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Review Article

Fungal Infections of the


Address correspondence to
Dr Anil A. Panackal, Laboratory
of Clinical Infectious Diseases,

Central Nervous System


National Institute of Allergy and
Infectious Diseases, National
Institutes of Health, Building 10,
Room 11N222, 9000
Rockville Pike, Bethesda,
MD 20892, Anil A. Panackal, MD; Peter R. Williamson, MD, PhD
anil.panackal@nih.gov.
Relationship Disclosure:
Dr Panackal is employed by ABSTRACT
the National Institute of
Allergy and Infectious Purpose of Review: This article summarizes current knowledge on the epidemiology,
Diseases (NIAID) as a staff clinical presentations, diagnosis, and management of selected fungal infections of the
clinician and receives research central nervous system (CNS). Key syndromes, differential diagnoses, and therapeutic
support from them as the lead
associate investigator on NIAID interventions according to host immune status and exposure are reviewed.
Study Protocol #93-I-0106. Recent Findings: Advancements in imaging of the brain and spinal cord, and mo-
Dr Panackal serves on the lecular DNA and antigen-based laboratory diagnostics afford improved sensitivity for
editorial board of the Journal of
Mycology and holds an academic CNS mycoses. Newer therapeutic strategies may improve outcomes if provided early
teaching appointment at and host immunosuppression is abrogated. Adjunctive corticosteroid use for disabling
Uniformed Services University neuroinflammation and cerebral edema in the setting of microbiological control may
of the Health Sciences as a
civilian. Dr Williamson serves be considered. In addition, nonspecific presentations and absence of fevers in patients
as a voting member on the without human immunodeficiency virus suggest that screening for Cryptococcus
Clinical and Laboratory Standards meningitis be performed in all patients with subcortical dementias using a simple CSF
Institute Anti-fungal
Subcommittee and on the or serum antigen test.
editorial board of the Journal of Summary: CNS fungal infections comprise a wide spectrum of clinical syndromes,
Mycology. Dr Williamson including abscesses, meningitis/meningoencephalitis, focal masses, stroke/vasculitides,
receives research support from
the National Institutes of immune reconstitution inflammatory syndrome (IRIS), and spinal pathologies such as
Health and serves as principle arachnoiditis. The main etiologies include Aspergillus, Cryptococcus, Candida, Mucorales,
investigator on NIAID Study dematiaceous molds, and dimorphic endemic fungi, with the route of acquisition
Protocol #93-I-0106.
Unlabeled Use of
being respiratory or traumatic inoculation with subsequent spread hematogenously or
Products/Investigational contiguously. Proper management focuses on early effective antifungal therapy and
Use Disclosure: surgery for large or compressive mass lesions. While adjunctive recombinant cytokine
Drs Panackal and Williamson
discuss the unlabeled/
or growth factor use has been supported in certain hosts with refractory infections,
investigational use of steroids IRIS-like reactions may occur, suggesting alternative approaches such as high-dose
in the management of cerebral pulse corticosteroids followed by taper.
edema related to increased
intracranial pressure from
fungal paradoxical Continuum (Minneap Minn) 2015;21(6):16621678.
immune responses.
* 2015, American Academy
of Neurology.
INTRODUCTION roids have broadened the scope of
Although invasive fungal infections potential affected hosts.2,3 The clin-
of the central nervous system (CNS) ical spectrum may range from acute
are uncommon, the associated mor- and fulminant among the immuno-
bidity and mortality can be quite high, compromised to indolent and insidious
especially among the immunosup- among the relatively immunocompe-
pressed. Aspergillus and Cryptococcus tent. Knowing the risk factors for in-
in the immunosuppressed are the most fection by etiology, including trauma,
common baseline etiologies,1 but re- neurosurgery, and a variety of immu-
cent outbreaks in previously healthy nosuppressive medications and cel-
individuals of Cryptococcus gattii in lular deficits, and early recognition of
the US Pacific Northwest and of Exse- characteristic syndromes, may permit
rohilum rostratum following epidural implementation of effective manage-
injection of contaminated corticoste- ment strategies.

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KEY POINTS
YEASTS puncture by an astute neurologist, h Cryptococcosis may
Cryptococcus resulting in successful treatment with present indolently in the
Infections by CryptococcusVmostly complete recovery of cognitive and immunocompetent
neoformansVcause an estimated psychiatric functioning. host, leading to delays
650,000 human immunodeficiency vi- C. gattii is a related yeast recently in diagnosis and
rus (HIV)Yrelated deaths among designated as a separate species that, consequent neurologic
1,000,000 HIV-associated cryptococcal importantly, has caused an outbreak sequelae such as cranial
of cases in previously healthy individ- neuropathies and
cases globally on an annual basis, with
a lower 3-month mortality rate in de- uals in the US Pacific Northwest.2 cognitive impairment.

veloped nations.4 C. gattii cases in the Pacific North- h Cryptococcus neoformans


