October 20, 2020
8 min read
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Weakness, blurred vision in a young woman with headaches

Fundus exam found optic nerve hyperemia in both eyes, RPE loss in the right macula and scattered yellow-white retinal lesions with a placoid appearance in both eyes.

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A 28-year-old woman presented to the department of ophthalmology at Lahey Hospital and Medical Center with 2 months of headaches and progressive visual changes in both eyes.

Christine Benador-Shen
Christine Benador-Shen
Malgorzata Dymerska Peterson
Malgorzata Dymerska Peterson

Two months before presentation, she was evaluated by an outside retina specialist for headache and blurred vision in her right eye. At that time, she was noted to have mild anterior uveitis in the right eye, but by report, no etiology was identified, and no medications were started. Over the next month, our patient developed several small scotomas in her left eye in addition to the blurred vision in her right eye. She also had several severe migraines with one requiring pain medication in the emergency department, which was unusual for her.

The patient’s medical history was notable for migraines, obesity, ADHD and a remote history of microscopic colitis diagnosed by biopsy for which she had never received therapy. A comprehensive review of systems was positive for headaches and neck stiffness. On social history, she did not use illicit drugs or alcohol. She had multiple sexual partners in the last 2 years, including a current relationship with a same-sex partner. She had no preceding viral illness before her vision changes and had no other systemic symptoms during this period. She did not have eye redness, discharge, pain or irritation and had no flashes or floaters.

Examination

The patient’s corrected visual acuity was 20/70 in the right eye and 20/30 in the left eye. There was no improvement with pinhole in either eye. Pupils were round and symmetric, and there was no afferent pupillary defect bilaterally. IOPs were 44 mm Hg in the right eye and 45 mm Hg in the left eye. Confrontation visual fields and extraocular movements were full. She had distortion on Amsler grid in the right eye, while the left eye was normal.

No abnormalities were observed on external exam. Anterior segment exam showed fine keratic precipitates in both eyes, 1+ anterior chamber cell in both eyes and 1+ vitreous cell in the left eye. Fundus exam showed optic nerve hyperemia in both eyes, normal vasculature without sheathing, retinal pigment epithelium (RPE) loss in the right macula and scattered yellow-white retinal lesions with a placoid appearance in both eyes (Figure 1).

Initial fundus photos
Figure 1. Initial color fundus photos of the right (a) and left (b) eyes showing posterior yellow-white placoid lesions and areas of retinal degeneration with RPE hyperpigmentation.

Source: Gavin Gorrell, MD and Sarkis Soukiasian, MD

OCT of the macula demonstrated scattered loss of the inner segment/outer segment junction and RPE in both eyes (Figure 2). Fluorescein angiography (FA) showed early hypofluorescence of the lesions followed by late staining in the transit eye (Figure 3).

Initial OCT macula
Figure 2. Initial OCT macula of the right (a) and left (b) eyes showing focal loss of the inner segment/outer segment junction and RPE in both eyes. Trace vitreous cell is seen in the right eye.
FA of the right eye
Figure 3. FA of the right eye (transit eye) on initial exam showed early hypofluorescent lesions in the macula (a) and diffuse mid-peripheral lesions with hyperfluorescent staining on late phase (b).

What is your diagnosis?

See answer below.

Blurred vision

The differential diagnosis for bilateral panuveitis in a young woman with worsening headaches includes infectious etiologies, systemic autoimmune diseases and inflammatory multifocal chorioretinopathies. Tuberculosis and syphilis were considered although she had no known exposures. Lyme disease was thought less likely but considered as she lived in an endemic area in the Northeast. Sarcoidosis and multifocal choroiditis with panuveitis were considered as well. Although less likely, metastasis to the choroid and masquerade syndromes were discussed.

Case continued

The patient was started on topical ocular antihypertensives for elevated IOP and topical steroids for panuveitis in both eyes.

