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Amit Salkar, MD Nicole Bernard, MD Bhairav Patel, MD Robert Mignacca, MD Dell Childrens Medical Center of Central Texas 7 th Annual Pediatric Conference Saturday, April 12, 2014 Slide 2 Discuss what was learned from each step in obtaining this child's diagnosis Identify areas of improvement in patient care Explain areas of group learning from the case presentation Slide 3 22-month-old, previously healthy male presents to an outside hospital with 2 days of emesis He is appropriately fluid resuscitated for mild- to-moderate dehydration CBC reveals a Hgb of 4.7, MCV of 45.6, RDW of 26.6, and platelets of 525 Transferred to DCMC for further evaluation Slide 4 Review of systems is negative Child is otherwise healthy His mother states that he is a picky eater and consumes ~ gallon of cows milk per day for the last several months Family history is unremarkable Slide 5 Vital signs are significant for tachycardia Physical exam reveals a pale, fussy but consolable toddler Otherwise, his physical exam is normal Slide 6 Child continues to have emesis and low urine output Additional fluid resuscitation is given His mother seems worried, stating that he has been very sleepy and not himself Slide 7 Acute emesis and altered mental status, and severe anemia raised suspicion for an intracranial process CT Head without contrast was ordered STAT, which led to the diagnosis Slide 8 Slide 9 Slide 10 Slide 11 Slide 12 Vein of Trolard (lateral) Slide 13 Slide 14 Deep cerebral venous thrombosis Associated bilateral deep white matter and right caudate nucleus venous infarctions Slide 15 Hypercoagubility work-up was initiated Transfused with 5 ml/kg of pRBCs Post-transfusion Hgb 4.3 (lower than initial value) Started on iron supplementation and Lovenox therapy Transfused again with pRBCs Slide 16 Although lethargy improved, patient continued to have some bouts of emesis and began complaining of headache Repeat imaging showed stable findings Symptoms were attributed to increase intracranial pressure from cerebral sinus venous thrombosis (CSVT) Slide 17 Symptoms of increased ICP gradually improved Discharged home 8 days after admission Instructed to follow-up with Hematology for ongoing management of Lovenox therapy and iron deficiency anemia (IDA) Slide 18 Hypercoagulability work-up initiated while inpatient reveals heterozygous mutation of the PT20210A allele Slide 19 Review CSVT in children, including definition, epidemiology, clinical manifestations, imaging, and risk factors Discuss the relationship between the PT20210A prothrombin gene mutation and CSVT Explore the association between IDA and CSVT Slide 20 Slide 21 Ischemic stroke consists of Arterial ischemic stroke (AIS) Cerebral sinus venous thrombosis (CSVT) [1] Childhood stroke Cerebrovascular event in patients 30 days to 18 years of age [2] Slide 22 Defined as thrombotic occlusion of cerebral veins or sinuses Associated with venous infarction in ~ 50% of cases Proportion of AIS to CSVT is ~ 3:1 Venous congestion leads to focal cerebral edema progressing to venous infarction and hemorrhage [1] Slide 23 Reported incidence of 0.67 per 100,000 children per year CSVT was more common in neonates [3] Slide 24 Decreased level of consciousness Headache Focal neurological signs such as hemiparesis Cranial nerve palsies [3] Slide 25 Drains majority of deep gray nuclear structures Located in the ventricles and deep basal cisterns Choroidal, septal, and thalamostriate veins converge to form the paired internal cerebral veins Internal cerebral veins and basal veins of Rosenthal join to form the great vein of Galen, which joins the inferior sagittal sinus to form the straight sinus Slide 26 Straight