Clinical Approach to Peripheral Neuropathy

Clinical Approach toPeripheral Neuropathy:Anatomic Localizationand Diagnostic Testing

Adina R. Alport, MD; Howard W. Sander, MD

ABSTRACTPurpose of Review: This article provides a clinical approach to peripheral neuropathybased on anatomic localization and diagnostic testing.Recent Findings: Advances have been made in the evaluation of small fiber neu-ropathy and in the known genetic causes of neuropathy.Summary: History and physical examination remain the most useful tools for evaluatingperipheral neuropathy. Characterization of a neuropathy aids in limiting the differentialdiagnosis and includes consideration of temporal profile (tempo of onset and duration),heredity, and anatomic classification. Anatomic classification involves (1) fiber type(motor versus sensory, large versus small, somatic versus autonomic), (2) portion of fiberaffected (axon versus myelin), and (3) gross distribution of nerves affected (eg, length-dependent, length-independent, multifocal). Diagnostic testing may include serologicand CSF evaluation, electrodiagnosis, skin biopsy, quantitative sensory testing, auto-nomic testing, nerve biopsy, confocal corneal microscopy, and laser Doppler imager flare.

Continuum Lifelong Learning Neurol 2012;18(1):13–38.

INTRODUCTIONThe prevalence of peripheral neurop-athy is estimated to be between 2%and 8%.1 Given the numerous causes ofpolyneuropathy, determining the etiol-ogy can be challenging.2 This articleprovides a framework for the clinicianto approach the diagnosis and testingof a patient with suspected polyneur-opathy. The terms neuropathy, polyneu-ropathy, and peripheral neuropathy willbe used synonymously in this article.

ANATOMYNeuropathic disorders encompass dis-eases of the neuron cell body (neuron-opathy) and their peripheral processes(peripheral neuropathy). Neuronopa-thies include anterior horn cell disor-

ders, which are termed motor neurondisease, and dorsal root ganglion disor-ders, which are termed sensory neuron-opathy or ganglionopathy. Peripheralneuropathies can be subdivided intotwo major categories: primary axonopa-thies and primary myelinopathies.

Neuropathies can be further subdi-vided on the basis of the diameter of theimpaired axon. Large myelinated axonsinclude motor axons and sensory axonsresponsible for proprioception, vibra-tion, and light touch. Thinly myelinatedaxons include sensory fibers responsiblefor light touch, pain, temperature, andpreganglionic autonomic functions.Small unmyelinated fibers convey pain,temperature, and postganglionic auto-nomic functions.

Address correspondence toDr Howard W. Sander,New York University Schoolof Medicine, 400 E. 34th St,RR-311, New York, NY 10016,[email protected].

Relationship Disclosure:Dr Alport reports nodisclosure. Dr Sander serveson the speakers’ bureau forGrifols and Walgreens and hasbeen an independent peerreviewer for IPRO andIMEDECS. Dr Sander has alsoserved as an expert witness.

Unlabeled Use ofProducts/InvestigationalUse Disclosure:Dr Alport reports no disclosure.Dr Sander discusses theunlabeled use of steroids andplasmapheresis for thetreatment of chronicinflammatory demyelinatingpolyradiculoneuropathy.

Copyright * 2012,American Academyof Neurology. All rightsreserved.

13Continuum Lifelong Learning Neurol 2012;18(1):13–38 www.aan.com/continuum

Review Article

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Peripheral nerve damage can com-prise a focal lesion of a single nerve(mononeuropathy) or multiple nerves(polyneuropathy). This article focuseson polyneuropathy. Because ‘‘sicknerves are liable to compression,’’ amononeuropathymay be superimposedon a polyneuropathy (eg, carpal tunnelsyndrome superimposed on a diabeticpolyneuropathy).

HISTORYNeuropathy may present with a varietyof signs and symptoms that allow theclinician to narrow the list of diagnosticpossibilities. Symptomsmay be classifiedas either negative or positive. Positivesymptoms reflect inappropriate sponta-neous nerve activity, whereas negativesymptoms reflect reduced nerve activ-ity. Negative motor symptoms includeweakness, fatigue, and wasting, andpositive symptoms include cramps,twitching, and myokymia. Weaknessmay not be appreciated until 50% to80% of nerve fibers are lost; positivesymptoms may present earlier in thedisease process. Negative sensory symp-toms include hypesthesia and gaitabnormalities such as ataxia. Othercommon symptoms include difficultydifferentiating hot from cold and wor-sening balance, especially in the darkwhen visual input is less able to com-pensate for proprioceptive loss. Positivesensory symptoms include burning orlancinating pain, buzzing, and tingling/paresthesia. Other symptoms includediscomfort to sensory stimuli that arenormally not painful (allodynia) and anincreased sensitivity to painful stimuli(hyperalgesia). Patients with hyperalge-sia may describe a sensation of walk-ing on hot coals. Symptoms suggestingautonomic nerve involvement includeearly satiety, bloating, constipation, diar-rhea, impotence, urinary incontinence,abnormalities of sweating (hyperhidro-sis, anhidrosis), and lightheadedness

associated with orthostasis. Patients withvasomotor instability may report coldextremities associated with skin colorand trophic changes.

It is helpful to ask about impair-ment in activities of daily living, suchas a change in handwriting, problemsfastening jewelry or buttons or insertingand turning keys, tripping on a carpetor a curb, falling, and having difficultyarising from a commode. Details regard-ing disease onset, duration, and pro-gression are quite important for furthercharacterization. The patient should bequeried regarding asymmetry at onset,location at first onset, involvement of thetrunk or cranial nerve region, and thespecific tempo of progression (mono-phasic, steadily progressive, fluctuating,or stepwise). Other important questionsregarding the history are similar to thosethat would be asked of any other patientwith a suspected neurologic disorder.These include questions concerningimpairment of consciousness, visual dis-turbances (eg, diplopia), dysphagia, dys-arthria, focal motor weakness, sensorydisturbances, radicular pain, autonomicdysfunction, and bowel and bladderdysfunction. Bowel and bladder dysfunc-tion is uncommon in polyneuropathy(apart from cauda equina syndrome)and should prompt a search for an al-ternative diagnosis.

The standard history and physical ex-amination serve as a general frameworkfor the approach to neuropathy. Socialhistory can include questions regardingoccupation (possibility of toxic expo-sures to solvents, glues, fertilizers, oils,and lubricants), sexual history (HIV,hepatitis C), recreational drug use (vas-culitis secondary to cocaine), excessivealcohol intake, dietary habits (eg, strictvegan diet), and smoking (paraneo-plastic disease). Drugs of abuse con-fer a severalfold risk: the toxic effectsof the agent drug or impurities plusthe behavior-related consequences,

KEY POINTS

h The peripheral nervoussystem consists of largemyelinated motor axonsand sensory axons thatconvey proprioception,vibration, and light touch;small myelinated axonsthat convey light touch,pain, temperature, andpreganglionic autonomicfunction; and smallunmyelinated axonsthat convey pain,temperature, andpostganglionicautonomic functions.

h Neuropathy symptomscan bemotor, sensory, orautonomic. Questionsregarding impairment inactivities of daily livingare informative.

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Clinical Approach


including HIV, hepatitis C, and nu-tritional deficiency. A childhood his-tory of ‘‘clumsiness’’ or poor athleticperformance suggests a hereditarycause.

Medical and family history shouldfocus on illnesses associatedwith neurop-athy, such as endocrinopathy (diabetesmellitus, hypothyroidism), renal insuffi-ciency, hepatic dysfunction, connectivetissue disorders, and cancer. Patientswith cancer may develop neuropathyrelated to nutritional deficiency, chemo-therapy side effects, or a paraneoplasticsyndrome. Surgical history should ad-dress bariatric surgery, multiple orthope-dic procedures, and multiple surgeriesfor ‘‘entrapped nerves.’’

The medication list should be re-viewed to determine a possible tempo-ral association between agent use andneuropathy onset. The ‘‘coasting effect’’of toxic neuropathy describes symptomprogression formonths to a year despiteagent discontinuation. HIV-related treat-ment and chemotherapeutic agents arethe most common causes of toxic neu-ropathy. Antibiotics such as quinolonesmay induce a neuropathy. Nonprescrip-tion medications should also be as-sessed. Vitamin B6 (pyridoxine) dosingexceeding 50 mg to 100 mg daily (andpossibly even lower doses) may induceneuropathy.

Review of systems should includedermatologic changes, arthralgias, dryeyes and mucous membranes, ortho-stasis, gastrointestinal symptoms, andconstitutional symptoms (fever, weightloss, night sweats).

PHYSICAL EXAMINATIONOrthostatic vital signs may identify evi-dence of dysautonomia. Skin and mu-cous membranes may demonstratevasculitic rashes (purpura, livedo retic-ularis), hyperpigmentation (polyneurop-athy, organomegaly, endocrinopathy,monoclonal gammopathy, and skin

changes [POEMS]), oral ulcers (Behcetdisease, HIV), salivary gland swelling, dryeyes or mouth (sarcoidosis, Sjogren syn-drome), extremity hair loss (hair follicledenervation), and gum ‘‘lead lines’’ (leadexposure). Integumentary changes maysuggest a specific diagnosis. For exam-ple, Mees lines in the nails may suggestarsenic or thallium poisoning; alopeciamay suggest hypothyroidism, systemiclupus erythematosus (SLE), amyloidosis,or thallium poisoning; curly hair maysuggest giant axonal neuropathy; anddistal calf hair loss may suggest distalsymmetric axonal polyneuropathy. Skel-etal deformities such as hammer toes,pes cavus, and kyphoscoliosis are sug-gestive of an inherited polyneuropathy.The feet should be specifically examinedfor signs of trauma in an insensate footthat could be an early indicator of animpending Charcot foot deformity.Nerve enlargement can suggest demye-linating neuropathy, neoplasia in neuro-fibromatosis, or possible leprosy. Easylocations to palpate nerves are the ulnarnerve in the ulnar groove and thesuperficial radial nerve with a rollingpalpation against the radius just prox-imal to the wrist.

