What's Your Diagnosis?

Young woman reports blurry vision in one eye, spots, floaters

A 29-year-old African American female presented upon referral from a fellow optometrist for retinal evaluation. Her chief complaint was blurry vision in the left eye that had been consistently present for 2 weeks. She reported that her central vision seemed most affected. She also reported seeing spots and floaters in her vision intermittently for 2 weeks.

Fundus photography at initial presentation.

Images: Haynes J and Rafieetary M

The patient’s medical history was positive for hypertension for which she was taking losartan/hydrochlorothiazide 50/12.5 mg 1 tablet daily. The patient had no past ocular history and reported no history of ocular trauma or ocular surgery. Her family medical history included diabetes and heart disease, but no ocular complications. She denied drinking, smoking and recreational drug use.

Mid-stage FA at 2 minutes and 50 seconds.

The patient’s autorefraction was -1.50 OU. Her best-corrected visual acuities were 20/20 OD and 20/150 OS. Her intraocular pressure measured with Tonopen (Reichert Technologies) was 15 mm Hg OD and 13 mm Hg OS. Confrontation visual fields and extra-ocular motilities were normal. A mild afferent pupillary defect was noted in the left eye.

Anterior segment examination revealed normal ocular structure in the right eye. The left eye had mild conjunctival injection, 1 to 2+ cells in the anterior chamber and 2+ cells in the anterior vitreous. The left eye lens was clear, and the iris was normal.

A: Multiple serous detachments (green stars) with pinpoint areas of hyper-reflectivity under them and membranous structure underlying serous detachments (yellow arrow) and choroidal folds (red arrow). B: Optic nerve edema, with overlying hyper-reflective points in the vitreous (blue arrow).

Dilated posterior segment examination again showed normal findings in the right eye. The left eye had significant disc edema with flame-shaped hemorrhages radiating from the disc. There was vascular tortuosity, 1+ vitreous haze and pigment mottling of the retina. Diffusely scattered areas of serous retinal detachments were also present.

Optical coherence tomography imaging was performed in areas overlying the macula and the optic disc of the left eye. The macular OCT scans clearly showed the areas of serous detachment and revealed choroidal folding.

In addition to this, there were pinpoint hyper-reflective spots in the region of serous detachment between the retinal pigment epithelium (RPE) and neurosensory retina and a subretinal membranous structure overlying the RPE. Diffuse pinpoint hyper-reflectivity could also be seen in the vitreous on OCT as well, due to vitreal inflammation. The OCT scan taken over the optic nerve showed optic nerve head swelling. No abnormalities were seen with OCT imaging of the right macula and optic nerve.

Widefield fluorescein angiography (FA) showed significant leakage surrounding the disc and patchy leakage in areas of serous retinal detachment in the left eye. There was also diffuse patchy staining in the midperipheral retina in the left eye. The right eye study was normal.

What’s your diagnosis?
See answer on the next page.

The differential diagnosis and etiology of panuveitic disease, especially when the optic nerve is involved, is broad and should include infectious disease such as syphilis, Lyme, Bartonella and tuberculosis. Other infectious diseases include cytomegalovirus, particularly in the immunocompromised, and herpetic conditions such as acute retinal necrosis, which may be present in an otherwise healthy adult. Autoimmune disease and malignancies must also be considered. In these categories, primary and secondary entities to rule out include: sarcoidosis, systemic lupus, Bechet’s disease and ocular malignancy such as intraocular lymphoma. Lastly, sympathetic ophthalmia, a rare condition seen in patients who have had severe injury or iatrogenic damage to one eye, may present with granulomatous uveitis in their previously normal eye. Therefore, history of trauma or surgery should always be considered.

In this case, consideration should be given for conditions that lead to serous retinal detachments and choroidal folds. Idiopathic uveal effusion syndrome can present with choroidal folds and serous retinal detachments or choroidal detachments. However, these patients will not present with ocular inflammation or optic nerve swelling. This condition also most commonly affects middle-aged males (Elagouz et al.).

