Strategies for treatment of childhood primaryangiitis of the central nervous systemJocelyne Beelen BMSc Susanne M Benseler MD PhD Anastasia Dropol HBSc Brianna Ghali BSc and
AbstractObjectiveChildhood primary angiitis of the CNS (cPACNS) is a devastating neurologic disease Nostandardized treatment protocols exist and evidence is limited to open-label cohort studies andcase reports The aim of this review is to summarize the literature and provide informedtreatment recommendations
MethodsA scoping review of cPACNS literature from January 2000 to December 2018 was conductedusing Ovid MEDLINE PubMed Embase Cochrane Database of Systematic ReviewsCochrane Central Register of Controlled Trials ClinicalTrialsgov Vasculitis FoundationEuropean Vasculitis Society CanVasc Google Scholar and Web of Science Potentially rele-vant articles were selected for full-text review using the STROBE checklist if they met thefollowing inclusion criteria (1) reported treatment (2) addressed pediatrics (3) focused onthe disease of interest (4) included ge5 patients (5) original research and (6) full-lengtharticles Reviews expert opinions editorials case reports with lt5 patients articles lackingtreatment information or non-English articles were excluded A standardized assessment toolmeasured study quality Treatment and outcomes were summarized
ResultsOf 2597 articles screened 7 studies were deemed high quality No trials were available so nometa-analysis was possible Overall treatment strategies recommended are induction withacute antithrombotic therapy subsequently followed by high-dose oral prednisone taper over3ndash12 months and long-term platelet therapy In angiography-positive progressivendashcPACNSand angiography-negativendashcPACNS we also recommend 6 months of IV cyclophosphamidetherapy with trimethoprimsulfamethoxazole as part of induction and maintenance therapywith mycophenolate mofetilmycophenolic acid
ConclusionNo grade-A evidence exists however this review provides recommendations for treatment ofcPACNS
From the Cumming School of Medicine (JB SMB AD) University of Calgary Alberta Canada Section of Rheumatology (SMB MT) Department of Pediatrics Alberta ChildrenrsquosHospital Alberta Childrenrsquos Hospital Research Institute Calgary Alberta Canada and University of Calgary (BG) Alberta Canada
Go to NeurologyorgNN for full disclosures Funding information is provided at the end of the article
The Article Processing Charge was funded by the authors
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal
Copyright copy 2019 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1
Childhood primary angiitis of the CNS (cPACNS) is an in-creasingly recognized inflammatory brain disease Previouslyhealthy children present with severe neurologic deficits thatleft untreated could lead to devastating neurologic insult andeven death Early recognition and intervention with targetedtherapy has led to better survival The term PACNS was firstcoined by Calabrese for adults in 19881 and has been adjustedfor the pediatric population patients lt18 years of age pre-senting with a newly acquired focal or diffuse neurologic orpsychiatric deficit without an underlying systemic disorder andevidence of vasculitis on angiography andor histopathology2
Classification of cPACNS is based on vessel size with 3 subtypesrecognized angiography-positive nonprogressive (APNP) andangiography-positive progressive (APP) disease affecting thelargemedium-sized vessels and angiography-negative (AN)disease affecting small cerebral vessels23 Children with APNP-cPACNS typically present with a monophasic event consisting offocal neurologic deficits and evidence of ischemic stroke on MRIwith corroborating angiography245 Patients with APP-cPACNSpresent with both focal and diffuse neurologic deficits45 andprogressive vessel narrowing on angiography beyond 3months ofdisease2 In contrast patients with AN-cPACNS exhibit normalangiography because of the difficulty in observing small vessels ondigital subtraction angiography (DSA) or magnetic resonanceangiography (MRA)67 However MRI is frequently abnormalcharacterized by multifocal inflammatory lesions not specific toany vessel distribution or territory89 Thus elective brain biopsy ismandated for diagnostic confirmation of AN-cPACNS4710
Children typically present with both focal and diffuse neurologicand psychiatric deficits together with seizures3479 The overallincidence of cPACNS remains unknown
Similar to many other pediatric diseases treatment is pre-dominantly derived from adult PACNS literature1011 Whiletherapeutic strategies for cPACNS have been described theycome largely from observational and open-label cohort studiesbecause of the absence of randomized control trials and are notstandardized across centers To date no scoping review of thepediatric literature on treatment of cPACNShas been performedTherefore in this review we aim to describe the evidence andefficacy of treatment regimens reported in the pediatric literature
MethodsSearch strategy and selection criteriaA scoping review of the literature was conducted for thetimeframe January 2000 to December 2018 Databases
utilized in the search were Ovid MEDLINE PubMedEmbase Cochrane Database of Systematic ReviewsCochrane Central Register of Controlled Trials Clin-icalTrialsgov Vasculitis Foundation EUVAS (EuropeanVasculitis Society) CanVasc Google Scholar and Web ofScience Searches were conducted with MeSH terms in-cluding vasculitis vasculitides angiitis angiitides arteritiscentral nervous system CNS brain cerebral PACNS pedi-atric adolescent child and infant
Studies were eligible if they met the following inclusion cri-teria (1) treatment reported (2) pediatric populationaddressed (3) focused on disease of interest cPACNS (4)included ge5 patients (5) original research and (6) full-lengtharticles Only articles written in English were includedReviews expert opinions editorials case reports and studieswithout treatment information were excluded Studies werescreened by perusing titles and abstracts for relative contentArticles deemed relevant were selected for full-text review andindividually assessed for inclusion criteria using the STROBEchecklist for cohort case-control and cross-sectional studiesby 2 of 4 reviewers JB AD BG and MT In case ofconflicting evaluations a third reviewer SMB was asked tomake the final decision Selected articles were assessed forquality Studies reporting data on the same population wereincluded individually and discussed together
Data analysisQuality was assessed through utilization of a modified versionof Pasma et al12 Quality Assessment Tool Questionsaddressed patient recruitment through sampling methodparticipation treatment and outcome measurements andconflict declaration Nonrelevant questions were droppedfrom the tool Three questions were deemed essential gt80participation reproducible treatment strategy and re-producible outcome measure A score of 1 was given to eachquestion on satisfaction of both reviewersrsquo assessment witha maximum total score of 6 A study with a total score of 4 orhigher and at least 2 of 3 essential questions was consideredhigh quality
Studies were evaluated for design location sample size andpatient demographics This information together with treat-ment strategies and outcomes was aggregated Studies werecompared by diagnostic subtype treatment regimen andoutcomes Acceptable study outcomes included mortality andneurologic outcome preferably using the Pediatric StrokeOutcome Measure (PSOM)13 a determinant of neurologic
GlossaryAN = angiography-negative APNP = angiography-positive nonprogressive APP = angiography-positive progressive ASA =aspirin CA = conventional angiography cPACNS = childhood primary angiitis of the CNS DSA = digital subtractionangiography IVMP = IV methylprednisolone MMF = mycophenolate mofetil MRA = magnetic resonance angiographyNASCET = North American Symptomatic Carotid Endarterectomy Trial PedsQL = Pediatric Quality of Life PGA =Physicians Global Assessment PSOM = Pediatric Stroke Outcome Measure vWF = von Willebrand factor
2 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
dysfunction across 4 domains sensorimotor language pro-duction language comprehension and cognitionbehavior
Role of funding sourceThere was no funding source for this study The corre-sponding authors had full access to all the data in the studyand final responsibility for the decision to submit forpublication
Data availabilityData not provided in this article including comprehensivetreatment and outcome summaries and search strategies areavailable to be shared by request
ResultsThe search strategy identified a total of 2596 articles with 1additional study identified by author MT (figure 1) Of 2597articles screened for title and abstract 110 articles had full-textretrieval for assessment of inclusion criteria and 9 originalarticles were included for detailed analysis24914ndash19 (figure 1)Reasons for article exclusion included treatment descriptionmissing (n = 24) exclusion of pediatric population (n = 8)not PACNS (n = 5) case reports lt5 children (n = 20) book
chaptersreviewseditorials (n = 39) and abstract only (n =5) Seven studies were deemed high quality after quality as-sessment was conducted Study characteristics are summa-rized in table Of 9 studies reviewed 4 described the samestudy population from Lahore Pakistan16ndash19 4 studies de-scribed the same population from Toronto Canada24914and 1 reported a case series from Los Angeles US15
The Pakistani group16ndash19 identified children lt16 years of agesubsequently diagnosed with cPACNS at their center betweenJanuary 2009 and December 2010 Diagnostic categorizationwas two-fold based on stroke characteristics and cPACNSsubtype A total of 68 patients were identified 50 presentedwith ischemic stroke 10 with hemorrhagic stroke and 8 withboth ischemic and hemorrhagic lesions Alternatively 51patients were classified as APNP-cPACNS and 17 as APP-cPACNS Diagnoses were based on conventional angiography(CA) andor MRA in all patients
Induction therapy 3 days of IV methylprednisolone (IVMP)andor IV immunoglobulin for 5 days with subsequent oralprednisone taper over 30 days was completed by 56 patientsPatients with ischemic stroke also received IV heparin andsubsequent oral anticoagulation therapy Supplementary
Figure 1 Prisma 2009 flow diagram
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Table Summarized description of included studies
Study Diagnosis of cPACNS Age (median y) Treatment Outcome
AN (n = 19) 9middot8 (5middot5ndash17middot8) Induction therapy 6 M (n = 14) Maintenance therapy 18 M (n = 13) Mortality (n = 19) Good neurologic outcomed on PSOM
Confirmatory biopsy (n = 19) IV cyclo + oral prednisone MMF or AZA + oral prednisone 0 pts 12 M 816 pts
Angiography methodsincluded MRA venographyand CA
79 pts AZA switched to MMF 24 M 913 pts
Confirmatory biopsy includedlesionalnonlesionalspecimen and lymphocyticvasculitis histology
Cellucciet al4
AP (n = 14) 9middot8 (3middot3ndash17middot8) ASA therapy (n = 14) IV cyclo x 6 M plusmn MMF or AZA (n = 27) Mortality (n = 39) Good neurologic outcomed on PSOM
AN (n = 25) AP-cPACNS AP-cPACNS 7 pts 0 pts 52 of patients at 12 mo
AP diagnosis based on CAandor MRA abnormalities(n = 14)
Oral prednisone 2-6 M or 12 M (n = 38) AN-cPACNS 23 pts Flare duringfollow-up (n = 39)
65 of patients at 24 mo
Continued
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Table Summarized description of included studies (continued)
Study Diagnosis of cPACNS Age (median y) Treatment Outcome
AN diagnosis based on brainbiopsy showing lymphocyticvasculitis (n = 22)
APNP-cPACNS 13 pts 3 pts did not receive IV cyclo 6 pts Summary scores significantly decreasedover time (p lt 0001)
Those who did not undergobrain biopsy had clinicalfeatures blood work andlumbar puncture consistentwith AN-cPACNS and negativemicrobiologic andantineuronal investigations
Abnormal DSA was found inthe 2 patients with normalMRA
Transitioned off heparin 1 pt MMF 2 pts
Gallagheret al15
AP (n = 5) 8 (5ndash11) Induction therapy (n = 5) Maintenance therapy (n = 3) Mortality (n = 5) Clinicalradiologic evaluation at last follow-up (n = 5)
AP diagnosis based on MRAabnormalities (n = 3) andorCA abnormalities (n = 4)
Oral prednisone plusmn IVMP plusmnanticoagulation + IV cyclo
Methotrexate or AZA plusmn ASA 0 pts Asymptomatic 3 pts
Lost to follow-up 1 pt
Residual deficits 1 pt
Abbreviations AN = angiography-negative AP = angiography-positive ASA = aspirin AZA = azathioprine CA = conventional angiography cPACNS = childhood primary angiitis of the CNS D = days DSA = digital subtractionangiography IV cyclo = IV cyclophosphamide IVIG = IV immunoglobulin IVMP = IV methylprednisolone M = months MRA = magnetic resonance angiography NP = nonprogressive P = progressive PSOM = pediatric strokeoutcome measure pts = patientsa Also described as ischemic stroke (n = 50) hemorrhagic stroke (n = 10) and both (n = 8)b Relapse defined as emergence of signs and symptoms of stroke confirmed with neuroimaging of brain after remissionc Complete neurologic recovery defined as neurologic deficit severity score of 0d Good neurologic outcome defined as le05 across any domain
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calcium and vitamin D were prescribed with anticonvulsantsantipsychotics antibiotics antivirals and antacids as neededA total of 12 patients died before completing inductiontherapy from complications involving cerebral artery andorparenchymal bleeding The remaining 41 patients were allo-cated to 24 months of maintenance therapy consisting ofeither aspirin (ASA) daily for ischemic stroke or together withdaily azathioprine for progressive arteriopathies Despitea clearly delineated therapeutic regimen the Pakistani groupreported conflicting data in regard to the number of patientsassigned to each therapy across the 4 studies Both the initialstudy by Malik et al19 and Alhaboob et al16 identified 41patients assigned to ASA alone and 15 patients to ASA to-gether with azathioprine for 24 months However Maliket al17 indicated that 40 patients were assigned to the 24months ASA only group and 16 patients to ASA and aza-thioprine with ASA duration increased to 60 months in thisstudy Malik et al18 did not provide details of inductiontherapy only that ischemic infarcts were initially treated withIV heparin From this group 40 patients were discharged onASA for 24 months and 14 received adjunctive azathioprinetherapy
The Pakistani group reportedmortality and morbidity acrossdifferent intervals Remission was described as a completeabsence of disease activity in clinical symptoms exam find-ings lab markers and imaging for at least 3 months andrelapse was defined as an emergence of signssymptoms ofstroke confirmed by neuroimaging (CA andor MRA) afterremission All 4 studies documented mortality at dischargein 12 patients (17middot6) Malik et al17ndash19 reported clinicalstate at time of discharge for all survivors defined as neu-rologic assessment for motor visual andor speech diffi-culties Normal examination was reported in 11 (20)minor disability in 14 (25) moderate disability in 11(20) and severe disability in 20 (35) patients Maliket al15 described relapse in a total of 30 patients (54)during maintenance therapy From the ASA only group 18patients (45) relapsed within the first 24 months whichresulted in 10 deaths and of the remaining 22 patients(55) who completed ASA therapy 5 relapsed and 5 diedOverall mortality in the ASA group was 1540 (38middot5) Ofthe 16 patients on maintenance with ASA and azathioprine2 patients (13) relapsed within 24 months and both sur-vived The number of deaths reported was 5 (31) 3patients died from massive cerebral hemorrhage and 2 of 3patients died after relapse within 6 months of successfullycompleting therapy Therefore the overall mortality duringmaintenance reported by Malik et al17 at a medium follow-up of 34 months was 20 (35middot7) of the initial 56 survivorseither as a direct result or as a complication of first or secondrelapse with 5 deaths reportedly due to non-cPACNS cau-ses Malik et al17 also reported the outcome at last follow-upusing the PSOM13 From the 32 patients assessed 8 (25)a normal outcome 10 (31) minor disabilities 10 (31)moderate disabilities 4 (13) severe disabilities and 4patients were lost to follow-up
The Canadian studies24914 similarly identified patients fromthe same center though each study varied in sample size anddiagnostic subtype Benseler et al2 identified 62 children lt18years of age between January 1990 to December 2002 di-agnosed with AP-cPACNS 42 APNP-cPACNS and 20 APP-cPACNS Diagnoses were based on MRA andor CAabnormalities
All patients received antithrombotic therapy with ASA hep-arin or warfarin A total of 41 patients (65) continued withthis treatment approach long-term 33 patients with APNP-cPACNS and 7 patients with APP-cPACNS In contrast 22patients (35) received immunosuppressive interventionwith steroids alone or a combination of steroids and IV cy-clophosphamide 9 (41) APNP-cPACNS and 13 (59)APP-cPACNS Benseler et al2 measured outcome at lastevaluation (mean 20 months) as complete neurologic re-covery defined as neurologic deficit severity score of 0 onPSOM any other deficit severity score was defined as in-complete recovery A total of 22 patients (35) madea complete neurologic recovery 13 (31) of APNP-cPACNSand 9 (45) of APP-cPACNS No deaths were reported
Hutchinson et al9 identified 19 patients lt18 years of age withAN-cPACNS diagnosis between January 2002 and December2009 MRA venography and CA were used Diagnosis in allpatients was based on a confirmatory biopsy Patients receivedinduction and maintenance therapy for 24 months Inductiontherapy was defined as 6 months of IV cyclophosphamidemonthly together with Pneumocystis jiroveci pneumonia pro-phylaxis oral prednisone daily supplementary calcium vita-min D and anticonvulsantsantipsychotics as neededThirteen patients (68) completed induction and went on tomaintenance therapy Maintenance consisted of an additional18 months of therapy with 5 patients (35) assigned tomycophenolate mofetil (MMF) and 9 (65) assigned toazathioprine with anticonvulsantsantipsychotics as neededSeven (78) of 9 patients on azathioprine switched to MMFbecause of treatment failure or intolerance Only 5 patients(36) completed maintenance therapy and were taken offmedication Primary outcome was assessed on PSOM at 24months with good outcome defined as a score of le0middot5 acrosseach of the 4 domains Secondary outcomes included treat-ment efficacy and safety determined by PSOM at 12 monthsand final follow-up disease flare and discontinuation ofimmunosuppressants Good neurologic outcome on PSOMat 12 months was reported in 8 (50) of 16 patients and 9(70) of 13 at final follow-up Disease flare during treatmentwas described in 8 patients (42) 219 (11) during in-duction 514 (36) during maintenance and 15 (20) offmedication No patients relapsed onMMF Of 5 patients whocompleted maintenance therapy 4 achieved remission de-fined as complete absence of disease activity in clinicalsymptoms examination findings lab markers and imaging forat least 3 months Safety was determined by mortality seriousinfection and each of cataracts avascular necrosis vertebralfractures or type II diabetes mellitus No patients in this study
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died however 2 were reported to have had a serious infectionrequiring hospital admission 1 developed cataracts 1 avas-cular necrosis and 3 with vertebral fractures No diabetesmellitus was reported Pediatric Quality of Life (PedsQL)20
was reported for both child and parent at final follow-uptogether with cognitive outcome testing by the Weschler In-telligence Scale for Children IV and Weschler Adult In-telligence Scale III at 14 months postdiagnosis Abnormalscores were defined as any index scores that were ge1 SDsbelow the mean of the normative sample The PedsQLquestionnaire was completed by 17 patients and 15 parentsmedian physical score was 78 (range = 0ndash100) for childrenand 66 (range = 9ndash100) for parents and median psychosocialscore 73 (range = 27ndash100) for children and 63 (range =37ndash100) for parents Cognitive outcome was assessed in 10children Full Scale Intelligence Quotient was reported asabnormal in 8 (80) working memory in all 10 (100)verbal comprehension in 7 (70) perceptual reasoning in 6(60) and processing speed in 5 (50)
Cellucci et al4 identified 39 patients lt18 years of age betweenJune 2001 and October 2010 diagnosed with cPACNS 14 AP-cPACNS not further subdivided and 25 AN-cPACNS AP-cPACNS diagnosis was based on CA andor MRA (n = 14)AN-cPACNS diagnosis was based on confirmatory biopsy in 22patients Patients without biopsy had features blood work andlumbar puncture consistent with AN-cPACNS Some patientswith AP-cPACNS were also represented in the Benseler et al2
study and in the Hutchinson et al9 study
All 14 patients with AP-cPACNS received ASA and 9 (64)received additional anticoagulation with unfractionatedlow-molecular weight heparin for 2 months High-dose predni-sone was prescribed in all but 1 patient with AP-cPACNSwith a varied tapering schedule 2ndash6 months in 6 patients(46) and 12 months in 7 (54) IV cyclophosphamide over6 months followed by MMF or azathioprine was given toa further 7 patients (54) with AP-cPACNS 1 patient withAP-cPACNS received anticoagulation therapy only High-dose prednisone with 12-months taper was prescribed in allpatients with AN-cPACNS IV cyclophosphamide for 6months in combination with azathioprine or MMF wasreported in 20 patients (80) with AN-cPACNS while aza-thioprine or MMF alone as inductionmaintenance therapywas described in 3 patients (12) with AN-cPACNS Twopatients (8) with AN-cPACNS did not receive therapyOutcomes were reported serially across 24 months and in-cluded disease activity as measured by the Physicians GlobalAssessment (PGA) a visual analog scale with a score of zeroindicating no disease activity and 10 indicating severe activityvon Willebrand factor (vWF) antigen levels where highnumbers indicate high disease activity with gt1middot40 IUmLbeing considered abnormal and neurologic outcome onPSOM with good outcome defined as a score of le0middot5 acrosseach domain Disease activity was elevated at time of di-agnosis but significantly decreased over time in all patients(p lt 0middot001) vWF antigen levels decreased over time (p lt
0middot001) PSOM summary scores decreased significantly overtime (p lt 0middot001) with 52 of patients having a good neu-rologic outcome at 12 months and 65 at 24 months A totalof 6 (15) developed disease flare during follow-up defined asan increase in PGA by at least 1 cm in presence of recurrentsymptoms laboratory changes andor MRI findings Nopatients died
Elbers et al14 described 27 patients lt18 years of age with AP-cPACNS diagnosed between January 1998 and December2013 Diagnosis was based on MRA and DSA abnormalitiesPatients might overlap with the Benseler et al2 and Cellucciet al4 studies Acute treatment with unfractionated heparinwas described in 23 patients (85) 5 subsequently transi-tioned to warfarin 17 to ASA and none in 1 ASA aloneor with immunosuppression was described in the remaining4 patients Two patients received chronic immunosuppres-sion with MMF and 1 received plasmapheresis IVMP to-gether with a 3-month oral steroid taper was described in 12patients with no long-term immunosuppression An addi-tional 7 patients were treated with acyclovir Outcomes in-cluded vascular imaging at 12 months assessed using theNorth American Symptomatic Carotid Endarterectomy Trial(NASCET) criteria and described as improved (normal an-giography improved flow or fewer abnormal vessels) stable(no change in flow abnormality or number of involved ves-sels) or worsened (involvement of new vessels or worseningof an existing flow abnormality by at least 1 point on follow-upimaging) and possibly discordant (worsened patients wherea new or worsening arterial abnormality coexisted with animproved or normalized vessel) as well as stroke recurrenceThe NASCET criteria scores vessel narrowing from 1 to 4progressing from normal (0ndash9) to mild (10ndash29)moderate (30ndash69) and severe stenosis (70ndash99) orcomplete occlusion (no flow detected) A total of 10 (37)patients were described as improved 4 of which receivedsteroids as treatment 6 (22) as stable 2 of which receivedsteroids and 11 (41) worsened with 7 described as dis-cordant 6 of which received steroids Stroke recurrence wasreported in 4 patients (15) No patients died
Gallagher et al15 described 5 cases of AP-cPACNS at theircenter with no fixed treatment regimen Diagnosis was basedonMRA andor CA abnormalities Two patients were treatedwith IVMP either at their first or subsequent disease pre-sentation All patients received IV cyclophosphamide how-ever 1 discontinued after the first infusion due to intoleranceAll patients received oral prednisone of varying doses 2 re-ceived short-term (lt6 months) steroid therapy 2 remainedon oral steroids long-term (gt6 months) and 1 was lost tofollow-up after 6 months One patient received long-termtreatment with azathioprine and 2 with methotrexate Four(80) of the 5 patients received anticoagulation therapy witheither ASA or warfarin during their illness No validatedoutcome measures were used to assess outcomes for thesepatients however at last follow-up 3 patients were reportedas neurologically asymptomatic 1 had mild residual deficits
8 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
and 1 was lost to follow-up but continued on treatment attheir last documented visit
DiscussionThis is the first scoping review of treatment in cPACNSDespite the paucity of randomized clinical trials evidence in
the literature offers support for treatment strategies ForAPNP-cPACNS the authors recommend treatment withlong-term antiplatelet therapy to reduce the risk of strokerelapse and mortality as reported in the Pakistani cohort16ndash19
The authors concur with CNS vasculitis expert opinion inrecommending short-term immunosuppressive with IVMPand acute antithrombotic therapy subsequently followed by
Figure 2 Recommended treatment protocol
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 9
high-dose oral prednisone (figure 2A)31021ndash23 In APP-cPACNS the authors support a combination of anti-coagulation and induction therapy with both IV steroids andIV cyclophosphamide with steroid taper (figure 2B)3415ndash19
to increase the prospect of neurologic recovery3101521ndash26
Induction therapy for AN-cPACNS should similarly consist ofIV steroids and IV cyclophosphamide (figure 2C) Evidencein the literature91021ndash24 for long-termmaintenance therapy inAPP-cPACNS and AN-cPACNS supports daily MMFmycophenolic acid in preference to azathioprine to avoidthe possibility of treatment failure or intolerance as reportedby Hutchinson et al9 and the Pakistani group (figures 2B2C)16ndash19
In refractory disease Batthish et al25 reported successful useof infliximab therapy in treating 2 cases of AN-cPACNS withgood control of inflammation and subsequent prevention ofbrain damage Rosati et al26 recently published a case series of4 patients with AP-cPACNS successfully treated with long-term MMF All revealed subsequent stability or improvementon MRIMRA with no progression of arterial disease and norelapses were reported in the follow-up period (range 10ndash42months)26 Sen et al24 also report successful maintenancetreatment with MMF in 3 cases of cPACNS that had failedmethotrexate or azathioprine and steroid treatment alone Nopatients were reported to have had recurring symptoms sideeffects or new lesions on MRI24
While this review provided a comprehensive review of treat-ment literature in cPACNS there were several limitationsBased on our quality assessment definition for Q4 a mini-mum of 1 reproducible reported outcome was sufficient tosatisfy outcome reproducibility Many studies satisfied thiscriterion by reporting mortality despite a lack of or irrepro-ducibility of supplementary outcomes Furthermore usinga validated measure like the PSOMwas sufficient to satisfy theQ5 requirement While the Pakistani group utilized thePSOM in outcome assessment the lack of outcome defi-nitions led to difficulty in result generalizability Finally whilethe same patient cohort was included in all 4 Pakistani groupstudies and treatment regimens were well described thenumber of patients reported to each treatment arm wasgrossly inconsistent and calculated incorrectly Despite thesecontradictions the studies sufficiently satisfied the re-producible treatment criterion and were consequently ratedhigh quality Therefore the authors believe that the qualityassessment for a number of studies reviewed is overstatedwere these studies to be rescored retrospectively they wouldbe deemed low quality Finally the case series by Gallagheret al15 despite meeting inclusion criteria only described casereports with inconsistent treatment regimens and lackedvalidated outcome measures
In conclusion available literature on treatment in cPACNS werethoroughly reviewed and findings summarized Based on theevidence and current expert opinion the authors provide rec-ommendations for cPACNS treatment strategies Rapid initiation
