A multimodality therapeutic application on Toxoplasma gondii encephalitis utilizing Spiramycin and 'de novo' Ferula asafetida in immunodeficient mice.

This study investigated a 'de Novo' medicinal herb, Ferula asafetida (FA), against toxoplasma encephalitis either alone or combined with spiramycin (SP). Female Swiss-Webster mice (n = 72) were divided into three batches. Batch-I received no DMS to serve as an immunocompetent control, batch-II was immune-suppressed with the DMS (0.25 mg/g/day) for 14 days pre-infection, whilst batch-III was immune-suppressed with the DMS on the same day of infection. All experimental mice were inoculated with Toxoplasma gondii ME49 cysts (n = 75). Each batch was split into four subgroups: Mono-SP, mono-FA, combined drug (SP + FA), or neither. Therapies were administered on day zero of infection in batches (I and II) and 35 days post-infection in batch (III). Treatments lasted for 14 days, and mice were sacrificed 60 days post-infection. Histopathological changes, cysts load, and CD4 and CD8 T-cells were counted in brain tissues. The cyst-load count in mice receiving SP + FA was significantly (p < .0001) the least compared to the mono treatments in all protocols. Interestingly, the combined therapy demolished the T-cell subsets to zero in immunocompetent and immunocompromised infected mice. In conclusion, F. asafetida might be a powerfully natural, safe vehicle of SP in the digestive system and/or across the brain-blood barrier to control toxoplasmosis even through immunodeficient conditions.

Hypericum perforatum extract and hyperforin inhibit the growth of neurotropic parasite Toxoplasma gondii and infection-induced inflammatory responses of glial cells in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Hypericum perforatum L. has been widely used as a natural antidepressant. However, it is unknown whether it is effective in treating infection-induced neuropsychiatric disorders. AIM OF THE STUDY: In order to evaluate the effectiveness of H. perforatum against infection with neurotropic parasite Toxoplasma gondii, which has been linked to neuropsychiatric disorders, this study investigated the anti-Toxoplasma activity using in vitro models. MATERIALS AND METHODS: Dried alcoholic extracts were prepared from three Hypericum species: H. perforatum, H. erectum, and H. ascyron. H. perforatum extract was further separated by solvent-partitioning. Hyperforin and hypericin levels in the extracts and fractions were analyzed by high resolution LC-MS. Anti-Toxoplasma activities were tested in vitro, using cell lines (Vero and Raw264), murine primary mixed glia, and primary neuron-glia. Toxoplasma proliferation and stage conversion were analyzed by qPCR. Infection-induced damages to the host cells were analyzed by Sulforhodamine B cytotoxicity assay (Vero) and immunofluorescent microscopy (neurons). Infection-induced inflammatory responses in glial cells were analysed by qPCR and immunofluorescent microscopy. RESULTS: Hyperforin was identified only in H. perforatum among the three tested species, whereas hypericin was present in H. perforatum and H. erectum. H. perforatum extract and hyperforin-enriched fraction, as well as hyperforin, exhibited significant anti-Toxoplasma property as well as inhibitory activity against infection-induced inflammatory responses in glial cells. In addition, H. perforatum-derived hyperforin-enriched fraction restored neuro-supportive environment in mixed neuron-glia culture. CONCLUSIONS: H. perforatum and its major constituent hyperforin are promising anti-Toxoplasma agents that could potentially protect neurons and glial cells against infection-induced damages. Further study is warranted to establish in vivo efficacy.

Adjunctive bradyzoite-directed therapy for reducing complications of congenital toxoplasmosis.

Congenital toxoplasmosis is caused by in utero infection of the fetus with the intracellular parasite Toxoplasma gondii. Upon infection, the parasite forms life-long cysts in fetal brain and eyes which are resistant to the currently accepted therapy of pyrimethamine and sulfadiazine. These cysts commonly reactivate later in life causing chorioretinitis and visual impairment, and rarely cause neurological complications. I hypothesize that adjunctive, bradyzoite-directed therapies have the potential to alleviate a significant burden of disease by reducing cyst burden in neonatal brain and eyes. Atovaquone is perhaps the most promising drug for further evaluation given its low side-effect profile, established safety, and efficacy in animal models reducing cyst burden. Very limited observational data in humans suggests atovaquone may prevent Toxoplasma-associated chorioretinitis recurrence. Clinical trials are needed to evaluate it and other potential drugs as adjunctive treatment in congenital toxoplasmosis.

