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Bricf Communication

Successful Treatment of CytomegalovirusPolyradiculopathy in a 9-year-old ChildWith Congenital HUlnanImmunodeficiency Virus InfectionAman Sohal, i\IHCPCH, Andrcw Riordan, i\ID, FRCPCH, DTi\lH,i\lac i\Iallcwa, i\IRCPCH, DTi\IH, Tom Solomon, PhD, FRCP, DTi\lH, andRachel Kneen, i\\HCPCH

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Cytomcgalo\'irus lumbosacral polyradiculopathy is awcll-documcnted complication of human immunodcfi­ciency \'irus in adults who hm'c a CD4 count of less than40/~1L. Patients prcscnt with an acute ascending flaccidparalysis of the 10ll'cr limbs with arcflexia, paresthcsia, andurinary and howel symptoms. Howc\'cr, it appears to hc rarcin childrcn with congenitally acquired immune dcficiency

Cytomegalo\'irus lumbosacral polyrndiculopathy in, acquircd immune dcficiency syndrome (AIDS) is

. uncommon in children, and the rcsponse to treat­ment is uncertain. \\le report <Ichild with cytomegalm'iruspolyradiculopathy who made an cxcel[ent neurq)ogica)recm'ery follO\\ing treatmcnt.

Case Report

A 9-year-old African girl presentcd 2 weeks after mri\'ingin the United Kingdom with weakness, inability to walk,and lumbar hackache. She also had <Icough, fm'er, hearingloss in thc [cft car, [oosc stools with central abdominal

IIccci\'ed February 11,2008. Ht'Ceh'cd reviseu .\Iay 14, 2008./\ccepl<:d forpublication June 13, 2008.

Frum Ihe Departments of i'\t'urulogy (AS, 1\11\1, RK) and .'.Iedical1\licrohiology (An), Liltle\mods Ncuroscience Founualion, RoyalI.hwpool Chiluren's NilS Trust, Alder lie)', Li\'erpool, Uniteu Kingdom;anu Dh'isions of Neurological Science, 1\lcdical 1\licrobiologr and Schoolof Tropical 1\leuicine, Unh'crsity of Li\wpool, Uniled Kinguom (T5).

The authors ha\'e no eonnicts of inlerest to disclose wilh rt'gard to thisarticle.

Auuress eorrespol\tlence to: Hache! Kneen, Deparllnen! of Neurology,Linle\\'oo"s Neuroscience foundalion, Hoya! Lh'erpool Children'si'\IISTrus!, Alder lIey, Li\'erpool, UK: e·mail: rachel.kneen@rlc.nhs.uk.

Sobal A, Hiordan A, 1\lallc\\'a 1\1,Solomon T, Kneen H. Successful trea!­men! of C}10megalO\'irus pol}Tauieulopalhy in a 9·ycar·old child \\ ith con­genital human immunout·ncit·ncr virus infection. } C/,i/d '""Cllro/.2009:2-1:215-218.

syndromc. \\lc rcport a 9-year-old child with congcnitalhuman immunodcficiency virus infection who presented withcytomcgalol'irus polywdiculopathy and made an cxccllentrcsponse to cytomcgalo\'irus treatment.

KC}"l'Onls; human immunmleficicncy virus; cytomegalo­virus; polyradiculopathy

pain, and wcight loss. She was horn to a human immunoo

deficiency virus (HIV)-positi\'c mother, and was thc sec­ond of 3 children of nonconsanguineous parents. Shc wasexclusively breast-fed and had normal' dC\'clopmenta[milcstoncs. About 6 months before prescntation she hadbeen treatcd for pulmonary tuberculosis. Details of thechild's history including drug regimen werc incompletebccause she had bcen [i\'ing with her grandmothcr for thepreceding 4 years.

Examination findings included pallor, dehydration,malnutrition (weight < O.4th centile), oral candidiasis,hcalcd zostcr scars in Icft thoracic 5/6 dermatomcs, andfingcr clubbing. Respiratory and abdominal examinationswere unremarkable. Ncurological assessment rC\'c<1ledphotophobia with no neck stiffness and right lower motorneuron facial weakness. She could sit unsupported but notwalk independently. Tone was decreased g[obally. Powcrwas 4/; powcr in all limbs. Dcep tendon reflexes werediminished at thc ankles and knccs, and plantar rcflcxeswere flexor. Sensory cxamination was not possible due tothe child's age and lack of cooperation (including languagebarrier). Thc lumbar area was not erythematous or tcndcr.O\'er the ncxt few days, she dcveloped flaccid paralysis ofthe lowcr limbs and urinary retention requiring catheteri­zation. Examination re\'ealed significant reduction inpowcr (Grade 0-'2 in all muscle groups), with the [eft lowerlimb more affcctcd than right, decrcased tone, absentreflexes <It the knces and ankles, and absent superficialabdominal reflcx.

