Dia Care-2005-Boulton-956-62.pdf

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Diabetic NeuropathiesA statement by the American Diabetes Association

ANDREWJ.M. BOULTON, MD, FRCP1,2

ARTHURI. VINIK, MD, PHD3JOSEPHC. AREZZO, PHD4

VERABRIL, MD5

EVAL. FELDMAN, MD, PHD6

ROYFREEMAN, MB, CHB7

RAYAZA. MALIK, PHD, MRCP1RAELENE E. MASER, PHD8

JAYM. SOSENKO, MS, MD2

DANZIEGLER, MD, FRCP9

The diabetic neuropathies are hetero-geneous, affecting different parts ofthe nervous system that present

with diverse clinical manifestations. Theymay be focal or diffuse. Most commonamong the neuropathies are chronic

sensorimotor distal symmetric polyneu-ropathy (DPN) and the autonomicneuropathies. DPN is a diagnosis of exclu-sion. The early recognition and appropri-ate management of neuropathy in thepatient with diabetes is important for anumber of reasons. 1) Nondiabetic neu-ropathies may be present in patients withdiabetes.2) A number of treatment op-tions exist for symptomatic diabetic neu-ropathy. 3) Up to 50% of DPN may beasymptomatic, and patients are at risk ofinsensate injury to their feet. As 80% ofamputations follow a foot ulcer or injury,early recognition of at-risk individuals,provision of education, and appropriatefoot care may result in a reduced inci-dence of ulceration and consequently am-putation.4) Autonomic neuropathy mayinvolve every system in the body. 5) Au-tonomic neuropathy causes substantialmorbidity and increased mortality, par-ticularly if cardiovascular autonomic neu-ropathy (CAN) is present. Treatment

should be directed at underlying patho-genesis. Effective symptomatic treatmentsare available for the manifestations ofDPN and autonomic neuropathy.

This statement is based on two recenttechnical reviews (1,2), to which the

reader is referred for detailed discussionand relevant references to the literature.

DEFINITIONS AND

CLASSIFICATION A n i n t e r n a -tionally agreed simple definition of DPNfor clinical practice is the presence ofsymptoms and/or signs of peripheralnerve dysfunction in people with diabetesafter the exclusion of other causes (3).However, the diagnosis cannot be madewithout a careful clinical examination ofthe lower limbs, as absence of symptomsshould never be assumed to indicate anabsence of signs. This definition conveysthe important message that not all pa-tients with peripheral nerve dysfunctionhave a neuropathy caused by diabetes.Confirmation can be established withquantitative electrophysiology, sensory,and autonomic function testing.

Numerous classifications of the vari-ety of syndromes affecting the peripheralnervous system in diabetes have been

proposed in recent years. The classifica-tion shown in Table 1 is based on thatoriginally proposed by Thomas (4).

DIAGNOSTIC CRITERIA

AND BRIEF CLINICAL

ASPECTS

A) Sensory neuropathies: clinicalfeatures1) Acute sensory neuropathy. Acutesensory neuropathy is rare, tends to fol-low periods of poor metabolic control

(e.g., ketoacidosis) or sudden change inglycemic control (e.g., insulin neuritis),and is characterized by the acute onset ofsevere sensory symptoms (as detailed be-low) with marked nocturnal exacerbationbut few neurologic signs on examinationof the legs.2) Chronic sensorimotor DPN. This isthe most common presentation of neu-ropathy in diabetes, and up to 50% ofpatients may experience symptoms, mostfrequently burning pain, electrical orstabbing sensations, parasthesiae, hy-perasthesiae, and deep aching pain. Neu-ropathic pain is typically worse at night,and the symptoms are most commonlyexperienced in the feet and lower limbs,although in some cases the hands mayalso be affected. As up to half of the pa-tients may be asymptomatic, a diagnosismay only be made on examination or, insome cases, when the patient presentswith a painless foot ulcer. Other patientsmay not volunteer symptoms but on in-quiry admit that their feet feel numb ordead. Examination of the lower limb usu-ally reveals sensory loss of vibration, pres-

sure, pain, and temperature perception(mediated by small and large fibers) andabsent ankle reflexes. Signs of peripheralautonomic (sympathetic) dysfunction arealso frequently seen and include a warmor cold foot, sometimes with distendeddorsal foot veins (in the absence of ob-structive peripheral vascular disease), dryskin, and the presence of calluses underpressure-bearing areas3) Diagnosis. The diagnosis of DPN canonly be made after a careful clinical exam-ination, and all patients with diabetes

