Lucas Ezequiel Serrano Sponton, Ali Ayyad, Eleftherios Archavlis, Florian Alexander Ringel

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1 SNI: Unique Cse Oservtions OPEN ACCESS For entire Editoril Bord visit : Editor: Ather Enm, M.D., Ag Khn University, Krchi, Sindh, Pkistn Cse Report Unique cse of trigeminl neurlgi due to Epstein Brr virus ssocited B cell lymphomtoid grnulomtosis of the Meckel s cve nd cvernous sinus: Importnt clinicl nd therpeutic implictions Lucs Ezequiel Serrno Sponton, Ali Ayyd, Eleftherios Archvlis, Florin Alexnder Ringel Deprtment of Neurosurgery, Minz University Hospitl, Lngeneckstrße 1, Minz, Germny E mil: *Lucs Ezequiel Serrno Sponton lucs.serrno@unimedizin minz.de; Ali Ayyd liyyd@we.de; Eleftherios Archvlis eleftherios.rchvlis@unimedizin minz.de; Florin Alexnder Ringel florin.ringel@unimedizin minz.de *Corresponding uthor Received: 11 Jnury 18 Accepted: 26 June 18 Pulished: 26 July 18 Astrct Bckground: Trigeminl neurlgi (TN) represents one of the most disling pin syndromes. Severl diseses hve een descried s etiologicl triggers of TN, vsculr compression of the trigeminl nerve eing the most frequent cuse. Here, we descrie for the first time rre cse of TN cused y n infiltrtion of n isolted Epstein Brr virus (EBV) B cell lymphomtoid grnulomtosis (LYG) mss into the Meckel s cve nd cvernous sinus. Cse Description: A 51 yer old womn undergoing immunosuppressnt tretment for Crohn s disese presented due to right sided TN. Mgnetic resonnce imging (MRI) scns reveled n isolted lesion ffecting the right Meckel s cve nd lterl wll of the cvernous sinus. We ccomplished tumor resection through sutemporl extrdurl pproch nd the ptient recovered successfully from surgery. Histologicl exmintion reveled n LYG, nd lood test confirmed low ut positive EBV counts. The immunosuppressnt therpy ws discontinued nd we ssumed wtchful witing mngement. During 41 months follow up there ws neither evidence of LYG recurrence nor n increse of EBV counts. Conclusions: LYG, n ngiodestructive disese ssocited with EBV rectivtion in the context of immune dysfunction nd often ssocited with n ggressive ehvior or even mlignnt trnsformtion, should e considered s rre differentil dignosis of TN ssocited with skull se lesions. The mngement of this rre disese is still controversil nd vries from limiting the tretment to correcting immune dysfunction up to chemotherpy. In this cse of Access this rticle online Wesite: DOI: /sni.sni_12_18 Quick Response Code: This is n open ccess journl, nd rticles re distriuted under the terms of the Cretive Commons Attriution-NonCommercil-ShreAlike 4.0 License, which llows others to remix, twek, nd uild upon the work non-commercilly, s long s pproprite credit is given nd the new cretions re licensed under the identicl terms. For reprints contct: reprints@medknow.com How to cite this rticle: Sponton LE, Ayyd A, Archvlis E, Ringel FA. Unique cse of trigeminl neurlgi due to Epstein-Brr-virus-ssocited B-cell lymphomtoid grnulomtosis of the Meckel's cve nd cvernous sinus: Importnt clinicl nd therpeutic implictions. Surg Neurol Int 2018;9: Brr virus ssocited-b cell-lymphomtoid-grnulomtosis-of-the-meckel s-cve-ndcvernous-sinus:-importnt-clinicl-nd-therpeutic-implictions/ 2018 Surgicl Neurology Interntionl Pulished y Wolters Kluwer - Medknow

2 n isolted mss, surgicl excision nd discontinution of immunosuppressnts were effective to prevent the relpse of the disese in long term follow up. Key Words: B cell lymphomtoid grnulomtosis, cvernous sinus, Meckel s cve, trigeminl neurlgi INTRODUCTION Trigeminl neurlgi (TN) represents one of the most disling pin syndromes tht ptients cn experience. The identifiction of its etiology in individul ptients is mndtory to rule out diseses tht my primrily require specil evlution nd tretment esides the phrmcologicl therpy directed to relief neuropthic pin. TN is ssocited in vst mjority of cses with