Risk factors and clinical manifesta- west outbreak have been associated and Cryptococcus gattii
more with pulmonary disease, while are leading causes of
tions. In the developed world, one-half meningitis among hosts
nonoutbreak strains have been associ-
of cases are HIV-associated. It continues both with and without
ated more with severe neurologic
to also be a significant problem in in- human immunodeficiency
sequelae.10Y12 Both have been associ-
dividuals who are not infected with HIV virus (HIV) infection and
ated with antiYgranulocyte-monocyte
in the developed world,5 infecting those have a tropism for
colony-stimulating factor (GM-CSF) auto- dopaminergic tracts.
immunosuppressed from solid organ
antibodies.13 The fungus inhabits the
transplant conditioning, primarily renal
soil and uses the virulence factor laccase
transplant recipients late after trans-
to protect itself from phytotoxins in its
plantation (median = 20 months) in up role as a plant pathogen of seedlings.
to one-third of cases.6,7 The remaining During human infections, it uses this
one-third of cases fall outside the HIV- same laccase as a neurotropic virulence
positive and transplant population, with factor, oxidizing neurocatecholamines
other readily identifiable risk factors, in- within dopaminergic tracts, particularly
cluding sarcoid, corticosteroid use, and the basal ganglia, to produce immuno-
hepatorenal failure. However, overall, ap- suppressive compounds such as mela-
proximately 13% to 18% of patients with nin.14 C. neoformans and C. gattii are
cryptococcal disease may have no known leading causes of meningitis among
underlying immunocompromising con- hosts both with and without HIV
ditions but contribute up to 35% to infection and have a tropism for dopa-
50% of the attributable mortality owing minergic tracts. This peculiar anatomic
to delays in diagnosis from slow presen- localization may explain a propensity
tations in an unsuspected host.8,9 Cryp- toward subcortical rather than frontal
tococcosis may present indolently in the pathologies, including gait distur-
immunocompetent host, leading to bances and dementias during chronic
delays in diagnosis and consequent neu- infections. Presentations with mental
rologic sequelae such as cranial neurop- status changes (often confused with
athies and cognitive impairment. dementia), seizures, or basilar menin-
A particularly challenging aspect of geal signs, including pseudoYMeniere
cryptococcal infections in patients disease, may occur; in the absence of
without HIV is the lack of fever and fever, these presentations make the
meningeal signs in a large fraction of diagnosis of cryptococcal disease diffi-
patients. In one exemplary case re- cult. Cranial neuropathies that affect
ferred to the National Institutes of cranial nerves II through VIII are not
Health (NIH), a previously healthy uncommon and may be related to ele-
patient was diagnosed with depres- vated intracranial pressure manifested
sion, and only after many months in a by papilledema, direct fungal invasion,
psychiatric facility underwent a lumbar or inflammation. Visual and hearing
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Fungal Infections

KEY POINTS
h Controlling both loss as well as cognitive impairment monitoring, and the latter may have
microbiological and and gait ataxia with or without urinary poor CNS penetration.21,22 A second
immunologic aspects of incontinence may accompany obstruc- important consideration is an apparent
infection is key to tive or nonobstructive hydrocephalus paradoxical immune response (immune
successful management and may be long- lasting, especially after reconstitution inflammatory syndrome
of cryptococcosis. delays in diagnosis.15 [IRIS] in individuals infected with HIV,
h An exuberant Diagnosis and management. CSF and a postinfectious immune response
inflammatory response examination is essential, both for pri- syndrome in previously healthy individ-
to cryptococcal antigen mary diagnosis and for staging in the uals without HIV infection), accompanied
in the setting of case of apparently localized skin or lung by cerebral edema, resulting in neuro-
microbiological control disease; it typically demonstrates low logic worsening evident during initial
may occur in non-HIV glucose, elevated protein, and high IgG therapy (Case 6-1) as well as after ini-
nontransplant hosts, indices, although cell counts can be quite tiation of antiretroviral therapy in pa-
reminiscent of the low, especially in HIV-related cases. Low tients who are infected with HIV, have
immune reconstitution cell count is a poor prognostic sign, as had a reduction in immunosuppression
inflammatory syndrome are persistent fungal growth and ele- following solid organ transplantation, or
seen in HIV and solid vated intracranial pressure.16 Crypto- are postpartum. During initial therapy,
organ transplant coccal antigen titers from the serum
patients; it may be increased intracranial pressures are com-
and CSF via enzyme immunoassay, latex
managed successfully mon and can be controlled by daily high-
agglutination, or the novel sensitive and
with judicious volume lumbar punctures both for
less expensive lateral flow assay (LFA)
corticosteroid use. mental status and preservation of vi-
are important in the diagnosis of cryp-
tococcal disease, including culture- sion.21 These elevations are caused by
negative cases.17 These simple tests a combination of increased cerebral
are highly sensitive and specific, can edema and outflow obstructions due to
be performed on either blood or CSF, arachnoiditis, as illustrated in Case 6-2,
and should be strongly considered as as well as obstructions within the
a screening test in patients with subcor- foramen of Monro or Luschka/
tical dementias. In addition, MRI may Magendie. Mannitol and acetazolamide
reveal focal masslike cryptococcomas should be avoided because they may
or granulomas, leptomeningeal be ineffective or cause worse out-
enhancement, hydrocephalus with or comes.29,30 Corticosteroids can provide
without transependymal flow, and di- ancillary improvement in cerebral
lated Virchow-Robin perivascular spaces edema and other neuroinflammation,
with gelatinous pseudocysts.18,19 but their use needs to be balanced with
Successful management can be effective microbiological control since
tricky and requires a consideration of steroids exacerbate cryptococcal infec-
both microbiological and immunologic tions. In addition, once inflammation is
aspects of the infection. Microbiolog- controlled with steroids, tapering of the
ical control is facilitated by the use of steroids must be individualized based
fungicidal drugs such as amphotericin on clinical presentation, MRI, and CSF
B for initial therapy with or without parameters (eg, glucose, protein, and
flucytosine, whereas fungistatic drugs cell count), as the process appears to
such as fluconazole result in poor initial be driven by fungal antigen load and
outcome and are reserved for subse- individual host responses. Careful atten-
quent therapy to complete a 12- to tion must be paid to microbiological
18-month course.20 Newer azoles such control and secondary infections while
as voriconazole (trough level 1 mg/L to on immunosuppressants such as ste-
5.5 mg/L) and posaconazole may have a roids, and frequent CSF monitoring is
role in salvage therapy but require level required. Surgical shunting of refractory
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Case 6-1
A 46-year-old woman from the Pacific Northwest developed difficulty managing her construction business.
Over the next 3 months, she developed intermittent fevers, weight loss, worsening headaches, and altered
mental status, which prompted her to seek medical attention. MRI of the brain with gadolinium demonstrated
multiple cystic lesions in the bilateral basal ganglia, the largest lesion on the left measuring 3.9 cm ! 3.9 cm !
3.5 cm. A chest CT revealed an 8-cm right midlung mass, which was biopsied and grew Cryptococcus gattii.
The isolate was genotyped at the Centers for Disease Control and Prevention (CDC) as VGIIa, consistent with
the predominant outbreak strain found in the Pacific Northwest.11 She was started on liposomal
amphotericin B and flucytosine, but the brain lesions enlarged (the largest left basal ganglia lesion
measuring 4.5 cm ! 4.4 cm ! 4.1 cm) (Figure 6-1A), prompting a stereotactic aspiration of this largest

