CIDP: mimics and chameleons

A Neligan, M M Reilly, M P Lunn

National Hospital for Neurologyand Neurosurgery,Queen Square, London, UK

Correspondence toDr Michael P Lunn, MRC Centrefor Neuromuscular Disease,National Hospital for Neurologyand Neurosurgery, QueenSquare, London WC1N 3BG,UK; michael.lunn@uclh.nhs.uk

Published Online First17 July 2014

To cite: Neligan A,Reilly MM, Lunn MP. PractNeurol 2014;14:399–408.

ABSTRACTThe diagnosis of chronic inflammatorydemyelinating polyradiculoneuropathy (CIDP) isusually straightforward, but atypicalpresentations can represent a significantdiagnostic challenge. This review highlights theclinical and electrophysiological ‘red flags’ thatshould make one consider an alternativediagnosis.

DEFINITION AND EPIDEMIOLOGYOF CIDPChronic inflammatory demyelinatingpolyradiculoneuropathy (CIDP) is clinic-ally defined as a ‘chronically progressive,stepwise or recurrent proximal and distalweakness and sensory dysfunction of allextremities, developing over at least2 months, with absent or reduced tendonreflexes in all limbs and sometimes withcranial nerve involvement’.1 Sensory dys-function is frequently present, mostusually affecting joint position and vibra-tion submodalities. Wasting is not prom-inent early in the disease. There areatypical forms, such as multifocalacquired demyelinating sensory andmotor neuropathy (MADSAM, or Lewis–Sumner syndrome), pure sensory or puremotor CIDP and focal or distal forms(distal acquired demyelinating sensorypolyneuropathy (DADS)).A recent study from South-East England

estimated the standardised prevalence rateof CIDP at 3 per 100 000, with a higherprevalence in males (range of estimatedprevalence 0.8–8.9 per 100 000 in the pre-vious eight studies).2 Most people withCIDP have a progressive rather than aspontaneously relapsing and remittingcourse, with a variable balance betweenmotor and sensory symptoms.The American Academy of Neurology

established diagnostic research criteria forCIDP in 1991.3 There have since beenfurther more practical diagnostic consensusguidelines from the European Federationof Neurological Societies/Peripheral NerveSociety (EFNS/PNS).1 These and other

proposed criteria typically comprise a com-bination of clinical and electrophysio-logical features (there have been 15 formalsets of published electrophysiological cri-teria for the diagnosis of CIDP4). Cases areclassified as definite, probable or possible,depending upon the number of criteria ful-filled. In most, finding a raised CSFprotein without CSF leucocytosis5 furthersupports the diagnosis. Clear evidence ofmacrophage-associated demyelination andremyelination, with or without a T-cellinflammatory endoneurial infiltrate in asensory nerve biopsy, remains the goldstandard supportive criterion (figure 1).There have been several validations ofthese diagnostic criteria, though none is100% sensitive or specific1 3; for example,the EFNS/PNS criteria1 show a positivepredictive value of 97% and negative pre-dictive value of 92%,6 and different valid-ation cohorts give widely varyingsensitivities and specificities.5

CIDP DIAGNOSIS IN PRACTICEMost CIDP cases are relatively straightfor-ward to diagnose. In practice, a clinicaldiagnosis of CIDP is made in people with▸ a subacute presentation of patchy motor

weakness and/or positive sensory symp-toms (paraesthesia);

▸ of at least 8 weeks duration;▸ with electrophysiological evidence of

demyelination on nerve conductionstudies;

▸ with or without a raised CSF protein;▸ in whom alternative diagnoses, particularly

hereditary neuropathies have been excluded.

CHAMELEONS: ATYPICALPRESENTATIONS OF CIDPWhile the diagnosis of CIDP is straightfor-ward in typical presentations with excel-lent expert agreement, there is lessuniversal diagnostic consensus in atypicalpresentations. This is reflected by theEFNS/PNS guidelines subdivision intodefinite, probable and possible CIDPcases, based on the clinical presentations.1

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In a review of four typical and seven atypical cases ofdefinite CIDP, a panel of 32 experts from 22 differentcentres confirmed CIDP in 97% of the typical cases,but in only 60% of the atypical cases.7

