neuroimunologia vasculitelor snc la copiii

8/3/2019 Neuroimunologia Vasculitelor SNC La Copiii

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REVISTA ROMNDE PEDIATRIE VOLUMUL LX, NR. 1, AN 201116

REFERATE GENERALE2

NEUROIMUNOLOGIA VASCULITELOR

SISTEMULUI NERVOS LA COPIL

Drd. Bogdan Istrate

Centrul de Cercetare Neurobiologie i Fiziologie Molecular, Bucureti

REZUMAT

Autorul face o prezentare detaliat a aspectelor de neuroimunologie molecular i clinic a vasculitelorsistemului nervos periferic i sistemului nervos central la copil. Sunt exemplificate i anumite trsturi clinice

n acest sens, articolul fiind concentrat asupra caracteristicilor preclinice.

Cuvinte cheie: neuroimunologie,vasculit, copil

Adresa de coresponden:Drd. Bogdan Istrate, Centrul de Cercetare Neurobiologie i Fiziologie Molecular, Bd. M. Koglniceanu, Nr. 36-46, Bucureti

Vasculitele sunt procese inflamatorii care afec-teaz vasele de snge (1). Prin definiie, orice procesinflamator este nsoit de o atingere vascular, ca-racterizat prin vasodilataie, permeabilitate vas-cular crescuti totodat extravazarea leucocitelor.Spre deosebire de alte reacii cu component infla-matorie, inflamaia vascular rmne limitat lanivelul peretelui vascular, cauznd distrucii i ne-

croze ale acestuia, ocluzia trombotic a lumenuluivascular i n cele din urm ischemia organuluiafectat.

Leziunile vasculitice tind a fi multifocale, curspndire n tot arborele vascular (2), n diferitecondiii patologice. Simptomele sunt acelea carevor arta distribuia, extinderea i tempo-ul proce-sului vasculitic. n acest sens, poate fi implicat unsingur organ sau pot fi implicate mai multe organe,de aici rezultnd o mare varietate a manifestrilorclinice.

Cursul natural depinde i de mecanismele imu-nitare care genereaz procesul vasculitic sau stau labaza sa, curs natural care va mai fi dependent i derspunsul reparativ al vasului lezat.

Vasculitidele, reprezint un grup heterogen deafeciuni, de asemenea cu patologie de tip infla-mator, dar care difer ca etiologie i manifestriclinice (3). Pot fi ntlnite la copil ca boli sistemice,afectnd mai multe organe (vasculite sistemice) sauca sindroame izolate, localizate la nivelul unuisingur organ (vasculite non-sistemice).

Vasculitele vaselor mari, de exemplu, sunt carac-terizate de o inflamaie cronic granulomatoas, ntimp ce vasculitele vaselor medii sunt caracterizate

predominant de necroz cu infiltrat inflamator pleo-morfic. Vasculitele vaselor mici, sunt tipic anticorp-mediate i pot fi att de natur granulomatoas, cti de natur necrozant.

Vasculitele sistemului nervos periferic i siste-

mului nervos central ridic probleme serioase, punndchiari viaa n pericol, cauznd afectri ischemice petetritoriul de distribuie al vaselor afectate.

Sindroamele vasculitice neurologice la copil sepot ntlni izolat i limitate doar la sistemul nervossau ca i parte component ale unor boli sistemice.Simptomatologia neurologic, mai ales la copil,

poate preceda boala sistemic, reprezentnd mani-festarea sa clinicfie principal, fie unic. Vascu-litele sistemului nervos reprezint o provocare

pentru clinician, fiind totodat chiar boli enig-

matice.Mecanisme patogenice

n general, vasculitele sunt considerate a fi afec-iuni autoimune declanate de un agent patogenexogen, de cele mai multe ori infecios sau desensibilizare imunologic la un autoantigen (1).

