Transcript Slide 1

CRYPTOCOCCAL
MENINGITIS
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Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
Cryptococcal
Meningitis
Sam Nightingale
Sam Nightingale is a neurology registrar and MRC clinical research
fellow. He is currently working with the Liverpool HIV Pharmacology
Group and the Liverpool Brain Infections Group setting up a
multicentre UK study to look at the CNS penetration of
antiretrovirals.
This session provides an overview of cryptococcal
meningitis in healthy and immunocompromised
individuals.
Edited by Prof Tom Solomon and Dr Agam Jung
Learning Objectives
CRYPTOCOCCAL
MENINGITIS
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Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
By the end of this session you will be able to:
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List the similarities and differences between the 2
main species of cryptococcus causing CNS disease in
humans
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Summarise the presentation and clinical features of
cryptococcal disease both within the CNS and
systemically
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Given a set of laboratory and CSF parameters,
correctly differentiate fungal meningitis from other
aetiologies
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Outline the principles of management of cryptococcal
meningitis
Introduction
CRYPTOCOCCAL
MENINGITIS
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Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
Cryptococcus neoformans and Cryptococcus gattii are encapsulated yeast,
which can be inhaled from the environment. Usually this results in harmless
colonisation of the airways. However in some situations, it may lead to
disseminated disease including serious and life threatening meningitis.
Most infections are associated with immunosuppression and around 80%-90%
of all patients with cryptococcosis have advanced HIV infection.
Cryptococcosis is an AIDS defining illness. Worldwide up to 15% of those with
AIDS will develop cryptococcal meningitis at some time. Incidence varies and in
parts of sub-Saharan Africa over 50% of those with HIV are affected.
In addition, CNS cryptococcosis is
frequently associated with immune
reconstitution inflammatory syndrome
(IRIS).
There are over 50 species of
Cryptococcus.
However
only
Cryptococcus
neoformans
and
Cryptococcus gattii are considered
pathogens in humans.
Cryptococcus Neoformans
This is a ubiquitous fungus found predominantly in aged bird droppings.
CRYPTOCOCCAL
MENINGITIS
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Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
Clinically evident infection usually only occurs in those with significant defects
in cell mediated immunity. By far the most common cause is AIDS.
However Cryptococcus neoformans can affect people with reticuloendothelial
malignancy, organ transplant recipients, sarcoidosis and those on long term
steroids.
Cryptococcus Gattii
CRYPTOCOCCAL
MENINGITIS
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Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
Cryptococcus gattii is not associated with birds but grows in the litter around
certain species of eucalyptus tree.
It is most common in tropical and subtropical areas. The highest incidence is
in Papua New Guinea and Northern Australia, although infections occur in
non-tropical areas such as North America and Europe.
Patients infected with Cryptococcus gattii are usually immunocompetent. In
contrast to Cryptococcus neoformans, Cryptococcus gattii rarely infects
immunosuppressed patients and is not associated with HIV infection.
Intracerebral mass lesions (Cryptococcomas) are more common with
Cryptococcus gattii than in Cryptococcus neoformans, presumably due to
their different host immune responses.
Clinical Features
CRYPTOCOCCAL
MENINGITIS
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Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
A typical acute presentation is headache and mild fever, often accompanied
by nausea and vomiting for a few days. Subacute and chronic presentations
can mimic other meningitides, particularly tuberculous meningitis, but with
cryptococccal infection, there tends to be a less aggressive meningeal
inflammatory response. For example, only one third of patients have classical
features of meningism, such as photophobia, neck stiffness or positive
Kernig's sign.
Severely
immunocompromised
patients may just have nonspecific
symptoms at presentation. In some
cases the only feature may be
confusion, with or without a low-grade
fever.
Cryptococcal infection prevents the
arachnoid granulations from resorbing
CSF effectively. As a result almost all
have raised intracranial pressure. CSF
pressure can become dangerously high
causing
papilloedema
and
communicating hydrocephalus.
