False Negative Toxoplasma Serology in an Immunocompromised Patient with PCR Positive Ocular Toxoplasmosis

Purpose: The authors report a case of a 60-year-old Caucasian male with a background of treated Chronic Lymphocytic Leukaemia (CLL) with secondary hypogammaglobulinaemia present with toxoplasma chorioretinitis and negative serum toxoplasma serology on presentation and on subsequent reactivation.

Methods: Retrospective case notes review with fundal photographs.

Results: In this case, on initial presentation and on recurrence, the patient’s serum anti-Toxoplasma IgG remained negative. The diagnosis was made on quantitative PCR of vitreous initially and aqueous humor on reactivation.

Conclusions: Despite negative serology, one must still consider ocular toxoplasmosis especially in CLL patients where the clinical picture could be compatible. Hypogammaglobulinaemia, the inability to produce IgG antibodies, is a well-recognized complication of CLL. Intraocular fluid sampling is essential in these cases where the sensitivity of PCR on either aqueous or vitreous humor has been shown to be higher in immunocompromised patients.     

Use of the polymerase chain reaction for diagnosis of ocular toxoplasmosis.

OBJECTIVE: To report a cohort of patients in whom polymerase chain reaction (PCR) was performed on vitreous samples and to place in perspective the current role of PCR in the diagnosis of ocular toxoplasmosis. DESIGN: Noncomparative case series. PARTICIPANTS: Fifteen patients in whom toxoplasmic retinochoroiditis was considered in the differential diagnosis and in whom the clinical presentation was not diagnostic and/or response to treatment was inadequate. INTERVENTION: Examination of vitreous fluid by PCR and of serum for the presence of Toxoplasma-specific antibodies. MAIN OUTCOME MEASURES: Presence of Toxoplasma gondii DNA, serologic test results, clinical findings, treatment, and outcome. RESULTS: In 7 of 15 patients, vitreous fluid examination results by PCR were positive for the presence of T. gondii DNA. Five of these seven patients had serologic test results consistent with Toxoplasma infection acquired in the distant past; the other two patients had serologic test results consistent with retinochoroiditis in the setting of acute toxoplasmosis. The PCR results influenced the management of these patients in six of the seven positive cases. In the eight patients in whom vitreous examination results were negative by PCR, either Toxoplasma serology was negative (6), the retinal lesions were caused by cytomegalovirus (1), or, on further consideration, the eye signs were not consistent with those of toxoplasmic retinochoroiditis (1). CONCLUSION: In patients in whom toxoplasmosis is considered in the differential diagnosis but in whom the presentation is atypical, PCR was frequently a useful diagnostic aid.     

Diagnostic approaches to severe, atypical toxoplasmosis mimicking acute retinal necrosis

PURPOSE: To describe the means of diagnosis and clinical features of atypical toxoplasmic chorioretinitis mimicking acute retinal necrosis. DESIGN: Observational case series. PARTICIPANTS: Twenty-two patients (25 eyes) with widespread chorioretinitis resulting from toxoplasmosis examined between 1990 and 2001. TESTING: Patients were diagnosed by various techniques, including polymerase chain reaction (PCR) of aqueous and vitreous, serum and intraocular antibody determination, culture of intraocular fluid, retinal biopsy, histopathologic examination, therapeutic trial of antibiotics active against toxoplasmosis, or a combination thereof. MAIN OUTCOME MEASURES: The primary outcome measure was diagnosis of disseminated toxoplasmic chorioretinitis by any combination of tests or by empiric use of specific antibiotics. The secondary outcome measure was visual and anatomic outcome of treatment. RESULTS: Mean age was 53.5 years (range, 19-77 years), with a median of 59.5 years. There were 9 women and 13 men. Six patients were infected with HIV, and 3 patients, 1 with HIV, had bilateral disease. Mean initial vision was 20/110 (median, 20/400; range, 20/20 to no light perception [NLP]). Sixteen patients (73%) had received oral or injectable corticosteroids and 11 (50%) had received antiviral therapy before the diagnosis of toxoplasmosis. Diagnosis was made solely by clinical response to antitoxoplasmosis medications in 4 patients. Sixteen patients were diagnosed based on evaluation of intraocular fluids and tissue by antibody determinations, culture, PCR, histopathologic examination, or a combination thereof. Visual acuity improved after treatment in 7 of 25 eyes (28%). Mean final visual acuity was 20/156 (median, 20/2500; range, 20/30 to NLP). Anatomically, 18 of 23 eyes with follow-up had healed or improved chorioretinitis. Retinitis was progressive in 1 eye, 2 eyes were enucleated, and 2 were phthisical. CONCLUSIONS: Diagnosis of atypical toxoplasmic chorioretinitis that mimics viral retinitis can be accomplished by several means. Prompt diagnosis may help avoid poor visual and anatomic outcomes after prolonged initial treatment with oral prednisone or antiviral medications.     