sinus drains to the torcular and subsequently to the transverse sinuses sigmoid sinuses internal jugular veins Variations of drainage are extremely common, which in part determines variable brain injury to thrombosis Slide 27 2005 American Academy of Neurology. Published by LWW_American Academy of Neurology.2 Figure 5 Anatomy of the deep cerebral venous system. (A, B) Axial and sagittal view of deep venous system and basal ganglia: 1. caudate nucleus; 2. thalamus; 3. basal veins (veins of Rosenthal); 4. internal cerebral veins; 5. great cerebral vein (vein of Galen). (C, D) Axial and sagittal maximum intensity projection (MIP) images of the deep venous system. (E-F) Axial and sagittal MIP images; the deep venous system is demarcated in red. The spectrum of presentations of venous infarction caused by deep cerebral vein thrombosis. van den Bergh, Walter; van der Schaaf, Irene; van Gijn, Jan Neurology. 65(2):192-196, July 26, 2005. Figure 5 Slide 28 Superior sagittal sinus Transverse sinus Torcular Sigmoid sinus Superior sagittal sinus Inferior sagittal sinus Basal vein of Rosenthal Internal cerebral veins Torcular Straight sinus Slide 29 Slide 30 Venous Drainage Slide 31 Catheter angiography - gold standard Invasive (complications of stroke, groin hematoma, femoral artery injury) Highest radiation exposure CT angiography Excellent sensitivity Requires administration of iodinated contrast Radiation exposure Slide 32 MR venography Excellent sensitivity Can be done without contrast (although not as good as contrast enhanced MRV and not great for partial thrombosis) Typically contrast is given Ultrasound - acceptable for dural sinuses in neonate Slide 33 Slide 34 Slide 35 Slide 36 Slide 37 Slide 38 Slide 39 Slide 40 Slide 41 Slide 42 Head and neck disorders 38% (of which 61% were infections) Otitis media, mastoiditis, and sinusitis (preschool children) Acute systemic diseases 31% Dehydration, sepsis [3] Slide 43 Chronic systemic diseases 54% Connective-tissue disorders Hematologic disorders Malignancy Cardiac disease Disorders requiring indwelling catheter [3] Slide 44 Coagulation disorders 32% Deficiencies in protein C, protein S, and antithrombin III, Factor V Leiden and PT20210A prothrombin gene mutations Presence of anticardiolipin antibody and Lupus anticoagulant [3] Slide 45 Iron-deficiency anemia 2005 review of 42 cases of children with CSVT by Sebire et al. published in Brain 50% had probable IDA [4] Increasing number of case reports and reviews describing IDA as a risk factor for CSVT [5-9] Slide 46 Common Low risk for pathology unless homocysteine is elevated If homocysteine is elevated, improvement can be seen with folic acid. Slide 47 Obesity Inactivity Pregnancy hormones Anesthesia/surgery Crush injury Tobacco Slide 48 Clinically, the balance between bleeding and clotting requires a significant change (or multiple less significant ones) to result in pathology Slide 49 Slide 50 Slide 51 Prothrombin (Factor II) functional point mutation on Cr 11 of non-coding region of prothrombin Increased protein expression [16-19] Increased protein stability [20] Slide 52 G20210a mutation 1-3% of general population Prevalence rates of G20210a in pediatric patients with thrombosis have shown to be 4-10% Population Caucasians, with few Middle Eastern, and Hispanic incidence Rare in Asian and African American [20-22] Slide 53 Zadro R, Herak DC. Inherited prothrombitc risk factors in children with first ischemic stroke. Biochem Med (Zagreb). 