Phase II trial of chemotherapy alone for primary CNS and intraocular lymphoma.

PURPOSE: Primary CNS lymphoma (PCNSL) and primary intraocular lymphoma (IOL) are usually treated with radiation therapy alone or in combination with chemotherapy. The neurotoxicity of these treatments can be substantial. This study attempts to define the toxicity and efficacy of the treatment of this disease with chemotherapy alone. PATIENTS AND METHODS: Fourteen nonimmunocompromised patients were accrued to a chemotherapy regimen that incorporated a 24-hour infusion of high-dose methotrexate total dose of 8.4 g/m2 with leucovorin rescue; thiotepa 35 mg/m2; vincristine 1.4 mg/m2; dexamethasone; and intrathecal cytarabine (Ara-C) and methotrexate (MTV) administered in 21-day cycles. Seven patients were prospectively followed up with formal neuropsychologic assessments for evidence of CNS toxicity. RESULTS: The response rate was 100% with 11 (79%) complete responses and three (21%) partial responses. Cumulative survival and progression-free survival rates at more than 4.5 years were 68.8% and 34.3%, respectively. Median survival has not been reached, and median progression-free survival was 16.5 months. Toxicity included severe leukoencephalopathy that was clearly attributable to chemotherapy (two patients), grade 3 or 4 neutropenia in 50% of the cycles administered, ileus (one patient), and seizures (two patients). Mucositis and renal and hepatic toxicity were mild and not therapy limiting. CONCLUSION: The MTV regimen is generally well tolerated and produces a high complete response rate. Chemotherapy alone should be investigated further in this disease to assess the necessity of initial radiation therapy, either alone or in combined modality regimens, for the achievement of optimal response and survival.

A phase I/II study of the protease inhibitor ritonavir in children with human immunodeficiency virus infection.

BACKGROUND: Ritonavir, a potent antiretroviral protease inhibitor, has been approved for the treatment of adults and children with human immunodeficiency virus (HIV) infection. In a phase I/II study, we assessed the safety, tolerability, and pharmacokinetic profile of the oral solution of ritonavir in HIV-infected children and studied the preliminary antiviral and clinical effects. METHODS: HIV-infected children between 6 months and 18 years of age were eligible. Four dose levels of ritonavir oral solution (250, 300, 350, and 400 mg/m given every 12 hours) were evaluated in two age groups (2 years). Ritonavir was administered alone for the first 12 weeks and then in combination with zidovudine and/or didanosine. Clinical and laboratory parameters were monitored every 2 to 4 weeks. RESULTS: A total of 48 children (median age, 7.7 years; range, 0.5 to 14.4 years) were included in this analysis. Dose-related nausea, diarrhea, and abdominal pain were the most common toxicities and resulted in discontinuation of ritonavir in 7 children. Ritonavir was well absorbed at all dose levels, and plasma concentrations reached a peak 2 to 4 hours after a dose. CD4 cells counts increased by a median of 79 cells/mm3 after 4 weeks of monotherapy and were maintained throughout the study. Plasma HIV RNA decreased by 1 to 2 log10 copies/mL within 4 to 8 weeks of ritonavir monotherapy, and this level was sustained in patients enrolled at the highest dose level of 400 mg/m for the 24-week period. CONCLUSIONS: The oral solution of ritonavir has potent antiretroviral activity as a single agent and is relatively well tolerated by children when administered alone or in combination with zidovudine or didanosine.

The paradoxical effect of tumor necrosis factor alpha (TNF-alpha) in endotoxin-induced uveitis.

PURPOSE: To investigate the role of TNF-alpha in endotoxin-induced uveitis (EIU) in mice. METHODS: To neutralize TNF-alpha activity, mice were pretreated with either repeated injections of this cytokine or a single injection of antibody against it. The mice were then injected intraperitoneally with 500 micrograms endotoxin, to induce lethal septic shock, or into the footpad with 200 micrograms to induce EIU. RESULTS: Although both pretreatments conferred protection against the systemic toxic effects of LPS, TNF-resistant mice and mice treated with anti-TNF-alpha antibody demonstrated an exacerbation of EIU when compared to control animals. CONCLUSIONS: Unlike its apparent participation in the systemic effect of endotoxin, TNF-alpha is not directly involved in the pathogenesis of EIU and may even protect against the inflammatory processes of this disease.

Recurrent intraocular inflammation in endotoxin-induced uveitis.