vsculr compression of the trigeminl nerve, followed more infrequently y inflmmtory nd tumor processes ffecting the nerve or its centrl pthwys. [1,2,5 7,9,15,16,18,24,29,33] Although grnulomtous diseses such s srcoidosis, tuerculosis, nd Wegener s grnulomtosis hve een descried to ffect the trigeminl nerve nd trigger TN due to infiltrtion of the skull se. [1,2,5 7,16,24,33] Till now, there re no reports of B cell lymphomtoid grnulomtosis (LYG) showing the infiltrtion of structures within the middle foss or cusing TN. We present for the first time the cse of 51 yer old womn receiving immunosuppressnt tretment due to Crohn s disese nd presenting TN cused y n infiltrtion of LYG mss into the Meckel s cve nd lterl wll of the cvernous sinus. LYG is n ngiodestructive disese ssocited with EBV rectivtion in the context of immune dysfunction. Its identifiction my e criticl due to the potentil of this disese to show very ggressive ehvior or even mlignnt trnsformtion. [10,23,28,35] In this report, we discuss the importnt clinicl nd therpeutic implictions of recognizing this entity s rre ut possile differentil dignosis of lesions ffecting the middle foss nd cusing TN. We lso review the literture ville on LYN to provide n insight into the mngement nd therpy tht might e pplicle in these cses. CASE REPORT A 51 yer old womn presented to our clinic ecuse she hd een suffering for the lsts 3 weeks from TN ffecting the right V1 V2 rnch. The ptient reported strong progression of pin s well s diplopi. Her neurologicl exmintion ws inconspicuous prt from the presence of right ducens nerve presis nd sensory loss corresponding to the V1 nd V2 dermtome. According to her clinicl records, she suffered from Crohn s disese nd hd received zthioprine s immunosuppressive therpy. Mgnetic resonnce imging (MRI) scns reveled heterogeneous T1 contrst enhncing lesion in the right Meckel s cve extending to the lterl wll of the cvernous sinus [Figure 1]. The lesion ws isointense c Figure 1: Preopertive xil (), coronl (), nd sgittl (c) MRI scns showing heterogeneous T1 contrst enhncing lesion involving the right Meckel s cve nd the lterl wll of the cvernous sinus corresponding in the histopthologicl nlysis to n Epstein Brr virus ssocited B cell lymphomtoid grnulomtosis

3 in T2 nd constructive interference in stedy stte (CISS) sequences nd did not show diffusion restriction. There ws no evidence of vsculr compression of the trigeminl nerve in the cereellopontine ngle [Figure 2]. Blood proes did not show ny norml vlues, nd protein levels in cererospinl fluid (CSF) were slightly incresed, especilly IgA nd IgG ntiodies. Oligoclonl nds were not detectle. We suggested surgicl explortion nd trigeminl nerve decompression in the Meckel s cve using right sutemporl extrdurl Dolenc pproch. During surgery, the lesion ws menle to e seprted from the durl envelope of the cvernous sinus nd ws completely resected [Figure 3]. After surgery, the ptient recovered successfully without ny new neurologicl deficits. Although the fcil sensory deficit remined unchnged, fcil pin nd diplopi from the ducens nerve presis resolved. No corticosteroids were dministered to the ptient, neither efore nor fter the surgery. Histopthologicl exmintion estlished the dignosis of Epstein Brr virus ssocited B cell lymphomtoid grnulomtosis (LYG) y showing the typicl trnsmurl vsculr infiltrtion of lymphocytes, epithelioid cells, nd histiocytes with ovl nucleus nd discrete nucleoles, necrotic epithelioid, nd gint cells on the orders nd reticulin fier infiltrtion [Figure 4]. Mycocteril infection ws excluded y Ziehl Neelsen stining, nd immunohistochemicl nlysis reveled T cells s well s clusters of CD20 positive B lymphocytes (some of them necrotic), smll CD1 positive nd S100 negtive cells, nd CD68+ mcrophges. As expected, nlysis of Epstein Brr virus (EBV) reveled virl lod of 380 copies/mm 3 in lood smples. Adominl nd thorcic