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Background

Howtotreat

History andexamination

Differentialdiagnosis

Investigations

Specific

neuropathies

Treatment

inside

www.aus t ra l i andoc to r . com.au

DR ROBERT HENDERSON,

director of neurology, Royal

Brisbane & Womens Hospital,

Brisbane, Queensland.

The author

Pull-out section

MANY doctors find it difficult todiagnose and manage peripheral neu-

ropathies. There is rarely a specificcause found and there is a lack oftargeted treatments available. Thisreview hopes to answer these threepoints and provide an approach to acomplex topic.

The pathology ofperipheral neuropathiesPeripheral neuropathies include all

disorders in which nerve structuresbeyond the spinal cord are affected.

Disorders of nerve roots are consid-ered with neuropathies.

It is worth remembering that thecell body for motor nerves is theanterior horn cell in the spinal cord,while the cell body for sensorynerves is the dorsal root ganglionusually located near where the nerveroot exits from the cerebrospinalfluid.

Motor nerve fibres (axons) termi-nate as terminal branches at the neu-

romuscular junctions that connectwith muscle fibres (figure 1, page34). Sensory nerve axons terminateat freely branching or specialised cor-puscular endings at the skin or othertissues. The axon is surrounded by amyelin sheath. The signal speed isgreatly increased by jumping alongthe nodes of Ranvier.

Neuropathies occur when there is

dysfunction of the axon or the sur-rounding protective myelin sheath.

Loss of the myelin sheath causesslowed conduction and, over time,damage to the underlying axon.Unmyelinated nerve fibres areslower-conducting nerve fibres andcarry autonomic and sensory infor-mation.

Most idiopathic and inherited neu-ropathies are length dependent, with

contd next page

PeripheralNEUROPATHY

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How to treat peripheral neuropathy

34 | Australian Doctor | 16 May 2008 www.australiandoctor.com.au

the neurotransmitter transportmechanisms failing at the end ofnerves. Transport mechanisms alsoappear vulnerable to toxic neuro-pathies. Recent work supports animportant role for mitochondria inmany disease processes.

When the nerve axon is dam-aged, either Wallerian degeneration(degeneration of the axon distal tothe most proximal site of injury)or a more generalised axonaldegeneration (a dying back phe-nomenon that affects the nerveaxon back to the cell body) occurs.

A different pathology occurs inmany immune disorders in whichthe surrounding, protective myelinsheath is damaged (segmentaldemyelination). Recovery is slow ifregrowth of the axon is needed butcan occur much more rapidly if theprocess is demyelination.

Initial presentations of aperipheral neuropathySensory symptoms

Sensory symptoms are the mostcommon presentation of a periph-eral neuropathy and can be con-sidered as positive (tingling, burn-ing and pain) or negative (loss oftouch and temperature). In general,most sensory neuropathies are

length-dependent, with feetinvolved before hands. Fingers areoften not involved until sensorysymptoms are noted at the mid-calflevel.

Although many patients describesensory symptoms as numbness,it is important to explore what ismeant by this term. It can varybetween positive and negativesymptoms or sometimes evenweakness.

Positive sensory symptoms areusually associated with uncomfort-able sensations. An ordinary stim-ulus produces an unpleasant,abnormal sensation (dysaesthesia)or unpleasant sensations arisingwithout apparent stimulus (paraes-thesia).

Negative sensory symptoms aresometimes considered less signifi-cant but are more worrying interms of disability, with balanceproblems, ulceration and Charcotjoints often resulting.

Asking the patient direct ques-tions is often useful Can youfeel when something is in yourshoe? Can you feel the temperatureof bathwater? Do you feel discom-fort when something rubs againstyour skin (allodynia)?. Difficultywalking at night may represent lossof the sense of joint position.

Motor symptoms

Motor symptoms such as weaknessare a less common presentation of aperipheral neuropathy than sensorysymptoms. Most motor symptomsbegin as gait and balance difficulties.When weakness becomes significant,a characteristic pattern occurs, withloss of foot dorsiflexion.

Falling or tripping are importantsymptoms to inquire about. Handweakness usually occurs later,when feet are more severelyaffected, and manifests as difficultywith fine motor control such as

turning a key or writing.

Autonomic symptoms

Autonomic symptoms are rarelyconsidered but are important indi-cators of involvement of smallnerve fibre pathways. Loss ofsweating is usually not recognisedby patients, but possible autonomicdysfunction is suggested by: Absence of odour on socks. Dry, cracked and ulcerated skin. Loss of sexual function in males. Dry mouth or eyes. Postural lightheadedness.

HistoryHISTORY is the mostimportant factor in diagnos-ing a peripheral neuropathy.The temporal history ofsymptoms allows the neu-ropathy to be categorisedinto a time-course of acute,subacute or chronic.

Coexisting diseases areoften important and, alongwith family history, the GPneeds to consider: Medications (prescribed

and complementary). Nutritional status (includ-

ing alcohol consumption). Travel history. Occupation Exposure to toxins.

While the common hered-itary neuropathies are usu-ally autosomal dominant, alack of family history doesnot exclude the possibility ofa sporadic new mutation.Direct questioning of familymembers for sensory symp-toms is often required.

ExaminationWhen examining for a possi-ble peripheral neuropathy,the two aims are to establishif a peripheral neuropathyexists and to determine if itis treatable. Certain patternsexist that make the exami-nation results easier to syn-thesise.

