2'ournal ofNeurology, Neurosurgery, and Psychiatry 1995;58:274-283

NEUROLOGICAL INVESTIGATIONS

Investigation of peripheral neuropathy

J G McLeod

Peripheral neuropathy is a common conditionthat is associated with many systemic dis-eases. Its exact prevalence in the communityis not known although epidemiological stud-ies have established the frequency of certainsubtypes-for example, Guillain-Barre syn-drome,' diabetic neuropathy,' and Charcot-Marie-Tooth disease.3 Because of thenumerous causes (well over 100) of periph-eral neuropathy and the likelihood of findingan underlying treatable condition, it is impor-tant to take a systematic approach to thediagnosis. Diagnostic algorithms for evalua-tion of neuropathies have been published.4Although it used to be believed that in morethan half the cases a cause was not found,6several large series have shown that afterintensive investigation only about 20% ofcases remain undiagnosed and these tend tohave a relatively good prognosis.7-

Pathological types ofperipheralneuropathyThere are three major pathological processesthat affect the peripheral nervous system:axonal degeneration, segmental demyelina-tion, and neuronopathy. It is important in theinvestigation of a peripheral neuropathy to beable to recognise the underlying pathologicalnature of the condition as it influences subse-quent management. Axonal degeneration is themost common pathology seen in systemic,metabolic, toxic, and nutritional disorders. Itcharacteristically has a predilection for largediameter and long fibres-distal axonopathyor dying back neuropathy. Segmental demyeli-nation is primary destruction of the myelinsheath leaving the axon intact, althoughaxonal degeneration may also be present indemyelinating neuropathies and secondarysegmental demyelination may be seen inaxonal degeneration. Electrophysiologicalstudies are helpful in differentiating primarydemyelination from axonal degeneration.Neuronopathies are those conditions in whichthe cell bodies of axons-anterior horn cellsor dorsal root ganglia are primarily affected.

Clinical evaluationThe most important parts of the investigationof suspected peripheral neuropathy are thetaking of an accurate history and the perfor-mance of a careful clinical examination.

Sensory symptoms are usually the presentingfeatures of neuropathy and include numb-ness, tingling, pins and needles in the handsand feet, burning sensations, pain in theextremities, sensations of walking on cottonwool, band like sensations around the wristsor ankles, unsteadiness on the feet, or stum-bling. Motor symptoms are usually those ofweakness and patients may find it difficult toturn keys in locks, unfasten buttons, andremove the tops of bottles and jars. In theearly stages of peripheral neuropathy, weak-ness is usually distal; however, early proximalweakness is a feature of inflammatory neu-ropathies and porphyric neuropathy.Autonomic symptoms, particularly posturalhypotension, impotence, sphincter distur-bances, diarrhoea, constipation, and drynessor excessive sweating of the extremities pointto damage of small myelinated and unmyeli-nated fibres. In the history, attention shouldbe paid to recent upper respiratory tract orother infections, alcohol and drug intake,diet, possible exposure to industrial and envi-ronmental toxins, family history, and symp-toms of systemic diseases. It is important tonote the tempo of the disease-acute, suba-cute or insidious onset; rapid or slow progres-sion; progressive, stepwise or relapsing andremitting course. Table 1 shows some of themore common causes of peripheral neuro-pathy with acute onset.

Signs are usually those of distal musclewasting and weakness, and sensory impair-ment, predominantly over distal regions andoften in a glove and stocking distribution. Indistal axonopathies, particularly in diabetes,there may be loss of sensation over the ventralregions of the trunk due to distal degenera-tion of the intercostal nerves. A truncal neu-ropathy, with a dermatomal distribution ofdysaesthesia and sensory loss, may also beseen in diabetes'0 as well as in Lyme disease"and Sjogren's syndrome'2 (table 1). In condi-tions that affect predominantly small fibres(amyloid neuropathy, Tangier disease, andsome cases of diabetic neuropathy) there maybe dissociated loss of sensation with loss ofpain and temperature sensation and preserva-tion of tactile sensation. Reflexes are usuallydepressed or absent but in mild cases, insmall fibre neuropathies, and when peripheralneuropathy is associated with pyramidal tractlesions, reflexes may be preserved. Carefulgeneral examination should seek evidence of

Department ofMedicine, Universityof Sydney, Sydney,NSW 2006, AustraliaJ G McLeod

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Table 1 Clinical types ofperipheral neuropathy

Acute onset:Guillain-Barre syndromePorphyriaToxic (for example, arsenic, nitrofurantoin)Serum sickness (postimmunisation)DiphtheriaMalignancyCritical illness polyneuropathyDiabetes, uraemia (rarely)

Predominantly motor:Guillain-Barre syndromePorphyriaDiphtheriaLeadCharcot-Marie-Tooth diseaseDiabetes (diabetic amyotrophy)

Predominantly sensory:LeprosyDiabetes (distal sensory polyneuropathy)Vitamin B 12 or thiamine deficiencyMalignancyHereditary sensory and autonomic neuropathyPrimary of familial amyloidosisUraemiaLyme diseaseSj6gren's syndrome

Radicular:Diabetic truncal neuropathyLyme diseaseSjogren's syndrome

Painful neuropathies:Alcohol, nutritional deficienciesDiabetes (acute painful neuropathy)Hereditary sensory and autonomic neuropathy(HSAN type 1)

ArsenicCryoglobulinaemiaLyme diseaseParaneoplastic sensory neuropathyVasculitic neuropathies

pes cavus or other skeletal deformities,enlarged nerves, skin lesions, arthritis, drymucous membranes, and enlargement ofliver, spleen, and lymph glands.The clinical features of the neuropathy

may indicate the underlying cause and enablethe most appropriate investigations to beundertaken (table 1). Mononeuropathy isusually due to direct compression or entrap-ment but may be the first manifestation ofdiabetic or vasculitic neuropathy. Mono-neuritis multiplex (multiple mononeuro-

pathy) is caused by vasculitis, leprosy,sarcoidosis, and some other conditions (table2).

Laboratory investigationsGeneral laboratory tests and nerve conduc-tion studies will be performed as the firststage of investigation in all patients unless thediagnosis is clinically obvious-for example,diabetic or alcoholic neuropathy; subsequent

Table 2 Causes of mononeuritis multiplex

Vascular:DiabetesPolyarteritis nodosaRheumatoid arthritisSystemic lupus erythematosusWegener's granulomatosisSjogren's syndromeNon-systemic vasculitis

Inflammatory:LeprosySarcoidosisLyme disease

Infiltrations:MalignancyAmyloidosis

Immune reactions:Immunisation, foreign serum and proteins

Trauma:Multiple nerve injuries

investigation will depend on the results ofthese initial studies.

GENERAL LABORATORY TESTSBasic laboratory investigations that should beperformed on all patients with peripheralneuropathy of undetermined aetiologyinclude urinalysis, haemoglobin, white cellcount, platelets, erythrocyte sedimentationrate, fasting blood glucose, serum elec-trolytes, serum proteins, serum protein elec-trophoresis and immunoelectrophoresis,serum creatinine, liver function tests, chestradiographs, and electrophysiological studies(see later). If these do not provide a diagno-sis, other special investigations may includethyroid function tests, serum vitamin E con-centrations, serum cholesterol and triglyc-erides, cryoglobulins, urinary heavy metalsand porphyrins, antinuclear antibodies,rheumatoid factor, Sj6gren's syndrome (SS)antibodies, (SS-A (anti-Ro) and SS-B (anti-La)), serology for Lyme disease and HIV,antiganglioside GM1 antibodies, Schirmer'stest, and screening for occult malignancy withendoscopic and radiological examinationsincluding skeletal surveys (table 3).

NERVE CONDUCTION STUDIESNerve conduction studies play a key part inconfirming the presence of peripheral neu-ropathy and in establishing its cause. Theyassist in determining whether the patient hasa mononeuropathy, mononeuritis multiplex,or a generalised peripheral neuropathy, and ifso, whether it is symmetric or asymmetric,whether both sensory and motor fibres areaffected, and whether the underlying pathol-ogy is that of axonal degeneration or segmen-tal demyelination as there is a correlationbetween the conduction velocity and theunderlying pathological process."1'7 Table 4shows the causes of segmental demyelinationand conduction velocities in the demyelinat-ing range.

