Primary Angiitis of the Central Nervous System:Neurologic Deterioration Despite Treatment

abstractPrimary angiitis of the central nervous system (PACNS) is an idiopathicvasculitis confined to the central nervous system. In children withPACNS, small-vessel (SV) involvement is characterized clinically by pro-gressive neurologic symptoms, multifocal lesions on brain imaging,occasional pseudo-tumor presentation, and normal angiogram resultsin most patients. Small case series of patients with SV PACNS withshort follow-up usually reveal favorable outcomes in children treatedwith immunosuppressive therapy. We report here the cases of 3 chil-dren with biopsy-confirmed SV PACNS and long-term follow-up whodeveloped different patterns of neurologic deterioration despite im-munosuppressive therapy. One patient had transient ischemic attacksshortly after initiation of corticosteroid treatment. Early ischemicevents probably result from residual thrombogenicity or residual in-flammation of recently affected vessels, which supports the use ofantiplatelet agents and suggests potential benefits of stronger immu-nosuppressive therapy. In contrast, the other 2 patients had later neu-rologic deterioration after corticosteroid withdrawal, which suggestsfailure of initial immunosuppressant treatment and the need for stron-ger agents, longer treatment duration, or both. All patients respondedto long-term treatment with corticosteroids combined with cytotoxicagents. This particular combination is probably indicated in manycases of SV PACNS, including those with neurologic deterioration thatoccurs during maintenance corticotherapy or after corticosteroidwithdrawal. In 1 case, SV PACNS recurred several years after discon-tinuation of combination therapy. Long-term relapses may reflect in-trinsic predispositions to SV PACNS rather than treatment failure.These cases highlight different chronological patterns of neurologicdeterioration despite immunosuppressive therapy, which supportsthe relevance of monitoring clinical, laboratory, and radiologic re-sponses to treatment and of long-term follow-up of patients with SVPACNS. Pediatrics 2011;127:e1086–e1090

AUTHORS: Xavier De Tiège, MD,a Patrick Van Bogaert,MD,a Alec Aeby, MD,a Isabelle Salmon, MD,b Hélène Parpal,MD,c Alexandre Y. Poppe, MD,c Calliope Maris, MD,b andSylvain Lanthier, MDc

Departments of aPediatric Neurology and bPathology, HôpitalErasme and Université Libre de Bruxelles, Brussels, Belgium;and cCerebrovascular Disease Centre, Department of Medicine,Centre de Recherche, Centre Hospitalier de l’Université deMontréal (CRCHUM) and Université de Montréal, Montreal,Québec, Canada

KEY WORDSangiitis, vasculitis, central nervous system, children, smallvessels

ABBREVIATIONSCNS—central nervous systemPACNS—primary angiitis of the central nervous systemSV—small vesselHSV—herpes simplex virusPET—positron emission tomographyMET—L-[methyl-11C]methionine

Drs De Tiège, Van Bogaert, Parpal, and Lanthier designed thestudy, collected the data, and drafted the manuscript; all theauthors contributed to analysis and interpretation of the data,revised the manuscript, and approved the final version of themanuscript.

www.pediatrics.org/cgi/doi/10.1542/peds.2009-2729

doi:10.1542/peds.2009-2729

Accepted for publication Jan 4, 2011

Address correspondence to Sylvain Lanthier, MD,CRCHUM–Hôpital Notre-Dame, 1560 Sherbrooke St East, SuiteGR-1159, Montreal, Quebec, Canada H2L 4M1.E-mail: sylanthier@gmail.com

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2011 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they haveno financial relationships relevant to this article to disclose.

e1086 De TIÈGE et al

Primary angiitis of the central nervoussystem (PACNS) is an idiopathic vascu-litis confined to the CNS. In children, itsclinical and radiologic features corre-late with affected vessel size.1 PACNSlimited to small vessels (SVs) presentswith progressive neurologic symp-toms, multifocal brain lesions, occa-sional pseudo-tumor manifestations,and a normal angiogram result inmost children.1,2 In case series, au-thors have described favorable out-comes for childhood SV PACNS treatedwith immunosuppressive agents.1,2

However, because of the small numberof cases reported and typically shortfollow-up, the clinical outcomes of SVPACNS warrant further study. We re-port here the long-term follow-up of 3children with biopsy-confirmed SVPACNS.