Gait

The gait can usually bequickly assessed whenpatients walk into the room,but Rombergs test is often ahelpful additional step. Apositive Rombergs test (theability to stand with the feettogether and eyes open, yetfalling with the eyes closed)represents loss of joint-posi-

tion sense, a large-fibre sen-sory function. This is differ-ent from the unsteady stancewith eyes open that oftenrepresents cerebellar or othercentral involvement.

Limb inspection

Muscle atrophy is a featureof neuropathies not usuallyseen with muscle or CNSconditions, unless disuse isprominent. On inspection ofthe distal limbs pes cavususually represents an inher-ited neuropathy but cannotbe detected unless the patient

removes their shoes. In addi-tion to the high-arch of thefoot, pes cavus is usuallyassociated with hammer-toes (flexion of the secondto fifth toes) and with lossof the muscle bulk in thelower part of the lower leg,described as inverted cham-pagne-bottle legs (figure 2).Pes cavus occurs as atrophicweakness of the foots intrin-sic muscles allows the longextensors of the toes to dor-siflex the toes, and the longflexors to shorten the foot,heighten the arch and flexthe distal toes.

Atrophy of the first dorsalinterosseous muscle in thehand is usually easily visible.Loss of hair and trophicchanges of the skin can benoted. Fasciculations may beseen in neuropathiesalthough they are not usu-ally a prominent feature.

Strength

Loss of muscle strength isusually a late sign in mostperipheral neuropathies.Usually only moderateweakness can be detected

with manual testing of footdorsiflexion or plantar flex-ion. More careful examina-tion of strength requires test-ing foot inversion andeversion and toe flexion andextension.

Weakness of foot dorsi-flexion can be examined byasking a patient to stand ontheir heels.

In the upper limb, loss offinger and thumb abductionis usually the first sign of anupper-limb neuropathy,although other patterns arehelpful to recognise (figure3).

Reflexes

Reflexes are very helpful inassessing a neuropathy. Asthe ankle reflex has an affer-ent sensory and efferentmotor component, the anklereflex will be absent in bothtypes of neuropathy.

In most significant neu-ropathies involving largefibres, the ankle reflex willbe reduced or absent andmost other reflexes will bereduced (ie, knee, biceps, tri-ceps and supinator reflexes).

By contrast, in neuropathiesthat only affect small nervefibres, the reflexes will beretained. Easily obtained orbrisk reflexes would suggestan alternative diagnosis to aperipheral neuropathy.

Sensation

The sensory examination isoften considered difficultand time-consuming. In themost common pattern ofneuropathies, all sensorymodalities (touch-pressure,pain, temperature, joint-position sense and vibration)are similarly affected.

A pattern that occurs ininherited and metabolic neu-ropathies is preferentialinvolvement of pain andtemperature. Involvement ofpredominantly vibration andjoint-position sense isuncommon but is the patternseen with vitamin B12 defi-ciency.

A simple method for thesensory examination is touse the 128Hz tuning forkto test both vibration andtemperature. A gentle tap ofthe tuning fork and place-

ment over the hallux is usu-ally felt in normal people,although in those over 60,loss of vibration over thehallux is not necessarilyabnormal and the ankleshould be tested in thesecases. Testing a central ref-erence is needed if there isany confusion as to themeaning of vibration.

Cold temperature over thedorsum and underside of thefoot can also be simply testedusing the tuning fork. Tem-perature is carried by thesame pathways as pain,which is more difficult to test.

Pain sensation is best testedusing a dressmakers pin orbranded pins such as Neu-rotips. Testing over the toesand dorsum of the foot canbe compared with a moreproximal location such as thethigh. Often repeated pres-sure of the pin is needed forpatients with a neuropathy tobe sure of sensation. Light-touch testing using a cottonball is subjective and rarelyhelpful, but can be tested in asimilar way to pain.

Joint-position sense can behelpful as an additionalassessment of the vibrationpathways.

General neurological

examination

When assessing a neuropa-thy it is helpful to examinefor more widespread neuro-logical involvement. Forexample, cognitive involve-ment, visual or hearingsymptoms or signs mightsuggest a metabolic processsuch as a mitochondrial dis-order. A dysmorphic appear-ance might suggest anunusual inherited process.

History and examination

Figure 2: Pes cavus and thedistal muscle wastingcharacteristic of an inheritedneuropathy.(Photo courtesy of

Professor Garth Nicholson.)

Figure 3: Atrophy of the abductor digiti minimi (arrow), indicating ulnar nerve pathology. Thepatient is trying to extend the fingers; the inability to do this represents an additional radialneuropathy.

Figure 1: The peripheral motor nerve.from previous page

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CLASSIFICATION of thecause of a peripheral neuropa-thy can be based on whethermotor, sensory and/or auto-nomic fibres are involved orwhether small and/or largenerve fibres are involved(tables 1 and 2). Other classi-fications are outlined in table3. My preference is to initiallyconsider small- and large-fibreinvolvement, as the distinctionbetween these neuropathiescan be made on history andexamination.

Small-fibre neuropathies(table 1) usually cause painand discomfort and are associ-ated with normal anklereflexes, normal nerve con-duction studies and, with someexceptions such as diabetes,are often relatively benign.

Large-fibre neuropathies(which usually also involvesmall fibres) can be dividedinto neuropathies that are pre-dominantly motor or sensoryand those that involve bothmotor and sensory function.

Occasionally other condi-tions can mimic a peripheralneuropathy. It is worth remem-bering that balance difficultycan represent sensory loss (lossof joint-position sense), weak-ness or more central problems.