One week later, the patient’s anterior chamber inflammation had resolved, and IOP was normal. The results of her complete blood count with differential, comprehensive metabolic panel, QuantiFERON Gold, ACE level, syphilis serology, HIV serology, Lyme antibody screening and chest X-ray were unremarkable.

Based on her negative laboratory results and the FA staining pattern, a diagnosis of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) was made. There was a concern for a serpiginous variant of APMPPE (sometimes called ampiginous) due to the significant ocular inflammation and the protracted course of her ocular symptoms. Because of this and given her recent headaches, an MRA of the brain was ordered to evaluate for any neurologic manifestations associated with APMPPE. The patient was started on prednisone 60 mg by mouth daily with a slow taper, in addition to ongoing topical ocular steroids.

Due to the COVID-19 pandemic, our patient had to leave the state to quarantine. She was not able to obtain the MRA or return for evaluation.

On a telemedicine visit 1 month later, she reported improvement in visual symptoms after starting oral steroids. However, during the taper from prednisone 10 mg per day to 6 mg per day, she developed retro-orbital headache with new-onset left-sided weakness and numbness. These symptoms lasted for 5 minutes and recurred over the next 3 days, eventually becoming constant. MRI of the brain done locally showed two white matter lesions that were thought to be migraine-related. No intervention was recommended. Prednisone was increased to 10 mg per day, and she had resolution of left-sided numbness. The patient decided to return to Lahey Hospital for further evaluation of persistent headaches and new neurologic symptoms.

Inpatient admission

Upon admission to the neurology service, vision had improved to 20/20 in the right eye and decreased to 20/60 in the left eye. IOPs were normal. The anterior chamber was quiet, and there was 1+ vitreous cell with some pigment in both eyes. Fundus exam was notable for RPE hyperpigmentation at the site of previous lesions (Figure 4). On OCT of the macula, there was some return of outer retinal structures (Figure 5). Indocyanine green (ICG) angiography demonstrated diffuse hypopigmented lesions indicating severe loss of the choriocapillaris layer (Figure 6). FA demonstrated mild progression in the right eye and significant progression in the left eye (Figure 7).

4-month follow-up
Figure 4. Color fundus photos of the right (a) and left (b) eyes at 4-month follow-up showing RPE hyperpigmentation at sites of previous lesions.
3 months after presentation
Figure 5. Macula OCT of the right (a) and left (b) eyes 3 months after presentation demonstrating partial return of RPE, external limiting membrane and photoreceptor volume.

Her neurologic exam was nonfocal. MRI of the brain demonstrated patchy ischemic lesions that had progressed compared with the prior study. MRA of the brain showed multifocal intracranial vascular stenosis. Lumbar puncture was remarkable only for a mild leukocytosis with lymphocytic predominance, but there were too few cells to assess clonality. CSF gram stain, bacterial and fungal culture, VZV, ACE level, Lyme, VDRL, oligoclonal bands and a COVID-19 nasal swab were normal. At that time, it was not known if COVID-19 could cause pro-thrombotic or microvascular pathology in both the retina and the brain. Given the MRA findings and otherwise unremarkable workup, her symptoms were thought to be due to central nervous system (CNS) vasculitis in the setting of recent diagnosis of APMPPE. She was instructed to continue prednisone 10 mg per day with an extended taper of 1 mg every 2 weeks.

ICG angiography
Figure 6. ICG angiography of the right (a) and left (b) eyes at 4-month follow-up with numerous hypofluorescent spots.
FA of the left eye
Figure 7. FA of the left eye demonstrating progression of disease from initial presentation (a) to 4-month follow-up (b).

Discussion

APMPPE is an immune-mediated chorioretinopathy that may have systemic symptoms. The etiology of this disease is not known, although it is thought to be an inflammatory or autoimmune vasculitis at the level of the choriocapillaris with secondary damage to the overlying RPE and outer retina. Patients often present in the second or third decade of life with rapid-onset blurred vision, scotomas, dysphotopsias and metamorphopsias. Symptoms are typically bilateral but may be asymmetric, and the second eye may develop symptoms days to weeks after the initial visual disturbance.

