Hansen’s Neuritis Revisited – A Clinicopathological Study

42 © 2018 Journal of Neurosciences in Rural Practice | Published by Wolters Kluwer - Medknow

Introduction: Leprosy affecting the nerve solely or with concomitant skinlesions is not an uncommon condition in clinical practice. It is responsiblefor extensive morbidity and often poses a diagnostic challenge. This studyaims to highlight the clinicopathological features of Hansen’s neuritis (HN).Materials and Methods: In this retrospective study, cases of histologicallydiagnosed HN, from January 2010 to July 2017, were reviewed in the light ofclinical features, treatmenthistory,andoutcome.Results:Therewere18casesofHNwhichaccountedfor3.97%oftotalnervebiopsysamples(n=453)and0.02%oftotalhistopathologysamples(n=81,013).Themale:femaleratiowas5:1inthecasesofHN.Agerangewas20–79yearswithameanageof42.4years(standarddeviation: ±14.03). Among the HN cases, there were 13 cases of pure neuriticleprosy (61.1%). Mononeuritis multiplex was the most common finding in thenerve conduction study. Six (33.3%) cases exhibited histological features ofborderline tuberculoid leprosy, followed by five (27.8%) cases of mid‑borderlinefeatures, three (16.7%) cases each of borderline lepromatous and burnt‑out HN,and one (5.6%) case of polar tuberculoid leprosy. Lepra bacilli were detectedon Fite‑Faraco stain in 44.4% cases.Conclusion: Diagnosis of HN depends onastute search for skin lesions, nerve thickening or tenderness, sensory or motorsymptoms,histopathologicalexamination,anddemonstrationofleprabacilli.

Keywords: Hansen’s neuritis, lepra bacilli, mononeuritis multiplex, pure neuritic leprosy

Hansen’s Neuritis Revisited – A Clinicopathological StudyNavya Jaiswal, Shrijeet Chakraborti, Kashinath Nayak1, Shivananda Pai2, B. P. Shelley3, Saraswathy Sreeram, K. C. Rakshith2, B. V. Suresh4, Z. K. Misri2, Hansraj Alva5, N. Shankar6

Address for correspondence: Dr. Shrijeet Chakraborti, Department of Pathology, Kasturba Medical College,

Lighthouse Hill Road, Mangalore - 575 001, Karnataka, India. E-mail: [email protected]

clinicopathological profile of Hansen’s neuritis (HN)diagnosedinourinstitute.

Materials and MethodsThe study was conducted in the Department ofPathology, Kasturba Medical College, Mangalore,Karnataka, India. Institutional Ethical Committee’spermissionwasobtainedbefore commencing this study.WeretrievedclinicopathologicaldataandslidesofallthehistologicallydiagnosedcasesofHNfromourarchives,during the period from January 2010 to July 2017.Thesampleswerereceivedinthedepartmentfromtheparentinstitute, other medical colleges, and hospitals in and

Original Article

Introduction

Hansen’s disease is a chronic granulomatousdisorder affecting the skin and nerves and

is caused by Mycobacterium leprae. The earliestclassification of this disease based on immunitystatus and response was given by Ridley and Joplingin 1966.[1] Wade in 1952 first proposed the disease“neuralleprosy,”inwhichonlyperipheralnerveswereinvolved. The technical committee of InternationalLeprosy Congress in 1953, held in Madrid, accepted“neuritic leprosy” as one subtype among the majorgroups of leprosy.[2] Neuritic leprosy is one ofthe important causes of inflammatory peripheralneuropathy worldwide, especially in the tropicalcountries. In the absence of skin involvement,pure neuritic leprosy (PNL) may clinically mimicvasculitic neuropathy. In this study, we describe the

DepartmentsofPathology,1Dermatologyand2Neurology,KasturbaMedicalCollege,ManipalUniversity,3DepartmentofNeurology,YenepoyaMedicalCollege,4DepartmentofNeurology,AJInstituteofMedicalSciences,5VinayaHospitalandResearchCentre,6MallikattaNeuroCenter,Mangalore,Karnataka,India

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Website: www.ruralneuropractice.com

DOI: 10.4103/jnrp.jnrp_438_17

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How to cite this article: Jaiswal N, Chakraborti S, Nayak K, Pai S, Shelley BP, Sreeram S, et al. Hansen’s neuritis revisited – A clinicopathological study. J Neurosci Rural Pract 2018;9:42-55.

Published online: 2019-09-02

Jaiswal, et al.: Hansen’s neuritis

43Journal of Neurosciences in Rural Practice ¦ Volume 9 ¦ Issue 1 ¦ January-March 2018

around Mangalore. All the cases were microscopicallyreviewed taking note of clinical details, includingfindings of nerve conduction study (NCS), whichwas collected from the medical records departmentand biopsy requisition forms. The corresponding skinbiopsieswerealsoreviewed.

