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Thromboembolic events are a known and potentially life-threatening extraintestinal manifestation of inflammatory bowel disease (IBD). The overall incidence of thrombosis in IBD is estimated to be between 1.3% and 7.5%.1,2 Reported cases of thrombosis are arterial or venous and occur most frequently in the deep leg veins and/or pulmonary vasculature. Unusual but reported sites of venous thrombosis include the cerebral sinuses, retinal vessels, and the heart. Although associations have been described between IBD and inherited prothrombotic states, the exact pathophysiology of thromboembolism in IBD remains unknown.
We present two cases of cerebral venous sinus thrombosis (CVST) in patients with IBD. A literature search of IBD and CVST yielded 31 additional cases (Table 1).3-29 The literature is reviewed including a discussion about presentation and treatment of CVST as well as current theories about thrombosis and IBD.
A 23-year-old nonsmoking woman, diagnosed with biopsy-confirmed ulcerative colitis (UC) at the age of 16, presented with headache, nausea, and vomiting of 3 days duration. The headache was located behind her eyes and in her neck. Associated symptoms included nausea and vomiting but no seizure activity, paresis, mental status changes, or photophobia. She was in the process of evaluation for colectomy due to persistent pancolitis and had received past treatment with azathioprine, mesalamine, and cyclosporine.
Her medical history was complicated by a deep venous thrombosis 10 months prior, suspected to be secondary to oral-contraception use. The earlier episode of thrombosis occurred concurrent with an acute flare. A hypercoaguable work-up administered at the time was negative. She was treated successfully with 6 months of heparin and low-molecular weight heparin and oral contraception was stopped.
On present physical examination, she was febrile to 38.8° C but otherwise stable. Her examination was unremarkable except for decreased range of neck motion due to pain. She showed no evidence of frank meningismus, photophobia, or neurologic deficits. Laboratory tests revealed a white blood cell count of 4,200 cells/µL, hemoglobin of 9.9 g/dL, and hematocrit of 29.6%. A lumbar puncture on admission was negative for meningitis and she proceeded to imaging studies. Magnetic resonance imaging (MRI) revealed acute bilateral maxillary sinusitis and left-sided otitis media with extension of infection to the left tentorium. An incidental note was made of a filling defect within the left lateral sinus. A magnetic resonance venogram (MRV) confirmed occlusion of the transverse sinuses and sigmoid sinuses. Finally, cerebral angiography (Figure 1) showed thrombosis of the left transverse sinus and cavernous sinus, and compromised but patent right transverse sinus, sigmoid, and right jugular veins.
Initially, it was thought that the venous thromboses were secondary to otitis media and sinusitis and the patient was treated with intravenous (IV) antibiotics with some improvement in her headache. Anticoagulation was not initiated due to the concern for intracerebral bleeding. However, she re-presented 5 days later with worsening headache and neck stiffness as well as a fever, despite administration of broad-spectrum antibiotics. She received intravenous heparin and warfarin with complete resolution of her headache and neck stiffness. A hypercoaguable work-up was negative for proteins C and S, Factor V Leiden, antithrombin III, homocysteine, antiphospholipid antibody syndrome, and prothrombin gene mutation during this hospitalization.
A 16-year-old nonsmoking male with biopsy-confirmed Crohn’s disease, involving the terminal ileum and diagnosed at the age of 12, presented with lethargy, significant anemia, and severe headaches of several weeks duration. There was no seizure activity or focal neurologic deficit noted on presentation. Small bowel follow-through revealed a 10-cm area of terminal ileum with stricture, an inflammatory mass, and entero-enteric fistulas. Medical management of his CD included azathioprine, prednisone, and mesalamine.
On physical examination, he was afebrile with stable vital signs. Examination revealed right lower quadrant abdominal pain with normal neurologic findings. His white blood cell count was 10,000 cells/µL, hemoglobin measured 10.3 g/dL, and hematocrit 31.6% after transfusion. Lumbar puncture was not performed. MRI revealed superior sagittal sinus and bilateral transverse sinus thrombosis. He was anticoagulated with heparin initially and maintained on warfarin with marked improvement in his headaches over several days. MRI performed 1 month after initiating anticoagulation showed evidence of recannalization of the superior sagittal sinus. Hypercoaguable workup revealed positive anticardiolipin antibodies.