computed tomogrphy (CT) scns reveled very smll intrpulmonry lesions without ffecting the lymph nodes. The ptient did not present ny systemic or respirtory symptoms. A multidisciplinry conference with the collegues of the hemtology nd gstroenterology deprtment decided to discontinue zthioprine nd strt tretment with rituxim only if the virl lod exceeded 10 3 /mm 3. The ptient ws followed up every 3 months in the first yer, every 6 months in the second, nd then once yerly. In the follow ups, no corticosteroids were prescried. Under surveillnce fter resection, there ws no crnil grnulom recurrence in further neuroimging studies performed every 6 months during the follow up [Figures 3 nd 5], nd EBV lod remined lower thn 10 3 /mm 3 ; hence, there ws no need of other specific therpies. Pin recurred fter period of pproximtely 6 months in which the ptient ws free of TN. A comined phrmcologicl therpy ws initited to reduce the pin nd showed initil success, ut unfortuntely filed to chieve complete symptomtic control in the long term. Becuse MRI scns consistently ruled out lesion c Figure 2: LYG lesion ws isointense in ntive T1 (), T2 (), nd CISS (c) sequences nd showed no diffusion restriction (d) in preopertive MRI scns Figure 3: Axil contrst enhnced T1 weighted MRI immeditely postopertive confirmed successful removl of the lesion () nd there ws no evidence of LYG relpse () 6 months fter surgery Figure 4: Histologicl tissue sections showing trnsmurl vsculr infiltrtion of lymphocytes, () epithelioid cells nd histiocytes () chrcteristic of LYG recurrence nd EBV lod persisted elow 10 3 /mm 3, we offered percutneous thermocogultion of the Gsserin gnglion, which ws refused y the ptient. DISCUSSION TN is known s one of the most disling pin syndromes. Although vsculr compression of the trigeminl nerve root d

4 Figure 5: Axil () nd coronl () contrst weighted T1 MRI imges fter 41 months follow up showing no locl recurrence of LYG t the Oersteiner Redlich zone in the cereellopontine ngle cn e identified s the cuse of TN in 80 90% of the cses, severl other conditions, such s demyelinted plques, tumor nd pseudotumor lesions, neurysms, nd rteriovenous mlformtions, hve een identified s triggers of TN. [1,2,5 7,9,15,16,18,24,29,33] Neuroimging is mndtory to investigte the etiology of trigeminl pin in ech individul ptient. It rules out diseses tht my primrily require specil evlution nd tretment exceeding the stndrd phrmcologicl therpy to relieve neuropthic pin nd contriutes to the ssessment of the optiml surgicl tretment option if the pin ecomes refrctory to mediction. Among tumor processes which cn ffect the trigeminl nerve nd trigger TN, neurinom nd meningiom re the most common, lthough mny other entities, included lymphom, hve een lredy descried. [3,9,12,17,22,25,30,34,36,37,40] More rrely, grnulomtous diseses, such s Wegener; s grnulomtosis, [1,7,24] tuerculosis, [16] nd srcoidosis [2,5,6,33] involving the Meckel s cve hve een descried s the etiology of TN. However, to our knowledge, there re no previous reports in the literture of LYG ffecting the Meckel s cve or descriing this entity s n etiologicl trigger of TN. LYG constitutes n extremely rre ngiocentric nd ngiodestructive process descried for the first time y Lieow nd collegues in the erly 1970s. It is chrcterized y nodulr lesions composed of mixed popultion of lymphoreticulr cells showing vsculr infiltrtion nd necrosis. [10,28] Its nturl history cn vry from reltively indolent course up to rpidly ftl evolution resemling high grde T cell lymphoms. [23,35] Indeed, cses of true trnsformtion into n ggressive lymphom hve een documented. [14,23,28] Therefore, the suspicion nd correct dignosis of this entity is fundmentl for the dequte mngement of ech individul ptient. More thn 90% of ptients suffering from LYG show symptomtic ilterl involvement of the lungs. [23,35] Most ptients consult due to systemic complins such