Nerve conduction studies should be per-formed on nerves that are clinically unaf-fected as well as those that are clinicallyaffected. In general, several nerves should bestudied in upper and lower limbs-for exam-ple, motor and sensory conduction in medianand ulnar nerves, motor conduction in com-mon peroneal and posterior tibial nerves, andsensory conduction in sural nerves. In somecases it may be appropriate to perform sen-sory conduction on radial, tibial, and saphe-nous nerves and to record mixed nerve actionpotentials in ulnar and common peronealnerves. Every clinical neurophysiology labora-tory should have established its own controlvalues. The age of the patient needs to betaken into account because nerve conductionvelocities in full term infants are about halfthe adult values but increase to the adultrange at 3 to 5 years of age; there is also areduction in conduction velocity after the ageof 40. Temperature of the limbs must be con-trolled or a temperature correction appliedbecause the conduction velocity changes by2-4 m/s/IC from 29 to 380C.'8-19

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Table 3 General laboratory investigations

Condition

Metabolic:Diabetes

Hypoglycaemia

UraemiaPorphyria

HypothyroidismAcromegaly

Deficiencies:B1 (thiamine)

Vitamin B6 (pyridoxine)

Vitamin B 12Vitamin E

Toxic:Arsenic, lead, mercury, thallium

Paraproteinaemias, dysproteinaemias:Multiple myeloma, Waldenstrom'smacroglobulinaemia, cryoglobulinaemia,monoclonal gammopathy of uncertainsignificance

Connective tissue disorders:Systemic lupus erythematosus, mixedconnective tissue disease, scleroderma,rheumatoid arthritis, polyarteritisnodosa, Sjogren's syndrome,Wegener's granulomatosis

Sjogren's syndrome

Inflammatory neuropathies:Acute inflammatory neuropathy

Chronic inflammatory demyelinatingpolyradiculoneuropathy

Infections:HIVLyme diseaseLeprosy

Hereditary neuropathies with knownbiochemical abnormalities:

Primary amyloid neuropathy

Familial amyloid polyneuropathyMetachromatic leukodystrophy

Krabbe's disease(globoid cell leukodystrophy)A ,B lipoproteinaemia (Bassen-Kornzweig disease)

An a lipoproteinaemia (Tangier disease)

Refsum's disease

Investigations

Urinalysis, fasting blood glucose, glucosetolerance testFasting blood glucose, serum insulin, orC peptide concentrationsBlood urea, serum creatine, urinalysisUrinary porphyrins, ALA, porphobilinogen.Total faecal porphyrins. Erythrocyteporphobilinogen deaminaseSerum free thyroxine, serum TSHSerum growth hormone concentrations

Erythrocyte transketolase activity +enhancement with thiamine pyrophosphateErythrocyte aspartate amino transferase +enhancement with pyridoxal-5-phosphateSerum B 12, Schilling testSerum vitamin E

24 hour urinary heavy metals

Hb, WCC, platelets, ESR, plasmaimmunoelectrophoresis, urinary Bence-Jones protein, radiological skeletalsurvey, bone marrow biopsy, plasmacryoglobulins

Hb, WCC, platelets, ESR, serumimmunoelectrophoresis, antinuclearantibodies, antidouble strandedDNA antibodies, rheumatoid factor, serumcomplement (C3, C4, CH50),antineutrophil cytoplasmic antibodiesAll above + anti-Sjogren's syndromeantibodies, Schirmer's test, lip biopsy

HIV, blood glucose, urinary porphyrins,Epstein-Barr virus, Campylobacterinfections, cytomegalovirus, mycoplasmaESR, serum immunoelectrophoresis, anti-ganglioside GMI antibodies, antinuclearantibodies, antineutrophilcytoplasmic antibodies

HIV serologyLyme serologyLepromin tests; skin, nasal scrapings;skin, nerve biopsy

Rectal, liver, renal, abdominal fat, nervebiopsy; serum immunoelectrophoresis;urinary Bence-Jones proteinSerum, tissue transthyretinBlood leucocyte, skin fibroblastarylsulphataseBlood leucocyte, skin fibroblastgalactosylceramide ,B galactisidaseAcanthocytes in blood, serum cholesterol,plasma low density and very low densitylipoproteinsSerum cholesterolPlasma high density lipoproteinsSerum phytanic acid. a oxidation ofphytanic acid in skin fibroblasts

Hb = haemoglobin; WCC = white cell count; ESR = erythrocyte sedimentation rate.

Motor conduction velocities should berecorded from surface electrodes to measurethe amplitudes of the muscle action potentialafter stimulation at distal and proximal sites;reduced amplitude of the muscle actionpotential at distal stimulation sites is indica-tive of axonal degeneration, or, rarely,demyelination in distal motor fibres. A signifi-cant reduction in the amplitude of the muscleaction potential on moving the stimulatingelectrode from a distal to a more proximalsite is supportive evidence of conductionblock.20 Conduction block is suspected ifthere is greater than 20% reduction in ampli-tude (provided there is less than a 15%change in duration of the muscle actionpotential between proximal and distal sites ofstimulation2' as dispersion and polyphasicaction potentials can cause phase cancella-

Table 4 Demyelinating neuropathiesInflammatory neuropathies:

Guillain-Barre SyndromeChronic inflammatory demyelinatingpolyradiculoneuropathyMotor neuropathy with multifocal conduction blockChronic inflammatory neuropathy associated withparaproteinaemiaInflammatory neuropathy associated with HIV infection

Hereditary neuropathies:HMSN type IHMSN type IIIRefsum's syndromeMetachromatic leukodystrophyKrabbe's disease

Metabolic neuropathies:Diabetes (sometimes)Uraemia (sometimes)

Toxic neuropathies:Perhexiline maleateAmiodoroneHexacarbons

Infections:Diphtheria

MalignancySome acute or subacute neuropathies associated withIymphoma, carcinoma

tion).22 Abrupt change in area, or amplitude,or both over a short segment of nerve, ratherthan a gradual reduction over a longer dis-tance, is strong evidence of conductionblock.22 Further evidence of demyelination istemporal dispersion (increased duration ofthe muscle action potential), prolonged distallatencies, and reduction in conduction veloc-ity to less than 80% of the lower limit of nor-mal in two or more motor nerves.2' 23

In axonal degeneration there is normal oronly mild slowing of conduction due to fallout of the damaged large diameter fibres, theremaining intact fibres having normal con-duction velocities. Other evidence of axonaldegeneration is a reduced muscle actionpotential and electromyographic evidence ofdenervation. It should be noted that milddegrees of slowing of conduction do notexclude the possibility of underlying segmen-tal demyelination in peripheral nerves.'5 17

Sensory conduction is usually impaired, withreduced amplitudes of action potentials inboth axonal degeneration and segmentaldemyelination. Although sensory actionpotentials are difficult to record over long dis-tances in diseased nerves, slowed conductionand dispersion of the action potentials can berecorded in segmental demyelination withappropriate techniques. Because motor andsensory conductions are routinely measuredonly in large diameter fibres with standardnerve conduction techniques, they may benormal in small fibre neuropathies.

F wavesF waves are late waves that can be recordedfrom muscles after supramaximal stimulationof the nerve and result from antidromic nerveimpulses causing anterior horn cells to back-fire.24 They provide a measure of conductionover the whole length of the motor nerve andare therefore a useful way of recording con-duction in proximal segments.'9

H reflexThe H reflex measures the conductionthrough afferent and efferent fibres in the

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monosynaptic reflex arc. It is most easilyrecorded from the calf muscles. It is usuallyabsent when the F wave and other nerve con-duction studies are abnormal.'9

Needle electromyographyWhen muscles are denervated, spontaneousfibrillation, positive sharp waves, and areduced interference pattern are recorded onneedle electromyography. Electromyographyis useful in confirming the presence of axonaldegeneration in the Guillain-Barre syn-drome.25 It should be borne in mind that den-ervation potentials may not appear until threeweeks after the onset of axonal degeneration.