Atypical presentations with pure motor or sensoryvariants, focal, monomelic or asymmetrical variants inthe context of comorbidities increase the likelihood ofan initial alternative diagnosis.In our practice, patients with CIDP occasionally

have previously received a different diagnosis. Withretrospect, it is usually possible to identify the point at

which, and why, that erroneous diagnosis was made.Sometimes it is entirely justifiable (see Guillain–Barrésyndrome below). Box 1 lists potential alternativediagnoses that turn out to be CIDP.A diagnosis of CIDP cannot be made until symp-

toms have progressed for over 8 weeks. Some CIDPpresentations are very acute (acute-CIDP or a-CIDP);a diagnosis of Guillain–Barré syndrome may entirelyreasonably later be revised to CIDP. Incidentally, theremay be a biological explanation for this, as such casesmay show a persistent Fas deficiency in T-cells.8

If symptoms are confined focally to a single limb(monomelic involvement), or even to a single nerve,they may be initially thought to be a focal compressionneuropathy, such as carpal tunnel syndrome or anulnar neuropathy—and should be considered whenpatients have had unsuccessful decompression surgery.This CIDP chameleon is more likely when there islimited electrophysiology, directed solely at a carpaltunnel or ulnar nerve at the clinician’s request, as itoften is in technician-run ‘carpal tunnel diagnostic ser-vices’. Occasionally there may be no positive electro-physiological criteria for peripheral nervedemyelination at a more comprehensive first examin-ation, but the clinician’s index of suspicion or progres-sion provokes a repeat examination.Similarly, pure sensory variants of CIDP may be

misdiagnosed as an idiopathic sensory axonal neur-opathy, a sensory neuronopathy or a sensory

Figure 1 Demyelination in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): teased nerve fibres demonstrating asegment of demyelination (A); a widened node of Ranvier with a remyelinated segment (B); electron microscopy of a demyelinatingfibre (C), and an onion bulb (D).

Box 1 CIDP chameleons. Potential initial misdiag-noses in atypical presentations of chronic inflammatorydemyelinating polyradiculoneuropathy (CIDP)

▸ Guillain–Barré syndrome▸ Motor neurone disease▸ Focal compression neuropathies (particularly ulnar and

median compression)▸ Charcot–Marie–Tooth 1X (CMT1X)▸ Idiopathic sensory neuropathy▸ Sensory neuronopathy▸ Sensory polyradiculopathy▸ Diabetic neuropathy▸ Neuropathy secondary to amyloidosis

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polyradiculopathy. Symptoms may be attributed to apre-existing condition, such as diabetes mellitus oramyloidosis. Idiopathic sensory axonal neuropathiesprogress linearly and slowly, and are seldom disabling.Diabetes mellitus does not usually cause a neuropathyunless severe or longstanding or both, and a signifi-cant neuropathy in a patient with mild diabetesshould make one consider an alternative diagnosis.Amyloid is likely to have prominent pain and asso-ciated autonomic dysfunction, both features thatwould be against a diagnosis of CIDP.Pure motor variants of CIDP may have a ‘motor

neurone disease’-like presentation, particularly if thepatient reports fasciculation and cramp, though willlack upper motor neurone signs and should be distin-guishable with neurophysiology. Sensory abnormalitiesin the nerve conduction studies push a diagnosis ofmultifocal motor neuropathy towards MADSAM orCIDP, when motor conduction blocks and dispersioncoexist.Electrophysiological evidence of patchy temporal

dispersion or conduction block (figure 2) in thecontext of a motor and/or sensory demyelinatingpolyneuropathy helps to distinguish CIDP from thehereditary demyelinating neuropathies, although dis-persion and block can occur in some of the hereditaryneuropathies, such as Charcot–Marie–Tooth-1X(CMT-X, see below), leading to diagnostic uncer-tainty. Nevertheless, clinicians often treat cases wherethere is diagnostic uncertainty as CIDP in the hopethat there will be some clinical improvement. A diag-nosis of CMT that turns out to be CIDP is unusual, asgenetic diagnosis is so much easier in 2014.

CIDP MIMICSThe differential diagnosis of a chronic acquired demye-linating polyneuropathy is relatively short, but thereare several CIDP mimics that should not be missed.Clinicians should be aware of the red flags that shouldprompt re-evaluation of the diagnosis of CIDP. Box 2lists the red flags that should prompt one to consideran alternative diagnosis, while box 3 lists the featuresthat positively support a diagnosis of CIDP.