PURPOSE: Endotoxin-induced uveitis (EIU) in rats and mice peaks 24 hours after endotoxin injection and is commonly assumed to be a monophasic disease. This study examined intraocular inflammation at later time points to determine whether endotoxin injection can induce recurrent intraocular inflammation in strains of mice with high or moderate levels of susceptibility to EIU. METHODS: EIU was elicited in two mouse strains with high (C3H/HeN) and moderate (FVB/N) susceptibility, by means of intraperitoneal injections of Salmonella typhimurium endotoxin. Inflammatory cells in the anterior and posterior segments of the eye were counted by a masked observer on histologic sections of eyes from 1 to 17 days after endotoxin injection. RESULTS: A bimodal distribution of inflammatory cell infiltration was noted in eyes from C3H/HeN mice. As previously reported, inflammation peaked at 24 hours after endotoxin injection. However, a second, more pronounced peak of intraocular inflammation occurred approximately 5 days after endotoxin injection. FVB/N mice had a single peak of intraocular inflammation 4 days after injection. CONCLUSIONS: Endotoxin injection in C3H/HeN elicits recurrent intraocular inflammation. The previously unrecognized second peak of inflammation is more severe than the initial inflammatory disease. Studies on this second inflammatory peak may be useful in determining the pathogenesis of recurrent uveitis in humans.

Monoclonal antibody against CD11b/CD18 inhibits endotoxin-induced uveitis.

PURPOSE: To examine the serial expression of cell adhesion molecules in C3H/HeN mice with endotoxin-induced uveitis, and to study the effect of treatment with a monoclonal antibody against Mac-1 on the development of endotoxin-induced uveitis. METHODS: Immunohistochemical staining was used to document the serial expression of Mac-1, intercellular adhesion molecule-1 (ICAM-1), and lymphocyte function-associated antigen-1 (LFA-1) in eyes of C3H/HeN mice with endotoxin-induced uveitis. Then, in two separate experiments, endotoxin-induced uveitis was produced in a total of 48 mice by injecting Salmonella typhimurium endotoxin into one hind footpad. At the time of endotoxin injection, 24 mice received an intraperitoneal injection of anti-Mac-1 antibody and 24 control mice received an intraperitoneal injection of rat IgG. Histopathologic sections of eyes taken 24 hours after endotoxin injection were graded by two masked observers on a scale of 0 to 4. RESULTS: Intercellular adhesion molecule-1 was first expressed on the ciliary body epithelium 6 hr after endotoxin injection and Mac-1 and LFA-1 were expressed on infiltrating inflammatory cells 12 hr after endotoxin injection. Treatment with anti-MAC-1 antibody significantly inhibited the development of ocular inflammation when compared with treatment with control IgG (P < 0.001). CONCLUSION: Intercellular adhesion molecule-1 is expressed in the eye before clinical or histologic signs of inflammation. Furthermore, treatment with antibody against Mac-1 significantly inhibits the development of endotoxin-induced uveitis in mice and suggests that anti-Mac-1 antibody may be useful for treating acute ocular inflammation.

The role of mast cells in endotoxin-induced uveitis.

PURPOSE: To investigate the role of mast cells in the induction of endotoxin-induced uveitis (EIU). METHODS: We previously showed that the mean mast cell number in the anterior uvea was greatest for Lewis rats, lowest for Brown Norway (BN) rats, and intermediate for LBNF1 rats. In the current experiment, we assessed the time of onset and severity of EIU in these three rat strains. We then studied changes in mast cell numbers in the anterior uvea during the induction period of EIU. RESULTS: Time of onset and severity of EIU were related to the number of mast cells in the anterior uvea. EIU occurred earliest in the Lewis rats, and the maximum mean grade of ocular inflammation on a scale of 0 (no inflammation) to 4 (severe inflammation) +/- standard error of the mean was 3.87 +/- 0.13 for Lewis rats, 1.06 +/- 0.06 for BN rats, and 1.19 +/- 0.12 for LBNF1 rats. The difference between the mean grade of inflammation in the Lewis rats and the other two strains was highly statistically significant (P < .001). In the Lewis rats, mast cell numbers +/- SEM decreased from 68.9 +/- 10.8 at baseline to 49.6 +/- 5.9 4 hr after lipopolysaccharide (LPS) injection and to 27.6 +/- 8.4 8 hr after LPS injection, suggesting that mast cell degranulation occurs before the development of EIU. CONCLUSION: Mast cells in the anterior uvea appear to potentiate endotoxin-induced ocular inflammation.

Endothelial leukocyte adhesion molecule-1 in endotoxin-induced uveitis.

