Successful management of an extensive intracranial sinus thrombosis in a patient undergoing IVF: case report and review of literature

CASE REPORT Successful management of an extensive intracranial sinus thrombosis in a patient undergoing IVF: case report and review of literature Fawaz Edris, M.D., F.R.C.S.C.,a Cecelia M. Kerner, M.D.,a Valter Feyles, Ph.D., F.R.C.S.C.,a Andrew Leung, M.D., F.R.C.S.C.,b and Stephen Power, M.D., F.R.C.S.C.a a

Department of Obstetrics and Gynecology, and b Department of Diagnostic Radiology and Nuclear Medicine, University of Western Ontario, London, Ontario, Canada

Objective: To report a successfully managed case of extensive intracranial sinus thrombosis that occurred during an IVF cycle, and to review the literature. Design: Case report and review of literature. Setting: University-affiliated teaching hospital. Patient(s): A 38-year-old nulliparous woman who developed severe ovarian hyperstimulation syndrome on luteal day (LD) 5 during an IVF cycle. Hemoconcentration was corrected, ascitis drained, and heparin prophylaxis started. On LD7, the patient complained of severe headache and neck pain. A magnetic resonance imaging (MRI) study of the head showed extensive cortical vein and dural sinus thrombosis, including the superior sagittal sinus and transverse sinuses. Intervention(s): The patient was fully heparinized using low-molecular-weight heparin. On LD15 she was discharged home on warfarin, after confirming a negative pregnancy test. Complete thrombophilia work-up was negative. Main Outcome Measure(s): Clinical outcome. Result(s): Repeat MRI 2 months later revealed patent superior sagittal sinus and transverse sinuses, unremarkable cortical veins, and no evidence of flow obstruction. The patient was asymptomatic, with no neurologic sequelae. Conclusion(s): Extensive intracranial sinus thrombosis in women undergoing IVF may present with minimal symptoms and can occur in the absence of pregnancy and thrombophilia and despite heparin prophylaxis and correction of hemoconcentration. Medical management was successful and left the patient with no neurologic sequelae. (Fertil Steril 2007;88:705.e9–14. 2007 by American Society for Reproductive Medicine.) Key Words: Intracranial sinus, IVF, OHSS, ovulation induction, thromboembolism

Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of ovulation induction. Arteriovenous thrombosis is a potential sequela to this syndrome. Although a majority of cases occur with severe OHSS, others have been described with moderate, mild, and absent OHSS (1–5). Fortunately, the incidence of this potentially lethal complication is estimated to be only 0.015%–0.04% (1, 6).

Herein, we describe a third case of intracranial sinus thrombosis. This case is unique in that extensive thrombosis involving multiple sinuses occurred in the absence of pregnancy and thrombophilia and despite heparin prophylaxis and correction of hemoconcentration.

Overall, 98 cases of thromboembolism complicating ovulation induction have been reported. The majority were associated with OHSS and pregnancy and usually involved the upper limbs, head, and neck areas (7–10). Only two cases were described in which an intracranial sinus was involved (10, 11).

CASE REPORT A 38-year-old Nigerian woman presented with 4 years of primary infertility attributed to tubal obstruction. Assisted reproductive treatment was planned with in vitro fertilization (IVF) technology. She was known to have multiple uterine fibroids, the largest measuring 10 cm in its maximum diameter. In an effort to shrink the fibroids before therapy, to facilitate folliculogenesis monitoring, the patient was treated with monthly 3.75 mg IM injections of a slow-release GnRH agonist (leuprolide acetate; Lupron Depot; Abbott, Lake Forest, IL) for 4 months. Surgical management was considered technically difficult and unlikely to improve her fertility.

Received July 12, 2006; revised and accepted December 13, 2006. Reprint requests: Dr. Fawaz Edris, Reproductive Endocrinology & Infertility (REI) Program, LHSC University Hospital, 339 Windermere Road, London, Ontario, N6A 5A5, Canada (FAX: 519-663-3162; E-mail: [email protected]).

