Visual function in human ocular toxoplasmosis

AIM: To assess functional impairment in terms of visual acuity reduction and visual field defects in inactive ocular toxoplasmosis. METHODS: 61 patients with known ocular toxoplasmosis in a quiescent state were included in this prospective, cross-sectional study. A complete ophthalmic examination, retinal photodocumentation and standard automated perimetry (Octopus perimeter, program G2) were performed. Visual acuity was classified on the basis of the World Health Organization definition of visual impairment and blindness: normal (> or =20/25), mild (20/25 to 20/60), moderate (20/60 to 20/400) and severe (<20/400). Visual field damage was correspondingly graded as mild (mean defect <4 dB), moderate (mean defect 4-12 dB) or severe (mean defect >12 dB). RESULTS: 8 (13%) patients presented with bilateral ocular toxoplasmosis. Thus, a total of 69 eyes was evaluated. Visual field damage was encountered in 65 (94%) eyes, whereas only 28 (41%) eyes had reduced visual acuity, showing perimetric findings to be more sensitive in detecting chorioretinal damage (p<0.001). Correlation with the clinical localisation of chorioretinal scars was better for visual field (in 70% of the instances) than for visual acuity (33%). Moderate to severe functional impairment was registered in 65.2% for visual field, and in 27.5% for visual acuity. CONCLUSION: In its quiescent stage, ocular toxoplasmosis was associated with permanent visual field defects in >94% of the eyes studied. Hence, standard automated perimetry may better reflect the functional damage encountered by ocular toxoplasmosis than visual acuity.

The antibody response in experimental ocular toxoplasmosis

BACKGROUND: The dynamics of the humoral immune response in ocular toxoplasmosis (OT) are poorly understood. We therefore investigated this process in a rabbit model of the disease. MATERIALS AND METHODS: Of 24 infection-naïve adult rabbits, 12 were left untreated and 12 were systematically infected with 5,000 tachyzoites of the non-cyst-forming BK strain of Toxoplasma gondii. Three months later, all rabbits were inoculated transvitreally with 5,000 tachyzoites of Toxoplasma gondii. Paired samples of aqueous humor and serum were analyzed temporally for their total and specific IgG contents. RESULTS: In infection-naïve rabbits with primary OT, specific IgG reached detectable levels in the inoculated eyes between 5 and 15 days after inoculation. In infection-immunized rabbits with secondary OT, a significant increase in specific IgG was regularly detected after 5 days. The antibody ratio C was diagnostic (>/=3) from day 15 onward in primary OT and from day 21 onward in secondary OT. In the uninfected partner eyes, the antibody ratio C was found sporadically diagnostic from day 15 onward in primary OT, but at no time in secondary OT. Specific IgG persisted both locally and in the serum until the end of the monitoring period (100 days). CONCLUSION: Our findings relating to the rabbit model of OT reveal three features of clinical relevance: a diagnostic window precedes the establishment of a humoral immune response; specific antibodies persist long after the cessation of disease activity; and in primary OT, the antibody ratio C may also increase in the uninfected partner eye.

Recurrence characteristics in European patients with ocular toxoplasmosis

BACKGROUND: The risk of function loss after each episode of ocular toxoplasmosis (OT) supports efforts to improve our understanding of the disease. Patients and methods: 139 patients with OT were contacted retrospectively and requested to complete a questionnaire addressing course and activity of their disease. This information was compared with that retrieved from their medical records. Sixty-three patients completed the questionnaire and were included in the study. They were allocated according to their median age to one of two groups (group 1: <20.9 years; group 2: >or=20.9 years). RESULTS: The mean reported age at the time of first ocular manifestation was 23.9 (median 20.9, range 0 to 70.5; SD 12.9) years. The clinical diagnosis was made 3.5 years later (p = 0.0008). The follow-up time was 6.5 (median 5.0; range 0.5 to 49.9; SD 7.6) years. The recurrence rate was higher in patients below 20.9 years (66%; n = 35) than in older patients (39%; n = 28; chi(2) test, p<0.05). Patients reporting only one episode were older at first manifestation (29.6 (median 25.6; range 10.6 to 70.5; SD 14.3) years; n = 29) than those reporting two episodes (17.9 (median 19.5; range 5.9 to 33.9; SD 7.8) years; n = 15 (p<0.05)). The proportion of patients who developed a recurrence was 54-63% after each episode without a tendency to enlarge, and the interval between successive episodes remained stable between 1.0 and 1.7 years for the first three recurrences. CONCLUSION: Younger OT patients carry a higher risk of developing a recurrence than older ones. After each episode, two-thirds of all OT patients will develop another one.