FIGURE 6-1 Imaging of the patient in Case 6-1. A, Large left basal ganglia lesion before
stereotactic biopsy (arrow) with multiple adjacent and contralateral lesions also
seen, showing variable degrees of enhancement (blood-brain-barrier disruption).
B, On follow-up, the main left basal ganglia lesion had decreased in size. Tapering of corticosteroids prior to
this exam resulted in edema on fluid-attenuated inversion recovery (FLAIR) imaging surrounding the
lesions and clinical deterioration. C, Reimplementation of higher-dose corticosteroids led to decreased
edema around some of the lesions and clinical improvement. These images exhibit the exuberant
inflammation that can be seen following microbiological control that can be likened to the immune
reconstitution inflammatory syndrome (IRIS) seen in patients with acquired immunodeficiency
syndrome or patients who have undergone organ transplantation.
Courtesy of Dima Hammoud, MD.

Continued on page 1666

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Fungal Infections

Continued from page 1665


mass 5 months after initial presentation, which was nondiagnostic for an additional pathogen or
disease. With a worsening cognitive status as marked by a Montreal Cognitive Assessment (MoCA)
score of less than 18, the patient was started on dexamethasone 4 mg IV every 6 hours after follow-up
CSF cultures were negative, resulting in marked improvement in her mental status (MoCA = 24).
Eventually, she was transitioned to voriconazole and tapered down on her corticosteroids to 1 mg
orally 2 times a day over the next 2 months, but her cognition promptly deteriorated again, coinciding
with increased inflammation around her brain lesions on imaging (Figure 6-1B). CSF cultures were again
negative. Immediate reinstitution of dexamethasone 4 mg orally every 12 hours resolved her altered
sensorium and resulted in reduction of the brain lesion enhancement best seen on fluid-attenuated
inversion recovery (FLAIR) and postcontrast T1-weighted images (Figure 6-1C). The patients plasma was
positive for blocking antiYgranulocyte-monocyte colony-stimulating factor (GM-CSF) autoantibodies
(ie, blocking of GM-CSFYinduced STAT-5 phosphorylation).23
Comment. While cryptococcal immune reconstitution inflammatory syndrome (IRIS) has been
described in patients who are human immunodeficiency virus (HIV)-positive receiving highly active
antiretroviral therapy (HAART)24 and solid organ transplant recipients following reduction in
immunosuppression,25 clinical deterioration after therapy initiation can also be due to exuberant
neuroinflammation in previously healthy hosts without known immunocompromising conditions,
following microbiological control (postinfectious immune response syndrome).26 In the latter group,
worsening CSF parameters, including a lymphocyte pleocytosis, low glucose, and high protein with
negative cultures, and stable to decreasing antigen titers are typical. Increases in enhancement of lesions
in postcontrast fluid-attenuated inversion recovery (FLAIR) MRI scans may be seen in such cases; it is
important to rule out microbiological failure or other infections, such as tuberculous meningitis, prior to
treating with corticosteroids.27

KEY POINTS obstructions is useful to preserve cor- while mucosal infections in HIV/acquired
h Central nervous system tical and visual function; cryptococcal immunodeficiency syndrome (AIDS) are
candidiasis may present infection alone should not be a con- extremely common, disseminated dis-
as embolic brain
traindication for surgery as this fungus ease in the absence of neutropenia is
microabscesses
does not typically form biofilms on uncommon. However, inherited dis-
following hematogenous
dissemination in
CNS catheters, although recurrent orders including autosomal recessive
neutropenic and other obstruction from infected debris may CARD9 immunodeficiency may lead to
susceptible hosts. require revision.31 spontaneous relapsing meningoence-
phalitis.34 Other risk factors include
h The possibility of Candida Candida
endophthalmitis should
extremes of age, indwelling catheters,
be evaluated in any Risk factors and clinical manifesta- injectable drug use, total parenteral nu-
patient with candidemia. tions. Despite candidemia being the trition, malignancy, immunosuppressive
fourth leading cause of positive blood drugs, broad-spectrum antibiotics, and
cultures, with a crude mortality of 40% mucosal disruption.32 Thus, the source
despite therapy,32 Candida CNS infec- of candidemia seeding the CNS may be
tion is uncommon. However, its impor- exogenous or endogenous. Impor-
tance is suggested by autopsy studies tantly, Candida endophthalmitis is
showing that patients dying of invasive a frequent and debilitating sequela
candidiasis have a high percentage of of bloodstream infections; all patients
CNS involvement, nearly 50%, with most with candidemia should have oph-
having antecedent cardiac involvement thalmologic examination as this entity
suggesting an embolic pathogenesis.33 A requires prolonged therapy and verifi-
primary risk factor for disseminated cation of cure.35 Other than neurosur-
candidiasis is neutropenia; interestingly, gical complications, such as infected