Central causes such as mul-tiple sclerosis can cause pre-dominant sensory symptoms.A clue is the retained or briskreflexes, especially the anklejerk, in CNS disorders. Spinalcord or nerve root pathologycan also similarly present withdistal sensory symptoms, forexample, people with bilateral

L5 and S1 nerve-root com-pression often notice sensorysymptoms in the feet.

Differential diagnosis

Investigations

EVEN in the most specialised neu-ropathy clinics, a cause for periph-eral neuropathy will not be foundin 25% of cases. Tests for a periph-eral neuropathy should be basedon a rational approach to the indi-vidual patients history and exami-nation in association with anunderstanding of treatable neu-ropathies and the rapidity of dis-ease progression and morbidity.

Nerve conduction studiesNerve conduction studies (NCS) arethe primary investigation used toconfirm a peripheral neuropathy butare only useful for large-fibre neu-ropathies. NCS should be consideredas an aid to the clinical examinationand are performed by most clinicalneurologists and occasionally byrehabilitation specialists.

In NCS, a nerve is stimulatedand the size and speed of a motoror sensory response is measured(figures 4 and 5, page 37). There isminor discomfort with most com-monly studied nerves if the testsare performed carefully.

NCS distinguish demyelinatingneuropathies from axonal neu-ropathies. They can also assess pro-gression of a neuropathy, deter-mine subclinical involvement ofnerves and guide further investiga-tions such as a sural nerve biopsy.They are also particularly helpful

for entrapment neuropathies suchas carpal tunnel syndrome.

NCS are usually performed withelectromyography (EMG), whichinvolves inserting a small record-ing electrode directly into muscle.In most chronic neuropathies, largemotor units are found in distalmuscles on EMG. In active disease,regular fibrillation potentials arefound. Abnormally large motorunits in proximal muscles on EMG

might support the diagnosis of aprocess at the nerve roots.

NCS/EMG are also helpful fordistinguishing neuropathies fromdisorders of the neuromuscularjunction and muscle (myopathies).

Cerebrospinal fluid examinationCSF examination is useful for mea-suring the level of protein (raised ininflammatory neuropathies) andfor cytology (malignancy).

Testing for small-fibreneuropathyTesting for small-fibre neuropathiesis less widely available, more sub-jective and often research based(most capital cities have one hospi-tal with an interest in this area).

Commercial equipment is avail-able for quantitative sensory test-ing, which is useful for quantify-ing the commonly tested sensorymodalities. Quantitative sudomo-tor axon reflex test (QSART) isused in some Australasian centresto quantify sweat loss in responseto an ionic current.

Thermoregulatory sweat testingis useful to assess patterns of sweat-ing, for example, a length-depen-dent pattern, but is time-consumingand not widely available.

Nerve biopsyNerve biopsy (figure 6, page 37) israrely performed because of theinvasive nature of the test andthe possibility of a residual areaof discomfort. The sural nerveabove the ankle is the only nervecommonly biopsied, and this isusually performed by neuro-surgeons.

A sural nerve biopsy may behelpful in diagnosing inflamma-tory conditions such as vasculitis,particularly in conditions such asChurg-Strauss disease, in which

Figure 4: Nerve conduction study of the ulnar motor nerve.Neuropathy screen

The history is the most important

indicator of which investigations will

be useful. Possible investigations

include:

FBC, electrolytes and LFTs

Vitamin B12

Fasting blood sugar

ESR, C-reactive protein

Serum and urine electrophoresis

Antinuclear antibodies, extractable

nuclear antigens

Antinuclear cytoplasmic antibodies

Rheumatoid factor

Hepatitis B and C, HIV

Cryoglobulins

Folate

Paraneoplastic antibodies

Red cell transketolase

Thyroid function tests

Vitamin E

Urinary porphyrins

Urinary heavy metals

Serum mitochondrial deletions

Table 2: Chronic puremotor and sensory

large-fibreneuropathies

Pure motor neuropathies

Multifocal motor neuropa-

thy with conduction block

Progressive muscular

atrophy (peripheral variantof motor neurone disease)

Chronic inflammatory

demyelinating polyradicu-

loneuropathy (CIDP)

Diabetes

Inherited

Sensory-predominant

neuropathies

Immune (eg, Sjgrens

syndrome)

Paraneoplastic

Toxic (especially due to

vincristine, cisplatin and

paclitaxel)

CIDP or paraproteinaemic

neuropathy

Idiopathic

Table 1: Small-fibre-predominant

neuropathies

Acute

Toxic

Acute form of Guillain-

Barr syndrome

Porphyria

Chronic

Idiopathic

Diabetes

Hereditary

Amyloid

Paraneoplastic

Table 3: Other classifications of peripheral neuropathies

Acute neuropathies (symptomsprogressing over days)

Guillain-Barr syndrome

Toxic

Vasculitis Rare: porphyria, diphtheria

Toxic neuropathies

Arsenic (subacute sensorimotor)

Lead (prominent motor)

Mercury (sensory)

Thallium (acute sensorimotor)

Hexacarbons

Methyl-n-butyl ketone

Methyl bromide

Ethylene oxide

Vitamin B6 excess

Nitrous oxide

Medications associated with

peripheral neuropathy

Chemotherapy agents (vincristine,paclitaxel, cisplatin)

Nitrofurantoin

Amiodarone

Statins

Isoniazid

Phenytoin

Chronic use of metronidazole

Thalidomide

Stavudine

(Medications associated with aneuropathy but now rarely used: ddC,perhexiline, chloramphenicol,hydralazine, dapsone)

Important causes of multipleperipheral mononeuropathies

Vasculitis Diabetes

Sarcoid

Inherited (liable to pressure palsies)

