10/03/2017 AshortHistoryofOnchocerciasis

AshortHistoryofOnchocerciasis
byGuidoKluxen

Discoveryofthemicrofilariae

In1874,JohnONeill,aBritishnavalsurgeonattachedtoHMSDecoyatCapeCoast
CastleintheGoldCoast(Ghana)becameintriguedbyanirritatingandintractableskin
diseasesomewhatresemblingscabieswhichafflictedmanypeoplelivinginpartsofthe
WestCoastofAfrica.Hedeterminedtolookforthecauseofthispeculiarcondition,which
wasknownlocallyascrawcraw,bystudyinganumberofpatientsinAddahFort
HospitalunderthecareofDr.ThompsonoftheGloverExpedition.Theconditionwas
characterizedbypapules,vesiclesandpustules.ONeillexaminedthecontentsofpustules
andvesiclesunderamicroscopebutfoundnothingotherthanleucocytes.Whenheturned
hisattentiontopapules,successattendedhiseffortsforhefoundanorganismwhichhe
hadnodoubt,wasthecauseofthecomplaint.Hereportedhisobservationsin1875.
Whenspecimenwereexaminedinadropofwaterunderamicroscope,microfilariaethat
wereeasilydetectablebyvirtueoftheirviolentcontortionswereoftenseen:Atthehead,
orbluntedextremity,twosmalldotsarenoticed,buttheirnaturecouldnotbedetermined
(Fig.1)(ONeill1875).

Fig.1:Unsheathedmicrofilariaefromcrawcraw
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ofONeillattheGoldCoast,Ghana(OriginalfromTheLancet1875).

Discoveryoftheadultworm

In1890,anunnamedGermandoctorworkingintheGoldCoast(Ghana),WestAfrica,
removedtwotumours,eachaboutthesizeofapigeonseggs,onefromthescalpandthe
otherfromthechest,fromtwoofthelocalinhabitants.Onexaminingthespecimens,he
foundthattheycontainedwormsandsentthemtoRudolfLeuckartinGermanyfor
identification.Bothtumourscontainedseveralfemaleandmaleworms,theformerbeing
about670mminlengthandthelatterabouthalfthatsizetheywerecoiledtogetherto
formaballwhichwasverydifficulttounravel.Themassofwormswassituatedinacavity
whichcontainedfluidladenwithembryos.Leuckartdidnotpublishnewsofthis
discovery,butinformedPatrickMansoninapersonalcommunication.Itwasleftto
Mansontopublishaskimpynoticeoftheparasite,withduetoacknowledgementto
Leuckart,inachapterhewroteonskindiseasesinthetropicsforDavidsonsbook
Hygieneanddiseaseofwarmclimates.ThesectiononthisparasitewaslabelledFilaria
volvulxus,thelatterapparentlybeingamistranscriptionofvolvulus(fromtheLatin
volvo,volvere=torollorturnround)whetherthiswasLeuckartsorMansons
designationwasnotindicatedinthetext,butwaspresumablyintendedtodrawattention
tothetwistedandcoiledintertwiningoftheworms.

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Fig.2:RudolfLeuckart(18221898),zoologistandhelminthologistinLeipzig,Germany,
discoveredOnchocercavolvulus

Onchocercavolvulus:
"Thetwistinghooktail"

LeuckarthadalsosentMansonahistologicalsectioncontainingafragmentoftheuterus
ofoneoftheworms,Mansonremarked:Ididnotseerepresentedintheembryoof
Filariavolvulusthesheath.ProfessorLeuckartmakesthesameremark.
ThenameOnchocercawasderivedfromacombinationoftheGreekwordONCHOS
meaninghookandKERKOSCERCOSmeaningtail(RaillietandHenry1910).

