Mononeuritis multiplex: an uncommon neurological manifestation of cytomegalovirus reactivation in an HIV-infected patient

CASE REPORT Open Access Mononeu i is mul iplex: an uncommon neu ological mani es a ion o cy omegalo i us eac i a ion in an HIV-in ec ed pa ien Ped o Palma 1,2* , And eia Cos a 3 , Raquel Du o 1,2 , Nélia Ne es 1,2 , Cândida Ab eu 1,2 and An ónio Sa men o 1,2 Abs ac Backg ound: Cy omegalo i us (CMV) eac i a ion wi h neu ological in ol emen in pa ien s wi h acqui ed immunode iciency synd ome (AIDS) is inc easingly a e since he in oduc ion o an i e o i al he apy (ART). Mani es a ions include encephali is, myeli is, poly adiculopa hy and, less commonly, mononeu i is mul iplex (MNM). We epo a case o dissemina ed CMV disease wi h gas oin es inal and pe iphe al and cen al ne ous sys em in ol emen in a pa ien wi h AIDS, mani es ing p ima ily as MNM. Case p esen a ion: A 31-yea old woman wi h AIDS p esen ed wi h a clinical pic u e o MNM. Elec omyog aphy con i med he clinical indings. CMV DNA was de ec ed in ce eb ospinal luid (CSF) and blood. Gas oin es inal in ol emen was his ologically documen ed. HIV RNA was also de ec ed in CSF and b ain MRI was consis en wi h HIV encephalopa hy. A diagnosis o dissemina ed CMV disease (wi h esophagi is, coli is, encephali is and MNM) and HIV encephalopa hy was made. T ea men consis ed o ganciclo i and osca ne , ollowed by main enance he apy wi h alganciclo i . E olu ion was a o able and alganciclo i was s opped a e sus ained immune eco e y ollowing ART ini ia ion. Conclusion: We discuss he diagnos ic app oach o CMV neu ological disease, wi h a ocus on MNM and CMV encephali is. Combina ion he apy wi h ganciclo i and osca ne should be conside ed o all o ms o neu ological in ol emen , al hough a ailable da a a e sca ce. Since he e is signi ican o e lap be ween CMV encephali is and HIV encephalopa hy, ART d ugs wi h highe CSF pene a ion may ha e o be conside ed. ART and immune eco e y a e essen ial o imp o e ou comes. Keywo ds: Mononeu i is mul iplex, CMV, HIV, AIDS Backg ound Mononeu i is Mul iplex (MNM) is an uncommon o m o pe iphe al neu opa hy, usually p esen ing wi h mo o and senso y symp oms in an asymme ic pa e n in ol ing wo o mo e pe iphe al ne es [1,2]. In HIV-in ec ed pa ien s wi h MNM, wo e iological mechanisms ha e been desc ibed: au oimmune, ypically a limi ed o m in pa ien s wi hou acqui ed immunode i- ciency synd ome (AIDS); and cy omegalo i us (CMV) eac i a ion, a gene alized o m in pa ien s wi h AIDS [2,3]. CMV eac i a ion in HIV pa ien s wi h ad anced disease mos equen ly p esen s as e ini is, coli is, and esophagi is. Neu ological in ol emen is less common and can mani es as encephali is, myeli is, poly adiculopa hy, and mononeu i is mul iplex. In he p e-an i e o i al he - apy (ART) e a, whe e up o 40% o HIV-in ec ed pa ien s wi h ad anced disease de eloped CMV disease [4,5], CMV MNM was al eady conside ed uncommon [6,7]. A mo e equen ype o neu ological disease, CMV * Co espondence: [email p o ec ed]; [email p o ec ed].p 1 In ec ious Diseases Depa men , Cen o Hospi ala de São João, Alameda P o esso He nâni Mon ei o, 4200-319 Po o, Po ugal 2 Ins i u o de Ino ação e In es igação em Saúde (I3S). G upo de I&D em Ne ologia e Doenças In eciosas, Ins i u o Nacional de Engenha ia Biomédica (INEB), Po o, Po ugal Full lis o au ho in o ma ion is a ailable a he end o he a icle © The Au ho (s). 