Case Report: Papilledema Secondary to Cerebral Venous Sinus Thrombosis after Severe COVID-19 Infection

SIGNIFICANCE

This case highlights ocular adverse effects of a rare, potentially life-threatening complication from coronavirus disease 2019 (COVID-19). Papilledema can occur because of increased intracranial pressure caused by cerebral venous sinus thrombosis, the incidence of which may be more likely in patients with a history of COVID-19 because of an induced hypercoagulable state.

PURPOSE

This case report presents a case of papilledema secondary to cerebral venous sinus thrombosis in a patient with a recent history of severe coronavirus disease (COVID-19).

CASE REPORT

A 29-year-old man hospitalized with a complicated course of coronavirus disease (COVID-19) was referred to the ophthalmology department for episodic blurry vision of both eyes and intermittent binocular diplopia. Clinical examination revealed diffuse bilateral optic disc edema. Magnetic resonance venography of the brain during his admission revealed subtotal occlusion of the right transverse sinus by thrombosis. At the time of diagnosis, the patient was already taking systemic anticoagulation therapy for treatment of a recent pulmonary embolism also thought to be induced by COVID-19. After additional treatment with acetazolamide, there was improvement in his optic nerve edema.

CONCLUSIONS

Cerebral venous sinus thrombosis, a serious and potentially life-threatening condition, can occur as a rare complication of COVID-19. In such cases, patients may develop increased intracranial pressure, papilledema, and subsequent vision loss. Magnetic resonance venography should be ordered in patients with suspected papilledema to help rule out the presence of cerebral venous sinus thrombosis.

As the coronavirus pandemic continues, more is being learned about possible adverse effects resulting from infection with this virus. Anterior segment findings such as conjunctivitis and ocular surface disease, along with posterior segment findings such as artery and vein occlusions, have all been described in patients with coronavirus disease 2019 (COVID-19).¹ From a neuro-ophthalmic perspective, potential associations have been found with optic neuritis, ischemic optic neuropathy, and multiple cranial neuropathies.¹ Papilledema may also be added to the ongoing list of potential ocular adverse effects of COVID-19.

Cerebral venous sinus thrombosis is a less frequently encountered cause of increased intracranial pressure leading to papilledema. Clinicians should be particularly aware of the increased incidence of cerebral venous sinus thrombosis in patients with a history of severe coronavirus disease and should consider asking patients presenting with bilateral optic disc edema if they have a history of COVID-19 infection. Including proper testing, such as magnetic resonance venography, in the workup of patients with bilateral optic disc edema is critical to diagnosing this potentially life-threatening condition.

CASE REPORT

A 29-year-old man was referred to the ophthalmology department during a complicated inpatient hospital stay for a severe case of COVID-19–related pneumonia. The patient originally presented to the emergency department with signs of severe respiratory distress. He was intubated and transferred to the intensive care unit on day 1. He was extubated on day 8 of his hospitalization, which is when he began experiencing episodes of blurry vision of both eyes and intermittent horizontal diplopia (Fig. 1). The course of the patient's condition was complicated over the next several weeks as he developed a pulmonary embolism, deep vein thrombosis, fungal empyema, and a small subarachnoid hemorrhage, the latter of which quickly resolved. On day 53, an ophthalmology consult was requested and performed.

FIGURE 1.

Clinical timeline: a 29-year-old man diagnosed with and treated for papilledema secondary to cerebral venous sinus thrombosis. CVST = cerebral venous sinus thrombosis; DVT = deep vein thrombosis; HVF = Humphrey visual field; ICP = intracranial pressure; MRV = magnetic resonance venography; OCT = optical coherence tomography; PE = pulmonary embolism; SAH = subarachnoid hemorrhage.

Before being hospitalized with coronavirus disease, the patient's medical history was remarkable only for obesity (body mass index of 37.1 kg/m²) and asthma. He had no history of other underlying medical conditions and did not take any medications regularly. His personal and family ocular history was unremarkable.

