**6. Treatment**

The standard treatment of toxoplasmic encephalitis is a combination of pyrimethamine and sulfadiazine (PY+S). They provide synergistic action, pyrimethamine being an inhibitor of dihydrofolate reductase while sulfadiazine inhibiting dihydrofolic acid synthetase, an enzyme involved in folic acid metabolism. Dose-related bone marrow suppression, thrombocytopaenia and anemia by this combination could occur. Hence, oral folinic acid (leucovorin) is routinely given to prevent those effects without inhibiting the action of pyrimethamine (Petersen & Liesenfeld, 2007). Dose, duration and adverse effects of those drugs are shown in table 4. Serum levels of pyrimethamine on a dose of 25-75 mg/day ranging from 1 to 4.5 mg/l and its CSF level is 10-25% of the serum level. Sulfadiazine is well absorbed with good penetration into CSF (Petersen & Liesenfeld, 2007).

TE mass lesion that is a feature helping to distinguish it from lymphoma. In comparison with TE and other infections, lymphoma displays high thallium uptake on SPET image. The rate of detection will be as high as 100% sensitivity and 89% specificity when the lesion is larger than 2 cm; otherwise it drops significantly if the lesion is smaller than 2 cm. PET imaging need more studies to determine its effectiveness (Lee et al, 2009). Among those techniques, none has high specificity and they are only useful when used in combination (Legrand et al, 2010). Moreover, they are costly and not widely available especially in

Routine laboratory tests of the cerebrospinal fluid (CSF) are not helpful for TE diagnosis because they are usually normal or non-specifically altered. Increased protein level could be seen in about 65% of patients, low glucose level in 8-52% and pleocytosis, predominantly mononuclear cells, in 27-40% (Collazos, 2003). Intrathecal level of *T. gondii* antibody is always low and of limited value for diagnosis because its sensitivity and specificity is about 60-70% (Collazos, 2003; Sukthana, 2006). Parasitic isolation from CSF is very rarely successful. Tachyzoites were seen in only 2 out of 6,090 examined ventricular CSF specimens and only 5 cases existed in the literature where a direct identification of *T. gondii* was possible by cytologic examination (Palm et al, 2008), however, those researchers reported a

Most patients with TE have an evidence of past infection showing a low titre of *T. gondii* antibody, but it helps the diagnosis. The absence of the antibody thus argues against TE diagnosis (Collazos, 2003; Sukthana, 2006). Nevertheless, it is not impossible since 3-5% of patients with TE have negative serological finding (Collazos, 2003). DNA-amplificationbased techniques greatly contribute to the diagnostic improvement. Blood PCR as a single test is not sensitive. CSF PCR produced disappointing results with low sensitivity (50%), although specificity is high (96%-100%) and the results usually are negative once specific anti-toxoplasmic therapy has been started (Collazos, 2003; Sukthana, 2006; CDC, 2009). Repeated testing and combining both CSF and blood PCR enhance sensitivity. Tachyzoitebradyzoite stage-specific primers could provide a more precise diagnosis of reactivated toxoplasmic encephalitis, especially in recurrent cases (Contini et al, 2002; Cultrera et al, 2002; Mahittikorn et al, 2010). Sukthana used duplex reverse transcriptase PCR (RT-PCR) technique containing tachyzoite (SAG1) and bradyzoite (BAG1) specific genes developed by our colleagues (Mahittikorn et al, 2010) to diagnose Thai TE cases. It was found that RT-PCR technique is simple, easy to perform, and provides 85% positive predictive value when

