Downregulation of the Central Noradrenergic System by Toxoplasma gondii Infection.

Toxoplasma gondii is associated with physiological effects in the host. Dysregulation of catecholamines in the central nervous system has previously been observed in chronically infected animals. In the study described here, the noradrenergic system was found to be suppressed with decreased levels of norepinephrine (NE) in brains of infected animals and in infected human and rat neural cells in vitro The mechanism responsible for the NE suppression was found to be downregulation of dopamine ß-hydroxylase (DBH) gene expression, encoding the enzyme that synthesizes norepinephrine from dopamine, with downregulation observed in vitro and in infected brain tissue, particularly in the dorsal locus coeruleus/pons region. The downregulation was sex specific, with males expressing reduced DBH mRNA levels whereas females were unchanged. Rather, DBH expression correlated with estrogen receptor in the female rat brains for this estrogen-regulated gene. DBH silencing was not a general response of neurons to infection, as human cytomegalovirus did not downregulate DBH expression. The noradrenergic-linked behaviors of sociability and arousal were altered in chronically infected animals, with a high correlation between DBH expression and infection intensity. A decrease in DBH expression in noradrenergic neurons can elevate dopamine levels, which provides a possible explanation for mixed observations of changes in this neurotransmitter with infection. Decreased NE is consistent with the loss of coordination and motor impairments associated with toxoplasmosis. Further, the altered norepinephrine synthesis observed here may, in part, explain behavioral effects of infection and associations with mental illness.

Clinically Approved Drugs against CNS Diseases as Potential Therapeutic Agents To Target Brain-Eating Amoebae.

Central nervous system (CNS) infections caused by free-living amoebae such as Acanthamoeba species and Naegleria fowleri are rare but fatal. A major challenge in the treatment against the infections caused by these amoebae is the discovery of novel compounds that can effectively cross the blood-brain barrier to penetrate the CNS. It is logical to test clinically approved drugs against CNS diseases for their potential antiamoebic effects since they are known for effective blood-brain barrier penetration and affect eukaryotic cell targets. The antiamoebic effects of clinically available drugs for seizures targeting gamma-amino butyric acid (GABA) receptor and ion channels were tested against Acanthamoeba castellanii belonging to the T4 genotype and N. fowleri. Three such drugs, namely, diazepam (Valium), phenobarbitone (Luminal), phenytoin (Dilantin), and their silver nanoparticles (AgNPs) were evaluated against both trophozoites and cysts stage. Drugs alone and drug conjugated silver nanoparticles were tested for amoebicidal, cysticidal, and host-cell cytotoxicity assays. Nanoparticles were synthesized by sodium borohydride reduction of silver nitrate with drugs as capping agents. Drug conjugated nanoconjugates were characterized by ultraviolet-visible (UV-vis) and Fourier transform infrared (FT-IR) spectroscopies and atomic force microscopy (AFM). In vitro moebicidal assay showed potent amoebicidal effects for diazepam, phenobarbitone, and phenytoin-conjugated AgNPs as compared to drugs alone against A. castellanii and N. fowleri. Furthermore, both drugs and drug conjugated AgNPs showed compelling cysticidal effects. Drugs conjugations with silver nanoparticles enhanced their antiacanthamoebic activity. Interestingly, amoeba-mediated host-cell cytotoxicity was also significantly reduced by drugs alone as well as their nanoconjugates. Since, these drugs are being used to target CNS diseases, their evaluation against brain-eating amoebae seems feasible due to advantages such as permeability of the blood-brain barrier, established pharmacokinetics and dynamics, and United States Food and Drug Administration (FDA) approval. Given the limited availability of effective drugs against brain-eating amoebae, the clinically available drugs tested here present potential for further in vivo studies.

Occurrence of Leishmania infantum in the central nervous system of naturally infected dogs: Parasite load, viability, co-infections and histological alterations.