Nutritional neuropathies

Alcohol abuse is one of the most common causes of peripheral neuropathies seen ingeneral practice, although the mechanism is poorly understood. Nutritional factorssuch as deficiency of thiamine and other B vitamins are likely important

Nicotinic acid (niacin) deficiency produces pellagra in a triad of GI symptoms, neuropa-thy and dementia. The neuropathy is usually a distal sensorimotor neuropathy indistin-guishable from thiamine deficiency

Pyridoxine (vitamin B6) deficiency of dietary cause is rarely seen but drugs such asisoniazid, hydralazine and penicillamine may deplete resources, producing a distalsensorimotor neuropathy

Vitamin B12 deficiency produces a sensory neuropathy; when this is severe, involve-ment of the posterior columns can produce imbalance and gait difficulties

Vitamin E deficiency occasionally is seen with disorders of fat malabsorption or, rarely,as an inherited disorder. A multisystem degeneration with sensory ataxia results

Important treatable neuropathies

Metabolic

B12 deficiency

Impaired glucose tolerance

InflammatoryAcute (Guillain-Barr syndrome) and chronic (chronic inflammatory demyelinating

polyneuropathy) demyelinating neuropathies

Paraproteinaemic neuropathy (IgG and IgA)

Sarcoidosis

Neoplastic

Paraneoplastic, usually associated with lung carcinoma, and anti-Hu positive ontesting of paraneoplastic antibodies

Causes of painful neuropathies

Diabetes (painful symmetric neuropathy, diabetic plexopathy, diabeticthoracoabdominal radiculopathy)

Idiopathic distal small-fibre neuropathy

Vasculitic neuropathy

Toxic neuropathies (due to alcohol, arsenic, thallium, vincristine, cisplatin)

HIV and treatment (dideoxynucleosides)

Amyloid

Paraneoplastic processes

Fabrys disease

Infections directly associated with neuropathy Hepatitis B and C

HIV Leprosy Cytomegalovirus and Epstein-Barr, herpes simplex and varicella zoster virusesNot seen in Australia Lyme disease, Chagas disease

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Inherited neuropathiesRECENT classifications sepa-rate inherited neuropathiesinto: Hereditary motor and sen-

sory neuropathy (HMSN). Hereditary sensory neuropa-

thy (HSN). Hereditary sensory and auto-

nomic neuropathy (HSAN).However, the old nomen-

clature of Charcot-MarieTooth (CMT) remains widelyknown and useful. Most(70%) adult-onset hereditaryneuropathies are CMT1A, forwhich genetic testing is widelyavailable. The typical profileis given in the Authors casestudy (Inherited neuropathy?,page 38).

The gene test for CMT1Aalso tests for deletion of thePMP22 gene on chromosome17, which is seen in hereditaryneuropathy with liability topressure palsy. Genetic testingis also available in Australiafor connexin 32 mutation,which is an X-linked neuropa-thy, and the mitofusin muta-tion, which causes progressivedistal wasting and weaknesswith milder involvement ofsensation.

An important practicalpoint is that patients withinherited peripheral neu-ropathies might be susceptibleto adverse effects on theperipheral nervous system ifthey are exposed to the med-ications shown in table 3(Medications associated withperipheral neuropathy, page36). There is no proven ther-apy for hereditary neu-ropathies, although footsurgery to correct deformitiesmay be helpful, particularly inchildren.

DemyelinatingneuropathiesGuillain-Barr syndrome is anacute motor-sensory neuropa-thy that develops most com-monly over 1-3 weeks. Itaffects children and adults ofall ages. About half of patientsreport a preceding respiratoryor GI illness.

Although the classic descrip-tion is of an ascendingpolyneuropathy often with

prominent sensory symptoms,proximal muscles may beinvolved early and the weak-ness usually develops rapidly,so that atrophy is not found.Within a few days, a keyfinding on examination isareflexia. Lumbar puncturemay show an elevated CSFprotein level, often>1000mg/dL, particularly ifperformed after the firstweek.

Admission to hospital iswarranted for all but mildcases, given the potentialprogression. Up to 25% ofcases require admission toan ICU, although in morethan 90% the prognosis isfavourable for a normalrecovery or minimal symp-toms.

Occasionally a prolongedcourse with axonal degener-ation occurs, and morbidityand mortality may occur inthe severely affected. Thecondition responds to IVimmunoglobulin or plasmaexchange.

The chronic form of Guil-lain-Barr syndrome is calledchronic inflammatorydemyelinating polyradicu-loneuropathy (CIDP). Thisform is less common but isusually slowly progressive(occasionally relapsing-remitting), with motor andsensory involvement. The

disease is insidious in onset,usually without an ante-cedent illness. Areflexia is akey finding on examination.The CSF protein level is ele-vated in most cases, andNCS show a demyelinatingpicture. Occasionally a suralnerve biopsy is required toconfirm the diagnosis.

Most cases respondfavourably to prednisone, butlong-term steroid-sparingagents such as azathioprineand methotrexate are usuallyrequired. Many patientsrespond well to plasmaexchange or IV immunoglob-ulin, although these therapiesare usually reserved for moresevere disease.

A similar neuropathy toCIDP occurs with serumparaprotein bands. In mostcases the association is withmonoclonal gammopathy ofunknown significance(MGUS), although multiplemyeloma and polyneuropa-thy, organomegaly, endo-crinopathy, monoclonalgammopathy and skinchanges (POEMS) syndromeneed to be distinguished.

