T OXOPLASMOSIS Learning Objectives Introduction Life Cycle Epidemiology Pathologenesis Clinical Overviews Diagnosis Serology Neuroimaging CSF examination

TOXOPLASMOSIS

• Learning Objectives• Introduction• Life Cycle• Epidemiology• Pathologenesis• Clinical Overviews• Diagnosis• Serology• Neuroimaging• CSF examination• Presumptive diagno

sis• Brain Biopsy algorit

hm• Treatment• Prophylaxis• Prognosis• Key Points• Summary• Self Assessment

Cerebral ToxoplasmosisDrs Sam Nightingale & Sylviane DefresSam Nightingale is a neurology registrar and MRC clinical research fellow. He runs the UK wide multi-centre PARTITION study looking at factors effecting the CNS penetration of antiretrovirals and the role of the CNS as a sanctuary site for HIV.

Sylviane Defres is an infectious diseases specialist registrar and clinical research fellow working on the NIHR funded ENCEPH-UK programme, a series interrelated of studies which include looking at the early clinical predictors of encephalitis and of outcome, with the aim of improving that outcome.

Edited by Prof Tom Solomon, Dr Agam Jung and Dr Sam Nightingale

This module provides an overview of the CNS manifestations of toxoplasmosis infection.

http://www.braininfectionsuk.org/

http://www.liv.ac.uk/infection-and-global-health

http://www.rlbuht.nhs.uk/

http://www.liv.ac.uk/neuroidcourse

http://www.thewaltoncentre.nhs.uk/

http://www.lstmliverpool.ac.uk/

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Learning Objectives

By the end of this session you will be able to: • Understand the epidemiology of toxoplasmosis

• Recall the life cycle of the pathogen Toxoplasma gondii.

• Describe the clinical features of CNS toxoplasmosis.

• Recognise which stage of HIV is at risk and give examples of other conditions predisposing to the disease.

• Outline the differences between presumptive and definitive diagnosis of toxoplasmosis and correctly identify which treatment approach is appropriate in a given clinical scenario.

• State the first-line and alternative treatments for CNS toxoplasmosis.

• Describe appropriate preventative measures and prophylaxis for those at risk.







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IntroductionCerebral toxoplasmosis is caused by infection with Toxoplasma gondii, an intracellular coccidian protozoan parasite that infects birds, mammals and humans. It has a worldwide distribution.

Although the first cases of cerebral toxoplasmosis were described in infants with congenitally acquired cerebral toxoplasmosis the most clinically evident cerebral toxoplasmosis is associated with HIV infection. Those with other causes of immunosuppression are also susceptible, including transplant recipients (particularly heart, lung kidney & bone marrow) and patients with haematological malignancies such as Hodgkin's disease. Also immunosuppression due to drugs including steroids and Anti-TNF therapies.

As with other opportunistic infections the incidence of toxoplasmosis in HIV infection has been dramatically reduced as a result of antiretroviral therapy.

Despite this, cerebral toxoplasmosis remains the most important neurological opportunistic infection in HIV infected patients around the world.

Cerebral toxoplasmosis- Axial T1-weighted MRI following gadolinium showing thick walled ring enhancing lesion with oedema, mass effect and midline shift (Image courtesy of Dr Ian Turnbull).







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Life Cycle of Toxoplasma gondiiT. gondii exists in 3 forms, oocysts, tachyzoites & tissue cysts (bradyzoites).

Although almost any mammal and some birds can be infected by T. gondii, only felines (wild & domesticated cats) can complete the reproductive cycle (definitive hosts). Felines (definitive hosts):

• Ingest all forms, in which invasion & replication can occur in the gut epithelium

• Excrete infectious oocysts in faecesNon-felines (intermediate hosts):

• Ingest oocysts which invade & replicate in the gut epithelium• Disseminates to tissues where they encyst, within the host cell cytoplasm

and lie dormant

Acquisition of T.gondii:• Ingestion of oocysts from the environment (contaminated water or food,

soil or cat faeces)• Ingestion of tissue cysts (bradyzoites) in meat (raw or undercooked)

In addition, in humans:• Vertical transmission from mother who acquires infection during gestation

(pregnancy)

• Less commonly:• Blood transfusion or organ transplantation (have been reported

from heart, lung, kidney or bone marrow)• Consumption of unpasteurized goat’s milk

Oocysts may remain viable in the environment for as long as 18 months

See pictures of the T.gondii forms & a diagram illustrating its life cycle on the following 2 pages.