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216 JOllrua/ of Chi/a ,'\cllw/o::r / Vol. 24, No.2, Fehruor}' 2009

Figure 2. T1 a\ial magnetic resunance imaging (;\IHI) of spine withgadolinium enhancement rewaling anterior ,lisl'laccmcnt of caudaequina with enhancement of nerye roo IS.

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Figure I. T2 a\inl magnetic reson'1I1ce imaging (;\IBI) brain scane.\hibiling generali/ed while mailer loss and prominence of laleral"cnlrides,

Initinl im'cstigations rC\'cn(cd hypcrnntrcmic dchydmtion(sodium 147 mEq/L), ancmia (hcmoglobin 6.8 gldL),mildly dc\'atcd inflnl11l11ntorymarkcrs (C-rcacth'c protein33 mglL), and a ncgati\'c intcrfcron gnl11l11nrdcnse nssnyfor tuberculosis. Human immunodeficiency \'irus nnti­body wns positivc with a viral load of 206 200 copics/mLand the CD4 count was undctcctable. Chcst mdiographwas consistent with bibnsal infcction but no signs ofrcccnt pulmonary tubcrculosis infcction. Lumbar punc­turc rc\'cnlcd turbid cerebrospinal fluid, whitc cell count1502/I1L (ncutrophils 1380/~IL, monocytcs 18h1L, dcgcn­cmtivc cclls J04/~IL), rcd blood cclls 36 OOO/~IL,glucose0.8 g/L (blood glucosc 4.7 glL), protein 3.05 glL, lactate5.5 mmol/L, ncgative Gram stain, negativc Zcil-Neilsonstnin, and no growth aftcr 5 dnys incubntion. i\lngncticrcsonancc imaging (i\IRI) of bmin rc\'calcd gcncmlizcdwhitc mattcr loss consistcnt with atrophy with slight pro­minencc of vcntriclcs (figurc I).

Shc was commcnccd on antitubcrculosis thcrapy(isoniazid, rifampicin, ethambutol, and pymzinamidc)without corticostcroids. In nddition, co-trimoxazolc pro­phylaxis nnd fluconnzolc wcre started. The followingdiffercntinl dingnoscs wcre considered: viral lumbosacral

pol}Tadiculopathy, conus medullnris or cauda equina syn­drome, polyneuropnthy, and lymphomatous spinnl mnss.

i\ lagnetic rcsonancc imaging of spinc rc\'cnlcd clump­ing and antcrior displacemcnt of the cauda equina withenhnnccmcnt of the ncn'c roots consistent with nm­

chnoiditis. Thcre was further cnhnnccmcnt along thcantcrior and postcrior aspcct of thc spinal cord followinggadolinium (Figurc 2). No signal abnormality wnsdctcctcd within thc cord. Ccrcbrospinal fluid polymcrascchain reaction (PCR) was posith'c for cytomcgalovirus(12 226000 copics/mL), and ncgativc for varicella zoster,hcrpcs simplcx virus, Epstcin-Barr virus, toxopbsmn, nndtuberculosis. Polymerasc elwin rcnction for cytomcgalo­\'irus wns also positi\'c in the hlood (1900 copics/mL).Ncurophysiology studics rcvcalcd i}bscncc of F-wH\'cS inthc lowcr limbs, which wn5 consistcnt with n proximnlconduction block to thc lowcr limbs usually sccn innrachnoiditis. An ophthalmology rcview re\'cnlcd bilntcralactivc cytomcgalo\'irus retinitis.

