Toxoplasmosis is a zoonosis caused by the obligate intracellular parasite, Toxoplasma gondii and has a worldwide distribution. Not only does it cause infection in humans and cats, it can infect virtually all warm-blooded animals including mammals and birds. The majority of horizontal transmission to humans is caused by ingestion of tissue cysts in infected meat, or by ingestion of water or food contaminated with sporulated oocysts from the environment, and less frequently directly from feline faeces. This leads to intestinal invasion and dissemination toward all organs. Seropositivity for toxoplasma infection in healthy people in the US varies between 10% to 40%, whereas in parts of Western Europe and Central America, the prevalence can be as high as 70% to 90%.
In patients with human immunodeficiency virus (HIV) infection, most cases of toxoplasmosis are reactivation disease occurring when the CD4 T-lymphocyte (CD4) cell count is < 50 cells/μL. Central nervous system (CNS) manifestations are the most common presentation of toxoplasmosis and include toxoplasma cerebral abscess and encephalitis; retinochoroiditis seen in congenital toxoplasmosis is rare in adults with HIV infection. Pulmonary and cardiac manifestations also occur. This section focuses on toxoplasma cerebral abscess and diffuse encephalitis, discussed jointly as toxoplasma encephalitis.
Toxoplasma cerebral abscesses evolve over weeks, with signs and symptoms referable to involved areas of the brain. Its predilection for the basal ganglia results in common presentations of movement disorders or chorea. As there may be multiple lesions, mixed neurological deficits such as visual loss, hemiparesis, aphasia, cerebellar signs and cranial nerve palsies, accompanied by seizures are common. Diffuse encephalitis may present sub-acutely with headaches, confusion and seizures over up to 8 weeks. Involvement of other organs such as lungs, eyes, heart, liver and pancreas, lead to retinochoroiditis, pneumonitis, myocarditis and other manifestations of disseminated infection. Primary infection with toxoplasma in a pregnant woman with HIV infection may lead to congenital toxoplasmosis in the foetus, vertical transmission in the first and second trimester having greater consequences, and may lead to severe congenital anomalies and abortion.
The diagnosis of toxoplasma encephalitis is most often presumptive, rather than definitive. A deﬁnitive diagnosis of toxoplasma encephalitis requires a suggestive clinical syndrome, one or more cerebral masses and a histological diagnosis, which necessitates a brain biopsy. A presumptive diagnosis is made with a suggestive clinical syndrome, positive IgG antibodies against toxoplasma and multiple lesions on brain imaging. Differential diagnoses include cerebral lymphoma, mycobacterial tuberculoma, cryptococcoma, cerebral abscess and progressive multifocal leukoencephalopathy, which usually involves white matter rather than grey matter, is non-contrast enhancing and usually has no associated mass effect.
The majority of clinicians rely initially on an empiric diagnosis, which can be established by an objective response, clinically and radiologically, to anti-T. gondii therapy in the absence of a likely alternative diagnosis. Brain biopsy is reserved for patients who fail to respond to specific therapy. Patients with HIV infection with toxoplasma encephalitis are almost uniformly serologically positive for anti-toxoplasma IgG antibodies.
Toxoplasmosis cerebral lesions are usually multiple with ring enhancement and are associated with oedema (Images 1 and 2), particularly common at the corticomedullary junction, basal ganglia and thalamus. Although an MRI or CT scan may demonstrate typical lesions, these imaging modalities are unable to reliably differentiate between toxoplasmosis and cerebral lymphoma. F-FDG PET/CT has shown promise in elucidating CNS pathology in patients with HIV infection.
An early brain biopsy is recommended in those patients with atypical MRI features, patients who are deteriorating neurologically and radiologically while on toxoplasmosis treatment, patients with a negative serum toxoplasma IgG antibody and patients who have been adherent to sulfamethoxazole prophylaxis.
Acute toxoplasmosis is rapidly fatal and requires urgent demonstration of tachyzoites in infected fluids – cerebrospinal fluid, bronchoalveolar lavage, bone marrow aspirate or tissues – by polymerase chain reaction (PCR) or microscopic examination by Giemsa stain. PCR has high specificity (96-100%) but variable sensitivity (50-98%) depending on the primers used. The sensitivity of the PCR is highest in the first week of treatment.
Computerised axial tomograph scan of toxoplasmosis showing contrast-enhancing mass with surrounding cerebral oedema Source: Jones PD, Beaman MH, Brew BJ. HIV and opportunistic neurological infections. In: Stewart G, editor. Managing HIV. Sydney: Australasian Medical Publishing Company, 1997:81. Used with permission.
