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Biomedical subjects

C E Thirkill

Publications and source records attributed to C E Thirkill.

At least 19 recordsLinked to original sources
PubMed2006

Immune-mediated paraneoplasia.

Cancers induce a loss of homeostasis through the uncontrolled production and release of a variety of biologically active cellular products, natural compounds produced in unnatural quantities within abnormal anatomical locations. Often, there is an immune response to which the cancerous growth may succumb, or have the characteristics required to survive. If, during its proliferation, the cancer should coincidentally express a potent autoantigen then the organ in which that antigen is normally located may be damaged by the resultant immune response. Paradoxically, this aberrant immunological activity rarely has any appreciable inhibitory effects on the causal cancer. This inconsistency may result from the cancer's ability to block the host's immunological activity, while the affected organ situated elsewhere has no such capacity. Some predisposition, such as trauma to the affected organ, may prove a prerequisite that provides access to hitherto immunologically privileged sites. The effects of the subsequent loss of tolerance are often the first indication of a health problem, prompting the patient to seek medical help. Immune-mediated paraneoplasia is identified by antibody activity with any of a small but growing collection of organ-specific antigens demonstrated to have a distinct disease association and an apparent involvement in autoimmunity. Examples of the most common are described as introduction to this unusual collection of autoimmune diseases, for which in some cases the cause is known, and these may provide insight into the cause of those that are not.

Autoantibodies↗
PubMed2005

Incidence of antiretinal antibodies in melanoma: screening of 77 serum samples from 51 patients with American Joint Committee on Cancer stage I-IV.

BACKGROUND: Patients with melanoma-associated retinopathy (MAR) experience different visual symptoms caused by the production of antitumoral antibodies that cross-react with retinal epitopes. Immunofluorescence assays of serum from patients with MAR on sectioned monkey or human retina characteristically reveal antibody activity located within the inner nuclear layer, with a focus of activity upon the membranes of bipolar cells. OBJECTIVES: We inquired into the association with disease of this serological abnormality by evaluating sera from patients with melanoma with no MAR-like signs or symptoms. METHODS: Groups of patients were selected with different stages of melanoma (American Joint Committee on Cancer stages I-IV). Seventy-seven serum samples from 51 patients with melanoma were examined by indirect immunohistochemical assay on sections of human retina. RESULTS: Of the 77 serum samples, 53 were found to contain antibodies reactive with various components of retina. Eight were from 17 sera from patients in stage I or II, 14 were from 23 sera from patients in stage III, and 31 were from 37 sera from patients in stage IV. Statistical analysis revealed a correlation between antibody activity and the stage of disease, with a higher percentage of antibody activity in advanced stages (P = 0.002). CONCLUSIONS: The presence of antiretinal antibodies in patients with melanoma without ocular symptoms appears to be more common than previously suspected. Antibody activity similar to that ascribed to the MAR syndrome appears in some patients with melanoma who have no MAR-like retinopathy. Follow-up studies will determine if patients with antiretinal antibodies go on to develop MAR and if staining intensity and staining patterns change over the course of the disease.

Adult↗
PubMed2003

Melanoma-associated retinopathy: high frequency of subclinical findings in patients with melanoma.

BACKGROUND: Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome with symptoms of night blindness, light sensations, visual loss, defect in visual fields, and reduced b-waves in the electroretinogram. Patients with MAR often suffer from a sudden onset of ocular symptoms that are believed to result from antibody production against melanoma-associated antigens that cross-react with corresponding epitopes on retinal depolarizing bipolar cells. OBJECTIVES: To correlate the frequency of subclinical symptoms suggestive of MAR in melanoma patients to different stages of disease, patient age, type and thickness of the primary tumour, form of therapy, S-100 level and tumour burden. METHODS: We analysed 28 patients with melanoma in stages I-IV (according to the American Joint Committee on Cancer tumour classification) for the presence of subclinical MAR symptoms using scotopic electroretinography, static and kinetic perimetry and nyctometry. RESULTS: Seven patients had clinical signs and symptoms consistent with MAR, 18 had some indications, while the remaining three had none. We found no correlation between clinical symptoms and stage of disease, tumour burden or S-100 level, but findings suggestive of MAR were observed more frequently in advanced stages of disease. CONCLUSIONS: Subclinical retinal involvement characteristic of MAR appears to be more common than previously suspected in patients with cutaneous malignant melanoma. Our findings in this small cohort seem to indicate that the percentage of patients with symptoms suggestive of MAR is higher in advanced stages of disease. Further clinical studies are required to evaluate if the presence of subclinical symptoms suggestive of MAR is correlated with a worse prognosis and a shortened progression-free and overall survival.