At the initial ophthalmologic examination, the patient's uncorrected Snellen distance visual acuity was 20/25 in the right eye and 20/30 in the left eye. Pupils were equal, round, and reactive to light without an afferent pupillary defect of either eye. Extraocular muscle movements were full in each eye without diplopia. Confrontation visual field testing was full to finger counting in each eye. The patient was found to have red-green color vision defects using Ishihara pseudoisochromatic plates (GF Health Products Inc., Atlanta, GA; 3/11 plates correct in the right eye, 1/11 plates correct in the left eye). Anterior segment evaluation of both eyes was unremarkable. Intraocular pressure of both eyes was measured to be 6 mmHg each using iCare (iCare Finland Oy, Vantaa, Finland) tonometry. Ophthalmoscopic examination of the posterior segment revealed marked optic disc edema of the right and left eyes. No significant optic disc hyperemia, pallor, or hemorrhages were noted. The maculae of both eyes were flat and dry without hemorrhages. At this time, the patient was in poor physical condition because of the severity of his illness, and it was unreasonable to have him ambulate to the eye clinic. Therefore, the initial ophthalmologic examination was done at bedside, and fundus photography and optical coherence tomography were not available. On the day of his ophthalmologic examination, the patient's blood pressure was measured to be 137/87 mmHg.

Although many differential diagnoses were considered in this case of bilateral optic disc edema, increased intracranial pressure was the initial leading working differential. Other differential diagnoses considered at this time were hypertensive optic neuropathy and optic neuritis. Nonarteritic anterior ischemic optic neuropathy caused by sleep apnea could also be considered in an obese man, although it was unlikely in this case given the other systemic factors. Hypertensive optic neuropathy was not likely because the patient's documented blood pressure during his inpatient stay did not exceed 166 mmHg systolic and 98 mmHg diastolic. Urgent MRI of the head with and without intravenous contrast was ordered along with magnetic resonance venography without contrast.

Magnetic resonance imaging showed no acute intracranial bleeding or intracranial mass. Magnetic resonance venography without contrast revealed subtotal occlusion of the right transverse sinus by thrombosis (Fig. 2).

FIGURE 2.

Magnetic resonance venography without contrast. (A) Axial view highlighting occluded right transverse sinus “(red circle). (B) Coronal view also highlighting the lack of venous flow through the right transverse sinus.

A blood workup was then ordered that included the following: cardiolipin antibodies (immunoglobulin G [IgG], IgM, IgA), antithrombin III, partial thromboplastin time, prothrombin, protein C, protein S, homocysteine, factor V Leiden, and factor VIII assay. Results of the workup were normal and ruled out underlying hereditary or acquired hypercoagulable state that would make the patient more likely to develop thromboembolic events. Of note, other blood tests done at this time revealed elevated d-dimer, the importance of which will be discussed later in this report.

The patient, who had intermittently been on and off anticoagulation therapy throughout his hospital stay (initially started after the development of pulmonary embolism, then discontinued after small subarachnoid hemorrhage developed and later restarted after resolution of the subarachnoid hemorrhage), was currently taking enoxaparin (Lovenox; Sanofi, Bridgwater, NJ). This therapy was transitioned to apixaban (Eliquis; Bristol-Myers Squibb, New York, NY) at the direction of the neurologist after discovery of the cerebral venous sinus thrombosis.

With the finding of cerebral venous sinus thrombosis, a radiological marker of increased intracranial pressure, elevated intracranial pressure was reasonably suspected, and the diagnosis of papilledema secondary to cerebral venous sinus thrombosis was made. Lumbar puncture was deferred at this time, given the patient's anticoagulation status, which carried an increased risk of bleeding complications during the procedure. The recommendation was made for the patient to start 500 mg oral acetazolamide twice daily for the first week, followed by 1 g oral acetazolamide twice daily thereafter.

Follow-up ophthalmic examination occurred 2 weeks later. The patient had been discharged from the hospital and was examined as an outpatient in the eye clinic. Uncorrected Snellen distance visual acuity was stable at 20/25 in the right eye and 20/30 in the left eye. Optical coherence tomography of the optic nerve was performed (Figs. 3A, B), confirming significant bilateral optic nerve head edema. Automated segmentation of the retinal nerve fiber layer by the optical coherence tomography software failed and can be challenging in cases of florid optic nerve edema.² However, it is clear on the B-scan infrared image that the nerve fiber layer is markedly thickened. Humphrey visual field (Carl Zeiss AG, Oberkochen, Germany) 24-2 testing at this visit showed an enlarged blind spot in each eye with a central/paracentral defect of the left eye (Fig. 4).