Ocular toxoplasmosis and AIDS. A case report

Ocular toxoplasmosis is uncommon in the natural course of AIDS. We report here in a case of a 27 year old man with cerebral toxoplasmosis involvement with neurological signs and coma. After an initial improvement with a sulfadiazine and pyriméthamine treatment, we noticed a foveal chorioretinitis with hyalitis in the right eye which deeply decreased the visual acuity (less than 20/400) strongly suggesting a toxoplasmic etiology. Then specific aspects such as serology, acquired or congenital toxoplasmosis, treatment are reviewed.     

Chorioretinitis in congenital toxoplasmosis

The goal of this study was to establish the incidence of chorioretinitis in 100 infants whose mothers presented a seroconversion during the pregnancy. It is a retrospective study over 6.5 years. There were 17 cases of latent congenital toxoplasmosis (56.7%) and 13 cases of clinical congenital toxoplasmosis (43.3%). Three infants presented with chorioretinitis: one at birth in a context of general stroke, the two others at 2 and 17 months after birth, despite treatment. The risk of retinochorioditis was the same in the case of latent or clinical congenital toxoplasmosis. The fall in the antibody titre was not a good criterion of cure; the percentage of lymphocytes in the cerebrospinal fluid could constitute a better criterion. This study confirmed the efficacy of systemic treatment of congenital toxoplasmosis.     

Retinocoroiditis toxoplásmica de presentación atípica en pacientes con enfermedades hematológicas malignas

In immunocompromised patients, toxoplasmosis may have atypical presentation with bilateral, extensive or multifocal involvement. We report a case series of atypical toxoplasmic retinocoroiditis in patients with malignant hematological diseases who are usually immunosuppressed. Four patients were diagnosed of atypical toxoplasmic retinochoroiditis, all of them had immunosuppression (100%) and half of them (50%) had received a bone marrow transplant. The polymerase chain reaction for toxoplasma was positive in 75% of cases, and in one case (25%) the diagnosis was made with clinical and serological criteria. One patient presented ocular toxoplasmosis despite being on prophylactic treatment with atovaquone. Patients with atypical ocular toxoplasmosis and hematological diseases are generally immunocompromised, but they do not always have history of a bone marrow transplant. The presentation may be due to a primary infection or a reactivation of the disease. The aqueous humor and/or vitreous polymerase chain reaction allow confirming the diagnosis to perform a proper treatment.     

Toxoplasmic chorioretinitis affecting the macula

To study macular changes in toxoplasmic chorioretinitis 41 patients with ocular toxoplasmosis were reviewed. Of the 41 patients, seven had central, large, deep, pigment ringed scars of congenital toxoplasmosis with poor central vision; squint was seen in two and nystagmus in two; 32, including 11 cases with a macular lesion, had recurrent active toxoplasmic chorioretinitis with a focal, yellowish-white, elevated lesion with indistinct borders mostly at the margin of an old scar and associated with vitreous opacities in all, secondary anterior uveitis in 28, macular oedema in 22, papilloedema in 14, and retinal perivasculitis in 16 cases; two had rare acquired toxoplasmic chorioretinitis affecting the macula. The results show that active toxoplasmic chorioretinitis often causes a widespread intraocular inflammation with vitritis, macular oedema, papilloedema, retinal perivasculitis and secondary anterior uveitis, and suggest a combined treatment of active lesions with antimicrobial agents and corticosteroids.     

