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Patient complains of dry eye, retinal exam shows new pallor
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A 56 year-old, white female presented for a routine eye examination with a chief complaint of dry eyes.
Her medical history was unremarkable. Her ocular history was positive for unspecified optic atrophy and peripheral branch retinal vein occlusion in the left eye 4 years prior, for which there was no definitive cause and no treatment. An extensive cardiovascular work-up was unremarkable at the time. She was taking no medications and reported no drug allergies. Her past family and social histories were unremarkable.
The patient’s refraction was +2.00 D -1.25 D x 080 OD, +0.50 D -1.00 D x 005 and +2.25 D add OU, and her best-corrected visual acuity was full in each eye with no limitations. Pupil testing revealed a relative afferent defect in the left eye. Ocular alignment was normal with an orthophoric position in all gazes. Additionally, she noted 10/10 color plates in the right eye and 6/10 color plates in the left eye. Intraocular pressure measured 11 mm Hg OU.
Images: DelGiodice M
The anterior segment exam revealed a reduced tear break-up time and 1+ nuclear sclerotic cataract, but otherwise was unremarkable. Fundus exam showed mild anterior vitreous cells, large white opacities inferiorly in the anterior peripheral retina and perivascular retinal pigment epithelial hyperplasia in the superior peripheral retina in both eyes. There was a prominent epiretinal membrane overlying each macula. The optic nerves showed a cup-to-disc ratio of 0.30 with superior-temporal disc pallor in the right eye and moderate diffuse pallor in the left eye. Although the patient did not notice a change in her vision, both eyes exhibited a loss of best-corrected visual acuity when compared to her previous visit 2 years ago.
A comparison of the optic nerves using digital photography showed new-onset pallor in the right and possible progression in the left eye; this raised a red flag. Subsequently, we ordered optical coherence tomography (OCT) of the disc and macula along with a visual field test. The OCT of the optic nerve showed a reduced average thickness of the retinal nerve fiber layer, greater in the left eye than the right, and the visual field showed mild inferior relative defects in the right eye and a mild cecocentral scotoma in the left eye. The macular OCT showed bilateral epiretinal membrane and cystoid macular edema (CME).
In light of the clinical findings, we diagnosed her as having bilateral, asymmetric optic atrophy and intermediate uveitis (IU). A thorough uveitis history was unremarkable. Because of the lack of historical data to link the clinical findings we did not have a leading diagnosis. With a history of past optic atrophy and peripheral retinal vascular changes, we developed differential diagnoses that included: sarcoidosis, multiple sclerosis (MS), intraocular lymphoma, Lyme disease, syphilis and tuberculosis.
Consequently, we ordered a complete blood count with differential and platelets, erythrocyte sedimentation rate, angiontensin-converting enzyme, lysozyme, Lyme titer, fluorescent treponemal antibody absorption, rapid plasma reagin and purified protein derivative. We also scheduled her for magnetic resonance imaging (MRI) of the brain and orbits with and without contrast and fat suppression.
All laboratory studies were negative. However, imaging studies revealed multiple periventricular white matter (PWM) lesions. Causes of PWM lesions are extensive but most commonly include normal senescent changes, hypertension, focal cerebrovascular accidents, demyelination, migraine, vitamin B6 (pyridoxine) deficiency and infectious or inflammatory-related vasculitis, including but not limited to Lyme disease and sarcoidosis.
Recommendations for this patient
The clinical findings of bilateral optic atrophy, IU and PWM lesions lead us to a presumptive diagnosis of MS. The nerve fiber layer was reduced, but the epiretinal membrane and edema did not allow for accurate ganglion cell inner plexiform analysis. She was subsequently referred to a neurologist who confirmed the diagnosis. Given the patient’s age, lack of acute MS lesions and progressive motor weakness, she is being followed without medication. However, we did discuss our findings with her neurologist and suggested treatment, given her optic nerve status and chronic inflammation.