From the 1Department of Medicine, Manchester Royal Infirmary, Manchester, U.K.; the 2Division of Endo-crinology, Diabetes & Metabolism, University of Miami School of Medicine, Miami, Florida; 3The StrelitzDiabetes Institute, Eastern Virginia Medical School, Norfolk, Virginia; the 4Department of Neuroscience,

Albert Einstein College of Medicine of Yeshiva University, Bronx, New York; the 5Department of Medicine(Neurology), University Health Network, University of Toronto, Toronto, Canada; the 6Department ofNeurology, University of Michigan, Ann Arbor, Michigan; the 7Department of Neurology, HarvardUniversity, Boston, Massachusetts; the 8Department of Medical Technology, University of Delaware,Newark, Delaware; and the 9German Diabetes Clinic, German Diabetes Center, Leibniz Institute at theHeinrich Heine University, Dusseldorf, Germany.

Address correspondence and reprint requests to (somatic) Prof. A.J.M. Boulton, Department of Medicine,Manchester Royal Infirmary, Oxford Road,Manchester, M13 9WL,U.K. E-mail: [email protected] (autonomic) Dr. Aaron Vinik, Director, Strelitz Diabetes Research Institute, 855 W. Brambleton Ave.,Norfolk, VA 23510. E-mail: [email protected].

Abbreviations: CAN, cardiovascular autonomic neuropathy; CIDP, chronic inflammatory demyelinatingpolyneuropathy; DAN, diabetic autonomic neuropathy; DPN, distal symmetric polyneuropathy; HRV, heartrate variability.

2005 by the American Diabetes Association.

R e v i e w s / C o m m e n t a r i e s / A D A S t a t e m e n t s

A D A S T A T E M E N T

956 DIABETESCARE, VOLUME28, NUMBER4, APRIL2005


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should be screened annually for DPN by

examining pinprick, temperature, and vi-bration perception (using a 128-Hz tun-ing fork), 10-g monofilament pressuresensation at the distal halluces, and anklereflexes. Combinations of more than onetest have 87% sensitivity in detectingDPN. Loss of 10-g monofilament percep-tion and reduced vibration perceptionpredict foot ulcers. Indeed, longitudinalstudies have shown that a simple clinicalexamination is a good predictor of futurefoot ulcer risk (5). The feet should be ex-amined for ulcers, calluses, and deformi-

ties, and footwear should be inspected.Different scoring systems have been de-veloped for monitoring progression or re-sponse to intervention in clinical trials.

Other forms of neuropathy, includingchronic inflammatory demyelinatingpolyneuropathy (CIDP), B

12deficiency,

hypothyroidism, and uremia, occur morefrequently in diabetes and should beruled out. The practitioner may wish torefer the more complex patient, or thosein whom diagnosis needs confirmation, toa neurologist for specialized examinationand testing.

The diagnosis of chronic DPN istherefore a clinical one and involves theexclusion of nondiabetic causes: investi-gations should be ordered as dictated byclinical findings and might typically in-clude serum B

12, thyroid function, blood

urea nitrogen, and serum creatinine. Acombination of typical symptomatologyand distal sensory loss with absent re-flexes, or the signs in the absence of symp-toms, is highly suggestive of DPN.

