HIV-infected individuals on long-term antiretroviral therapy are at higher risk for ocular disease.

Introduction of antiretroviral therapy (ART) has dramatically reduced the incidence of infectious ocular diseases in human immunodeficiency virus (HIV)-infected individuals. However, the effects of long-term ART and chronic HIV infection on the eye are ill-defined. This study determined the occurrence and severity of ocular diseases among 342 participants in a rural South African setting: HIV-naïve (n = 105), HIV-infected ART-naïve (n = 16), HIV-infected on ART for 36 months (long-term ART; n = 165). More HIV-infected participants presented with an external eye condition, in particular blepharitis, than HIV-naïve individuals (18% vs. 7%; age-adjusted odds ratio (aOR) = 2·8, P < 0·05). Anterior segment conditions (particularly keratoconjunctivitis sicca and pterygium) were also more common (50% vs. 27%; aOR = 2·4; P < 0·01). Compared with individuals on short-term ART, participants receiving long-term ART were more likely to have clinically detectable cataract (57% vs. 38%; aOR = 2·2, P = 0·01) and posterior segment diseases, especially HIV retinopathy (30% vs. 11%; aOR = 3·4, P < 0·05). Finally, long-term ART was significantly associated with presence of HIV retinopathy (P < 0·01). These data implicate that ocular disease is more common and of more diverse etiology among HIV-infected individuals, especially those on long-term ART and suggest that regular ophthalmological monitoring of HIV-infected individuals on ART is warranted.

Clinical and corneal microbial profile of infectious keratitis in a high HIV prevalence setting in rural South Africa.

The purpose of this investigation was to determine the clinical and corneal microbial profile of infectious keratitis in a high human immunodeficiency virus (HIV) prevalence setting in rural South Africa. Data in this cross-sectional study were collected from patients presenting with symptoms of infectious keratitis (n = 46) at the ophthalmology outpatient department of three hospitals in rural South Africa. Corneal swabs were tested for herpes simplex virus type 1 (HSV-1) and 2 (HSV-2), varicella zoster virus (VZV) and adenovirus DNA by real-time polymerase chain reaction (PCR) and for bacteria and fungi by culture. Based on clinical history, disease characteristics and laboratory results, 29 (63 %) patients were diagnosed as viral keratitis, including 14 (48 %) viral keratitis cases complicated by bacterial superinfection, and 17 (37 %) as bacterial keratitis. VZV and HSV-1 DNA was detected in 11 (24 %) and 5 (11 %) corneal swabs, respectively. Among clinically defined viral keratitis cases, a negative viral swab was predominantly (93 %) observed in cases with subepithelial inflammation and was significantly associated with an increased duration of symptoms (p = 0.003). The majority of bacteria cultured were Gram-positive (24/35), including Staphylococcus epidermidis and S. aureus. Viral aetiology was significantly associated with a history of herpes zoster ophthalmicus (p < 0.001) and a trend was observed between viral aetiology and HIV infection (p = 0.06). Twenty-one (47 %) keratitis cases were complicated by anterior uveitis, of which 18 (86 %) were HIV-infected cases with viral keratitis. The data implicate a high prevalence of herpetic keratitis, in part complicated by bacterial superinfection and/or uveitis, in HIV-infected individuals presenting with infectious keratitis in rural South Africa.

Low level IGF-1 and common variable immune deficiency: an unusual combination.

A relation between growth hormone (GH) deficiency and immunoglobulin deficiency has been suggested previously in a few cases. We describe a patient with an insulin-like growth factor 1 (IGF-1) deficiency and common variable immune deficiency and briefly review earlier publications on the possible interaction between IGF-1 and the immune system. IGF-1 is the downstream mediator of GH. In this patient, GH and IGF-1 levels were both low. The GH response to a GH-releasing hormone test was normal whereas no subsequent IGF-1 response was seen. In our cohort of 14 patients with hypogammaglobulinaemia, two turned out to have slightly decreased IGF-1 serum levels and one patient with a thymoma had an increased IGF-1 level. Even though IGF-1 may be connected to B lymphocyte differentiation, in this patient we hypothesise there is a common impairment in the IGF-1 and IgG pathways.

[Behçet's disease and the possibilities of modern tumour necrosis factor inhibiting medication]. / De ziekte van Behçet en de mogelijkheden van moderne tumornecrosisfactor-remmende medicatie.