The neuropathy of mono-clonal gammopathy usuallyaffects males from the sixthand seventh decades, with aslowly progressive course.Plasma exchange may be ofbenefit, especially for

patients with IgG and IgAmonoclonal bands.

Impaired glucose toleranceand diabetic neuropathyDiabetes is associated with dif-ferent clinical syndromes ofperipheral neuropathy. Thedistal, symmetrical,sensory-greater-than-motorneuropathy is the most com-monly recognised neuropathyof diabetes and is associatedwith retinopathy.

Other forms of neuropathyoccasionally seen in patientswith diabetes are: A painful, asymmetric proxi-

mal plexopathy (also calleddiabetic amyotrophy).

Mononeuritis multiplex. Pure autonomic neuropathy

(involving sphincterfunction and circulatoryreflexes).

Painful thoracoabdominalradiculopathy.

Diabetic cranial neuropathies(usually ophthalmoplegia).Recently the association of a

predominantly sensory neu-ropathy with impaired glucosetolerance has become clearer.

Although only about 15%of patients with diabetes havesymptoms and signs of a neu-ropathy, subclinical involve-ment may be found in up to50%. Neuropathy is mostcommonly found in peopleover 50 with diabetes. Goodlong-term control of diabetes isimportant for preventing pro-gression and strict glucose con-trol may reduce painful neu-ropathic symptoms.

Common chronicperipheral entrapmentmononeuropathiesCarpal tunnel syndrome dueto compression of the mediannerve at the wrist results incharacteristic numbness of thehand at night. This usuallyresponds well to decompres-sion of the transverse wrist lig-ament.

Compression of the ulnarnerve in the cubital tunnel atthe elbow (or less commonlyin Guyons canal at the wrist)produces sensory change in thefifth finger and half of thefourth finger and clawing of

the hand. Surgery is less clearlyof benefit for ulnar nerve com-pression at the elbow, butdemonstration of a block onNCS may help predict successafter surgery.

Meralgia paraestheticaresults from compression ofthe lateral femoral cutaneousnerve of the thigh, producingnumbness over the lateralthigh. Weight loss is of benefit.Surgery to relieve the com-pression is rarely helpful.

Posterior interosseous neu-ropathy (a branch of the radialnerve) produces a wrist drop.Most cases are idiopathicalthough compression fromthe supinator muscle is impli-cated in some patients.

Foot drop results fromcommon peroneal (fibular)nerve entrapment at the headof the fibula. It needs to be dis-tinguished from more proxi-mal causes such as a L5radiculopathy. Care is neededto avoid this neuropathy inimmobilised patients. Rarelysurgical decompression is help-ful.

Neuropathy associatedwith systemic diseaseBesides diabetes, progressivesensorimotor neuropathies canbe associated with systemicdisease. Carcinomas and lym-phomas are associated withneuropathies either throughdirect infiltration or as a para-neoplastic phenomenon.

Vasculitic disorders ofteninvolve the peripheral nervoussystem although this varieswith the disease. Neuropathyis relatively commonly seen inChurg-Strauss syndrome, pol-yarteritis nodosa, Sjgrenssyndrome and rheumatoidarthritis, whereas Wegenersgranulomatosis and SLE areuncommonly associated with aneuropathy.

The pattern in vasculiticneuropathy is classically thatof a mononeuritis multiplex,but in practice a distal sensori-motor pattern of neuropathy isnot uncommon. Occasionallya vasculitis can be confined tothe peripheral nerves. A raisedESR and C-reactive proteinmay be a clue.

Specific neuropathies

peripheral nerves are more commonly involved. Asural nerve biopsy may also be helpful in diagnosinginfiltrative conditions such as amyloidosis, althougha skin or rectal biopsy may obviate the need for thesural nerve biopsy.

When to refer to a neurologistWhile most neuropathies are managed by the GP, aninitial assessment by a neurologist is often helpful,particularly if the neurologist has an interest in neu-romuscular diseases. In common practice, the GPhas usually performed the tests for benign and treat-able neuropathies.

Reasons for urgent referral of a patient to hospitalwould include acute progressive presentation (with-in one week) with ascending sensory or motorsymptoms, or when Guillain-Barr syndrome or atoxic cause are a clinical concern. Progressive, dis-abling neuropathies deserve investigation. Whenthere is a concern about an inherited neuropathy,investigations and referral to a geneticist may behelpful.

Figure 5: Information obtained from nerve conduction studies includes size ofresponses, conduction velocity and the pattern of the waveforms.

Figure 6: Sural nerve biopsy showing the myelin sheathssurrounding motor, sensory and autonomic axons.

Although onlyabout 15% ofpatients withdiabetes havesymptoms andsigns ofneuropathy,subclinicalinvolvementmay be found

in up to 50%.

Within a few days, a key finding onexamination in acute Guillain-Barrsyndrome is areflexia.

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NEUROPATHIES are veryrarely curable. CIDP respondsto immunosuppression orimmunomodulation (IVimmunoglobulin or plasmaexchange). Paraproteinaemicneuropathy and vasculiticneuropathies respond toimmunosuppression. Vitamindeficiencies respond to sup-plementation.

The focus on treatment ofneuropathies is usually onreducing exposure to thecause. Peripheral neuropathiesrarely lead to mortality. Themainstay of treatment is min-imising the associated comor-bidity.

Pain managementRegardless of the underlyingcause, management of neuro-pathic pain is identical. Thereare different approaches tomanagement of pain but mostapproaches rarely providecomplete relief. Most patientsrequire more than simpleanalgesics (aspirin, paraceta-mol or NSAIDs).