FIGURE 3.

Optical coherence tomography of the optic nerve head. (A) At the initial presentation in the right eye. Note the segmentation error of the B-scan (red arrow), which leads to a significant underestimation of the true retinal nerve fiber layer thickness. (B) At the initial presentation in the left eye. A less significant segmentation error is present (red arrow). (C) Six months after initial presentation, the right eye shows significant improvement in optic nerve edema. Also, note the more appropriate nerve fiber layer segmentation. (D) Six months after initial presentation, the left eye also shows significant improvement in optic nerve head edema.

FIGURE 4.

Humphrey visual field testing at initial presentation. (A) The left eye shows an enlarged blind spot and a central/paracentral defect. (B) The right eye shows an enlarged blind spot.

The patient was followed numerous times by neuro-ophthalmology and neurology over the next several months. At 6 months after the initial ophthalmologic examination, the patient's optic nerve head edema showed marked improvement bilaterally on optical coherence tomography testing (Figs. 3C, D). Although the improvement in the right eye is difficult to quantify because of segmentation errors at baseline, the retinal nerve fiber layer global thickness of the left eye decreased from 260 μm at baseline examination to 90 μm at 6 months. Visual field testing at this time showed essentially stable enlarged blind spot in both eyes along with a persistent central/paracentral defect of the left eye (Fig. 5). Anticoagulation was discontinued at the direction of neurology (after 6 months of treatment). Despite improvement in optic disc edema, the patient's color vision defects continued to fluctuate. At this time, the patient was now off anticoagulants, and it was deemed safe for the patient to undergo a lumbar puncture, which showed persistently elevated cerebrospinal fluid pressure with an opening pressure of 34 cm of water. Magnetic resonance venography was then repeated and showed a stable venous sinus thrombosis. The patient had also developed nephrolithiasis, making long-term use of acetazolamide challenging (particularly at the dose required to achieve the desired therapeutic effect) necessitating other options to be considered for treatment. The patient was then referred to the neuro-ophthalmology department at a well-known academic medical center to evaluate his candidacy for cerebral venous sinus stenting. Subsequent neuroimaging at this institution, including magnetic resonance venography, showed no significant change. Repeat lumbar puncture revealed persistently elevated opening cerebrospinal fluid pressures. The patient was determined to be a good candidate for a venous stent and is awaiting the procedure.

FIGURE 5.

Humphrey visual field testing at 6-month follow-up. (A) The left eye shows a stable enlarged blind spot and persistent central/paracentral defect. (B) The right eye shows persistent enlarged blind spot.

DISCUSSION

Cerebral venous sinus thrombosis is a rare form of thromboembolic stroke that affects the cerebral venous system. Sinus thrombosis is thought to cause occlusion of a venous sinus, backflow of blood, and eventually cerebral edema that causes neurological defects and potentially death.³ Clinical presentation of cerebral venous sinus thrombosis is often variable, and ocular effects are sometimes the earliest signs. The most common presentation of venous sinus thrombosis includes signs of increased intracranial pressure such as headache and papilledema.⁴ Risk factors for the development of cerebral venous sinus thrombosis include conditions or events that lead to either vessel wall injury, blood stasis, or hypercoagulability.⁴ These conditions include mechanical trauma, hereditary thrombophilia (such as factor V Leiden or antiphospholipid syndrome), or acquired hypercoagulability (from pregnancy, oral contraceptive pill use, or infection).⁴ As previously mentioned, the patient in this case report underwent hematologic testing to rule out underlying hereditary or acquired hypercoagulable condition. These tests included cardiolipin antibodies (IgG, IgM, IgA), antithrombin III, partial thromboplastin time, prothrombin, protein C, protein S, homocysteine, factor V Leiden, and factor VIII assay (Table 1).

TABLE 1.

A summary of hematologic testing done to rule out underlying hypercoagulability (all results)

Test	Normal value	Result
Cardiolipin antibodies  (IgA, IgG, IgM) (U/mL)	<20	<2 (not detected)
Antithrombin III assay (%)	80–135 (of normal)	130
Partial thromboplastin  time (s)	25.1–36.5	31.4
Prothrombin time (s)	10.7–12.9	14.8
Protein C (%)	70–180 (of normal)	139
Protein S (s)	70–150 (of normal)	153
Homocysteine (μmol/L)	<11.4	8.2
Factor V Leiden mutation	Variant not detected	Variant not detected
Factor VIII assay (%)	50–180 (of normal)	84
d-Dimer assay (ng/dL)	0–230	5031

IgA = immunoglobulin A; IgG = immunoglobulin G; IgM = immunoglobulin M; ng/dL = nanograms/deciliter; U/ml = units per milliliter;μmol/L = micromole/liter.

