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Introduction: Immune‑mediated peripheral neuropathy is the term applied to aspectrumof peripheral nerve disorderswhere immune dysregulation plays a role.Therefore,theyaretreatable.Weanalyzedthecasesseeninthepast3yearsbyusand evaluated the clinical, laboratory, and outcome parameters in these patients.Patients and Methods:Consecutivepatientsseenbytheauthorsanddiagnosedasimmune‑mediatedneuropathywereanalyzedforetiology,pathology,andoutcomeassessed.Results:A totalof sixtypatients,31acuteand29chronicneuropathies,were identified. Their subtypes treatment and outcome assessed. Males weresignificantly more in both acute and chronic cases. Miller Fisher 4, AMAN 1,paraplegic type 1, motor dominant type 19, Sensory‑motor 1, MADSAM 3,Bifacial 2. Nonsystemic vasculitiswas seen in 16 out of 29 chronic neuropathyandHIV,POEMS,anddiabetesmellitusoneeach.Discussion:Thereisaspectrumof immune‑mediated neuropathy which varies in clinical course, response totreatment, etc., Small percentage of uncommon cases are seen. In this group,mortality was nil and morbidity was minimal. Conclusion: Immune‑mediatedneuropathies are treatable and hence should be diagnosed early for good qualityoutcome.

Keywords: Acute inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating neuropathy, criteria, POEMS syndrome

Immune‑mediated Neuropathies Our Experience over 3 YearsSadanandavalli Retnaswami Chandra, Venkata Raviteja Karru1, M. A. Mukheem Mudabbir, Subashree Ramakrishnan1, Anitha Mahadevan2

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DOI: 10.4103/jnrp.jnrp_376_17

variants, motor neuropathy with multifocal conductionblock (MMN), vasculitic neuropathy, sarcoid,paraproteinemicneuropathy, andmiscellaneous.[1,2]Theyare called acute if duration of progression is <4weeks,subacute if up to 8 weeks, and chronic if >8 weeks.A 3‑6‑10 approach is suggested by Sapersten et al.,with three goals, six questions, and ten patterns.[3] Thegoals are to know the cause, site, and plan treatment.Questionsarewhatsysteminthenerveisaffectedthatismotor, sensory,autonomicormixed,distributionpatternanalysis of nature of sensory involvement, uppermotorneuronaffectedornot,temporalevolution,andheredity.Thepatterns are proximal anddistal symmetrical, distalsensory, asymmetrical distalwith sensory, asymmetrical

Introduction

Immune‑mediated disorders of peripheral nervoussystem form a group of disorders where immune

dysregulation plays an important role in disordersaffecting peripheral nerves. It is important to recognizethemas theyarepotentially treatable ifdiagnosedearly.Peripheralnervous system is thepartofnervous systemconstituted by cranial nerves 2–12: Roots, plexuses,and nerves. Each nerve contains nerve fascicle,myelin,Schwancells,fibrocytescollagen,andbloodvessels.Thedisorders that predominantly affect myelin constitutedemyelinating disorders, which affect nerve cell bodybecomeneuranopathy,whichaffectaxonsisaxonopathyand vasculitic neuropathy when vasa nervorum areaffectedandmixedaffectingallinvariouscombinations.They can be acute, chronic, relapsing‑remitting, etc.The common syndromes included in this group areGuillain–Barre syndrome (GBS) and variants, chronicinflammatory demyelinating neuropathy (CIDP) and

DepartmentsofNeurology,1Neurocentreand2Neuropathology,NationalInstituteofMentalHealthandNeurosciences,Bengaluru,Karnataka,India

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How to cite this article: Chandra SR, Karru VR, Mudabbir MA, Ramakrishnan S, Mahadevan A. Immune-mediated neuropathies our experience over 3 years. J Neurosci Rural Pract 2018;9:30-5.

Address for correspondence: Prof. Sadanandavalli Retnaswami Chandra,

Faculty Block, Neurocentre, National Institute of Mental Health and Neurosciences, Bengaluru - 560 029, Karnataka, India.

E-mail: drchandrasasi@yahoo.com

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Original Article

Published online: 2019-09-02

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Chandra, et al.: Immune‑mediated neuropathies our experience over 3 years

proximal and distal sensory, asymmetrical distal motor,symmetrical distal sensory with upper motor neuroninvolvement, symmetrical weakness, focal midlineproximal, asymmetrical with proprioceptive loss, andthosewithautonomicnervoussystemfeatures.

