Dx and Rx Inflamatory Neuropathy

doi: 10.1136/jnnp.2008.158303 2009 80: 249-258J Neurol Neurosurg Psychiatry

M P T Lunn and H J Willison neuropathiesDiagnosis and treatment in inflammatory

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Diagnosis and treatment in inflammatoryneuropathies

M P T Lunn,1 H J Willison2

1 Centre for NeuromuscularDisease, National Hospital forNeurology and Neurosurgery,London, UK; 2 Division of ClinicalNeurosciences, SouthernGeneral Hospital, Glasgow, UK

Correspondence to:Dr M P T Lunn, Centre forNeuromuscular Disease andDepartment of MolecularNeuroscience, National Hospitalfor Neurology and Neurosurgery,Queen Square, LondonWC1N 3BG, UK;[email protected]

Received 28 October 2008Revised 28 October 2008Accepted 13 November 2008

ABSTRACTThe inflammatory neuropathies are a large diverse groupof immune-mediated neuropathies that are amenable totreatment and may be reversible. Their accurate diagnosisis essential for informing the patient of the likely courseand prognosis of the disease, informing the treatingphysician of the appropriate therapy and informing thescientific community of the results of well-targeted,designed and performed clinical trials. With the advent ofbiological therapies able to manipulate the immuneresponse more specifically, an understanding of thepathogenesis of these conditions is increasingly impor-tant. This review presents a broad overview of thepathogenesis, diagnosis and therapy of inflammatoryneuropathies, concentrating on the most commonlyencountered conditions.

The inflammatory neuropathies are a diverse groupof peripheral nerve disorders linked by theirimmune-related pathogenesis (see table 1). Theinflammatory contribution to this is better under-stood for some disorders than others. They arecharacterised by inflammatory pathology withinthe peripheral nerves associated with destructionof myelin and/or axons. The inflammatory neuro-pathies are typified by the idiopathic demyelinat-ing neuropathies, both acute and chronic, and theclosely related neuropathies associated with para-proteinaemia. However, vasculitic, infectious andparainfectious, paraneoplastic and, more recently,diabetic plexopathy,1 among others, are included.Some of these may be thought of as primarydisorders of the peripheral nervous system (eg,Guillain–Barre syndrome and chronic inflamma-tory demyelinating polyradiculoneuropathy(CIDP)) and others secondary to a systemicimmune process with subsequent involvement ofthe peripheral nerves (eg, the neuropathies asso-ciated with vasculitis and the connective tissuediseases). The review focuses on Guillain–Barresyndrome, chronic inflammatory demyelinatingpolyradiculoneuropathy, multifocal motor neuro-pathy with conduction block, paraproteinaemicneuropathy and the neuropathies with a vasculiticpathogenesis. It does not cover POEMS syndrome(polyneuropathy, organomegaly, endocrinopathy,M-protein, and skin changes), paraneoplastic neu-ropathies, infectious neuropathies, sarcoid andgranulomatous conditions or the inflammatoryneuropathies associated with diabetes because oftheir rarity2 and/or a lack of evidence to supporttreatment recommendations.3

This review focuses on the current approachesto diagnosis and up-to-date evidence-basedtreatment, some of which is derived from our

understanding of the pathogenesis of the diseases.The response to some treatments has helped usunderstand more about the pathogenesis of others.However, since the practical translation of severaldecades of increasing understanding is only justfiltering through to practical application topatients, new experimental and emerging therapiesnot currently in widespread use will be discussed.These may be put into more routine practical usein the near future.

GUILLAIN–BARRE SYNDROMEIn 1916, Georges Guillain, Jean-Alexandre Barreand Andre Strohl published two cases of ‘‘radicu-loneuritis,’’ known today as the Guillain–Barresyndrome (GBS).4 Extensive pathological andimmunological research suggests a continuousspectrum of disease pathologies involving cellularmechanisms and antibodies directed to nervecomponents (9–14).

GBS is an acute, monophasic, bilateral andrelatively symmetrical sensorimotor, flaccid paraly-sis with or without respiratory or cranial nerveinvolvement which reaches a nadir within less than4 weeks. Following the eradication of polio, GBS isthe commonest cause of acute neuromuscularweakness worldwide. The incidence is about 1.2–1.8 per 100 000 population5–7 with a lifetime risk ofabout 1:1000. There is no sex difference. It affectsall ages including children and infants but is morefrequent in older age groups. Infection withCampylobacter jejuni is the initiating event in about30–35% of cases, varying according to geography,resulting in a postinfectious autoimmune responsetargeted at nerve antigens. Other infectious agents,including cytomegalovirus, Mycoplasma pneumo-niae, Haemophilus influenzae, Epstein–Barr virusand human immunodeficiency virus (HIV), arealso known to precipitate GBS. In some popula-tions, a seasonal variation in the incidence isreported, coinciding with the seasonal incidenceof predisposing infections.8 In the developed world,GBS is synonymous with acute inflammatorydemyelinating neuropathy (AIDP), but axonalvariants (occurring in 3–5% of cases in thedeveloped world) are far more common in China,Japan and Mexico (see below). Outcomes havechanged little in the last 20 years. Five to 8% ofpeople die, and 20% are dead or disabled at12 months. The simple but practical ErasmusGBS outcome Score (EGOS)9 uses age, severity ofweakness at nadir and presence or absence ofdiarrhoea to predict the chance of walking at6 months.

The clinical diagnosis of GBS is supported byinvestigations that may be normal in the early

Review

J Neurol Neurosurg Psychiatry 2009;80:249–258. doi:10.1136/jnnp.2008.158303 249




stages of disease. As well as the classical clinical diagnosticcharacteristics (ascending weakness, reflex loss and elevatedcerebrospinal fluid (CSF) protein), pain, cranial nerve involve-ment and autonomic disturbances with arrhythmias and labileblood pressure are often features. Papilloedema may occur,which, if unrecognised and untreated, may lead to blindness.The differential diagnosis of acute neuromuscular weakness(table 5) should always be considered and excluded. A clinicaldiagnosis of GBS should be questioned if there is persistentasymmetrical weakness, bladder or bowel involvement, or asensory level suggestive of spinal-cord pathology. Some patientsmay progress to tetraparesis and require ventilation in as littleas 48 h, and vigilance in the early stages is crucial. As well asrespiratory function, bulbar weakness with aspiration isimportant to identity and monitor from an early stage.

