a Diagnostic yield of IENF quantifica- vasive technique that can detect small need for experts in the field to provide tion. No study assessing sensitivity and sensory corneal nerve fiber loss in diabetic periodic updates. specificity in DPN alone is available. neuropathy (63), idiopathic SFN, and However, several studies in SFN, which Fabry disease. Corneal nerve fiber dam- included patients with DPN, have been age correlates with IENF loss and the se- Acknowledgments— S.T. has received hon- published. In a study of 58 patients with verity of neuropathy in diabetic patients oraria from Eli Lilly, Boehringer Ingelheim,

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Pfizer, Shwartz Pharma, and UCB. V.S. has re- Manchester, Manchester, U.K.; Vera Bril, Beth Israel Deaconess Medical Center, ceived research support, consulting fees, or MD, Department of Neurology, University Harvard Medical School, Boston, Massa- honoraria from Boehringer Ingelheim, Daiichi of Toronto, Toronto, Ontario, Canada; Nor- chusetts; Loretta Vileikyte, MD, PhD, De- Sankyo Europe, Eli Lilly, Laborest, miro Ver- man Cameron, PhD, University of Aber- partment of Medicine, University of bandstoffe, Pfizer, and Schwarz. A.V. has re- deen, Aberdeen, U.K.; Mary Cotter, PhD, Manchester, Manchester, U.K.; Aaron ceived research grants from the National Institutes of Health/National Institute on Ag- University of Aberdeen, Aberdeen, U.K.; Vinik, MD, PhD, Strelitz Diabetes Re- ing, American Diabetes Association, Abbott, Peter J. Dyck, MD, Department of Neurol- search Institutes, Eastern Virginia Medi- GlaxoSmithKline, sanofi-aventis, Arcion Ther- ogy, Mayo Clinic, Rochester, Minnesota; cal School, Norfolk, Virginia; Dan Ziegler, apeutics, Eli Lilly, and Merck Research Labs. John England, MD, Department of Neurol- MD, Institute for Clinical Diabetology, A.V. has served as a consultant for Ansar, As- ogy, Louisiana State University Health Sci- German Diabetes Center, Leibniz Center traZeneca, Eli Lilly, KV Pharmaceuticals, ences Center, New Orleans, Louisiana; Eva for Diabetes Research, Heinrich Heine Merck, Novartis Pharmaceuticals, R.W. John- Feldman, MD, PhD, Department of Neurol- University, Du¨ sseldorf, Germany, and the son Pharmaceutical Research Institute, sanofi- ogy, University of Michigan, Ann Arbor, Department of Metabolic Diseases, Uni- aventis, Takeda, and Tercica and also has Michigan; Roy Freeman, MD, Beth Israel versity Hospital, Du¨ sseldorf, Germany; served on the speaker’s bureau for Abbott, An- Deaconess Medical Center, Harvard Med- Doug Zochodne, MD, Department of sar, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline Beecham, Merck, No- ical School, Boston, Massachusetts; Si- Clinical Neuroscience, University of Cal- vartis Pharmaceuticals, Pfizer, sanofi-aventis, mona Frontoni, MD, Department of gary, Calgary, Alberta, Canada; and and Takeda. No other potential conflicts of Internal Medicine, University of Tor Ver- Teresa Jones, MD, National Institute of interest relevant to this article were reported. gata, Rome, Italy; Jannik Hilsted, MD, Diabetes and Digestive Kidney Diseases S.T. contributed to the discussion and Copenhagen University Hospital, Copen- observer, Bethesda, Maryland. wrote, reviewed, and edited the manuscript. hagen, Denmark; Michael Horowitz, MD, A.J.M.B. researched data, contributed to the PhD, Department of Medicine, University discussion, wrote the manuscript, and re- of Adelaide, Adelaide, Australia; Peter References viewed and edited the manuscript. P.J.D. re- Kempler, MD, PhD, I Department of Med- 1. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, searched data, contributed to the discussion, icine, Semmelweis University, Budapest, Klein R, Pach JM, Wilson DM, O’Brien and reviewed and edited the manuscript. R.F. PC, Melton LJ 3rd, Service FJ. 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