Expression of endothelial leukocyte adhesion molecule-1 (ELAM-1) on endothelial cells leads to the attachment of polymorphonuclear leukocytes. The sequential expression of ELAM-1 and major histocompatibility complex (MHC) class II antigen was examined in the eyes of 59 Lewis rats with endotoxin-induced uveitis (EIU) after the injection of Salmonella typhimurium endotoxin. The eyes were enucleated at 2-hr intervals. Hematoxylin and eosin-stained paraffin-embedded sections and immunohistochemically stained cryostat sections were graded by two masked observers. The MHC class II antigen was expressed on cells in the iris and ciliary body 4 hr after injection of endotoxin and on the corneal endothelium, 8 hr postinjection. It was found that ELAM-1 was expressed first on cells of the ciliary body and iris 10 hr after the injection of endotoxin and on the corneal endothelium, 22 hr postinjection. Clinical and histopathologic disease developed 16 hr postinjection. Adherence of polymorphonuclear cells to the corneal endothelium was observed at the time of ELAM-1 expression. In conclusion, expression of ELAM-1 on ocular tissue occurred in EIU and appeared to promote polymorphonuclear cell accumulation in the anterior segment of the eye.

Topical cyclosporine inhibits mast cell-mediated conjunctivitis.

PURPOSE: Allergic conjunctivitis is a common condition caused by a mast cell-mediated hypersensitivity reaction to immunoglobulin E-bound allergens. The purpose of this study was to investigate the effect of topical cyclosporine A on the development of mast cell-mediated conjunctivitis in mice. METHODS: Allergic conjunctivitis was induced in C57BL/6 mice by topical applications of compound 48/80, a mast cell degranulating agent. In two separate experiments, mice were treated with topical cyclosporine A (0.05%, 0.2%, or 0.4%), prednisolone acetate 1%, or phosphate-buffered saline. Twenty-four hours after compound 48/80 instillation, the number of neutrophils, eosinophils, lymphocytes, macrophages, and the number of preserved goblet cells and undegranulated mast cells in the conjunctiva were counted by a masked observer. RESULTS: In both experiments, treatment with all three doses of cyclosporine A resulted in a statistically significant reduction in the number of infiltrating neutrophils and eosinophils compared to saline-treated controls. There was no significant difference in the treatment effect of cyclosporine and prednisolone acetate. In addition, there was increased preservation of goblet cells in the cyclosporine A-treated animals. Immunohistochemical staining showed a reduction in infiltrating lymphocytes and a smaller reduction in infiltrating macrophages in animals treated with cyclosporine compared to saline-treated controls. CONCLUSIONS: Topical cyclosporine A was effective in inhibiting the development of mast cell-mediated allergic conjunctivitis in mice. This study suggests that topical cyclosporine A may be effective in treating allergic conjunctivitis in humans.

Inhibition of leukocyte sticking and infiltration, but not rolling, by antibodies to ICAM-1 and LFA-1 in murine endotoxin-induced uveitis.

PURPOSE: Cell-adhesion molecules are critical elements in intravascular rolling and sticking of leukocytes during acute inflammation. In this process, selectins are thought to be involved in initial adhesion and rolling, and integrin-Ig superfamily interactions are believed primarily to mediate stronger adhesion and transendothelial migration. This study clarifies the role of two adhesion molecules, intercellular adhesion molecule (ICAM)-1 and leukocyte functional antigen (LFA)-1, in endotoxin-induced uveitis (EIU). METHODS: Intravital microscopy was used to record the movement and location of leukocytes in the irises of mice with uveitis induced by intravitreal injection of 250 ng Escherichia coli endotoxin. Each mouse concurrently received an intraperitoneal injection of monoclonal neutralizing antibodies for ICAM-1, LFA-1, or both or control irrelevant antibodies. RESULTS: Mice treated with endotoxin and control antibodies had an inflammatory response that was clearly present at the 6- and 24-hour time points and was mostly resolved by 48 hours. Mice that received anti-ICAM-1 or anti-LFA-1 had significantly fewer cells infiltrating their irises at 6 and 24 hours. Detailed analysis of the 6-hour time point recordings revealed that neither anti-ICAM-1 nor anti-LFA-1 significantly reduced the number of leukocytes rolling on venule endothelial surfaces, but the treatments reduced the number of firmly adherent cells. CONCLUSIONS: These data confirm previous reports that ICAM-1 and LFA-1 are important mediators of EIU. The dynamic in vivo images clearly support the hypothesis that integrin-mediated cell adhesion is more critical for the firm adhesion of sticking cells than for leukocyte rolling.