0015-0282/07/$32.00 doi:10.1016/j.fertnstert.2006.12.024

Fertility and Sterility Vol. 88, No. 3, September 2007 Copyright ª2007 American Society for Reproductive Medicine, Published by Elsevier Inc.

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A month after the fourth dose of leuprolide acetate, serum E2 indicated adequate suppression. A baseline ultrasound revealed normal ovaries, although the left ovary was displaced above the pelvic brim by the fibroids, rendering it inaccessible vaginally. Based on age and body mass index (26.5 kg/m2), she was started on an empirical dose of 225 IU SC recombinant (r) FSH (Gonal-F; Serono, Bari, Italy). On stimulation day 4, E2 level was147 pmol/L and Gonal-F was increased to 375 IU. On stimulation day 14, the right ovary contained 10 follicles (%1.3 cm  1, 1.4–1.6 cm  1, 1.7–1.8 cm  2, 1.9– 2.0 cm  5, 2.1–2.2 cm  1) and the left had 6 (1.7–1.8 cm  1, 1.9–2.0 cm  3, R2.3 cm  2). Serum E2 was 3,346.5 pmol/L and 250 mg rhCG (Ovidrel; Serono, Bari, Italy) was administered that night. After 34 hours, 6 oocytes were retrieved from the right ovary, of which 4 fertilized. Because of the large fibroids and the risk of preterm birth, only 1 embryo (9-cells, grade C) was transfered on luteal day (LD) 3 (LD3). On LD4, she presented with mild to moderate abdominal pain, nausea, and vomiting. Urine color and volume were normal and she denied shortness of breath. Ultrasound revealed moderate ascites with a fluid pocket measuring 7 and 2.8 cm at her right and left paracolic gutters, respectively. The right and left ovaries measured 8 cm  9 cm and 8 cm  6 cm, respectively. Laboratory workup revealed: hemoglobin (Hgb) 15.4 g/dL, hematocrit (Hct) 0.47, white blood cells (WBC) 11.5  103/mL, platelets (Plt) 257,000/mL, urea 3.3 mmol/L, creatinine (Cr) 106 mmol/L, mildly elevated liver enzymes, and normal electrolytes and coagulation profile. The patient received IV fluid treatment with normal saline (NS) and analgesia. Her condition improved and she was discharged home. On LD5, she came back feeling unwell, complaining of worsening abdominal pain, severe nausea, and vomiting. Ultrasound revealed gross ascites. The right and left ovaries measured 11 cm  8 cm and 9 cm  7 cm, respectively. Laboratory workup revealed hemoconcentration: Hgb 17.1 g/dL, Hct 0.51, WBC 16.9  103/mL, Plt 267,000/mL, Cr 118 mmol/L, and potassium 6.2 mmol/L. Assessment on admission indicated severe dehydration (tachycardia, hypotension, and undetected JVP) and depleted intravascular volume. The patient therefore was aggressively resuscitated with 2 L NS. An intra-abdominal indwelling catheter was placed under ultrasound guidance for continuous paracentesis. The patient was put on an initial maintained flow rate of 250 cc/h NS to compensate for fluid loss, including drained ascites and urine output. Over 6 days, 10.5 L of fluid were drained. Thromboembolism prophylaxis was initiated using 5,000 IU unfractionated heparin administered SC twice daily (bid). Blood work on LD6 confirmed correction of her hemoconcentration; however, she continued to have severe nausea and vomiting despite 50 mg IV dimenhydrinate (Gravol) every 4 hours. Ranitidine (150 mg, IV, every 8 hours) and ondansetron (4 mg, IV, bid) were given as required. 705.e10