Cranial nerve assessment shouldinclude assessment for anosmia (Refsumdisease, vitamin B12 deficiency), opticatrophy (inherited neuropathies withcentral and peripheral demyelination),anisocoria or impaired pupillary light re-flexes (parasympathetic dysautonomia),impaired ocular motility (botulism,Miller Fisher syndrome), facial weakness(Guillain-Barre syndrome [GBS]), and tri-geminal sensory loss (Sjogren syndrome).A comprehensive motor examinationshould assess muscle bulk, includingobservation for intrinsic hand and footmuscle atrophy, hyperexcitability, tone,and strength using the Medical ResearchCouncil scale. Many neuropathies pres-ent with a relative symmetry of weak-ness. Dynamometry can be used for

KEY POINT

h History should includetimeline of diseaseprogression, socialhistory, family history,medical history (includingunderlying conditionsassociated withneuropathy), surgicalhistory, and review ofneurotoxic medications.



more precise strength measurement.Because most neuropathies cause distalweakness, the intrinsic foot musclesmay be affected first, resulting in clawedfeet and hammer toes. Weakness offlexion and extension of the small toesand weakness of great toe extensionmay occur early in the disease. Theangle between the shin and the unsup-ported foot should be approximately130 degrees. A larger angle suggestsankle dorsiflexion weakness. In thehands, the second and fifth digit ab-ductors are often affected first.

The sensory examination should beapproached with peripheral nerve anat-omy and types of disease patterns inmind. It can be divided into small andlarge fiber evaluation. Assessment oflarge fiber function includes vibration,joint position, and light touch, andsmall fiber assessment includes pin-prick and temperature. Romberg test-ing also evaluates large fiber function.

Light touch evaluates low thresholdmechanoreception and is mediated byboth small and large fibers. Monofilamentprobes can grade severity of loss. Detec-tion of lightest touch or stroking repre-sents a measure of low-threshold sensoryperception. Impairment of perception to10-g microfilaments is associated withincreased risk of unappreciated trauma.

Small fiber evaluation may be per-formed by examining pain and tem-perature using a pin or broken cottonapplicator stick. The goal is to applysharp stimuli without applying signifi-cant pressure. Difficulty distinguishingbetween sharp and dull stimuli indicatesloss of nociceptive fibers relative to low-threshold mechanoreceptor fibers.

While performing the sensory exami-nation, think anatomically to discerndifferent patterns of numbness, includ-ing the following:

& Mononeuropathy& PolyneuropathyVdistal symmetric

& PolyneuropathyVsymmetric butlength-independent

& PolyneuropathyVmultifocal& Radiculopathy (including suspended

sensory level, saddle anesthesia)& Plexopathy& Central causes (syrinx, heminumbness,

thoracoabdominal sensory level)

During light touch and pin testing,ask the patient whether the tested areasfeel the same or different from otherareas. Attempt to establish an area ofrelatively normal sensation for com-parison. Compare proximal and distallocations; the face, arm, and leg; and theright and left sides. Most major derma-tomes and nerves should be covered. Asuggested initial screen involves testingbilaterally at the forehead, cheek, chin,lateral upper arm, palmar surfaces ofdigits two and five, lateral thigh, calf (an-teromedial, anterolateral), distal dorsumof great toe, and lateral sole toward theplantar aspect. Temperature sensationcan be assessed with ice water, but atuning fork may be sufficiently cold andis readily available.

Vibratory perception is best assessedwith a 128-Hz tuning fork. The malleo-lus, tibial tuberosity, finger, and wristcan be assessed. The time interval untilperception of vibration is lost is mea-sured. A young adult should appreciatevibration at the great toe for a minimumof 15 seconds; this valuemay decline by1 second per decade. Vibratory percep-tion of less than 10 seconds at the greattoe is abnormal at any age. A quantita-tive tuning fork can bemore precise. Tominimize the time needed to performthe vibratory examination, we suggestan alternative testing method. Initialtesting uses only a very light percussionof the tuning fork. If vibration is de-tected, then vibratory perception isconsidered normal in that location. Ifvibratory perception is not detected,then a moderate or a strong percussion

KEY POINTS

h Weakness of flexion andextension of the smalltoes and weakness ofgreat toe extension maybe an early sign of motordysfunction.

h The sensory examinationshould be approachedwith knowledge ofperipheral nerve anatomyand types of diseasepatterns.


Clinical Approach


can be used. This leads to a rapid andrelatively reproducible vibratory percep-tion assessmentwith four possible grades.

Joint position testing is less sensitivethan vibratory testing for large fiberfunction and may only be impaired insevere cases. Joint position is tested inthe large toe and second finger at thedistal interphalangeal joint. The digitshould be held at the lateral bordersand themovement excursion should beminimal. Proximal joints are tested ifdistal impairment is present.

Reflex impairment aids in determi-nation of a lower motor neuron locali-zation. Reinforcement can augmenthypoactive reflexes. Ankle hyporeflexiaor areflexia is common in large fiberneuropathy, but ankle reflexes are typi-cally preserved with small fiber neurop-athy (SFN). Reflexes may be preservedin a mild to moderate large fiber neu-ropathy. Reflexes diminish with age;an absent ankle jerk at age 80 may benormal.

Gait examination can reveal subtleweakness not noted on manual muscletesting, especially with toe, heel, andtandem walking; squatting; and hop-ping. Footdrop may result in a steppagegait that is sometimes audible. In length-dependent neuropathy, patients havemore difficulty heel walking than toewalking. A wide-based gait or difficultywith tandem walking may highlightsubtle sensory ataxia.

CONFIRMATION OF ANEUROPATHYOn the basis of the history and physicalexamination, the physician should assesswhether the signs and symptoms corre-late with a neuropathy. The first step isto confirm that the signs and symptomscorrespond to a neurologic diseaserather than a primarily psychiatric dis-order.3 Next, diseases of the brain(multiple sclerosis, cerebrovascular dis-

ease) and the spine (cervical spondy-lotic myelopathy, multiple sclerosis,poliomyelitis related to West Nile virus)that may masquerade as neuropathyshould be excluded. Some neuropathiesmay coexist with CNS disease. Alterna-tive neuromuscular disorders shouldalso be considered, including polyra-diculopathy (multiple compressive radi-culopathies related to spondylosis,subarachnoid space infection, or ma-lignancy), ALS, neuromuscular junctiondisease, and myopathy. MRI may aid inlocalization.

CHARACTERIZATION OF ANEUROPATHYThe history and physical examination areoften able to confirm a polyneuropathy.However, electrodiagnostic studies, skinbiopsy, quantitative sensory testing, andother testing may be needed. Thesetests are described in the next section.In addition to confirming a polyneurop-athy, these tests may help with the nextstep of evaluation, characterization of theneuropathy. Characterization of a neu-ropathy includes consideration of thetemporal profile (tempo of onset andduration), heredity, and anatomic classi-fication. Anatomic classification involves(1) fiber type (motor versus sensory,large versus small, somatic versus au-tonomic), (2) portion of fiber affected(axon versus myelin), and (3) grossdistribution of nerves affected (eg,length-dependent, length-independent,multifocal).

Characterization of the neuropathyhelps the clinician minimize the test-ing needed to determine the etiology ofthe neuropathy. Diabetic neuropathy isthe most common cause of neuropathyin theUnited States and has several phe-notypes, which are discussed in detailin the article ‘‘Diabetic Neuropathy’’ inthis issue of .

KEY POINTS

h Ankle jerk hyporeflexiaor areflexia is commonwith length-dependentneuropathy, but anklereflexes are normal withsmall fiber neuropathy.

h Gait examination canreveal weakness notidentified on manualmuscle testing. Thepatient may be asked toheel, toe, and tandemwalk; squat; and hop.

h Characterization of aneuropathy includesconsideration of thetemporal profile (tempoof onset and duration),heredity, and anatomicclassification. Anatomicclassification includes(1) fiber type (motorversus sensory, largeversus small, somaticversus autonomic),(2) portion of fiberaffected (axon versusmyelin), and (3) grossdistribution of nervesaffected (eg,length-dependent,length-independent,multifocal).

h Characterization of aneuropathy helps theclinician minimize thetesting needed todistinguish among thenumerous toxic,hereditary, andacquired disorders.



Onset and Duration ofClinical CourseMost neuropathies are chronic and pro-gressive with an insidious onset. Thus, aneuropathy that has an alternate onsetor course may direct the clinician to alimited differential diagnosis. A knownprecise date of onset is suggestive ofan infectious neuropathy. Hyperacutelesions presenting over 24 to 72 hoursare rare andmay reflect vasculitic lesionscausing mononeuropathy multiplex.

An acute onset with presentationand progression over 1 month or lesssuggests GBS, vasculitis, porphyria, aninfectious etiology (eg, diphtheria,Lyme disease), or toxic/drug exposure(eg, arsenic, thallium, chemotherapeu-tic agents, dapsone). In a critical illnesssetting, development of weakness overdays is most likely related to criticalillness myopathy with thick filament(myosin) loss, but may be caused bycritical illness neuropathy.

Subacute onset of neuropathy over6 months or less can suggest toxicneuropathy, nutritional deficiency, ma-lignancy, paraneoplastic syndromes(sensory neuronopathy), and some me-tabolic abnormalities. A neuropathy witha relapsing and remitting course sug-gests demyelination and subsequentremyelination. Possible etiologies in-clude chronic inflammatory demyelin-ating polyneuropathy (CIDP), porphyria,and hereditary neuropathy with liabilityto pressure palsies (HNPP). Repeatedtoxic exposures should also be consid-ered. Vasculitis may also have this tem-poral profile.

HeredityA genetic etiology should be consideredin a generalized polyneuropathy. Familyhistory, lack of positive sensory symp-toms, early age at onset, symmetry, as-sociated skeletal abnormalities, and veryslowly progressive course may alert the

clinician. HNPP is an exception, as it of-ten presents with a relapsing and remit-ting course.

Patients with inherited neuropathiestend to have a relative paucity of symp-toms in comparison to their physicalexamination signs. Genetic neuropa-thies are covered in more detail in thearticle ‘‘Charcot-Marie-Tooth Diseaseand Related Genetic Neuropathies’’ inthis issue of .