Formalin‑fixed, paraffin‑embedded transverse andlongitudinal sections of nerve segments were stainedwith hematoxylin and eosin, Masson trichrome, andFite‑Faraco (Fite) stains. Simultaneously, the transversesections were also stained with Kulchitsky Pal (KPal)stain (for myelin), after secondarily fixing of the nervebiopsies in Fleming’s solution. In the nerve and skinbiopsies, the bacillary index (BI) was computed basedon Ridley’s scoring scheme.[3] Microscopic pathologyin the nerve was categorized into indeterminate[4]and burnt‑out/healed Hansen’s categories as well asin addition to the five classes of Ridley and Joplingscheme.

All the demographic data, clinical findings, and resultsofmicroscopicexaminationweretabulatedandanalyzedbymean, standarddeviation (SD),andpercentages.Theresults were laid out in the form of graph and tables.Statisticalmethodscouldnotapplyinthisstudybecauseof small sample size. Sincere attempts were made tocollectthefollow‑updatainallthecases.

ResultsIn the above‑mentioned period, a total number of81,013 samples were received in the pathologydepartment for histopathological examination, ofwhich there were 1982 skin biopsies (2.45% of totalhistopathology samples). Hansen’s disease of the skinwas diagnosed in 131 (6.6% of total skin biopsiesand 0.16% of total histopathology cases). During thesame time span, 453 nerve biopsies (0.56% of totalhistopathology samples) were received for etiologicaldiagnosis of peripheral neuropathy. HN was diagnosedin 18 (3.97% of total nerve biopsy samples and 0.02%oftotalhistopathologysamples).

Sural nerve was biopsied in 16 cases, followed byright greater auricular nerve and cutaneous branch ofleft radial nerve in one case each. The male: femaleratiowas5:1 in thecasesofHNwith15 (83.3%)casesdiagnosed in men. Age range was 20–79 years witha mean age of 42.4 years (SD ± 14.03). Maximumnumber of male patients presented in the age groupof 41–50 years (5 cases, 27.8%), followed by threecases (16.7%) each in the age groups of 21–30 yearsand31–40years,twocases(11.1%)in51–60years,andone case (5.6%) each in the age groups of 11–20 yearsand 71–80 years. The three female cases belonged

to the age groups of 31–40 years, 41–50 years, and51–60years(5.6%each)[Table1].

Skin lesions consistent with leprosy were presentin 5 out of 18 cases (27.78%) of HN, and in other2 cases, there was no information available on skinaffection by lepra bacilli. Hence, there were 13 casesof PNL (61.1%) among the HN cases, and theseaccounted for 2.8%cases of all nerve biopsy (n = 453)samples. Case 1 had a single hypopigmented andhypoesthetic skin patch in left buttock, and Case 4had multiple hypopigmented macules in the trunk anderythematouspatchesinboththelegs.Histopathologicalexamination of the skin biopsies in Cases 1 and 4revealed borderline tuberculoid (BT) (BI: zero) andborderline lepromatous (BL) (BI: 5) morphology,respectively. The corresponding nerve biopsies in boththese cases showed BB morphology. Cases 11, 16,and 18 also had skin lesions which were not biopsied.Age range in PNL was 20–56 years with a mean ageof 40.6 years (SD± 10.78).Maximumnumber ofmalepatients was in the age group of 41–50 years (4 cases;30.7%), followedby twocases (15.4%) each in the agegroups of 21–30 years, 31–40 years, and 51–60 years,and one case (7.7%) in the age group of 11–20 years.One female case (7.7%) each presented in the agegroupsof31–40yearsand41–50years.

The patients had myriad signs and symptoms. Mostof the cases (44.4%; 8 out of 18 cases) presentedwith features of sensory loss and motor weaknesswith variation in spatial and temporal distribution. In4cases (22.2%),oneormultipleperipheralnerveswerethickened. Three cases (16.7%) had nonhealing trophiculcers in the foot.Two(11.1%)patientswerealcoholicsandonecase(5.6%)hadretroviraldisease.Two(11.1%)cases each had clinical history of peripheral neuropathyandmononeuritismultiplex.Case1presentedwithlowermotor neuron palsy of bilateral facial nerves of 5 daysduration[Figure1], involvingonly theupperfibers,andCase 18 had claw hand for 2 years. Rheumatoid factorpositivity was noted in Case 6, and there was familyhistory of leprosy in skin in Case 14. There were noclinicaldetailsavailableinCase9[Table1].