A dingnosis of cytomcgalovirus lumbosacral polyradi­culopathy was madc, and shc wns commcnccd on intravc­nous ganciclovir and foscnrnct ns \\"ell as highly acth'crctroviral thcmpy. Hcr lowcr limb 'paralysis bcgan toimprovc within 3 wccks of C}tomcgnlovirus trcntment nndby 6 wccks shc wns nblc to walk without support. maddercontrol imprm'ed and cnthcterization wns stoppcd. Arcpeat ophthalmology rc\'iew at 6 wccks rcvcalcd hilntcralinncth'c cytomegalo\'irus retinitis. In \'icw of this, and ancxcellent clinical rcsponsc, ganciclo\'ir wns stoppcd after10 wccks. Rcpent ccrcbrospinal fluid nnalysis rc\'caledl10rmnl paramctcrs but PCR was still positi\'c for cytomc­galm'irus (25 640 copics/mL). Within 2 wccks, thc right

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Figure 2. 1'1 H\ia'i magnetic resonanCe imaging (J\j BI) of spine with

gaJolin!u!B e':lhrll1cerncnt rc\'(:,aling anterior displacen1t.>nt or Ci.lUdil

1.:,tjuia4.1with e>nhnnc('ment or l1cr;e roots.

figure 1. T2 axial mognelic reSO'lHncf' imaging li\IRJJ brain scan

e~hibjting ~L'ner;]Jjl.ed \'\hitt' matter ioss and prol11irlcnce of latcrai\t"'!itrides.

Initial investigutiuns revealed hypernntremic dehydmtion(sodium 147m Eq/I.). anemia (hemoglobin 6.8 g/dL),mildly elevated inflammatory murkers (C-reHclive protein33 mg/L), and a negative interferon gamma release assayfor tube,·culosis. Human immunodeficiency virus anti­

hody was positive with a viral load or 206 200 copies/mLand the CD4 count was undetectable. Chest radiugraphwas consistent with bibasa[ infection but no signs of

recent pulmonary LUbcrcu]osis infection. Lumhnr punc­\lire revealed turbid cerehrospinal fluid, white cdl COnf'll

i 'j02/pL (neutrophils 1380/pL, mU!1ocytes 18/p I.• degen­craUn: cells !04htL), red blood cells 3(i ()OO/~IL. glucose

0.8 g/I. (h!ood glucose 4.7 g/L), protein 3.05 g/L, lactate5.5 mmoJiL, negalive Cram stain. negative Zei!-Neilson

stain, and no growth aftcr <; days incubation .. Magnet icresonance imaging (MRI) of brain revealed genercl1i7edwhite malter loss consistent with atrophy with slight pro­

minence of ventricles (Figure 1).She was commenced on antituberculosis therapy

(isoniazid, rifampicin, ethamhutol. and pyrazinamide)without cD,ticoskroids. I n ~I(k]jtion, co-trimoxazo!e pro­

phylaxis and fluconazole were started. The followingdil'ferentiai diugnoses were considered: vim! lumbosacral

po1yradicuJopathy. conus mcdulJaris or ('<tucla cquina syn­drome, l1olyncuropMhy, and lymphomatous spinal mass .

.\Jagnetic resonance imagini4 of spine revcaled dump­ing [md anterior displacement of the cauda equina withenhHncerncnt of the nerve roots consistent with af<!­

chnoiditis. There was further en}wnccmcnt along t1w

anterior and pusterior aspect of the spinal cord foJlowing

gadolinium (Figure 2). No signed abnormality wasdetected within the cor(.!. Cerebrospinal fluid polymerase

chain reactIon (PCn) was positive For cytomegalovirus

(J 2 226 000 copies/m U. and negative for varicdh'1 zoster.nei'pes simplex virus. Epstein-Barr virus, toxopiasma. andtuberculosis. Polymerase chain reaction for cytomegalo­

virus was also positive in the blood (1900 copics/m! .).Neurophysiology sludies re\'ca]ed absence of F-waves inthe lower limbs, \\hkh was consistent with a proximaiconduction block to the lower limus usual1y seen in

arachDoidilis. An ophthalrno1ngy review revealed bibtemlactive cytornegalovitus retinitis.