with the recommended therapeutic interventions would serve tooptimize survival and prevent permanent brain injury in patientswith cPACNS to achieve the best possible outcome
AcknowledgmentThe authors would like to thank librarian Rachel Zhao for hercontribution to the development and application of the searchstrategy
Study fundingNo targeted funding
DisclosureJ Beelen reports no disclosures S Benseler serves on theeditorial board for Neurology Neuroimmunology amp Neuro-inflammation A Dropol B Ghali and M Twilt reports nodisclosures Go to NeurologyorgNN for full disclosures
Publication historyReceived byNeurology Neuroimmunology amp Neuroinflammation January24 2019 Accepted in final form March 4 2019
References1 Calabrese LH Mallek JA Primary angiitis of the central nervous system Report of 8
new cases review of the literature and proposal for diagnostic criteria Medicine(Baltimore) 19886720ndash39
2 Benseler SM Silverman E Aviv RI et al Primary central nervous system vasculitis inchildren Arthritis Rheum 2006541291ndash1297
3 Benseler SM deVeber G Hawkins C et al Angiography-negative primary centralnervous system vasculitis in children a newly recognized inflammatory central ner-vous system disease Arthritis Rheum 2005522159ndash2167
4 Cellucci T Tyrrell PN Sheikh S Benseler SM Childhood primary angiitis of thecentral nervous system identifying disease trajectories and early risk factors forpersistently higher disease activity Arthritis Rheum 2012641665ndash1672
Appendix Authors
Name Location Role Contribution
JocelyneBeelenBMSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Evaluated literaturecompiled the datadrafted the manuscriptcompleted manuscriptrevisions
SusanneBenselerMD PhD
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper revised the papercritically for intellectualcontent
AnastasiaDropolHBSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Conceptualized thepaper evaluated theliterature compiledthe data drafted themanuscript
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper completed theliterature searchevaluated the literaturerevised the papercritically for intellectualcontent
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
5 Cellucci T Tyrrell PN Twilt M Sheikh S Benseler SM Distinct phenotype clustersin childhood inflammatory brain diseases implications for diagnostic evaluationArthritis Rheumatol 201466750ndash756
6 Splendiani A Catalucci A Limbucci N Turner M Krings T Gallucci M Pediatricinflammatory diseases part III small vessels vasculitis Neuroradiol J 201225715ndash724
7 Elbers J Halliday W Hawkins C Hutchinson C Benseler SM Brain biopsy inchildren with primary small-vessel central nervous system vasculitis Ann Neurol201068602ndash610
8 Aviv RI Benseler SM DeVeber G et al Angiography of primary central nervoussystem angiitis of childhood conventional angiography versus magnetic resonanceangiography at presentation AJNR Am J Neuroradiol 2007289ndash15
9 Hutchinson C Elbers J Halliday W et al Treatment of small vessel primary CNSvasculitis in children an open-label cohort study Lancet Neurol 201091078ndash1084
10 Twilt M Benseler SM The spectrum of CNS vasculitis in children and adults Nat RevRheumatol 2011897ndash107
11 Salvarani C Brown RD Jr Calamia KT et al Primary central nervous systemvasculitis analysis of 101 patients Ann Neurol 200762442ndash451
12 Pasma A vanrsquot Spijker A Hazes JM Busschbach JJ Luime JJ Factors associated withadherence to pharmaceutical treatment for rheumatoid arthritis patients a systematicreview Semin Arthritis Rheum 20134318ndash28
13 Kitchen L Westmacott R Friefeld S et al The pediatric stroke outcome measurea validation and reliability study Stroke 2012431602ndash1608
14 Elbers J Armstrong D Yau I Benseler S Vascular imaging outcomes of childhoodprimary angiitis of the central nervous system Pediatr Neurol 20166353ndash59
15 Gallagher KT Shaham B Reiff A et al Primary angiitis of the central nervous systemin children 5 cases J Rheumatol 200128616ndash623
16 Alhaboob AA Hasan GM Malik MA Rehman MZ Therapeutic benefits and sideeffects of Azathioprine and Aspirin in treatment of childhood primary arterial strokeAnn Neurosci 20142110ndash13
17 Malik MA Ahmad N Malik H Maintenance treatment of childhood primary angiitisof central nervous system with spirin and azathioprine Pediatr Ther 20133174ndash179
18 Malik MA Choudry GR Malik H Recurrence prevention of childhood primaryangiitis of central nervous system by combination of azathioprine and aspirin Am JMed Stud 2013122ndash27
19 Malik MA Zia-ur-Rehman M Nadeem MM et al Childhood primary angiitis of thecentral nervous system J Coll Physicians Surg Pak 201222570ndash574
20 Varni JW Burwinkle TM Seid M Skarr D The PedsQL 40 as a pediatric populationhealth measure feasibility reliability and validity Ambul Pediatr 20033329ndash341
21 Twilt M Benseler SM Childhood inflammatory brain diseases pathogenesis di-agnosis and therapy Rheumatology (Oxford) 2014531359ndash1368
22 Gowdie P Twilt M Benseler SM Primary and secondary central nervous systemvasculitis J Child Neurol 2012271448ndash1459
23 Moharir M Shroff M Benseler SM Childhood central nervous system vasculitisNeuroimaging Clin N Am 201323293ndash308
24 Sen ES Leone V AbinunM et al Treatment of primary angiitis of the central nervoussystem in childhood with mycophenolate mofetil Rheumatology (Oxford) 201049806ndash811
25 Batthish M Banwell B Laughlin S et al Refractory primary central nervous systemvasculitis of childhood successful treatment with infliximab J Rheumatol 2012392227ndash2229
26 Rosati A Cosi A Basile M et al Mycophenolate mofetil as induction and long-termmaintaining treatment in childhood primary angiitis of the central nervous systemJoint Bone Spine 201784353ndash356
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 11
DOI 101212NXI000000000000056720196 Neurol Neuroimmunol Neuroinflamm
Jocelyne Beelen Susanne M Benseler Anastasia Dropol et al Strategies for treatment of childhood primary angiitis of the central nervous system
This information is current as of May 3 2019
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is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
Childhood primary angiitis of the CNS (cPACNS) is an in-creasingly recognized inflammatory brain disease Previouslyhealthy children present with severe neurologic deficits thatleft untreated could lead to devastating neurologic insult andeven death Early recognition and intervention with targetedtherapy has led to better survival The term PACNS was firstcoined by Calabrese for adults in 19881 and has been adjustedfor the pediatric population patients lt18 years of age pre-senting with a newly acquired focal or diffuse neurologic orpsychiatric deficit without an underlying systemic disorder andevidence of vasculitis on angiography andor histopathology2
Classification of cPACNS is based on vessel size with 3 subtypesrecognized angiography-positive nonprogressive (APNP) andangiography-positive progressive (APP) disease affecting thelargemedium-sized vessels and angiography-negative (AN)disease affecting small cerebral vessels23 Children with APNP-cPACNS typically present with a monophasic event consisting offocal neurologic deficits and evidence of ischemic stroke on MRIwith corroborating angiography245 Patients with APP-cPACNSpresent with both focal and diffuse neurologic deficits45 andprogressive vessel narrowing on angiography beyond 3months ofdisease2 In contrast patients with AN-cPACNS exhibit normalangiography because of the difficulty in observing small vessels ondigital subtraction angiography (DSA) or magnetic resonanceangiography (MRA)67 However MRI is frequently abnormalcharacterized by multifocal inflammatory lesions not specific toany vessel distribution or territory89 Thus elective brain biopsy ismandated for diagnostic confirmation of AN-cPACNS4710
Children typically present with both focal and diffuse neurologicand psychiatric deficits together with seizures3479 The overallincidence of cPACNS remains unknown
Similar to many other pediatric diseases treatment is pre-dominantly derived from adult PACNS literature1011 Whiletherapeutic strategies for cPACNS have been described theycome largely from observational and open-label cohort studiesbecause of the absence of randomized control trials and are notstandardized across centers To date no scoping review of thepediatric literature on treatment of cPACNShas been performedTherefore in this review we aim to describe the evidence andefficacy of treatment regimens reported in the pediatric literature
MethodsSearch strategy and selection criteriaA scoping review of the literature was conducted for thetimeframe January 2000 to December 2018 Databases
utilized in the search were Ovid MEDLINE PubMedEmbase Cochrane Database of Systematic ReviewsCochrane Central Register of Controlled Trials Clin-icalTrialsgov Vasculitis Foundation EUVAS (EuropeanVasculitis Society) CanVasc Google Scholar and Web ofScience Searches were conducted with MeSH terms in-cluding vasculitis vasculitides angiitis angiitides arteritiscentral nervous system CNS brain cerebral PACNS pedi-atric adolescent child and infant
Studies were eligible if they met the following inclusion cri-teria (1) treatment reported (2) pediatric populationaddressed (3) focused on disease of interest cPACNS (4)included ge5 patients (5) original research and (6) full-lengtharticles Only articles written in English were includedReviews expert opinions editorials case reports and studieswithout treatment information were excluded Studies werescreened by perusing titles and abstracts for relative contentArticles deemed relevant were selected for full-text review andindividually assessed for inclusion criteria using the STROBEchecklist for cohort case-control and cross-sectional studiesby 2 of 4 reviewers JB AD BG and MT In case ofconflicting evaluations a third reviewer SMB was asked tomake the final decision Selected articles were assessed forquality Studies reporting data on the same population wereincluded individually and discussed together
Data analysisQuality was assessed through utilization of a modified versionof Pasma et al12 Quality Assessment Tool Questionsaddressed patient recruitment through sampling methodparticipation treatment and outcome measurements andconflict declaration Nonrelevant questions were droppedfrom the tool Three questions were deemed essential gt80participation reproducible treatment strategy and re-producible outcome measure A score of 1 was given to eachquestion on satisfaction of both reviewersrsquo assessment witha maximum total score of 6 A study with a total score of 4 orhigher and at least 2 of 3 essential questions was consideredhigh quality
Studies were evaluated for design location sample size andpatient demographics This information together with treat-ment strategies and outcomes was aggregated Studies werecompared by diagnostic subtype treatment regimen andoutcomes Acceptable study outcomes included mortality andneurologic outcome preferably using the Pediatric StrokeOutcome Measure (PSOM)13 a determinant of neurologic
GlossaryAN = angiography-negative APNP = angiography-positive nonprogressive APP = angiography-positive progressive ASA =aspirin CA = conventional angiography cPACNS = childhood primary angiitis of the CNS DSA = digital subtractionangiography IVMP = IV methylprednisolone MMF = mycophenolate mofetil MRA = magnetic resonance angiographyNASCET = North American Symptomatic Carotid Endarterectomy Trial PedsQL = Pediatric Quality of Life PGA =Physicians Global Assessment PSOM = Pediatric Stroke Outcome Measure vWF = von Willebrand factor
2 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
dysfunction across 4 domains sensorimotor language pro-duction language comprehension and cognitionbehavior
Role of funding sourceThere was no funding source for this study The corre-sponding authors had full access to all the data in the studyand final responsibility for the decision to submit forpublication
Data availabilityData not provided in this article including comprehensivetreatment and outcome summaries and search strategies areavailable to be shared by request
ResultsThe search strategy identified a total of 2596 articles with 1additional study identified by author MT (figure 1) Of 2597articles screened for title and abstract 110 articles had full-textretrieval for assessment of inclusion criteria and 9 originalarticles were included for detailed analysis24914ndash19 (figure 1)Reasons for article exclusion included treatment descriptionmissing (n = 24) exclusion of pediatric population (n = 8)not PACNS (n = 5) case reports lt5 children (n = 20) book
chaptersreviewseditorials (n = 39) and abstract only (n =5) Seven studies were deemed high quality after quality as-sessment was conducted Study characteristics are summa-rized in table Of 9 studies reviewed 4 described the samestudy population from Lahore Pakistan16ndash19 4 studies de-scribed the same population from Toronto Canada24914and 1 reported a case series from Los Angeles US15
The Pakistani group16ndash19 identified children lt16 years of agesubsequently diagnosed with cPACNS at their center betweenJanuary 2009 and December 2010 Diagnostic categorizationwas two-fold based on stroke characteristics and cPACNSsubtype A total of 68 patients were identified 50 presentedwith ischemic stroke 10 with hemorrhagic stroke and 8 withboth ischemic and hemorrhagic lesions Alternatively 51patients were classified as APNP-cPACNS and 17 as APP-cPACNS Diagnoses were based on conventional angiography(CA) andor MRA in all patients
Induction therapy 3 days of IV methylprednisolone (IVMP)andor IV immunoglobulin for 5 days with subsequent oralprednisone taper over 30 days was completed by 56 patientsPatients with ischemic stroke also received IV heparin andsubsequent oral anticoagulation therapy Supplementary
Figure 1 Prisma 2009 flow diagram
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 3
Table Summarized description of included studies
Study Diagnosis of cPACNS Age (median y) Treatment Outcome
AN (n = 19) 9middot8 (5middot5ndash17middot8) Induction therapy 6 M (n = 14) Maintenance therapy 18 M (n = 13) Mortality (n = 19) Good neurologic outcomed on PSOM
Confirmatory biopsy (n = 19) IV cyclo + oral prednisone MMF or AZA + oral prednisone 0 pts 12 M 816 pts
Angiography methodsincluded MRA venographyand CA
79 pts AZA switched to MMF 24 M 913 pts
Confirmatory biopsy includedlesionalnonlesionalspecimen and lymphocyticvasculitis histology
Cellucciet al4
AP (n = 14) 9middot8 (3middot3ndash17middot8) ASA therapy (n = 14) IV cyclo x 6 M plusmn MMF or AZA (n = 27) Mortality (n = 39) Good neurologic outcomed on PSOM
AN (n = 25) AP-cPACNS AP-cPACNS 7 pts 0 pts 52 of patients at 12 mo
AP diagnosis based on CAandor MRA abnormalities(n = 14)
Oral prednisone 2-6 M or 12 M (n = 38) AN-cPACNS 23 pts Flare duringfollow-up (n = 39)
65 of patients at 24 mo
Continued
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Table Summarized description of included studies (continued)
Study Diagnosis of cPACNS Age (median y) Treatment Outcome
AN diagnosis based on brainbiopsy showing lymphocyticvasculitis (n = 22)
APNP-cPACNS 13 pts 3 pts did not receive IV cyclo 6 pts Summary scores significantly decreasedover time (p lt 0001)
Those who did not undergobrain biopsy had clinicalfeatures blood work andlumbar puncture consistentwith AN-cPACNS and negativemicrobiologic andantineuronal investigations
Abnormal DSA was found inthe 2 patients with normalMRA
Transitioned off heparin 1 pt MMF 2 pts
Gallagheret al15
AP (n = 5) 8 (5ndash11) Induction therapy (n = 5) Maintenance therapy (n = 3) Mortality (n = 5) Clinicalradiologic evaluation at last follow-up (n = 5)
AP diagnosis based on MRAabnormalities (n = 3) andorCA abnormalities (n = 4)
Oral prednisone plusmn IVMP plusmnanticoagulation + IV cyclo
Methotrexate or AZA plusmn ASA 0 pts Asymptomatic 3 pts
Lost to follow-up 1 pt
Residual deficits 1 pt
Abbreviations AN = angiography-negative AP = angiography-positive ASA = aspirin AZA = azathioprine CA = conventional angiography cPACNS = childhood primary angiitis of the CNS D = days DSA = digital subtractionangiography IV cyclo = IV cyclophosphamide IVIG = IV immunoglobulin IVMP = IV methylprednisolone M = months MRA = magnetic resonance angiography NP = nonprogressive P = progressive PSOM = pediatric strokeoutcome measure pts = patientsa Also described as ischemic stroke (n = 50) hemorrhagic stroke (n = 10) and both (n = 8)b Relapse defined as emergence of signs and symptoms of stroke confirmed with neuroimaging of brain after remissionc Complete neurologic recovery defined as neurologic deficit severity score of 0d Good neurologic outcome defined as le05 across any domain
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calcium and vitamin D were prescribed with anticonvulsantsantipsychotics antibiotics antivirals and antacids as neededA total of 12 patients died before completing inductiontherapy from complications involving cerebral artery andorparenchymal bleeding The remaining 41 patients were allo-cated to 24 months of maintenance therapy consisting ofeither aspirin (ASA) daily for ischemic stroke or together withdaily azathioprine for progressive arteriopathies Despitea clearly delineated therapeutic regimen the Pakistani groupreported conflicting data in regard to the number of patientsassigned to each therapy across the 4 studies Both the initialstudy by Malik et al19 and Alhaboob et al16 identified 41patients assigned to ASA alone and 15 patients to ASA to-gether with azathioprine for 24 months However Maliket al17 indicated that 40 patients were assigned to the 24months ASA only group and 16 patients to ASA and aza-thioprine with ASA duration increased to 60 months in thisstudy Malik et al18 did not provide details of inductiontherapy only that ischemic infarcts were initially treated withIV heparin From this group 40 patients were discharged onASA for 24 months and 14 received adjunctive azathioprinetherapy
The Pakistani group reportedmortality and morbidity acrossdifferent intervals Remission was described as a completeabsence of disease activity in clinical symptoms exam find-ings lab markers and imaging for at least 3 months andrelapse was defined as an emergence of signssymptoms ofstroke confirmed by neuroimaging (CA andor MRA) afterremission All 4 studies documented mortality at dischargein 12 patients (17middot6) Malik et al17ndash19 reported clinicalstate at time of discharge for all survivors defined as neu-rologic assessment for motor visual andor speech diffi-culties Normal examination was reported in 11 (20)minor disability in 14 (25) moderate disability in 11(20) and severe disability in 20 (35) patients Maliket al15 described relapse in a total of 30 patients (54)during maintenance therapy From the ASA only group 18patients (45) relapsed within the first 24 months whichresulted in 10 deaths and of the remaining 22 patients(55) who completed ASA therapy 5 relapsed and 5 diedOverall mortality in the ASA group was 1540 (38middot5) Ofthe 16 patients on maintenance with ASA and azathioprine2 patients (13) relapsed within 24 months and both sur-vived The number of deaths reported was 5 (31) 3patients died from massive cerebral hemorrhage and 2 of 3patients died after relapse within 6 months of successfullycompleting therapy Therefore the overall mortality duringmaintenance reported by Malik et al17 at a medium follow-up of 34 months was 20 (35middot7) of the initial 56 survivorseither as a direct result or as a complication of first or secondrelapse with 5 deaths reportedly due to non-cPACNS cau-ses Malik et al17 also reported the outcome at last follow-upusing the PSOM13 From the 32 patients assessed 8 (25)a normal outcome 10 (31) minor disabilities 10 (31)moderate disabilities 4 (13) severe disabilities and 4patients were lost to follow-up
The Canadian studies24914 similarly identified patients fromthe same center though each study varied in sample size anddiagnostic subtype Benseler et al2 identified 62 children lt18years of age between January 1990 to December 2002 di-agnosed with AP-cPACNS 42 APNP-cPACNS and 20 APP-cPACNS Diagnoses were based on MRA andor CAabnormalities
All patients received antithrombotic therapy with ASA hep-arin or warfarin A total of 41 patients (65) continued withthis treatment approach long-term 33 patients with APNP-cPACNS and 7 patients with APP-cPACNS In contrast 22patients (35) received immunosuppressive interventionwith steroids alone or a combination of steroids and IV cy-clophosphamide 9 (41) APNP-cPACNS and 13 (59)APP-cPACNS Benseler et al2 measured outcome at lastevaluation (mean 20 months) as complete neurologic re-covery defined as neurologic deficit severity score of 0 onPSOM any other deficit severity score was defined as in-complete recovery A total of 22 patients (35) madea complete neurologic recovery 13 (31) of APNP-cPACNSand 9 (45) of APP-cPACNS No deaths were reported
Hutchinson et al9 identified 19 patients lt18 years of age withAN-cPACNS diagnosis between January 2002 and December2009 MRA venography and CA were used Diagnosis in allpatients was based on a confirmatory biopsy Patients receivedinduction and maintenance therapy for 24 months Inductiontherapy was defined as 6 months of IV cyclophosphamidemonthly together with Pneumocystis jiroveci pneumonia pro-phylaxis oral prednisone daily supplementary calcium vita-min D and anticonvulsantsantipsychotics as neededThirteen patients (68) completed induction and went on tomaintenance therapy Maintenance consisted of an additional18 months of therapy with 5 patients (35) assigned tomycophenolate mofetil (MMF) and 9 (65) assigned toazathioprine with anticonvulsantsantipsychotics as neededSeven (78) of 9 patients on azathioprine switched to MMFbecause of treatment failure or intolerance Only 5 patients(36) completed maintenance therapy and were taken offmedication Primary outcome was assessed on PSOM at 24months with good outcome defined as a score of le0middot5 acrosseach of the 4 domains Secondary outcomes included treat-ment efficacy and safety determined by PSOM at 12 monthsand final follow-up disease flare and discontinuation ofimmunosuppressants Good neurologic outcome on PSOMat 12 months was reported in 8 (50) of 16 patients and 9(70) of 13 at final follow-up Disease flare during treatmentwas described in 8 patients (42) 219 (11) during in-duction 514 (36) during maintenance and 15 (20) offmedication No patients relapsed onMMF Of 5 patients whocompleted maintenance therapy 4 achieved remission de-fined as complete absence of disease activity in clinicalsymptoms examination findings lab markers and imaging forat least 3 months Safety was determined by mortality seriousinfection and each of cataracts avascular necrosis vertebralfractures or type II diabetes mellitus No patients in this study
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 7
died however 2 were reported to have had a serious infectionrequiring hospital admission 1 developed cataracts 1 avas-cular necrosis and 3 with vertebral fractures No diabetesmellitus was reported Pediatric Quality of Life (PedsQL)20
was reported for both child and parent at final follow-uptogether with cognitive outcome testing by the Weschler In-telligence Scale for Children IV and Weschler Adult In-telligence Scale III at 14 months postdiagnosis Abnormalscores were defined as any index scores that were ge1 SDsbelow the mean of the normative sample The PedsQLquestionnaire was completed by 17 patients and 15 parentsmedian physical score was 78 (range = 0ndash100) for childrenand 66 (range = 9ndash100) for parents and median psychosocialscore 73 (range = 27ndash100) for children and 63 (range =37ndash100) for parents Cognitive outcome was assessed in 10children Full Scale Intelligence Quotient was reported asabnormal in 8 (80) working memory in all 10 (100)verbal comprehension in 7 (70) perceptual reasoning in 6(60) and processing speed in 5 (50)
Cellucci et al4 identified 39 patients lt18 years of age betweenJune 2001 and October 2010 diagnosed with cPACNS 14 AP-cPACNS not further subdivided and 25 AN-cPACNS AP-cPACNS diagnosis was based on CA andor MRA (n = 14)AN-cPACNS diagnosis was based on confirmatory biopsy in 22patients Patients without biopsy had features blood work andlumbar puncture consistent with AN-cPACNS Some patientswith AP-cPACNS were also represented in the Benseler et al2
study and in the Hutchinson et al9 study
All 14 patients with AP-cPACNS received ASA and 9 (64)received additional anticoagulation with unfractionatedlow-molecular weight heparin for 2 months High-dose predni-sone was prescribed in all but 1 patient with AP-cPACNSwith a varied tapering schedule 2ndash6 months in 6 patients(46) and 12 months in 7 (54) IV cyclophosphamide over6 months followed by MMF or azathioprine was given toa further 7 patients (54) with AP-cPACNS 1 patient withAP-cPACNS received anticoagulation therapy only High-dose prednisone with 12-months taper was prescribed in allpatients with AN-cPACNS IV cyclophosphamide for 6months in combination with azathioprine or MMF wasreported in 20 patients (80) with AN-cPACNS while aza-thioprine or MMF alone as inductionmaintenance therapywas described in 3 patients (12) with AN-cPACNS Twopatients (8) with AN-cPACNS did not receive therapyOutcomes were reported serially across 24 months and in-cluded disease activity as measured by the Physicians GlobalAssessment (PGA) a visual analog scale with a score of zeroindicating no disease activity and 10 indicating severe activityvon Willebrand factor (vWF) antigen levels where highnumbers indicate high disease activity with gt1middot40 IUmLbeing considered abnormal and neurologic outcome onPSOM with good outcome defined as a score of le0middot5 acrosseach domain Disease activity was elevated at time of di-agnosis but significantly decreased over time in all patients(p lt 0middot001) vWF antigen levels decreased over time (p lt
0middot001) PSOM summary scores decreased significantly overtime (p lt 0middot001) with 52 of patients having a good neu-rologic outcome at 12 months and 65 at 24 months A totalof 6 (15) developed disease flare during follow-up defined asan increase in PGA by at least 1 cm in presence of recurrentsymptoms laboratory changes andor MRI findings Nopatients died
Elbers et al14 described 27 patients lt18 years of age with AP-cPACNS diagnosed between January 1998 and December2013 Diagnosis was based on MRA and DSA abnormalitiesPatients might overlap with the Benseler et al2 and Cellucciet al4 studies Acute treatment with unfractionated heparinwas described in 23 patients (85) 5 subsequently transi-tioned to warfarin 17 to ASA and none in 1 ASA aloneor with immunosuppression was described in the remaining4 patients Two patients received chronic immunosuppres-sion with MMF and 1 received plasmapheresis IVMP to-gether with a 3-month oral steroid taper was described in 12patients with no long-term immunosuppression An addi-tional 7 patients were treated with acyclovir Outcomes in-cluded vascular imaging at 12 months assessed using theNorth American Symptomatic Carotid Endarterectomy Trial(NASCET) criteria and described as improved (normal an-giography improved flow or fewer abnormal vessels) stable(no change in flow abnormality or number of involved ves-sels) or worsened (involvement of new vessels or worseningof an existing flow abnormality by at least 1 point on follow-upimaging) and possibly discordant (worsened patients wherea new or worsening arterial abnormality coexisted with animproved or normalized vessel) as well as stroke recurrenceThe NASCET criteria scores vessel narrowing from 1 to 4progressing from normal (0ndash9) to mild (10ndash29)moderate (30ndash69) and severe stenosis (70ndash99) orcomplete occlusion (no flow detected) A total of 10 (37)patients were described as improved 4 of which receivedsteroids as treatment 6 (22) as stable 2 of which receivedsteroids and 11 (41) worsened with 7 described as dis-cordant 6 of which received steroids Stroke recurrence wasreported in 4 patients (15) No patients died
Gallagher et al15 described 5 cases of AP-cPACNS at theircenter with no fixed treatment regimen Diagnosis was basedonMRA andor CA abnormalities Two patients were treatedwith IVMP either at their first or subsequent disease pre-sentation All patients received IV cyclophosphamide how-ever 1 discontinued after the first infusion due to intoleranceAll patients received oral prednisone of varying doses 2 re-ceived short-term (lt6 months) steroid therapy 2 remainedon oral steroids long-term (gt6 months) and 1 was lost tofollow-up after 6 months One patient received long-termtreatment with azathioprine and 2 with methotrexate Four(80) of the 5 patients received anticoagulation therapy witheither ASA or warfarin during their illness No validatedoutcome measures were used to assess outcomes for thesepatients however at last follow-up 3 patients were reportedas neurologically asymptomatic 1 had mild residual deficits
8 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
and 1 was lost to follow-up but continued on treatment attheir last documented visit