B) Focal and multifocalneuropathiesMononeuropathies may have a suddenonset and can occur as a result of involve-ment of the median (5.8% of all diabeticneuropathies), ulnar (2.1%), radial(0.6%), and common peroneal nerves.Cranial neuropathies are extremely rare(0.05%); involve primarily cranial nervesIII, IV, VI, and VII; and are thought tooccur due to a microvascular infarct,which, in the majority, resolves spontane-ously over several months. Electrophysi-ological studies show a reduction in bothnerve conduction and amplitude sugges-tive of underlying demyelination and ax-onal degeneration. In contrast, up to one-third of patients with diabetes have anentrapment. Common nerves involved arethe ulnar, median, peroneal, and medial

plantar nerves. Spinal stenosis is also com-mon in people with diabetes and needs tobe distinguished fromthe proximal neurop-athies and amyotrophy. Electrophysiologi-cal studies are most helpful in identifyingblocks in conduction at the entrapmentsites. Entrapments may require decompres-sion, but initial management should be ex-pectant with strong reassurance to thepatient for recovery (6).

Diabetic amyotrophy typically occursin older patients with type 2 diabetes, andin some cases, an immune-mediated

epineurial microvasculitis has been dem-onstrated in nerve biopsies. Clinical fea-tures of amyotrophy include severeneuropathic pain and uni- or bilateralmuscle weakness and atrophy in theproximal thigh muscles. When an unusu-ally severe, predominantly motor neurop-athy and progressive polyneuropathydevelops in diabetic patients, one mustconsider CIDP and spinal stenosis. Thediagnosis of CIDP is often overlooked andthe patient simply labeled as having dia-betic neuropathy: progressive symmetric

or asymmetric motor deficits, progressivesensory neuropathy in spite of optimalglycemic control together with typicalelectrophysiological findings, and an un-usually high cerebro-spinal fluid proteinlevel all suggest the possibility of an un-derlying treatable demyelinating neurop-athy (7). As immunomodulatory therapywith combinations of corticosteroids,plasmapheresis, and intravenous immuneglobulin can produce a relatively rapidand substantial improvement in neurologi-cal deficits and electrophysiology in some

cases of CIDP, referral to a neurologist isindicated if this diagnosis is suspected.

C) Autonomic neuropathy (814)Diabetic autonomic neuropathy (DAN)results in significant morbidity and maylead to mortality in some patients with

diabetes. The most common dysauto-nomic features are listed in Table 2, to-gether with their associated symptomsand management. The symptoms of auto-nomic dysfunction should be elicitedcarefully during the history, particularlysince many of these symptoms are poten-tially treatable.

Major clinical manifestations of DANinclude resting tachycardia, exerciseintolerance, orthostatic hypotension,constipation, gastroparesis, erectile dys-function, sudomotor dysfunction, im-

paired neurovascular function, brittlediabetes, and hypoglycemic autonomicfailure. CAN is the most prominent focusof autonomic dysfunction because of thelife-threatening consequences of thiscomplication and the availability of directtests of cardiovascular autonomic func-tion. However, neuropathies involvingother organ systems should also be con-sidered in the optimal care of patientswith diabetes.

CardiovascularCAN is the most studied and clinicallyimportant form of DAN. The reportedprevalence of CAN varies widely depend-ing on the cohort studied and the meth-ods of assessment. The presence ofautonomic neuropathy may limit an indi-viduals exercise capacity and increase therisk of an adverse cardiovascular eventduring exercise.CAN may be indicatedbyresting tachycardia (100 bpm), orthos-tasis (a fall in systolic blood pressure20mmHg upon standing) without an appro-priate heart rate response, or other distur-bances in autonomic nervous system

function involving the skin, pupils, gas-trointestinal, or genitourinary systems.Sudden death and silent myocardial isch-emia have been attributed to CAN in dia-betes. Resting and stress thalliummyocardial scintigraphy is an appropriatenoninvasive test for the presence and ex-tent of macrovascular coronary artery dis-ease in these individuals. Hypotensionand hypertension after vigorous exerciseare more likely to develop in patients withautonomic neuropathy, particularlywhen starting an exercise program. Be-

Table 1Classification of diabetic neuro-pathy

Generalized symmetric polyneuropathiesAcute sensory

Chronic sensorimotorAutonomic

Focal and multifocal neuropathies

Cranial

Truncal

Focal limbProximal motor (amyotrophy)

Coexisting CIDP

Adapted from Thomas (4). Note: Clinicians shouldbe alert for treatable neuropathies (CIDP, monoclo-nal gammopathy, vitamin B

12 deficiency, etc.) oc-

curring in patients with diabetes.