Patient and treatment pathways for toxoplasmosis in the United States: data analysis of the Vizient Health Systems Data from 2011 to 2017.

Toxoplasmosis causes substantial morbidity and mortality in the United States (US). Clinical manifestations to toxoplasmosis vary and there is limited information on incidence or treatment patterns in the US. Treatment pathways for pyrimethamine-based regimens and trimethoprim-sulfamethoxazole (TMP-SMX) for toxoplasmosis hospitalizations were investigated using the Vizient Health Systems inpatient and outpatient data. Between January 1st, 2011 and December 31st, 2017, 10,273 hospital visits from 4,736 unique patients received a primary or secondary ICD-9/ICD-10 diagnosis for toxoplasmosis. The projected annual hospital visits with a diagnosis of toxoplasmosis was 68,821, corresponding to a total annual incidence of 9,832 comprising ocular toxoplasmosis of 2,169, toxoplasmic encephalitis of 1,399, unspecified toxoplasmosis of 4,368, congenital toxoplasmosis of 381, multisystemic toxoplasmosis of 69 and other toxoplasmosis of 1,446. Only 16.3% of the study population received treatment with pyrimethamine-based regimens or TMP-SMX. Pyrimethamine-based regimens were used significantly more often than TMP-SMX in toxoplasmic encephalitis (88.7% vs 79.6%, p = 0.01), other toxoplasmosis (85.0% vs 79.2%, p = 0.04), and unspecified toxoplasmosis (87.6% vs 77.9%, p = 0.03) in hospitals with 300 beds or more. A significantly higher percentage of visits with TMP-SMX as first-line treatment switched to pyrimethamine-based regimens compared to visits initiated on pyrimethamine-based treatments (26.7% vs 4.1%, p < .001). Ocular toxoplasmosis patients receiving pyrimethamine-based therapy were more likely to be discharged home compared to TMP-SMC at rates of 72.4% and 55.2%, respectively. Our analysis of commercial insurance records suggest toxoplasmosis is undertreated. Overall, pyrimethamine-based regimens are favored over TMP-SMX, have higher rates of discharge home, and have lower switch rates.

Hidroterapia no equilíbrio dinâmico e nas atividades de vida diária de pacientes com neurotoxoplasmose associada à síndrome da imunodeficiência adquirida / Hydrotherapy on dynamic balance and in activities of daily living in patients withneurotoxoplasmosis associated with the acquired immune deficiency syndrome

INTRODUÇÃO: Por comprometer as células de defesa do organismo, o Vírus da Imunodeficiência Humana torna o indivíduo vulnerável ao aparecimento de diversas doenças, entre elas a neurotoxoplasmose. OBJETIVO: Verificar a influência de um protocolo de hidroterapia no equilíbrio dinâmico e nas atividades de vida diária de pacientes com neurotoxoplasmose associada à Síndrome da Imunodeficiência Adquirida (SIDA). MÉTODOS: Participaram 15 voluntários, três (20%) do sexo feminino e 12 (80%) do masculino, com média de idade de 37,44±5,5 anos e diagnóstico de neurotoxoplasmose decorrente da SIDA, cadastrados na Unidade de Referência Especializada em Doenças Infectocontagiosas Parasitárias Especiais. Foram submetidos à avaliação do equilíbrio dinâmico pelo Índice de Marcha Dinâmico e à avaliação das atividades de vida diária pelo Índice de Barthel, pré- e pós-hidroterapia, em piscina à temperatura média de 35°C, três vezes por semana em dias alternados, durante 50 minutos, totalizando oito semanas, ou seja, 24 sessões. Foi utilizado o teste de Shapiro-Wilk para análise de variâncias do Índice de Marcha Dinâmica e do Índice de Barthel, e o teste t de Student para as comparações pré e pós-tratamento e nível de significância de α=0.05. RESULTADOS: O equilíbrio dinâmico, considerando o escore total, apresentou significância estatística (p<0,0001), quando comparado pós-teste (20,3±2,5) em relação ao pré-teste (13,2±3,2). Quanto às atividades de vida diária, foi evidenciado valor estatisticamente significante (p=0,049) no pós-teste (98,8±2.2) quando comparado ao pré-teste (95,6±3.9). CONCLUSÃO: Neste estudo, o protocolo de hidroterapia melhorou o equilíbrio dinâmico e as atividades de vida diária de pacientes com neurotoxoplasmose associada à SIDA.