Zoonotic visceral leishmaniasis is caused by the protozoan Leishmania infantum and little is known about the occurrence and pathogenesis of this parasite in the CNS. The aims of this study were to evaluate the occurrence, viability and load of L. infantum in the CNS, and to identify the neurological histological alterations associated with this protozoan and its co-infections in naturally infected dogs. Forty-eight Leishmania-seropositive dogs from which L. infantum was isolated after necropsy were examined. Cerebrospinal fluid (CSF) samples were analyzed by parasitological culture, quantitative real-time PCR (qPCR) and the rapid immunochromatographic Dual Path Platform test. Brain, spinal cord and spleen samples were submitted to parasitological culture, qPCR, and histological techniques. Additionally, anti-Toxoplasma gondii and anti-Ehrlichia canis antibodies in serum and distemper virus antigens in CSF were investigated. None of the dogs showed neurological signs. All dogs tested positive for L. infantum in the CNS. Viable forms of L. infantum were isolated from CSF, brain and spinal cord in 25% of the dogs. Anti-L. infantum antibodies were detected in CSF in 61% of 36 dogs. Inflammatory histological alterations were observed in the CNS of 31% of the animals; of these, 66% were seropositive for E. canis and/or T. gondii. Amastigote forms were associated with granulomatous non-suppurative encephalomyelitis in a dog without evidence of co-infections. The highest frequency of L. infantum DNA was observed in the brain (98%), followed by the spinal cord (96%), spleen (95%), and CSF (50%). The highest L. infantum load in CNS was found in the spinal cord. These results demonstrate that L. infantum can cross the blood-brain barrier, spread through CSF, and cause active infection in the entire CNS of dogs. Additionally, L. infantum can cause inflammation in the CNS that can lead to neurological signs with progression of the disease.

Central Nervous System Parasitosis and Neuroinflammation Ameliorated by Systemic IL-10 Administration in Trypanosoma brucei-Infected Mice.

Invasion of the central nervous system (CNS) by African trypanosomes represents a critical step in the development of human African trypanosomiasis. In both clinical cases and experimental mouse infections it has been demonstrated that predisposition to CNS invasion is associated with a type 1 systemic inflammatory response. Using the Trypanosoma brucei brucei GVR35 experimental infection model, we demonstrate that systemic delivery of the counter-inflammatory cytokine IL-10 lowers plasma IFN-γ and TNF-α concentrations, CNS parasitosis and ameliorates neuro-inflammatory pathology and clinical symptoms of disease. The results provide evidence that CNS invasion may be susceptible to immunological attenuation.

An outbreak of Sarcocystis calchasi encephalitis in multiple psittacine species within an enclosed zoological aviary.

A total of 5 psittacine birds in an enclosed zoological exhibit, including 2 princess parrots and 3 cockatoos of 2 different species, developed severe central nervous system clinical signs over a 2-3-month period and died or were euthanized. Histologically, all birds had a lymphoplasmacytic and histiocytic encephalitis with intralesional protozoa consistent with a Sarcocystis species in addition to intramuscular tissue sarcocysts. By immunohistochemical staining, merozoites in brain and tissue cysts in muscle did not react with polyclonal antisera against Sarcocystis falcatula, Sarcocystis neurona, Toxoplasma gondii, and Neospora caninum, or with a monoclonal antibody to S. neurona. Transmission electron microscopy on sarcocyst tissue cyst walls from 2 birds was morphologically consistent with Sarcocystis calchasi. Polymerase chain reaction (PCR) amplification and sequencing of partial 18S ribosomal RNA from muscle tissue cysts and brain schizonts from 3 birds was consistent with a clade containing S. calchasi and Sarcocystis columbae but could not distinguish these closely related Sarcocystis species. However, PCR amplification and sequencing of the internal transcribed spacer 1 RNA segment in the brain from 2 birds and muscle from 2 birds specifically identified the isolates as S. calchasi. The current report documents that multiple psittacine species are susceptible intermediate hosts of S. calchasi, and that infection can cause encephalitis resulting in significant morbidity and mortality in psittacine aviaries.

Toxoplasmosis.

Toxoplasma gondii, an Apicomplexan, is a pathogic protozoan that can infect the central nervous system. Infection during pregnancy can result in a congenial infection with severe neurological sequelae. In immunocompromised individuals reactivation of latent neurological foci can result in encephalitis. Immunocompetent individuals infected with T. gondii are typically asymptomatic and maintain this infection for life. However, recent studies suggest that these asymptomatic infections may have effects on behavior and other physiological processes. Toxoplasma gondii infects approximately one-third of the world population, making it one of the most successful parasitic organisms. Cats and other felidae serve as the definite host producing oocysts, an environmentally resistant life cycle stage found in cat feces, which can transmit the infection when ingested orally. A wide variety of warm-blooded animals, including humans, can serve as the intermediate host in which tissue cysts (containing bradyzoites) develop. Transmission also occurs due to ingestion of the tissue cysts. There are three predominant clonal lineages, termed Types I, II and III, and an association with higher pathogenicity with the Type I strains in humans has emerged. This chapter presents a review of the biology of this infection including the life cycle, transmission, epidemiology, parasite strains, and the host immune response. The major clinical outcomes of congenital infection, chorioretinitis and encephalitis, and the possible association of infection of toxoplasmosis with neuropsychiatric disorders such as schizophrenia, are reviewed.