DiscussionThis is the first scoping review of treatment in cPACNSDespite the paucity of randomized clinical trials evidence in
the literature offers support for treatment strategies ForAPNP-cPACNS the authors recommend treatment withlong-term antiplatelet therapy to reduce the risk of strokerelapse and mortality as reported in the Pakistani cohort16ndash19
The authors concur with CNS vasculitis expert opinion inrecommending short-term immunosuppressive with IVMPand acute antithrombotic therapy subsequently followed by
Figure 2 Recommended treatment protocol
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 9
high-dose oral prednisone (figure 2A)31021ndash23 In APP-cPACNS the authors support a combination of anti-coagulation and induction therapy with both IV steroids andIV cyclophosphamide with steroid taper (figure 2B)3415ndash19
to increase the prospect of neurologic recovery3101521ndash26
Induction therapy for AN-cPACNS should similarly consist ofIV steroids and IV cyclophosphamide (figure 2C) Evidencein the literature91021ndash24 for long-termmaintenance therapy inAPP-cPACNS and AN-cPACNS supports daily MMFmycophenolic acid in preference to azathioprine to avoidthe possibility of treatment failure or intolerance as reportedby Hutchinson et al9 and the Pakistani group (figures 2B2C)16ndash19
In refractory disease Batthish et al25 reported successful useof infliximab therapy in treating 2 cases of AN-cPACNS withgood control of inflammation and subsequent prevention ofbrain damage Rosati et al26 recently published a case series of4 patients with AP-cPACNS successfully treated with long-term MMF All revealed subsequent stability or improvementon MRIMRA with no progression of arterial disease and norelapses were reported in the follow-up period (range 10ndash42months)26 Sen et al24 also report successful maintenancetreatment with MMF in 3 cases of cPACNS that had failedmethotrexate or azathioprine and steroid treatment alone Nopatients were reported to have had recurring symptoms sideeffects or new lesions on MRI24
While this review provided a comprehensive review of treat-ment literature in cPACNS there were several limitationsBased on our quality assessment definition for Q4 a mini-mum of 1 reproducible reported outcome was sufficient tosatisfy outcome reproducibility Many studies satisfied thiscriterion by reporting mortality despite a lack of or irrepro-ducibility of supplementary outcomes Furthermore usinga validated measure like the PSOMwas sufficient to satisfy theQ5 requirement While the Pakistani group utilized thePSOM in outcome assessment the lack of outcome defi-nitions led to difficulty in result generalizability Finally whilethe same patient cohort was included in all 4 Pakistani groupstudies and treatment regimens were well described thenumber of patients reported to each treatment arm wasgrossly inconsistent and calculated incorrectly Despite thesecontradictions the studies sufficiently satisfied the re-producible treatment criterion and were consequently ratedhigh quality Therefore the authors believe that the qualityassessment for a number of studies reviewed is overstatedwere these studies to be rescored retrospectively they wouldbe deemed low quality Finally the case series by Gallagheret al15 despite meeting inclusion criteria only described casereports with inconsistent treatment regimens and lackedvalidated outcome measures
In conclusion available literature on treatment in cPACNS werethoroughly reviewed and findings summarized Based on theevidence and current expert opinion the authors provide rec-ommendations for cPACNS treatment strategies Rapid initiation
with the recommended therapeutic interventions would serve tooptimize survival and prevent permanent brain injury in patientswith cPACNS to achieve the best possible outcome
AcknowledgmentThe authors would like to thank librarian Rachel Zhao for hercontribution to the development and application of the searchstrategy
Study fundingNo targeted funding
DisclosureJ Beelen reports no disclosures S Benseler serves on theeditorial board for Neurology Neuroimmunology amp Neuro-inflammation A Dropol B Ghali and M Twilt reports nodisclosures Go to NeurologyorgNN for full disclosures
Publication historyReceived byNeurology Neuroimmunology amp Neuroinflammation January24 2019 Accepted in final form March 4 2019
References1 Calabrese LH Mallek JA Primary angiitis of the central nervous system Report of 8
new cases review of the literature and proposal for diagnostic criteria Medicine(Baltimore) 19886720ndash39
2 Benseler SM Silverman E Aviv RI et al Primary central nervous system vasculitis inchildren Arthritis Rheum 2006541291ndash1297
3 Benseler SM deVeber G Hawkins C et al Angiography-negative primary centralnervous system vasculitis in children a newly recognized inflammatory central ner-vous system disease Arthritis Rheum 2005522159ndash2167
4 Cellucci T Tyrrell PN Sheikh S Benseler SM Childhood primary angiitis of thecentral nervous system identifying disease trajectories and early risk factors forpersistently higher disease activity Arthritis Rheum 2012641665ndash1672
Appendix Authors
Name Location Role Contribution
JocelyneBeelenBMSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Evaluated literaturecompiled the datadrafted the manuscriptcompleted manuscriptrevisions
SusanneBenselerMD PhD
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper revised the papercritically for intellectualcontent
AnastasiaDropolHBSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Conceptualized thepaper evaluated theliterature compiledthe data drafted themanuscript
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper completed theliterature searchevaluated the literaturerevised the papercritically for intellectualcontent
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
5 Cellucci T Tyrrell PN Twilt M Sheikh S Benseler SM Distinct phenotype clustersin childhood inflammatory brain diseases implications for diagnostic evaluationArthritis Rheumatol 201466750ndash756
6 Splendiani A Catalucci A Limbucci N Turner M Krings T Gallucci M Pediatricinflammatory diseases part III small vessels vasculitis Neuroradiol J 201225715ndash724
7 Elbers J Halliday W Hawkins C Hutchinson C Benseler SM Brain biopsy inchildren with primary small-vessel central nervous system vasculitis Ann Neurol201068602ndash610
8 Aviv RI Benseler SM DeVeber G et al Angiography of primary central nervoussystem angiitis of childhood conventional angiography versus magnetic resonanceangiography at presentation AJNR Am J Neuroradiol 2007289ndash15
9 Hutchinson C Elbers J Halliday W et al Treatment of small vessel primary CNSvasculitis in children an open-label cohort study Lancet Neurol 201091078ndash1084
10 Twilt M Benseler SM The spectrum of CNS vasculitis in children and adults Nat RevRheumatol 2011897ndash107
11 Salvarani C Brown RD Jr Calamia KT et al Primary central nervous systemvasculitis analysis of 101 patients Ann Neurol 200762442ndash451
12 Pasma A vanrsquot Spijker A Hazes JM Busschbach JJ Luime JJ Factors associated withadherence to pharmaceutical treatment for rheumatoid arthritis patients a systematicreview Semin Arthritis Rheum 20134318ndash28
13 Kitchen L Westmacott R Friefeld S et al The pediatric stroke outcome measurea validation and reliability study Stroke 2012431602ndash1608
14 Elbers J Armstrong D Yau I Benseler S Vascular imaging outcomes of childhoodprimary angiitis of the central nervous system Pediatr Neurol 20166353ndash59
15 Gallagher KT Shaham B Reiff A et al Primary angiitis of the central nervous systemin children 5 cases J Rheumatol 200128616ndash623
16 Alhaboob AA Hasan GM Malik MA Rehman MZ Therapeutic benefits and sideeffects of Azathioprine and Aspirin in treatment of childhood primary arterial strokeAnn Neurosci 20142110ndash13
17 Malik MA Ahmad N Malik H Maintenance treatment of childhood primary angiitisof central nervous system with spirin and azathioprine Pediatr Ther 20133174ndash179
18 Malik MA Choudry GR Malik H Recurrence prevention of childhood primaryangiitis of central nervous system by combination of azathioprine and aspirin Am JMed Stud 2013122ndash27
19 Malik MA Zia-ur-Rehman M Nadeem MM et al Childhood primary angiitis of thecentral nervous system J Coll Physicians Surg Pak 201222570ndash574
20 Varni JW Burwinkle TM Seid M Skarr D The PedsQL 40 as a pediatric populationhealth measure feasibility reliability and validity Ambul Pediatr 20033329ndash341
21 Twilt M Benseler SM Childhood inflammatory brain diseases pathogenesis di-agnosis and therapy Rheumatology (Oxford) 2014531359ndash1368
22 Gowdie P Twilt M Benseler SM Primary and secondary central nervous systemvasculitis J Child Neurol 2012271448ndash1459
23 Moharir M Shroff M Benseler SM Childhood central nervous system vasculitisNeuroimaging Clin N Am 201323293ndash308
24 Sen ES Leone V AbinunM et al Treatment of primary angiitis of the central nervoussystem in childhood with mycophenolate mofetil Rheumatology (Oxford) 201049806ndash811
25 Batthish M Banwell B Laughlin S et al Refractory primary central nervous systemvasculitis of childhood successful treatment with infliximab J Rheumatol 2012392227ndash2229
26 Rosati A Cosi A Basile M et al Mycophenolate mofetil as induction and long-termmaintaining treatment in childhood primary angiitis of the central nervous systemJoint Bone Spine 201784353ndash356
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 11
DOI 101212NXI000000000000056720196 Neurol Neuroimmunol Neuroinflamm
Jocelyne Beelen Susanne M Benseler Anastasia Dropol et al Strategies for treatment of childhood primary angiitis of the central nervous system
This information is current as of May 3 2019
ServicesUpdated Information amp
httpnnneurologyorgcontent64e567fullhtmlincluding high resolution figures can be found at
httpnnneurologyorgcgicollectionall_pediatricAll Pediatricfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2019 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
dysfunction across 4 domains sensorimotor language pro-duction language comprehension and cognitionbehavior
Role of funding sourceThere was no funding source for this study The corre-sponding authors had full access to all the data in the studyand final responsibility for the decision to submit forpublication
Data availabilityData not provided in this article including comprehensivetreatment and outcome summaries and search strategies areavailable to be shared by request
ResultsThe search strategy identified a total of 2596 articles with 1additional study identified by author MT (figure 1) Of 2597articles screened for title and abstract 110 articles had full-textretrieval for assessment of inclusion criteria and 9 originalarticles were included for detailed analysis24914ndash19 (figure 1)Reasons for article exclusion included treatment descriptionmissing (n = 24) exclusion of pediatric population (n = 8)not PACNS (n = 5) case reports lt5 children (n = 20) book
chaptersreviewseditorials (n = 39) and abstract only (n =5) Seven studies were deemed high quality after quality as-sessment was conducted Study characteristics are summa-rized in table Of 9 studies reviewed 4 described the samestudy population from Lahore Pakistan16ndash19 4 studies de-scribed the same population from Toronto Canada24914and 1 reported a case series from Los Angeles US15
The Pakistani group16ndash19 identified children lt16 years of agesubsequently diagnosed with cPACNS at their center betweenJanuary 2009 and December 2010 Diagnostic categorizationwas two-fold based on stroke characteristics and cPACNSsubtype A total of 68 patients were identified 50 presentedwith ischemic stroke 10 with hemorrhagic stroke and 8 withboth ischemic and hemorrhagic lesions Alternatively 51patients were classified as APNP-cPACNS and 17 as APP-cPACNS Diagnoses were based on conventional angiography(CA) andor MRA in all patients
Induction therapy 3 days of IV methylprednisolone (IVMP)andor IV immunoglobulin for 5 days with subsequent oralprednisone taper over 30 days was completed by 56 patientsPatients with ischemic stroke also received IV heparin andsubsequent oral anticoagulation therapy Supplementary
Figure 1 Prisma 2009 flow diagram
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 3
Table Summarized description of included studies
Study Diagnosis of cPACNS Age (median y) Treatment Outcome
AN (n = 19) 9middot8 (5middot5ndash17middot8) Induction therapy 6 M (n = 14) Maintenance therapy 18 M (n = 13) Mortality (n = 19) Good neurologic outcomed on PSOM
Confirmatory biopsy (n = 19) IV cyclo + oral prednisone MMF or AZA + oral prednisone 0 pts 12 M 816 pts
Angiography methodsincluded MRA venographyand CA
79 pts AZA switched to MMF 24 M 913 pts
Confirmatory biopsy includedlesionalnonlesionalspecimen and lymphocyticvasculitis histology
Cellucciet al4
AP (n = 14) 9middot8 (3middot3ndash17middot8) ASA therapy (n = 14) IV cyclo x 6 M plusmn MMF or AZA (n = 27) Mortality (n = 39) Good neurologic outcomed on PSOM
AN (n = 25) AP-cPACNS AP-cPACNS 7 pts 0 pts 52 of patients at 12 mo
AP diagnosis based on CAandor MRA abnormalities(n = 14)
Oral prednisone 2-6 M or 12 M (n = 38) AN-cPACNS 23 pts Flare duringfollow-up (n = 39)
65 of patients at 24 mo
Continued
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Table Summarized description of included studies (continued)
Study Diagnosis of cPACNS Age (median y) Treatment Outcome
AN diagnosis based on brainbiopsy showing lymphocyticvasculitis (n = 22)
APNP-cPACNS 13 pts 3 pts did not receive IV cyclo 6 pts Summary scores significantly decreasedover time (p lt 0001)
Those who did not undergobrain biopsy had clinicalfeatures blood work andlumbar puncture consistentwith AN-cPACNS and negativemicrobiologic andantineuronal investigations
Abnormal DSA was found inthe 2 patients with normalMRA
Transitioned off heparin 1 pt MMF 2 pts
Gallagheret al15
AP (n = 5) 8 (5ndash11) Induction therapy (n = 5) Maintenance therapy (n = 3) Mortality (n = 5) Clinicalradiologic evaluation at last follow-up (n = 5)
AP diagnosis based on MRAabnormalities (n = 3) andorCA abnormalities (n = 4)
Oral prednisone plusmn IVMP plusmnanticoagulation + IV cyclo
Methotrexate or AZA plusmn ASA 0 pts Asymptomatic 3 pts
Lost to follow-up 1 pt
Residual deficits 1 pt
Abbreviations AN = angiography-negative AP = angiography-positive ASA = aspirin AZA = azathioprine CA = conventional angiography cPACNS = childhood primary angiitis of the CNS D = days DSA = digital subtractionangiography IV cyclo = IV cyclophosphamide IVIG = IV immunoglobulin IVMP = IV methylprednisolone M = months MRA = magnetic resonance angiography NP = nonprogressive P = progressive PSOM = pediatric strokeoutcome measure pts = patientsa Also described as ischemic stroke (n = 50) hemorrhagic stroke (n = 10) and both (n = 8)b Relapse defined as emergence of signs and symptoms of stroke confirmed with neuroimaging of brain after remissionc Complete neurologic recovery defined as neurologic deficit severity score of 0d Good neurologic outcome defined as le05 across any domain
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calcium and vitamin D were prescribed with anticonvulsantsantipsychotics antibiotics antivirals and antacids as neededA total of 12 patients died before completing inductiontherapy from complications involving cerebral artery andorparenchymal bleeding The remaining 41 patients were allo-cated to 24 months of maintenance therapy consisting ofeither aspirin (ASA) daily for ischemic stroke or together withdaily azathioprine for progressive arteriopathies Despitea clearly delineated therapeutic regimen the Pakistani groupreported conflicting data in regard to the number of patientsassigned to each therapy across the 4 studies Both the initialstudy by Malik et al19 and Alhaboob et al16 identified 41patients assigned to ASA alone and 15 patients to ASA to-gether with azathioprine for 24 months However Maliket al17 indicated that 40 patients were assigned to the 24months ASA only group and 16 patients to ASA and aza-thioprine with ASA duration increased to 60 months in thisstudy Malik et al18 did not provide details of inductiontherapy only that ischemic infarcts were initially treated withIV heparin From this group 40 patients were discharged onASA for 24 months and 14 received adjunctive azathioprinetherapy
The Pakistani group reportedmortality and morbidity acrossdifferent intervals Remission was described as a completeabsence of disease activity in clinical symptoms exam find-ings lab markers and imaging for at least 3 months andrelapse was defined as an emergence of signssymptoms ofstroke confirmed by neuroimaging (CA andor MRA) afterremission All 4 studies documented mortality at dischargein 12 patients (17middot6) Malik et al17ndash19 reported clinicalstate at time of discharge for all survivors defined as neu-rologic assessment for motor visual andor speech diffi-culties Normal examination was reported in 11 (20)minor disability in 14 (25) moderate disability in 11(20) and severe disability in 20 (35) patients Maliket al15 described relapse in a total of 30 patients (54)during maintenance therapy From the ASA only group 18patients (45) relapsed within the first 24 months whichresulted in 10 deaths and of the remaining 22 patients(55) who completed ASA therapy 5 relapsed and 5 diedOverall mortality in the ASA group was 1540 (38middot5) Ofthe 16 patients on maintenance with ASA and azathioprine2 patients (13) relapsed within 24 months and both sur-vived The number of deaths reported was 5 (31) 3patients died from massive cerebral hemorrhage and 2 of 3patients died after relapse within 6 months of successfullycompleting therapy Therefore the overall mortality duringmaintenance reported by Malik et al17 at a medium follow-up of 34 months was 20 (35middot7) of the initial 56 survivorseither as a direct result or as a complication of first or secondrelapse with 5 deaths reportedly due to non-cPACNS cau-ses Malik et al17 also reported the outcome at last follow-upusing the PSOM13 From the 32 patients assessed 8 (25)a normal outcome 10 (31) minor disabilities 10 (31)moderate disabilities 4 (13) severe disabilities and 4patients were lost to follow-up
The Canadian studies24914 similarly identified patients fromthe same center though each study varied in sample size anddiagnostic subtype Benseler et al2 identified 62 children lt18years of age between January 1990 to December 2002 di-agnosed with AP-cPACNS 42 APNP-cPACNS and 20 APP-cPACNS Diagnoses were based on MRA andor CAabnormalities
All patients received antithrombotic therapy with ASA hep-arin or warfarin A total of 41 patients (65) continued withthis treatment approach long-term 33 patients with APNP-cPACNS and 7 patients with APP-cPACNS In contrast 22patients (35) received immunosuppressive interventionwith steroids alone or a combination of steroids and IV cy-clophosphamide 9 (41) APNP-cPACNS and 13 (59)APP-cPACNS Benseler et al2 measured outcome at lastevaluation (mean 20 months) as complete neurologic re-covery defined as neurologic deficit severity score of 0 onPSOM any other deficit severity score was defined as in-complete recovery A total of 22 patients (35) madea complete neurologic recovery 13 (31) of APNP-cPACNSand 9 (45) of APP-cPACNS No deaths were reported
Hutchinson et al9 identified 19 patients lt18 years of age withAN-cPACNS diagnosis between January 2002 and December2009 MRA venography and CA were used Diagnosis in allpatients was based on a confirmatory biopsy Patients receivedinduction and maintenance therapy for 24 months Inductiontherapy was defined as 6 months of IV cyclophosphamidemonthly together with Pneumocystis jiroveci pneumonia pro-phylaxis oral prednisone daily supplementary calcium vita-min D and anticonvulsantsantipsychotics as neededThirteen patients (68) completed induction and went on tomaintenance therapy Maintenance consisted of an additional18 months of therapy with 5 patients (35) assigned tomycophenolate mofetil (MMF) and 9 (65) assigned toazathioprine with anticonvulsantsantipsychotics as neededSeven (78) of 9 patients on azathioprine switched to MMFbecause of treatment failure or intolerance Only 5 patients(36) completed maintenance therapy and were taken offmedication Primary outcome was assessed on PSOM at 24months with good outcome defined as a score of le0middot5 acrosseach of the 4 domains Secondary outcomes included treat-ment efficacy and safety determined by PSOM at 12 monthsand final follow-up disease flare and discontinuation ofimmunosuppressants Good neurologic outcome on PSOMat 12 months was reported in 8 (50) of 16 patients and 9(70) of 13 at final follow-up Disease flare during treatmentwas described in 8 patients (42) 219 (11) during in-duction 514 (36) during maintenance and 15 (20) offmedication No patients relapsed onMMF Of 5 patients whocompleted maintenance therapy 4 achieved remission de-fined as complete absence of disease activity in clinicalsymptoms examination findings lab markers and imaging forat least 3 months Safety was determined by mortality seriousinfection and each of cataracts avascular necrosis vertebralfractures or type II diabetes mellitus No patients in this study
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 7
died however 2 were reported to have had a serious infectionrequiring hospital admission 1 developed cataracts 1 avas-cular necrosis and 3 with vertebral fractures No diabetesmellitus was reported Pediatric Quality of Life (PedsQL)20
was reported for both child and parent at final follow-uptogether with cognitive outcome testing by the Weschler In-telligence Scale for Children IV and Weschler Adult In-telligence Scale III at 14 months postdiagnosis Abnormalscores were defined as any index scores that were ge1 SDsbelow the mean of the normative sample The PedsQLquestionnaire was completed by 17 patients and 15 parentsmedian physical score was 78 (range = 0ndash100) for childrenand 66 (range = 9ndash100) for parents and median psychosocialscore 73 (range = 27ndash100) for children and 63 (range =37ndash100) for parents Cognitive outcome was assessed in 10children Full Scale Intelligence Quotient was reported asabnormal in 8 (80) working memory in all 10 (100)verbal comprehension in 7 (70) perceptual reasoning in 6(60) and processing speed in 5 (50)
Cellucci et al4 identified 39 patients lt18 years of age betweenJune 2001 and October 2010 diagnosed with cPACNS 14 AP-cPACNS not further subdivided and 25 AN-cPACNS AP-cPACNS diagnosis was based on CA andor MRA (n = 14)AN-cPACNS diagnosis was based on confirmatory biopsy in 22patients Patients without biopsy had features blood work andlumbar puncture consistent with AN-cPACNS Some patientswith AP-cPACNS were also represented in the Benseler et al2
study and in the Hutchinson et al9 study
All 14 patients with AP-cPACNS received ASA and 9 (64)received additional anticoagulation with unfractionatedlow-molecular weight heparin for 2 months High-dose predni-sone was prescribed in all but 1 patient with AP-cPACNSwith a varied tapering schedule 2ndash6 months in 6 patients(46) and 12 months in 7 (54) IV cyclophosphamide over6 months followed by MMF or azathioprine was given toa further 7 patients (54) with AP-cPACNS 1 patient withAP-cPACNS received anticoagulation therapy only High-dose prednisone with 12-months taper was prescribed in allpatients with AN-cPACNS IV cyclophosphamide for 6months in combination with azathioprine or MMF wasreported in 20 patients (80) with AN-cPACNS while aza-thioprine or MMF alone as inductionmaintenance therapywas described in 3 patients (12) with AN-cPACNS Twopatients (8) with AN-cPACNS did not receive therapyOutcomes were reported serially across 24 months and in-cluded disease activity as measured by the Physicians GlobalAssessment (PGA) a visual analog scale with a score of zeroindicating no disease activity and 10 indicating severe activityvon Willebrand factor (vWF) antigen levels where highnumbers indicate high disease activity with gt1middot40 IUmLbeing considered abnormal and neurologic outcome onPSOM with good outcome defined as a score of le0middot5 acrosseach domain Disease activity was elevated at time of di-agnosis but significantly decreased over time in all patients(p lt 0middot001) vWF antigen levels decreased over time (p lt
0middot001) PSOM summary scores decreased significantly overtime (p lt 0middot001) with 52 of patients having a good neu-rologic outcome at 12 months and 65 at 24 months A totalof 6 (15) developed disease flare during follow-up defined asan increase in PGA by at least 1 cm in presence of recurrentsymptoms laboratory changes andor MRI findings Nopatients died
Elbers et al14 described 27 patients lt18 years of age with AP-cPACNS diagnosed between January 1998 and December2013 Diagnosis was based on MRA and DSA abnormalitiesPatients might overlap with the Benseler et al2 and Cellucciet al4 studies Acute treatment with unfractionated heparinwas described in 23 patients (85) 5 subsequently transi-tioned to warfarin 17 to ASA and none in 1 ASA aloneor with immunosuppression was described in the remaining4 patients Two patients received chronic immunosuppres-sion with MMF and 1 received plasmapheresis IVMP to-gether with a 3-month oral steroid taper was described in 12patients with no long-term immunosuppression An addi-tional 7 patients were treated with acyclovir Outcomes in-cluded vascular imaging at 12 months assessed using theNorth American Symptomatic Carotid Endarterectomy Trial(NASCET) criteria and described as improved (normal an-giography improved flow or fewer abnormal vessels) stable(no change in flow abnormality or number of involved ves-sels) or worsened (involvement of new vessels or worseningof an existing flow abnormality by at least 1 point on follow-upimaging) and possibly discordant (worsened patients wherea new or worsening arterial abnormality coexisted with animproved or normalized vessel) as well as stroke recurrenceThe NASCET criteria scores vessel narrowing from 1 to 4progressing from normal (0ndash9) to mild (10ndash29)moderate (30ndash69) and severe stenosis (70ndash99) orcomplete occlusion (no flow detected) A total of 10 (37)patients were described as improved 4 of which receivedsteroids as treatment 6 (22) as stable 2 of which receivedsteroids and 11 (41) worsened with 7 described as dis-cordant 6 of which received steroids Stroke recurrence wasreported in 4 patients (15) No patients died
Gallagher et al15 described 5 cases of AP-cPACNS at theircenter with no fixed treatment regimen Diagnosis was basedonMRA andor CA abnormalities Two patients were treatedwith IVMP either at their first or subsequent disease pre-sentation All patients received IV cyclophosphamide how-ever 1 discontinued after the first infusion due to intoleranceAll patients received oral prednisone of varying doses 2 re-ceived short-term (lt6 months) steroid therapy 2 remainedon oral steroids long-term (gt6 months) and 1 was lost tofollow-up after 6 months One patient received long-termtreatment with azathioprine and 2 with methotrexate Four(80) of the 5 patients received anticoagulation therapy witheither ASA or warfarin during their illness No validatedoutcome measures were used to assess outcomes for thesepatients however at last follow-up 3 patients were reportedas neurologically asymptomatic 1 had mild residual deficits
8 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
and 1 was lost to follow-up but continued on treatment attheir last documented visit
DiscussionThis is the first scoping review of treatment in cPACNSDespite the paucity of randomized clinical trials evidence in
the literature offers support for treatment strategies ForAPNP-cPACNS the authors recommend treatment withlong-term antiplatelet therapy to reduce the risk of strokerelapse and mortality as reported in the Pakistani cohort16ndash19
The authors concur with CNS vasculitis expert opinion inrecommending short-term immunosuppressive with IVMPand acute antithrombotic therapy subsequently followed by
Figure 2 Recommended treatment protocol
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 9
high-dose oral prednisone (figure 2A)31021ndash23 In APP-cPACNS the authors support a combination of anti-coagulation and induction therapy with both IV steroids andIV cyclophosphamide with steroid taper (figure 2B)3415ndash19
to increase the prospect of neurologic recovery3101521ndash26
Induction therapy for AN-cPACNS should similarly consist ofIV steroids and IV cyclophosphamide (figure 2C) Evidencein the literature91021ndash24 for long-termmaintenance therapy inAPP-cPACNS and AN-cPACNS supports daily MMFmycophenolic acid in preference to azathioprine to avoidthe possibility of treatment failure or intolerance as reportedby Hutchinson et al9 and the Pakistani group (figures 2B2C)16ndash19