SymptomentriasaccordingtoRobles

ThefirstpersonstomentionocularonchocerciasiswereRodolfoRoblesandPacheco
LunainGuatemalain1915/1916.Ophthalmicsymptomsandsignsweremarkedinthe
Triassic,alsoknownasMorbusRobles:1.Filarialworminfectionofanadult
OnchocercainAmerica,2.Erisipeladelacosta,redskininflammationofthecoast,askin
diseaselocatedontheface,3.Conjunctivitisandiritisoftheanteriorsegmentoftheeye

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(PachecoLuna1918).
In1915,Robleswasconsultedbyawomenconcerningrecurrenterysipelasoftheface
whichwasaccompaniedbyfever,aburningsensation,pruritusandpoorvision(Fig.4),
buthedidnotknowthecause.Afterwardshesawaboywiththesamefeatures:Oedemaof
theeyelids,theforehead,andthesuperiorlip.Onhisforeheadwasatumourthesizeofa
cherry.ItwasthislumpthatRoblesexcisedandfirstdiscoveredtheadultOnchocercain
theAmericasandlaterremarked:Iunderstoodthenthattheerysipelaslesionssurely
wereduetothepresenceofthisparasite(Robles1917).
Inthecoffeeproducingdistricts,havingaltitudesbetween2,500to5,000feet,over95
percentofthepopulationinanareaofvolcanoesareIndianswhoareespeciallyexposed
tothebitesofSimuliidaeandaninfectionwithonchocerciasis.

Fig.3:RodolfoRoblesdiscoveredonchocerciasis
oftheAmericasinGuatemala

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Fig.4:In1915,RodolfoRobleswasconsultedbythiswomen
withanerysipelasofthefaceasthereasonwasstillunknown.

Brumptgaveadetaileddescriptionoftheparasite(Brumpt1919),andaftercomparingit
withthespecimenscollectedbyhimintheCongo,decidedthatitwasadifferentspecies
whichhenamedO.caecutienstoindicatethattheparasitecausedblindness(fromthe
Latincaecus=blind).Butthetwoweremorphologicallyindistinguishableandthere
wasnoconsistentdifferenceexistingbetweenthem.

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Fig.5:mileBrumpt(18771951)

ItwastheitchingandconsequentscratchingwhichledtotherediscoverybyMontpellier
andLacroix(1920)ofmicrofilariaeintheintegumentwhichwerethesameasONeills
parasites.ButBrumptcouldnotbelieveit(Brumpt1920).Inthemiddleofthe1920s,it
wasbecomingclearthattheunsheathedmicrofilariaeobtainedfromO.volvulusadults
wereindeedthesamemicrofilariaeseenintheskin.Finally,despitethereservationsof
somescepticssuchasBrumpt,itseemedcertaininretrospectthatthefilariaeseeninthe
skin50yearsearlierbyONeillwereindeedO.volvulusmicrofilariae.
MontpellierandLacroixconstantlyfoundmicrofilariaeinthedermallayeroftheskin
examiningmembersofnativetroopsinAfricasufferingwithaformofitchorcraw
craw.TheyconcludedthatthecrawcrawdescribedbyONeillisadermal
manifestationofonchocerciasistermedglefilarienne(Fig.6).

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Fig.6:Glefilarienne(OriginalfromMontpellierandLacroix1920)

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Fig.7:DonaldBreadalbaneBlacklock(18791955),borninScotland.

SimuliumdamnosumTheobald:
Modeoftransmissionofonchocerciasis

In1923,theBriton,DonaldBreadalbaneBlacklock,begantoinvestigatethemodeof
transmissionofonchocerciasisinSierraLeone.Sincethemicrofiariaewerenotinthe
bloodbutintheskin,hepostulatedthatanyarthropodecapableoftransmittingtheworms
mustbeabletodamagetheskinanddislodgethelarvaeinitseffortstoreachblood.
Accordingly,hefirstlookedattheCongofloormaggot,Auchmeromyialuteola,whichwas
commoninthehouses,butnosignsoftheparasiteswerefound.In1923/24,heobserved
thattheblackflypropheticallynamedSimuliumdamnosumbyTheobaldin1903
(Theobald1903)wasbitingviciouslyandingreatnumbersnearthestreamssupplying
severalofthevillagesinanendemicareaofonchocerciasis.Furthermore,henoticedthat
theinsectwasslowindrawingblood,whichreinforcedhisideathatitmustbeinflicting
severedamage.Hethereforecaught100specimensandexaminedthemforlarvae,but
findingnothing,abandonedthesearchtemporarily.In1925,heresumedthisoperationat
anothervillage,thistimewithsuccess.780flieswerecapturedwhilebitingrandomly

