Grand Rounds at the New England Eye Center

Woman reports progressive, painless vision loss in left eye

The right eye had an epiretinal membrane, and peripheral venous sheathing was seen in both eyes.

A 52-year-old woman presented to the New England Eye Center with a 2-week history of progressive, painless vision loss in the left eye. Her complete ocular and systemic review of systems was negative, including eye pain, floaters and neurologic symptoms. The patient’s medical history was notable for hypertension, hyperlipidemia, gout and nephrolithiasis treated with laser lithotripsy in 2016. Her ocular history and family history were noncontributory. Her prescribed medications included metoprolol, colchicine, allopurinol, amlodipine and simvastatin. She had no known drug allergies. She denied the use of alcohol, tobacco and recreational drugs.

Examination

Upon examination, best corrected visual acuity was 20/25 in the right eye and finger counting at 5 feet in the left eye. She had an afferent pupillary defect in the left eye. IOPs were within normal limits. Color plates were full in the right eye (11/11) and decreased in the left eye (8/11). Motility was full and painless. Anterior segment slit lamp examination was unremarkable in both eyes.

Dilated fundus examination revealed trace cell in the anterior vitreous and peripheral venous sheathing in both eyes. In the right eye, there was an epiretinal membrane and the optic nerve appeared crowded but otherwise normal. In the left eye, the inferior and nasal margins of the optic nerve appeared blurred. The vessels were normal in course, but peripheral venous sheathing was again noted. The macula and peripheral retina were otherwise normal without retinitis, snowballs or snowbanks (Figure 1).

Figure 1. Fundus photography of the right and left eyes shows an epiretinal membrane in the macula of the right eye and peripheral venous sheathing in both eyes.

Source: Sarah Thornton, MD, and Nora Muakkassa, MD

Figure 2. OCT RNFL of the right and left eyes reveals mild edema of the left optic nerve. The right optic nerve thickness is within normal limits.
Figure 3. Fluorescein angiography reveals peripheral venous leakage bilaterally. In the left eye, leakage of the disc is evident in late frames.
Figure 4. 30-2 Humphrey visual field testing of the right and left eyes. The left eye (pictured on the left) shows a severely depressed visual field. The right eye (pictured on the right) shows a grossly full field.

Imaging

OCT of the retinal nerve fiber layer (RNFL) confirmed mild edema of the left optic nerve (Figure 2). Macular OCT revealed an epiretinal membrane in the right eye and no abnormalities in the left eye. Fluorescein angiography revealed leakage of the peripheral retinal veins bilaterally. In the left eye, disc leakage was evident in late frames (Figure 3). Humphrey visual field 30-2 testing was essentially full in the right eye and diffusely depressed in the left eye (Figure 4).

What is your diagnosis?

See answer on next page.

Optic neuritis

Optic neuritis classically manifests as a triad of decreased vision, pain with ocular movement and decreased color vision. Other findings may include relative afferent pupillary defect and disc edema, although retrobulbar optic neuritis may present without disc swelling.

Retinal periphlebitis describes inflammation of retinal veins. It is believed to be caused by the breakdown of the blood-retinal barrier in the presence of inflammatory cytokines. On clinical exam, it may manifest as venous sheathing, which may be focal with “skip areas” present. On fluorescein angiography, leakage is frequently seen in regions of venous sheathing. Retinal periphlebitis has been reported in the setting of acute optic neuritis at an incidence of about 12%. This finding has been associated with an increased risk for multiple sclerosis development.

Given the concurrent findings of retinal phlebitis and optic neuritis, MS was a strong consideration in our patient. However, there is a broad differential diagnosis for retinal vasculitis in the setting of optic neuritis, which includes a number of other infectious, inflammatory and neoplastic etiologies.

Infectious causes include ocular tuberculosis and syphilis. Retinal vasculitis has rarely been reported in association with Lyme disease, so this diagnosis may be considered in endemic regions. The herpes virus family can cause a peripheral retinal vasculitis early in the disease course, although lack of retinitis is atypical.

Inflammatory etiologies of optic neuritis and retinal periphlebitis include MS, as described above. Neuromyelitis optica may be considered in the setting of severe vision loss and other neurologic symptoms. Sarcoidosis, Behçet’s disease, granulomatosis with polyangiitis, and systemic lupus erythematosus are other rare causes of retinal periphlebitis with optic neuritis. Neoplastic etiologies such as leukemia should be considered for their ability to cause retinal vasculitis and infiltrative optic neuropathy.