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On LD7, she complained of severe headache, lethargy, and neck pain, and was found slightly confused. A neurologic consultation was obtained immediately and magnetic resonance imaging (MRI) of the head, including MR venography (MRV), was performed. The MRV demonstrated loss of flow in the superior sagital sinus, transverse sinus, and multiple cortical veins compatible with venous thrombosis (Fig. 1). There were multiple small scattered foci of T2 high signal, predominantly in the periventricular white matter, compatible with parenchymal edema due to venous hypertension. She was transfered to the neuro-observational unit for 2 days. In collaboration with the hematology team, the patient was fully heparinized using 8,000 IU low-molecular-weight heparin (LMWH; Fragmin; Pfizer, Kirkland, Quebec, Canada) SC bid, later switched to 16,000 IU once daily. On LD9 her lethargy and confusion improved, but she continued to have head and neck pain. On LD10, her neck pain improved and she became more mobile. The following day, her headache began to resolve. The pregnancy test was negative on admission and on LD12. She was started on warfarin sodium, and, after an overlap with therapeutic doses of LMWH, the latter was discontinued when the international normalized ratio was 2.2. The patient was discharged home on LD15 on 2.5 mg of warfarin sodium and oral ketorolac tromethamine (Toradol, Hoffman-Laroche, Mississauga, ON, Canada), for analgesia. Thrombophilia workup, including protein C, protein S, and antithrombin III deficiencies as well as antiphospholipid antibody syndrome (IgG and IgM anticardiolipin antibodies and lupus anticoagulant), factor V Leiden (resistance to activated factor V), prothrombin gene mutation (G20210A), and homocysteinemia, was negative. The patient went home with residual mild headache that subsequently resolved. Followup assessments were arranged with the hematology, neurology, and infertility services. The follow-up MRI 2 months after her presentation revealed dramatic improvement (Fig 2). The MRV revealed normal flow in the dural sinuses and cortical veins, and most of the white matter changes resolved. A few areas of white matter signal abnormality remained, compatible with ischemic change. The patient was asymptomatic, clinically intact, with no neurologic sequelae. Warfarin was discontinued 4.5 months later. The patient’s written consent and Institutional Review Board approval for publication were obtained. DISCUSSION We present a case of extensive intracranial thrombosis in a patient after controlled ovarian stimulation in an IVF protocol. This severe manifestation of OHSS occurred in the absence of pregnancy and thrombophilia and despite heparin prophylaxis and hemoconcentration correction. The two previously described cases of intracranial sinus thrombosis occurred in the context of a documented

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FIGURE 1 Cerebral venous thrombosis and parenchymal edema on luteal day 7. Sagittal maximum intensity projection image from time-of-flight magnetic resonance venography (A) and axial T2 image at the level of the lateral ventricles (B). (A) There is absence of signal in the superior sagittal sinus (large arrows), the straight sinus (small arrow), transverse sinuses bilaterally (arrowhead), which corresponds with venous thrombosis. (B) There are several small foci of periventricular high signal (black arrowheads) compatible with edema from venous hypertension.

Edris. Intracranial sinus thrombosis during IVF Fertil Steril 2007.

pregnancy (10, 11). Thrombophilia workup was either not done or did not include all currently known investigations. Presenting symptoms were severe neurologic manifestations, such as seizures, hemiparesis, and hemiplegia. In comparison, our case showed that pregnancy and/or thrombophilia are not prerequisites for the development of extensive intracranial sinus thrombosis. Presenting symptoms can be limited to headache and neck pain. In addition, the development of such thrombosis may occur with the use of either recombinant or urinary gonadotropins and in the present case occurred despite heparin prophylaxis and hemoconcentration correction. The present case demonstrates the success of LMWH and warfarin in treating extensive intracranial thrombosis, preventing its progression, deterioration of patient’s condition, and the need for surgical intervention (Table 1) (12). Ou et al. (10) compared the characteristics of 65 women who developed thromboembolism while undergoing ovulation induction. Among them, 18 had intracranial thromboembolism. The mean onset for clot formation in the latter group was 10.2 days after oocyte retrieval, which is much earlier than those of other sites (24.8, 30.2, and 39.8 days for lower extremity, upper extremity, and neck, respectively). The majority of intracranial clots (61%) were associated with severe OHSS. The present case followed these patterns of presentaFertility and Sterility

