tambahann inf ssp

7/28/2019 Tambahann INF SSP

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Diagnosis infeksi jamur pada susunan saraf pusat seringkali sukar dan sangat tergantung dari kesiagaan

klinisi. Selain gejala klinis, sangat penting dilakukan pemeriksaan radiologis paru-paru dan organ lainnya,

skin test,antibodi serum dan pemeriksaan cairan serebrospinal. Isolasi kuman dari lesi dan cairan

serebrospinal merupakan pembantu diagnostik yang penting. Pada meningitis, perlu dilakukan

pemeriksaan CT scan dan MRI. Perubahan cairan serebrospinal pada meningitis jamur seperti pada

meningitis tuborkulosa. Tekanan meningikat bervariasi, pleiositosis moderat, biasanya kurang adri 1000

sel/mm3, dengan predominan limfosit. Kecuali pada kasus yang akut, sel dapat meningkat lebih dari

1000/mm3 dengan predominan polimorfonuklear. Glukosa bisanya agak menurun (subnormal) dan protein

meningkat kadang-kadang sampai pada kadar yang sangat tinggi. Diagnosis spesifik dapat dibuat dari

hapusan cairan serebrospinal dan dari kultur dan juga dengan menemukan antigen spesifik dengan

immunodifusion latex particle aggregation atau perbandingan antigen recognition test. Pemeriksaan cairan

serebrospinal harus termasuk pemeriksaan tubercle basilli dan leukosit abnormal oleh karena banyak

terjadi infeksi bersama jamur dengan tuberkulosa dan leukemia atau limfoma.

c. Patologi

Ada tiga pola dasar infeksi jamur pada susunan saraf pusat yaitu, meningitis kronis, vaskulitis dan invasi

parenkimal. Pada infeksi Cryptococcal jaringan otak menunjukkan adanya meningitis kronis pada

leptomeningen basal yang dapat menebal dan mengeras oleh reaksi jaringan penyokong dan dapat

mengobstruksi aliran likuor dari foramen Luschka dan Magendi sehingga terjadi hidrosefalus. Pada

jaringan otak terdapat substansi gelatinosa pada ruang subarakhnoid dan kista kecil didalam parenkim

yang terletak terutama pada ganglia basilis pada distribusi arteri lentikulostriata. Lesi parenkimal terdiri

dari agregasi atau gliosis. Infiltrat meningen terdiri dari sel-sel inflamasi dan fibroblast yang bercampur

dengan Cryptococcus. Bentuk granuloma tidak sering ditemukan pada beberapa kasus terlihat reaksi

inflamasi kronis dan reaksi granulomatosa sama dengan yang terlihat pada M.tuberculosa dengan segala

bentuk komplikasinya.

Menurut Prockop,perubahan susunan saraf pusat termasuk infiltrasi meningen oleh sel mononuklear dan

organisme. Organisme ini dapat tersebar pada parenkim otak dengan reaksi inflamasi yang minimal atau

tanpa reaksi inflamasi. Kadang-kadang terdapat abses pada jaringan otak dan granuloma pada meningen

otak dan medula spinalis.


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Gejala klinis infeksi jamur pada susunan saraf pusat tidak spesifik seperti akibat infeksi bakteri. Pasien

paling sering mengalami gejala sindroma meningitis atau sebagai meningitis yang tidak ada perbaikan

atau semakin progresif selama observasi (paling kurang empat minggu). Manifestasi klinis lainnya berupa

kombinasi beberapa gejala seperti demam, nyeri kepala, letargi, confise, mual, muntah, kaku kuduk atau

defisit neurologik.

Sering kali hanya satu atau dua gejala utama yang dapat ditemukan pada gejala awal. Misalnya pasien

datang ke klinis hanya dengan keluhan demensia subakut tanpa gejala lainnya.

Waktu terjadinya penyakit sangat vital dan penting dalam mempertimbangkan diagnosis meningitis jamur.

Beberapa kasus sebagai meningitis akut,kebanyakan subakut dan beberapa kronis.

Gambaran klinis selain meningitis yang sering ditemukan yaitu gambaran ensefalitis. Sering kali pasien

didagnosa sebagai meningitis TBC sampai akhirnya ditemukan diagnosa yang benar dengan

ditemukannya jamur dalam cairan serebrospinal. Diagnosa meningitis jamur dapat ditegakkan dengan

kultur dalam medium sabouraud. Granuloma besar pada serebrum, serebrum atau batang otak memberikan

gejala seperti space occupaying lesion lainnya. Diagnosa granuloma dapat ditegakkan dari pemeriksaan

CT scan dan MRI.

d. Diagnosa

Diagnosa ditegakkan berdasarkan gejala klinis dan pemeriksaan tambahan seperti, laboratorium cairan

serebrospinal. Gambaran cairan serebrospinal infeksi Cryptococcus sama dengan meningitis tuberkulosa.

Tekanan biasanya meningkat terdapat peningkatan jumlah sel dari 10-500 sel/mm3. protein meningkat dan

glukosa menurun biasanya sekitar 15- 35 mg. Diagnosa dapat dibuat dengan menemukan organisme ini

dalam cairan serebrospinal dengan pewarnaan tinta India, kultur dalam media sabouraud dan berasarkan

hasil inokulasi pada hewan percobaan. Jamur ini juga dapat dikultur dari urine, darah, fases, sputum dan

sum-sumvtulang. Pemeriksaan antigen Cryptococcus pada serum dan cairan serebrospinal dapat

menegakkan diagnosa, dapat dikultur dari urine, darah, feses, sputum dan sum-sum tulang.