Morphological and molecular characterization of bovine coenurosis in Sardinia, Italy.

Coenurosis is a central nervous system disease of wild and domestic ruminants caused by Coenurus cerebralis, a bladder worm stage of Taenia multiceps). Even in Sardinia island, this metacestode seems to be widespread in sheep (Scala et al. Vet Parasitol 143(3-4):294-298, 2007) where coenurosis is an important health problem (Varcasia et al. Parasitol Res 99(5):622-626, 2006) the last and unique report of coenurosis in cattle was in 1990 (Cubeddu et al. 1990). In the present paper, a case of bovine coenurosis in Sardinia was described 22 years after the first report with a morphological a biomolecular characterization. A 2-year-old Limousine bull was euthanized in the Bolotana (NU) municipality (Central Sardinia). The remote anamnesis achieved from the farmer reporting that the bull showed neurological symptoms from 1 year of age previously classified as nutritional problems by the farm's veterinary. The breeder also says that the bull have by self-produced the skull fracture by hitting a gaff in the farm. The skull was opened and the brain removed and carefully examined showing two coenurus cysts containing clear fluid with numerous scoleces both in the right hemisphere. Morphological features of the cysts and mt-DNA sequencing confirm that the parasites were T. multiceps Coenuri.

Leishmania amastigotes in the central nervous system of a naturally infected dog.

A 4-year-old male Labrador Retriever dog was presented with a 10-day history of tetraplegia, depression, and absent postural reflexes. The cerebrospinal fluid was positive for Leishmania spp. DNA. At necropsy, a 2-cm long mass was observed adhered to C(7) and C(8) left spinal nerves. Microscopically, nerve fiber destruction together with mixed inflammatory infiltration was observed in the spinal nerves. Cervical spinal cord sections showed multifocal, diffuse granulomatous inflammation in the white matter. In the brain, perivascular infiltrates were observed in some areas together with subtle pallor of the parenchyma. Immunohistochemistry for Leishmania infantum confirmed the presence of amastigotes in the spinal nerves, spinal cord, brain parenchyma, and choroid plexuses. The current study describes the presence of Leishmania amastigotes in nervous tissue inciting radiculoneuritis, myelitis, and mild meningoencephalitis, suggesting a likely route by which L. infantum amastigotes reach and affect the central nervous system parenchyma.

Neuroangiostrongyliasis due to Angiostrongylus cantonensis in gang-gang cockatoos (Callocephalon fimbriatum).

CASE REPORT: Four gang-gang cockatoos from an aviary in Sydney displayed severe neurological signs. Three were necropsied and histopathology of the brains and spinal cords revealed migrating nematodes, which were identified as Angiostrongylus cantonensis. The migrating larval nematodes created tracts of malacia in the brain, but elicited little inflammatory cell infiltration. However, adult nematodes that had emerged onto the meningeal surface of the spinal cord evoked a marked non-suppurative reaction. Detailed histological examination of other tissues revealed larvae embedded in arterioles in the gastrointestinal serosa, lung and heart, which were associated with a significant granulomatous response. The latter lesions were consistent with our understanding of the pathogenesis of infection with this parasite, but have not been previously described, probably as a result of limited sampling. CONCLUSIONS: Angiostrongylus cantonensis is still present in the Sydney area and can cause significant disease in exposed animals, including birds. It also highlights potential human health problems.

Cerebrospinal nematodiasis outbreak in an urban outdoor aviary of cockatiels (Nymphicus hollandicus) in southern California.

An outbreak of cerebrospinal nematodiasis due to Baylisascaris sp. was documented in an urban outdoor aviary in southern California. Thirty-four out of 35 cockatiels (Nymphicus hollandicus, 97%) showed a variety of neurological signs including ataxia, lateral recumbency, opisthotonus, and torticollis. Thirteen carcasses were submitted for necropsy; the histological lesions were restricted to the central nervous system (brain and spinal cord) and were predominantly degenerative, characterized by multifocal white matter vacuolation, gliosis, axonal swelling, gitter cell infiltration, and mild hemorrhage, rarely accompanied by mild granulomatous inflammation and mild lymphocytic perivascular cuffs. Nematode larvae morphologically compatible with Baylisascaris sp. were observed in the brain of 5 birds, away from the lesion site.