It has been suggested that patients infected with severe acute respiratory syndrome coronavirus 2—the virus responsible for COVID-19—may have a predisposition to developing venous and arterial thromboembolic diseases.⁵ This is particularly true because it relates to patients with severe cases of COVID-19 and their propensity for developing venous thromboembolic events such as pulmonary embolism, deep vein thrombosis, myocardial infarction, and stroke (as was the case for our patient who developed a pulmonary embolism and deep vein thrombosis in addition to cerebral venous sinus thrombosis).⁶ In patients with severe COVID-19, d-dimer testing may be indicated because elevated d-dimer levels have been associated with a higher risk of thromboembolic events.⁶ As shown in Table 1, our patient had significantly elevated d-dimer at initial evaluation. Several cases of COVID-19–induced cerebral venous sinus thrombosis have also been reported in the literature.⁷ Cases of cerebral venous sinus thrombosis from COVID-19 infection, although rare, are associated with a high mortality rate (20% in one study).⁸ Several mechanisms for the development of these ischemic events have been proposed and include systemic inflammation, hypercoagulable state, and alterations in the normal coagulation cascade due to vascular endothelial injury.⁷

The term papilledema is reserved for optic disc edema caused specifically by increased intracranial pressure. The causes of increased intracranial pressure leading to papilledema are numerous, the most common being intracranial tumors, idiopathic intracranial hypertension, obstructive hydrocephalus, and cerebral venous sinus thrombosis.⁹ Because papilledema may be the initial presenting sign of increased intracranial pressure, eye care clinicians must be able to correctly diagnose the condition and initiate the proper workup.

Symptoms of increased intracranial pressure often include headache, transient visual obscurations, and occasionally intermittent diplopia. Clinical signs of papilledema include elevation and swelling of the optic nerve head, obscuration of the margins of the optic disc, and peripapillary hemorrhages or cotton-wool spots. An additional sign that is present in some cases of increased intracranial pressure is an abduction deficit due to stretching of the abducens nerve as it courses through Dorello's canal.¹⁰

Although cerebral venous sinus thrombosis is a relatively rare cause of papilledema, accounting for approximately 2% of papilledema cases encountered in the eye clinic setting, it should be included in the differential diagnosis of patients with optic disc edema, especially in the presence of prior or current infection with severe acute respiratory syndrome coronavirus 2.⁹ In addition to MRI of the head with and without gadolinium contrast, magnetic resonance venography should also be ordered if papilledema is suspected. Magnetic resonance venography can be particularly helpful in diagnosing cerebral venous sinus thrombosis because testing will show a lack of venous flow through the sinus where the thrombosis has occurred (Figs. 2A, B). Although computed tomography venography has also been shown to be effective in detecting cerebral venous sinus thrombosis, consideration needs to be given to the increased risks of radiation exposure, increased iodine contrast material allergy, and use in patients with poor kidney function.¹¹

Treatment of papilledema is directed at the cause of increased intracranial pressure and may include a combination of medical and surgical methods. In cases of cerebral venous sinus thrombosis, the mainstays of treatment are anticoagulation and hydration. Systemic carbonic anhydrase inhibitors, such as acetazolamide, may also be used to assist in lowering intracranial pressure. Surgical means such as stenting procedures may occasionally be required to facilitate venous or cerebral spinal fluid drainage, thereby lowering intracranial pressure and reducing papilledema.

CONCLUSIONS

Cerebral venous sinus thrombosis is a rare but severe complication of COVID-19 infection. Patients with cerebral venous sinus thrombosis may present to eye care practitioners with papilledema and symptoms such as headache, transient visual obscurations, and diplopia. In patients with optic disc edema, cerebral venous sinus thrombosis should be included in the list of differential diagnoses, and magnetic resonance venography should be included in the workup along with MRI of the head with and without gadolinium contrast, especially in patients with a history of COVID-19 infection.