Adult↗
PubMed2001

Clinical and immunologic characteristics of melanoma-associated retinopathy syndrome: eleven new cases and a review of 51 previously published cases.

OBJECTIVE: To evaluate the signs, symptoms, and immune responses of patients with melanoma-associated retinopathy (MAR) syndrome. MATERIALS AND METHODS: We reviewed the clinical and immunologic findings of 62 MAR syndrome patients. They include 25 patients from our institution (11 not previously reported) and 37 patients reported from other institutions. RESULTS: There were 33 men and seven women (no gender information is available for the remaining 22 cases). Age at onset of the visual disturbance averaged 57.5 years (range, 30-78). Visual acuity of 20/60 or better was initially present in 82%. Fundus examination was normal in 44%, optic disc pallor was present in 23%, and retinal vessel attenuation was present in 30%. Vitreous cells were present in 30%. The latency from melanoma diagnosis to recognition of MAR syndrome averaged 3.6 years (range, 2 months to 19 years). Seven patients sustained visual improvement with various treatment regimens, especially with intravenous immunoglobulin and cytoreductive surgery (metastasectomy). Indirect immunohistochemical staining of the bipolar layer was typical, but several other retinal elements were also reactive. Tissue from a metastatic melanoma excised from one of the patients expressed antigens that reacted with antiretinal antibodies. CONCLUSION: MAR syndrome demonstrates diverse clinical and immunologic features. Treatment, especially intravenous immunoglobulin and cytoreductive surgery (metastasectomy), improves vision in some cases.

Adult↗
PubMed2000

Retinal pigment epithelial hypersensitivity, an association with vision loss: RPE hypersensitivity complicating paraneoplastic retinopathies.

PURPOSE: Paraneoplastic retinopathies are currently identified and classified according to specific anti-retina antibody reactions. These cancer-induced retinal degenerations can be accompanied by changes in the character of the retinal pigment epithelium (RPE) indicative of additional, and superimposed, pathologic activity. The antibody reactions of 11 paraneoplastic retinopathy patients were evaluated to identify those whose immunologic abnormalities included indications of RPE hypersensitivity. The pathologic significance of this anomaly was evaluated upon viable monolayers of RPE, in the presence and absence of complement. METHODS: Comparisons of antibody reactions were made using: (1) indirect immunohistochemistry on sections of rhesus monkey eyes; (2) Western blot reactions on extracts of rhesus monkey retina and in vitro-propagated rhesus RPE; and (3) an evaluation of antibody influence upon the metabolic activity of viable monolayers of rhesus RPE cells. RESULTS: Indirect immunohistochemistry on sections of monkey eyes identified antibodies reactive with RPE in four of the 11 cancer patients. The same four were found to identify a 57 kd protein component of these cells in Western blot reactions of RPE and to inhibit the metabolic activity of viable RPE cells through actions enhanced by the addition of complement. One subject from the reference comparison control group, a cancer-free patient with age-related macular degeneration, also exhibited comparable antibody activity with RPE. CONCLUSIONS: RPE hypersensitivity can present as a superimposed immunologic complication to the retinal degenerations of paraneoplastic retinopathies and those unrelated to malignancies. When activated, humoral aspects of the immune response are able to impart pathologic effects that inhibit RPE homeostasis and, consequently, the essential supportive functions of these cells. Since this immunologic abnormality is not confined to cancer patients, it should be considered potentially harmful when encountered in association with any type of vision loss.

Animals↗
PubMed1999

Clinical and immunocytochemical findings in a case of melanoma-associated retinopathy.

OBJECTIVE: To describe an unusual case of melanoma-associated retinopathy (MAR). DESIGN: Retrospective, observational case report and experimental study. PARTICIPANTS: A 61-year-old man with a history of cutaneous melanoma, acquired bilateral central scotomas, and night blindness. INTERVENTION: Serial full-field electroretinography (ERG) and Goldmann perimetry were performed. Serum was screened for cancer-associated retinopathy (CAR) antibodies by Western blotting. Sections of human and rat retina were examined by immunofluorescence microscopy to determine whether retinal cells were reactive with this patient's serum. A metastatic workup was performed. MAIN OUTCOME MEASURES: Electroretinography, Goldmann visual field testing, and immunocytochemistry were performed. RESULTS: The results were as follows: (1) The ERG showed a profound loss of the b-wave amplitude and a "negative" b-wave characteristic of congenital stationary night blindness; (2) a central scotoma and peripheral constriction were identified on Goldmann visual field tests; (3) as in other patients with MAR, bipolar cells in human and rat retinas were immunolabeled with this patient's serum; and (4) a previously unsuspected focus of metastatic melanoma was discovered. CONCLUSIONS: Recognition of this condition may help to identify an occult focus of metastatic melanoma.