The standard treatment of toxoplasmic encephalitis is a combination of pyrimethamine and sulfadiazine (PY+S). They provide synergistic action, pyrimethamine being an inhibitor of dihydrofolate reductase while sulfadiazine inhibiting dihydrofolic acid synthetase, an enzyme involved in folic acid metabolism. Dose-related bone marrow suppression, thrombocytopaenia and anemia by this combination could occur. Hence, oral folinic acid (leucovorin) is routinely given to prevent those effects without inhibiting the action of pyrimethamine (Petersen & Liesenfeld, 2007). Dose, duration and adverse effects of those drugs are shown in table 4. Serum levels of pyrimethamine on a dose of 25-75 mg/day ranging from 1 to 4.5 mg/l and its CSF level is 10-25% of the serum level. Sulfadiazine is

well absorbed with good penetration into CSF (Petersen & Liesenfeld, 2007).

tachyzoites and bradyzoites of *T. gondii* directly seen in lumbar CSF cytology.

compared with CDC diagnostic criteria (to be published).

**6. Treatment** 

resource-poor settings (Sukthana, 2006).

Treatment with PY+S has some limitations including 1) poor compliance due to side effects, particularly sulfadiazine; 2) the large number of pills needed; 3) unavailability in some countries; 4) high cost and 5) lack of an intravenous form. Nearly half of treated patients develop adverse effects such as gastrointestinal upset or rashes (Table 4) and require a change of therapy. Clindamycin is an alternative drug in the case of intolerance to sulfacompounds. A 600 mg every 6 hours for 3-6 weeks by oral or intravenous route is recommended (Mariuz & Steigbigel, 2001; Sukthana, 2006; Dedicoat & Livesley, 2008). The efficacy and adverse effects of the combination between pyrimethamine and clindamycin (PY+C) seem to be comparable with pyrimethamine and sulfadiazine (PY+S) combination (Table 5). However, when using PY+C as a maintenance regimen, the relapse rate was twice higher (P = .02) than those who received PY+S (Katlama et al, 1996). Diarrheoa was more frequent on PY+C, while skin rash and fever were more commonly encountered in the PY+S group. More drug discontinuation occurred in the PY+S than in PY+C group (11 vs. 30%, p=.001). Therefore, Katlama et al (1996) suggested that a combination of pyrimethamine and clindamycin is a good alternative for acute treatment but is less effective for long-term prevention of the relapses.


Table 4. Recommended dose, duration and adverse effects of the standard and alternative drug regimens for toxoplasmic encephalitis (Modified from Mariuz & Steigbigel, 2001).

Cotrimoxazole or trimethoprim-sulfamethoxazole (TMP-SMZ) is another regimen that has been studied and recommended as an alternative treatment in particular areas that pyrimethamine and sulfadiazine are not available especially in developing world (Torr et al, 1998; Béraud et al, 2009). Its efficacy was as high as 70-85.5%, while the mortality rate was low (Table 5). TE relapse occurrence was around one-third of the patients and successfully re-treated by TMP-SMZ. Rash and neutropaenia were the most common side effects which occurred in 12-13.8% of patients but only half required treatment discontinuation. With its low cost, availability in parenteral form with excellent diffusion into the CNS and wide availability in developing countries, TMP-SMZ thus could be the first-line drug regimen for

Toxoplasmic Encephalitis 299

patients had a clinical response after 5, 7 and 14 days of treatment (Luft et al, 1993). Seizures and headache could not be used to assess the clinical response to therapy. Complete radiological response was defined as disappearance of all initial lesions and the absence of any new lesion. Those who showed clinical response, neuroradiographic abnormalities were also improved within 2-6 weeks in 91% (Mariuz & Steigbigel, 2001). Since patients may have more than one complication, follow-up brain imaging was recommended 10-14 days after starting therapy in each case (Chang et al, 1995). Brain biopsy should be considered in patients who clinically deteriorated after 3 days of treatment or showed no clinical improvement after 10-14 days of therapy. Treatment failure occurs if there is progression of either relevant symptoms and signs or new abnormalities developed within the first 10 days. Many patients died or still had neurological dysfunctions despite receiving standard or alternative therapy as well as

