Elevated Episcleral Venous Pressure (EVP)
Elevated episcleral venous pressure (EVP) is a clinical finding which may be associated with elevated intraocular pressure (IOP) and glaucoma if left chronically untreated. In many cases the diagnosis is secondary to an underlying etiology, however it can also be idiopathic if all other causes are excluded. The idiopathic form can be familial or sporadic. In German literature idiopathic elevated EVP leading to secondary open angle glaucoma has been termed Radius-Maumenee Syndrome.
Based on the Goldmann equation, intraocular pressure (IOP) is the rate of aqueous humor production divided by the facility of outflow plus EVP. The average EVP ranges from 8-10 mmHg, although can transiently change based on head positioning. There is a linear relationship and 0.83±0.21 mmHg rise in EVP correlates to a 1 mmHg rise in IOP.
In the conventional drainage pathway, aqueous humor flows through the efferent channels of the canal of Schlemm and then through the anterior ciliary venous circulation before converging with the episcleral venous plexus at Tenon’s capsule and the conjunctiva. Given the paucity of capillary networks in episcleral vessels, arteriovenous vasculature anastomosis predominate. The aqueous in the episcleral venous plexus will then drain into the superior ophthalmic vein and enters the cavernous sinus above the annulus of Zinn, before flowing into the internal jugular vein and into the right atrium via the superior vena cava. Any obstruction along this pathway may cause elevated EVP.
If there is increased venous pressure downstream to the episcleral anastomoses, then there is subsequent decrease in outflow of blood from the orbit and aqueous. Thus, in chronic cases, elevated EVP can cause blood reflux into Schlemm’s canal. This can subsequently raise IOP chronically, which can lead to glaucomatous damage due to secondary open angle glaucoma.
Etiologies can range from venous obstruction to arteriovenous anomalies and can be acute or chronic in nature.
Any history of head trauma is a risk factor for developing a carotid cavernous sinus, dural fistula or other arteriovenous anomaly which can lead to the development of elevated EVP. Therefore, it is important to elicit the timing of any trauma and do a full review of systems, including any previous infectious exposures, to rule out life or vision threatening causes of elevated EVP.
Jugular Vein Obstruction
Congestive Heart Failure
Thrombosis of cavernous sinus or orbital vein
Vasculitis involving episcleral or orbital vein
Superior Vena Cava Syndrome (Mediastinal Tumor)
Carotid-Cavernous Sinus Fistula (acute vs. chronic)
Typically, when patients present for evaluation of elevated EVP it is due to chronic eye redness that has not responded to previous treatment and often is misdiagnosed as chronic conjunctivitis. They are usually unaware of their condition or underlying cause and typically do no describe pain or irritation. It is important to ask about recent trauma, specifically craniofacial, that can suggest a carotid cavernous sinus (high flow) or dural (low flow) fistula. A complete past medical history should be obtained to rule out etiologies that may cause venous obstruction, including but not limited to hyperthyroidism, amyloidosis, congestive heart failure, hypercoagulable states, vasculitis, superior vena cava syndrome and Sturge-Weber Syndrome.
Clinical exam is the gold standard for diagnosing elevated EVP. Typically, on physical examination, the episclera is injected and demonstrates the pathognomonic corkscrew episcleral vessels without inflammation (Figure 1). It is important to perform gonioscopy, which can show an open angle with blood reflux in Schlemm’s canal or hyalinization of the wall of Schlemm’s canal due to chronic accumulation of blood. Other signs include chemosis, proptosis and the presence of an orbital bruit, however, these are specific signs for elevated EVP. If the elevated EVP is secondary to a carotid-cavernous fistula, then pulsatile exophthalmos can sometimes be seen. The IOP can often times be elevated in the affected eye. Ancillary testing would include a optic coherence tomography (OCT) scan and Humphrey Visual Field testing to assess for glaucomatous changes.
- Ataxia Telangiectasia
- Acute Closed Angle Glaucoma
- Episcleral Nodule
- Corneal lesion near limbus
- Foreign body
- Herpetic Keratitis
- Uveal Neoplasm
- Polycythemia vera
A complete workout to rule out underlying etiology should be done when elevated EVP is suspected. In the setting of detecting an arteriovenous fistula, cerebral angiography is the gold standard, however, orbital Doppler ultrasound is a non-invasive method which can confirm dilation of the superior ophthalmic vein. Other modalities for diagnosis include orbital ultrasound, ultrasound biomicroscopy (UBM), computerized axial tomography, and magnetic resonance imaging.
There are diagnostic modalities that measure EVP however are not routinely used in clinical practice. Direct cannulation is a direct method and can be done with the complete occlusion or partial vessel occlusion method; this is the most accurate test. Indirect methods include the venomanometer pressure chamber, torsion balance, and air jet.
The episcleral venomanometer is a device that has a dome-shaped silicone ring on its tip. It is mounted on the slit-lamp and the silicone ring is used to gradually compress the episcleral veins until they blanch. EVP is considered the pressure needed to blanch the episcleral veins.
Recently, several non-invasive in-vivo methods have been introduced to measure the episcleral venous outflow. One method is hemoglobin video imaging which assesses the laminar flow in the episcleral veins (i.e., the separation between blood and aqueous within the veins). An interference filter is used and the eye is exposed to a light with a wave length corresponding to the hemoglobin absorption spectrum. The aqueous appears clear since it is devoid of hemoglobin, while the appear darker (Figure 2).