tion. Ou et al. (10) also found that only 47% of the intracranial group had full neurologic recovery, as opposed to 91% in those that had clots elsewhere. Although the exact intracranial location and type of clot (arterial or venous) in those who did not have full neurologic recovery are diverse, the two cases in which intracranial sinuses were involved had residual neurologic findings (10, 11). Our patient was fortunate to have no neurologic sequelae. In Ou et al.’s review (10), two women died, both suffering intracranial thrombosis. Our patient had different intracranial involvement than those who died; however, cerebral venous thrombosis generally has a mortality rate of 5%–30%, and that appeared to be more lethal when cerebral sinuses were involved (13). Patients usually present with sudden-onset headache that can be associated with vomiting, seizure, papillioedema, or altered level of consciousness (13). To minimize potential fatality, it is critical to have low threshold for investigating patients at risk, even if they present with a symptom as simple as sudden-onset headache. Computerized tomography (CT) and MRI are the primary imaging modalities used in the diagnosis of cerebral venous thrombosis (CVT). The classic finding on unenhanced CT is a hyperdense dural sinus or cortical vein. However, this finding is present in only 25% of cases (14). With an enhanced CT, 705.e11

FIGURE 2 Resolution of venous thrombosis and parenchymal edema after 2 months of anticoagulation therapy. (A) Magnetic resonance venography demonstrates complete recanalization of the dural sinuses and cortical veins. These vessels have normal caliber and smooth margins. (B) The axial T2 image shows resolution of the white matter changes seen previously.

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contrast in a dural sinus can surround an intraluminal thrombus, creating the empty delta sign which is described in 29% of patients with sinus thrombosis (14). Unenhanced MRI has greater sensitivity than unenhanced CT in the detection of CVT (15). In addition, MRI better demonstrates associated abnormalities in the brain parenchyma, such as edema and early hemorrhage. Magnetic resonance venography demonstrates flow in the venous structures and depicts CVT as filling defects. However, MRV specificity is limited by poor spatial resolution and can be affected by numerous artifacts. Highly detailed evaluation of the venous structures can be achieved with CT venography, which is the acquisition of thin section images during the venous phase of contrast transit through the cerebral vascular system. The major drawback of CT venography is the relatively high radiation dose, which perhaps should limit its use to cases in which MRI and MRVare inconclusive, contraindicated, or unavailable (15). In the present case, because of the high clinical suspicion for CVT, an MRI with MRV was performed. The pathogenesis of thromboembolism in patients undergoing ovulation induction is not fully understood. Immobilization and mechanical obstruction (16), severe OHSS (17), hemoconcentration (17), hyperestrogenism (18), altered coagulation factors (19–22), and changes in plasma renin activity (23) have all been claimed as the underlying factor for clot formation in women undergoing ovulation induction. Others 705.e12

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have refuted these theories (1–5, 7–10, 24–26). At present, the literature has failed to identify a specific thrombogenic factor that can explain the occurrence of thromboembolic events in patients undergoing ovulation induction. Because clots in unusual anatomic locations are characteristic of venous thrombosis in patients with underlying thrombophilia (27), screening patients undergoing IVF for inherited and acquired thrombophilia conditions has been recommended. Studies looking at the prevalence of thrombophilia in this population reached different conclusions. One found the prevalence to be significantly higher in patients with severe OHSS (17/20 ¼ 85%) compared with control subjects (11/41 ¼ 27%) (28), whereas another found the prevalence to be low and not statistically significant between all groups (severe OHSS 0/20, non-severe OHSS 1/40 ¼ 2.5%, control 2/100 ¼ 2%) (29). The difference between the two studies could simply be due to the different patient populations tested. Several factors however, may have led to the results of the former study: The authors reported high prevalence of thrombophilia in their control arm, which suggests a selection bias, and they tested for thrombophilia conditions during the acute stage of severe OHSS. A recent study showed that patients developing severe OHSS have higher E2 level and that transient hormone-mediated changes in functional coagulation assays can occur (30). Our IVF patient had a negative thrombophilia screen, thus providing an