A 25-year-old woman was admitted after having had a fever for one month, headache, nausea, vomiting, dysarthria and right-sided hemiparesis. A 35-year-old man was admitted because of severe loss of vision and a history of focal retinochoroiditis. Both were suffering from Behçet's disease. Behçet's disease can present with systemic symptoms that might be related to aberrant T-cell functions. It is treated with a variety of immunoregulatory drugs. Recently, treatment with tumour necrosis factor (TNF) alpha-inhibiting molecular designed drugs such as infliximab or etanercept has improved the therapeutic prospective of Behçet patients. Both of the patients described above developed refractory disease and responded to treatment with these new drugs.

Anti-TNF-alpha therapy for sight threatening uveitis.

AIM: To describe the effect of additional treatment with anti-TNF-alpha therapy in a case series of 13 patients with serious sight threatening uveitis. METHODS: 13 patients with serious sight threatening uveitis were included, of whom six had Behçet's disease, five had idiopathic posterior uveitis, one had sarcoidosis, and one birdshot retinochoroiditis. Onset and course of ocular inflammation, inflammatory signs, and visual acuity were assessed. Patients were treated with 200 mg (approximately 3 mg/kg) infliximab infusion. Repeat infusions were given based on clinical response. RESULTS: Infliximab treatment resulted in an effective suppression of ocular inflammation in all patients. In patients with non-Behcet's disease uveitis visual acuity in six out of eight improved or was stable. In patients with Behcet's disease visual acuity in five out of six improved or was stable. CONCLUSION: Anti-TNF-alpha treatment may be of value in the treatment of uveitis, and in patients with Behçet's disease, leading to suppression of ocular inflammation, vasculitis, and improvement of vision in the majority. Based on these results a controlled masked study is warranted.

Somatostatin receptor 2A expression in choroidal neovascularization secondary to age-related macular degeneration.

PURPOSE: The growth of ocular neovascularization is regulated by a balance between stimulating and inhibiting growth factors. Somatostatin affects angiogenesis by inhibiting the growth hormone-insulin-like growth factor axis and also has a direct antiproliferative effect on human retinal endothelial cells. The purpose of our study is to investigate the expression of somatostatin receptor (sst) subtypes and particularly sst subtype 2A (sst2A) in normal human macula, and to study sst2A in different stages of age-related maculopathy (ARM), because of the potential anti-angiogenic effect of somatostatin analogues. METHODS: Sixteen eyes (10 enucleated eyes, 4 donor eyes, and 2 surgically removed choroidal neovascular [CNV] membranes) of 15 patients with eyes at different stages of ARM were used for immunohistochemistry. Formaldehyde-fixed paraffin-embedded slides were incubated with a polyclonal anti-human sst2A antibody. mRNA expression of five ssts and somatostatin was determined in the posterior pole of three normal human eyes by reverse transcriptase-polymerase chain reaction. RESULTS: The immunohistochemical expression of sstA in newly formed endothelial cells and fibroblast-like cells was strong in fibrovascular CNV membranes. mRNA of sst subtypes 1, 2A, and 3, as well as somatostatin, was present in the normal posterior pole; sst subtypes 4 and 5 were not detectable. CONCLUSIONS: Most early-formed CNV in ARM express sst2A. The presence of mRNA of sst subtype 2A was observed in normal human macula, and subtypes 1 and 3 and somatostatin are also present. sst2A receptors bind potential anti-angiogenic somatostatin analogues such as octreotide. Therefore, somatostatin analogues may be an effective therapy in early stages of CNV in ARM.

Chemoattractant and neutrophil degranulation activities related to interleukin-8 in vitreous fluid in uveitis and vitreoretinal disorders.