Workup and management

Laboratory testing was performed to evaluate for the infectious and inflammatory etiologies described above. QuantiFERON Gold, rapid plasma reagin, fluorescent treponemal antibody absorption, angiotensin-converting enzyme, lysozyme, human leukocyte antigen B51, anti-double stranded DNA, complete blood count and basic metabolic panel were all normal. Anti-nuclear antibody testing was weakly positive at 1:40.

MRI and MRA revealed left optic nerve enhancement consistent with optic neuritis as well as multiple white matter lesions highlighted on fluid-attenuated inversion recovery (FLAIR) imaging consistent with demyelinating disease (Figure 5).

The findings were determined to be consistent with MS. Given the degree of her vision loss, the patient was admitted to Tufts Medical Center for 3 days of intravenous Solu-Medrol (methylprednisolone sodium succinate, Pfizer). At this point, she recalled a neurologic history that she had previously denied. Twelve years ago, she had experienced an episode of transient arm weakness and difficulty speaking. At that time, she underwent MRI at an outside hospital that was reportedly significant for “brain lesions.” She never returned for treatment or follow-up to address these findings.

The patient was discharged on a 5-week prednisone taper and was referred to a neurologist. She underwent further imaging including an MRI of the cervical spine, which revealed an old focus of demyelination at C3 anteriorly with no other findings. The patient was started on dimethyl fumarate for MS treatment.

Two months later, the patient followed up with an outside ophthalmologist. Her visual acuity had improved from finger counting to 20/25 in the left eye. Her disc edema had resolved, and 30-2 Humphrey visual field testing showed grossly full fields in each eye (Figure 6).

Figure 5. Axial T1 fat saturated MRI shows left optic enhancement consistent with left optic neuritis (a). Axial T2 FLAIR MRI shows multiple periventricular white matter lesions consistent with demyelinating disease (b). Coronal T1 MRI confirms left optic nerve enhancement (c).
Figure 6. Imaging from 2-month follow-up visit. OCT RNFL of the right and left eyes reveals resolution of left optic nerve edema. The right optic nerve thickness is within normal limits (a). 30-2 Humphrey visual field testing of the right and left eyes. The fields are grossly full with scattered nonspecific defects in both eyes (b).

Discussion

Multiple sclerosis is a demyelinating disease of the central nervous system (CNS) that often involves the visual pathway. Optic neuritis is one of the most common ophthalmologic findings in MS, affecting up to 70% of patients. Oculomotor abnormalities, including internuclear ophthalmoplegia, abnormal saccades and nystagmus, are observed in about 30% to 50% of MS patients. Uveitis is present in approximately 1% of those with MS, with intermediate uveitis reported at a tenfold higher frequency in MS patients. Another ophthalmologic feature of MS is retinal periphlebitis, which is believed to affect the peripheral retina in about 10% of individuals.

The significance of retinal periphlebitis in MS is not entirely clear. Histopathologic analysis has demonstrated that these perivenous infiltrates are analogous to the venous inflammation observed in CNS demyelinating lesions. Retinal periphlebitis has been correlated with MS disease severity, and its presence is associated with an increased likelihood of MS relapse in a 2-year period. These findings support the theory that retinal periphlebitis is an anterior manifestation of CNS demyelinating plaques in MS.

Rarely, MS-associated retinal periphlebitis can progress to occlusive disease, leading to ischemia and neovascularization of the retina or the anterior segment. Kotoula and colleagues described a patient with no medical history who presented with bilateral neovascularization of the iris and neovascular glaucoma later determined to be caused by MS-associated occlusive vasculitis. The patient was successfully treated with panretinal photocoagulation and anti-VEGF therapy, and was subsequently started on systemic MS therapy with no ocular disease recurrence over the next 3 years.

Treatment of MS-associated uveitis can often be accomplished with topical and/or systemic corticosteroids. In patients with recurrence or no response to initial treatment, immunosuppressive agents may be considered. There is promising evidence to support the use of interferon-beta therapy in MS-associated uveitis, as this agent has good efficacy in MS and is associated with fewer side effects. Anti-tumor necrosis factor agents such as infliximab, which are used to treat juvenile idiopathic arthritis-associated uveitis, should be avoided in MS, as they may worsen demyelinating lesions.