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Case 6-2
A 24-year-old southern California man developed worsening headache,
neck stiffness, night sweats, and weakness over 3 months, prompting
hospital admission. Contrast-enhanced brain MRI revealed a 1.1-cm
lesion in the left basal ganglia and T2/fluid-attenuated inversion
recovery (FLAIR) enhancement of the periventricular white matter and
leptomeninges diffusely. CSF sampling via lumbar puncture demonstrated
an elevated opening pressure of 55 cm water and grew Cryptococcus
gattii (genotype VGIII). C. gattii genotype III, distinct from the major
outbreak strain in the Pacific Northwest (VGIIa, as noted in Case 6-1),
appears to be more commonly found in southern California. A lumbar
drain with conversion to a ventriculostomy and then a ventriculoperitoneal
shunt were placed with subsequent replacement because of malfunction
over the next 2 months. He was treated intermittently with liposomal
amphotericin B and flucytosine over 6 weeks and then transitioned to
consolidation voriconazole. However, he then developed episodes of
urinary incontinence, fever, and lower extremity weakness over the
ensuing month. Neurologic examination showed intact upper extremity
and left lower extremity strength and sensation but diminished strength in
the right lower extremity (4/5); deep tendon reflexes were asymmetric
(biceps 2+ bilaterally, knees 3+ bilaterally, ankles: right 2+, left: clonus).
Postvoid residual bladder scan showed 258 mL urine. Spine MRI
with gadolinium corroborated the clinical findings, with clumping and FIGURE 6-2 Imaging of the
patient in Case 6-2.
thickening of the cauda equina but no epidural or paraspinal masses Sagittal postcontrast
T1-weighted MRI of the lumbar
(Figure 6-2), consistent with cryptococcal lumbar spinal arachnoiditis spine revealing abnormal spinal
leading to cauda equina and lower spinal cord dysfunction. nerve root enhancement (arrows).
Spinal nerve root clumping is
Comment. Spinal arachnoiditis is a likely underrecognized clinical consistent with the clinical
manifestation of cryptococcosis and can present with extradural or findings in the case description.
intradural (intramedullary and extramedullary) lesions. Intramedullary Courtesy of Dima Hammoud, MD.
pathology typically presents with a sensory level and weakness, whereas
extramedullary phenomena may or may not.28 Accessing the spinal
subarachnoid space safely may be another follow-up challenge in cases where this space becomes
obliterated due to adhesions. The management of these syndromes is under active investigation at
the National Institutes of Health (NIH).

ventriculostomy, hardware (Candida bosis or subarachnoid hemorrhage from KEY POINT


is a fungus that readily forms biofilms rupture of mycotic aneurysms or vascu- h Cryptococcal spinal
on prosthetic material), or wound, the lar invasion.38 arachnoiditis may be an
underrecognized entity
majority of CNS candidiasis cases are Diagnosis and management. Men-
that can present as
associated with disseminated candidia- ingeal infection produces changes similar
cauda equina or conus
sis. In adults, the disease is the second to those seen in other fungal meningit- medullaris syndromes.
most common cause of scattered brain ides with a CSF pleocytosis characterized
microabscesses after Staphylococcus by a neutrophilic or monocytic predom-
aureus36 with little involvement of the inance, reductions in glucose, and eleva-
meninges and is chronic, whereas, in tions in protein. However, few CSF
neonates, it presents as an acute men- parameter changes may be seen in more
ingitis.37 Rarely, CNS Candida can pres- immunosuppressed individuals. CSF
ent as a brain abscess with vascular Gram stain is positive in only a minority
involvement and basilar artery throm- of cases; negative cultures have been

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Fungal Infections

KEY POINTS
h Liposomal amphotericin reported frequently39 and may be op- MOLDS
B and fluconazole are timized by use of large-volume CSF Aspergillus
the treatments of choice culture (30 mL). A fungal cell wall com- Risk factors and clinical manifesta-
in susceptible central ponent in the CSF, 1,3-$-D-glucan, has tions. Aspergillus species are ubiqui-
nervous system been used in diagnosis, although its tous septated molds that have a
candidiasis cases. presence is not specific for Candida, higher propensity to invade the tissue
h Cerebral aspergillosis and it has been used in iatrogenic men- and vasculature with increasing immu-
may present as a focal ingitis outbreaks due to other fungi (see
nosuppression (Table 6-1), particularly
mass resulting in the section on diagnosis and manage-
from quantitative and qualitative neutro-
hemiparesis or seizures, ment of Aspergillus species).40,41 MRI
has been useful in visualizing micro- penia, hematologic malignancies, chronic
or invade blood vessels
to cause hemorrhage or abscesses that can identify biopsy tar- granulomatous disease, end-stage AIDS,
thrombosis as in the gets and help monitor therapy. Etiologies transplantation, and autoimmune dis-
cavernous sinus can be grouped as C. albicans versus eases requiring corticosteroids.46 In-
syndrome, which is a non-albicans species; the former cate- tracranial spread may occur in 10% to
neurosurgical emergency. gory usually responds to azoles, whereas 20% of cases, with focal masses being
the latter may not. Despite its apparent more common than meningoencephali-
poor CNS penetration, amphotericin B tis. The lungs and paranasal sinuses are
has a long history of clinical use and the primary routes of infection. Fever,
is the preferred agent.35 Fluconazole headache, changes in mental status,
achieves good CSF penetration42 but cranial nerve deficits due to cavernous
has generally been shown to have less venous thrombosis, and focal neuro-
efficacy than amphotericin B products logic signs including hemiparesis and
in CNS candidiasis, especially liposomal
seizures may occur. Nasal stuffiness, ear
compounds; liposomal amphotericin B
discharge, and periorbital pain may
shows the best CNS delivery com-
pared with the other formulations,35,43,44 occur in the trans-sinus route with sub-
while flucytosine may show synergy.44 sequent proptosis, ophthalmoplegia,
Cross-azole resistance may occur in chemosis, and visual loss. Skull base
some cases.45 Although echinocandins involvement may lead to multiple cranial
(such as caspofungin, micafungin, and nerve palsies and other syndromes that
anidulafungin) have excellent activity present indolently over months. The
against Candida species, their levels anterior and middle cerebral arteries are
are undetectable in the CSF and only most usually involved, resulting in stroke
10% to 20% in the brain parenchyma, syndromes that present acutely. Rela-
making them substandard choices in tively immunocompetent hosts dem-
CNS candidiasis.44 This is an important onstrate a contained fibrous capsule. In
point, as echinocandins have become such patients, immune workup should
the standard initial therapy in dissemi- include assays for neutrophil function-
nated Candida infections, highlighting
ality such as the dihydrorhodamine flow
the need to diagnose CNS and optic
cytometryYbased assay.47 Spinal syn-
involvement during fungemia. A related
point is that echinocandins are inactive dromes such as epidural abscess are rare.
against other neurologic fungal infec- The case fatality proportion was 50% to
tions, such as cryptococcosis, empha- 100% in some series but less in others.48,49
sizing the need for definitive fungal Another important syndrome is cav-
identification. In situations of neurosur- ernous sinus thrombosis, characterized
gical device infection, hardware must be by orbital pain, ophthalmoplegia, ptosis,
removed as Candida biofilms are diffi- and proptosis. This is a neurosurgical
cult to eradicate. emergency, requiring astute assessment