Uveitis induced by lymphocytes sensitized against a transgenically expressed lens protein.

PURPOSE: Previously established experimental models for lens-associated uveitis (LAU) are all mediated by antibodies. The present study analyzed the features of a novel experimental intraocular inflammatory eye disease that is mediated by lymphocytes targeted at a lens antigen. METHODS: Conventional technologies were used to generate three lines of transgenic (Tg) mice, expressing hen egg lysozyme (HEL) under the control of the alphaA-crystallin promoter. To induce intraocular inflammation, these Tg mice were injected with lymphocytes from syngeneic wild-type donors sensitized against HEL. Before their injection, the cells were stimulated in culture with HEL. To release lenticular material, some eyes were capsulotomized. Ocular histopathologic changes were examined by routine methods. Levels of HEL antibody were measured by enzyme-linked immunosorbent assay, whereas cellular immunity was determined by the lymphocyte proliferation assay. RESULTS: Intraocular inflammation developed in HEL-Tg mice injected with syngeneic lymphocytes sensitized against HEL. The severity of inflammation was directly related to the number of injected cells, as well as to the accessibility of HEL. The most intense inflammation was seen in Tg mice in which the lens was disintegrated due to high production of HEL. In mice with no apparent lenticular changes the inflammation was enhanced by capsulotomy. The inflammation affected all segments of the eye and persisted for at least 39 days after adoptive transfer of cells. Four days after cell injection, the inflammation consisted of subacute infiltration, with both mononuclear and polymorphonuclear leukocytes, whereas more chronic infiltration was seen at later times. Vigorous cellular immunity but no antibody to HEL was found in recipient mice, thus demonstrating the exclusive participation of cellular immunity in the pathogenesis of this experimental disease. CONCLUSIONS: Transgenic mice expressing HEL in their lenses develop intraocular inflammation after injection of syngeneic lymphocytes sensitized against HEL. This experimental disease is a novel cell-mediated model for LAU.

Immunotolerance against a foreign antigen transgenically expressed in the lens.

PURPOSE: To extend our knowledge concerning immunotolerance against autologous lens crystallins, transgenic (Tg) mice that express a foreign antigen in their lens were generated, and the immune response against the antigen in these mice was analyzed. METHODS: Conventional techniques were used to generate lines of Tg mice that express soluble (S-) or membrane-bound (M-) hen egg lysozyme (HEL) under the control of the alphaA-crystallin promoter. The presence of HEL in various organs was determined by the particle concentration fluorescence immunoassay (PCFIA), and reverse transcription-polymerase chain reaction technique was used to detect mRNA transcripts of the molecule. To examine the development of immunity (or tolerance), Tg mice and their wild-type controls were immunized with HEL (25 microg) in Freund's complete adjuvant and 14 days later were tested for immune response against the antigen. Cellular immunity was measured by the lymphocyte proliferation assay and cytokine production, and humoral immunity was determined by enzyme-linked immunosorbent assay. RESULTS: Eyes of the high copy number M-HEL Tg mice were dystrophic, with disrupted lens, whereas no morphologic changes were detected in the eyes of the other Tg mouse lines. All Tg mice exhibited tolerance to HEL by their cellular and humoral immune compartments. The state of immunotolerance to HEL was retained in the Tg mice for as long as 10 months after removal of the main depot of this protein, by enucleation. Measurable amounts of HEL were found in the eyes of all Tg mice, but the protein could not be detected in the serum or in other organs by the sensitive PCFIA (with a threshold of 1 ng/ml). Yet, HEL mRNA was found in the thymus of the Tg mice, suggesting that minute amounts of the protein are expressed in this organ. CONCLUSIONS: The unresponsiveness to HEL in the Tg mice seems to be due to a "central" mechanism of tolerance, mediated by a minuscule amount of HEL in the thymus. Conversely, the much larger amounts of HEL in the peripheral depot, the eyes, play a minor role if any in the tolerogenic process. It is further proposed that a similar mechanism of central tolerance is responsible for the immunotolerance against autologous lens crystallins.

The diagnosis and management of uveitis.