CVST is a recognized thrombotic complication of IBD. Although most cases have been reported in patients with UC, CVST is also seen in patients with Crohn’s disease. A majority of cases involve the dural sinuses. The most commonly reported site of dural sinus thrombosis is the sagittal sinus. In this review of 33 reported cases, the median age of onset of thrombosis is 28 years, with a male to female ratio of 1.6:1. The presenting symptom of CVST in both of our case reports was severe headache. This is consistent with a prospective study of 59 patients with CVST (of any cause) that also found headache to be the presenting complaint in 95% of cases.30 Other, less common, presentations included focal seizures with or without secondary generalization (47%), unilateral or bilateral paresis (43%) and papilledema (41%).30
CVST is diagnosed with an imaging study showing a filling defect. Currently, the preferred diagnostic modality is MRI.31 Cerebral angiography and computed tomography contrast venography have also been used. Lumbar puncture is often done in the work-up of headache to exclude infectious etiologies, though there are no specific cerebral spinal fluid abnormalities associated with CVST.
The etiology of thromboembolism including CVST in patients with IBD remains unclear. There are studies that implicate hypercoaguability in the pathogenesis of IBD, whereas others relate prothrombotic inherited states with IBD. Investigators have looked at IBD and hyperhomocysteinemia, Factor V Leiden, activated protein C, prothrombin mutations, anticardiolipin antibodies, antithrombin III deficiency, and protein S deficiency. Despite many studies in this field, the incidence and mechanism of inherited prothrombotic states in IBD remains incompletely understood and controversial. Furthermore, although we did so in our two cases, it is unclear if IBD patients with thromboembolic events including CVST should be screened for inherited prothrombotic states. Current guidelines suggest screening in any patient with thromboembolism who is less than 50 years old, has a family history of venothromboembolism among one or more first degree relatives, has unusual sites of spontaneous thrombosis (which include CVST), or has had a massive venous thrombosis. We suggest testing for prothrombotic states in IBD patients who present with CVST because a positive result (as discovered in 1 of our patients) would require prolonged anticoagulation and have implications for further testing in family members.
Presently, there are no accepted guidelines for management of patients with CVST. Recent studies suggest that anticoagulation, even in patients with evidence of hemorrhage, is associated with improved survival and resolution of symptoms.32,33 A single, randomized trial compared intravenous heparin with placebo in the treatment of venous sinus thrombosis of any cause, though it is not stated specifically if patients with IBD were included. The study was stopped after only 20 patients were enrolled due to deaths in the nonanticoagulated group. Eight of 10 patients in the heparin group recovered complete neurologic function, whereas only 1 patient in the placebo group did. There were no deaths in the heparin group and 3 in the placebo group.32 Another trial compared low-molecular weight heparin (LMWH) to placebo for 3 weeks in the treatment of CVST. There was no benefit seen in the LMWH group, though there was no increased risk of hemorrhage either.33 Meta-analysis of these trials shows that with heparin therapy there is a 70% relative risk reduction of death and a 56% reduction of death or dependency compared to placebo.34
Of the cases presented in this review, eight were successfully treated with anticoagulation, but it remains unclear how long to continue anticoagulation. For patients with deep venous thromboembolism or pulmonary embolism, the duration of anticoagulation depends on risk factors such as presence of a hypercoagulable state, cancer, age of the patient, and additional risks of clotting such as smoking.35 Patients with IBD and thrombosis have chronic risk factors due to their systemic disease and should remain on anticoagulation therapy for at least 12 months and perhaps indefinitely.
Although treatment with heparin is accepted, the use of thrombolytics for CVST remains controversial. A retrospective study comparing local urokinase therapy with systemic heparin in 40 patients with superior sagittal sinus thrombosis found no statistical difference in hemorrhagic complications and comparable neurologic outcomes.36 There is one case report of successful thrombolytic therapy in CVST and UC.27 Further study is needed before thrombolytic therapy can be recommended routinely.
We thank Nobuyo Zemsky for her help in translating the Japanese texts.