Central serous retinopathy results in serous retinal detachments. These patients will typically have a thicker-than-average choroid, but choroidal folds are not seen in these cases. Additional ocular inflammation and optic disc edema is also absent.

Jessica Haynes

This patient’s diagnosis

The diagnosis of this patient was determined to be an autoimmune-mediated condition called Vogt-Koyanagi-Harada’s (VKH) disease. This condition is a fairly common cause of panuveitis in more darkly pigmented individuals. The disease typically presents bilaterally, but fellow eye involvement may be delayed. While the exact pathophysiology of VKH is not entirely understood, it is thought to be a T-cell mediated autoimmune response against melanocytes. In the eye, this autoimmune attack initiates in the choroid. Nonocular structures such as skin, meninges and the inner ear may also be involved in the autoimmune response yielding additional systemic symptoms; however, the presence or absence of these symptoms varies case to case and may depend on the stage of the disease.

Mohammad Rafieetary

VKH has classically been divided into four stages: prodromal, acute uveitic, convalescent and chronic recurrent. The prodromal phase may present with symptoms mistaken for a viral infection such as fever, headache and neck stiffness. Ocular symptoms such as orbital pain and photosensitivity can occur. Hearing loss, vertigo and tinnitus may also be present. The acute phase of VKH results in a panuveitis or posterior uveitis with multiple serous retinal detachments. Low-grade vitritis and nongranulomatous anterior uveitis are often present. Optic disc hyperemia is a common finding in the acute phase and may be bilateral or unilateral. In the convalescent phase, there is resolution of the serous retinal detachments with depigmentation of the choroid. This results in orange-red discoloration of the retina that is classically called “sunset glow fundus.” The recurrent phase is characterized by bouts of recurrent granulomatous anterior uveitis.

OCT findings

OCT findings in VKH have become well documented, with certain findings being quite distinct for patients with VKH. Multiple serous retinal detachments are often visualized with OCT. One study in particular found that high serous detachments greater than 450 microns are particularly characteristic of VKH (Liu et al.). Alterations of the choroid can also be visualized with OCT. Utilization of enhanced depth imaging OCT shows choroidal thickening early in the course of the disease. Later in the disease course, prominent choroidal folds develop.

Hyper-reflective points in the cystic spaces within serous retinal detachments can also be seen on OCT and are thought to be inflammatory debris. The findings of a hazy, thick band above the RPE at the base of serous retinal detachments has also been well-documented and described as a “subretinal membranous structure.” This is thought to be inflamed photoreceptor outer segments that have been separated from the inner segments (Liu et al.). This could explain why those with acute phase VKH often present with such dramatic vision loss.

FA, ICG

FA and indocyanine green angiography (ICG) provide useful information in the diagnosis of VKH as well. In the acute phase of the disease, early stage FA shows delayed choroidal filling due to active choroidal inflammation. Mid-phase FA often shows numerous pinpoint areas of hyper-fluorescence, giving a “starry sky” appearance that is highly suggestive of VKH. Throughout the FA study, there will be continued pooling in areas of serous retinal detachments and, frequently, continued leakage surrounding the disc.

This fundus photo and OCT after 3 weeks of high-dose systemic steroids show significant resolution of subretinal detachments and improved optic nerve edema.

Because ICG is a better method to visualize choroidal circulation, it has been described by some as the ideal method for monitoring patients for response to therapy and for recurrences of the disease, as it may show the earliest signs of inflammation, which originate in the choroid. ICG features in VKH include early phase patchy hypofluorescence, hazy leakage from larger choroidal vessels in the stroma during the mid-phase and diffuse choroidal leakage during the late phase of the study. In addition to these findings, the papillitis that ensues from this condition can be so severe that disc hyperfluorescence may also be seen. This is a sign not typically present in ICG studies because the largely protein-bound ICG molecules do not usually leak from retinal circulation.