Acute inflammatory demyelinating polyradiculoneuropathy(AIDP) is the commonest form of GBS presenting in theWestern world. Acute motor axonal neuropathy (AMAN) andacute motor and sensory axonal neuropathy (AMSAN) arerecognised electrophysiological variants which otherwise maylook similar at presentation. Functional (eg, pure sensory GBS)and regional (eg, Fisher syndrome) variants exist (see table 1)which are distinguished by their clinical features, supported byelectrophysiological abnormalities.10

Since the diagnosis of GBS is clinical, investigations areperformed to exclude the differential diagnoses and assist in theprognosis by differentiating neurophysiological subtypes andestablishing the severity of denervation.11 Nerve-conductionabnormalities occur at some point in 85% of patients. In AIDP,acute patchy, proximal and distal demyelination is supported bythe presence of prolonged F-waves and delayed distal motorlatencies, conduction block and the reduction in median sensoryamplitudes where sural sensory amplitudes are retained.12

Elevated CSF protein may be absent during the first week.The presence of more than 10 cells/mm3, and certainly morethan 50 cells/mm3, should prompt a search for an alternativediagnosis. Antibody seroconversion to C jejuni in acute andconvalescent sera may be supportive, as is the isolation of Cjejuni from stool. The presence of IgG antibodies to gangliosidesmay be supportive of the diagnosis (eg, anti-GQ1b in Fisher

syndrome13), assist in differentiating GBS subtypes (eg, anti-GD1a antibodies in AMAN14) or help with predicting theseverity of the illness (eg, anti-GM1 antibodies15). Otherhaematological, biochemical and immunological blood testsexclude possible alternatives. The syndrome of inappropriatesecretion of ADH (SIADH), which may be severe with Na levelsreduced to 105–120 mEq/l, occurs in GBS, and hence electro-lytes should continue to be monitored during the acute phase.

Advances in the understanding of the pathogenesis of GBShave helped in understanding effective treatment modalitiesand have just begun to suggest new ones. Effective specifictreatments target the humoral arm of the immune system16

although other strategies are now being developed. In general,the treatment of GBS is broad in its approach and aims tosupport and nurse the patient safely through a period ofimmobility and hasten recovery to as near normal as possible.The advent of invasive ventilation decreased the mortality tothe 5–8% reported by most modern epidemiological studies, butup to 20% remain disabled and dependent at 2 years.17 18

Vigilance for and management of autonomic complications,prevention of aspiration pneumonias and prophylaxis for DVThave all reduced morbidity and mortality. Advances in painmanagement, physiotherapy and rehabilitation techniques havereduced morbidity, but there are no randomised controlled trials(RCT) so far.19 Since GBS is a postinfectious autoimmunephenomenon, by the time disease is evident the initiating eventis usually over, and treatment of the initiating infectious agentis not effective.

As an autoimmune disease, it might seem intuitive thatsteroids should be effective in the treatment of GBS. Despitecase reports and small series from the 1950s onwards which

Table 1 Differential diagnosis of inflammatory peripheral neuropathies:idiopathic inflammatory neuropathy

Acute

Acute inflammatory demyelinating polyradiculoneuropathy

Acute motor axonal neuropathy

Acute motor–sensory axonal neuropathy

Fisher Syndrome and other regional variants

Pharyngeal–cervical–brachial

Paraparetic

Facial palsies

Pure oculomotor

Functional variants of Guillain–Barre syndrome

Pure dysautonomia

Pure sensory Guillain–Barre syndrome

Ataxic Guillain–Barre syndrome

Subacute

Subacute inflammatory demyelinating polyradiculoneuropathy

Chronic

Chronic inflammatory demyelinating polyradiculoneuropathy

Multifocal motor neuropathy with conduction block

Chronic relapsing axonal neuropathy

Chronic ataxic sensory neuronopathy

Table 2 Differential diagnosis of inflammatory peripheralneuropathies: paraproteinaemia associated withneuropathy

Multiple myeloma

Solitary myeloma (osseous and extraosseous)

Lymphoma

Chronic lymphocytic leukaemia

Waldenstrom macroglobulinaemia (lymphoplasmacytoid lymphoma)

Cryoglobulinaemia

Cold agglutinin disease

Primary amyloid light chain amyloidosis

Monoclonal gammopathy of undetermined significance

Table 3 Differential diagnosis of inflammatory peripheralneuropathies: vasculitic causes of neuropathy

Primary vasculitis

Microscopic polyangiitis

Polyarteritis nodosa

Churg–Strauss disease

Wegener vasculitis

Non-systemic vasculitic neuropathy (isolated nerve vasculitis)

Temporal arteritis

Systemic autoimmune diseases with associated vasculitis

Rheumatoid arthritis

Systemic lupus erythematosus

Sjogren syndrome

Mixed connective tissue disease

Other

Serum sickness

Infectious, malignant, related to chemotherapy

Review

250 J Neurol Neurosurg Psychiatry 2009;80:249–258. doi:10.1136/jnnp.2008.158303




were supportive of this, they are of no clear benefit when usedalone or in combination with intravenous immunoglobulin(IVIG), may indeed slow recovery and should not be used.20

The use of plasma exchange (PE) in GBS was first describedover 30 years ago.21 Six randomised but not fully blinded trialsincluding 649 participants comparing PE to no treatment haveshown individually and in meta-analysis the benefit of PE.22

Plasma exchange significantly reduces need for ventilation (27%to 14%, relative risk 0.53, 95% CI 0.39 to 0.74, p = 0.0001),increases rate of recovery (relative risk of 1 grade improvementat 4 weeks 1.70, CI 1.42 to 2.03, p,0.00001) and reduces time towalking with aid in a severe group (30 vs 44 days, p,0.01). Inmild GBS (Hughes Grade 1–2) two exchanges are probablyadequate. In more severe disease, four exchanges are beneficial,and six give no benefit over four.23 24 Although clearly beneficialaccess to PE is variable, it can be associated with significant sideeffects, and discontinuation rates of 10–14% are reported.22

The use of IVIG is more recent.25 The standard dose is 0.4 g/kg/day for 5 days and is beneficial if started within 2 weeks ofdisease onset and probably within four.26 In those who haveadequate cardiovascular reserve and no acute complications,IVIG can be administered rapidly. No randomised placebo-controlled trials of IVIG have been performed for ethicalreasons. However, analysis of trials of IVIG versus PE hasconcluded that they are of equivalent efficacy. Since theincidence of side effects with IVIG is lower than with PE,26

IVIG is now generally preferred as the first-line agent, if it isavailable.