CASE REPORTS

Case 1

A 15-year-old boy presented with pro-gressive left-hand weakness followedby left-sided seizures. Brain MRI re-vealed a right centrum semiovale non-enhancing tumor-like lesion. Results ofangio-MRI were unremarkable. He un-derwent lesionectomy. Pathology re-vealed transmural T-lymphocyte in-filtrates of the SVs of the whitematter, cortex, and leptomeninges,and granulomas were limited to afew vessels. Isolated neurosarcoid-osis was considered unlikely in theabsence of extravascular CNSgranulomas.3 Extensive blood and ra-diologic investigations revealed no ev-idence of specific disease. Cerebrospi-nal fluid analysis revealed normal cellcount, cytology, proteinorachia, andglycorrhachia, and cultures and her-pes simplex virus (HSV) polymerasechain reaction were negative. Granulo-matous SV PACNS was diagnosed andtreated with methylprednisolone 1g/day intravenously for 3 days, fol-lowed by prednisone 0.8 mg/kg per

day. One week later, after prednisonewas reduced to 0.7 mg/kg per day, heexperienced 3 transient episodes ofleft-hand weakness. Examination re-vealed no additional deficits. Results ofa selective cerebral angiogram wereunremarkable. Aspirin was added andthe prednisone dose was increased to1 mg/kg per day for 1 month and ta-pered over 16 additional months whilemonthly pulses of cyclophosphamidewere started. Because of adverse ef-fects, cyclophosphamide was replacedafter 6 pulses with methotrexate 20mg/wk for 12 months. Immunosup-pressant treatment was completed 22months after presentation. Brain MRIat that time revealed no lesions otherthan the lesionectomy site. Six yearsafter presentation, he remainedasymptomatic.

Case 2

A 9-year-old boy with progressiveheadaches presented with secondarilygeneralized seizure. Examination andblood test results were unremarkable.Electroencephalography revealed left

parietal-occipital spike and waves.Brain MRI revealed a left occipitalgadolinium-enhancing tumor-like le-sion (Fig 1A). Brain positron emissiontomography (PET) showed an increasein L-[methyl-11C]methionine (MET) up-take by the lesion (Fig 1A). Valproateand dexamethasone 0.5 mg/kg per daywere started. Stereotactic brain bi-opsy performed under MRI and MET-PET guidance 12 days later revealednonspecific ischemic neurons andgliosis. Corticosteroids were discon-tinued. He was discharged with val-proate. Two months after presenta-tion, he remained asymptomatic.Repeat brain MRI showed resolution ofthe occipital lesion but detected newgadolinium-enhancing left mesiotem-poral, midbrain, and thalamic lesions(Fig 1B). Results of extensive bloodtests were unremarkable. Cerebro-spinal fluid analyses revealed pleo-cytosis (40 leukocytes per �L, 91%lymphocytes), hyperproteinorachia(50 mg/dL), a positive HSV-2 polymer-ase chain reaction result, and nega-

FIGURE 1Case 2: sequential brain MRI with fluid attenuation inversion recovery sequences and T1-weightedsequences coregistered with MET PET. A, At presentation: left occipital pseudo-tumor taking upMET. B,At 8 weeks: pseudo-tumor regression and new left thalamic, mesiotemporal, and mesencephaliclesions. C, At 18 weeks: increase in size and MET uptake of the lesions.

CASE REPORTS

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tive culture results. Results of HSV-2serology and intrathecal secretion ofanti-HSV-2 immunoglobulin G werenegative. Whole-body PET combinedwith computed tomography using[18F]-fluorodeoxyglucose revealed in-creased glucose metabolism in thecervical and thoracic spinal cord andno extra-CNS inflammation. Within 1month, the leftmesiotemporal and tha-lamic lesions grew in size slightly, andspinal MRI confirmed a cervical cordlesion. One month later, the child de-veloped recurrent headaches, acutephotophobia, emesis, and incoherentspeech. Examination revealed bilateralpyramidal signs. MRI identified an in-crease in size of the left-brain lesionswith edema and mass effect (Fig 1C).PET revealed increased MET uptakewithin the temporal and thalamic le-sions (Fig 1C). Stereotactic temporalbrain biopsy under MRI and MET-PETguidance revealed SV granulomatous,nonnecrotic infiltration by T- andB-lymphocytes and multinucleated gi-ant cells but no intranuclear viral in-clusion or extravascular granulomas(Fig 2). Results of angio-MRI were un-remarkable. Granulomatous SV PACNSwas diagnosed.Methylprednisolone 60mg/day intravenously was adminis-tered for 2 days, followed by pred-nisolone 2 mg/kg per day. One monthlater, no residual neurologic symp-toms remained, and MRI revealed al-most complete resolution of the brainand spinal cord lesions (Fig 3A). Pred-nisolone was tapered because of aCushingoid appearance. At 0.2 mg/kgper day, headaches recurred and heexperienced simple partial status epi-lepticus that responded to antiepilep-tic therapy. Brain MRI revealed a reap-pearance of previous lesions (Fig 3B).After increasing the prednisolone doseto 1 mg/kg per day, he rapidly becameasymptomatic. Two months later, hisbrain lesions had almost completelyregressed. Attempts to discontinuecorticosteroids and use cytotoxic