Mecanismele cu specificitate imunologic vorfidirijate de depunerea complexelor imune, activareasistemului complement, cito-toxicitatea anticorp-mediat, i nu n ultimul rnd de hipersensibilitatea


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REVISTA ROMNDE PEDIATRIE VOLUMUL LX, NR. 1, AN 2011 17

de tip ntrziat ce i va aduce contribuia chiari nprocesul de formare al granuloamelor.

n orice caz, patogeneza vasculitelor este extremde complexi nu doar un singur organ afectat sauun singur proces imunitar ne poate explica boala nsine. n schimb, multiplele mecanisme imunoge-netice sunt implicate cu probabilitatea de a acionasimultan sau secvenial cu predominan variabil,depinznd de particularitatea procesului vasculitic.

esutul vascular, considerat adesea ca fiind oint pasiv, este implicat n mod activ n procesul

inflamator (4). Celulele endoteliale formeaz mu-coasa lumenului vascular (intima), n condiii nor-male asigurnd o suprafa non-adeziv i anti-trombotic. Ca rspuns la semnalul inflamator,ele vorfi supuse unor schimburi funcionale impor-tante, producnd o varietate de efectori moleculari,facilitnd n acest mod, recrutarea i transmigrareacelulelor cu potenial inflamator (5).

esutul vascular neted intraperiferic (adventicea),joac de asemenea un rol important n inflamaiavascular. Reeaua sa capilar (vasa vasorum) poateoferi o poart de intrare pentru patogeni i celuleinflamatorii, iar macrofagele sale rezidente servescca i indicatori ai locului de recunoatere al anti-genelor.

Imunologie general (Autoanticorpi)

Autoanticorpii joac un rol important n pato-geneza sindroamelor vasculitice primare la copil,fiind patogeni i cu efect pleomorfic servind n acestfel ca i markeri ai sindroamelor vasculitice spe-

cifice. n acest sens, doi autoanticorpi au fost des-crii:

Anticorpii anti-citoplasm ai neutrofilelor

(ANCA);

Anticorpii anti-celule endoteliale (AECA).

Anticorpii anti-citoplasm ai neutrofilelor(ANCA), sunt o constatare clasic a vasculitelor,asociai cu grupul vasculitelor primare, incluzndGranulomatoza Wegener, Poliarterita microscopic,Granulomatoza alergic (Sindromul Churg-Strauss), entiti clinice, cunoscute dealtfel i subdenumirea desindroame ANCA. Au fos descrii cai anticorpi care reacioneaz cu citoplasma neutro-filelori monocitelor, (fiind clasificai pe baza me-todelor de imunomarcare pe granulocitele fixate cuetanol), ca anti-citoplasmatici (c-ANCA), i peri-nucleari (p-ANCA). n primul rnd, anticorpiiANCA sunt de tip IgG, i de tipul moleculelor sub-claselor IgG

1i IgG

4, fiind identificate i izotipuri

ale IgM. Cu toate acestea, c-ANCA i p-ANCA,leag antigene specifice, conferind o asocieredistinctiv n sindroamele particulare vasculitelor.

Aspecte de Neuroimunologie Moleculari Clinic

Titrul anticorpilor anti-P3/cANCA corelat cuactivitatea bolii ca i evoluia sa, este asociat chiar

i cu reactivarea bolii precum i persistena remisi-unilor ulterioare, reprezentnd dealtfel i un factorde recidiv (8).

n condiii normale, complexele imune activeazcomplementul i ncorporeaz componenta C

3b,

care la rndul su leag receptorul 1 pentru com-plement (CR1) pe suprafaa eritrocitelor. Hematiilelegate de complexele imune sunt transportate nficat i splin, unde vorfi eliminate de ctre macro-fagele rezidente prin receptorii Fc ai lor (FcR). ncondiii patologice, cum arfi un exes de antigeni,

deficien de complement sau o expresie aberantori disfuncie a FcR, complexele imune se distrugsau se evacueaz printr-un mecanism de eliminarei se vor depune n peretele vascular, subendotelial(9). Odatdepuse n peretele vascular, complexele

TABELUL 2. Clasificarea vasculitelor care afecteaz sistemul nervos

Vasculite

primare

Vasculitide

sistemice

Arterita temporal cu celule gigante, Arterita Takayasu, Poliarterita nodoas, BoalaKawasaki, Granulomatoza Wegener, Sindromul Churg-Strauss, Poliangeita microscopic,Purpura Henoch-Schonlein

Vasculite non-

sistemice

Angeita primar a sistemului nervos central (PACNS/APSNC), Neuropatia vasculitic non-sistemic

Vasculite

secundare

Boli de colagen Lupus eritematos sistemic, Boli mixte de collagen, Artrita reumatoid, Sindromul Sjgren

Infecii HIV, HSV, CMV, VZV, T. pallidum, B. burgdorferi, S. aureus, rickettsiae, Aspergillus,Candida, Coccidioides, Mucomycetes

Alte boli

inflamatorii

Sarcoidoz, Sindrom Cogan, Febra familial Mediteranean, Diabetus mellitus, Boalagref contra gazd