Treatment, prognosis

The goal of treatment for this condition is to stifle acute inflammation and then prevent recurrences of the disease. Treatment of acute disease requires high dose oral or intravenous steroids. Early diagnosis and initiation of treatment is critical in reaching the best visual outcomes. After initial resolution of inflammation, long-term, slow tapering of steroids is needed to prevent recurrence. Patients are often on steroid therapy for several years. More recently, long-term therapy has been supplemented with immunomodulators such as methotrexate, cyclosporine and Humira (adalimumab, AbbVie). Anterior segment inflammation can be managed with topical steroids and cycloplegia.

Patients may also develop additional retinal complications such as choroidal neovascular (CNV) membranes, macular holes and epimacular membranes. CNVs are reported to respond well to anti-VEGF therapy, and ocular surgery may be indicated for vitreoretinal interface disease. Complications from patient management and long-term inflammation, such as increased intraocular pressure or cataract formation, must also be addressed as they arise.

The prognosis of those diagnosed with VKH is highly variable. Earlier diagnosis and initiation of therapy with slow taper of steroids does result in better prognosis for patients. In addition, supplementation of treatment with immunomodulators has been shown to achieve improved visual outcomes and lower risk of recurrences. Patients presenting with visual acuity greater than 20/200, less severe anterior chamber inflammation and absence of additional systemic signs have a better prognosis as well. Even with early and aggressive therapy, there are still a good number of patients who develop recurrent and chronic disease with poor resultant vision. Those with chronic inflammation are more at risk for additional ocular complications as described earlier. Patients who develop these complications tend to have poorer visual outcomes.

This patient’s follow-up, outcomes

At the initial examination, the patient was diagnosed with likely VKH disease due to her classic signs and was started on high dose steroids of 50 mg twice daily. A medical work-up was also ordered to rule out infectious etiologies and additional autoimmune disease. The patient’s results were normal aside from slightly elevated white blood cell count and high ESR of 31.

The patient was followed 3 weeks after initiation of therapy with significant improvement in both signs and symptoms. Visual acuity in the left eye improved after 3 weeks to 20/20. There was a decrease in both vitreous and anterior chamber inflammation. Fundus examination showed remarkable improvement, and OCT imaging showed significant improvement in serous detachments. The patient was kept on oral steroids with a slow taper over 6 months. At the end of the tapering period, the right eye became involved, and oral steroid treatment was re-initiated.

Secondary attempts of steroid tapering were again unsuccessful with recurrence of inflammation and the development of chronic optic nerve head edema in the left eye. At her last follow-up, which was 18 months after initial presentation, the patient was referred to a rheumatologist in order to comanage her condition and supplement treatment with immune-modulators. The patient’s vision remains 20/20 OD and is currently 20/60 OS.

During courses of high-dose steroids, the patient suffered from elevated blood sugar, which was managed by her primary care physician. The patient’s ocular care was supplemented with topical steroids and cycloplegia for anterior segment inflammation. She also had one treatment of sub-Tenon’s Kenalog (triamcinolone acetate, Bristol-Myers Squibb) injection in both eyes during the course of her disease.

VKH is a fairly common cause of panuveitis in darkly pigmented individuals. Early diagnosis and initiation of treatment is important in reaching the best visual outcomes for patients. Additional etiologies of panuveitis should be considered and ruled out with laboratory testing in these patients, as the diagnosis of VKH is made based on clinical signs and exclusion of other causes.

Disclosures: Haynes reports no relevant financial disclosures. Rafieetary reports he is a consultant for Alcon, Genentech, Heidelberg and Regneron. Semes is an advisor or on the speakers bureau for Alcon, Allergan, Bausch + Lomb, Genentech, Maculogix, OptoVue, Shire and ZeaVision. He is a stockholder with HPO.