Guillain–Barre syndromeIt is themost common acute type of immune‑mediatedperipheral neuropathy, generally monophasic and rarelyrecurrent, with several subtypes. Incidence is 1–2/lakhpopulation. The different types are acute inflammatorydemyelinating polyneuropathy (AIDP), acute motoraxonal polyneuropathy (AMAN), Acute motorsensory axonal polyneuropathy, Miller Fisher variant,focal variants such as cervico brachio pharyngealsyndromes, acute pandysautonomia, sensory variant,etc., often precipitated by infections, vaccines, sera,surgery secondary to immune‑mediated break down ofblood‑nervebarrier,etc.,CD3+T‑cellsandmacrophagesare often seen. Activated complement and membraneattack complexes are also seen.Antibody againstmajorgangliosides, GM1, GD1a, GD1ab, GaLNAc‑, are seeninAMAN variant. GQ1Bb inMiller Fisher variant andcausedamageprobablybymolecularmimicry.

Clinical featuresPain,paresthesias,andweakness,autonomicdysfunctions,and cranial nerve palsy especially seventh nerve arecommon. Mortality is 5%–10% and morbidity is about20%–30%.[4] The patterns are based on fiber type asmotor, sensory, autonomic and mixed, topography ascervicofacial, paraparetic, Miller Fisher and unusualforms, course asmonophasicversus relapsing, andbasedon pathology as axonal versus demyelinating. Treatmentis supportive and disease‑modifying drugs such asintravenous immunoglobulin 0.4 g/kg/day for 5 days orplasmaexchange.Mycophenolatemofetil2000g/dayandmethylprednisolonefor6weeksalsotried.[5]Eculizumab,a monoclonal antibody, is tried recently in view of itsefficacyinpreventingcomplementactivation.[6]

CriteriaNINDS critertia: Features required for the diagnosis[7]

Progressive motor weakness of more than one limb,areflexia.

Features strongly supportive of the diagnosisa. ClinicalfeaturesShort progression, relative symmetry, mild sensorysymptoms or signs, and cranial nerve involvement.Recovery, autonomic dysfunction, and absence of feverattheonset.

b. Cerebrospinalfluidfeaturesc. Electrodiagnosticfeatures.

Features casting doubt on the diagnosisMarked persistent asymmetry of weakness, Persistentbladder,orboweldysfunction,Bladderorboweldysfunctionat onset. More than 50 cells/mm3 in cerebrospinalfluid (CSF), presence of polymorphonuclear cells in CSF,Sharpsensorylevel.

Features that rule out the diagnosisA current history of hexacarbon abuse, abnormalporphyrin metabolism, recent diphtheria, and leadneuropathy.

A purely sensory syndromeDiagnosisofbotulism,poliomyelitis,myastheniagravis,ortoxicneuropathy.

TreatmentPlasmaexchange,immunoglobulins,andsupportivecare.[8]

Chronic inflammatory demyelinating neuropathyA chronic distal and proximal sensory‑motorpolyneuropathy has a very variable course. Often itpresentsasfairlysymmetrical,sensorymotor,distalandproximalwith rarely cranial nerve palsy and progressesbeyond 8 weeks, unlike GBS. More than fifteendiagnostic criteria are there with less sensitivity butrelatively good specificity.[9] Austin in 1958 classifiedthem into motoneuropathy with multifocal conductionblock(MMN),multifocalacquireddemyelinatingsensoryand motor neuropathy (MADSAM) (Lewis‑Sumnerdisease), distal neuropathy with IgM, IgA, IgG,anti‑MAG paraproteinemia, sensory predominanttype, and polyneuropathy, organomegaly, endocrinedysfunction, monoclonal band, skin changes (POEMS)syndrome.[10] CIDP associated with vasculitis purelyneurological or with systemic vasculitis, it can be withHIV,hereditaryneuropathy,andalsodiabetesmellitus.

CSF protein is elevated and sural nerve biopsy showspatchy demyelination and mononuclear infiltrates.Steroids, IVIg, and plasma exchange are all used in acase‑basedway.Azathioprineandcyclophosphamideareusedformaintenancetherapy.

