INVASIVE MYCOSES

IN THE BRAIN

Livio Pagano

Istituto di Ematologia

Università Cattolica del Sacro Cuore

Roma

3rd Trends in Medical Mycology

28 - 31 October 2007

Lingotto Conference Centre

Torino, Italy

Systemic Mycoses and CNS

Opportunistic Fungal

Pathogens

Aspergillus spp

Zygomycosis

Fusarium spp

Scedosporium spp

Cryptococcus neoformans

Candida spp

Primary Fungal

Pathogens

Histoplasma capsulatum

Coccidioides immitis

Paracoccidioides brasiliensis

Patways of spread to the CNSDirect:

•Skull fracture

•Neurosurgical device

Olfactory:

• Via sino-nasal

Hematogenous:

•Spread from lung

•Blood dissemination

Clinical manifestation of CNS

Fungal Involvement

Meningitis (acute,

subacute, chronic)

Meningo-

Encephalitis

Candida

Cryptococcus

Trichosporon

Coccidioides immitis

Brain abscess

Aspergillus

Zygomycetes

Scedosporium

Phaeohyphomycosis

Fungal brain abscess:

Patients at risk

Aspergillus Zygomycetes Scedosporium Phaeohyphomy

cosis

AML AML Near-drowing None

HSCT Ketoacidotic

Diabetes

Steroids SOT

SOT HSCT None Hematological

malignancies

Steroids Steroids Trauma Trauma

HIV HIV Diabetes Drug-abuse

Kleinschmidt-DeMasters, Human Pathol 2002; Nesky et al, CID 2000, Revankar et al, CID 2004; Pagano et al, Exp Rev Anti Infct Ther 2005

Prevalence of CNS localization

Aspergillus

(in vivo)

6 -7% Patterson et al, Medicine 2000

Pagano et al, Haematologica 2001

Aspergillus

(at autopsy)

23-59% Groll et al, J Infect 1996

Kleinschmidt-DeMasters, Human Pathol 2002

Zygomycetes 16-28% Roden et al, Clin Infect Dis 2006

Pagano et al, Br J Haematol 2001

Scedosporium 13% Caira et al, Haematologica 2007

Phaeohyphomycosis 87% Revankar et al, CLin Infect Dis 2004

Signs and symptoms are the same for

all brain fungal infections

Fever 40-80%

Cerebral hemorrhage 35-50%

Altered mental status 30-50%

Hemiplegia/paresis 19-35%

Cranial nerve abnormalities 30%

Epilepsy/seizure 5-25%

Nausea/vomiting 10-20%

Ptosis 10%

Headache 10%

Pagano et al, Exp Rev Anti Infect Ther 2005Mattiuzzi & Giles , Br J Haematol 2005

ASPECIFIC

Radiological features of brain abscess

Typical imaging patterns at brain CT/MRI

Multiple cortical and subcortical complex lesions with different degree of edema

Multiple ring-enhancing lesions

Dural enhancement with adjacent enhancing lesions of paranasal sinuses

Ashdown et al, AJR Am Roentgenol 1994; Oner at al, Acta Radiol 2006

But the radiological feature does not allow a precise etiological diagnosis:

The pictures could compatible with abscess due to:

Zygomycetes, Scedosporium, Phaeohyphomycoses, Cryptococcus, Candida

It could be due also to:

Metastastic carcinoma, Primary CNS lymphoma, Multifocal glioma,

Acute demyelinating disease (ADEM), Tubercolosis, Toxoplasmosis,

Bacteria (i.e. Nocardia)

In 90-95% of cases, brain

abscess is secondary to a

pulmonary localization

In other 5-10% of cases,

CNS abscess was an

unique manifestation.

Invasive diagnostic

approach needed!

But when biopsy is not possible, CSF

studies are useful for diagnosis?

Culture usually negative (particularly for Aspergillus and Zygomycetes)

Galactomannan test in CSF could be diagnostic for

aspergillosis

PCR for aspergillosis frequently positive

No tests available for Zygomycetes, Scedosporium,

Phaeohyphomycetes

Kami et al, Br J Haematol 1999; Viscoli et al, J Clin Microbiol 2003; Klingspor & Jalal, Clin Microbiol Infect 2006

CEREBRAL HYPERTENSION CONTROINDICATES

LUMBAR PUNCTURE

Attributable Mortality Rate for

brain abscess

Aspergillus 80-96% Patterson et al, Medicine 2000

Lin et al, Clin Infect Dis 2001

Pagano et al, Haematologica 2001

Zygomycetes ~90% Pagano et al, Haematologica 2004

Scedosporium 57-75% Caira et al, Haematologica 2007

Nesky et al, Clin Infect Dis 2000

Phaeohyphomycosis 73% Revankar et al, CLin Infect Dis 2004

Therapeutical approach of brain

abscesses:

Surgery represent the first choice !Stereotactic drainage or surgical excision of the brain abscess

is mandatory whenever possible !!