Mucomyrcosis

Gejala klinis biasanya dimulai dengan tanda-tanda infeksi sinus paranasalis seperti hidung tersumbat,

sekret dari hdung kadang-kadang berdarah, nyeri pada daerah sinus dan demam. Jika tidak diobati,

penyakit ini akan menyebar keotak melalui lamina kribriformis atau setelah terlibatnya tulang tengkorak.

Kemudian terjadi gejala-gejala lobus frontalis dan meningen basalis bersama dengan penurunankesadaran, drowsyness, nyeri kepala, perubahan status mental. Gejala neurologis yang sering terjadi yaitu


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proptis,kelumpuhan mata dan hemiplegi yang mana keadaan ini berhubungan dengan terlibatnya arteri

arteri orbitalis dan karotis danjaringan disekitarnya. Organisme ini dapat menginvasi meningen atau dapat

menembus otak sehingga menimbulkan ensefalitis jamur dan dapat menyebabkan Infark dan perdarahan

otak.

Beberapa hifa terdapat didalam trombus dandinding pembuluh darah dan sering sekali masuk ke dalam

parenkim sekitarnya. Biasanya penyakit ini cepat berakibat fatal dalam beberapa hari atau minggu.

Diagnosa penyakit ini ditegakkan berdasarkan pemeriksaan sputum, cairan serebrospinal atau eksudat

jaringan sinus paranasalis. Kultur rhizopus dapat membantu tapi bukan merupakan diagnostik oleh karena

kebanyakan merupakan kontaminan.

Terapi terdiri dari pemberian Amphotericin B dan kontrol faktor predisposisi seperti diabetes melitus. Juga

diperlukan drainase lokal dan operasi jaringan nekrotik secepatnya untuk mencegah penyebaran penyakit.

Kandida

Bentuk patologi infeksi susunan saraf pusat oleh candida berupa penyebaran mikro abses intraparenkimal,

granuloma nonkaseosa, abses besar, meningitis. Pada kebanyakan kasus diagnosis belum dapat ditegakkan

pada saat pasien masih hidup, kemungkinan oleh karena sukarnya menemukan organisme pada cairan

serebrospinal .

Prognosis biasanya jelek walaupun dengan penggunaan amphotericin B.

Aspergillosis

Manifestasi klinis penyakit ini berupa gangguan nervus kranialis pada sekitar daerah infeksi, abses serebri,

granuloma kranial dan spinal pada duramater. Keadaan ini tidak bermanifestasi sebagai meningitis. Pada

beberapa kasus penyakit ini didapat di rumah sakit ditandai dengan adanya gejala infeksi paru yang tidak

mempan terhadap antibiotik. Diagnosis biasanya ditegakkan ndengan melakukan biopsi atau dengan

kultur.

Coccidiodo

. Reaksi patologi dan gambaran kliniknya pada meningen dan cairan serebrospinal sangat mirip dengan

meningitis tuberkulosa.


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Perfect JR. Diagnosis and treatment of fungal meningitis, in infectious of central nervous systems. New

York: Raven Press, 1991: 729-37

C

NS clinical manifestations, neuroimaging

(CT or MRI) and CSF cytochemical

characteristics are main criteria of

diagnosis. In addition, diagnosis is also

made by fungal tests including direct and

culture examination of CNS biopsy and

CSF. Grocott's methenamine silver (GMS)

staining is usually usedfor biopsy staining.

Causative agents have several morphology

and size based on disease type. Branched

septate hyphae indicate Aspergillus,

Cephalosporium and Penicilliumwhereas

non-septate hyphae were seen in CNS

infection due to Zygomycetes. Melanized

fungi including; Cladosporium, Exophiala,

Wangiella are presented as dematiaceous

elements [38,39]. Yeast forms (up to 20 m

in diameter) were usually seen in CNS

caused byBlastomyces dermatitidis,

Candida species, C. neoformans, H.

capsulatum, Sporotrichumand


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Paracoccidioides. The presence of spherule

indicates CNS infection with C. immitis

Treatment

A high rate of morbidity and mortality of

patients with fungal infections of CNS are

caused by several factors, such as organ

transplant, chemotherapy, ICU

hospitalization, immunocompromised

patients and haematological malignancies.

The treatment of fungal CNS infection is

influenced by multiple factors including, the

host, the pathogen and its drug

susceptibility, drug delivery across the

blood-brain barrier and drug activity in the

CNS, brain and spinal cord [39].

Amphotericin B is a polyene antibiotic that

binds to ergosterols in the cell wall of fungi

and increased cell permeability. K

+

leakage

due to this permeability causes cell death

[41]. Amphotericin B and/or flucytosine in

combination are recommended for CNS

infections especially caused by Candida

and C. neoformans[42-44].

Fluconazole as intravenous or oral


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preparations has more activity against

yeasts (Candidaand Cryptococcus) than

filamentous fungi and iswidely distributed

throughout body tissues, including the CSF

Itraconazole has a wider spectrum activity

against fungi than fluconazole. It has been

used successfully to treat CNS infections

due to Aspergillusspecies however its

penetration into CSF is poor. High CSF

levels of voriconazole (0.08-3.93g/ml) in

fungal meningitis patients have been

reported to achieve rapidly. CSF levels

from 0.08 to 3.93 g/ml are reported (CSF:

serum ratios of 0.22-1) [39]. In addition,

posaconazole as an oral medication is also

presented as valuable alternative for CNS

fungal infection therapy [45].