There is interest in old and newer drugs which may bepromising for GBS treatment in the near future. Sodium-channel blockade significantly protects axons in EAN fromdamage,27 and agents are being explored which could translatethis finding into human studies. Inhibitors of complementactivation that prevent the formation of membrane attackcomplex are highly effective in abrogating neuronal andneuromuscular junction damage in animal models.28–30 Sinceone of these agents, Eculizumab, is already licensed for use inparoxysmal nocturnal haemoglobinuria (PNH)31 its potentialuse in GBS is eagerly awaited.

CHRONIC INFLAMMATORY DEMYELINATINGPOLYRADICULONEUROPATHY (CIDP) INCLUDING MOTOR CIDPAND LEWIS–SUMNER SYNDROMECIDP is defined by the presence of progressive or relapsingproximal and distal weakness with sensory loss and/or cranialnerve involvement reaching a nadir in more than 8 weeks withabsent or reduced reflexes in all limbs.32 The prevalence is about

3–4/100 000, with equal numbers of men and women affected.33

Patients present more usually with a progressive course, butrelapses with a GBS-like pattern are known to occur. Weaknessmay be variable, and often positive sensory features includingparaesthesiae are present, but pain is seldom a feature. Cranialnerve and respiratory muscle involvement are uncommon,although both occur. The clinical examination may rarely revealthickened superficially palpable nerves (ulnar at the elbow,superficial radial at the wrist, peroneal or posterior auricular(table 6)).

The diagnosis is made clinically with the support ofelectrophysiological studies which show evidence of a motorand sensory demyelinating polyradiculoneuropathy, oftenpatchy and often with evidence of conduction block or temporaldispersion that distinguish CIDP from hereditary demyelinatingneuropathies.32 Many sets of criteria have been published, allwith their individual drawbacks, but iterative and computer-based technologies are now being employed to improvesensitivity and specificity.34 The diagnosis is supported by thepresence of raised CSF protein without cells (approximately 75–90% of cases35), thickened and/or enhancing roots on MRI of thecervical or lumbar spine, a positive response to immunomodu-latory treatment (see below) or unequivocal quantitative biopsyfeatures consistent with demyelination and remyelination withor without actively visualised macrophage-associated demyeli-nation.32

Understanding the immunopathogenesis of CIDP has laggedbehind other inflammatory neuropathies. Inflammatory infil-trates of T cells and macrophages are a consistent pathologicalfinding in biopsy specimens.36 Models of chronic or relapsinginflammation are few16 but emerging models37 and may providetools for future work. In comparison with GBS, in CIDP weunderstand little about the initial stages of disease induction.Humoral factors, probably antibodies, are present in some serawhich are able to bring about demyelination in passive transferto animals.38 Numbers of circulating T cells are increased, andelevations in inflammatory cytokines and chemokines arerecordable in the nerves, serum and CSF of subjects withCIDP.16 39–41 Alterations in matrix metalloproteinases,42 Zo-1 andclaudin43 facilitate cellular transendothelial migration of cells.Within the nerve levels of inflammatory mediators such asTNF-alpha, NO and MMPs are all increased, contributing tomyelin, axon and other cellular damage. How the pathologicalprocesses result in the recognised phenotypic variants of CIDP isnot clear. Motor predominant forms of CIDP may behave morelike multifocal motor neuropathy with conduction block (seelater) when treated. The Lewis–Sumner syndrome (multifocalacquired demyelinating sensory and motor neuropathy(MADSAM)) behaves more like CIDP. Chronic inflammatorysensory polyneuropathy (CISP), relapsing axonal neuropathy(CRAN) and relapsing sensory ataxic neuropathy are all rarephenotypic variants which respond to treatment in a similarway to CIDP.

As with other inflammatory neuropathies, CIDP is treatedwith immunosuppressants, with variable levels evidence for theefficacy of each. ‘‘First line’’ treatment for CIDP is accepted assteroids, IVIG or plasma exchange (PE, if available and notcontraindicated). Austin recognised steroids were an efficacioustreatment for the condition 50 years ago44 in his report of asingle steroid responsive patient who relapsed on steroidwithdrawal. Large case series45–47 indicated that up to 65–95%of patients respond to steroid. The only RCT of steroids forCIDP48 reported a statistically significant benefit to impairment.The trial has design problems, and when analysed with more

Table 4 Differential diagnosis of inflammatory peripheral neuropathies:other inflammatory neuropathies

Inflammatory neuropathy associated with infection

HIV neuropathies, including cytomegalovirus neuropathy

Leprosy

Lyme disease

Chagas disease

Granulomatous conditions

Sarcoidosis

Paraneoplastic

Subacute sensory neuropathy/neuronopathy—small-cell lung carcinoma andanti-Hu Abs

Other paraneoplastic tumour-antibody syndromes

Metabolic

Diabetic lumbosacral plexopathy

Review





modern, rigorous, statistical analysis, the improvement is notstatistically significant, but the trend is for benefit.49 However,clinical experience indicates that steroids are efficacious, albeitwith significant side effects. It should be noted that somepredominantly motor CIDP patients or those with multifocalmotor neuropathy with conduction block may worsen withsteroids,50 usually recovering shortly after withdrawal.Furthermore, cushingoid side effects are undesirable and maybe both dose- and treatment-limiting in the longer term.

Intravenous immunoglobulin is clearly of both short-termand long-term benefit for patients with CIDP. A number ofsmall uncontrolled studies are available, but the most reliableevidence of efficacy in the short term comes from the six high-quality RCTs performed in the last 15 years.51 From the meta-analysis of the 170 included patients, the relative risk forimprovement of disability was between 2.47 (95% CI 1.02 to6.01) and 3.17 (95% CI 1.74 to 5.75). Recently, the largest studyof IVIG in CIDP was published (117 patients), and this was thefirst to look at the long-term effect of IVIG in both inducing andmaintaining remission in CIDP.52 The immediate response rateto IVIG was 54% vs 21% in the placebo group (absolute riskreduction (ARR) 34%, CI 17 to 50), and the ARR formaintaining stability in prolonged treatment was also 34%,giving a number needed to treat of three. The use ofsubcutaneous IVIG preparations may reduce in-patient costsand improve the patient experience of treatment.53 At present,only patients with relatively small dose requirements wouldseem to be suitable, but this method of administration may gainpopularity as appropriate products, infusion regimens andcommunity support are made available.

