Broad locations of antigenic regions for anti-TRPM1 autoantibodies in paraneoplastic retinopathy with retinal ON bipolar cell dysfunction.

PURPOSE: Cancer-associated retinal ON bipolar cell dysfunction (CARBD), which includes melanoma-associated retinopathy (MAR), has been reported to be caused by autoantibodies against the molecules expressed in ON bipolar cells, including TRPM1. The purpose of this study was to determine the antigenic regions of the autoantibodies against TRPM1 in the sera of CARBD patients, in whom we previously detected anti-TRPM1 autoantibodies. METHODS: The antigenic regions against TRPM1 in the sera of eight CARBD patients were examined by Western blots using HEK293T cells transfected with the plasmids expressing FLAG-tagged TRPM1 fragments. The clinical course of these patients was also documented. RESULTS: The clinical course differed among the patients. The electroretinograms (ERGs) and symptoms were improved in three patients, deteriorated in one patient, remained unchanged for a long time in one patient, and were not followable in three patients. Seven of the eight sera possessed multiple antigenic regions: two sera contained at least four antigen recognition regions, and three sera had at least three regions. The antigen regions were spread over the entire TRPM1 protein: five sera in the N-terminal intracellular domain, six sera in the transmembrane-containing region, and six sera in the C-terminal intracellular domain. No significant relationship was observed between the location of the antigen epitope and the patients' clinical course. CONCLUSIONS: The antigenic regions of anti-TRPM1 autoantibodies in CARBD patients were present not only in the N-terminal intracellular domain, which was reported in an earlier report, but also in the transmembrane-containing region and in the C-terminal intracellular domain. In addition, the antigenic regions for TRPM1 were found to vary among the CARBD patients examined, and most of the sera had multiple antigenic regions.

Presumed cancer-associated retinopathy (CAR) mimicking Sudden Acquired Retinal Degeneration Syndrome (SARDS) in canines.

OBJECTIVE: To describe functional and structural features of presumed cancer-associated retinopathy (CAR) mimicking sudden acquired retinal degeneration syndrome (SARDS) in dogs and describe treatment outcomes. ANIMALS: Subjects were 17 dogs from 8 eight US states and Canada diagnosed with SARDS or immune-mediated retinitis (IMR) by 12 ophthalmologists. Nine eyes from seven deceased patients were used for microarray (MA), histology, or immunohistochemical (IHC) analysis. PROCEDURES: Dogs underwent complete ophthalmic examination, including retinal photography, optical coherence tomography (OCT), chromatic pupil light reflex testing (cPLR), and electroretinography (ERG), in addition to complete systemic examination. Histology, microarray, and IHC analysis were performed in CAR retinas to evaluate histological and molecular changes in retinal tissue. RESULTS: None of the patients evaluated satisfied previously established criteria for diagnosis of SARDS (flat ERG+ no red - good blue PLR), and all were diagnosed with IMR. All patients were diagnosed with a cancer: meningioma (24%), sarcoma (18%), pituitary tumor (12%), and squamous cell carcinoma (12%), other (34%). Median survival time was 6 months from diagnosis (range 1-36 months). Most frequent systemic abnormalities were as follows: proteinuria (78%); elevated liver enzymes (47%); and metabolic changes (PU/PD, polyphagia - 24%). Immunosuppressive therapy resulted in the reversal of blindness in 44% of treated patients, with 61% of all treated patients recovering and/or maintaining vision. Median time for preservation of vision was 5 months (range 1-35 months). CONCLUSIONS: Observed changes are highly suggestive of immune-mediated damage in IMR-CAR eyes. A relatively high percentage of patients with CAR responded positively to immunosuppressive therapy.

Occurrence of major anti-retinal autoantibodies associated with paraneoplastic autoimmune retinopathy.