Blotting, Western↗
PubMed1999

An unusual type of cancer-associated retinopathy in a patient with ovarian cancer.

We studied a case of unusual retinopathy in a 35-year-old woman who presented with bilateral visual deterioration due to retinal pigmentary mottling and serous elevation in the posterior pole. Two years before, she had undergone hysterectomy and bilateral salphingo-oophorectomy for ovarian cancer. Her electroretinogram became subnormal, and her fluorescein angiogram exhibited multiple deep retinal pigment epithelial leakages and subretinal dye pooling in both eyes. Corticosteroid therapy failed to prevent visual loss. She was found to possess antibodies against retinal 45 kd protein. This led to a diagnosis of cancer-associated retinopathy with atypical protein profile. We report a rare variety of cancer-associated retinopathy in a patient with-ovarian cancer.

Adenocarcinoma↗
PubMed1999

The 22-kDa antigen in optic nerve and retinal diseases.

OBJECTIVE: Patients with unexplained visual loss were evaluated for the possibility of immunologic involvement. Antibody reactions were sought that might identify a common indication of retinal hypersensitivity. METHODS: The enzyme-linked immunosorbent assay (ELISA) and Western blot analysis were used to identify autoantibody reactions with retina and optic nerve components. Comparisons were made with the autoantibody reaction of normal subjects and patients with recognized forms of retinal decay: macular degeneration, retinitis pigmentosa, diabetic retinopathy, and paraneoplastic retinopathy. RESULTS: Eight patients, one man and seven women, were found to produce an autoantibody reaction with retina and optic nerve, including a novel 22-kDa neuronal antigen present within the retina and optic nerve. One of the eight had retinopathy associated with melanoma (MAR Syndrome). Seven of the eight patients had electroretinogram abnormalities, varying from mild to severe. Six displayed features of optic atrophy. One patient with progressive visual loss had visual function stabilized after immunosuppressive therapy. CONCLUSIONS: In the eight cases described, unexplained visual loss was associated with autoantibody reactions with retina and optic nerve, including a common antibody reaction with a 22-kDa neuronal antigen found in the retina and optic nerve. All the patients had either an abnormal electroretinogram or optic atrophy. Six patients had both. The 22-kDa immunologic marker may not be directly involved in the patient's vision loss, but rather may be related to a nonspecific destruction of retina and optic nerve. However, the marker may be useful in identifying a specific subgroup of patients for further analysis.

Adult↗
PubMed1998

Paraneoplastic optic neuropathy and autoantibody production in small-cell carcinoma of the lung.

A 59-year-old woman presented with acute-onset, bilateral, painless loss of vision, dysarthria, and ataxia. Ophthalmoscopy showed bilateral optic disc edema. A magnetic resonance scan of the head was normal. Chest radiography showed mediastinal adenopathy. Mediastinoscopy and biopsy identified small-cell carcinoma of the lung. An autoantibody to optic nerve and retina was demonstrated in the patient's serum. An electroretinogram was normal. The patient was diagnosed with a paraneoplastic optic neuropathy and paraneoplastic cerebellar syndrome. After treatment for her lung cancer, the patient remains stable from a visual and neurologic standpoint.

Acute Disease↗
PubMed1997

Autoimmune retinopathy in the absence of cancer.

PURPOSE: To report the clinical and immunologic features of two patients with progressive retinal degeneration and circulating antiretinal antibodies without systemic malignancy. METHODS: Two patients were followed up for 5 to 7 years. Comprehensive medical and ophthalmic examinations and visual function testing included manual perimetry and standardized electroretinography. Patient sera were tested for antiretinal antibodies by Western blot and immunoperoxidase indirect cytochemistry techniques. RESULTS: Two patients had family history of autoimmune disease. Each had severe monocular visual loss with photopsia, a ring scotoma, and abnormal electroretinogram despite a normal-appearing ocular fundus. One had a flat electroretinogram; the other had inner retina dysfunction, with selective b wave loss and abnormal oscillatory potentials. Both patients' sera had antiretinal antibodies that specifically labeled the inner plexiform layer of donor retina by indirect immunoperoxidase testing. Neither had any sign of cancer. CONCLUSIONS: In two patients without systemic malignancy, the symptoms, perimetric findings, and normal fundus appearance resembled cancer associated retinopathy. Electroretinography and antibody findings indicating dysfunction of the inner retina are distinct from those of cancer-associated retinopathy. These two cases raise the possibility of an autoimmune mechanism for retinal degeneration that is not cancer associated. Further study is necessary to determine the role of antiretinal antibodies in these patients.