Plasma exchange was first reported as of benefit in CIDP in1979.54 55 Initial reports were followed by a large number oflargely positive case series. Two RCTs exist comparing PE withsham exchange, one as a parallel group study56 and one as acrossover trial.57 Both demonstrated a short-term benefit, butthere are no longer-term studies to look at the reported relapsesafter PE withdrawal or the effects of continued maintenancetherapy.

IVIG, steroids and PE have all been compared in two trials.When IVIG was compared with steroid treatment58 or PE,59 nosignificant difference in efficacy between IVIG and either of thecomparators was found. However, side-effect profiles are verydifferent and may lead in guiding therapy. The cost benefits ofthese therapies in the short and long term remain a matter ofdebate; although IVIG is the most expensive option in the shortterm in 2008, it probably has the fewest short-term side effectsand appears to have a favourable long-term risk profile.

Azathioprine, methotrexate, ciclosporin, mycophenolatemofetil, cyclophosphamide, interferons beta and alpha, tacroli-mus, rituximab, alemtuzemab, etanercept and stem celltransplants have all been used in the treatment of CIDP.60

Methotrexate has been the subject of a recent RCT, reportedonly in abstract.61 At a dose of 15 mg per day, this trial did notshow any reduction in the need for ongoing steroid or IVIG useover the 28-week course of the trial. However, neither the finalstudy design nor the dose of methotrexate used may have beenadequate to produce a meaningful result, and further plans areawaited. A number of uncontrolled studies of azathioprineexist, all reporting benefit in a proportion of patients,45–47 62

either alone or in combination. The only RCT (not-blinded)demonstrated no benefit to azathioprine but was probably toosmall to draw conclusions from.63 Interferon-beta has shownpromise in anecdotal studies, but the only RCT published so farshowed no benefit. This was again in the context of low dosageand short time course (22 mg three times per week for 12 weeksonly), and further RCTs are under way. However, expense is amajor concern, and improvements may have to be substantial tojustify therapy in the current health economic climate. Of theother agents, ciclosporin has shown promise, being generallywell tolerated, and cyclophosphamide is probably beneficial butcarries substantial toxicity. Mycophenolate is less toxic butawaits an RCT, and patients treated with tacrolimus, etaner-cept and stem-cell transplants are sparse.64–67

The future of treatment for CIDP may lie in more specificbiological agents targeted at key points in the pathophysiolo-gical pathway. Rituximab is an agent on which attention is

Table 5 Differential diagnosis of acute neuromuscular weakness

Electrolyte disorders

Hypokalaemia, hyperkalaemia, hyponatraemia, hypocalcaemia, hypermagnesaemia

Porphyria

Infections

Viral

Poliomyelitis, West Nile Virus, HIV, rabies

Bacterial

Diphtheria, brucellosis

Toxins

Snake venoms, spider venom, fish and shellfish toxins, tick bite paralysis, botulism (dietary or drug-related)

Arsenic, lead, thallium, organophosphate

Nitrofurantoin, lithium, gold, gangliosides

Paraneoplastic neuropathies (sensory, sensorimotor, motor)

Myasthenic disorders

Myasthenia gravis, Lambert–Eaton Myasthenic Syndrome

Neuromuscular blocking drugs (especially in renal failure)

Myopathies

Inflammatory myopathy, rhabdomyolysis syndromes

Acid maltase deficiency

Acute myosin deficiency (drugs, eg, steroids, transplants, critical illness)

Periodic paralysis

Critical illness neuromyopathy

Spinal-cord lesions

Hyperventilation

Review





focused for future RCTs. Response rates may be up to 60%,perhaps more often when associated with underlying patholo-gies such as MGUS (Lunn, INC unpublished data). A singlefavourable report of alemtuzemab (Campath-1H) exists, andfurther reports are awaited.68 Eculizumab is also a possibletherapy.

MULTIFOCAL MOTOR NEUROPATHY WITH CONDUCTION BLOCK(MMNCB)During the 1980s, the entity of an asymmetrical, slowlyprogressive predominantly distal upper-limb motor syndromewas recognised.69 Furthermore, some of these cases had arelapsing remitting course, and some were recognised as beingresponsive to treatment with intravenous immunoglobulin(IVIG). Many had previously been diagnosed as motor neurondisease or spinal muscular atrophy. However, the lack of uppermotor neuron signs, neurophysiological testing demonstratingthe presence of focal areas of conduction block and the presencein the serum of antibodies to ganglioside GM1 identified theseas a unique inflammatory neuropathy, and the concept ofmultifocal motor neuropathy with conduction block (MMNCB)was born.

The prevalence of MMNCB remains unknown but isestimated to be about 1:100 000. The protracted and chronicnature of the disease means the incidence is very much lowerthan this. It occurs more commonly in males (3:1) and presentsmainly between 20 and 50 years of age, although up to 20% ofcases may present later.

Typically a patient presents with progressive or sometimesstepwise asymmetrical weakness affecting the upper limbs. Ifthe presentation is late, there may be a history of staticweakness or spontaneous remission. A single nerve (or nervebranch) territory, such as a radial or posterior interosseous nerveor median or ulnar intrinsic hand weakness, is common earlyon, but weakness may spread to affect one or more other limbs,sometimes becoming confluent. Patients frequently complain ofcramps, often outside clinically affected areas, fatigue andtwitching. Involvement of cranial or respiratory nerves isunusual but reported. Mild sensory symptoms and signs arenot uncommon and should not exclude the diagnosis.

At an early stage, weakness without wasting in identifiablenerve territories is typical. Occasionally, neurogenic musclehypertrophy is evident, especially in areas affected by cramp.70

Fasciculation or, even rarely, myokimia is seen, which may beexacerbated by exercise.

The diagnosis on MMNCB is both clinical and electrophy-siological with evidence of conduction block on nerve conduc-tion studies. In advanced cases with substantial and confluentdenervation atrophy, conduction block may be difficult todemonstrate. The definition of conduction block continues toprovoke controversy, and the use of standardised criteria is notuniversal. The European Federation of Neurological Societies/

Peripheral Nerve Society have recently published diagnosticcriteria71 which will be iteratively updated in the future.

The decision about when, and whether, to treat is notstraightforward. Static mild weakness affecting one or a fewnerves may not indicate any therapy, although prolongeduntreated conduction block may eventually be accompanied byirrecoverable axonal loss72 73 Since MMNCB has a presumedautoimmune basis, therapeutic approaches have been immuno-logically based.