Boulton and Associates

DIABETESCARE, VOLUME 28, NUMBER4, APRIL 2005 957


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constipation, diarrhea, fecal inconti-nence) are common, and any section of

the gastrointestinal tract may be affected.Gastroparesis should be suspected in in-dividuals with erratic glucose control.Upper-gastrointestinal symptoms shouldlead to consideration of all possiblecauses, including autonomic dysfunction.Evaluation of gastric emptying should bedone if symptoms are suggestive. Bariumstudies or referral for endoscopy may berequired. Constipation is the most com-mon lower-gastrointestinal symptom butcan alternate with episodes of diarrhea.Endoscopy may be required to rule outother causes.

GenitourinaryDAN is also associated with genitourinarytract disturbances, including bladderand/or sexual dysfunction. Evaluation ofbladder dysfunction should be performedin individuals with diabetes who have re-current urinary tract infections, pyelone-phritis, incontinence, or a palpablebladder. In men, DAN may cause loss ofpenile erection and/or retrograde ejacula-tion. A complete work-up for impotencein men should include history (medical

and sexual); psychological evaluation;hormone levels; measurement of noctur-nal penile tumescence; tests to assess pe-nile, pelvic, and spinal nerve function;cardiovascular autonomic function tests;and measurement of penile and brachialblood pressure.

EPIDEMIOLOGY

DPNDPN is a common disorder. Although es-timates vary, it appears that at least one

manifestation of DPN is present in at least20% of adult diabetic patients. DPN has

been associated with a number of modifi-able and nonmodifiable risk factors, in-cluding the degree of hyperglycemia,lipidand bloodpressure indexes, diabetesduration, and height. DPN has been lessconsistently associated with cigarettesmoking and alcohol consumption.

DANPrevalence data for DAN range from 1.6to 90% depending on tests used, popula-tions examined, and type and stage of dis-ease. Risk factors for the development ofDAN include diabetes duration, age, andlong-term poor glycemic control. DANmay cosegregate with factors predispos-ing to macrovascular events such as raisedblood pressure and dyslipidemia. Thus,in addition to good glycemic control,lipid modulation and blood pressure con-trol may be beneficial in the prevention ofDAN. There are no true population-basedstudies using radioisotopic techniquesthat quantify gastric emptying in diabeticpatients, but cross-sectional studies haveindicated that 50% of outpatients with

long-standing diabetes have delayed gas-tric emptying and up to 76% of diabeticoutpatients indicate that they have one ormore gastrointestinal symptom, the mostcommon of which is constipation. Bothupper- and lower-gastrointestinal symp-toms occur more frequently in individu-als with diabetes than in control subjects,but the symptoms are nonspecific and oc-cur in the general population (12,13).Specific symptoms such as bloating aftermeals, vomiting of previously ingestedfood, and alternating constipation and ex-

plosive diarrhea should lead to furtherevaluation (Table 4).

Genitourinary bladder dysfunctionhas been shown in 4387% of individualswith type 1 diabetes. Diabetic womenhave a fivefold higher risk of unrecog-nized voiding difficulty compared withnondiabetic women. The history andphysical are generally noncontributory,and the patient should be referred to aurologist for urodynamic studies.

The prevalence of erectile dysfunc-tion in diabetic men ranges from 27 to75% (14).

MANAGEMENT

A) PreventionThe DCCT (Diabetes Control and Compli-cations Trial) has shown definitively that intype 1 diabetic patients,the risk of DPNandautonomic neuropathy canbe reduced withimproved blood glucose control. Althoughdata from a small number of trials are muchless strong for type 2 diabetic patients,DCCT data and data from epidemiologicstudies(including studiesof type2 patients)strongly suggest that optimal blood glucosecontrol helps to prevent DPN and auto-

nomic neuropathy inboth type 1 and type 2diabetic patients. There have been no defi-nitely positive prevention studies of otherrisk factor modifications for DPN, but theimprovement of lipid and blood pressureindexes, and the avoidance of cigarettesmoking and excess alcohol consumption,are already recommended for the preven-tion of other complications of diabetes.