The findings of NCS available in 13 (72.2%) casesrevealed a common pattern of mononeuritis multiplexwith severe degree of sensory more than motoraxonopathy.InCase14,NCSrecordedaxonalneuropathyinvolvingthebilateralmedian,rightsuperficialperoneal,saphenous, sural, and posterior tibial nerves. Sevencases had a clinical diagnosis of HN, of which threecaseshaddifferential diagnosesofCharcot‑Marie‑Toothdisease, vasculitic neuropathy and diabetic neuropathy.In one (5.6%) case each, the provisional diagnosis


44 Journal of Neurosciences in Rural Practice ¦ Volume 9 ¦ Issue 1 ¦ January-March 2018

Table 1: Clinicopathological summary of Hansen’s neuritis casesCase number

Age (years)/sex

Clinical features

Skin involvement

NCS Provisional clinical diagnosis

Site of biopsy

Histological findings in nerve biopsy

Skin biopsy findings

Treatment Follow‑up

1 25/male

Inabilitytocompletelycloseeyessince5days.Examinationrevealedlowermotorneuronparesisofbilateralfacialnervesinvolvingonlytheupperfibres.Bilateralgreaterauricularnerve,supratrochlearnerve,ulnarandposteriortibialnerveswerethickened

Singlehypopigmentedandhypoaestheticskinpatchinleftbuttock

Mononeuritismultiplex,sensorymorethanmotoraxonopathy

Hansen’sneuritis

Rightgreaterauricularnerve

BB;BI:2Completelossofallmyelinatedfibres.Foamyhistiocytes,interspersedwithlymphocytes,plasmacellsinendoneuriumalongwithfewpoorlyformedepithelioidgranulomas.Perineuriumandepineuriumshowdenselymphohistiocyticinfiltratesandaroundbloodvessels

BT;BI:0PandermalepithelioidgranulomaswithoutLanghansgiantcells

MDTforMBleprosy

Completerecovery

2 20/male

Slowlyprogressivenumbnessoverleftmedialmalleolus,lateralaspectofleftfootandantero‑medialaspectofleftlegof2yearsdurationwithslippingoffootwear.Examinationrevealeddiminishedsensationofpainandtemperature,absentleftanklereflex.Nonervethickening

Absent Mononeuritismultiplex,sensorymorethanmotoraxonopathy

N/A Leftsuralnerve

BB;BI:0Severedegreelossofallmyelinatedfibres.Endoneuriumeffacedbypoorlyformedepithelioidgranulomas,fewfoamymacrophagesandinterspersedplasmacells.Theperineuriumshowlymphocyticinfiltrate.Theepineuriumshowperivascularlymphocyticinfiltrate

MDTforMBleprosy

Completerecovery

3 49/female

Consistentwithmononeuropathymultiplex.Nonervethickening

Absent Mononeuritismultiplex,sensorymorethanmotoraxonopathy

DiabeticneuropathyorHansen’sneuritis

Rightsuralnerve

BT;BI:0Severedegreelossofallmyelinatedfibres.Epithelioidgranulomas

MDTforMBleprosy

Completerecovery

Contd...



Table 1: Contd...Case number

Age (years)/sex

Clinical features

Skin involvement


Site of biopsy




involvingtheendo‑,peri‑,andepineurium.Denseperivascularlymphoplasmacyticinfiltrateintheepineurium

4 44/male

Reducedsensationleftlittlefingerof5yearsduration.Examinationrevealedbilateralasymmetriclossofpainandtemperaturesensationinlegs.Bilateralulnarandsuralnerveswerethickened

Multiplehypopigmentedmaculesinthetrunkanderythematouspatchesinboththelegs

Mononeuritismultiplex,sensorymorethanmotoraxonopathy

Hansen’sneuritis

Rightsuralnerve

BB;BI:5Completelossofallmyelinatedfibres.Endo‑,peri‑andepineurialill‑definedaggregatescomposedofhistiocytesandlymphocytes.Moderateperivascularlymphoplasmacyticinfiltrateinendo‑andepineurium

BL;BI:5Lympho‑andfoamyhistiocyticinfiltratearoundtheupperdermalbloodvesselsanddermalnerves

MDTforMBleprosy

Completerecovery

5 30/male

Trophiculcerinleftfoot.Decreasedsensationinupperlimbs.Nonervethickening

Absent Axonalneuropathy

N/A Leftsuralnerve

BL;BI:5(globipresent)Completelossofallmyelinatedfibres.Moderatelymphohistiocyticinfiltrateinvolvingtheendoneuriumandperineurium.Perineuriumisthickened.Denseperivascularlymphocyticinfiltrateintheepineurium

MDTforMBleprosy

Completerecovery

6 45/male

Peripheralneuropathy.Rheumatoidfactorpositive

Absent N/A Rheumatoidvasculitis

Rightsuralnerve

BL;BI:4Completelossofallmyelinatedfibers.Endoneuriumisinfiltratedbynumerouslymphocytes,foamyhistiocytes,andfewepithelioidhistiocytes.

MDTforMBleprosy

N/A

Contd...