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KEY POINT

TABLE 6-1 Susceptible Populations for Central Nervous System h The signs of cavernous
Fungal Infections and Predominant Clinical Presentations venous sinus thrombosis
include orbital pain,
Predominant Clinical ophthalmoplegia, ptosis
Underlying Condition Fungus Presentation and proptosis, and
HIV/AIDS, tumor necrosis Cryptococcus Meningoencephalitis may be preceded by
factor inhibitors nasal stuffiness
Histoplasma Meningitis
depending on
Neutropenia Candida Meningitis, abscess pathogenesis.
Aspergillus Abscess, infarction Consideration of host
Solid organ transplants Candida Meningitis, abscess immune status is key
Aspergillus Abscess, infarction to understanding
Cryptococcus Meningoencephalitis central nervous
system aspergillosis.
Hematopoietic stem cell Aspergillus Abscess, infarction
transplant/steroids Mucorales Sinopulmonary, abscess, infarction
Scedosporium Abscess
Neurosurgery Candida Abscess
Iatrogenic Exserohilum Meningitis, infarction, cauda
equina signs
Previously healthy Blastomyces Meningitis, abscess
Histoplasma Meningitis, abscess
Coccidioides Meningitis, meningoencephalitis
AIDS = acquired immunodeficiency syndrome; HIV = human immunodeficiency virus.

and early intervention to improve out- ophthalmoplegia, hypoesthesia, and the


comes (Figure 6-350). Although stroke cavernous sinus syndrome.1
syndromes from fungal infectionYrelated Diagnosis and management. The
vasculitis and thrombosis are rare, these differential diagnosis includes gliomas
can occur as a consequence of angio- and other brain tumors, metastasis,
invasive molds, including Aspergil- lymphoma, dural-based meningiomas,
lus and Mucor, more commonly than tuberculomas, toxoplasmosis, pyogenic
yeasts like Candida and Cryptococcus. abscess, and other mycoses. Diagnosis
Brain parenchymal aspergillosis may is made via tissue biopsy culture and
histopathology, but biomarkers such
cause strokelike syndromes via cerebral
as serum galactomannan and 1,3-$-D-
infarction, mycotic aneurysms, or hem-
glucan or polymerase chain reaction
orrhage; ring lesions with abscess forma-
(PCR) are becoming increasingly used
tion via hematogenous dissemination; with high negative predictive values.
and direct tissue plane invasion from the These biomarkers have not yet been
paranasal sinuses. The latter is the pre- sufficiently validated for the CSF, although
dominant pathogenesis in rhinocerebral reports supporting their successful use
Mucorales infections (discussed later in exist.51 Nonetheless, CSF sampling may
this article). Sinocranial aspergillosis may be difficult when a mass effect is present.
result in focal intracranial granulomas The main brain MRI findings include in-
with consequent skull-base syndromes, farction, abscesslike ring-enhancing
such as orbital apex, that affect cranial lesions following infarction, dural or
nerves II to V and lead to blindness, vascular infiltration from paranasal sinus

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Fungal Infections

KEY POINT
h Voriconazole with or
without surgery is the
treatment of choice for
cerebral aspergillosis.

FIGURE 6-3 Imaging of a 60-year-old woman who had been receiving corticosteroids for 1 year
for pancytopenia of unclear etiology. She developed a left-sided headache and
diplopia, and initial imaging was unrevealing; however, her symptoms worsened,
and she developed left-sided ophthalmoplegia, proptosis, chemosis, fever, and right-sided
weakness. Brain MRI and magnetic resonance angiogram (MRA) revealed a left cavernous
sinus mass enveloping the internal carotid artery to a point of partial stenosis. A, Axial
T1-weighted postcontrast MRI revealing left cavernous sinus enlargement by an isointense
lesion with ring enhancement (black arrow). B, 3D time of flight (3D-TOF) magnetic resonance
angiography showing a cavernous sinus mass and occlusion of the intracavernous carotid artery
(black arrow mark).
Reprinted with permission from Urculo E, et al, Acta Neurochir (Wien).50 link.springer.com/article/10.1007%2Fs00701-
004-0449-3?LI=true. B 2005 Springer-Verlag.

or orbit, and extradural occupying in- group of clinically aggressive aseptate


filtrates. Ischemic lesions may be visu- molds that infect the same patient pop-
alized using MRI diffusion-weighted ulations as Aspergillus. Mucormycosis
imaging. Irregular space-occupying le- must be distinguished from aspergil-
sions that are hypointense or isointense losis because of its aggressive course,
on T1 but bright on postgadolinium T1 requirement for surgical debridement,
and dim on T2 correlate with brain tis- and poor response to voriconazole ther-
sue coagulative necrosis.49,52 Voricona- apy often used against Aspergillus. An
zole has good CNS penetration and is older term for mucormycosis was zygo-
the treatment of choice in the majority mycosis, but this has recently been dis-
of cases that are due to Aspergillus fumi- carded because of reclassification using
gatus, with 35% to 47% response and sequence-based DNA phylogeny.56 De-
31% to 43% overall 1-year survival that layed diagnosis results in significantly
were differential by host type.53,54 higher mortality,57 emphasizing the need
Higher-dose liposomal amphotericin B, for all consulting physicians to be aware
posaconazole, and itraconazole may be
of this important differential. Indeed,
alternatives, although the latter two have
84% of patients who had leukemia or
poor CNS penetration but should be
received stem cell transplantation were
taken with fatty meals to increase ab-
receiving ineffective therapy for mucor-
sorption with a target trough between
mycosis at the time of diagnosis.58 Mu-
0.5 to 1.5 mcg/mL.55 Adjunctive surgery
cormycosis should rise in the differential
may decrease mortality from approxi-
mately 50% to 25%.48,53 in patients with prolonged neutropenia,
especially in the setting of leukemia,
Mucorales high-risk hematopoietic stem cell trans-
Risk factors and clinical manifestations. plantation (eg, recipients of matched
Mucormycosis is a disease caused by a unrelated and haploidentical donors or