B) Pathogenetic treatments (1619)Recent experimental studies suggest amultifactorial pathogenesis of diabetic

Table 3Oral symptomatic therapy of painful neuropathy

Drug class Drug Daily dose (mg) NNT NNH Side effects

Tricyclics Amitriptyline 25150 2.4 (2.03.0) 2.7 (2.13.9) Imipramine 25150 2.4 (2.03.0) 2.7 (2.13.9)

SSRIs Paroxetine 40 ND ND

Citalopram 40 ND ND Anticonvulsants Gabapentin 9001,800 3.7 (2.48.3) 2.7 (2.23.4)

Pregabalin 150600 3.3 (2.35.9) 3.7 Carbamazepine 200400 3.3 (2.09.4) 1.9 (1.42.8) Topiramate Up to 400 3.0 (2.34.5) 9.0

Opioids Tramadol 50400 3.4 (2.36.4) 7.8 Oxycodone CR 1060 ND ND

Data are median (range) unless otherwise indicated. See refs. 2, 19, and 20. ND, not determined; NNH, number needed to treat to harm one patient; NNT, numberneeded to treat to achieve pain relief in one patient; SSRI, selective serotonin reuptake inhibitor.




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neuropathy. Studies in animal modelsand cultured cells provide a conceptualframework for the cause and treatment ofdiabetic neuropathy. However, limitedtranslational work in diabetic patientscontinues to generate much debate andcontroversy over the cause(s) of humandiabetic neuropathy, and to date we haveno effective long-term treatment. A sum-mary of the drugs that have/are beingstudied in clinical trials is provided in Ta-ble 2 (19).

C) Symptomatic treatments1) DPN (2,3,2022). The first step inmanagement of patients with DPN shouldbe to aim for stable and optimal glycemiccontrol. Although controlled trial evi-dence is lacking, several observationalstudies suggest that neuropathic symp-toms improve not only with optimizationof control but also with the avoidance ofextreme blood glucose fluctuations. Manypatients will require pharmacologicaltreatment for painful symptoms: several

agents have efficacy confirmed in pub-lished randomized controlled trials, al-though with the exception of Duloxetineand Pregabalin, none of the others is spe-cifically licensed for the management ofpainful DPN (Table 3). An algorithm forthe management of symptomatic DPN isprovided in Fig. 1.

Although a detailed discussion of allthese agents is provided in the recent tech-nical review (2), some comment will bemade on the more commonly used agents.

Table 4Treatment of autonomic neuropathy

Symptoms Tests Treatments

Cardiac

Exercise intolerance, early fatigue andweakness with exercise

HRV, multigated angiography (MUGA) thalliumscan, 123I metaiodobenzlyguanidine (MIBG)

scan

Graded supervised exercise, ACE inhibitors,

-blockers

Postural hypotension, dizziness,

lightheadedness, weakness, fatigue,syncope

HRV, measure blood pressure standing and

supine, measure catecholamines

Mechanical measures, clonidine, midodrine,

octreotide

Gastrointestinal

Gastroparesis, erratic glucose control Gastric emptying study, barium study Frequent small meals, prokinetic agents(metoclpramide, domperidone,

erythromycin)Abdominal pain or discomfort, early

satiety, nausea, vomiting, belching,bloating

Endoscopy, manometry, electrogastrogram Antibiotics, antiemetics (phenergan,

compazine, tigan, scopolamine), bulkingagents, tricyclic antidepressants, pancreatic

extracts, pyloric Botox, gastric pacing,enteral feeding

Constipation Endoscopy High-fiber diet and bulking agents, osmoticlaxatives, lubricating agents and prokinetic

agents used cautiouslyDiarrhea, often nocturnal alternating

with constipation and incontinence

Trials of soluble fiber, gluten and lactose

restriction, anticholinergic agents,cholestyramine, antibiotics, clonidine,

somatostatin, pancreatic enzymesupplements

Sexual dysfunctionErectile dysfunction History and physical examination, HRV, penile-

brachial pressure index, nocturnal peniletumescence

Sex therapy, psychological counseling,

sildenafil, vardenafil, tadalafil, prostaglandinE1 injection, device or prosthesis