In refractory disease Batthish et al25 reported successful useof infliximab therapy in treating 2 cases of AN-cPACNS withgood control of inflammation and subsequent prevention ofbrain damage Rosati et al26 recently published a case series of4 patients with AP-cPACNS successfully treated with long-term MMF All revealed subsequent stability or improvementon MRIMRA with no progression of arterial disease and norelapses were reported in the follow-up period (range 10ndash42months)26 Sen et al24 also report successful maintenancetreatment with MMF in 3 cases of cPACNS that had failedmethotrexate or azathioprine and steroid treatment alone Nopatients were reported to have had recurring symptoms sideeffects or new lesions on MRI24
While this review provided a comprehensive review of treat-ment literature in cPACNS there were several limitationsBased on our quality assessment definition for Q4 a mini-mum of 1 reproducible reported outcome was sufficient tosatisfy outcome reproducibility Many studies satisfied thiscriterion by reporting mortality despite a lack of or irrepro-ducibility of supplementary outcomes Furthermore usinga validated measure like the PSOMwas sufficient to satisfy theQ5 requirement While the Pakistani group utilized thePSOM in outcome assessment the lack of outcome defi-nitions led to difficulty in result generalizability Finally whilethe same patient cohort was included in all 4 Pakistani groupstudies and treatment regimens were well described thenumber of patients reported to each treatment arm wasgrossly inconsistent and calculated incorrectly Despite thesecontradictions the studies sufficiently satisfied the re-producible treatment criterion and were consequently ratedhigh quality Therefore the authors believe that the qualityassessment for a number of studies reviewed is overstatedwere these studies to be rescored retrospectively they wouldbe deemed low quality Finally the case series by Gallagheret al15 despite meeting inclusion criteria only described casereports with inconsistent treatment regimens and lackedvalidated outcome measures
In conclusion available literature on treatment in cPACNS werethoroughly reviewed and findings summarized Based on theevidence and current expert opinion the authors provide rec-ommendations for cPACNS treatment strategies Rapid initiation
with the recommended therapeutic interventions would serve tooptimize survival and prevent permanent brain injury in patientswith cPACNS to achieve the best possible outcome
AcknowledgmentThe authors would like to thank librarian Rachel Zhao for hercontribution to the development and application of the searchstrategy
Study fundingNo targeted funding
DisclosureJ Beelen reports no disclosures S Benseler serves on theeditorial board for Neurology Neuroimmunology amp Neuro-inflammation A Dropol B Ghali and M Twilt reports nodisclosures Go to NeurologyorgNN for full disclosures
Publication historyReceived byNeurology Neuroimmunology amp Neuroinflammation January24 2019 Accepted in final form March 4 2019
References1 Calabrese LH Mallek JA Primary angiitis of the central nervous system Report of 8
new cases review of the literature and proposal for diagnostic criteria Medicine(Baltimore) 19886720ndash39
2 Benseler SM Silverman E Aviv RI et al Primary central nervous system vasculitis inchildren Arthritis Rheum 2006541291ndash1297
3 Benseler SM deVeber G Hawkins C et al Angiography-negative primary centralnervous system vasculitis in children a newly recognized inflammatory central ner-vous system disease Arthritis Rheum 2005522159ndash2167
4 Cellucci T Tyrrell PN Sheikh S Benseler SM Childhood primary angiitis of thecentral nervous system identifying disease trajectories and early risk factors forpersistently higher disease activity Arthritis Rheum 2012641665ndash1672
Appendix Authors
Name Location Role Contribution
JocelyneBeelenBMSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Evaluated literaturecompiled the datadrafted the manuscriptcompleted manuscriptrevisions
SusanneBenselerMD PhD
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper revised the papercritically for intellectualcontent
AnastasiaDropolHBSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Conceptualized thepaper evaluated theliterature compiledthe data drafted themanuscript
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper completed theliterature searchevaluated the literaturerevised the papercritically for intellectualcontent
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
5 Cellucci T Tyrrell PN Twilt M Sheikh S Benseler SM Distinct phenotype clustersin childhood inflammatory brain diseases implications for diagnostic evaluationArthritis Rheumatol 201466750ndash756
6 Splendiani A Catalucci A Limbucci N Turner M Krings T Gallucci M Pediatricinflammatory diseases part III small vessels vasculitis Neuroradiol J 201225715ndash724
7 Elbers J Halliday W Hawkins C Hutchinson C Benseler SM Brain biopsy inchildren with primary small-vessel central nervous system vasculitis Ann Neurol201068602ndash610
8 Aviv RI Benseler SM DeVeber G et al Angiography of primary central nervoussystem angiitis of childhood conventional angiography versus magnetic resonanceangiography at presentation AJNR Am J Neuroradiol 2007289ndash15
9 Hutchinson C Elbers J Halliday W et al Treatment of small vessel primary CNSvasculitis in children an open-label cohort study Lancet Neurol 201091078ndash1084
10 Twilt M Benseler SM The spectrum of CNS vasculitis in children and adults Nat RevRheumatol 2011897ndash107
11 Salvarani C Brown RD Jr Calamia KT et al Primary central nervous systemvasculitis analysis of 101 patients Ann Neurol 200762442ndash451
12 Pasma A vanrsquot Spijker A Hazes JM Busschbach JJ Luime JJ Factors associated withadherence to pharmaceutical treatment for rheumatoid arthritis patients a systematicreview Semin Arthritis Rheum 20134318ndash28
13 Kitchen L Westmacott R Friefeld S et al The pediatric stroke outcome measurea validation and reliability study Stroke 2012431602ndash1608
14 Elbers J Armstrong D Yau I Benseler S Vascular imaging outcomes of childhoodprimary angiitis of the central nervous system Pediatr Neurol 20166353ndash59
15 Gallagher KT Shaham B Reiff A et al Primary angiitis of the central nervous systemin children 5 cases J Rheumatol 200128616ndash623
16 Alhaboob AA Hasan GM Malik MA Rehman MZ Therapeutic benefits and sideeffects of Azathioprine and Aspirin in treatment of childhood primary arterial strokeAnn Neurosci 20142110ndash13
17 Malik MA Ahmad N Malik H Maintenance treatment of childhood primary angiitisof central nervous system with spirin and azathioprine Pediatr Ther 20133174ndash179
18 Malik MA Choudry GR Malik H Recurrence prevention of childhood primaryangiitis of central nervous system by combination of azathioprine and aspirin Am JMed Stud 2013122ndash27
19 Malik MA Zia-ur-Rehman M Nadeem MM et al Childhood primary angiitis of thecentral nervous system J Coll Physicians Surg Pak 201222570ndash574
20 Varni JW Burwinkle TM Seid M Skarr D The PedsQL 40 as a pediatric populationhealth measure feasibility reliability and validity Ambul Pediatr 20033329ndash341
21 Twilt M Benseler SM Childhood inflammatory brain diseases pathogenesis di-agnosis and therapy Rheumatology (Oxford) 2014531359ndash1368
22 Gowdie P Twilt M Benseler SM Primary and secondary central nervous systemvasculitis J Child Neurol 2012271448ndash1459
23 Moharir M Shroff M Benseler SM Childhood central nervous system vasculitisNeuroimaging Clin N Am 201323293ndash308
24 Sen ES Leone V AbinunM et al Treatment of primary angiitis of the central nervoussystem in childhood with mycophenolate mofetil Rheumatology (Oxford) 201049806ndash811
25 Batthish M Banwell B Laughlin S et al Refractory primary central nervous systemvasculitis of childhood successful treatment with infliximab J Rheumatol 2012392227ndash2229
26 Rosati A Cosi A Basile M et al Mycophenolate mofetil as induction and long-termmaintaining treatment in childhood primary angiitis of the central nervous systemJoint Bone Spine 201784353ndash356
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 11
DOI 101212NXI000000000000056720196 Neurol Neuroimmunol Neuroinflamm
Jocelyne Beelen Susanne M Benseler Anastasia Dropol et al Strategies for treatment of childhood primary angiitis of the central nervous system
This information is current as of May 3 2019
ServicesUpdated Information amp
httpnnneurologyorgcontent64e567fullhtmlincluding high resolution figures can be found at
httpnnneurologyorgcgicollectionall_pediatricAll Pediatricfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2019 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
Table Summarized description of included studies
Study Diagnosis of cPACNS Age (median y) Treatment Outcome
AN (n = 19) 9middot8 (5middot5ndash17middot8) Induction therapy 6 M (n = 14) Maintenance therapy 18 M (n = 13) Mortality (n = 19) Good neurologic outcomed on PSOM
Confirmatory biopsy (n = 19) IV cyclo + oral prednisone MMF or AZA + oral prednisone 0 pts 12 M 816 pts
Angiography methodsincluded MRA venographyand CA
79 pts AZA switched to MMF 24 M 913 pts
Confirmatory biopsy includedlesionalnonlesionalspecimen and lymphocyticvasculitis histology
Cellucciet al4
AP (n = 14) 9middot8 (3middot3ndash17middot8) ASA therapy (n = 14) IV cyclo x 6 M plusmn MMF or AZA (n = 27) Mortality (n = 39) Good neurologic outcomed on PSOM
AN (n = 25) AP-cPACNS AP-cPACNS 7 pts 0 pts 52 of patients at 12 mo
AP diagnosis based on CAandor MRA abnormalities(n = 14)
Oral prednisone 2-6 M or 12 M (n = 38) AN-cPACNS 23 pts Flare duringfollow-up (n = 39)
65 of patients at 24 mo
Continued
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Table Summarized description of included studies (continued)
Study Diagnosis of cPACNS Age (median y) Treatment Outcome
AN diagnosis based on brainbiopsy showing lymphocyticvasculitis (n = 22)
APNP-cPACNS 13 pts 3 pts did not receive IV cyclo 6 pts Summary scores significantly decreasedover time (p lt 0001)
Those who did not undergobrain biopsy had clinicalfeatures blood work andlumbar puncture consistentwith AN-cPACNS and negativemicrobiologic andantineuronal investigations
Abnormal DSA was found inthe 2 patients with normalMRA
Transitioned off heparin 1 pt MMF 2 pts
Gallagheret al15
AP (n = 5) 8 (5ndash11) Induction therapy (n = 5) Maintenance therapy (n = 3) Mortality (n = 5) Clinicalradiologic evaluation at last follow-up (n = 5)
AP diagnosis based on MRAabnormalities (n = 3) andorCA abnormalities (n = 4)
Oral prednisone plusmn IVMP plusmnanticoagulation + IV cyclo
Methotrexate or AZA plusmn ASA 0 pts Asymptomatic 3 pts
Lost to follow-up 1 pt
Residual deficits 1 pt
Abbreviations AN = angiography-negative AP = angiography-positive ASA = aspirin AZA = azathioprine CA = conventional angiography cPACNS = childhood primary angiitis of the CNS D = days DSA = digital subtractionangiography IV cyclo = IV cyclophosphamide IVIG = IV immunoglobulin IVMP = IV methylprednisolone M = months MRA = magnetic resonance angiography NP = nonprogressive P = progressive PSOM = pediatric strokeoutcome measure pts = patientsa Also described as ischemic stroke (n = 50) hemorrhagic stroke (n = 10) and both (n = 8)b Relapse defined as emergence of signs and symptoms of stroke confirmed with neuroimaging of brain after remissionc Complete neurologic recovery defined as neurologic deficit severity score of 0d Good neurologic outcome defined as le05 across any domain
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calcium and vitamin D were prescribed with anticonvulsantsantipsychotics antibiotics antivirals and antacids as neededA total of 12 patients died before completing inductiontherapy from complications involving cerebral artery andorparenchymal bleeding The remaining 41 patients were allo-cated to 24 months of maintenance therapy consisting ofeither aspirin (ASA) daily for ischemic stroke or together withdaily azathioprine for progressive arteriopathies Despitea clearly delineated therapeutic regimen the Pakistani groupreported conflicting data in regard to the number of patientsassigned to each therapy across the 4 studies Both the initialstudy by Malik et al19 and Alhaboob et al16 identified 41patients assigned to ASA alone and 15 patients to ASA to-gether with azathioprine for 24 months However Maliket al17 indicated that 40 patients were assigned to the 24months ASA only group and 16 patients to ASA and aza-thioprine with ASA duration increased to 60 months in thisstudy Malik et al18 did not provide details of inductiontherapy only that ischemic infarcts were initially treated withIV heparin From this group 40 patients were discharged onASA for 24 months and 14 received adjunctive azathioprinetherapy
The Pakistani group reportedmortality and morbidity acrossdifferent intervals Remission was described as a completeabsence of disease activity in clinical symptoms exam find-ings lab markers and imaging for at least 3 months andrelapse was defined as an emergence of signssymptoms ofstroke confirmed by neuroimaging (CA andor MRA) afterremission All 4 studies documented mortality at dischargein 12 patients (17middot6) Malik et al17ndash19 reported clinicalstate at time of discharge for all survivors defined as neu-rologic assessment for motor visual andor speech diffi-culties Normal examination was reported in 11 (20)minor disability in 14 (25) moderate disability in 11(20) and severe disability in 20 (35) patients Maliket al15 described relapse in a total of 30 patients (54)during maintenance therapy From the ASA only group 18patients (45) relapsed within the first 24 months whichresulted in 10 deaths and of the remaining 22 patients(55) who completed ASA therapy 5 relapsed and 5 diedOverall mortality in the ASA group was 1540 (38middot5) Ofthe 16 patients on maintenance with ASA and azathioprine2 patients (13) relapsed within 24 months and both sur-vived The number of deaths reported was 5 (31) 3patients died from massive cerebral hemorrhage and 2 of 3patients died after relapse within 6 months of successfullycompleting therapy Therefore the overall mortality duringmaintenance reported by Malik et al17 at a medium follow-up of 34 months was 20 (35middot7) of the initial 56 survivorseither as a direct result or as a complication of first or secondrelapse with 5 deaths reportedly due to non-cPACNS cau-ses Malik et al17 also reported the outcome at last follow-upusing the PSOM13 From the 32 patients assessed 8 (25)a normal outcome 10 (31) minor disabilities 10 (31)moderate disabilities 4 (13) severe disabilities and 4patients were lost to follow-up
The Canadian studies24914 similarly identified patients fromthe same center though each study varied in sample size anddiagnostic subtype Benseler et al2 identified 62 children lt18years of age between January 1990 to December 2002 di-agnosed with AP-cPACNS 42 APNP-cPACNS and 20 APP-cPACNS Diagnoses were based on MRA andor CAabnormalities
All patients received antithrombotic therapy with ASA hep-arin or warfarin A total of 41 patients (65) continued withthis treatment approach long-term 33 patients with APNP-cPACNS and 7 patients with APP-cPACNS In contrast 22patients (35) received immunosuppressive interventionwith steroids alone or a combination of steroids and IV cy-clophosphamide 9 (41) APNP-cPACNS and 13 (59)APP-cPACNS Benseler et al2 measured outcome at lastevaluation (mean 20 months) as complete neurologic re-covery defined as neurologic deficit severity score of 0 onPSOM any other deficit severity score was defined as in-complete recovery A total of 22 patients (35) madea complete neurologic recovery 13 (31) of APNP-cPACNSand 9 (45) of APP-cPACNS No deaths were reported
Hutchinson et al9 identified 19 patients lt18 years of age withAN-cPACNS diagnosis between January 2002 and December2009 MRA venography and CA were used Diagnosis in allpatients was based on a confirmatory biopsy Patients receivedinduction and maintenance therapy for 24 months Inductiontherapy was defined as 6 months of IV cyclophosphamidemonthly together with Pneumocystis jiroveci pneumonia pro-phylaxis oral prednisone daily supplementary calcium vita-min D and anticonvulsantsantipsychotics as neededThirteen patients (68) completed induction and went on tomaintenance therapy Maintenance consisted of an additional18 months of therapy with 5 patients (35) assigned tomycophenolate mofetil (MMF) and 9 (65) assigned toazathioprine with anticonvulsantsantipsychotics as neededSeven (78) of 9 patients on azathioprine switched to MMFbecause of treatment failure or intolerance Only 5 patients(36) completed maintenance therapy and were taken offmedication Primary outcome was assessed on PSOM at 24months with good outcome defined as a score of le0middot5 acrosseach of the 4 domains Secondary outcomes included treat-ment efficacy and safety determined by PSOM at 12 monthsand final follow-up disease flare and discontinuation ofimmunosuppressants Good neurologic outcome on PSOMat 12 months was reported in 8 (50) of 16 patients and 9(70) of 13 at final follow-up Disease flare during treatmentwas described in 8 patients (42) 219 (11) during in-duction 514 (36) during maintenance and 15 (20) offmedication No patients relapsed onMMF Of 5 patients whocompleted maintenance therapy 4 achieved remission de-fined as complete absence of disease activity in clinicalsymptoms examination findings lab markers and imaging forat least 3 months Safety was determined by mortality seriousinfection and each of cataracts avascular necrosis vertebralfractures or type II diabetes mellitus No patients in this study
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 7
died however 2 were reported to have had a serious infectionrequiring hospital admission 1 developed cataracts 1 avas-cular necrosis and 3 with vertebral fractures No diabetesmellitus was reported Pediatric Quality of Life (PedsQL)20
was reported for both child and parent at final follow-uptogether with cognitive outcome testing by the Weschler In-telligence Scale for Children IV and Weschler Adult In-telligence Scale III at 14 months postdiagnosis Abnormalscores were defined as any index scores that were ge1 SDsbelow the mean of the normative sample The PedsQLquestionnaire was completed by 17 patients and 15 parentsmedian physical score was 78 (range = 0ndash100) for childrenand 66 (range = 9ndash100) for parents and median psychosocialscore 73 (range = 27ndash100) for children and 63 (range =37ndash100) for parents Cognitive outcome was assessed in 10children Full Scale Intelligence Quotient was reported asabnormal in 8 (80) working memory in all 10 (100)verbal comprehension in 7 (70) perceptual reasoning in 6(60) and processing speed in 5 (50)
Cellucci et al4 identified 39 patients lt18 years of age betweenJune 2001 and October 2010 diagnosed with cPACNS 14 AP-cPACNS not further subdivided and 25 AN-cPACNS AP-cPACNS diagnosis was based on CA andor MRA (n = 14)AN-cPACNS diagnosis was based on confirmatory biopsy in 22patients Patients without biopsy had features blood work andlumbar puncture consistent with AN-cPACNS Some patientswith AP-cPACNS were also represented in the Benseler et al2
study and in the Hutchinson et al9 study
All 14 patients with AP-cPACNS received ASA and 9 (64)received additional anticoagulation with unfractionatedlow-molecular weight heparin for 2 months High-dose predni-sone was prescribed in all but 1 patient with AP-cPACNSwith a varied tapering schedule 2ndash6 months in 6 patients(46) and 12 months in 7 (54) IV cyclophosphamide over6 months followed by MMF or azathioprine was given toa further 7 patients (54) with AP-cPACNS 1 patient withAP-cPACNS received anticoagulation therapy only High-dose prednisone with 12-months taper was prescribed in allpatients with AN-cPACNS IV cyclophosphamide for 6months in combination with azathioprine or MMF wasreported in 20 patients (80) with AN-cPACNS while aza-thioprine or MMF alone as inductionmaintenance therapywas described in 3 patients (12) with AN-cPACNS Twopatients (8) with AN-cPACNS did not receive therapyOutcomes were reported serially across 24 months and in-cluded disease activity as measured by the Physicians GlobalAssessment (PGA) a visual analog scale with a score of zeroindicating no disease activity and 10 indicating severe activityvon Willebrand factor (vWF) antigen levels where highnumbers indicate high disease activity with gt1middot40 IUmLbeing considered abnormal and neurologic outcome onPSOM with good outcome defined as a score of le0middot5 acrosseach domain Disease activity was elevated at time of di-agnosis but significantly decreased over time in all patients(p lt 0middot001) vWF antigen levels decreased over time (p lt
0middot001) PSOM summary scores decreased significantly overtime (p lt 0middot001) with 52 of patients having a good neu-rologic outcome at 12 months and 65 at 24 months A totalof 6 (15) developed disease flare during follow-up defined asan increase in PGA by at least 1 cm in presence of recurrentsymptoms laboratory changes andor MRI findings Nopatients died
Elbers et al14 described 27 patients lt18 years of age with AP-cPACNS diagnosed between January 1998 and December2013 Diagnosis was based on MRA and DSA abnormalitiesPatients might overlap with the Benseler et al2 and Cellucciet al4 studies Acute treatment with unfractionated heparinwas described in 23 patients (85) 5 subsequently transi-tioned to warfarin 17 to ASA and none in 1 ASA aloneor with immunosuppression was described in the remaining4 patients Two patients received chronic immunosuppres-sion with MMF and 1 received plasmapheresis IVMP to-gether with a 3-month oral steroid taper was described in 12patients with no long-term immunosuppression An addi-tional 7 patients were treated with acyclovir Outcomes in-cluded vascular imaging at 12 months assessed using theNorth American Symptomatic Carotid Endarterectomy Trial(NASCET) criteria and described as improved (normal an-giography improved flow or fewer abnormal vessels) stable(no change in flow abnormality or number of involved ves-sels) or worsened (involvement of new vessels or worseningof an existing flow abnormality by at least 1 point on follow-upimaging) and possibly discordant (worsened patients wherea new or worsening arterial abnormality coexisted with animproved or normalized vessel) as well as stroke recurrenceThe NASCET criteria scores vessel narrowing from 1 to 4progressing from normal (0ndash9) to mild (10ndash29)moderate (30ndash69) and severe stenosis (70ndash99) orcomplete occlusion (no flow detected) A total of 10 (37)patients were described as improved 4 of which receivedsteroids as treatment 6 (22) as stable 2 of which receivedsteroids and 11 (41) worsened with 7 described as dis-cordant 6 of which received steroids Stroke recurrence wasreported in 4 patients (15) No patients died
Gallagher et al15 described 5 cases of AP-cPACNS at theircenter with no fixed treatment regimen Diagnosis was basedonMRA andor CA abnormalities Two patients were treatedwith IVMP either at their first or subsequent disease pre-sentation All patients received IV cyclophosphamide how-ever 1 discontinued after the first infusion due to intoleranceAll patients received oral prednisone of varying doses 2 re-ceived short-term (lt6 months) steroid therapy 2 remainedon oral steroids long-term (gt6 months) and 1 was lost tofollow-up after 6 months One patient received long-termtreatment with azathioprine and 2 with methotrexate Four(80) of the 5 patients received anticoagulation therapy witheither ASA or warfarin during their illness No validatedoutcome measures were used to assess outcomes for thesepatients however at last follow-up 3 patients were reportedas neurologically asymptomatic 1 had mild residual deficits
8 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
and 1 was lost to follow-up but continued on treatment attheir last documented visit
DiscussionThis is the first scoping review of treatment in cPACNSDespite the paucity of randomized clinical trials evidence in
the literature offers support for treatment strategies ForAPNP-cPACNS the authors recommend treatment withlong-term antiplatelet therapy to reduce the risk of strokerelapse and mortality as reported in the Pakistani cohort16ndash19
The authors concur with CNS vasculitis expert opinion inrecommending short-term immunosuppressive with IVMPand acute antithrombotic therapy subsequently followed by
Figure 2 Recommended treatment protocol
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high-dose oral prednisone (figure 2A)31021ndash23 In APP-cPACNS the authors support a combination of anti-coagulation and induction therapy with both IV steroids andIV cyclophosphamide with steroid taper (figure 2B)3415ndash19
to increase the prospect of neurologic recovery3101521ndash26
Induction therapy for AN-cPACNS should similarly consist ofIV steroids and IV cyclophosphamide (figure 2C) Evidencein the literature91021ndash24 for long-termmaintenance therapy inAPP-cPACNS and AN-cPACNS supports daily MMFmycophenolic acid in preference to azathioprine to avoidthe possibility of treatment failure or intolerance as reportedby Hutchinson et al9 and the Pakistani group (figures 2B2C)16ndash19
In refractory disease Batthish et al25 reported successful useof infliximab therapy in treating 2 cases of AN-cPACNS withgood control of inflammation and subsequent prevention ofbrain damage Rosati et al26 recently published a case series of4 patients with AP-cPACNS successfully treated with long-term MMF All revealed subsequent stability or improvementon MRIMRA with no progression of arterial disease and norelapses were reported in the follow-up period (range 10ndash42months)26 Sen et al24 also report successful maintenancetreatment with MMF in 3 cases of cPACNS that had failedmethotrexate or azathioprine and steroid treatment alone Nopatients were reported to have had recurring symptoms sideeffects or new lesions on MRI24
While this review provided a comprehensive review of treat-ment literature in cPACNS there were several limitationsBased on our quality assessment definition for Q4 a mini-mum of 1 reproducible reported outcome was sufficient tosatisfy outcome reproducibility Many studies satisfied thiscriterion by reporting mortality despite a lack of or irrepro-ducibility of supplementary outcomes Furthermore usinga validated measure like the PSOMwas sufficient to satisfy theQ5 requirement While the Pakistani group utilized thePSOM in outcome assessment the lack of outcome defi-nitions led to difficulty in result generalizability Finally whilethe same patient cohort was included in all 4 Pakistani groupstudies and treatment regimens were well described thenumber of patients reported to each treatment arm wasgrossly inconsistent and calculated incorrectly Despite thesecontradictions the studies sufficiently satisfied the re-producible treatment criterion and were consequently ratedhigh quality Therefore the authors believe that the qualityassessment for a number of studies reviewed is overstatedwere these studies to be rescored retrospectively they wouldbe deemed low quality Finally the case series by Gallagheret al15 despite meeting inclusion criteria only described casereports with inconsistent treatment regimens and lackedvalidated outcome measures
In conclusion available literature on treatment in cPACNS werethoroughly reviewed and findings summarized Based on theevidence and current expert opinion the authors provide rec-ommendations for cPACNS treatment strategies Rapid initiation
with the recommended therapeutic interventions would serve tooptimize survival and prevent permanent brain injury in patientswith cPACNS to achieve the best possible outcome
AcknowledgmentThe authors would like to thank librarian Rachel Zhao for hercontribution to the development and application of the searchstrategy
Study fundingNo targeted funding
DisclosureJ Beelen reports no disclosures S Benseler serves on theeditorial board for Neurology Neuroimmunology amp Neuro-inflammation A Dropol B Ghali and M Twilt reports nodisclosures Go to NeurologyorgNN for full disclosures
Publication historyReceived byNeurology Neuroimmunology amp Neuroinflammation January24 2019 Accepted in final form March 4 2019
References1 Calabrese LH Mallek JA Primary angiitis of the central nervous system Report of 8
new cases review of the literature and proposal for diagnostic criteria Medicine(Baltimore) 19886720ndash39
2 Benseler SM Silverman E Aviv RI et al Primary central nervous system vasculitis inchildren Arthritis Rheum 2006541291ndash1297
3 Benseler SM deVeber G Hawkins C et al Angiography-negative primary centralnervous system vasculitis in children a newly recognized inflammatory central ner-vous system disease Arthritis Rheum 2005522159ndash2167
4 Cellucci T Tyrrell PN Sheikh S Benseler SM Childhood primary angiitis of thecentral nervous system identifying disease trajectories and early risk factors forpersistently higher disease activity Arthritis Rheum 2012641665ndash1672
Appendix Authors
Name Location Role Contribution
JocelyneBeelenBMSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Evaluated literaturecompiled the datadrafted the manuscriptcompleted manuscriptrevisions
SusanneBenselerMD PhD
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper revised the papercritically for intellectualcontent
AnastasiaDropolHBSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Conceptualized thepaper evaluated theliterature compiledthe data drafted themanuscript