Space Occupying Lesion Cryptococcomas
CRYPTOCOCCAL
MENINGITIS
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Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
CNS parenchymal invasion leads to
abscesses and granuloma in up to
11%. Lesions are round, often
multiple and may or may not
enhance. The common differentials
of CNS space occupying lesions
HIV are toxoplasmosis, primary
CNS lymphoma or tuberculomas.
Clinical presentation depends on
the location of the lesions. Focal
neurological signs and seizures are
common. Lesions can occur
throughout the CNS but are more
common in the basal ganglia and
cerebellum. In addition, invasion of
blood vessels can result in cerebral
infarction
Figure:
T2
MRI
showing
cryptococcomas in the posterior fossa
of an HIV positive individual. Image
courtesy of Ian Turnbull.
Cryptococcal immune Reconstitution
Inflammatory Syndrome (IRIS)
CRYPTOCOCCAL
MENINGITIS
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Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
Immune reconstitution inflammatory
syndrome (IRIS) describes a phenomenon
where HIV positive patients starting
antiretroviral therapy develop atypical
manifestations of opportunistic pathogens
as CD4 count improves.
Cryptococcal IRIS may present as a clinical
worsening or new presentation of
cryptococcal
disease
following
antiretroviral treatment, particularly if
treatment was started at a low CD4 count
and immune recovery was rapid. It is
thought to be caused by recovery of
cryptococcus specific immune responses.
Cryptococcal IRIS may present with lymphadenitis, meningitis or pulmonary
lesions. Intracerebral mass lesions are more common due to the increased
inflammatory response. It tends to occur a few months after starting antiretroviral
therapy, but can occur some years later and so is often difficult to diagnose.
IRIS does not represent treatment failure or reactivation of infection and therefore
does not require antifungal therapy. Treatment is aimed at controlling the
inappropriate immune response and systemic corticosteroids are beneficial.
Cryptococcosis in Other Sites
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CRYPTOCOCCAL
MENINGITIS
Cryptococci disseminate widely and may infect any organ, most commonly
lymphadenitits, prostatitis and skin or bone lesions. Cutaneous
manifestations occur in 10%-15% of cases. Umbilicated papules initially
resemble molluscum contagiosum, later becoming confluent and forming
larger ulcerated lesions.
Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
Pulmonary infection can cause
pneumonia,
ARDS
and
cavitating lesions. Although the
lung is the presumed site of
entry to body, most patients do
not have pulmonary symptoms.
Bone lesions are usually
osteolytic or resemble cold
abscesses,
sometimes
misdiagnosed as tuberculosis.
Rarely other organs are
involved
in
causing
chorioretinitis, hepatitis and
renal abscess.
Figure: Field stain showing cryptococci in
the lungs.
Diagnosis
Imaging
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CRYPTOCOCCAL
MENINGITIS
Diagnosis must be made without delay as early symptoms can progress rapidly to life
threatening illness. There should be a low threshold for lumbar puncture in any HIV
positive individual presenting with non-specific symptoms such as mild headache or
confusion.
Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
Brain
imaging
may
reveal
communicating
hydrocephalus,
mass lesions (cryptococcomas) or
basal meningeal enhancement.
MRI is more sensitive than CT and
is particularly useful if there are
focal neurological signs.
The contrast enhanced CT
opposite shows basal menengeal
enhancement (1). Hydrocephalus
and rained intracranial pressure is
demonstrated by the prominent
temporal
horns
(2)
and
effacement of the sulci (3).
Diagnosis
CRYPTOCOCCAL
MENINGITIS
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Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
Lumbar Puncture I
The most important test for cryptococcosis is lumbar puncture. Even if disease appears to
be restricted to organs outside the CNS, a lumbar puncture must be performed to
exclude subclinical CNS involvement.
In most cases there is a moderate mononuclear cell pleocytosis of around 20 to 200
cells/mm3 although higher counts can be seen. Protein is elevated and CSF/plasma
glucose ratio mildly decreased (see table opposite)
However the CSF may be normal in up to 25% of cases, particularly in early infection.
Diagnosis
Lumbar Puncture II
CRYPTOCOCCAL
MENINGITIS
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Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
Papilloedema is common but not necessarily a contraindication to LP if imaging
excludes a space occupying lesion, as it is usually due to communicating hydrocephalus
from decreased resorption.