A 29-year-old African American female presented upon referral from a fellow optometrist for retinal evaluation. Her chief complaint was blurry vision in the left eye that had been consistently present for 2 weeks. She reported that her central vision seemed most affected. She also reported seeing spots and floaters in her vision intermittently for 2 weeks.

Fundus photography at initial presentation.

Images: Haynes J and Rafieetary M

The patient’s medical history was positive for hypertension for which she was taking losartan/hydrochlorothiazide 50/12.5 mg 1 tablet daily. The patient had no past ocular history and reported no history of ocular trauma or ocular surgery. Her family medical history included diabetes and heart disease, but no ocular complications. She denied drinking, smoking and recreational drug use.

Mid-stage FA at 2 minutes and 50 seconds.

The patient’s autorefraction was -1.50 OU. Her best-corrected visual acuities were 20/20 OD and 20/150 OS. Her intraocular pressure measured with Tonopen (Reichert Technologies) was 15 mm Hg OD and 13 mm Hg OS. Confrontation visual fields and extra-ocular motilities were normal. A mild afferent pupillary defect was noted in the left eye.

Anterior segment examination revealed normal ocular structure in the right eye. The left eye had mild conjunctival injection, 1 to 2+ cells in the anterior chamber and 2+ cells in the anterior vitreous. The left eye lens was clear, and the iris was normal.

A: Multiple serous detachments (green stars) with pinpoint areas of hyper-reflectivity under them and membranous structure underlying serous detachments (yellow arrow) and choroidal folds (red arrow). B: Optic nerve edema, with overlying hyper-reflective points in the vitreous (blue arrow).

Dilated posterior segment examination again showed normal findings in the right eye. The left eye had significant disc edema with flame-shaped hemorrhages radiating from the disc. There was vascular tortuosity, 1+ vitreous haze and pigment mottling of the retina. Diffusely scattered areas of serous retinal detachments were also present.

Optical coherence tomography imaging was performed in areas overlying the macula and the optic disc of the left eye. The macular OCT scans clearly showed the areas of serous detachment and revealed choroidal folding.

In addition to this, there were pinpoint hyper-reflective spots in the region of serous detachment between the retinal pigment epithelium (RPE) and neurosensory retina and a subretinal membranous structure overlying the RPE. Diffuse pinpoint hyper-reflectivity could also be seen in the vitreous on OCT as well, due to vitreal inflammation. The OCT scan taken over the optic nerve showed optic nerve head swelling. No abnormalities were seen with OCT imaging of the right macula and optic nerve.

Widefield fluorescein angiography (FA) showed significant leakage surrounding the disc and patchy leakage in areas of serous retinal detachment in the left eye. There was also diffuse patchy staining in the midperipheral retina in the left eye. The right eye study was normal.

What’s your diagnosis?
See answer on the next page.

PAGE BREAK

The differential diagnosis and etiology of panuveitic disease, especially when the optic nerve is involved, is broad and should include infectious disease such as syphilis, Lyme, Bartonella and tuberculosis. Other infectious diseases include cytomegalovirus, particularly in the immunocompromised, and herpetic conditions such as acute retinal necrosis, which may be present in an otherwise healthy adult. Autoimmune disease and malignancies must also be considered. In these categories, primary and secondary entities to rule out include: sarcoidosis, systemic lupus, Bechet’s disease and ocular malignancy such as intraocular lymphoma. Lastly, sympathetic ophthalmia, a rare condition seen in patients who have had severe injury or iatrogenic damage to one eye, may present with granulomatous uveitis in their previously normal eye. Therefore, history of trauma or surgery should always be considered.

In this case, consideration should be given for conditions that lead to serous retinal detachments and choroidal folds. Idiopathic uveal effusion syndrome can present with choroidal folds and serous retinal detachments or choroidal detachments. However, these patients will not present with ocular inflammation or optic nerve swelling. This condition also most commonly affects middle-aged males (Elagouz et al.).