2012;22 (3):298-310. [23] Slide 54 CSVT is associated with inherited prothrombotic risk Laugesaar et al. showed 3 fold increase risk of CSVT in children with PT G20210A, showing significant risk both on Meta-analysis (OR 11.9; 95%CI) and Case-control (OR 3.3; 95% CI) studies [24] Slide 55 Retrospective review (Young et al.) of 374 thrombotic events in 26 hospital centers, 10% (38 children) had G20210A mutation [25] 92% of VT had an acquired risk factor 54% had an additional inherited risk factor Majority of VTE were older children (96% > 2 years) Slide 56 Excluding neonates the mean age was 10.6 years Only 25% with FH thrombotic event CSVT manifested in 6 of 34 thrombotic events Slide 57 Slide 58 2007 case-controlled study published in Pediatrics by Maguire JL, et. al. Studied children aged 12 to 38 months who were previously healthy with no identifiable risk factors for stroke Case patients had lower median hemoglobin levels and MCV and higher platelet counts [7] Slide 59 2007 case-controlled study published in Pediatrics by Maguire JL, et. al. Children with IDA accounted for more than half of all stroke cases Children with stroke were 10 times more likely to have IDA than controls [7] Slide 60 2014 case-controlled study published in Annals of Hematology Very similar to study by Maguire, except for having a higher number of case patients 57.1% of stroke cases had IDA and no other identified cause, compared to 26% of controls [9] Slide 61 2014 case-controlled study published in Annals of Hematology Previous healthy children who developed stroke were 3.8 times more likely to have IDA than healthy children who did not develop stroke Significant interaction between IDA and thrombocytosis among studied cases [9] Slide 62 Hypercoaguable state directly related to iron- deficiency and/or anemia IDA causes microcytosis and reduced RBC deformability Turbulence replaces laminar blood flow, allowing platelets to come in contact with endothelium, initiating coagulation cascade and development of thrombus [6] Slide 63 Thrombocytosis secondary to IDA Iron inhibits platelet production, which explains thrombocytosis in IDA Iron also required for synthesis of essential platelet components and therefore needed for maximum platelet production above steady-state levels Bump in platelets observed when iron is initially replaced [6] Slide 64 Anemic hypoxia Mismatch between oxygen supply and end-artery oxygen demand leads to ischemia and infarction [2] Slide 65 Patient continues to follow-up with Hematology for ongoing management of anticoagulation (6 months duration) and IDA Repeat MRV Brain with contrast ~ 1 month after discharge showed resolution of thrombosis Slide 66 No evidence of neurologically sequelae Due for repeat imaging around the time of discontinuation of Lovenox Slide 67 Include intracranial process on differential for children presenting with emesis Recognize risk factors for CSVT Consider IDA as potential risk factor for CSVT, although the literature is still evolving Prevention of IDA can be simple as taking a good diet history and educating parents about proper nutrition Slide 68 [1] Kirton A, deVeber G. Therapeutic Approaches and Advances in Pediatric Stroke. The Journal of the American Society for Experimental NeuroTherapeutics. 2006;3:133-142. [2] Lynch JL, Hirtz DG, deVeber G, Nelson KB. Report of the National Institue of Neurological Disorders and Stroke Workshop on Perinatal and Childhood Stroke. Pediatrics. 2002;109:116-123. [3] deVeber G, Andrew M, Adams C, et al. Cerebral sinovenous thrombosis in children. N Engl J Med. 2001;345:417423. [4] Sebire G, Tabarki B, Saunders D, et al. Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome. Brain. 2005;128:477489. [5] Hartfield DS, Lowry NJ, Keene DL, Yager JY. Iron Deficiency: A Cause of Stroke in Infants and Children. Pediatr Neurol.1997;16:50-53. [6] Benedict SL, Bonkowsky JL, Thompson JA, et al. Cerebral Sinovenous Thrombosis in Children: Another Reason to Treat Iron Deficiency Anemia. J Child Neurol. 