PURPOSE: To investigate whether the cytokine interleukin-8 (IL-8), a strong chemoattractant and activator for neutrophils, is responsible for neutrophil infiltration and degranulation in the eye in uveitis. METHODS: IL-8 and elastase were measured with specific enzyme-linked immunoassays in vitreous fluid samples obtained from 69 patients with various uveitis entities. Vitreous fluid of nonuveitis patients and eye bank eyes served as controls. The chemotactic activity of vitreous fluid was tested with the Boyden chamber technique. RESULTS: IL-8 was detected in 45% of the vitreous fluid samples from uveitis patients and in 26% of vitreous fluid samples from nonuveitis patients. Vitreous fluid samples with IL-8 levels exceeding 100 pg/ml were chemotactic for neutrophils. This chemotactic activity could be blocked by 41% to 79% with a monoclonal anti-IL-8 antibody. Elastase levels in vitreous fluid of uveitis patients with detectable IL-8 were significantly higher than those in vitreous fluid samples with no detectable IL-8. CONCLUSION: These results indicate that IL-8 participates in the inflammatory processes in the eye by attracting and degranulating neutrophils. It is suggested that these processes contribute to the pathogenesis of tissue destruction in uveitis.

Fuchs' heterochromic iridocyclitis is not associated with ocular toxoplasmosis.

To analyze the association between Fuchs' heterochromic iridocyclitis (FHI) and toxoplasmosis, we performed ocular examinations and used various specific laboratory tests to establish a role for Toxoplasma gondii in the pathogenesis of FHI. Results were compared with those for other types of uveitis and healthy controls. Of the 88 patients with FHI, nine (10.2%) had toxoplasmosislike scars, but an association could not be proved by the indirect immunofluorescence antibody test or enzyme-linked immunosorbent assay, or by a test for cellular immunity to Toxoplasma antigen. Analysis of aqueous humor samples for Toxoplasma antibodies in patients with FHI also yielded negative results. On the basis of the negative results of these laboratory tests, we concluded that FHI is not associated with ocular toxoplasmosis.

Presumed acquired ocular toxoplasmosis.

OBJECTIVE: To describe the clinical characteristics and laboratory findings of eight patients with focal chorioretinitis presumably caused by acquired toxoplasmosis. DESIGN: Case series. SETTING: Referral hospitals in the Netherlands. PATIENTS: Eight patients, aged 42 to 75 years, with unilateral focal chorioretinitis and laboratory evidence of a recently acquired infection with Toxoplasma gondii. MAIN OUTCOME MEASURES: Findings from ocular examination and analysis of both serum and aqueous humor samples for Toxoplasma and viral antibodies. RESULTS: All patients had unilateral focal chorioretinitis without associated old scars in the posterior pole. Patients treated with systemic or periocular corticosteroids not accompanied by antiparasitic medication showed a rapid increase of inflammation. All eight patients had Toxoplasma IgM antibodies in their serum samples, seven of whom had high Toxoplasma IgG titers. Five of eight patients had increased intraocular production of IgG antibodies against T gondii. CONCLUSION: Unilateral focal chorioretinitis in patients of any age should alert the clinician to consider acquired ocular toxoplasmosis in the differential diagnosis.

Iris nodules in Fuchs' heterochromic uveitis.

Four black patients with Fuchs' heterochromic uveitis had multiple nodules in the iris. The iris nodules were small, transparent, and scattered across the whole surface of the iris (Busacca's nodules) but increased in density toward the pupillary border. All four patients also had nodules at the pupillary border (Koeppe's nodules). Repeated etiologic screening for systemic diseases in these patients was noncontributory. Unilateral multiple iris nodules without the formation of synechiae may be encountered as part of Fuchs' heterochromic uveitis syndrome and may be important in the identification of Fuchs' heterochromic uveitis, especially in black patients.

The predictive value of serum angiotensin converting enzyme and lysozyme levels in the diagnosis of ocular sarcoidosis.

We determined the serum angiotensin converting enzyme and lysozyme levels in 221 patients with uveitis and in 67 control subjects. Angiotensin converting enzyme and lysozyme levels were found to be age dependent. Of the 221 patients, 12 had sarcoidosis. In patients with uveitis who had an angiotensin converting enzyme level above 50 units/l (mean + 2 S.D.), the sensitivity of the test was 84%, the specificity was 95%, and the predictive value was 47%. In these same patients the sensitivity was 60% for a lysozyme level above 8 mg/l (mean + 2 S.D.), the specificity was 76%, and the predictive value was 12%.

Treatment and prognosis of secondary glaucoma in Fuchs' heterochromic iridocyclitis.