Somatosensory evoked potentialsSomatosensory potentials may be useful indetecting abnormalities of conduction inproximal segments when conventional nerveconduction studies are normal.25 Walsh et aP6found them more useful than the F waves inthe Guillain-Barre syndrome although othershave had a different experience.27

EXAMINATION OF CSFA lumbar puncture with examination of CSFis unrewarding in most cases of axonal neu-ropathy but should be performed in demyeli-nating neuropathies. In the Guillain-Barresyndrome the CSF protein rises during thefirst week. The white cell count varies withthe time of lumbar puncture and is raised inabout 10% of cases.2829 An increased whitecell count raises the possibility of HIV infec-tion or Lyme disease.2830 CSF protein is alsoraised in chronic inflammatory demyelinatingpolyradiculoneuropathy (CIDP) and mayhelp to distinguish this condition from hered-itary demyelinating neuropathies. A high CSFprotein suggests inflammatory causes anddemyelination of spinal roots or both. In myexperience, oligoclonal IgG bands are presentin the CSF of about 6% of cases of Guillain-Barre syndrome, and 16% of cases of CIDP.

QUANTITATTVE SENSORY TESTINGQuantitative sensory testing is the use of psy-chophysical methods for measuring abnor-malities of the different modalities ofsensation. With these techniques, quantitativevalues for thresholds of vibration, touch-pressure, and warm and cold sensation maybe obtained on individual patients and com-pared with control values. These investiga-tions are not routinely employed in theinvestigation of peripheral neuropathy but are

Table S Genetic tests for hereditary neuropathies

Chromosome GeneDisease location product Genetic defect

CMT Ia (HMSN Isa) 17pl 1.2-12 PMP22 DuplicationPoint mutation

CMT Tb (HMSN Ib) 1q21.2, 23 Po Point mutationCMT X (HMSN-X) Xql3 Connexin-32 Point mutationHereditary liability to pressure 1 7p. 1 1.2,12 PMP22 Deletion

palsies (Tomaculous Point mutationneuropathy)

Familial amyloid polyneuropathy 18ql 1.2,12.1 Transthyretin, Apo Al Point mutations(most types) + 2 unidentified genes

on chromosomes 9 and 11

useful in detecting early sensory abnormali-ties in people exposed to occupational andenvironmental toxins, in controlled clinicaltrials, and in epidemiological studies.3'

AUTONOMIC FUNCTION STUDIESAutonomic dysfunction is a common compli-cation of peripheral neuropathies althoughoften it is mild and of little relevance. In someconditions, however, there may be profounddisturbance of autonomic function includingorthostatic hypotension, impairment of bloodpressure, heart rate and bladder control, andimpotence. Diseases that primarily affectsmall fibres in peripheral nerves or causeacute demyelination of small myelinatedfibres are those most likely to cause auto-nomic dysfunction. These include acutedysautonomia, familial and primary amyloi-dosis, Guillain-Barre syndrome, diabetes,porphyria, Chagas' disease, and some heredi-tary sensory and autonomic neuropathies.'2"There are many available tests from whichto select; tests of both sympathetic andparasympathetic function should be includedand it is generally necessary to find abnormal-ities in two or more of these tests to confirmthe presence of autonomic dysfunction.33Tests of autonomic function that can be read-ily undertaken in the clinical neurophysiologylaboratory are heart rate variation with respi-ration, Valsalva ratio, heart rate response tostanding or tilting, blood pressure response tosustained hand grip, and the sympathetic skinresponse.34 Autonomic function studies,together with quantitative sensory testing andsural nerve biopsy, are the most useful waysof confirming a diagnosis of small fibreneuropathy.'6

MOLECULAR GENETICSThere are now several hereditary neu-ropathies in which the gene locus has beenidentified and the number is rapidly increas-ing with advances in recombinant DNA tech-nology. The types of genetic analysis availableto the clinician fall into two groups: linkagestudies for conditions in which the region ofthe gene on the chromosome has been identi-fied but the defective gene has not beencloned, and mutation analysis or positionalcloning in those conditions in which the genehas been cloned.'7-'9

Table 5 shows the hereditary peripheralneuropathies in which the gene has beenidentified.

SURAL NERVE BIOPSYNerve biopsy is a valuable method for estab-lishing a cause of peripheral neuropathy inspecific circumstances.'404' It should not beperformed simply to establish the presence ofperipheral neuropathy as clinical evaluationand nerve conduction studies are nearlyalways adequate for this purpose. It shouldonly be undertaken where the biopsy can beevaluated by a laboratory experienced in thetechniques of light and electron microscopy,teased fibre studies, and the use of immuno-histochemical methods of staining. Biopsies

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should only be undertaken after full clinicaland electrophysiological assessment andwhen other laboratory investigations havebeen completed. It is usually performed onthe sural nerve but sometimes the radial sen-sory nerve is more appropriate. Whole nerveor fascicular biopsies are undertaken in differ-ent centres. Although not required in thosecases where the diagnosis is certain from fam-ily history or from other investigations, nervebiopsy may confirm a diagnosis of chronicinflammatory demyelinating polyradiculoneu-ropathy (CIDP),42 43 hereditary motor andsensory neuropathy (HMSN),448 hereditarysensory and autonomic neuropathy(HSAN),49 primary and familial amyloid neu-ropathy,50-53 vasculitis,54 57 sarcoidosis,98 giantaxonal neuropathy,5960 hereditary liability topressure palsies (tomaculous neuropathy),6'and hexacarbon (n-hexane and methyl n-butyl ketone) neuropathy.62 Specific appear-ances may be seen in the nerve biopsy in IgMK paraproteinaemic neuropathy,63 metachro-matic leukodystrophy,64 66 Krabbe's dis-ease,6667 Fabry's disease,6869 and Friedreich'sataxia.70 In some cases of vasculitis, sarcoido-sis, amyloidosis, sensory perineuritis, andchronic inflammatory neuropathy, the biopsyis essential for diagnosis.

In general, nerve biopsy is of little diagnos-tic value in metabolic disorders and alcoholicand nutritional neuropathies, in which theappearances are non-specific. There is a casefor performing biopsies in patients withchronic neuropathies of undetermined causewhen all other investigations have been com-pleted. The morphometry of peripheralnerves is related to age and every laboratoryshould have its own established control valuesfor different age groups.

Application of investigations to specifictypes of peripheral neuropathyHEREDITARY NEUROPATHIESCharcot-Marie-Tooth disease (hereditary motorand sensory neuropathy, peroneal muscularatrophy)Charcot-Marie-Tooth disease (CMT) is agenetically heterogeneous disorder. There arefour major types: HMSN I (CMT la and lb),HMSN II (CMT 2), X linked (CMT-X), andHMSN III (Dej&rine-Sottas disease).3 HMSNI and II are usually dominant although someautosomal recessive cases have been described.Dej&rine-Sottas disease (HMSN III) is autoso-mal recessive.Nerve conduction studies-Nerve conductionstudies are of considerable value in the initialcategorisation of Charcot-Marie-Tooth diseaseinto different subtypes. Although there is someoverlap, motor conduction velocities in bothHMSN Ia and b are greatly slowed (medianmotor conduction velocity < 38 m/s) and sen-sory conduction is impaired. By contrast, thereis only mildly impaired or normal motor con-duction velocity in HMSN II.3 4446 71-74 Bradleyet a145 suggested that there was also an inter-mediate type of Charcot-Marie-Tooth diseasewith intermediate conduction velocities