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper completed theliterature searchevaluated the literaturerevised the papercritically for intellectualcontent
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
5 Cellucci T Tyrrell PN Twilt M Sheikh S Benseler SM Distinct phenotype clustersin childhood inflammatory brain diseases implications for diagnostic evaluationArthritis Rheumatol 201466750ndash756
6 Splendiani A Catalucci A Limbucci N Turner M Krings T Gallucci M Pediatricinflammatory diseases part III small vessels vasculitis Neuroradiol J 201225715ndash724
7 Elbers J Halliday W Hawkins C Hutchinson C Benseler SM Brain biopsy inchildren with primary small-vessel central nervous system vasculitis Ann Neurol201068602ndash610
8 Aviv RI Benseler SM DeVeber G et al Angiography of primary central nervoussystem angiitis of childhood conventional angiography versus magnetic resonanceangiography at presentation AJNR Am J Neuroradiol 2007289ndash15
9 Hutchinson C Elbers J Halliday W et al Treatment of small vessel primary CNSvasculitis in children an open-label cohort study Lancet Neurol 201091078ndash1084
10 Twilt M Benseler SM The spectrum of CNS vasculitis in children and adults Nat RevRheumatol 2011897ndash107
11 Salvarani C Brown RD Jr Calamia KT et al Primary central nervous systemvasculitis analysis of 101 patients Ann Neurol 200762442ndash451
12 Pasma A vanrsquot Spijker A Hazes JM Busschbach JJ Luime JJ Factors associated withadherence to pharmaceutical treatment for rheumatoid arthritis patients a systematicreview Semin Arthritis Rheum 20134318ndash28
13 Kitchen L Westmacott R Friefeld S et al The pediatric stroke outcome measurea validation and reliability study Stroke 2012431602ndash1608
14 Elbers J Armstrong D Yau I Benseler S Vascular imaging outcomes of childhoodprimary angiitis of the central nervous system Pediatr Neurol 20166353ndash59
15 Gallagher KT Shaham B Reiff A et al Primary angiitis of the central nervous systemin children 5 cases J Rheumatol 200128616ndash623
16 Alhaboob AA Hasan GM Malik MA Rehman MZ Therapeutic benefits and sideeffects of Azathioprine and Aspirin in treatment of childhood primary arterial strokeAnn Neurosci 20142110ndash13
17 Malik MA Ahmad N Malik H Maintenance treatment of childhood primary angiitisof central nervous system with spirin and azathioprine Pediatr Ther 20133174ndash179
18 Malik MA Choudry GR Malik H Recurrence prevention of childhood primaryangiitis of central nervous system by combination of azathioprine and aspirin Am JMed Stud 2013122ndash27
19 Malik MA Zia-ur-Rehman M Nadeem MM et al Childhood primary angiitis of thecentral nervous system J Coll Physicians Surg Pak 201222570ndash574
20 Varni JW Burwinkle TM Seid M Skarr D The PedsQL 40 as a pediatric populationhealth measure feasibility reliability and validity Ambul Pediatr 20033329ndash341
21 Twilt M Benseler SM Childhood inflammatory brain diseases pathogenesis di-agnosis and therapy Rheumatology (Oxford) 2014531359ndash1368
22 Gowdie P Twilt M Benseler SM Primary and secondary central nervous systemvasculitis J Child Neurol 2012271448ndash1459
23 Moharir M Shroff M Benseler SM Childhood central nervous system vasculitisNeuroimaging Clin N Am 201323293ndash308
24 Sen ES Leone V AbinunM et al Treatment of primary angiitis of the central nervoussystem in childhood with mycophenolate mofetil Rheumatology (Oxford) 201049806ndash811
25 Batthish M Banwell B Laughlin S et al Refractory primary central nervous systemvasculitis of childhood successful treatment with infliximab J Rheumatol 2012392227ndash2229
26 Rosati A Cosi A Basile M et al Mycophenolate mofetil as induction and long-termmaintaining treatment in childhood primary angiitis of the central nervous systemJoint Bone Spine 201784353ndash356
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DOI 101212NXI000000000000056720196 Neurol Neuroimmunol Neuroinflamm
Jocelyne Beelen Susanne M Benseler Anastasia Dropol et al Strategies for treatment of childhood primary angiitis of the central nervous system
This information is current as of May 3 2019
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is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
Table Summarized description of included studies (continued)
Study Diagnosis of cPACNS Age (median y) Treatment Outcome
APP and APNP diagnosesbased on CA andor MRAabnormalities (n = 68)
AN (n = 19) 9middot8 (5middot5ndash17middot8) Induction therapy 6 M (n = 14) Maintenance therapy 18 M (n = 13) Mortality (n = 19) Good neurologic outcomed on PSOM
Confirmatory biopsy (n = 19) IV cyclo + oral prednisone MMF or AZA + oral prednisone 0 pts 12 M 816 pts
Angiography methodsincluded MRA venographyand CA
79 pts AZA switched to MMF 24 M 913 pts
Confirmatory biopsy includedlesionalnonlesionalspecimen and lymphocyticvasculitis histology
Cellucciet al4
AP (n = 14) 9middot8 (3middot3ndash17middot8) ASA therapy (n = 14) IV cyclo x 6 M plusmn MMF or AZA (n = 27) Mortality (n = 39) Good neurologic outcomed on PSOM
AN (n = 25) AP-cPACNS AP-cPACNS 7 pts 0 pts 52 of patients at 12 mo
AP diagnosis based on CAandor MRA abnormalities(n = 14)
Oral prednisone 2-6 M or 12 M (n = 38) AN-cPACNS 23 pts Flare duringfollow-up (n = 39)
65 of patients at 24 mo
Continued
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Table Summarized description of included studies (continued)
Study Diagnosis of cPACNS Age (median y) Treatment Outcome
AN diagnosis based on brainbiopsy showing lymphocyticvasculitis (n = 22)
APNP-cPACNS 13 pts 3 pts did not receive IV cyclo 6 pts Summary scores significantly decreasedover time (p lt 0001)
Those who did not undergobrain biopsy had clinicalfeatures blood work andlumbar puncture consistentwith AN-cPACNS and negativemicrobiologic andantineuronal investigations
Abnormal DSA was found inthe 2 patients with normalMRA
Transitioned off heparin 1 pt MMF 2 pts
Gallagheret al15
AP (n = 5) 8 (5ndash11) Induction therapy (n = 5) Maintenance therapy (n = 3) Mortality (n = 5) Clinicalradiologic evaluation at last follow-up (n = 5)
AP diagnosis based on MRAabnormalities (n = 3) andorCA abnormalities (n = 4)
Oral prednisone plusmn IVMP plusmnanticoagulation + IV cyclo
Methotrexate or AZA plusmn ASA 0 pts Asymptomatic 3 pts
Lost to follow-up 1 pt
Residual deficits 1 pt
Abbreviations AN = angiography-negative AP = angiography-positive ASA = aspirin AZA = azathioprine CA = conventional angiography cPACNS = childhood primary angiitis of the CNS D = days DSA = digital subtractionangiography IV cyclo = IV cyclophosphamide IVIG = IV immunoglobulin IVMP = IV methylprednisolone M = months MRA = magnetic resonance angiography NP = nonprogressive P = progressive PSOM = pediatric strokeoutcome measure pts = patientsa Also described as ischemic stroke (n = 50) hemorrhagic stroke (n = 10) and both (n = 8)b Relapse defined as emergence of signs and symptoms of stroke confirmed with neuroimaging of brain after remissionc Complete neurologic recovery defined as neurologic deficit severity score of 0d Good neurologic outcome defined as le05 across any domain
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calcium and vitamin D were prescribed with anticonvulsantsantipsychotics antibiotics antivirals and antacids as neededA total of 12 patients died before completing inductiontherapy from complications involving cerebral artery andorparenchymal bleeding The remaining 41 patients were allo-cated to 24 months of maintenance therapy consisting ofeither aspirin (ASA) daily for ischemic stroke or together withdaily azathioprine for progressive arteriopathies Despitea clearly delineated therapeutic regimen the Pakistani groupreported conflicting data in regard to the number of patientsassigned to each therapy across the 4 studies Both the initialstudy by Malik et al19 and Alhaboob et al16 identified 41patients assigned to ASA alone and 15 patients to ASA to-gether with azathioprine for 24 months However Maliket al17 indicated that 40 patients were assigned to the 24months ASA only group and 16 patients to ASA and aza-thioprine with ASA duration increased to 60 months in thisstudy Malik et al18 did not provide details of inductiontherapy only that ischemic infarcts were initially treated withIV heparin From this group 40 patients were discharged onASA for 24 months and 14 received adjunctive azathioprinetherapy
The Pakistani group reportedmortality and morbidity acrossdifferent intervals Remission was described as a completeabsence of disease activity in clinical symptoms exam find-ings lab markers and imaging for at least 3 months andrelapse was defined as an emergence of signssymptoms ofstroke confirmed by neuroimaging (CA andor MRA) afterremission All 4 studies documented mortality at dischargein 12 patients (17middot6) Malik et al17ndash19 reported clinicalstate at time of discharge for all survivors defined as neu-rologic assessment for motor visual andor speech diffi-culties Normal examination was reported in 11 (20)minor disability in 14 (25) moderate disability in 11(20) and severe disability in 20 (35) patients Maliket al15 described relapse in a total of 30 patients (54)during maintenance therapy From the ASA only group 18patients (45) relapsed within the first 24 months whichresulted in 10 deaths and of the remaining 22 patients(55) who completed ASA therapy 5 relapsed and 5 diedOverall mortality in the ASA group was 1540 (38middot5) Ofthe 16 patients on maintenance with ASA and azathioprine2 patients (13) relapsed within 24 months and both sur-vived The number of deaths reported was 5 (31) 3patients died from massive cerebral hemorrhage and 2 of 3patients died after relapse within 6 months of successfullycompleting therapy Therefore the overall mortality duringmaintenance reported by Malik et al17 at a medium follow-up of 34 months was 20 (35middot7) of the initial 56 survivorseither as a direct result or as a complication of first or secondrelapse with 5 deaths reportedly due to non-cPACNS cau-ses Malik et al17 also reported the outcome at last follow-upusing the PSOM13 From the 32 patients assessed 8 (25)a normal outcome 10 (31) minor disabilities 10 (31)moderate disabilities 4 (13) severe disabilities and 4patients were lost to follow-up
The Canadian studies24914 similarly identified patients fromthe same center though each study varied in sample size anddiagnostic subtype Benseler et al2 identified 62 children lt18years of age between January 1990 to December 2002 di-agnosed with AP-cPACNS 42 APNP-cPACNS and 20 APP-cPACNS Diagnoses were based on MRA andor CAabnormalities
All patients received antithrombotic therapy with ASA hep-arin or warfarin A total of 41 patients (65) continued withthis treatment approach long-term 33 patients with APNP-cPACNS and 7 patients with APP-cPACNS In contrast 22patients (35) received immunosuppressive interventionwith steroids alone or a combination of steroids and IV cy-clophosphamide 9 (41) APNP-cPACNS and 13 (59)APP-cPACNS Benseler et al2 measured outcome at lastevaluation (mean 20 months) as complete neurologic re-covery defined as neurologic deficit severity score of 0 onPSOM any other deficit severity score was defined as in-complete recovery A total of 22 patients (35) madea complete neurologic recovery 13 (31) of APNP-cPACNSand 9 (45) of APP-cPACNS No deaths were reported
Hutchinson et al9 identified 19 patients lt18 years of age withAN-cPACNS diagnosis between January 2002 and December2009 MRA venography and CA were used Diagnosis in allpatients was based on a confirmatory biopsy Patients receivedinduction and maintenance therapy for 24 months Inductiontherapy was defined as 6 months of IV cyclophosphamidemonthly together with Pneumocystis jiroveci pneumonia pro-phylaxis oral prednisone daily supplementary calcium vita-min D and anticonvulsantsantipsychotics as neededThirteen patients (68) completed induction and went on tomaintenance therapy Maintenance consisted of an additional18 months of therapy with 5 patients (35) assigned tomycophenolate mofetil (MMF) and 9 (65) assigned toazathioprine with anticonvulsantsantipsychotics as neededSeven (78) of 9 patients on azathioprine switched to MMFbecause of treatment failure or intolerance Only 5 patients(36) completed maintenance therapy and were taken offmedication Primary outcome was assessed on PSOM at 24months with good outcome defined as a score of le0middot5 acrosseach of the 4 domains Secondary outcomes included treat-ment efficacy and safety determined by PSOM at 12 monthsand final follow-up disease flare and discontinuation ofimmunosuppressants Good neurologic outcome on PSOMat 12 months was reported in 8 (50) of 16 patients and 9(70) of 13 at final follow-up Disease flare during treatmentwas described in 8 patients (42) 219 (11) during in-duction 514 (36) during maintenance and 15 (20) offmedication No patients relapsed onMMF Of 5 patients whocompleted maintenance therapy 4 achieved remission de-fined as complete absence of disease activity in clinicalsymptoms examination findings lab markers and imaging forat least 3 months Safety was determined by mortality seriousinfection and each of cataracts avascular necrosis vertebralfractures or type II diabetes mellitus No patients in this study
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 7
died however 2 were reported to have had a serious infectionrequiring hospital admission 1 developed cataracts 1 avas-cular necrosis and 3 with vertebral fractures No diabetesmellitus was reported Pediatric Quality of Life (PedsQL)20
was reported for both child and parent at final follow-uptogether with cognitive outcome testing by the Weschler In-telligence Scale for Children IV and Weschler Adult In-telligence Scale III at 14 months postdiagnosis Abnormalscores were defined as any index scores that were ge1 SDsbelow the mean of the normative sample The PedsQLquestionnaire was completed by 17 patients and 15 parentsmedian physical score was 78 (range = 0ndash100) for childrenand 66 (range = 9ndash100) for parents and median psychosocialscore 73 (range = 27ndash100) for children and 63 (range =37ndash100) for parents Cognitive outcome was assessed in 10children Full Scale Intelligence Quotient was reported asabnormal in 8 (80) working memory in all 10 (100)verbal comprehension in 7 (70) perceptual reasoning in 6(60) and processing speed in 5 (50)
Cellucci et al4 identified 39 patients lt18 years of age betweenJune 2001 and October 2010 diagnosed with cPACNS 14 AP-cPACNS not further subdivided and 25 AN-cPACNS AP-cPACNS diagnosis was based on CA andor MRA (n = 14)AN-cPACNS diagnosis was based on confirmatory biopsy in 22patients Patients without biopsy had features blood work andlumbar puncture consistent with AN-cPACNS Some patientswith AP-cPACNS were also represented in the Benseler et al2
study and in the Hutchinson et al9 study
All 14 patients with AP-cPACNS received ASA and 9 (64)received additional anticoagulation with unfractionatedlow-molecular weight heparin for 2 months High-dose predni-sone was prescribed in all but 1 patient with AP-cPACNSwith a varied tapering schedule 2ndash6 months in 6 patients(46) and 12 months in 7 (54) IV cyclophosphamide over6 months followed by MMF or azathioprine was given toa further 7 patients (54) with AP-cPACNS 1 patient withAP-cPACNS received anticoagulation therapy only High-dose prednisone with 12-months taper was prescribed in allpatients with AN-cPACNS IV cyclophosphamide for 6months in combination with azathioprine or MMF wasreported in 20 patients (80) with AN-cPACNS while aza-thioprine or MMF alone as inductionmaintenance therapywas described in 3 patients (12) with AN-cPACNS Twopatients (8) with AN-cPACNS did not receive therapyOutcomes were reported serially across 24 months and in-cluded disease activity as measured by the Physicians GlobalAssessment (PGA) a visual analog scale with a score of zeroindicating no disease activity and 10 indicating severe activityvon Willebrand factor (vWF) antigen levels where highnumbers indicate high disease activity with gt1middot40 IUmLbeing considered abnormal and neurologic outcome onPSOM with good outcome defined as a score of le0middot5 acrosseach domain Disease activity was elevated at time of di-agnosis but significantly decreased over time in all patients(p lt 0middot001) vWF antigen levels decreased over time (p lt
0middot001) PSOM summary scores decreased significantly overtime (p lt 0middot001) with 52 of patients having a good neu-rologic outcome at 12 months and 65 at 24 months A totalof 6 (15) developed disease flare during follow-up defined asan increase in PGA by at least 1 cm in presence of recurrentsymptoms laboratory changes andor MRI findings Nopatients died
Elbers et al14 described 27 patients lt18 years of age with AP-cPACNS diagnosed between January 1998 and December2013 Diagnosis was based on MRA and DSA abnormalitiesPatients might overlap with the Benseler et al2 and Cellucciet al4 studies Acute treatment with unfractionated heparinwas described in 23 patients (85) 5 subsequently transi-tioned to warfarin 17 to ASA and none in 1 ASA aloneor with immunosuppression was described in the remaining4 patients Two patients received chronic immunosuppres-sion with MMF and 1 received plasmapheresis IVMP to-gether with a 3-month oral steroid taper was described in 12patients with no long-term immunosuppression An addi-tional 7 patients were treated with acyclovir Outcomes in-cluded vascular imaging at 12 months assessed using theNorth American Symptomatic Carotid Endarterectomy Trial(NASCET) criteria and described as improved (normal an-giography improved flow or fewer abnormal vessels) stable(no change in flow abnormality or number of involved ves-sels) or worsened (involvement of new vessels or worseningof an existing flow abnormality by at least 1 point on follow-upimaging) and possibly discordant (worsened patients wherea new or worsening arterial abnormality coexisted with animproved or normalized vessel) as well as stroke recurrenceThe NASCET criteria scores vessel narrowing from 1 to 4progressing from normal (0ndash9) to mild (10ndash29)moderate (30ndash69) and severe stenosis (70ndash99) orcomplete occlusion (no flow detected) A total of 10 (37)patients were described as improved 4 of which receivedsteroids as treatment 6 (22) as stable 2 of which receivedsteroids and 11 (41) worsened with 7 described as dis-cordant 6 of which received steroids Stroke recurrence wasreported in 4 patients (15) No patients died
Gallagher et al15 described 5 cases of AP-cPACNS at theircenter with no fixed treatment regimen Diagnosis was basedonMRA andor CA abnormalities Two patients were treatedwith IVMP either at their first or subsequent disease pre-sentation All patients received IV cyclophosphamide how-ever 1 discontinued after the first infusion due to intoleranceAll patients received oral prednisone of varying doses 2 re-ceived short-term (lt6 months) steroid therapy 2 remainedon oral steroids long-term (gt6 months) and 1 was lost tofollow-up after 6 months One patient received long-termtreatment with azathioprine and 2 with methotrexate Four(80) of the 5 patients received anticoagulation therapy witheither ASA or warfarin during their illness No validatedoutcome measures were used to assess outcomes for thesepatients however at last follow-up 3 patients were reportedas neurologically asymptomatic 1 had mild residual deficits
8 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
and 1 was lost to follow-up but continued on treatment attheir last documented visit
DiscussionThis is the first scoping review of treatment in cPACNSDespite the paucity of randomized clinical trials evidence in
the literature offers support for treatment strategies ForAPNP-cPACNS the authors recommend treatment withlong-term antiplatelet therapy to reduce the risk of strokerelapse and mortality as reported in the Pakistani cohort16ndash19
The authors concur with CNS vasculitis expert opinion inrecommending short-term immunosuppressive with IVMPand acute antithrombotic therapy subsequently followed by
Figure 2 Recommended treatment protocol
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 9
high-dose oral prednisone (figure 2A)31021ndash23 In APP-cPACNS the authors support a combination of anti-coagulation and induction therapy with both IV steroids andIV cyclophosphamide with steroid taper (figure 2B)3415ndash19
to increase the prospect of neurologic recovery3101521ndash26
Induction therapy for AN-cPACNS should similarly consist ofIV steroids and IV cyclophosphamide (figure 2C) Evidencein the literature91021ndash24 for long-termmaintenance therapy inAPP-cPACNS and AN-cPACNS supports daily MMFmycophenolic acid in preference to azathioprine to avoidthe possibility of treatment failure or intolerance as reportedby Hutchinson et al9 and the Pakistani group (figures 2B2C)16ndash19
In refractory disease Batthish et al25 reported successful useof infliximab therapy in treating 2 cases of AN-cPACNS withgood control of inflammation and subsequent prevention ofbrain damage Rosati et al26 recently published a case series of4 patients with AP-cPACNS successfully treated with long-term MMF All revealed subsequent stability or improvementon MRIMRA with no progression of arterial disease and norelapses were reported in the follow-up period (range 10ndash42months)26 Sen et al24 also report successful maintenancetreatment with MMF in 3 cases of cPACNS that had failedmethotrexate or azathioprine and steroid treatment alone Nopatients were reported to have had recurring symptoms sideeffects or new lesions on MRI24
While this review provided a comprehensive review of treat-ment literature in cPACNS there were several limitationsBased on our quality assessment definition for Q4 a mini-mum of 1 reproducible reported outcome was sufficient tosatisfy outcome reproducibility Many studies satisfied thiscriterion by reporting mortality despite a lack of or irrepro-ducibility of supplementary outcomes Furthermore usinga validated measure like the PSOMwas sufficient to satisfy theQ5 requirement While the Pakistani group utilized thePSOM in outcome assessment the lack of outcome defi-nitions led to difficulty in result generalizability Finally whilethe same patient cohort was included in all 4 Pakistani groupstudies and treatment regimens were well described thenumber of patients reported to each treatment arm wasgrossly inconsistent and calculated incorrectly Despite thesecontradictions the studies sufficiently satisfied the re-producible treatment criterion and were consequently ratedhigh quality Therefore the authors believe that the qualityassessment for a number of studies reviewed is overstatedwere these studies to be rescored retrospectively they wouldbe deemed low quality Finally the case series by Gallagheret al15 despite meeting inclusion criteria only described casereports with inconsistent treatment regimens and lackedvalidated outcome measures
In conclusion available literature on treatment in cPACNS werethoroughly reviewed and findings summarized Based on theevidence and current expert opinion the authors provide rec-ommendations for cPACNS treatment strategies Rapid initiation
with the recommended therapeutic interventions would serve tooptimize survival and prevent permanent brain injury in patientswith cPACNS to achieve the best possible outcome
AcknowledgmentThe authors would like to thank librarian Rachel Zhao for hercontribution to the development and application of the searchstrategy
Study fundingNo targeted funding
DisclosureJ Beelen reports no disclosures S Benseler serves on theeditorial board for Neurology Neuroimmunology amp Neuro-inflammation A Dropol B Ghali and M Twilt reports nodisclosures Go to NeurologyorgNN for full disclosures
Publication historyReceived byNeurology Neuroimmunology amp Neuroinflammation January24 2019 Accepted in final form March 4 2019
References1 Calabrese LH Mallek JA Primary angiitis of the central nervous system Report of 8
new cases review of the literature and proposal for diagnostic criteria Medicine(Baltimore) 19886720ndash39
2 Benseler SM Silverman E Aviv RI et al Primary central nervous system vasculitis inchildren Arthritis Rheum 2006541291ndash1297
3 Benseler SM deVeber G Hawkins C et al Angiography-negative primary centralnervous system vasculitis in children a newly recognized inflammatory central ner-vous system disease Arthritis Rheum 2005522159ndash2167
4 Cellucci T Tyrrell PN Sheikh S Benseler SM Childhood primary angiitis of thecentral nervous system identifying disease trajectories and early risk factors forpersistently higher disease activity Arthritis Rheum 2012641665ndash1672
Appendix Authors
Name Location Role Contribution
JocelyneBeelenBMSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Evaluated literaturecompiled the datadrafted the manuscriptcompleted manuscriptrevisions
SusanneBenselerMD PhD
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper revised the papercritically for intellectualcontent
AnastasiaDropolHBSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Conceptualized thepaper evaluated theliterature compiledthe data drafted themanuscript
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper completed theliterature searchevaluated the literaturerevised the papercritically for intellectualcontent
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
5 Cellucci T Tyrrell PN Twilt M Sheikh S Benseler SM Distinct phenotype clustersin childhood inflammatory brain diseases implications for diagnostic evaluationArthritis Rheumatol 201466750ndash756
6 Splendiani A Catalucci A Limbucci N Turner M Krings T Gallucci M Pediatricinflammatory diseases part III small vessels vasculitis Neuroradiol J 201225715ndash724
7 Elbers J Halliday W Hawkins C Hutchinson C Benseler SM Brain biopsy inchildren with primary small-vessel central nervous system vasculitis Ann Neurol201068602ndash610
8 Aviv RI Benseler SM DeVeber G et al Angiography of primary central nervoussystem angiitis of childhood conventional angiography versus magnetic resonanceangiography at presentation AJNR Am J Neuroradiol 2007289ndash15
9 Hutchinson C Elbers J Halliday W et al Treatment of small vessel primary CNSvasculitis in children an open-label cohort study Lancet Neurol 201091078ndash1084
10 Twilt M Benseler SM The spectrum of CNS vasculitis in children and adults Nat RevRheumatol 2011897ndash107
11 Salvarani C Brown RD Jr Calamia KT et al Primary central nervous systemvasculitis analysis of 101 patients Ann Neurol 200762442ndash451
12 Pasma A vanrsquot Spijker A Hazes JM Busschbach JJ Luime JJ Factors associated withadherence to pharmaceutical treatment for rheumatoid arthritis patients a systematicreview Semin Arthritis Rheum 20134318ndash28
13 Kitchen L Westmacott R Friefeld S et al The pediatric stroke outcome measurea validation and reliability study Stroke 2012431602ndash1608
14 Elbers J Armstrong D Yau I Benseler S Vascular imaging outcomes of childhoodprimary angiitis of the central nervous system Pediatr Neurol 20166353ndash59
15 Gallagher KT Shaham B Reiff A et al Primary angiitis of the central nervous systemin children 5 cases J Rheumatol 200128616ndash623
16 Alhaboob AA Hasan GM Malik MA Rehman MZ Therapeutic benefits and sideeffects of Azathioprine and Aspirin in treatment of childhood primary arterial strokeAnn Neurosci 20142110ndash13
17 Malik MA Ahmad N Malik H Maintenance treatment of childhood primary angiitisof central nervous system with spirin and azathioprine Pediatr Ther 20133174ndash179
18 Malik MA Choudry GR Malik H Recurrence prevention of childhood primaryangiitis of central nervous system by combination of azathioprine and aspirin Am JMed Stud 2013122ndash27
19 Malik MA Zia-ur-Rehman M Nadeem MM et al Childhood primary angiitis of thecentral nervous system J Coll Physicians Surg Pak 201222570ndash574
20 Varni JW Burwinkle TM Seid M Skarr D The PedsQL 40 as a pediatric populationhealth measure feasibility reliability and validity Ambul Pediatr 20033329ndash341
21 Twilt M Benseler SM Childhood inflammatory brain diseases pathogenesis di-agnosis and therapy Rheumatology (Oxford) 2014531359ndash1368
22 Gowdie P Twilt M Benseler SM Primary and secondary central nervous systemvasculitis J Child Neurol 2012271448ndash1459
23 Moharir M Shroff M Benseler SM Childhood central nervous system vasculitisNeuroimaging Clin N Am 201323293ndash308
24 Sen ES Leone V AbinunM et al Treatment of primary angiitis of the central nervoussystem in childhood with mycophenolate mofetil Rheumatology (Oxford) 201049806ndash811
25 Batthish M Banwell B Laughlin S et al Refractory primary central nervous systemvasculitis of childhood successful treatment with infliximab J Rheumatol 2012392227ndash2229
26 Rosati A Cosi A Basile M et al Mycophenolate mofetil as induction and long-termmaintaining treatment in childhood primary angiitis of the central nervous systemJoint Bone Spine 201784353ndash356
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 11
DOI 101212NXI000000000000056720196 Neurol Neuroimmunol Neuroinflamm
Jocelyne Beelen Susanne M Benseler Anastasia Dropol et al Strategies for treatment of childhood primary angiitis of the central nervous system
This information is current as of May 3 2019
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is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