A non-pharmacologicalapproach to pain manage-ment is important. Goodfootwear and the use of footcreams that maintain thehealth of skin prevent com-plications and are a usefulplace to start. Managementof infection and ulcers isimportant to prevent morewidespread complications.Physical therapies, TENS,

acupuncture and hypnosismay reduce the perception ofpain.

Several different pharma-cological classes of medica-tion have been shown to besafe and effective in manag-ing neuropathic pain. Anolder therapy is the tricyclicantidepressants (amitriptyline[Endep] or nortriptyline [Alle-gron]) which are often benefi-cial, particularly if sleep is dis-rupted by pain. Their use maybe limited by daytime drowsi-ness or dry mouth. A dose of10mg at night with 10mgincrements after five days is a

commonly used regimen.Often two or more weeks arerequired for assessment ofpain relief.

Sodium-channel blockers

are now rarely used formanaging neuropathic pain,although occasionally carba-mazepine 100mg bd is effec-tive. Carbamazepine remainsfirst line for conditions suchas trigeminal neuralgia.

Mexiletine, structurallysimilar to lignocaine, may beof benefit for sharp lancinat-ing pain. Mexiletine mayexacerbate cardiac arrhyth-mias and is usually reservedfor use by pain specialistswhen other therapies havefailed.

Gabapentin (eg, Neurontin)and pregabalin (Lyrica) arenewer agents with provenefficacy in clinical trials, par-ticularly with painful diabeticneuropathy. The favourableside effect profile has encour-aged their widespread use.However, neither have PBSreimbursement for neuro-pathic pain.

A typical dose regimen forgabapentin of 300mg tdscosts about $100/month,although many pain special-ists, neurologists and rehabil-itation specialists are able toprescribe these drugs through

the hospital system.Gabapentin is usually startedat 100mg or 300mg daily andthen, for either strength,increased by one tablet every

three days. The maximumdose is 3600mg per day individed doses.

Weight gain, drowsinessand GI symptoms are in-frequently reported withgabapentin. Most patientswith idiopathic, painfulperipheral neuropathiesreport a modest benefit fromgabapentin or pregabalin.

Tramadol, a non-narcoticcentrally acting analgesic,appears modestly effective forsome patients with neuro-pathic pain, with evidence

derived from diabetes studies.Topical therapies such as

analgesic creams and cap-saicin are occasionally help-ful. Capsaicin is believed toproduce relief of pain bydepleting substance P in sen-sory terminals, and is usuallyapplied 3-4 times a day.EMLA cream may providerelief from painful feet orfocal neuropathic pain.

Narcotics are rarely of ben-efit for managing chronicpain associated with a neu-ropathy. However, oxy-codone has been shown to beof benefit for post-herpetic

neuralgia.Chronic pain leads to

altered illness behaviour andtreatment of associateddepression may be important.

DisabilityFor many, the disability asso-ciated with a neuropathy is amajor concern. When footdrop and difficulty with walk-ing occurs, an ankle-footorthotic device can preventfalls and allow a normal gait.Assessment by physiothera-pists and occupational thera-pists may help some patients.

Common clinical courseMost chronic, idiopathic sen-sory-predominant neu-ropathies that occur after age30 run an indolent or slowlyprogressive course. For most,the description of a glove-and-stocking neuropathydescribes the distribution ofsymptoms.

While many patients wishto know the clinical courseand whether they will endup in a wheelchair, they canbe reassured that this out-come is relatively uncommon.Often a cause for a progres-sive neuropathy is identifiedand therapy can change theoutcome.

Areas of clinicalcontroversySome clinical entities remainof uncertain significance. Thetarsal tunnel syndrome, inwhich compression of thetibial nerve occurs at themedial ankle (similar to thecarpal tunnel syndrome), isbelieved to cause burning

pain in the toes and sole ofthe foot.

Percussion at the medialankle is occasionally able toreproduce the symptoms, andNCS may show a block.However, it is less clear thatsurgery is of benefit and manycases are probably due tomore proximal or distalcauses.

Thoracic outlet syndrome(compression of the lowertrunk of the brachial plexusas it passes above a cervicalrib or rudimentary ligament)very rarely causes a true neu-rogenic syndrome in which

wasting of the thenar emi-nence and clawing of thehand occurs, usually with ill-defined numbness along themedial forearm and hand.

NCS define the lesion andthere is a favourable responseto surgery. Far more com-monly encountered is a syn-drome of pain along themedial forearm and hand, forwhich surgery is of doubtfulbenefit.

Areas of researchcontroversyThe physiological basis formany neuropathies remainsunknown. Even the mecha-nism of many of the diabeticvariants is poorly understood.

The cause of pain in periph-eral neuropathies is not clear.For example, there is no clini-copathological differencebetween painful and non-painful diabetic neuropathy,and no correlation betweensural nerve biopsy specimensand pain descriptions.

Besides an association with

autonomic changes, reflex sym-pathetic dystrophy (or causal-gia) remains an unknownentity, particularly in theabsence of nerve dysfunction.

Like after you have been at thedentistA 58-YEAR-old woman had noticedloss of sensation in both feet, whichbegan in the toes. Some discomfortwas present, which she described astingling, like the sensation in yourmouth after you have been at the

dentist. There was no weakness orbalance difficulties.

The patient was in otherwise goodhealth and taking no regular med-ications. She was unsure of anyfamily history of neurological symp-toms. Her examination showednormal strength, reflexes and sen-sory examination, with subjectivediminution/alteration in pin-prick

and light touch below the ankle levelbilaterally.