s fever, weight loss, nd mlise, which re followed y respirtory symptoms such s cough nd shortness of reth nd present in pproximtely 50% nd 30% of cses, respectively. [23] Blood exmintions usully show norml leucocyte counts nd inflmmtory prmeters. [35] We my remrk tht no systemic or pulmonry symptomtology ws present in our ptient t the time of dignosis or during the follow up. Other orgns such s the kidneys, skin, nd centrl nervous system (CNS) re lso frequently ffected y LYG. Indeed, n involvement of CNS might occur in 25 50% of ptients, [23,35] lthough in such cses ffection of the CNS hs een lwys descried either s multiple, smll, intrprenchymtous rin lesions, s lrger heterogeneous ring enhncing rin msses, or s leptomeningel infiltrtion long the sl cisternl spce. [32] These lesions re chrcterized y normlly incresed signl intensity on FLAIR nd T2 weighted MR imges, s well s y punctte or liner centrl contrst enhncement in T1 sequences. [32] If leptomeninges re ffected, MRI scns will show diffuse contrst enhncement within the sl cisterns. In the series pulished y Ptslides et l., only one ptient developed lesion in the suprsellr re. [32] An isolted ffection of

5 the skull se, s in our ptient, hs not een reported yet in LYG ptients. Confusion, txi, hemipresis, nd seizures re mong the most common mnifesttions of neurologicl involvement. Others, including crnil nerve dysfunction nd peripherl neuropthy ffecting usully the lower extremities, hve een reported only spordiclly. Bell s plsy, diplopi, trnsient lindness, proptosis, defness, nd vertigo re lredy descried mnifesttions of crnil nerve dysfunction ssocited with LYG. [23,35] In ll ptients, leptomeningel involvement ws responsile for the symptoms, not isolted msses within the skull se, s in our ptient. No cse of TN hs een reported erlier in the pulished series of LYG nd the only cse existing of trigeminl infiltrtion ws gin cused y leptomeningel involvement of the sl cisterns. [23,35] In the histologicl exmintion, mononucler cells comprising T lymphocytes, plsm cells, nd histiocytes re ccompnied y only smll numer of B lymphocytes showing EBV positivity. However, the key feture comprehends the ngiocentric nd ngiodestructive nture of the lesions with trnsmurl vsculr infiltrtion of T cells nd histiocytes showing vrious degrees of necrosis. [10,35] These chrcteristics should e meticulously considered to differentite this entity from other diseses which cn ffect the cvernous sinus or Meckel s cve, cn trigger TN, nd my histopthologiclly resemle some fetures of LYG, such s srcoidosis, Wegener s grnulomtosis, or lymphom. The pthophysiology of this disese hs een linked to lck of control of EBV infected B cells. In this context, it is greed tht recruitment of intrvsculr T cells induced y EBV infection my medite the vsculr dmge seen in histologicl specimens. [20] Aprt from EBV lod counts, serch for IgG nd IgM ntiodies directed ginst EBV should e performed in ll ptients. Underlying this EBV rectivtion, functionl immune dysregultion hs een seen in lmost ll ptients suffering from LYG [20,41] nd, consistent with this oservtion, the occurrence of LYG hs een ssocited with severl utoimmune diseses, congenitl immunodeficiencies, nd conditions following either leukemi therpy or orgn trnsplnttion. [23,27,31] In ddition, discontinuing immunosuppressnts hs een oserved to induce remission in ptients with LYG, nd this option my e considered for ech ptient, if resonle. [35] In more severe cses with evidence of progressive disese, ptients hve een treted with corticosteroids, rituxim, interferon α 2, nd chemotherpeutic gents such s prednisone, etoposide, vincristine, cyclophosphmide, nd doxorucin. [4,8,13,14,19,21,23,38] Although progression nd mlignnt trnsformtion justify the use of these strtegies, ecuse n immunodeficiency underlies the pthophysiology of this disese, there re concerns whether tretment with corticosteroids