Table Summarized description of included studies (continued)
Study Diagnosis of cPACNS Age (median y) Treatment Outcome
AN diagnosis based on brainbiopsy showing lymphocyticvasculitis (n = 22)
APNP-cPACNS 13 pts 3 pts did not receive IV cyclo 6 pts Summary scores significantly decreasedover time (p lt 0001)
Those who did not undergobrain biopsy had clinicalfeatures blood work andlumbar puncture consistentwith AN-cPACNS and negativemicrobiologic andantineuronal investigations
Abnormal DSA was found inthe 2 patients with normalMRA
Transitioned off heparin 1 pt MMF 2 pts
Gallagheret al15
AP (n = 5) 8 (5ndash11) Induction therapy (n = 5) Maintenance therapy (n = 3) Mortality (n = 5) Clinicalradiologic evaluation at last follow-up (n = 5)
AP diagnosis based on MRAabnormalities (n = 3) andorCA abnormalities (n = 4)
Oral prednisone plusmn IVMP plusmnanticoagulation + IV cyclo
Methotrexate or AZA plusmn ASA 0 pts Asymptomatic 3 pts
Lost to follow-up 1 pt
Residual deficits 1 pt
Abbreviations AN = angiography-negative AP = angiography-positive ASA = aspirin AZA = azathioprine CA = conventional angiography cPACNS = childhood primary angiitis of the CNS D = days DSA = digital subtractionangiography IV cyclo = IV cyclophosphamide IVIG = IV immunoglobulin IVMP = IV methylprednisolone M = months MRA = magnetic resonance angiography NP = nonprogressive P = progressive PSOM = pediatric strokeoutcome measure pts = patientsa Also described as ischemic stroke (n = 50) hemorrhagic stroke (n = 10) and both (n = 8)b Relapse defined as emergence of signs and symptoms of stroke confirmed with neuroimaging of brain after remissionc Complete neurologic recovery defined as neurologic deficit severity score of 0d Good neurologic outcome defined as le05 across any domain
6NeurologyN
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calcium and vitamin D were prescribed with anticonvulsantsantipsychotics antibiotics antivirals and antacids as neededA total of 12 patients died before completing inductiontherapy from complications involving cerebral artery andorparenchymal bleeding The remaining 41 patients were allo-cated to 24 months of maintenance therapy consisting ofeither aspirin (ASA) daily for ischemic stroke or together withdaily azathioprine for progressive arteriopathies Despitea clearly delineated therapeutic regimen the Pakistani groupreported conflicting data in regard to the number of patientsassigned to each therapy across the 4 studies Both the initialstudy by Malik et al19 and Alhaboob et al16 identified 41patients assigned to ASA alone and 15 patients to ASA to-gether with azathioprine for 24 months However Maliket al17 indicated that 40 patients were assigned to the 24months ASA only group and 16 patients to ASA and aza-thioprine with ASA duration increased to 60 months in thisstudy Malik et al18 did not provide details of inductiontherapy only that ischemic infarcts were initially treated withIV heparin From this group 40 patients were discharged onASA for 24 months and 14 received adjunctive azathioprinetherapy
The Pakistani group reportedmortality and morbidity acrossdifferent intervals Remission was described as a completeabsence of disease activity in clinical symptoms exam find-ings lab markers and imaging for at least 3 months andrelapse was defined as an emergence of signssymptoms ofstroke confirmed by neuroimaging (CA andor MRA) afterremission All 4 studies documented mortality at dischargein 12 patients (17middot6) Malik et al17ndash19 reported clinicalstate at time of discharge for all survivors defined as neu-rologic assessment for motor visual andor speech diffi-culties Normal examination was reported in 11 (20)minor disability in 14 (25) moderate disability in 11(20) and severe disability in 20 (35) patients Maliket al15 described relapse in a total of 30 patients (54)during maintenance therapy From the ASA only group 18patients (45) relapsed within the first 24 months whichresulted in 10 deaths and of the remaining 22 patients(55) who completed ASA therapy 5 relapsed and 5 diedOverall mortality in the ASA group was 1540 (38middot5) Ofthe 16 patients on maintenance with ASA and azathioprine2 patients (13) relapsed within 24 months and both sur-vived The number of deaths reported was 5 (31) 3patients died from massive cerebral hemorrhage and 2 of 3patients died after relapse within 6 months of successfullycompleting therapy Therefore the overall mortality duringmaintenance reported by Malik et al17 at a medium follow-up of 34 months was 20 (35middot7) of the initial 56 survivorseither as a direct result or as a complication of first or secondrelapse with 5 deaths reportedly due to non-cPACNS cau-ses Malik et al17 also reported the outcome at last follow-upusing the PSOM13 From the 32 patients assessed 8 (25)a normal outcome 10 (31) minor disabilities 10 (31)moderate disabilities 4 (13) severe disabilities and 4patients were lost to follow-up
The Canadian studies24914 similarly identified patients fromthe same center though each study varied in sample size anddiagnostic subtype Benseler et al2 identified 62 children lt18years of age between January 1990 to December 2002 di-agnosed with AP-cPACNS 42 APNP-cPACNS and 20 APP-cPACNS Diagnoses were based on MRA andor CAabnormalities
All patients received antithrombotic therapy with ASA hep-arin or warfarin A total of 41 patients (65) continued withthis treatment approach long-term 33 patients with APNP-cPACNS and 7 patients with APP-cPACNS In contrast 22patients (35) received immunosuppressive interventionwith steroids alone or a combination of steroids and IV cy-clophosphamide 9 (41) APNP-cPACNS and 13 (59)APP-cPACNS Benseler et al2 measured outcome at lastevaluation (mean 20 months) as complete neurologic re-covery defined as neurologic deficit severity score of 0 onPSOM any other deficit severity score was defined as in-complete recovery A total of 22 patients (35) madea complete neurologic recovery 13 (31) of APNP-cPACNSand 9 (45) of APP-cPACNS No deaths were reported
Hutchinson et al9 identified 19 patients lt18 years of age withAN-cPACNS diagnosis between January 2002 and December2009 MRA venography and CA were used Diagnosis in allpatients was based on a confirmatory biopsy Patients receivedinduction and maintenance therapy for 24 months Inductiontherapy was defined as 6 months of IV cyclophosphamidemonthly together with Pneumocystis jiroveci pneumonia pro-phylaxis oral prednisone daily supplementary calcium vita-min D and anticonvulsantsantipsychotics as neededThirteen patients (68) completed induction and went on tomaintenance therapy Maintenance consisted of an additional18 months of therapy with 5 patients (35) assigned tomycophenolate mofetil (MMF) and 9 (65) assigned toazathioprine with anticonvulsantsantipsychotics as neededSeven (78) of 9 patients on azathioprine switched to MMFbecause of treatment failure or intolerance Only 5 patients(36) completed maintenance therapy and were taken offmedication Primary outcome was assessed on PSOM at 24months with good outcome defined as a score of le0middot5 acrosseach of the 4 domains Secondary outcomes included treat-ment efficacy and safety determined by PSOM at 12 monthsand final follow-up disease flare and discontinuation ofimmunosuppressants Good neurologic outcome on PSOMat 12 months was reported in 8 (50) of 16 patients and 9(70) of 13 at final follow-up Disease flare during treatmentwas described in 8 patients (42) 219 (11) during in-duction 514 (36) during maintenance and 15 (20) offmedication No patients relapsed onMMF Of 5 patients whocompleted maintenance therapy 4 achieved remission de-fined as complete absence of disease activity in clinicalsymptoms examination findings lab markers and imaging forat least 3 months Safety was determined by mortality seriousinfection and each of cataracts avascular necrosis vertebralfractures or type II diabetes mellitus No patients in this study
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 7
died however 2 were reported to have had a serious infectionrequiring hospital admission 1 developed cataracts 1 avas-cular necrosis and 3 with vertebral fractures No diabetesmellitus was reported Pediatric Quality of Life (PedsQL)20
was reported for both child and parent at final follow-uptogether with cognitive outcome testing by the Weschler In-telligence Scale for Children IV and Weschler Adult In-telligence Scale III at 14 months postdiagnosis Abnormalscores were defined as any index scores that were ge1 SDsbelow the mean of the normative sample The PedsQLquestionnaire was completed by 17 patients and 15 parentsmedian physical score was 78 (range = 0ndash100) for childrenand 66 (range = 9ndash100) for parents and median psychosocialscore 73 (range = 27ndash100) for children and 63 (range =37ndash100) for parents Cognitive outcome was assessed in 10children Full Scale Intelligence Quotient was reported asabnormal in 8 (80) working memory in all 10 (100)verbal comprehension in 7 (70) perceptual reasoning in 6(60) and processing speed in 5 (50)
Cellucci et al4 identified 39 patients lt18 years of age betweenJune 2001 and October 2010 diagnosed with cPACNS 14 AP-cPACNS not further subdivided and 25 AN-cPACNS AP-cPACNS diagnosis was based on CA andor MRA (n = 14)AN-cPACNS diagnosis was based on confirmatory biopsy in 22patients Patients without biopsy had features blood work andlumbar puncture consistent with AN-cPACNS Some patientswith AP-cPACNS were also represented in the Benseler et al2
study and in the Hutchinson et al9 study
All 14 patients with AP-cPACNS received ASA and 9 (64)received additional anticoagulation with unfractionatedlow-molecular weight heparin for 2 months High-dose predni-sone was prescribed in all but 1 patient with AP-cPACNSwith a varied tapering schedule 2ndash6 months in 6 patients(46) and 12 months in 7 (54) IV cyclophosphamide over6 months followed by MMF or azathioprine was given toa further 7 patients (54) with AP-cPACNS 1 patient withAP-cPACNS received anticoagulation therapy only High-dose prednisone with 12-months taper was prescribed in allpatients with AN-cPACNS IV cyclophosphamide for 6months in combination with azathioprine or MMF wasreported in 20 patients (80) with AN-cPACNS while aza-thioprine or MMF alone as inductionmaintenance therapywas described in 3 patients (12) with AN-cPACNS Twopatients (8) with AN-cPACNS did not receive therapyOutcomes were reported serially across 24 months and in-cluded disease activity as measured by the Physicians GlobalAssessment (PGA) a visual analog scale with a score of zeroindicating no disease activity and 10 indicating severe activityvon Willebrand factor (vWF) antigen levels where highnumbers indicate high disease activity with gt1middot40 IUmLbeing considered abnormal and neurologic outcome onPSOM with good outcome defined as a score of le0middot5 acrosseach domain Disease activity was elevated at time of di-agnosis but significantly decreased over time in all patients(p lt 0middot001) vWF antigen levels decreased over time (p lt
0middot001) PSOM summary scores decreased significantly overtime (p lt 0middot001) with 52 of patients having a good neu-rologic outcome at 12 months and 65 at 24 months A totalof 6 (15) developed disease flare during follow-up defined asan increase in PGA by at least 1 cm in presence of recurrentsymptoms laboratory changes andor MRI findings Nopatients died
Elbers et al14 described 27 patients lt18 years of age with AP-cPACNS diagnosed between January 1998 and December2013 Diagnosis was based on MRA and DSA abnormalitiesPatients might overlap with the Benseler et al2 and Cellucciet al4 studies Acute treatment with unfractionated heparinwas described in 23 patients (85) 5 subsequently transi-tioned to warfarin 17 to ASA and none in 1 ASA aloneor with immunosuppression was described in the remaining4 patients Two patients received chronic immunosuppres-sion with MMF and 1 received plasmapheresis IVMP to-gether with a 3-month oral steroid taper was described in 12patients with no long-term immunosuppression An addi-tional 7 patients were treated with acyclovir Outcomes in-cluded vascular imaging at 12 months assessed using theNorth American Symptomatic Carotid Endarterectomy Trial(NASCET) criteria and described as improved (normal an-giography improved flow or fewer abnormal vessels) stable(no change in flow abnormality or number of involved ves-sels) or worsened (involvement of new vessels or worseningof an existing flow abnormality by at least 1 point on follow-upimaging) and possibly discordant (worsened patients wherea new or worsening arterial abnormality coexisted with animproved or normalized vessel) as well as stroke recurrenceThe NASCET criteria scores vessel narrowing from 1 to 4progressing from normal (0ndash9) to mild (10ndash29)moderate (30ndash69) and severe stenosis (70ndash99) orcomplete occlusion (no flow detected) A total of 10 (37)patients were described as improved 4 of which receivedsteroids as treatment 6 (22) as stable 2 of which receivedsteroids and 11 (41) worsened with 7 described as dis-cordant 6 of which received steroids Stroke recurrence wasreported in 4 patients (15) No patients died
Gallagher et al15 described 5 cases of AP-cPACNS at theircenter with no fixed treatment regimen Diagnosis was basedonMRA andor CA abnormalities Two patients were treatedwith IVMP either at their first or subsequent disease pre-sentation All patients received IV cyclophosphamide how-ever 1 discontinued after the first infusion due to intoleranceAll patients received oral prednisone of varying doses 2 re-ceived short-term (lt6 months) steroid therapy 2 remainedon oral steroids long-term (gt6 months) and 1 was lost tofollow-up after 6 months One patient received long-termtreatment with azathioprine and 2 with methotrexate Four(80) of the 5 patients received anticoagulation therapy witheither ASA or warfarin during their illness No validatedoutcome measures were used to assess outcomes for thesepatients however at last follow-up 3 patients were reportedas neurologically asymptomatic 1 had mild residual deficits
8 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
and 1 was lost to follow-up but continued on treatment attheir last documented visit
DiscussionThis is the first scoping review of treatment in cPACNSDespite the paucity of randomized clinical trials evidence in
the literature offers support for treatment strategies ForAPNP-cPACNS the authors recommend treatment withlong-term antiplatelet therapy to reduce the risk of strokerelapse and mortality as reported in the Pakistani cohort16ndash19
The authors concur with CNS vasculitis expert opinion inrecommending short-term immunosuppressive with IVMPand acute antithrombotic therapy subsequently followed by
Figure 2 Recommended treatment protocol
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 9
high-dose oral prednisone (figure 2A)31021ndash23 In APP-cPACNS the authors support a combination of anti-coagulation and induction therapy with both IV steroids andIV cyclophosphamide with steroid taper (figure 2B)3415ndash19
to increase the prospect of neurologic recovery3101521ndash26
Induction therapy for AN-cPACNS should similarly consist ofIV steroids and IV cyclophosphamide (figure 2C) Evidencein the literature91021ndash24 for long-termmaintenance therapy inAPP-cPACNS and AN-cPACNS supports daily MMFmycophenolic acid in preference to azathioprine to avoidthe possibility of treatment failure or intolerance as reportedby Hutchinson et al9 and the Pakistani group (figures 2B2C)16ndash19
In refractory disease Batthish et al25 reported successful useof infliximab therapy in treating 2 cases of AN-cPACNS withgood control of inflammation and subsequent prevention ofbrain damage Rosati et al26 recently published a case series of4 patients with AP-cPACNS successfully treated with long-term MMF All revealed subsequent stability or improvementon MRIMRA with no progression of arterial disease and norelapses were reported in the follow-up period (range 10ndash42months)26 Sen et al24 also report successful maintenancetreatment with MMF in 3 cases of cPACNS that had failedmethotrexate or azathioprine and steroid treatment alone Nopatients were reported to have had recurring symptoms sideeffects or new lesions on MRI24
While this review provided a comprehensive review of treat-ment literature in cPACNS there were several limitationsBased on our quality assessment definition for Q4 a mini-mum of 1 reproducible reported outcome was sufficient tosatisfy outcome reproducibility Many studies satisfied thiscriterion by reporting mortality despite a lack of or irrepro-ducibility of supplementary outcomes Furthermore usinga validated measure like the PSOMwas sufficient to satisfy theQ5 requirement While the Pakistani group utilized thePSOM in outcome assessment the lack of outcome defi-nitions led to difficulty in result generalizability Finally whilethe same patient cohort was included in all 4 Pakistani groupstudies and treatment regimens were well described thenumber of patients reported to each treatment arm wasgrossly inconsistent and calculated incorrectly Despite thesecontradictions the studies sufficiently satisfied the re-producible treatment criterion and were consequently ratedhigh quality Therefore the authors believe that the qualityassessment for a number of studies reviewed is overstatedwere these studies to be rescored retrospectively they wouldbe deemed low quality Finally the case series by Gallagheret al15 despite meeting inclusion criteria only described casereports with inconsistent treatment regimens and lackedvalidated outcome measures
In conclusion available literature on treatment in cPACNS werethoroughly reviewed and findings summarized Based on theevidence and current expert opinion the authors provide rec-ommendations for cPACNS treatment strategies Rapid initiation
with the recommended therapeutic interventions would serve tooptimize survival and prevent permanent brain injury in patientswith cPACNS to achieve the best possible outcome
AcknowledgmentThe authors would like to thank librarian Rachel Zhao for hercontribution to the development and application of the searchstrategy
Study fundingNo targeted funding
DisclosureJ Beelen reports no disclosures S Benseler serves on theeditorial board for Neurology Neuroimmunology amp Neuro-inflammation A Dropol B Ghali and M Twilt reports nodisclosures Go to NeurologyorgNN for full disclosures
Publication historyReceived byNeurology Neuroimmunology amp Neuroinflammation January24 2019 Accepted in final form March 4 2019
References1 Calabrese LH Mallek JA Primary angiitis of the central nervous system Report of 8
new cases review of the literature and proposal for diagnostic criteria Medicine(Baltimore) 19886720ndash39
2 Benseler SM Silverman E Aviv RI et al Primary central nervous system vasculitis inchildren Arthritis Rheum 2006541291ndash1297
3 Benseler SM deVeber G Hawkins C et al Angiography-negative primary centralnervous system vasculitis in children a newly recognized inflammatory central ner-vous system disease Arthritis Rheum 2005522159ndash2167
4 Cellucci T Tyrrell PN Sheikh S Benseler SM Childhood primary angiitis of thecentral nervous system identifying disease trajectories and early risk factors forpersistently higher disease activity Arthritis Rheum 2012641665ndash1672
Appendix Authors
Name Location Role Contribution
JocelyneBeelenBMSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Evaluated literaturecompiled the datadrafted the manuscriptcompleted manuscriptrevisions
SusanneBenselerMD PhD
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper revised the papercritically for intellectualcontent
AnastasiaDropolHBSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Conceptualized thepaper evaluated theliterature compiledthe data drafted themanuscript
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper completed theliterature searchevaluated the literaturerevised the papercritically for intellectualcontent
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
5 Cellucci T Tyrrell PN Twilt M Sheikh S Benseler SM Distinct phenotype clustersin childhood inflammatory brain diseases implications for diagnostic evaluationArthritis Rheumatol 201466750ndash756
6 Splendiani A Catalucci A Limbucci N Turner M Krings T Gallucci M Pediatricinflammatory diseases part III small vessels vasculitis Neuroradiol J 201225715ndash724
7 Elbers J Halliday W Hawkins C Hutchinson C Benseler SM Brain biopsy inchildren with primary small-vessel central nervous system vasculitis Ann Neurol201068602ndash610
8 Aviv RI Benseler SM DeVeber G et al Angiography of primary central nervoussystem angiitis of childhood conventional angiography versus magnetic resonanceangiography at presentation AJNR Am J Neuroradiol 2007289ndash15
9 Hutchinson C Elbers J Halliday W et al Treatment of small vessel primary CNSvasculitis in children an open-label cohort study Lancet Neurol 201091078ndash1084
10 Twilt M Benseler SM The spectrum of CNS vasculitis in children and adults Nat RevRheumatol 2011897ndash107
11 Salvarani C Brown RD Jr Calamia KT et al Primary central nervous systemvasculitis analysis of 101 patients Ann Neurol 200762442ndash451
12 Pasma A vanrsquot Spijker A Hazes JM Busschbach JJ Luime JJ Factors associated withadherence to pharmaceutical treatment for rheumatoid arthritis patients a systematicreview Semin Arthritis Rheum 20134318ndash28
13 Kitchen L Westmacott R Friefeld S et al The pediatric stroke outcome measurea validation and reliability study Stroke 2012431602ndash1608
14 Elbers J Armstrong D Yau I Benseler S Vascular imaging outcomes of childhoodprimary angiitis of the central nervous system Pediatr Neurol 20166353ndash59
15 Gallagher KT Shaham B Reiff A et al Primary angiitis of the central nervous systemin children 5 cases J Rheumatol 200128616ndash623
16 Alhaboob AA Hasan GM Malik MA Rehman MZ Therapeutic benefits and sideeffects of Azathioprine and Aspirin in treatment of childhood primary arterial strokeAnn Neurosci 20142110ndash13
17 Malik MA Ahmad N Malik H Maintenance treatment of childhood primary angiitisof central nervous system with spirin and azathioprine Pediatr Ther 20133174ndash179
18 Malik MA Choudry GR Malik H Recurrence prevention of childhood primaryangiitis of central nervous system by combination of azathioprine and aspirin Am JMed Stud 2013122ndash27
19 Malik MA Zia-ur-Rehman M Nadeem MM et al Childhood primary angiitis of thecentral nervous system J Coll Physicians Surg Pak 201222570ndash574
20 Varni JW Burwinkle TM Seid M Skarr D The PedsQL 40 as a pediatric populationhealth measure feasibility reliability and validity Ambul Pediatr 20033329ndash341
21 Twilt M Benseler SM Childhood inflammatory brain diseases pathogenesis di-agnosis and therapy Rheumatology (Oxford) 2014531359ndash1368
22 Gowdie P Twilt M Benseler SM Primary and secondary central nervous systemvasculitis J Child Neurol 2012271448ndash1459
23 Moharir M Shroff M Benseler SM Childhood central nervous system vasculitisNeuroimaging Clin N Am 201323293ndash308
24 Sen ES Leone V AbinunM et al Treatment of primary angiitis of the central nervoussystem in childhood with mycophenolate mofetil Rheumatology (Oxford) 201049806ndash811
25 Batthish M Banwell B Laughlin S et al Refractory primary central nervous systemvasculitis of childhood successful treatment with infliximab J Rheumatol 2012392227ndash2229
26 Rosati A Cosi A Basile M et al Mycophenolate mofetil as induction and long-termmaintaining treatment in childhood primary angiitis of the central nervous systemJoint Bone Spine 201784353ndash356
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 11
DOI 101212NXI000000000000056720196 Neurol Neuroimmunol Neuroinflamm
Jocelyne Beelen Susanne M Benseler Anastasia Dropol et al Strategies for treatment of childhood primary angiitis of the central nervous system
This information is current as of May 3 2019
ServicesUpdated Information amp
httpnnneurologyorgcontent64e567fullhtmlincluding high resolution figures can be found at
httpnnneurologyorgcgicollectionall_pediatricAll Pediatricfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2019 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
calcium and vitamin D were prescribed with anticonvulsantsantipsychotics antibiotics antivirals and antacids as neededA total of 12 patients died before completing inductiontherapy from complications involving cerebral artery andorparenchymal bleeding The remaining 41 patients were allo-cated to 24 months of maintenance therapy consisting ofeither aspirin (ASA) daily for ischemic stroke or together withdaily azathioprine for progressive arteriopathies Despitea clearly delineated therapeutic regimen the Pakistani groupreported conflicting data in regard to the number of patientsassigned to each therapy across the 4 studies Both the initialstudy by Malik et al19 and Alhaboob et al16 identified 41patients assigned to ASA alone and 15 patients to ASA to-gether with azathioprine for 24 months However Maliket al17 indicated that 40 patients were assigned to the 24months ASA only group and 16 patients to ASA and aza-thioprine with ASA duration increased to 60 months in thisstudy Malik et al18 did not provide details of inductiontherapy only that ischemic infarcts were initially treated withIV heparin From this group 40 patients were discharged onASA for 24 months and 14 received adjunctive azathioprinetherapy
The Pakistani group reportedmortality and morbidity acrossdifferent intervals Remission was described as a completeabsence of disease activity in clinical symptoms exam find-ings lab markers and imaging for at least 3 months andrelapse was defined as an emergence of signssymptoms ofstroke confirmed by neuroimaging (CA andor MRA) afterremission All 4 studies documented mortality at dischargein 12 patients (17middot6) Malik et al17ndash19 reported clinicalstate at time of discharge for all survivors defined as neu-rologic assessment for motor visual andor speech diffi-culties Normal examination was reported in 11 (20)minor disability in 14 (25) moderate disability in 11(20) and severe disability in 20 (35) patients Maliket al15 described relapse in a total of 30 patients (54)during maintenance therapy From the ASA only group 18patients (45) relapsed within the first 24 months whichresulted in 10 deaths and of the remaining 22 patients(55) who completed ASA therapy 5 relapsed and 5 diedOverall mortality in the ASA group was 1540 (38middot5) Ofthe 16 patients on maintenance with ASA and azathioprine2 patients (13) relapsed within 24 months and both sur-vived The number of deaths reported was 5 (31) 3patients died from massive cerebral hemorrhage and 2 of 3patients died after relapse within 6 months of successfullycompleting therapy Therefore the overall mortality duringmaintenance reported by Malik et al17 at a medium follow-up of 34 months was 20 (35middot7) of the initial 56 survivorseither as a direct result or as a complication of first or secondrelapse with 5 deaths reportedly due to non-cPACNS cau-ses Malik et al17 also reported the outcome at last follow-upusing the PSOM13 From the 32 patients assessed 8 (25)a normal outcome 10 (31) minor disabilities 10 (31)moderate disabilities 4 (13) severe disabilities and 4patients were lost to follow-up
The Canadian studies24914 similarly identified patients fromthe same center though each study varied in sample size anddiagnostic subtype Benseler et al2 identified 62 children lt18years of age between January 1990 to December 2002 di-agnosed with AP-cPACNS 42 APNP-cPACNS and 20 APP-cPACNS Diagnoses were based on MRA andor CAabnormalities
All patients received antithrombotic therapy with ASA hep-arin or warfarin A total of 41 patients (65) continued withthis treatment approach long-term 33 patients with APNP-cPACNS and 7 patients with APP-cPACNS In contrast 22patients (35) received immunosuppressive interventionwith steroids alone or a combination of steroids and IV cy-clophosphamide 9 (41) APNP-cPACNS and 13 (59)APP-cPACNS Benseler et al2 measured outcome at lastevaluation (mean 20 months) as complete neurologic re-covery defined as neurologic deficit severity score of 0 onPSOM any other deficit severity score was defined as in-complete recovery A total of 22 patients (35) madea complete neurologic recovery 13 (31) of APNP-cPACNSand 9 (45) of APP-cPACNS No deaths were reported