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KEY POINTS
cord blood, or who are T-cell depleted), as well as by Calcofluor white fluores- h Rhinocerebral disease is
or exposure to voriconazole. Diabetic cent stain. However, lack of septae (that the major manifestation
ketoacidosis and corticosteroid-associated protect other hyphal molds such as of central nervous system
hyperglycemia, IV drug use, and iron Aspergillus from injury during biopsy) mucormycosis that must
overload states (eg, massive transfusions results in leakage of cellular material and be diagnosed early in
following major trauma) as well as de- rapid death after hyphae breakage, re- at-risk hosts, such as those
feroxamine chelation are also unique risk sulting in poor microbiological recovery with poorly controlled
diabetes mellitus with
factors for mucormycosis.59,60 Rhino- of Mucorales after biopsy (40% to 50%).
sinus pain, to
cerebral disease is the major CNS mani- CSF offers poorer yield. Therapy nor-
improve outcomes.
festation, especially in uncontrolled mally includes aggressive debridement
diabetes mellitus or stem cell transplant with clean surgical edges and high-dose h High-dose liposomal
amphotericin B and
recipients. The mold traverses tissue liposomal amphotericin BYbased regi-
aggressive surgical
planes inferiorly to the palate and sphe- mens accompanied by reductions in
debridement, with or
noid sinus, laterally to the cavernous immunosuppression with or without without adjunctive
sinus and orbits, and cranially via the adjunctive therapy such as cytokine granulocyte infusions or
orbital apex or cribriform plate to the support, granulocyte transfusions, or cytokine therapy, is the
brain. Sinusitis, periorbital cellulitis, and hyperbaric oxygen.63 Posaconazole has major management
facial numbness or pain with or without activity against certain species and strategy for central
associated ocular cranial neuropathies may be used effectively as salvage or nervous system
in combination with liposomal ampho- mucormycosis.
in a susceptible host should trigger a
high index of suspicion and early inter- tericin B but has poor CNS penetration; h Central nervous system
vention.60 Several anatomic findings on serum levels must be monitored. Mor- disease caused by
imaging include rhinoorbital disease, tality remains high at 25% to 40%.61 dark-pigmented molds
(eg, Cladophialophora
with or without cerebral invasion, bantiana and
accompanied by bony destruction.61 Dematiaceous Fungi (Focus on Exserohilum rostratum)
A strong tropism for invasion of blood Exserohilum rostratum) carries high mortality
vessels also results in a propensity for Risk factors and clinical manifestations. regardless of host
infarction and necrosis in both neuro- Dematiaceous fungi are soil-based and immune status.
logic and pulmonary lesions.62 All such darkly pigmented, being melanized,
immunosuppressed patients should and classified as phaeohyphomycosis.
have rapid evaluation by otolaryngolo- Cladophialophora bantiana has his-
gy and biopsy of suspicious lesions. torically caused CNS disease in half
Typically, sinus lesions are necrotic, but of the cases; in three-quarters of these,
this sign is unreliable, especially early in patients had no known immunodefi-
the disease; thus, absence of tissue ne- ciency, but mortality was nondifferential
crosis in the appropriate host should by immune status (71% to 74%). This
not preclude tissue biopsy. was followed by Rhinocladiella
Diagnosis and management. Sinus mackenziei in the Middle East, but
CT may show fluid-filled sinuses; bony Ochroconis, Wangiella, and Bipolaris
destruction is a late finding. MRI is have also been reported pathogens.
more sensitive and can identify cavern- Single-lesion brain abscess via hema-
ous sinus thrombosis and perineural togenous dissemination after inhala-
intradural spread.60 On biopsy, lack of tion was the primary manifestation.64
septa in the hyphae, with irregular However, more recently, Exserohilum
diameters, is an important histologic rostratum was identified as the major
feature that distinguishes Mucorales pathogen (20% or more) in the largest
from Aspergillus, evident on Grocott- recorded fungal outbreak to date. This
Gomori methenamine-silver stain (GMS) was the consequence of contamination

