Peripheral Neuropathy

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Abstract

Peripheral n gic -cialties. Phy g f oefciently a ymthey have a igh oclinically str pa yconsultatio do esymptomso evi .Easily den nt eyield of laperipherarecomme

From the DepartmentNeurology (J.C.W., P.J.Band Department of

CONCISE REVIEW FOR CLINICIANSAnesthesiology, DivisionPain Medicine (J.C.W.),Clinic, Rochester, MN.

940I n adults, chronic neurologic disease symp-toms are one of the most common reasonsfor physician visits (even if headache isexcluded),1,2 and evaluation of sensory distur-bance, including peripheral neuropathy, is one

neuropathy in the general population is 2.4%and increases with age to an estimated 8% inthose older than 55 years.4,5 Peripheral neu-ropathy is more common in patients with dia-betes mellitus, human immunodeciency virus

of.D.)

of

Mayoboratory and other diagnostic testing is reviewed for the evaluation of length-dependent, sensorimotorl neuropathies (the most common form of neuropathy), and an algorithmic approach with dosingndations is provided for the treatment of neuropathic pain associated with peripheral neuropathy.

2015 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2015;90(7):940-951ofcoderstand how to clinically dene forms of neuropathy to identify those that maybenet from specialty consultation and those that can be evaluated and treatedwithout further consultation; (2)understand the roleof laboratory andelectrodiag-nostic testing in the evaluation of length-dependent sensorimotor peripheral neu-ropathies; and (3) understand a practical algorithmic approach toneuropathic painassociated with peripheral neuropathy and appropriate dosing guidelines.Disclosures: As a provider accredited byACCME,MayoClinicCollege of Med-icine (Mayo School of Continuous Professional Development) must ensure bal-ance, independence, objectivity, and scientic rigor in its educational activities.Course Director(s), Planning Committee members, Faculty, and all others who

europathy is one of the most prevalent neurolosicians are facedwith3distinct challenges in carinnd effectively screen (in less than 2minutes) an asdisorder in which peripheral neuropathy is hatifypatientspresentingwith symptomsofneuron and what testing is appropriate for those whof painful peripheral neuropathy. In this concise red clinical patterns of involvement are used to idethe 5 most common reasons for neurologicnsultation.3 The prevalence of peripheral

Mayo Clin Proc. n July 2015www.mayoclinicproceedings.org ncompletion of the online test and evaluation, you can instantly download andprint your certicate of credit.Estimated Time: The estimated time to complete each article is approxi-mately 1 hour.Hardware/Software: PC or MAC with Internet access.Date of Release: 7/1/2015Expiration Date: 6/30/2017 (Credit can no longer be offered after it haspassed the expiration date.)Privacy Policy: http://www.mayoclinic.org/global/privacy.htmlQuestions? Contact [email protected].

conditions encountered by physicians of all speor patientswithperipheral neuropathy: (1) how tptomatic patient for peripheral neuropathywhenly prevalent (eg, diabetes mellitus), (2) how tthy todeterminewhowouldbenet fromspecialtnot need consultation, and (3) how to treat th

ew,we address these 3 commonclinical scenariosify patients in need of neurologic consultation, thJames C. Watson, MD, and P. James B. Dyck, MD

CME Activity

Target Audience: The target audience for Mayo Clinic Proceedings is primar-ily internal medicine physicians and other clinicians who wish to advancetheir current knowledge of clinical medicine and who wish to stay abreastof advances in medical research.Statement of Need: General internists and primary care physicians mustmaintain an extensive knowledge base on a wide variety of topics coveringall body systems as well as common and uncommon disorders. Mayo ClinicProceedings aims to leverage the expertise of its authors to help physiciansunderstand best practices in diagnosis and management of conditionsencountered in the clinical setting.Accreditation: Mayo Clinic College of Medicine is accredited by the Accred-itation Council for Continuing Medical Education to provide continuing med-ical education for physicians.Credit Statement: Mayo Clinic College of Medicine designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s).Physicians should claim only the credit commensurate with the extent of

are in a position to control the content of this educational activity are requiredto disclose all relevant nancial relationships with any commercial interest relatedto the subjectmatterof theeducational activity. Safeguardsagainst commercialbiashave been put in place. Faculty also will disclose any off-label and/or investigationaluse of pharmaceuticals or instruments discussed in their presentation. Disclosureof this informationwill bepublished incoursematerials so that thoseparticipants inthe activity may formulate their own judgments regarding the presentation.In their editorial and administrative roles, William L. Lanier, Jr, MD, Terry L.Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the con-tent of this program but have no relevant nancial relationship(s) with industry.The authors report no competing interests.Method of Participation: In order to claim credit, participants must com-plete the following:1. Read the activity.2. Complete the online CME Test and Evaluation. Participants must achieve

a score of 80% on the CME Test. One retake is allowed.ipheral Neuropathy: ADiagnosis and SPractical Approach tomptom Managementinfection, and dysproteinemic disorders and inthose receiving chemotherapy. In patients with

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reduced or absent vibration sensation in isola-diabetes, for example, length-dependent senso-rimotor peripheral neuropathy is evident in 8%at the time of diagnosis6,7 but increases in fre-quency with disease duration to 30% to66%,6-9 depending on whether the neuropathyis dened by clinical or electrophysiologiccriteria.

The primary care physician is presentedwith 3 distinct clinical challenges in caring forpatients with peripheral neuropathy: (1) howto efciently and effectively screen (in less than2 minutes) an asymptomatic patient for periph-eral neuropathy when they have a disorder inwhich peripheral neuropathy is highly prevalent(eg, diabetes mellitus), (2) how to clinically strat-ify patients presenting with symptoms of neu-ropathy to determine who would benet fromspecialty consultation and what testing is appro-priate for those who do not need consultation,and (3) how to treat the symptoms of painfulperipheral neuropathy.

SCREENING FOR PERIPHERALNEUROPATHYThe recognition of peripheral neuropathy in pa-tients with disorders in which it is highly prev-alent may affect the management for thatdisease. Annual screening for peripheral neu-ropathy is recommended in diabetic pa-tients.10,11 Physicians must be able to screenthese patients in an efcient manner during re-turn ofce visits that are often focused on othercomponents of the disease and its treatments.Most recommendations for ofce screening forneuropathy have utilized light touch perceptionto a 10-g Semmes-Weinstein monolament,vibration testing with a 128-Hz tuning fork,supercial pain (pinprick) perception, ortesting of ankle deep tendon reexes.12-16 Clin-ical history alone is an insufcient screen torecognize peripheral neuropathy.15 Althoughmost patients with objective evidence of dia-betic length-dependent peripheral neuropathyare clinically asymptomatic, they remain atrisk for injury to insensate feet.17

If single-modality screening is used, monol-ament light touch or vibration testing appears tobe more sensitive and specic than supercialpain (pinprick) or ankle reex testing.12,13,15

PERIPHERAL NEUROPATHYBecause peripheral neuropathies may affectdifferent types of nerve bers to different degrees,single-modality testing may miss 25% to 50%of those with diabetic neuropathy.15 In diabetic

Mayo Clin Proc. n July 2015;90(7):940-951 n http://dx.doi.org/10.1www.mayoclinicproceedings.orgtion should not be overinterpreted in elderlypatients and should instead prompt furtherhistory and consideration of other sensory mo-dalities to determine its relevance.