Anatomic ClassificationThere are several different ways toclassify a neuropathy anatomically. Thetypes of classification fall into threemaingroups: nerve fiber type, portion of fiberaffected, and distribution of nerves af-fected in the body.

Fiber type. Classification by fiber typeincludes motor versus sensory, somaticversus autonomic, and small versus largefiber size. Many neuropathies involve acombination of fiber subtypes.

Motor versus sensory. It is rare forneuropathy syndromes to be purelymotor or sensory. Although most neu-ropathies are mixed, they may predomi-nantly reflect dysfunction of one fibertype. It is relatively common for pa-tients to notice only motor or sensorysymptoms but to have the examinationor diagnostic testing confirm that bothfiber types are involved. During historytaking, sensory symptoms often over-shadow motor symptoms. Motor nervesymptoms are infrequently the sole pre-sentation. This is related to many fac-tors, including the exquisite sensitivityof the sensory system, the earlier in-volvement of the sensory system, andthe redundancy and reserve built intothe motor system. Intrinsic foot muscleweakness often goes unnoticed by thepatient.

Neuropathieswith predominantmotorinvolvement include GBS, CIDP, multi-focal motor neuropathy (MMN), por-phyria, diphtheria, lead intoxication,

KEY POINTS

h Most neuropathies arechronic and progressivewith an insidious onset;an acute onset over 1month or less suggestsGuillain-Barre syndrome,vasculitis, porphyria, aninfectious etiology (eg,diphtheria, Lyme disease),or toxic/drug exposure(eg, arsenic, thallium,chemotherapeuticagents, dapsone).

h A genetic cause ofneuropathy should beconsidered in patientswith a family history ofneuropathy, lack ofpositive sensorysymptoms, early ageat onset, symmetry,associated skeletalabnormalities, or veryslowly progressivecourse.


Clinical Approach


botulism, hereditary neuropathies, andtoxic exposure related to dapsone,amiodarone, and vincristine. Pure sen-sory neuropathy is rare and can resultfrom diabetes mellitus, vitamin B12

deficiency, HIV, amyloidosis, leprosy,Sjogren syndrome, sarcoidosis, uremia,paraneoplastic syndromes, pyridoxine(vitamin B6) intoxication, and hereditaryneuropathies.

Somatic versus autonomic. Autonomicdysfunction may be seen as a compo-nent of a generalized polyneuropathyor a distal small fiber sensory neurop-athy or may occur as a result of apredominantly autonomic neuropathy.Although autonomic nerves outnumbersomatic nerves, autonomic neuropathysymptoms are less common than so-matic nerve symptoms. When auto-nomic symptoms predominate, themost common causes are diabetes mel-litus, amyloidosis, and GBS. If the onsetis acute or subacute, the main con-siderations are autoimmune autonomicganglionopathy, paraneoplastic syn-dromes, GBS, botulism, toxic neurop-athies, and acute porphyria. In chronicpredominantly autonomic neuropathies,considerations include diabetes, amyloi-dosis (primary and familial), inheriteddiseases (eg, hereditary sensory and au-tonomic neuropathy [HSAN]), Fabry dis-ease, Sjogren syndrome, and toxic andinfectious neuropathy, including HIV.

Fiber size. In many polyneuropa-thies, small fibers are predominantlyaffected, causing patients to report painas theirmain symptom. Common causesof SFN include diabetes, glucose intoler-ance, toxins (especially alcohol), Fabrydisease, Tangier disease, HIV, amyloido-sis, connective tissue disease (Sjogrensyndrome, SLE), sarcoidosis, HSANs,idiopathy, and drugs (eg, antiretrovirals).A more detailed list of less commoncauses can be found in a textbook byHerskovitz and colleagues.4 This topic isalso discussed in detail in the article

‘‘Painful Small Fiber Neuropathies’’ inthis issue of . Amyloidneuropathy may cause severe pain.Isolated SFN may evolve to includelarge fibers.

Axonopathy versus myelinopathy. Aneuropathy may be classified as pre-dominantly or initially involving theSchwann cell, causing demyelination, orinvolving the axon itself. This classifica-tion can be made electrodiagnosticallyor pathologically. Features suggestiveof a demyelinating neuropathy includeweakness without atrophy, a length-independent distribution with a proxi-mal predominant or asymmetric/patchydistribution either clinically or electro-diagnostically, early involvement of proxi-mal reflexes, and myokymia. On theother hand, distal reflex loss (ankle jerk)with preserved proximal reflexes iscommon in length-dependent neurop-athy. The etiology of demyelinating neu-ropathy includes genetic neuropathy(Charcot-Marie-Tooth disease [CMT]type 1, HNPP, Refsum disease, meta-chromatic leukodystrophy), CIDP, GBS,MMN, paraproteinemia-related neuropa-thy, diphtheria, infectious neuropathy(HIV, Lyme disease, leprosy, hepatitisC, diphtheria), and, less commonly,toxin-related neuropathy (eg, n-hexane,amiodarone). CIDP may be associatedwith systemic disease, including infec-tions, inflammatory bowel disease, met-abolic conditions, and connective tissuedisorders.

Distribution. A final way to anatom-ically classify neuropathy is based onthe global distribution of the neurop-athy throughout the body and thelocation along the nerve pathway. Theinitial question is whether a neuropathyis symmetric. The next question islength dependency. Most neuropathiesare symmetric and length-dependent.They are most commonly attributedto metabolic, idiopathic, inherited, ortoxic conditions.5 Distal dying-back

KEY POINTS

h Prominent autonomicneuropathy symptomssuggest diabetesmellitus, amyloidosis, orGuillain-Barre syndrome.

h Features suggestingdemyelinatingneuropathy includeweakness withoutatrophy, alength-independentdistribution with aproximal predominant orasymmetric/patchydistribution eitherclinically orelectrodiagnostically,early involvement ofproximal reflexes,and myokymia.



axonopathies have a classic symmetriclength-dependent pattern of symptomevolution. Sensory symptoms start inthe feet, which are supplied by thelongest axons. After dysesthesia andnumbness ascend to the calves, the fin-gertips become affected. The legs, fore-arms, and eventually the anterior chestmay be affected. Motor symptomatol-ogy first affects the intrinsic foot mus-cles, causing toe flexor weakness andclawed toes. Anterior tibial compart-ment muscle weakness then causesankle dorsiflexion weakness. Plantarflexion is relatively preserved, possiblyrelated to the functional redundancy ofthe large bulk of posterior compartmentmusculature. The intrinsic hand musclesbecome involved only after the calf mus-cles are involved. Motor weakness isusually greater in extensor groups thanin corresponding flexor groups. Unfortu-nately, despite adequate and thoroughevaluation, many chronic sensorimotoraxonopathies remain idiopathic.6

In contrast, length-independentneuropathies or asymmetric neuropa-thies may begin proximally or have apatchy distribution. They are commonlyimmune mediated or infectious andassociated with demyelination. Althoughdemyelinating neuropathy may affectany nerve segment, the segments tra-versing the subarachnoid space and themost distal segments may be moresusceptible to metabolic and immuno-logic changes because of a weakerblood-nerve barrier. Length-independentneuropathies run a spectrum from aclear mononeuropathy multiplex to aneuropathy with mild patchiness orasymmetry noted on clinical or electro-diagnostic examination. The termmono-neuropathy multiplex traditionally refersto individual nerve involvement in astepwise temporal progression. Withsevere disease, this may result in a con-fluent pattern similar to asymmetricpolyneuropathy. Vasculitis and multiple

nerve involvement with infectious, met-abolic, and toxic neuropathies or withHNPP cause this pattern. The differentialdiagnosis of length-independent neuro-pathy includes CIDP (demyelinatingneuropathyVespecially multifocal ac-quired demyelinating sensory andmotorneuropathy [MADSAM] variant), MMN,Lyme disease, HIV, sarcoidosis, carci-noma, amyloidosis, lymphoma, porphy-ria, leprosy, and Tangier disease.

A neuropathy with significant earlyproximal involvement raises the pos-sibility of a demyelinating neuropathy.Combined proximal and distal weaknessis the hallmark of CIDP. In particular,hip flexor weakness is suggestive ofCIDP, as it is frequently involved andcannot be attributed to L4-S1 com-pressive polyradiculopathy. However,demyelinating neuropathy may mimica length-dependent pattern, as thelonger fibers have a higher probabilityof being affected.

In a predominantly sensory neurop-athy, asymmetric, proximal, or patchydistribution of dysfunction suggests asensory neuronopathy directly affect-ing the dorsal root ganglia initially.Sensory involvement of lips and mouthsuggest a length-independent process.The differential diagnosis of dorsalroot ganglionopathy is limited and in-cludes heavy metals, paraneoplasticsyndromes, Sjogren syndrome, HIV,pyridoxine toxicity, cisplatinum, andidiopathic. A limited number of neu-ropathies involve the cranial nerves.Celiac neuropathymay include facial sen-sory symptoms (Case 1-1). Acute facialdiplegia suggests GBS. CIDP and thegelsolin variety of amyloidosis also causefacial diplegia. The facial palsies associ-ated with Lyme disease and sarcoidosismay occur either simultaneously or sepa-rated in time. In Melkersson-Rosenthalsyndrome recurrent facial paralysis, lipand facial swelling, and fissured tongueoccur.

KEY POINTS

h Most neuropathies aresymmetric andlength-dependent andare commonly attributedto metabolic, idiopathic,inherited, or toxicconditions. Handsymptoms begin once legsymptoms have ascendedtoward the knees.

h A neuropathy withsignificant early proximalinvolvement, especiallyhip flexor weakness,raises the possibility ofa demyelinatingneuropathy. Combinedproximal and distalweakness is the hallmarkof chronic inflammatorydemyelinatingpolyradiculoneuropathy.