Adult↗
PubMed1997

Paraneoplastic retinopathy associated with metastatic cutaneous melanoma of unknown primary site.

PURPOSE: To describe further the clinical and immunological features of cutaneous melanoma-associated retinopathy, which is an infrequent form of paraneoplastic syndrome. METHODS: We studied the salient clinical and immunological aspects of a 66-year-old man with metastatic cutaneous melanoma to lymph nodes of unknown primary site who developed melanoma-associated retinopathy. RESULTS: There was gradual loss of vision in the left eye. Colour vision and night vision were not affected. Visual fields showed arcuate defects. A full-field electroretinogram demonstrated attenuation of the b-wave amplitude in the left eye. The a-wave was intact. Indirect immunofluorescence techniques showed that the antibody reactions took place mainly in the outer plexiform layer of the retina. CONCLUSIONS: Bipolar cells seem to be the target in melanoma-associated retinopathy. Contrary to previous reports, night blindness may not be a universal finding.

Aged↗
PubMed1997

Paraneoplastic retinopathy: a novel autoantibody reaction associated with small-cell lung carcinoma.

We present the case of a 74-year-old man with rapidly progressive bilateral visual loss, optic disc pallor, retinal arteriolar attenuation, and an abnormal electroretinogram with a 90% reduction in cone function and a 50% reduction in rod function. He was examined for a suspected cancer-associated retinopathy (CAR). Although he was found not to have expressed the previously reported 23-kd CAR antibody, high titers were found of an antibody to a 60-kd retinal protein, which as yet remains unidentified. An initial clinical search for an underlying cancer was unsuccessful, but 2 months later a mediastinal mass was found on chest x-rays, and biopsy confirmed a diagnosis of small-cell lung carcinoma. Combined therapy with oral corticosteroids and plasmapheresis resulted in a recovery of vision from counting fingers to 20/200 in the right eye and 20/40 to 20/25 in the left eye. Conventional chemotherapeutic management of the small-cell lung carcinoma was instituted, and the modest visual recovery was maintained. The visual improvement as well as lung tumor regression were accompanied by a decline in antibody titers from 1:2,000 pretreatment to 1:200 during the course of therapy. The absence of reactivity with the previously described 23-kd retinal antigen of the CAR syndrome does not exclude the diagnosis of paraneoplastic retinopathy in patients fitting the clinical profile of this disease.

Aged↗
PubMed1997

Melanoma-associated paraneoplastic retinopathy: case report and review of the literature.

A 51-year-old white male suffering from metastatic malignant melanoma of the skin presented with lymph node metastases and paraneoplastic retinopathy 4 years after resection of the primary tumour. There were no cerebral metastases. Ocular symptoms consisting of night blindness and sensations of 'shimmering lights' persisted after total resection of the inguinal lymph node metastases and administration of dacarbazine and prednisone. Perimetry of both eyes was abnormal with concentric restriction. Electroretinography showed significantly reduced amplitudes in both eyes. Only 11 patients with melanoma-associated retinopathy (MAR) have been described. High titres of autoantibodies against whole retina extract were detected by enzyme-linked immunosorbent assay (ELISA) reactions. Indirect immunohistochemistry showed strong autoantibody activity against retinal bipolar cells.

Autoantibodies↗
PubMed1996

Lung cancer-induced blindness.

Early investigations into the pathogenesis of vision loss in cancer patients noted the higher incidence with small cell carcinoma of the lung (SCCL), a neoplasia with suspected neuroendocrine origins [2-5,12,20,25,56,63,64]. The cause and effect relationship between the cancer and retinal deterioration was recognized, but the processes involved were not understood. Research eventually identified a sub-group of paraneoplastic retinopathy patients who exhibited indications of retinal hypersensitivity through their production of autoantibodies reactive with a single photoreceptor protein. The discovery of a small cell lung cancer culture actively expressing this same retinal autoantigen, provided tangible evidence to define a molecular basis for at least one type of paraneoplastic retinopathy. The identification of this immunologic anomaly illustrates how blindness can occur in some cancer patients, through the serendipitous initiation of ocular hypersensitivity, with vision loss developing as a cancer-induced autoimmune retinopathy.

Autoimmune Diseases↗