As pressure is raised evenly throughout the CSF compartment, there is no increased
risk of tentorial or brainstem herniation. In fact, by reducing the CSF pressure, lumbar
puncture is essential treatment for raised intracranial pressure in this situation.
Diagnosis
Lumbar Puncture III
CRYPTOCOCCAL
MENINGITIS
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Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
Definitive diagnosis is established by the identification of fungal hyphae with India ink
staining in 60-80%. Repeating lumbar puncture three or more times and centrifuging
larger volumes of CSF, increases the diagnostic yield. The detection of cryptococcal
antigen (CrAg), a capsular polysaccharide, is more sensitive. It is positive in around
95% of cases and has a high specificity.
CSF opening pressure is almost always
elevated and may cause ischaemic
pressure on the optic nerve
threatening sight. Often large
volumes of CSF have to be removed to
bring the pressure below 20cm H2O.
In refractory cases requiring repeated
lumbar puncture, a lumbo-peritoneal
or ventriculo-peritoneal CSF shunt
may be necessary.
Acetozolamide which reduces CSF
production may help in milder cases.
Steroids, which are often helpful in
reducing the pressure associated with
space
occupying
lesions,
are
ineffective
in
communicating
hydrocephalus such as this.
Blood
Most HIV-related cryptococcal CNS infections occur at a CD4 count less than 100
cells/ul and are rarely seen at CD4 counts above 200 cells/ul.
CRYPTOCOCCAL
MENINGITIS
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Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
Full blood count and other routine bloods may be normal even in advanced
cryptococcal disease.
Fungal blood cultures may be positive indicating disseminated cryptococcaemia.
Cryptococcal antigen (CrAg) in the blood at a titre >1:8 is almost as sensitive as CSF.
However a falling titre during therapy is not a reliable indicator of when to stop
treatment.
Blood cultures are also often positive in disseminated disease.
Extraneurological
CRYPTOCOCCAL
MENINGITIS
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Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
Extraneurological features may be present in up to 20%. A chest xray may
reveal diffuse pulmonary infiltrates, lobar consolidation or cavitating
lesions, which may resemble tuberculosis. High resolution CT scan is more
sensitive than chest xray if pulmonary involvement is suspected.
Bronchoalveolarlavage can identify the causative organism. Cutaneous
lesions should be biopsied and evaluated with fungal stains and cultures.
Urine should also be cultured even if renal or urinary tract disease is not
clinically evident.
Management
CRYPTOCOCCAL
MENINGITIS
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Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
Before treatment was available, cryptococcal meningitis was invariably fatal. With
effective treatment the mortality rate remains up to 25%. Treatment is lengthy,
complicated and potentially toxic and should initially be managed on an inpatient
basis.
Standard treatment is with intravenousamphotericin B with oralflucytosine for 2
weeks followed by fluconazole for 8-10 weeks. Fluconazolecan can also be used at
induction as a less toxic alternative to amphotericin B, particularly in those with
renal impairment. Itraconazole has been shown to be less effective
Management II
CRYPTOCOCCAL
MENINGITIS
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Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
Treatment should be considered successful when CSF culture and constituents have
returned to normal, although protein can remain elevated for some time longer.
Treatment is curative in immunocompetant individuals. However, in HIV prolonged
suppressive treatment is required with oral fluconazole at a lower dose until CD4
count is greater than 200 cells/ul for more than 6 months and serum cryptococcal
antigen is negative.
Antiretroviral therapy should be continued. When initiating antiretroviral therapy in
those with cryptococcal meningitis, prior antifungal treatment may reduce the risk of
immune reconstitution inflammatory syndrome (IRIS).
Primary prophylaxis or avoidance of exposure has not been shown to be of benefit,
even in endemic areas.
Cryptococcomas
Treatment is the same as for cryptococcal meningitis. Early in therapy new lesions may
arise and existing lesions enlarge as a result of the inflammatory response associated
with treatment. This does not necessarily represent failure of therapy and lesions tend
to shrink over time if treatment is continued.