Sarcocystis calchasi-associated neurologic disease in a domestic pigeon in North America.

Tissue cysts of a protozoan parasite were present in the skeletal muscle of a domestic pigeon (Columba livia f. domestica) with neurologic disease in Minnesota, USA. The animal had a severe granulomatous meningoencephalitis. The cysts were slender, up to 1 mm long and up to 0.03 mm in diameter. The cysts had a smooth wall without projections. Size and wall morphology were compatible with Sarcocystis calchasi. Polymerase chain reaction using S. calchasi-specific primers resulted in a specific amplicon from the skeletal muscle but not from the brain. Sequencing of the highly variable genomic regions ITS1 and D2 revealed 100% nucleic acid identity with the German strain of S. calchasi. Sarcocystis calchasi is the cause of an emerging lethal disease in pigeons in Germany. This is the first description of the parasite outside of Germany.

Development of lesions and tissue distribution of parasite in lambs orally infected with sporulated oocysts of Toxoplasma gondii.

The host-pathogen interaction is as a key feature during the formation of tissue cysts of Toxoplasma gondii within intermediate hosts. In this study, we investigated whether oral infection of lambs with T. gondii oocysts may be used as an experimental model in sheep to study this interaction, with the main objective being to detect the presence and distribution of lesions and parasite within different organs at different time points after oral infection. Lambs were infected with 5 × 10(3) and 5 × 10(5) sporulated T. gondii oocysts and culled at 2, 3, 5 and 6 weeks post-infection (WPI). During the infection, rectal temperature of the animals and serological antibodies against T. gondii were monitored. The presence of inflammatory lesions and parasite were evaluated through histological and immunohistochemical methods at different organs (brain, liver, lung, heart and lymph nodes). The lambs showed no clinical signs other than fever, and lesions appeared mainly in the brain, characterized by glial foci and perivascular cuffs, and in the heart, denoted by foci of interstitial myositis. Tissue cysts and tachyzoite-like structures were observed at all time points studied in the brain, where together with the glial foci they appeared mainly in the cerebral cortex of the forebrain and in the midbrain, but also in the heart, lung and lymph nodes. This study shows that oral infection with sporulated oocysts in lambs may provide a model for investigating the host-parasite interaction in situ during the development of tissue cysts.

Unusual location of hydatid cysts in pediatric patients.

OBJECTIVE/AIMS: To emphasize the importance of diagnosis and treatment of unusually localized hydatid cysts in pediatric cases. METHODS: Hydatid cyst patients of two departments were listed who had undergone surgery between January 2001 and December 2008. Of the 7 pediatric patients, 3 were chosen as the ones with unusual localization. Cyst removal with Dowling's technique was performed in 2 cases and total removal of the cyst wall was achieved after cyst aspiration in the other patient. RESULTS: Two patients did not show any signs of recurrence. Some of the cranial multiple cysts of the patient who had undergone her first surgery in another clinic with cyst rupture were successfully removed in our clinic. Six months later, she was admitted with spinal seedings. CONCLUSION: Hydatid cyst removal without rupture should be the surgical goal in all cases. Radiological evaluation is of utmost importance for differential diagnosis. When a cystic lesion is found in the central nervous system on radiological evaluation, hydatid disease must be considered in countries where the disease is endemic and surgery is to be planned emergently especially for pediatric cases with increased intracranial pressure. The study focuses on the strategy for the correct diagnosis and the appropriate treatment of unusually localized hydatid cysts.

[Epidemiology of extrapulmonary hydatid cysts: 265 Tunisian cases]. / Epidémiologie des kystes hydatiques extrapulmonaires : 265 cas en Tunisie.

AIM OF STUDY: The authors wanted to analyze the epidemiological features of extrapulmonary hydatid cysts and compare their results with those reported in literature. METHODS: Two hundred and sixty-five cases of extrapulmonary hydatid cysts collected from 1990 to 2007 were retrospectively studied. RESULTS: One hundred and one male and 164 female patients (sex ratio M/F=0.61 mean age 38.7 years) were included. In our series, hydatid cysts involved mainly the kidney (24.1%), the central nervous system (22.6%), the liver (19.6%) and the spleen (11.3%). CONCLUSION: Contrary to published data, our results show that hydatid cysts of the kidney and of the central nervous system are more frequent than hepatic location which ranks 3rd. Such unusual results may be due to a selection bias.