agents as corticosteroid-sparingagents resulted in recurrent head-aches and reappearance of lesions onMRI. Thirty-eight months after initialpresentation, sustained clinical andradiologic stabilization was finallyachieved with a combination of oralmycophenolate mofetil 1.5 g/day andprednisolone 0.3 mg/kg per day. After30 months on this regimen, he re-mained asymptomatic, and brain MRIrevealed almost complete resolutionof all CNS lesions.

Case 3

The presentation and initial outcomeof this 10-year-old girl have been re-ported.1 She presented with left-sidedfocal seizures. Six weeks later, she hadheadaches, nausea, and left hemipare-sis. Brain MRI revealed subcorticallacune-like lesions and 2 larger

right parietal gadolinium-enhancinglesions. Cerebral angiography re-vealed a single small-artery stenosis.Results of extensive blood analyses,chest radiography, transthoracicechocardiography, abdominal ultra-sonography, and spinal MRI werenormal. Cerebrospinal fluid openingpressure, cell count, cytology, pro-teinorachia, and glycorrhachia werealso normal, and cultures and HSVpolymerase chain reaction were nega-tive. Brain biopsy revealed SV non-granulomatous, nonnecrotic, lympho-cytic angiitis. She was administeredprednisone 2 mg/kg per day for 8weeks. Prednisone was tapered be-cause of adverse effects, and head-aches recurred 10 weeks later. Repeatbrain computed tomography showedno additional lesions. Her blood leuko-

FIGURE 2Case 2: temporal stereotactic biopsy (hematoxylin and eosin stain). Shown are SV infiltration bylymphocytes, multinucleated giant cells (arrow), and nonnecrotic granulomas.

FIGURE 3Case 2: brainMRI with fluid attenuation inversion recovery sequences. A, At 22weeks: almost completeresolution of the brain lesions with residual hypersignal in the left mesiotemporal region. B, At 28weeks: recurrence of the left thalamic, mesencephalic, and temporal lesions.

e1088 De TIÈGE et al

cyte level, erythrocyte sedimentationrate, and C-reactive protein level wereall elevated. She responded to predni-sone 2 mg/kg per day combined withoral cyclophosphamide 2 mg/kg perday for 20 months. She was subse-quently lost to follow-up and off medi-cation for 7 years and then experi-enced episodes of left-sided photopsiafollowed by convulsions. She reporteddeterioration of her residual left hemi-paresis during the previous 4 years.Examination showed left-sideddystonic tremor, mild spastic hemi-paresis, hemisensory deficit, andhemianopia. Electroencephalographyrevealed right occipital spike andwaves. Brain MRI revealed newacute, right pallidal, frontal, and oc-cipital infarcts. Results of repeatblood and cerebrospinal fluid analy-ses and cerebral angiography werenormal. She was treated with anti-convulsants, prednisone 1 mg/kg perday for 4 months tapered over 2 ad-ditional months, and pulses of cyclo-phosphamide 1 g/m2 per month for 8months. Eight years after cessationof immunosuppressive agents (ie, 18years after initial symptoms), shehad no additional symptoms ofPACNS and brain MRI revealed nonew lesions.