Importantly, screening is meant to identifywhether an asymptomatic patient, at risk for pe-ripheral neuropathy secondary to a systemic dis-ease, is likely or unlikely to have a peripheralneuropathy. Alone, it is insufcient to fullycharacterize the neuropathy or direct the neces-sity of further diagnostic tests or consultations.Patients with a positive screening result (ie,clinical signs of probable neuropathy) requirefurther clinical history and examination andcan be evaluated similarly to a patient who pre-sents with clinical symptoms concerning forneuropathy.

EVALUATING PATIENTS PRESENTINGWITH CLINICAL SIGNS OR SYMPTOMSSUGGESTING PERIPHERAL NEUROPATHY

Clinically Stratifying Patients WithPeripheral NeuropathySensory symptoms (eg, numbness, tingling),weakness, autonomic symptoms (eg, earlysatiety, impotence, orthostatic hypotension,sweat abnormalities), or neuropathic (burning,stabbing, electrical) pain may suggest the pres-ence of a peripheral neuropathy. Once a neu-ropathy is suspected (from patient historyor screening examination in at-risk patients),the clinical history and a detailed examinationcohorts, combination testing of vibration plus10-g monolament testing provides the bestbalance of an efcient (less than 2-minute),sensitive (90%), and specic (85%-89%)screen for diabetic peripheral neuropathy andcorrelates with the development of diabeticfoot ulcers.15-17 Light touch with a cottonswab is often substituted for monolamenttesting in clinical practice, although its effecton sensitivity and specicity is unknown.

There is an age-related decline in vibrationsensation, with almost one-quarter of thoseolder than age 65 years and one-third of thoseolder than 75 years having absent vibrationsensation on clinical examination.18 As such,(including strength, sensation, reexes, andgait) allow the neuropathy to be categorizedby either clinical symptom distribution (lengthdependent, length independent, or multifocal)

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or by which clinical modality is affected (motor,sensory, autonomic, or some combination).

The most common pattern of clinicalinvolvement is that of a length-dependent pe-ripheral neuropathy. This form of neuropathy issymmetric, and symptoms begin in the longest

TABLE 1. Neuropathies in

d Acute, subacute in onsetd Rapidly progressived Severe, functionally limitind Length independent (polyd Multifocald Motor predominantd Associated with severe dy

942nerves at their terminals (ie, distal foot). Negative(lack of feeling) or positive (prickling, tingling,burning) sensory symptoms usually precedemotor weakness. The symptoms ascend insidi-ously up the leg, with hand symptoms oftenbecoming evident around the time leg symptomsapproach the knee. Upper limb involvement maynever occur. Development of symptoms in thehands and feet at the same time is atypical for adiabetic length-dependent neuropathy and mayindicate coexisting carpal tunnel syndrome oran alternative cause of neuropathy (eg, a toxic eti-ology). Proprioception is spared relative to othersensory modalities in mild to moderate length-dependent neuropathies and only becomesaffected as the neuropathy severity progresses.Patients with notable early proprioceptive def-icits (gait ataxia, imbalance with eyes closed)require further evaluation for posterior columndisease (eg, vitamin B12 deciency) or for sen-sory cell body dysfunction (a sensory ganglion-opathy as seen in Sjgren syndrome or aparaneoplastic disorder). In length-dependentneuropathies, as the sensory signs and symp-toms progress, weakness and reex abnormal-ities develop distally.

The majority of peripheral neuropathies arelength dependent, sensory predominant, andclinically mild to moderate in severity withoutmajor functional limitations. These neuropathiescan often be effectively evaluated and managedwithout specialty consultation.

Sensory and/or motor symptoms in amore diffuse, length-independent pattern (ie,involving both proximal and distal limbs) sug-gest a polyradiculoneuropathy. Although theseneuropathies may still be sensory predominant,

Which Specialty Consultation Would Be Benecial

gRegardless of clinical pattern or affected modalityradiculoneuropathy)

sautonomia

Mayo Clin Proc. n July 2015motor manifestations are usually more evidentthan in length-dependent neuropathies. Reexescan be useful in these cases because they are glob-ally reduced or absent. Rare patients present withmultifocal clinical symptoms (eg, a wrist drop,followed by a foot drop). As multifocal processesprogress, further neurologic decits accrue, andthe processmay begin to lookmore diffuse. Care-ful history and examination are necessary torecognize these multifocal neuropathies.

Polyradiculoneuropathies and multifocalneuropathies have a distinct differential diagnosisfrom that for length-dependent neuropathies.Etiologies include sarcoidosis, amyloidosis,and neoplastic, paraneoplastic, vasculitic, in-fectious, and inammatory immune-mediatedcauses (such as chronic inammatory demye-linating polyradiculoneuropathy), all of whichhave distinct treatment algorithms. Patientswith a polyradiculoneuropathy or a multifocalneuropathy therefore warrant specialtyconsultation.

Patients with pure motor or autonomicsigns and symptoms are uncommon andwould benet from neurologic consultation.Those with isolated sensory symptoms thatare mild and length dependent can be evalu-ated similarly to those with length-dependentsensorimotor peripheral neuropathies, where-as patients with severe or diffuse sensoryneuropathies causing gait ataxia and proprio-ceptive dysfunction would benet from spe-cialty consultation.

Regardless of clinical pattern of involvement,patients with acute or subacute onset of symp-toms or progressive or functionally limiting neu-ropathies should be considered for neurologicconsultation (Table 1). Similarly, cliniciansshould refer any patient when there is clinicaluncertainty.

Evaluation of Length-Dependent PeripheralNeuropathiesThe combination of history (including familyhistory), examination, ancillary testing, andserologic evaluation yields the etiology of alength-dependent peripheral neuropathy in74% to 82% of cases.19 Importantly, althoughthe etiology of 20% to 25% of these neuropa-

MAYO CLINIC PROCEEDINGSthies remains uncertain, the natural history ofthese idiopathic neuropathies is that theyprogress slowly and are unlikely to causesevere physical disability.19

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considered.8 In up to 10% of diabetic patients,neurologic decits can be attributed to an alterna-tive cause.8 Inherited neuropathy is one of thecommon alternative causes. Although diabetesis the likely cause in diabetic patients presentingwith a length-dependent peripheral neuropathy,a limited screening laboratory evaluation (eg,serum protein immunoxation electrophoresis,vitamin B12 with methylmalonic acid, thyroidstudies) for other treatable metabolic disordersis reasonable before attributing the neuropathyto diabetes.