Clinical Approach


DIAGNOSTIC TESTINGLaboratory and Genetic TestingDetermining which laboratory tests touse to evaluate a neuropathy is challeng-ing. Numerous tests are available, andthey can be expensive. The AAN pub-lished practice parameters to guide labo-ratory and genetic testing in distalsymmetric polyneuropathy.1 The prac-tice parameters recommend the fol-lowing tests: fasting blood glucose,electrolytes to assess renal and liver func-tion, complete blood count and differ-ential, serum vitamin B12, erythrocytesedimentation rate, thyroid-stimulatinghormone or thyroid function tests, and

serum immunofixation electrophoresis(IFE).

The tests with the highest yield ofabnormality are blood glucose, vitaminB12 with methylmalonic acid and homo-cysteine, and IFE. The 2-hour glucosetolerance test is more sensitive thanhemoglobin A1c and fasting plasmaglucose and should be considered ifthe initial testing is normal. Vitamin B12deficiency is a common treatable causeof neuropathy. Attention should be paidto the numeric value. When the vitaminB12 level is less than 400 pg/mL, themetabolites methylmalonic acid andhomocysteine should be tested to

KEY POINT

h Blood testing for theetiology of a neuropathyshould include fastingblood glucose,electrolytes to assessrenal and liver function,complete blood countand differential, vitaminB12, erythrocytesedimentation rate,thyroid-stimulatinghormone or thyroidfunction tests, andserum immunofixationelectrophoresis.

Case 1-1A 45-year-old teacher presented with a 6-month history of progressivebilateral foot, right thigh, and left face paresthesia. She denied loss ofvision, diplopia, dysarthria, dysphagia, incontinence, limb weakness, orbalance difficulty. She was recently diagnosed with hypertension andstarted on atenolol. She was married with three children. She dranksocially and smoked one pack of cigarettes per day. She had a familyhistory of diabetes and ovarian cancer. Physical examination wasremarkable for reduced sensation to pinprick in the V2 distribution of theleft face and reduced sensation to pinprick in the right thigh and foot. Theremainder of the neurologic examination was normal. MRI of the brainwas normal. Electrodiagnostic testing of the legs, including bilateral suraland superficial peroneal responses, was normal. Blink reflex responseswere normal. Skin biopsy revealed normal right distal leg intraepidermalnerve fiber density and reduced right thigh intraepidermal nerve fiberdensity. Serum gliadin IgG and transglutaminase antibody levels wereelevated. Laboratory testing for the following was normal: completeblood count, metabolic profile, 2-hour glucose tolerance test, hemoglobinA1c, Lyme disease, angiotensin-converting enzyme, anti-Hu antibodies,HIV, antinuclear antibodies, erythrocyte sedimentation rate, C-reactiveprotein, double-stranded DNA, SS-A, SS-B, and gliadin IgA. Duodenalbiopsy revealed severe villous flattening, crypt hyperplasia, andintraepithelial lymphocytosis.

Comment. This patient has a length-independent small fiber sensorypolyneuropathy, which is confirmed by a decreased intraepidermal nervefiber density. A diagnosis of celiac disease (gluten-sensitive enteropathy)is suspected based upon the elevated gliadin IgG and transglutaminaseantibodies and is confirmed by the duodenal biopsy findings. Celiacneuropathy may occur in patients without gastrointestinal complaints.

Multifocal neuropathy affecting the arms more than the legs also raisesthe possibility of lead toxicity and porphyria. In leprosy, the nerves runningclosest to the surface of the body are most vulnerable because the cooltissue temperatures favor the mycobacterial growth.



increase diagnostic yield.7 Serum IFEis more sensitive than serum proteinelectrophoresis in detecting monoclonalgammopathy. When the laboratoryresults return, specifically check whetherIFE was performed, because phlebot-omy laboratories do not always performIFE as an independent test in additionto the serum protein electrophoresis. Anegative IFE report will typically includea statement that a monoclonal gam-mopathy was not detected. QuantitativeIgs (IgG, IgA, IgM) may suggest an un-derlying lymphoproliferative disorder. Ifthe initial tests are not revealing, sero-logic tests focusing on individual dis-eases should be considered.

Laboratory evaluation of suspectedvasculitis and connective tissue disorders(eg, Sjogren syndrome, SLE, rheumatoidarthritis, mixed connective tissue disease,Wegener granulomatosis) may includeC-reactive protein, antinuclear antibody,double-stranded DNA, rheumatoid fac-tor, proteinase 3, myeloperoxidase,complement, angiotensin-convertingenzyme, SS-A and SS-B, hepatitis B andC panels, and cryoglobulin. For infec-tious conditions, consider Lyme disease,rapid plasma reagin, and HIV. In a pre-dominantly sensory neuropathy, espe-cially in a patient who smokes, considertesting for anti-Hu antibodies, which areassociated with paraneoplastic neurop-athy. Celiac disease was seen in 2.5%of neuropathy patients at a referral cen-ter.8 Testing for antigliadin IgG and IgAand transglutaminase should be con-sidered if initial laboratory tests arenondiagnostic.

Serum and urine screening for heavymetal analysis is rarely useful unlessheavy metal exposure is suspected. Ifincreased urinary arsenic is detected,fractionation can distinguish between in-nocuous organic arsenic from food (eg,shellfish) and toxic inorganic arsenic.Copper deficiency neuropathy can be as-sessed with a serum copper level. This

should be considered especially if a con-comitant myelopathy is present or a pre-disposing factor such as bariatric surgeryor excess zinc intake has occurred. Avitamin E level may also be considered,especially if the history suggests impairedfat absorption. Chronic neuropathy maybe associated with IgM paraproteinemiasuch as myelin-associated glycoprotein(MAG), sulfatide, and GD1b antibodies.In demyelinating neuropathy with veryprolonged distal latencies, consider anti-MAG. If MMN is suspected, consider anti-GM1. In patients with variants of GBS,consider testing for anti-GQ1b, anti-GM1, and anti-GD1a.

In neuropathy with significant auto-nomic involvement, consider evaluationfor amyloidosis (fat pad aspirate, rectalbiopsy, transthyretin/genetic testing),urinary porphyrins, paraneoplastic anti-body panel (including ganglionic acetyl-choline receptor antibody, anti-Hu),HSAN syndromes (genetic testing), andFabry disease ("-galactosidase assay).

Genetic testing is most effectivewhen it is tailored to the clinical pre-sentation, inheritance pattern, and elec-trodiagnostic classification. Currently,CMT phenotypes have been linked to44 loci with mutations in 50 genes. Theefficiency of genetic testing can be im-proved with a stepwise evaluation. Forexample, hereditary demyelinating neu-ropathy is attributable to duplication ofthe peripheral myelin protein 22 gene,PMP22, in 70% of cases, so it is rec-ommended for initial testing. The mostcommon mutation associated with axo-nal CMT is the mitofusion 2 gene,MFN2. A detailed genetic testing algo-rithm is available in the AAN practiceparameters.1

Additional testing may be warrantedif a specific disease is suspected. Thistesting may include chest x-ray or CT forsarcoidosis; PET scan or CT of chest,abdomen, and pelvis for malignancy;skeletal survey and bone marrow biopsy

KEY POINT

h Genetic testing is mosteffectivewhen tailored tothe clinical presentation,inheritance pattern, andelectrodiagnosticclassification.


Clinical Approach


for lymphoproliferative disease; salivarygland biopsy for Sjogren syndrome;endoscopy and duodenal biopsy forceliac disease; and colonoscopy for in-flammatory bowel disease.

If an infectious, immune-mediated,or neoplastic cause of a neuropathy issuspected, CSF can be evaluated. Malig-nancy and infection (eg, HIV, cytome-galovirus, Lyme disease, West Nile virus)cause a pleocytosis, whereas a dysim-mune neuropathy is typically associatedwith elevated protein with normal cellcounts (cytoalbuminologic dissocia-tion). MRI may document nerve rootenhancement in CIDP, show nerve rootclumping in arachnoiditis, or revealnerve enlargement in tumors.

For an extensive list of tests to con-sider in neuropathy see Herskovitz andcolleagues.4 Despite an extensive searchfor an etiology, the neuropathy remainsidiopathic in a substantial number ofpatients, most commonly in elderly pa-tients with mild disease.

Electrodiagnostic TestingElectrodiagnostic testing refers to nerveconduction studies (NCSs) and needleEMG. These tests are the standard forlarge fiber polyneuropathy diagnosisand are normal in purely SFN. EMGmay help exclude mimics of polyneu-ropathy, such as myopathy, neuronop-athy, plexopathy, or polyradiculopathy.For example, sensory nerve action po-tentials (SNAPs) are preserved in pre-ganglionic conditions, single myotomesare affected in radiculopathy, multiplenerves are affected in plexopathy, andparaspinal abnormalities suggest radi-culopathy. As an extension of the clinicalexamination, electrodiagnosis augmentsthe ability to assess the relative motorversus sensory involvement, the severityof the neuropathy, and the distributionof neuropathic dysfunction. Addition-ally, electrodiagnosis may determinethe relative extent of axonopathy versus

myelinopathy. Demyelination may beclassified as uniform or patchy. Electro-diagnostic studies may be repeated tomonitor disease progression. Althoughthe examination may be uncomfortable,risk is minimal. Adequate sampling ofnerves is necessary to assess for a mono-neuropathy multiplex and for asymme-try. In neuropathy, electrodiagnosticevaluation should include a minimumof two limbs. Additional limbs should beevaluated if the initial testing is not suf-ficiently diagnostic, if there is any clini-cal or electrophysiologic suggestion ofasymmetry or a length-independent pro-cess, or if there is a concern regardingmultiple diagnoses.

NCSs involve electrical stimulation ofa nerve and recording over a nerve ormuscle, usually using surface electrodes.The size and shape (amplitude, dura-tion, area, and phases) of the resultantaction potential waveform are assessed.Recording from sensory nerves yieldsa SNAP, and recording from musclesyields a compound muscle actionpotential (CMAP). Reported parametersmay include latency, amplitude, con-duction velocity (CV), and duration. Fora CMAP, a distal latency is reported forthe terminal segment, as a pure nerveCV cannot be calculated given the in-cluded neuromuscular junction trans-mission time. Low-amplitude SNAPsmay require averaging to increase thesignal to noise ratio. F wave studies re-flect conduction over the entire lengthof a motor nerve. The tibial H reflex isthe electrophysiologic equivalent of theS1 reflex and assesses both sensory andmotor nerve conduction. H reflex mini-mal latency prolongation is nonspecificand may be seen in early neuropathy.Erb point, axillary, and cervical or lum-bosacral root stimulation may assessconduction block and slowing in proxi-mal nerve segments.