UNUSUAL SYMPTOMS AND HISTORICALFINDINGSProminent pain is unusual in CIDP, and significantpain in the context of a mononeuritis multiplex, evenwith demyelinating features on electrophysiology, sug-gests a vascultic neuropathy. Significant calf muscleaching is often an early feature of POEMS syndrome(polyneuropathy, organomegaly, endocrinopathy, Mprotein and skin changes) and should prompt a searchfor other features of the syndrome, including manda-tory serum paraprotein.Other features in the history, which typically should

exclude a diagnosis of CIDP at onset, include an

Figure 2 Conduction block from the elbow to the axilla in themedian nerve with slowing in all segments (reduction inamplitude and area) in a patient with chronic inflammatorydemyelinating polyradiculoneuropathy (CIDP).

Box 2 Red flags

Red flags for the diagnosis of typical chronic inflamma-tory demyelinating polyradiculoneuropathy (CIDP):Symptoms in the history

▸ Background history of a slowly progressive neuropathy▸ ‘Prominent’ pain symptoms, or significant early

muscle aching▸ No (or minimal) symptomatic sensory disturbance▸ Comorbid conditions or other systemic features

(oedema, weight loss, organomegaly, skin or nailpigmentation, rash, or gynaecomastia)

Signs in the examination▸ Cranial nerve involvement or papilloedema (figure 3)▸ Significant lower motor neurone wasting, espe-

cially in early disease▸ Respiratory muscle involvement▸ Head drop▸ Significant relative dominant hand weakness with

median/ulnar separation*Signs or investigation findings

▸ Autonomic involvement▸ Sphincter disturbance

Anomalous response to treatment▸ Failure to respond to adequate and reasonable

trials of treatment▸ Rapid and continued progression of symptoms

*Relative weakness of the dominant hand with median/ulnar separation suggests an alternative diagnosis, suchas CMT1X[9] but is not of itself diagnostic of any singlecondition.

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associated fever or known intercurrent infections(Lyme disease, diphtheria) or drug or toxin exposureknown to potentially cause neuropathy (hexacarbons,amiodarone). Clearly, a family history should be dili-gently sought (this often takes more effort than onewould think) as this entirely changes the diagnosticpathway.

UNUSUAL SIGNSThe presence of upper motor neurone signs, promin-ent sphincter or respiratory involvement shouldprompt the clinician to consider an alternative or sec-ondary diagnosis. Upper motor neurone signs do notoccur in CIDP, but second diagnoses, such as cervicalspondylosis, are not infrequent. There have been casesof coexisting myasthenia gravis.Persistent asymmetrical hand weakness with a

weaker dominant hand and greater median thanulnar nerve involvement in the dominant hand(weaker abductor pollicis brevis compared to firstdorsal interosseous), in the context of poor treatmentresponse, and especially if there is a long slowly pro-gressive history, suggest an alternative diagnosis ofCharcot–Marie–Tooth disease IX (CMT-X).9 Thereis often a clue in the correlated electrophysiology,which may also show the same pattern, as well asassociated dispersion and block. Finding dispersionand block may lead to an initial inflammatorydiagnosis.

UNUSUAL INVESTIGATION FINDINGSEarly significant axonal involvement is unusual, iden-tified either on examination by early wasting or fas-ciculation or on nerve conduction studies. Even inthe context of prominent demyelinating features, ifthere is a background of confirmed diabetes melli-tus, then axonal loss is more likely to be from dia-betic neuropathy rather than from CIDP. Earlyreports of an epidemiological causal associationbetween CIDP and diabetes mellitus appear to havebeen incorrect.10

An IgM monoclonal gammopathy may be associatedwith high titre antibodies to myelin-associated glyco-protein (MAG).1 An anti-MAG antibody without the‘typical’ phenotype of anti-MAG neuropathy may notbe relevant although may be associated with unusualpathologies. We have seen amyloid deposition andvasculitis (sometimes with a mixed cryoglobulinaemia)caused by IgM paraproteins, without the ‘typical’phenotype. Most relevant anti-MAG antibodies arereported as ‘strong positive’ on the current widelyused Buhlmann ELISA.