Provisional clinical diagnosis wasidiopathic small-fibre neuropathy.

This neuropathy is usually rela-tively benign, without progressivedisability. Management of pain isusually the focus of treatment.

An inherited neuropathy?A 22-year-old man complained ofpoor balance and difficulties playingtennis, perhaps increased at night. Thesymptoms had been noticed for fiveyears and were slowly progressing.

On examination, pes cavus wasnoted, along with the patientsinability to stand on his heels. There

was loss of vibration at the halluxand reduced sensation to pin-prickto the ankle level. On specific ques-tioning, a sister had been investigatedfor a neuropathy.

Provisional diagnosis was Charcot-Marie-Tooth type I (inherited neu-ropathy genetic testing is available).

This is the most common inher-ited neuropathy and usually gradualdisability occurs over time. Manypatients will not require wheelchairassistance, in distinction from otherinherited neuropathies. There is nospecific treatment, but there may begenetic implications.

Treatment and prognosis

Authors case studies

Summary Peripheral neuropathy describes motor or sensory symptoms

and signs that result from dysfunction of axons or the

surrounding myelin sheath.

While the cause of a neuropathy can often be identified, even

in specialised neuropathy clinics 25% of neuropathies remain

idiopathic. There are many different classifications of neuropathies,

which are variably helpful for individual patients. One

classification is separation into small- and large-nerve-fibre

disorders, with the latter then divided into those disorders

affecting motor, sensory or both types of nerves.

Neuropathies are rarely curable; the focus is usually on man-

aging pain and the disability that arises.

Evidence-based practiceAcute (Guillain-Barr syndrome), chronic inflammatory

demyelinating polyradiculoneuropathy, and multifocal

motor neuropathy, have evidence of benefit using

immunomodulatory therapy. For many other types of

neuropathy, randomised trials are needed.

There is no effective therapy for hereditary neuropathies

besides surgery to correct deformity.

Surgical treatment of overt carpal tunnel syndrome is more

effective than simple therapies such as splinting. The

evidence is less clearly established for other compressive

neuropathies.

There is level A evidence for the efficacy of tricyclic anti-

depressants, gabapentin and pregabalin in neuropathic pain.

However, most of the randomised controlled trials of neuro-

pathic pain were limited to patients with postherpetic neuralgia

and diabetic neuropathies. Some conditions, such as HIV-

associated polyneuropathy, are recognised as more refractory.

Further readingDyck PJ, et al (editors).

Peripheral Neuropathy. 2nd

edn. WB Saunders,

Philadelphia, 1993.

Online resources A useful reference for

inherited neuropathies is

the genetic web site

Online Inheritance in

Man:

www.ncbi.nlm.nih.gov/

Omim

Most patients require more thansimple analgesics (aspirin,

paracetamol or NSAIDs).

8/10/2019 P. neuro

6/6

Case studyMRS H, 82, complains oflong-term burning in herfeet at night. The burningwakes her from sleep, ismainly in the soles and toes,

and when the sheets touchthem it is excruciatinglypainful. At times she hasplaced a cold foot bath nearthe bed in an attempt to getsome relief. Walking is verypainful if she gets up duringthe night.

Besides hypertension andosteoarthritis she is in rea-sonably good health. Thereare no symptoms during theday and examination of thefoot is normal.

Questions for the authorThese symptoms seem to becommon in the elderly

regardless of diabetic status.Could you describe yourapproach to assessment ofthese types of cases?

The severity of symptoms,degree of disability and an

elderly patients comorbidi-ties guide the approach tomanagement and need for

referral to a neurologist.Motor symptoms or balancedifficulties require an

answer; mild peripheral dis-comfort less so.

On examination, testingof the ankle reflexes mayshow loss if there is large-fibre involvement, but the

description favours pre-dominant involvement ofsmall-nerve fibres testingof pain and temperaturemay be helpful. Given thepatients age, testing ofvibration may not be reli-able. Secondary depressionand the effect on sleep maybe worth considering, assymptoms are usually notdescribed as excruciating.

Are there specific clues youwould use to differentiatebetween vascular and neu-rological causes?

This clinical picture

favours an idiopathic sen-sory neuropathy. Occasion-ally it can be hard to sepa-rate these two causes if theproblem is peripheral painand overlap does exist, for

example, in diabetes. Thenature of symptoms isimportant, as described inthis article, but the exami-nation may also be helpful,particularly looking for

trophic changes, testing ofthe ankle reflex and painand temperature pathwaysand the peripheral pulses.

What is your approach tomanagement of these typesof cases?

Given the patients age,management may need tobe carefully considered. Ifsimple therapies and physi-cal care of the feet areunhelpful, pharmacologicaltherapy may be required. Iwould be cautious of usingamitriptyline because of theanti-cholinergic side effects,

but 10mg at night mightjust improve the neuro-pathic symptoms and hersleep. Equally, gabapentinmay well be effective forthis patient.


40 | Australian Doctor | 16 May 2008 www australiandoctor com au

HOW TO TREAT Editor: Dr Martine Walker

Co-ordinator: Julian McAllan

Quiz: Dr Wendy Morgan

INSTRUCTIONS

Complete this quiz online and fill in the GP evaluation form to earn 2 CPD or PDP points. We no longer accept quizzes

by post or fax.

The mark required to obtain points is 80%. Please note that some questions have more than one correct

answer.