Echinocandins as intravenous infusion

significantly bound to fungal proteins with

half-live compatible. Clinical studies have

shown that echinocandins are used to treat

Candidaand Aspergillusinfections.

F TREATMENT

The class of polyene antibiotics includes intravenous

amphotericin B preparations and topical nystatin. Poly-enes bind to ergosterol, the principalcomponent of


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fungal cell membranes, leading to pore formation and

cell death. The agents also bind, albeit with lower avidity,

to the cholesterol in mammalian cell membranes,

accounting for their significant toxicity. There may also

be antifungal activity via oxidation and the generation of

free radicals [35].

CSF levels of amphotericin B are generally undetectable,

although it has been shown to have efficacy in treatment

of CNS infections. The lipid formulations of amphoter-icin preferentially distribute to the

mononuclear phago-cytic system, reducing their toxicity. Renal failure, the

most common treatment-limiting toxicity, is reduced

with lipid-based formulations that allow higher doses

to be administered [36]. Potentiation of nephrotoxicity

may occur with calcineurin inhibitors (e.g. cyclopsporine,

tacrolimus) and aminoglycosides commonly used in bone

marrow and organ transplant recipients [34].

Amphotericin B or a lipid-based preparation is indicated

for treatment of severe infections caused by Candida,

Blastomyces, Coccidioidies, Cryptococcus,andHistoplasma.

Of note, a retrospective series of patients with CNS

aspergillosis treated with amphotericin B alone or in

combination with itraconazole or fluctyosine showed

no clinical efficacy, leading the authors [37] to conclude

that voriconazole may be the preferred agent in this

setting

Azoles

These are compounds that target ergosterol biosynthesis


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by inhibiting lanosterol 14-ademethylase, altering cell

membrane integrity and causing cell death or growth

arrest. The tageted enzyme is cytochrome P-450 depen-dent and azoles also inhibit other P-

450-dependent

enzymes in the respiratory cycle of the fungi. Available

agents in this class include fluconazole, itraconazole, vor-iconazole, posaconazole, and the

investigational agent

ravuconazole. Itraconazole has limited oral bioavailability

and no measurable CSF levels, but does have some

penetration into inflamed meninges and brain tissue.

Voriconazole is available both orally and parenterally

and achieves CSF levels that exceed trough plasma levels.

There is a significant individual variability in metabolism,

and measurement of serum levels should be considered

when treating serious CNS infections. Pharmacokinetic

studies [38,39] of posaconazole demonstrated improved

oral absorption when coadministered with a fatty meal,

although there are no reliable data on CSF penetration.

The primary toxicity of the second generation triazoles

is related to their cross inhibition of human cytochrome

P-450 enzymes and influence on metabolism of other

350 Inflammatory diseases and infection

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is

prohibited.

drugs, which can prolong the QT interval, which may place

patients at risk for cardiac arrhythmias. In addition, dose

adjustment is required for the coadministration of cyclos-porine, tacrolimus and sirolimus

[40]. Experience with

voriconazole has identified transient elevation of liver

enzymes, hallucinations and visual disturbances, which


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can occur in up to 40% of patients, as the major adverse

events, with a relatively low rate of therapy discontinuation

[1

]. Voriconazole and posaconazole have been noted

to have increased clearance with cimetidine, phenytoin

and rifabutin, likely via their common pathway via

CYP3A4 [1

].

Fluconazole prophylaxis in the HSCT and cancer popu-lation has been associated with

increased rates of infec-tion with resistant organisms such as C. glabrataandC.

kruseiistrains, although the morbidity of these infections

is low [33]. In South Africa, there are reports of increasing

cryptococcal resistance to fluconazole, with rates as high

as 12.7% in general isolates and above 70% in the setting

of clinical relapse [41]. Thus, recent prior antifungal use

should be considered when choosing an antifungal

therapy. Fluconazole is effective against candidiasis,

histoplasmosis, blastomycosis, paracoccidioidomycosis,

and mild cases and stable phase treatment of cryptococ-cosis. Voriconazole is emerging as

the first-line therapy

for invasive aspergillosis, fusarosis, and scedosporosis.

Posaconazole is effective in treating invasive aspergillosis

in the setting of resistance to or intolerance of alternate

agents and has enhanced activity against zygomycoses

and dematiaceous mold infections [42 4


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Flucytosine

Flucytosine is a fluorinated pyrimidine analogue taken up

by the fungal enzyme cytosine permease and incorporated,

causing RNA miscoding and inhibiting DNA synthesis.

Flucytosine resistance can develop at the level of the

cytosine permease or at the cytosine deaminase and devel-ops rapidly in the setting of

monotherapy. Flucytosine

penetrates the CNS well [50]. Primary side effects are

hepatotoxicity and bone marrow suppression, which can be

minimized by therapeutic drug-level monitoring [51].

Flucytosine has activity againstCandida, Cryptococcusand

Saccharomycesand has been demonstrated to have syner-gistic action with amphotericin B

in induction therapy for

cryptococcal meningitis [33]. If amphotericin B is not a

therapeutic option, flucytosine may be combined with

fluconazole for treatment of cryptococcal meningitis or

severe candidiasis [33]

F

Clinical syndromes of CNS infection have been reviewed

elsewhere [1

,2

,3,20]. The most important CNS fungal

syndromes that bring patients to medical attention are

meningitis and brain abscess with or without vascular


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invasion (Table 2).

