Spotlight Case: I Survived Cancer, Now I Can’t See!

  • author profile pictureBozho Todorich, MD, PhD
  • author profile picturePrithvi Mruthyunjaya, MD
  • author profile picturePaul Hahn, MD, PhD, Duke University Eye Center

Case history

A 77-year-old woman complained of a symptomatic paracentral scotoma after uncomplicated cataract surgery in her left eye. She described the scotoma as a “thick grey streak” in her left inferotemporal visual field. The patient demonstrated constricted peripheral visual fields in both eyes and was initially referred to a glaucoma specialist, who did not note any evidence of glaucoma and subsequently referred her to the Duke Eye Center Retina Service for further evaluation.

Her medical history was significant for stage II non-small cell lung cancer (NSCLC), for which she underwent right upper-lobe resection 7 years prior. She maintained ongoing oncologic surveillance with no evidence of recurrence.

Figure 1. Fundus photographs show clear media, optic nerve pseudopallor, and mild ERM with retinal vessel attenuation, but otherwise relatively unremarkable appearance of the posterior pole of both eyes.

On examination, her visual acuity (VA) was 20/20 in the right eye and 20/25 in the left eye, with a left afferent pupillary defect (APD). Anterior segment examination was normal. On dilated fundus examination, optic nerves were normal, but she had trace epiretinal membrane (ERM) with mildly attenuated retinal vessels bilaterally (Figure 1) and a few scattered hyperpigmented retinal pigment epithelium (RPE) changes in the midperiphery of both eyes (not captured with fundus photography).

Fundus autofluorescence (FAF) imaging showed normal perifoveal autofluorescence with a surrounding ring of abnormal hyperautofluorescence and patchy hypoautofluorescence in the midperiphery of both eyes corresponding to RPE changes observed on fundoscopic examination (Figure 2).

Spectral-domain OCT (SD-OCT) demonstrated a mild ERM with subtle distortion of the foveal contour. There was central preservation of the outer retinal layers, including the ellipsoid zone, but diffuse perimacular outer retinal thinning was apparent, worse in the left eye (Figure 3).

Humphrey visual field (HVF) (Carl Zeiss Meditec, Inc, Dublin, CA) testing showed peripheral visual field constriction bilaterally, which was more advanced in the left eye (Figure 4). Multifocal electroretinography (ERG) imaging showed near-extinguished macular ERG responses in both eyes (Figure 5).  
  

Differential diagnosis

Based on the patient’s presentation, imaging findings, and history of lung cancer, cancer-associated retinopathy (CAR) was suspected. Other considerations in the differential diagnosis included:

  • Retinitis pigmentosa
  • Rod-cone dystrophy
  • Toxic retinopathy
  • White-dot syndromes; eg, acute zonal occult outer retinopathy (AZOOR)

She underwent serological testing with an antiretinal auto-antibody panel, which confirmed the diagnosis of CAR. Western blot testing was positive for 23 kDa (recoverin, low titer), 30 kDa (carbonic anhydrase II), 40 kDa (aldolase), 46 kDa (enolase), and 96 kDa proteins. Immunohistochemistry showed moderate staining of the outer nuclear layer of the retina.
 

Patient course

Figure 2. FAF imaging shows perifoveal hyperautofluorescence. Coarse patchy hypoautofluorescence areas in the midperiphery of both eyes correspond to RPE changes also noted on fundus examination.

The patient was promptly referred back to hematology/oncology for metastatic survey, which showed no evidence of recurrent or secondary malignancy. Steroids and steroid-sparing immunosuppressive agents were discussed as treatment options but were not pursued because of the ongoing concern that lowering the patient’s immune surveillance may increase her risk for recurrence of NSCLC.

Instead, she was administered 15 treatments of plasmapheresis over a 3-month period. Although plasmapheresis was discontinued due to fatigue, the patient noted definite improvement in her visual symptoms and subjective visual field. The left APD had resolved, and her examination remained otherwise stable with no change on OCT or in visual field testing. 
  