Central serous retinopathy results in serous retinal detachments. These patients will typically have a thicker-than-average choroid, but choroidal folds are not seen in these cases. Additional ocular inflammation and optic disc edema is also absent.

Jessica Haynes

This patient’s diagnosis

The diagnosis of this patient was determined to be an autoimmune-mediated condition called Vogt-Koyanagi-Harada’s (VKH) disease. This condition is a fairly common cause of panuveitis in more darkly pigmented individuals. The disease typically presents bilaterally, but fellow eye involvement may be delayed. While the exact pathophysiology of VKH is not entirely understood, it is thought to be a T-cell mediated autoimmune response against melanocytes. In the eye, this autoimmune attack initiates in the choroid. Nonocular structures such as skin, meninges and the inner ear may also be involved in the autoimmune response yielding additional systemic symptoms; however, the presence or absence of these symptoms varies case to case and may depend on the stage of the disease.

Mohammad Rafieetary

VKH has classically been divided into four stages: prodromal, acute uveitic, convalescent and chronic recurrent. The prodromal phase may present with symptoms mistaken for a viral infection such as fever, headache and neck stiffness. Ocular symptoms such as orbital pain and photosensitivity can occur. Hearing loss, vertigo and tinnitus may also be present. The acute phase of VKH results in a panuveitis or posterior uveitis with multiple serous retinal detachments. Low-grade vitritis and nongranulomatous anterior uveitis are often present. Optic disc hyperemia is a common finding in the acute phase and may be bilateral or unilateral. In the convalescent phase, there is resolution of the serous retinal detachments with depigmentation of the choroid. This results in orange-red discoloration of the retina that is classically called “sunset glow fundus.” The recurrent phase is characterized by bouts of recurrent granulomatous anterior uveitis.

OCT findings

OCT findings in VKH have become well documented, with certain findings being quite distinct for patients with VKH. Multiple serous retinal detachments are often visualized with OCT. One study in particular found that high serous detachments greater than 450 microns are particularly characteristic of VKH (Liu et al.). Alterations of the choroid can also be visualized with OCT. Utilization of enhanced depth imaging OCT shows choroidal thickening early in the course of the disease. Later in the disease course, prominent choroidal folds develop.

Hyper-reflective points in the cystic spaces within serous retinal detachments can also be seen on OCT and are thought to be inflammatory debris. The findings of a hazy, thick band above the RPE at the base of serous retinal detachments has also been well-documented and described as a “subretinal membranous structure.” This is thought to be inflamed photoreceptor outer segments that have been separated from the inner segments (Liu et al.). This could explain why those with acute phase VKH often present with such dramatic vision loss.

PAGE BREAK

FA, ICG

FA and indocyanine green angiography (ICG) provide useful information in the diagnosis of VKH as well. In the acute phase of the disease, early stage FA shows delayed choroidal filling due to active choroidal inflammation. Mid-phase FA often shows numerous pinpoint areas of hyper-fluorescence, giving a “starry sky” appearance that is highly suggestive of VKH. Throughout the FA study, there will be continued pooling in areas of serous retinal detachments and, frequently, continued leakage surrounding the disc.

This fundus photo and OCT after 3 weeks of high-dose systemic steroids show significant resolution of subretinal detachments and improved optic nerve edema.

Because ICG is a better method to visualize choroidal circulation, it has been described by some as the ideal method for monitoring patients for response to therapy and for recurrences of the disease, as it may show the earliest signs of inflammation, which originate in the choroid. ICG features in VKH include early phase patchy hypofluorescence, hazy leakage from larger choroidal vessels in the stroma during the mid-phase and diffuse choroidal leakage during the late phase of the study. In addition to these findings, the papillitis that ensues from this condition can be so severe that disc hyperfluorescence may also be seen. This is a sign not typically present in ICG studies because the largely protein-bound ICG molecules do not usually leak from retinal circulation.