2018 Open Access This a icle is dis ibu ed unde he e ms o he C ea i e Commons A ibu ion 4.0 In e na ional License (h p://c ea i ecommons.o g/licenses/by/4.0/), which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided you gi e app op ia e c edi o he o iginal au ho (s) and he sou ce, p o ide a link o he C ea i e Commons license, and indica e i changes we e made. The C ea i e Commons Public Domain Dedica ion wai e (h p://c ea i ecommons.o g/publicdomain/ze o/1.0/) applies o he da a made a ailable in his a icle, unless o he wise s a ed. Palma e al. BMC In ec ious Diseases (2018) 18:554 h ps://doi.o g/10.1186/s12879-018-3501-2 encephali is, was epo ed in 1% o cases [6,8]. Au opsy s udies, howe e , ecognized CMV in ec ion o he cen al ne ous sys em (CNS) in 12 o 28% o pa ien s wi h AIDS [6,9]. Simila ly o o he oppo un- is ic in ec ions, since he in oduc ion o ART he incidence o CMV disease dec eased conside ably, wi h ecen ly epo ed incidence a es o < 0.50 pe 100 pe son-yea s [10,11]. We desc ibe a case o dissemina ed CMV disease in a pa ien wi h AIDS, mani es ing p ima ily as MNM. We ocus on he neu ological in ol emen o CMV and dis- cuss he diagnos ic challenges and ea men app oach o his inc easingly uncommon mani es a ion. Case epo A 31-yea -old whi e woman p esen ed wi h se e e bu n- ing pain wi h ingling sensa ion and asymme ic weak- ness o he lowe limbs ha , o e a six-mon h pe iod, g adually wo sened and p og essed o in ol e he uppe limbs; she was hen unable o walk o ea alone. She had been diagnosed wi h HIV in ec ion i e yea s ea lie a ano he e ia y ca e hospi al bu e used ollow-up. On admission, she was unde nou ished and he neu o- logical examina ion e ealed: le ha gy, diso ien a ion and psychomo o slowing; asymme ically diminished mo o s eng h (Medical Resea ch Council Scale) in he ou limbs (g ade 2/5 in igh uppe limb ex ension; g ade 3/5 in bila e al lowe limb ex ension; g ade 4/5 in he emaining); symme ical deep endon e lexes apa om absen igh b achio adialis and bila e al pa ella e lexes; impai ed pin-p ick sensibili y in he igh ulna and adial dis ibu ion. The emainde physical examina ion was un ema kable. B ain MRI (Fig. 1) was consis en wi h HIV encephal- opa hy and elec omyog aphy (EMG) wi h he diagnosis o MNM (se e e con luen mul i ocal demyelina ion and axonal loss in bo h uppe and lowe limbs). CD4 cell coun was 75 cells/μL (8%) and HIV RNA was 633000 copies/mL. CMV DNA in blood was 64000 cop- ies/mL; CMV an igen was nega i e. CMV IgG an ibodies we e posi i e and IgM an ibodies nega i e; u he mo e, elec onic medical eco ds om i e yea s ea lie con- i med p io CMV IgG se oposi i i y, sugges ing CMV e- ac i a ion. Ce eb ospinal luid (CSF) analysis e ealed 7 cells, p o ein o 1.19 g/dL and glucose o 49 mg/dL; nega- i e bac e ial and ungal cul u es; posi i e CMV DNA (14400 cp/mL) and HIV RNA (184222 cp/mL). Gas o- in es inal in ol emen (esophageal and colonic) by dis- semina ed CMV disease was his ologically documen ed, e en hough he pa ien epo ed no ela ed symp oms; e inal in ol emen was excluded. Wi h dissemina ed CMV disease as he mos likely cause o MNM, she s a ed IV ganciclo i (5 mg/kg e e y 12 h). Due o no signi ican clinical imp o emen , ea men was in ensi ied 7 days la e wi h he associ- a ion o IV osca ne (90 mg/kg e e y 12 h). Combin- a ion he apy was main ained o h ee weeks, a e which CMV DNA became unde ec able in blood (she e- used a new lumba punc u e) and o al alganciclo i 900 mg/day was s a ed as main enance he apy. She ini- ia ed ART wi h em ici abine/ eno o i and dolu eg a i ollowing wo weeks o combina ion he apy a ge ed a Fig. 1 B ain MRI. Axial T1 (a-b), T2/FLAIR (c-d), DWI (e- ) and ADC- map (g-h). Bila e al ela i ely symme ic pe i en icula and deep whi e ma e T2/FLAIR hype in ensi y p edominan ly in he pos e io sup a en o ial a ea. A eas o es ic ed di usion we e no obse ed Palma e al. BMC In ec ious Diseases (2018) 18:554 Page 2 o 5 CMV disease and slow, bu ob ious, clinical esponse. He neu ological symp oms, bo h neu ocogni i e and mo o , g adually imp o ed