Diabetes can cause other patterns of neu-

th-Dependent Peripheral

igen if dry eyes/mouth and

lectrophoresis) (10%)

ease, human immunode-Serologic Evaluation. The American Academyof Neurology has published a practice parameterfor the evaluation of clinically mild to moderate,symmetric, sensory-predominant length-depen-dent peripheral neuropathies.19 The highest-yield testing includes screens for diabetes melli-tus, vitamin B12 with methylmalonic acid, andserum protein immunoxation electrophoresis(SPIEP).19 A practical evaluation for chronic,length-dependent peripheral neuropathy is pre-sented in Table 2. Clinical practice reviews haverevealed poor adherence to screening recom-mendations.20 In a review of 1031 cases of pe-ripheral neuropathy, more than 400 patterns ofdiagnostic testingwere identied.20 In an analysisof patients without known diabetes mellitus toexplain their neuropathy, low-cost, high-yieldstudies were underutilized (fasting glucose,

944idiopathic, chronic, sensory-predominant,length-dependent peripheral neuropathies.Impaired glucose tolerance has been noted tobe more prevalent in those with idiopathicneuropathy than in controls.28-30 It has beensuggested that 25% to 50% of idiopathic neu-ropathies (especially painful small-ber neu-ropathies) may be explained by IGT.19 Theglucose tolerance test is more sensitive inidentifying IGT than fasting glucose or hemo-globin A1c measurements, and many haveadvocated its use as a standard laboratoryscreen in unexplained length-dependent neu-ropathies.19,30 These associations, however,have not proven cause and effect, and otherstudies have not found this association.31

A recent large, controlled trial has addressedthis question.32 Patients with new-onset diabetesmellitus or IGT and healthy controls had clini-cally blinded assessments (history, examination,nerve conduction studies, quantitative sensorytesting) for evidence of large- or small-berperipheral neuropathy, as well as nephropathyand retinopathy. Although as expected, patientswith new-onset type 2 diabetes had a higherprevalence of peripheral neuropathy, retinop-athy, and nephropathy than healthy controls orpatients with IGT, there was no difference inthe prevalence of clinically or electrophysiologi-cally dened peripheral neuropathy, retinopathy,or nephropathy between the IGT cohort and thehealthy control cohort. This study strongly chal-lenges the assertion that IGT causes peripheralneuropathy or is a frequent cause of idiopathicneuropathies. If a patient being evaluated for aperipheral neuropathy has evidence of IGT, analternative etiology should be considered (bydening clinical pattern of involvement, labora-tory and electrophysiologic testing, and familyhistory). If this same patient subsequently hasprogression to diabetes, the patient is at risk forthe diabetes worsening the neuropathy.

Vitamin B12 Deciency. In the nervous system,vitamin B12 is integral in the initial developmentof and maintenance of myelin.33 Vitamin B12deciency can cause classic subacute combineddegeneration or an isolated peripheral neuropa-thy without central nervous system involve-

34ment. In patients presenting with a length-dependent peripheral neuropathy, the serumB12 level should be measured. Among patientswith low-normal serum B12 levels (200-500 pg/

Mayo Clin Proc. n July 2015mL [to convert to pmol/L, multiply by 0.7378]),5% to 10% will have elevated serum methyl-malonic acid concentrations indicating cellularB12 deciency.

19 Adding methylmalonic acid(with or without homocysteine) to a screen ofserum B12 level improves the yield of identifyingcellular B12 deciency as a cause of neuropathyfrom 2% to 8%.34,35

Dysproteinemias. Up to 10% of peripheralneuropathies are associated with dysproteine-mias (a 6-fold increase over the general popula-tion), with the majority being a monoclonalgammopathy of undetermined signicance(MGUS).36 Evaluation by SPIEP is more sensitivein identifying a monoclonal protein than serumprotein electrophoresis (SPEP); SPEP misses17% of all monoclonal proteins identied withimmunoxation and 30% of all IgM monoclonalgammopathies.37Themost commonmonoclonalprotein associated with peripheral neuropathy isIgM. For the evaluation of patients presentingwith peripheral neuropathy, SPIEP is recom-mended over SPEP.19

The nding of a monoclonal protein neces-sitates further evaluation, and possible hemato-logic evaluation, to exclude disorders such asamyloidosis, multiple myeloma, osteoscleroticmyeloma (POEMS [polyneuropathy, organome-galy, endocrinopathy, monoclonal protein, skinabnormalities] syndrome), lymphoma, Walden-strm macroglobulinemia, or cryoglobulinemia.

Most MGUS neuropathies occur in thesetting of IgM, IgG, or IgA paraproteinemias(IgM being the most common) and usuallycause axonal, length-dependent sensorimotorneuropathies (although polyradiculoneuropa-thies can also occur). Most IgM paraproteine-mias are associated with an MGUS; however,some are associated with a distinct demyelin-ating (distinguishing it from MGUS-associatedaxonal neuropathies) clinical syndrome with se-vere symmetric distal sensory-predominant def-icits (distal acquired demyelinating symmetricneuropathy).38,39 Two-thirds of patients withdistal acquired demyelinating symmetric neu-ropathy have serum antimyelin-associatedglycoprotein antibodies.38 This syndrome isimportant because it may respond to immuno-

40

MAYO CLINIC PROCEEDINGSmodulatory treatments.The peripheral neuropathy associated with

POEMS syndrome is typically a uniform mixeddemyelinating and axonal length-independent


polyradiculoneuropathy in the setting of an IgGor IgA paraproteinemia with a l light chain.41

POEMS syndrome is associated with osteoscler-otic myeloma and increased levels of serumvascular endothelial growth factor.

Electrophysiologic characterization of theneuropathy and neurologic consultation shouldbe considered in patients with non-MGUS para-proteinemias, IgM paraproteinemias, and/orfunctionally limiting neuropathies.

Other Laboratory Tests. Although patientspresenting with a thyroid disorder often haveneuromuscular complaints, hypothyroidism isan uncommon cause of a length-dependent pe-ripheral neuropathy. Because hypothyroidism isa prevalent treatable disorder, however, patientspresenting with peripheral neuropathy arecommonly tested for this disease.35

In geographic regions where Lyme diseaseis prevalent or in patient populations with riskfactors for human immunodeciency virusinfection, routine screening may be appro-priate as part of the evaluation of peripheralneuropathy.

