Extensive Cerebral Venous Sinus Thrombosis Due to Medroxyprogesterone Acetate

ABSTRACT

This retrospective patient report describes a unique case of cerebral venous sinus thrombosis arising from hormonal contraceptive use, and the management of said thrombosis and its secondary ophthalmic manifestations. The patient initially presented with significant visual decline, headaches, florid disc oedema, and vessel tortuosity, due to extensive sinus thromboses that were causing increased intracranial pressure. It was determined that the root cause of the thrombosis was the use of injectable medroxyprogesterone acetate, leading to a hypercoagulable state. Optic nerve sheath fenestration was performed for this patient as an early intervention. The patient, though ultimately experiencing some vision loss, was able to recover and retain limited unilateral central vision, despite a protracted hospital course. We hope to propose that optic nerve sheath fenestration, in conjunction with anti-coagulation therapy, may be a consideration for patients with similar presentations on an individualised basis, in order to prevent vision loss from cerebral venous sinus thrombosis. Though studies are limited, we believe early intervention may be what allowed our patient to retain some central vision, and suggest more studies be done into the utility of this procedure for patients with this clinical vignette.

Introduction

Cerebral venous sinus thrombosis (CVST) is a rare, potentially life-threatening condition, which frequently manifests with elevated intracranial pressure (ICP) and visual decline. Misdiagnosis, often as idiopathic intracranial hypertension (IIH), may occur without comprehensive workup. Predisposing risk factors, including hormonal contraceptive use and concurrent risk factors for venous thrombosis, must be considered.^1,2 We describe a female patient who developed extensive CVST secondary to medroxyprogesterone acetate (Depo-Provera; Pfizer, New York City, USA) injections. This case describes the complexity of CVST management, highlighting surgical intervention with optic nerve sheath fenestration (ONSF) as an important treatment consideration.

Case report

A 28-year-old obese female presented with a four-day history of bilateral, decreased, “tunnel vision”, associated with headache, tinnitus, and pulsatile “whooshing” in both ears. Her history was significant for bipolar disorder, as well as medroxyprogesterone acetate injections every 3 months for contraception. The patient was using this form of contraception, for at least 1 year prior to presentation to our clinic. Her baseline visual acuity was 20/100 in the right eye (OD) and 20/200 in the left eye (OS). Her pupils were minimally reactive. Confrontation visual fields were severely diminished, with small central islands in both eyes (OU). Colour vision was significantly decreased OU. Dilated fundus examination (DFE) revealed florid 5+ disc oedema and profound vessel tortuosity OU. An orbital ultrasound revealed increased optic nerve sheath diameters, with the right and left nerves measuring 7.5 mm and 6.8 mm, respectively (upper limit of normal is 5 mm) (Figure 1). A non-contrast head computed tomography (CT) scan showed hyperdense, dilated superior sagittal, transverse, and straight sinuses consistent with extensive CVST, confirmed on subsequent head magnetic resonance imaging (MRI) and magnetic resonance venography (MRV) (Figure 2).

Figure 1.

Optic nerve ultrasound. (a) Right optic nerve measuring 7.5 mm. (b) Left optic nerve measuring 6.8 mm. Standard diameter measurement is up to 5 mm

Figure 2.

MRI and MRV. (a) Coronal MRI with arrow indicating site of central venous sinus thrombosis. (b) Axial MRI with arrow indicating site of central venous sinus thrombosis. (c) Coronal MRV showing areas of dampened contrast in the sinuses due to thrombosis. (d) Sagittal MRV revealing thrombosis of superior sagittal sinus

The patient was admitted to the neuro-intensive care unit (N-ICU) on a heparin drip and intravenous acetazolamide (Diamox; Teva Pharmaceuticals, North Wales, USA) 250 mg once daily. A higher Diamox dosage was considered, but there were concerns that dehydration may exacerbate the thrombosis. A lumbar puncture (LP) was deferred due to herniation risk in the setting of extensive CVST. Depo-Provera and her bipolar medication, lithium, were discontinued as possible contributors to high intracranial pressure.^2,3 Haematology/oncology was also consulted, and a full hypercoagulation panel was negative.

Due to the patient’s severe disc oedema, constricted visual fields (OD worse than OS), and likely highly elevated ICP, an ONSF OD was performed on the second day of admission. The ONSF was thought to impart less risk to the patient than increasing her Diamox dosage and/or performing an LP. Her visual acuity initially improved post-procedure, but subsequently declined to 20/200 OU on post-op day (POD) 1, and then to no light perception (NLP) OU on POD 2. IV solumedrol 1 mg/kg was infused daily for 3 days, with a small visual improvement. On POD 3, however, her vision OS declined again. Thus, ONSF in the left eye was performed, with subsequent visual improvement to 20/70 OD and 20/200 OS. Anti-coagulation therapy was continued the same day post-procedure.