In axonal neuropathy, reducedSNAP amplitudes typically develop first,

KEY POINT

h Electrodiagnostic studiesare helpful in determiningthe location of peripheralnervous systeminvolvement, thepopulation of nervesaffected (motor versuslarge fiber sensory), theseverity and distributionof involvement, theportion of nerve affected(axon versus myelin),and the chronicity andregeneration status.



followed by reduced CMAP amplitudes.CVs are usually normal or only mini-mally affected until sufficient loss oflarge, fast-conducting fibers occurs. Inlength-dependent axonal polyneurop-athy, initially SNAP amplitudes arereduced in distal nerves (sural andsuperficial peroneal). Thereafter, CMAPamplitudes of the peroneal nerves arereduced, followed by the tibial and thenulnar and median nerves.

In demyelinating neuropathy, distallatency prolongation and CV slowingmay occur, with reduction of amplitudeless likely early in the course. Additionalfindings may include conduction block(reduction in amplitude of proximalcompared to the distal CMAP with-out a significant increase in duration);temporal dispersion9 across a nervesegment (reduction in amplitude of

proximal compared to the distal CMAPwith a significant increase in duration[Figure 1-1]); temporal dispersion ofthe distal response (multiphasic wave-form or prolonged [longer than 9milliseconds] distal CMAP duration);markedly prolonged F wave minimallatency; and F wave impersistence,chronodispersion, or absence. Thesedemyelinating findings are due to anincreased range of nerve fiber conduc-tion velocities caused by uneven in-volvement by demyelination or nerveinexcitability related to demyelination(Case 1-2). Severely prolonged motordistal latencies raise the possibility ofanti-MAG neuropathy. Blink reflexesmay show prolonged R1 latencies indemyelinating neuropathy. Unfortu-nately, the above demyelinating fea-tures may not be detectable in a

FIGURE 1-1 A, Temporal dispersion indicating demyelination. Tibial compound muscle action potentials (CMAPs). Note themultiphasic waveforms and the prolonged CMAP durations (33 and 31 milliseconds). A prolonged distal latency(10.7 milliseconds) and slowed conduction velocity (16.7 m/s) are also present. B, Peroneal CMAPs. Focal

demyelination in the ankle-fibular head (FH) segment is indicated by the highly multiphasic waveform with below-FH stimulationalong with a 116% increase in total duration (22.7 milliseconds) in comparison to ankle stimulation (10.5 milliseconds). Theankle and popliteal fossa CMAPs are also multiphasic. C, Tibial CMAPs with proximal temporal dispersion. The increased duration ofthe proximal response, along with relative preservation of the area, indicate the presence of temporal dispersion and not aconduction block.

Modified with permission from Sander HW, Oh SJ. Temporal dispersion terminology: multiphasic and multiturn CMAPs. J Clin Neuromuscul Dis 2006;7(3):173Y174.


Clinical Approach


demyelinating neuropathy because ofeither lack of sampling of affected nervesor secondary axonal loss with low am-plitude or absent responses in severedisease. Asymmetry, sural sparing, anddissociation between motor and sensoryfunction in the same nerve should raise

the possibility of acquired demyelinat-ing neuropathy or a mononeuropathymultiplex. Various electrodiagnostic cri-teria have been established for CIDP.10,11

Recent criteria have been created forclinical rather than research use and havegreater sensitivity. Uniform demyelinating

KEY POINT

h Nerve conduction findingsin axonal neuropathyinclude reduced sensorynerve actionpotential andcompound muscle actionpotential (CMAP)amplitudes. Findings indemyelinatingneuropathy includeconduction velocityslowing, distal latencyprolongation, conductionblock, temporaldispersion, prolonged(greater than9 milliseconds) distalCMAP duration,markedly prolonged Fwave minimal latency,and Fwave impersistence,chronodispersion, orabsence. Asymmetry,sural sparing, anddissociation betweenmotor and sensoryfunction in the samenerve suggest possibleacquired demyelinatingneuropathy or amononeuropathymultiplex.

Case 1-2A 69-year-old man with diabetes presented with a 4-year history of tinglingand numbness affecting the feet and hands, difficulty with stair climbing,and imbalance in the shower when closing his eyes. The symptoms wereprogressive, although there were a few intervening months in which thesymptoms seemed to have lessened. He was a retired used car salesman andlived with his wife. He denied alcohol or tobacco use. Diabetes wasdiagnosed 6 years ago and was controlled by diet and weight loss. Hishistory was significant for hypothyroidism that was treated withlevothyroxine and benign prostatic hypertrophy. Neurologic examinationrevealed 4/5 weakness of bilateral iliopsoas and extensor hallucis longusmuscles and 4+/5 weakness of bilateral abductor digiti minimi and tibialisanterior muscles. Sensory examination revealed diminished light touchperception in a bilateral glove distribution to the wrist and in a stockingdistribution to the midfoot. Vibratory perception was diminished in thetoes. Ankle reflexes were absent. Romberg test was positive.

Hemoglobin A1C and fasting blood sugar were mildly elevated. Theantinuclear antibody was borderline positive. The serum thyroid peroxidaseantibody level was markedly elevated. Laboratory testing for the followingwas normal: complete blood count, metabolic profile, thyroid-stimulatinghormone, rheumatoid factor, Lyme disease, angiotensin-converting enzyme,HIV, C-reactive protein, double-stranded DNA, SS-A, SS-B, GM1, andantiYmyelin-associated glycoprotein antibody. Motor nerve conductionstudies revealed moderate conduction slowing and multiphasic responsesin bilateral peroneal, right tibial, and right ulnar nerves, with normal toslightly low compound muscle action potential amplitudes. Bilateralperoneal distal compound muscle action potentials had increased duration.F wave responses were moderately prolonged. Bilateral tibial H reflexeswere absent. Sensory nerve conduction studies revealed right median andulnar mild conduction slowing with normal bilateral sural and superficialperoneal responses. Needle EMG revealed only a decreased interferencepattern in bilateral tibialis anterior muscles.

Comment. This patient clinically has a length-independentsensorimotor large fiber polyneuropathy. Electrodiagnostic studies confirma length-independent, demyelinating, motor-greater-than-sensorypolyneuropathy. A diagnosis of chronic inflammatory demyelinatingpolyneuropathy (CIDP) is established based on the clinical history,physical examination, and electrodiagnostic findings. CIDP responds toimmunotherapy and may be treated with IVIg, plasmapheresis, or steroids.It is common for patients with CIDP to have concomitant autoimmunediseases or additional isolated laboratory markers suggestingautoimmunity. CIDP may also occur in association with diabetes.



features are more commonly associ-ated with hereditary neuropathies thanwith acquired neuropathies. Conduc-tion block and temporal dispersion areusually seen in acquired conditions.

Needle EMG assesses electrical ac-tivity of voluntary muscles. At rest, thepresence of fibrillation potentials andpositive sharp waves indicates sponta-neous discharge of individual musclefibers. This finding suggests activedenervation of muscle fibers, but it alsooccurs in some myopathies, likely dueto muscle fiber splitting. Motor unit po-tential (MUP) morphology may suggesta neurogenic lesion with reinnervation(increased duration, amplitude, andpolyphasia) or amyopathic lesion (briefduration, low amplitude, and poly-phasia). A caveat is that MUPs in earlyreinnervation resemble MUPs of myop-athy. With activation, the recruitmentpattern may be divided into two com-ponents: interference pattern and firingrate. In neuropathy, there may be anincreased firing frequency in associa-tion with a decreased interference pat-tern. In myopathy, there may be anearly recruitment of MUPs with a low-amplitude envelope of the interferencepattern. Needle EMG is useful to local-ize the distribution of dysfunction. Itis also useful in defining the chronicityof an axonopathy based on the dis-tribution and the amplitude of fibrilla-tion and sharp waves as well as MUPmorphology.

Neurophysiologic TestingMagnetic stimulation may assess con-duction in proximal segments such asthe femoral nerve or cauda equina, butin general it has limited application inperipheral neuropathy. Documenta-tion of cauda equina CV slowing canaid in diagnosis of a demyelinatingneuropathy.12

Somatosensory-evoked potentials(SSEPs) may localize sensory symptoms

to the nerve/plexus/root and evaluateproximal nerve segments that are inad-equately assessed by NCSs. SSEPs maybe absent or delayed because of rootdemyelination. SSEPs may be record-able even if SNAPs are absent because ofcentral amplification and can documentCV slowing. Yiannikas and Vucic high-lighted the use of SSEPs to diagnosedifferent phenotypes of CIDP.13

Quantitative Sensory TestingQuantitative sensory testing (QST) in-volves administration of vibration, warm,cold, and heat pain stimuli to the greattoe or index finger to determine thethreshold to the sensation. Vibrationsensory threshold measures large-diam-eter sensory fibers. Thermal and heatpain thresholds evaluate small unmyeli-nated fibers, which are not assessed withNCSs. QST is noninvasive and can berepeated to monitor progression.14

QST instruments use different algo-rithms to determine thresholds. Com-parisons cannot easily bemade betweenalgorithms.15 In the method of limits,stimulus intensity is gradually increaseduntil the patient indicates perception.In the method of levels, individualstimuli are delivered and the patientindicates whether the stimulus was per-ceived. This method is reaction time-independent. Data can be reported inabsolute units of stimulus intensity orin steps specified as ‘‘just noticeabledifferences.’’ See Figure 1-2 for an ex-ample of QST.16 Results are expressedas age- and sex-adjusted percentiles.

QST has been validated to detect andcharacterize sensory neuropathy. Stud-ies of patients with diabetes with mini-mal or no symptoms have found thermalsensation testing to be more sensitivethan vibratory testing or NCSs. However,other studies have found NCSs andvibratory testing to be more sensitivethan thermal testing. This discrepancy ispotentially explained by changes in the

KEY POINTS

h Uniform demyelinatingfeatures are morecommonly associatedwith hereditaryneuropathies thanacquired neuropathies.Conduction block andtemporal dispersion areusually seen in acquiredconditions.

h Magnetic stimulation andsomatosensory-evokedpotentials may assist inidentifying root, plexus,and proximal nerve (eg,femoral) demyelination.