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Life Cycle: Different forms of Toxoplasma gondii

• Oocyst (unsporulated)

• Sporulated oocysts – (contain sporozoites)– Sporulation occurs in

environment.

• Tachyzoites

(able to invade

host Cells)

• Tissue cyst;

Bradyzoites







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Life Cycle of Toxoplasma gondii III







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Epidemiology ISeroprevalence rates of toxoplasmosis vary significantly among countries. • Rate of approximately 15% in USA• Rates between 50-88% in some Western European and African countries.

There has been a 25-40% decline in the seroprevalence over a 10 year period from 1994-2004, shown below in USA & some western countries, but rises in other parts of the world. This appears to be due to a fall in incidence infection in childhood and therefore leaves more women susceptible in pregnancy

Human susceptibility varies according to several factors including proximity to cats, dietary habits, climate, and sanitation. In France, for example, the higher seroprevalence is probably due to a high consumption of raw and lightly cooked meat.

9% (was 22%)

70%

4.3 %

11-15% (was 25%)

50-60% (was 80-90%)







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Epidemiology II: HIV

Cerebral toxoplasmosis is an AIDS defining illness and usually occurs at CD4 counts below 100 cells/mm3. It is very rare over 200 CD4 cells/mm3.

Knowledge of the patient's country of origin is rarely helpful as the commonest cause of a CNS mass lesion in a HIV person is toxoplasmosis, even in areas where tuberculosis is endemic.

The seroprevalence rate of toxoplasmosis in HIV infected patients is similar to that of the general population

The incidence of infection in cat owners is equal to that in non-cat owners

Incidence CNS toxoplamosis has decreased from 5.4/1000 person-yrs (1990-92) to 2.2/1000 (96-98) with HAART and the use of effective anti- T.gondii prophylactic regimens

Interestingly, cerebral toxoplasmosis is rare in the paediatric HIV population.

In those HIV positive individuals with a CD4 count <100 and who are seropositive for T.gondii there is a 30% probability of developing reactivated toxoplasmosis if effective prophylaxis is not taken.

20-47% of HIV positive individuals not on treatment (ARVs or prophylactic antibiotics) are likely to go on to get cerebral toxoplasmosis.







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PathogenesisT.gondii enters via the intestinal epithelial cells where they can then spread to lymph nodes and distant organs via the blood or lymph systems. It can invade virtually all cell types and survives within a vacuole with cells, where it is protected from the host’s humoral and cellular immune system.

Due to parasite competition, the host cell will disintegrate releasing tachyzoites that invade surrounding tissues.

If the tachyzoites differentiate into bradyzoites this replication and disintegration process takes longer. These bradyzoites must transform into tachyzoites to invade surrounding tissues

In healthy individuals, the immune system effectively eliminates fast replicating tachyzoites & the bradyzoites replicate slowly enough that no serious damage occurs.

Left unchecked by the immune system, fast replicating tachyzoites invade and kill multiple cells resulting in large lesions. If this occurs in the brain and is untreated the damage could lead to hydrocephalus, retinochoroidenitis or fatal necrotic encephalitis.







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PathogenesisThere are 3 clonal strains of T.gondii:

Strain I

Strain II

Strain III

Congenital toxoplasmosis

AIDS

Severe ocular disease

Strain 3 is seen much more commonly in animals than humans, but when it does occur in humans causes severe ocular disease. Strain 2 is the most common in humans.

Atypical and recombinant strains have been identified with increasing frequency in regions other than USA & Europe, some of which have been associated with more severe disease even in the immunocompetent.







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Pathology

Most commonly there are multiple areas of focal necrotising encephalitis which contain tissue cysts and extracellular tachyzoites.

Multiple miliary granulomas or a diffuse necrotising encephalitis can occur.