Abuzul de droguri

i medicamenteCocain, Amfetamin, Heroin, Vaccinuri, Interferon, Antibiotice

Maligniti Limfom Hodgkin, Limfom non-Hodgkin, Granulomatoza limfomatoid, Cancerul renal,Cancerul pulmonar

*Adaptare dup Balabanov i Duffy-2005


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imune vor cauza alterri vasculare, prin mecanismemultiple i diferite. Pe lng acestea sunt activareacomplementului i formarea complexului de atacmembranar (C

5b

ai C

9), care distruge direct celulele

enedoteliale i vor produce factori chemotactici C3a

i C5a, ce vor atrage leucocitele. Complexele imune

se pot lega direct de Fc-R-sau CR care leagleucocitele. Activarea celulelor endoteliale ileucocitele induc o erxpresie crescut a moleculelorde adeziune i eliberarea de citokine pro-inflamatorii(7).

Puseul inflamator activeazi calea intrinsec acoagulrii, conducnd spre tromboz i ocluzie a

peretelui vascular.Hepatita cu virus B, asociat Poliarteritei no-

doase, este un exemplu clasic de vasculit mediat prin complexe imune (10,11).Vasele afectate vor

arta o arie de necroz fibrinoid, depunere deimunoglobuline, Ag-HBs i complement. Au fostobservate niveluri sczute ale fraciilor C

2i C

4ale

complementului la aceti pacieni, iar deficiena naceste fracii ale complementului se crede a fi unadintre cauzele ce promoveaz depunerea abundentde complexe imune n esutul vascular (12).

VASCULITELE SISTEMULUI NERVOS

PERIFERIC

Vasculitele ce afecteaz sistemul nervos pe-riferic cauzeaz sindroame cu specificitate neuro-logic: Neuropatia Vasculitic. Sunt afeciuni re-lativ rare, cu o inciden estimat la aproximativ 2la 7 cazuri/1.000.000 de copii (14).

Sunt clasificate de obicei n mai multe catgorii,depinznd de prezena sau de absena unei cauzecare le identific (vasculite primare, idiopatice sauvasculite secundare), cu implicare sistemic (vascu-lite sistemice i vasculite non-sistemice).

Neuropatia vasculitic este frecvent asociat (ncazul neuropatologiei pediatrice), cu boli sistemicevariate, cum arfi infeciile, vasculitidele primare,colagenozele, malignitile, care pot precede simp-tomele sistemice ori sfie singura lor manifestareclinic.

Semnificaia punerii diagnosticului de neuropatievasculitic const n faptul c ar putea fi i omanifestare comun a unui numr de boli sistemice,care pot pune n pericol viaa copilului dar pot finc tratate.

Patogeneza neuropatiei vasculitice, i a dezor-dinilor sistemice care o nsoesc, este de mult timpcunoscut, din documentele de specialitate ce da-teaz nc din 1962, prin cercetri ntreprinse deKussmaul i Maier.

Natura acestei asocieri neuropatie vasculitic/dezordine sistemic, rmne nc neclar.

Originea inflamaiei vasculare n ceea ce priveteneuropatiile periferice este sugerat de prezenasimptomelori testelor de laborator, odat cu dis-funciile multiorganice i a procesului inflamator

sistemic.n orice caz, neuropatia poate fi ntlnit ca unsindrom izolat, chiar i n absena unei perturbrisistemice, iar n aceast privin, toate testele delaborator pot fi normale sau negative. Pe de alt

parte, neuropatia vasculitic, nu este singura entitateclinic asociat cu o boal sistemic inflamatoriesau o boal poliorganici alte sindroame precum

poliradiculopatia demielinizant acut sau cronic,neuropatia motorie multifocal sau amiloidoza. nacest sens sunt utile i studiile de electrodiagnostic,

pentru a demonstra pierderile axonale cu distribuieasimetric i de asemenea delimitarea extinderii

procesului neuropatic. Ceea ce poate induce neroare (putnd fii o capcan de diagnostic), arfi

prezena unui bloc de conducere, la originea cruiademielinizarea focal/demielinizarea axonal poatefi adus n discuie.

Biopsia combinatorie nerv-muchi, cum arfi o prelevare din nervul superficial peroneal i dinmuchiul peroneus brevis, ar putea fi o alegere

bun, deoarece completeaz diagnosticul.Procesele vasculitice care afecteaz sistemul

nervos periferic implic n primul rnd vasanevorum a nervilor periferici, ce reprezint reeauade anastomoz intrinsec a vaselor care asiguridistribuie fluxul sanguin pe tot traiectul nervului.

