GUIDELINE FOR THE MANAGEMENT OF TOXOPLASMOSIS ENCEPHALITIS Full title of guideline Guideline for the management of toxoplasmosis encephalitis Author Dr P Venkatesan (ID consultant) Division and specialty Medicine, Infectious Diseases Scope (Target audience, Trustwide (adults) state if Trustwide) Review date 18.03.2021 Explicit definition of patient Any adult patient with suspected or confirmed toxoplasmosis group to which it applies (e.g. inclusion and exclusion criteria, diagnosis) Changes from previous Updated with reference to international guidance, with alterations in version (not applicable if this hierarchy of treatment and a greater role for co-trimoxazole is a new guideline) Summary of evidence base this guideline has been created from 1. UK BHIVA Opportunistic Infection Guidelines https://www.bhiva.org/oi-guidelines.aspx 2. US Opportunistic Infection Guidelines available at https://aidsinfo.nih.gov/guidelines
GUIDELINE FOR THE MANAGEMENT OF TOXOPLASMA ENCEPHALITIS A. Introduction Toxoplasma gondii is an intracellular protozoan parasite with an infectious reservoir in many animals. The domestic cat is the definitive host and cats excrete oocysts in faeces, which infect other animals. Humans are infected by ingesting bradyzoites (see picture above) found in cysts in meat from farm animals. Vertical transmission from mother to foetus is also possible. Transmission through breast feeding and other human to human transmission have not been documented. Exposure to Toxoplasma can be assessed by serology. 10-50% of adults in the USA are seropositive while in Paris the prevalence is nearly 90%. 80 to 90% of infections in immunocompetent hosts are asymptomatic. Primary infection may give a glandular fever like (mononucleosis) presentation though isolated lymphadenopathy may be more common. Benign symptoms may continue for up to 12 months. Congenital toxoplasmosis can be acquired if the mother has a primary infection during gestation or perhaps up to 3 months prior to becoming pregnant. There is a 5% risk of abortion or still birth if acquired in the first trimester. The classical disease pattern in the foetus is of cerebral calcification, chorioretinits, and hydrocephalus, though hepatic involvement and ascites is also seen. In HIV positive patients disease is usually due to reactivation of previous Toxoplasma infection. Less than 16% of patients with biopsy proven or treatment responsive disease are seronegative. Immunocompromised HIV patients may fail to produce antibodies or seronegative patients may be those presenting with primary infection and who have not yet mounted a serological response. Toxoplasma encephalitis usually presents when the CD4 count is less than 100 cells/mm 3. Disease is usually seen in the brain but may also occur in the spinal cord, the retina and in the lung.
B. Assessment and diagnosis Risk groups Toxoplasma encephalitis is encountered mainly amongst individuals with CD4 counts <100cells/mm 3 but should be considered in any HIV-infected individual with neurological symptoms or signs. It should also be considered in any individual not known to be infected with HIV but with focal CNS lesions. Clinical features The typical presenting features are 1. Focal neurological deficit (75%) hemiplegia or speech disturbance 2. Confusion 3. Headache (50%) 4. Personality change 5. Focal or generalized seizures (15-30%) 6. Fever (40-50%) The clinical features are due to a multifocal cerebritis. Toxoplasma can cause other problems including choroidoretinitis, pneumonitis, hepatosplenomegaly, myocarditis, and rash, but these are rare in HIV patients. Investigations Imaging Diagnosis relies on compatible imaging and cerebrospinal fluid examination to exclude other possible disease processes. CT is the first line for imaging due to speed and availability. Using contrast, multiple ring enhancing lesions, often in the cerebral cortex at the grey-white interface and the basal ganglia are seen. MRI is more sensitive than CT and may give more information in terms of number of lesions and help distinguish between other differential diagnoses. MRI should be performed at some point if no lesions are identified, and suspicion of intra-cranial pathology is high. The differential diagnosis of space occupying lesions in HIV positive patients includes 1. Toxoplasma encephalitis (50-70%)y 2. Primary cerebral lymphoma (20-30%) 3. Progressive multifocal leukoencephalopathy (10-20%) 4. Tuberculoma (both MTb and MAI) 5. Cryptococcomas 6. Bacterial or fungal cerebral abscess. 7. More rarely secondary lymphoma, metastatic KS, CVA, emboli from infective endocarditis
Serology In newly diagnosed patients with HIV, baseline Toxoplasma serology should be requested. In a patient known to the unit serology should be available and help with considering the differential diagnosis. Further Toxoplasma serology should be requested. As mentioned above up to 16% of patients have negative serology and this should not preclude initiation of empirical toxoplasma treatment. Lumbar puncture An LP should be performed if there are no contra-indications, and only after imaging. The CSF glucose is typically normal with raised protein in around 50% of patients and a mildy raised number of lymphocytes. Toxoplasma is not usually cultured in the laboratory but may be detected by PCR, with a reported sensitivity of ~50% and specificity >96%. CSF anti-toxoplasma antibody titres are positive in 30-60% of HIV infected patients with clinical disease from toxoplasmosis. C. Management (Evidence grade 1b) In patients with multiple ring enhancing lesions and who are HIV positive, treatment should be commenced straightaway and even before any confirmatory serology or CSF examination. If empirical treatment is correct one expects clinical improvement in ~90% by two weeks. HIV positive patients should be treated for > 6 weeks, or 4-6 weeks after resolution of symptoms, on a suitable regimen. 1 st line Therapy Sulfadiazine Pyrimethamine Weight > 60 kg give 1.5 g qds orally Weight < 60 kg give 1 g qds orally 200mg oral loading dose and then Weight > 60 kg give 75mg od orally, Weight <60 kg give 50 mg od orally Folinic acid 15mg od (titrating up in 15 mg increments to 60 mg if necessary for bone marrow protection (This regime also provides prophylactic protection against PCP)