Diagnosis of toxoplasmic retinochoroiditis with atypical clinical features

PURPOSE: To determine the value of aqueous humor analysis for confirming the diagnosis of ocular toxoplasmosis in patients who present with atypical clinical features and to relate the results of local antibody production and polymerase chain reaction (PCR) with the extent of active retinitis and the immune status of the patient. DESIGN: Retrospective case series. METHODS: Sixty-seven consecutive patients with retinitis or retinochoroiditis that was clinically consistent with atypical ocular toxoplasmosis underwent diagnostic anterior chamber paracentesis and serological studies. The aqueous humor was analyzed both by PCR to detect Toxoplasma gondii B1 gene and by the Goldman-Witmer coefficient to determine levels of local anti-T. gondii antibody production. RESULTS: In nine of the 67 cases, PCR was positive for T. gondii; seven of these were negative for local antibody production. All nine patients had illnesses associated with immunosuppression or advanced old age and all had active retinitis with a mean area of 11.5 disk areas (DA). Twenty-five of the remaining 58 cases were positive for local antibody production. These 25 had a mean area of active retinitis measuring 2.6 DA, and 24 of these patients were immunocompetent. All 34 cases with laboratory evidence of ocular toxoplasmosis diagnosed by either method responded to anti-T. gondii agents. The remaining 33 were negative for T. gondii infection by these two methods; some had laboratory evidence of other infections. CONCLUSIONS: Although in the present study, the sensitivity and specificity of the aqueous humor PCR and Goldman-Witmer coefficient could not be ascertained in the laboratory diagnosis of toxoplasmic retinochoroiditis, the PCR method appears to confirm the diagnosis in immunocompromised individuals with large atypical foci of retinitis. Conversely, determination of local antibody production may be appropriate for proper diagnosis in immunocompetent individuals presenting with small foci of retinitis.     

Detection of Treponema pallidum in the vitreous by PCR

BACKGROUND: Ocular involvement of syphilis still poses a clinical challenge due to the chameleonic behaviour of the disease. As the serodiagnosis has significant limitations, the direct detection of Treponema pallidum (TP) in the vitreous represents a desirable diagnostic tool. METHODS: Real-time polymerase chain reaction (PCR) for the detection of TP was applied in diagnostic vitrectomies of two patients with acute chorioretinitis. Qualitative verification of TP by real-time PCR and melting point analysis according to a modified protocol was ruled out. Patients underwent complete ophthalmological examination with fundus photographs, fluorescein angiography, serological examination, antibiotic treatment and follow-up. RESULTS: In two cases of acute chorioretinitis of unknown origin, real-time PCR of vitreous specimens of both patients provided evidence of TP and was 100% specific. Initial diagnosis of presumed viral retinitis was ruled out by PCR of vitreous specimen. Patients were treated with systemic antibiotics and showed prompt improvement in visual function and resolution of fundus lesions. CONCLUSIONS: With real-time PCR, detection of TP in the vitreous was possible and delivered a sensitive, quick and inexpensive answer to a disease rather difficult to assess. In cases of acute chorioretinitis, the use of PCR-based assays of vitreous specimens in the diagnostic evaluation of patients is advisable. Although syphilitic chorioretinitis is a rare disease, PCR should include search for TP, as diagnostic dilemmas prolong definitive treatment in a sight-threatening disease.     

The chorioretinal location of Toxoplasma infection

Considered rare and occurring only in immunocompromised patients or patients with severe infection, Toxoplasma gondii chorioretinitis--as a unique presenting sign of toxoplasmosis appears to occur with increased frequency over the last few years in immunocompetent patients. The typical clinical picture (central chorioretinal lesion with recurrent vasculitic reactions) and positive IgG Toxoplasma gondii serology confirmed our diagnosis. Negative Toxoplasma IgG serology in the mothers of 2 patients excluded the possibility of congenital toxoplasmosis. Clinicians should be aware of the possibility of increased frequency of ocular toxoplasmosis in immunocompetent patients.     

