Transcript Toxoplasmosis - braininfectionsuk.org

TOXOPLASMOSIS
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
Cerebral
Toxoplasmosis
Drs Sam Nightingale & Sylviane Defres
Sam 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.
This module provides an overview of the CNS
manifestations of toxoplasmosis infection.
Edited by Prof Tom Solomon, Dr Agam Jung and Dr Sam Nightingale
Learning Objectives
TOXOPLASMOSIS
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
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.
Introduction
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
Cerebral 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 T1weighted MRI following gadolinium
showing thick walled ring enhancing
lesion with oedema, mass effect and
midline shift (Image courtesy of Dr
Ian Turnbull).
Life Cycle of Toxoplasma gondii
TOXOPLASMOSIS
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
T. 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 faeces
Non-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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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
Life Cycle: Different forms of
Toxoplasma gondii
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Oocyst (unsporulated)
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Sporulated oocysts
– (contain sporozoites)
– Sporulation occurs in
environment.
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Tachyzoites
(able to invade
host Cells)
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Tissue cyst;
Bradyzoites
Life Cycle of Toxoplasma gondii III
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
Epidemiology I
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
Seroprevalence 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.
50-60%
4.3 %
(was 80-90%)
11-15%
(was 25%)
9%
(was 22%)
70%
Epidemiology II: HIV
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
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 (199092) 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.
Pathogenesis
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
T.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.
Pathogenesis
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
There are 3 clonal strains of T.gondii:
Strain
I
Strain
II
Congenital
toxoplasmosis
Strain
III
Severe ocular
disease
AIDS
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.
Pathology
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
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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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
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 gestation
44% risk of transmission @ 26 weeks gestation
71% risk of transmission @ 36 weeks gestation
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
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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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
Clinical Overview 3 – Congenital
infection
Diagnosis 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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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
Clinical Overview 4 –
Immunocompetent adult
Primary 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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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
Clinical Overview 5 –
Immunocompromised Adult
Whilst 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.
Diagnosis
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
The 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.
Toxoplasma Microbiology/ Serology
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
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.
Neuroimaging I
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
MRI 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.
Alone, neither MRI nor CT can differentiate
among the multiple possible aetiologies of
brain lesions in AIDS patients.
Differential diagnosis includes:
Cryptococcosis
Histoplasmosis
Aspergillosis
Tuberculosis
Trypanosomiasis
RIGHT: Coronal MRI, T2-weighted, showing
CNS lymphoma
bilateral toxoplasmosis (arrows).
Neuroimaging II
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
A 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.
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.
DWI/SPECT
There 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).
CSF Examination
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
Lumbar 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.
Presumptive diagnosis
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
In 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 AND
3. 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.
Brain Biopsy Algorithm
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
Treatment I
TOXOPLASMOSIS
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
Immunocompetent, 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.
Treatment II
TOXOPLASMOSIS
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
There 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.
Treatment III: Adjunctive Therapies
TOXOPLASMOSIS
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
Steroids
Steroids 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.
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-convulsants
These 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 decompression
Surgical decompression is occasionally necessary in severe cases where
there is potentially fatal mass lesions with midline shift.
Prophylaxis
Patients with negative toxoplasma serology
TOXOPLASMOSIS
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
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.
Prognosis
TOXOPLASMOSIS
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
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.
Key Points
TOXOPLASMOSIS
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
• 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.
Summary
TOXOPLASMOSIS
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•
Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
Having 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 HIVinfected adults and adolescents. Centers for Disease Control and Prevention,
National Institutes of Health, Infectious Diseases Society of America/ HIV
Medicine Association. 2009.
Question 1
TOXOPLASMOSIS
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Learning Objectives
Introduction
Life Cycle
Epidemiology
Pathologenesis
Clinical Overviews
Diagnosis
Serology
Neuroimaging
CSF examination
Presumptive
diagnosis
Brain Biopsy
algorithm
Treatment
Prophylaxis
Prognosis
Key Points
Summary
Self Assessment
Indicate 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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