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Fungal Infections

KEY POINTS
h An iatrogenic outbreak of compounding pharmacy lots of plete surgical resection of mass lesions
in 2013 of Exserohilum preservative-free methylprednisolone may lead to better outcomes than
rostratumYcontaminated acetate for epidural, spinal, or para- partial resection.64
methylprednisolone spinal injections to treat chronic mus-
lots for musculoskeletal culoskeletal pain.3 As of October 23, Other Molds
injection resulted in 2013, 751 iatrogenic cases were iden- Scedosporium apiospermum (sexual
meningitis, vertebrobasilar tified by the Centers for Disease Control or perfect stage: Pseudallescheria
stroke, and and Prevention (CDC) with 64 deaths boydii) can form brain abscesses
spinal syndromes. (case fatality ratio = 8.5%).65 Symptoms (mostly in the frontal lobe followed
h Central nervous system began approximately 40 days follow- by the parietal area) in immunocom-
scedosporiosis may ing exposure. One-third of those af-
present shortly after
promised hosts and after near drown-
fected developed meningitis, while 5%
near drowning or ing (with aspiration of polluted water)
had posterior circulation strokes (ische-
aspiration of or trauma. Meningitis and spinal cord
mic more often than hemorrhagic). Al-
polluted water. involvement are less common. The
though the majority of cerebrovascular
events affected the vertebrobasilar sys- incubation period may be 1 to 3 weeks
tem, many affected the basal ganglia, in near-drowning victims and more var-
and 85% of deaths were associated with iable in the transplant host, up to 1 year.
stroke. Forty-three percent had spinal The clinical presentation can vary and
or paraspinal infections presenting as may include headache, altered mental
epidural abscess, vertebral osteomyelitis/ status, and focal neurologic signs. As
diskitis, arachnoiditis, and cauda equina with Aspergillus and Mucorales, angio-
syndrome. Accordingly, fever, head- invasive sequelae may occur. Diagnosis
ache, and back pain were the most com- can be made antemortem in up to two-
mon symptoms.66,67 thirds of cases via histopathology or
Diagnosis and management. culture of tissue or occasionally CSF
Melanin-binding Masson-Fontana stain (especially with the presence of heavy
can be used to identify these molds in neutrophilic pleocytosis), and their
tissue. In the iatrogenic fungal menin- hyphal appearance resembles acute-
gitis outbreak, although most had pleo- angle septated Aspergillus. Mortality
cytosis, glucose was lower and protein may exceed 70% regardless of immune
was slightly high in the CSF in stroke status.69 Despite the often histologic
compared to nonstroke CNS cases, al- diagnostic confusion with Aspergillus,
though hypoglycorrhachia was uncom- voriconazole with or without adjunc-
mon overall. Higher CSF white blood
tive surgery is also the treatment of
count was an independent risk factor
choice, with 56% clinical response.54
for mortality. Most diagnoses were con-
In general, combining antifungals with
firmed by PCR using internal transcribed
surgery may improve survival.54,69 Ocu-
spacer (ITS) sequence comparison and
culture of CSF or tissue.68 MRI identi- lar infections including keratitis and end-
fied several asymptomatic cases. High- ophthalmitis may occur after trauma
dose voriconazole 6 mg/kg 2 times a day and less commonly endogenously. Sce-
and liposomal amphotericin B 5 mg/kg/d dosporium prolificans is an even more
to 6 mg/kg/d for at least 6 months virulent species that is a rare cause of
has been advocated in complicated CNS disease via hematogenous dis-
E. rostratum disease. Nonetheless, flu- semination in immunocompromised
cytosine, posaconazole, itraconazole, hosts (including hematopoietic stem
and isavuconazole have activity against cell transplant recipients or those with
this and many other etiologies. Com- chronic granulomatous disease). The

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KEY POINTS
prognosis is dismal and may require atic occurs in one-third of cases.73 CSF h A careful travel and
voriconazole and surgery in combina- may occasionally reveal an eosinophilic exposure history is
tion with terbinafine.70 pleocytosis with elevated protein and necessary when a
low glucose, but culture is positive in clinical suspicion for
DIMORPHIC ENDEMIC FUNGI only about 15%, requiring complement central nervous system
(FOCUS ON NORTH AMERICA) fixation titers that may have a diagnostic disease due to the
These fungi are geographically restricted yield of greater than 70%.72 The clinical endemic mycoses
and exist as tissue-invasive yeast forms microbiology laboratory should be no- coccidioidomycosis,
tified if this diagnosis is suspected so histoplasmosis, and
at human body temperature but as
that appropriate specimen handling blastomycosis exists.
molds in the environment. Therefore,
a careful travel and exposure history may be performed. Fluconazole is the h While Coccidioides may
must be taken to anticipate diagnosis. drug of choice, affording nearly 80% cause an eosinophilic
The main etiologies in North America clinical response,74 but intrathecal am- meningitis, both
photericin B has also been advocated.75 Coccidioides and
include Blastomyces dermatitidis in
Histoplasma can also
the US midwestern states and Canadian Lifelong suppressive therapy may be
cause a chronic basilar
provinces that border the Great Lakes needed, as relapse can occur.76 None-
meningitis with clinical
and St. Lawrence River, as well as theless, 40% mortality has remained in features that resemble
southeastern and south central states; the postazole era.72 cryptococcosis.
Histoplasma capsulatum around the Progressive disseminated histoplas-
Ohio and Mississippi River basins; and mosis may occur after exposure to soil
Coccidioides immitis and Coccidioides contaminated by avian droppings or
posadasii in the arid southwestern bat guano from endemic areas, or
United States. The use of tumor necro- among patients with AIDS or other
sis factor (TNF)-" antagonists in- cellular immune deficits, the latter of
creases the risk for disseminated disease which may be subclinical. Among those
in all three following inhalation of with disseminated histoplasmosis, CNS
the fungus. 71 disease may occur in 5% to 10% as
Disseminated coccidioidomycosis manifested by focal parenchymal le-
occurs after exposure to dust from sions of the brain or spinal cord and
endemic areas, especially among high- chronic meningoencephalitis with or
risk groups such as African Americans, without ischemic strokes due to em-
Filipinos, Hispanics, those in late preg- boli or small vessel vasculitis, as can be
nancy, and those who are immunocom- seen in cryptococcosis and the other
promised because of AIDS or transplant endemic mycoses. CSF reveals high
conditioning or genetic mutations. CNS protein and hypoglycorrhachia with
involvement may occur in up to half, a myeloid pleocytosis. Urine, serum,
presenting as a chronic basilar meningitis and CSF Histoplasma galactomannan
with headache, low-grade fever, weight antigen (quantitative enzyme immu-
loss, and mental status changes, but one- noassay) may be positive, but cross-
third of patients may lack meningismus. reaction with Blastomyces is frequent.
Hydrocephalus and ischemic vasculitis CSF culture requires multiple high-
may complicate up to 40% of cases volume sampling to increase yield.77
months later.72 MRI may reveal pre- Biopsy of mass lesions may be positive
dominantly leptomeningeal enhance- by culture and histopathology.78 Cor-
ment of the basilar cisterns and middle ticosteroids may be inadvertently
cerebral artery cisterns. Hydrocephalus given rather than antifungal therapy
with transependymal flow may require for presumed noninfectious vasculitis,
shunting. Spinal nerve root enhancement which can lead to clinical deteriora-
and clumping that may be asymptom- tion. 79 Liposomal amphotericin B
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Fungal Infections