We also discussed the medical and surgical options with our patient in regard to treatment of intermediate uveitis, macular edema and epiretinal membrane. She was referred to a retinal specialist for consideration of periocular sub-Tenon steroid injection. Currently, she has undergone one periocular injection in each eye. Both the vitritis and macular edema are resolving nicely and her visual acuity is stable. She is scheduled to return for visual field testing.
Intermediate uveitis incidence, etiology
Intermediate uveitis (IU) is described as inflammation of the anterior vitreous, ciliary body and peripheral retina. According to the Standardization of Uveitis Nomenclature working group’s international workshop for reporting clinical data, the term IU should be used to describe a subtype of uveitis where the vitreous is the major site of the inflammation and there is an associated systemic disease. Conversely, the diagnostic term pars planitis should be used only for that subset of IU where there is inflammation of the uvea, vitreous and peripheral retina in the absence of systemic disease.
IU has been reported in 1.4% to 22% of uveitis patients (Vitale et al., McCannel et al., Rodriguez et al.). Although the disease affects patients in all age groups, it is predominantly seen in the third and fourth decade and is bilateral in 70% to 90% of cases (Vitale et al., Chan et al.). According to Thouvenot and colleagues, uveitis was identified in 0.7% of patients with MS, similar to the incidence found in a literature review. On the contrary, optic neuritis (ON) is the most frequent ophthalmic manifestation of MS, occurring in approximately 30% of cases. The clinical features of uveitis in MS generally manifest as bilateral, intermediate uveitis with an age range of 19 to 62 years (Manohar Babu et al.).
Patients with IU typically present with minimal symptoms that may include floaters or blurred vision. In advanced cases, visual loss can be attributed to associated optic nerve involvement, dense vitritis or CME. Vitreous snowballs are yellow-white inflammatory aggregates found in the mid-vitreous and inferior retinal periphery. Snowbanks are exudates on the pars plana usually located inferiorly, and their presence is most often associated with a more severe form of the disease. Macular edema and maculopathy are the leading causes of visual loss, with an incidence of 12% to 51%, according to Manohar Babu and colleagues. Epiretinal membranes occur in 34.6% to 36% eyes (Malinowski et al., Donaldson et al.). Malinowski and colleagues reported that optic nerve involvement in the form of disc edema was seen in 3% to 38.6% of eyes with IU, and optic neuritis with or without MS was seen in 7.4% of eyes with pars planitis. Lastly, retinal changes include arteriole and venule tortuosity, perivascular venule sheathing, neovascularization and retinal detachment.
Uveitis and MS share common genetic risk factors and autoantigens. Both diseases involve the same type of T-cell immune response in which lymphocytic infiltration of the retinal venules leads to vasculitis. Major histocompatibility complex class II antigen expression has been found on the vascular endothelium and is likely responsible for initiating the recruitment of activated CD4+ cells, the predominant cell type found in the vitreous.
The differential diagnosis of IU and optic atrophy includes infectious conditions such as Lyme disease, toxoplasmosis, toxocariasis, tuberculosis, syphilis, human lymphotropic virus Type 1, Epstein-Barr virus and cat-scratch disease. Noninfectious entities include MS, sarcoidosis and non-Hodgkin’s lymphoma.
Recommended testing
Because there are a number of causes, a shotgun approach to laboratory testing and imaging is not recommended. Detailed clinical findings with a concentration on the duration of symptoms, number of recurrences and associated systemic findings allows for better localization of the problem. Approximately 3% to 27% of patients with MS develop IU, and 7.8% to 14.8% of patients with IU develop MS, according to Manohar Babu and colleagues. More specifically, MS-related IU is typically characterized by bilateral pars plana snowbanks, retinal periphlebitis and panuveitis.
