ORIGINAL CONTRIBUTION A Case of Autoimmune-Related Retinopathy and Optic Neuropathy Syndrome Treated by Autologous Nonmyeloablative Hematopoietic Stem Cell Transplantation Yu Oyama, MD, Richard K. Burt, MD, Charles Thirkill, PhD, Eissa Hanna, MD, Kevin Merrill, MD, and John Keltner, MD Abstract: Autoimmune-related retinopathy and op- Several treatments based on standard therapy for tic neuropathy (ARRON) syndrome is characterized autoimmune disorders have been tried in ARRON syn- by visual loss and often the presence of antibodies drome with variable success, including prednisone, intra- against retinal or optic nerve antigens in the absence venous methylprednisolone (IVMP), immunosuppressive of cancer. Limited success has been reported in treat- agents, plasma exchange, and intravenous immunoglobulin ment of ARRON syndrome with medications that (IVIg) (1,9–16). We describe what we believe to be the first suppress the immune system. In many patients, cur- reported patient to be treated with autologous HSCT. rent strategies are insufficient to control the disease. A 47-year-old woman with progressive visual and hearing loss attributed to ARRON syndrome that was CASE REPORT resistant to conventional therapies underwent autol- In February 2001, a 47-year-old Caucasian woman ogous hematopoietic stem cell transplantation (HSCT). presented for evaluation of visual loss. Her vision had Clinical manifestations appeared to stabilize. This deteriorated over the preceding 7 months with complaints report suggests that autologous HSCT may have of worsening glare from fluorescent lights, blurred vision in a therapeutic role in ARRON syndrome. both eyes, and impaired night and color vision. She did not report photopsias. Her visual loss coincided with the onset (J Neuro-Ophthalmol 2009;29:43–49) of bilateral progressive hearing loss and episodes of high- pitched tinnitus. In addition, she described the sensation of n autoimmune-related retinopathy and optic neuropathy ‘‘pins and needles’’ in her feet that over the next several I(ARRON) syndrome, it is unclear whether antibodies months had evolved into bilateral lower extremity against retina and optic nerve cause the visual loss or numbness and paresthesias. Over a 6-year follow-up, the whether they represent an epiphenomenon related to non- patient developed bladder incontinence, disturbance in specific breakdown of retinal and optic nerve proteins or are balance, and Sjo¨gren syndrome (17). part of the normal pattern of antibody distribution (1–8). In 1992, she had had Mycoplasma pneumonia and For this reason, the condition is labeled ‘‘autoimmune- shortly thereafter chronic fatigue, polyarticular arthritis, related’’ rather than ‘‘autoimmune.’’ and hypothyroidism with a thyroid biopsy yielding a benign nodule. Family history included a malignant melanoma in an identical triplet sister, her brother, and a cousin. Neither of Department of Medicine (YO, RKB), Division of Immunotherapy, her triplet siblings had connective tissue disease. Northwestern University Feinberg School of Medicine, Chicago, Illinois; and Department of Ophthalmology and Vision Science (CT, EH, KM, JK), In March 2001, our evaluation showed a visual acuity University of California, Davis, Davis, California. of 20/30-1 in the right eye and 20/25-1 in the left eye. This work was supported by an unrestricted grant from Research to Color vision tested on the American Optical Hardy-Rand- Prevent Blindness and by National Eye Institute Core Grant 1 P30 Rittler (AOHRR) plates was 2/6 in the right eye and 1/6 in EY12576-04. the left eye (Note that the patient eventually lost color Address correspondence to John Keltner, MD, Department of Ophthalmology and Vision Science, Department of Neurology, and vision: 0/6 in both eyes on the AOHRR plates). Pupils were Department of Neurological Surgery, University of California, Davis, of normal size and reactivity without afferent defect. Davis, CA 95616; E-mail: [email protected] There was no evidence of inflammation in the eye. J Neuro-Ophthalmol, Vol. 29, No. 1, 2009 43 J Neuro-Ophthalmol, Vol. 29, No. 1, 2009 Oyama et al Ophthalmoscopy demonstrated moderate optic disc pallor Humphrey visual fields could no longer be obtained, and with attenuated blood vessels bilaterally. Goldmann perimetry showed generalized constriction. Humphrey (stimulus size III) visual field examination In September 2003, the patient was found to have showed further deterioration compared with an examination very low counts of lymphocyte subsets compared with performed 1 month earlier. The mean deviation in the right a normal lymphocyte phenotype done in 2001. Serologic eye had decreased from 9.1 to 13.38 dB with overall testing for anti-heat shock protein (hsp)-70, associated with depression; the mean