Autoantibodies (AAbs) against retinal antigens can be found in patients with cancer and unexplained vision loss unrelated to the cancer metastasis. Cancer-associated retinopathy (CAR) is a rare paraneoplastic visual syndrome mediated by AAbs. Our goal was to determine whether CAR patients with different malignancies have a specific AAb or repertoire of AAbs that could serve as biomarkers for retinal disease. We found AAbs against 12 confirmed retinal antigens, with α-enolase being the most frequently recognized. The significant finding of the study was a high incidence of anti-aldolase AAbs in colon-CAR, anti-CAII in prostate-CAR, and anti-arrestin in skin melanoma patients thus these AAbs could serve as biomarkers in the context of clinical presentation and could support the diagnosis of CAR. However, a lack of AAb restriction to any one antigenic protein or to one retinal cellular location makes screening for a CAR biomarker challenging.

Collapsin Response-Mediator Protein 5-Associated Retinitis, Vitritis, and Optic Disc Edema.

PURPOSE: Collapsin response-mediator protein 5 (CRMP5) immunoglobulin G (IgG) has been associated with paraneoplastic optic neuritis, vitritis, retinitis, or a combination thereof, but few reports of these findings exist in the literature. We reviewed the neuro-ophthalmic findings and visual outcomes in a large series of CRMP5 IgG-positive patients to characterize further its clinical phenotype and response to treatment. DESIGN: Retrospective case series. PARTICIPANTS: Seventy-six patients with CRMP5 autoimmunity examined at the Mayo Clinic, Rochester, Minnesota. METHODS: Single academic medical center chart review of all CRMP5 IgG-positive (serum titer, >1:240) patients seen between 2001 and 2017. MAIN OUTCOME MEASURES: Neuro-ophthalmic manifestations and outcomes of CRMP5 autoimmunity, coexisting neural autoantibody presence and paraneoplastic associations, and the impact of immunosuppressant therapy. RESULTS: Twenty-nine of 76 patients (38%) demonstrated neuro-ophthalmic manifestations. Of the 29 patients with neuro-ophthalmic findings, the median age was 67 years (range, 33-88 years) and 20 (69%) were women. Cancer was diagnosed in 62% of the patients (small-cell carcinoma in 83%). Neuro-ophthalmic symptoms occurred before the diagnosis of cancer in 72%. Seventeen of 29 patients (59%) showed ocular (i.e., anterior visual pathway or intraocular) manifestations; presenting median visual acuity was 20/50 (range, 20/20-counting fingers) and the final median visual acuity was 20/40 (range, 20/20-hand movements). Fourteen of 17 patients (82%) demonstrated optic neuropathy, with 12 of these patients also showing retinitis or uveitis. Three of 17 patients (18%) showed retinitis or uveitis without optic neuropathy. All 12 patients with optic neuropathy and a documented fundus examination at visual symptom onset demonstrated optic disc edema. No patients showed optic nerve enhancement on magnetic resonance imaging. Twelve of 29 patients (41%) demonstrated ocular motility dysfunction consisting of central nystagmus and diplopia. Among those receiving immunosuppressive therapy, visual function improved in 50%. CONCLUSIONS: In our cohort of 29 CRMP5 IgG-positive patients with neuro-ophthalmic manifestations, optic neuropathy presented with optic disc edema, often associated with uveitis, retinitis, or both. The combination of retinitis, vitritis, and optic disc edema without optic nerve enhancement should prompt serologic testing for CRMP5 IgG to expedite vision-sparing immunosuppressant therapy and a targeted search for a systemic cancer.

A case of melanoma-associated retinopathy with autoantibodies against TRPM1.

PURPOSE: To report a case of melanoma-associated retinopathy (MAR) with autoantibodies against the transient receptor potential cation channel, subfamily M, member 1 (TRPM1) with asymmetric severe vision loss. METHODS: We evaluated a patient with heel skin melanoma showing progressive vision loss in both eyes confirmed with a baseline ophthalmic examination, fluorescein angiography, spectral domain optical coherence tomography (OCT), visual field test, and full-field electroretinogram (ERG). Immunofluorescence assays and western blot analysis revealed autoantibodies in the patient's serum. RESULTS: The patient's best-corrected visual acuities were 20/50 in the right eye and hand motion in the left eye. Visual field test showed severely depressed visual fields especially in the left eye. Fluorescein angiography and OCT revealed extrafoveal choroidal neovascularization in the left eye. The patient had an electronegative ERG, suggesting MAR, and autoantibodies against TRPM1 and aldolase C were detected in the patient's blood sample. CONCLUSIONS: The clinical features of MAR patients with positive anti-TRPM1 autoantibodies can be manifested as severe vision loss, and the identification of autoantibodies can be helpful for confirming the diagnosis.