AUTONOMIC INVOLVEMENTIn contrast to Guillain–Barré syndrome, CIDP rarelyhas autonomic features. When present, autonomicdysfunction is never significant and mainly manifestsas bowel and bladder complaints. Baroreflex-mediatedperipheral vasoconstriction is relatively spared inCIDP and therefore significant orthostatic hypoten-sion is uncommon.11 Any significant autonomic fea-tures should lead one to consider alternativediagnoses, especially amyloid, diabetic neuropathy,and rarely vasculitis or even a second diagnosis.

Box 3 Features supporting a diagnosis of chronicinflammatory demyelinating polyradiculoneuropathy(CIDP)

Features supporting CIDP*▸ Elevated CSF protein with CSF white cell count <10/

mm3

▸ MRI evidence of hypertrophy or enhancement of thenerve roots (cervical, brachial, lumbrosacral or caudaequina)

▸ Abnormal sensory electrophysiology in at least onenerve

▸ Objective clinical improvement following immunomo-dulatory therapy

▸ Unequivocal evidence of demyelination and/or remye-lination by electron microscopy or teased fibre ana-lysis in nerve biopsy† (figure 1)

*Modified from box 5 in the EFNS/ Peripheral NerveSociety (PNS) CIDP guidelines.1

†Other features on biopsy that support a diagnosis ofCIDP include direct visualisation of inflammatory infil-trates of T cells and macrophage in association withdemyelination.

Figure 3 Thickened 3rd nerves in a patient with chronicinflammatory demyelinating polyradiculoneuropathy (CIDP).

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THE EFFICACY OF IMMUNE-MODULATORYTHERAPIES IN CIDPFour recent Cochrane reviews have evaluated the effi-cacy of treatments in CIDP,12–15 which include thethree standard therapies. The evidence for the efficacyof corticosteroids is based on two randomised con-trolled trials, with patients treated with corticosteroidshaving improved neuropathy impairment scores after12 weeks compared to patients randomised to no treat-ment. There was no statistical difference in remissionrates at 1 year in people treated with standard doseoral prednisolone compared to monthly high-dose oraldexamethasone.12 Nevertheless, oral corticosteroidsare typically employed as first-line treatment in cases ofnewly diagnosed CIDP. The quality of the evidence forthe efficacy for intravenous immunoglobulin andplasma exchange is moderate to high, with plasmaexchange providing significant short-term improve-ments in disability, clinical impairment and motornerve conduction velocities, although there may berapid deterioration postexchange.13 The evidence forintravenous immunoglobulin from the eight publishedrandomised controlled trials confirms that intravenousimmunoglobulin improves disability for at least 2–6 weeks compared to placebo, with comparable effi-cacy to plasma exchange and oral corticosteroids.14

Only one study (the ICE trial) had long-term follow-upand reported that the benefit of intravenous immuno-globulin on disability persisted for 24, and possibly48 weeks, compared to placebo.16 There was no sig-nificant difference in the mean disability scores inpeople treated with intravenous immunoglobulin orplasma exchange at 6 weeks.17 Similarly, there was nodifference in improvement in disability between peopletreated with prednisolone and intravenous immuno-globulin at 6 weeks.14 There was no significant differ-ence in the frequency of side effects between the threetreatment modalities although a more recent rando-mised controlled trial found that people treated with a6-month course of intravenous immunoglobulin wereless likely to stop treatment because of inefficacy,intolerance or adverse effects compared to treatmentwith intravenous methylprednisolone.18 Intravenousmethylprednisolone, however, produced a more sus-tained remission when stopped, if it were tolerated forthe full course.

UNUSUAL RESPONSE TO IMMUNOTHERAPYSeventy per cent of patients respond to one oranother of the three standard therapies, and probably90% respond overall.5 A failure to respond to treat-ment, or rapid deterioration of symptoms despite anadequate trial of treatment with at least two treatmentmodalities, should prompt a re-evaluation of thediagnosis.Motor-predominant forms of CIDP present with

clinical motor involvement only, but sensory involve-ment on electrical studies. Motor CIDP often behaves

more like multifocal motor neuropathy with conduc-tion block; these cases may worsen with corticosteroidtreatment, and more rarely plasma exchange, butusually respond to treatment with intravenousimmunoglobulin. Other conditions, such asMADSAM (Lewis–Sumner syndrome), chronic inflam-matory sensory polyneuropathy, DADS and relapsingsensory ataxic neuropathy, are all considered atypicalvariants of classical CIDP. Although the clinician maybe fortunate in treating such patients effectively, atyp-ical variants have a somewhat unpredictable and typic-ally poorer treatment response compared to typicalCIDP.5 A careful clinical history and examination anduse of appropriately comprehensive electrical studiescan differentiate these clinically important variants.The DADS acronym is confusingly also applied toanti-MAG neuropathies (see below), and this may bebecause some laboratory tests in current use areunable to detect all anti-MAG antibodies.