Life-long maintenance/secondary prophylaxis, after acute-therapeutic phase, using half the dose of therapeutic drugs to prevent TE recurrence is necessary because the available drugs are ineffective against the tissue cyst that could later be reactivated (Sukthana, 2006). The use of highly active antiretroviral therapy (HAART) suppresses the HIV viral load and improves the CD4 count, followed by a strong reduction of opportunistic infections, including TE. It has been confirmed in randomized, controlled clinical trials that maintenance/secondary prophylaxis could be safely discontinued after HAART administration and immune restoration successfully occurred. Table 2 and sections 3.3

HIV-infected patients with CD4 count <200 cell/mm3 and positive *T. gondii* antibody is indicated to receive primary prophylaxis preventing toxoplasmosis reactivation. Drug regimens, outcomes and recommendation provided in Table 2 and section 3.2 entitled 'TE during prophylaxis regimen period'. Serological study identifying the past infection is prudent in HIV-infected individual, appropriate primary prophylaxis should thus be

Prevention of *Toxoplasma* infection comprise two important measures i.e. infected-meats and contamination by oocyst from cat excreta. HIV-infected persons with negative *T. gondii* antibody should be recommended to consume only well-cooked meats or those frozen for at least 24 hours. Properly cooked until the internal temperature is over 60C, correctly smoked or cured in the brine are safe, but microwave cooking is not (Mariuz & Steigbigel, 2001). Noteworthy, increasing animal-friendly production systems might increase *T. gondii* prevalence if cooking practice is not proper. Chumpolbanchorn et al (2009) demonstrated 64.03% *T. gondii* antibody in Thai free-range chickens, while low prevalence (2.3%) was found in animal-friendly pig production systems in the

Limiting exposure to cats, their litter and soil contamination with cat fecaes are things to be practised as well as avoiding infective oocysts by daily disposal cat litter and thorough hand

washing, keeping cats indoor and feeding with canned or well-cooked food.

developing adverse effects (Table 5).

administered.

**7. Preventive measures** 

Netherlands (Kijlstra et al, 2004).

**6.2 Maintenance (secondary) and primary prophylaxis** 

entitled 'TE during HAART period' provide more details.

curative treatment and prophylaxis of TE, especially in resource-poor settings (Torr et al, 1998; Dedicoat & Livesley, 2008; Béraud et al, 2009).

Atovaquone was studied as salvage therapy in AIDS patients with TE who were intolerant or failed PY+S or PY+C therapy (Torres et al, 1997). With a dose of 750 mg four times daily, 52% and 37% of patients were clinically and radiologically improved during the acutetherapy phase (the first 6 weeks), respectively, while 26% and 15% remained clinically or radiologically improved by week 18. Few patients' adverse effects that were associated with and resulted in discontinuation of atovaquone were severe rash, fever, hepatomegaly, and toxic epidermal necrolysis. Commonly reported adverse events that did not result in discontinuation of therapy were fever, headache, diarrhea, nausea, and rash.


Table 5. Outcome of TE cases after receiving different drug regimens therapy.\*including complete or partial response defined as a resolution of TE or a greater than 50% improvement in the graded neurological examination. C = clindamycin; ND = no data; PY = pyrimethamine; S = sulfadiazine; TMP-SMZ = trimethoprim-sulfamethoxazole; vs. = versus; wk = week(s).

#### **6.1 Clinical response and outcome**

A complete response to standard therapy includes absence of neurological sequelae expected within 10-14 days. Luft and colleagues found that 50%, 86% and over 90% of

curative treatment and prophylaxis of TE, especially in resource-poor settings (Torr et al,

Atovaquone was studied as salvage therapy in AIDS patients with TE who were intolerant or failed PY+S or PY+C therapy (Torres et al, 1997). With a dose of 750 mg four times daily, 52% and 37% of patients were clinically and radiologically improved during the acutetherapy phase (the first 6 weeks), respectively, while 26% and 15% remained clinically or radiologically improved by week 18. Few patients' adverse effects that were associated with and resulted in discontinuation of atovaquone were severe rash, fever, hepatomegaly, and toxic epidermal necrolysis. Commonly reported adverse events that did not result in