Melanoma-associated retinopathy.

Melanoma-associated retinopathy (MAR) is a rare paraneoplastic autoimmune manifestation of cutaneous malignant melanoma. Patients classically present with acute onset night blindness, positive visual phenomena and visual field defects, and typically have significantly reduced quality of life as a result. Early recognition of MAR is of prognostic significance as it can precede the diagnosis of primary or metastatic malignant melanoma, and early treatment can lower the risk of irreversible immunological damage to the retinal cells with improved visual outcomes. The focus of our review article is therefore to raise awareness of MAR and present the latest evidence relating to the investigation and management of this condition.

Small cell carcinoma presenting as ocular paraneoplastic syndrome due to CRMP-5.

We report the case of a lady who presented with 3 weeks of visual floaters and optic disc swelling. Subsequent investigations revealed deep white matter changes on brain imaging, and enlarged mediastinal nodes. The presence of anti-CRMP-5 antibodies finally led to the diagnosis of a paraneoplastic syndrome, and mediastinal lymph node biopsy confirmed the diagnosis of small-cell lung cancer. The learning points from this case include that optic neuritis can be the only presenting feature of a paraneoplastic neurological syndrome, and the usefulness of anti-neuronal antibody measurement as a diagnostic marker of an underlying paraneoplastic disease process. The great challenge is to recognise these tumour-associated autoimmune system presentations early, as they often appear long before the primary cancer is evident. Prompt treatment leads to an earlier reduction in circulating auto-antibody possibly due to reduction in tumour size, and thus less likelihood of permanent neuronal damage.

CLINICAL COURSE OF PARANEOPLASTIC RETINOPATHY WITH ANTI-TRPM1 AUTOANTIBODY IN JAPANESE COHORT.

PURPOSE: To report the clinical course of eyes with paraneoplastic retinopathy caused by an autoantibody against transient receptor potential cation channel, subfamily M, member 1 (TRPM1). METHODS: Ten paraneoplastic retinopathy patients with retinal ON-bipolar cell dysfunction, including six melanoma-associated retinopathy, from eight institutions in Japan were evaluated for the presence of an anti-TRPM1 antibody. The results of ophthalmic examinations and the presence of anti-TRPM1 antibody were analyzed. RESULTS: Five patients were positive for the anti-TRPM1 antibody. These patients had similar clinical findings in both eyes at the time of diagnosis; relatively preserved best-corrected visual acuity, absence of fundus and optical coherence tomography abnormalities, and specific abnormalities of the electroretinography (ERG); and negative-type ERGs with bright stimulus flashes. One patient whose retinal ON-bipolar cells remained dysfunctional for the entire testing period, although the anti-TRPM1 antibody had disappeared. On the other hand, the ERGs recovered in 2 cases within 2 years after the onset. One case progressed to additional impairment of the photoreceptors with deterioration of ERGs. One case died and the clinical course was unavailable. CONCLUSION: Paraneoplastic retinopathy patients with retinal ON-bipolar cell dysfunction possess autoantibodies against TRPM1 at the onset of the disease process; however, the clinical course of these eyes can be different.

Unique epitopes for carbonic anhydrase II autoantibodies related to autoimmune retinopathy and cancer-associated retinopathy.

