the poor prognosis of central nervous system cryptococcosis among nonimmunosupressed patients

8/13/2019 The Poor Prognosis of Central Nervous System Cryptococcosis Among Nonimmunosupressed Patients

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BRIEF REPORT CID 2006:42 (15 May) 1443

B R I E F R E P O R T

The Poor Prognosis of Central

Nervous System Cryptococcosisamong NonimmunosuppressedPatients: A Call for Better DiseaseRecognition and Evaluation ofAdjuncts to Antifungal Therapy

Ismail Zafer Ecevit,1 Cornelius J. Clancy,1,3 Ilona M. Schmalfuss,2,3

and M. Hong Nguyen1,3

Departments of 1Medicine and 2Radiology, University of Florida College

of Medicine, and 3Veterans Affairs Medical Center, Gainesville, Florida

We describe 9 nonimmunosuppressed patients with central

nervous system cryptococcosis. Morbidity and mortality

were high, especially among patients with cerebral infarcts.

This was attributed to delayed diagnosis and apparent se-

quelae of overwhelming host immune responses. We present

clues suggesting the diagnosis. Increased recognition and

timely diagnosis of this condition may improve outcomes.

CNS cryptococcosis is a common fungal infection among im-

munocompromised patients, especially among those with cell-

mediated immune dysfunction, but it is rare among immu-

nocompetent hosts. We recently encountered 9 cases of CNS

cryptococcosis in nonimmunosuppressed hosts. The majority

of the patients died, and the remaining experienced neurolog-

ical sequelae. In this report, we review our experience at the

University of Florida (Gainesville) from 1997 through January

2005.

Results. Four of the patients had been previously healthy,

and 3 only had hypertension. One patient had asymptomatic

hepatitis C virus infection. The final patient had an indwelling

ventriculoperitoneal shunt in place for 38 years (table 1).

The median time from the onset of symptoms to diagnosis

of CNS cryptococcosis was 44 days (range, 7 days to 1 year).

Only 2 patients (patients 2 and 6) had the diagnosis of CNS

Received 27 November 2005; accepted 7 February 2006; electronically published 11 April

2006.

Reprints or correspondence: Dr. M. Hong Nguyen, University of Florida College of Medicine,

1600 SW Archer Rd., PO Box 100277, JHMHC, Gainesville, FL 32610 (nguyemt

@medicine.ufl.edu).

Clinical Infectious Diseases 2006;42:14437

2006 by the Infectious Diseases Society of America. All rights reserved.

1058-4838/2006/4210-0015$15.00

cryptococcosis established 2 weeks after their initial presen-

tation. Seven (78%) of 9 patients had 3 visits to a physician

before the diagnosis, and 6 (67%) of 9 had 4 visits. The

common misdiagnoses were migraine or cluster headache, tran-

sient ischemic attacks or cerebrovascular accidents, carcinoma,

chronic infection, and sinusitis.

The most common complaint during the initial visits was

headache (8 [89%] of 9 patients). None of the patients, how-

ever, had headache as the sole symptom. The common asso-

ciated symptoms are presented in figure 1. The major com-

plaints that prompted the hospital admission were neurological

signs and symptoms and lethargy (figure 1). At the time of

admission, 5 (56%) of 9 patients had a Glasgow Outcome Score

of

3 (table 1).Eight (89%) of 9 patients had cryptococcal meningitis (CM),

and 2 patients (22%) had cryptococcoma. One of the 2 patients

with cryptococcoma also developed CM. All isolates were Cryp-

tococcus neoformansserotype A (C. neoformansvar. grubii).

In general, MRI performed with gadolinium was more sen-

sitive than noncontrast CT for detecting abnormalities (data

not shown). MRIs depicted edema, enhancement of leptomen-

inges and parenchyma, subtle infarcts, and dilated Virchow-

Robins spaces that were missed by noncontrast CT. The most

common neuroradiologic findings for CM were leptomeningeal

enhancement (in 100% of patients), cerebral edema (in 89%),

hydrocephalus (in 67%), infarcts (in 44%), and dilated Vir-chow-Robin spaces (in 44%) (table 1).