(25-45 m/s) and intermediate changes onnerve biopsy. It is likely that some of thesecases were CMT-X as slow conduction veloci-ties are found in affected males with CMT-X(< 40 m/s) and intermediate range motor con-duction velocities (> 40 mIs) in affected orobligate female carriers.75 In HMSN III(Dejerine-Sottas disease) motor conductionvelocities are typically grossly slowed (< 12m/s). 47 487 It may be a genetically heteroge-neous condition.76Sural nerve biopsy-Sural nerve biopsy is help-ful in distinguishing the different types ofHMSN when they are not clearly separated onthe basis of electrophysiological studies.44 487In HMSN la and b there is a reduction in thedensity of fibres, evidence of segmentaldemyelination on light and electron micro-scopy and teased nerve fibres, and in mostmyelinated fibres the myelin sheath is ofappropriate diameter for the axon. In HMSNII there is a reduction in the density of myeli-nated fibres but no evidence of demyelination.In HMSN III onion bulbs are prominent andthe myelin sheath is abnormally thin relative tothe axon diameter.Genetic studies-Most cases of HMSN I aretype la, which is linked to chromosome 17.There is usually a duplication on17pll.2-1279-8' in which region the PMP22gene is located. In some cases of the disease, apoint mutation of the coding region of PMP22has been demonstrated where an identicalmutation also occurs in the tremblermouse.8-84 Duplication in this region has alsobeen shown in nine out of 10 sporadic casesthat had been considered to be recessive.85 Ithas been suggested that overdosage of PMP22caused by the DNA duplication is the mecha-nism for producing the HMSNIa phenotype.A deletion in the same region that is dupli-cated in HMSNIa is found in hereditary neu-ropathy with liability to pressure palsies.8687 Ithas been shown that the gene involved is alsoPMP22. A frame shift or null mutation wasfound, indicating that underdosage of PMP22is the cause of this condition.88The gene mutation in HMSN lb has been

located near the Duffy locus on chromosome1 where HMSN Ib was originally mapped bylinkage analysis.8990 A point mutation in thegene for Po (1q21 .2q23) was subsequentlyfound when Po was mapped to this region.91HMSN type II is genetically heteroge-

neous; the gene for one of the forms of auto-somal dominant HMSN II (CMT 2) hasbeen localised to chromosome lp36.92The gap junction protein connexin-32 has

been identified for the gene mutation inCMT X (Xql3).93

Dejerine-Sottas disease (HMSN III) nowseems to be a heterogeneous disorder. Caseshave been reported with mutations of PMP22and Po genes.94

Amyloid neuropathyPeripheral neuropathy is a feature of primaryamyloidosis and several types of familial amy-loid polyneuropathy. Dysaesthesiae, loss ofpain and temperature sensation in the

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extremities, and autonomic dysfunction (pos-tural hypotension, impotence, impairedsweating, bladder disturbance) are character-istic features. Distal sensory loss, predomi-nantly of pain and temperature sense, arefound on examination. Nerve conductionstudies and electromyography are consistentwith axonal neuropathy. Autonomic functionstudies are abnormal. Sural nerve biopsy isusually diagnostic and shows amyloiddeposits in blood vessels and endoneuriumon Congo red staining and there is selectiveloss of small myelinated and unmyelinatedfibres. The diagnosis of amyloidosis may alsobe established by abdominal fat, rectum, kid-ney, and liver biopsy.50 53 A high proportion ofpatients with primary amyloidosis have mon-oclonal proteins on immunoelectrophoresis ofurine and blood, and some have multiplemyeloma. Immunohistochemical staining oftissue amyloid identifies protein specifictypes-AL in primary amyloidosis and AF infamilial types. The amyloid in familialpolyneuropathy is not derived from immuno-globulin and therefore abnormal immuno-globulins are not present in the serum. Inmost, but not all, types of familial poly-neuropathy (Portuguese, Indian, Germanand Jewish, and Appalachian types), thereis a prealbumin (transthyretin) fraction inthe serum and a point mutation in thetransthyretin gene (chromosome 1 8q. 11.2,q12. 1). The Finnish type of amyloidosis hasbeen located on 9q33 and the Iowa type on1 1q33-q24. The Van Allen type is due to agenetic defect of apolipoprotein Al.35

Hereditary disorders of lipid metabolismMetachromatic leukodystrophy-Metachro-matic leukodystrophy is associated withperipheral neuropathy that may sometimes bea presenting feature in adult cases. Nerveconduction studies are consistent with thesegmental demyelination that is seen on suralnerve biopsy together with metachromaticgranular inclusions in Schwann cells.6466Diagnosis may be established in the labora-tory by determination of reduced arylsul-phatase concentrations in blood leucocytesand skin fibroblasts, and by the finding ofintracellular deposits of metachromatic mate-rial on microscopic examination of urinarysediment.66 There is a mutation of the geneencoding for arylsulphatase A on chromo-some 22q-13qter.'8Krabbe's disease (globoid cell leukodystrophy)-Krabbe's disease is autosomal recessive,affects children in the first year of life, and isassociated with peripheral neuropathy. Nervebiopsy shows loss of myelinated fibres, andinclusions in Schwann cells and macrophagesthat are diagnostic.6667 Assay of the enzymegalactosylceramide ,B galactosidase in leuco-cytes, serum, or cultured fibroblasts willestablish the diagnosis without the need forbiopsy.66A-fl lipoproteinaemia (Bassen-Kornzweig dis-ease)-Peripheral neuropathy is associatedwith a progressive ataxia resemblingFriedreich's ataxia.45 There is moderate slow-

ing of motor conduction, and nerve biopsyshows segmental demyelination and loss oflarge diameter fibres. The diagnosis can beconfirmed by laboratory investigations whichshow acanthocytes in the peripheral blood,low serum cholesterol and low density andvery low density lipoproteins. Genetic testingis not available.An-a lipoproteinaemia (Tangier disease)-Peripheral neuropathy is usually present. Thepresence of large orange tonsils is characteris-tic. Sural nerve biopsy shows reduced num-bers of myelinated and unmyelinated fibresand lipid droplets may be seen in Schwanncells.96 Plasma high density lipoproteins aregreatly reduced.Fabry's disease-This is associated with apainful neuropathy and a selective loss ofsmall myelinated and unmyelinated fibresmay be seen in the sural nerve biopsy.68 69 It isan X linked recessive disorder. Glycolipidgranules may be seen in perineurial andendothelial cells in peripheral nerve.68 Thereis a deficiency of the enzyme ceramidetrihex-sosidase that results in the accumulation ofceramidetrihexaside in tissues. Diagnosis maybe established by enzyme assay of a galactosi-dase which is reduced on leucocyte and skinfibroblast preparations.97Refsum's disease-Refsum's disease is a rareautosomal recessive disorder characterised bydemyelinating hypertrophic neuropathy,retinitis pigmentosa, ataxia, ichthyosis, anddeafness. Motor nerve conduction is veryslow due to demyelination; with onion bulbformation that may be seen on sural nervebiopsies. There is impaired a-oxidation ofphytanic acid causing an accumulation ofphytanic acid in the tissues.98 Diagnosis ismade from the clinical picture and byincreased serum phytanic acid and defectivea oxidation of phytanic acid by skin fibrob-lasts.Friedreich's ataxia-Friedreich's ataxia is asso-ciated with a sensory neuropathy.Electrophysiological studies typically showsmall or absent sensory potentials and normalmotor conduction and on sural nerve biopsythere is a selective loss of large diameterfibres.70 Other spinocerebellar degenerationsmay be associated with a mild neuropathyaffecting myelinated fibres of all diameters.99

INFLAMMATORY NEUROPATHIESGuillain-Barre syndromeIn the first instance, a clinical diagnosis ofperipheral neuropathy must be establishedand other conditions such as transversemyelitis, spinal cord compression, botulism(pure motor features), and myasthenia gravis(pure motor features) must be excluded.Other causes of acute neuropathy (toxins,drugs, nutritional deficiencies, porphyria,Lyme disease, acute neuropathy of the criti-cally ill, vasculitis, and malignancy) are elimi-nated by clinical evaluation and appropriatetests. Antecedent precipitating factors (forexample, immunisation, Campylobacter,Epstein-Barr virus, and mycoplasma infec-tions) should be sought. The CSF may show

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the typical abnormalities of increased proteinand low white cell count; a high white cellcount raises the suspicion of HIV, Lyme dis-ease, and other infections.28 30 100 Nerve con-duction studies are essential for diagnosis butmay be normal in the early stages in whichcase recording of F waves and somatosensoryevoked potentials should be undertaken toseek evidence of impairment of proximal con-duction. Three or more nerves should bestudied in upper and lower limbs as theperipheral nerve demyelination may be asym-metric and patchy.25 Serial studies should beundertaken if the diagnosis is in doubt.Electromyography should be performed aftertwo or three weeks if recovery is slow, ormuscle wasting has developed, to ascertainthe extent of axonal degeneration. Nerve con-duction studies should be repeated if recoveryis delayed; persistent slowing of conduction,conduction block, and dispersion should raisethe suspicion of chronic inflammatorydemyelinating polyneuropathy with acuteonset but it should be borne in mind thatelectrophysiological evidence of demyelina-tion may persist in typical Guillain-Barre syn-drome for many weeks.