Evidence from four randomised controlled trials and threemore recent retrospective studies shows that IVIG is effective inthe initial treatment of MMNCB in 70–86% of cases,74–77

improving both strength and disability. Conduction blocksmay disappear, correlating with clinical improvement. Responseto treatment, however, is not predicted by the presence of CB ortitres of anti-GM1 antibodies. In some cases where conductionblock is not found or the diagnosis remains in question, IVIGmay be used as a diagnostic trial. Dosages and infusion regimesare individualised, but expert opinion would be that MMNCBmay respond to lower doses of IVIG than CIDP (0.4–1 g/kg) butthat these may be required more frequently (eg, every 4–6 weeks) in most patients. However, axonal degeneration in thelong term may be prevented by the use of higher IVIG doses.78

Although treatment is still often given in medical facilities, IVIGis increasingly administered at home, helped by the low-dosageregimens, and subcutaneous high-concentration IVIG formula-tion. Long-term use of IVIG is associated with maintainedimprovement in most patients who respond.75 77

In theory, other immunosuppressant agents should also beeffective in MMNCB. Oral and intravenous steroids aregenerally ineffective in high or low dosage and frequently makeMMNCB worse.79 80 They are best avoided on the basis ofanecdotal and retrospective reports.76 80 Likewise, plasmaexchange (PE) has limited effectiveness81 and again mayprecipitate clinical worsening and the appearance of conductionblocks at previously unaffected sites.82 Cyclophosphamide wasreported to be effective in at least 13 case reports and smallseries through the late 1980s and 1990s.83 Induction dosages inthe order of 3 g/m2 were used, followed by oral therapy, and anumber of related severe adverse events were subsequentlyreported.50 84 Hence, cyclophosphamide has fallen out of routineuse. The lower-dose pulsed intravenous regimes used in lupusnephritis may well be associated with fewer side effects buthave yet to be shown to work in MMNCB. Following anecdotalreports of benefit85 mycophenolate mofetil (1 g twice per day)has been the subject of an RCT86 which showed no benefitcompared with placebo.

Ciclosporin, interferon beta 1a, azathioprine, methotrexate,autologous bone marrow transplantation and rituximab have allbeen reported as treatment for MMNCB. Rituximab use hasbeen reported by the greatest number of authors,87–90 andalthough no serious adverse events have been reported,responses were both variable and modest. Ciclosporin,91 beta-interferon 1a,92 93 methotrexate94 and azathioprine95 have beenreported to stabilise a small number of patients, but none are inwidespread use. Autologous stem-cell transplantation had nolong-term benefit.96

PARAPROTEINAEMIC NEUROPATHYNeuropathy occurs in association with a paraprotein (mono-clonal gammopathy) more often than by chance alone.97 Aparaprotein may be produced by one of a number of plasma celldyscrasias (table 2). Multiple myeloma is the commonestmalignant gammopathy (1% of all malignancy) but is only

Table 6 Causes of thickened nerves

Chronic inflammatory demyelinating polyradiculoneuropathy

Hypertrophic Charcot Marie Tooth diseases (especiallyCMT1a and hereditary neuropathy with liability to pressure palsies)

Neurofibromatosis

Refsum disease

Leprosy

Infiltration (lymphoma/secondary deposits)

Amyloidosis

Acromegaly

Review





associated with overt neuropathy in about 3–4% of cases.98

Waldenstrom macroglobulinaemia accounts for only 2% of allgammopathy. An MGUS is the most common paraproteinaemicdisorder associated with a neuropathy. The prevalence ofMGUS paraproteins rises with age from 1% aged 50, to 3% at70 and 7–8% aged 80, and of these, between 30 and 70% areassociated with a neuropathy.99–101 Of those MGUS associatedwith neuropathy, IgM paraproteins are over-represented. Thereis a wealth of evidence to indicate that many of the IgMparaproteins, especially those with activity against myelin-associated glycoprotein (MAG), are pathogenic, including anti-body activity against peripheral nerve epitopes, antibody boundto nerve at putative target sites, the presence of complementdeposits, passive and active transfer and immunisation experi-ments in animals102 and a response to treatment in some.103 IgGand IgA paraproteins are less frequently found and, in manycases, may be a chance association, as so far descriptions ofactivity against peripheral nerve epitopes for IgG and IgAparaproteins are rare. Furthermore, in many cases, they respondsimilarly to cases of CIDP. As yet, the origin of MGUSparaproteins is unknown, but increasing evidence suggests thatthey may be driven by an antigen, possibly carbohydrate.104

The demyelinating neuropathy associated with IgM MGUSassociated paraprotein with anti-MAG activity has a clinicallyrecognisable phenotype. Patients tend to be in the 6th or 7thdecade of life, and males are over-represented. They presentwith a slowly progressive predominantly sensory neuropathy,which only later has significant motor involvement. Commoncomplaints are of distal sensory disturbance, unsteadiness(usually without falls) and an upper-limb tremor. Vibrationloss may be profound compared with pain and temperaturedisturbance. Electrophysiological studies are notable for distalmotor latencies prolonged out of proportion to the motorconduction velocity resulting in a short Terminal Latency Indexof ,0.25,105 a useful clinical measure. Anti-MAG paraprotei-naemic demyelinating peripheral neuropathy (PDPN) has alsobeen termed DADS-M (distal acquired demyelinating sensoryneuropathy with M-protein). In some cases, no paraprotein canbe found in the same phenotype of patient, termed DADS-I(idiopathic).106 An IgM paraprotein is detected by immunofixa-tion and is usually associated with a k-light chain. Anti-MAG

activity is now easily sought with one of the commerciallyavailable ELISA-based anti-MAG testing kits, although westernblotting of brain myelin is also widely used. A biopsydemonstrating widening of the intraperiod line of the myelinlamellae is relatively specific but seldom conducted.