OCCAM’S RAZOR, HICKAM’S DICTUM ANDCRABTREE’S BLUDGEONWhen considering any neurological diagnosis, notleast CIDP, it is practical and useful to remain in touchwith Occam’s razor. Occam’s razor can be sum-marised as ‘entities must not be multiplied beyondnecessity’,19 which in medical terms can be para-phrased as ‘when investigating a patient with multiplesymptoms, a single unifying diagnosis should besought rather than two or more unrelated ones’.A singular unifying diagnosis is not always possible,but the application of Hickam’s dictum (multiplesymptoms and signs may be due to more than onecondition, or more commonly ‘a man can have asmany diseases as he damn well pleases’20) should beinfrequent under the age of 80 years. One shouldalways be aware, and be wary, of applying Crabtree’sbludgeon (‘no set of mutually inconsistent observa-tions can exist for which some human intellect cannotconceive a coherent explanation, however compli-cated’21), if applied, should prompt the clinician tostep back and re-evaluate Occam. Usually, the diagno-sis is straightforward and unifying, and the diseasewill behave like it is supposed to.22

POTENTIAL ALTERNATIVE DIAGNOSESSo what are the alternatives? Box 4 lists some geneticand acquired conditions that can lead to diagnosticconfusion.

GENETIC MIMICSPossibly the most common genetic CIDP misdiagnosisis CMT-X.23 This is caused by one of a large numberof mutations in the GJB1 gene, which encodes for thegap junction protein connexion-32. CMT-X is oftenelectrically patchy and can sometimes have evidenceof temporal dispersion and conduction block on nerveconduction studies (unlike most other forms of CMT)

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(figure 2). The lack of response to treatment andminimal electrophysiological progression over timeshould lead one to suspect the diagnosis. One mightelicit a X-linked family history with detailed question-ing, and sometimes with the examination of mildlyaffected and asymptomatic female relatives. Recessivedemyelinating neuropathies are uncommon but needto be kept in mind even if there is an equivocalresponse to intravenous immunoglobulin. Even when

there is a recognised genetic diagnosis, the conditionmay be ascribed to CMT1A with a superimposedinflammatory polyneuropathy (Hickam’s dictum).Cases with CMT4C (SH3TC2, previouslyKIAA1985)24 usually have early onset in the first orsecond decade, delayed or difficulty walking, andoften cranial nerve involvement (figure 3) and highlyspecific features on electron microscopy of longitudin-ally extended Schwann cell cytoplasmic processes onperipheral nerve biopsy.24

CMT4J (figure 4)25 presents with rapid progressiveasymmetrical weakness, and a demyelinating neur-opathy. Both have been misdiagnosed with CMT1Aand CIDP on occasion and, therefore, should be con-sidered in the differential diagnoses in cases of treat-ment failure.Recently, there has been a description of a new

recessive phenotype (autosomal recessive spasticataxia of Chavenoix–Sauvigny or ARSACS), associat-ing a demyelinating neuropathy with ataxia and spasti-city: most of these patients have a mutation in sacsin.Although spasticity and cerebellar features are usuallyprominent, there are phenotypic variants with onlyneuropathy.26 A nerve biopsy may contain significantnumbers of lipofuscin granules.Another important genetic diagnosis is transthyretin

familial amyloid polyneuropathy (TTR-FAP),27 par-ticularly in cases of sporadic (non-familial)TTR-FAP.28 TTR-familial amyloid polyneuropathy isan autosomal dominant genetic condition with multi-system involvement. It is caused by one of severalmutations in the transthyretin gene with the V30Mmutation being the most common mutation in peoplewith Portuguese ancestry.28 The classical presentationis one with a length-dependent sensorimotor predom-inantly small-fibre polyneuropathy (although somemay have some demyelinating features), and auto-nomic dysfunction (postural hypotension intermittentdiarrhoea, weight loss and impotence). There areother rare non-TTR forms of familial amyloid poly-neuropathy. The diagnosis is typically confirmed onbiopsy of nerve, rectum or abdominal fat.27 28 Thereis an easily available genetic test for TTR mutations,which can be performed without resorting to biopsy ifthe diagnosis is suspected.MNGIE (mitochondrial neurogastrointestinal ence-