A 52-year-old woman presented to the New England Eye Center with a 2-week history of progressive, painless vision loss in the left eye. Her complete ocular and systemic review of systems was negative, including eye pain, floaters and neurologic symptoms. The patient’s medical history was notable for hypertension, hyperlipidemia, gout and nephrolithiasis treated with laser lithotripsy in 2016. Her ocular history and family history were noncontributory. Her prescribed medications included metoprolol, colchicine, allopurinol, amlodipine and simvastatin. She had no known drug allergies. She denied the use of alcohol, tobacco and recreational drugs.

Examination

Upon examination, best corrected visual acuity was 20/25 in the right eye and finger counting at 5 feet in the left eye. She had an afferent pupillary defect in the left eye. IOPs were within normal limits. Color plates were full in the right eye (11/11) and decreased in the left eye (8/11). Motility was full and painless. Anterior segment slit lamp examination was unremarkable in both eyes.

Dilated fundus examination revealed trace cell in the anterior vitreous and peripheral venous sheathing in both eyes. In the right eye, there was an epiretinal membrane and the optic nerve appeared crowded but otherwise normal. In the left eye, the inferior and nasal margins of the optic nerve appeared blurred. The vessels were normal in course, but peripheral venous sheathing was again noted. The macula and peripheral retina were otherwise normal without retinitis, snowballs or snowbanks (Figure 1).

Figure 1. Fundus photography of the right and left eyes shows an epiretinal membrane in the macula of the right eye and peripheral venous sheathing in both eyes.

Source: Sarah Thornton, MD, and Nora Muakkassa, MD

Figure 2. OCT RNFL of the right and left eyes reveals mild edema of the left optic nerve. The right optic nerve thickness is within normal limits.
Figure 3. Fluorescein angiography reveals peripheral venous leakage bilaterally. In the left eye, leakage of the disc is evident in late frames.
Figure 4. 30-2 Humphrey visual field testing of the right and left eyes. The left eye (pictured on the left) shows a severely depressed visual field. The right eye (pictured on the right) shows a grossly full field.

Imaging

OCT of the retinal nerve fiber layer (RNFL) confirmed mild edema of the left optic nerve (Figure 2). Macular OCT revealed an epiretinal membrane in the right eye and no abnormalities in the left eye. Fluorescein angiography revealed leakage of the peripheral retinal veins bilaterally. In the left eye, disc leakage was evident in late frames (Figure 3). Humphrey visual field 30-2 testing was essentially full in the right eye and diffusely depressed in the left eye (Figure 4).

What is your diagnosis?

See answer on next page.

PAGE BREAK

Optic neuritis

Optic neuritis classically manifests as a triad of decreased vision, pain with ocular movement and decreased color vision. Other findings may include relative afferent pupillary defect and disc edema, although retrobulbar optic neuritis may present without disc swelling.

Retinal periphlebitis describes inflammation of retinal veins. It is believed to be caused by the breakdown of the blood-retinal barrier in the presence of inflammatory cytokines. On clinical exam, it may manifest as venous sheathing, which may be focal with “skip areas” present. On fluorescein angiography, leakage is frequently seen in regions of venous sheathing. Retinal periphlebitis has been reported in the setting of acute optic neuritis at an incidence of about 12%. This finding has been associated with an increased risk for multiple sclerosis development.

Given the concurrent findings of retinal phlebitis and optic neuritis, MS was a strong consideration in our patient. However, there is a broad differential diagnosis for retinal vasculitis in the setting of optic neuritis, which includes a number of other infectious, inflammatory and neoplastic etiologies.

Infectious causes include ocular tuberculosis and syphilis. Retinal vasculitis has rarely been reported in association with Lyme disease, so this diagnosis may be considered in endemic regions. The herpes virus family can cause a peripheral retinal vasculitis early in the disease course, although lack of retinitis is atypical.

Inflammatory etiologies of optic neuritis and retinal periphlebitis include MS, as described above. Neuromyelitis optica may be considered in the setting of severe vision loss and other neurologic symptoms. Sarcoidosis, Behçet’s disease, granulomatosis with polyangiitis, and systemic lupus erythematosus are other rare causes of retinal periphlebitis with optic neuritis. Neoplastic etiologies such as leukemia should be considered for their ability to cause retinal vasculitis and infiltrative optic neuropathy.

