Case report/Kazuistyka
Bilateral peripheral facial palsy secondary to Waldenström's macroglobulinemia.
A case report and literature review
Margarita Sánchez-Orgaz
1,*, Karina Spiess
1,
Miguel Angel Canales-Albendea
2, Alvaro Arbizu-Duralde
1, Ricardo Romero-Martín
1, Pilar Moliá Clos
11OphthalmologyService,UniversityHospitalLaPaz,Madrid,Spain
2HematologyandHemotherapyService,UniversityHospitalLaPaz,Madrid,Spain
Introduction
Idiopathic facial nerve palsy (FNP), or Bell's palsy, is the mostprevalentacutedisorderaffectingthe seventhcranial nerve with an incidence of 20–30 patients per 100000.
Conversely,bilateral FNPisrare,representing lessthan 2%
of all the facial palsies and affecting five patients per 100000. Most of these patients have serious underlying medicalconditionsandneedtobeevaluatedcarefully[1].
Waldenström's macroglobulinemia (WM) is a rare low- gradeB-celllymphomacharacterizedbyinvolvementofthe reticuloendothelial system by lymphoplasmacytoid cells
which secrete monoclonal IgM. Uncontrolled production of this immunoglobulin increasesserum viscosity and causes tumor cell infiltrationof the tissues.Up to47%of patients with WM develop symptomatic peripheral neuropathy but cranial nerve palsies are rare in this condition [2]. We describeacaseofWMpresentingasbilateralFNP.
Case report
A59-yearoldladyattendedtheemergencyroompresenting symptoms of left facial numbness and weakness, inability to close her left eye and asymmetry of the mouth. The actahaematologicapolonica 45(2014) 374–377
article info
Articlehistory:
Received:28.07.2014 Accepted:16.10.2014
Availableonline:27October2014
Keywords:
Bilateralperipheralfacialpalsy
Facialdiplegia
Macroglobulinemia
Rituximab
abstract
A 59-year old woman who attended theemergency department because ofa bilateral peripheral facial nerve palsy(FNP). BilateralFNP is uncommon, an idiopathic cause is unlikelyandconsequentlyacomprehensivestudyisindicated.AnIgMmonoclonalgam- mopathy was detected on serum protein electrophoresis of our patient. Bone marrow biopsyshowedthepresenceoflymphoplasmocytoidcells.Onthebasisofthesefindings thediagnosis of Waldenström'smacroglobulinemia (WM) wasmade. Secondary cranial nervepalsiesarerarelyseeninthiscondition.ThisreportdescribesacaseofbilateralFNP asinitialpresentationofaWaldenström'smacroglobulinemiaanddiscusstreatment.
©2014PolskieTowarzystwoHematologówiTransfuzjologów,InstytutHematologiii Transfuzjologii.PublishedbyElsevierUrban&PartnerSp.zo.o.Allrightsreserved.
*Correspondingauthorat:PaseoCastellana261,28046Madrid,Spain.Tel.:+34653540699.
E-mailaddress:msorgaz@gmail.com(M.Sánchez-Orgaz).
ContentslistsavailableatScienceDirect
Acta Haematologica Polonica
journal homepage:www.elsevier.com/locate/achaem
http://dx.doi.org/10.1016/j.achaem.2014.10.004
0001-5814/©2014PolskieTowarzystwoHematologówiTransfuzjologów,InstytutHematologiiiTransfuzjologii.PublishedbyElsevier Urban&PartnerSp.zo.o.Allrightsreserved.
patientwas diagnosed as aleft Bell's palsy and treatment with prednisone 30mg three times a day was prescribed.
Two days later, she returned because of worsening symp- toms; the facial weakness became bilateral and she had secondary dysarthria. Examination revealed bilateral lower motor neuron FNP (Fig. 1). The rest of the neurological examinationwasunremarkable.Thepatienthadnomedical history of interest, except for a recent trip to Kenya and Tanzania, where she referred a mosquito-bite. She had takenantimalarialprophylaxiswithproguanilcorrectly.
Thecompletebloodcount,biochemicalanalysis,chestX- ray and head computer tomography were normal. The patient was hospitalized under the care of the neurology departmentwith thesuspectof bilateralGuillain-Barré syn- drome. She started treatment with intravenous corticoster- oidsandoraldoxycyclineuntilLymediseasewasruledout.
Lumbarpuncturerevealedproteinorrachia(463mg/L)and anincreaseofIgMindex(0.23),adenosinedeaminase(5m/L) and neuron specific enolase (35.1ng/ml). Serological tests for various agents including Borrelia burgdorferi (Lyme dis- ease), syphilis and Epstein-Barr virus were negative. Like- wise,the culture of cerebrospinalfluidand tumor cytology werebothnegative.