Clinical Approach


predominant fiber type involved over thedisease course. Thus, combined thermaland vibratory evaluation is beneficial andprovides higher sensitivity. HIV neurop-athy, Fabry neuropathy, toxic neuropa-thy, and demyelinating neuropathy havebeen evaluated using QST. Vibration andcooling thresholds appear most reliableand reproducible compared to warmingand heat pain.

QST has limitations. It is time-consuming (takes at least 1 to 2 hours),requires special equipment, and is apsychophysiologic tool requiring patientcooperation. Inattention can lead toinaccuracy. Detecting malingering orother nonorganic abnormalities is chal-lenging. Therefore, QST should not beused in resolving medicolegal matters.QST cannot differentiate between cen-tral and peripheral nervous system dys-function. An AAN QST consensus reportstates: ‘‘Its [QST’s] role is only estab-lished when used as one of several toolsin the evaluation of neurologic disor-ders,’’ and ‘‘QST is probably or possiblyuseful in identifying small and large fibersensory abnormalities.’’15

Autonomic TestingAutonomic testing may complementevaluation of polyneuropathy.17,18 Sym-pathetic and parasympathetic functionare assessed using cardiovagal, adren-ergic, and sudomotor indices. Sym-pathetic sudomotor testing includessympathetic skin response (SSR), quan-titative sudomotor axon reflex testing(QSART), and thermoregulatory sweattesting (TST). Cardiovascular evaluationincludes heart rate variability assess-ment during deep breathing (HRDB),Valsalva maneuver, and blood pressureresponse to standing and tilt. In SFN,sudomotor dysfunction is more likely tobe identified than cardiovagal dysfunc-tion. Many standard EMG machines canassess SSR and R-R interval. These testsare rapid and easily performed. Speci-

alized laboratories are needed for theother studies mentioned.

The SSR measures changes in handand foot skin resistance in response toan arousal stimulus, often electrical,that elicits a startle response. An ab-sent response is considered abnormal.Quantitative criteria are not uniformlyestablished. Some consider a side-to-side amplitude asymmetry of greaterthan 50% abnormal. This test is rela-tively insensitive for detection of milddysfunction.

KEY POINT

h Although quantitativesensory testing is useful inidentifying both small andlarge fiber neuropathy,it is time-consuming,dependent on patientcooperation, not trulyobjective, and unable tolocalize dysfunction.

FIGURE 1-2 Examples of the 4-2-1 stepping algorithm forcooling thresholds. The broken line at thetop is from a patient with painful diabetic

neuropathy, and the solid line is from a normal control. Nullstimuli are shown at the bottom (dotted line). Stimuli are startedat level 13, and the control senses the first two stimuli. In thenormal study, after the first turn point at stimulus 5, the patientfails (f ) to note the stimulus, and the step is reduced to two justnoticeable differences (JNDs). After the second turn point, thestimuli are refined to 1 JND, and a threshold of 10 JND (80thpercentile) is determined. The patient with neuropathy fails tonote the first three true stimuli at 13, 17, and 21 JND and twonull stimuli (not shown). The intervals are refined until anabnormal threshold of 23 JND (98th percentile) is determined.This threshold corresponded to a physical change of j20-C(36-F) in skin temperature.

Reprinted with permission from Lacomis D. Small-fiber neuropathy. MuscleNerve 2002;26(2):173Y188.



TST involves administering con-trolled heat stimulus and visualizingthe sweat pattern response using indi-cator powders. Areas of reduced sweat-ing are computed as a percentage oftotal anterior body surface. Patientswith neuropathy have hypohidrosis oranhidrosis. TST sensitivity in SFN ishigh, especially for detection of distalloss of sweating; however, the test isnot routinely available, as it requires adedicated room and is messy and time-consuming. SSR and TST are nonlocal-izing with regard to central versusperipheral sites of dysfunction.

QSART assesses postganglionic sudo-motor nerve fibers with high sensitivityand specificity (Figure 1-3).19 Axons inskin are activated via acetylcholineiontophoresis, resulting in an initialdirect sweat response. Antidromictransmission to an axon branch pointelicits an orthodromic response leadingto a secondary sweat response of sweatglands adjacent to the site of primarystimulation. Sweat is measured with

sweat cells, which are generally placedat four locations. In distal SFN, themost distal site may have a reduced orabsent response. QSART is the mostsensitive physiologic autonomic test indistal SFN, with a sensitivity of 75% to90%.20 Intraepidermal nerve fiber loss(somatic C fiber involvement) andQSART abnormality (autonomic C fiberinvolvement) are often correlated.

In normal physiology, the heart rateincreases with inspiration and decreaseswith expiration. HRDB assesses variabil-ity in successive R-R intervals at sixbreaths/minute. The variation is largelyrelated to parasympathetic/vagal nervepathways and is reduced in autonomicdysfunction. HRDB has a sensitivity ofapproximately 80% in assessment ofpolyneuropathy.20

Valsalva maneuver assesses cardiova-gal and sympathetic vasomotor func-tion. It involves blowing against airwayresistance at predetermined pressure,causing abrupt elevation of intratho-racic and intra-abdominal pressures.Technically, the maneuver consists offour phases, with phases II and IVplaying the greatest diagnostic role(Figure 1-4).21 Phase I, during the first2 to 3 seconds of forced expiration,is associated with a brief decrease inheart rate and increase in blood pres-sure caused by aortic compressionfrom increased intrathoracic and intra-abdominal pressure. During phase II(continued straining), the blood pres-sure first decreases (reflecting reducedvenous return causing diminished strokevolume) and then increases. This issecondary to a baroreceptor-mediatedincrease in sympathetic activity withresultant increased heart rate and pe-ripheral vasoconstriction. In phase III,the abrupt release of the strain causespassive blood pressure decline and aresultant increase in heart rate. In phaseIV (continued relief), the blood pres-sure overshoots baseline because of

KEY POINTS

h Sympathetic sudomotortesting includessympathetic skinresponse, quantitativesudomotor axonreflex testing, andthermoregulatory sweattesting. Cardiovascularevaluation includes heartrate deep breathing,Valsalva maneuver, andblood pressure responseto standing and tilt.

h In small fiber neuropathy,sudomotor testing ismore sensitive thancardiovagal testing.

FIGURE 1-3 A, Normal quantitative sudomotoraxon reflex testing (QSART) in ahealthy control. B, Abnormal

QSART in a patient with dysfunction of thepostganglionic sympathetic sudomotor axon due tosmall fiber neuropathy. In contrast to the patientwith small fiber neuropathy, sweating increases inthe healthy control during mental arithmetic (1),during acoustic stimulation (2), and prior toacetylcholine iontophoresis (3).

Reprinted with permission from Hilz MJ, Dutsch M. Quantitativestudies of autonomic function. Muscle Nerve 2006;33(1):6Y20.


Clinical Approach


persistent peripheral vasoconstriction inthe setting of a normalized venous re-turn and stroke volume. Baroreceptor-mediated vagal stimulation with reflexbradycardia and peripheral vasodilationthen occurs. In patients with baroreflexfailure, the blood pressure falls progres-sively in phase II and in phase IV bloodpressure recovery time is prolongedwith no pressure overshoot. The Valsalvaratio reflects parasympathetic functionand is defined as the ratio of the fastestheart rate during or after phase II tothe slowest heart rate in phase IV (afterrelease of strain). A ratio below 1.10 isabnormal.

Orthostatic hypotension associatedwith neuropathy occurs when small mye-linated and unmyelinated baroreflex fibersin splanchnic vasculature are damaged.Tilt-table testing can quantify and providedetail regarding orthostatic changes.

The composite autonomic scale is a10-point scale that combines adrener-

gic, sudomotor, and cardiovagal testingand can be used to increase sensitivityand specificity for documenting auto-nomic dysfunction.

Nerve BiopsyHistorically, nerve biopsy (NB) was usedto assess the etiology, pathologic local-ization, and severity of nerve damage. Inthe last two decades, NB has become lessimportant because of progress in electro-diagnostic, laboratory, and genetic test-ing. Currently, the search for an etiologyis the main indication for an NB. NBevaluation should not be performedbefore adequate clinical, electrophysio-logic, and laboratory assessment. Theyield of an NB depends on a number offactors, including patient selection, nervesampled, laboratory experience, andtechniques of evaluation.22

NB is helpful in only a small subsetof patients. The yield is best in an acute/subacute, asymmetric, multifocal, severe

KEY POINT

h Nerve biopsy evaluationshould not be performedbefore adequate clinical,electrophysiologic, andlaboratory assessment.

FIGURE 1-4 Blood pressure and heart rate response to Valsalva maneuver in a normal participant (A) and a patient withbaroreflex-sympathoneural and baroreflex-cardiovagal failure (B). The patient has a progressive fall in bloodpressure during the maneuver and slow blood pressure recovery after the maneuver, with absence of a pressure

overshoot in phase IV. Concurrent heart rate changes are blunted for given changes in blood pressure.

Reprinted with permission from Goldstein DS, Low PA. Clinical evaluation of the autonomic nervous system. Continuum Lifelong Learning Neurol2007;13(6):33Y49. Copyright B 2007, American Academy of Neurology. All rights reserved.



progressive neuropathy. It is most help-ful in mononeuropathy multiplex orsuspected vasculitis. AAN practice pa-rameters support the usefulness of NBin the diagnosis of inflammatory dis-eases such as vasculitis, sarcoidosis,and CIDP; infectious diseases such asleprosy; or infiltrative disorders suchas tumor or amyloidosis.20 It is alsorecommended in progressive diffusecryptogenic neuropathy. NB is rarelyinformative in distal symmetric axonalneuropathies associated with toxic andmetabolic conditions. Hereditary neu-ropathies are better diagnosed withblood testing, although NB may helpdirect DNA analysis to a particular gene(Table 1-1).