Age (years)/sex

Clinical features

Skin involvement


Site of biopsy




Perineuriumisfocallythickened.Peri‑andepineuriumhasdenselymphocyticinfiltrateandscatteredhistiocytes

7 50/male

Rightcommonperonealnerveandleftulnarnervepalsywiththickening

Absent Mononeuritismultiplex

N/A Leftsuralnerve

BB;BI:2Completelossofallmyelinatedfibers.Endoneuriumshowedperivascular,moderate‑to‑denselymphohistiocyticinfiltrate,andsparseneutrophilicinfiltratealongwithepithelioidgranulomasandfoamyhistiocytes.Endoneurialcapillariesarehyalinizedwithprominentendothelialcells.Perineuriumisthickenedwithmoderatelymphohistiocyticinfiltrate.Epineuriumhadmoderateperivascularlymphohistiocyticinfiltrateandneovascularization

MDTforMBleprosy

Completerecovery

8 38/female

Peripheralneuropathy,nonhealingulcerinrightfoot

Absent N/A N/A Leftsuralnerve

Burnt‑outHansen’sneuritis;BI:0Completelossofallmyelinatedfibres.Densecollagenizationintheendoneurium.Endo‑,peri‑,andepineuriumhadmoderateperivascular

N/A N/A

Contd...




Age (years)/sex

Clinical features

Skin involvement


Site of biopsy




lymphoplasmacyticinfiltrate.Focalepithelioidhistiocytesaggregateswereseen.Nutrientbloodvesselshowedsubendothelialfibrosisandmedialhypertrophy

9 42/male

N/A N/A N/A N/A Rightsuralnerve

BT;BI:0Completelossofallmyelinatedfibres.Moderateendo‑,peri,‑andepineuriallymphohistiocyticinflammation.Denseperivascularlymphocyticinfiltratewithfocalneovascularizationintheepineurium.Nutrientbloodvesselshowedsubendothelialfibrosis,medialhypertrophy,andcalcification

N/A N/A

10 51/male

Rightulnarnervethickening.Distalmuscleweakness

Bilaterallowerlimbtrophiculcer

Mononeuritismultiplex

NA Leftsuralnerve

BT;BI:0Completelossofallmyelinatedfibres.Endoneurialepithelioidgranulomasrimmedbylymphocyticandinterspersedplasmacells.Prominentendoneurialcapillaries

Peri‑andepineuriumshowedmoderatetodenselymphoplasmacyticinfiltrateandneovascularization

MDTforMBleprosy

Completerecovery

Contd...




Age (years)/sex

Clinical features

Skin involvement


Site of biopsy




11 32/male

Tingling,numbnessanddecreasedsensationinbothlowerlimbsandhandssince1year

Reddishraisedlesionovertoes,fingers,andextremitiessince2months


Hansen’sneuritis

Leftradialcutaneousnerve

BL;BI:6(globipresent)Asymmetric,moderatedegreelossofmyelinatednervefibres.Partialeffacementoffasciculararchitecturebymoderatelymphohistiocyticinfiltrateandfoamcellsintheendoneurium.Peri‑andepineuriumshowedmoderatetodenselymphohistiocyticandill‑definedepithelioidcellaggregates

Notdone MDTforMBleprosy

Completerecovery

12 38/male

Alcoholic.Since3yearsprogressiveasymmetricaltosymmetricalupperandlowerlimbweakness,andcompleteclawhand

Absent N/A Hansen’sneuritisorCharcotMarieToothdisease

Leftsuralnerve

BT;BI:0Severedegreelossofsmallandlargemyelinatednervefibres,endo‑,andperineurial,well‑defined,epithelioidgranulomaswithlymphoplasmacyticinfiltrate.Epineuriumshowsperivascularlymphoplasmacyticinfiltrate

MDTforMBleprosy

Mildmotorweaknesspersisting.Clawhandpersisting

13 56/male


NA NA Hansen’sneuritis

Rightsuralnerve

BT;BI:1Completelossofmyelinatednervefibres.Endoneurialepithelioidgranulomaswithlymphoplasmacyticrimming,andscatteredfoamyhistiocytes.

MDTforMBleprosy

N/A

Contd...




Age (years)/sex

Clinical features

Skin involvement


Site of biopsy




Peri‑andepineuriumexhibitsdenseshowslymphocyticinfiltrateadmixedwithplasmacellsandfewhistiocytes

14 25/male

2.5monthshistoryofasymmetricalmultiplesensorypainfulsmallfibermononeuropathies.RightarmwastingHistoryofskinHansen’sinthebrother(detailsNA)

Absent Bilateralmedian,rightsuperficialperoneal,saphenous,suralandposteriortibialnerves:Axonalneuropathy

Hansen’sneuritisorVasculiticneuropathy

Rightsuralnerve

BT;BI:0Completelossofmyelinatednervefibresandendoneurialfibrosis.Epithelioidgranulomasadmixedwithfewfoamyhistiocytesandrimmedbylymphocytesarenotedinendo‑,peri‑andepineurialcompartment.Epineurialcompartmentalsoshowsmoderateperivascularlymphocyticinfiltrate

MDTforMBleprosy

Resolutionofsensorysymptoms

15 36/male

Alcoholic.Rightfootdropsince4months.Historyoftraumainrightleg8monthsback.Rightdorsiflexionatankleweak.Externalhallucislongusmuscleweakonrightside.Sensorylossindorsumofrightfoot

Absent Axonalneuropathyinrightperonealnerve

Vasculiticneuropathy

Rightsuralnerve

TT;BI:0Severedegreelossofmyelinatedfiber.NecrotizingepithelioidgranulomaswithLanghansgiantcellsinvolvingtheendo‑,peri‑,andepineurium.Granulomasarerimmedbydenselymphocyticinfiltrateandplasmacells.Epineurialperivascular,denselymphohistiocyticinfiltrate

MDTforMBleprosy

Resolutionofsensorysymptoms.Significantimprovementinfootdrop

Contd...




