Grand Rounds at the New England Eye Center

Woman presents with vision loss and cough

The right eye had an elevated white lesion with associated retinal hemorrhages and two white pre-retinal infiltrates, while the left eye had snowballs and a snowbank.

A 45-year-old woman with no significant medical or ocular history presented to the New England Eye Center with 1 year of floaters and gradual loss of vision in the left eye as well as flashes in the right eye. She first noted the symptoms while living in Cambodia. She sought treatment but could not recall any interventions or details. She then emigrated to Boston 6 months before presentation. At the initial visit, she denied any joint, back or muscle pain or skin lesions. However, she did report a dry cough.

Examination

Upon examination, best corrected visual acuity was 20/40 in the right eye and 20/150 eccentrically in the left eye. Pupils were equal, round and sluggish with no relative afferent defect. IOP was 14 mm Hg in the right eye and 13 mm Hg in the left eye. The conjunctiva and sclera in both eyes were white and quiet. The anterior chambers demonstrated 2+ cell bilaterally. There were 2+ nuclear sclerotic cataracts in both eyes. The dilated exam revealed 3+ vitreous cell and 2+ vitreous haze bilaterally. In the right eye, there was cystoid macular edema. Inferior to the optic nerve, there was an elevated white lesion with multiple associated retinal hemorrhages and two white pre-retinal infiltrates. The left eye demonstrated cystoid macular edema, snowballs and a snowbank inferiorly (Figures 1a and 1b).

 pre-retinal snowballs and pre-retinal hemorrhages
Figure 1. Color fundus photos of the right eye (a) and left eye (b) demonstrating pre-retinal snowballs and pre-retinal hemorrhages.

Source: Lauren Bierman, MD, Nora Muakkassa, MD, and Lana Rifkin, MD

disc leakage, macular leakage and diffuse microvascular leakage
Figure 2. Heidelberg fluorescein angiography of the left eye demonstrating disc leakage, macular leakage and diffuse microvascular leakage.
“eruption” from the choroid into the vitreous
Figure 3. Posterior segment OCT through peripheral choroidal lesion in the right eye demonstrating “eruption” from the choroid into the vitreous.

During the initial visit, fluorescein angiography showed optic disc leakage, macular leakage and diffuse microvascular leakage (Figure 2). Spectral-domain OCT of the retinal lesions demonstrated an elevated chorioretinal lesion that extended through the retina into the vitreous (Figure 3).

What is your diagnosis?

See answer on next page.

Bilateral panuveitis

In a patient with no systemic symptoms other than cough, the differential diagnosis for bilateral panuveitis includes sarcoidosis, tuberculosis, syphilis and idiopathic panuveitis. Sarcoid uveitis is characterized by granulomatous inflammation with keratic precipitates, vitritis, phlebitis and chorioretinal lesions. It is often associated with pulmonary disease. Similarly, tuberculosis presents with a granulomatous uveitis and must be high on the list given her pulmonary symptoms and emigration from a high prevalence area. Syphilis should also be considered in this patient as it is well known to cause bilateral panuveitis.

Before presentation, the patient had a lab workup including Lyme titers, ANA and RPR, all of which were negative. Further, a chest X-ray showed no hilar adenopathy or pulmonary opacities. Her previous tuberculin spot (T-SPOT.TB) was reported positive; however, the patient did not recall being treated for tuberculosis. Further testing was performed, including ACE, lysozyme, FTA-Abs, QuantiFERON-TB Gold and a chest CT. ACE, lysozyme and FTA-Abs were unremarkable, and the CT of the chest did not reveal any cardiopulmonary disease. QuantiFERON-TB Gold returned positive, which along with her positive T-SPOT.TB and clinical presentation is consistent with ocular tuberculosis.

Discussion

Mycobacterium tuberculosis (MTB), the agent responsible for tuberculosis (TB), is an acid-fast staining obligate aerobe transmitted by aerosolized droplets with a high affinity for highly oxygenated tissues such as the apices of the lung and the choroid. In the United States in 2011, the incidence of TB was 3.4 in 100,000; however, worldwide it affects nearly one-third of the population. The incidence of ocular TB remains low, accounting for approximately 0.6% of all uveitis cases in the United States, and varies depending on risk factors and geographic region.

Ocular manifestations of TB can be either primary ocular TB, in which the eye is the primary site of entry, or more commonly secondary ocular TB, which occurs via hematogenous dissemination or by contiguous spread from adjacent structures. Ocular TB can affect nearly every ocular structure and can mimic findings seen in other conditions such as sarcoidosis and syphilis. The most common manifestation of secondary ocular TB is uveitis, and it can present as anterior, intermediate, posterior or panuveitis. Presentation can include, but is not limited to, mutton fat keratic precipitates, iris nodules, posterior synechiae, secondary glaucoma, retinal vasculitis and multiple deep yellow lesions, or tubercles, in the posterior pole. Tubercles can be numerous, even up to several hundred, ranging from 0.5 mm to 3 mm in diameter, or can be single, up to 14 mm in diameter. It is unknown whether these findings are a result of a direct mycobacterial infection or a hypersensitivity response.