This high power view of toxplasma tachyzoites (small arrow) in the brain shows numerous small blue parasites through the parenchyma. They may have emerged from the bradycyst seen towards the right hand side (large arrow).







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Clinical Overview 1 – Congenital infection

Transplacental infection

•Transplacental infection can result in spontaneous abortion, stillbirth or a child with a mental or physical handicap.

•Incidence maternal infection during pregnancy ranges 1-8/2000 (highest in France)

•Immunocompetent women, infected prior to pregnancy, virtually never transmit T. gondii to the foetus.

•Immunocompromised women may have parasitaemias during pregnancy despite preconceptional infection.

•Acute infection in the mother is usually asymptomatic.

•Maternal diagnosis is best made by paired serology 2 weeks apart.

Risk of foetal infection increases with advancing gestational age at the time of maternal seroconversion:

15% risk of transmission @ 13 weeks gestation44% risk of transmission @ 26 weeks gestation71% risk of transmission @ 36 weeks gestation







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Clinical Overview 2 – Congenital infection

Sequelae of transplacental/ foetal infection

• Intracranial lesions (calcification or ventricular dilatation),• Disseminated infection in infancy,• Serious neurological impairment (eg seizures in infancy, microcephaly,

cerebral palsy)• Retinochoroiditis

Intracranial lesions & neurological impairment are more likely to occur the earlier the seroconversion is(this is not the case for retinochoroiditis). Stillbirth or neonatal death is rare.

80% of live-born infected infants show no signs of congenital toxoplasmosis. Of the 20% that do show signs of congenital toxoplasmosis:

• 14% have retinochoroiditis, • 9% have intracranial lesions: of which ~5% have serious neurological

sequelae.The risk of bilateral visual impairment worse than 6/12 Snellen ranges from 2-9%.

RIGHT: Severe active toxoplasma chorioretinitis.







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Clinical Overview 3 – Congenital infectionDiagnosis of foetal infection prenatally

Purposes:• Mainly to aid the decision of whether to change the prenatal

treatment from spiromycin to pyrimethamine-sulfonamide, although there is little evidence that the latter is any more effective.

• Also to aid any decision regarding Termination Of Pregnancy• Exclusion of foetal infection prenatally to prevent unnecessary

postnatal treatment

Best method of diagnosis:• PCR amniotic fluid; accuracy varies between labs and

techniques.• Sensitivity of PCR increases with gestational age at maternal

seroconversion (33% 1st to 76% 2nd & 3rd trimester)• Foetal USS to see intracranial calcification or hydrocephalus

(only appear after 21 weeks gestation)







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Clinical Overview 4 – Immunocompetent adultPrimary infection;

• Usually asymptomatic in 80-90% of cases• In the remainder there is usually a flu-like illness with lymphadenitis

• Bilateral symmetrical non-tender lymph nodes • 20-30% have constitutional symptoms of fever chills and sweats. • Also headaches, myalgias, pharyngitis, maculopapular rash or

hepatosplenomegaly may occur• Usually self limiting, lasting approximately weeks to months.

• Very rarely myocarditis, pericarditis, pyomyositis, pneumonitis, hepatitis or encephalitis can occur

• Chorioretinitis• T.gondii is one of the commonest causes of chorioretinitis in

immunocompetent hosts. It is a differential of CMV retinitis. Typically it is acquired congenitally or postnatally. In this circumstance, there is usually bilateral eye involvement with scarring and frequent recurrences due to reactivation. Clusters of episodes can occur after prolonged disease free intervals. Older individuals are at higher risk of reactivation than younger

• Adults with acute infection usually have unilateral eye disease and there is an absence of prior scarring

• It can occur without other CNS involvement and is treated in the same manner as CNS toxoplasmosis. ( see later)

• Latent infection can persist for life







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Clinical Overview 5 – Immunocompromised AdultWhilst CNS toxoplasmosis can occur during the primary infection, this is rare and it usually represents reactivation of latent infection. Primary infection in the immunocompromised host can be severe and life threatening.

Most commonly this reactivation is in HIV positive individuals but the clinical presentation below can be similar in those who are immunocompromised for other reasons.