Age (years)/sex

Clinical features

Skin involvement


Site of biopsy




16 55/female

Nonhealingulcerinleftfootsince10years,andhadreceivedtreatmentforleprosy.Knowncaseofretroviraldisease

Previousskinlesion(detailsN/A)


N/A Rightsuralnerve

Burnt‑outHansen’sneuritis;BI:0Completelossofsmallandlargemyelinatednervefibres,markedendoneurialsclerosis,andmildlymphocyticinfiltrate.Peri‑andepineurialmild‑to‑moderatelymphocyticinfiltrate.Epineurialneovascularization,subendothelialfibrosisandmildtomoderateperivascularlymphocyticinfiltrate

Notdone Notreatment

N/A

17 48/male

Paraesthesiaofbilateralfootandlefthandfor2‑3years,lossofsensationinrightfootfor2‑3months,bilaterallyweakankledorsiflexion,gradedsensorylossbilaterallyinbothupperandlowerlimbs

Absent Sensorymorethanmotoraxonopathy

Nutritionalneuropathy

Leftsuralnerve

BB;BI:6(globipresent)Asymmetric,moderatedegreelossofmyelinatednervefibres.Endo‑andperineurialpoorlyformedepithelioidgranulomas,withlymphocytesandfoamcells.Epineurialmoderateperivascularlymphocyticinfiltrate

MDTforMBleprosy

On‑goingtreatment

18 79/male

Knowncaseofmotorneurondisease.Historyofbilateralclawhandof2yearsduration

Hypopigmentedskinlesioninleftlowerlimb.Slitskinsmear:Negativeforleprabacilli

Severemotorandsensoryaxonalpolyneuropathy

HealedHansen’sneuritis

Leftsuralnerve

Burnt‑outHansen’sneuritis;BI:0Completelossofsmallandlargemyelinatednervefibres,markedendoneurialsclerosisandmildtomoderatelymphocyticinfiltrate.Perineuriumisthickenedand

Notdone Notreatment

Contd...




Age (years)/sex

Clinical features

Skin involvement


Site of biopsy




exhibitsmoderatelymphocyticinfiltrate.Medialhypertrophyinnutrientvesselwithmoderate,perivascularlymphohistiocyticinfiltrate

BB:Mid‑borderline,BI:Bacillaryindex,BL:Borderlinelepromatous,BT:Borderlinetuberculoid,N/A:Notavailable,MB:Multibacillary,MDT:Multidrugtherapy,NCS:Nerveconductionstudy,TT:Tuberculoid

was burnt‑out HN, vasculitic neuropathy, rheumatoidvasculitis, and nutritional neuropathy. Provisionalclinical diagnosis was not available in seven (38.9%)cases[Table1].

In the nerve biopsies examined, six (33.3%) casesexhibitedhistological featuresofBT leprosy [Figure2],followed by five (27.8%) cases of mid‑borderline (BB)features [Figure 1], three (16.7%) cases each of BL[Figure3]andburnt‑outHN[Figure4],andone(5.6%)caseofpolar tuberculoid (TT) leprosy[Figure5].Therewasnocaseofpolar lepromatous (LL)or indeterminatemorphology among the cases studied. Among theHN cases which had concomitant skin lesions, therewere two cases of BB (Case 1 and 4) and healed HNeach (Case 16 and 18), and one case (Case 11) BL.Therewere six cases havingBT histology, followed bythree cases ofBB, two cases each ofBL, and one caseeachofburnt‑outHNandTTmorphologyamongthe13PNLcases.

Complete loss of myelinated fiber loss was seen in12 (66.7%) cases and among them four cases showedBTmorphology,followedbythreecaseseachofBBandburnt‑outmorphology,andtwocasesofBLmorphology.Severedegreeofmyelin losswasnoted infour(22.2%)cases, and among them two cases had BT, and onecase each had BB and TT morphology. Two (11.1%)cases (BLandBBmorphology)hadmoderatedegreeofmyelinated fiber loss. Among six cases of BT leprosyin the nerves, three (50%) cases exhibited well‑definedendo‑, peri‑, and endoneurial epithelioid granulomas,whereas endo‑ and perineurial epithelioid granulomaswere seen in two (33.33%) cases and only endoneurialgranulomas in one (16.67%) case. Among five casesof BB leprosy in the nerves, three (60%) casesexhibited poorly defined granulomas involving only theendoneurialcompartment,one(20%)caseeachinvolvingall three and both endo‑ and perineurial compartments.The only case of TT showed necrotizing epithelioid

granulomashavingLanghan’sgiantcellsandrimmedbydense lymphoplasmacytic infiltrate, involving theendo‑,peri‑, and epineurium. Hence, epithelioid granulomaswere detectable in 66.67% (12) cases.All three (100%)cases of BL did not show granulomas; rather, thefascicles were effaced by sheets of lymphohistiocyticinfiltrateandinterspersedfoamcells.