Figura 1. Biopsie combinatorie (nerv-muchi) de la un

pacient cu vasculit non-sistemic a S.N.P. Seciune laparafin H.E. Se observ: A) proces inflamator vascularacut, cu necrozfibrinoid, inflltrat celulari ocluzialumenului vascular. B) proces inflamator vascular cronic,

cu obliterarea i redirecionarea lumenului vascular (DupBalabanovi Duffy,2005)


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Implicarea nervilor periferici, din poliangeitamicroscopic se ntlnete la 20% dintre copii,uneori fiind chiar imperceptibil.

Particularitatea patologic a acestor sindroamevasculitice primare este uneori dificil deoarece, deexemplu, infiltrarea granulomatoassau/i infiltratul

cu eozinofile au fost observate nu numai n sistemulnervos periferic, ci i n alte organe.Neuropatia vasculitic reumatoid este de obicei

ntlnit n bolile sero-pozitive cu leziuni articularei extra articulare. Managementul neuropatiei vascu-litice, depinde n general de identificarea mecanis-melor care stau la baza procesului vasculitic.

De asemenea, neuropatia vasculitic este o boalvaso-ocluziv, care necesiti terapie anticoagulant

pe lng cea anti-inflamatorie. Copiii cu neuropatievasculitic prezint deficit neurologic dobndit, focal

sau difuz. Acest deficit variaz n funcie de pacient.

VASCULITELE SISTEMULUI NERVOS CENTRAL

Vasculitele sistemului nervos central la copilsunt mai puin cunoscute. Criteriile de diagnostic

propuse n 1997 de Calabrase (15) sunt: deficitulneurologic dobndit, studiile histopatologice iimagistice ale angeitelor sistemului nervos central,n absena unei vasculite sistemice sau a altor con-diii n care caracteristicile angiografice i patolo-gice potfi secundare. Neuropatiile craniene multiplecu impact asupra funciei vederii i a motilitiioculare sunt caracteristici frecvente, rezultnd dinexpansiunea local a proceselor granulomatoase.

Patogenez

Patogeneza vasculitei sistemului nervos centralrmne nc neelucidat. Ca n multe boli infla-matorii, cercetrile sunt concentrate pe dou ariimajore: mecanismele int i susceptibilitatea

gazdei. Infeciile reprezint un factor important.

Clasificare

Spectrul vasculitelor primare ale sistemului ner-vos central la copil (cPACNS) include trei entitidistincte:

cPACNS progresiv angiografic pozitiv;cPACNS neprogresiv angiografic pozitiv;cPACNS a vaselor mici cu angiografie negativ.

Deficitul neurologic este prezent n toate aceste

trei forme i poatefi

focal sau difuz.Studii de laboratori imagistice

analiza markerilor inflamatori din lichidulcefalo-rahidian (citologie i proteine);

angiografie;rezonan magnetic nuclear;tomografie computerizat;angiografie convenional care poate de-monstra o stenoz a vaselor arteriale cerebrale.

Biopsia cerebral poate fi util la copiii cu deficit

neurologic progresiv, cu analize anormale ale li-chidului cefalo-rahidian, dar cu angiografie normal.Pacienii cu angiografie pozitiv asupra inflamaieivaselor proximale pot prezenta o neconcludendatorit vasodilataiei i schimbrilor ischemice aleesutului cerebral accesibil biopsiei.

Angeita izolat a sistemului nervos central poateavea i implicare patologic la distan.

Vasculitele sistemului nervos central sunt greude diagnosticat, denotnd o mare varietate de sin-droame, de semne neurologice, fiind lipsite de

markeri specifici de diagnostic.Manifestrile clinice pot fi nespecifice, i pot fi

influenate de ariile ischemice din sistemul nervoscentral. Spectrul este foarte larg, copilul poate s

prezinte migren, encefalopatie, sindroame psihia-trice, demen, convulsii, meningit, paralizie.

Angeita granulomatoas nu are faz clinic pro-domal ndelungat. Diagnosticul, n acest caz, sestabilete prin biopsie leptomeningeal, n timp cemeningita cronic este una dintre cele mai frecventemanifestri. S-au raportat hemoragii n sistemul

nervos central la 11% dintre cazuri, cea mai frec-ventfiind hemoragia intracerebral, urmat de he-moragia subarahnoidian. Aceste aspecte sunt deobicei n relaie cu un anevrism rupt al artereicerebrale meningeale.

n aceste cazuri de vasculite ale sistemului ner-vos central, Rezonana Magnetic Nuclear estemult mai sensibilfade Tomografia Computerizat(exceptnd cazurile de hemoragie cerebral).