Headmagneticresonanceimaging(MRI)showedbilateral asymmetrical enhancement of the facialnerves, withleft- sidedpredominance.
Nerve conduction studies showed no alteration of per- ipheral nerve conduits, consequently Guillain-Barré was ruledout.Atthattime,facialelectroneurography(ENG)was inconclusive, while a month later, it revealed a mixed lesion:axonalanddemyelinatingwithmoresevereaffection oftheleftside.
Amonoclonal IgMspikewas detected inserum protein electrophoresiswithanincreased levelof b2-microglobulin.
Bone marrow biopsy revealednodular intertrabecular infil- tration by a low grade B non-Hodgkin lymphoma. The immunophenotypeprofileof the lymphoplasmocytoidcells wasCD20+,CD3 , CD5 , CD23 ,bcl-6-and CD10 consis- tent with the diagnosis of WM. The patient received six cycles of ambulant systemic chemotherapy and immu- notherapy based on DRC-scheme: dexamethasone, rituxi- mab(375mg/m3)and cyclophosphamide,spaced overeight weeks.Treatmentwithartificialtearsandointmentandeye patching during night was prescribed because of the high riskofexposurekeratopathy.
Threemonthslater,thedemyelinatingcomponentrecov- eredonENGandreinnervationofbothfacialnervesbegan.
Improvement correlated with a dramatic decrease in IgM levels,antibodytitlesandcirculatingBcells.Lagophthalmos (inabilitytoclosetheeyes)improvedand,ophthalmological examination showed onlymildpunctatesuperficialkerato- pathyinthelefteye.
Nine months after diagnosis, IgM levels have declined more. The patient presents a mild facial asymmetry with absenceoflagophthalmosinbotheyes(Fig.2),thesmilewas restored and the nasolabial fold has been corrected. The electromyogram(EMG)showsanimprovementofbothfacial nervereinnervationandfunctionalrecoveryespeciallyofthe orbicularis oculi muscle and the lips. As well, a moderate incrementofthemotoractivitycouldbedetected.
AberrantreinnervationwasdemonstratedbyEMG,clini- cally expressedbysinkynesis,and apathologicalspread of the reflex response of bothfacial nerves to unusual terri- tories,especiallyontheleftside.
The patients will continue treatment with rituximab- cycleseveryeightweeksuntiltwoyearcompletion.
Discussion
Bilateral FNPisan infrequentdisease anda seriousunder- lyingmedicalconditionshouldbesuspected.Possiblecauses include infectious, autoimmune and metabolic diseases, tumors,toxicandcongenitaldisorders.Thereareseveralviral andbacterialagentswhichcanproducebilateralorrecurrent FNP.Lymedisease,causedbyspirocheteBorreliaburgdorferi,is the most commoninfectious etiology, followed by Epstein- Barrvirus.Guillain-BarréSyndrome(inflammatorypost-infec- tious polyradiculoneuritis) is another important cause of bilateralFNPtoberuledout,becauseupto50%offatalcases can occur. As well, intrapontine and prepontine tumors should beexcluded. There isone reported case of bilateral FNPandacutemyeloidleukemia[3].
WMisconsideredanindolentformofB-cellnon-Hodgkin lymphoma,alsoknownaslymphoplasmocyticlymphomaby theWorldHealthOrganization(WHO)classification.
Infiltrationbylymphoplasmacyticcells,predominantlyof thebonemarrowtogetherwithanIgMmonoclonalgammo- pathy, is considereda diagnostic finding [4]. WM accounts for 1–2% of all hematologic malignancies and in terms of
Fig.1–Thepatienttendaysafterfacialpalsy.Inabilitytoclosebotheyes,speciallytheleft
acta haematologicapolonica 45 (2014)374–377
375
pathogenic evolution, the condition straddles between monoclonal gammopathy of unknown significance (MGUS) andmultiplemyeloma.Thediseasemostcommonlyaffects men above 60 years of age. Typically manifestations are diffuselymphadenopathies,cytopeniasandamarkedlyele- vatederythrocytesedimentationrate.Clinicalsymptomsare duetothemonoclonalIgMprotein,tissueinfiltrationbythe lymphoplasmocytic cells,or both[5]. Hyperviscosityretino- pathyis themost commonocular abnormality reportedin WM[6].Peripheralneuropathy(PN)isafrequent complica- tion of IgM monoclonal gammopathy, occurring in15–30%
ofpatientswitheitherMGUS,mostcommonly,orWM.