Cerebral abscesses are the most common form of reactivation. Extracerebral toxoplasmosis is much harder to determine the incidence of:

• Series have shown ocular, pulmonary and disseminated infection. • Rare cases involve bladder, skin, liver, lymph nodes and pericardium.

Often these are only detected at autopsy

Patients present with focal neurological signs relating to one or more mass lesions in the CNS, although a diffuse encephalitis can occur.

• Headache, confusion, fever, behavioral changes & altered mental status are common. Focal neurological defects & seizures are also common.

• Extrapyramidal signs and movement disorders can occur as there is a predilection for deeper structures in the region of the basal ganglia and midline.

• Onset can be insidious with fever and confusion, or acute with symptoms appearing over hours.

Although headache with fever is common, meningitic signs are unusual.







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DiagnosisThe threshold for investigation should be low in any HIV positive individual presenting with focal neurology, encephalopathy or seizures. The important differentials in this context are primary CNS lymphoma (PCNSL) and tuberculous granulomata or abscess.

Definitive diagnosis can only be achieved by brain biopsy, however this can usually be avoided by using serology, neuroimaging and observing response to presumptive treatment.

LEFT: T1-weighted MRI with contrast showing a developing tuberculoma in the left Sylvian fissue. Image courtesy of Dr Milne Anderson.

RIGHT: T1-weighted MRI with gadolinium showing primary CNS lymphoma in HIV. Image courtesy of Tom Solomon.







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Toxoplasma Microbiology/ Serology

IgM appears within 1 week of the acute infection.IgG becomes positive in approximately 2 weeks.

Serology in acute infection;IgM positive & IgG negative at the start, with both positive two weeks later is indicative of acute infection. But typically both are positive.

IgG avidity testing may help. IgG antibodies made early in infection bind to antigen less avidly than antibodies produced later. So the presence of high avidity suggests infection occurred at least 3-5 months earlier.

CNS toxoplasmosis is almost always a reactivation and serology is positive in 85% of cases.

Although the absence of antibodies makes the diagnosis less likely, they do NOT exclude the diagnosis. Seronegative cases can occur as a result of loss of antibody with increasing immunosuppression or rarely in primary infection.

•IgM is rarely positive and usually not helpful. •PCR testing has variable sensitivities and specificities; newer probes are

being investigated.•Culture is rarely performed but may be useful in neonates.







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Neuroimaging IMRI is more sensitive than CT. Toxoplasmosis usually causes multiple solid or cystic spherical lesions with ring enhancement, surrounding oedema and mass effect. The below image shows a T1-weighted MRI with gadolinium showing toxoplasmosis with mass effect:

They can be located anywhere in the CNS but have a predilection for the grey/white interface or basal ganglia. The more lesions there are, the more likely the cause is toxoplasmosis.

RIGHT: Coronal MRI, T2-weighted, showing bilateral toxoplasmosis (arrows).

Alone, neither MRI nor CT can differentiate among the multiple possible aetiologies of brain lesions in AIDS patients.Differential diagnosis includes:

CryptococcosisHistoplasmosisAspergillosisTuberculosisTrypanosomiasisCNS lymphoma







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Neuroimaging IIA single lesion favours lymphoma, but there is overlap and no appearance is pathognomonic. CNS tuberculomas appear similar to toxoplasmosis on imaging. Around 60% of these will have an abnormal chest x-ray. Progressive multifocal leucoencephalopathy (PML) does not produce mass effect.

DWI/SPECTThere has been some interest in diffusion weighted MRI or thallium SPECT (Single Photon Emission Computed Tomography) scans to differentiate between focal encephalitis, abscesses and lymphoma.

However the differences are neither specific nor sensitive so these tests are not routinely used. They may be of some value in cases where brain biopsy is not possible, for example due to location of the lesion (see further reading).

RIGHT: Cerebral toxoplasmosis. Axial T1-weighted MRI following gadolinium showing two thick walled ring enhancing lesions within the right basal ganglia with mild local mass effect. Image courtesy of Dr Ian Turnbull.