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TABLE 1 Comparison of three cases of intracranial sinus thrombosis associated with ovarian stimulation protocols. Reference Treatment Site of thrombosis

Presentation Onseta OHSSb Folliculogenesis Follicular maturation Thrombophilia workup Prophylactic heparin Pregnancy Management

Outcomej

Waterstone (11) Ovulation induction Right transverse sinus, internal cerebral vein, vein of Galen Headache, hemiparesis, focal seizure 12 Severe hMGc hCGc

Ou (10) IVF

Edris (this report) IVF

Superior sagittal sinus

Seizures, hemiplegia

Cortical vein, superior, transverse, and sigmoidal sinuses Severe headache and neck pain

20 Moderate Purified FSHd hCGe

8 Severe Purified FSH rhCGf

Not done

Partially negativeg

All negative

No

No

Yesh

Biochemical Unfractionated heparin and warfarin

Clinical Medical thrombolysis, operative thrombectomy, and heparini Alive, weakness of extremities, seizures

None LMWH and warfarin

Alive, impaired handwriting

Alive, no neurologic sequelae

Note: FSH ¼ follicular stimulating hormone; hCG ¼ human chorionic gonadotropin; hMG ¼ human menopausal gonadotropin; IVF ¼ in vitro fertilization; LMWH ¼ low-molecular-weight heparin; OHSS ¼ ovarian hyperstimulation syndrome. a Days after ovulation induction. b Using the Golan criteria (12). c Manufacturer not specified. d Gonal-F; Serono, Aubonne, Switzerland. e Pregnyl; Organon, Oss, Holland. f Ovidrel; Serono, Bari, Italy. g Tested only for antiphospholipid antibody syndrome, protein C, protein S, and antithrombin III deficiencies. h Unfractionated heparin, 5,000 IU SC bid. i Medical thrombolysis: 480,000 IU urokinase; operative thrombectomy: microballoon maceration of the clot; heparin: not specified. j Follow-up: Waterstone 28 months, Ou until delivery. Edris. Intracranial sinus thrombosis during IVF. Fertil Steril 2007.

additional case to support the excellent work done by Fabregues et al. (29), in which they concluded that thrombophilia screening is not cost-effective in the IVF general population. On the other hand Mara et al. (8) suggested screening IVF patients at risk of thrombosis, such as those with severe OHSS. They found the prevalence of thrombophilia in this group to be 4.1% (2/49); however the prevalence in a control group was not assessed. Fertility and Sterility

The present patient had already been screened for sickle cell disease and found to be only a carrier. Therefore, her sickle cell status was unlikely to be a factor contributing to her clinical presentation. At least two cases have been reported in which thrombosis occurred during IVF treatment despite the use of a prophylactic dose of heparin. In the first case, testing for thrombophilia was not performed (31). In the other, the patient tested positive for resistance to activated 705.e13

protein C (32). Our patient developed extensive thrombosis despite a prophylactic dose of heparin and a negative screen for all known thrombophilia conditions. We felt that the dose of heparin was adequate given her body mass index; however one cannot rule out the possibility of an ‘‘asymptomatic’’ clot being formed well before hemoconcentration was corrected or prophylactic heparin initiated. A better understanding of the pathogenesis of this condition will hopefully provide a rationale for its prevention. Acknowledgments: The authors are grateful for the assistance of Brenda McFalls, R. N.

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