Chronic inflammatory demyelinatingpolyradiculoneuropathy (CIDP)Typically the onset is subacute, the peak ofdisability being reached later than four weeks;however, it may have a more rapid onset. Thediagnosis is confirmed by evidence ofdemyelination from nerve conductionstudies.4243 101 These may help differentiate itfrom the demyelination seen in hereditarydemyelinating neuropathies HMSN types Iand III and Refsum's syndrome in which theconduction velocities are uniformly slow in allnerves and conduction block and dispersionof the action potential are uncommon. 102Protein in CSF is usually increased.4243 101Other types of demyelinating neuropathy(paraproteinemic, vasculitic, leprosy, Lymedisease, HIV infections) must be excluded byappropriate investigations. If there is doubtabout the diagnosis, confirmation should beobtained from sural nerve biopsy as thepatient is likely to be committed to a longcourse of immunotherapy with its attendantrisks.103 The progress can be monitored bynerve conduction studies although thechanges of improvement or deterioration willlag behind those of the clinical features.

Paraproteinemic neuropathiesParaproteins may be found on immunoelec-trophoresis during the investigation of patientswith peripheral neuropathy, and the findingshould arouse suspicion of multiple myeloma,Waldenstrom macroglobulinaemia, cryoglobu-linaemia, primary amyloidosis, and other dys-proteinaemias. Bone marrow aspiration,examination for urinary Bence-Jones protein,and radiological skeletal survey should be per-formed; if these investigations are normal it islikely that the patient has a benign monoclonalgammopathy, or monoclonal gammopathy ofundetermined significance.'04

Benign monoclonal gammopathy-There is anassociation between benign monoclonal para-proteins in the blood and peripheral neuropa-thy. 105 IgM paraproteins are particularlyassociated with a chronic demyelinating senso-rimotor neuropathy, tending to occur in olderpeople and being accompanied by a posturaltremor.62 Sural nerve biopsy often showsdemyelination with widely spaced myelinlamellae being seen on electron microscopy,particularly in the presence of IgM K.62 IgAand IgG proteins may also be associated withdemyelinating neuropathies. The relationbetween paraproteinemia and CIDP is uncer-tain. 106 107

Multifocal motor neuropathy with persistentconduction blockThis is a rare condition in which there is anasymmetric chronic demyelinating neuropa-thy affecting predominantly motor nerves andclear electrical evidence of conduction block.It presents with asymmetric weakness andwasting with a motor neuron disease-like pic-ture and increased antiganglioside GM1 anti-bodies in about 80% of cases.'08 109 Motornerve conduction studies show conductionblock and slowing localised to sharply cir-cumscribed areas in nerve trunks.1"0 Sensoryconduction is normal, at least in the earlystages of the disease, and sural nerve biopsyshows only minor changes.'08 1 11 112 Biopsy ofaffected segments of nerves show subperi-neurial oedema, onion bulb formations, anddemyelinated and remyelinated axons.1"3 Therelation of this condition to CIDP is unclear.

Vasculitic neuropathyVasculitic neuropathies (polyarteritis nodosa,Churg-Strauss syndrome, Waldenstrom'smacroglobulinaemia, rheumatoid arthritis,mixed connective tissue diseases, Sjogren'ssyndrome, non-systemic vasculitis, systemiclupus erythematosus) classically present asmononeuritis multiplex although about halfthe patients have a clinical picture of asym-metric or symmetric generalised sensorimotorpolyneuropathy.54 In most cases there will beevidence of systemic disease and raised ery-throcyte sedimentation rate; the presence ofincreased titres of antinuclear antibodies andrheumatoid factor will confirm the diagnosis.Nerve conduction studies are consistent withan axonal neuropathy. Nerve biopsy usuallyshows pathological changes of vasculitis insmall vessels in the endoneurium and per-ineurium and acute severe axonal degenera-tion. Non-systemic vasculitic neuropathy isbeing increasingly recognised; up to 30% ofall vasculitic neuropathies fall into thisgroup.54-57 Some cases may have increasederythrocyte sedimentation rate and anti-nuclear antibodies titres but in most there areno serological markers and diagnosis can bemade only on sural nerve biopsy.

Sjogren's syndromeSjogren's syndrome is often difficult to diag-nose in the early stages as it may present as asymmetric or asymmetric predominantly

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sensory neuropathy in which there is evidenceof vasculitis on sural biopsy57 114115 beforesystemic symptoms of dry eyes, arthritis, andother manifestations of the disease becomeobvious and before titres of autoantibodies toRo(SS-A) and La(SSB) become raised.Another manifestation of Sj6gren's syndromemay be an ataxic sensory neuronopathy inwhich the primary pathology is dorsal rootganglionitis."5 116

INFECTIONSHIV infectionsSymptomatic neuropathy affects about 5% to10% of patients infected with HIV. Acuteinflammatory polyneuropathy of the Guillain-Barre type most often occurs at the time ofseroconversion.'00 117 The CSF cell count maybe raised.100117 Subacute multifocal neuropa-thy of a demyelinating type with inflamma-tory pathology is the most common pattern ofneuropathy before the onset of cellularimmunosuppression."7 The CSF may be nor-mal or show increased protein or white cellcount. At the late stage of HIV infections anacute lumbrosacral polyradiculopathy or mul-tifocal neuropathy may be caused bycytomegalovirus infection. It is important todiagnose cytomegalovirus neuropathy as it istreatable."7 118

LeprosyLeprosy should be considered in mononeu-ropathy or multiple mononeuropathy withpredominantly sensory symptoms in patientswho live or have lived in endemic regions.Nerve biopsy is useful in the diagnosis andnerve conduction studies are helpful in identi-fying affected nerves."7 119

1 Alter M. The epidemiology of Guillain-Barre Syndrome.Ann Neurol 1990;27(suppl):S7-12.

2 Melton LJ, Dyck PJ. Epidemiology. In: Dyck PJ,Thomas PK, Asbury AK, Winegrad AI, Porte D, eds.Diabetic neuropathy. Philadelphia: WB Saunders,1987:27-35.

3 Dyck PJ, Chance PF, Lebo RV, Carney JA. Hereditarymotor and sensory neuropathies. In: Dyck PJ, ThomasPK, Griffin JW, Low P, Poduslo JF, eds. Peripheralneuropathy 3rd ed. Philadelphia: WB Saunders,1993:1094-136.

4 Asbury AK, Gilliatt RW, eds. Peripheral nerve disorders.London: Butterworths, 1984:12.

5 Schaumburg HH, Berger AR, Thomas PK. Disorders ofthe penipheral nerves. 2nd ed. Philadelphia: FA Davis,1992:26-32.

6 Miller H. Polyneuritis. BMJ 1966;2:1219-25.7 Dyck PJ, Oviatt RF, Lambert EH. Intensive evaluation

of referred unclassified neuropathies yields improveddiagnosis. Ann Neurol 1981;10:222-6.

8 McLeod JG, Tuck RR, Pollard JD, Cameron JC, WalshJC. Chronic polyneuropathy of undetermined cause. JfNeurol Neurosurg Psychiatry 1984;47:530-5.

9 Notermans NC, Wokke JHJ, Franssen H, van der GraafY, Vermeulen M, van den Berg LH, et al. Chronicidiopathic polyneuropathy presenting in middle or oldage: a clinical and electrophysiological study of 75patients. Jf Neurol Neurosurg Psychiatry 1993;56:1066-71.

10 Stewart JD. Diabetic truncal neuropathy: Topography ofthe sensory deficit. Ann Neurol 1989;25:233-8.

11 Pachner AR, Steere AC. The triad of neurologic mani-festations of Lyme disease: meningitis, cranial neuritisand radiculoneuritis. Neurology 1985;35:47-53.