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CSF ExaminationLumbar puncture is frequently contraindicated due to the presence of a mass lesion and can usually be avoided, as suggestive radiology with positive serology is sufficient evidence to start presumptive treatment for toxoplasmosis.

The CSF usually shows a mononuclear pleocytosis with normal glucose ratio. PCR for toxoplasmosis in the CSF is specific (96-100%) but has a low sensitivity. CSF antibody testing is unhelpful.

The detection of Epstein-Barr virus (EBV) in the CSF by PCR indicates primary CNS lymphoma. PCR for Mycobacterium tuberculosis is positive in the CSF in 60% of tuberculous abscesses. Tuberculous granuloma may occur in association with TB meningitis.







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Presumptive diagnosisIn HIV positive individuals with a CD4 count< 100 cells/μl there is a 90% probablity of toxoplamsa encephalitis if;

1. IgG positive,2. No effective prophylaxis was being taken AND3. There are multiple ring enhancing lesions on the

neuroimaging

If all 3 are not present then biopsy or other diagnostic tests should be performed. This includes PCR testing for other organisms like EBV, Mycobacterium tuberculosis, Cryptococcus neoformans in patients with focal brain lesions who were on prophylaxis or were seronegative.

Definitive diagnosis rests with demonstration of the parasite in biopsy material from an affected area of brain.

If there has been no response to treatment within two weeks, then a biopsy should be considered. With a single cerebral lesion, particularly if serology is negative, biopsy should be performed prior to treatment, as primary CNS lymphoma needs to be considered.

See British HIV Association (BHIVA) algorithm on following page.







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Brain Biopsy Algorithm







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Treatment IImmunocompetent, non-pregnant, patients generally do not require treatment unless their symptoms are severe. Treatment is the same as for immunosuppressed, though usually lower doses are possible and duration is for 2-4 weeks whereas in immunsuppressed duration of therapy for the acute atage is 6 weeks.

1st line therapy for cerebral toxoplasmosis is pyrimethamine combined with sulphadiazine or clindamycin .

Pyrimethamine is myelotoxic & should be given together with folinic acid. Folic acid, although cheaper, is ineffective as it cannot be converted in the presence of Pyrimethamine. Allergy & side effects are common with this regime. Along with bone marrow suppression it may cause rash, nausea or vomiting.

Suladiazine too may cause rash, fever, leukopaenia, hepatitis, nausea or vomiting or crystalluria.

Clindamycin is an effective alternative to Sulphadiazine in patients with Sulfonamide allergy or difficulty swallowing pills. Side effects may include, rash, fever, nausea diarrhoea including Clostridium difficile associated diarrhoea.

Alternatives include• Pyrmethamine (+folinic acid) + azithromycin• Pyrimethamine (+folinic acid) + atovaquone• Sulphadiazine + atovaquone• Co-trimoxazole can also be considered if pyrmethamine is not tolerated The same dosage as for Pneumocystis jiroveci (previously known as Pneumocystis carinii or, PCP).

Other drugs are under evaluation including Clarithromycin.







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Treatment IIThere may be less relapses with the pyrmethamine (+ folinic acid) + suphadiazine combination, however it does have a higher incidence of cutaneous hypersensitivity reactions.

Also if on this combination, additional prophylaxis for Pneumocystis jirovecii is not required.

Treatment is for 6 weeks. Often an improvement can be observed within the first few days. During the 1st 2 weeks of treatment a careful neurological examination is more important than radiographic studies. Indeed repeat imaging should be deferred for 2-3 weeks unless there has been clinical worsening or lack of clinical improvement. If there has been no clinical or radiological improvement after two weeks of adequate therapy, the diagnosis is probably not toxoplasmosis. Alternative diagnoses should be considered and a brain biopsy may be necessary.

Resistance to the frequently used drug combinations has not yet been convincingly described, so changing the toxoplasmosis therapy is not useful in such cases.

After the treatment course of 6 weeks is Completed, the doses can be reduced for secondary prophylaxis.







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Treatment III: Adjunctive Therapies

Steroids often lead to temporary improvement in primary CNS lymphoma (PCNSL) lesions. This makes diagnosis difficult if using steroids when treating presumptively for toxoplasmosis as both toxoplasmosis and PCNSL will improve on this treatment.