Another non-invasive method is erythrocyte-mediated angiography. This technique is based on injecting autologous, indocyanine green–labelled red blood cells into the individual and then direct visualization of these erythrocytes using scanning laser ophthalmoscopy. This allows for accurate quantification of the episcleral blood flow.
The aim of management should revolve around first treating the primary underlying etiology. If no etiology is determined for the elevated EVP then treatment is similar to that of primary open angle glaucoma (POAG).
Traditionally, medical therapy is aimed at decreasing aqueous humor production and increasing uveoscleral outflow. Medications that enhance outflow through the conventional pathway are not as effective. Beta blockers and carbonic anhydrase inhibitors are classically favored in treatment of elevated EVP. Given its action on the arterial vasculature, Apraclonidine may be considered as it decreases blood flow to the eye.
Recently, several glaucoma medications have been proposed to improve the episcleral venous outflow and reduce the EVP:
A- Topical Rho-Kinase inhibitors
Several mechanisms have been proposed to explain the IOP-lowering effect of topical netarsudil (Rhopressa; Aerie Pharmaceuticals), including reducing aqueous humor production and facilitating aqueous outflow. However, recently, several studies have shown its effect on episcleral venous outflow.
Sit and colleagues used automated venomanometry to measure the EVP after the instillation of topical netarsudil 0.02%. They reported a statistically significant reduction in the mean diurnal EVP by -0.79 mm. Another prospective study by Kim and colleagues used a new technique called erythrocyte-mediated angiography to measure the episcleral venous outflow. They showed a significant increase in the episcleral venous outflow after the instillation of topical netarsudil.
Kaufmann and colleagues retrospectively evaluated the effectiveness of topical netarsudil in 6 eyes with Sturge-Weber-syndrome-associated glaucoma with elevated EVP. The mean follow-up period was 18.7±11.8 months. They reported a statistically significant IOP reduction from a mean of 26.2±4.5 mmHg on 3.3±1.2 glaucoma medications into 17.6±1.4 mmHg at the last follow-up after adding topical netarsudil (P=0.003).
Topical ripasudil is another rho-kinase inhibitor that is approved in Japan and Korea. A prospective study by Suzuki and colleagues investigated its effect on aqueous outflow in episcleral venous vasculature compared to latanoprost. The study included 16 healthy, non-glaucomatous eyes. They used hemoglobin video imaging to evaluate the changes in the aqueous column before and after topical ripasudil. They reported a significant increase in the aqueous column width eight hours after the use of topical ripasudil, suggesting enhancement of episcleral venous outflow.
B- Intracameral Bimatoprost Implant (Durysta)
The effect of the intracameral prostaglandin analogues on the EVP differs from that of topical prostaglandin analogues. Intracameral bimatoprost induces a selective dilation of the episcleral venous system without affecting the episcleral arteries or connecting arteriovenous anastomoses. This results in enhancing the episcleral venous outflow. On the other hand, topical prostaglandin analogues cause dilation of the episcleral vasculatures (arteries, veins, and connecting anastomoses).
QLS-111 (Qlaris Bio) is a novel, promising topical drug that selectively targets the episcleral vasculature, reducing EVP. It acts as a vasodilator through an ATP-sensitive potassium channel modulation mechanism. The drug is currently being developed, with preliminary data showing significant IOP reduction and no significant adverse events. 
Surgical therapy should be considered if patients are refractory to medical therapy. The aim should be to bypass the trabecular outflow, therefore selective laser trabeculoplasty (SLT) and micro-pulse laser trabeculoplasty (MLT) has not been classically recommended. However, a recent study by Khatib and colleagues evaluated episcleral venous outflow in eight eyes who had undergone SLT. Using hemoglobin video imaging, they demonstrated a significant increase in the aqueous column in the episcleral vasculature following SLT. Several studies are currently conducted to evaluate the episcleral venous outflow before and after various glaucoma procedures using erythrocyte-mediated angiography.
Trabeculectomy and sclerotomy are appropriate surgical options. Eyes with elevated EVP have been reported to be at higher risk for uveal effusion syndrome. Therefore, special consideration is needed to prevent hypotony during surgery. Prophylactic sclerotomies or scleral windows may be necessary. One case recommends a surgical technique where a tight trabeculectomy with multiple adjustable sutures, the sutures can then be used to titrate the IOP gradually and therefore prevent acute shallowing of the anterior chamber intraoperatively. Other reports suggest maintaining the anterior chamber with injection of balance salt solution and viscoelastic, in addition to adjustable suture placement on the scleral flap. Medical management post operatively can include use of cycloplegic agents and glucocorticoids to reduce inflammation.
The major complication for untreated elevated EVP is development of secondary open angle glaucoma. Elevated EVP can also lead to acute angle closure glaucoma as suprachoroidal hemorrhage with subsequent forward displacement of the lens-iris diaphragm. Rarely, neovascular glaucoma can occur as a result of ocular ischemia.
Follow up for these cases varies depending on the underlying etiology and IOP. If following for secondary open angle glaucoma, frequent follow up is needed with routine IOP checks, gonioscopy, OCT, and visual fields to monitor and prevent glaucomatous progression.
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