If the patient has not already undergone baseline testing, it is recommended to obtain a complete blood count with differential and platelets, erythrocyte sedimentation rate, fluorescent treponemal antibody absorption antibodies and purified protein derivative (PPD) skin test; a PPD test is needed to exclude tuberculosis, and a negative reading will allow for the potential use of systemic corticosteroids. Additional laboratory tests include angiotensin-converting enzyme and lysozyme for sarcoidosis and antinuclear antibody for systemic lupus erythematosus-related autoimmune vasculitis. Immunoglobulins G and M for toxoplasmosis, Bartonella henslae and toxocariasis should only be ordered if the clinical findings are attributable. In this case, no evidence of neuroretinitis was present, making this an unlikely diagnosis. Neuroimaging should be strongly considered in patients with bilateral disease with optic nerve involvement and associated neurologic symptoms, because sarcoidosis, MS and non-Hodgkin’s lymphoma may present in a similar fashion.
Treatment
After determining the cause and initiating the appropriate systemic treatment, treatment of the uveitis should commence when the visual acuity drops as a result of vitritis, CME or progression of neovascularization because there is a greater risk of tractional retinal detachment.
In 1984, Kaplan was the first to advocate a four-step treatment approach of IU. Periocular corticosteroids of either methylprednisolone (40 mg) or triamcinolone acetonide (20 mg) are given through the posterior sub-Tenon route; improvement in at least two Snellen lines was seen in 12 out of 18 patients at a median of 3 weeks.
If local therapy is not effective or if severe bilateral disease is seen at presentation, oral corticosteroids are indicated. If this treatment fails, is not tolerated or is contraindicated, systemic immunomodulatory therapy should be offered. Lastly, when all other treatment fails and pars plana snowbanks are present, peripheral retinal ablation using cryotherapy or indirect laser photocoagulation is performed. In the event all treatment modalities fail to control the inflammation, a pars plana vitrectomy with peripheral laser photocoagulation to the snowbank may be performed with concomitant systemic immunomodulatory therapy.
This case highlights the importance of recognizing the relationship of MS and IU. While the incidence of MS for all types of uveitis is less than 1%, there is a much greater association with the intermediate form. We recommend ordering MRI of the brain and orbit with and without contrast in the setting of IU and associated optic nerve involvement.
- References:
- Chan SM, et al. Can J Ophthalmol. 2007;42(6):860-864.
- Donaldson MJ, et al. Am J Ophthalmol. 2007;144(6):812-817.
- Helm CJ, et al. Am J Ophthalmol. 1995;120(1):55-64.
- Jabs DA, et al. Am J Ophthalmol. 2005;140(3):509-516.
- Kaplan HJ. Intermediate uveitis (pars planitis, chronic cyclitis): a four-step approach to treatment. In: Saari KM, ed. Uveitis Update. Amsterdam: Experta Medica; 1984:169–172.
- Malinowski SM, et al. Ophthalmology. 1993;100(6):818-824.
- Manohar Babu B, et al. Indian Journal of Ophthalmology. 2010;58(1):21-27.
- McCannel CA, et al. Am J Ophthalmology. 1996;121(1):35-46.
- Rodriguez A, et al. Arch Ophthalmol. 1996;114(5):593-539.
- Thouvenot E, et al. Multiple sclerosis international. 2012;doi:10.1155/2012/372361
- Vitale AT, Zierhut M, Foster CS. Intermediate Uveitis. In: Foster CS, Vitale AT, eds. Diagnosis and Treatment of Uveitis. Philadelphia: W.B. Saunders and Company; 2002:844–857.
- For more information:
- Michael DelGiodice, OD, FAAO, practices in Clifton and Pompton Lakes, N.J. He can be reached at mdelgiodice@yahoo.com.
- Michael Trottini, OD, practices in Princeton, N.J., and can be reached at drtrottini@outlookeyecare.com.
- Edited by Leo P. Semes, OD, FAAO, who can be reached at lsemes@uab.edu.
Disclosures: DelGiodice and Trottini report no relevant financial disclosures.