T2-weighted image of a patient with central nervous system toxoplasmosis, showing three space occupying lesions surrounded by cerebral oedema Source: Bruce J Brew, St Vincent’s Hospital, Sydney, NSW. Used with permission.
Most studies on toxoplasma encephalitis management in patients with HIV infection were conducted prior to the antiretroviral therapy era. The treatment of toxoplasma encephalitis requires combination therapy with sulfadiazine 1000 mg four times a day (or 1500 mg four times a day if weight is more than 60 kg) and pyrimethamine 200 mg loading dose followed by 50 mg daily (or 75 mg daily if weight if more than 60 kg). Leucovorin (folinic acid) 10 mg daily is given to prevent haematological toxicity. If sulfadiazine is not tolerated, it may be replaced by clindamycin 600 mg four times a day. Alternative regimens based variously on trimethoprim and sulfamethoxazole combination, atovaquone and dapsone have been reported. The use of pyrimethamine and sulfadiazine was associated with improved survivaI in a retrospective study and showed trends towards improved survival in a randomised unblinded study when compared to pyrimethamine and clindamycin, though most study deaths were not directly due to toxoplasmosis. Induction therapy should be given for a minimum of 6 weeks if there is radiological and clinical improvement.
The side effects of commonly used antimicrobials are listed in Table 1. Regular clinical review during therapy is recommended with monitoring of haematological and biochemical parameters.
|Sulfadiazine||Fever, rash (including Stevens-Johnson syndrome), anaemia, haemolysis, leukopenia and thrombocytopenia, crystalluria and renal impairment, anorexia, abdominal pain, nausea, vomiting and diarrhoea, headaches|
|Clindamycin||Anorexia, nausea, vomiting and diarrhoea|
|Pyrimethamine||Rash, anorexia, nausea and diarrhoea|
|Macrolides||Anorexia, abdominal pain, nausea, vomiting and diarrhoea Rash, abnormal liver function tests|
|Dapsone||Rash (including Stevens-Johnson syndrome), haemolytic anaemia (need to exclude glucose-6-phospate-dehydrogenase deﬁciency)|
Cerebral imaging should be repeated after 2-3 weeks to look for radiological improvement and again at the end of induction so as to obtain a baseline before maintenance therapy.  A progressive increase in the size of radiological lesions, accompanied by lack of clinical improvement despite 2 weeks of induction therapy, should trigger consideration of an alternative diagnosis and a brain biopsy. Dexamethasone at 4 mg four times a day tapering over a few days is often administered in the presence of cerebral oedema or mass effect though there are no randomised controlled trials to support this approach. Anticonvulsants may be considered in those patients with seizures but should not be given prophylactically to all patients.Patients with severe toxoplasmosis often require intensive care for respiratory failure and shock. In a retrospective study of patients with cerebral toxoplasmosis admitted to intensive care, a CD4 cell count of < 25 cells/μL and a Glasgow coma scale of 8 or less, was associated with poorer outcomes at 3 months (Odds ratio 2.7, 95% Confidence Interval of 1.1-6.7, and 3.1, 1.2-7.7 respectively). Death and clinical progression is higher in patients with lower CD4 cell counts (< 100 cells/μL) and cognitive symptoms.
Primary prophylaxis against T. gondii infection is recommended in patients with a CD4 cell count of <100 cells/μL. Trimethoprim and sulfamethoxazole (cotrimoxazole) for combined toxoplasma and Pneumocystis jiroveciipneumonia prophylaxis is the treatment of choice and a double-strength daily dose is recommended.
Secondary prophylaxis or maintenance therapy with a combination of sulfadiazine 2 g/day plus pyrimethamine 25 mg/day in divided doses is recommended; alternatives exist
Discontinuing primary prophylaxis appears to be safe if there is a sustained response to antiretroviral therapy with a CD4 cell count >200 cells/µL for at least 3 months. Discontinuing secondary prophylaxis is possible if there is a sustained increase in CD4 cell counts to >200 cells/µL after antiretroviral therapy (e.g. >6 months). Some clinicians suggest repeating imaging before cessation.
Optimal timing of commencing antiretroviral therapy
Optimal timing of commencing antiretroviral therapy. There are no studies examining the optimal timing of antiretroviral therapy in toxoplasma encephalitis. Most clinicians commence treatment early.
Toxoplasma-associated immune reconstitution inflammatory syndrome
Cases of unmasking toxoplasmosis-associated immune reconstitution inflammatory syndrome (IRIS) have been reported but this syndrome is relatively rare and has not been a subject of much research to date.