The current role of NB in CIDP iscontroversial. Patients with CIDP mayerroneously be classified as having anaxonal neuropathy on electrodiagnosticstudies because of sampling error inpatchy disease. NB should be consid-ered on a case-by-case basis for patientswith cryptogenic neuropathy with atypi-cal clinical or electrodiagnostic featuresor a rapidly deteriorating course.23

In axonopathy, NB findings includefiber loss, evidence of sprouting, andmyelin breakdown material. In demyeli-nating neuropathy, the axons have inap-propriately thin myelin sheaths relativeto the diameter of the axons. Whenrepetitive episodes of demyelinationinvolve the same internode, Schwanncell proliferation creates concentricallyoriented layers termed ‘‘onion bulbs’’(Figure 1-5).24 Tomacula are sausage-shaped myelin outfoldings observed onteased myelinated fibers and are mostcommonly observed in hereditary neu-ropathy, especially HNPP. The charac-teristic lesion of necrotizing vasculitison nerve and muscle biopsy is fibrinoidnecrosis of the endothelium and trans-mural inflammatory cell infiltration.

Sensory nerves are biopsied underlocal anesthesia. MRI and ultrasound

may aid in nerve selection. The surgeonshould be familiar with nerve identifi-cation and specimen handling. Total NBis more informative than fascicular bi-opsy. Favored nerves include the suralnerve above the lateral malleolus, thesuperficial peroneal nerve, or, less com-monly, the superficial radial nerve at thewrist. When vasculitis, amyloidosis, orgranulomatous disease is suspected, abiopsy of adjacent muscle may be per-formed. Following a sensory NB, sensoryloss in the nerve distribution will occur.Dyck reported that 30% of patients ex-perienced subjective and objective sen-sory abnormalities that resolved overtime. Vallat and colleagues reported thatapproximately 60% of patients had nosymptoms after sural NB.25

General pathologic evaluation usesfrozen sections, conventional paraffinsections, epoxy (plastic) sections for lightand electron microscopy, and teasedmyelinated fibers. Frozen tissue is usu-ally not fixed before cutting sections. Thetissue is fixed in formalin for paraffinsections and in glutaraldehyde for semi-thin plastic sections, electron micro-scopy, and teased fibers.26

Paraffin sections followed by routinehematoxylin and eosin staining is themost efficient method to screen forinterstitial lesions such as inflammatorycells, neoplastic infiltration, and bloodvessel changes. It is particularly helpfulfor detecting vasculitis, amyloidosis,and sarcoidosis.

Frozen sectioning allows for immu-nostaining. This may detect immuno-logically active cells in vasculitis anddeposition of Igs (eg, IgM antibody toMAG) and complement components.Light microscopic analysis of resin-embedded material assesses for loss ofmyelinated fibers, onion bulb forma-tion, and size of affected fibers. Quanti-fying the number of myelinated fibersper unit area of endoneurium may benecessary to determine significant loss.

KEY POINTS

h Nerve biopsy yield is bestin an acute/subacute,asymmetric, multifocal,progressive neuropathy.

h The AAN practiceparameters recommendnerve biopsy in thediagnosis of inflammatorydiseases such as vasculitis,sarcoidosis, andchronic inflammatorydemyelinatingpolyradiculoneuropathy;infectious diseases suchas leprosy; or infiltrativedisorders such as tumoror amyloidosis.

h Nerve biopsy is alsorecommended in diffusecryptogenic neuropathybut is rarely informativein distal symmetricaxonal neuropathyassociated with toxic andmetabolic conditions.


Clinical Approach


Electron microscopy is useful in ex-amining unmyelinated nerve fibers; eval-uating ultrastructural features, includingcytoplasmic organelles and storagemate-rials; and evaluating for demyelination.Diseases assessed by electron micro-scopy include CIDP; neuropathy due toa gammopathy (anti-MAG); hereditary

neuropathies, including those that alsoaffect the CNS; and toxic neuropathies.

Teased myelinated fiber examinationusually involves grading 50 to 100 fibersfor pathologic abnormalities. Quantita-tive studies in internodal length andmyelinated fiber diameter are per-formed. Normally there is little variation

TABLE 1-1 Summary of Clinical Situations When Nerve Biopsy May Be Very Useful orIndispensable for the Diagnosis

Disease Groups Condition Comments on Nerve Biopsy

Acquiredneuropathies

Immune-mediatedneuropathies

Vasculitis Diagnostic yield is variable andmay be improved in combinationwith a muscle biopsy at the same site

May be particularly useful whenvasculitis is confined to peripheralnerves

Chronic inflammatorydemyelinatingpolyneuropathy (CIDP)

May be helpful in patients withclinically atypical presentations orwhen nerve conduction studies arenot diagnostic

Neuropathy associated withmonoclonal gammopathy

May be extremely helpful todemonstrate:

(1) presence of lymphomatousinfiltrates

(2) amyloidosis

(3) endoneurial deposits(intramyelinic or interstitial)

Exception: patients with IgMantiYmyelin-associated glycoproteinneuropathy

Toxic neuropathies Various drug-inducedneuropathies, particularlythose causing demyelinatingneuropathies

May help differentiate a toxicneuropathy from another type ofneuropathy (eg, amiodarone-inducedneuropathy with electrophysiologicfeatures suggestive of CIDP)

Hereditaryneuropathies

Charcot-Marie-Toothdisease (CMT)

CMT-like presentation insporadic cases

May suggest a hereditary neuropathyin the absence of a family history

May direct the search for specificgene mutations in some cases

Storage disorders Storage disorders withperipheral nervous systeminvolvement

May reveal accumulation ofabnormal material in Schwann cellsor endothelial cells

Reprinted with permission from Vallat JM, Vital A, Magy L, et al. An update on nerve biopsy. J Neuropathol Exp Neurol 2009;68(8):833Y844.



between internodal lengths in singlefibers in early adulthood, but graduallyincreasing variation of internodal lengthsoccurs with age.

Teased fibers may demonstrate ademyelinating neuropathy with areas ofsegmental demyelination. In subacute or

chronic neuropathies, thinly myelinatedsegments and short internodes can beevidence of remyelination but can alsobe caused by a chronic axonal disorder.Tomacula may be seen on teased fiberpreparation. Myelin ovoids indicate ac-tive axonal degeneration, and uniformlyshortened internodes are thought to becaused by axonal regeneration.

Skin BiopsyOver the past two decades, understand-ing of cutaneous innervation has dra-matically increased, leading to improveddiagnostic and therapeutic techniques.27

Skin biopsy is becoming the standardfor assessment of unmyelinated cutane-ous nerves. The intraepidermal smallnerve fibers convey pain and tempera-ture sensation from the skin and main-tain autonomic function. The neurologicexamination may miss subtle sensoryabnormalities. Conventional electrodiag-nostic studies assess only large nervefibers.

Skin sampling is performed by skinpunch or by the less common skin blistertechnique.28 With a skin punch, a 3 mmdiameter, 3 mm to 4 mm thick speci-men is removed using local anestheticwithout sutures and is fixed in parafor-maldehyde. A small scar may occur.Although biopsy is a simple office pro-cedure, pathologic analysis is complex.Intraepidermal nerve fiber density(IENFD) is quantified and morphologicfeatures are assessed. Complications(infection, excessive bleeding, and pro-longed healing) occur in fewer than0.5% of patients.29 Immunohistochemi-cal staining is performed, most com-monly with protein gene product 9.5, acytoplasmic neuronal marker. Sections50 Hm thick are cut perpendicular tothe epidermis. Using bright field lightmicroscopy, the linear IENFD is calcu-lated by counting the nerve fibers thatcross the epidermal basement mem-brane. The isolated fragments of nerve

FIGURE 1-5 Electron micrographs of a sural nerve biopsyin chronic inflammatory demyelinatingpolyradiculoneuropathy specimen

([times]2870).A, shows that the axons have relatively thin myelinsheaths (asterisk), a finding suggesting remyelination. Somerelatively large, unmyelinated axons indicative of demyelination(arrows) are also visible. B, shows a Schwann cell filled withmyelin debris (asterisk). Stacks of cytoplasmic lamellae (arrows)indicate a loss of unmyelinated axons and myelinated axons. An‘‘onion bulb’’ (arrowhead) surrounds an unmyelinated axon, afinding indicating demyelination. The bars represent 3.48 6m.

Reprinted from Sander HW, Hedley-Whyte ET. Case records of theMassachusetts General Hospital: weekly clinicopathological exercises.Case 6-2003: a nine-year-old girl with progressive weakness and areflexia.N Engl J Med 2003;348(8):735Y743. CopyrightB 2003, with permission fromthe Massachusetts Medical Society.


Clinical Approach


fibers in the epidermis can also becounted (Figure 1-6A, B). An alternativetechnique uses fluorescence labelingwith or without confocal microscopy.Strict counting rules and intensive train-ing have led to high interrater and in-trarater reliability. The morphology ofunmyelinated nerve fibers is assessed.Qualitative changes in neuropathy in-clude attenuation of fibers, large glob-ular and fusiform-shaped swelling,dystrophic change, and tortuous and in-creasing complex branching. Large axo-nal swelling is a predegenerative changepredictive of nerve fiber degeneration(Figure 1-6C). In several studies, isolatedmorphologic abnormalities were notedin 20% to 29% of patients with normalIENFD.30 Unfortunately, methods to re-liably quantitate qualitative changes inmorphology are lacking. In addition toIENFD, staining may also be performedfor amyloidosis.

IENFD is compared to normativereference data, which are currently avail-able for the bright field immunohis-tochemistry technique for the foot,proximal and distal thigh, distal leg, distalforearm, trunk, and heel. The procedureis most commonly performed in thedistal leg calf and in the proximal lateralthigh. IENFDbelow the fifth percentile isgenerally considered abnormal. MeanIENFD gradually diminishes with age.Men have a slightly lower IENFD thanwomen. There is no relationship be-tween IENFD and race, height, or weight.

Quantitative nerve fiber analysis ofthe dermis has been limited. Several re-searchers have developed techniques toquantify the subepidermal nerve plexus.Other researchers are investigatingabnormally short myelin internodes asa possible diagnostic technique for de-myelinating disorders.