DISCUSSION

These cases highlight different chro-nologies of neurologic deterioration inchildhood SV PACNS despite immuno-suppressive therapy, each with differ-ent pathophysiological and therapeu-tic implications. Ischemic events thatoccurred shortly after initiating immu-nosuppressive therapy (case 1) mayhave reflected residual thrombogenic-ity or residual inflammation of re-cently affected vessels, which sup-ports the use of antiplatelet agents2

and potential benefits of stronger im-munosuppressive therapy. In contrast,symptoms that recurred when cortico-steroids were withdrawn after appar-

ent disease control (cases 2 and 3)suggest a resurgence of vasculitiscaused by insufficient initial immuno-suppressive therapy, which supportsthe need for stronger immunosup-pressive treatments, longer treatmentduration, or both. The optimal typeand duration of immunosuppressivetherapy for childhood SV PACNS re-mains unknown. In general, high-dosecorticosteroids are primarily usedfor rapid control of inflammation,whereas corticosteroids, cytotoxicagents, or a combination of both areall options for maintenance therapy.2

Fewer relapses have been reported foradults with PACNS who received corti-costeroids and cyclophosphamide for12 months (10%) compared with thosewho received the same combinationfor 6 months (30%) or received corti-costeroid monotherapy (90%).4 Simi-larly, we observed long-term clinicaland radiologic stabilization with thecombination of corticosteroids and cy-totoxic drugs (cases 1–3). This combi-nation is probably indicated for manypatients with SV PACNS, includingthose with neurologic deteriorationthat occurs during maintenance corti-cotherapy or on corticosteroid with-drawal. Finally, SV PACNS can recuryears after discontinuation of pro-longed and effective combination ther-apy (case 3). Long-term relapses mayreflect intrinsic predispositions to SVPACNS, which implies that long-termfollow-up is recommendable.

Many authors have recommended CNSbiopsy to confirm SV PACNS and ex-clude conditions that can mimic thedisease (eg, acute disseminated en-cephalomyelitis, isolated neurosar-coidosis).1,2,5 Ideally, a wedge-shapedbrain sample including leptomeningesof a radiologically affected area shouldbe obtained by open biopsy. However,in some instances, the affected areasmay not be appropriate for open bi-opsy. In our study, we performed ste-

reotactic biopsy to diagnose SV PACNS(case 2). Among the blood-brain bar-rier rupture sites revealed by gadolin-ium enhancement on MRI, those withactive inflammation documented by in-creased MET uptake on PET were tar-geted to limit the risk of sampling er-ror. We suggest that stereotacticbiopsy guided byMRI andMET PET is aninteresting alternative to open biopsy,because it is less traumatic and bettersuited for deep-seated brain lesions.Moreover, the use of whole-body [18F]-fluorodeoxyglucose PET combinedwithcomputed tomography can help sup-port SV-PACNS diagnosis by excludingextra-CNS inflammation.

CNS biopsy revealed a granuloma-tous vasculitis in cases 1 and 2. Aprevious report suggested that gran-ulomas might signal an aggressiveor advanced form of childhood SVPACNS1; however, these 2 cases dem-onstrate that long-term clinical andradiologic stabilization of granulo-matous SV PACNS can be achievedwith immunosuppressive therapy.One case report of granulomatousSV PACNS of the spinal cord de-scribed response to prednisonewithout short-term recurrence.6 Incontrast, a favorable response toimmunosuppressive therapy isdescribed in reports on pediatricseries of SV PACNS. Three childrenhad no recurrence 8 to 24 monthsafter initiating corticosteroids aloneor combined with cyclophosph-amide.1 Four children treated withcorticosteroids for at least 6 months,of which 3 also received cytotoxicagents for 6 to 22 months, experi-enced no recurrence during afollow-up of 14 to 59 months.2 How-ever, case 3 and other reports5,7 re-veal that nongranulomatous SVPACNS can recur despite prolongedimmunosuppressant treatment thatcombines corticosteroids and cyto-toxic agents.

CASE REPORTS

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CONCLUSIONS

This report emphasizes the poten-tial for neurologic deterioration de-spite immunosuppressive therapy inpatients with SV PACNS, whichunderlines the importance of moni-toring response to treatment.Long-term follow-up is recommend-able after discontinuation of immu-

nosuppressant treatment becauseof possible recurrences, sometimeseven after several years of clinicalquiescence.

ACKNOWLEDGMENTSThis article was prepared with theassistance of the Research SupportOffice at Centre Hospitalier del’Université de Montréal. Dr Lanthier

has received funding from the Fonda-tion des Gouverneurs de l’Espoir forthe creation and implementation of adatabase on PACNS; Dr Poppe isprincipal investigator of this data-base. We thank the Fondation desGouverneurs de l’Espoir for support-ing research on cerebral vasculitisin children.

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