Anti-convulsantsThese should be given to those with a history of seizures but should not be given routinely for seizure prophylaxis to all patients with cerebral toxoplasmosis

Surgical decompressionSurgical decompression is occasionally necessary in severe cases where there is potentially fatal mass lesions with midline shift.

SteroidsSteroids may be necessary to reduce intracranial pressure, however in those with advanced immunosuppression the duration of steroid treatment should be limited due to the risk of further opportunistic infection.

Indications may include radiographic evidence of midline shift, signs of critically elevated intracranial pressure or clinical deterioration within the first 48 hours of therapy.







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ProphylaxisPatients with negative toxoplasma serology

These individuals should be counselled about avoiding eating undercooked meat and about the risks of infection form cats. This is not specifically to avoid household cats entirely but may include using gloves when carefully cleaning out cat litter.

Primary Prophylaxis

• All IgG-positive patients with less than 100 CD4 cells/μl require primary prophylaxis with co-trimoxazole (same dose as for PJP prophylaxis). • In cases of allergy to co-trimoxazole, desensitization may be considered.• Alternatives are dapsone plus pyrimethamine or high-dose dapsone alone.• Primary prophylaxis can be discontinued if CD4 count remains >200 cells/μl for at least three months.

Secondary Prophylaxis

• Following treated CNS infection, maintenance therapy should be continued until CD4 is above 200 cells/μl for 6 months. If the CD4 count drops below 200 again, prophylaxis should be reinstated.• If immune reconstitution does not occur, lifelong maintenance therapy is necessary.• In secondary prophylaxis the same drugs are used as for primary therapy, but at half the dose.







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Prognosis

Prognosis depends on whether or not immune restoration can be achieved. Residual neurological impairment occurs in around 40% and seizures are common.

Relapses may occur long after treatment due to intracerebral persistence, sometimes at CD4 counts significantly higher than associated with the initial infection. Enhancement on MRI indicates that lesions have become active.







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Key Points•Toxoplasmosis is the most common cause of multiple mass

lesions in advanced HIV. It can also present with a diffuse encephalitis.

•Toxoplasma gondii is excreted in cat faeces, and forms tissue cysts in animals including humans.

•Infection is usually asymptomatic. 30-65% of the world's population have been exposed through contaminated water or undercooked meat.

•The differential diagnosis in HIV includes primary CNS lymphoma and tuberculosis. In most situations presumptive treatment for toxoplasmosis can be given and response to treatment observed.

•Following successful treatment, prophylactic anti-toxoplasma therapy should be continued until immune function has been restored.







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SummaryHaving completed this session you will now be able to:

•Recall the life cycle of the pathogen Toxoplasma gondii.•Describe the clinical features of CNS toxoplasmosis.•Recognise which stage of HIV is at risk and give examples of other

conditions predisposing to the disease.•Outline the differences between presumptive and definitive diagnosis of

toxoplasmosis and correctly identify which treatment approach is appropriate in a given clinical scenario.

•State the first-line and alternative treatments for CNS toxoplasmosis.•Describe appropriate preventative measures and prophylaxis for those at

risk.

Further reading:

Neuroradiology (2006) 48:715–720. Analysis of the utility of diffusion-weighted MRI and apparent diffusion coefficient values in distinguishing central nervous system toxoplasmosis from lymphoma. Paul C. Schroeder et al.

Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents. Centers for Disease Control and Prevention, National Institutes of Health, Infectious Diseases Society of America/ HIV Medicine Association. 2009.







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Question 1Indicate whether it would be appropriate to give presumptive

treatment for toxoplasmosis and observe response for the following situation:

A 32-year-HIV positive lady from India presents with decreased GCS. Her partner says she has been unwell for 2 weeks with fever, headache and weight loss. MRI shows multiple enhancing mass lesions, and diffuse meningeal enhancement. Chest X-ray is abnormal. Toxoplasma serology is positive.

Yes

No







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Documents

T OXOPLASMOSIS Learning Objectives Introduction Life Cycle Epidemiology Pathologenesis Clinical Overviews Diagnosis Serology Neuroimaging CSF examination