Meningitis generally presents with headache, meningis-mus, photophobia, papilledema,

diminished conscious-ness, and, in advanced cases, seizure or complications

from increased intracranial pressure (e.g. 6th nerve palsy).

The cardinal features may be variably present in immu-nocompromised patients; thus high

clinical suspicion is

required. Fungal meningitis can have a variable pace and

severity and may be clinically indistinguishable from

bacterial causes of a chronic meningitis.

Fungal brain abscesses typically present with a focal

neurological abnormality, headache and/or seizure, which

is the consequence of local destruction or compression of

adjacent brain tissue. Certain fungal pathogens, in particu-lar Aspergillus, will often have a

degree of angioinvasion

that can produce simultaneous infarction and/or meningi-tis. Clinical evidence for

angioinvasive disease includes

the presence of a new stroke-like syndrome and/or menin-geal signs. Other presentations of

brain abscesses include

direct extension to the CNS from preexisting sinusitis or

osteomyelitis and infections associated with foreign bodies

including shunts or prior head trauma. As fungal and bacterial syndromes overlap, a careful

review of host risk

factors should raise suspicion for a fungal cause that will

direct appropriate evaluation and management.

Manfes

Aspergilosis

Aspergillus brain abscess is a severe complication of


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hematological malignancies and cancer chemotherapy,

and, until recently, was almost uniformly fatal [23].

The Transplant Associated Infections Surveillance

Network demonstrated that the incidence of proven or

probable invasiveAspergillusat 12 months was 0.5% for

autologous HSCT, 2.3% for allogeneic, human leukocyte

antigen (HLA)-matched donor, 3.2% after an HLA-mismatched related donor and 3.9% from

an unrelated

donor [24

]. Additional specific risk factors for CNS

fungal infection include solid-organ transplant, GvHD,

HIV, liver disease and sarcoidosis.

Of more than 100Aspergillusspecies that are known, the

most virulent pathogen isA. fumigatus,butA. niger,A. flavus

andA. terrus(which is relatively amphotericin resistant)

can cause human disease. CNS infections withAspergillus

are typically seeded hematogenously but may also occur

via direct spread from the anatomically adjacent sinuses,

favoring the frontal and temporal lobes. In a series of

71 cases of invasive aspergillosis, 94% involved the

CNS, the vast majority of which were brain abscesses.

Uncommon presentations ofAspergillusCNS infection

include basilar meningitis, myelitis, carotid artery invasion,

dural abscesses and mycotic aneurysm [25].

Pathologic features ofAspergillusCNS infection include a

necrotizing vasculitis, consistent with the species vaso-centric tropism. The radiological

appearance of lesions is

variable, with frequently associated edema, hemorrhage


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and ring enhancement. Given the vascular tropism,

multiple areas of infarction with or without associated

hemorrhage may be suggestive [26,27]. Cerebrospinal

fluid (CSF) findings are generally nondiagnostic [28]

Diagnosis

The appropriate presentation in at-risk hosts should spur

testing to identify a fungal pathogen. Fungemia is seen

with a few species, includingCandidaspp.,Histoplasma

capsulatum, Cryptococcus neoformansandAspergillus terreus

but rarely with otherAspergillusspp. such asAspergillus

fumigatus [29]. CSF sampling is indicated in all patients

with meningitis and may show a lymphocytic pleocy-tosis (Cryptococcus, Candida),

neutrophilic predominance

(Aspergillus, Blastomycosis) or eosinophilia (Coccidioides)

[20]. Care is required prior to sampling the CSF to ensure

that increased intracranial pressure does not place the

patient at undue risk from the lumbar puncture (e.g.

noncommunicating hydrocephalus). In cases of neurosur-gery or device-

relatedCandidameningitis, pleocytosis

may be absent. CSF glucose is generally low and protein

high, with exceptionally high levels seen in cryptococcal

infections [20]. CSF antigen testing is available for

CryptococcusandHistoplasma, with sensitivity and speci-ficity rates reported in some series

above 90% [20,30].

Testing for serum beta glucan may be useful for identify-ing the presence of an invasive

fungal infection (with the

notable exceptions ofCryptococcusand zygomycetes) with


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sensitivity rates, in some series, of 6477%, although

specificity may be decreased in the presence of concurrent

bacteremia [31,32]. Serum assay for galactomannan is

reported in some series to have a 95% sensitivity and

specificity for invasiveAspergillusinfections. CSF assays

for galactomannan are under investigation and may prove

to have clinical utility [33]. A positive serum galactoman-nan assay in the setting of a

radiographic brain lesion

should prompt empiric antifungal therapy targeted to treat

invasive aspergillosis. If noninvasive methods fail to define

a pathogen, the risks and benefit of brain biopsy should be

weighed against empiric antifungal therapy.

Cryptococcus diagnosis

Cryptococcus neoformansis a common cause of fungal menin-gitis in immunocompromised

patients, especially in those

with cell mediated immune deficits such as organ transplan-tation, lymphoma, or HIV. Onset

may be insidious and

headache is often present; however, fever may not be a

feature. CSF is usually clear and typically reveals a

lymphocytosis, low glucose, and elevated protein level. A

definitive diagnosis relies on positive culture; however,

crypotococcal infection can be suspected earlier by direct

examination of the CSF on India ink stain, which has a

sensitivity of 50%, or, if capsular antigen is present, on latex

agglutination testing, which has a sensitivity of 95%.