phalomyopathy) can occasionally present with a demyelin-ating peripheral neuropathy and be misdiagnosed asCIDP.29 In such cases, neuroimaging (looking for leucoen-cephalopathy), testing urinary thymidine and uridine, andscreening for thymidine phosphorylase (TYMP) muta-tions, should be considered, particularly if there is subse-quent development of prominent ocular (ptosis, externalophthalmoplegia) or gastrointestinal symptoms.30

ACQUIRED MIMICSAmong the potential acquired diagnoses to consider isthat of the POEMS syndrome. While the diagnosis of

Box 4 Potential genetic and acquired chronicinflammatory demyelinating polyradiculoneuropathy(CIDP) mimics

Alternative diagnoses to consider in treatment failure CIDPGenetic Mimics

▸ GJB1 mutations (CMT1X)▸ Transthyretin familial amyloid polyneuropathy

(TTR-FAP)▸ CMT 4C (SH3TC2 mutations)▸ CMT4J (FIG 4)▸ HSAN1 (SPTLC1)▸ CMT1A (homogenous slowing)▸ CMT1b▸ HNPP▸ GDAP1▸ MNGIE and rare mitochondrial disorders

Acquired Mimics▸ POEMS▸ Paraprotein related (MGUS/WM/lymphoma) (IgM

associated)▸ AL amyloid▸ Treated-related fluctuations in GBS (GBS-TRF)▸ Diabetic neuropathy/Diabetic lumbro-sacral radicu-

loplexus neuropathy (DLRPN)▸ Vasculitis

POEMS: polyneuropathy, organomegaly, endocrinopathy,M protein and skin changes

Box 5 Second-line investigations to be consideredin treatment failure chronic inflammatory demyelin-ating polyradiculoneuropathy (CIDP)

Second-line investigations in treatment failure CIDP▸ Detailed family history (including ethnicity)▸ Developmental history▸ Repeat nerve conduction studies▸ Repeat serum electrophoresis with immunofixation,

serum-free light-chains and Bence Jones protein▸ Serum vascular endothelial growth factor (VEGF)▸ Nerve root/plexus/peripheral nerve imaging (MRI/U/S)▸ GJB1 gene sequencing or other genetic requests▸ Nerve biopsy

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POEMS syndrome in its advanced presentation is notdifficult, up to 50% present with an initial, evenacute, (demyelinating or mixed demyelinating/axonal)polyneuropathy,31 32 leading to a diagnosis of CIDP.Features that help distinguish the polyneuropathy of

POEMS from that of CIDP include a distal dominantpainful polyneuropathy (prominent neuropathic footpain, or even less severe but typical calf aching), morefrequent muscle atrophy, distal dominant lower limbweakness31 and more rapid onset of inability to walkindependently (median period of 9.5 months fromonset).32

A paraprotein (or monoclonal lymphoproliferativedisorder) is an essential major criterion in the diagno-sis (Dispenzieri criteria), and may only be discoveredwith a serum immunofixation, Bence Jones protein,or serum-free light-chain analysis. Electrophysiologicalfeatures that favour POEMS include the absence ofconduction block (rare), predominant nerve conduc-tion slowing in the intermediate rather than the distalnerve segments, and more severe involvement in thelower rather than the upper limbs.33 Clinical suspicionof POEMS should lead to measurement of serum levelof vascular endothelial growth factor (VEGF), whichis typically elevated and supports the diagnosis.Indeed, the presence of an elevated serum VEGF-Alevel of twice the upper limit of normal in thecontext of a demyelinating polyneuropathy and aparaprotein, and the absence of hypoxia or iron defi-ciency anaemia, is almost pathognomonic for POEMSsyndrome and should prompt other appropriate inves-tigations to support the diagnosis and to stage thedisease.Polyneuropathy with IgM monoclonal gammopathy

of undetermined significance (IgM MGUSP) is animmune-mediated polyneuropathy in most cases. It istypically characterised by a predominantly distal andsensory impairment with about half havingantimyelin-associated glycoprotein (anti-MAG) anti-bodies.34 Electrophysiologically prolonged distalmotor latencies often occur in IgM MGUSP, whichhelps distinguish it from CIDP. Making this diagnosisis important, as all people with IgM MGUSP shouldbe investigated for a malignant blood dyscrasia.34 Inpeople with an IgM MGUSP, a later age of onset anddemyelinating features are associated with a worseprognosis, while the presence of anti-MAG antibodiessuggests a better prognosis.35