ONLINE ONLY

1. Which TWO statements regarding the

pathophysiology of peripheral neuropathies

are correct?a) Myelinated nerve fibres are slower-conducting

nerve fibres that carry autonomic and sensory

information

b) Neuropathies occur when there is dysfunction

of the axon or the surrounding protective

myelin sheath

c) Recovery is slower if the pathological process

is demyelination rather than axonal damage

d) Most idiopathic and inherited neuropathies

are length dependent, with neurotransmission

failing at the end of nerves

2. Which TWO statements regarding

aetiology and classification of peripheral

neuropathies are correct?

a) The cause of a peripheral neuropathy can be

identified in about 90% of cases

b) Small-fibre neuropathies usually cause painand discomfort and are associated with

absent ankle reflexes

c) Large-fibre neuropathies usually also involve

small-nerve fibres

d) Large-fibre neuropathies can be divided into

neuropathies that are predominantly motor or

sensory, and those that involve both motor

and sensory function


nutritional neuropathies are correct?

a) Alcohol abuse is one of the more common

causes of peripheral neuropathies seen in

general practice

b) Vitamin B12 deficiency produces a sensory

neuropathy

c) Dietary deficiency of pyridoxine (vitamin B6) is

a common cause of peripheral neuropathyd) Nicotinic acid (niacin) deficiency produces a

distal sensorimotor neuropathy that is easily

distinguishable from the neuropathy of

thiamine deficiency

4. Which TWO statements regarding initial

presentations of peripheral neuropathies are

correct?

a) Motor symptoms are the most common

presentation of a peripheral neuropathy

b) In general, most sensory neuropathies are

length dependent, with feet involved before

hands

c) Most motor symptoms begin as gait and

balance difficulties

d) Loss of sweating due to autonomic

dysfunction is frequently recognised by

patients


assessment of a patient with a possible

peripheral neuropathy are correct?

a) A sensory pattern commonly found in many

neuropathies is predominant involvement of

vibration and joint-position sense

b) Loss of muscle strength is usually an early

sign in most peripheral neuropathies

c) A positive Rombergs test represents loss of

joint-position sense

d) The ankle reflex may be absent in both

sensory and motor neuropathies

6. Which TWO statements regarding nerve

conduction studies (NCS) are correct?

a) NCS are useful in both large- and small-fibre

neuropathiesb) NCS can be used to assess the size and

speed of sensory, but not motor, responses

c) NCS can distinguish demyelinating

neuropathies from axonal neuropathies

d) In conjunction with electromyography, NCS

may be helpful in distinguishing neuropathies

from disorders of the neuromuscular junction

and muscle

7. Tom, 65, presents with an acute motor-

sensory neuropathy. After initial assessment

you suspect Guillain-Barr syndrome (GBS).

Which TWO statements about GBS are

correct?

a) About half of patients with GBS report a

preceding respiratory or GI illness

b) Proximal muscle weakness is always a late

sign in acute GBSc) A key finding on examination in GBS is

areflexia

d) About 25% of cases of acute GBS require

admission to hospital

8. John, 55, has type 1 diabetes. Which TWO

statements regarding diabetic neuropathy

are correct?

a) About 10% of patients with diabetes have

clinical evidence of neuropathy, although

subclinical involvement may be found in up to

25%

b) The most commonly recognised neuropathy

of diabetes is the painful, asymmetric,

proximal plexopathy (diabetic amyotrophy)

c) Patients with diabetes occasionally may have

a pure autonomic neuropathy

d) Good long-term control of diabetes isimportant for preventing progression of

diabetic neuropathy

9. Which TWO statements regarding chronic

peripheral entrapment mononeuropathies are

correct?

a) Surgical treatment of carpal tunnel syndrome

is no more effective than splinting

b) Wrist drop occurs as a result of neuropathy of

the posterior interosseous branch of the

median nerve

c) Weight loss may be of benefit in meralgia

paraesthetica (numbness due to compression

of the lateral femoral cutaneous nerve of the

thigh)

d) Foot drop may result from entrapment of the

common peroneal nerve at the head of the

fibula, but needs to be distinguished frommore proximal causes

10. Which TWO statements regarding the

management of peripheral neuropathies are

correct?

a) Neuropathies are rarely curable, so the focus

usually is on managing pain and the disability

that arises

b) A non-pharmacological approach to pain

management is important

c) Most patients with neuropathic pain can be

adequately treated with simple analgesics

(aspirin, paracetamol or NSAIDs)

d) Narcotic analgesics are very useful in the

management of neuropathic pain

www.australiandoctor.com.au/cpd/ for immediate feedback

CPD QUIZ UPDATEThe RACGP now requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the 2008-10 triennium. You

can complete this online along with the quiz at www.australiandoctor.com.au. Because this is a requirement, we are no longer able to accept the quiz by post

and fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online.

NEXT WEEK To coincide with the newly released ninth edition of theAustralian Immunisation Handbook, next weeks How to Treat presents an aid to help GPs maintain currency with the latest immunisationguidelines. The authors are Dr Joanne Molloy, GP in Geelong, Victoria; Medical Officer of Health for the City of Greater Geelong; manager of the immunisation program for the GP Association of Geelong;

and member of the Australian Technical Advisory Group on Immunisation (ATAGI), and Professor Terry Nolan, head, Melbourne school of population health, University of Melbourne; head, vaccine and

immunisation research group, Murdoch Childrens Research Institute and MSPH; chair of ATAGI; and general paediatrician at the Royal Childrens Hospital, Melbourne, Victoria.

DR MATILDA METLEDGESydney, NSW

GPs contribution

Peripheral neuropathy 16 May 2008

How to Treat Quiz

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