deviation in the left eye had decreased autoimmune inner ear disease, showed positive results. from 11.44 to 14.72 dB with a superior altitudinal defect. Antiphospholipid antibody (APA) IgM was elevated (14.9), Neuro-otologic examination demonstrated bilateral consistent with a generalized autoimmune disorder. vestibular dysfunction with disruption of the vestibulo- In January 2004, the patient was referred to ocular reflex and bilateral sensorineural hearing loss that Northwestern University for evaluation of an autologous proved to be progressive over the course of follow-up. nonmyeloablative HSCT protocol approved by the institu- On neurologic examination, the patient exhibited tional review board and Food and Drug Administration decreased vibratory sensation in the toes and could not Investigational New Drug (IND) 11669. Hematopoietic perform a tandem gait. Quantitative sensory studies and stem cells (HSCs) were harvested. The immune ablative nerve biopsy, showing axonal and demyelinating changes, regimen was 200 mg/kg intravenous cyclophosphamide were consistent with a sensorimotor peripheral neuropathy. and 20 mg CAMPATH-1H. Brain MRI in January 2001 did not reveal any evidence of In September 2004, unmanipulated autologous stem a demyelinating disease. cells were infused. White blood cell and platelet counts Additional studies with normal results included com- recovered on day 10. plete screening for heavy metals, human immunodeficiency In March 2005, she reported increased energy, virus, hepatitis, paraneoplastic disorders, serum homocysteine, improved gait, vision, and hearing, as well as decreased and Lyme titer; immune electrophoresis; and SS-A/Ro, spasms of the lower extremities and complete resolution of SS-B/La, rheumatoid factor (RF), antinuclear antibodies bladder dysfunction. Her chief complaints were extremity (ANA), antimicrosomal antibodies (AMA), anti-neutrophil pain and photophobia and foreign body sensation in the cytoplasmic antibodies (ANCA), double-stranded DNA, eyes attributed to dryness. anti-smooth muscle antibody (ASMA), fluorescent trepo- In June 2005, audiometric testing showed a 5–10 dB nemal antibody absorption test (FTA-ABS), VDRL test, improvement in pure tone threshold and a 10–15 dB rapid plasma reagin (RPR) and microhemagglutination improvement in speech reception threshold. Subsequent Treponema pallidum (MHA-TP), and vitamin B12. studies have demonstrated the patient’s hearing to be stable. Hematologic testing demonstrated macrocytosis. In April 2006, serum was collected again and reeval- Results of lumbar puncture, colonoscopy, chest CT, uated for antibody activity against pig retina (Table 1A) and mammogram, dermatologic skin survey, and bone marrow optic nerve (Table 1B). After HSCT, there was a reduction biopsy were negative. On Western blotting, the patient’s in the total number of antibodies against both target tissues. serum did not demonstrate any cancer-related retinal pro- But there was also some new antibody activity. The sig- teins. In the absence of malignancy, the patient’s condition nificance of these changes is unknown. was considered most consistent with ARRON syndrome. In August 2006, ganzfeld electroretinography (ERG) In April 2001, the patient began treatment with 20 mg and multifocal electroretinography (mfERG) showed slight prednisone three times daily (Fig. 1). improvement relative to results from July 2004. The The patient’s serum collected in December 2001 was pretransplant photopic B wave measured at 67.1 mVs right evaluated for antibody activity against pig retina (Table eye and 66.5 mVs left eye had improved to 75.4 mVs right 1A) and optic nerve (Table 1B). Specific regions of eye and 88.9 mVs left eye (normal: 75.9–175.9 mVs). reactivity on the Western blot, designated by their respec- Similarly, the photopic flicker had improved from 62.0 mVs tive molecular masses, were compared with the relative right eye and 57.1 mVs left eye to 72.0 mVs right eye and incidence of antibody activity of serum from 100 normal 77.8 mVs left eye (normal: 62.3–212.1 mVs). The scotopic postmenopausal women volunteers as control serum. B wave had improved from 400.6 mVs right eye and Table 1A reports the findings when the patient’s sera 376.5 mVs left eye to 458.5 mVs right eye and 468.9 mVs and the sera of the normal control population were reacted left eye (normal: 353.9–752.1 mVs). Although the right eye against pig retina. Table 1B reports the results of reactions mfERG revealed no difference after treatment, the left eye against pig optic nerve. mfERG demonstrated resolution of three of four points that Despite prednisone treatment and other immunologic were beyond 2 SDs from normal in the paracentral region. treatments outlined in Fig 1, the patient gradually lost