IgM paraproteins with antigen-targeting activity have alsobeen found with a number of other neuropathy phenotypeswhere the association is rare, and causation is less definite.Antisulfatide antibodies are associated with sensorimotor andsensory neuropathies of demyelinating and axonal phenotypes.Paraparoteinaemic anti-GM1 antibody activity may be found inrare cases of MMNCB. The Chronic Ataxic Neuropathy withOphthalmoplegia, Agglutinins and Disialosyl Antibodies(CANOMAD) has antibodies that react with the group ofgangliosides displaying a ‘‘disialosyl’’ epitope.107

Few IgG and IgA paraproteins have been demonstrated tohave anti-nerve activity so far, but these are also found inassociation with demyelinating and axonal neuropathies. Thedemyelinating neuropathies often look clinically like CIDP. Thecausative nature of these associations remains unknown butpatients with paraproteins tend to be older, have more sensorycomplaints and respond less well to treatment.103 108

A high index of suspicion is required to detect an MGUS, asoutside the classical anti-MAG PDPN phenotype there are noclues to its presence. A serum protein electrophoresis will detectabout 60% of paraproteins; an immunofixation is essential toincrease sensitivity to about 90%109 through its ability to pickout the monoclonal spike from the background electrophoreticsmear which is not immunoparesed, as it is in myeloma. Once aparaprotein is identified, skeletal survey and bone marrowaspirate and trephine are mandatory for initial diagnosis,followed by annual screening of the paraprotein level to detectmalignant change (about 1% per person per year110).

Immunotherapies aimed at reducing levels of antibody or thecells that produce them have been the focus of treatment in adiverse array of therapeutic protocols. IVIG has been shown tobe of benefit in IgM paraproteinaemic neuropathies in RCT atup to 4 weeks.111 Cyclophosphamide and prednisolone incombination may be effective in the longer term, but the toxicside effects limit its applicability in what is usually a relativelyslowly progressive disease.112 113 Fludarabine may also be

Table 7 Cochrane reviews of interventions for inflammatory neuropathies

Corticosteroids for chronic inflammatory demyelinating polyradiculoneuropathy

Corticosteroids for Guillain–Barre syndrome

Cytotoxic drugs and interferons for chronic inflammatory demyelinating polyradiculoneuropathy

Immunosuppressant and immunomodulatory treatments for multifocal motor neuropathy

Immunosuppressive treatment for non-systemic vasculitic neuropathy

Immunotherapy for IgM antimyelin-associated glycoprotein paraprotein-associated peripheral neuropathies

Interventions for renal vasculitis in adults

Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy

Intravenous immunoglobulin for Guillain–Barre syndrome

Intravenous immunoglobulin for multifocal motor neuropathy

Plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy

Plasma exchange for Guillain–Barre syndrome

Treatment for Fisher syndrome, Bickerstaff brainstem encephalitis and related disorders

Treatment for human immunodeficiency virus-related distal symmetrical polyneuropathy (protocol stage)

Treatment for idiopathic and hereditary neuralgic amyotrophy (brachial neuritis) (protocol stage)

Treatment for IgG and IgA paraproteinaemic neuropathy

Treatment for paraneoplastic neuropathies (title stage)

Treatment for polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome

Treatment for the neurological complications of Lyme disease (protocol stage)

Vitamin B for treating peripheral neuropathy

Review





effective in the longer term, but benefit has been shown only inopen studies and case series.114 115 The results of trials ofrituximab are eagerly awaited in 2008/2009. Interferon alphawas no better than placebo in a single trial,116 but other openstudies have been more positive. Positive case reports and seriesusing steroids (prednisolone or dexamethasone), chlorambucil,melphalan, cladribine, ciclosporin-A and stem-cell transplanta-tion all exist. Therapies are individually tailored to patientstaking into account the need for treatment when disability andprogression are both considered, the age and fitness of thepatient, the nature of the paraprotein and financial provision forincreasingly expensive treatment.

For IgG and IgA paraprotein associated neuropathies,demyelinating phenotypes respond better to treatment thanaxonal phenotypes.117 Nevertheless, patients with a CIDP-likepresentation and a paraprotein do not respond as well aspatients without a paraprotein.62 Plasma exchange has beenshown to be of benefit over placebo (sham exchange) in a singleRCT.118

VASCULITIC NEUROPATHYThe vasculitic neuropathies present special challenges toneurologists in terms of diagnosis and treatment.Unfortunately, there is little published research specific toneuropathy to guide diagnosis and treatment, most beingderived from renal, rheumatological or pulmonary practice. Theclinical problem is confounded by the very wide range ofneuropathy phenotypes that occur in the context of systemicautoimmune diseases, many of which are likely to have a diverseunderlying causation, beyond vasculitis as the primary pathol-ogy. Clinical guidelines and RCTs are however now beingconceived to address this need.

Vasculitic neuropathy occurs in the context of a primaryvasculitic illness (eg, Churg–Strauss syndrome (CSS) or micro-scopic polyangiitis (MPA)) or triggered by a connective tissuedisease (eg, SLE or rheumatoid arthritis) or infection (eg, HIV,Lyme disease) (see table 3). It may also present in isolationwithout systemic manifestation as a non-systemic vasculiticneuropathy (NSVN). Classifications of primary vasculitis basedupon pathology and affected vessel size119 or clinical features120

are common, but they are non-concordant,121 possibly outdatedand not strictly helpful in guiding treatments for the neuro-pathic element of the disease.

Vasculitic peripheral neuropathy is rare. It is estimated that25–33% of cases of vasculitic peripheral neuropathy areNSVN.122 123 Vasculitic neuropathy occurs in between 20 and80% of cases of primary vasculitis124 125 and is in the diagnosticcriteria for CSS where it is a feature in up to 78%.126 127 In thesecondary vasculitides, the presence of vasculitic neuropathy ismore variable, occurring in 2–7% of patients with rheumatoidarthritis,128 up to 70% of patients with cryoglobulinaemia (withor without Hepatitis C infection)129 130 and 0.3–1% of patientswith HIV.131

The rapid and accurate diagnosis of vasculitic neuropathy isimportant for preventing the accumulation of disability,choosing appropriate treatment and ensuring that toxic agentsare not used unnecessarily in the long term. One of the primaryaims of the clinician should be to make a rapid tissue diagnosisand identify all systems involved, engaging other specialistswhere necessary.

Typically, the patient presents with the acute or subacuteonset of single or multiple mononeuropathies (83%),132 usuallysensorimotor and most often painful. Some NSVN is moreslowly progressive, but pain and/or asymmetry (clinically or

electrically) should alert the clinician to the possibility. Lessthan 20% of cases present with a symmetrical glove andstocking neuropathy,132 and in rheumatoid arthritis such aneuropathy is seldom vasculitic. Typically the lower limbs aremore commonly affected (peroneal and sciatic), but upper-limbinvolvement is not infrequent. The cranial nerves may beinvolved, including the optic nerve with arteritic ischaemic opticneuropathy.133 Symptoms and signs of systemic involvementshould be carefully sought. A history of fever, weight loss, nightsweats, myalgia, arthralgia, abdominal pain, haematuria andpulmonary symptoms may be recent, historical or welldeveloped and current, but may be entirely absent or quitesubtle.

