Cerebral toxoplasmosis

– Christian Hoffmann –

Although the incidence in Europe has been drastically reduced as a result of ART (Abgrall 2001), cerebral toxoplasmosis (or toxoplasmic encephalitis, TE) remains the most important neurological OI in HIV-infected patients. At present, it is typically diagnosed in patients with hitherto unknown HIV infection or in those not under regular routine care (Hoffmann 2007). TE almost always results from the reactivation of a latent infection with Toxoplasma gondii, an intracellular parasite that infects birds, mammals and humans. Prevalence rates vary considerably worldwide (Porter 1992). Whereas Toxoplasma gondii is relatively rare in the US, seroprevalence rates in some regions within central Europe are as high as 90%. Toxoplasma gondii has an affinity to the CNS. Extracerebral organ manifestations (heart, muscle, liver, intestine, lung) are rare and often only detected at autopsy.

Cerebral toxoplasmosis is potentially life threatening, and treatment is complicated. In severe cases, there may be residual neurological syndromes with significant disabilities, like hemiparesis. It is not rare to see a remaining lifelong susceptibility to seizures as a result of defective healing. It should be noted that relapses may occur even after long periods of time due to intracerebral persistence.

In Western countries, there is some evidence that the situation of an HIV-infected patient developing TE in recent years differs from TE patients seen during the early years of the HIV epidemic (Hoffmann 2007). Patients with TE today usually do not take antiretroviral therapy or any prophylaxis. They are likely to be diagnosed with HIV at the time of TE diagnosis, and TE is much more frequently the AIDS-defining illness in these patients than in the pre-HAART era.

Signs and symptoms

Clinical symptoms depend on the localization of lesions with acute or peracute onset within a few days. The major signs include focal neurological deficits such as paresis, speech problems or sensory loss (Porter 1992). A febrile psychosyndrome with confusion is also frequently an early sign. It is not unusual to see an epileptic seizure as the initial presentation, in the absence of other symptoms. Headaches with fever or subfebrile temperatures are always suspicious. Meningitic signs, however, are less typical. Atypical manifestations in patients with immune reconstitution under ART have been described (Ghosn 2003).

A fairly rare, but important manifestation is Toxoplasma chorioretinitis. It causes impairment of vision, is an important differential diagnosis to CMV retinitis and may occur on its own (Rodgers 1996). Toxoplasma chorioretinitis should be treated in exactly the same way as cerebral toxoplasmosis.


Cerebral toxoplasmosis seldomly occurs above a CD4 T cell count of 100 cells/µl; over 200 CD4 cells/µl it is very rare (Bossi 1998). In contrast, it should always be expected below 100 CD4 T cells/µl. A CT or MRI scan of the head should be performed promptly with in a week in every case of focal neurological deficit, but also if seizures occur in significantly immunocompromised patients. In this instance, a MRI is superior to a CT scan and almost always shows more visible lesions. A third of cases have either solitary, several (2-5) or multiple lesions, respectively. In approximately nine out of ten cases, ring enhancement is found around the lesions, often accompanied by edema. Hemorrhage may occasionally occur.

For all radiologically detected lesions, the most likely diagnosis is cerebral toxoplasmosis. In addition, the most important differential diagnosis is an “atypical” cerebral toxoplasmosis. Furthermore, the more lesions there are, the more likely the diagnosis of toxoplasmosis. However, the distinction between toxoplasmosis and a bacterial abscess or a cerebral lymphoma may be difficult. Other rare differential diagnoses include PML, infarcts, tuberculomas and cryptococcomas. “HIV-unrelated” diseases such as brain tumors or vascular diseases should also be considered.

A brain biopsy is not obligatory. Suspicion of toxoplasmosis (clinically and radiologically) justifies a treatment attempt without before it comes to this. Response to therapy then confirms the diagnosis. However, if the patient does not improve clinically within one week, or even worsens, then stereotactical brain biopsy cannot be avoided, and in this case, should not be postponed. The cerebrospinal fluid (CSF), which also does not necessarily have to be analyzed if there are clear radiological findings (several lesions with contrast enhancement), usually shows moderate pleocytosis and slightly elevated total protein. Our experience with Toxoplasma PCR from CSF has not been good. A negative result never excludes toxoplasmosis.