High titers of anti-carbonic anhydrase II (anti-CA II) autoantibodies were detected in sera of patients with autoimmune retinopathies (AR), including cancer-associated retinopathy (CAR) and also in normal population. The goal was to investigate whether unique immunodominant epitopes for anti-CAII autoantibodies occur in AR and CAR. A cohort of 216 patients with symptoms of AR and CAR and healthy controls, seropositive for anti-CA II autoantibodies were analyzed for the prevalence of CAII major domains. Autoantibody titers against CAII in sera were determined by ELISA. Biotinylated 12-mer synthetic peptides, overlapping the entire sequence of CAII, were coated onto a microplate and monospecific sera were tested for their ability to bind specific peptides by ELISA. We identified 3 epitopes common for AR, CAR and control subjects but the key epitopes were significantly different between sera from different groups (p = 0.009). Ninety one percent of AR sera predominantly reacted with the N-terminal epitope 85-90 (p < 0.0001), which corresponded to the catalytic core of the enzyme. The major epitope for 77% of CAR autoantibodies was found to be reactive with the peptide 218-222 (P = 0.0005) clustered within the α-helix. The analysis of epitope position in a 3D structure of the native CAII revealed their partial or full exposure on the protein surface. Anti-CAII autoantibodies from normal healthy controls did not share the major determinants with either group of patients. We also observed an epitope shift in antibody recognition from the AR-like epitope profile to the CAR-like profile in a patient who developed cancer 2 years after initial symptoms of vision loss (p < 0.0001). In conclusion, autoantibodies against CAII recognized different epitopes, depending whether they originated in patients with or without cancer. Also, antibodies targeted different determinates within the molecule during the development of retinopathy from non-paraneoplastic to paraneoplastic, suggesting an intramolecular epitope spreading phenomenon. Accurate distinction between AR and CAR is critical in designing immunotherapies and better diagnosis for those two conditions.

Recoverin-associated retinopathy secondary to Warthin tumor of parotid gland.

PURPOSE: To present a case of photoreceptor degeneration associated with a benign Warthin tumor of the parotid gland. CASE REPORT: A 57-year-old man visited our clinic complaining of blurred vision in both eyes. His best-corrected visual acuity was 0.07 in the right and 0.04 in the left eyes. All components of the full-field electroretinograms (ERGs) were reduced in both eyes. The focal macular ERGs were extinguished in both eyes, which was consistent with the deterioration of the outer retina in optical coherence tomographic images. Positron emission tomography showed (18)F-fluorodeoxy glucose accumulation in the left parotid gland. Parotidectomy was performed, and the histopathology of the specimen had features compatible with a Warthin tumor without malignancy. Western blot analysis of the patient's sera detected an antibody against recoverin. In addition, the tumor tissue had an aberrant expression of recoverin. CONCLUSION: The findings in this case indicate that recoverin-associated retinopathy can develop secondary to a benign Warthin tumor.

Autoimmune retinopathy and antiretinal antibodies: a review.

PURPOSE: To review the current state for diagnosis and management of autoimmune retinopathy. METHODS: A review of the literature was performed, encompassing autoimmune retinopathy including paraneoplastic retinopathy (cancer-associated retinopathy, melanoma-associated retinopathy, and bilateral diffuse uveal melanocytic proliferation) and non-paraneoplastic autoimmune retinopathy. Based on this review, current principles and techniques for diagnosis and the treatments reported for autoimmune retinopathy are discussed with the aim to clarify some of the confusion that exists regarding this complex entity. RESULTS: Autoimmune retinopathy encompasses a spectrum of retinal degeneration phenotypes. The clinical features, fundus characteristics, and electroretinogram findings for paraneoplastic and non-paraneoplastic retinopathy are reviewed. The different antiretinal antibodies reported in these entities are described. The diagnostic approaches for detecting these antiretinal antibodies and their limitations are covered. The treatments reported for autoimmune retinopathy and their outcomes are reviewed. CONCLUSION: Among the myriad of antiretinal antibodies reported, challenges persist in determining which antibodies are pathogenic and which are benign and what factors cause antiretinal antibodies to become pathologic. There also remain difficulties in the detection and accurate measurement of antiretinal antibodies, and the response to therapeutic intervention in autoimmune retinopathy is variable.

A case of paraneoplastic optic neuropathy and outer retinitis positive for autoantibodies against collapsin response mediator protein-5, recoverin, and α-enolase.