A diagnosis uf (.·ytol1Jcga!ovirus lumbosacra! poiyradi­

culopathy was made. and she was commenced on Intrave­nous gcmeic!ovir and foscurnet as wdl as highly activeretrovirai thempy. Her lower limb paralysis began toimprove within 3 'v\'ceks of cytomegalovirus treatment andby (, weeks she was able to w81k \\ithout support. Kiadder

control improved and catheterization was stupped. ,,\repeat ophthalmology review at (, weeks rcvcaled bilateralindctive cytomegalovirus retinitis. In view of this, and anexcel1cnt clinka! response. gancic!ovir was slopped after10 vveeks. Hepeat ccrcbrospin<tl fluid analysis revealednormal parameters hut PCR was stiJJ positive for cytome­galovirus (25 640 copies/mL). Within 2 weeks. the right

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Successful Trentment of Cytomcgnlodrus l'ol)rmJiculopnthy in n 9-Yl'nr·oJtJ Child I Sollill elill 217

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I facial palsy rcturncd; thcrefore, intrm'cnous gancicJO\'irwas rcstartcd. Subscqucnt cxamination of cercbrospinalfluid continued to show normal values hut persistence ofcytoniegalo\'irus, which remained sensith'e to ganciclodrand foscarnet.

About 3 months aftcr admission she de\'elopcd pancy­topenia. nonc marrow examination rc\'caled abnormalitiesconsistent with hemophagocytic Iymphohistiocytosis. Thisdid not imprO\'e with continucd highly acth'e retro\'iraltherapy treatment. About 4 wccks prior to the onset ofpancytopenia she had a repeat CD.J count, which wasundetcctahle. She became incrcasingly unwell with gen­eral malaise and se\'ere abdominal symptoms. Followingdiscussion with her family, a palliath'e approach was takenand the child died 8 months after prcsentation.

Discussion

Cytomcgalodrus infection is one of the most importantopportunistic infections in the latc stages of AIDS and canaffect multiple organs. I The most common manifest:1tionof neurological cytomegalovirus disease in HIV infectionis retinitis followed by encephalitis, myclitis, multifocalpolyneurop:1thy, and polyradiculopathy.2

Cytomegalovirus polyradiculopathy is well dcscrihed inadults and can be the initial presentation of AIDS inapproximately 13% of cases.3 It appears to be uncommonin children \\'ith AIDS. The reasons for this are unclear. To

our knowledge, only I similar case has heen repo~ted inthe French medical literature in a child.4 Human immu­

nodeficiency virus-infected patients become susceptibleto cytomegalo\'irus polyradiculopathy' when the CD4T-cell count is less than 40hlL. Cytomegalovirus poly­radiculop:1thy typically affects the lumbosacral region andpresents with ascending lower extremity weakness withdiminished decp tendon reflexes that progress to areflexia.6

It may also present with paresthesia, urinary retention,and fecal incontinence. In AIDS, polyradiculopathy canalso occur due to other etiologies, including toxoplasmo­sis, s}1)hilis, lymphoma, tuberculosis, cryptococcus,Varicella-Zoster virus, Epstein-narr virus, and Herpes­simplex virus.7oB

Ccrebrospinal fluid studies and spinal imaging are use­ful diagnostic aids in cytomegalovirus polyradiculopathy.Our patient had a mild, predominantly ncutrophilie pleo­cytosis with an elevated protein and low glucose ratio thatis t}1)ical of cytomegalodrus polyradiculopathy in theimmunocompromised host. A review of 103 adult caseswith cytomegalo\'irus polyradiculopath/ exhibited mean\'alucs in cerebrospinal fluid white cell count of 651 ±I 053/~IL with an m'eragc of 68% neutrophils with protein2.28 ± 1.78 g/L; cerebrospinal fluid/serum glucose ratioof 0.48 ± 0.17 g/L. This contrasts with the immunocom­petent host, who exhihits a predominantly lymphocytic

response. Positi\'e detcction of cytomcgalo\'irus incerebrospinal fluid ami blood with PCR aids to confirmthe diagnosis.7,s Our patient had the characteristic findingof f'lr higher le\'els in the cerebrospinal fluid than blood.Cytomegalovirus can he cultured in up to 60% of ecrc­brospinal fluid samplesY In cerehrospinal fluid samples,cytomegalovirus PCR has a sensiti\'ity of 92% and specifi­city of 94%.3

Imaging can also be \'ery useful in cytomegaloviruspolyradiculopathy. i\lagnetic resonance imaging of thespine may show meningeal cnhanccment consistcnt witharachnoiditis and thickened ner\'e roots. 10 There may alsohe cvidence of root or cauda equina thickening. i\Iagneticresonance imaging is also useful to exclude cauda equinaor spinal cord compressi\'e lesions rcsulting from lym­phoma, s}1)hilis, or toxoplasmosis. Electrophysiology stud­ics show wide sprcad dener\'ation and prolonged or absentf.-wa\'cs.' Our patient therefore had t}-pical i\1R1 spinalimaging and neurophysiology study Findings.