12 Malinow K, Yannakakis GD, Glusman SM, Edlow DW,Griffin J, Pestronk A, et al. Subacute sensory neu-ronopathy secondary to dorsal root ganglionitis in pri-mary Sjogren's syndrome. Ann Neurol 1986;20:535-7.

13 Gilliatt RW. Nerve conduction in human and experi-mental neuropathies. Proceedings of the Royal Society ofMedicine 1966;59:989-93.

14 Thomas PK. The morphological basis for alterations innerve conduction in peripheral neuropathy. Proceedingsof the Royal Society ofMedicine 1971;64:295-8.

15 McLeod JG, Prineas JW, Walsh JC. The relationship ofconduction velocity to pathology in peripheral nerves: astudy of the sural nerve in 90 patients. In: Desmedt JE,ed. New developments in electromyography and clinicalneurophysiology. Vol 2. Basel: Karger, 1973:248-58.

16 Behse F, Buchthal F. Sensory action potentials andbiopsy of the sural nerve in neuropathy. Brain 1978;101:473-93.

17 Logigian EL, Kelly JJ, Adelman S. Nerve conductionand biopsy correlation in over 100 consecutive patientswith suspected polyneuropathy. Muscle Nerve1994;17: 101-20.

18 Daube JR. Nerve conduction studies. In: Aminoff M, ed.Electrodiagnosis in clinical neurology. 3rd ed. New York:Churchill Livingstone, 1992:283-326.

19 Kimura J. Nerve conduction studies and electromyogra-phy. In: Dyck PJ, Thomas PK, Low PA, Griffin JW,Poduslo JF, eds. Peripheral neuropathy. 3rd ed.Philadelphia: WB Saunders, 1993:598-644.

20 Cornblath DR, Sumner AJ, Daube G, Gilliatt RW,Brown WF, Parry GJ, et al. Conduction block in clini-cal practice. Muscle Nerve 1991;14:869-71.

21 Cornblath DR. Electrophysiology in Guillain-Barre syn-drome. Ann Neurol 1990;27(suppl):S17-20.

22 Asbury AK, Comblath DR. Assessment of current diag-nostic criteria for Guillain-Barre syndrome. Ann Neurol1990;27(suppl):S21-4.

23 Sumner AJ. Electrophysiology of the inflammatorydemyelinating polyneuropathies. In: McLeod JG, ed.Inflammatory neuropathies. Bailliere's Clinical Neurology3:1. London: Bailliere Tindall, 1994:25-44.

24 McLeod JG, Wray SH. An experimental study of the F-wave in the baboon. Jf Neurol Neurosurg Psychiatry1966;29: 196-200.

25 McLeod JG. Electrophysiological studies in the Guillain-Barre syndrome. Ann Neurol 1981;9(suppl):20-7.

26 Walsh JC, Yiannikas C, McLeod JG. Abnormalities ofproximal conduction in acute idiopathic polyneuritis:comparison of short latency evoked potentials andF-waves. Jf Neurol Neurosurg Psychiatry 1984;47:197-200.

27 Olney K, Aminoff MJ. Electrodiagnostic features of theGuillain-Barre syndrome. The relative sensitivity of dif-ferent techniques. Neurology 1990;40:471-5.

28 Hughes RAC. Guillain-Barri syndrome. Heidelberg:Springer-Verlag, 1990.

29 McLeod JG, Walsh JC, Prineas JW, Pollard JD. Acuteidiopathic polyneuritis. A clinical and electrophysiolog-ical study. J Neurol Sci 1976;27:145-62.

30 Ropper AH, Wijdicks EFM, Truax BT. Guillain-Barrisyndrome. Philadelphia: FA Davis, 1991.

31 Dyck PJ, Kames J, O'Brien PC, Zimmerman IR.Detection thresholds of cutaneous sensation inhumans. In: Dyck PJ, Thomas PK, Griffin JW, LowPA, Poduslo JF, eds. Peripheral neuropathy 3rd ed.Philadelphia: WB Saunders, 1993:706-28.

32 McLeod JG, Tuck RR. Disorders of the autonomic ner-vous system: Part I. Pathophysiology and clinical fea-tures. Ann Neurol 1987;21:419-23.

33 McLeod JG, Tuck RR. Disorders of the autonomic ner-vous system: Part II. Investigation and treatment. AnnNeurol 1987;21:519-29.

34 McLeod JG. Autonomic dysfunction in peripheral nervedisease. J Clin Neurophysiol 1993;10:51-60.

35 Low PA, McLeod JG. The autonomic neuropathies. In:Low PA, ed. Clinical autonomic disorders. Boston: LittleBrown, 1993:395-421.

36 Stewart JD, Low PA. Small-fiber neuropathy. In: LowPA, ed. Clinical autonomic disorders. Boston: LittleBrown, 1993:653-66.

37 Harding AE. The DNA laboratory and neurologicalpractice. Jf Neurol Neurosurg Psychiatry 1993;56:229-33.

38 Martin JB. Molecular genetics in neurology. Ann Neurol1993;34:757-73.

39 MacMillan JC, Harper PS. Clinical genetics in neurolog-ical disease. J Neurol Neurosurg Psychiatry 1994;57:7-15.

40 McLeod JG, Walsh JC, Little JM. Sural nerve biopsy.MedJAust 1969;1:1092-6.

41 Dyck PJ, Gianni C, Lais A. Pathologic alterations ofnerve. In: Dyck PJ, Thomas PK, Griffin JW, Low PA,Poduslo JF, eds. Peripheral neuropathy. 3rd ed.Philadelphia: WB Saunders, 1993:514-95.

42 Dyck PJ, Lais AC, Ohta M, Bastron JA, Okazaki H,Groover RV. Chronic inflammatory polyradiculoneu-ropathy. Mayo Clin Proc 1975;50:621-37.

43 Prineas JW, McLeod JG. Chronic relapsing polyneuritis.J Neurol Sci 1976;27:427-58.

44 Buchthal F, Behse F. Peroneal muscular atrophy andrelated disorders I. Clinical manifestations as related tonerve biopsy findings, nerve conduction and elec-tromyography. Brain 1977;l00:41-66.

45 Bradley WG, Madrid R, Davis CJF. The peroneal mus-cular atrophy syndrome-clinical, genetic, electrophys-iological and nerve biopsy findings Part 3. Clinicalelectrophysiological and pathological correlations. jNeurol Sci 1977;32:123-36.

46 Low PA, McLeod JG, Prineas JW. HypertrophicCharcot-Marie-Tooth disease. Light and electronmicroscope studies of the sural nerve. Jf Neurol Sci1978;35:93-1 15.

47 Dyck PJ, Lambert EH, Sanders K, O'Brien PC. Severehypomyelination and marked abnormality of conduc-tion in Dejerine Sottas hypertrophic neuropathy:

281

on Novem

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/J N

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sychiatry: first published as 10.1136/jnnp.58.3.274 on 1 March 1995. D

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McLeod

myelin thickness and compound action potential ofsural nerve in vitro. Mayo Clin Proc 1971;46:432-43.

48 Ouvrier RA, McLeod JG, Conchin TE. The hyper-trophic forms of hereditary motor and sensoryneuropathy. A study of hypertrophic Charcot-Marie-Tooth disease (HMSN type I) and Dejerine Sottas dis-ease (HMSN type III) in childhood. Brain 1987;110:121-48.

49 Dyck PJ. Neuronal atrophy and degeneration predomi-nantly affecting peripheral sensory and autonomic neu-rons. In: Dyck PJ, Thomas PK, Griffin JW, Low PA,Poduslo JF, eds. Peripheral neuropathy. 3rd ed.Philadelphia: WB Saunders, 1993:1065-93.

50 Dyck PJ, Lambert EH. Dissociated sensation in amyloi-dosis: compound action potential, quantitative histo-logic and teased-fiber and electron microscopic studiesof sural nerve biopsies. Arch Neurol 1969;20:490-507.

51 Thomas PK, King RHM. Peripheral nerve changes inamyloid neuropathy. Brain 1974;97:395-406.

52 Hersch MI, McLeod JG. Peripheral neuropathy associ-ated with amyloidosis. In: Vinken PJ, Bruyn GW,Klavans HL, eds. Handbook of clinical neurology.Amsterdam: Elsevier, 1987;57:429-44.