Treatment is with combined amphotericin B and 5 flouro-cytosine. C neoformans may also

cause cerebral or spinal

Absces


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Cryptococcosis

Guideline 2

Among patients with HIV infection, cryptococcosis most

commonly occurs as a subacute meningitis or meningoen-cephalitis with fever, malaise, and

headache (591). Classic

meningeal symptoms and signs, such as neck stiffness and

photophobia, occur in only one fourth to one third of patients.

Encephalopathic symptoms, including lethargy, altered menta-tion, personality changes,

and memory loss, usually resulting

from elevated intracranial pressure, occurs in small groups of

patients.

Analysis of CSF usually demonstrates a mildly elevated serum

protein; glucose ranging from low to normal; a pleocytosis

consisting mostly of lymphocytes, although some patients have

no cells; and a positive Gram or India ink stain for numerous

yeasts. The opening pressure in the CSF is usually elevated, with

pressures >20 cm H2O occurring in up to 75% of patients.

When cryptococcosis occurs in the HIV-infected patient,

disseminated disease is common. Virtually any organ can be

involved, and skin lesions mimicking molluscum contagiosum

are frequently observed. In addition, isolated pulmonary infec-tion is evident; symptoms and

signs include cough and dyspnea

in association with an abnormal chest radiograph.

Diagnosis

Cryptococcal antigen is almost invariably detected in CSF at


16/28

high titer in patients with meningitis or meningoencephalitis.

The serum cryptococcal antigen is also almost always positive

in cases of CNS disease and in other instances of disseminated

infection. As such, testing for serum cryptococcal antigen is

a useful initial screening tool in diagnosing cryptococcosis

in HIV-infected patients (593). Up to 75% of patients with

HIV-associated cryptococcal meningitis have routine blood

cultures positive for C. neoformans

Histoplasmosis

Clinical Manifestations

Disseminated histoplasmosis usually occurs in patients

with CD4+

counts


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respiratory tract

The diagnosis of meningitis can be difficult. A lymphocytic

pleocytosis is usually associated with elevated protein and low

glucose. Fungal stains are usually negative, and CSF cultures

are positive in a minority of cases (619). Histoplasmaantigen

or anti-Histoplasma antibodies can be detected in CSF in up

to 70% of cases and either is diagnostic. For some patients,

none of these tests are positive, and a presumptive diagnosis

of Histoplasmameningitis is appropriate if the patient has dis-seminated histoplasmosis and

findings of CNS infection not

explained by another cause

Cicoccidiodo

Clinical Manifestations

Among persons with HIV infection, six common syndromes

have been described (634). These are focal pneumonia, diffuse

pneumonia (presenting as apparent PCP), cutaneous involve-ment, meningitis, liver or

lymph node involvement, and posi-tive coccidioidal serology tests without evidence of

localized

infection. Focal pneumonia is most common in those with

CD4+

counts >250 cells/L, whereas the other syndromes

usually occur in more immunosuppressed patients. Symptoms

of meningitis are headache and progressive lethargy. The CSF

profile demonstrates a low glucose with elevated protein and


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a lymphocytic pleocytosis.

Diagnosis

The diagnosis of coccidioidomycosis is confirmed by culture

of the organism from clinical specimens or by demonstration of

the typical spherule on histopathologic examination of involved

tissue. Blood cultures are positive in a minority of patients,

usually in those with diffuse pulmonary disease. Coccidioidal

IgM and IgG serology, performed by EIA, immunodiffusion, or

classical tube precipitin or complement fixation methodology,

is useful in diagnosis although it may be less frequently positive

among patients with low CD4

+

counts than among immu-nocompetent persons. Complement fixation IgG antibody is

frequently detected in the CSF in coccidioidal meningitis and

is useful in establishing this diagnosis. Culture of the CSF is

positive in fewer than one third of patients with meningitis

BAGUS Best practice

Step-by-step diagnostic approach

Diagnosis involves collation of symptoms, signs and investigation results. Often empiric treatment mayneed to be initiated before definitive diagnosis is made. Key tests include brain imaging, CSF analysis,

and blood cultures. If repeated examination of the CSF, blood and urine remains inconclusive,

histopathological examination for fungi and culture of the brain, meninges and cisternal or ventricular

fluid may be considered. [23]

Clinical history, clinical signs

Cryptococcal meningitis:

May present in a variety of ways; clinical features are not specific. Meningoencephalitis is the most frequent manifestation of cryptococcosis.
http://bestpractice.bmj.com/best-practice/monograph/541/resources/references.html#ref-23http://bestpractice.bmj.com/best-practice/monograph/541/resources/references.html#ref-23


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HIV-infected individuals and organ transplant recipients are the major risk groups, but it can also

present in immunocompetent adults and children. [58]

Typically presents with progressive headache (70% to 90%), and fever (50% to 90%) of several

weeks' duration. [46] [47]

Symptoms may progress to include nausea, vomiting, behavioural change, drowsiness and

seizures.

Diplopia and subsequently reduced visual acuity reflect the development of raised intracranial

pressure.

Cough and dyspnoea are not infrequent and may reflect pulmonary involvement.

The rate of progression of symptoms may depend on host immunity so that some patients without

major immune deficits present a more chronic course.

Significant incidence and higher mortality when associated with immune reconstitutioninflammatory syndrome after initiation of antiretroviral therapy. [59]

Cryptococcal meningitis:

Signs may be absent or minimal.

Meningismus is present in only 20% to 50% of patients on presentation. [46] [47]

Additional signs may include: altered mental status, reduced visual acuity, papilloedema, cranial

nerve palsies, and other focal neurological deficits.