Celiac disease was found to be responsiblefor 2.5% of peripheral neuropathy cases present-ing to a tertiary referral center.42 Usually, thesepatients have sensory-predominant neuropa-thies and associated gastrointestinal symptoms,although neurologic signs and symptoms mayprecede gastrointestinal symptoms and somerecommend screening all patients.42 Antietissuetransglutaminase antibodies are the most sensi-tive serologic screen, but their specicity islimited in association with neurologic disease,and conrmation with small-bowel biopsyshould be obtained before attributing neuropa-thy to celiac disease.42,43

Copper deciency can mimic vitamin B12deciency clinically (with a myelopathy andsensory-predominant neuropathy) and shouldbe considered when patients have a history ofbariatric surgery or multiple nutritional de-ciencies or if high zinc exposure (nutritionalsupplement or in some denture pastes) issuspected.44,45

Vitamin E deciency may be considered inpatients at risk for fat malabsorption.

PERIPHERAL NEUROPATHYToxic Neuropathies. Many neuropathies arethe result of toxic effects of prescribed medica-tions. Contextual cues that a neuropathy may

Mayo Clin Proc. n July 2015;90(7):940-951 n http://dx.doi.org/10.1www.mayoclinicproceedings.orgbe related to medication toxicity include theuse of a known neurotoxic medication (eg,chemotherapeutic agents), temporal onset ofsymptoms with initiation or dosage adjustmentof an implicated medication, worsening symp-toms with higher dosages, onset of symptomsin the hands and feet concomitantly, and symp-tom stabilization or resolution following discon-tinuation of the offending agent.46 Of note,although most toxic neuropathies show at leaststabilization soon after the toxic agent is dis-continued, some medications (particularlyplatinum-based chemotherapeutic agents) mayremain active for several weeks or months afterdiscontinuation, and stabilization or improve-ment may not be evident immediately.47

Excessive, long-term alcohol use can causeperipheral neuropathy, usually in the context ofother systemic complications including nutri-tional deciencies, particularly thiamine de-ciency. Long-term alcohol use may also have adirect neurotoxic effect.46

A comprehensive list of potentially neuro-toxic medications or supplements is beyondthe scope of this article but has been addressedby others.46,48

Hereditary Neuropathies. Inherited neurop-athies are the most common inherited neuro-muscular condition worldwide and likelyrepresent the most commonly overlooked eti-ology of peripheral neuropathy.49-51 In fact,they may be the most common cause of pe-ripheral neuropathy (although this has notbeen rmly established). Charcot-Marie-Toothdisease, also referred to as hereditary motorand sensory neuropathy, is the most commonform of hereditary neuropathy and can becategorized into axonal and demyelinatingforms. InWestern countries, these neuropathiesare most commonly autosomal and X-linkeddominant.52

Clinically, a hereditary neuropathy is sug-gested by an insidious onset of symptomswith a slow progressive course over years,distal-predominant motor greater than sensorycomplaints, lack of positive sensory symptoms(dysesthesias, burning), associated structuralfoot and ankle deformity (pes cavus, hammer-

toes, and inverted champagne bottle legs withvery thin ankles), and a family history of neurop-athy. It is common that family members are un-aware of a family history even when one is

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TABLE 3. Neuropathic Pain Treatment Tiersa

Agent DosingMaximumdosage Precautions

Common and notableadverse effects

Comorbidconditions treated Comments

Tier 1

AnticonvulsantsGabapentinb 300 mg at bedtime, increase every 4-7

d by 300-mg increments initially to 3times daily, then to goal of 1800mg/d as necessary to 3600 mg/d

3600 mg/ d(split TID)

Renal insufciency (dosage adjust);risk of seizure if abruptly stopped

Sedation, dizziness, confusion,edema, tremor

Seizure disorder, sleepdisturbance, chronicmigraine, hot ashes

100-mg increments available for slowertitration; no notable drug interactions

Pregabalinb 75 mg twice daily; after 4-7 d, increaseby same dosage to goal of 300 mg/das necessary to 600 mg/d

600 mg/d(split BID)

Renal insufciency (dosage adjust);risk of seizure if abruptly stopped;psychiatric disease or addictionhistory (euphoria risk)

Sedation, dizziness, confusion,edema, tremor, euphoria(Schedule V controlledsubstance)

Seizure disorder, sleepdisturbance,bromyalgia, centralpain related to spinalcord injury, anxiety

Can split 3 times daily but better compliancewith 2 times daily dosing with similarefcacy; 25- and 50-mg dosing availablefor slower titration; no notable druginteractions

AntidepressantsAmitriptyline,

nortriptylineb10-25 mg at bedtime, increase every

4-7 d to goal of 100 mg atbedtime

150 mg/d Risk of serotonin syndrome; cautionif cardiac disease or dysrhythmiahistory

Sedation, dry mouth,orthostatic hypotension,confusion, weight gain,urinary retention,constipation, blurred vision

Depression,bromyalgia, chronicmigraine, sleepdisturbance, irritablebowel syndrome

Goal dosing for pain usually inadequate formood effect; higher dosages (w100mg/d) often necessary for neuropathicpain; secondary amine TCAs(nortriptyline, desipramine) have loweradverse effect prole than tertiary amineTCAs (amitriptyline)

Duloxetineb 20-30 mg once daily, then increaseweekly by same dosage to goal of60 mg/d

120 mg/d(split BID)

Risk of serotonin syndrome; increasedbleeding risk (care withanticoagulants), withdrawal syndromeswith abrupt discontinuation, cautionwith hepatic failure

Sedation, fatigue, nausea,hyperhidrosis, dizziness,modest hypertension

Depression, anxiety,bromyalgia, chronicmusculoskeletal pain,urinary incontinence

Dosing for neuropathic pain is adequate fortreatment of depression/anxiety

Supplementsa-Lipoic acid 600 mg once daily 600 mg/d Caution if tendency toward

hypoglycemiaNausea, rash, hypothyroidism None Generally well tolerated

Acetyl-L-carnitine

1000 mg 3 times per day 3000 mg/d(split TID)

None Nausea, bloating, agitation None Generally well-tolerated

TopicalsLidocaine

(5%) patch

Apply patch for 12 h 3 patches perapplication

Avoid over broken skin Localized skin irritation; nonotable systemic toxicity

None May cut patch to shape

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TABLE 3. Continued

Agent DosingMaximumdosage Precautions

Common and notableadverse effects

Comorbidconditions treated Comments

Tier 1, continued

Capsaicin (8%)patch

Should be placed by medical staff trainedin its usage using nonlatex gloves;pretreat area with 4% topical lidocainefor 60 min, conrm anesthesia, applypatch(es) to affected area (may cut toshape) for 60 min, wipe clean withprovided soap

4 patches perapplication

Avoid face or placing over broken skin Localized skin irritation; nonotable systemic toxicity

None Postprocedural skin irritation common;prescription oral analgesics frequentlyrequired for 7-10 d after application;single application may provide pain relieffor up to 3 mo