nd chemotherpy could lso hve the potentil of worsening the clinicl course. Unfortuntely, due to the infrequent presenttion of this disese, there is lck of medicl studies systemticlly proving the effectiveness of these tretments, nd few pulished series hve reported conflicting results. Furthermore, lck of cses reporting n involvement of the skull se mkes it difficult to predict the effectiveness of these gents for the tretment of ptients like the one we present in this rticle. Discontinution of zthioprine, regulr control of EBV virl counts, s well s clinicl nd neuroimging follow up seem to hve een resonle strtegy for our ptient who did not show evidence of relpse or progressive disese during 41 months of follow up. We ssumed tht the recurrence of TN fter 6 months must hve een ssocited with postsurgicl dhesions/scrring nd not to relpse of LYG or EBV rectivtion. It is importnt to consider tht MRI scns performed t the time of pin recurrence nd further on repetedly demonstrted no LYG mss relpse. Furthermore, EBV counts remined <10 3 /mm 3, nd there were no clinicl fetures of ctive systemic EBV infection long the complete follow up. Although locl EBV rectivtion cnnot e completely excluded s possile cuse of TN recurrence (due to the fct tht EBV counts hd lredy een <10 3 /mm 3 t the time of dignosis), in scenrio of locl EBV ctivtion we would hve expected progressive findings in consecutive MRI scns s well s further neurologicl deteriortion of the ptient, neither hd occurred. The role of surgery my e deted in cses such s the one presented. First, in our ptient, surgery ws clerly indicted to otin mteril for histopthologicl dignosis. The typicl locliztion of LYG lesion within the Meckel s cve nd cvernous sinus hd not een descried efore, thus mking the preopertive tenttive dignosis of this disese unlikely in our cse. Furthermore, the MRI chrcteristics shown y this lesion were unspecific. The inhomogeneous contrst enhncement in T1 weighted imges resemled fetures tht re commonly descried in other diseses which hve een reported to ffect the cvernous sinus nd surrounding structures, such s lymphom, tuerculom, srcoidosis, or Wegener s grnulomtosis. [1,2,5 7,16,24,26,33] Furthermore, the nodulr involvement of the lungs is lso common feture tht might occur in ll these diseses. Interestingly, we my remrk the sence of diffusion restriction in MRI shown y the LYG mss in our ptient. Although unspecific, restriction in diffusion weighted MRI is usully oserved in inflmmtory processes such s srcoidosis or tuerculosis, s well s frequently in dense cellulr tumors such s lymphoms. [26] Fr from eing le to generlize our findings, this chrcteristic, leit nonspecific feture could eventully help to suspect this disese in future cses. Perhps MRI spectroscopy

6 performed on similr lesions could e of gret interest in the future to identify possile key fetures tht my e helpful to differentite nd individulize these lesions. In ddition, the determintion of EBV ntiodies or positive virl lod cn e helpful to suspect this disese, however, these prmeters do not replce the need of histopthologicl exmintion. EBV infection infect the mjority of world popultion nd remins symptomtic in most cses. [11,39] Furthermore, other entities which hve een descried to ffect the cvernous sinus, such s Burkitt lymphom, cn e lso ssocited with EBV infection, mking the differentition of these entities possile only y tissue exmintion. [12,17,22,40] As surgery ws indicted in our ptient, the next dilemm we fced ws whether just iopsy for dignostic purposes or n ttempt to remove the mss, followed in oth cses y immunosuppressnt discontinution nd/or chemotherpy, would e the most resonle pproch for cses similr to the one we descrie. This question my e difficult to nswer given the infrequent presenttion of LYG nd it is consequentilly difficult to predict response y only dopting conservtive strtegy, considering