INTRODUCTION: For compromising the defense cells of the body, the Human Immunodeficiency Virus makes the individual vulnerable to the emergence of various diseases, including the neurotoxoplasmosis. OBJECTIVE: To determine the effect of a hydrotherapy protocol in dynamic balance and the activities ofdaily living of patients with cerebral toxoplasmosis associated with the Acquired Immuno Deficiency Syndrome (AIDS). METHODS: 15 volunteers participated, three (20%) were female and 12 of them (80%) were male; mean age 37.44±5.5 years, diagnosed with cerebral toxoplasmosis resulting from AIDS registered in Specialized Reference Unit on Infectious Diseases Parasitic Infectious Specials. Underwent evaluation of dynamic balance by the Dynamic Gait Index and the activities of daily living by Barthel Index, pre and post hydrotherapy, in the pool at an average temperature of 35°C, 3 times per week on alternate days, lasting 50 minutes, a total of 8 weeksor 24 sessions. We used the Shapiro-Wilk test for analysis of the Dynamic Gait Index and Barthel Index variances, and T Student test for pre and post-treatment comparison and significance level of α=0.05. RESULTS: Total score of dynamic balance presented statistically significance (p<0.0001), comparison post-test (20.3±2.5) compared to pre-test (13.2±3.2). As for the activities of daily living was evidenced statistically significant value (p=0.049),and the post-test (98.8±2.2) compared to pre-test (95.6±3.9). CONCLUSION: In this study, hydrotherapy protocol improved the dynamic balance and the activities of daily living of patients with cerebral toxoplasmosis associated with AIDS.

Latent toxoplasmosis reduces gray matter density in schizophrenia but not in controls: voxel-based-morphometry (VBM) study.

OBJECTIVES: To address the role of latent T. gondii infection in schizophrenia we studied the influence of latent toxoplasmosis on brain morphology. METHODS: An optimized voxel-based morphometry of magnetic resonance imaging was analyzed by analysis of variance with diagnosis and seropositivity as factors in 44 schizophrenic patients (12 T. gondii positive) and 56 controls (13 T. gondii positive). RESULTS: Grey matter (GM) volume was reduced in schizophrenia patients compared with controls in the cortical regions, hippocampus and in the caudate. In the schizophrenia sample we found a significant reduction of GM volume in T. gondii positive comparing with T. gondii-negative patients bilaterally in the caudate, median cingulate, thalamus and occipital cortex and in the left cerebellar hemispheres. T. gondii-positive and -negative controls did not differ in any cluster. Among participants seropositive to T. gondii the reduction of GM in the schizophrenia subjects was located in the same regions when comparing the entire sample (11,660 over-threshold voxels (P ≤ 0.05, FWR corrected). The differences between T. gondii-negative patients and controls consisted only of 289 voxels in temporal regions. CONCLUSIONS: Our study is the first to document that latent toxoplasmosis reduces GM in schizophrenia but not in controls.

Unusual cause of dementia in an immunocompetent host: toxoplasmic encephalitis.

A 69-year-old male was presented with a 2-month history of cognitive decline. The most profound deficit was observed in short-term verbal and visual memory and recognition. He was otherwise healthy, apart from atrial fibrillation diagnosed 5 months before. Brain MRI revealed T2 hyperintensities in the left thalamus, right pulvinar thalami, both putamina and right head of caudate nucleus without diffusion restriction on DWI sequences. CSF examination revealed elevated proteins. He was HIV negative. The course of the disease was complicated with gram negative sepsis and the patient died 14 days later. Autopsy revealed the brain lesions to have been caused by toxoplasmic encephalitis. Toxoplasmic encephalitis is an extremely rare cause of rapidly progressive dementia in immunocompetent patients. In patients with multiple lesions, hyperintense on T2 and hypointense on T1 weighted sequences, without diffusion restriction and some expansive effect, infectious causes should be considered, even in the absence of classical signs of infectious diseases and CSF pleocythosis.