Differenzialdiagnose der infektiösen posterioren Uveitis

Infektiöse Ursachen bilden die größte ätiologische Gruppe posteriorer Uveitiden. Als Einzeldiagnosen stehen die Toxoplasmose als infektiöse Erkrankung und der Morbus Behçet als nicht infektiöse Erkrankung an erster Stelle. Bei akuten Entzündungsprozessen immunkompetenter Patienten ist eine exakte Diagnose häufig infolge einer recht dichten Glaskörperinfiltration schwierig zu stellen. In diesen Fällen trägt die Beurteilung des Krankheitsverlaufs zur Differenzialdiagnose wesentlich bei. Virale Netzhautnekrosen verschlechtern sich typischerweise hochakut, Sehstörungen und klinische Symptome bei Morbus Behçet und Toxoplasmose nehmen innerhalb weniger Tage bis 2 Wochen zu, während andere Erkrankungen einen eher schleichenden Verlauf zeigen. Die Dauer der Erkrankung und systemische Grunderkrankungen sind bei der ersten okulären Manifestation häufig nicht bekannt. Grundsätzlich ist die Sehfunktion bedroht, wenn die Makula in den entzündlichen Prozess einbezogen ist, wenn häufige Rezidive zu einer Beteiligung der Makula führen, aber auch wenn sich Sekundärkomplikationen wie ein Makulaödem entwickeln. Bei Kindern muss außerdem an die Gefahr einer Amblyopie infolge entzündlicher Medientrübungen gedacht werden, insbesondere bei Glaskörpertrübungen. Deshalb ist eine rasche interdisziplinäre diagnostische Abklärung und darauf basierende Therapiestrategie erforderlich. Diese muss einerseits ätiologisch abgestützt sein, andererseits sollte sie rechtzeitig steroidsparende Immunsuppresiva und eventuell chirurgische Maßnahmen beinhalten.

Ocular manifestations in congenital toxoplasmosis

BACKGROUND: Retinochoroiditis is the most common ocular manifestation of congenital toxoplasmosis, but other associated ophthalmological pathologies can also occur. The aim of this study was to determine the nature of the latter in treated cases of the disease and to assess their impact on visual function. METHODS: Four hundred and thirty consecutive children with serologically confirmed congenital toxoplasmosis were included in this study. Data were prospectively collected using standardized ophthalmological assessment forms. The presence of retinochoroiditis and of associated pathologies was ascertained, and their impact on visual function was assessed. RESULTS: After a median follow-up of 12 years [range 0.6-26 years], 130 children manifested retinochoroiditis. We detected 22 foci of retinochoroiditis at birth and 264 additional ones during the follow-up period. Of these, 48 (17%) were active when first diagnosed. Twenty-five of the 130 children (19%) had other associated ocular pathologies. Of these, 21 (16%) had a strabismus, which was due to macular lesions in 86% of the cases; 7 (5.4%) presented with unilateral microphthalmia, and 4 (3%) with cataracts. Most of these events were detected after the onset of retinochoroiditis. None of the children presented with ocular involvement in the absence of chorioretinal lesions. Macular lesions occurred more frequently in children with associated pathologies (p<0.0001), and associated pathologies were likewise more common in individuals with macular lesions (p=0.0003). Visual impairment occurred in 31/130 cases, and in all but 3 of these eyes it was due not to an associated pathology but to macular retinochoroiditis. CONCLUSIONS: At the end of the follow-up period, ocular involvement existed in 30% of the treated children with congenital toxoplasmosis. Associated eye pathologies were manifested less frequently than anticipated. They may occur later in life and are an indirect marker of the severity of congenital toxoplasmosis, but they do not have a direct impact on visual acuity. The overall functional prognosis of congenital toxoplasmosis is better than would be expected on the basis of literature findings, with only 2 of the 130 children suffering bilateral visual impairment.

Long-term impact of treated congenital toxoplasmosis on quality of life and visual performance