BACKGROUND: Specific cross-reacting autoimmunity against recoverin or collapsin response mediator protein (CRMP)-5 is known to cause cancer-associated retinopathy or paraneoplastic optic neuropathy, respectively. We report a rare case with small cell lung carcinoma developing bilateral neuroretinitis and unilateral focal outer retinitis positive for these antibodies. CASE PRESENTATION: A 67-year-old man developed bilateral neuroretinitis and foveal exudation in the right eye. Optical coherence tomography showed a dome-shaped hyperreflective lesion extending from inner nuclear layer to the photoreceptor layer at the fovea in the right eye. Single-flash electroretinography showed normal a-waves in both eyes and slightly reduced b-wave in the left eye. Results of serological screening tests for infection were within normal limits. The patient's optic disc swelling and macular exudation rapidly improved after oral administration of prednisolone. Systemic screening detected lung small cell carcinoma and systemic chemotherapy was initiated. Immunoblot analyses using the patient's serum detected autoantibodies against recoverin, CRMP-5, and α-enolase, but not carbonic anhydrase II. Neuroretinitis once resolved after almost remission of carcinoma on imaging but it recurred following the recurrence of carcinoma. CONCLUSIONS: The development of neuroretinitis in this cancer patient with anti-retinal and anti-optic nerve antibodies depended largely on the cancer activity, suggesting the possible involvement of paraneoplastic mechanisms. Patients with paraneoplastic optic neuropathy and retinopathy are likely to develop autoimmune responses against several antigens, thus leading to various ophthalmic involvements.

Diagnosis of occult melanoma using transient receptor potential melastatin 1 (TRPM1) autoantibody testing: a novel approach.

PURPOSE: To report the first case of melanoma-associated retinopathy (MAR) and underlying occult melanoma diagnosed based on the presence of serum transient receptor potential melastatin 1 (TRPM1) autoantibodies. DESIGN: Interventional case report with basic science correlation. PARTICIPANTS: One patient with MAR. INTERVENTION: Testing for the presence of serum TRPM1 autoantibodies. MAIN OUTCOME MEASURES: Diagnosis of an occult melanoma involving the axillary lymph nodes (unknown primary site) and MAR based on the presence of TRPM1 autoantibodies in the patient's serum. RESULTS: The patient's clinical exam was remarkable for mild intraocular inflammation in both eyes and retinal hemorrhages with an apparent choroidal neovascularization in the left eye, which was confirmed by fluorescein angiography and indocyanine green angiography testing. Humphrey visual field 30-2 SITA-fast (Humphrey Visual Field Analyzer, Carl Zeiss Meditec, Inc, Dublin, CA) demonstrated diffuse depression in both eyes out of proportion to the clinical exams, prompting electroretinography testing that revealed an electronegative response. Dark-adapted thresholds were markedly elevated and mediated by cones. Due to concern for MAR, a systemic work-up for melanoma was performed by the primary care physician that was unrevealing. Given our continued clinical suspicion for MAR, the patient's serum was sent for evaluation for TRPM1 autoantibodies. The patient's serum applied to normal human retina exhibited positivity in the inner nuclear layer. Application of the patient's serum to wild-type and TRPM1 knockout mouse retina revealed strongly labeled bipolar cells in the wild-type retina, but not in the TRPM1 knockout retina, indicating TRPM1-dependent immunoreactivity. The antigen was confirmed as TRPM1 by labeling of TRPM1-transfected human embryonic kidney 293 cells. Additional systemic work-up prompted by this finding resulted in identification of an occult metastatic melanoma involving the axillary lymph nodes with an unknown primary site. The patient underwent surgical excision of the occult melanoma without evidence of other sites of metastases. He also received intravenous immunoglobulin therapy and his vision has stabilized. CONCLUSIONS: This is the first reported case of a melanoma-associated retinopathy diagnosed utilizing the innovative approach of testing for serum TRPM1 autoantibodies.

Melanoma-associated retinopathy treated with ipilimumab therapy.

Melanoma-associated retinopathy (MAR) is a rare autoimmune syndrome in patients with melanoma characterized by visual disorders. MAR is induced by the degeneration of bipolar cells of the retina and the presence of serum autoantibodies against retina proteins. Ipilimumab, an anti-cytotoxic T lymphocyte-associated antigen 4 antibody, improves survival in previously treated patients with metastatic melanoma, but is responsible for a spectrum of immune-related adverse events. Administration of ipilimumab to patients with autoimmune diseases (such as MAR or vitiligo) is actually not recommended. We report a patient presenting with MAR occurring during a melanoma relapse. Surgery and chemotherapy had no effect on visual acuity and melanoma increased. In the absence of alternative antitumoral treatment, we focused on the vital prognosis and treated the patient with ipilimumab. Two years after the treatment the patient is free from new metastasis but has presented with exacerbation of vitiligo and MAR. In the very rare case of melanoma with autoimmune disease without a therapy option, ipilimumab could be discussed, taking into account the fact that it can be effective on tumor burden but can also increase autoimmunity.