Vaginal dryness Vaginal lubricants

Bladder dysfunctionFrequency, urgency, nocturia, urinary

retention, incontinence

Cystometrogram, postvoiding sonography Bethanechol, intermittent catheterization

Sudomotor (sweating) dysfunction

Anhidrosis, heat intolerance, dry skin,hyperhidrosis

Quantitative sudomotor axon reflex, sweat test,skin blood flow

Emollients and skin lubricants, scopolamine,glycopyrrolate, botulinum toxin, vasodilators

PupillomotorVisual blurring, impaired adaptation to

ambient light, impaired visceralsensation

Pupillometry, HRV Care with driving at night, recognition of

unusual presentations of myocardialinfarction

Diabetic neuropathies



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Tricyclic drugs. The usefulness of thetricyclic drugs, such as Amitriptyline andImipramine, has been confirmed in sev-eral randomized controlled trials. Al-t hough ine xpe nsive a nd ge ne ra l lyefficacious in the management of neuro-pathic pain, side effects, particularly anti-c h o l i n e r g i c ( d r y m o u t h , u r i n a r yretention, etc.), can be troublesome andlimit their use in many patients. The cen-tral side effects, such as fatigue and

drowsiness, are also common, so it is ad-vised to start at 25 mg before bed andgradually increase the dose, if necessary,to a maximum of 150 mg.

Anticonvulsants. Gabapentin is nowthe most commonly prescribed anticon-vulsant that has been proven to be effica-cious in the treatment of neuropathicpain. As most patients require at least 1.8g/day for relief of symptoms, it is advis-able to start at 300 mg at bedtime andthen increase over days to the dosage thatachieves symptomatic relief. This gradual

titration of drug dosage until the thera-peutic effect is realized is advisable, as it isfelt that this may lessen the severity of sideeffects that may be experienced if thedrugis introduced at a high dose on day 1. Thestructurally related compound Pregabalinhas recently been confirmed to be usefulin painful diabetic neuropathy in a ran-domized controlled trial (20). In contrast

to Gabapentin, which is usually given inthree daily doses, Pregabalin is effectivewhen given twice daily. As noted in Table 4,all of these agents are prone to side effects,typically central in nature such as drowsi-ness. Finally, Topiramate, another anticon-vulsant used in complex partial seizures,was recently shown to be efficacious in themanagement of neuropathic pain (21).

Figure 1Alg ori thm for manage ment ofsymptomatic DPN (1). Note that nonpharma-cological, topical, or physical therapies mightbe useful at any stage. These include acupunc-ture, capsaicin, glyceryl trinitrate spray/patches, etc. (2).

Table 5Diagnostic tests of CAN

Resting heart rate

100 bpm is abnormal.

Beat-to-beat HRV*

With the patient at rest and supine (not having had coffee or a hypoglycemic episode thenight before), heart rate is monitored by ECG or autonomic instrument while the patient

breathes in and out at six breaths per minute, paced by a metronome or similar device. Adifference in heart rate of15 bpm is normal, 10 bpm is abnormal. The lowest normal

value for the expiration-to-inspiration ratio of the R-R interval is 1.17 in people 2024

years of age. There is a decline in the value with age.

Heart rate response to standing*

During continuous ECG monitoring, the R-R interval is measured at beats 15 and 30 afterstanding. Normally, a tachycardia is followed by reflex bradycardia. The 30:15 ratio is

1.03.

Heart rate response to the Valsalva maneuver*The subject forcibly exhales into the mouthpiece of a manometer to 40 mmHg for 15 s

during ECG monitoring. Healthy subjects develop tachycardia and peripheral

vasoconstriction during strain and an overshoot bradycardia and rise in blood pressurewith release. The ratio of longest R-R to shortest R-R should be 1.2.

Systolic blood pressure response to standingSystolic blood pressure is measured in the supine subject. The patient stands, and the

systolic blood pressure is measured after 2 min. Normal response is a fall of10 mmHg,borderline is a fall of 1029 mmHg, and abnormal is a fall of30 mmHg with symptoms.