2004;19:526-531. [7] Maguire JL, deVeber G, Parkin PC. Association Between Iron-Deficiency Anemia and Stroke in Young Children. Pediatrics. 2007;120:1053-1057. [8] Mehta PJ, Chapman S, Jayam-Trouth A, et al. Acute Ischemic Stroke Secondary to Iron Deficiency Anemia: A Case Report. Case Reports in Neurological Medicine. 2012; 2012: Article ID 487080, 5 pages. doi:10.1155/2012/487080 Slide 69 [9] Azab SFA, Abdelsalam SM, Saleh SHA, et al. Iron deficiency anemia as a risk factor for cerebrovascular events in early childhood: a case-control study. Ann Hematol. 2014;93:571-576. [10] Barron TF, Gusnard DA, Zimmerman RA, Clancy RR. Cerebral venous thrombosis in neonates and children. Pediatr Neurol. 1992;8: 112-6. [11] Carvalho KS, Bodensteiner JB, Connolly PJ, Garg BP. Cerebral venous thrombosis in children. J Child Neurol. 2000;16: 574-80. [12] Bonduel M, Sciuccati G, Hepner M, Torres AF, Pieroni G, Frontroth JP. Prethrombotic disorders in children with arterial ischemic stroke and sinovenous thrombosis. Arch Neurol. 1999;56:967-71. [13] Heller C, Heinecke A, Junker R, Knofler R, Kosch A, Kurnik K, et al. Childhood Stroke Study Group. Cerebral venous thrombosis in children: a multifactorial origin. Circulation. 2003;108:1362-7. [14] Barnes C, Newall F, Furmedge J, et al. Cerebral sinus venous thrombosis in children. J Paediatr Child Health. 2004;40:53-55. [15] Yager JY, Hartfield DS. Neurologic Manifestations of Iron Deficiency in Childhood. Pediatr Neurol. 2002;27:85-92. Slide 70 [16] Andrew M. Developmetal homestasis: relevance to thromboembolic complications in pediatric pateints. Thromb Haemost. 1995; 47: 415-525. [17] Kenet G, Nowak-Gottl U. Venous thromboembolism in neonates and children. Best Practice and research clinical haematology. 2012 Sept; 25(3): 333-344. [18] Balasa V, Gruppo RA, Glueck CJ, Stroop D, Becker A, Pillow A, Wang P.The relationship of muation in the MTHFR, prothrombin, and PAI-1 genes to plasma levels of homocysteine, prothrombin, and PAI-1 in children and adults. Thromb Haemost 1999: 81: 739-44. [19] Poort SR, Rosendaal FR, Reigsma PH, Bertina RM. A common genetic variant in the 30- untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-703. [20] Gelfi C, Vigano A, rpamonti M, Wait R, Begum S, Biguzzi E, Castaman G, Faioni EM. A proteomic analysis of changes in prothrombin and plasma proteins associated with the G20210A mutation. Proteomics, 2005 Jul; 4(7):2151-9 [20] Rosendaal FR. Venous thrombosis: the role of genes, environment, and behavior. Hematology Am Soc Hematol Educ Program. 2005;1:112. [21] Coen Herak D, Radic Antolic M, Lenicek Krleza J, Pavic M, Dodig S, Duranovic V, et al. Inherited prothrombotic risk factors in children with stroke, transient ischemic attack, or migraine. Pediatrics April 2009; 123:4 e653-e660. Slide 71 [22] Kenet G, Lutkhoff LK, Albisetti M, Bernard T, Bonduel M, Brandao L, et al. Impact of thrombophilia on arterial ischemic stroke or cerebral sinovenous thrombosis in children: a systematic review & meta analysis of observational studies. Circulation 2010;121.1838-47. [23] Zadro R, Herak DC. Inherited prothrombitc risk factors in children with first ischemic stroke. Biochem Med (Zagreb). 2012;22 (3):298-310. [24] Laugesaar R, Kahre T, Kolk A, Uustalu U, Kool P, Talvik T. Factor V Leiden and prothrombin 20210G>A [corrected] mutation and paediatric ischaemic stroke: a case-control study and two meta-analyses. Acta Pediatr 2010;99:1168-74. [25] Young G, Manco-Johnson M, Gil JC, Dimichele DM, Tarantino MD, Abshire T, Nugent DJ. Clinical Manifestations of the prothrombin G20210A mutation in children : A pediatric coagulation cosortium study. J Thromb Haemost. 2003;958-62.