Of the whole spectrum of peripheral neuropathies, the typicalpattern consists inachronicprogressivesymmetric and predominantly distal polyneuropathy, but also other symmetric polyneuropathies, cranial nerve palsies, mono- neuropathies and mononeuritis multiplex. Isolated cranial neuropathiesarerareinWM[2].About25%ofpatientswith WM suffer from central nervous system (CNS) symptoms secondarytoincreasedbloodviscosity(Bing-Neelsyndrome) leading to anoxic damage and hemorrhages of the brain tissues. In the context of CNS involvement cranial nerve palsies are more common. We found a case report of bilateral sixth nerve palsy in a patient with Bing-Neel syndrome [7]. To our knowledge there is no case report about facial diplegia secondary to this entity. Moreover, during literature review we have only foundone reportof isolatedtrochlearnervepalsy[8],anotherofunilateralfacial nerve palsy [9], in the absence of other nervous system manifestations.
IgMhasbeenfoundtohaveanti-nerveantibodyactivity.
The most frequently reported antigen recognized by this monoclonal IgM is myelin-associated glycoprotein (MAG).
The mechanism by which anti-MAG enters the nerve and causes demyelinationand neuraldamage isunclear. Other neuralantigens have alsobeen associatedwithpolyneuro- pathiesincludingseveralanti-gangliosides(antiGM1),sulfa- tide and tri-sulfated heparin disaccharide [10]. Non- antibody-mediated mechanisms have alsobeen implicated
inpatientswithoutantineuralreactivityofIgMparaprotein:
cryoglobulinemia, direct lymphoplasmacytic infiltration of thenerves,andvasculitis.
Anti-gangliosides and anti-sulfatides were not detected inourpatientbutanti-MAGwerepositive,sowethink,that in our case the mechanism involved was autoimmune. In addition, improvement of the FNP after rituximab and corticosteroids supports the antibody mediated response ratherthantumoralnerveinfiltration.
Awatchandwaitstrategyisrecommendedinasympto- matic patients with WM (almost a third of them), with periodicexaminationseverysixmonths.
Administrationofintravenousimmunoglobulinisoneof the mostcommonlyused first-linetherapiesforanti-MAG antibody associated polyneuropathy in MGUS. The treat- ment seems to provide short-term benefit, although data from prospectivelong-term studiesareunavailable [11].It seems reasonable to provide this treatment to patients withWMandIgM-relatedneuropathy,inconjunctionwith tumor-directedtreatments.Asperthepreviousrecommen- dations ofIWWM-4,dexamethasone,rituximab,andcyclo- phosphamide(DRC)remainstheprimarychoice.Rituximab isachimericantibodythattargetstheB-cellantigenCD20 (375mg/m3 weekly for 4 weeks). Further doses or main- tenance schedules can be considered [12]. A consensus panel has recently updated treatment for WM [13]. The treatment ofIgM-relatedneuropathy may initiallyinvolve a course of plasmapheresis, especially in symptomatic patients withanaggressive courseandcirculating antibo- dies against peripheral nerve glycoproteins or lipids expected to receive rituximab. Systemic chemotherapy with rituximabimprove sensory functions in several stu- dies. Single-agentrituximabcanbeconsidered asthe first intervention in patients with mild, slowly progressive neuropathy. In patients with severe or refractory disease, the combination offludaravine (a nucleoside analog) and rituximab may be considered. Bendamustine/rituximab may achieve paraprotein reductions but there is limited experienceinIgM-relatedneuropathy.
Fig.2–Thepatientninemonthsafterfacialpalsy.Recoveryoflagophthalmosandocclusionofbotheyes acta haematologicapolonica 45 (2014) 374–377
376
Ourpatient received treatment withchemotherapy and immunotherapybasedonDRC-schemewithgoodresponse.
Fludaravine-rituximabiseffectivebuttoxic,andDRCissafe.
The identification of the somatic mutations MyD88 and CXCR4offersthe opportunityfor amoretargeted approach [14,15].
Novelagentssuchasabrutinib,Ixazomib,oprozomiband obinutuzumab (GA-101) a new monoclonal anti-CD20 anti- body recently approved, are being studied. A prospective, open-label, single stage, phase 2 study concludes that, carfilzomib(second-generationproteasome inhibitor),ritux- imab anddexamethasone (CaRD)offers aneuropathy-spar- ingapproachfortreatingWM.
Autologousstem celltransplantationmaybeconsidered inyoungpatientswithchemosensitivediseaseandinnewly diagnosedpatientswithveryhigh-riskfeatures.