Workup and management

Laboratory testing was performed to evaluate for the infectious and inflammatory etiologies described above. QuantiFERON Gold, rapid plasma reagin, fluorescent treponemal antibody absorption, angiotensin-converting enzyme, lysozyme, human leukocyte antigen B51, anti-double stranded DNA, complete blood count and basic metabolic panel were all normal. Anti-nuclear antibody testing was weakly positive at 1:40.

PAGE BREAK

MRI and MRA revealed left optic nerve enhancement consistent with optic neuritis as well as multiple white matter lesions highlighted on fluid-attenuated inversion recovery (FLAIR) imaging consistent with demyelinating disease (Figure 5).

The findings were determined to be consistent with MS. Given the degree of her vision loss, the patient was admitted to Tufts Medical Center for 3 days of intravenous Solu-Medrol (methylprednisolone sodium succinate, Pfizer). At this point, she recalled a neurologic history that she had previously denied. Twelve years ago, she had experienced an episode of transient arm weakness and difficulty speaking. At that time, she underwent MRI at an outside hospital that was reportedly significant for “brain lesions.” She never returned for treatment or follow-up to address these findings.

The patient was discharged on a 5-week prednisone taper and was referred to a neurologist. She underwent further imaging including an MRI of the cervical spine, which revealed an old focus of demyelination at C3 anteriorly with no other findings. The patient was started on dimethyl fumarate for MS treatment.

Two months later, the patient followed up with an outside ophthalmologist. Her visual acuity had improved from finger counting to 20/25 in the left eye. Her disc edema had resolved, and 30-2 Humphrey visual field testing showed grossly full fields in each eye (Figure 6).

Figure 5. Axial T1 fat saturated MRI shows left optic enhancement consistent with left optic neuritis (a). Axial T2 FLAIR MRI shows multiple periventricular white matter lesions consistent with demyelinating disease (b). Coronal T1 MRI confirms left optic nerve enhancement (c).
Figure 6. Imaging from 2-month follow-up visit. OCT RNFL of the right and left eyes reveals resolution of left optic nerve edema. The right optic nerve thickness is within normal limits (a). 30-2 Humphrey visual field testing of the right and left eyes. The fields are grossly full with scattered nonspecific defects in both eyes (b).

Discussion

Multiple sclerosis is a demyelinating disease of the central nervous system (CNS) that often involves the visual pathway. Optic neuritis is one of the most common ophthalmologic findings in MS, affecting up to 70% of patients. Oculomotor abnormalities, including internuclear ophthalmoplegia, abnormal saccades and nystagmus, are observed in about 30% to 50% of MS patients. Uveitis is present in approximately 1% of those with MS, with intermediate uveitis reported at a tenfold higher frequency in MS patients. Another ophthalmologic feature of MS is retinal periphlebitis, which is believed to affect the peripheral retina in about 10% of individuals.

The significance of retinal periphlebitis in MS is not entirely clear. Histopathologic analysis has demonstrated that these perivenous infiltrates are analogous to the venous inflammation observed in CNS demyelinating lesions. Retinal periphlebitis has been correlated with MS disease severity, and its presence is associated with an increased likelihood of MS relapse in a 2-year period. These findings support the theory that retinal periphlebitis is an anterior manifestation of CNS demyelinating plaques in MS.

Rarely, MS-associated retinal periphlebitis can progress to occlusive disease, leading to ischemia and neovascularization of the retina or the anterior segment. Kotoula and colleagues described a patient with no medical history who presented with bilateral neovascularization of the iris and neovascular glaucoma later determined to be caused by MS-associated occlusive vasculitis. The patient was successfully treated with panretinal photocoagulation and anti-VEGF therapy, and was subsequently started on systemic MS therapy with no ocular disease recurrence over the next 3 years.

PAGE BREAK

Treatment of MS-associated uveitis can often be accomplished with topical and/or systemic corticosteroids. In patients with recurrence or no response to initial treatment, immunosuppressive agents may be considered. There is promising evidence to support the use of interferon-beta therapy in MS-associated uveitis, as this agent has good efficacy in MS and is associated with fewer side effects. Anti-tumor necrosis factor agents such as infliximab, which are used to treat juvenile idiopathic arthritis-associated uveitis, should be avoided in MS, as they may worsen demyelinating lesions.