the reltively poor knowledge we hve out the nturl history of the disese s well s the lck of similr cses ffecting the skull se. Although there hve een spordic reports of LYG remission fter discontinuing immunosuppressnts or chemotherpy, [35] none of these cses were deling with lesions locted in the skull se. On one hnd, in our experience, the fesiility to remove the mss y n experienced neurosurgeon enled us not only to get enough mteril for histopthologicl nlysis ut lso to resolve the prolem of mss effect versus relevnt neurovsculr structures s well s to void leving ehind in situ lesion which is known to hve the potentil of ggressive mlignnt trnsformtion. [14,23,28] On the other hnd, iopsy nd immunosuppressnt discontinution dded or not to chemotherpy nd followed y nrrow wit nd see strtegy could e resonle in cse of lesions difficult to remove. In those cses, strict follow up with MRI t short term intervls must e mndtory. CONCLUSIONS The cse we present here provides relevnt clinicl nd therpeutic implictions. We descrie for the first time LYG s rre ut existing differentil dignosis of Meckel s cve nd cvernous sinus msses ssocited with TN. As the periopertive evlution nd tretment my significntly differ etween LYG nd other tumor nd inflmmtory entities, we recommend eing wre of this disese, especilly in ptients with prior history of EBV infection, utoimmune disese, nd/or undergoing immunosuppressive therpy. In such ptients, the presence of systemic symptoms s well s signs of pulmonry, skin, kidney, eye, or even intrcererl nd leptomeningel involvement my e helpful to suspect the dignosis, ut their sence does not rule out LYG, s hs een oserved in our ptient. If LYG is suspected, serching for EBV titers my lso e useful to orientte the dignosis, long with thorcic nd dominl CT scns to detect whether other orgns, especilly the lungs, re ffected. However, in ll cses, histopthologicl exmintion is mndtory to confirm the dignosis. In our cse, we hve oserved tht the removl of LYG loclized in the Meckel s cve nd cvernous sinus my e fesile nd sfe. Performed y experienced hnds, surgery my correlte with trnsient pin relief. In our ptient, discontinuing immunosuppressive therpy ws followed y the reduction nd stiliztion of EBV counts nd prevention of relpse or progression of the disese. Whether corticosteroids, rituxim, interferon α 2, or chemotherpy should e considered in cse of recurrent disese is still n open question. We cnnot provide ny recommendtion for the use of these gents sed on our experience. Ethicl stndrds nd conflict of interest The mnuscript does not contin clinicl studies or identity ptient dt nd the uthors declre tht they hve no conflict of interest. Declrtion of ptient consent The uthors certify tht they hve otined ll pproprite ptient consent forms. In the form the ptient(s) hs/hve given his/her/their consent for his/her/ their imges nd other clinicl informtion to e reported in the journl. The ptients understnd tht their nmes nd initils will not e pulished nd due efforts will e mde to concel their identity, ut nonymity cnnot e gurnteed. Finncil support nd sponsorship Nil. Conflicts of interest There re no conflicts of interest. REFERENCES 1. Andrews JT, Kountkis SE. Wegener's grnulomtosis of the skull se. Am J Otolryngol 1996;17: Aris M, Iglesis A, Vil O, Brs J, Conde C. MR imging findings of neurosrcoidosis of the gsserin gnglion: An unusul presenttion. Eur Rdiol 2002;12: Arimoto H, Shirotni T, Nku H, Hshizume K, Ski Y, Mtsukum S. Primry mlignnt lymphom of the cvernous sinus-cse report. Neurol Med Chir (Tokyo) 2000;40: Armitge JO. My tretment pproch to ptients with diffuse lrge B-cell lymphom. Myo Clin Proc 2012;87: Bngiyev L, Korncki S, Mikolenko I. Rre isolted trigeminl nerve srcoidosis mimicking schwnnom. Clin Imging 2015;39: Brksick S1, Shh-Hque S, El-Hddd B, Mouss R. Neurosrcoidosis

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