Prognosis
CRYPTOCOCCAL
MENINGITIS
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Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
A number of adverse prognostic markers have been identified including
abnormal mental status, CSF opening pressure >25 cm H20, CSF
cryptococcal antigen titre>1:1024, CSF white cell count >20 cells/ml and
culture of cryptococcus outside the CSF.
Without treatment cryptococcal
meningitis is invariably fatal.
Despite effective treatment the
mortality rate remains up to 25%.
Of those who survive, 40% have
significant neurological deficits,
including loss of vision, decreased
cognitive function, and cranial
nerve palsies.
Hydrocephalus can occur as a late
complication. Relapse can occur in
up to 25%. Cure may not be
possible and in some patients lifelong
suppressive
anti-fungal
therapy may be required.
Figure: CT scan showing gross obstructive
hydrocephalus this can occur as an early or
late complication of cryptococcal meningitis
Session Key Points
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CRYPTOCOCCAL
MENINGITIS
• Cryptococcal meningitis can be caused by C. neoformans or C. gattii. C.
neoformans affects those with advanced immunosupression, however C.
gattii can affect the immunocompetent
Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
• Cryptococcal meningitis typically presents with headache, confusion +/fever. Meningeal irritation is not a prominent feature. Onset may be over
weeks. Symptoms are variable and can be mild
• Cryptococcus can present as part of an immune reconstitution
inflammatory syndrome (IRIS)
• Crytptococcal meningitis can be associated with mass lesions
(cryptococcomas)
• The affect of cryptococcus on CSF resorbtion often causes raised
intracranial pressure and papilloedema. However lumbar puncture is not
contraindicated as this is a communicating hydrocephalus.
• Antifungal treatment is lengthy. In HIV positive patients, suppressive
treatment should be continued until immune function has been restored
Summary
Having completed this session you will now be able to:
CRYPTOCOCCAL
MENINGITIS
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Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
• List the similarities and differences between the 2 main species of
cryptococcus causing CNS disease in humans
• Summarise the presentation and clinical features of cryptococcal
disease both within the CNS and systemically
• Given a set of laboratory and CSF parameters, correctly differentiate
fungal meningitis from other aetiologies
• Outline the principles of management of cryptococcal meningitis
References/ further reading
Clin Infect Dis. 2000 Apr;30(4):710-8. Epub 2000 Apr 20.Practice guidelines for the management
of cryptococcal disease. Infectious Diseases Society of America. Saag MS et al.
Kaplan JE, Masur H, Holmes KK. Guidelines for preventing opportunistic infections among HIVinfected persons--2002. Recommendations of the U.S. Public Health Service and the Infectious
Diseases Society of America. MMWR Recomm Rep. Jun 14 2002;51:1-52.
J Infect. 2005 Dec;51(5):e289-97. Cryptococcal immune reconstitution inflammatory syndrome:
report of four cases in three patients and review of the literature.Skiest DJ, Hester LJ, Hardy RD.
The Lancet Infectious Diseases, Volume 10, Issue 11, Pages 791 - 802, November 2010
Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals:
proposed clinical case definitions Lewis J Haddow PhD ab, Prof Robert Colebunders PhD cd, et al
on behalf of the International Network for the Study of HIV-associated IRIS (INSHI).
Question 1
CRYPTOCOCCAL
MENINGITIS
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Learning Objectives
Introduction
C.Neoformans
C. Gatti
Clinical Features
Space Occupying
Cryptococcus
IRIS
Cryptococcus in
other sites
Diagnosis
Extra-neurological
Management
Prognosis
Key Points
Summary
Self assessment
Select the single best answer from the options given. Click on the
answer to see if it is correct and read an explanation.
A 35-year-old HIV positive lady with a 3 week history of fever and
headache. CD4 count 350 cells/ul.
CSF: WCC 200 mm3 (100% lymphocytes). Protein 2g, serum:CSF
glucose 25%.
Select one answer from the list below.
a. Bacterial meningitis
b. Cryptococcus neoformans meningitis
c.
Cryptococcus gattii meningitis
d.
Tuberculosis meningitis
e. Viral meningitis