CriteriaForCIDP,therearemorethan15diagnosticcriteria.Theparameters included are clinical, electrophysiological,and others such as CSF and biopsy. CommonlyAmericanacademyofneurologycriteriaisused.[11]

Classical CIDP is sensory‑motor distal and proximalwith features of patchy demyelination, axonopathy, andinflammation. CSF shows elevated proteins especiallyIgG.

Distal‑acquired demyelinating symmetric showssymmetrical distal, elevated IgGk, and anti‑Gm1antibodynegative.

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• MADSAM, asymmetrical, proximal, multifocal,demyelinationcommon,andCSFoftennormal.

• MMNasymmetricalupper limb,distalnervepattern,anti‑GM1antibodyoccasionallypresent.

Multifocal motor neuropathy[12]

Distal muscle weakness, which is purely sensory, isseen. Upper limbs more affected than lower. Malesmore than females with wasting and fasciculations areseen.GM1,GD1a,andGD1barecommonlyassociated.As it is purely motor it resembles motor neurondisease. Axonal degeneration with electrophysiologicalconductionblock isseen.Steroidsandplasmaexchangeare not useful. IVIg gives partial response and mostlyrequires long‑term maintenance. Cyclophosphamide,mycophenolate, monoclonal, and anti‑CD20 givevariablereports.

Polyneuropathy associated with monoclonal gammapathy[13]

About 10% of neuropathy fall in this category.Monoclonal gammopathy of unknown significance,Waldenstrom gammopathy, POEMS, IgM andparaprotein‑associated neuropathy. Rarely, IgG‑ andIgA‑associatedsyndromesareseen.

POEMS syndrome is the term applied to a syndromeof polyneuropathy, organomegaly, endocrinopathy, Mprotein, and skin changes. Major criteria are VEGF(Vascular endothelial growth factor) elevated orvascular endothelial growth factor, polyneuropathy,monoclonal plasma‑proliferative disorder, scleroticbone lesion, and Castleman disease. Minor criteria aresclerotic bone lesions, edema, papilledema, endocrine,and skin changes such as hypertrichosis, hemangioma,raynauds, white nails, clubbing, thrombocytosis, andpolycythemia. Castleman disease is the term applied tothe presence of angiofollicular lymph node hyperplasia.Feverandweight loss,pachymeningitis,andstrokescanoccur. Treatment involves multidisciplinary approachwithtreatmentofallaccompaniments,treatmentofbonelesions,plasmapheresis,autologousstemcellstransplant,thalidomide, lenalidomide, bortezomib, bevacizumab,an anti‑VEGF antibody, etc., IgM neuropathy isless responsive to plasma exchange than IgA‑ orIgG‑associated ones. Rituximab, interferon alpha, andthalidomidearealsotried.

Role of electrophysiologyElectrophysiology is useful in confirming acquiredinflammatory neuropathy from inherited ones,quantify the affected nerves, screen for variants andElectromyographypattern,andpredictingprognosis.[14]

BiopsyBiopsy of the nerves is very useful in confirming thediagnosis, quantifying the pathology, and predictingoutcome. Pathological changes are distinct in AIDP,CIDP, and vasculitic neuropathy. Vasculitic neuropathyshows inflammatory infiltrate within the vessel walland one or more signs of vascular destruction such asfibrinoid necrosis, vascular/perivascular hemorrhage,or endothelial cell disruption; Loss/fragmentation ofinternal elastic lamina; loss/fragmentation/separation ofsmooth muscle cells in media; and acute thrombosis;leukocytoclasia. Chronic lesion shows signs ofhealing or repair: nerve biopsy showing mononuclearinflammatory cells in the vessel wall and one or moreof the following: intimal hyperplasia; fibrosis of themedia; adventitial/periadventitial fibrosis; and chronicthrombosiswithrecanalization.

Miscellaneous immune‑mediated neuropathiesVasculitis of varying types, sarcoid, and Behcets arealso secondary immune‑related syndromes. Each of thesubtypeshas furthercriteriawhicharemorespecific forthesubtype.