KEY POINTS
h Lifelong suppressive (5.0 mg/kg/d for a total of 175 mg/kg in appearance from tissue biopsies using
azole therapy following given over 4 to 6 weeks) followed by GMS, hematoxylin and eosin (H&E), or
initial treatment may be itraconazole (200 mg 2 or 3 times a day) periodic acidYSchiff (PAS) staining, in
necessary to avoid for at least 1 year is the suggested which Blastomyces appears larger with
relapses due to central treatment for CNS histoplasmosis, a double refractile wall and broad-based
nervous system infection with monitoring of itraconazole trough bud compared to Histoplasma, can be
from endemic fungi, serum levels and CSF Histoplasma made, even from concomitant alterna-
particularly among antigen. Voriconazole or posaconazole tively infected sites.84 Fortunately, the
immunocompromised may be effective step-down alterna- recommended treatment regimen is the
hosts. tives.80 Lifelong suppressive therapy same as for CNS histoplasmosis except
h Syndromic diagnosis of with such triazoles may be necessary that step-down therapy may also include
central nervous system in those for whom effective immune re- fluconazole 800 mg/d or voriconazole
fungal infections may constitution is not possible, as relapse 200 mg to 400 mg 2 times a day to com-
permit earlier may occur.81 plete at least 12 months of therapy, deter-
implementation of
Of extrapulmonary blastomycosis mined by CSF abnormality resolution
effective therapy
cases, 5% to 10% involve the CNS. and being off immunosuppression.82,83
pending confirmatory
diagnosis, with broad
Risk factors include diabetes mellitus
and cellular immune deficits conferred CONCLUSION
initial antifungal
coverage for a spectrum by corticosteroids, AIDS, or transplan- CNS mycoses carry a tremendous mor-
of potential etiologies tation. In the pre-HAART era, as many bidity and mortality such that early
followed by narrowing as 40% of patients with AIDS who had recognition of neurologic syndromes
the spectrum once blastomycosis had CNS disease.82 As with implementation of efficacious
definitive diagnosis is with the other mycoses, nonspecific management is paramount. Cryptococ-
established. Such an headache, focal neurologic deficits, al- cus may cause focal masses in the basal
approach may tered mental status, vision changes, ganglia, meningitis, vasculitis, and spi-
improve outcomes. and seizures predominate. However, nal arachnoiditis. Even with therapy,
dissemination to the CNS from the IRIS-like syndromes with consequent
lung is accompanied by spread to neurologic sequelae may occur in the
more common sites, such as the skin, setting of microbiological control of
bone, and genitourinary tract, in ap- this neurotrophic fungus. Candida
proximately 75%; concomitant puru- may cause multiple microabscesses in
lent vertebral osteomyelitis may occur. the brain via hematogenous spread
MRI may reveal diffuse meningeal en- in a susceptible, usually neutropenic,
hancement or mass lesions in the basal host; endophthalmitis; or neurosurgi-
ganglia or cerebellum more commonly cal hardware-associated disease with
than other areas.83 While serum immu- meningitis. Angioinvasive molds such
nodiffusion tests are highly specific, as Aspergillus, Scedosporium, and Mu-
false negatives may occur in 20% to corales may cause mass lesions that
35%. Unfortunately, CSF findings may erode into blood vessels to cause
be variable, and high cross-reactivity ischemic or hemorrhagic stroke syn-
with the Histoplasma antigen enzyme dromes and cavernous sinus thrombo-
immunoassay may make the Blastomyces sis syndrome, which is a neurosurgical
antigen test result not definitive, given emergency. The iatrogenic fungal men-
the overlapping areas of endemicity. ingitis and spinal syndrome outbreak
Thus, culture of serial high-volume CSF primarily caused by E. rostratum
sampling is the gold standard, and ven- heightened clinician awareness to con-
tricular fluid sampling may be more sider medical vehicles for CNS fungal
sensitive than lumbar fluid sampling. infections. Finally, a careful travel and
Nonetheless, histopathologic differences exposure history is particularly critical
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when considering the US endemic my- transplant recipients: results of the
Transplant-Associated Infection Surveillance
coses (coccidioidomycosis, histoplasmo- Network (TRANSNET). Clin Infect Dis
sis, and blastomycosis) as a cause of 2010;50(8):1101Y1111. doi:10.1086/651262.
CNS disease. 7. Neofytos D, Fishman JA, Horn D, et al.
Epidemiology and outcome of invasive
fungal infections in solid organ transplant
ACKNOWLEDGMENTS
recipients. Transpl Infect Dis 2010;12(3):
The authors would like to thank Sarah 220Y229. doi:10.1111/j.1399-3062.2010.00492.x.
Kranick, MD, formerly from the Na- 8. Bratton EW, El Husseini N, Chastain CA,
tional Institute of Neurological Disor- et al. Comparison and temporal trends of
ders and Stroke (NINDS) at the NIH, three groups with cryptococcosis:
HIV-infected, solid organ transplant, and
for her contribution to the case findings HIV-negative/non-transplant. PLoS One
for Case 6-2 and Dima Hammoud, MD, 2012;7(8):e43582. doi:10.1371/
of Radiology and Imaging Sciences at journal.pone.0043582.
NIH Clinical Center, for supplying the 9. Brizendine KD, Baddley JW, Pappas PG.
images for Figure 6-1 and Figure 6-2. Predictors of mortality and differences in
clinical features among patients with
This research was supported in part by Cryptococcosis according to immune status.
the Intramural Research Program of the PLoS One 2013;8(3):e60431. doi:10.1371/
NIH/National Institute of Allergy and journal.pone.0060431.
Infectious Diseases/Division of Intramu- 10. Harris JR, Lockhart SR, Debess E, et al.
ral Research/Laboratory of Clinical Infec- Cryptococcus gattii in the United States:
clinical aspects of infection with an
tious Diseases. The views herein do not
emerging pathogen. Clin Infect Dis
reflect the official opinions of the 2011;53(12):1188Y1195. doi:10.1093/
Uniformed Services University of Health cid/cir723.
Sciences or the Department of Defense. 11. Chen SCA, Slavin MA, Heath CH, et al.
Clinical manifestations of Cryptococcus
gattii infection: determinants of neurological
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