Antifungal drugs should be associated to the surgical approach

Coleman et al, Neurosurgery 1995, reported a high percentage of success with this combined approach

Pharmacokinetics and Pharmacodynamics

of drugs effective in CSF/CNS tissue

CSF levels

(% of blood level)

Brain tissue levels

tissue/plasma ratio

Amphotericin B* <2 ≤0.2

ABLC* < 2 0.2

L-AmB* >2 1.2

Flucytosine High: 75 High

Caspofungin Low ≤0.2

Itraconazole Low ≤0.3

Voriconazole** High: 60-80 2

Posaconazole*** High 1

*Groll et al. J Infect Dis, 2000; Barrett et al, Clin Ther 2003 -** Leu et al, Clin Ther 2003, Torres et al, Lancet 2005; ***Groll & Walsh, Mycoses 2006

AmB compound in the treatment of

cerebral aspergillosis

Setting N°

treated

CR/PR Failure

Pagano et al, CID 1996

Acute

leukemia

10 0 10

Lin et al, CID 2001 Meta-analysis 35 1 34

Jantunen et al,

BMT 2003HSCT 12 0 12

Baddley et al, Clin Transplant 2002 *

SOT/HSCT 11 1 10

Siddiqui et al, Neurosurgery 2004

Immunocompetent 13 5 7

Schwartz et al, Mycoses 2007

HSCT/AML 18 0 18

Voriconazole therapy for cerebral

aspergillosis

N° cases CR/PR Stable Failure

Walsh et al

Ped Infect Dis J 20026 3 1 2

Denning et al,

CID 200219 3 5 11

Perfect et al,

CID 200312 4 / 8

Schwartz et al, Blood 2005

81

(78%*)

7/21

(35%)

13 40

* refractory

Combined therapy:

Kind of combination

1966-2001

N° cases

treated

Response

complete/partial

ABLC /L-AmB/AmB + Itra 10 5

AmB/L-AmB + Flucytosine 21 14

AmB + Rifampicine 7 5

2003-2007

Voriconazole + Caspo 7 6

AmB/ABCL + Voriconazole 6 6

AmB + Caspo 4 2

Steinbach et al, CID 2003; Marr et al. CID 2004; Damaj et al. Ann Hematol 2004 ; Gea-Banacloche et al. 43rd ICAAC; Tavverin et al. CMI 2004; Bethell et al. J Ped Hem Onc

2004; Kontoyiannis et al. Cancer 2003; Cocchi et al, Scand J Infect 2005; Sterba et al, J Ped Hem Onc 2005; Gubler et al, Infection 2007; Ehrmann et al, Int Care Med 2005

AmB compounds in the treatment of

proven/probable CNS zygomycosis

1

3

5

7

9

11

13

15

1 2

1

2

ECMM ZygoMycosis Survey databaseLarkin et al, Infect Med 2003

ABCL treatment

CLEAR Database collectio

AmB/ L-AmB

European multicentric study 2004-2007

Recovered: 12Patients: 13

92%

83%6 5

24

14

0

5

10

15

20

25

d-AmB L-AmB

cases

recovered

80%

58%

Posaconazole in the treatment of

proven/probable CNS zygomycosis

0

2

4

6

8

10

12

14

Van Burik et al, CID 2006Greenberg et al, AAC 2006

Patients: 14 Recovered: 10

71%

All refractory or resistant

POS 800 mg/d (200 mg x4 o 400 mg x2)

Duration therapy ranged from 8 to 1004d

0

2

4

6

8

10

12

Patients: 11 Recovered: 8

72%

All refractory or resistant

POS 800 mg/d (200 mg x4 o 400 mg x2)

Duration therapy ranged from 6 to 1005 d

Treatment of CNS abscess due to

other fungi

Data in literature are scanty; above all single

case report

Scedosporiosis: AmB compounds no efficacy !

Voriconazole better

Phaeohyphomycoses: only combined therapy,

particularly with AmB+ 5 Fluocytosine, seems

characterized from a better outcomeNesky et al, CID 2000; Revankar et al, CID 2004

Fungal meningo-encephalitis:

Patients at riskCandida Cryptococcus Trichosporon Coccidoides

Hematological

malignacy

HIV Hematological

malignancy

Endemic

Neurosurgery -

CSF derivative

system

SOT Cancer HIV

Premature

neonate

Lymphomas -

ALL

SOT HSCT

Intravascular

catheters

Steroids Newborn Steroids

Steroids

Diagnosis

Candida Isolation of Candida sp from the CSF or

Detection of mannan antigen in CSF

while Meningeal biopsy is not diagnostic

Cryptococcus India ink stain + on direct examination of the CSF

(60-85%)

Pleocytosis, ↓ glucose concentrations, and ↑ protein

concentrations (40%)

CSF opening pressure is greater (70%)

ELISA for detection of cryptococcal polysaccharide

antigen (CRAG) sensitive and specific in >90%

Coccidoides 70% of cases have negative CSF cultures

Useful the determination of CSF CFAs titers

Microscopic identification of spherules in biopsy

material

Attributable Mortality Rate for

meningo-encephalitis

Candida sp 10 -30% Pappas et al, CID 2004

Cryptococcus sp 14%- Singh N et al, JID 2007

Trichosporon sp ~ 50% Girmenia et al, J Clin Microbiol 2005

Coccidoides 30-50% Blair et al , Arch Intern Med 2005

First Line Second Line

Candida AmB + 5-FC

Fluco

IDSA-Pappas et al, CID 2004

Caspofungin

Liu et al, J Clin Micr 2004

L-AmB; Voriconazole

Cryptococcus AmB + 5-FC

AmB

Flu or Itra

IDSA-Saag et al, CID 2000

ABCL CLEAR- Baddour et

al, CID 2005

Vori Perfect et al, CID 2003

L-AmB

Coccidioides Fluco

Itra

IDSA-Galgiani et al, CID 2000

intrathecal AmB

Vori – Posa ( in vitro and in

animal model)

Trichospon sp Fluco Walsh et al, Clin

Microbil Infect 2004

Vori Morace et al, Int J

Antimicrob Agents 2005

Treatment regimens for meningo-

encephalitis

FinallyFor each fungal agent there is a target

therapy !

Try to arrive always to a proven diagnosis !

Clinicians

Microbiology

Histology