Tier 2

AntidepressantsVenlafaxineb 37.5 mg once (extended release) or

twice (immediate release) daily;increase by 75 mg/d weekly to initialgoal of 150 mg/d

225 mg/d Risk of serotonin syndrome;withdrawal syndrome with abruptdiscontinuation; caution with cardiacdisease or poorly controlledhypertension

Sedation, nausea, dizziness,headache, insomnia,nervousness, abnormalejaculation, modesthypertension (dosage >150mg/d)

Depression, anxiety,panic attacks, socialphobia, hot ashes

Similar mechanism of action to duloxetine;consider trial if duloxetine not covered byinsurance; higher dosages (150-225mg/d) required for neuropathic pain;increasing blockage of norepinephrinereuptake at higher dosages causesincreased risk of hypertension

AnalgesicsTramadol 50 mg twice daily; increase every

4-7 d to maximum of 100 mg perdose 4 times per day

400 mg/d Caution if history of addiction,analgesic misuse or diversion, severepsychiatric comorbidities, seizuredisorder, taking other serotonergicagents, hepatic or renal dysfunction

Nausea, constipation, sedation,dizziness, ushing, seizures(dosages >400 mg/d)

Is a nonspecic analgesicthat will covermultiple pain types

Blocks reuptake of serotonin andnorepinephrine (like antidepressants) inaddition to being m-opioid receptoragonist; risk of serotonin syndrome whenused with other serotonergic agents

Tier 3

AnalgesicsTapentadol 50 mg every 4-6 h prn; increase every

4-7 d to maximum of 100 mgevery 4 h prn

600 mg/d Caution if history of addiction,analgesic misuse or diversion, severepsychiatric comorbidities, seizuredisorder, taking other serotonergicagents, hepatic dysfunction

Nausea, sedation, constipation,dizziness, pruritus,headache, hypotension,respiratory depression,seizure


FDA approved for painful diabeticperipheral neuropathy; blocks reuptake ofserotonin and norepinephrine (likeantidepressants) in addition to beingm-opioid receptor agonist; risk ofserotonin syndrome when used withother serotonergic agents

Opioids 15 mg oral immediate release morphine(or another opioid of equianalgesicdose such as 10 mg oxycodone) 3-4times per day, transition to long-actingagents if regular use of short-actingagents

No maximumdosage

Caution if history of addiction,analgesic misuse or diversion,severe psychiatric comorbidities

Nausea, sedation, constipation,dizziness, pruritus,headache, respiratorydepression


Neuropathic pain studies used long-actingagents that should not be used in opioid-naive patients; begin with short-actingagents

aBID twice daily; FDA US Food and Drug Administration; prn as needed; TID 3 times daily; TCA tricyclic antidepressant.bAll antidepressants and anticonvulsants carry an FDA warning that they may paradoxically cause worsening mood or emerging suicidality in a very small percentage of patients. Patients should be aware of both physical andemotional adverse effects of medications.

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948present. All patients with an idiopathic neurop-athy should be encouraged to discuss thisfurther with their family. If a family member ac-companies the patient, a screening examinationmay suggest the diagnosis.

Algorithms have been developed to directsequential genetic testing in suspected casesof hereditary neuropathy based on the inheri-tance pattern and whether the neuropathy isaxonal or demyelinating.19,52 Indiscriminate,nondirected serologic screens for hereditaryneuropathies are expensive, have low yield,and often do not alter management, especiallyif there are no clinical features or family historyto suggest a hereditary neuropathy.

Other Diagnostic TestsNerve Conduction Studies and Electromyo-graphy. In patients presenting with neurologicsigns or symptoms suggestive of a peripheral neu-ropathy, electromyography (EMG) and nerveconduction studies (NCSs) are useful to conrmthe suspected diagnosis, exclude mimickers (S1radiculopathies in a patient with foot symptomsor carpal tunnel syndrome in a patient withhand paresthesias), localize the process (lengthdependent, length independent, multifocal),conrm the modalities affected (sensory, motor),dene whether the neuropathy is secondary toaxonal loss, demyelination, or both, and denethe severity of the neuropathy. In cases of mild,nonefunctionally limiting length-dependentneuropathies in which there is little clinical un-certainty, EMG may not be necessary. Electro-myography/NCSs are central to the evaluation ofcases with diagnostic uncertainty, length-independent or multifocal processes, function-ally limiting neuropathies, or any neuropathysevere enough to require neurologic consultation.Because the electrophysiologic pattern and path-ophysiology are so central to the evaluation ofatypical neuropathies, specialists will likely preferto perform their own EMGs in patients withlength-independent, multifocal, or severe neu-ropathies. Electromyography can still be usefuldirectly to the nonspecialist for conrming thesuspected diagnosis and excluding commonmimickers such as mononeuropathies orradiculopathies.Electromyography/NCSs assess the func-tion and integrity of large, myelinated Abeta nerve bers. They do not assess smallnerve bers (C ber and small myelinated A

Mayo Clin Proc. n July 2015delta). As such, normal ndings on EMG donot exclude a small-ber peripheral neuropa-thy (which clinically presents with prominentpain, sensory loss, and dysautonomia).

Test of Small Nerve Fiber Function. A num-ber of tests can evaluate possible small-berperipheral neuropathies (autonomic reexscreen, testing of sweat function, quantitativesensory testing, and epidermal skin biopsy fornerve ber density); however, some are notwidely available. Like peripheral pain pathways,the autonomic nervous system is under thecontrol of small thinly myelinated and unmy-elinated bers. As such, tests of sweat (sudo-motor) function, heart rate variability torespiration and Valsalva maneuver, blood pres-sure, and heart rate response to tilt (orthostatichypotension) can objectively identify smallnerve ber dysfunction. These autonomic testsare most useful in neuropathies with notableautonomic impairment. In the evaluation ofsmall-ber neuropathies without clinical dys-autonomia, tests of sweat function are moreuseful. All of these autonomic and sweat testscan be substantially inuenced by medications,adversely affecting specicity.

Skin biopsy is a validated technique fordetermining intraepidermal nerve ber density(somatic unmyelinated C-ber nerve termi-nals) and has increasing availability. It has asensitivity of 90% in diagnosing a small-berneuropathy, with specicity of 95% to 97%.19

Quantitative sensory testing refers tocontrolled applications of large- and small-ber sensations to the skin to determine thethreshold for detection. In small-ber neurop-athies, the response to thermal (hot and cold)stimuli is most pertinent, and the heat-painthreshold has very good sensitivity for asmall-ber neuropathy. Patient cooperation isnecessary for an accurate measurement,although testing paradigms can help identifyinconsistencies suggesting malingering orinattentiveness.