and she began a ehabili a- ion p og am. She was ans e ed o a ehabili a ion cen e and discha ged a e wo mon hs. Follow up a h ee mon hs o ART ini ia ion showed CD4 cell coun imp o emen (313 cells/μL (27%)) and unde ec able HIV RNA. A e 6 mon hs o sus ained im- mune eco e y (CD4 cell coun 722 cells/μL (24%)) and i ologic supp ession, main enance he apy wi h algan- ciclo i was s opped. A 12 mon hs o ini ial symp oms, she showed no neu- ocogni i e impai men and was able o e u n o he no mal daily ac i i ies. Mo o s eng h imp o ed globally o no mali y besides g ade 4/5 in igh -hand inge s ex- ension and in he lowe limb ex ension; pin-p ick sens- ibili y emained impai ed in he igh uppe limb. She epo ed neu opa hic pain in he lowe limbs, which was managed wi h p egabalin 225 mg wice daily. EMG was consis en wi h ne e egene a ion in he uppe limbs and, o a lesse ex en , in he igh lowe limb. Discussion and conclusions In his pa ien , he e idence o dissemina ed CMV dis- ease and he p esen a ion wi h asymme ic neu ological signs, wi h EMG indings consis en wi h MNM, was su icien o he clinical diagnosis o CMV MNM. CMV mononeu i is mul iplex can be ex ensi e, in ol - ing se e al limbs o c anial ne es. Bo h a classic p esen- a ion wi h pain ul, p og essi e, mul i ocal de ici s and a mo e apidly p og essi e synd ome, in ol ing mul iple ne e dis ibu ions, ha e been desc ibed in pa ien s wi h ad anced AIDS [7]. EMG is key in he con i ma ion o clinical indings, ypically showing a neu opa hy wi h mul i ocal demyelina ion and axonal loss [2,7,12]. While no necessa y o a clinical diagnosis o CMV MNM, polyme ase chain eac ion (PCR) de ec ion o CMV DNA in CSF has been shown o co ela e wi h all o ms o CMV neu ological disease (sensibili y and spe- ci ici y o > 90%) [13,14], e en in cases o isola ed pe - iphe al neu opa hy [14]. PCR o plasma o whole blood is also aluable as i can be used as a sensi i e “su oga e ma ke ”o CMV eac i a ion and subsequen disease and is less p one o alse nega i es compa ed o an ige- nemia assays [15,16]. Mo eo e , se ial quan i a i e PCR es ing o specimens is help ul o moni o esponse o ea men [15]. Ne e biopsy may p o ide addi ional con i ma ion as CMV has been demons a ed in mac o- phages, ib oblas s, and endoneu ial cells in he supe i- cial ne es o pa ien s wi h MNM [17]. In ou pa ien , CMV DNA de ec ion in he CSF coupled wi h signs o al e ed men al s a us sugges ed a mo e ex ensi e neu o- logic in ol emen o CMV disease. Howe e , simul an- eous CMV encephali is and HIV encephalopa hy we e conside ed since HIV RNA was also de ec ed in CSF and MRI indings we e consis en wi h he la e . The diagnosis o CMV encephali is can be pa icula ly challenging. Pa ien s o en p esen wi h p og essi e al- e ed men al s a us which may be di icul o dis inguish om HIV encephalopa hy [6,8,9]. In con as o HIV encephalopa hy, CMV encephali is has a mo e apid on- se (mean onse o less han ou weeks) and symp oms o deli ium, con usion, apa hy, and wi hd awal a e mo e equen [6,8]. Ye , o he non-dis inguishing neu o- logical mani es a ions, such as o ge ulness, memo y impai men , and psychomo o slowing, a e also common [6]. A mo e dis inc ype o CMV encephali is cha ac e - ized by en iculoencephali is has also been desc ibed and p esen s wi h apidly p og essi e con usion and le ha gy [6,8], wi h a iably associa ed adiculopa hy and c anial ne e de ici s [8]. MRI may show mul iple hype ense oci dis ibu ed widely in he b ain o pe i- en icula enhancemen on T2-weigh ed images, al- hough hese indings a e inconsis en ly p esen and la gely non-speci ic [18,19]. Con e sely, HIV encephal- opa hy ypically shows widesp ead hype in ense lesions on T2-weigh ed/FLAIR, localized bila e ally in he deep whi e ma