APMPPE is associated with cerebral vasculitis, stroke, transient ischemic attack, meningoencephalitis, seizures and sensorineural hearing loss. It is a rare disease, and the incidence of neurologic manifestations is not reported. A retrospective case series found that the onset of neurologic symptoms occurred from the onset of visual symptoms to 1 year afterward, with an average of 50 days. This study also found cerebral vasculitis to be the most common neurologic complication, occurring in 50% of patients with neurologic symptoms. Thus, it is imperative that all patients diagnosed with APMPPE are counseled on potential neurologic symptoms and the importance of urgent workup, including cerebral angiography if symptoms develop.

Diagnosis of APMPPE is made clinically based on the patient’s presentation, exam and characteristic imaging findings, with the appropriate exclusion of infectious and systemic causes. Patients may present with a quiet anterior chamber or have anterior uveitis with mild vitritis. Fundoscopic exam shows multiple creamy yellow-white placoid lesions, usually posterior to the equator. New lesions may appear several weeks after the onset of symptoms. Eventually, the lesions become hyperpigmented with RPE pigment clumping.

FA shows early hypofluorescence and late staining of lesions. ICG angiography demonstrates numerous hypofluorescent spots, often more than are visible on fundoscopic exam. This supports the hypothesis that the initial insult is to the choriocapillary vasculature with subsequent RPE and outer retinal degeneration. OCT demonstrates disruption of the outer segment architecture, including RPE disruption and loss of the external limiting membrane and inner segment/outer segment junction.

APMPPE is typically self-limited. Treatment with corticosteroids is reserved for cases with central macular involvement or cerebral vasculitis. The clinical picture guides the workup, but several diseases that may present similarly should be evaluated before initiating therapy. Infectious etiologies should be considered, including viral, bacterial and fungal retinitis, toxoplasmosis, TB and syphilis. The differential also includes autoimmune diseases such as lupus, sarcoidosis and Vogt-Koyanagi-Harada disease, and neoplasms such as intraocular lymphoma and choroidal metastasis. Two similar “white-dot” diseases that likely lie on a spectrum with APMPPE are serpiginous choroidopathy and relentless placoid chorioretinitis.

Serpiginous choroidopathy resembles APMPPE but is recurrent. Initial lesions are often peripapillary and extend centrifugally in a serpentine pattern. Relentless placoid chorioretinitis (RPC) has a similar appearance to APMPPE but is recurrent. Lesions can start in the mid and far periphery before involving the posterior pole, which differentiates RPC from APMPPE or serpiginous choroidopathy. This distinction is important as both serpiginous choroidopathy and RPC require systemic immunosuppressive therapy.

Case continued

Two weeks after discharge, the patient developed right-sided hemiparesis, slurred speech and right facial droop without any new visual symptoms. She was taken to the emergency department by ambulance. CT angiogram of the brain showed bilateral posterior cerebellar artery stenosis. She was given tissue plasminogen activator. MRI of the brain demonstrated multiple leptomeningeal- and parenchymal-enhancing lesions and a new left basal ganglia infarct with hemorrhagic conversion (Figure 8). She was treated with intravenous methylprednisolone and had improvement in her right hemiplegia over several days.

MRI of the brain
Figure 8. MRI of the brain showing acute left basal ganglia infarct with hemorrhagic conversion.

Our patient is now undergoing physical therapy. She is followed by rheumatology and was started on long-term immunomodulatory therapy to treat APMPPE complicated by CNS vasculitis and stroke. She did not have recurrence of neurologic or ophthalmic symptoms 1 month after starting azathioprine.

Although APMPPE is a rare disease, our patient’s clinical course underscores the importance of recognizing this entity and its potential systemic complications such as cerebral vasculitis, which may present simultaneously or months after the initial ophthalmic insult.