53 Kyle RA, Dyck PJ. Amyloidosis and neuropathy. In:Dyck PJ, Thomas PK, Griffin JW, Low PA, PodusloJF, eds. Peripheral neuropathy. 3rd ed. Philadelphia: WBSaunders, 1993:1294-309.

54 Hawke SHB, Davies L, Pamphlett R, Guo Y-P, PollardJD, McLeod JG. Vasculitic neuropathy: a clinical andpathological study. Brain 1991;114:2175-90.

55 Dyck PJ, Benstead TJ, Conn DL, Stevens JC,Windebank AJ, Low PA. Non-systemic vasculitic neu-ropathy. Brain 1987;110:843-53.

56 Said G, Lacroix-Ciaudo C, Fujimura H, Blas C, FauxN. The peripheral neuropathy of necrotizing arteritis: aclinicopathological study. Ann Neurol 1988;23:461-5.

57 Davies L. Vasculitic neuropathy. In: McLeod JG, ed.Inflammatory neuropathy. Bailliere's Clinical Neurology3:1. London: Bailliere Tindall, 1994:193-210.

58 Gainsborough N, Hall SM, Hughes RAC, Leibowitz S.Sarcoid neuropathy. J Neurol 1991 ;238: 177-80.

59 Asbury AK, Gale MK, Cox SC, Baringer JR, Berg BO.Giant axonal neuropathy: a unique case with segmentalneurofilamentous masses. Acta Neuropathol (Berl)1972;20:237-47.

60 Prineas JW, Ouvrier RA, Wright RG, Walsh JC, McLeodJG. Giant axonal neuropathy-generalised disorder ofcytoplasmic microfilament formation. J NeuropatholExp Neurol 1976;35:458-70.

61 Meier C, Moll C. Hereditary neuropathy with liability topressure palsies. Report of two families and review ofthe literature. J Neurol 1982;228:73-95.

62 Korobkin R, Asbury AK, Sumner AJ, Nielsen SL. Glue-sniffing neuropathy. Arch Neurol 1975;32:158-62.

63 Smith IS, Kahn SN, Lacey BW, King RHM, Eames RA,Whybrew DJ, Thomas PK. Chronic demyelinatingneuropathy associated with benign IgM parapro-teinaemia. Brain 1983;106:169-95.

64 Webster H de F. Schwann cell alterations in metachro-matic leukodystrophy. Preliminary phase and electronmicroscopic observations. 3 Neuropathol Exp Neurol1962;21:524-54.

65 Thomas PK, King RHM, Kocen RS, Brett EM.Comparative ultrastructural observations on peripheralnerve abnormalities in the late infantile, juvenile andlate onset forms of metachromatic leukodystrophy.Acta Neuropathol (Berl) 1977;39:237-45.

66 Thomas PK. Other inherited neuropathies. In: Dyck PJ,Thomas PK, Griffin JW, Low PA, Poduslo JF.Peripheral neuropathy 3rd ed. Philadelphia: WBSaunders, 1993:1194-218.

67 Dunn HG, Lake BD, Dolman CL, Wilson J. The neu-ropathy of Krabbe's infantile cerebral sclerosis. Brain1969;92:329-44.

68 Kocen RS, Thomas PK. Peripheral nerve involvement inFabry disease. Arch Neurol 1970;22:81-8.

69 Ohnishi A, Dyck PJ. Loss of small peripheral sensoryneurons in Fabry disease. Histologic and morphomet-ric evaluation of cutaneous nerves, spinal ganglia, andposterior columns. Arch Neurol 1974;31:120-7.

70 McLeod JG. An electrophysiological and pathologicalstudy of the peripheral nerves in Friedreich's ataxia. 7Neurol Sci 197 1;12:333-49.

71 Dyck PJ, Lambert EH. Lower motor and primary sen-sory neuron disease with peroneal muscular atrophy I.Neurologic, genetic and electrophysiological findings inhereditary polyneuropathies. Arch Neurol 1968;18:603-18.

72 Dyck PJ, Lambert EH. Lower motor and primary sen-sory neuron disease with peroneal muscular atrophy. IINeurologic, genetic and electrophysiologic findings invarious neuronal degenerations. Arch Neurol 1968;18:619-25.

73 Thomas PK, Calne DB. Motor nerve conduction veloc-ity in peroneal muscular atrophy: evidence for geneticheterogeneity. _7 Neurol Neurosurg Psychiatry 1974;37:68-75.

74 Brust JCM, Lovelace RE, Devi S. Clinical features ofCharcot-Marie-Tooth syndrome. Acta Neurol Scand1978;58(suppl 68):1-142.

75 Nicholson GA, Nash JA. Intermediate nerve conductionvelocities define X-linked Charcot-Marie-Tooth neu-ropathies. Neurology 1993;43:2558-64.

76 Harding AE, Thomas PK. The clinical features of hered-

itary motor and sensory neuropathies type I and II.Brain 1980;103:259-80.

77 Vance J, Nicholson GA, Yamaoka L. Linkage ofCharcot-Marie-Tooth disease Type Ia to chromosome17. Exp Neurol 1989;104:186-9.

78 Chance PF, Lupski JR. Inherited neuropathies: Charcot-Marie-Tooth disease and related disorders. In:Harding AE, ed. Genetics in neurology. Bailliere's clinicalneurology 3:2. London: Bailliere Tindall, 1994:373-85.

79 MacMillan JC, Upadyaya M, Harper PS. Charcot-Marie-Tooth disease type Ia (CMT Ia). Evidence fortrisomy of the region pl 1.2 of chromosome 17 inSouth Wales families. JfMed Genet 1992;29:12-3.

80 Lupski JR, de Oca-Luna RM, Slaugenhaupt S, Pentao L,Guzzetta V, Trask BJ, et al. DNA duplication associ-ated with Charcot-Marie-Tooth disease type Ia. Cell199 1;66:219-32.

81 Matsunami N, Smith B, Ballard L, Lensch MW,Robertson M, Albertsen H, et al. Peripheral myelinprotein -22 gene maps in the duplication in chromo-some 17pl 1.22 associated with Charcot-Marie-ToothIA. Nature Genet 1992;1:176-9.

82 Patel PI, Roa VB, Welcher AA, Schoener-Scott R, TraskB, Pentao L, et al. The gene for the peripheral myelinprotein PMP-22 is a candidate for Charcot-Marie-Tooth disease type Ia. Nature Genet 1992;1:157-65.

83 Roa BB, Garcia CA, Suter U, Kulpa DA, Wise CA,Mueller J, et al. Charcot-Marie-Tooth disease type Ia:association with a spontaneous point mutation in thePMP22 gene. New EnglJ7 Med 1993;329:96-101.

84 Valentijn LJ, Baas F, Wolteman RA, et al. Identical pointmutation of the peripheral myelin protein-22 inTrembler-J mouse and Charcot-Marie-Tooth diseasetype 1A. Nature Genet 1992;2:288-91.

85 Hoogendijk JE, Hensels GW, Gabreels-Festen AA.De novo mutation in hereditary sensory and motorneuropathy type I. Lancet 1992;339:1081-2.

86 Verhaale D, Lofgren A, Nelis E, Dehaene I, Theys P,Lammens N, et al. Deletion in the CMT Ia locus onchromosome 17pIl .2 in hereditary neuropathy withliability to pressure palsies. Ann Neurol 1994;35:704-8.

87 Reisecker F, Lebelhuber F, Lexner R, Radner G,Rosenkranz W, Wagner K. A sporadic form of heredi-tary neuropathy with liability to pressure palsies: clini-cal electrodiagnostic and molecular genetic findings.Neurology 1994;44:753-7.

88 Nicholson GA, Valentijn LJ, Cheryson AK, KennesonML, Bragg TL, De Kroon RN, et al. Frameshift muta-tion in the PMP22 gene in hereditary neuropathy witha liability to pressure palsies. Nature Genet 1994;6:263-6.

89 Bird TD, Ott J, Giblett ER. Evidence for linkage ofCharcot-Marie-Tooth to the Duffy locus on chromo-some 1. Am _Hum Genet 1982;34:388-94.