The diagnosis and management of uveitis is complicated and challenging. The protean signs and symptoms seen in patients with uveitis may lead to a diagnostic dilemma. A carefully taken history with particular attention to demographic factors and meticulous physical examination are crucial to guiding diagnostic testing. Tailoring the diagnostic approach in patients with uveitis frequently yields useful data in contrast to blanketing every possible uveitic entity. It is also important to distinguish among various aetiologies, including infectious and neoplastic causes which may respond to specific therapy. Medical treatment of noninfectious uveitis must have clear objectives including reduction of inflammation, relief of symptoms and restoration of visual functioning. Familiarity with possible symptoms and signs of adverse drug reactions is essential early in the course of treatment so that their effects may be minimised. Appropriate therapy of presumed autoimmune uveitis is based on disease severity, presence or absence of bilateral disease and the health status of the patient.

Unrecognized drug dependence in psychiatrically hospitalized elderly patients.

The psychiatric in-patient records of 90 patients greater than or equal to 65 years of age were reviewed retrospectively to determine the prevalence of chemical dependence and if lack of recognition and treatment of chemical dependence resulted in serious complications. Nineteen of the 90 patients were characterized as drug dependent and ten of these patients were neither recognized nor detoxified. Seven of the ten nondetoxified patients, but only one of the nine detoxified patients, experienced serious medical complications typically requiring transfer to a medical floor or medical intensive care unit. Unrecognized chemically-dependent patients were significantly more likely to be female benzodiazepine abusers, while recognized chemically dependent patients were significantly more likely to be male alcohol abusers.

Immunologic mechanisms of uveitis. New targets for immunomodulation.

The uvea consists of the choroid, ciliary body, and iris, and inflammation of the uveal tract is termed uveitis. Nevertheless, uveitis is commonly used to more generally describe intraocular inflammation involving not only the uvea, but also the retina, vitreous, and sclera. Fifty years ago, infectious organisms such as syphilis and tuberculosis were thought to be the cause of most forms of uveitis. Since that time, many causes of uveitis have been described as infectious and noninfectious. Scientists have shown that the immune response plays a critical role in the development of infectious and noninfectious forms of the disease. With a more detailed understanding of the immune mechanisms leading to the development of uveitis, we are now able to develop new therapeutic approaches based on targeting various components of the immune response.

Visual functioning and general health status in patients with uveitis.

OBJECTIVE: To measure the visual functioning and quality of life in patients with uveitis. METHODS: Consecutive adult patients with noninfectious uveitis were enrolled. The Medical Outcomes Study 36-Item Short Form (SF-36) and the National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) were administered by a trained interviewer. Sociodemographic and clinical data were also collected. RESULTS: Seventy-six patients were enrolled. The overall NEI VFQ-25 score was significantly lower among patients with uveitis than in a normal reference group (P<.001). The SF-36 physical (PCS) and mental (MCS) component summary scores were also significantly lower among patients with uveitis than in the general US population (P<.007). Among patients with uveitis, visual acuity, binocular involvement, intensity of therapy, employment status, and PCS and MCS scores were all significantly associated with overall NEI VFQ-25 scores in multivariable analysis. Medical comorbidity, ocular comorbidity, and NEI VFQ-25 scores were significantly associated with PCS scores. Medical comorbidity and NEI VFQ-25 scores were significantly associated with MCS scores. Regression models including NEI VFQ-25 scores explained an additional 7% of the variance in PCS scores and 16% of MCS scores. Models including both PCS and MCS scores explained an additional 12% of the variance in NEI VFQ-25 scores. CONCLUSIONS: Patients with uveitis reported markedly poorer visual functioning and general health status than normal subjects. Patients with more severe uveitis have poorer visual functioning and general health status than patients with milder disease. Visual functioning and general health status measurement contribute complementary information and should both be performed in patients with uveitis to measure the effect of disease and its therapy on their quality of life.

Expression of cell adhesion molecules in posterior uveitis.

Cells in the eye express surface molecules that direct leukocyte migration during ocular inflammation. We studied the expression of intercellular adhesion molecule-1, lymphocyte function-associated antigen-1, and endothelial leukocyte adhesion molecule-1 in six enucleated eyes from patients with uveitis and in seven normal control eyes. Lymphocyte function-associated antigen-1 was expressed on infiltrating lymphocytes and intercellular adhesion molecule-1 was expressed on endothelial cells of retinal and choroidal blood vessels and the retinal pigment epithelium in all uveitic eyes, but in none of the normal control eyes. Ocular inflammatory cells stained strongly positive for tumor necrosis factor alpha in all eyes with uveitis, but four of six uveitic eyes showed mild staining for tumor necrosis factor beta and interferon gamma. Cell adhesion molecules are expressed in eyes with posterior uveitis and may be regulated by cytokines such as tumor necrosis factor alpha.