Discussion

Autoimmune retinopathy (AIR) is a rare disease entity in which abnormal antibodies are raised against retinal antigens, resulting in progressive retinal degeneration and acute or subacute vision loss.[1-3] AIR can present as a paraneoplastic syndrome in the context of underlying malignancy such as melanoma (melanoma-associated retinopathy, or MAR); other cancers such as lung, breast, or gynecologic malignancies (cancer-associated retinopathy, or CAR); or more commonly as nonparaneoplastic AIR.[4]

The 2 auto-antibodies most commonly associated with CAR include the 23 kDa antirecoverin antibody and the 46 kDa anti-enolase antibody.[3,5]
 

Clinical features

Figure 3. SD-OCT imaging of the patient’s maculae (top row) demonstrates loss of the outer retinal layers with mild ERM and disruption of the foveal contour. There was no intraretinal or subretinal fluid. The extent of retinal thinning in both eyes is better appreciated on the thickness maps (bottom row).

The clinical diagnosis of AIR is challenging and requires a high diagnostic suspicion. Diagnosis is based on:

  • Symptoms
  • Clinical exam
  • ERG changes
  • Positive auto-retinal antibodies

The clinical features of different manifestations of AIR are generally similar but nonspecific.

Patients generally have some but not all of the following symptoms:[6]

  • Acute or subacute vision loss
  • Photopsias
  • Visual field changes
  • Nyctalopia

Fundus examination is often initially normal but can show subtle abnormalities including:

  • Mild optic nerve pallor
  • Retinal vessel attenuation
  • RPE changes
  • Vitreous cells (rarely)

Ancillary testing is helpful in raising the index of suspicion in favor of AIR if the following features are present:

  • Macular SD-OCT with loss of outer retinal layers but foveal sparing (“flying saucer” sign)
  • Perifoveal fundus hyperautofluorescence, which corresponds to areas of outer retinal thinning[7]
  • Decreased rod/cone responses on full-field or multifocal ERG testing and/or “negative ERG” (selective reduction in amplitude of the b-wave with a normal a-wave)[8]
  • Variable peripheral visual field constriction

Figure 4. HVF 24-2 testing shows bilateral peripheral visual field constriction, which was more advanced in the left eye than the right eye.

Although helpful if present, FAF and SD-OCT changes are nonspecific and seen in a number of other retinal degenerations. Conversely, a number of patients with AIR may have seemingly normal FAF and SD-OCT. The detection of circulating antiretinal antibodies as detected on Western blot and confirmatory immunohistochemistry (IHC) aid in the diagnosis in the appropriate clinical context.[7]
 

Management

There are limited case series and reports that address management of AIR.[9] Once AIR is confirmed by antibody and ancillary testing, we recommend prompt initiation of systemic workup for occult malignancy, especially if the patient has no known history of cancer. This should be facilitated in collaboration with the patient’s primary care physician.

Figure 5. Multifocal ERG imaging shows significant attenuation in ERG responses in both eyes, which was more severe in the left eye (bottom panel). Normal ERG is given as a reference (top panel).

If underlying malignancy is identified, prompt referral to an oncologist is warranted. However, successful surgery, chemotherapy, and radiation treatment of the underlying tumor does not correlate well with visual recovery.

Despite thorough workup, in our experience, two-thirds of patients will have no identifiable underlying malignancy, and in those patients, systemic immunosuppression can aid in visual recovery or disease stabilization. Systemic corticosteroids have been shown to decrease titers of circulating antiretinal antibodies, although the value of this effect in predicting visual outcome is yet to be determined.[10] Local periocular or intravitreal steroid administration may also demonstrate benefit in select cases.[11]

The length of immunosuppression is typically chronic, and steroid-sparing agents are often administered concurrently with or instead of steroids. These include:[10]

  • Infliximab
  • Azathioprine
  • Mycophenolate mofetil
  • Cyclosporine
  • Rituximab

The treatment response is varied, reflecting the complex nature of disease, heterogeneity of retinal auto-antibodies, and variable time delay in initiation of treatment. Nonetheless, there is no clear evidence that immunosuppression can reverse structural loss of outer retinal layers with accompanying ERG and visual field changes. The treatment goal in those patients may be stabilization of visual function.

In the case of our patient, we chose to avoid systemic immunosuppression because of at least a theoretical concern that lowering immune surveillance may increase risk of recurrence of the primary tumor. Two approaches can be considered in such a setting:

  • Plasmapharesis[12]
  • Intravenous gamma globulin[13]

While our patient responded well to plasmapheresis alone, the prospective safety and efficacy data of these approaches in CAR and MAR are lacking.
 