Pancreatic neuroendocrine paraneoplastic optic neuropathy: confirmation with antibody to optic nerve and hepatic metastasis.

A 68-year-old woman presented with bilateral visual loss as the only clinical manifestation of an occult pancreatic nonsecretory neuroendocrine tumor (NET). The suspected diagnosis of paraneoplastic optic neuropathy was confirmed using immunofluorescence assays to demonstrate the presence of antibodies in the patient's serum that reacted with antigen(s) in the optic nerve and in the pancreatic NET hepatic metastasis. Treatment of the underlying cancer was followed by marked improvement in visual function.

Blepharospasm and apraxia of eyelid opening associated with anti-Hu paraneoplastic antibodies: a case report.

PURPOSE: To report a case of blepharospasm associated with anti-Hu paraneoplastic antibodies that was treated successfully with botulinum toxin A. DESIGN: Case report. PARTICIPANTS: A 57-year-old man had altered mental status and a 20-pound weight loss at presentation. Evaluation revealed an occult small-cell lung cancer. Despite initiating appropriate chemotherapy, his mental status worsened and over the course of several weeks, he was unable to open his eyes because of forceful orbicularis contractions. Neuroimaging and cerebrospinal fluid studies found no evidence of intracranial metastases. However, his paraneoplastic panel was positive for anti-Hu antibodies. He was diagnosed with paraneoplastic encephalitis and blepharospasm. INTERVENTION: Intravenous Solu-Medrol (Pharmacia & Upjohn Co, Bridgewater, NJ) and periocular injections of botulinum toxin A. MAIN OUTCOME MEASURES: Ocular disease control. RESULTS: Intravenous Solu-Medrol improved his mental status, but did not change his ocular symptoms. Subsequent botulinum toxin A injections allowed spontaneous eyelid opening. CONCLUSIONS: Although paraneoplastic blepharospasm is rare, it is an important diagnosis to be aware of because paraneoplastic disorders often herald an occult tumor. This is the only case of paraneoplastic blepharospasm that the authors know of that was the result of anti-Hu antibodies as well as the only case that was treated with botulinum toxin A.

Bilateral paraneoplastic optic neuropathy and unilateral retinal compromise in association with prostate cancer: a differential diagnostic challenge in a patient with unexplained visual loss.

We report a 77-year-old Caucasian man with a 1-year complaint of unexplained visual loss and a 4-year history of prostate cancer. A complete ophthalmologic exam, Goldmann visual fields (GVFs), intravenous fluorescein angiography (IVFA), macular and disc optical coherence tomography (OCT), pattern-reversal visual evoked potentials (PVEPs), and flash electroretinograms (ERGs) were performed. On examination, visual acuity was reduced bilaterally. Fundus exam showed juxtapapillary changes (OS > OD) and, in OS, disc pallor, peripheral RPE dropout and whitish retinal discoloration along the arcades. OCTs were normal OU. Cancer-associated retinopathy (CAR) was suspected. A flash ERG was normal OD and markedly reduced and electronegative OS. An IVFA showed bilateral juxtapapillary staining and changes highly suggestive of sequelae of central retinal artery occlusion (CRAO) OS , in which a cilioretinal artery existed along the papillomacular bundle. GVFs showed bilateral blind spot enlargement and centrocecal scotomas, and PVEPs were delayed. These findings suggested cancer-associated optic neuropathy (CAON), confirmed by presence of anti-optic nerve autoantibodies (auto-Abs). No anti-retinal auto-Abs were found. CAON is a less common paraneoplastic manifestation than CAR and it is rarely observed in association with prostate cancer. A combination of visual function testing methods permitted the recognition, in this highly unusual case, of the concurrent presence of unilateral ERG changes most likely attributable to CRAO complications in OS, in all likelihood unrelated to CAON, and not to be confused with unilateral CAR. Auto-Ab testing in combination with visual function tests helps achieve a better understanding of the pathophysiology of vision loss in paraneoplastic visual syndromes.