The overall mortality rate was 44%, and the rate was 50%

for patients with CM. Two patients were initially treated with

fluconazole (400 mg daily). Both patients had persistent CSF

cultures positive for C. neoformans; therapy was switched to

amphotericin B. Overall, cultures sterilized for 89% of patients

with CM; for 50% of these patients, the cultures sterilized

within 14 days. For 75% of the patients who died, the CSF

cultures had sterilized antemortem.

Worsening clinical status was observed in 3 patients (patients

46), despite an initial clinical response to antifungal therapy

and sterilization of CSF; the times from initiation of therapyto the paradoxical worsening status were 13, 19, and 25 days,

respectively. Neuroradiological studies revealed new or wors-

ening leptomeningeal enhancement (in 3 patients), new or

worsening cerebral infarcts (in 2), diffuse brain edema leading

to herniation (in 2), and numerous new cystic lesions (in 1).

Three patients had opening pressures 55 cm H2O. Six pa-

tients had hydrocephalus, all of whom had opening pressures

130 cm H2O; the severity of hydrocephalus in all patients was


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Figure 1. Presenting symptoms for nonimmunosuppressed patients

with CNS cryptococcosis during initial clinic visits and at admission.

only minimal to mild. All patients underwent repeated lumbar

punctures to reduce opening pressures. In addition, 4 patients

underwent either temporary ventriculostomy, lumbar drain, or

permanent ventriculoperitoneal shunt placement.

Cerebral herniation due to generalized brain edema com-

plicated CM in 2 patients. In both patients, cerebral herniation

developed despite performance of ventriculostomy or place-

ment of a ventriculoperitoneal shunt. Three patients developed

seizures during therapy.

All 5 survivors experienced neurological sequelae that pre-

cluded them from returning to work. Sequelae included diz-ziness (in 4 patients), short-term memory loss (in 4), severe

depression (in 1), cranial nerve palsies (in 1), deafness (in 1),

and blindness (in 1).

Discussion. The most striking finding from this review was

the poor outcome of CM in our nonimmunosuppressed hosts.

The mortality rate was 44%, which is greater than previously

reported rates for HIV-infected and HIV-uninfected patients

[27]. Furthermore, all 5 survivors experienced neurological

sequelae. The high mortality and morbidity rates were partic-

ularly surprising, because 77% of patients had no significant

underlying diseases, and 89% were aged !60 years. In addition,

all patients received aggressive treatment of their elevated in-tracranial pressure.

There are several potential explanations for the poor out-

come among our patients. First, studies often group all HIV-

uninfected patients together and do not specifically address

cryptococcosis among nonimmunosuppressed patients; it is

possible that outcomes in this subgroup are worse than gen-

erally recognized. In addition, our study was conducted at

teaching institutions that serve as referral centers for large cach-

ement areas. As such, we might have disproportionately cared

for patients with severe disease.

At least 3 factors are likely to have contributed to the poor

outcomes. First, the diagnosis was frequently delayed. Second,

suboptimal initial antifungal therapy, as evidenced by the pro-

longed duration of positive CSF culture results, may also have

been a contributing factor. Two patients received fluconazole

as initial therapy, even though the Infectious Diseases Societyof Americas practice guidelines discourage this strategy [8].

Furthermore, 2 patients did not receive 5-flucytosine in con-

junction with amphotericin B; 5-flucytosine shortens the du-

ration of positive culture results [2, 3]. Finally, our patients

relatively intact host immune responses might have contributed

to disease severity. Highlighting this possibility, 3 patients ex-

perienced paradoxical clinical worsening of their conditions,

despite receiving antifungal therapy, having improvement in

CSF pleocytosis and cryptococcal antigen titers, and sterilizing

CSF cultures. The clinical decline was accompanied by new

neuroradiologic findings, including brain edema, cortical andlaminar necrosis, worsening leptomeningeal enhancement, ce-

rebral infarcts, and the development of cystic lesions. Similar

paradoxical worsening has been reported in patients without

AIDS who were infected with C. neoformansvar. gattii[9, 10]

and in solid organ transplant recipients with CM [11]. Indeed,

our observations also evoke immune reconstitution inflam-

matory syndrome, which has been reported in patients with

AIDS and CM after they start receiving HAART [1116]. Dur-

ing immune reconstitution inflammatory syndrome, HAART

induces restoration of immune function, resulting in an ex-

aggerated inflammatory response to treated infection and a

worsening of clinical symptoms and radiographic findings [16].