In children, headache and fever are most common symptoms. [61]

Atypical features include subacute dementia and visual loss.

Histoplasmal meningitis:

Fever, headache and neck stiffness due to a subacute or chronic meningitis. [23]

Focal neurological symptoms due to focal brain or spinal cord lesions and stroke syndromes. [23]

Behavioural and mental status changes secondary to encephalitis. [23]

Patients with CNS involvement associated with disseminated infection may also report high fevers,

weight loss, and mouth ulcers.

Coccidioidal meningitis:
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Headache, fever, nausea, vomiting, and behavioural changes.

The most common complication of coccidioidal meningitis is hydrocephalus, which can occur as a

presenting feature or as a late complication. [10]

Symptoms of hydrocephalus include headache, nausea, blurred or double vision, coordination or

gait disturbance, memory loss, confusion, changes in personality, and urinary incontinence.

May also present with focal neurological symptoms secondary to cerebral infarction due to arteritis

of small- to mid-sized blood vessels.

Candidal meningitis:

Adult candidal meningitis may present with acute or subacute symptoms of meningitis, with fever

and headache being the most common reported symptoms. [60]

Neonates with candidal meningitis are often premature and present initially with symptoms of

respiratory distress. [32] [33] [34]

Clinical signs

Histoplasmal meningitis:

Meningismus and focal neurological signs.

Signs of disseminated histoplasmosis include splenomegaly, hepatomegaly, and lymphadenopathy.

Histoplasmosis is the most endemic mycosis in Europe. [62]

Coccidioidal meningitis:

Meningismus (about 50%).

Signs of hydrocephalus (altered mental status and gait).

Focal neurological signs related to cerebral infarction.

Candidal meningitis:

Meningismus may be found, although it is not common in neurosurgical patients with candidal

meningitis.

Patients commonly present with altered mental status. Focal clinical presentations, cranial nerve involvement, papilloedema, and seizures are uncommon

manifestations of candidal meningitis.

An examination of the patient should be performed looking for signs of disseminated candidiasis.

For example, fundoscopy may reveal invasion of the retina, and the Infectious Diseases Society of

America recommends at least one ophthalmological examination in patients with suspected

disseminated candidiasis. [56]

Investigations
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Brain imaging with CT or MRI is performed in all patients with suspected fungal meningitis.View image

If cryptococcal meningitis is suspected, imaging should always precede lumbar puncture. Imaging may be

normal or may demonstrate, for example, communicating hydrocephalus (also common with coccidioidal

meningitis), fungal granuloma, or vasculitic complications.

Lumbar puncture is also part of the routine evaluation. CSF is tested for glucose, WBC and differential,protein, culture, antibodies/antigens, India ink stain (Cryptococcus) and opening pressure. However,

repeated sampling of large volumes of CSF often required for the diagnosis of non-HIV-associated

cryptococcal meningitis, coccidioidal meningitis, histoplasmosis, and candidal meningitis. Cryptococcal

meningitis by non-capsulated forms of cryptococci is rare but would be difficult to diagnose without CSF

culture. [63]

Up to 3 sets of blood cultures should be taken in all patients; they may be positive when candidal,

histoplasmal, or cryptococcal meningitis is associated with disseminated disease.

Specific tests include:

CSF cryptococcal antigen test

Serum antibody and antigen testing for histoplasmosis.

Urine antigen testing for histoplasmosis.

Immunodiffusion tests (IgM and IgG) and the complement fixation test (IgG) for

coccidioidomycosis: positive results support the diagnosis of coccidioidal meningitis when other

causes of meningitis are excluded, and the presence of coccidioidal IgG antibody in the CSF is

virtually diagnostic of coccidioidal meningitis. [10]Negative results from an experienced

laboratory in patients with untreated disseminated disease are rare.

Positive cultures together with microscopy and immunological testing in serum and CSF remain the

current standard for diagnosis of fungal CNS infections. However, specific diagnosis may be delayed due

to slow growth in culture, cross-reactivity in case of antigen detection, and inadequate antibody response.

There are early data favouring CSF PCR as an adjunctive diagnostic tool.

Histopathological examination

If repeated examination of the CSF, blood and urine remains inconclusive, histopathological examination

for fungi and culture of the brain, meninges and cisternal or ventricular fluid may be considered. [23]

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Bagusss

Common fungal agents of meningitis include Cryptococcus neoformans, Candida albicans,Histoplasma

capsulatum,Blastomycoses, and Coccidiodes immitis[Table 3]and [Table 4]. Susceptible patients are

usually either immunocompromised or have undergone direct neurosurgical interventions, such as shunt

placement. The primary method of spread in most cases involves respiratory infection with subsequent

hematogenous dissemination. [32] Symptoms are typical of those of meningitis, including fever, headache,

AMS, nausea, vomiting, and neck stiffness, in addition to complications of abscess, papilledema, seizures,

and focal neurologic deficits. [32] LP for fungal meningitis usually reveals a lymphocytic prevalence with

mild depressions in glucose and increased protein.[29]

Table 3: Risk factors, transmission, and treatment of fungal meningitis [32],[33],[35],[37],

[40],[44],[45],[46],[50],[51]

Click here to view

Table 4: Signs and symptoms of central nervous system infections

Click here to view

AIDS and cancer patients are especially prone to cryptococcal meningitis, with the incidence of

cryptococcosis dramatically increasing since the rise of the AIDS epidemic. [33],[34] In a multistate case-

control study performed by Hajjeh et al, 86% of patients sampled with cryptococcosis had HIV.[35]These
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patients often do not present with the same symptoms as found in immunocompetent patients, often

experiencing a relatively sudden onset of symptoms vs a more subacute course in immunocompetent

patients. [32],[36]Pigeon droppings are one of the important carriers ofCryptococcus; smoking is another

significant risk factor. [35]Diagnosis can be made via direct microscopic examination using India Ink

staining; cytology or histopathology, serologies, and culture after 48 h can also be used.

