Contributed by Jansen N Seheult1, Mike Meyers2, Irina Chibisov1,2
1 Department of Pathology, University of Pittsburgh, Pittsburgh, PA
2 Institute for Transfusion Medicine, Pittsburgh, PA
A 22 year old obese female with a BMI of 34.3 kg/m2 and no significant past medical presented to the ED with left-sided facial droop. She was diagnosed by Bell's palsy and started on oral corticosteroid therapy. A routine laboratory workup, including Lyme disease testing was negative. Over the next two to three weeks, the patient developed left-sided ptosis, left lateral and upper gaze paralysis, progressive left-sided visual loss and partial right-sided visual obscuration. She also complained of pulsating "tinnitus" and bi-frontal morning headaches. She was referred by her primary care physician to the ED, where she underwent an extensive workup.
The differential diagnosis included a space-occupying lesion, infection including fungal disease, cerebral sinus thrombosis, paraneoplastic syndrome, CNS autoimmune disease and vasculitis.
The patient denied taking oral contraceptive pills, any other estrogen containing contraception or other medications and a careful history did not identify any provoking factors for thrombosis. She denied fevers, chills, sweats or other systemic symptoms. She denied recent travel. She had no prior pregnancies and was not sexually active. She has a family history of type II Diabetes Mellitus and a history of provoked DVT post-operatively in her maternal grandfather.
A magnetic resonance imaging (MRI) scan with contrast was performed, which was initially reported as unremarkable (see Figure 1).
Figure 1: Axial MRI with contrast showing sections at the levels of the lateral ventricles and the cerebellum/ optic nerves. On initial review, the images were reported as unremarkable. Further review demonstrated the presence of sagittal sinus hyper-intensity with a swirling effect and bulging of the optic nerves bilaterally.
A spinal tap demonstrated an elevated opening pressure of 31 cmH2O but was otherwise unremarkable:
Due to the evidence of intracranial hypertension on lumbar puncture, a second opinion was sought on the MRI performed earlier. Further review demonstrated the presence of sagittal sinus hyper-intensity with a swirling effect and bulging of the optic nerves bilaterally.
A computed tomography (CT) scan with contrast was ordered to evaluate the extent of thrombosis (see Figure 2).
Figure 2: CT with contrast showing extensive left subtotal dural venous sinus thrombosis, involving the superior sagittal sinus, straight sinus and transverse sinus (red arrows).
There was extensive left-sided subtotal dural venous sinus thrombosis, involving the superior sagittal sinus, straight sinus and transverse sinus; partial empty sella; and buckling of the optic nerves bilaterally, suggestive of intracranial hypertension.
The patient was also found to have a microcytic, hypochromic anemia on admission with a hemoglobin level of 6.3 g/dL and was transfused 2 units of packed red blood cells. Further treatment included anticoagulation with warfarin using a heparin bridge and intracranial thrombectomy due to the high clot burden. Four days later, bilateral optic nerve fenestration was performed for worsening of visual acuity and ventriculoperitoneal shunt was inserted for management of intracranial hypertension.
A coagulation work-up was conducted in parallel to investigate for the underlying cause of her cerebral sinus thrombosis. The results of the initial investigations are shown in Table 1. The hypercoagulable workup was negative for a lupus anticoagulant, anticardiolipin antibodies and beta-2 glycoprotein-I antibodies on two separate occasions in September and early October 2014. On initial testing, the patient was noted to have elevated factor VIII:C activity with the highest level of 5.54 U/mL, but repeat testing in the steady state demonstrated normal levels (1.47 U/mL). The low APTT was likely secondary to the elevated factor VIII:C as part of the acute phase response. Protein C activity was mildly decreased at 64%, but repeat testing while temporarily off warfarin demonstrated a normal Protein C activity (96%). The rest of the hypercoagulable workup was unremarkable. Flow cytometric tests performed for glycosylphosphatidylinositol (GPI)-linked antigens and fluorescent aerolysin (FLAER) on peripheral blood cells to rule out paroxysmal nocturnal hemoglobinuria (due to the combination of anemia and thrombosis) were negative.
Table 1: Results of initial laboratory workup for a hypercoagulable state was unremarkable apart from an elevated factor VIII:C activity level and a borderline low protein C activity level.
Due to the patient's age and extensive clot burden, further tests were performed to investigate for an underlying defect in fibrinolysis. Repeat testing showed a persistently elevated PAI-1 activity level with a corresponding elevation of the PAI-1 antigen concentration. The patient was also found to be homozygous for the PAI-1 4G/4G polymorphism. JAK2 testing was negative and repeat protein C activity levels were within the normal range.
Table 3: Testing of the fibrinolytic pathway demonstrated an elevated PAI-1 activity and antigen level with homozygosity for the PAI-1 4G/4G polymorphism.
a PAI-1 Activity level measured using Zymutest PAI-1 Activity ELISA- based assay.
b PAI-1 4G/5G genotype determined using allele-specific PCR described by Falk et al. (1).
c PAI-1 Antigen level measured using Zymutest PAI-1 Antigen ELISA- based assay.