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selectedboysand2.6%oftheinsectscontainedlarvaemorphologicallyidenticalwith
O.volvulusmicrofilariae.Thereupon,hesubmittedtwomenwhowereknowntohave
O.volvulusmicrofilariaeintheirskin,butwerenotinfectedwithanyotherfilarial
parasite,tothefliesandfoundthat17%ofSimuliidaecontainedmicrofilariae.Whenflies
werepermittedtobiteonlyona4inchbandaroundthepatientsbody,thisareaincluding
nodulesnearthetrochanters,80%oftheinsectsbecameinfected.Thedevelopmentofthe
L3larvaeintheflyisdemonstratedinBlacklocksoriginalfigure(Fig.8).Onlythefemale
wasfoundbiting,andthebitinghabitisdiurnal(Blacklock1926/1927).

Fig.8:DiagramtoillustratethedevelopmentofO.volvuluslarvaeinthetissuesof
Simuliumdamnosum(Blacklock1927).I=Larvafrominfectedskin,II=larvainmid
gut,III=larvainthoracicmuscles(earlystage),IV=Larvainthoracicmuscles(late
stage),V=Larvainheadandlabium,A=Antenna,B.C.=Bloodcoagulum,T.M.=
Thoracicmuscles,L=Labium,L.e.=Labrumepipharynx,H.=Hypopharynx,M.=
Mandible,Mx.=Maxilla,Mx.P.=Maxillarypalp.Theinfectivestagelarvae(V)are
nowtermedL3larvae,andstageIlarvaearenowtermedmicrofilariae.

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Fig.9:SimuliumdamnosumTheobald(Photo:Hj.Trojan)

TheobservationsofHissetteradicallychangedtheway
oflookingatonchocerciasis

Theearlyinvestigatorsofonchocerciasisfrom18741930inAfricamadenomentionatall
ofaconcomitantsevereeyedisease.PublicationsoftheobservationsinCentralAmerica
byRodolfoRoblesandmileBrumptin1917/1919promptedsomespecialistsintropical
medicinetolookforeyediseaseassociatedwithAfricanonchocerciasis.However,there
didnotseemtobeanyeyediseaseleadingtoblindness(Flleborn1924).OnlyOuzilleau
andhiscolleaguesrecordedin1921thatoneofthe16infectedpersonsof27inhabitants
theyhadfoundinavillagenearBrazzavillehadkeratitis.Blacklock(1927)reportedthat
hecouldfindnoevidenceofeyediseaseinpatientswithonchocerciasisinSierraLeone.
Itwasnotuntil1930/1931thatJeanHissettereportedthat20%ofpatientswith
onchocerciasiswereblindinanonchocerciasisfocusontheSankuruRiverintheBelgian
Congo,andthat50%ofthevillagerssufferedfromeyetroubles.Twoyearslater,hefound
asecondfocuswiththesamepathologyontheUleRiver.Hissettedescribedthe
pathomechanismofthisblindnessinalongpaperin1932andinadditiontoadescription
ofanterioreyedisease,hedrewattentiontoanassociationwithchororetinitis.Twoyears
latertheHarvardAfricanExpeditiontotheBelgianCongounderRichardPearsonStrong
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withfiveAmericancolleagueswasorganizedatBelgiumsexpense.Hismembershadto
checkDr.JeanHissettesreportsbecausethereweredoubtsabouthisfindings.
ConfrontedbythiscommissionintheformoftheHarvardAfricanExpedition,Hissette
traveledoncemoretotheSankuruwiththeAmericansastheseventhmemberofthe
expeditionandshowedthem"his"riverblindnesspatients.TheAmericansfinally
confirmedalltheobservationsonriverblindnesscausedbyonchocerciasisinthe
AmericanJournalofTropicalMedicine(Strong1938)thathadalreadybeen
communicatedbyHissette(1932).