It has been proposed that, during CM, the normally protective

Th1 cytokine response is shifted to an immunosuppressive Th2

response [8, 17]. It is possible that antifungal therapy reduces

the burden ofC. neoformans, thereby facilitating the reversion

of a Th2 response to Th1. This might lead to an exuberant

host response against residual sites of disease. Because our pa-

tients did not have known T cell defects, an overexuberant

immune reconstitution could result in worse outcomes than

those observed in patients with impaired immunity.

A Glasgow Outcome Score 3 at presentation, a CSF glu-

cose level of30 mg/dL, and cerebral infarcts were associatedwith death (table 2). Cerebral infarcts are well-recognized

complications of chronic meningitis. In our study, 44% of

patients had cerebral infarcts. Our finding that cerebral in-

farcts during CM were associated with a 100% mortality rate

is consistent with the findings of a previous report [18]. It is

generally accepted that the pathogenesis of infarcts during

chronic meningitis results from the host immune response to

infecting organisms. This triggers the development of menin-


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1446 CID 2006:42 (15 May) BRIEF REPORT

Table 2. Indicators of a poor prognosis for CNS cryptococcosis.

Factor

Proportion

of patients

who died (%)

Pa

Factor

present

Factor

absent

Infarcts 4/4 (100) 0/5 (0) .008

Glasgow outcome score 3 4/5 (80) 0/4 (0) .048

CSF glucose level of !30 mg/dL 4/5 (80) 0/4 (0) .048

aDetermined using Fishers exact test.

geal inflammation and vasculitis of traversing perforating ves-

sels, which in turn leads to infarcts.

The implication of the host immune response in the disease

process among nonimmunosuppressed patients with CM sug-

gests that anti-inflammatory measures may have an adjunctive

role in therapy. In patients with tubercular meningitis, ad-

junctive treatment with dexamethasone improves survival rates

[19]. The role of corticosteroids in HIV-uninfected patientswith CM remains controversial [8]. Nevertheless, case reports

have reported benefits for selected patients [10]. Although we

cannot advocate the use of corticosteroids among such patients,

our findings suggest that follow-up studies that involved well-

defined subgroups are warranted.

It is notable that all patients in this study were infected with

C. neoformans var. grubii. Nevertheless, the clinical manifes-

tations among our patients more closely resembled thosecaused

byC. neoformansvar.gattii.C. neoformansvar.grubiipredom-

inantly infects immunocompromised individuals, whereas C.

neoformansvar. gattiiinfection occurs almost exclusively among

immunocompetent hosts [20]. Compared with C. neoformansvar. grubii, C. neoformansvar. gattiigenerally more frequently

invades the brain parenchyma and causes neurological sequelae

[20, 21]. It has been proposed that differences in clinical man-

ifestations between the 2 varieties may stem from inherent dif-

ferences in pathobiology [22]. Findings from our study, how-

ever, suggest that reported clinical differences may reflect that

C. neoformansvar.grubiiiinfections have simply been less well-

characterized among immunocompetent hosts. It is also pos-

sible that the poor outcomes among our patients resulted from

highly virulent strains ofC. neoformans.In patients with more

intact immunity, less virulent strains may not be able to over-

come host defenses and to cause disease.

In conclusion, CNS cryptococcosis is uncommon in non-

immunosuppressed hosts, but it causes significant mortality

and long-term morbidity. It is often not considered during the

evaluation of nonimmunosuppressed patients. CM should be

included in the differential diagnosis for all patients who present

with chronic headache, particularly if the patients also have one

of the following characteristics: fever, weakness or anorexia,

neurological complaints, or abnormal neuroradiologicfindings.

Because the host immune response appears to contribute to

the disease process, studies of the potential roleof corticosteroid

treatment may be warranted.

Acknowledgments

We would like to thank Dr. John Wingard for his review of this man-

uscript and valuable suggestions. This work was performed as part of the

University of Florida Mycology Research Unit (National Institutesof Health

PO1 AI 061537; to M.H.N. and C.J.C.).

Potential conflicts of interest. All authors: no conflicts.

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the poor prognosis of central nervous system cryptococcosis among nonimmunosupressed patients

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