The patient remained stable for approximately 3 weeks on anti-coagulation and 750 mg of Diamox daily, when her vision OS declined again. A lumbar drain was placed, recording an opening pressure of 30 mmHg. Her visual field constriction improved slightly over the week the drain was in place. Neurosurgery was ultimately consulted and a ventriculoperitoneal (VP) shunt was placed.

Within days of VP shunt placement, the visual acuity improved to 20/20 OD, although the vision in OS remained unchanged. However, the shunt clotted, presumably from holding anti-coagulation perioperatively. Unfortunately, re-initiation of anti-coagulation led to two episodes of intraventricular haemorrhage (IVH). Another lumbar drain confirmed persistently elevated ICP, indicating VP shunt failure. The failed VP shunt was removed and a lumboperitoneal shunt was placed. Sadly, the patient developed complications, including bilateral pulmonary emboli, sepsis, multi-organ failure, and suspected Stevens-Johnson syndrome. After a prolonged N-ICU hospital course, she was stabilised and discharged with the lumboperitoneal shunt in place. At 5 months after discharge, she was 20/20 OD (although with a severely constricted visual field), yet remained NLP OS. Fortunately, she has maintained her small central island of vision OD for over 2 years since hospital discharge.

Discussion

As this case highlights, CVST can lead to rapid vision loss. Treatment for most patients with CVST begins with treating the underlying cause, in addition to anti-coagulation, unless contraindicated. The aetiology of our patient’s CVST was suspected to be medroxyprogesterone acetate. Oral contraceptives (OCPs) are well documented as a risk factor for developing venous sinus thrombosis.^1,2 Women of reproductive age that used OCPs were 7.9 times more likely to develop CVST than those who did not use OCPs.¹ A systematic review examined 857 studies to determine if the thrombotic risk translated from OCPs to other forms of hormonal contraception, yet found the odds of developing CVST from other hormonal contraceptives to be “largely unknown”.¹ A study by van Hylckama found injectable depot-medroxyprogesterone acetate contraception was associated with a 3.6-fold (95% CI, 1.8 to 7.1 fold) increased risk of deep venous thromboses of the extremities, compared with non-users.²

Hitosugi et al. reported a case of dural sinus thrombosis occurring in a patient using medroxyprogesterone acetate for about 4 months.⁴ She had developed marked superior sagittal sinus thromboses, which was posthumously determined to be caused by medroxyprogesterone acetate, due to lack of trauma or inciting factors. However, this patient had a history of hypercoagulable state due to metastatic lung disease. Two other cases demonstrated the development of CVST in two young women taking norethindrone acetate for abnormal uterine bleeding.^5,6 Norethindrone acetate has a similar mechanism of action as medroxyprogesterone acetate as both are progestin-based hormonal treatments. These patients developed thromboses in shorter periods after taking norethindrone acetate (7 and 50 days, respectively) and their medication regiment was a daily oral pill as opposed to a tri-monthly injection. Additionally, these two cases highlight patients that were utilising progestin-based treatment for abnormal uterine bleeding, as opposed to our patient who was using the injections specifically for birth control. This is important, as a study by Vasilakas had determined there was “no effect with progestagens alone used for contraception, whereas there was a substantial association with the higher dose progestagens used for other reasons”.⁷ Overall, these aforementioned cases had hypercoagulable states reported, such as malignancy, polycystic ovarian syndrome or hyperhomocysteinaemia, highlighting a difference with our patient, who did not have a pre-existing medical condition that would have led to a hypercoagulable state, nor was she using the injections for abnormal uterine bleeding.

Our case is significant as it links medroxyprogesterone acetate specifically to extensive CVST. Given our patient’s extent of CVST, it also raises the possibility whether this form of hormonal depot may lead to more extensive thrombosis, and subsequently higher rates of morbidity and mortality.

This case, in particular, demonstrates the complexities in managing CVST, and the unpredictable nature of its complications. In cases of CVST with primarily visual involvement or severe vision loss at presentation, we suggest considering ONSF as a first-line therapy, in conjunction with anti-coagulation, for the management of visual decline in CVST. Although the small, but significant risk of severe vision loss caused by the ONSF procedure must be weighed, ONSF has been well documented as an effective measure to treat visual symptoms associated with increased ICP.^8,9 It also poses less life-threatening complications to the patient and does not require prolonged discontinuation of anti-coagulation, as opposed to other higher risk methods of lowering ICP (i.e., lumbar drain placement or shunting). We believe early ONSF in our patient largely contributed to the recovery and maintenance of central vision OD, despite her complicated and prolonged hospital course.