A factor found in the IgG fraction of serum of patients with paraneoplastic bilateral diffuse uveal melanocytic proliferation causes proliferation of cultured human melanocytes.

PURPOSE: To determine if there is a factor in the serum of patients with bilateral diffuse uveal melanocytic proliferation (BDUMP) that causes melanocytic proliferation. METHODS: Human melanocytes and melanoma cells were grown and exposed to serum or plasma of patients with BDUMP, other neoplastic conditions, or control media. Preliminary studies using serum were conducted in an unmasked fashion. In addition, IgG-depleted and IgG-enriched plasma was also tested in a similar fashion. Experiments using plasma were conducted triple masked. To show that the proliferation was melanocyte selective, human dermal fibroblasts, keratinocytes, and ovarian cancer cells were treated with plasma of the BDUMP cases or controls, and the effect of this exposure on their proliferation was quantified. RESULTS: At 72 hours, the serum of BDUMP patients caused statistically significant increased proliferation of normal human melanocytes. Further studies at 6 days demonstrated similar findings. In addition, melanocytes grown in BDUMP serum exhibited a disorganized morphology with foci of multilayered cells. Cultured melanoma cells also showed statistically significant increase in growth in serum from BDUMP patients compared with controls. Masked plasma studies further confirmed these findings and showed that the IgG fraction appeared to contain the melanocyte growth-stimulating factor. The human fibroblasts, keratinocytes, and ovarian cancer cells did not show an increase in growth with the BDUMP plasma treatment. CONCLUSION: Patients with BDUMP have a factor in the IgG fraction that selectively causes melanocyte proliferation. How it causes proliferation of human melanocytes and melanoma cells needs to be further elucidated.

Autoantibody against transient receptor potential M1 cation channels of retinal ON bipolar cells in paraneoplastic vitelliform retinopathy.

BACKGROUND: Paraneoplastic retinopathy is caused by the cross-reaction of neoplasm-directed autoantibodies against retinal antigens and results in retinal damage. Paraneoplastic vitelliform retinopathy, a presumed paraneoplastic retinopathy with features of atypical melanoma-associated retinopathy, has recently been reported in patients with metastatic melanoma. Ocular ultrastructure and its autoantibody localization of paraneoplastic vitelliform retinopathy are still indefinable. This is the first report of anti-transient receptor potential M1 antibody directly against human retinal bipolar dendritic tips in a melanoma patient with paraneoplastic vitelliform retinopathy. CASE PRESENTATION: We present a pair of postmortem eyes of an 80-year-old male with metastatic cutaneous melanoma, who developed paraneoplastic vitelliform retinopathy. The autopsied eyes were examined with light microscopy, immunohistochemistry, and transmission electron microscopy. Microscopically, the inner nuclear layer and outer plexiform layer were the most affected retinal structures, with local thinning. The lesions extended to the outer nuclear layer, resulting in focal retinal degeneration, edema, and atrophy. No active inflammation or melanoma cells were observed. Immunohistochemistry showed tightly compact bipolar cell nuclei (protein kinase C alpha/calbindin positive) with blur/loss of ON bipolar cell dendritic tips (transient receptor potential M1 positive) in diffusely condensed outer plexiform layer. The metastatic melanoma cells in his lung also showed immunoreactivity against transient receptor potential M1 antibody. Transmission electron microscopy illustrated degenerated inner nuclear layer with disintegration of cells and loss of cytoplasmic organelles. These cells contained many lysosomal and autophagous bodies and damaged mitochondria. Their nuclei appeared pyknotic and fragmentary. The synapses in the outer plexiform layer were extensively degenerated and replaced with empty vacuoles and disintegrated organelles. CONCLUSION: This case provides a convincing histological evidence of melanoma-associated autoantibodies directly against transient receptor potential M1 channels that target the ON bipolar cell structures in the inner nuclear and outer plexiform layers in paraneoplastic vitelliform retinopathy.