Diagnostik und Differenzialdiagnostik bei akuter retinaler Nekrose

Multiple viruses have been identified as causative agents in acute retinal necrosis (ARN). Retinal biopsies, analysis of intraocular antibody synthesis, and polymerase chain reaction (PCR) have identified varicella zoster virus, herpes simplex virus types 1 and 2, and cytomegalovirus. The differential diagnosis of ARN includes atypical ocular toxoplasmosis, some white dot syndromes, and other forms of retinal vasculitides such as Behçet’s disease. Because therapeutic intervention varies greatly in these acute situations, identification of the causative agent is essential. Serology is rarely helpful, whereas analysis of aqueous humor or vitreous samples provides clues to the etiology. Aqueous humor antibody testing and PCR have demonstrated excellent diagnostic power with high sensitivity and high specificity. This review is intended to provide an overview of the diagnostics and differential diagnosis of this rare but important disorder.     

Reactivation West Nile Virus Infection-related Chorioretinitis

West Nile Virus is a relatively uncommon infection that can involve retinal and choroidal inflammation leading to photopsias, photophobia, and orbital pain. The diagnosis is made by clinical history, serology, and characteristic funduscopic exam and fluorescein angiography findings. Treatment involves primarily supportive care as there are no known effective anti-viral agents. Visual recovery is usually full. Here we present a case of West Nile Virus Infection Related chorioretinitis that demonstrated active linear chorioretinal lesions approximately one year after the initial infection was diagnosed and treated. The patient noted new onset blurry vision and floaters for two weeks prior to presentation. Antibody titers to West Nile Virus increased from baseline levels indicating active infection. This represents the first case of reactivation West Nile Virus Infection Related chorioretinitis that has been documented.     

Reactivation West Nile virus infection-related chorioretinitis

West Nile Virus is a relatively uncommon infection that can involve retinal and choroidal inflammation leading to photopsias, photophobia, and orbital pain. The diagnosis is made by clinical history, serology, and characteristic funduscopic exam and fluorescein angiography findings. Treatment involves primarily supportive care as there are no known effective anti-viral agents. Visual recovery is usually full. Here we present a case of West Nile Virus Infection Related chorioretinitis that demonstrated active linear chorioretinal lesions approximately one year after the initial infection was diagnosed and treated. The patient noted new onset blurry vision and floaters for two weeks prior to presentation. Antibody titers to West Nile Virus increased from baseline levels indicating active infection. This represents the first case of reactivation West Nile Virus Infection Related chorioretinitis that has been documented.     

Serology in ocular toxoplasmosis.

The diagnostic value of toxoplasma serology in ocular disease was evaluated in the following groups of patients: (I) uveitis cases of various causes (n = 291); (II) consecutive posterior and panuveitis patients (n = 60); (III) patients with definite congenital and ocular toxoplasmosis (n = 8); (IV) cases of clinical ocular toxoplasmosis (n = 25); and control patients with uveitis of non-toxoplasma origin (n = 12). No relation was observed between the level of the dye test titres and the diagnosis of ocular toxoplasmosis (groups I and II). During the active stages of the disease no typical change of the titres occurred in several longitudinally studied patients with toxoplasmosis. In group III one case was discovered to be negative by the dye test despite active ocular disease; however, IgG antibodies against toxoplasma were detected by the ELISA technique. In group IV, which was investigated by the ELISA technique, 100% of the toxoplasmosis patients were positive for IgG versus 58% of the control patients. Circulating immune complexes containing IgG and toxoplasma antigen were detected in seven of 25 toxoplasmosis patients (28%) and in two of 12 control patients (16%). Our study shows that the definite diagnosis of ocular toxoplasmosis or its exclusion by serological means only is not yet feasible. The possible superiority of the ELISA test to the dye test warrants further investigation.     