After reviewing the records of 111 patients with Fuchs' heterochromic iridocyclitis, we studied the therapy and prognosis of secondary glaucoma in 30 of these 111 patients (27%) who had glaucoma or could be considered glaucoma suspects. Maximal medical therapy was unsuccessful in 22 of the 30 patients (73%). Surgical intervention (mostly trabeculectomies, half with 5-fluorouracil) successfully controlled intraocular pressure (< or = 21 mm Hg with or without medication) in 13 of the 18 operated-on patients (72%) after a mean follow-up of 26 months. All successfully operated-on patients retained a visual acuity of 20/80 or better. We had favorable results, possibly because of modern surgical techniques (use of 5-fluorouracil, sodium hyaluronate) or earlier surgical intervention, or both.

Birdshot chorioretinopathy and Lyme borreliosis.

Two patients in whom ocular Lyme disease was suspected and who had antibodies to Borrelia burgdorferi developed birdshot chorioretinopathy and carried the HLA-A29 antigen. In a series of 11 patients with birdshot chorioretinopathy who carried the HLA-A29 antigen, three patients had antibodies against B. burgdorferi as determined by either immunofluorescence assay, enzyme-linked immunosorbent assay, Western blot analysis, or a combination of these tests. Further studies will be necessary to evaluate whether this is a false-positive reaction or whether B. burgdorferi has a causative role in the pathogenesis of birdshot chorioretinopathy.

Analysis of local antibody production in the vitreous humor of patients with severe uveitis.

We analyzed the local antibody production in vitreous humor samples collected during vitrectomy in patients with severe vision-threatening uveitis. In 24 patients, paired serum and undiluted vitreous humor samples were collected and tested for antibodies against Toxoplasma gondii, herpes simplex virus, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, and Toxocara canis. Total IgG and the Goldmann-Witmer coefficient were determined. The initial diagnosis of ocular toxoplasmosis could be confirmed in six of the seven patients. The seventh patient showed a local antibody production against herpes simplex virus. One of the three patients with chronic panuveitis at initial diagnosis showed a local antibody production against T. gondii. These last two findings resulted in a change in medical treatment. Analysis of local antibody production in vitreous humor samples is a valuable diagnostic tool.

Immunohistochemical analysis of iris biopsy specimens from patients with Fuchs' heterochromic cyclitis.

Using immunohistochemical techniques, we analyzed iris biopsy specimens from eight patients with Fuchs' heterochromic cyclitis, seven patients with various other types of uveitis, and eight glaucoma patients without uveitis. No specific abnormalities related to Fuchs' heterochromic cyclitis could be detected. Four of the patients with Fuchs' heterochromic cyclitis and four of the patients with uveitis showed evidence of an inflammatory cell infiltrate, which was a mixture of interleukin-2 receptor-negative T helper and suppressor cells, B lymphocytes, and plasma cells. Only an occasional T lymphocyte could be seen in two of the patients without uveitis. The class II antigen HLA-DR was expressed on iris stromal cells in every patient in the Fuchs' heterochromic cyclitis group and uveitis group and in six of the patients in the nonuveitis group. In six of the Fuchs' heterochromic cyclitis patients, including two without immunohistochemical evidence of inflammatory cell infiltrate, histologic abnormalities were present on hematoxylin and eosin sections.

HLA typing in birdshot chorioretinopathy.

We examined 49 patients with birdshot chorioretinopathy in whom HLA typing had been performed. Of these 49 patients, 47 (95.9%) had the HLA-A29 antigen. The HLA-B12 (B44) antigen was also significantly associated with the disease, but this antigen is known to be in linkage disequilibrium with the antigen HLA-A29. The HLA-A2 antigen was less frequent in patients with birdshot chorioretinopathy than in the control group of normal European individuals (20% as compared to 44.6%).

Immune deposits in iris biopsy specimens from patients with Fuchs' heterochromic iridocyclitis.

To investigate whether Fuchs' heterochromic iridocyclitis may be an immune complex vasculitis, we used an immunofluorescence technique to detect immunoglobulins and complement in iris biopsy specimens from nine patients with Fuchs' heterochromic iridocyclitis, 12 patients with other types of uveitis, and nine patients with glaucoma but without uveitis. No specific immune deposits were observed in the irises of the patients with Fuchs' heterochromic iridocyclitis. Immunoglobulin G, IgA, IgM, and complement were detected in patients with Fuchs' heterochromic iridocyclitis and patients with uveitis, and these results differed significantly (P less than .05) from the group without uveitis. The immune deposits were found only in the iris vessel walls. No light-microscopic evidence of an inflammatory vascular process could be detected. Further studies are necessary to investigate whether the immune reactants originate from the circulation or result from local formation.