Primary AL amyloidosis is an acquired condition char-acterised by abnormal proliferation and deposition ofmonoclonal immunoglobulin light chain in tissues; 15%have a dominant peripheral neuropathy.36 When thereis a peripheral neuropathy in the context of primary ALamyloidosis, this is typically predominantly a symmet-rical sensory neuropathy with minimal motor involve-ment. Moreover, autonomic features are oftenprominent in addition to systemic symptoms, such asunexplained weight loss, fatigue and constipation.

Features that may not be prominent at presentation, butdevelop subsequently and suggest primary AL amyloid-osis, include non-diabetic nephrotic syndrome, non-ischaemic cardiomyopathy, hepatomegaly or elevatedalkaline phosphatase level with normal imaging.37

Almost all patients with primary amyloidosis havean elevated level of the responsible free light chain,underlying the importance of detailed immunofixa-tion of serum or urine.Another alternative diagnosis is treatment-related

fluctuation in GBS (GBS-TRF), reported in 8–16% ofcases of GBS.38 The treatment strategy and long-termprognosis differ considerably between the two condi-tions. In differentiating GBS-TRF from acute-onsetCIDP, a diagnosis of acute CIDP should be consideredin a person previously diagnosed with GBS if there isclinical deterioration more than 9 weeks after onset,or if clinical deterioration occurs on three or moreoccasions.39

Diabetic neuropathy may occasionally have ademyelinating pattern and meet the electrophysio-logical criteria for CIDP, resulting in diagnostic confu-sion.40 Similarly vasculitic neuropathy may rarely bemistaken for CIDP with the diagnosis only confirmedafter a nerve biopsy.

SECOND-LINE INVESTIGATIONSBox 5 gives a summary of the second-line investigationsto detect mimics, or for cases of treatment failure. Theclinician should first return to the history with a view todiscovering any suggestion of a family or developmentalhistory. A detailed family history should be obtainedwith particular focus on ethnicity (Irish/Portuguese/Mediterranean), which may suggest FAP. Other aspectsin the history, such as the revelation of persistent ‘toewalking’, poor athletic performance during schoolyears, difficulty in shoe fitting as a child, or failure to beable to wear high heels, are quite revealing. These fea-tures may require active history taking, and suggest amore chronic course and favour a genetic rather than anacquired aetiology. Nerve conduction studies should berepeated looking for evidence of rapid electrophysio-logical progression; alternatively, these may show com-plete stability, suggesting a genetic cause. Serum proteinelectrophoresis has only a 60% sensitivity for detectingparaproteins in the context of neuropathy (immunopar-esis is rare) so immunofixation (95% sensitivity) andurinary Bence Jones protein should be performed, andserum-free light-chain analysis (a few additional cases)considered. MR scanning of the brachial and lumbrosa-cral plexuses with gadolinium should be requestedlooking for evidence of nerve root or plexus hyper-trophy or enhancement (figure 4).41 Useful sequencesare STIR and T1 weighted images, with and withoutgadolinium, but data continue to emerge on the specifi-city and sensitivity of MRI findings.42 In cases wherethere has been no significant deterioration over timeeither clinically or electrophysiologically, it is reasonable

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to consider sequencing of the GJB1 gene, or an alterna-tive genetic diagnosis.A nerve biopsy generally remains a last resort in