The breadth of clinical presentations and the lack of a gold standard test to diagnose intraocular TB make the diagnosis a challenge. In addition, typical constitutional symptoms, including fever, night sweats and weight loss, may be absent because only 10% of infected individuals develop symptomatic disease. Extrapulmonary disease occurs in about 20% of patients with TB, with 50% to 60% of these patients having no evidence of pulmonary TB and unremarkable chest X-rays. Therefore, while radiologic studies can be helpful in making a diagnosis of intrathoracic TB, the findings may be normal in extrathoracic TB. Furthermore, being a paucibacillary disease, it is uncommon to demonstrate MTB by culture, smear or histopathology from examination of intraocular fluids. Therefore, culturing of ocular samples is rarely undertaken. In addition, PCR has low sensitivity, and there is a lack of standardization of PCR techniques. Diagnosis of ocular TB, therefore, is clinical and relies upon an examination consistent with TB, confirmed exposure to active TB, exposure to an endemic area, response to therapy and laboratory evidence of exposure.

There are no consensus guidelines among uveitis experts regarding the treatment of ocular TB, including duration, regimen, or the use of concurrent oral corticosteroids or immunomodulatory therapy; however, all agree that treatment requires multidrug therapy and should be co-managed with an infectious disease specialist. The CDC recommends RIPE therapy (rifampin, isoniazid, pyrazinamide and ethambutol) for patients with active pulmonary or extrapulmonary TB. Most studies analyzing the efficacy of treatment of ocular TB prescribed RIPE therapy for at least 6 months, with a maximum duration between 12 and 19 months. A corticosteroid or other immunosuppressive agent can be added to reduce the damage caused by delayed-type hypersensitivity reaction, although the role and duration of such remain controversial.

Clinical course continued

At the initial visit, the patient was immediately started on topical difluprednate six times daily in both eyes and cyclopentolate nightly in both eyes for ocular inflammation and given concern for ocular TB. The patient was referred for an urgent infectious disease consultation. She was then started on RIPE therapy by infectious disease for presumed ocular TB. After 6 weeks, BCVA was 20/40-2 in the right eye and 20/200 in the left eye. Exam demonstrated improvement in the vitritis with trace vitreous cell in the right eye and 1+ vitreous cell in the left eye. The snowballs appeared to be consolidating, and the cystoid macular edema improved in both eyes. In consultation with the infectious disease specialist, treatment with oral prednisone was initiated while continuing on quadruple antibiotic therapy. She continues to improve and is currently being followed by our uveitis and retina specialists.

A 45-year-old woman with no significant medical or ocular history presented to the New England Eye Center with 1 year of floaters and gradual loss of vision in the left eye as well as flashes in the right eye. She first noted the symptoms while living in Cambodia. She sought treatment but could not recall any interventions or details. She then emigrated to Boston 6 months before presentation. At the initial visit, she denied any joint, back or muscle pain or skin lesions. However, she did report a dry cough.

Examination

Upon examination, best corrected visual acuity was 20/40 in the right eye and 20/150 eccentrically in the left eye. Pupils were equal, round and sluggish with no relative afferent defect. IOP was 14 mm Hg in the right eye and 13 mm Hg in the left eye. The conjunctiva and sclera in both eyes were white and quiet. The anterior chambers demonstrated 2+ cell bilaterally. There were 2+ nuclear sclerotic cataracts in both eyes. The dilated exam revealed 3+ vitreous cell and 2+ vitreous haze bilaterally. In the right eye, there was cystoid macular edema. Inferior to the optic nerve, there was an elevated white lesion with multiple associated retinal hemorrhages and two white pre-retinal infiltrates. The left eye demonstrated cystoid macular edema, snowballs and a snowbank inferiorly (Figures 1a and 1b).

 pre-retinal snowballs and pre-retinal hemorrhages
Figure 1. Color fundus photos of the right eye (a) and left eye (b) demonstrating pre-retinal snowballs and pre-retinal hemorrhages.

Source: Lauren Bierman, MD, Nora Muakkassa, MD, and Lana Rifkin, MD

disc leakage, macular leakage and diffuse microvascular leakage
Figure 2. Heidelberg fluorescein angiography of the left eye demonstrating disc leakage, macular leakage and diffuse microvascular leakage.
“eruption” from the choroid into the vitreous
Figure 3. Posterior segment OCT through peripheral choroidal lesion in the right eye demonstrating “eruption” from the choroid into the vitreous.

During the initial visit, fluorescein angiography showed optic disc leakage, macular leakage and diffuse microvascular leakage (Figure 2). Spectral-domain OCT of the retinal lesions demonstrated an elevated chorioretinal lesion that extended through the retina into the vitreous (Figure 3).

What is your diagnosis?

See answer on next page.