Allthree(100%)casesofburnt‑outHNwerecharacterizedby dense endoneurial collagenization or sclerosis,mild‑to‑moderate lymphohistiocytic inflammationin all the three compartments which was localizedpredominantlyaroundbloodvesselsandthickenednutrientvessels. Foam cells were seen in eight (44.4%) cases,which includedallcasesofBLandBB,and twocasesofBT.Plasmacellswerepresent inall casesofBTandTT.Perineurial thickening was present in four (22.2%) casesof HN, which included two cases of BL, and one caseeach of BB and burnt‑out HN. Out of 18 HN biopsies,epineurial perivascular inflammation, neovascularization,and vascular thickening were present in 17 (94.44%),4 (22.22%),and3 (16.67%)cases, respectively [Table1].There were not any microscopic features to differentiatebetweenPNLandHNwithskinlesions.

BI in HN cases ranged from 0 to 6 in five (83.33%)out of six cases of BT leprosy and three (100%) casesof burnt‑out HN. One case each of TT (100%) andBL (33.3%)hadaBIof zero. leprabacilliweredetectedonFite‑Faracostainin8(44.4%)outof18cases.BIwas1and4inonecaseeachofBT(16.7%)andBL(33.3%),respectively.Towardthelepromatousendofthespectrum,density of lepra bacilli in the tissue increased with aBI of 2 in 2 cases ofBB, toBI‑5 in 1 case each ofBBand BL and BI‑6 in 1 case each of BB and BL. Globiwere encountered in 3 (16.67%) out of 18 cases, that iscases‑5(BL;BI‑5),‑11(BL;BI‑6),and‑17(BB;BI‑6).

Out of 18 cases, 14 cases were classified asmultibacillary (MB) and treated with multidrug



therapy (MDT). In twocases, treatmenthistorywasnotavailableandtwocasesofburnt‑outHNdidnotreceiveany treatment. Complete recovery was seen in eightcases.Therewasresolutionofsensorysymptomsintwocases, persistence of motor weakness and foot drop in

one case each. One case is still undergoing MB‑MDTand three cases were lost to follow‑up. Lepra reactionswerenotreportedinanyofthecases.

DiscussionIn 1903, Albert Neisser described a “neural type ofleprosy/lepranervorum”for thefirst timeandadded thesametothealreadyaccepted“nodular”and“anesthetic”forms of leprosy.[5] The Indian Association ofLeprologists(IALs)includedthedistinctformof“neuralleprosy” in theirofficial sixgroupclassification in1955and named it “polyneuritic leprosy.”[5] HN clinicallymanifests as thickened or tender nerves leading tosensory,motor,orautonomicdisturbancesandformationof trophiculcers aswell as lossof tissue.WorldHealthOrganization(WHO)in1997classifiedHansen’sdiseasebased on number skin lesions as paucibacillary (PB) (1lesion),PB (2–5 lesions), andMB (>5 lesions).[6]Later,WHOcategorizedLL,BL,andBBcasesof theRidley–Joplingclassification,withabacteriological indexof≥2at any site in the initial skin smears asMB leprosy.Onthe other hand, PB leprosy included indeterminate, TT,andBTwith abacteriological indexof<2.At leastoneof the cardinal signs is mandatory for the diagnosis ofleprosy, which include definite loss of sensation in apale(hypopigmented)orreddishskinpatch,a thickenedor enlarged peripheral nerve with a loss of sensationand/orweakness of themuscles supplied by that nerve,or the presence of acid‑fast bacilli in a slit‑skin smear.The cases can be classified as PB or MB based onnumberofskinlesionswhenslit‑skinsmearexamination

Figure 2:Case 3 borderline tuberculoid – (a)Distinct inflammationinendo‑andperineurium,markedendoneurialfibrosis(inset,Massontrichrome)andseverelossofmyelinatednervefibers(×40,HandE);(b) thickened perineurium and epineurial perivascular inflammation(×100, H and E); (c) thickened perineurium and endoneurialinflammation(×100,HandE);(d)epithelioidgranuloma(×400,HandE)

dc

ba

Figure 1: Case 1 mid‑borderline – (a) Thickened right greaterauricularnerve;(b)bilaterallowermotorneuronfacialpalsyexhibitinglagophthalmos; (c and d) gross of thickened right greater auricularnerve; (e) whole‑mount view of transverse section of thickenednerve; (f) enlarged fascicles (×40,HandE); (g) fascicles completelyeffaced by inflammatory cells (×100,H and E); (h)mononuclearcells, foam cells, and histiocytes (×200,H andE); (i and j) poorlyformedgranuloma(×400,HandE);(k)fewremnantmyelinatednervefibers (×400,KPal); (l) leprabacilli (OIF,Fite); (m) (×40,HandE),(n) (×100,H andE), (o) (×400,H andE);well‑defined epithelioidgranulomainpapillaryandreticulardermis