diagnosis, but should definitely be considered, butnot always performed, in all cases of treatmentfailure, particularly if there are other red flags(box 1). Ideally, the biopsy should be performed in acentre with surgeons and neuropathologists experi-enced in nerve biopsies and processing. The targetshould be a sensory nerve with evidence of involve-ment on nerve conduction studies (sural nerve, super-ficial peroneal or, more rarely, the superficial radial orthe dorsal ulnar nerves). Typical findings of CIDP onbiopsy include an inflammatory infiltrate of T cells(>5 lymphocytes per fascicule) and macrophages inthe endoneurium; unequivocal evidence of demyelin-ation and remyelination is far less common5, althoughmuch more convincing for CIDP. Teased fibre analysisand cross-sectional and longitudinal electron micros-copy are very valuable.1 (figure 1). Particular attentionshould be paid for evidence of vasculitis or amyloiddeposition, with the biopsy sent to a dedicated neuro-muscular pathologist if appropriate. There are severaltechniques of Congo red staining, some more success-ful than others.43 Additionally, a full panel of immu-nohistochemical inflammatory markers is essential.In cases where atypical POEMS syndrome is sus-

pected, serum VEGF should be measured, a suralnerve biopsy considered in addition to body imaging,looking for evidence of organomegaly, and blood testsfor evidence of endocrine involvement. Investigationsfor an underlying malignancy, including CT/positronemission tomography (PET), should be initiatedin cases of rapid progression or non-response totreatment.

Recent research using MRI to evaluate sciatic nervecross-sectional area can help to differentiate betweeninherited and inflammatory neuropathies.44 While stilla research tool at present, it offers the potential of anobjective pathological marker to complement clinicalinvestigations in cases of diagnostic uncertainty.

OTHER TREATMENT OPTIONS/REGIMENSUltimately, most cases of treatment failure retain a diag-nosis of CIDP, as 70% of people with CIDP respond toany one of the first-line treatments with corticosteroids,intravenous immunoglobulins, or plasma exchange,with a further 10% responding to a combination oftreatments.1 5 Interestingly, while 80% respond to oneof the first-line treatments,5 people with a monophasicor a relapsing–remitting course (as opposed to a chronicprogressive course) or a greater than twofold CSFprotein increase (≥0.84 g/L) show a better response totreatment with intravenous immunoglobulin.6

However, overall, 10% of people with definite CIDPwill be in the treatment failure group.While the management of refractory CIDP is not the

primary focus of this article and is covered in muchgreater depth elsewhere,45 brief mention of therapeuticstrategies employed at our institution is appropriate. Incases where people with a secure diagnosis of CIDPfail to improve following a combination of treatmentwith corticosteroids, intravenous immunoglobulin andplasma exchange, combination therapy with plasmaexchange followed by intravenous immunoglobulinmay be trialled. Oral immunosuppression (methotrex-ate, azathioprine, mycophenolate mofetil, or ciclos-porin) is often used despite lack of controlled trialevidence. Failing this, consideration is given to the useof pulsed cyclophosphamide (Cyclops regimen)46 or

Figure 4 Spinal root hypertrophy in a patient with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): SagittalT2-weighted MRI of the cervical (A) and lumbosacral (B) spine with axial images at the level of L4 (C) and S1 (D) demonstratingextensive and diffuse hypertrophy of the spinal nerve roots. There is associated enlargement of the spinal canal and posteriorscalloping of the vertebral bodies. Hypertrophy of the lumbosacral plexus bilaterally is also shown (arrows). Note the multilevelvertebral insufficiency fractures from chronic prednisolone treatment.41

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rituximab,15 although high-quality data are lacking,other than in case reports and series. Other treatmentoptions, reported as single case reports or small caseseries, include interferons (α and β), alemtuzemab, eta-nercept, fingolimod and stem cell transplantation.15

CONCLUSIONS/SUMMARYWe have tried to highlight the clinical and electro-physiological features that should make one consideran alternative diagnosis in cases where CIDP fails torespond to appropriate standard therapy. In particular,we have considered potential alternative diagnosesand features that help distinguish such conditionsfrom CIDP.We have also considered the CIDP chameleons that

may be initially misdiagnosed in atypical presenta-tions. In the end, in most cases of treatment failure, adiagnosis of CIDP will be retained, but it is importantto consider alternative diagnoses, particularly whendifferent treatment regimens may be required.

Acknowledgements We wish to thank Professor SebastianBrandner for kindly providing us with the images of the nervebiopsy. We also wish to thank Dr Zane Jaunmuktane for herhelpful comments on the different methods for staining ofamyloid on nerve biopsy.Contributors All authors were involved in the concept of thestudy, drafting of and approval of the final manuscript.Competing interests None.Provenance and peer review Commissioned; externally peerreviewed. This paper was reviewed by Haider Katifi,Southampton, UK.

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