An updated serology should be available for every patient. Up to 97% of patients with cerebral toxoplasmosis have IgG antibodies, and so a negative result, which should be repeated in another laboratory if there is any doubt, makes toxoplasmosis unlikely. Some clinicians use levels of IgG titers or increased titers as indicators (Derouin 1996), but this approach has not been properly validated. IgM is only rarely positive, and therefore usually does not help. PCR from the blood also has little relevance (review: Bretagne 2003).


Treatment of cerebral toxoplasmosis is difficult. The most frequently used combinations are usually effective (resistance has not yet been convincingly described), but require modification in at least half of the patients due to side effects – particularly allergies. Sulfadiazine and clindamycin are presumably equally effective in combination with pyrimethamine (Dannemann 1992). However, one large European study demonstrated a trend, though not significant, in favor of sulfadiazine (Katlama 1996). Co-trimoxazole may also be an option. According to a Cochrane analysis, the available evidence fails to identify a superior regimen which can be considered as the gold standard (Dedicoat 2006).

We recommend that sulfadiazine and pyrimethamine be used for an initial attempt as oral treatment. In cases of sulfonamide allergy, sulfadiazine should be substituted with oral or intravenous clindamycin from the beginning. In addition, all disoriented patients should receive clindamycin infusions, at least for adherence reasons. Because of the high rate of allergies under sulfadiazine, however, some clinicians oppose this treatment. We do not share this perspective, since clindamycin is also allergenic. Moreover, clindamycin can cause pseudomembranous colitis.

A loading dose for pyrimethamine during the first few days has been propagated since the first published study (Leport 1988). However, it has not yet been proven whether or not it is necessary. Even the dosages vary. For example, in the US, 200 mg is recommended for the first day (followed by 50-75 mg depending on the body weight); in many European countries, 100 mg is often given for three days, followed by 50 mg. It should be noted that, in contrast to clindamycin, pyrimethamine is also active in the presence of an intact blood brain barrier, and therefore, is sometimes the only effective agent.

Due to the myelotoxicity of sulfonamides and pyrimethamine, which inhibits transformation of folic acid to folinic acid, it is imperative to substitute sufficiently with folinic acid which unfortunately is expensive. Folic acid which is much cheaper is ineffective since it cannot be converted in the presence of pyrimethamine (Luft 2000).

Good results have also been reported with intravenous co-trimoxazole, with administration of the same dosages as for PCP (Canessa 1992, Béraud 2009). In two randomized studies on patients with ocular or cerebral toxoplasmosis, co-trimoxazole was as effective as sulfadiazine/pyrimethamine (Torre 1998, Soheilian 2005). If allergies or intolerance to both sulfonamides and clindamycin occur, then a combination of atovaquone and pyrimethamine is a possible alternative (Chirgwin 2002). A combination of azithromycin plus pyrimethamine could be another alternative (Bosch-Driessen 2002).

Acute therapy lasts for a period of four weeks and at best, six weeks duration or possibly even longer for the less effective reserve therapies. Treatment success can be assessed clinically in the first 14 days. While often an improvement in the symptoms can be observed within a few days. A patient who has not improved at all after two weeks of therapy or has even deteriorated, probably does not have toxoplasmosis. If this occurs, the the diagnosis has to be reviewed and an urgent brain biopsy must be performed. Changing the TE therapy is not useful in such cases and just expends valuable time. Antiretroviral therapy should be initiated as soon as possible. Drugs with the potential of allergic reactions (abacavir, when HLA-testing is not possible, but also NNRTIs, fosamprenavir, darunavir) should be avoided.

A control MRI is recommended for stable patients after two weeks at the earliest. Significant resolution of lesions is often only visible after four weeks. In cases of increased intracranial pressure or extensive edema, steroids are given (8 mg dexamethasone q 6-8 h). Steroids also should be given for a limited duration, as there is a significantly increased risk of aspergillosis. All treatment combinations require initial monitoring of blood count, glucose, transaminases and renal parameters at least three times weekly. Maintenance therapy with the reduced dose should only be initiated if lesions have resolved by at least 75%.