[33]

Amphoterecin is the agent of choice in cryptococcal meningitis, and should be administered along with

flucytosine for 2 weeks, followed by fluconazole for a minimum of 10 weeks. [37],[38] Highly active

antiretroviral therapy for HIV-infected patients is the most efficacious method for cryptococcal

prevention. [32],[39]Once infected, however, lifelong fluconazole (or itraconazole in patients that cannot

tolerate fluconazole) therapy is required, especially in AIDS patients with CD4 cell counts below 100. [32],

[37],[40]

Coccidioidal meningitis usually occurs in epidemics, but affects a few hundred people a year at baseline,

primarily in the southwestern United States. [41],[42]Diagnosis is usually via serology, as meningitis is

usually the result of disseminated pulmonary infection. Although previously treated with amphoterecin,

these patients often require chronic therapy, prompting a switch to azoles, including fluconazole and

itraconazole as the agent of choice for both induction and maintenance; addition of amphoterecin to

treatment regimen is still indicated for azole failure. [42],[43]Amphoterecin can be administered either

intravenously or intrathecally. Histoplasmoses and blastomycoses produce a meningitis similar to

coccidiomycoses, and are transmitted similarly, that is, respiratory infection followed by blood-borne

spread into the meninges and occasionally brain parenchyma, due to the genetic similarities between these

species. [44]

However, unlike coccidiomycosis, histoplasmosis and blastomycosis species tend to be found in central

United States around the Mississippi and Ohio river valleys. Compared with histoplasmosis,

blastomycosis is less prevalent yet poses more serious infection in those that manage to acquire it.

Diagnosis for isolated CNS histoplasmosis infections may require multiple diagnostic modalities,

including CSF testing, serologies, or culture. [44],[45] Culture is the definitive method in the diagnosis of

most fungal meningitis, as serologies may reveal false positives and PCR remains unproven, yet may

necessitate obtaining several tissue or fluid samples before one returns positive for a culture. [44],[45],[46]

There are no reliable skin or serologic tests to confirm previous blastomycosis infection, and half of the

patients infected suffer symptoms for almost a month before diagnosis is made. [44] Due to its less common

incidence combined with potentially severe sequelae, clinical suspicion must be high for blastomycosis.

Treatment for both consists of liposomal amphoterecin B, which has been found to achieve better brain

tissue concentrations with less nephrotoxicity than standard deoxycholate amphoterecin formation. [45]

Itraconazole and fluconazole are recommended in patients unable to tolerate amphoterecin, while there

have been several case studies reporting successful treatment of blastomycosis with vorizonazole. [47],[48],[49]

AIDS patients may frequently require an azole for lifelong suppressive therapy, or until CD4 counts rise

above 200. [46]

Out of the 150 species ofCandida known, Candida albicans is the major human pathogen.[50]Although

frequently present as a vaginal infection in immunocompetent patients, often seen after antibiotic therapy,Candida has the potential to disseminate and cause meningitis primarily in immunosuppressed, especially
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neutropenic, individuals. [50] In addition to meningitis, candidiasis can cause a vertebral osteomyelitis

manifested by chronic progressive lower back pain that can eventually lead to nerve root compression

syndromes and loss of function, as well as an endophthalmitis manifest by retinal lesions, which can

eventually lead to blindness.[50]

As blood cultures can be fairly unreliable with poor sensitivity, more reliable techniques, such as the 1,3-

-glucan assay, are used to diagnose invasive candidiasis. [50] Definitive diagnosis of candidal meningitis,

however, is made similar to other fungal meningitis via culture and isolation ofCandida species from the

CSF. [50]

Treatment for Candida meningitis involves amphoterecin B and usually flucytosine due to its ability to

penetrate the blood-brain barrier. In patients for whom amphoterecin-induced nephrotoxicity is a

significant problem, fluconazole or the echinocandins may be used. [51]

IJCHS

Cerebral abscesses can frequently present with a new-onset headache that can evolve over

several hours to several weeks, accompanied by focal neurologic deficits. Lethargy, nuchal

rigidity, nausea, vomiting, and new-onset seizures often accompany the development of

abscesses.

[89],[90]

The two major causes of brain abscesses include hematogenous spread ofpathogens across the blood-brain barrier and via direct contiguous spread from the sinuses

after a sinus infection, with the latter accounting for over 70% of all brain abscesses. [89] A

minor etiology involves direct trauma to the skull implanting the pathogenic organism. The

differential diagnosis for brain abscesses always involves neoplasm, although abscesses

tend to be more acute in their onset and are often accompanied by other systemic

symptoms, such as fever and leukocytosis, although these are usually present in only half of

all affected patients, and positive blood cultures found in far fewer. History will also be of

paramount importance in detecting the likelihood of abscess vs tumor, and it is important to

ask about preceding sinus infections, systemic infections, and possible head trauma.