Neurophysiological investigation may emphasise the patchy,multifocal and asymmetric nature of the disease with axonalsensorimotor involvement outwith entrapment sites.Occasionally, large fibre fallout can lead to the misinterpreta-tion of reduced conduction velocities and increased latencies asindicative of demyelination.

Testing of serum, CSF and urine is usually helpful. In NSVN,the investigations may be normal. In systemic vasculiticneuropathy, abnormalities of full blood count, ESR, CRP, ureaand electrolytes, liver function tests, complement, antinuclearantibody, extractable nuclear antigen antibody, rheumatoidfactor and anti-CCP may aid diagnosis and classification.Antineutrophil cytoplasmic antibody positivity (anti-myeloper-oxidase or anti-PR3) helps to classify the vasculitis into CSS,Wegener granulomatosis or MPA. A negative result does notexclude the diagnosis of vasculitic neuropathy. The CSF isuseful to diagnose or exclude diseases which may mimicvasculitis such as HIV or Lyme disease. Urine for red cell castsand proteinuria helps identify renal glomerular and tubularinvolvement. Body imaging can identify organ involvementsuch as lung fibrosis. More recently, fluorodeoxyglucosepositron emission tomography has been successfully used toidentify large- and small-vessel vasculitis in primary andsecondary vasculitis, but this awaits formal trial.134–136

A tissue diagnosis of vasculitis is highly desirable, as thepatient is likely to receive prolonged and sometimes intenseimmunosuppression. Any affected tissue may be selected, and adirected skin, lung or renal biopsy may have greater sensitivityand less morbidity than nerve biopsy.132 Nerve biopsy should bedirected towards a recently clinically and electrophysiologicallyaffected sensory nerve. Where this is difficult, the sural orsuperficial peroneal nerve may be selected, the latter giving theopportunity to sample muscle.137 138 Fibrinoid necrosis andinvasion and destruction of the vessel wall by inflammatorycells are typical but not always typically seen. Evidence ofischaemic neuronal loss with patchy axonal loss, vesselocclusion and neovascularisation and perineural thickening isoften evident with haemosdierin around affected vessels.139

The optimal treatment of vasculitic neuropathy is not welldefined,123 132 and there are no RCTs to guide the clinician.140

Treatment can often be decided in conjunction with specialistswith expertise in the management of vasculitis in othersystems. The decision to treat is based upon both the severityof the vasculitis and the potential for further disability toaccumulate.

For vasculitis not associated with viral infection or cryoglo-bulinaemia, steroids are the first choice of treatment.Prednisolone in a dose of 1 g/kg is usually recommended, oftenwith a pulse of three 1 g intravenous injections of methylpred-nisolone as ‘‘induction.’’ Continuation of steroid for severalmonths with gradual tailing off will be required. However,

Review





relapse rates are higher when patients are not treated initiallywith cyclophosphamide,123 132 and hence cyclophosphamide mayoften now be included in the induction regimen. Given thatpulsed intravenous cyclophosphamide has a lower cumulativedose, equivalent efficacy, similar remission induction and fewershort- and long-term side effects than oral cyclophosphamide,pulsed intravenous therapy is recommended, in a regime similarto the EUVAS CYCLOPS trial (http://www.vasculitis.org/protocols/cyclops.pdf). Antiemetics should be routinely pre-scribed, and MESNA, fluids and increased voiding are encour-aged to reduce acute and chronic bladder toxicity.Cyclophosphamide should be nearly always indicated forWegener granulomatosis and MPA, as these may be moreaggressive, and their tendency to relapse is higher, between 8and 18% in the first year after treatment stops.141 Followingcyclophosphamide induction, an oral immunosuppressant(steroid sparing agent) should be immediately introduced.Methotrexate (15–20 mg weekly), azathioprine (2.0–2.5 mg/kg)or mycophenolate mofetil may all be effective. Oral steroidsshould be tailed to 20 mg daily during the cyclophosphamidecourse and then more slowly as the oral immunosuppressantmaintains remission. Overall, 2 years of treatment should beachieved before attempting withdrawal of immunosuppressant.

The treatment of nerve vasculitis associated with hepatitisviruses is slightly different. Hepatitis B virus associated vasculitisis treated with interferon-a2b or lamivudine and plasmaexchange,142 and hepatitis C with pegylated interferon-a2b or-a2a and ribavarin.143 144 Rituximab is showing promise forsystemic vasculitis with and without cryoglobulinaemia.145 146

Close monitoring for side effects of treatments over a longperiod of time is crucial, and counselling patients prior toembarking on therapy is important to help them understand thenature of the disease and its likely outcomes, untreated ortreated.

The immunotherapy of neuropathies associated with sys-temic connective tissue diseases (CTDs) that are not believed tohave a vasculitic basis, but nevertheless may be dysimmune inorigin, is a complicated area with little in the way of high-quality evidence on which to base treatment. Often, vasculitis isexcluded through the investigations above. Immunosuppressionappropriate to the CTD and guided by rheumatologists isusually then used in pragmatic therapy.

CONCLUSIONSInflammatory neuropathies are diverse in their presentation andfeatures, and hence their diagnostic strategy and therapy. As wecome to understand more of the pathogenesis of theseconditions, and therapeutics become increasingly targeted andspecific, the options for treatment broaden and hopefully theefficacy and safety will improve.

AUTHORS’ NOTEThe Cochrane Database of Systematic reviews (http://www.cochrane.org) summarises the available evidence-based litera-ture on randomised controlled trials of interventions. TheNeuromuscular Group (http://www.neuromuscular.cochrane.org) coordinates reviews of neuromuscular interventions anddiagnostic test accuracy. The available reviews relevant to thisarea are listed in table 7, but these are updated and expanded ona regular basis.

Competing interests: None.

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faecal incontinence (n = 4) or erectile dys-function (n = 3; all male patients). Anorectalelectrophysiology was performed in twopatients, both consistent with bilateralpudendal neuropathies (Web table 1). MRIstudies (fig 1) showed: scattered cerebralwhite matter hyperintensities in all threepatients in whom this test was performed;asymmetrical left frontotemporal atrophyconsistent with clinical FTD and an atrophiccord especially around the conus in II:18;and fatty change and atrophy of the glutealmuscles and low muscle volume in thequadriceps and hamstring groups in III:14.A muscle biopsy from II:14 is shown inonline fig 2.