Application of polymerase chain reaction method (PCR) in diagnosis of endophthalmitis

PURPOSE: The goal of this study is to determine the usefulness of the PCR method in the diagnosis of endophthalmitis. MATERIALS AND METHODS: 30 clinical specimens 18 AH and 12 VF were obtained from 20 eyes with the clinical diagnosis of endophthalmitis. These included: 14 cases after cataract surgery, 1 case post trabeculectomy, 2 cases after penetrating traumas, and 3 cases after endogenous endophthalmitis. The same samples were analysed using 2 different methods: 1. conventional microbiological techniques (microscopy and diagnostic culture) and 2. PCR directed at 16S rDNA using universal primers. RESULTS: In the aqueous humor the causative pathogen was identified in one case (5.2%) by using diagnostic culture compared with seven cases (39%) by using PCR methods. In the vitreous samples the pathogen was identified in one case (9%) by using conventional method compared with five cases (50%) by using PCR. Microscopic preparation was difficult to evaluate in all samples. CONCLUSIONS: PCR performed on aqueous humor and vitreous fluid is a reliable tool for diagnosis of causative organism particularly in smear and culture negative specimens. By using universal primers we are able to detect the presence of pathogen in case of endophthalmitis and than potentially by using DNA probe hybridization to determine the species of the bacteria. The discrimination between infection or non-infection endophthalmitis plays the main role in a succesful therapy.     

Presumed toxoplasmosic anterior optic neuropathy

Purpose: To describe the clinical findings and course of toxoplasmic anterior optic neuropathy and to differentiate primary and secondary involvement. Methods: Retrospective observational case series from a tertiary referral institution. Clinical and photographic charts of 13 patients with toxoplasmosis with direct optic nerve head involvement were reviewed and data were collected throughout the length of follow-up. Results: Toxoplasmic anterior optic neuropathy was divided into two types. Type I was defined as secondary infectious involvement of the optic nerve head from an adjacent focus of chorioretinitis that resolved with chorioretinal scarring. Type II was defined as primary involvement of the optic nerve head that resolved without chorioretinal scarring. Visual acuity improved after treatment in both Type I and Type II patients; however, the visual prognosis was worse in Type I patients due to macular involvement. Eighty-three percent of Type II patients had a final visual acuity equal to or better than 20/25 compared to 50% of Type I patients. Visual field defects were present in all patients, most frequently arcuate or altitudinal (62%). Delay in diagnosis was common (54%), especially in Type II patients (71%). Vitreous inflammation was absent on the initial examination in 31% of the patients. Conclusion: Toxoplasmic anterior optic neuropathy is an uncommon manifestation of ocular toxoplasmosis. Delays in diagnosis are common because of the frequent lack of typical chorioretinitis or vitreous inflammation. Adjacent macular involvement strongly influences visual outcome.     

Efficacy of specific chemotherapy in the prevention of recurrences of toxoplasmic chorioretinitis during the 4 years following the treatment

The effectiveness of a curative or preventive therapy in toxoplasmic retinochoroiditis is difficult to evaluate clinically. The goal of the present paper was to study the recurrence rate of ocular toxoplasmosis during a four years period following a Pyrimethamine-sulfadiazine therapy. Some case had received previous therapy (systemic steroids alone or in combination with Spiramycin) which had not effected a lasting cure. In this series of 54 patients diagnosed as having active toxoplasmosis chorioretinitis, the combination of Pyrimethamine and Sulfadiazine seems statistically more effective than other reported treatments. The recurrence rate in a four years follow up study was 40 percent. The benefit of the therapy is more obvious in severe toxoplasmosis uveitis (with severe vitreous reaction, high recurrence rate, macular lesions). The treatment was less effective when indicated after an ineffective previous therapy. The dosage and the duration of the therapy must be adapted to each case. No complication was experienced during the treatment. In order to prevent recurrent toxoplasmosis uveitis Pyrimethamine-Sulfadiazine therapy appears to be the only effective synergistic therapy.     