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is not available. It is recommended that the patientshould be treated as aMBHansen’s casewhenever theclassificationofanindividualcaseisindoubt.[7]ThereistheabsenceofanyWHOguidelinesforsubclassificationofPNLasPBorMBdiseaseoritstreatment.[8]In1982,IALre‑christened“polyneuriticleprosy”as“pureneuritictypeofleprosy.”[2]Singleormultiplelargernervetrunksor their branches are enlarged in PNL with sensoryloss in the corresponding dermatome, with neither skinlesions nor slit‑skin smear positivity. Microscopy mayreveal TT, borderline nonspecific, or even lepromatousmorphology alongwith acid‑fast bacilli.[2]According tothe present National Leprosy Eradication Programmeguidelines in India for therapeuticpurpose, involvementof one or more nerve trunks is considered as PB andMB,respectively.[9]

In 2014, throughout the world, 213,899 people werenewly diagnosed with Hansen’s disease, whichcorresponds to a detection rate of 3.0/100,000 ofpopulation.SoutheastAsianregionregisteredthehighestincidence of 8.12/100,000 of population. The overallregisteredprevalence in theworldandSoutheastAsia is0.25 and 0.63/100,000 population, respectively. Of thenewly diagnosed cases, 94% patients were reported in13 countries: Bangladesh, Brazil, Democratic Republicof Congo, Ethiopia, India, Indonesia, Madagascar,Myanmar, Nepal, Nigeria, the Philippines, Sri Lanka,and the United Republic of Tanzania. MB casesconstituted 61% of the patients, of which 74% weremales.[10]

India contributes to more than 50% of new casesdetected globally every year. In the year 2011–2012,

Figure 3:Case5borderlinelepromatous–(a)Inflammationinendo‑,peri‑,andepineurium(×40,HandE);(b)thickenedperineurium(×100,HandE);(c)markedendoneurialfibrosisandseverelossofmyelinatednervefibres(×100,Massontrichrome);(d)endoneurialinflammation(×200,HandE);(e)denselymphocyticinfiltrateadmixedwithfoamcells(×400,HandE);(f)numerousleprabacilliandglobi(OIF,Fite)

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Figure 4:Case8burnt‑outHansen’s–(a)(×40,HandE),(b)(×100,HandE):mildlymphocyticinfiltrateinendo‑,peri‑,andepineurium;(c)neovascularizationandmildperivascularlymphocyticinfiltrateinepineurium(×400,HandE);(d)(×40,Massontrichrome),(d)inset,(e)(×100,Massontrichrome):Densecollagenizationintheendoneurium;(f)completelossofmyelinatednervefibers(×100,KPal)

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127,000 new caseswere diagnosedwith an annual newcasedetectionrateof10.35/100,000ofpopulation.AsonApril1,2012,atotalof83,000casesareonrecordwithaprevalencerateof0.68/10,000population.[9]Accordingto Indian data, PNL constituted about 4%–18% ofleprosypatients.[11]The incidence is reportedlyhigher inSouth India comprising up to 18% of new cases. PNLis more common in men,[12] as in the present study. Inthe study by Mendiratta et al., most number of casesoccurred in the age group of 15–30 years,[12] unlike thepreponderance in 40–50 years revealed in the presentstudy.

Among 46 cases of PNL, peripheral nerves werethickened in 32.6% cases, followed my trophic ulcersin 21.7% cases, muscle wasting, claw hand, and footdrop in 15.2%, 10.8%, and 8.7% cases, respectively.[13]Mononeuritis multiplex was the most frequent clinicaland electrophysiological pattern of nerve dysfunction,withsensory (89%ofallcases)more thanmotor (81%)dysfunction and predominant axonal neuropathy[14]comparable to the current study. Bilateral facial palsyis less common than unilateral facial palsy and theincidence of the same in leprosy varies from 3% to24.59%.[15] Reddy et al. described dichotomy betweenimmunological grading of skin and nerve lesions incases where both are involved simultaneously, with thenerve showing lower spectrum of the disease,[16] andsuchafindingwasnotedonlyincase‑4.