Nerve Biopsy. A nerve biopsy may be useful toassess for possible inammatory-mediated neu-ropathies (vasculitis, sarcoidosis, chronic inam-

MAYO CLINIC PROCEEDINGSmatory demyelinating polyradiculoneuropathy),some infectious neuropathies (leprosy), or inl-trative neuropathies (carcinoma, lymphoma,amyloidosis, polyglucosan bodies). These


neuropathies are frequently severe, progres-sive, and not otherwise explained by serologicand other ancillary testing. Neurologicconsultation should be obtained before nervebiopsy. The sural nerve is most commonlybiopsied, although the nerve selected forbiopsy should be clinically involved. Impor-tantly, a sural nerve biopsy is not indicatedjust because a neuropathy is idiopathic andunexplained by serologic and ancillarytesting.

SYMPTOMATIC MANAGEMENT OFPERIPHERAL NEUROPATHYThe primary goal in the evaluation of neuropa-thy is to identify the etiology and if possible treatthe underlying cause. However, even when theneuropathy has a treatable etiology (such as dia-betes mellitus, vitamin B12 deciency, or toxicexposure), treatment serves primarily to preventfurther progression of the neuropathic symp-toms. Symptoms present at the start of treat-ment or when a toxic agent is removed mayimprove and occasionally resolve. However,more commonly patients are left with lingeringsymptoms from the pretreatment neurogenicinjury. In these cases and in those in whichthe neuropathy is idiopathic or untreatable,management is symptomatic.

Because most patients with a length-dependent peripheral neuropathy have sensory-predominant symptoms, patients should becounseled on the importance of foot care andproperly tted footwear. Patients should monitortheir feet for early signs of ulceration or injurythat sensory loss may mask.

One of themost limiting symptoms frompe-ripheral neuropathy is neuropathic pain. Amongdiabetic patients with neuropathy, 11% to 26%have neuropathic pain.21-23 Common neuro-pathic pain descriptors (burning, pins and nee-dles, electrical, or shooting pain), whetherused alone or in standardized surveys meant toidentify neuropathic pain, are limited in regardto sensitivity and specicity.53 In one diabeticcohort of patients with lower limb pain, thepain was attributable to diabetic neuropathy inonly one-third of cases.21 Allodynia (pain froma nonpainful stimulus such as the light touch

PERIPHERAL NEUROPATHYof clothing) or hyperalgesia (excessive painfulresponse to a normally painful stimulus suchas pinprick) are highly specic for neuropathicpain but are uncommon.

Mayo Clin Proc. n July 2015;90(7):940-951 n http://dx.doi.org/10.1www.mayoclinicproceedings.orgPatients with neuropathic pain can be chal-lenging to treat and have annual health careexpenditures three times higher than thosewithout pain.54 As with any chronic pain state,comorbid depression, anxiety, and sleep distur-bances are common, occurring in up to one-half of those with painful neuropathy.55

Several consensus algorithms for the treat-ment of chronic neuropathic pain have been pro-posed and compared.56-60 Only one has focusedexplicitly on painful diabetic peripheral neuropa-thy.61 However, because most randomizedcontrolled trials for neuropathic pain have beenperformed for painful diabetic neuropathy orpostherpetic neuralgia, this guideline mirrorsthe other algorithms (Table 3). First-line agentsinclude anticonvulsants that block thea2-d ligandof the presynaptic calcium channel (gabapentinor pregabalin) and thereby decrease nociceptivetransmission, tricyclic antidepressants (secondaryamines such as nortriptyline and desipraminehave a lower adverse effect prole than tertiaryamines such as amitriptyline), or selectiveserotonin-norepinephrine reuptake inhibitors(duloxetine). The choice of rst-line agents isbased on patient comorbidities. For example, pa-tients with comorbid depression may benetfrom duloxetine, which can be used to treatboth the depression and the neuropathic painwith similar dosing, whereas the effective dosageof tricyclic antidepressants for neuropathic painis usually insufcient for therapeutic treatmentof depression or anxiety. Similarly, tricyclic anti-depressants, duloxetine, or pregabalin may be agood rst-line agent in patients with comorbidbromyalgia, whereas patients with comorbidchronic migraine may benet from gabapentinor a tricyclic antidepressant. Comorbidities mayalso relatively contraindicate a particular agent.For example, tricyclic antidepressants shouldbe avoided or used with caution in patientswith preexisting orthostatic hypotension, cardiacdysrhythmia, or urinary hesitancy. Patients withsmall areas of localized pain may be able to betreated with topical agents (Table 3).

Effective dosages for neuropathic pain havebeen dened (Table 3), but failed medication tri-als are commonly caused by inadequate dosing. Ifa patient has a partial response to arst-line agent,

a second rst-line agent with a distinct mecha-nism of action should be added to the rst agent.Combination therapy utilizing neuropathic painmedications with different mechanisms of action

016/j.mayocp.2015.05.004 949

opioid analgesics. These agents are efcacious

tered in the primary care setting. In patients

gammopathy of undetermined signicance; NCS = nerveconduction study; POEMS = polyneuropathy, organo-

20. Callaghan B, McCammon R, Kerber K, Xu X, Langa KM,

950megaly, endocrinopathy, monoclonal protein, skin abnor-malities; SPEP = serum protein electrophoresis; SPIEP =serum protein immunoxation electrophoresis

Correspondence: Address to James C. Watson, MD,Department of Neurology, Mayo Clinic, 200 First St SW,Rochester, MN 55905 ([email protected]).

REFERENCES1. St Sauver JL, Warner DO, Yawn BP, et al. Why patients visit their

doctors: assessing the most prevalent conditions in a denedAmerican population. Mayo Clin Proc. 2013;88(1):56-67.

2. Hsiao CJ, Donald K, Cherry DK, Beatty PC, Rechtsteiner EA.with systemic disease such as diabetes mellitus,peripheral neuropathy can be efciently identi-edor ruled out by screeningwith a combinationof vibration and light touch testing.Most periph-eral neuropathies are length dependent, sensorypredominant, and clinically mild to moderate inseverity without notable functional limitations.These neuropathies can usually be effectivelyworked up and managed without specialtyconsultation. The highest-yield screening is fordiabetes mellitus, vitamin B12 with methylma-lonic acid, SPIEP, and family history suggestingan inherited neuropathy. Neuropathies that arelength independent (polyradiculoneuropathies),multifocal, severe, functionally limiting, orrapidly progressive warrant neurologic consulta-tion. Neuropathic pain can be effectively treatedwith an algorithmic approach.

Abbreviations and Acronyms: EMG = electromyography;IGT = impaired glucose tolerance; MGUS = monoclonalfor neuropathic pain but have a higher long-term risk prole and should only be used in care-fully selected patients with predened pain reliefand functional goals. If these goals are not met,then analgesics can be considered a failed trialsimilar to other neuropathic pain agents.