Studii de laborator

analize uzuale;hemoleucograma completi formula leuco-citar efectuat microscopic;ionograma seric;coagulograma complet;

profil renal i hepatic.Imunologie - proteina C reactiv

crioglobuline;factor reumatoid;anticorpi ANA, SS-A (Ro)/SS-B (La);

anticorpi antifosfolipidici; serologie HIV i sifilis.Confirmarea histopatologic a vasculitei siste-

mului nervos central este necesar. Totui, biopsiacerebral rmne limitat de o serie de factori, iar


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biopsia ante-mortem poate s aibe rezultate negativela 25% dintre cazuri (7).

Implicarea sistemului nervos central n vas-culitele sistemice este variabili chiar impredic-tibil. Pe lng vasculitele vaselor cerebrale mari,Arterita Temporal cu Celule Gigante, rmne

cauza cea mai frecvent a disfunciilor neuro-logice.Prezentarea clasic a arteritei temporale include

migrena, sensibilitatea scalpului n regiunea tem-poral, claudicaia gurii, polimialgie reumatic.

Biopsia de arter temporal poate fi util. Deasemenea, n neuropatologia pediatric se mai ntl-

nesc i arteriopatia cerebral tranzitorie, angiopatiapost-vaccinal etc.

CONCLUZII

Vasculitele sitemului nervos central ct i ale

sitemului nervos periferic la copil, implici parti-ciparea unor fenomene neuroimunitare. Uneoriaceste vasculite sunt subdiagnosticate i n acelaitimp reprezint o provocare pentru clinician. Dateleanatomopatologice cu studiile de laboratori celeimagistice vin s completeze diagnosticul oferindtotodati certitudinea acestuia.

Neuroimmunology of vasculitis of the nervous system in child

Bogdan Istrate

Research Center of Neurobiology and Molecular Physiology, Bucharest

ABSTRACT

The author makes a detailed presentation of molecular and clinical neuroimmunology aspects, concerning

the peripheral and central nervous system vasculitis in child. Certain clinical features are exemplified, this

article being focused on preclinical characteristics.

Key words: neuroimmunology, vasculitis, child

The vasculitis are inflammatory processes, af-fecting blood vessels (1). By definition, aninflammatory process is accompanied by vasculardamage, defined by vasodilation, increased vascular

permeability and leukocyte extravasation as well.In contradistinction to other inflammatory com-

ponents, the vascular inflammation remains limited

at the level of the vascular wall, causing its des-truction and necrosis, thrombotic occlusion of thevascular lumen and, finally ischemia of the affectedorgan.

The vasculitic lesions tend to be multifocal,spreading throughout the vascular tree (2), indifferent pathological situations. The symptomsreflect the distribution, expansion and the tempo ofthe vasculitic process. In this respect, a single ormultiple organs may be involved, resulting a largevariety of clinical manifestations. The natural

course is dependent on the immunitary mechanismswhich generate the origin of the vasculitic process,natural course being dependent also on thereparative response of the damaged vessel. Vas-culitis are a heterogeneous group of disorders, with

inflammatory pathology as well, but different inetiology, pathogenesis and clinical manifestations(3). In child, they can occur as systemic diseasesaffecting multiple organs (systemic vasculitis) or asisolated syndromes of a single organ (non-systemicvasculitis).

For example, the vasculitis of large vessels are

defi

ned by a chronic granulomatous infl

ammation,while the medium vessels vasculitides are charac-terized predominantly by necrosis or pleomorphicinflammatory infiltrate. Vasculitis of the smallvessels are typically antibody-mediated and may begranulomatous or necrotic of the central or peri-

pheral nervous system, raising serious issues, beinglife-threatening, causing ischemic damages in theterritory distribution of affected vessels.

In table 1 are classified the vasculitides affectingthe nervous system.

The neurological vasculitic syndromes in child,occur isolated and may be limitated only at the levelof the nervous system, and, as a component part ofsome systemic diseases. The neurological sympto-matology, especially in child, may precede a


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systemic disease, representing also its clinicalmanifestation, either main or unique.

The vasculitis of the nervous system representsa challenge for the clinician, being also enigmaticdiseases.

Pathogenic mechanisms

Generally, the vasculitis are considered to beautoimmune diseases, triggered by an exogenous

pathogen agent, commonly infections, or immune

sensitization to an autoantigen (1). Specific im-munological mechanisms will be directed to thedeposition of immune complexes, followed bycomplement activation, autoantibody-mediated cy-totoxicity and last but not least by the delayed-typesensibility reactions, with granuloma formation. Inany case, the pathogenesis of vasculitis is extremelycomplex and not just an affected organ or only aimmunitary process may explain the disease.Instead, the multiple immunogenetic mechanismsare involved with the probability to act simul-

taneously or sequentially, predominant variable,depending on the particularities of the vasculitic

process. The vascular tissue, considered often asbeing a passive target, is actively involved in thevasculitic process (4). The endothelial cells formingthe mucosa of the vascular lumen (intima), ensuringin normal conditions a non-adhesive and anti-thrombotic surface. As a response to the inflam-matory signal they will be subjected to importantand functional changes, producing in this way avariety of the molecular effectors, thus facilitatingthe recruitment and transmigration of cells witinflammatory potential (5).

The smooth intraperipheral vascular tissue(adventitia), plays an important role as well in the

vascular inflammation. Its capillary network (vasavasorum) can be an entrance gateway for pathogensand inflammatory cells and resident macrophagesserving as indicators of the antigen recognitionsite.

General immunology (Autoantibodies)

Autoantibodies play an important role in thepathogenesis of the primary vasculitis syndromesin child, being pathogens and with pleomorphic

effects, thus, serving as markers of the specificvasculitic syndromes.

In this regard two autoantibodies have beendescribed:

Antineutrophilic cytoplasmic antibodies

(ANCA)

Anti-endothelial cells antibodies (AECA).

Antineutrophilic cytoplasmic antibodies(ANCA) are classically founded in vasculitides,

being associated with primary vasculitides group,as Wegener Granulomatosis, microscopic polyar-

teritis.Alergic granulomatosis (Churg-Strauss syn-

drome) are clinical entities, known also as ANCAsyndrome. They were described as anti-bodieswhich react with neutrophilic and monocytecytoplasm (being classified based on immunolo-gical methods with ethanol fixed granulocytes) asanti-cytoplasmic (c-ANCA), and perinuclear(p-ANCA).

Firstly, ANCA antibodies are IgG molecules andtypes of IgG1 and IgG4 subclasses, being alsoidentified IgM isotypes. Nevertheless, c-ANCAand p-ANCA, binds specific antigens, giving adistinctive combination of the specific vasculiticsyndromes.

TABLE 1.Classification of the vasculitides affecting the nervous system

Primary

vasculitides

Systemic

vasculitides

Giant-cell (temporal) arteritis, Takayasu arteritis, polyarteritis nodosa, Kawasaki disease,

Wegener granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, Hennoch-

Schonlein purpura

Non-systemic

vasculitis

Primary angiitis of the central nervous system (PACNS), non-systemic vasculitic

neuropathy.

Secondary

vasculitides

Connective tissue

disorders

Systemic lupus erythematosus, mixed connective tissue disorder, rheumatoid arthritis,

Sjogren syndrome.Infections HIV, HSV, CMV, VZV, T. pallidum, B. burgdorferi, S. aureus, rickettsiae, Aspergillus,

Candida, Coccidioides, Mucomycetes

Other inflammatory

disorders

Sarcoidosis, inflammatory bowel disease, Cogan syndrome, familial Mediterranean

fever, diabetes mellitus, graft-versus-host disease.

Drugs and

substances of abuse

Cocaine, amphetamines, heroin, vaccines, interferon, antibiotics

Malignancies Hodgkin lymphoma, non-Hodgkin lymphoma, lymphomatoid granulomatosis, renal

cancer, lung cancer.

*After Balabanov and Duffy, 2005


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Clinical and molecular neuroimmunology aspects

Anti-P3/c-ANCA antibody titer, correlated with

disease activity, is associated even with diseasereactivation, as well as with persistence and sub-sequent remission, besides, in this respect repre-senting a factor of relapse (8). Normally, immuncecirculating complexes activates the complementcascade and incorporates C

3b compound, which, in

turn binds the receptor 1 for complement (CR1) onthe erythrocyte surface. Red blood cells, binded toimmune circulating complexes, are transported tothe liver and spleen, from where they will be eli-minated by the resident macrophages, via their F

c

receptors (FcR). In pathological conditions, such as

antigen excess, complement deficiency, or anaberrant expression or dysfunction of F

cR, immune

complexes are destroyed or evacuated trough anelimination mechanism, and will be deposed on thesubendothelial vascular wall (9). Once deposed,in the vascular wall, the immune complexes willcause vascular alterations via multiple and differentmechanisms. Besides the complement activationand formation of the membrane attack complex(C

5b

aand C

9) which destroy directly the endothelial

cells, chemotactic factors C3a and C

5a will be

produced and attract the leucocytes. The immunecomplexes can be directly binded by F

c-R or CR

which bind the leukocytes. The endothelial cellsactivation and leukocytes, induce a higherexpression of adhesion molecules and pro-inflam-matory cytokines release (7).

The inflammatory burst activates the intrinsic pathway of the coagulation cascade leading tothrombosis and occlusion of the vascular wall.B-virus Hepatitis associated with polyartheritisnodosa is a classic example of immune complexesmediated vasculitis (10,11). Affected vessels willexpose areas of fi brinoid necrosis and immuno-globulins deposits, HBSAg and complement. Lowlevels of C2 and C4 complement compounds have

been observed in these patients, and deficiency inthe complement fractions is belived to be one of thecauses which promote the deposition of immunecomplexes in the vascular wall (12).

VASCULITIS OF THE PERIPHERAL NERVOUS

SYSTEM

Vasculitis affecting the peripheral nervous sys-tem cause syndromes with neurological specificity:Vasculitic Neuropathy. They are relatively rarediseases with an estimated incidence of approx. 2to 7 cases/1.000.000 children (14).

They are classified into several categories, de-pending on the presence or absence of an identifyingcause (primary idiophatic or secondary vasculitis)and with systemic involvement (systemic vasculitisand non-systemic vasculitis).Vasculitic neuropathyis frequently associated (in neuropediatric patho-

logy) with different systemic diseases, such as in-fectious diseases, primary vasculitis, connectivetissue disorders, malignancies, which may precedethe systemic symptoms being even the only clinicalmanifestation. The diagnostic significance of thevasculitic neuropathy is given by the fact that itcould be a common manifestation of a large numberof systemic diseases, putting into danger the childslife, but could be still treated. The pathogenesis ofthe vasculitic neuropathy and of the systemic disor-ders which accompanying it is known a long time

ago, from specialty literature papers, since 1962 inKussmaul and Maier research studies. The natureof these associations: vasculitic neuropathy sys-temic disorder, remains still unclear. The origin ofvascular inflammation regarding the peripheralneuro pathies is suggested by the presence of thesymptoms and laboratory tests along with multi-organ dysfunction and systemic inflammatory pro-cess.

Anyway, the neuropathy can occur as an isolated

syndrome, even in the absence of systemic dis-turbance, and, in this respect, all laboratory inves-tigations could be in negative or in normal range.On the other hand, the vasculitic neuropaty is notonly the one clinical entity associated with aninflammatory systemic disease or multi-organdisease or other syndromes such as acute or chronicdemyelinating polyradiculopathy, motor multifocalneuro pathy or amyloidosis. In this sense, theelectrodiagnostic studies are necessary, in order todemonstrate the axonal loss with asymmetric dis-

tribution as well as the delineation of the neuropathic process. A fact which may be misleading (beingalso a diagnostic trap) would be the presence of aconduction block, and at its origin, the axonal/focaldemyelination should be taken in consideration.

Combinatorial muscle-nerve biopsy, such asperoneal superficial nerve sampling and peroneusbrevis muscle may represent a good choice in orderto elucidate the diagnostic.

The vasculitic process damaging the peripheralnervous system, involves firstly the vasa nevorumof the peripheral nerves, which represent the in-trinsic anastomosis network of blood vessels thatensuring and distributing the bloodstream in all thenerve trajectory.


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The involvement of the peripheral nerves, frommicroscopic polyangiitis occur at 40% in children,sometimes being imperceptible.The pathologic par-ticularity of these primary vasculitic syndromes isthe granulomatous infiltrations and/or eosinophilicinfiltrate, observed not only at the level of the peri-

pheral nervous system, but also in other organs.Vasculitic rheumatoid neuropathy is usually

found in sero-positive diseases with joint and extra- joint lesions. Vasculitic neuropathy managementde pends generally on the mechanisms staying atthe basis of the vasculitic phenomena. Likewise,vasculitic neuropathy is a vaso-occlusive diseasewhich requires anti-coagulant therapy besides anti-inflammatory therapy. Children with vasculiticneurophaty, present aquired focal or diffuse neuro-logic deficit, which varies from patient to patient.

VASCULITIS OF THE CENTRAL NERVOUS

SYSTEM

Vasculitis of the central nervous system in child areless known. The diagnostic criteria proposed in 1997

by Calabrase (15), are the acquired neurological deficit,pathological and imagistic studies of the central nervoussystem angiitis, in the absence of a systemic vasculitisor other conditions in which angiographic and patho-

logical findings may be secondary.Multiple cranial neuropathies with impact on

visual function and ocular motility are the commonfeatures, resulted from the local expansion of thegranulomatous process.

Pathogenesis

The pathogenesis of the central nervous systemvasculitis remains unknown. As in many inflam-matory diseases, the research studies are centeredon two major areas: the target mechanisms and hostsusceptibility, infections also represent an importantfactor.

Classification

The spectrum of the primary central nervoussystem vasculitis in child (c PACNS) includes threedistinct entities:

c PACNS progressive, angiographic positivec PACNS unprogressive, angiographic positivec PACNS of small vessels with negativeangiography

The neurologic deficit make felt its presence inall these three forms, and may be focal or diffuse aswell.

Laboratory and imagistic studies

the inflammatory markers of the cerebrospinalfluid assay (cytology and proteins)angiographymagnetic resonance imaging (MRI)computed tomography (CT)

conventional angiography which may refl

ect a stenosis of the arterial cerebral vessels.The brain biopsy may be useful in children with

progressive neurologic deficit with an abnormalcerebrospinal fluid analysis, but with normal angio-graphic imaging. The patients with positive angio-graphy of the proximal vessels inflammation, may

present an inconclusive report due to the vaso-dilatation and ischemic changes occurs in the braintissue accessible to biopsy. Isolated angiitis of thecentral nervous system may also have pathological

implications at the distance. Vasculitis of the centralnervous system are difficult to be diagnosticated,denoting a wide variety of syndromes, neurologicalsigns, but are lacked in the diagnostic specificmarkers. The clinical manifestation could be non-specific and may be influenced by the ischemicareas in the central nervous system. The spectra isvery large, the child could present migraine, ence-

phalopathy, psychiatric syndromes, dementia,seizures, meningitis and palsy.

Granulomatous angiitis has not a prodromalcharacteristic. In this case, the diagnostic is esta- blished trough the leptomeningeal biopsy, whilechronic meningitis is one of the most commonmanifestations.

Figure 1. Combinatory biopsy (nerve-muscle) from a

patient with non-systemic vasculitis of P.N.S. Parafin

sample. H.E.stain. A) Vascular inflammatory process with

fibrinoid necrosis, celular infiltrate and vascular lumen

occlusion. B) Chronic vascular inflammatory process with

obliteration of vascular lumen (after Balabanov and Duffy,

2005).


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Hemorrhages in the central nervous system werereported in 11% of cases, the intracerebral he-morrhage being most frequent, followed by sub-arachnoid bleeding. These aspects are usually inrelation with a ruptured aneurysm of the cerebralmeningeal artery. In these cases, of central nervous

system vasculitis, Magnetic Nuclear Resonance ismore sensitive than Computed Tomography (excep-ting the situations in which cerebral hemorrhagesoccur).

Laboratory studies

routine assays;complete cell blood count microscopically

performed;ANA, SS-A (R

o) / SS-B (L

a) antibodies;

antiphospholipidic antibodies;HIV and lues serology.

Histopathological confirmation of the centralnervous system vasculitis is required. Brain tissue

biopsy remains limited to a number of factors, and

ante-mortem biopsy may have negative findings in25% of cases (7). Involvement of the centralnervous system is variable and even impredictible.Among vasculitis of large cerebral vessels, GiantCell Temporary Arteritis, remains the main causeof the neurological dysfunctions.

The classical presentation of temporal arteritis,include the migraine, scalp sensitivity in temporalarea, mouth claudication and polymyalgia rheu-matica.

CONCLUSIONS

Vasculitis of the central and peripheral nervoussystem in child, involves the contribution of im-munitary phenomena. Sometimes these vasculitisare misdiagnosed and at the same time represent a

challenge for the clinician. Anatomopathologicaldata along with laboratory and imagistic studies,complete and clarify the diagnostic.

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REFERENCES

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