e [18], a pic u e ha mo e closely esembled he MRI indings in ou pa ien . Simila ly o CMV neu ological disease, HIV RNA de ec ion in CSF co e- la es signi ican ly (albei weakly) wi h he p esence o HIV encephalopa hy in un ea ed pa ien s, an associ- a ion no seen in pa ien s on ART [20,21]. Howe e , CNS oppo unis ic in ec ions may also inc ease in a- hecal HIV eplica ion [22]. T ea men o all o ms o CMV neu ologic disease is simila , al hough da a a e sca ce. Mos au ho s ecom- mend ganciclo i o osca ne , o a combina ion o bo h d ugs. Combina ion he apy may be conside ed in hose p e iously ea ed wi h CMV-di ec ed d ugs (hence wi h isk o d ug- esis an i us) and in pa ien s wi h disease p og ession unde mono he apy [8]. Fosca ne le els in CSF a y widely, achie ing 0 o 3.4 imes o plasma con- cen a ion (mean alues o 23%) [23]. A s udy o he pha macokine ics o ganciclo i in plasma and CSF in a nonhuman p ima e model showed ha he d ug pene- a es in o he CSF ollowing IV adminis a ion (CSF o plasma a ea unde he cu e o 15.5%+/−7.1%) [24]. The e o e, ano he a ionale o combina ion he apy use is o inc ease CSF pene a ion due o he a iable le els achie ed by ei he d ug alone. Despi e being ela i ely well ole a ed, his egimen may be limi ed by inc eased side e ec s, pa icula ly bone ma ow supp es- sion wi h ganciclo i and neph o oxici y wi h osca ne [23,25]. The e a e no da a on CSF pene a ion o cido o- i and he e o e i should be a oided [8,25]. Op imal du a ion o ini ial he apy is unknown and should be guided by an imp o emen o clinical symp oms [6,8,9]. Palma e al. BMC In ec ious Diseases (2018) 18:554 Page 3 o 5 Ou pa ien was ea ed wi h combina ion he apy con- side ing hese e i yo hedisease, ex ensi e neu o- logical in ol emen and slow ini ial imp o emen wi h ganciclo i alone. Addi ionally, as wi h o he oppo unis ic in ec ions, ini- ia ion o ART and e e sal o p o ound immunode i- ciency is conside ed essen ial o success ul managemen [26,27]. Op imal iming o ART ini ia ion is no well de- ined and he decision o s a ART ea ly in he cou se o CMV disease mus be weighed agains he isk o CMV immune econs i u ion in lamma o y synd ome (IRIS). None heless, da a on CMV IRIS p esen ing as neu o- logical disease a e limi ed: a case o CMV encephali is was epo ed in an HIV-in ec ed pa ien wi h CMV coli is on ART and alganciclo i (al hough wi h adhe ence issues), whe e IRIS may ha e played a ole [28]. Repo s o im- mune eco e y u ei is ollowing ea ly ART ini ia ion in pa ien s wi h CMV e ini is a e mo e commonly desc ibed h oughou he li e a u e [29–31]. Conside ing he ex en- si e in ol emen o CMV disease in ou pa ien , ART was ini ia ed a e an ob ious clinical imp o emen wi h com- bina ion he apy o CMV was obse ed. Op imiza ion o ART using d ugs ha pene a e e - ec i ely in o he CSF has been shown o imp o e he ou come o pa ien s wi h neu ological symp oms and de ec able HIV i al loads in he CSF [32,33]. The possi- bili y o associa ed HIV encephalopa hy mo i a ed ou choice o include dolu eg a i in he ART egimen since concen a ions in he CSF ha e been shown o be simila o unbound plasma concen a ions, achie ing he a- peu ic le els in he CNS [34]. This pa ien ou come was a o able: clinical imp o e- men was ob ious, CMV i emia was clea ed and no sig- ni ican side e ec s we e obse ed. In he p e-ART e a, ou comes o CMV- ela ed neu ological disease we e gen- e ally poo , wi h a epo ed median su i al o less han h ee mon hs [6,9]. Fu he mo e, CMV MNM was de- sc ibed wi h simul aneous encephali is, poly adiculopa hy o e ini is leading o dea h wi hin a ew days o weeks i le un ea ed [6]. The imp o ed su i al o HIV-in ec ed pa ien s and dec easing incidence o CMV disease in ecen yea s deno es ha p ognosis is dependen