90 Stebbins NB, Conneally PM. Linkage of dominantlyinherited Charcot-Marie-Tooth neuropathy to Duffylocus in an Indiana family. Am .7 Hum Genet 1982;34:195A.

91 Hayasaka K, Ohnishi A, Takoda G, Fukushima Y,Murai Y. Mutation of the myelin Po gene in Charcot-Marie-Tooth neuropathy type 1. Biochem Biophys ResCommun 1993;194:1317-22.

92 Denton PH, Ben Othmane K, Loeb D, Lennon F,Statjich JM, Gaskell P, et al. Genetic heterogeneity ofCharcot-Marie-Tooth Type 2 disease and mapping ofthe Charcot-Marie-Tooth 2a locus on chromosome1p36. Muscle Nerve 1994;1 (suppl):S229.

93 Bergoffen J, Scherer SS, Wang S, Scott MO, Bone LJ,Paul DL, et al. Connexin mutations in X-linkedCharcot-Marie-Tooth. Science 1993;262:2039-42.

94 Roa BB, Dyck PJ, Marks HG, Chance PF, Lupski JR.Dejerine-Sottas syndrome associated with point muta-tion in the peripheral nerve myelin protein 22(PMP22) gene. Nature Genet 1993;5:269-73.

95 Hayasaka K, Himoro M, Sawaishi Y, Nanao K,Takahashi T, Takada G, et al. De novo mutation in themyelin Po gene in Dejerine-Sottas disease (hereditarymotor and sensory neuropathy type III). Nature Genet1993;5:266-8.

96 Dyck PJ, Ellefson RD, Yao JK, Herbert PN. Adult-onsetof Tangier disease 1. Morphometric and pathologicstudies suggesting delayed degradation of neutral lipidsafter fiber degeneration. _7 Neuropathol Exp Neurol1978;37:119-37.

97 Brady RO. Fabry disease. In: Dyck PJ, Thomas PK,Griffin JW, Low PA, Poduslo JF, eds. PeripheralNeuropathy. 3rd ed. Philadelphia: WB Saunders,1993;1 169-78.

98 Skjeldal OH, Stokke 0, Refsum S. Phytanic acid storagedisease. Clinical, genetic and biochemical aspects. In:Dyck PJ, Thomas PK, Griffin JW, Low PA, PodusloJN, eds. Peripheral Neuropathy. 3rd ed. Philadelphia:WB Saunders, 1993:1149-60.

99 McLeod JG, Evans WA. Peripheral neuropathy in spin-ocerebellar degenerations. Muscle Nerve 1981;4:51-61.

100 Comblath DR, McArthur JC, Parry GJG, Griffin JW.Peripheral neuropathies in human immunodeficiencyvirus infections. In: Dyck PJ, Thomas PK, Griffin JW,Low PA, Poduslo AN, eds. Peripheral Neuropathy. 3rded. Philadelphia: WB Saunders, 1993:1343-53.

101 McCombe PA, Pollard JD, McLeod JG. Chronic inflam-matory demyelinating polyradiculoneuropathy. Brain

282

on Novem

ber 9, 2020 by guest. Protected by copyright.

http://jnnp.bmj.com

/J N

eurol Neurosurg P

sychiatry: first published as 10.1136/jnnp.58.3.274 on 1 March 1995. D

ownloaded from

Investigation ofperipheral neuropathy

1987;110:1617-30.102 Lewis RA, Sumner AJ. The electrodiagnostic distinctions

between chronic familial and acquired demyelinativeneuropathies. Neurology 1982;32:592-6.

103 Pollard JD. Chronic inflammatory demyelinatingpolyradiculoneuropathy. In: McLeod JG, ed.Inflammatory Neuropathy. Bailliere's clinical neurology1:1. London: Bailliere Tindall, 1994:107-27.

104 Kyle 1978. Monoclonal gammopathy of undeterminedsignificance-natural history of 241 cases. Am J Med1978;64:814-26.

105 Kahn SN, Riches PG, Kohn J. Paraproteinaemia in neu-rological disease: incidence, association, and classifica-tion of monoclonal immunoglobulins. J Clin Pathol1980;33:617-21.

106 Bleasel AF, Hawke SHB, Pollard JD, McLeod JG. IgGmonoclonal paraproteinaemia and peripheral neuropa-thy. Jf Neurol Neurosurg Psychiatry 1993;56:52-7.

107 Thomas PK, Willison HJ. Paraproteinaemic neuropathy.In: McLeod JG, ed. Inflammatory neuropathies.BalliJre's clinical neurology 3:1. London: BailliereTindall, 1994:129-47.

108 Pestronk A, Comblath DR, Ilyas AA, Baba H, QuarlesRH, Griffin JW, et al. A treatable multifocal motorneuropathy with antibodies to GM1 ganglioside. AnnNeurol 1988;24:73-8.

109 Pestronk A, Chaudhry V, Feldman EL, Griffin JW,Comblath DR, Denys EH, et al. Lower motor neuronsyndromes defined by pattems of weakness, nerve con-duction abnormalities and high titres of antiglycolipidantibodies. Ann Neurol 1990;27:315-26.

110 Krarup C, Stewart MB, Sumner AJ, Pestronk A, LiptonSA. A syndrome of asymmetric limb weakness withmotor conduction block. Neurology 1990;40:118-27.

111 Lange DJ, Trojaborg W, Latov N, Hays AP, YoungerDS, Uncini A, et al. Multifocal motor neuropathy withconduction block: Is it a distinct clinical entity?Neurology 1992;42:497-505.

112 Prineas JW. Pathology of inflammatory demyelinatingneuropathies. In: McLeod JG, ed. Inflammatory neu-ropathies. Bailliere's clinical neurology 3:1. London:Bailliere Tindall, 1994:1-24.

113 Kaji R, Oka N, Tsuji T, Mezaki T, Nishio T, Akiguchi I,Kimura J. Pathological findings at the site of conduc-tion block in multifocal motor neuropathy. Ann Neurol1993;33:152-8.

114 Mellgren S, Conn DL, Stevens JC, Dyck PJ. Peripheralneuropathy in primary Sjogren's syndrome. Neurology1989;39:390-4.

115 Gemignani F, Marbini A, Pavesi G, Di Vittorio S,Managelli P, Cenacchi G, Mancia D. Peripheral neu-ropathy associated with primary Sjogren's syndrome. JNeurol Neurosurg Psychiatry 1994;57:983-6.

116 Griffin JW, Comblath DR, Alexander E. Ataxic sensoryneuropathy and dorsal root ganglionitis associated withSjogren's syndrome. Ann Neurol 1990;27:304-15.

117 Said G. Inflammatory neuropathies associated withknown infections (HIV, leprosy, Chagas' disease, Lymedisease). In: McLeod JG, ed. Inflammatory neu-ropathies. Bailliire's clinical neurology 3:1. London:Bailliere Tindall, 1994:149-72.

118 So YT, Olney RK. Acute lumbosacral polyradiculoneu-ropathy in acquired immunodeficiency syndrome:Experience in 23 patients. Ann Neurol 1994;35:53-8.

119 Sabin TD, Swift TR, Jacobson RR. Leprosy. In: DyckPJ, Thomas PK, Griffin JW, Low PA, Poduslo AN,eds. Peripheral neuropathy. 3rd ed. Philadelphia: WBSaunders, 1993:1354-79.

NEUROLOGICAL STAMP

Atropa belladonna (deadly nightshade)

Atropa belladonna is a member of the nightshade familysolanaceae. Its botanical name is derived from Atroposwho, in Greek mythology, cut the thread of life. The redsap enlarges the pupils of the eye. The plant was namedat the time of the Italian Renaissance in the days of theinfamous Borgia family, when the ready availability ofpoison was popular. The ladies of the court used one ofthese poisons, belladonna, not to kill their rivals but tobeautify and enlarge their pupils.The solanaceous alkaloids are among the earliest effec-

tive treatments for parkinsonism. Belladonna containsatropine, scopolamine, and hyoscyamine. The ripeberries are sweet tasting and poisonous and attractive tochildren.A medicinal plant series published and produced by

Yugoslavia in 1965 shows the belladonna flower (StanleyGibbons 1161, Scott 775).

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