DISCUSSIONIBMPFD presents as a multisystem disorderaffecting brain, skeletal and cardiac muscle,3

spinal cord and bone.1 4 The R155H muta-tion, an arginine-to-histidine substitution inthe N-terminal CDC48 domain of the VCPprotein, results in loss of VCP function5 andis found exclusively in individuals affectedwith IBMPFD.1 Clinical reports of thisdisease are scarce.1 2 4 Family membersusually presented with proximal weakness,progressing to wheelchair disability andpremature death. The average age of muscleweakness onset, as a familial average, was34, contrasting with previous studies (432

and 574). The dementia frequency withinthis pedigree was 44% compared with 30%,1

70%,4 and 100%4 in other studies. As somepatients may have prematurely died ofmyopathy- or cardiomyopathy-related com-plications, it was difficult to assess FTDpenetrance.

Four out of five investigated members ofthis pedigree had echocardiographic featuresof cardiomyopathy.3 This is the first clinicaldescription of cardiomyopathy in a molecu-larly confirmed VCP mutation. Recentpostmortem findings have found a dilatedand hypertrophic cardiomyopathy in onepatient with IBMPFD.3

The new observation in this pedigree isthe presence of prominent sphincter distur-bance involving bladder, bowel and erectilefunction in all five assessed pedigree mem-bers. Other factors could partially explainthese symptoms: for example, functionalobstructive defaecation may be partlyresponsible for the clinical picture of puden-dal neuropathy seen in III:13. However, this

is associated with a reduction in sphinctertone, a feature not seen during anorectalphysiology. Moreover, III:15 had pudendalneuropathy with no history of longstandingconstipation. In III:13, III:14 and III:15,erectile failure may be partly explained bypsychogenic factors. Nonetheless, the simi-larity of sphincter symptoms between allpatients and in particular four relativelyyoung patients (III:3, III:13, III:14, III:15) isstriking. We therefore conclude thatIBMPFD is likely to be associated withsphincter disturbance. The presence ofspinal cord atrophy in one patient (II:18)and previous work showing ubiquitin-posi-tive nuclear inclusion bodies in the spinalcord in IBMPFD4 suggest that sphincterdisturbance in IBMPFD could arise fromboth spinal cord and nerve pathology.

Brain MRI demonstrated a mild excess ofwhite matter abnormalities in all threeexamined. Right temporal lobe atrophy andcord atrophy were seen in an older patient,correlating with her clinical FTD. This is inagreement with one other MRI brain studyof IBMPFD,3 while another described pro-gressive cerebral atrophy with prominentcallosal and frontal white matter loss.5

Spinal cord atrophy is a previously unde-scribed feature of IBMPFD and is consistentwith pathological findings of spinal cordinclusion bodies.4 A recent report describesMRI muscle findings in IBMPFD of ‘‘fattydegeneration’’ throughout predominantlyproximal muscle groups,3 in agreement withcurrent findings.

Members of this pedigree had been pre-viously given other diagnoses includingvarious muscular dystrophies and spinalmuscular atrophy. MND had been diag-nosed in some patients because of denerva-tion on neurophysiology (online table 1).

In conclusion, IBMPFD is a multisystemdisorder, which should be considered in thedifferential diagnosis of autosomal domi-nant neuromuscular disorders, especiallywhen there is a prominent history ofdementia or ‘‘MND.’’ Sphincter involve-ment is a likely associated clinical featureof the disease.

T D Miller,1 A P Jackson,2 R Barresi,3 C M Smart,1

M Eugenicos,4 D Summers,1 S Clegg,5 V Straub,3

J Stone1

1 Department Clinical Neurosciences, University ofEdinburgh, Western General Hospital, Edinburgh, UK; 2 MRCHuman Genetics Unit, Western General Hospital, Edinburgh,

UK; 3 Institute of Human Genetics, University of Newcastleupon Tyne, International Centre for Life, Newcastle uponTyne, UK; 4 Gastrointestinal Unit, Western General Hospital,Edinburgh, UK; 5 South East of Scotland Clinical GeneticsService, Western General Hospital, Edinburgh, UK

Correspondence to: Dr J Stone, Department ClinicalNeurosciences, University of Edinburgh, Western GeneralHospital, Crewe Road, Edinburgh EH4 2XU, UK;[email protected]

Acknowledgements: L Strain is thanked for technical helpin establishing the VCP mutation analysis.

Funding: None.

Competing interests: None.

Patient consent: Obtained.

c An additional table and figures are published online only athttp://jnnp.bmj.com/content/vol80/issue5

Received 5 March 2008Revised 4 June 2008Accepted 8 July 2008

J Neurol Neurosurg Psychiatry 2009;80:583–584.doi:10.1136/jnnp.2008.148676

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body myopathy associated with Paget disease of boneand frontotemporal dementia is caused by mutantvalosin-containing protein. Nat Genet 2004;36:377–81.

2. Kovach MJ, Waggoner B, Leal SM, et al. Clinicaldelineation and localization to chromosome 9p13.3–p12 of a unique dominant disorder in four families:hereditary inclusion body myopathy, Paget disease ofbone, and frontotemporal dementia. Mol Genet Metab2001;74:458–75.

3. Hubbers CU, Clemen CS, Kesper K, et al. Pathologicalconsequences of VCP mutations on human striatedmuscle. Brain 2006;130:381–93.

4. Guyant-Marechal L, Laquerriere A, Duyckaerts C, etal. Valosin-containing protein gene mutations: clinicaland neuropathologic features. Neurology2006;67:644–51.

5. Krause S, Gohringer T, Walter MC, et al. Brain imagingand neuropsychology in late-onset dementia due to anovel mutation (R93C) of valosin-containing protein.Clin Neuropathol 2007;26:232–40.

CORRECTION

doi:10.1136/jnnp.2008.158303corr1

M P T Lunn, H J Willison. Diagnosis andtreatment of inflammatory neuropathies (JNeurol Neurosurg Psychiatry 2009;80:249–58).There is a dosage error in this paper. In thelast paragraph on page 255 the dose ofprednisolone should be 1mg/kg not 1g/kg asprinted.

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Dx and Rx Inflamatory Neuropathy

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