InthestudybyHuiet al.in46casesofPNL,therewere47.8%casesofBT,followedby23.9%,13%,and10.8%cases of BL, TT, and BB, respectively.[13] Endoneurial,perineurial, and epineurial inflammation was seen in

39.8%,39.8%,and27.7%cases,respectively.Epithelioidgranulomasweredescribed in13.2%cases.Fibrosiswasmostcommon(34.7%cases)inperineurialcompartment,followed by endoneurial and epineurial compartmentsin 31.6% and 26.3% cases, respectively. Reduction inmyelinatedfibreswasnotedin55.6%cases.Mononuclearinfiltrate and foamy macrophages were encountered in42.3%and19%cases.Endoneurialedemawasdescribedin7.8%cases.In19%cases,perineurialenlargementwasnoted.Microfasciclesarenest‑likestructurescomposedofavariablequantityofsmallmyelinatedornonmyelinatedfibres and Schwann cells and surrounded by perineurialcells.Thesestructureswerediscernedin10.42%samples.In the same study, mononuclear cell infiltrate andfibrosis were seen in all three compartments in almostall the cases, epithelioid granulomas in 66.7% cases,foam cells in 44.4% cases, and perineurial thickeningin 33.3% cases[17] Microfascicles were not seen in anyof thecases in thepresent study.Another study reportedepithelioid granulomas in 14% cases.[13] Reduction inmyelinated fibres was noted in 55.6% cases,[16] unlikemoderate‑to‑complete degree of myelinated fiberloss in all the cases in this study. Loss of myelinatedfiber and Schwann cells is consistent with decrease inimmunohistochemical stainingofneurofilament in100%HNbiopsies,nervegrowthfactorreceptorlossin81.8%,PGP 9.5 staining loss in 100%, and loss of S‑100 aswell asmyelin basic protein immunoreactivity in 90.9%caseseach.[18]Caseousnecrosiswasrecordedinonecaseof TT (case‑15; present study) as was reported by Huietal.[13]

Tests forHansen’sdisease includeslit‑skin smears, skinand nerve biopsies, polymerase chain reaction (PCR),

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Figure 5:Case15polartuberculoid–(a)Enlargedfascicleswithmoderateendo‑,peri‑,andepineurialinflammation,andepithelioidgranulomas(×40,H andE); (b) granulomawithLanghans giant cell (arrow) in epineurium (×200,H andE); (c) caseating (asterix) epithelioid granuloma(×40,HandE);(d)caseating(asterix)epithelioidgranulomaandLanghansgiantcell(arrow)(×400,HandE);(e)completelossofmyelinatednervefibers(×200,KPal);(f)moderatedegreelossofmyelinatednervefibres(×200,KPal)



Lepromin test,andserumassays forphenolicglycolipid1 antibody (anti‑PLG1).[19] Anti‑PLG1 titer correlateswith bacterial load, being higher in lepromatousthan TT cases.[4] It can be useful for monitoringchemotherapy as titers correlate with the BI followingtreatment.[20] Antunes et al. demonstrated lepra bacilliin 36.1% (52 out of 144) cases byFite‑Faraco stain. Inthe Lepra‑negative cases, diagnosis of PNL was basedon thePCRdetectionofM. leprae (28outof92cases)andpositivityofanti‑PLG1 in the rest.[17] In thepresentstudy,leprabacilliwerehighlightedbyFite‑Faracostainin 44.4% cases, comparable to 47.8% in the study byHuiet al.[13]Other ancillary testswere not done for thecasesreviewedinourstudy.

ConclusionHN is a debilitating but a completely treatable disease.Mononeuritis multiplex is the most common clinicalpresentation. Histological features such asmononuclearinflammation and foamcells in all compartments of theperipheral nerve, epithelioid granulomas, dense fibrosis,and less commonly perineurial thickening, with orwithoutpositivity for leprabacilliareclues todiagnosisof HN.Knowing themorphological spectrum ofHN isof cardinal importance because of the curable nature ofthedisease.Lastbutnot the least,HNisoneof thefewneurologicaldiseaseswith idiosyncratic clinical featuresand therefore a diligent neurological examination alongwithnervebiopsyexaminationisqualifiedfor.

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.

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2. Rao PN, Suneetha S. Pure neuritic leprosy: Current status andrelevance.IndianJDermatolVenereolLeprol2016;82:252‑61.

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13. Hui M, Uppin MS, Challa S, Meena AK, Kaul S. Pureneuritic leprosy: Resolving diagnostic issues in acid fastbacilli(AFB)‑negativenervebiopsies:AsinglecentreexperiencefromSouthIndia.AnnIndianAcadNeurol2015;18:292‑7.

14. JardimMR,Antunes SL, SantosAR,NascimentoOJ, Nery JA,Sales AM, et al. Criteria for diagnosis of pure neural leprosy.JNeurol2003;250:806‑9.

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17. Antunes SL, Chimelli L, Jardim MR, Vital RT, Nery JA,Corte‑Real S, et al. Histopathological examination of nervesamples from pure neural leprosy patients:Obtainingmaximuminformationtoimprovediagnosticefficiency.MemInstOswaldoCruz2012;107:246‑53.

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Hansen’s Neuritis Revisited – A Clinicopathological Study

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