Inconclusion,althoughanidiopathicetiologyispossible in bilateral FNP, efforts should be undertaken to identify a specific cause in each patient because some of the diagnostic possibilities are life-threatening and potentially fatal.
Updateresultsfrom thephase2DRCstudyindicatethat thisisaneffectivestrategyformanypatientswithWMand paraprotein-related neuropathy. For patients with short- lasting remission, progressive disease or resistance to a first-line therapy, second-line treatment with agents of differentclass,alone or incombinationis indicated.Large, well designed randomized trials are required to establish moreselectiveandsaferimmune-therapiesfortheseneuro- pathies.
Authors' contributions/Wkład autorów
Accordingtoorder.
Conflict of interest/Konflikt interesu
Nonedeclared.
Financial support/Finansowanie
Nonedeclared.
Ethics/Etyka
Thework describedin this article has been carriedout in accordance with TheCode of Ethics of the World Medical Association(Declaration of Helsinki)for experimentsinvol- ving humans; EU Directive 2010/63/EU for animal experi- ments;UniformRequirementsformanuscriptssubmittedto Biomedicaljournals.
Acknowledgements/Podziękowania
ToDr.SusanaSantiagoPérez,NeurophysiologyService.
references/pi smiennictwo
[1] KeaneJR.Bilateralseventhnervepalsy:analysisof 43casesandreviewoftheliterature.Neurology1944;44 (7):1198–1202.
[2] BaehrungJM,HochbergEP,RajeN,etal.Neurological manifestationsofWaldenstrom'smacroglobulinemia.Clin PractNeurol2008;4(10):547–556.
[3] PereiraM,FariaF,FalcaoLM.Bilateralfacialpalsyandacute myeloidleukemia:anunusualassociation.ActaMedPort 2012;25(4):250–253.
[4] TreonSP,PattersonCJ,KimbyE,StoneMJ.Specialissueon Waldenstrom'smacroglobulinemia.Reportsfromthe5th InternationalWorkshoponWaldenstrom's
macroglobulinemia,October15–19,2008;Stockholm, Sweden.ClinLymphomMyeloma2009;9(1):10–112.
[5] StoneJM,PascualV.PathophysiologyofWaldenstrom's macroglobulinemia.Haematologica2010;95(3):359–364.
[6] OrellanaJ,FriedmanA.Ocularmanifestationofmultiple myeloma,Waldenstrom'smacroglobulinemiaand benignmonoclonalgammopathy.SurvOphthalmol1981;26 (3):157–169.
[7] BhattiM,YuanC,WinterW,etal.Bilateralsixthnerve paresisintheBing-Neelsyndrome.Neurology2005;64 (3):576–577.
[8] MoulisH,MamusSW.Isolatedtrochlearnervepalsyina patientwithWaldenstrom'smacroglobulinemia:complete recoverywithcombinationtherapy.Neurology1989;39 (10):1399.
[9] SushilK,SimaD,GoyalJL,ChauhanVS.Bilateralorbital tumorformationandisolatedfacialpalsyinWaldenstrom's macroglobulinemia.IntOphthalmol2005;26:235–237.
[10] NobleOracioE.AntigendeterminationinIgMparaproteins- relatedneuropathies.ClinLymphomaMyeloma2009;9 (1):107–109.
[11] LunnMP,Nobile-OrazioE.ImmunotherapyforIgManti- myelin-associatedglycoproteinparaproteinassociated peripheralneuropathies.CochraneDatabaseofSystematic Reviews2006.Art.No:CD002827.
[12] TreonSP.Updateontreatmentrecommendationsfromthe ThirdInternationalWorkshoponWaldenstrom's
macroglobulinemia.Blood2006;107:3442–3446.
[13] DimopoulosMA,KastritisE,OwenRG,etal.Treatment recommendationsforpatientswithWaldenstrom's macroglobulinemia(WM)andrelateddisorders:IWWM-7 consensus.Blood2014;124(9):1404–1411.
[14] HunterZR,XuL,YangG,etal.Thegenomiclandscapeof Waldenstrom'smacroglobulinemiaischaracterizedby highlyrecurringMYD88andWHIM-likeCXCR4mutations, andsmallsomaticdeletionsassociatedwithB-cell lymphomagenesis.Blood2014;123(11):1637–1646.
[15] RoccaroAM,SaccoA,JimenezC,etal.C1013G/CXCR4acts asadrivermutationoftumorprogressionandmodulatorof drugresistanceinlymphoplasmacyticlymphoma.Blood 2014;123(26):4120–4131.
acta haematologicapolonica 45 (2014)374–377