PAGE BREAK

Bilateral panuveitis

In a patient with no systemic symptoms other than cough, the differential diagnosis for bilateral panuveitis includes sarcoidosis, tuberculosis, syphilis and idiopathic panuveitis. Sarcoid uveitis is characterized by granulomatous inflammation with keratic precipitates, vitritis, phlebitis and chorioretinal lesions. It is often associated with pulmonary disease. Similarly, tuberculosis presents with a granulomatous uveitis and must be high on the list given her pulmonary symptoms and emigration from a high prevalence area. Syphilis should also be considered in this patient as it is well known to cause bilateral panuveitis.

Before presentation, the patient had a lab workup including Lyme titers, ANA and RPR, all of which were negative. Further, a chest X-ray showed no hilar adenopathy or pulmonary opacities. Her previous tuberculin spot (T-SPOT.TB) was reported positive; however, the patient did not recall being treated for tuberculosis. Further testing was performed, including ACE, lysozyme, FTA-Abs, QuantiFERON-TB Gold and a chest CT. ACE, lysozyme and FTA-Abs were unremarkable, and the CT of the chest did not reveal any cardiopulmonary disease. QuantiFERON-TB Gold returned positive, which along with her positive T-SPOT.TB and clinical presentation is consistent with ocular tuberculosis.

Discussion

Mycobacterium tuberculosis (MTB), the agent responsible for tuberculosis (TB), is an acid-fast staining obligate aerobe transmitted by aerosolized droplets with a high affinity for highly oxygenated tissues such as the apices of the lung and the choroid. In the United States in 2011, the incidence of TB was 3.4 in 100,000; however, worldwide it affects nearly one-third of the population. The incidence of ocular TB remains low, accounting for approximately 0.6% of all uveitis cases in the United States, and varies depending on risk factors and geographic region.

Ocular manifestations of TB can be either primary ocular TB, in which the eye is the primary site of entry, or more commonly secondary ocular TB, which occurs via hematogenous dissemination or by contiguous spread from adjacent structures. Ocular TB can affect nearly every ocular structure and can mimic findings seen in other conditions such as sarcoidosis and syphilis. The most common manifestation of secondary ocular TB is uveitis, and it can present as anterior, intermediate, posterior or panuveitis. Presentation can include, but is not limited to, mutton fat keratic precipitates, iris nodules, posterior synechiae, secondary glaucoma, retinal vasculitis and multiple deep yellow lesions, or tubercles, in the posterior pole. Tubercles can be numerous, even up to several hundred, ranging from 0.5 mm to 3 mm in diameter, or can be single, up to 14 mm in diameter. It is unknown whether these findings are a result of a direct mycobacterial infection or a hypersensitivity response.

The breadth of clinical presentations and the lack of a gold standard test to diagnose intraocular TB make the diagnosis a challenge. In addition, typical constitutional symptoms, including fever, night sweats and weight loss, may be absent because only 10% of infected individuals develop symptomatic disease. Extrapulmonary disease occurs in about 20% of patients with TB, with 50% to 60% of these patients having no evidence of pulmonary TB and unremarkable chest X-rays. Therefore, while radiologic studies can be helpful in making a diagnosis of intrathoracic TB, the findings may be normal in extrathoracic TB. Furthermore, being a paucibacillary disease, it is uncommon to demonstrate MTB by culture, smear or histopathology from examination of intraocular fluids. Therefore, culturing of ocular samples is rarely undertaken. In addition, PCR has low sensitivity, and there is a lack of standardization of PCR techniques. Diagnosis of ocular TB, therefore, is clinical and relies upon an examination consistent with TB, confirmed exposure to active TB, exposure to an endemic area, response to therapy and laboratory evidence of exposure.

PAGE BREAK

There are no consensus guidelines among uveitis experts regarding the treatment of ocular TB, including duration, regimen, or the use of concurrent oral corticosteroids or immunomodulatory therapy; however, all agree that treatment requires multidrug therapy and should be co-managed with an infectious disease specialist. The CDC recommends RIPE therapy (rifampin, isoniazid, pyrazinamide and ethambutol) for patients with active pulmonary or extrapulmonary TB. Most studies analyzing the efficacy of treatment of ocular TB prescribed RIPE therapy for at least 6 months, with a maximum duration between 12 and 19 months. A corticosteroid or other immunosuppressive agent can be added to reduce the damage caused by delayed-type hypersensitivity reaction, although the role and duration of such remain controversial.

Clinical course continued

At the initial visit, the patient was immediately started on topical difluprednate six times daily in both eyes and cyclopentolate nightly in both eyes for ocular inflammation and given concern for ocular TB. The patient was referred for an urgent infectious disease consultation. She was then started on RIPE therapy by infectious disease for presumed ocular TB. After 6 weeks, BCVA was 20/40-2 in the right eye and 20/200 in the left eye. Exam demonstrated improvement in the vitritis with trace vitreous cell in the right eye and 1+ vitreous cell in the left eye. The snowballs appeared to be consolidating, and the cystoid macular edema improved in both eyes. In consultation with the infectious disease specialist, treatment with oral prednisone was initiated while continuing on quadruple antibiotic therapy. She continues to improve and is currently being followed by our uveitis and retina specialists.