on adequa e an i e o i al ea men and immune econs i u- ion. The impac o he choice o ART egimen on he pa- ien neu ological imp o emen (besides he ob ious bene i o immune eco e y) is di icul o asce ain. CSF e alua ion a ollow-up migh ha e been aluable o de e - mine he e ec in CSF HIV i al load since CNS compa men aliza ion o HIV has also been epo ed [32]. Du a ion o main enance he apy o CMV ollowing neu ological disease is deba able. Howe e , conside ing bo h he isk o ec udescence o a se ious disease and he isk o IRIS, awai ing immune econs i u ion (i.e., a sus ained ise o CD4 cell coun ≥100–150/μL and unde ec able HIV RNA o mo e han 6 mon hs) may be wise be o e s opping main enance he apy [26,27]. In conclusion, CMV neu ological disease is inc easingly uncommon since he in oduc ion o ART. This pa ien wi h AIDS p esen ed p edominan ly wi h a clinical pic u e o MNM, ha ha bo ed a dissemina ed CMV disease. The widesp ead a ailabili y o highly sensi i e and speci ic PCR echniques can signi ican ly sho en he ime o diagnosis o CMV eac i a ion. While he spec um o neu ological in ol emen o CMV disease in HIV-in ec ed pa ien s can be di e se, i is associa ed wi h high mo bimo ali y and isk o apid p og ession i le un ea ed. Since CSF pene- a ion o he a ailable an i i als a ies widely, combin- a ion he apy wi h ganciclo i and osca ne should be conside ed. The isk o IRIS should be weighed in when deciding he iming o ART ini ia ion and he o e lap in mani es a ions o CMV and HIV in ec ion o he CNS may also be a ac o du ing he selec ion o ART egi- mens, a o ing d ugs wi h highe CSF pene a ion e icacy. None heless, ART ini ia ion and subsequen immune e- co e y we e essen ial o he a o able ou come epo ed, which con as ed as ly om he na u al cou se o CMV neu ological disease in he p e-ART e a. Abb e ia ions AIDS: Acqui ed immunode iciency synd ome; ART: An i e o i al he apy; CMV: Cy omegalo i us; CNS: Cen al ne ous sys em; CSF: Ce eb ospinal luid; EMG: Elec omyog aphy; HIV: Human de iciency i us; IRIS: Immune econs i u ion in lamma o y synd ome; MNM: Mononeu i is mul iplex; PCR: Polyme ase chain eac ion Acknowledgmen s No applicable. Funding No applicable. A ailabili y o da a and ma e ials Da a sha ing is no applicable o his a icle as no da ase s we e gene a ed o analyzed du ing he cu en s udy. Au ho s’con ibu ions PP, AC, RD, and NN we e esponsible o he pa ien ’s ca e and managemen du ing hospi aliza ion and ollow-up a e discha ge, collec ed all signi ican clinical in o ma ion, and d a ed his manusc ip . CA and AS e iewed, ed a ed and gi en signi ican con ibu ion o he inal e sion. All au ho s ead and app o ed he inal manusc ip . E hics app o al and consen o pa icipa e No applicable. Consen o publica ion W i en in o med consen was ob ained om he pa ien o publica ion o da a and images con ained in his case epo . A copy o he w i en consen is a ailable o e iew by he Edi o o his jou nal. Compe ing in e es s The au ho s decla e ha hey ha e no compe ing in e es s. Publishe ’sNo e Sp inge Na u e emains neu al wi h ega d o ju isdic ional claims in published maps and ins i u ional a ilia ions. Palma e al. BMC In ec ious Diseases (2018) 18:554 Page 4 o 5 Au ho de ails 1 In ec ious Diseases Depa men , Cen o Hospi ala de São João, Alameda P o esso He nâni Mon ei o, 4200-319 Po o, Po ugal. 2 Ins i u o de Ino ação e In es igação em Saúde (I3S). G upo de I&D em Ne ologia e Doenças In eciosas, Ins i u o Nacional de Engenha ia Biomédica (INEB), Po o, Po ugal. 3 Neu ology Depa men , Cen o Hospi ala de São João, Alameda P o esso He nâni Mon ei o, 4200-319 Po o, Po ugal. Recei ed: 21 May 2018 Accep ed: 2 No embe 2018 Re e ences 1. Swash M, Schwa z M. 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