Background: Long-term evolution of congenital toxoplasmosis is not documented. We assessed the outcome of treated congenital toxoplasmosis in a cohort of adult individuals who had undergone ante- and postnatal treatment to provide information for pediatricians and parents on the evolution of the disease. Methods: We conducted a questionnaire study on 126 adults with congenital toxoplasmosis (mean age: 22.2 years; age range: 18–31 years) monitored regularly until the time of inclusion. The main outcome measures were quality of life (Psychological General Well-Being Index) and visual function (VF14 questionnaire), and the outcomes were correlated with disease-specific factors. Results: Of the 102 patients (80.9%) who were finally included in the study, 12 (11.8%) presented neurologic effects and 60 (58.8%) manifested ocular lesions; in the latter category, 13 individuals (12.7%) had reduced visual function. The overall global quality-of-life score (74.7 ± 14.2) was close to the expected normal range for the general population (73.7 ± 15.3). Overall, visual function was only slightly impaired (M = 97.3; 95% confidence interval, 95.8–98.8). Although disease-independent critical life circumstances were associated with a reduced Psychological General Well-Being Index, this index was not influenced by any of the clinical characteristics of congenital toxoplasmosis. Neurologic pathologies, reduced visual acuity, foveal location of the retinal lesion, and squinting contributed to decreased visual function at follow-up. Conclusions: Our data reveal that treated congenital toxoplasmosis has little effect on the quality of life and visual function of the affected individuals. These encouraging findings may help to alleviate the anxiety of affected individuals and their parents.

Ocular involvement in paediatric haemolytic uraemic syndrome

The aim of this study was to estimate the frequency and severity of ocular involvement in paediatric patients with haemolytic uraemic syndrome (HUS).

The ocular motor features of adult-onset alexander disease: a case and review of the literature

A 51-year-old Chinese man presented with gaze-evoked nystagmus, impaired smooth pursuit and vestibular ocular reflex cancellation, and saccadic dysmetria, along with a family history suggestive of late-onset autosomal dominant parkinsonism. MRI revealed abnormalities of the medulla and cervical spinal cord typical of adult-onset Alexander disease, and genetic testing showed homozygosity for the p.D295N polymorphic allele in the gene encoding the glial fibrillary acidic protein. A review of the literature shows that ocular signs are frequent in adult-onset Alexander disease, most commonly gaze-evoked nystagmus, pendular nystagmus, and/or oculopalatal myoclonus, and less commonly ptosis, miosis, and saccadic dysmetria. These signs are consistent with the propensity of adult-onset Alexander disease to cause medullary abnormalities on neuroimaging.

Distribution of amyloid precursor protein and amyloid-beta in ocular hypertensive C57BL/6 mouse eyes

Amyloid precursor protein (APP) and amyloid-beta (Abeta) appear to participate in the pathophysiology of retinal ganglion cell (RGC) death in glaucoma. We, therefore, determined the distribution of APP and Abeta in the retinas of C57BL/6 mice after induction of chronic ocular hypertension.

The ocular pulse amplitude at different intraocular pressure: a prospective study

To investigate changes in ocular pulse amplitude (OPA) during a short-term increase in intraocular pressure (IOP) and to assess possible influences of biometrical properties of the eye, including central corneal thickness (CCT) and axial length.

Funduscopy in adult zebrafish and its application to isolate mutant strains with ocular defects

Funduscopy is one of the most commonly used diagnostic tools in the ophthalmic practice, allowing for a ready assessment of pathological changes in the retinal vasculature and the outer retina. This non-invasive technique has so far been rarely used in animal model for ophthalmic diseases, albeit its potential as a screening assay in genetic screens. The zebrafish (Danio rerio) is well suited for such genetic screens for ocular alterations. Therefore we developed funduscopy in adult zebrafish and employed it as a screening tool to find alterations in the anterior segment and the fundus of the eye of genetically modified adult animals.A stereomicroscope with coaxial reflected light illumination was used to obtain fundus color images of the zebrafish. In order to find lens and retinal alterations, a pilot screen of 299 families of the F3 generation of ENU-treated adult zebrafish was carried out.Images of the fundus of the eye and the anterior segment can be rapidly obtained and be used to identify alterations in genetically modified animals. A number of putative mutants with cataracts, defects in the cornea, eye pigmentation, ocular vessels and retina were identified. This easily implemented method can also be used to obtain fundus images from rodent retinas.In summary, we present funduscopy as a valuable tool to analyse ocular abnormalities in adult zebrafish and other small animal models. A proof of principle screen identified a number of putative mutants, making funduscopy based screens in zebrafish feasible.

Isolation and genotyping of Toxoplasma gondii causing fatal systemic toxoplasmosis in an immunocompetent 10-year-old cat

A 10-year-old male, neutered domestic shorthair cat was presented with fever, anorexia, vomiting, and diarrhea. Serologic testing for Feline immunodeficiency virus and Feline leukemia virus were negative. Fine-needle aspirates of mesenteric lymph nodes revealed the presence of banana-shaped apicomplexan parasites. The cat died after 4 days of hospitalization. Postmortem polymerase chain reaction (PCR) analysis confirmed the presence of Toxoplasma gondii in all examined organs. Parasites were ex vivo isolated in outbred mice and subsequently transferred into cell culture. Genotyping, using genetic markers for SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and Apico for PCR-restriction fragment length polymorphism, revealed infection with type II T. gondii displaying type II alleles at all loci except Apico, which exhibited a type I allele. This is the most frequently identified genotype among cats acting as definitive hosts in central Europe, but to the authors' knowledge, it has never been associated with systemic toxoplasmosis in an adult, immunocompetent cat.