> **Drug Regimen [Reference]**

> > TMP-SMZ vs. PY+ S [Dedicoat & Livesley, 2008]

70% vs. 70% (RR 1.0, 95% CI 0.74-1.33)\*

61 - 80% 68% vs. 62% ND

58-60% 12% vs. 22%

0% vs. 0% 3.2%

TMP-SMZ

[Bérau et al, 2009]

85.5%

ND

TE relapsed in 30% of patients

13.8% (only 7.4% required treatment interruption)

PY+C vs. PY+ S [Dedicoat & Livesley, 2008]

19% vs. 6% (RR 3.17,95% CI 0.67-15.06)

48.5% (RR 0.95,95% CI 0.55-1.64)\*

18-55% 46.2%vs.

25% 72-73% vs.

Not response 5-12% ND ND 7.4%

Table 5. Outcome of TE cases after receiving different drug regimens therapy.\*including

improvement in the graded neurological examination. C = clindamycin; ND = no data; PY = pyrimethamine; S = sulfadiazine; TMP-SMZ = trimethoprim-sulfamethoxazole; vs. = versus;

A complete response to standard therapy includes absence of neurological sequelae expected within 10-14 days. Luft and colleagues found that 50%, 86% and over 90% of

complete or partial response defined as a resolution of TE or a greater than 50%

discontinuation of therapy were fever, headache, diarrhea, nausea, and rash.

PY+C

[Mariuz & Steigbigel, 2001]

6-20% during the first 3 wk

71% by day 7 and 91% by day 14

Partial response 68-95% - -

Adverse effect 40% 60-62% vs.

1998; Dedicoat & Livesley, 2008; Béraud et al, 2009).

**Outcome** 

Mortality rate

clinical response

neurological response

radiological response

**6.1 Clinical response and outcome** 

Complete response

wk = week(s).

patients had a clinical response after 5, 7 and 14 days of treatment (Luft et al, 1993). Seizures and headache could not be used to assess the clinical response to therapy. Complete radiological response was defined as disappearance of all initial lesions and the absence of any new lesion. Those who showed clinical response, neuroradiographic abnormalities were also improved within 2-6 weeks in 91% (Mariuz & Steigbigel, 2001). Since patients may have more than one complication, follow-up brain imaging was recommended 10-14 days after starting therapy in each case (Chang et al, 1995). Brain biopsy should be considered in patients who clinically deteriorated after 3 days of treatment or showed no clinical improvement after 10-14 days of therapy. Treatment failure occurs if there is progression of either relevant symptoms and signs or new abnormalities developed within the first 10 days. Many patients died or still had neurological dysfunctions despite receiving standard or alternative therapy as well as developing adverse effects (Table 5).

#### **6.2 Maintenance (secondary) and primary prophylaxis**

Life-long maintenance/secondary prophylaxis, after acute-therapeutic phase, using half the dose of therapeutic drugs to prevent TE recurrence is necessary because the available drugs are ineffective against the tissue cyst that could later be reactivated (Sukthana, 2006). The use of highly active antiretroviral therapy (HAART) suppresses the HIV viral load and improves the CD4 count, followed by a strong reduction of opportunistic infections, including TE. It has been confirmed in randomized, controlled clinical trials that maintenance/secondary prophylaxis could be safely discontinued after HAART administration and immune restoration successfully occurred. Table 2 and sections 3.3 entitled 'TE during HAART period' provide more details.

HIV-infected patients with CD4 count <200 cell/mm3 and positive *T. gondii* antibody is indicated to receive primary prophylaxis preventing toxoplasmosis reactivation. Drug regimens, outcomes and recommendation provided in Table 2 and section 3.2 entitled 'TE during prophylaxis regimen period'. Serological study identifying the past infection is prudent in HIV-infected individual, appropriate primary prophylaxis should thus be administered.