2 nd Line Therapy (in decreasing order of preference Clindamycin 600mg qds orally or intravenous Pyrimethamine doses as above (This above regime does not provide prophylactic protection against PCP) Co-trimoxazole Atovaquone Macrolides 60/mg/kg/day in divided doses 750mg qds (but absorption variable, and better with food), sulphadiazine or pyrimethamine/folinic acid doses as above clarithromycin 500 g bd orally or azithromycin 1500 mg/day orally pyrimethamine/folinic acid, doses as above Adjuvant therapy Steroids should not be used routinely. If there is a severe mass effect dexamethasone could be considered, starting at 2-4 mg every 6 hours and tapering off if there is good effect over the course of days-weeks. One aspect of caution is that the diagnosis may not in fact be toxoplasmosis, and steroids may compromise the diagnosis of lymphoma. Sometimes steroids are used for IRIS, but this is rare with toxoplasma encephalitis. Fits should be controlled with anti-epileptics and there are issues over drug interactions with anti-retroviral agents. The choice should be discussed with pharmacy. There is no evidence to support the use of prophylactic anti-epileptics. Side effects of treatment Sulfadiazine Pyrimethamine Clindamycin leucopaenia, nausea, vomiting, diarrhea, hepatitis, fever, rash, headache, renal problems including renal failure (often three or more weeks into treatment) and crystalluria. rash, pancytopenia, headache, GI upset. rash, bone marrow upset, GI disturbance including C.difficile diarrhea. Maintenance therapy Once acute treatment has been completed then secondary chemoprophylaxis should be continued. This is because current drugs do not eradicate cyst forms of the organisms in
the brain or elsewhere and relapse rates are high without prophylaxis. Discontinuation of secondary chemoprophylaxis may be considered if the CD4 count consistently exceeds 200 for over 6 months. Essentially all of the first line drugs must be continued, but at reduced dose Sulfadiazine 2 to 4 g per day in 2 or 4 divided doses orally Pyrimethamine 25-50 mg od orally Folinic acid 15mg od (titrating up in 15 mg increments to 60 mg if necessary for bone marrow protection) Second line agents are dosed as follow Clindamycin 600 mg tds may be used in place of sulfadiazine, together with pyrimethamine Co-trimoxazole 960 mg bd Atovaquone 750 mg qds, (but absorption variable, and better with food) sulphadiazine or pyrimethamine/folinic acid Prevention Patients should be advised not to eat undercooked red meat or raw shellfish, to wash their hands after handling soil and not to change cat litter trays. Co-trimoxazole prophylaxis for PCP can provide some primary protection against toxoplasmosis. However we normally use co-trimoxazole 480 mg od, and a dose of 960 mg od is preferred for toxoplasmosis. Dapsone does not protect against toxoplasmosis and would have to be supplemented with pyrimethamine folinic acid. Atovaquone does protect against toxoplasmosis. Evidence for these approaches dates from the 1990s. However the additional pill burden and potential toxicities of using doses and agents other than co-trimoxozole 480 mg od for primary toxoplasma prophylaxis has to be balanced against the impact of viral load control and CD4 restoration in this group with initiation of highly active anti-retrovirals. Commencing anti-retrovirals Initiating ART occurs once baseline HIV resistance and HLA typing are back, usually > 3 weeks after starting Toxoplasma treatment, but not sooner so as to discern overlapping toxicities of Toxoplasma and HIV treatment. Reports of IRIS relating to CNS toxoplasmosis are relatively rare (~5%).
D. Nursing issues Isolation / precautions Once a patient is diagnosed with toxoplasma encephalitis they do not require isolation and standard precautions for HIV should be observed. Observations Neuro-obs (pulse/bp/temp/rr/oxygen saturation/pupils/gcs) - frequency depends on clinical condition [warning signs are falling pulse, rising BP, falling GCS, pupillary changes] Fluid balance is important especially when sulfadiazine is used as the risk of crystalluria can be minimized with fluid intake of 2-3 litres a day. Early warning score when indicated Disturbed patient Some patients may exhibit disturbed behaviour. Sedation if confused and difficult to manage may be appropriate if causing distress or danger to patient or others. Haloperidol in doses of 0.5-10mg should be used, benzodiazepines such as lorazepam 1mg, and titrated to response. If deteriorating, then consider a higher level of care. As in all patients with underlying chronic conditions this should only be considered if improvement can be expected with appropriate treatment. E. References 3. UK BHIVA Opportunistic Infection Guidelines https://www.bhiva.org/oi-guidelines.aspx 4. US Opportunistic Infection Guidelines available at https://aidsinfo.nih.gov/guidelines 5. Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet 2004;363:1965-76. 6. Further recent references on www.medadvocates.org
AUDIT FORM Toxoplasmosis Date : Please print off the guideline together with this audit form. Place the audit form on the front of the notes and complete the form at discharge or when dictating the discharge summary. On completion please return this audit form to Dr Venkatesan. Hospital number : History and examination adequate Investigations as per guideline Management as per guideline Discharge and follow up as per guideline Outcomes Full recovery Complications (please state) Death (please give details) Near misses / Serious incidents Could we have done better?