Take-home points

  1. AIR is rare but results in visually devastating progressive retinal degeneration.
  2. AIR diagnosis has been enhanced by characteristic multimodal retinal imaging findings.
  3. Once suspected, workup of AIR includes ancillary ophthalmic testing, serologic confirmation with antiretinal antibodies, and a systemic workup for underlying malignancy.
  4. Goal of treatment is stabilization of visual loss. While treatment algorithms are not well established, aggressive and chronic immunosuppressive therapy may slow down and rarely improve visual dysfunction. 
  5. The chronic nature of the treatment of AIR requires a multidisciplinary approach, often involving the patient’s primary care physician, rheumatologist, and oncologist.
  6. Visual prognosis does not correlate well with the status of the primary malignancy and/or titer of circulating antiretinal antibodies.
      

References

1. Sawyer RA, Selhorst JB, Zimmerman LE, Hoyt WF. Blindness caused by photoreceptor degeneration as a remote effect of cancer. Am J Ophthalmol. 1976;81(5): 606-613.

2. Saito W, Kase S, Ohguro H, Furudate N, Ohno S. Slowly progressive cancer-associated retinopathy. Arch Ophthalmol. 2007;125(10):1431-1433. doi:10.1001/archopht.125.10.1431.

3. Rahimy E, Sarraf D. Paraneoplastic and non-paraneoplastic retinopathy and optic neuropathy: evaluation and management. Surv Ophthalmol. 2013;58(5):430-458. doi:10.1016/j.survophthal.2012.09.001.

4. Weleber RG, Watzke RC, Shults WT, et al. Clinical and electrophysiologic characterization of paraneoplastic and autoimmune retinopathies associated with antienolase antibodies. Am J Ophthalmol. 2005;139(5):780-794. doi:10.1016/j.ajo.2004.12.104.

5. Grewal DS, Fishman GA, Jampol LM. Autoimmune retinopathy and antiretinal antibodies: a review. Retina. 2014;34(5):827-845. doi:10.1097/IAE.0000000000000119.

6. Keltner JL, Thirkill CE, Yip PT. Clinical and immunologic characteristics of melanoma-associated retinopathy syndrome: eleven new cases and a review of 51 previously published cases. J Neuroophthalmol. 2001;21(3):173-187.

7. Pepple KL, Cusick M, Jaffe GJ, Mruthyunjaya P. SD-OCT and autofluorescence characteristics of autoimmune retinopathy [published online December 5, 2012]. Br J Ophthalmol. 2013;97(2):139-144. doi:10.1136/bjophthalmol-2012-302524.

8. Koh AH, Hogg CR, Holder GE. The incidence of negative ERG in clinical practice. Doc Ophthalmol. 2001;102(1):19-30.

9. Grange L, Dalal M, Nussenblatt RB, Sen HN. Autoimmune retinopathy [published online September 29, 2013]. Am J Ophthalmol. 2014;157(2):266-272.e1. doi:10.1016/j.ajo.2013.09.019.

10. Ferreyra HA, Jayasundera T, Khan NW, He S, Lu Y, Heckenlively JR. Management of autoimmune retinopathies with immunosuppression. Arch Ophthalmol. 2009;127(4):390-397. doi:10.1001/archophthalmol.2009.24.

11. Handler MZ, Mruthyunjaya P, Nelson K. Melanoma-associated retinopathy: a presenting sign of metastatic disease. J Am Acad Dermatol. 2011;65(1):e9-11. doi:10.1016/j.jaad.2010.09.015.

12. Murphy MA, Thirkill CE, Hart WM Jr. Paraneoplastic retinopathy: a novel autoantibody reaction associated with small-cell lung carcinoma. J Neuroophthalmol. 197;17(2):77-83.

13. Guy J, Aptsiauri N. Treatment of paraneoplastic visual loss with intravenous immunoglobulin: report of 3 cases. Arch Ophthalmol. 1999;117(4):471-477. doi:10.1001/archopht.117.4.471.

 

Financial disclosures

Dr. Todorich - None.

Dr. Mruthyunjaya – ALLERGAN, INC: Advisory Board, Honoraria.

Dr. Hahn - None.

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