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Diagnostic and Therapeutic Challenges

Liu, Hongtao Drs.; Luo, Yan; Duan, Mei; Zhang, Junjun; Cantrill, Herbert L.

Section Editor(s): McDonald, H. Richard

doi: 10.1097/IAE.0000000000001321
Diagnostic and Therapeutic Challenges
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RETINA®, The Journal of Retinal and Vitreous Diseases, encourages readers to submit Diagnostic and Therapeutic Challenges to retina@retinajournal.com. Cases for the Diagnostic and Therapeutic Challenges section should include a detailed history of the patient, the diagnosis, the workup, the management, and finally, the question or questions that the submitter wishes to have answered by the consultants.

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This case is submitted by Drs. Hongtao Liu, Yan Luo, Mei Duan, and Junjun Zhang, Department of Ophthalmology and Ophthalmic Lab, West China Hospital, Sichuan University, Chengdu, Sichuan, China; commented by Dr. Herbert L. Cantrill, Minneapolis, Minnesota.

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Case Report

A 35-year-old Asian man was referred with 8 months' duration of painless decrease in central vision in both eyes. There was no antecedent history of trauma or inflammation. His remaining medical history was unremarkable.

Two months after onset of symptoms, a diagnosis of cytomegalovirus (CMV) retinitis, and then serpiginous choroiditis was made because of his clinical features: yellowish-white lesions and macular edema (Figure 1, A–D). High-dose glucocorticoids and acyclovir were prescribed. However, his visual acuity did not improve.

Fig. 1

Fig. 1

Visual acuity was 20/400 in both eyes. On slit-lamp examination, no inflammatory cells were observed in the anterior chamber or the vitreous (Figure 2E). Fundus examination showed geographical whitish-yellow choroidal lesions in the posterior pole of both eyes (Figure 2, A and B). Compared with half a year earlier, the lesions were significantly enlarged and had spread to the macular region. The late-phase fluorescein angiogram disclosed hyperfluorescent subretinal lesions in both eyes (Figure 2, A and B). Optical coherence tomography showed a large neurosensory detachment at the fovea with subretinal hyperreflective areas in the subretinal space of both eyes (Figure 2, C and D). B-scan ultrasonography showed banding echoes with retinal detachment of the right eye and echoes with retinal detachment of the left eye (Figure 2, H and I). Optical computed tomography scan showed retinal detachment combined with hemorrhage of both eyes (Figure 2F). Biochemical examination findings were within normal limits.

Fig. 2

Fig. 2

Serologic investigation showed no evidence of acute infectious disease. Laboratory workup revealed negative titers for TB antibody, HCV antibody, and HIV antibody. Titers of immunoglobulin M(IgM) and IgG were negative for cytomegalovirus, Rubella virus, Herpes simplex virus, Toxoplasma gondii and Treponema pallidium. General medical examination found a right upper limb capillary hemangioma and left upper limb skin pigmentation (Figure 2G).

This case is presented for discussion of diagnosis and management.

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Dr. Herbert L. Cantrill (Minneapolis, Minnesota)

Liu et al present a diagnostic challenge of a 35-year-old Asian man presenting with painless progressive loss of vision in both eyes. His past eye and medical history are negative. Examination 2 months after onset of symptoms showed bilateral fibrotic lesions in the macula. Fluorescein angiography in the right eye showed multiple hyperfluorescent lesions surrounding the macula, which leaked during the late phase of the study. Angiography of the left eye showed late staining of subretinal fibrosis. Optical coherence tomography showed diffuse retinal thickening with subretinal fluid in the right eye, and retinal thickening with hyperreflective subretinal material in the left eye. He was treated with high-dose steroids and acyclovir with no improvement in vision. Reexamination 4 months later showed expansion of the subretinal fibrotic lesions in both eyes. Fluorescein angiography at this stage showed staining of subretinal fibrosis in both eyes. Optical coherence tomography showed retinal thickening with hyperreflective subretinal material in both eyes. Serologic testing for infectious processes was negative. No further treatment was performed.

This case has the clinical features of the progressive subretinal fibrosis syndrome (PSF). The condition was originally described by Palestine, Nussenblatt, Parver, and Knox in 1984.1 They were the first to use the term “progressive subretinal fibrosis.” There are, however, previously reported cases, including “disciform macular degeneration in young adults” by Doran and Hamilton2 in 1982. Other cases can be found in reports by Dryer and Gass in patients with multifocal choroiditis and uveitis, and in cases of punctate inner choroiditis reported by Watzke et al.3,4 Progressive subretinal fibrosis is a rare condition occurring in younger healthy individuals with devastating effects on their vision.