CONCLUSIONPeripheral neuropathy is commonly encoun-has been repeatedly found to be more efcaciousthan single-agent treatment.62 If a rst-line agentfails, taper the agent and try another rst-lineagent. Second- and third-line agents includeNational Ambulatory Medical Care Survey: 2007 summary.Natl Health Stat Report. 2010;27:1-32.

3. Centers forDisease Control and Prevention. National AmbulatoryMedical Care Survey factsheet: neurology. Centers for Disease

Mayo Clin Proc. n July 2015Control and Prevention website. http://www.cdc.gov/nchs/data/ahcd/NAMCS_2010_factsheet_neurology.pdf. Accessed May13, 2015.

4. Martyn CN, Hughes RA. Epidemiology of peripheral neuropa-thy. J Neurol Neurosurg Psychiatry. 1997;62(4):310-318.

5. Italian General Practitioner Study Group (IGPSG). Chronicsymmetric symptomatic polyneuropathy in the elderly: a eldscreening investigation in two Italian regions, I: Prevalence andgeneral characteristics of the sample. Neurology. 1995;45(10):1832-1836.

6. Partanen J, Niskanen L, Lehtinen J, Mervaala E, Siitonen O,Uusitupa M. Natural history of peripheral neuropathy in pa-tients with non-insulin-dependent diabetes mellitus. N Engl JMed. 1995;333(2):89-94.

7. Boulton AJM. Management of diabetic peripheral neuropathy.Clin Diabetes. 2005;23(1):9-15.

8. Dyck PJ, Kratz KM, Karnes JL, et al. The prevalence by stagedseverity of various types of diabetic neuropathy, retinopathy,and nephropathy in a population-based cohort: the RochesterDiabetic Neuropathy Study [published correction appears inNeurology. 1993;43(11):2345]. Neurology. 1993;43(4):817-824.

9. Gregg EW, Sorlie P, Paulose-Ram R, et al. Prevalence of lower-extremity disease in the US adult population 40 years of agewith and without diabetes: 1999-2000 National Health andNutrition Examination Survey. Diabetes Care. 2004;27(7):1591-1597.

10. American Diabetes Association. Standards of medical care indiabetesd2014. Diabetes Care. 2014;37(suppl 1):S14-S80.

11. Boulton AJ, Armstrong DG, Albert SF, et al. Comprehensivefoot examination and risk assessment: a report of the TaskForce of the Foot Care Interest Group of the American Dia-betes Association, with endorsement by the American Associ-ation of Clinical Endocrinologists. Diabetes Care. 2008;31(8):1679-1685.

12. Perkins BA, Olaleye D, Zinman B, Bril V. Simple screening testsfor peripheral neuropathy in the diabetes clinic. Diabetes Care.2001;24(2):250-256.

13. Olaleye D, Perkins BA, Bril V. Evaluation of three screeningtests and a risk assessment model for diagnosing peripheralneuropathy in the diabetes clinic. Diabetes Res Clin Pract.2001;54(2):115-128.

14. Kamei N, Yamane K, Nakanishi S, et al. Effectiveness ofSemmes-Weinstein monolament examination for diabetic pe-ripheral neuropathy screening. J Diabetes Complications. 2005;19(1):47-53.

15. Al-Geffari M. Comparison of different screening tests for diag-nosis of diabetic peripheral neuropathy in primary health caresetting. Int J Health Sci (Qassim). 2012;6(2):127-134.

16. Armstrong DG, Lavery LA, Vela SA, Quebedeaux TL,Fleischli JG. Choosing a practical screening instrument to iden-tify patients at risk for diabetic foot ulceration. Arch Intern Med.1998;158(3):289-292.

17. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: astatement by the American Diabetes Association. DiabetesCare. 2005;28(4):956-962.

18. Odenheimer G, Funkenstein HH, Beckett L, et al. Comparisonof neurologic changes in successfully aging persons vs the totalaging population. Arch Neurol. 1994;51(6):573-580.

19. England JD, Gronseth GS, Franklin G, et al. Practice Parameter:evaluation of distal symmetric polyneuropathy: role of labora-tory and genetic testing (an evidence-based review); report ofthe American Academy of Neurology, American Associationof Neuromuscular and Electrodiagnostic Medicine, and Amer-ican Academy of Physical Medicine and Rehabilitation.Neurology. 2009;72(2):185-192.

MAYO CLINIC PROCEEDINGSFeldman E. Tests and expenditures in the initial evaluation ofperipheral neuropathy. Arch Intern Med. 2012;172(2):127-132.

21. Davies M, Brophy S, Williams R, Taylor A. The preva-lence, severity, and impact of painful diabetic peripheral


PERIPHERAL NEUROPATHYneuropathy in type 2 diabetes. Diabetes Care. 2006;29(7):1518-1522.

22. Argoff CE, Cole BE, Fishbain DA, Irving GA. Diabetic peripheralneuropathic pain: clinical and quality-of-life issues. Mayo ClinProc. 2006;81(4, suppl):S3-S11.

23. Van Acker K, Bouhassira D, De Bacquer D, et al. Prevalenceand impact on quality of life of peripheral neuropathy withor without neuropathic pain in type 1 and type 2 diabetic pa-tients attending hospital outpatients clinics. Diabetes Metab.2009;35(3):206-213.

24. Diabetes Control and Complications Trial Research Group. Theeffect of intensive treatment of diabetes on the development andprogression of long-term complications in insulin-dependentdiabetes mellitus. N Engl J Med. 1993;329(14):977-986.

25. Fullerton B, Jeitler K, Seitz M, Horvath K, Berghold A,Siebenhofer A. Intensive glucose control versus conventionalglucose control for type 1 diabetes mellitus. Cochrane DatabaseSyst Rev. 2014;2:CD009122.

26. Hemmingsen B, Lund SS, Gluud C, et al. Targeting intensive gly-caemic control versus targeting conventional glycaemic controlfor type 2 diabetes mellitus. Cochrane Database Syst Rev. 2013;11:CD008143.

27. Dyck PJ, Norell JE, Dyck PJ. Microvasculitis and ischemia in dia-betic lumbosacral radiculoplexus neuropathy. Neurology. 1999;53(9):2113-2121.

28. Singleton JR, Smith AG, Bromberg MB. Increased prevalence ofimpaired glucose tolerance in patients with painful sensory neu-ropathy. Diabetes Care. 2001;24(8):1448-1453.

29. Singleton JR, Smith AG, Bromberg MB. Painful sensory poly-neuropathy associated with impaired glucose tolerance. MuscleNerve. 2001;24(9):1225-1228.

30. Sumner CJ, Sheth S, Grifn JW, Cornblath DR, Polydefkis M.The spectrum of neuropathy in diabetes and impaired glucosetolerance. Neurology. 2003;60(1):108-111.

31. Fujimoto WY, Leonetti DL, Kinyoun JL, Shuman WP,Stolov WC, Wahl PW. Prevalence of complications amongsecond-generation Japanese-American men with diabetes,impaired glucose tolerance, or normal glucose tolerance.Diabetes. 1987;36(6):730-739.