Hutchinson et al9 identified 19 patients lt18 years of age withAN-cPACNS diagnosis between January 2002 and December2009 MRA venography and CA were used Diagnosis in allpatients was based on a confirmatory biopsy Patients receivedinduction and maintenance therapy for 24 months Inductiontherapy was defined as 6 months of IV cyclophosphamidemonthly together with Pneumocystis jiroveci pneumonia pro-phylaxis oral prednisone daily supplementary calcium vita-min D and anticonvulsantsantipsychotics as neededThirteen patients (68) completed induction and went on tomaintenance therapy Maintenance consisted of an additional18 months of therapy with 5 patients (35) assigned tomycophenolate mofetil (MMF) and 9 (65) assigned toazathioprine with anticonvulsantsantipsychotics as neededSeven (78) of 9 patients on azathioprine switched to MMFbecause of treatment failure or intolerance Only 5 patients(36) completed maintenance therapy and were taken offmedication Primary outcome was assessed on PSOM at 24months with good outcome defined as a score of le0middot5 acrosseach of the 4 domains Secondary outcomes included treat-ment efficacy and safety determined by PSOM at 12 monthsand final follow-up disease flare and discontinuation ofimmunosuppressants Good neurologic outcome on PSOMat 12 months was reported in 8 (50) of 16 patients and 9(70) of 13 at final follow-up Disease flare during treatmentwas described in 8 patients (42) 219 (11) during in-duction 514 (36) during maintenance and 15 (20) offmedication No patients relapsed onMMF Of 5 patients whocompleted maintenance therapy 4 achieved remission de-fined as complete absence of disease activity in clinicalsymptoms examination findings lab markers and imaging forat least 3 months Safety was determined by mortality seriousinfection and each of cataracts avascular necrosis vertebralfractures or type II diabetes mellitus No patients in this study
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 7
died however 2 were reported to have had a serious infectionrequiring hospital admission 1 developed cataracts 1 avas-cular necrosis and 3 with vertebral fractures No diabetesmellitus was reported Pediatric Quality of Life (PedsQL)20
was reported for both child and parent at final follow-uptogether with cognitive outcome testing by the Weschler In-telligence Scale for Children IV and Weschler Adult In-telligence Scale III at 14 months postdiagnosis Abnormalscores were defined as any index scores that were ge1 SDsbelow the mean of the normative sample The PedsQLquestionnaire was completed by 17 patients and 15 parentsmedian physical score was 78 (range = 0ndash100) for childrenand 66 (range = 9ndash100) for parents and median psychosocialscore 73 (range = 27ndash100) for children and 63 (range =37ndash100) for parents Cognitive outcome was assessed in 10children Full Scale Intelligence Quotient was reported asabnormal in 8 (80) working memory in all 10 (100)verbal comprehension in 7 (70) perceptual reasoning in 6(60) and processing speed in 5 (50)
Cellucci et al4 identified 39 patients lt18 years of age betweenJune 2001 and October 2010 diagnosed with cPACNS 14 AP-cPACNS not further subdivided and 25 AN-cPACNS AP-cPACNS diagnosis was based on CA andor MRA (n = 14)AN-cPACNS diagnosis was based on confirmatory biopsy in 22patients Patients without biopsy had features blood work andlumbar puncture consistent with AN-cPACNS Some patientswith AP-cPACNS were also represented in the Benseler et al2
study and in the Hutchinson et al9 study
All 14 patients with AP-cPACNS received ASA and 9 (64)received additional anticoagulation with unfractionatedlow-molecular weight heparin for 2 months High-dose predni-sone was prescribed in all but 1 patient with AP-cPACNSwith a varied tapering schedule 2ndash6 months in 6 patients(46) and 12 months in 7 (54) IV cyclophosphamide over6 months followed by MMF or azathioprine was given toa further 7 patients (54) with AP-cPACNS 1 patient withAP-cPACNS received anticoagulation therapy only High-dose prednisone with 12-months taper was prescribed in allpatients with AN-cPACNS IV cyclophosphamide for 6months in combination with azathioprine or MMF wasreported in 20 patients (80) with AN-cPACNS while aza-thioprine or MMF alone as inductionmaintenance therapywas described in 3 patients (12) with AN-cPACNS Twopatients (8) with AN-cPACNS did not receive therapyOutcomes were reported serially across 24 months and in-cluded disease activity as measured by the Physicians GlobalAssessment (PGA) a visual analog scale with a score of zeroindicating no disease activity and 10 indicating severe activityvon Willebrand factor (vWF) antigen levels where highnumbers indicate high disease activity with gt1middot40 IUmLbeing considered abnormal and neurologic outcome onPSOM with good outcome defined as a score of le0middot5 acrosseach domain Disease activity was elevated at time of di-agnosis but significantly decreased over time in all patients(p lt 0middot001) vWF antigen levels decreased over time (p lt
0middot001) PSOM summary scores decreased significantly overtime (p lt 0middot001) with 52 of patients having a good neu-rologic outcome at 12 months and 65 at 24 months A totalof 6 (15) developed disease flare during follow-up defined asan increase in PGA by at least 1 cm in presence of recurrentsymptoms laboratory changes andor MRI findings Nopatients died
Elbers et al14 described 27 patients lt18 years of age with AP-cPACNS diagnosed between January 1998 and December2013 Diagnosis was based on MRA and DSA abnormalitiesPatients might overlap with the Benseler et al2 and Cellucciet al4 studies Acute treatment with unfractionated heparinwas described in 23 patients (85) 5 subsequently transi-tioned to warfarin 17 to ASA and none in 1 ASA aloneor with immunosuppression was described in the remaining4 patients Two patients received chronic immunosuppres-sion with MMF and 1 received plasmapheresis IVMP to-gether with a 3-month oral steroid taper was described in 12patients with no long-term immunosuppression An addi-tional 7 patients were treated with acyclovir Outcomes in-cluded vascular imaging at 12 months assessed using theNorth American Symptomatic Carotid Endarterectomy Trial(NASCET) criteria and described as improved (normal an-giography improved flow or fewer abnormal vessels) stable(no change in flow abnormality or number of involved ves-sels) or worsened (involvement of new vessels or worseningof an existing flow abnormality by at least 1 point on follow-upimaging) and possibly discordant (worsened patients wherea new or worsening arterial abnormality coexisted with animproved or normalized vessel) as well as stroke recurrenceThe NASCET criteria scores vessel narrowing from 1 to 4progressing from normal (0ndash9) to mild (10ndash29)moderate (30ndash69) and severe stenosis (70ndash99) orcomplete occlusion (no flow detected) A total of 10 (37)patients were described as improved 4 of which receivedsteroids as treatment 6 (22) as stable 2 of which receivedsteroids and 11 (41) worsened with 7 described as dis-cordant 6 of which received steroids Stroke recurrence wasreported in 4 patients (15) No patients died
Gallagher et al15 described 5 cases of AP-cPACNS at theircenter with no fixed treatment regimen Diagnosis was basedonMRA andor CA abnormalities Two patients were treatedwith IVMP either at their first or subsequent disease pre-sentation All patients received IV cyclophosphamide how-ever 1 discontinued after the first infusion due to intoleranceAll patients received oral prednisone of varying doses 2 re-ceived short-term (lt6 months) steroid therapy 2 remainedon oral steroids long-term (gt6 months) and 1 was lost tofollow-up after 6 months One patient received long-termtreatment with azathioprine and 2 with methotrexate Four(80) of the 5 patients received anticoagulation therapy witheither ASA or warfarin during their illness No validatedoutcome measures were used to assess outcomes for thesepatients however at last follow-up 3 patients were reportedas neurologically asymptomatic 1 had mild residual deficits
8 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
and 1 was lost to follow-up but continued on treatment attheir last documented visit
DiscussionThis is the first scoping review of treatment in cPACNSDespite the paucity of randomized clinical trials evidence in
the literature offers support for treatment strategies ForAPNP-cPACNS the authors recommend treatment withlong-term antiplatelet therapy to reduce the risk of strokerelapse and mortality as reported in the Pakistani cohort16ndash19
The authors concur with CNS vasculitis expert opinion inrecommending short-term immunosuppressive with IVMPand acute antithrombotic therapy subsequently followed by
Figure 2 Recommended treatment protocol
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 9
high-dose oral prednisone (figure 2A)31021ndash23 In APP-cPACNS the authors support a combination of anti-coagulation and induction therapy with both IV steroids andIV cyclophosphamide with steroid taper (figure 2B)3415ndash19
to increase the prospect of neurologic recovery3101521ndash26
Induction therapy for AN-cPACNS should similarly consist ofIV steroids and IV cyclophosphamide (figure 2C) Evidencein the literature91021ndash24 for long-termmaintenance therapy inAPP-cPACNS and AN-cPACNS supports daily MMFmycophenolic acid in preference to azathioprine to avoidthe possibility of treatment failure or intolerance as reportedby Hutchinson et al9 and the Pakistani group (figures 2B2C)16ndash19
In refractory disease Batthish et al25 reported successful useof infliximab therapy in treating 2 cases of AN-cPACNS withgood control of inflammation and subsequent prevention ofbrain damage Rosati et al26 recently published a case series of4 patients with AP-cPACNS successfully treated with long-term MMF All revealed subsequent stability or improvementon MRIMRA with no progression of arterial disease and norelapses were reported in the follow-up period (range 10ndash42months)26 Sen et al24 also report successful maintenancetreatment with MMF in 3 cases of cPACNS that had failedmethotrexate or azathioprine and steroid treatment alone Nopatients were reported to have had recurring symptoms sideeffects or new lesions on MRI24
While this review provided a comprehensive review of treat-ment literature in cPACNS there were several limitationsBased on our quality assessment definition for Q4 a mini-mum of 1 reproducible reported outcome was sufficient tosatisfy outcome reproducibility Many studies satisfied thiscriterion by reporting mortality despite a lack of or irrepro-ducibility of supplementary outcomes Furthermore usinga validated measure like the PSOMwas sufficient to satisfy theQ5 requirement While the Pakistani group utilized thePSOM in outcome assessment the lack of outcome defi-nitions led to difficulty in result generalizability Finally whilethe same patient cohort was included in all 4 Pakistani groupstudies and treatment regimens were well described thenumber of patients reported to each treatment arm wasgrossly inconsistent and calculated incorrectly Despite thesecontradictions the studies sufficiently satisfied the re-producible treatment criterion and were consequently ratedhigh quality Therefore the authors believe that the qualityassessment for a number of studies reviewed is overstatedwere these studies to be rescored retrospectively they wouldbe deemed low quality Finally the case series by Gallagheret al15 despite meeting inclusion criteria only described casereports with inconsistent treatment regimens and lackedvalidated outcome measures
In conclusion available literature on treatment in cPACNS werethoroughly reviewed and findings summarized Based on theevidence and current expert opinion the authors provide rec-ommendations for cPACNS treatment strategies Rapid initiation
with the recommended therapeutic interventions would serve tooptimize survival and prevent permanent brain injury in patientswith cPACNS to achieve the best possible outcome
AcknowledgmentThe authors would like to thank librarian Rachel Zhao for hercontribution to the development and application of the searchstrategy
Study fundingNo targeted funding
DisclosureJ Beelen reports no disclosures S Benseler serves on theeditorial board for Neurology Neuroimmunology amp Neuro-inflammation A Dropol B Ghali and M Twilt reports nodisclosures Go to NeurologyorgNN for full disclosures
Publication historyReceived byNeurology Neuroimmunology amp Neuroinflammation January24 2019 Accepted in final form March 4 2019
References1 Calabrese LH Mallek JA Primary angiitis of the central nervous system Report of 8
new cases review of the literature and proposal for diagnostic criteria Medicine(Baltimore) 19886720ndash39
2 Benseler SM Silverman E Aviv RI et al Primary central nervous system vasculitis inchildren Arthritis Rheum 2006541291ndash1297
3 Benseler SM deVeber G Hawkins C et al Angiography-negative primary centralnervous system vasculitis in children a newly recognized inflammatory central ner-vous system disease Arthritis Rheum 2005522159ndash2167
4 Cellucci T Tyrrell PN Sheikh S Benseler SM Childhood primary angiitis of thecentral nervous system identifying disease trajectories and early risk factors forpersistently higher disease activity Arthritis Rheum 2012641665ndash1672
Appendix Authors
Name Location Role Contribution
JocelyneBeelenBMSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Evaluated literaturecompiled the datadrafted the manuscriptcompleted manuscriptrevisions
SusanneBenselerMD PhD
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper revised the papercritically for intellectualcontent
AnastasiaDropolHBSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Conceptualized thepaper evaluated theliterature compiledthe data drafted themanuscript
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper completed theliterature searchevaluated the literaturerevised the papercritically for intellectualcontent
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
5 Cellucci T Tyrrell PN Twilt M Sheikh S Benseler SM Distinct phenotype clustersin childhood inflammatory brain diseases implications for diagnostic evaluationArthritis Rheumatol 201466750ndash756
6 Splendiani A Catalucci A Limbucci N Turner M Krings T Gallucci M Pediatricinflammatory diseases part III small vessels vasculitis Neuroradiol J 201225715ndash724
7 Elbers J Halliday W Hawkins C Hutchinson C Benseler SM Brain biopsy inchildren with primary small-vessel central nervous system vasculitis Ann Neurol201068602ndash610
8 Aviv RI Benseler SM DeVeber G et al Angiography of primary central nervoussystem angiitis of childhood conventional angiography versus magnetic resonanceangiography at presentation AJNR Am J Neuroradiol 2007289ndash15
9 Hutchinson C Elbers J Halliday W et al Treatment of small vessel primary CNSvasculitis in children an open-label cohort study Lancet Neurol 201091078ndash1084
10 Twilt M Benseler SM The spectrum of CNS vasculitis in children and adults Nat RevRheumatol 2011897ndash107
11 Salvarani C Brown RD Jr Calamia KT et al Primary central nervous systemvasculitis analysis of 101 patients Ann Neurol 200762442ndash451
12 Pasma A vanrsquot Spijker A Hazes JM Busschbach JJ Luime JJ Factors associated withadherence to pharmaceutical treatment for rheumatoid arthritis patients a systematicreview Semin Arthritis Rheum 20134318ndash28
13 Kitchen L Westmacott R Friefeld S et al The pediatric stroke outcome measurea validation and reliability study Stroke 2012431602ndash1608
14 Elbers J Armstrong D Yau I Benseler S Vascular imaging outcomes of childhoodprimary angiitis of the central nervous system Pediatr Neurol 20166353ndash59
15 Gallagher KT Shaham B Reiff A et al Primary angiitis of the central nervous systemin children 5 cases J Rheumatol 200128616ndash623
16 Alhaboob AA Hasan GM Malik MA Rehman MZ Therapeutic benefits and sideeffects of Azathioprine and Aspirin in treatment of childhood primary arterial strokeAnn Neurosci 20142110ndash13
17 Malik MA Ahmad N Malik H Maintenance treatment of childhood primary angiitisof central nervous system with spirin and azathioprine Pediatr Ther 20133174ndash179
18 Malik MA Choudry GR Malik H Recurrence prevention of childhood primaryangiitis of central nervous system by combination of azathioprine and aspirin Am JMed Stud 2013122ndash27
19 Malik MA Zia-ur-Rehman M Nadeem MM et al Childhood primary angiitis of thecentral nervous system J Coll Physicians Surg Pak 201222570ndash574
20 Varni JW Burwinkle TM Seid M Skarr D The PedsQL 40 as a pediatric populationhealth measure feasibility reliability and validity Ambul Pediatr 20033329ndash341
21 Twilt M Benseler SM Childhood inflammatory brain diseases pathogenesis di-agnosis and therapy Rheumatology (Oxford) 2014531359ndash1368
22 Gowdie P Twilt M Benseler SM Primary and secondary central nervous systemvasculitis J Child Neurol 2012271448ndash1459
23 Moharir M Shroff M Benseler SM Childhood central nervous system vasculitisNeuroimaging Clin N Am 201323293ndash308
24 Sen ES Leone V AbinunM et al Treatment of primary angiitis of the central nervoussystem in childhood with mycophenolate mofetil Rheumatology (Oxford) 201049806ndash811
25 Batthish M Banwell B Laughlin S et al Refractory primary central nervous systemvasculitis of childhood successful treatment with infliximab J Rheumatol 2012392227ndash2229
26 Rosati A Cosi A Basile M et al Mycophenolate mofetil as induction and long-termmaintaining treatment in childhood primary angiitis of the central nervous systemJoint Bone Spine 201784353ndash356
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 11
DOI 101212NXI000000000000056720196 Neurol Neuroimmunol Neuroinflamm
Jocelyne Beelen Susanne M Benseler Anastasia Dropol et al Strategies for treatment of childhood primary angiitis of the central nervous system
This information is current as of May 3 2019
ServicesUpdated Information amp
httpnnneurologyorgcontent64e567fullhtmlincluding high resolution figures can be found at
httpnnneurologyorgcgicollectionall_pediatricAll Pediatricfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2019 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
died however 2 were reported to have had a serious infectionrequiring hospital admission 1 developed cataracts 1 avas-cular necrosis and 3 with vertebral fractures No diabetesmellitus was reported Pediatric Quality of Life (PedsQL)20
was reported for both child and parent at final follow-uptogether with cognitive outcome testing by the Weschler In-telligence Scale for Children IV and Weschler Adult In-telligence Scale III at 14 months postdiagnosis Abnormalscores were defined as any index scores that were ge1 SDsbelow the mean of the normative sample The PedsQLquestionnaire was completed by 17 patients and 15 parentsmedian physical score was 78 (range = 0ndash100) for childrenand 66 (range = 9ndash100) for parents and median psychosocialscore 73 (range = 27ndash100) for children and 63 (range =37ndash100) for parents Cognitive outcome was assessed in 10children Full Scale Intelligence Quotient was reported asabnormal in 8 (80) working memory in all 10 (100)verbal comprehension in 7 (70) perceptual reasoning in 6(60) and processing speed in 5 (50)
Cellucci et al4 identified 39 patients lt18 years of age betweenJune 2001 and October 2010 diagnosed with cPACNS 14 AP-cPACNS not further subdivided and 25 AN-cPACNS AP-cPACNS diagnosis was based on CA andor MRA (n = 14)AN-cPACNS diagnosis was based on confirmatory biopsy in 22patients Patients without biopsy had features blood work andlumbar puncture consistent with AN-cPACNS Some patientswith AP-cPACNS were also represented in the Benseler et al2
study and in the Hutchinson et al9 study
All 14 patients with AP-cPACNS received ASA and 9 (64)received additional anticoagulation with unfractionatedlow-molecular weight heparin for 2 months High-dose predni-sone was prescribed in all but 1 patient with AP-cPACNSwith a varied tapering schedule 2ndash6 months in 6 patients(46) and 12 months in 7 (54) IV cyclophosphamide over6 months followed by MMF or azathioprine was given toa further 7 patients (54) with AP-cPACNS 1 patient withAP-cPACNS received anticoagulation therapy only High-dose prednisone with 12-months taper was prescribed in allpatients with AN-cPACNS IV cyclophosphamide for 6months in combination with azathioprine or MMF wasreported in 20 patients (80) with AN-cPACNS while aza-thioprine or MMF alone as inductionmaintenance therapywas described in 3 patients (12) with AN-cPACNS Twopatients (8) with AN-cPACNS did not receive therapyOutcomes were reported serially across 24 months and in-cluded disease activity as measured by the Physicians GlobalAssessment (PGA) a visual analog scale with a score of zeroindicating no disease activity and 10 indicating severe activityvon Willebrand factor (vWF) antigen levels where highnumbers indicate high disease activity with gt1middot40 IUmLbeing considered abnormal and neurologic outcome onPSOM with good outcome defined as a score of le0middot5 acrosseach domain Disease activity was elevated at time of di-agnosis but significantly decreased over time in all patients(p lt 0middot001) vWF antigen levels decreased over time (p lt
0middot001) PSOM summary scores decreased significantly overtime (p lt 0middot001) with 52 of patients having a good neu-rologic outcome at 12 months and 65 at 24 months A totalof 6 (15) developed disease flare during follow-up defined asan increase in PGA by at least 1 cm in presence of recurrentsymptoms laboratory changes andor MRI findings Nopatients died
Elbers et al14 described 27 patients lt18 years of age with AP-cPACNS diagnosed between January 1998 and December2013 Diagnosis was based on MRA and DSA abnormalitiesPatients might overlap with the Benseler et al2 and Cellucciet al4 studies Acute treatment with unfractionated heparinwas described in 23 patients (85) 5 subsequently transi-tioned to warfarin 17 to ASA and none in 1 ASA aloneor with immunosuppression was described in the remaining4 patients Two patients received chronic immunosuppres-sion with MMF and 1 received plasmapheresis IVMP to-gether with a 3-month oral steroid taper was described in 12patients with no long-term immunosuppression An addi-tional 7 patients were treated with acyclovir Outcomes in-cluded vascular imaging at 12 months assessed using theNorth American Symptomatic Carotid Endarterectomy Trial(NASCET) criteria and described as improved (normal an-giography improved flow or fewer abnormal vessels) stable(no change in flow abnormality or number of involved ves-sels) or worsened (involvement of new vessels or worseningof an existing flow abnormality by at least 1 point on follow-upimaging) and possibly discordant (worsened patients wherea new or worsening arterial abnormality coexisted with animproved or normalized vessel) as well as stroke recurrenceThe NASCET criteria scores vessel narrowing from 1 to 4progressing from normal (0ndash9) to mild (10ndash29)moderate (30ndash69) and severe stenosis (70ndash99) orcomplete occlusion (no flow detected) A total of 10 (37)patients were described as improved 4 of which receivedsteroids as treatment 6 (22) as stable 2 of which receivedsteroids and 11 (41) worsened with 7 described as dis-cordant 6 of which received steroids Stroke recurrence wasreported in 4 patients (15) No patients died
Gallagher et al15 described 5 cases of AP-cPACNS at theircenter with no fixed treatment regimen Diagnosis was basedonMRA andor CA abnormalities Two patients were treatedwith IVMP either at their first or subsequent disease pre-sentation All patients received IV cyclophosphamide how-ever 1 discontinued after the first infusion due to intoleranceAll patients received oral prednisone of varying doses 2 re-ceived short-term (lt6 months) steroid therapy 2 remainedon oral steroids long-term (gt6 months) and 1 was lost tofollow-up after 6 months One patient received long-termtreatment with azathioprine and 2 with methotrexate Four(80) of the 5 patients received anticoagulation therapy witheither ASA or warfarin during their illness No validatedoutcome measures were used to assess outcomes for thesepatients however at last follow-up 3 patients were reportedas neurologically asymptomatic 1 had mild residual deficits
8 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
and 1 was lost to follow-up but continued on treatment attheir last documented visit
DiscussionThis is the first scoping review of treatment in cPACNSDespite the paucity of randomized clinical trials evidence in
the literature offers support for treatment strategies ForAPNP-cPACNS the authors recommend treatment withlong-term antiplatelet therapy to reduce the risk of strokerelapse and mortality as reported in the Pakistani cohort16ndash19
The authors concur with CNS vasculitis expert opinion inrecommending short-term immunosuppressive with IVMPand acute antithrombotic therapy subsequently followed by
Figure 2 Recommended treatment protocol
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 9
high-dose oral prednisone (figure 2A)31021ndash23 In APP-cPACNS the authors support a combination of anti-coagulation and induction therapy with both IV steroids andIV cyclophosphamide with steroid taper (figure 2B)3415ndash19
to increase the prospect of neurologic recovery3101521ndash26
Induction therapy for AN-cPACNS should similarly consist ofIV steroids and IV cyclophosphamide (figure 2C) Evidencein the literature91021ndash24 for long-termmaintenance therapy inAPP-cPACNS and AN-cPACNS supports daily MMFmycophenolic acid in preference to azathioprine to avoidthe possibility of treatment failure or intolerance as reportedby Hutchinson et al9 and the Pakistani group (figures 2B2C)16ndash19
In refractory disease Batthish et al25 reported successful useof infliximab therapy in treating 2 cases of AN-cPACNS withgood control of inflammation and subsequent prevention ofbrain damage Rosati et al26 recently published a case series of4 patients with AP-cPACNS successfully treated with long-term MMF All revealed subsequent stability or improvementon MRIMRA with no progression of arterial disease and norelapses were reported in the follow-up period (range 10ndash42months)26 Sen et al24 also report successful maintenancetreatment with MMF in 3 cases of cPACNS that had failedmethotrexate or azathioprine and steroid treatment alone Nopatients were reported to have had recurring symptoms sideeffects or new lesions on MRI24
While this review provided a comprehensive review of treat-ment literature in cPACNS there were several limitationsBased on our quality assessment definition for Q4 a mini-mum of 1 reproducible reported outcome was sufficient tosatisfy outcome reproducibility Many studies satisfied thiscriterion by reporting mortality despite a lack of or irrepro-ducibility of supplementary outcomes Furthermore usinga validated measure like the PSOMwas sufficient to satisfy theQ5 requirement While the Pakistani group utilized thePSOM in outcome assessment the lack of outcome defi-nitions led to difficulty in result generalizability Finally whilethe same patient cohort was included in all 4 Pakistani groupstudies and treatment regimens were well described thenumber of patients reported to each treatment arm wasgrossly inconsistent and calculated incorrectly Despite thesecontradictions the studies sufficiently satisfied the re-producible treatment criterion and were consequently ratedhigh quality Therefore the authors believe that the qualityassessment for a number of studies reviewed is overstatedwere these studies to be rescored retrospectively they wouldbe deemed low quality Finally the case series by Gallagheret al15 despite meeting inclusion criteria only described casereports with inconsistent treatment regimens and lackedvalidated outcome measures
In conclusion available literature on treatment in cPACNS werethoroughly reviewed and findings summarized Based on theevidence and current expert opinion the authors provide rec-ommendations for cPACNS treatment strategies Rapid initiation
with the recommended therapeutic interventions would serve tooptimize survival and prevent permanent brain injury in patientswith cPACNS to achieve the best possible outcome
AcknowledgmentThe authors would like to thank librarian Rachel Zhao for hercontribution to the development and application of the searchstrategy
Study fundingNo targeted funding
DisclosureJ Beelen reports no disclosures S Benseler serves on theeditorial board for Neurology Neuroimmunology amp Neuro-inflammation A Dropol B Ghali and M Twilt reports nodisclosures Go to NeurologyorgNN for full disclosures
Publication historyReceived byNeurology Neuroimmunology amp Neuroinflammation January24 2019 Accepted in final form March 4 2019
References1 Calabrese LH Mallek JA Primary angiitis of the central nervous system Report of 8
new cases review of the literature and proposal for diagnostic criteria Medicine(Baltimore) 19886720ndash39
2 Benseler SM Silverman E Aviv RI et al Primary central nervous system vasculitis inchildren Arthritis Rheum 2006541291ndash1297
3 Benseler SM deVeber G Hawkins C et al Angiography-negative primary centralnervous system vasculitis in children a newly recognized inflammatory central ner-vous system disease Arthritis Rheum 2005522159ndash2167
4 Cellucci T Tyrrell PN Sheikh S Benseler SM Childhood primary angiitis of thecentral nervous system identifying disease trajectories and early risk factors forpersistently higher disease activity Arthritis Rheum 2012641665ndash1672
Appendix Authors
Name Location Role Contribution
JocelyneBeelenBMSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Evaluated literaturecompiled the datadrafted the manuscriptcompleted manuscriptrevisions
SusanneBenselerMD PhD
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper revised the papercritically for intellectualcontent
AnastasiaDropolHBSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Conceptualized thepaper evaluated theliterature compiledthe data drafted themanuscript