Sweat gland nerve fiber density(SGNFD) is assessed by skin biopsy witha manual or automated analysis. Sweatglands have sympathetic sudomotor

FIGURE 1-6 A, Normal intraepidermal nerve fiber density(IENFD). Small nerve fibers (arrow) in theepidermal layer of a skin biopsy with normal

IENFD. B, Abnormal IENFD. Skin with abnormally low IENFD,consistent with a small fiber neuropathy. C, Axonal bulbing.Skin with abnormally low IENFD, consistent with a small fiberneuropathy. The arrowheads point to epidermal nerve fibers,and just below is an axonal swelling.

Figure courtesy of Therapath, New York, New York.



innervation; therefore, SGNFD is com-plementary to IENFD, which measuressomatic nerves (Figure 1-7).31 The bi-opsy requires a thicker specimen (6mmto 8 mm) than IENFD to allow for ade-quate sampling. Reduced SGNFD isconcordant with symptoms of sudo-motor dysfunction. In a recent study,20% of skin biopsies found low SGNFDas the sole abnormality.32

Skin biopsies can distinguish neurop-athy from radiculopathy because radi-culopathy does not affect postganglionicfibers. Skin biopsy may help evaluate thelength dependence of a neuropathy bycomparing proximal and distal IENFDs.

In length-independent neuropathy, re-duced IENFD is equal or more promi-nent proximally. However, severe length-dependent neuropathy may causeIENFD reduction at all sites.

In the studies evaluated by the AANpractice parameter, IENFD diagnosticsensitivity ranged from 45% to 90% andspecificity was 95% to 97%. In a study of67 patients with SFN, 88% had reduceddistal leg IENFD while sensory NCSswere normal.33 The high specificity indi-cates that IENFD is a good tool to verifya neuropathy, but a normal IENFD doesnot exclude neuropathy.20 In a largestudy, 11% of patients with SFN basedon clinical examination andQST had nor-mal IENFD.33 IENFD is correlated withobjective SFN signs. The rate of false-negative IENFD is higher in patientswith symptoms but without signs.29

The literature on the agreement be-tween QST and IENFD is conflicting.IENFD correlates with thermal and noci-ceptive detection thresholds; however,correlation with other measures is un-certain, possibly because biopsy andQST are performed in different areas.Most studies report that IENFD has ahigher sensitivity than QST for SFN.34

IENFD correlation with vibratory thresh-old is more likely with combined largeand small fiber neuropathy.

Skin biopsies have proven useful lon-gitudinally. IENFD may reliably predictrisk of neuropathy in asymptomatic in-dividuals. In SFN, progressive IENFDreduction correlates with neuropathyprogression. Improved IENFD with re-generation is associated with reducedneuropathic pain and sensory symp-toms. It is unknown what IENFD mag-nitude of change is meaningful, andIENFD improvement can serve as a re-liable surrogate for evaluation of thelong-term course of polyneuropathyeither clinically or in research studies.Currently, IENFD is used as a secondaryoutcome in therapeutic trials.30

KEY POINT

h Skin biopsy is the bestcurrently available test forsmall fiber neuropathy.Intraepidermal nerve fiberdensity and nerve fibermorphology areassessed. The mostcommon biopsy sites arethe distal calf andproximal lateral thigh.

FIGURE 1-7 A, Normal skin sweat gland nerve fiberdensity. B, Abnormal skin sweat gland nervefiber density.

Figure courtesy of Therapath, New York, New York.


Clinical Approach


Recent AdvancesTwo of the latest techniques used toinvestigate SFN are corneal confocalmicroscopy and laser Doppler imagerflare (LDIF). Additionally, Meissner cor-puscle (MC) density evaluation (using invivo reflectance confocal microscopy)and skin wrinkling evaluation are in theearly stages of development for clinicalapplication.

Corneal confocal microscopy. Invivo laser corneal confocal microscopy(IVCCM) is used to image the sub-basalnerve plexus, which is composed of Adelta and C fibers from the ophthalmicnerve that penetrate Bowman layers tobecome subjacent to the basal epithelialcells. Corneal nerve fiber density (CNFD),corneal nerve fiber length (CNFL), cornealnerve branching, and corneal nerve fibertortuosity are assessed (Figure 1-8).35

Reductions in CNFL and CNFD corre-spond to polyneuropathy severity. Serialexamination has found early nerve regen-eration (an increase in CNFD and CNFL)following pancreatic transplantation indiabetes. IVCCM has been evaluated inimpaired glucose tolerance, diabetes,36

Fabry disease, chemotherapy-inducedneuropathy, anti-MAG neuropathy, andlength-independent polyneuropathy/

ganglionopathy (Sjogren disease andCrohn disease). This noninvasive andrepeatable technique is particularlypromising in length-independent SFN/ganglionopathy because of the proximallocation.

The major limitation of IVCCM islimited availability of equipment andtrained examiners. Some ophthalmolo-gists have cautioned that the findingsare nonspecific and may be seen inamiodarone-induced keratopathy andpostphotorefractive keratectomy. Thus,more extensive normative data andlarger confirmatory studies are neededbefore IVCCM can become a standarddiagnostic procedure.

Laser Doppler imager flare. LDIFevaluates skin C fiber axon reflex re-sponse to heating (44-C [111.2-F]), withlaser Doppler to measure the area ofvasodilation in the neurogenic flare. Theflare area is dependent on the receptivefield size of the activated axons and isproportional to nerve fiber density. LDIFis reduced in neuropathy37 and withlocal anesthetics (Figure 1-9).38 Pre-liminary data39 found LDIF to be moresensitive than quantitative thermal thresh-olds to detect SFN. Additionally, studiesin patients with diabetes have shown

KEY POINTS

h Analysis of sweat glandnerve fiber density iscomplementary tointraepidermal nerve fiberdensity in small fiber nerveevaluation, as they assessautonomic and somaticnerves, respectively.

h Skin biopsy may helpdifferentiate betweenlength-dependent andlength-independentneuropathy. Inlength-dependentneuropathy, proximalintraepidermalnerve fiber density(IENFD) is relativelypreserved, whereas inlength-independentneuropathy, proximalIENFD may be equal ormore affected than distalIENFD. In radiculopathy,IENFD is normal.

h Two of the latesttechniques recommendedto investigate small fiberneuropathy are cornealconfocal microscopy andlaser Doppler imager flare.Additionally, Meissnercorpuscle density (using invivo reflectance confocalmicroscopy) and skinwrinkling evaluationare in the early stagesof development.

FIGURE 1-8 Frame from corneal confocal microscopy(original magnification � 3700). Decreaseddensity of nerve fibers in Bowman layer in a

patient with length-independent small fiber sensory neuropathy (asseen in Case 1-1) (A) compared with that in a normal control (B).

Reprinted from Gemignani F, Ferrari G, Vitetta F, et al. Non-length dependentsmall fibre neuropathy: confocal microscopy study of the corneal innervation.J Neurol Neurosurg Psychiatry 2010;81(7):731Y733. Copyright B 2010, withpermission from BMJ Publishing Group Ltd.



LDIF abnormalities prior to neurop-athy detection with currently availablemethods.

Meissner corpuscle density.MCs areskin mechanoreceptors that have oneor more myelinated nerves at the baseand contain a lobulated network ofA beta and unmyelinated fibers. MCscan be assessed using in vivo reflectanceconfocal microscopy (Figure 1-10).40

Fingertip MC density on skin biopsyparalleled reduction in IENFD in 25 pa-tients with suspected neuropathy. Moreextensive experience, including norma-tive data, is needed before this non-invasive method is widely used.

Stimulated skin wrinkling. A simple,noninvasive, bedside technique recentlydescribed is the use of stimulated skinwrinkling to assess small fiber function.Skin wrinkling is triggered by vasocon-striction that may be induced by immer-sion in water or by administration ofa eutectic mixture of local anesthetics(EMLA). Water immersionYinduced va-soconstriction is mediated by postgan-glionic sympathetic fibers. EMLA causesvasoconstriction possibly by acting oncalcium channels in postganglionic neu-rons and smooth muscle cells. An ab-normal result reliably predicts abnormal

FIGURE 1-9 Laser Doppler imager flare technique. The solidcircle represents the extent of the skin heater.The eutectic mixture of local anesthetics

(lidocaine and prilocaine) blocks the axon reflex. Theneurogenic (small fiber) component of the hyperemia isdetermined by the ratio of hyperemic area to stimulus areabefore and after anesthesia.

LDIFT = laser Doppler imager flare technique.

Reprinted with permission from Green AQ, Krishnan ST, Rayman G. C-fiberfunction assessed by the laser Doppler imager flare technique andacetylcholine iontophoresis. Muscle Nerve 2009;40(6):985Y991.

FIGURE 1-10 A, Identification of Meissner corpuscles (MCs) with in vivo reflectance confocal microscopy. Glabrous skin fromthe hand showing a dermal papilla with two MCs (arrows) and an empty papilla (arrowhead). B, Hairy skin ofthe forearm showing the expected absence of MCs in papillae (arrows). C, A higher magnification in vivo

reflectance confocal microscopy image of an MC showing its capsule (arrowhead) and internal lobulated structure (arrow). D, AnMC capsule (arrows) and heterogeneous bright signal on in vivo reflectance confocal microscopy of its internal axonal network.

Reprinted from Herrmann DN, Boger NJ, Jansen C, Alessi-Fox C. In vivo confocal microscopy of Meissner’s corpuscles as a measure of sensory neuropathy.Neurology 2007;69(23):2121Y2127. Copyright B 2007, with permission from AAN Enterprises, Inc. All rights reserved.


Clinical Approach


IENFD in sensory neuropathy, althougha normal result did not correlate withnormal IENFD.41

ACKNOWLEDGMENTWe thank Dr Arthur P. Hays, Dr DanielL. Menkes, and Dr Max Hilz for conceptdevelopment and editorial assistanceand Ms Kathy Harris for administrativeassistance.

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Clinical Approach


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Clinical Approach to Peripheral Neuropathy