32. Dyck PJ, Clark VM, Overland CJ, et al. Impaired glycemia anddiabetic polyneuropathy: the OC IG Survey. Diabetes Care.2012;35(3):584-591.

33. Stabler SP. Vitamin B12 deciency. N Engl J Med. 2013;368(2):149-160.

34. Saperstein DS, Wolfe GI, Gronseth GS, et al. Challenges in theidentication of cobalamin-deciency polyneuropathy. ArchNeurol. 2003;60(9):1296-1301.

35. Smith AG, Singleton JR. The diagnostic yield of a standardizedapproach to idiopathic sensory-predominant neuropathy. ArchIntern Med. 2004;164(9):1021-1025.

36. Kelly JJ Jr, Kyle RA, OBrien PC, Dyck PJ. Prevalence of mono-clonal protein in peripheral neuropathy. Neurology. 1981;31(11):1480-1483.

37. Kahn SN, Bina M. Sensitivity of immunoxation electrophoresis fordetecting IgM paraproteins in serum. Clin Chem. 1988;34(8):1633-1635.

38. Katz JS, Saperstein DS, Gronseth G, Amato AA, Barohn RJ.Distal acquired demyelinating symmetric neuropathy.Neurology. 2000;54(3):615-620.

39. Saperstein DS, Katz JS, Amato AA, Barohn RJ. Clinical spectrumof chronic acquired demyelinating polyneuropathies. MuscleNerve. 2001;24(3):311-324.

40. Mygland A, Monstad P. Chronic acquired demyelinating sym-metric polyneuropathy classied by pattern of weakness. ArchNeurol. 2003;60(2):260-264.Mayo Clin Proc. n July 2015;90(7):940-951 n http://dx.doi.org/10.1www.mayoclinicproceedings.org41. Mauermann ML, Sorenson EJ, Dispenzieri A, et al. Uniform demy-elination and more severe axonal loss distinguish POEMS syn-drome from CIDP. J Neurol Neurosurg Psychiatry. 2012;83(5):480-486.

42. Chin RL, Sander HW, Brannagan TH, et al. Celiac neuropathy.Neurology. 2003;60(10):1581-1585.

43. McKeon A, Lennon VA, Pittock SJ, Kryzer TJ, Murray J. Theneurologic signicance of celiac disease biomarkers. Neurology.2014;83(20):1789-1796.

44. Kumar N, Gross JB Jr, Ahlskog JE. Copper deciency myelop-athy produces a clinical picture like subacute combined degen-eration. Neurology. 2004;63(1):33-39.

45. Thaisetthawatkul P, Collazo-Clavell ML, Sarr MG, Norell JE,Dyck PJ. A controlled study of peripheral neuropathy after bar-iatric surgery. Neurology. 2004;63(8):1462-1470.

46. Morrison B, Chaudhry V. Medication, toxic, and vitamin-relatedneuropathies. Continuum (Minneap Minn). 2012;18(1):139-160.

47. Windebank AJ, Grisold W. Chemotherapy-induced neuropa-thy. J Peripher Nerv Syst. 2008;13(1):27-46.

48. England JD, Asbury AK. Peripheral neuropathy. Lancet. 2004;363(9427):2151-2161.

49. Braathen GJ, Sand JC, Lobato A, Hyer H, Russell MB. Geneticepidemiology of Charcot-Marie-Tooth in the general popula-tion. Eur J Neurol. 2011;18(1):39-48.

50. Skre H. Genetic and clinical aspects of Charcot-Marie-Toothsdisease. Clin Genet. 1974;6(2):98-118.

51. Braathen GJ. Genetic epidemiology of Charcot-Marie-Toothdisease. Acta Neurol Scand Suppl. 2012;(193):iv-22.

52. Saporta MA. Charcot-Marie-Tooth disease and other inheritedneuropathies. Continuum (Minneap Minn). 2014;20(5, PeripheralNervous System Disorders):1208-1225.

53. Haanp M, Attal N, Backonja M, et al. NeuPSIG guidelines onneuropathic pain assessment. Pain. 2011;152(1):14-27.

54. Berger A, Dukes EM, Oster G. Clinical characteristics and eco-nomic costs of patients with painful neuropathic disorders.J Pain. 2004;5(3):143-149.

55. Sadosky A, Schaefer C, Mann R, et al. Burden of illness associ-ated with painful diabetic peripheral neuropathy among adultsseeking treatment in the US: results from a retrospective chartreview and cross-sectional survey. Diabetes Metab Syndr Obes.2013;6:79-92.

56. OConnor AB, Dworkin RH. Treatment of neuropathic pain: anoverview of recent guidelines. Am J Med. 2009;122(10, suppl):S22-S32.

57. Dworkin RH, OConnor AB, Audette J, et al. Recommenda-tions for the pharmacological management of neuropathicpain: an overview and literature update. Mayo Clin Proc. 2010;85(3, suppl):S3-S14.

58. Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the phar-macological treatment of neuropathic pain: 2010 revision. Eur JNeurol. 2010;17(9):1113-e88.

59. Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmaco-logical treatment of neuropathic pain. Pain. 2010;150(3):573-581.

60. Dworkin RH, OConnor AB, Backonja M, et al. Pharmacologicmanagement of neuropathic pain: evidence-based recommen-dations. Pain. 2007;132(3):237-251.

61. Bril V, England J, Franklin GM, et al. Evidence-based guideline:treatment of painful diabetic neuropathy: report of the Amer-ican Academy of Neurology, the American Association ofNeuromuscular and Electrodiagnostic Medicine, and the Amer-ican Academy of Physical Medicine and Rehabilitation.Neurology. 2011;76(20):1758-1765.

62. Chaparro LE, Wiffen PJ, Moore RA, Gilron I. Combinationpharmacotherapy for the treatment of neuropathic pain inadults. Cochrane Database Syst Rev. 2012;7:CD008943.016/j.mayocp.2015.05.004 951

Peripheral Neuropathy: A Practical Approach to Diagnosis and Symptom ManagementScreening for Peripheral NeuropathyEvaluating Patients Presenting With Clinical Signs or Symptoms Suggesting Peripheral NeuropathyClinically Stratifying Patients With Peripheral NeuropathyEvaluation of Length-Dependent Peripheral NeuropathiesSerologic EvaluationDiabetic NeuropathyImpaired Glucose ToleranceVitamin B12 DeficiencyDysproteinemiasOther Laboratory TestsToxic NeuropathiesHereditary Neuropathies

Other Diagnostic TestsNerve Conduction Studies and ElectromyographyTest of Small Nerve Fiber FunctionNerve Biopsy

Symptomatic Management of Peripheral NeuropathyConclusionReferences

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Peripheral Neuropathy