Treatment, prognosis

The goal of treatment for this condition is to stifle acute inflammation and then prevent recurrences of the disease. Treatment of acute disease requires high dose oral or intravenous steroids. Early diagnosis and initiation of treatment is critical in reaching the best visual outcomes. After initial resolution of inflammation, long-term, slow tapering of steroids is needed to prevent recurrence. Patients are often on steroid therapy for several years. More recently, long-term therapy has been supplemented with immunomodulators such as methotrexate, cyclosporine and Humira (adalimumab, AbbVie). Anterior segment inflammation can be managed with topical steroids and cycloplegia.

Patients may also develop additional retinal complications such as choroidal neovascular (CNV) membranes, macular holes and epimacular membranes. CNVs are reported to respond well to anti-VEGF therapy, and ocular surgery may be indicated for vitreoretinal interface disease. Complications from patient management and long-term inflammation, such as increased intraocular pressure or cataract formation, must also be addressed as they arise.

The prognosis of those diagnosed with VKH is highly variable. Earlier diagnosis and initiation of therapy with slow taper of steroids does result in better prognosis for patients. In addition, supplementation of treatment with immunomodulators has been shown to achieve improved visual outcomes and lower risk of recurrences. Patients presenting with visual acuity greater than 20/200, less severe anterior chamber inflammation and absence of additional systemic signs have a better prognosis as well. Even with early and aggressive therapy, there are still a good number of patients who develop recurrent and chronic disease with poor resultant vision. Those with chronic inflammation are more at risk for additional ocular complications as described earlier. Patients who develop these complications tend to have poorer visual outcomes.

PAGE BREAK

This patient’s follow-up, outcomes

At the initial examination, the patient was diagnosed with likely VKH disease due to her classic signs and was started on high dose steroids of 50 mg twice daily. A medical work-up was also ordered to rule out infectious etiologies and additional autoimmune disease. The patient’s results were normal aside from slightly elevated white blood cell count and high ESR of 31.

The patient was followed 3 weeks after initiation of therapy with significant improvement in both signs and symptoms. Visual acuity in the left eye improved after 3 weeks to 20/20. There was a decrease in both vitreous and anterior chamber inflammation. Fundus examination showed remarkable improvement, and OCT imaging showed significant improvement in serous detachments. The patient was kept on oral steroids with a slow taper over 6 months. At the end of the tapering period, the right eye became involved, and oral steroid treatment was re-initiated.

Secondary attempts of steroid tapering were again unsuccessful with recurrence of inflammation and the development of chronic optic nerve head edema in the left eye. At her last follow-up, which was 18 months after initial presentation, the patient was referred to a rheumatologist in order to comanage her condition and supplement treatment with immune-modulators. The patient’s vision remains 20/20 OD and is currently 20/60 OS.

During courses of high-dose steroids, the patient suffered from elevated blood sugar, which was managed by her primary care physician. The patient’s ocular care was supplemented with topical steroids and cycloplegia for anterior segment inflammation. She also had one treatment of sub-Tenon’s Kenalog (triamcinolone acetate, Bristol-Myers Squibb) injection in both eyes during the course of her disease.

VKH is a fairly common cause of panuveitis in darkly pigmented individuals. Early diagnosis and initiation of treatment is important in reaching the best visual outcomes for patients. Additional etiologies of panuveitis should be considered and ruled out with laboratory testing in these patients, as the diagnosis of VKH is made based on clinical signs and exclusion of other causes.

Disclosures: Haynes reports no relevant financial disclosures. Rafieetary reports he is a consultant for Alcon, Genentech, Heidelberg and Regneron. Semes is an advisor or on the speakers bureau for Alcon, Allergan, Bausch + Lomb, Genentech, Maculogix, OptoVue, Shire and ZeaVision. He is a stockholder with HPO.