Cytomegalo\'irus polyradiculopathy is unh'Cfsally fatalif untrcatcd. Once diagnosed, treatment should be startcdpromptly. Patients arc usually commenccd on ganciclovir,5 mg/kg intrm'enously e\'ery 12 hours (induction thcrapy)for 10 to 14 days followcd by 5 mg/kg intrm'enously perday, 5 days a week (maintenance therapy).9 If patient isalready recei\'ing treatmcnt with ganciclovir or they areganciclovir-resistant, then foscarnet can be added at90 mg/kg intra\'enously once a day. I I G:mcicJo\'ir canimpro\'e or stahilize o\'er half the patients under treat­ment. In a case series of 56 adults with cytomegaloviruspolyradiculopathy, 36% impro\'ed, 25% stabili7_ed, and39% continucd to progress.3

Patients may show a dramatic response but a pro­longed coursc of treatment may be necessary beforc anyimpro\'ements are seen. Thcrefore, a prolonged or evenindcfinite course of treatment should he gh'cn if tolcr­ated. II Some patients may exhibit viral drug resistanceleading to treatment failure.12 In this situation, a combi­nation of ganciclovir and foscarnet may be more effecti\'ebut this is associated with more sidc effccts. f.oscarnct

may cause renal toxicity and ganciclO\'ir causes bone mar­row suppression; therefore, close monitoring of renal andbone marrow function is mandatory.

The long-term prognosis of cytomegalovirus polyradi­culopathy in children is unknown. Howe\'cr, our patienthad a dramatic and sustained improvemcnt to trcatment,which enabled her to discontinue urinary catheterizationwhich she found \'Cry distressing. She also made a goodfunctional recovery and was independently mobile within6 weeks of treatment. Unfortunately, she developed hemo­phagocytic Iymphohistiocytosis, which is a rare complica­tion of many different infections including herpes virusesand is often fatal without hone marrow transplant. 13If shehad not de\'eloped hemophagocytic Iymphohistiocytosis, itis prohable that she would ha\'c survi\'ed with an excellent

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218 Joumal of Child Neurology / Vol. 24, ~o. 2, February 2009

quality of lifc. Early recognition is Iikcly to h3\'c improvedher outcome and thereforc cytomcgalovirus pol)'radiculo­path)' should be considercd in a child with human immu­nodcficicncy syndromc who dcvclops a new onsct of lowcrlimb wcakness. Treatment courses can be long and diffi­cult to administcr but in our cxperiencc the potcntialbencfits would outwcigh these difficultics. We thereforerecommcnd anticytomcgalovirus trcatment as soon aspolyradiculopathy secondary to cytomegalovirus isstrongly suspcctcd or proven in children with AIDS.

Acknowledgment

The authors thank Dr L3\\Tence Abernethy for the i\IRIimagcs.

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4. Quartier P, Khouri J, i\laout F, ct al. [Early diagnosis and

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9. Lange DJ. AAEi\1 minimonograph #41: neuromuscular diseases

associated with HIV·I infection. Muscle J'Ven·e. 1994; 17: 16-30.

10. i\liller Hr, rox JD, Thomas 1', et al. Acute lumbosacral polyra­diculopathy due to C)'tomegalO\irus in admnced IlIV disease:

CSF findings in 17 patients. J Neural Neurosllrg Psycllintr)'.1996;61 :456-460.

I I. Kim YS, Hollander H. Polrradiculopathy due to c)'tomegalo­

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prolonged therap)' and rc\ic\\' of the literature. Clill Illfect Dis.1993;17:32-37.

12. Cohen ilA, i\IcArthur JC, Grohman S, Patterson n, Glass JD.

Neurologic prognosis of cytomegalO\;rus polrradiculomrclopa­th)' in AIDS. Neurology. 1993;43(3 pt 1):493-499.

13. Rouphacl NG, Tabt; NJ, Vaughan C, Cunningham K,

i\lorcira n, Gould C. Infections associatedwith haemophagocy­tic s)'ndrome. Urucet Illfect Dis. 2007;7:814-822.

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