Diastolic blood pressure response to isometric exercise

The subject squeezes a handgrip dynamometer to establish a maximum. Grip is thensqueezed at 30% maximum for 5 min. The normal response for diastolic blood pressure is

a rise of16 mmHg in the other arm.

ECG QT/QTc intervals

The QTc should be 440 ms.

Spectral analysisVery-low-frequency peak2 (sympathetic dysfunction)Low-frequency peak2 (sympathetic dysfunction)High-frequency peak2 (parasympathetic dysfunction)Low-frequencytohigh-frequency ratio2 (sympathetic imbalance)

Neurovascular flowUsing noninvasive laser Doppler measures of peripheral sympathetic responses to

nociception.

From Vinik A, Erbas T, Pfeifer M, Feldman E, Stevens M, Russell J: Diabetic autonomic neuropathy, 2004.InThe Diabetes Mellitus Manual: A Primary Care Companion to Ellenberg and Rifkins 6th Edition. Inzucchi SE,Ed. New York, McGraw Hill, 2004, p. 351. *These can now be performed quickly (15 min) in thepractitioners office usingstand-alone devices that are operator friendly. Lowest normalvalue of expiration-

to-inspiration ratio: age 2024 years, 1.17; 2529, 1.15; 3034, 1.13; 3539, 1.12; 4044, 1.10; 4549,1.08; 5054, 1.07; 5559, 1.06; 6064, 1.04; 6569, 1.03; and 7075, 1.02. ECG, electrocardiogram.




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Other agents. The 5-hydroxytrypta-mine and Norepinephrine reuptake in-hibitor Duloxetine has recently beenapproved by the Food and Drug Admin-istration for the treatment of neuropathicpain. However, at the time this statementwas being prepared, the evidence of effi-

cacy of this agent was only published inabstract form (22).

In cases of severe pain, certain agentsmay be used in combination (e.g., an anti-depressant and an anticonvulsant) or com-bined with a topicalor nonpharmacologicaltreatment (2) (Fig. 1). All patients withDPN, whether symptomatic or not, are atincreased risk of foot ulceration (2) andshould be considered for podiatric referraland foot care education.2) Autonomic neuropathy. Treatmentapproaches to the management of auto-

nomic neuropathy are summarized in Ta-ble 4.

RECOMMENDATIONS FOR

SCREENING FOR AND

TREATMENT OF DIABETIC

NEUROPATHY

A. Tight glycemic controlFor all diabetic patients, maintain aggres-sive control of blood glucose, HbA

1c,

blood pressure, and lipids with pharma-cological therapy and/or lifestyle changes

B. Screening1) Chronic sensorimotor DPN. All pa-tients with diabetes should be screenedfor DPN at diagnosis of type 2 diabetesand 5 years after the diagnosis of type 1diabetes and at least annually by examin-ing sensory function in the feet andchecking ankle reflexes. One or more ofthe following can be used to assess sen-sory function: pinprick, temperature, andvibration perception (using a 128-Hz tun-ing fork), or pressure sensation (using a

10-g monofilament pressure sensation atthe distal halluces). Any history of neuro-pathic symptoms should be elicited, and acareful clinical examination of the feetand lower limbs should be performed.The feet should be examined for ulcers,calluses, and deformities, and footwearshould be inspected at each diabetes carevisit. All patients with DPN, whethersymptomatic or not, require foot care ed-ucation and consideration for podiatricreferral.

2) Autonomic neuropathy. Based onexpert consensus and clinical experience(level E), screening should be instituted atdiagnosis of type 2 diabetes and 5 yearsafter the diagnosis of type 1 diabetes.Screening might comprise a history andan examination for signs of autonomic

dysfunction. Tests for HRV, including ex-piration-to-inspiration ratio and responseto the Valsalva maneuver and standing,may be indicated. If screening is negative,this should be repeated annually; if posi-tive, appropriate diagnostic tests andsymptomatic treatments should be insti-tuted (Tables 4 and 5).

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Diabetic neuropathies


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