Primary ocular Epstein-Barr virus-associated non-Hodgkin's lymphoma in a patient with AIDS: a clinicopathologic report

OBJECTIVE: To report an unusual case of chronic multifocal chorioretinitis with vitritis in a patient with acquired immunodeficiency syndrome (AIDS) that was resistant to antiviral and antitoxoplasmic medication and required a retinal biopsy for definitive diagnosis. METHODS: Vitreous biopsy, pars plana vitrectomy, and retinal biopsy were performed. The vitreous biopsy material was sent for bacterial, fungal, and viral culture, and the vitreous cassette was sent for cytology. The retinal biopsy material was divided and sent for polymerase chain reaction testing for toxoplasmosis and virology and pathologic tissue analysis. RESULTS: Vitreous cytology showed a mixed population of lymphocytes and histiocytes, but all other microbiologic and virologic studies were negative. Tissue analysis revealed an infiltrate of atypical mononuclear cells extending from the inner limiting membrane through the outer plexiform layer characteristic of a B cell, non-Hodgkin's lymphoma of the central nervous system (NHL-CNS). In situ hybridization for the Epstein-Barr virus (EBV) was positive. An extensive systemic evaluation did not show evidence of extraocular tumor. CONCLUSION: Although rare, primary ocular NHL-CNS can be seen in patients with AIDS, and its clinical presentation often closely resembles other disorders. To our knowledge, this case represents the first ocular NHL in which EBV is shown to be associated.     

Lymphocytic choriomeningitis virus: an underdiagnosed cause of congenital chorioretinitis

PURPOSE: To elucidate the role and clinical spectrum of congenital lymphocytic choriomeningitis virus infection as a cause of chorioretinopathy, congenital hydrocephalus, and macrocephaly or microcephaly in the United States. METHODS: We performed complete ophthalmologic surveys of all residents at Misericordia, a home for the severely mentally retarded in Chicago, and prospectively evaluated all patients with chorioretinitis or chorioretinal scars during a 36-month period at Children's Memorial Hospital, also located in Chicago. Sera for patients demonstrating chorioretinal scars (a sign of intrauterine infection) were tested for Toxoplasma gondii, rubella virus, cytomegalovirus, and herpes simplex virus and lymphocytic choriomeningitis virus antibodies. RESULTS: Four of 95 patients examined at the home had chorioretinal scars, and two of these patients had normal T. gondii, rubella virus, cytomegalovirus, and herpes simplex virus titers and dramatically elevated titers for lymphocytic choriomeningitis virus. Three of 14 cases of chorioretinitis at the hospital had normal T. gondii, rubella virus, cytomegalovirus, and herpes sim-plex virus titers and elevated lymphocytic choriomeningitis virus antibody titers. (A fourth case, diagnosed in 1996, was reported 2 years ago.) CONCLUSIONS: Lymphocytic choriomeningitis virus was responsible for visual loss in two of four children secondary to chorioretinitis in a population of severely retarded children. The six new cases of lymphocytic choriomeningitis virus chorioretinitis identified in these two populations over the last 3 years, compared with the total number ever reported in the United States (10 cases), suggests that lymphocytic choriomeningitis virus may be a more common cause of congenital chorioretinitis than previously believed. Because its consequences for visual and psychomotor development are devastating, we conclude that the workup for congenital chorioretinitis should include lymphocytic choriomeningitis virus serology, especially if T. gondii, rubella virus, cytomegalovirus, and herpes simplex virus titers are negative.     

The aetiology of ocular toxoplasmosis in Melbourne

The biological mothers of 23 patients presenting with acute chorioretinal toxoplasmosis had sera screened for the presence of antibodies to Toxoplasma gondii. Twenty-two of the mothers (96%) had positive serology and one (4%) had negative serology. This is consistent with the hypothesis that most cases of ocular toxoplasmosis are congenital in origin, but indicates that some cases are due to acquired toxoplasmosis.