Ophthalmic Features of Systemic Capillary Leak Syndrome

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Article initiated by:

Lucy Mudie MD MPH, Michael T Yen, MD, Angelica M. Garcia

All contributors:

Michael T Yen, MD, Lucy Mudie MD MPH, Nagham Al-Zubidi, MD

Assigned editor:

Michael T Yen, MD, Noor Laylani, MD

Review:

Assigned status Up to Date

 by Michael T Yen, MD on December 18, 2024.

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Contributing Editors:	add

Original article contributed by Lucy I. Mudie MD MPH, Angelica M. Garcia BS, Michael T. Yen MD

ICD-10 code I78. 8

Disease Entity

Idiopathic systemic capillary leak syndrome (SCLS), also known as Clarkson Disease, is a constellation of findings related to transient and severe leakage of fluids and macromolecules from capillaries into tissues. The triad of SCLS is hypotension, hypoalbuminemia and hemoconcentration, without other causes of shocks. Systemically, peripheral edema and pulmonary edema are commonly found, however, the leakage of fluid may occur into any tissue, and a variety of ocular symptoms have also been documented in cases of SCLS. The most reported ocular findings are conjunctival chemosis, choroidal effusions and increased intraocular pressure.

Etiology

SCLS can be idiopathic, however the cascade can also be triggered by certain medications, viruses, or autoimmune inflammatory skin diseases. Anti-cancer drugs such as gemcitabine, clofarabine, monoclonal antibodies, and therapeutic growth factors have been documented as secondary causes of SCLS. One case reported ocular manifestations due to SCLS in a patient who had been given combination therapy with pembrolizumab and an HLA-directed vaccine. Viral triggers of SCLS include dengue, herpes zoster, and influenza A and B. Finally, SCLS has been reportedly triggered by complications of autoimmune disease, such as occurred in a case of protein-losing gastroenteropathy due to Sjogren’s disease.

Many cytokines have been implicated in SCLS, although the exact pathophysiology is unknown. There appears to be an association with increased mononuclear cell IL-2 receptor expression and increased production of cytokines CXCL10, CCL2, IL-1β, IL-8, and IL-12. Patients with SCLS have also been shown to have increased serum concentrations of CD8+ and CD25+ T cells, increased expression of TNF-α, and increased VEGF-D. The final common pathway of these mediators is vascular endothelial dysfunction with widening of inter-cellular gaps allowing for the leakage of macromolecules and transudation of fluid.

Epidemiology

SCLS is very rare with less than 500 cases documented since 1960. Its exact incidence and the incidence of ocular manifestations associated with it are unknown. Older men seem to be affected by SCLS more often than women with the median age of diagnosis at 48 years old.

Diagnosis

SCLS is a clinical diagnosis based on the constellation of signs of capillary leakage, such as generalized edema and refractory hypotension, and supported by laboratory work-up showing hypoalbuminemia, paraproteinemia and hemoconcentration, specifically elevated hematocrit and hemoglobin. The leakage of fluid and macromolecules can also lead to a hypercoagulable state and result in thromboembolic events. The ocular manifestations of SCLS may include acute angle closure glaucoma, choroidal effusion, chemosis, and even non-arteritic ischemic optic neuropathy.

Symptoms

Patients may initially present with non-ocular symptoms related to SCLS such as shortness of breath due to pulmonary edema or pleural effusion, rapid decline, fatigue, or generalized or localized pain. Blurred vision was the first ocular symptoms in patients with SCLS that were later found to have acute angle closure. A patient with SCLS with both bilateral choroidal effusions and acute angle closure presented to ophthalmology with blurred vision and eye pain. Three patients who presented with either bilateral or unilateral chemosis reported symptoms such as increased lacrimation, photophobia, itching, and foreign body sensation with intact visual acuity.

Signs

The systemic signs of SCLS include diffuse peripheral edema, pericardial or pleural effusions, and hypotension, although any organ may be affected by the fluid shift. Patients often present with facial puffiness or periorbital edema, and this may include eyelid edema and conjunctival chemosis. The conjunctival chemosis may be so profound that it causes lagophthalmos and exposure keratopathy. There may also be significant orbital congestion leading to proptosis, dilated and tortuous conjunctival vessels and elevated intraocular pressure (IOP). Other ocular signs include a shallow anterior chamber with elevated IOP, mimicking acute angle closure, due to increased episcleral venous pressure, ciliary body effusion and/or anterior rotation of the ciliary body. Choroidal effusions seem to be a common ocular sign in SCLS; they are thought to be due to the rapid decrease in serum albumin and will often be bilateral due to the systemic nature of SCLS. Apart from findings from direct fluid shifts in/around the eye, there may be secondary ocular affects: a prior case report associated NAION with SCLS due to the profound hypotension and hypercoagulable state induced by SCLS.