Cerebral toxoplasmosis in an allogeneic peripheral stem cell transplant recipient: case report and review of literature.

We present a patient who underwent allogeneic peripheral stem cell transplantation (PSCT) for chronic myelocytic leukemia. Twenty months after the PSCT he experienced status epilepticus. Magnetic resonance imaging (MRI) revealed a focus in the ventral thalamus-hypothalamus region. Using stereotactic biopsy with histology and specific polymerase chain reaction investigation from brain tissue, cerebral toxoplasmosis was diagnosed and treated with antiparasitic therapy. Early recognition of such serious and potentially lethal disease enabled prompt specific treatment. This case report emphasizes the role of stereotactic biopsy in diagnosis of cerebral toxoplasmosis. Other methods such as MRI are non-invasive but not sufficiently specific and sensitive.

Invasive pneumococcal disease in patients infected with HIV: still a threat in the era of highly active antiretroviral therapy.

We studied all human immunodeficiency virus (HIV)-infected patients with invasive pneumococcal disease who received their diagnosis during 1996-2002 to investigate the incidence of this disease in the highly active antiretroviral therapy era and to study the influence of CD4 lymphocyte count on the clinical presentation and outcome of disease. The overall incidence of invasive pneumococcal disease was 11.3 cases per 100,000 person-years in adult patients without known HIV infection and 677 cases per 100,000 person-years in HIV-infected patients. This incidence remained stable over the study period. Clinical presentation, severity of illness, and number of recurrent episodes were similar in patients with CD4+ cell counts of >200 or < or =200 cells/ microL. Patients receiving trimethoprim-sulfamethoxazole (TMP-SMZ) were more likely to present with TMP-SMZ-resistant pneumococci than were those who were not receiving this agent (76.7% vs. 43.6%; P=.007). The mortality rate was high (21%).

A Case of Cerebral Toxoplasmosis in a Patient with Acquired Immune Defeciency Syndrome / 감염과화학요법

Toxoplasmosis is one of the most common opportunistic infection of the central nervous system in patients with acquired immunodeficiency syndrome(AIDS). There have been few reports of cerebral toxoplasmosis in patients with AIDS in Korea. In most cases, the diagnosis was assisted by serology and neuroradiologic findings. Making a reliable diagnosis of acute cerebral toxoplasmosis is difficult in patients with AIDS because of the lack of specificity of serologic data and neuroradiological findings. We report a case of 32-year-old man who presented with decreased mentality and fever. Brain MRI showed multiple ill-defined mass-like lesions in both basal ganglia and right thalamus. Stereotatic brain biopsy revealed small parasitic cysts which were filled with toxoplasmic bradyzoites in inflammatory brain tissue.

A Case of Cerebral Toxoplasmosis in a Patient with Acquired Immune Defeciency Syndrome / 감염과화학요법

Toxoplasmosis is one of the most common opportunistic infection of the central nervous system in patients with acquired immunodeficiency syndrome(AIDS). There have been few reports of cerebral toxoplasmosis in patients with AIDS in Korea. In most cases, the diagnosis was assisted by serology and neuroradiologic findings. Making a reliable diagnosis of acute cerebral toxoplasmosis is difficult in patients with AIDS because of the lack of specificity of serologic data and neuroradiological findings. We report a case of 32-year-old man who presented with decreased mentality and fever. Brain MRI showed multiple ill-defined mass-like lesions in both basal ganglia and right thalamus. Stereotatic brain biopsy revealed small parasitic cysts which were filled with toxoplasmic bradyzoites in inflammatory brain tissue.

Dystonia in AIDS: report of four cases.

