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Cerebral venous sinus thrombosis and iron deficiency anemia presenting as bilateral disc edema in a child

Published:November 22, 2018DOI:https://doi.org/10.1016/j.jcjo.2018.08.014

      Case presentation

      A 30-month-old female presented upon referral from her pediatrician with new-onset esotropia. History was significant for a recent viral illness with associated vomiting, headache, and weight loss without irritability or change in behaviour. Sudden-onset esodeviation of the right eye (OD) was noted 2 weeks before presentation. Past medical history was significant for iron deficiency anemia diagnosed 2 months before for which she had been started on oral iron replacement therapy (ferrous sulfate 112.5 mg twice daily). External examination demonstrated a right head turn of 15 to 20 degrees. The child was able to fix and follow in both eyes (OU) with motility demonstrating an abduction deficit OD and full motility in the left eye (OS). Pupillary examination was normal without afferent defect. Dilated examination revealed 4+ disc edema in both eyes (OU).
      With significant disc edema and concern for a right sixth nerve palsy, the patient was sent for emergent imaging to rule out mass or thrombosis with elevated intracranial pressure. Upon hospitalization, the patient was noted to be dehydrated, iron deficient, and anemic with a hemoglobin (Hb) of 9.0 (range, 13.5−17.5 g/dL), mean corpuscular volume (MCV) of 54.8 (range, 80−96 fL/RBC), mean corpuscular hemoglobin of 14.3 (range, 33−36 g/dL), ferritin of 9 (range, 8−252 ng/mL), and red blood cell distribution width of 23.9 (range, 39−46 fL). A computerized tomographic scan was obtained demonstrating a nonocclusive, superior sagittal sinus thrombosis (Figs. 1 and 2). D-dimer was elevated at 0.63 and protein C activity was high at 113. Complete thrombophilia workup was negative revealing no molecular defect predisposing to clot formation. Lumbar puncture was negative for infection or abnormal protein content. The patient was started on subcutaneous enoxaparin 19 mg, 0.19 mL, twice daily and continued on oral treatment for her iron deficiency anemia. She was discharged 3 days after admission with home enoxaparin and iron therapy.
      Fig 1
      Fig. 1Magnetic resonance venography: 3-dimensional reconstruction of the intracranial veins showing attenuated signal in the superior saggital sinus; remaining major venous sinuses appear patent.
      Fig 2
      Fig. 2Computed tomographic scan: Postcontrast T1 weighted axial and sagittal images of the brain show a central filling defect in the posterior portion of the superior sagittal sinus consistent with thrombus. The presence of contrast around the thrombus confirms the nonocclusive nature of the clot.
      Three months after initiation, iron replacement was discontinued with noted resolution of the patient's microcytic anemia; posttreatment laboratory values included Hb 13.2, MCV 68, and ferritin 20. Magnetic resonance imaging after 3 months of anticoagulation showed interval improvement of the chronic, nonocclusive thrombus of the superior sagittal sinus. Anticoagulation was continued for a total of 6 months and then discontinued.
      At her most recent ophthalmology follow-up 13 months after her initial visit, her visual acuity measured 20/20 and 20/25, respectively, with no evidence of disc edema or pallor on dilated fundoscopic examination. She had been off of enoxaparin for 6 months without clot recurrence.