Fig.10:RiverblindpeoplefromtheSankuruRegion1930

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Fig.11:MicrofilariaeofOnchocercavolvulusintheChorioideaofanenucleatedeyefrom
theSankuruRiver1931(OriginalhistologybyJeanHissette,microfilariaeareblackand
stretched)

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Fig.12:TheSankuruRiverRegionandUleRiverRegionoftheBelgianCongo

Hissettesfindingspromptedrenewedeffortstofindocularcomplicationsof
onchocerciasisinotherpartsofAfrica,nowknownasriverblindness.In1944,Harold
Ridleyfoundthatslightlymorethanonethirdofpatientswithonchocerciasisinaregion
oftheGoldCoast(Ghana)hadevidenceofeitheranteriororposteriordiseaseoftheeye,
withnearlyhalfofthembeingblindornearlyblind.RidleysmonographOcular
onchocerciasis(1945)wasofconsiderablesuccessinriverblindnessresearch.

ThenumericaldistributionofmicrofilariaeofOnchocercavolvulusintheskinofman
followsaclearpatternwhichisrelatedtothedistributionandseverityoftheskinandeye
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lesions.Fortheeyechangesandblindnessthisisespeciallytheregionoftheheadand
neck(Kershawetal.1954).

Choyce(1958)confirmedthatthescaredfundus,hithertothoughttobedueto
onchocerciasis,wasidenticalwiththechorioidalsclerosisdescribedbySorsby(1939).
ThiscouldbethefactinBonjongo,Cameroonswherehefoundsuchchanges
indistinguishableforhim.Sorsbyschorioidalsclerosisisageneticdiseasetransmittedin
adominantfashion.NoevidencewasfoundofvitaminAdeficiencyasacauseof
chorioretinitisinonchocerciasis(Woodruffetal.1963).

Onchocercavolvulushasnotbeentransmittedexperimentallytohumansbyinfectedflies,
butepidemiologicalevidencesuggeststhattheprepatentperiodisbetween3to18months.
Theadultwormsmaylivefor15yearsandarecapableofproducingmicrofilariaeforupto
tenyears(Robertsetal.1967),whilemicrofilariaemaypersistforfrom6monthsto3
years(Duke1968).

OnOctober21,1987,Merckofficials(MSDMerckSharp&Dohme)saidthattheywould
bedonatingtheirdrugIvermectintoaffectedareasforaslongasitmightbeneeded.
Diethylcarbamazineandsuramincausedseveresideeffectsinsomanyindividuals.
Ivermectincanbegivenasatabletonaonceayearbasisandhasminimalsideeffects.
ThedrugisdistributedbyMerck,inclosecollaborationwithWHO,anindependent
committeeofexpertsintropicalmedicine,TheWorldBank,TheCarterCentreinAtlanta,
Georgia/USA,andaboutadozenNGDOs(nongovernmentaldevelopingorganizations)
inseveraldifferentcountries.

MostoftheevidencesupportingaroleforWolbachiainthepathogenesisoffilarial
diseasesstemsfromadversereactionsininfectedindividuals.Forexample,systemic
treatmentofonchocerciasispatientswithdiethylcarbamazine(DEC)causesrapiddeathof
themicrofilariaeintheskinandeyes,resultingoftensevereposttreatmentsideeffectthe
socalledMazzottireaction.TheseverityoftheMazzottireactionisdependentonthe
numberofmicrofilariaecontainingWolbachiaintheskinandeyes(HoeraufandPfarr
2007).AndthiswasalsothefactwhenHissetteinducedtheerysipelasinalittle12year
oldboyattheUlein1933(Hissette1933,Kluxen2011)byneedlinghisheadnodulesand
killingthewormsinit.Reactionsincludefever,headache,dizziness,myalgia,arthralgia,
tachycardia,ciliaryinjection,severepruritus,enlargementoflymphnodesanderysipelas
ofthecoast.

Whilealive,themicrofilariaeappeartocauselittleornoinflammation,evenbeinginthe
anteriorchamber.However,whentheydie,eitherbynaturalattritionorafter
chemotherapy,thehostresponsetodegeneratingwormscanresultinocular
inflammation(keratitis,uveitis,chorioretinitis,opticneuritis)thatcausesprogressiveloss
ofvision.Blindnessthereforetendstooccurinadulthoodaftermanyyearsofinfection.

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