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper completed theliterature searchevaluated the literaturerevised the papercritically for intellectualcontent
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
5 Cellucci T Tyrrell PN Twilt M Sheikh S Benseler SM Distinct phenotype clustersin childhood inflammatory brain diseases implications for diagnostic evaluationArthritis Rheumatol 201466750ndash756
6 Splendiani A Catalucci A Limbucci N Turner M Krings T Gallucci M Pediatricinflammatory diseases part III small vessels vasculitis Neuroradiol J 201225715ndash724
7 Elbers J Halliday W Hawkins C Hutchinson C Benseler SM Brain biopsy inchildren with primary small-vessel central nervous system vasculitis Ann Neurol201068602ndash610
8 Aviv RI Benseler SM DeVeber G et al Angiography of primary central nervoussystem angiitis of childhood conventional angiography versus magnetic resonanceangiography at presentation AJNR Am J Neuroradiol 2007289ndash15
9 Hutchinson C Elbers J Halliday W et al Treatment of small vessel primary CNSvasculitis in children an open-label cohort study Lancet Neurol 201091078ndash1084
10 Twilt M Benseler SM The spectrum of CNS vasculitis in children and adults Nat RevRheumatol 2011897ndash107
11 Salvarani C Brown RD Jr Calamia KT et al Primary central nervous systemvasculitis analysis of 101 patients Ann Neurol 200762442ndash451
12 Pasma A vanrsquot Spijker A Hazes JM Busschbach JJ Luime JJ Factors associated withadherence to pharmaceutical treatment for rheumatoid arthritis patients a systematicreview Semin Arthritis Rheum 20134318ndash28
13 Kitchen L Westmacott R Friefeld S et al The pediatric stroke outcome measurea validation and reliability study Stroke 2012431602ndash1608
14 Elbers J Armstrong D Yau I Benseler S Vascular imaging outcomes of childhoodprimary angiitis of the central nervous system Pediatr Neurol 20166353ndash59
15 Gallagher KT Shaham B Reiff A et al Primary angiitis of the central nervous systemin children 5 cases J Rheumatol 200128616ndash623
16 Alhaboob AA Hasan GM Malik MA Rehman MZ Therapeutic benefits and sideeffects of Azathioprine and Aspirin in treatment of childhood primary arterial strokeAnn Neurosci 20142110ndash13
17 Malik MA Ahmad N Malik H Maintenance treatment of childhood primary angiitisof central nervous system with spirin and azathioprine Pediatr Ther 20133174ndash179
18 Malik MA Choudry GR Malik H Recurrence prevention of childhood primaryangiitis of central nervous system by combination of azathioprine and aspirin Am JMed Stud 2013122ndash27
19 Malik MA Zia-ur-Rehman M Nadeem MM et al Childhood primary angiitis of thecentral nervous system J Coll Physicians Surg Pak 201222570ndash574
20 Varni JW Burwinkle TM Seid M Skarr D The PedsQL 40 as a pediatric populationhealth measure feasibility reliability and validity Ambul Pediatr 20033329ndash341
21 Twilt M Benseler SM Childhood inflammatory brain diseases pathogenesis di-agnosis and therapy Rheumatology (Oxford) 2014531359ndash1368
22 Gowdie P Twilt M Benseler SM Primary and secondary central nervous systemvasculitis J Child Neurol 2012271448ndash1459
23 Moharir M Shroff M Benseler SM Childhood central nervous system vasculitisNeuroimaging Clin N Am 201323293ndash308
24 Sen ES Leone V AbinunM et al Treatment of primary angiitis of the central nervoussystem in childhood with mycophenolate mofetil Rheumatology (Oxford) 201049806ndash811
25 Batthish M Banwell B Laughlin S et al Refractory primary central nervous systemvasculitis of childhood successful treatment with infliximab J Rheumatol 2012392227ndash2229
26 Rosati A Cosi A Basile M et al Mycophenolate mofetil as induction and long-termmaintaining treatment in childhood primary angiitis of the central nervous systemJoint Bone Spine 201784353ndash356
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 11
DOI 101212NXI000000000000056720196 Neurol Neuroimmunol Neuroinflamm
Jocelyne Beelen Susanne M Benseler Anastasia Dropol et al Strategies for treatment of childhood primary angiitis of the central nervous system
This information is current as of May 3 2019
ServicesUpdated Information amp
httpnnneurologyorgcontent64e567fullhtmlincluding high resolution figures can be found at
httpnnneurologyorgcgicollectionall_pediatricAll Pediatricfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2019 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
and 1 was lost to follow-up but continued on treatment attheir last documented visit
DiscussionThis is the first scoping review of treatment in cPACNSDespite the paucity of randomized clinical trials evidence in
the literature offers support for treatment strategies ForAPNP-cPACNS the authors recommend treatment withlong-term antiplatelet therapy to reduce the risk of strokerelapse and mortality as reported in the Pakistani cohort16ndash19
The authors concur with CNS vasculitis expert opinion inrecommending short-term immunosuppressive with IVMPand acute antithrombotic therapy subsequently followed by
Figure 2 Recommended treatment protocol
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 9
high-dose oral prednisone (figure 2A)31021ndash23 In APP-cPACNS the authors support a combination of anti-coagulation and induction therapy with both IV steroids andIV cyclophosphamide with steroid taper (figure 2B)3415ndash19
to increase the prospect of neurologic recovery3101521ndash26
Induction therapy for AN-cPACNS should similarly consist ofIV steroids and IV cyclophosphamide (figure 2C) Evidencein the literature91021ndash24 for long-termmaintenance therapy inAPP-cPACNS and AN-cPACNS supports daily MMFmycophenolic acid in preference to azathioprine to avoidthe possibility of treatment failure or intolerance as reportedby Hutchinson et al9 and the Pakistani group (figures 2B2C)16ndash19
In refractory disease Batthish et al25 reported successful useof infliximab therapy in treating 2 cases of AN-cPACNS withgood control of inflammation and subsequent prevention ofbrain damage Rosati et al26 recently published a case series of4 patients with AP-cPACNS successfully treated with long-term MMF All revealed subsequent stability or improvementon MRIMRA with no progression of arterial disease and norelapses were reported in the follow-up period (range 10ndash42months)26 Sen et al24 also report successful maintenancetreatment with MMF in 3 cases of cPACNS that had failedmethotrexate or azathioprine and steroid treatment alone Nopatients were reported to have had recurring symptoms sideeffects or new lesions on MRI24
While this review provided a comprehensive review of treat-ment literature in cPACNS there were several limitationsBased on our quality assessment definition for Q4 a mini-mum of 1 reproducible reported outcome was sufficient tosatisfy outcome reproducibility Many studies satisfied thiscriterion by reporting mortality despite a lack of or irrepro-ducibility of supplementary outcomes Furthermore usinga validated measure like the PSOMwas sufficient to satisfy theQ5 requirement While the Pakistani group utilized thePSOM in outcome assessment the lack of outcome defi-nitions led to difficulty in result generalizability Finally whilethe same patient cohort was included in all 4 Pakistani groupstudies and treatment regimens were well described thenumber of patients reported to each treatment arm wasgrossly inconsistent and calculated incorrectly Despite thesecontradictions the studies sufficiently satisfied the re-producible treatment criterion and were consequently ratedhigh quality Therefore the authors believe that the qualityassessment for a number of studies reviewed is overstatedwere these studies to be rescored retrospectively they wouldbe deemed low quality Finally the case series by Gallagheret al15 despite meeting inclusion criteria only described casereports with inconsistent treatment regimens and lackedvalidated outcome measures
In conclusion available literature on treatment in cPACNS werethoroughly reviewed and findings summarized Based on theevidence and current expert opinion the authors provide rec-ommendations for cPACNS treatment strategies Rapid initiation
with the recommended therapeutic interventions would serve tooptimize survival and prevent permanent brain injury in patientswith cPACNS to achieve the best possible outcome
AcknowledgmentThe authors would like to thank librarian Rachel Zhao for hercontribution to the development and application of the searchstrategy
Study fundingNo targeted funding
DisclosureJ Beelen reports no disclosures S Benseler serves on theeditorial board for Neurology Neuroimmunology amp Neuro-inflammation A Dropol B Ghali and M Twilt reports nodisclosures Go to NeurologyorgNN for full disclosures
Publication historyReceived byNeurology Neuroimmunology amp Neuroinflammation January24 2019 Accepted in final form March 4 2019
References1 Calabrese LH Mallek JA Primary angiitis of the central nervous system Report of 8
new cases review of the literature and proposal for diagnostic criteria Medicine(Baltimore) 19886720ndash39
2 Benseler SM Silverman E Aviv RI et al Primary central nervous system vasculitis inchildren Arthritis Rheum 2006541291ndash1297
3 Benseler SM deVeber G Hawkins C et al Angiography-negative primary centralnervous system vasculitis in children a newly recognized inflammatory central ner-vous system disease Arthritis Rheum 2005522159ndash2167
4 Cellucci T Tyrrell PN Sheikh S Benseler SM Childhood primary angiitis of thecentral nervous system identifying disease trajectories and early risk factors forpersistently higher disease activity Arthritis Rheum 2012641665ndash1672
Appendix Authors
Name Location Role Contribution
JocelyneBeelenBMSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Evaluated literaturecompiled the datadrafted the manuscriptcompleted manuscriptrevisions
SusanneBenselerMD PhD
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper revised the papercritically for intellectualcontent
AnastasiaDropolHBSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Conceptualized thepaper evaluated theliterature compiledthe data drafted themanuscript
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper completed theliterature searchevaluated the literaturerevised the papercritically for intellectualcontent
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
5 Cellucci T Tyrrell PN Twilt M Sheikh S Benseler SM Distinct phenotype clustersin childhood inflammatory brain diseases implications for diagnostic evaluationArthritis Rheumatol 201466750ndash756
6 Splendiani A Catalucci A Limbucci N Turner M Krings T Gallucci M Pediatricinflammatory diseases part III small vessels vasculitis Neuroradiol J 201225715ndash724
7 Elbers J Halliday W Hawkins C Hutchinson C Benseler SM Brain biopsy inchildren with primary small-vessel central nervous system vasculitis Ann Neurol201068602ndash610
8 Aviv RI Benseler SM DeVeber G et al Angiography of primary central nervoussystem angiitis of childhood conventional angiography versus magnetic resonanceangiography at presentation AJNR Am J Neuroradiol 2007289ndash15
9 Hutchinson C Elbers J Halliday W et al Treatment of small vessel primary CNSvasculitis in children an open-label cohort study Lancet Neurol 201091078ndash1084
10 Twilt M Benseler SM The spectrum of CNS vasculitis in children and adults Nat RevRheumatol 2011897ndash107
11 Salvarani C Brown RD Jr Calamia KT et al Primary central nervous systemvasculitis analysis of 101 patients Ann Neurol 200762442ndash451
12 Pasma A vanrsquot Spijker A Hazes JM Busschbach JJ Luime JJ Factors associated withadherence to pharmaceutical treatment for rheumatoid arthritis patients a systematicreview Semin Arthritis Rheum 20134318ndash28
13 Kitchen L Westmacott R Friefeld S et al The pediatric stroke outcome measurea validation and reliability study Stroke 2012431602ndash1608
14 Elbers J Armstrong D Yau I Benseler S Vascular imaging outcomes of childhoodprimary angiitis of the central nervous system Pediatr Neurol 20166353ndash59
15 Gallagher KT Shaham B Reiff A et al Primary angiitis of the central nervous systemin children 5 cases J Rheumatol 200128616ndash623
16 Alhaboob AA Hasan GM Malik MA Rehman MZ Therapeutic benefits and sideeffects of Azathioprine and Aspirin in treatment of childhood primary arterial strokeAnn Neurosci 20142110ndash13
17 Malik MA Ahmad N Malik H Maintenance treatment of childhood primary angiitisof central nervous system with spirin and azathioprine Pediatr Ther 20133174ndash179
18 Malik MA Choudry GR Malik H Recurrence prevention of childhood primaryangiitis of central nervous system by combination of azathioprine and aspirin Am JMed Stud 2013122ndash27
19 Malik MA Zia-ur-Rehman M Nadeem MM et al Childhood primary angiitis of thecentral nervous system J Coll Physicians Surg Pak 201222570ndash574
20 Varni JW Burwinkle TM Seid M Skarr D The PedsQL 40 as a pediatric populationhealth measure feasibility reliability and validity Ambul Pediatr 20033329ndash341
21 Twilt M Benseler SM Childhood inflammatory brain diseases pathogenesis di-agnosis and therapy Rheumatology (Oxford) 2014531359ndash1368
22 Gowdie P Twilt M Benseler SM Primary and secondary central nervous systemvasculitis J Child Neurol 2012271448ndash1459
23 Moharir M Shroff M Benseler SM Childhood central nervous system vasculitisNeuroimaging Clin N Am 201323293ndash308
24 Sen ES Leone V AbinunM et al Treatment of primary angiitis of the central nervoussystem in childhood with mycophenolate mofetil Rheumatology (Oxford) 201049806ndash811
25 Batthish M Banwell B Laughlin S et al Refractory primary central nervous systemvasculitis of childhood successful treatment with infliximab J Rheumatol 2012392227ndash2229
26 Rosati A Cosi A Basile M et al Mycophenolate mofetil as induction and long-termmaintaining treatment in childhood primary angiitis of the central nervous systemJoint Bone Spine 201784353ndash356
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 11
DOI 101212NXI000000000000056720196 Neurol Neuroimmunol Neuroinflamm
Jocelyne Beelen Susanne M Benseler Anastasia Dropol et al Strategies for treatment of childhood primary angiitis of the central nervous system
This information is current as of May 3 2019
ServicesUpdated Information amp
httpnnneurologyorgcontent64e567fullhtmlincluding high resolution figures can be found at
httpnnneurologyorgcgicollectionall_pediatricAll Pediatricfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2019 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
high-dose oral prednisone (figure 2A)31021ndash23 In APP-cPACNS the authors support a combination of anti-coagulation and induction therapy with both IV steroids andIV cyclophosphamide with steroid taper (figure 2B)3415ndash19
to increase the prospect of neurologic recovery3101521ndash26
Induction therapy for AN-cPACNS should similarly consist ofIV steroids and IV cyclophosphamide (figure 2C) Evidencein the literature91021ndash24 for long-termmaintenance therapy inAPP-cPACNS and AN-cPACNS supports daily MMFmycophenolic acid in preference to azathioprine to avoidthe possibility of treatment failure or intolerance as reportedby Hutchinson et al9 and the Pakistani group (figures 2B2C)16ndash19
In refractory disease Batthish et al25 reported successful useof infliximab therapy in treating 2 cases of AN-cPACNS withgood control of inflammation and subsequent prevention ofbrain damage Rosati et al26 recently published a case series of4 patients with AP-cPACNS successfully treated with long-term MMF All revealed subsequent stability or improvementon MRIMRA with no progression of arterial disease and norelapses were reported in the follow-up period (range 10ndash42months)26 Sen et al24 also report successful maintenancetreatment with MMF in 3 cases of cPACNS that had failedmethotrexate or azathioprine and steroid treatment alone Nopatients were reported to have had recurring symptoms sideeffects or new lesions on MRI24
While this review provided a comprehensive review of treat-ment literature in cPACNS there were several limitationsBased on our quality assessment definition for Q4 a mini-mum of 1 reproducible reported outcome was sufficient tosatisfy outcome reproducibility Many studies satisfied thiscriterion by reporting mortality despite a lack of or irrepro-ducibility of supplementary outcomes Furthermore usinga validated measure like the PSOMwas sufficient to satisfy theQ5 requirement While the Pakistani group utilized thePSOM in outcome assessment the lack of outcome defi-nitions led to difficulty in result generalizability Finally whilethe same patient cohort was included in all 4 Pakistani groupstudies and treatment regimens were well described thenumber of patients reported to each treatment arm wasgrossly inconsistent and calculated incorrectly Despite thesecontradictions the studies sufficiently satisfied the re-producible treatment criterion and were consequently ratedhigh quality Therefore the authors believe that the qualityassessment for a number of studies reviewed is overstatedwere these studies to be rescored retrospectively they wouldbe deemed low quality Finally the case series by Gallagheret al15 despite meeting inclusion criteria only described casereports with inconsistent treatment regimens and lackedvalidated outcome measures
In conclusion available literature on treatment in cPACNS werethoroughly reviewed and findings summarized Based on theevidence and current expert opinion the authors provide rec-ommendations for cPACNS treatment strategies Rapid initiation
with the recommended therapeutic interventions would serve tooptimize survival and prevent permanent brain injury in patientswith cPACNS to achieve the best possible outcome
AcknowledgmentThe authors would like to thank librarian Rachel Zhao for hercontribution to the development and application of the searchstrategy
Study fundingNo targeted funding
DisclosureJ Beelen reports no disclosures S Benseler serves on theeditorial board for Neurology Neuroimmunology amp Neuro-inflammation A Dropol B Ghali and M Twilt reports nodisclosures Go to NeurologyorgNN for full disclosures
Publication historyReceived byNeurology Neuroimmunology amp Neuroinflammation January24 2019 Accepted in final form March 4 2019
References1 Calabrese LH Mallek JA Primary angiitis of the central nervous system Report of 8
new cases review of the literature and proposal for diagnostic criteria Medicine(Baltimore) 19886720ndash39
2 Benseler SM Silverman E Aviv RI et al Primary central nervous system vasculitis inchildren Arthritis Rheum 2006541291ndash1297
3 Benseler SM deVeber G Hawkins C et al Angiography-negative primary centralnervous system vasculitis in children a newly recognized inflammatory central ner-vous system disease Arthritis Rheum 2005522159ndash2167
4 Cellucci T Tyrrell PN Sheikh S Benseler SM Childhood primary angiitis of thecentral nervous system identifying disease trajectories and early risk factors forpersistently higher disease activity Arthritis Rheum 2012641665ndash1672
Appendix Authors
Name Location Role Contribution
JocelyneBeelenBMSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Evaluated literaturecompiled the datadrafted the manuscriptcompleted manuscriptrevisions
SusanneBenselerMD PhD
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper revised the papercritically for intellectualcontent
AnastasiaDropolHBSc
Cumming School ofMedicine Universityof Calgary Calgary
Author Conceptualized thepaper evaluated theliterature compiledthe data drafted themanuscript
Alberta ChildrenrsquosHospital Universityof Calgary Calgary
Author Conceptualized thepaper completed theliterature searchevaluated the literaturerevised the papercritically for intellectualcontent
10 Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 NeurologyorgNN
5 Cellucci T Tyrrell PN Twilt M Sheikh S Benseler SM Distinct phenotype clustersin childhood inflammatory brain diseases implications for diagnostic evaluationArthritis Rheumatol 201466750ndash756
6 Splendiani A Catalucci A Limbucci N Turner M Krings T Gallucci M Pediatricinflammatory diseases part III small vessels vasculitis Neuroradiol J 201225715ndash724
7 Elbers J Halliday W Hawkins C Hutchinson C Benseler SM Brain biopsy inchildren with primary small-vessel central nervous system vasculitis Ann Neurol201068602ndash610
8 Aviv RI Benseler SM DeVeber G et al Angiography of primary central nervoussystem angiitis of childhood conventional angiography versus magnetic resonanceangiography at presentation AJNR Am J Neuroradiol 2007289ndash15
9 Hutchinson C Elbers J Halliday W et al Treatment of small vessel primary CNSvasculitis in children an open-label cohort study Lancet Neurol 201091078ndash1084
10 Twilt M Benseler SM The spectrum of CNS vasculitis in children and adults Nat RevRheumatol 2011897ndash107
11 Salvarani C Brown RD Jr Calamia KT et al Primary central nervous systemvasculitis analysis of 101 patients Ann Neurol 200762442ndash451
12 Pasma A vanrsquot Spijker A Hazes JM Busschbach JJ Luime JJ Factors associated withadherence to pharmaceutical treatment for rheumatoid arthritis patients a systematicreview Semin Arthritis Rheum 20134318ndash28
13 Kitchen L Westmacott R Friefeld S et al The pediatric stroke outcome measurea validation and reliability study Stroke 2012431602ndash1608
14 Elbers J Armstrong D Yau I Benseler S Vascular imaging outcomes of childhoodprimary angiitis of the central nervous system Pediatr Neurol 20166353ndash59
15 Gallagher KT Shaham B Reiff A et al Primary angiitis of the central nervous systemin children 5 cases J Rheumatol 200128616ndash623
16 Alhaboob AA Hasan GM Malik MA Rehman MZ Therapeutic benefits and sideeffects of Azathioprine and Aspirin in treatment of childhood primary arterial strokeAnn Neurosci 20142110ndash13
17 Malik MA Ahmad N Malik H Maintenance treatment of childhood primary angiitisof central nervous system with spirin and azathioprine Pediatr Ther 20133174ndash179
18 Malik MA Choudry GR Malik H Recurrence prevention of childhood primaryangiitis of central nervous system by combination of azathioprine and aspirin Am JMed Stud 2013122ndash27
19 Malik MA Zia-ur-Rehman M Nadeem MM et al Childhood primary angiitis of thecentral nervous system J Coll Physicians Surg Pak 201222570ndash574
20 Varni JW Burwinkle TM Seid M Skarr D The PedsQL 40 as a pediatric populationhealth measure feasibility reliability and validity Ambul Pediatr 20033329ndash341
21 Twilt M Benseler SM Childhood inflammatory brain diseases pathogenesis di-agnosis and therapy Rheumatology (Oxford) 2014531359ndash1368
22 Gowdie P Twilt M Benseler SM Primary and secondary central nervous systemvasculitis J Child Neurol 2012271448ndash1459
23 Moharir M Shroff M Benseler SM Childhood central nervous system vasculitisNeuroimaging Clin N Am 201323293ndash308
24 Sen ES Leone V AbinunM et al Treatment of primary angiitis of the central nervoussystem in childhood with mycophenolate mofetil Rheumatology (Oxford) 201049806ndash811
25 Batthish M Banwell B Laughlin S et al Refractory primary central nervous systemvasculitis of childhood successful treatment with infliximab J Rheumatol 2012392227ndash2229
26 Rosati A Cosi A Basile M et al Mycophenolate mofetil as induction and long-termmaintaining treatment in childhood primary angiitis of the central nervous systemJoint Bone Spine 201784353ndash356
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 11
DOI 101212NXI000000000000056720196 Neurol Neuroimmunol Neuroinflamm
Jocelyne Beelen Susanne M Benseler Anastasia Dropol et al Strategies for treatment of childhood primary angiitis of the central nervous system
This information is current as of May 3 2019
ServicesUpdated Information amp
httpnnneurologyorgcontent64e567fullhtmlincluding high resolution figures can be found at
httpnnneurologyorgcgicollectionall_pediatricAll Pediatricfollowing collection(s) This article along with others on similar topics appears in the
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httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
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httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2019 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
5 Cellucci T Tyrrell PN Twilt M Sheikh S Benseler SM Distinct phenotype clustersin childhood inflammatory brain diseases implications for diagnostic evaluationArthritis Rheumatol 201466750ndash756
6 Splendiani A Catalucci A Limbucci N Turner M Krings T Gallucci M Pediatricinflammatory diseases part III small vessels vasculitis Neuroradiol J 201225715ndash724
7 Elbers J Halliday W Hawkins C Hutchinson C Benseler SM Brain biopsy inchildren with primary small-vessel central nervous system vasculitis Ann Neurol201068602ndash610
8 Aviv RI Benseler SM DeVeber G et al Angiography of primary central nervoussystem angiitis of childhood conventional angiography versus magnetic resonanceangiography at presentation AJNR Am J Neuroradiol 2007289ndash15
9 Hutchinson C Elbers J Halliday W et al Treatment of small vessel primary CNSvasculitis in children an open-label cohort study Lancet Neurol 201091078ndash1084
10 Twilt M Benseler SM The spectrum of CNS vasculitis in children and adults Nat RevRheumatol 2011897ndash107
11 Salvarani C Brown RD Jr Calamia KT et al Primary central nervous systemvasculitis analysis of 101 patients Ann Neurol 200762442ndash451
12 Pasma A vanrsquot Spijker A Hazes JM Busschbach JJ Luime JJ Factors associated withadherence to pharmaceutical treatment for rheumatoid arthritis patients a systematicreview Semin Arthritis Rheum 20134318ndash28
13 Kitchen L Westmacott R Friefeld S et al The pediatric stroke outcome measurea validation and reliability study Stroke 2012431602ndash1608
14 Elbers J Armstrong D Yau I Benseler S Vascular imaging outcomes of childhoodprimary angiitis of the central nervous system Pediatr Neurol 20166353ndash59
15 Gallagher KT Shaham B Reiff A et al Primary angiitis of the central nervous systemin children 5 cases J Rheumatol 200128616ndash623
16 Alhaboob AA Hasan GM Malik MA Rehman MZ Therapeutic benefits and sideeffects of Azathioprine and Aspirin in treatment of childhood primary arterial strokeAnn Neurosci 20142110ndash13
17 Malik MA Ahmad N Malik H Maintenance treatment of childhood primary angiitisof central nervous system with spirin and azathioprine Pediatr Ther 20133174ndash179
18 Malik MA Choudry GR Malik H Recurrence prevention of childhood primaryangiitis of central nervous system by combination of azathioprine and aspirin Am JMed Stud 2013122ndash27
19 Malik MA Zia-ur-Rehman M Nadeem MM et al Childhood primary angiitis of thecentral nervous system J Coll Physicians Surg Pak 201222570ndash574
20 Varni JW Burwinkle TM Seid M Skarr D The PedsQL 40 as a pediatric populationhealth measure feasibility reliability and validity Ambul Pediatr 20033329ndash341
21 Twilt M Benseler SM Childhood inflammatory brain diseases pathogenesis di-agnosis and therapy Rheumatology (Oxford) 2014531359ndash1368
22 Gowdie P Twilt M Benseler SM Primary and secondary central nervous systemvasculitis J Child Neurol 2012271448ndash1459
23 Moharir M Shroff M Benseler SM Childhood central nervous system vasculitisNeuroimaging Clin N Am 201323293ndash308
24 Sen ES Leone V AbinunM et al Treatment of primary angiitis of the central nervoussystem in childhood with mycophenolate mofetil Rheumatology (Oxford) 201049806ndash811
25 Batthish M Banwell B Laughlin S et al Refractory primary central nervous systemvasculitis of childhood successful treatment with infliximab J Rheumatol 2012392227ndash2229
26 Rosati A Cosi A Basile M et al Mycophenolate mofetil as induction and long-termmaintaining treatment in childhood primary angiitis of the central nervous systemJoint Bone Spine 201784353ndash356
NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 6 Number 4 | July 2019 11
DOI 101212NXI000000000000056720196 Neurol Neuroimmunol Neuroinflamm
Jocelyne Beelen Susanne M Benseler Anastasia Dropol et al Strategies for treatment of childhood primary angiitis of the central nervous system
This information is current as of May 3 2019
ServicesUpdated Information amp
httpnnneurologyorgcontent64e567fullhtmlincluding high resolution figures can be found at
httpnnneurologyorgcgicollectionall_pediatricAll Pediatricfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2019 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
DOI 101212NXI000000000000056720196 Neurol Neuroimmunol Neuroinflamm
Jocelyne Beelen Susanne M Benseler Anastasia Dropol et al Strategies for treatment of childhood primary angiitis of the central nervous system
This information is current as of May 3 2019
ServicesUpdated Information amp
httpnnneurologyorgcontent64e567fullhtmlincluding high resolution figures can be found at
httpnnneurologyorgcgicollectionall_pediatricAll Pediatricfollowing collection(s) This article along with others on similar topics appears in the
Permissions amp Licensing
httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in
Reprints
httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online
Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2019 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright
is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm
