Arq Neu ro p siq u iat r 2003;61(4):1026-1029
CEREBRAL SINOVENOUS THROM BOSIS
IN A NEPHROTIC CHILD
M arcelo M asruha Rodrigues
1, Lilian Rocha Zardini
2,
M aria Crist ina de Andrade
3, Crist ina M alzoni Ferreira M angia
3,
João Tomas de Abreu Carvalhaes
4, Luiz Celso Pereira Vilanova
5ABSTRACT - Nep hrotic synd rom e in infancy and child hood is know n to b e associated w ith a hyp ercoag ulab le state and throm b oem b olic com p lications, b ut cereb ral sinovenous throm b osis (CST) is a very rare and serious one, w ith only a few isolated rep orts in the literature. A case is p resented of a 9-year-old b oy w ith nep hrotic syn d ro m e t h a t a cu t ely d evelo p ed sig n s a n d sym p t o m s o f in t ra cra n ia l h yp ert en sio n syn d ro m e. CST w a s diagnosed on cranial CT and MRI and he gradually recovered after treatm ent with anticoagulants. The diagnosis of CST should b e consid ered in any p atient w ith nep hrotic synd rom e w ho d evelop s neurolog ic sym p tom s. The d iscussion of this case, coup led w ith a review of the literature, em p hasizes that early d iag nosis is essential for institution of anticoag ulation therap y and a successful outcom e. This rep ort also illustrates the d ifficulties that m ay b e encountered in m anag ing such a p atient.
KEY WORDS: cereb ral venous throm b osis, sag ittal sinus throm b osis, nep hrotic synd rom e, child .
Trombose venosa cerebral em uma criança com síndrome nefrótica
RESUMO - A sínd rom e nefrótica na criança é sab id am ente associad a a um estad o d e hip ercoag ulab ilid ad e e com p licações trom b oem b ólicas, entretanto a trom b ose venosa cereb ral (TVC) é um a com p licação m uito rara e g rave, com p oucos relatos na literatura. Relatam os o caso d e um m enino d e 9 anos com sínd rom e nefrótica q ue ag ud am ente d esenvolveu sinais e sintom as d e um a sínd rom e d e hip ertensão intracraniana. TVC foi d iag nosticad a através d e CT e IRM d e crânio e o p aciente g rad ualm ente se recup erou ap ós o tratam ento com anticoag ulantes. O d iag nóstico d e TVC d eve ser consid erad o em q ualq uer p aciente com sínd rom e nefrótica q ue d esenvolva sintom as neurológ icos. A d iscussão d este caso, associad a à revisão d a literatura, enfatiza q ue o d iag nóstico p recoce é essencial p ara instituição d a terap ia anticoag ulante e p ara o b om p rog nóstico. Este relato tam b ém ilustra a d ificuld ad e em m anejar este tip o d e p aciente.
PALAVRAS-CHAVE: trom b ose venosa cereb ral, trom b ose d o seio sag ital, sínd rom e nefrótica, criança.
Dep art m en t s o f Neu ro lo g y / Neu ro su rg ery an d Ped iat rics, Fed eral Un iversit y o f São Pau lo , São Pau lo SP, Brazil: 1Resid en t , Dep art m en t o f Neu ro lo g y an d Neu ro su rg ery; 2Resid en t , Dep art m en t o f Ped iat rics; 3Asso ciat ed Ph ysician , Dep art m en t o f Ped iat rics; 4Asso ciat ed Pro fes-so r, Dep artm en t o f Ped iatrics; 5Asso ciat ed Pro fesso r, Dep art m en t o f Neu ro lo g y an d Neu ro su rg ery.
Received 14 Ap ril 2003, received in fin al fo rm 20 Ju n e 2003. Accep t ed 9 Ju ly 2003.
Dr. Marcelo Masruha Rodrigues - Federal Universit y of São Paulo, Division of Child Neurology, Department of Neurology and Neurosurgery - Rua Botucatu 720 - 04023-900 São Paulo SP - Brazil. E-mail: mmasruha@ig.com.br
Art erial an d ven o u s t h ro m b o ses are w ellreco g -n ized classic co m p licat io -n s o f -n ep h ro t ic sy-n d ro m e, h o w ever t h ese are far less freq u en t in ch ild ren t h an in adults1 Cerebral sinovenous throm bosis (CST)
asso-ciated w ith n ep h ro tic syn d ro m e in ch ild ren is extre-m ely rare an d o n ly a few iso lat ed rep o rt s exist in t h e literature2-13.
CASE
A 9-year-old white b oy with steroid -resp onsive nep hro-t ic syn d ro m e o f u n d ehro-t erm in ed cau se, d iag n o sed w h en h e w as 4-years-o ld , acu t ely d evelo p ed a severe g en eralized t h ro b b in g h ead ach e fo u r d ays p rio r t o ad m issio n t o t h e São Pau lo Ho sp it al. He d escrib ed it as co n t in u o u s, w it h
p hotop hob ia and p honop hob ia, w ithout relieving factors. Eig h t d ays p rio r t o t h e o n set o f t h at clin ical p ict u re h e st art ed w it h vo m it in g an d u p p er ab d o m in al p ain n o t re-lat ed t o fo o d in t ake, w it h w o rsen in g sig n s an d sym p t o m s of nep hrotic synd rom e. He w as on tap ered treatm ent w ith alt ern at e d ay, sin g le d o se o f p red n iso n e. An eso p h ag o -g ast ro d u o d en o sco p y w as p erfo rm ed , d isclo sin -g a severe n o n -e ro sive g a st rit is a n d ra n it id in e w a s st a rt e d . Pa st m edical history was negative for m igraine headaches, head t rau m a, feb rile illn ess, su b st an ce ab u se, vit am in in t ake o r t h ro m b o p h leb it is. Fam ily h ist o ry w as u n rem arkab le.
Arq Neu ro p siq u iat r 2003;61(4) 1027
rem a rka b le m en in g ea l irrit a t io n sig n s (n u ch a l rig id it y, Bru d zin ski sig n an d Kern ig sig n ) an d p ap illed em a. Th e re-m aind er of the exare-m ination was within norre-m al lire-m its. Nor-m al values were obtained for the following laboratory data: co m p let e b lo o d co u n t (CBC), seru m elect ro lyt es, g lu co se, u rea an d creat in in e. Seru m alb u m in w as 1.7 g /d L an d 24-h u rin e p ro t ein excret io n w as 18 g /d ay.
Noncontrast-enhanced cranial CT revealed the dense-triangle sign and the contrast enhanced phase showed a dilated straight sinus and the em pty-delta sign (Fig 1). There was no m ass effect, m idline shift or venous stroke im age. Cranial m agnetic resonance im aging (MRI) and m agnetic resonance venography (MRV) demonstrated superior sagittal and left transverse sinus throm bosis. There were no cere-bral parenchym a or brainstem lesions (Figs 2 and 3).
A lo ad in g d o se o f h ep arin o f 50 U/kg w as g iven IV fo llo w ed b y a co n t in u o u s in fu sio n o f 10 U/kg p er h o u r a n d m o rp h in e w a s g ive n t o p ro vid e a n a lg e sia . We
Fig 2 Sagittal T1-W image reveals increased signal intensity w ithin t he superior sagit t al sinus and in t he region of t he venous confluence.
Fig 1 Axial cont rast -enhanced cranial CT show s a filling defect in t he region of t he venous conf luence (t he empt y delt a sign) associat ed w it h a dilat ed st raight sinus.
1028 Arq Neu ro p siq u iat r 2003;61(4)
at t em p t ed t o m ain t ain t h e p art ial t h ro m b o p last in t im e (PTT) b et w een 64 t o 80 s, w it h a co n t ro l o f 32 s. Ho w ever, d esp it e d o ses as h ig h as 30 U/kg p er h o u r, t h e in crease in PTT could not be sustained. The nephrotic state was treated w it h p red n iso n e (2 m g /kg /d ay) an d rem issio n o f t h e n e-p h ro t ic syn d ro m e o ccu rred 5 d ays aft er t h e in st it u t io n o f t h at t reat m en t . At t h is t im e t h e d esired levels o f an t ico a-g u lat io n w ere ach ieved an d t w o d ays lat er Warfarin at 0,1 m g /kg /d ay w as ad d ed w it h su ccessfu l co n t ro l o f p ro -t h ro m b in -t im e. Th e ch ild g rad u ally m ad e a co m p le-t e cli-n ical reco very o ver 2 w eeks.
DISCUSSION
Cereb ral sin o ven o u s th ro m b o sis in ch ild ren is a rare d iso rd er b u t o n e th at is in creasin g ly d iag n o sed b ecau se o f g reat er clin ical aw aren ess, sen sit ive n eu -ro im ag in g tech n iq u es, an d th e su rvival o f ch ild ren w it h p revio u sly let h al d iseases t h at co n fer a p red is-p o sitio n to sin o ven o u s th ro m b o sis14 It h as b een
re-co g n ized sin ce th e 19th cen t u ry, u su ally asso ciat ed
w ith trau m a o r p yo g en ic in fectio n s, like m asto id itis, sin u sit is an d facial cellu lit is. Ho w ever, t h e d evelo p -m en t an d u se o f an t ib io t ics g reat ly red u ced t h e in
ci-dence of septic throm bosis15 Aseptic CST is now m ore
com m on and have been reported in association with acute and chronic system ic diseases (Table). Idiopathic CST represents only 3 percent of cases in children14.
Nep h ro tic syn d ro m e is d efin ed b y a u rin ary p ro -tein level exceeding 3.5 g per 1.73 m2 of body-surface
area p er d ay. It is asso ciat ed w it h a h yp erco ag u lab le state arising due to various factors like - low zym ogen fact o rs (fact o r IX an d fact o r XI), in creased p ro co a-gulatory cofactors (factor V and factor VIII), increased fib rin o g en levels, d ecreased co ag u lat io n in h ib it o rs: an tith ro m b in III (b u t p ro tein C an d p ro tein S in crea-sed ), alt ered fib rin o lyt ic syst em (α2an t ip lasm in in -creased and p lasm inog en d e-creased ), in-creased p la-telet reactivity and altered endothelial-cell function16.
Dehydration secondary to gastritis with vom iting and steroid therap y were ad d itional risk factors in our patient.
Th ro m b o sis o f vario u s vessels h as b een rep o rted , b ut CST associated with nep hrotic synd rom e ap p ears to b e very rare an d o n ly a few iso lated rep o rts exist in the literature2-13. Divekar et al. rep orted only 1 case
Table 1. Condit ions associat ed w it h asept ic CST in children.
1. Pro co ag u lan t d ru g s Oral co n tracep tives Asp arag in ase
2. Head in ju ry an d st ran g u lat io n 3. Preg n an cy an d p u erp eriu m 4. Po st o p erat ive st at es 5. Hem at o lo g ic d iso rd er
Iro n d eficien cy Sickle cell d isease Beta-th alassaem ia m ajo r
Prim ary o r seco n d ary p o lycyt h em ia Prim ary o r seco n d ary t h ro m b o cyt h em ia Paro xysm al n o ct u rn al h em o b lo b in u ria 6. In flam m ato ry b o w el d isease
Cro h n d isease Ulcerat ive co lit is
7. Perin at al co m p licat io n s (n eo n at al g ro u p ) Hyp o xia at b irt h
Prem at u re ru p t u re o f m em b ran es Mat ern al in fect io n
Placen t al ab ru p t io n Gestatio n al d iab etes 8. Ho m o cyst in u ria 9. Maln u t rit io n
10. Co n n ect ive-t issu e d isease Syst em ic lu p u s eryt h em at o su s Beh çet d isease
An t ip h o sp h o lip id an t ib o d y syn d ro m e 11. Nep h ro t ic syn d ro m e
12. Hyp ern at rem ic d eh yd rat io n 13. Diab et ic ket o acid o sis 14. Ost eo p et ro sis
15. Ab n o rm al lo cal h em o d yn am ics Art erio ven o u s m alfo rm at io n s Du ral art erio ven o u s fist u la Moyam oya d isease Stu rg e-Web er syn d ro m e 16. Ca n cer
17. In h erit ed co ag u lat io n d iso rd ers Fact o r V (Leid en ) m u t at io n
G20210A p ro t h ro m b in -g en e m u t at io n Pro t ein S d eficien cy
Pro t ein C d eficien cy An t it h ro m b in III d eficien cy
Arq Neu ro p siq u iat r 2003;61(4) 1029
o f CST o u t o f 700 ch ild ren w it h n ep h ro t ic syn d ro m e fo llo w ed o ver a p erio d o f 17 years6.
Th e d iag n o sis o f CST sh o u ld b e co n sid ered in an y p atient w ith nep hrotic synd rom e w ho d evelop s neu-ro lo g ic sym p t o m s. Th o se are d ifferen t b et w een t h e n eo n ate an d n o n n eo n ate g ro u p s. In th e latter, th e clin ica l fin d in g s a re sim ila r t o t h o se rep o rt ed in ad ults: a d ecreased level of consciousness, head ache and focal neurolog ical sig ns such as hem ip aresis and cran ialn erve p alsies. In co n t rast , t h e p rim ary n eu -ro lo g ic m an ifest at io n s in n eo n at es are seizu res an d d iffu se n eu ro lo g ic sig n s14. We h ave fo u n d , h o w ever,
o n ly o n e case o f CST asso ciat ed w it h co n g en it al n e-p h ro t ic syn d ro m e9.
Ph ysical exam in at io n m ay reveal fin d in g s o f in -creased in t racran ial p ressu re o r fo cal d eficit s as p re-viously described. Our patient presented papilledem a an d m en in g eal irritatio n sig n s, b o th seco n d ary to in tracran ial h yp erten sio n . Lu m b ar p u n ctu re sh o u ld be done if infection is suspected but is non diagnostic fo r CST. Th e CSF m ay sh o w in creased p ressu re an d m ild ly increased red b lood cells d ue to m icrohem orrh ag es. Ot orrh er n o n sp ecific fin d in g s d escrib ed are in -crea sed eryt h ro cyt e sed im en t a t io n ra t e a n d m ild leu ko cyt o sis. EEG fin d in g s are n o n sp ecific15.
In the p resence of the ap p rop riate clinical history, cranial CT p rovid es an excellent screening p roced ure. In m ost cases, as the one presented here, a diagnosis of sinus throm bosis can be m ade on the basis of the CT findings. The noncontrast-enhanced scan may show the p resence of sm all ventricles, cereb ral swelling, hem orrhagic and ischem ic infarcts, intracerebral he-m atohe-m as, the dense-triangle sign and the cord sign. The contrast enhanced scan can disclose the so-called em pty delta sign, gyral or tentorial enhancem ent and dilated transcerebral or m edullary veins17.
MRI w ith m ag n etic reso n an ce ven o g rap h y, b eca-u se o f it s n o n in vasiven ess an d h ig h sen sit ivit y, is t h e p referred m o d alit y fo r d iag n o sis an d fo llo w -u p o f cereb ral ven o u s th ro m b o sis. Th e n o rm al flo w vo id seen in vein s an d sin u ses o n n o n co n trast-en h an ced MRI is rep laced b y sig n als t h at are h yp erin t en se o r iso in t en se t o b ra in , d ep en d in g o n t h e seq u en ce u tilized an d th e ag e o f th e th ro m b u s18.
Th e t reat m en t o f ch o ice is h ep arin , fo llo w ed b y oral anticoag ulation, ad m inistered as long as the p a-t ien a-t h as n ep h ro a-t ic p ro a-t ein u ria, an alb u m in level b e-lo w 2 g /d L, o r b o th16. Difficu lt y in an t ico ag u lat io n
w as en co u n t ered in o u r case as in all cases rep o rt ed in th e literatu re. Lo ss o f ATIII in th e n ep h ro tic u rin e m ay b e an im p o rt an t cau se o f t h e failu re o f an t ico
a-g u lat io n w it h h ep arin . Lara-g e am o u n t s o f ad m in ist e-red h ep arin m ay also b e lo st in th e n ep h ro tic u ri-n e16. Fresh fro zen p lasm a w as g iven t o co rrect an
-t i-t h ro m b in -3 levels in so m e rep o r-t ed cases w i-t h a g o o d resp o n se (red u ctio n o f tim e to ach ieve th e d e-sire an t ico ag u lat io n level)2,4,6,12. Th e lo n g t erm n eu
-rologic outcom e of sinovenous throm bosis in children is unclear and the best available estim ate is that after a m ean of 2.1 years, 77 percent of neonates and 52 percent of nonneonates are neurologically norm al19.
Ea rly re co g n it io n , im m e d ia t e in st it u t io n o f a n t i-coagulation therapy and control of nephrotic syndro-m e are essential syndro-m easures to ensure a good prognosis.
Acknowledgments- We wish to thank the pediatric hou-sestaff for providing m edical care for this patient and Dr. Mar-celo Freire for preparing the im ages and reviewing of text.
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