During the acute phase of the disease, which is often missed, there are multiple hypopigmented choroidal lesions in the posterior pole and mid-peripheral retina. There are minimal signs of inflammation. The choroidal lesions heal with the formation of multiple stellate zones of subretinal fibrosis. During the final phase of the disease, the areas of fibrosis enlarge and coalesce forming large placoid subretinal scars, particularly in the macula.

During the acute phase of the disease, the condition can resemble other forms of multifocal choroiditis, such as multifocal choroiditis and uveitis, acute multifocal placoid pigment epitheliopathy, multiple evanescent white dot syndrome, punctate inner choroiditis, and birdshot chorioretinopathy. It could also be confused with other forms of infectious choroiditis such as TB, syphilis, and various bacterial and fungal infections. Sympathetic ophthalmia resembles PSF, but has a history of injury or surgery. Finally, systemic conditions such as sarcoid and lymphoma can present with a picture of multifocal choroiditis. It is the relatively rapid progression with the formation of multiple areas of subretinal fibrosis, which distinguishes this condition from other forms of multifocal choroiditis.

Treatment has usually been ineffective. Systemic steroids and immunosuppressive therapy have been used without much benefit. There are reports of the use of rituximab (monoclonal CD20 antibody) and infliximab (anti-TNF agent) claiming limited success.5,6 The rational is based on previous histopathologic studies of PSF cases showing lymphocytic infiltration of the choroid with a predominance of T lymphocytes. Presumably, treatment would be most effective during the acute phase of the disease, which is transient, and often missed.

Progressive subretinal fibrosis seems to be an autoimmune disease process directed against the choroid, retinal pigment epithelium, and retina. The triggering mechanism is unknown. There are no known genetic associations or markers. The unique feature of the condition is retinal pigment epithelium metaplasia, which results in large fibrotic subretinal scars. This seems to be a nonspecific response to cellular injury. The unique clinical features of PSF are unmistakable, and for those clinicians who have treated patients with the condition, unforgettable.

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Editor's Note

Drs. Liu, Luo, Duan, and Zhang present the case of a man with bilateral visual loss. Dr. Herb Cantrill has consulted on this case.

Dr. Cantrill believes the diagnosis to be PSF, and reviews the literature starting with the original description by Palestine et al in 1984. The early findings of this condition include the formation of multiple hypopigmented choroidal lesions in the posterior pole and midperiphery. The lesions become associated with fibrosis, which enlarge to form placoid subretinal scars. Dr. Cantrill gives us a differential diagnosis for the early phase of this condition.

  • I. Inflammation
    • A. Multifocal choroiditis and uveitis
    • B. Acute multifocal placoid pigment epitheliopathy
    • C. Multiple evanescent white dot syndrome
    • D. Punctate inner choroiditis
    • E. Birdshot chorioretinopathy
    • F. Sarcoidosis
    • G. Sympathetic ophthalmia
  • II. Infections
    • A. Tuberculosis
    • B. Syphilis
    • C. Fungal infections
    • D. Other bacterial infections
  • III. Neoplasm
    • A. Lymphoma

Dr. Cantrill believes that the rapid progression of multiple areas of subretinal fibrosis distinguishes this condition from the others.

Treatment has been ineffective, although limited success has been achieved with rituximab and infliximab. Progressive subretinal fibrosis syndrome seems to be an autoimmune disease with unknown genetic associations or genetic markers. The devastating feature of this condition is exuberant subretinal metaplasia and scarring.

We thank Drs. Liu, Luo Duan, and Zhang for this case, and Dr. Herb Cantrill for his insightful consultation.

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References

1. Palestine A, Nussenblatt R, Parver L, Knox D. Progressive subretinal fibrosis and uveitis. Br J Ophthalmol 1984;68:667–673.
2. Doran R, Hamilton A. Disciform macular degeneration in young adults. Trans Ophthal Soc UK 1982;102:471–480.
3. Dreyer R, Gass J. Multifocal choroiditis and Panuveitis. A syndrome that mimics Ocular Histoplasmosis. Arch Ophthalmol 1984;102:1776–1784.
4. Watzke R, Packer R, Folk J, et al Punctate inner Choroidopathy. Am J Ophthalmol 1984;98:572–584.
5. Cornish K, Kuffova L, Forrester J. Treatment of diffuse subretinal fibrosis uveitis with rituximab. Br J Ophthalmol 2015;99:153–154.
6. Adan A, Sanmarti R, Bures A, Casaroli-Marano R. Successful treatment with infliximab in a patient with diffuse subretinal fibrosis syndrome. Am J Ophthalmol 2007;143:533–534.
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