Patients and MethodsFiftyconsecutivepatientsseenasinpatientbytheauthorsin the last 3 years were evaluated in detail clinically.All of them underwent CSF study, electrocardiography,electrolytes, blood sugar, electrophysiological studiesmotor conduction velocity, sensory conduction velocity,F‑wave latencyofbothmedian,ulnarcommonperonealnerve, and sural nerves. HBsAG, HIV in all cases.Vasculitic workup and other workup were done basedon clinical requirements. Patients were classified asAIDP based onNINCDS criteria[15] andCIDP based onAmerican academy of neurology criteria.[1,16] Figure 1shows classical histopathological features in AIDP

Figure 1: Subperineurial edema, endoneurial and perivascularinflammation,andactivedemylelination

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in our case series. In AIDP, unless there are atypicalfeatures, there is no indication for nervebiopsy.Biopsyshows subperineurial edema, with inflammation bothendoneurial and perivascularwith active demyelination.Figure 2 shows classical features in CIDP in our caseseries. InCIDP, there is definitive indication for biopsyto establish the diagnosis. Patients’ nerve biopsy showsendoneural inflammation, onion bulb formation, andactive remyelination. Figure 3 shows skin changes in apatientwithvasculiticneuropathy.

ResultsWe had a total of sixty patients. Thirty‑one were acuteand 29 were chronic [Figure 4]. There were 25 maleand 6 female acute cases, age range varied from 2 to70 years. Miller fisher variant was seen in four cases.AMAN variant was noted in 1 case, paraplegic type1 case, motor dominant type 19 cases, sensorimotor 1case,MADSAM type3 cases, andbifacial type2 cases[Figures 5 and 6]. Figure 7 shows AIDP subtypes;Figure8showsCIDPsubtypes.CIDPcaseswere29andagedistributionwas27–74years,males19and females

10 and vasculitic cause in 16 and HIV associated in1 case; POEMS syndrome in 1 case presented withhypertrichosis, telangiectasia, edema, trophic changes,and osteosclerotic bone lesion. He also hadM band inserum electrophoresis [Figure 9]. Juvenile diabetes andCIDPwasnoted in1case,chronic relapsing in3cases,andclassicalin7cases.

TreatmentAll patients with AIDP received supportive treatmentand plasmapheresis. Two of the patients neededintravenous immunoglobulin in view of poor response toplasmapheresis.Twopatientsneededventilatorcare.Therewas nomortality in this group. Patients with CIDPweretreatedwith steroids 1–3mg/kg and azathioprine2.5mg/kg or methotrexate or cyclophosphamide 1–2 mg/kg orcyclosporine 3–7 mg/kg to start with and maintain with1‑3mg/kg added for steroid‑sparing effect. If there is noresponsetosteroidsin6weeks,0.4mg/kg/dayIVIggivenfor5daysmonthly,lowdosesteroidpulsescanbeadded.

Figure 2: Histopathology of chronic inflammatory demyelinatingpolyneuropathyshowingendoneuralinflammation,onionbulbformationandremylelination

Figure 4:Thedistributionofacuteandchronicneuropathiesinourseries

Figure 3:Erythematouspatchinapatientwithvasculiticneuropathy

Figure 5:Genderdistribution inchronic inflammatorydemyelinatingpolyneuropathy

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Rituximab,aCD20monoclonalantibody,canalsobetried.Weused azathioprine in 23 cases and 6 patients receivedcyclophosphamide‑basedonpoortreatmentresponse.

OutcomeOur follow‑up for both groups is 6 months to 3 years.Therewasnomortality in eithergroup.Twopatients inAIDP group needed >1 year to recover. Among CIDPpatientsoutof29at thetimeof thelastfollow‑up,mildsensory symptoms were reported in nine cases. Motordeficitsrecoveredinallcases.

DiscussionImmune mediated neuropathies are a large spectrumof neuropathies. They may be acuteVs Chronic,mildlydisablingtoseriousones,canbeassociatedwithsystemicillness or occur involving peripheral nerves only.recognition of the condition in its totality is importantfor deciding optimum treatment,planning prognosis andpredictinglongtermoutcome.

ConclusionInthis3‑yearfollowupthestudyofpatientsseenbytheauthors,therewasnomortality.Morbiditywasverylessin both groups. Therefore, it is mandatory to recognizethese patients early and start treatment early so thatthereisverygoodqualityoflife.