      Discussion

      Pediatric venous sinus thrombosis is an increasingly recognized cause of significant morbidity and mortality in the pediatric population. Incidence of pediatric cerebral venous sinus thrombosis (CVST) is estimated at 0.4 to 0.7/100,000 children per year and may be underestimated due to a paucity of localizing signs on initial presentation and an inappropriately low index of suspicion on the part of the provider.
      • Beri S
      • Khan A
      • Hussain N
      • Gosalakkal J
      Severe anemia causing cerebral venous sinus thrombosis in an infant.
      • deVeber G
      • Andrew M
      • Adams C
      • et al.
      Cerebral sinovenous thrombosis in children.
      Etiologies vary by age and include systemic illness, fever, hypoxic ischemic injury, postlumbar puncture, head and neck infections, anemia, autoimmune disorders, renal disease, malignancy, cardiac disease, and drugs. Underlying prothrombotic disorders have been identified in 33 to 50% of affected patients, with anticardiolipin antibody as the most common coagulopathy attributable in children.
      • Habis A
      • Hobson W
      • Greenberg R
      Cerebral sinovenous thrombosis in a toddler with iron deficiency anemia.
      • deVeber G
      • Andrew M
      • Adams C
      • et al.
      Cerebral sinovenous thrombosis in children.
      Presenting features include lethargy, weakness, altered mental status, headache, nausea, and vomiting. Physical signs may include seizures, tense fontanels in neonates, and focal neurologic defects with ischemic tissue damage resulting in hemiparesis, decreased sensation, and cranial nerve defects.
      • Habis A
      • Hobson W
      • Greenberg R
      Cerebral sinovenous thrombosis in a toddler with iron deficiency anemia.
      • deVeber G
      • Andrew M
      • Adams C
      • et al.
      Cerebral sinovenous thrombosis in children.
      Signs and symptoms may be subtle and variable requiring a high index of suspicion for appropriate recognition and work-up.
      • Sebire G
      • Tabarki B
      • Saunders DE
      • et al.
      Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome.
      In the neonatal period, CVST is more commonly attributable to perinatal insult and acquisition of clotting factors via maternal transmission; older children affected by CVST are more likely to demonstrate systemic illness contributing to a hypercoagulable state.
      • Habis A
      • Hobson W
      • Greenberg R
      Cerebral sinovenous thrombosis in a toddler with iron deficiency anemia.
      Of those diagnosed, 20% experience an associated hematological disease with iron deficiency anemia as a noted and treatable etiology of CVST.
      • Sebire G
      • Tabarki B
      • Saunders DE
      • et al.
      Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome.
      • Hartfield D
      • Lowry N
      • Keene D
      • Yager JY
      Iron deficiency: a cause of stroke in infants and children.
      Iron deficiency is a common problem in pediatric populations worldwide with approximately 7 to 9% of U.S. children aged 1 to 3 years affected.
      • Brotanek JM
      • Gosz J
      • Weitzman M
      • Flores G
      Iron deficiency in early childhood in the United States: risk factors and racial/ethnic disparities.
      Two to 3% of U.S. toddlers have clinically significant iron deficiency anemia, usually attributable to poor dietary iron intake.
      • Habis A
      • Hobson W
      • Greenberg R
      Cerebral sinovenous thrombosis in a toddler with iron deficiency anemia.
      The peak age of diagnosis of iron deficiency anemia is between 12 and 36 months of age.
      • Maguire J
      • deVeber G
      • Parkin P
      Association between iron-deficiency anemia and stroke in young children.
      Multiple case reports and series have identified a causal relationship between iron deficiency anemia and the development of CVST.
      • Hartfield D
      • Lowry N
      • Keene D
      • Yager JY
      Iron deficiency: a cause of stroke in infants and children.
      In one series by Sebire et al., microcytic anemia was documented in a majority of all patients presenting with CVST, irrespective of age; the data also demonstrated a trend of microcytosis in previously healthy children affected by CVST, further implicating iron deficient states with the development of clot.
      • Sebire G
      • Tabarki B
      • Saunders DE
      • et al.
      Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome.
      In a series by Maguire et al., children diagnosed with vaso-occlusive strokes were 10 times more likely to have iron deficiency anemia than control subjects.
      • Maguire J
      • deVeber G
      • Parkin P
      Association between iron-deficiency anemia and stroke in young children.
      How iron deficient states contribute to hypercoagulability remains controversial and appears to involve multiple pathophysiologic processes including excessive platelet production, reactive thrombocytosis, and alterations in local blood flow leading to stasis and further red blood cell deformation.
      • Beri S
      • Khan A
      • Hussain N
      • Gosalakkal J
      Severe anemia causing cerebral venous sinus thrombosis in an infant.
      • Benedict S
      • Bonkowsky J
      • Thompson J
      • et al.
      Cerebral sinovenous thrombosis in children: another reason to treat iron deficiency anemia.
      Diagnosis of CVST revolves around positive imaging studies with magnetic resonance venography being the preferred modality.
      • deVeber G
      • Andrew M
      • Adams C
      • et al.
      Cerebral sinovenous thrombosis in children.
      Treatment of CVST predominantly involves anticoagulation and potential thrombolysis with concurrent treatment of associated iron deficiency anemia, dehydration, and additional systemic abnormalities. Children requiring anticoagulation are generally treated for 3 to 6 months with no proven benefit for extension beyond.
      • Sebire G
      • Tabarki B
      • Saunders DE
      • et al.
      Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome.
      Prognosis can be poor, with short-term follow-up data suggesting persistent neurologic deficits in 38% of children, seizures in 15%, and death occurring in 8%.
      • Habis A
      • Hobson W
      • Greenberg R
      Cerebral sinovenous thrombosis in a toddler with iron deficiency anemia.
      With the prevalence of iron deficiency anemia, ease of treatment, and association of microcytic anemia with the development of devastating CVST, practitioners should maintain a high index of suspicion for both disease states and consider obtaining routine iron laboratory studies if sourced signs and symptoms suggest. The pediatric ophthalmologist plays a unique role in the detection of CVST given the variability and relative paucity of definitive, systemic examination findings. Iron deficiency anemia and resultant CSVT should be added to the differential of any child with bilateral optic disc edema.

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