Detection of intraocular antibody production to herpesviruses in acute retinal necrosis syndrome.

In order to improve the determination of the causative agent in acute retinal necrosis syndrome, we evaluated the detection of intraocular antibody production to herpesviruses in 28 patients with this disease. Intraocular antibody production was determined by calculation of the Goldmann-Witmer coefficient whereby specific antibody titers in the inflamed eye and circulation are related to the total IgG content in ocular fluid and serum. Specific antibody titers to herpesviruses and Toxoplasma were determined by the indirect immunofluorescence technique. Thirty-five patients with ocular toxoplasmosis, cataract, or proliferative vitreoretinal disorders were tested as controls. By this technique, intraocular antibody production to varicella zoster virus or herpes simplex virus could be established in 16 (57%) of the patients with the typical clinical features of acute retinal necrosis, compared to none of the controls. Of the 33 affected eyes, 21 (64%) had a visual outcome of less than 20/200. We concluded that detection of intraocular antibody production to herpesviruses may be a useful diagnostic tool in establishing the causative agents in acute retinal necrosis.

Therapy for ocular toxoplasmosis.

We conducted a prospective multicenter study of the efficacy of current therapeutic strategies for ocular toxoplasmosis in 149 patients. Treatment consisted of the following three triple-drug combinations: group 1, pyrimethamine, sulfadiazine, and corticosteroids; group 2, clindamycin, sulfadiazine, and corticosteroids; and group 3, trimethoprim, sulfamethoxazole and corticosteroids. Patients with peripheral retinal lesions were not treated systemically. No difference in the duration of inflammatory activity was observed between treated and untreated patients (P = .5). The most important factor predicting the duration of inflammatory activity was the size of the retinal lesion itself, independent of the treatment (P < .001). We found a reduction in size of the retinal inflammatory lesion for 49% of the pyrimethamine-treated patients (17 of 35) compared to 20% of the untreated patients (eight of 41) (P < .01). However, the most frequent occurrence of side effects was also associated with pyrimethamine medication (26%, nine of 35). The mean recurrence rate after three years of follow-up was 49% for all patients (60 of 122 patients), with no differences between treated and untreated patients (P = .6).

Serologic and polymerase chain reaction analysis of intraocular fluids in the diagnosis of infectious uveitis.

PURPOSE: Infectious uveitis entities are usually rapidly progressive blinding diseases that can be prevented by prompt administration of specific antimicrobial therapy. With the aim of improving early diagnosis in patients with infectious uveitis, intraocular fluid samples from patients with sight-threatening posterior uveitis were investigated to determine the causative agent. METHODS: Thirty-eight patients with acquired immunodeficiency syndrome (AIDS) and retinitis, eight immunosuppressed patients with retinitis, 16 immunocompetent patients with acute retinal necrosis, and 22 immunocompetent patients with toxoplasmic retinochoroiditis were analyzed by polymerase chain reaction for the presence of herpesviruses and Toxoplasma gondii DNA and for local antibody production against these microorganisms. RESULTS: In patients with AIDS and retinitis, polymerase chain reaction was positive for cytomegalovirus DNA in 21 (91%) of the 23 ocular fluid samples obtained during active cytomegalovirus retinitis, whereas local antibody production analysis was negative in all cases. In acute retinal necrosis, varicella-zoster virus or herpes simplex virus could be established as the inciting agent in 81% of the cases, using the combination of both techniques. Polymerase chain reaction was positive in all samples obtained within two weeks after the onset of disease. Toxoplasma gondii DNA was detected in 4 of 13 samples (31%) from immuno-competent patients with active toxoplasmic retinochoroiditis; in each case, local antibody production was also detected. In contrast, no local antibody production was observed in two of three samples from transplant recipients that were positive for T. gondii DNA. All the control samples tested were negative for the above-mentioned tests. CONCLUSIONS: In patients with AIDS, polymerase chain reaction analysis is preferable above local antibody production in detecting the inciting agent of retinitis. In other cases, the combination of both techniques can make a valuable contribution to the diagnosis.