Imaging

Figure 1: Brightness scan (B scan) of non-appositional choroidal effusions from a patient with systemic capillary leak syndrome. This patient also had effusions of their ciliary body causing angle occlusion and persistently elevated IOP despite being pseudophakic and on multiple IOP-lowering medications. Their effusions responded to systemic and topical corticosteroids. (Image courtesy of Lucy I. Mudie, MD, MPH)

There are no specific imaging findings for SLCS, rather, imaging may show varying degrees of edema of affected organs- from pulmonary edema to pericardial effusions to intestinal edema. When SCLS affects the eye, the patient may have choroidal effusions, which can be seen on neuro-imaging and ophthalmic ultrasonography (Figure 1).

Laboratory test

The hallmark of SCLS is hypoalbuminemia without albuminuria. Serum total protein is usually low, and urinalysis may show trace protein. Some patients may present with an acute kidney injury (AKI), while others may have normal glomerular filtration rate (GFR) and creatinine. Other laboratory findings include elevated hematocrit suggestive of hemoconcentration and a monoclonal gammopathy of unknown significance on serum protein electrophoresis (SPEP). This monoclonal gammopathy has been reported in as many as 80% of patients with SCLS, although there are usually no other signs of myeloma and there does not appear to be any increased risk of progression to myeloma.

Differential diagnosis

The differential diagnosis of SCLS includes sepsis, angioedema and anaphylaxis. If risk factors such as use of ovarian-stimulating agents are present, then ovarian hyperstimulation syndrome may also be on the differential. Other rare syndromes that can have SCLS-like presentation are hemophagocytic lymphohistiocytosis (HLH), viral hemorrhagic fever, ricin-poisoning and snake-bite envenomation.

Management

Medical therapy

The mainstay of therapy for SCLS is intravenous immunoglobulin G (IVIG). IVIG is typically given at 1g/kg/day for 2-3 days in the acute phase, and in some patients a maintenance infusion of upto 2g/kg monthly may be required. Theophylline and beta-2 agonists such as terbutaline have also been used as maintenance therapy for their ability to constrict smooth muscle and prevent leakage of fluid and macromolecules. Systemic steroids, high-dose vasopressors and supportive therapies such as intubation, ventilation, thromboembolism prophylaxis, and renal replacement therapy are usually involved in the management of acute SCLS, although the hypotension and edema may progress even with these supportive therapies.

For the ophthalmic manifestations, systemic and topical or periocular corticosteroids have been used to treat the choroidal and ciliary body effusions with some success in three reports, although another case series did not find as favorable response. Topical IOP-lowering therapy and topical lubrication have also been reported as supportive therapy. Given the documented elevation in concentration of VEGF-D in SCLS, it has been suggested that VEGF-D and VEGFR3 may be potential targets in the future, and there is one case report of systemic intravenous bevacizumab being used in SCLS, however the patient did not show any clinical response to this therapy. There are no case reports of periocular/ intravitreal anti-VEGF therapy being used in SCLS.

Surgery

There is no known surgical treatment for SCLS. Laser peripheral iridotomy and/or cataract extraction may be considered if there are signs of angle closure, although even in pseudophakic eyes, patients with SCLS may present with shallow anterior chambers and occluded angles due to ciliary body effusions. Likewise, choroidal effusions in SCLS are typically resistant to surgery or laser. For the conjunctival chemosis and exposure keratopathy, a temporary tarsorrhaphy could be considered, however this can create a tight orbit and potentially risk orbital compartment syndrome.

Prognosis

Despite the rarity of SCLS and current incomplete understanding of the disease process, new treatments have led to a relatively favorable prognosis for SCLS. A cohort study from a European collaborative research group suggested the five- and 10-year survival rates in SCLS patients with a monoclonal gammopathy treated with IVIG were 91% and 77%, respectively, compared with 47% and 37% in patients not treated with IVIG. The only available data on visual prognosis comes from individual case reports in which most patients had preserved visual acuity. The patient with SCLS associated-NAION did have a permanent visual field defect, but central visual acuity remained 20/25.

Additional Resources

https://rarediseases.org/rare-diseases/systemic-capillary-leak-syndrome/