32 cases of sympathetic ophthalmia. A retrospective study at the National Eye Institute, Bethesda, Md., from 1982 to 1992.

OBJECTIVE: To examine the relationship between visual outcome and the clinical management of patients with sympathetic ophthalmia. METHODS: Thirty-two patients with sympathetic ophthalmia who were seen at the National Eye Institute, Bethesda, Md, between 1982 and 1992, were retrospectively reviewed. RESULTS: There were equal numbers of males and females. Sympathetic ophthalmia occurred after trauma in 23 patients and surgery in nine patients. Sixteen of the 32 patients had a final visual acuity of 20/40 or better; 10 patients had a visual acuity worse than 20/200. Good visual outcome was associated with early and aggressive treatment with corticosteroids, sometimes in combination with other immunosuppressive agents. Poor visual acuity was associated with glaucoma, chorioretinal scars in the macula, and persistent uncontrolled inflammation. CONCLUSION: Prompt and aggressive use of antiinflammatory therapy can improve the visual outcome of patients with sympathetic ophthalmia.

Apoptosis in patients with posterior uveitis.

BACKGROUND: Apoptosis plays a part in the pathogenesis of autoimmune diseases. OBJECTIVE: To investigate the expression of apoptotic markers in the eyes of patients with uveitis. METHODS: With the use of immunohistochemical and in situ apoptotic detection techniques, apoptotic molecules (Fas or Fas ligand [FasL]) and nuclear DNA fragmentation were examined in 8 enucleated eyes with Behçet's disease (1), sarcoidosis (1), subretinal fibrosis and uveitis (1), sympathetic ophthalmia (4), and the Vogt-Koyanagi-Harada syndrome (1); in 5 chorioretinal biopsy specimens with acute retinal necrosis (2), multifocal choroiditis (1), sarcoidosis (1), and subretinal fibrosis and uveitis (1); and in 3 normal control eyes. RESULTS: Fas and FasL were constitutively expressed in the normal human retina, but they were expressed much less in the choroid. Increased expression of Fas and FasL was found in the retina, chorioretinal scar, and choroidal granulomas in uveitic eyes. However, Fas and FasL expression was absent in the biopsy specimens with acute retinal necrosis, and little Fas or FasL was noted on infiltrating lymphocytes. DNA fragmentation was also identified in eyes with chorioretinal scar and gliosis. CONCLUSIONS: Apoptosis occurs in uveitic eyes and may play a regulatory role in limiting ocular inflammation. In uveitic eyes, a dysregulation of the Fas-FasL apoptotic pathway may lead to gliosis and fibrosis.

Primary intraocular lymphoma with a low interleukin 10 to interleukin 6 ratio and heterogeneous IgH gene rearrangement.

Primary intraocular lymphoma is almost always a central nervous system B-cell non-Hodgkin lymphoma. Primary intraocular lymphoma is commonly diagnosed by demonstrating lymphoma cells in the vitreous or cerebrospinal fluid. An interleukin (IL) 10 to IL-6 ratio greater than 1.0 in these fluids and the detection of immunoglobulin gene rearrangement are useful adjuncts in the diagnosis of primary intraocular lymphoma. We report a case of primary intraocular lymphoma diagnosed by chorioretinal biopsy in which no malignant cells were identified in the vitreous and in which the IL-10 to IL-6 ratio was less than 1.0. The detection of IgH gene rearrangement heterogeneity in the tumor cells by polymerase chain reaction, a high tumor mitotic figure rate, and the rapid onset of multiple brain lesions suggest an aggressive malignant neoplasm.

A clinicopathologic report of the retinal lesions associated with didanosine.

Didanosine, a purine analogue with antiretroviral activity, is used in the treatment of human immunodeficiency virus disease. Associated toxic effects of didanosine include pancreatitis, peripheral neuropathy, and retinopathy. The retinal lesions associated with didanosine therapy were studied in a 6-year-old girl with acquired immunodeficiency syndrome. Gross examination disclosed multiple well-circumscribed depigmented lesions in the midperipheral retina. Microscopic examination of these lesions showed multiple areas of retinal pigment epithelial (RPE) loss, some surrounded by areas of hypertrophy or hypopigmentation of the RPE. Partial loss of the choriocapillaris and neurosensory retina were also noted in areas of diseased RPE. Transmission electron microscopy showed numerous membranous lamellar inclusions and cytoplasmic bodies in the RPE cells. These data show that didanosine primarily affects the RPE and that the choriocapillaris and overlying neurosensory retina are also dystrophic in areas of RPE loss.