CT or MRI are indicated whenever abscess is suspected, with MRI being more sensitive and

specific for detecting various aspects of the abscess, including mass effects, surrounding

edema, and response to therapy. [90] Abscesses tend to be located most commonly in the

frontal and parietal lobes. [89] Fungal abscesses, though, are more poorly localized upon CT

or MRI, and LP plays little value in the workup of brain abscesses as the abscess tends to be

more focally confined to one part of the brain and organisms are rarely found in the CSF,

leading to false negatives. Furthermore, the risk of possibly fatal transtentorial brain

herniation far outweighs the meager sensitivity of detecting causative organism via LP. [89]

Treatment for bacterial abscesses includes either administration of antibiotics alone, or

surgical removal of abscess via excision or aspiration. If surgery or aspiration is employed,
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antibiotics should concomitantly be administered for 3-6 weeks, whereas if antibiotics are

given alone a longer course should be employed extending from 6 to 8 weeks. [90],[91]

Indications for surgical removal include when an abscess is in direct proximity to the

ventricular system due to risk of spillage of organisms into the ventricles, when the abscess

is in the posterior fossa due to potential mass effects, including compression of the

brainstem, or when the abscess is sufficiently large enough, for example >3 cm in diameter,

to warrant removal. [90] Serial CT or MRI scans are the diagnostic modality of choice to

monitor treatment of abscesses, and the resolution of abscesses correlates proportionally to

size seen on imaging, although in cases where antibiotics are given alone there is often a

lag with imaging remaining positive weeks longer. [89] Recovery rate correlates with the size

of abscess and degree of neurologic dysfunction primarily, with younger patients tending to

fare best while immunosuppressed patients often fare worst. [90],[92]

Before aspiration, a good history is helpful in identifying the likely causative organism of an

abscess. Patients should be asked about recent infections, especially those affecting the

sinus cavities, as well as about any potential intravenous drug usage, immunocompromisedstates, steroid usage, and congenital cardiac conditions, all of which can predispose to the

formation of particular abscesses. Streptococcal infections are among the most common

causes of brain abscesses, and frequently result from parameningeal spread into the cranial

cavity. Anaerobic organisms, such as Bacteroides, Peptococcus, Peptostreptococcus, and

Prevotella also frequently enter the brain by way of contiguous spread from either nasal or

oropharyngeal origins. [89],[90]Staphylococcus aureus, however, while possibly residing the

patient's nares, is frequently induced via intravenous drug usage and resulting

hematogenous metastases and is far more common in the heroin and steroid-injecting

population.

Less frequent causes including Candida are also found in increased amounts in IV drug

users, as well as chronically immunosuppressed patients. Although fungal abscesses are

relatively rare in the general population, in a study of 58 patients with histology- or culture-

proven brain abscess diagnosed between January 1984 and March 1992 at the Fred

Hutchinson Cancer Research Center in Seattle, a fungus was isolated in 92% of the cases,

withAspergillus being the most frequent culprit at 58% followed by Candida, underscoring

the need to suspect alternative causes of brain abscess in specific patient populations. [92]

The treatment of choice for streptococcal abscesses includes a third-generation

cephalosporin, such as ceftriaxone. Anaerobic abscesses respond best to metronidazole,whereas empiric therapy for the treatment of brain abscesses usually involves a

combination of both anaerobic and streptococcal coverage. In patients suspected of being

infected with S. aureus, the prospect of methicillin resistance must be taken into account,

and empiric treatment with vancomycin is indicated. Suspected Candida infections should

employ an antifungal agent, such as amphoterecin B and flucytosine, often followed by an

oral agent, such as fluconazole, which has good penetration into the CSF
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Table 3: Risk factors, transmission, and treatment of fungal meningitis[32],[33],[35],[37],[40],[44],[45],[46],[50],[51]


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REVIEW ARTICLE

Year : 2012 | Volume : 2 | Issue : 2 | Page : 82-97

Infections of the nervous system

Vevek Parikh, Veronica Tucci, Sagar Galwankar

University of California, San Francisco, CA, USA

Date of Web Publication 16-Jun-2012

Etiology and Management of Chronic Meningitis

Renee R. Koski, BS, PharmD, CACP, FMPA

Professor, Pharmacy Practice

Ferris State University, College of PharmacyUPHEC, Marquette, Michigan
http://www.ijciis.org/searchresult.asp?search=&author=Vevek+Parikh&journal=Y&but_search=Search&entries=10&pg=1&s=0http://www.ijciis.org/searchresult.asp?search=&author=Veronica+Tucci&journal=Y&but_search=Search&entries=10&pg=1&s=0http://www.ijciis.org/searchresult.asp?search=&author=Sagar+Galwankar&journal=Y&but_search=Search&entries=10&pg=1&s=0http://www.ijciis.org/article.asp?issn=2229-5151;year=2012;volume=2;issue=2;spage=98;epage=103;aulast=Vandsehttp://www.ijciis.org/searchresult.asp?search=&author=Vevek+Parikh&journal=Y&but_search=Search&entries=10&pg=1&s=0http://www.ijciis.org/searchresult.asp?search=&author=Veronica+Tucci&journal=Y&but_search=Search&entries=10&pg=1&s=0http://www.ijciis.org/searchresult.asp?search=&author=Sagar+Galwankar&journal=Y&but_search=Search&entries=10&pg=1&s=0


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Dean Van Loo, PharmD

Associate Professor, Pharmacy Practice

Ferris State University, College of Pharmacy

Pharmacy Department, Bronson Methodist Hospital

Kalamazoo, Michigan

1/20/2010

US Pharm. 2010;35(1):HS-2-HS-8.

tambahann inf ssp

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