Meningoencefalitis granulomatosa por Balamuthia mandrillaris: Reporte de un caso y revisión de la literatura / Granulomatous amoebic meningoencephalitis by Balamuthia mandrillaris: case report and literature review

Durante los últimos años, otra ameba de vida libre, Balamuthia mandrillaris, ha sido identificada como agente etiológico de meningoencefalitis granulomatosa amebiana (MGA) en humanos. Presentamos el caso de una escolar de sexo femenino, inmunocompetente en quien se realizó el diagnóstico post mortem de MGA por este agente. Consultó por aparición de lesiones eritematosas e induradas que comprometían la zona centro-facial. En biopsia cutánea se evidenció una lesión granulomatosa con RPC positiva para secuencias génicas de Mycobacterium atípico, por lo que se inició tratamiento para micobacteriosis atípica extrapulmonar. Evolucionó con compromiso neurológico progresivo, falleciendo aproximadamente un año después de iniciar los síntomas. La necropsia reveló una MGA, cuyo estudio posterior demostró la presencia de B. mandrillaris. La infección por B. mandrillaris debe ser considerada en el diagnóstico diferencial de una enfermedad granulomatosa crónica que evoluciona con compromiso neurológico.

Updates on morphobiology, epidemiology and molecular characterization of coenurosis in sheep.

Taenia multiceps (Leske, 1780) is a taeniid cestode that in its adult stage lives in the small intestine of dogs and other canids. The metacestode, previously known as Coenurus cerebralis, is usually found in the nervous system including brain and spinal cord in sheep and other ruminants. The presence of cysts typically leads to neurological symptoms that in the majority of cases result in the death of the animal from starvation after some weeks. Coenurosis could cause high losses in sheep farms because the disease affects young animals that the farmers grow up each year as replacements of the older individuals. Coenurosis is also a zoonosis with more than 100 human cases described in literature, of which the last in Italy and almost 5 reported in Sardinia. In the last years, the popularity of coenurosis has increased in sheep breedings because of the necessity to operate a differential diagnosis from another neurological disease, scrapie, particularly in atypical cases of coenurosis that could occur also in adult (2-3 years of age) sheep.

Astroglial cells in primary culture: a valid model to study Neospora caninum infection in the CNS.

The protozoan Neospora caninum has a veterinary importance because it causes abortion in cattle and neuromuscular alterations in dogs. We infected rat astrocytes, in vitro, with different concentrations of N. caninum. Astrocytes responded to infection by producing the pro-inflammatory cytokine TNF-alpha and the neurotoxic-free radical NO, 24 and 72 h post-infection. These data suggest that astrocytes, which are essential for brain function, are targets for the parasite and this represents a practical and valid model to study the effects of N. caninum on the CNS.

Radiculomeningomyelitis due to Halicephalobus gingivalis in a horse.

An adult horse was euthanatized following a clinical diagnosis of cauda equina neuritis. Significant gross postmortem and histopathologic findings were limited to the sacral spinal cord and cauda equina. The sacral spinal cord, meninges, and spinal nerve roots were expanded and partially effaced by sclerosing granulomatous inflammation with necrosis. The lesion contained numerous nematode larvae and fewer adults with a rhabditiform esophagus having a corpus, isthmus, and valved bulb. Female nematodes were amphidelphic and didelphic with reflexed ovaries. These morphologic features confirm Halicephalobus gingivalis as a novel cause of clinical signs in this case of cauda equina neuritis.

Imagen de la neurocisticicercosis por tomografía computada en los niños / CR imaging of neurocysticercosis in children

Revisaron los expedientes clínicos y estudios de Tomografía Computada (TC) de 71 pacientes con diagnóstico de neurocisticercosis con el fin de valorar la edad de presentación, los síntomas predominantes, la utilidad de la TC y el tipo de lesión más frecuente. La edad de los pacientes estuvo en el rango de 1 a 18 años por lo que se infiere que la edad no excluye el diagnóstico. Se encontró que los síntomas clínicos más comunes fueron las crisis convulsivas y la cefalea. La CT fue anormal en 93 por ciento de los pacientes lo que confirma que este estudio sigue siendo de gran utilidad, sobre todo en países en desarrollo en donde no se cuenta con resonancia magnética. La lesión que predominó fue la parenquimatosa y de ésta, la variedad encefalítica, lo que concuerda con lo informado en la literatura