Declaration of patient consentThe authors certify that they have obtained allappropriate patient consent forms. In the form thepatient(s) has/have given his/her/their consent for his/her/their images and other clinical information to bereportedinthejournal.Thepatientsunderstandthattheirnamesand initialswillnotbepublishedanddueeffortswill be made to conceal their identity, but anonymitycannotbeguaranteed.

Financial support and sponsorshipNil.

Conflicts of interestTherearenoconflictsofinterest.

Figure 6:Gender distribution in acute inflammatory demyelinatingpolyneuropathypatients

Figure 8:Chronicinflammatorydemyelinatingpolyneuropathysubtypedistribution

Figure 7:Acute inflammatorydemyelinatingpolyneuropathysubtypedistribution

Figure 9:Hypertrichosis,telangiectasia,edemalegswithpsoriasiformskinchanges(Thisistypicalofpoemssyndrome)

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References1. Köller H, Kieseier BC, Jander S, Hartung HP. Chronic

inflammatory demyelinating polyneuropathy. N Engl J Med2005;352:1343‑56.

2. Lehmann HC, Meyer Zu Horste G, Kieseier BC, Hartung HP.Pathogenesis and treatment of immune‑mediated neuropathies.TherAdvNeurolDisord2009;2:261‑81.

3. Saperstein DS, Katz JS, Amato AA, Barohn RJ. Clinicalspectrum of chronic acquired demyelinating polyneuropathies.MuscleNerve2001;24:311‑24.

4. Hughes RA, Cornblath DR. Guillain‑barré syndrome. Lancet2005;366:1653‑66.

5. Garssen MP, van Koningsveld R, van Doorn PA, Merkies IS,Scheltens‑de Boer M, van Leusden JA, et al. Treatment ofguillain‑barré syndrome with mycophenolate mofetil: A pilotstudy.JNeurolNeurosurgPsychiatry2007;78:1012‑3.

6. Yamaguchi N, Misawa S, Sato Y, Nagashima K, Katayama K,Sekiguchi Y, et al. A prospective, multicenter, randomizedphase II study to evaluate the efficacy and safetyof eculizumabin patients with Guillain‑Barré syndrome (GBS): Protocol ofJapaneseeculizumabtrialforGBS(JET‑GBS).JMIRResProtoc2016;5:e210.

7. AsburyAK,CornblathDR.AssessmentofcurrentdiagnosticcriteriaforGuillain‑Barrésyndrome.AnnNeurol1990;27 Suppl:S21‑4.

8. van Doorn PA, Ruts L, Jacobs BC. Clinical features,pathogenesis, and treatment ofGuillain‑Barré syndrome. LancetNeurol2008;7:939‑50.

9. Tackenberg B, Lünemann JD, Steinbrecher A,Rothenfusser‑Korber E, Sailer M, Brück W, et al.Classifications and treatment responses in chronicimmune‑mediated demyelinating polyneuropathy. Neurology2007;68:1622‑9.

10. DispenzieriA,KyleRA,LacyMQ,RajkumarSV,TherneauTM,LarsonDR,et al. POEMS syndrome:Definitions and long‑termoutcome.Blood2003;101:2496‑506.

11. Cornblath DR, Asbury AK, Albers JW, Feasby TE. Researchcriteria for diagnosis of chronic inflammatory demyelinatingpolyneuropathy(CIDP).Neurology1991;41;617‑8.

12. OlneyRK,LewisRA,PutnamTD,CampelloneJVJr.,AmericanAssociation of Electrodiagnostic Medicine. Consensus criteriafor the diagnosis ofmultifocalmotor neuropathy.MuscleNerve2003;27:117‑21.

13. Said G, Krarup C. Neuropathy and monoclonal gammopathy.PeripherNerveDisord2013;115:443.

14. RajaballyYA,DurandMC,MitchellJ,OrlikowskiD,NicolasG.Electrophysiological diagnosis of guillain‑barré syndromesubtype: Could a single study suffice? J Neurol NeurosurgPsychiatry2015;86:115‑9.

15. Van derMeché FG,VanDoorn PA,Meulstee J, Jennekens FG,GBS‑consensus group of the Dutch Neuromuscular ResearchSupport Centre. Diagnostic and classification criteria for theGuillain‑Barrésyndrome.EurNeurol2001;45:133‑9.

16. SanderHW,LatovN.ResearchcriteriafordefiningpatientswithCIDP.Neurology2003;60:S8‑15.