Dystonia is a rare complication of acquired immune deficiency syndrome (AIDS). We report four such cases related to three different causes. Cases 1 and 2 both developed dystonia secondary to biopsy-proven progressive multifocal leukoencephalopathy. One had left arm dystonia, whereas the other had bilateral upper limb dystonia. One patient had associated akinesia and rigidity. Imaging demonstrated frontal and/or parietal white matter lesions but no basal ganglia abnormalities. Case 3 developed hemidystonia and cervical dystonia from biopsy-proven toxoplasmosis with a lesion in the thalamus. Case 4 suffered from AIDS dementia complex and developed cervical dystonia while taking risperidone therapy. We also review previously reported cases of dystonia in AIDS patients with the same causes and discuss the issue of increased vulnerability of the basal ganglia to HIV infection which, in turn, leads to increased sensitivity to neuroleptics. When dystonia is seen in AIDS patients, its pattern may be a clue to the ultimate cause.

Effectiveness of twice-weekly pyrimethamine-sulfadoxine as primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmic encephalitis in patients with advanced HIV infection.

The safety and efficacy of a fixed 25 mg pyrimethamine-500 mg sulfadoxine combination supplemented with 15 mg folinic acid twice a week as primary prophylaxis of Pneumocystis carinii pneumonia (PCP) and toxoplasmic encephalitis was evaluated in 106 patients infected with the human immunodeficiency virus. All patients had a CD4+ T-lymphocyte count of less than 100 cells/microl at study entry. Efficacy in this single-arm open-label prospective study was analyzed on an as-treated basis. No patient received highly active antiretroviral treatment, including protease inhibitors or non-nucleoside reverse transcriptase inhibitors, while on study medication. PCP developed in four patients, one of whom had been noncompliant. No PCP episode occurred in the first year. Probabilities of freedom from PCP were 0.97 (95%CI, 0.92-1) after 24 months and 0.93 (95%CI, 0.84-1) after 36 months. Of 74 (69.8%) patients positive for anti-toxoplasma IgG antibodies, one noncompliant patient developed toxoplasmic encephalitis after 24 months. Allergic reactions were observed in 18 (17%) patients and resulted in permanent discontinuation in 7 (6.6%) patients. One (0.9%) patient who had continued prophylaxis despite progressive hypersensitivity reactions developed a serious adverse reaction (Stevens-Johnson syndrome). The median survival of study participants was 29 months, with relentless progression of AIDS accounting for most deaths. The prophylaxis regimen studied appeared safe and effective for primary prophylaxis of PCP and toxoplasmic encephalitis. Severe adverse events can likely be prevented by discontinuation of prophylaxis at the time allergic reactions are noted. Rechallenge frequently results in tolerance. Efficacy and safety compare favorably with previously studied regimens. This simple prophylactic regimen may provide a convenient alternative for patients failing or intolerant to approved regimens.

Chagasic granulomatous encephalitis in immunosuppressed patients. Computed tomography and magnetic resonance imaging findings.

American trypanosomiasis (Chagas' disease), a zoonosis caused by Trypanosoma cruzi with a high incidence in Latin America, may induce an uncommon form of localized encephalitis termed "chagoma", found in few immunocompromised patients. The computed tomography (CT) and magnetic resonance imaging (MRI) findings of brain chagoma are reported for 3 males (ages 32, 32 and 9 yr), the first 2 infected with human immunodeficiency virus (HIV) and the third with acute lymphoblastic leukemia. Diagnosis was confirmed by biopsy. CT disclosed a single, supratentorial, nodular-shaped lesion that substantially enhanced with contrast material, localized in parietal or frontal lobes. T1-weighted MRI showed hypointense lesions that enhanced with gadolinium-diethylenetriaminepentaacetic acid, corresponding to extensive hyperintense areas on T2-weighted images, producing mass effect. The imaging pattern of brain chagoma presented here is similar to that of cerebral toxoplasmosis and should be considered in the differential diagnosis of an intracerebral mass lesion in immunocompromised patients.

A clinical-parasitological monotherapy cure in the treatment of experimental infection by a highly virulent strain of Toxoplasma gondii.

Toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome (AIDS) is treated classically with pyrimethamine plus sulfadiazine. Unfortunately, up to 40% of these patients are unable to complete the course of therapy because of adverse reactions to sulfonamides. This study considers the possible usefulness of monotherapies in the treatment of acute toxoplasmosis, producing parasitological cures 2-3 months after the date of infection. With this therapy, the main adverse effects are suppressed. Groups of mice infected with the RH strain of Toxoplasma gondii were treated with pyrimethamine alone, sulfadiazine alone, and pyrimethamine plus sulfadiazine for 7 d. Treatment with pyrimethamine plus sulfadiazine produced clinical cures in 100% of the infected mice 1 month after infection. Treatment with pyrimethamine gave a 60% survival rate (clinical cure) at 1 month postinfection. Finally, treatment with sulfadiazine produced a 60% survival rate at 1 month postinfection. Although the antitoxoplasmic regimen with pyrimethamine plus sulfadiazine has proven to be effective in intensive treatment of toxoplasmic encephalitis, relapses occur in more than 80% of cases after cessation of antitoxoplasmic therapy, making secondary prophylaxis mandatory. In this study the efficacy of treatment was also evaluated in terms of parasitological cure. None of the three therapies showed parasitological cure after 1 month of treatment. When the intervals were extended to a 3-month observation, monotherapy with pyrimethamine and sulfadiazine alone produced a parasitological cure.

[Sulfadiazine nephrolithiasis and nephropathy]. / Sulfadiazin-Nephrolithiasis und-Nephropathie.

Sulfadiazine-nephropathy and -nephrolithiasis were well known complications of high dose sulfadiazine therapy 50 years ago. In the last few years high dose sulfadiazine therapy has been widely used for treatment of toxoplasmic encephalitis in AIDS patients. As a consequence sulfadiazine-nephropathy and -nephrolithiasis have become increasingly common. We describe 2 patients with the typical picture of these complications. Therapy is based on the fact that the solubility of sulfadiazine and its acetylated metabolite are markedly improved at higher urine-pH levels. Urine alkalinization is also effective for prophylaxis during sulfadiazine treatment. We present our guidelines for prophylaxis and treatment of these complications.

[Therapeutic alternatives for cases of cerebral toxoplasmosis in patients with AIDS: clarithromycin and atovaquone]. / Alternativas terapéuticas para casos de toxoplasmosis cerebral en pacientes con SIDA: claritromicina y atovacuona.

BACKGROUND: Cerebral toxoplasmosis is the most common opportunistic infection of the central nervous system in AIDS patients. Its rate varies between 3-40% according to the prevalence of toxoplasmosis in the different geographic areas. Conventional treatments used for this pathology are: sulphadiacin or clindamycin plus pyrimethamine, but all can occasionally produce severe side effects. Therefore, the search for new alternative therapies is recommended. METHODS: Two cases of encephalic toxoplasmosis in AIDS patients who developed severe toxicity to conventional treatment with pyrimethamine and sulphadiacin and later to clindamycin are described. RESULTS: The first patient had a complete clinical and neuroradiological curation using clarithromycin 2 g/day and pyrimethamine 50 mg/day for 6 weeks. At 22 months follow up with a maintenance dose of 1 g/day of clarithromycin, the patient still remains asymptomatic. The second patient was successfully treated with atovaquone (750 mg/6 h) for 8 weeks and at 12 months of follow up with a maintenance dose of 750 mg/8 h remains asymptomatic. CONCLUSIONS: The authors believe that clarithromycin and atovaquone may constitute valid alternatives for the treatment of cerebral toxoplasmosis. Nonetheless, their use may, at present, be recommended only as an alternative for the cases of therapeutic failure or severe intolerance when the usual schedules are used.

[Usefulness of folinic acid in cytopenia induced by antiparasitic drugs in AIDS patients]. / Utilité de l'acide folinique dans les cytopénies induites par les médicaments antiparasitaires au cours du SIDA.

The scientific basis for using folinic acid in combination with the antiparasitic drugs prescribed to AIDS patients has been reviewed. In vitro and experimental data are unclear. On the basis of folinic acid metabolism and pharmacology and of clinical experience, we suggest that folinic acid should not be systematically added to the curative treatment of pneumocystosis with cotrimoxazole. Folinic acid may be added to prophylactic regimens using high-dose cotrimoxazole (i.e. 800 mg sulfamethoxazole twice a day) and in malnourished patients. It should be administered as soon as cytopenia occurs in the course of treatment. Concerning toxoplasmosis, the addition of folinic acid is recommended in doses of 10 to 20 mg/day in acute therapy and 5 to 10 mg/day in maintenance therapy. Dosage must be adjusted to the results of blood counts.