Kinetics of ocular and systemic antigen-specific T-cell responses elicited during murine cytomegalovirus retinitis

Cytomegalovirus (CMV) reactivation in the retina of immunocompromized patients is a cause of significant morbidity as it can lead to blindness. The adaptive immune response is critical in controlling murine CMV (MCMV) infection in MCMV-susceptible mouse strains. CD8(+) T cells limit systemic viral replication in the acute phase of infection and are essential to contain latent virus. In this study, we provide the first evaluation of the kinetics of anti-viral T-cell responses after subretinal infection with MCMV. The acute response was characterized by a rapid expansion phase, with infiltration of CD8(+) T cells into the infected retina, followed by a contraction phase. MCMV-specific T cells displayed biphasic kinetics with a first peak at day 12 and contraction by day 18 followed by sustained recruitment of these cells into the retina at later time points post-infection. MCMV-specific CD8(+) T cells were also observed in the draining cervical lymph nodes and the spleen. Presentation of viral epitopes and activation of CD8(+) T cells was widespread and could be detected in the spleen and the draining lymph nodes, but not in the retina or iris. Moreover, after intraocular infection, antigen-specific cytotoxic activity was detectable and exhibited kinetics equivalent to those observed after intraperitoneal infection with the same viral dose. These data provide novel insights of how and where immune responses are initiated when viral antigen is present in the subretinal space.

Ocular penetration of caspofungin in a rabbit uveitis model

BACKGROUND: Little is known about the ocular penetration of echinocandin antifungals. We studied the ocular distribution of systemically administered caspofungin in a rabbit uveitis model. METHODS: Caspofungin (1 mg/kg per day) was given intravenously to rabbits as a single dose or as repeated daily doses on 7 days starting 24 h after induction of unilateral uveitis by intravitreal endotoxin injection. Caspofungin concentrations were determined by high-performance liquid chromatography in the cornea, aqueous humor, vitreous humor, and serum 4, 8, 16, and 24 h after administration of a single dose and 24 h after the last of seven doses. RESULTS: The mean caspofungin concentration in the aqueous of the inflamed eye 4 and 8 h after single-dose administration was 1.30 +/- 0.39 mug/ml and 1.12 +/- 0.34 mug/ml, respectively. Drug concentrations decreased to 0.24 +/- 0.09 mug/ml at 16 h and 0.26 +/- 0.14 mug/ml at 24 h. In the vitreous of inflamed eyes drug levels were undetectable at all time points. No drug was found in the aqueous of inflamed eyes 24 h after the last of seven repeated doses, and the vitreous only contained trace amounts. In the corneas of inflamed eyes concentrations reached 1.64 +/- 0.48 mug/g at 4 h, peaked at 2.16 +/- 1.14 mug/g at 8 h, and declined to 1.87 +/- 0.52 mug/g and 1.49 +/- 0.48 mug/g at 16 and 24 h, respectively. After repeated dosing, corneal concentrations of caspofungin were 0.8 and 1.0 mug/g and below the limit of detection in two of four animals. In non-inflamed eyes no drug was detectable in the aqueous and vitreous humor, and the corneas at any time point. CONCLUSIONS: In our model, caspofungin reached therapeutically relevant levels in the aqueous and cornea but not in the vitreous humor of inflamed eyes. Intraocular drug deposition was critically dependent on a disrupted blood-eye barrier. These findings suggest a limited role for caspofungin in the treatment of fungal endophthalmitis.

Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement

Claudins are major components of tight junctions and contribute to the epithelial-barrier function by restricting free diffusion of solutes through the paracellular pathway. We have mapped a new locus for recessive renal magnesium loss on chromosome 1p34.2 and have identified mutations in CLDN19, a member of the claudin multigene family, in patients affected by hypomagnesemia, renal failure, and severe ocular abnormalities. CLDN19 encodes the tight-junction protein claudin-19, and we demonstrate high expression of CLDN19 in renal tubules and the retina. The identified mutations interfere severely with either cell-membrane trafficking or the assembly of the claudin-19 protein. The identification of CLDN19 mutations in patients with chronic renal failure and severe visual impairment supports the fundamental role of claudin-19 for normal renal tubular function and undisturbed organization and development of the retina.