Exposure prophylaxis: IgG-negative patients can protect themselves from primary infection by not eating raw or undercooked meat (lamb, beef, pork, game, etc.). It has not been proven, despite widespread opinion, that infection occurs by mere contact with cats, the definitive hosts of Toxoplasma gondii. To date, the only study that has seriously investigated this conjecture could not prove endangerment as a result of proximity to cats (Wallace 1993). Nevertheless, stricter measures of hygiene should be followed (e.g. gloves should be used when handling for the cat litter box, details in: Kaplan 2002).

Primary prophylaxis: All IgG-positive patients with less than 100 CD4 T cells/µl require primary prophylaxis. The drug of choice is co-trimoxazole. In cases of co-trimoxazole allergy, desensitization may be considered (see PCP). An alternative is dapsone plus pyrimethamine or high-dose dapsone. Primary prophylaxes can be discontinued safely if CD4 T cells are above 200/µl for at least three months.

Maintenance therapy/secondary prophylaxis: In the absence of immune reconstitution, patients with cerebral toxoplasmosis require lifelong maintenance therapy or secondary prophylaxis, as there are otherwise recurrences in nearly all cases. It usually consists of half the dose of the acute therapy (Podzamczer 2000). However, clindamycin is presumably less suitable, as it cannot cross the intact blood-brain barrier (Luft 2000). Co-trimoxazole seems to be not as effective for secondary prophylaxis, but should be considered because it is simple. However, it definitely requires higher doses than those used to treat PCP (Ribera 1999, Duval 2004). With immune reconstitution (at least six months above 200 CD4 T cells/µl), secondary prophylaxis can probably be stopped (Benson 2004, Miro 2006). When possible, an updated MRI scan should be available beforehand. If there is enhancement, then it may mean that lesions have become active even after years – and there is a risk of a recurrence. A recurrence even after five years has been observed, despite CD4 T cells levels being around 200/µl.

Treatment/prophylaxis of cerebral toxoplasmosis (daily doses, if not specif. otherwise)

Acute therapy

Duration: always at least four weeks

First choice


Sulfadiazine 2-3 tbl. at 500 mg qid plus

pyrimethamine2 tbl. at 25 mg bid (for 3 days, then halve dose) plus leucovorin 3 x 1 tbl. at 15 mg/week

First choice

Clindamycin +

Clindamycin 1 amp. at 600 mg i.v. qid or 1 tbl. at 600 mg qid plus

pyrimethamine2 tbl. at 25 mg bid (for 3 days, then halve dose) plus leucovorin 3 x 1 tbl. at 15 mg/week


Atovaquone +

Atovaquone suspension 10 ml bid (1500 mg bid) plus pyrimethamine2 tbl. at 25 mg bid (for 3 days, then halve dose) plus leucovorin 3 x 1 tbl. at 15 mg/week

Maintenance therapy


As for acute

As for acute therapy, but halve dose

Discontinue if > 200 CD4 cells/µl for > 6 months (if MRI is normal or without contrast enhancement)



Co-trimoxazole 1 tbl. at 960 mg qd

Primary prophylaxis

First choice


Co-trimoxazole 1 tbl. at 480 mg qd



Dapsone 2 tbl. at 50 mg qd


Dapsone +

Dapsone1 tbl. at 50 mg qd plus pyrimethamine2 tbl. at 25 mg/week plus leucovorin 2 tbl. at 15 mg/week

This and other cases (Stout 2002, Ghosn 2003) have shown that quantitative measurement of CD4 T cells on ART does not always reflect the quality of the TG-specific immune response. As a result, there have been increasing efforts in recent years to improve the characterization of this specific immune response via ELISPOT. Studies have made known that the Toxoplasma-specific immune response remains poor in approximately 10-20% of patients on ART, despite good CD4 T cell counts (Fournier 2001, Miro 2003). In the future, ELISPOT testing may allow identification of patients who are at risk of recurrence despite good CD4 counts and who should therefore continue with secondary prophylaxis.


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1 Comment

Filed under Cerebral toxoplasmosis, Part 3 - AIDS

One response to “Cerebral toxoplasmosis

  1. Ijaj mulla

    My father has multiple lesions in brainstem with csf igg for toxo ve & Tbpcr negative With montoux test ve (18-19mm) from a week dr started pyri with clindamycin but condition is still deacrising so what to do?

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