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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YEASTS
Cryptococcus
Infections by CryptococcusVmostly
neoformansVcause an estimated
650,000 human immunodeficiency vi-
rus (HIV)Yrelated deaths among
1,000,000 HIV-associated cryptococcal
cases globally on an annual basis, with
a lower 3-month mortality rate in de-
veloped nations.4
Risk factors and clinical manifesta-
tions. In the developed world, one-half
of cases are HIV-associated. It continues
to also be a significant problem in in-
dividuals who are not infected with HIV
in the developed world,5 infecting those
immunosuppressed from solid organ
transplant conditioning, primarily renal
transplant recipients late after trans-
plantation (median = 20 months) in up
to one-third of cases.6,7 The remaining
one-third of cases fall outside the HIV-
positive and transplant population, with
other readily identifiable risk factors, in-
cluding sarcoid, corticosteroid use, and
hepatorenal failure. However, overall, ap-
proximately 13% to 18% of patients with
cryptococcal disease may have no known
underlying immunocompromising con-
ditions but contribute up to 35% to
50% of the attributable mortality owing
to delays in diagnosis from slow presen-
tations in an unsuspected host.8,9 Cryp-
tococcosis may present indolently in the
immunocompetent host, leading to
delays in diagnosis and consequent neu-
rologic sequelae such as cranial neurop-
athies and cognitive impairment.
A particularly challenging aspect of
cryptococcal infections in patients
without HIV is the lack of fever and
meningeal signs in a large fraction of
patients. In one exemplary case re-
ferred to the National Institutes of
Health (NIH), a previously healthy
patient was diagnosed with depres-
sion, and only after many months in a
psychiatric facility underwent a lumbar
Continuum (Minneap Minn) 2015;21(6):16621678
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KEY POINTS
puncture by an astute neurologist, h Cryptococcosis may
resulting in successful treatment with present indolently in the
complete recovery of cognitive and immunocompetent
psychiatric functioning. host, leading to delays
C. gattii is a related yeast recently in diagnosis and
designated as a separate species that, consequent neurologic
importantly, has caused an outbreak sequelae such as cranial
of cases in previously healthy individ- neuropathies and
uals in the US Pacific Northwest.2 cognitive impairment.
C. gattii cases in the Pacific North- h Cryptococcus neoformans
west outbreak have been associated and Cryptococcus gattii
more with pulmonary disease, while are leading causes of
meningitis among hosts
nonoutbreak strains have been associ-
both with and without
ated more with severe neurologic
human immunodeficiency
sequelae.10Y12 Both have been associ-
virus (HIV) infection and
ated with antiYgranulocyte-monocyte
have a tropism for
colony-stimulating factor (GM-CSF) auto- dopaminergic tracts.
antibodies.13 The fungus inhabits the
soil and uses the virulence factor laccase
to protect itself from phytotoxins in its
role as a plant pathogen of seedlings.
During human infections, it uses this
same laccase as a neurotropic virulence
factor, oxidizing neurocatecholamines
within dopaminergic tracts, particularly
the basal ganglia, to produce immuno-
suppressive compounds such as mela-
nin.14 C. neoformans and C. gattii are
leading causes of meningitis among
hosts both with and without HIV
infection and have a tropism for dopa-
minergic tracts. This peculiar anatomic
localization may explain a propensity
toward subcortical rather than frontal
pathologies, including gait distur-
bances and dementias during chronic
infections. Presentations with mental
status changes (often confused with
dementia), seizures, or basilar menin-
geal signs, including pseudoYMeniere
disease, may occur; in the absence of
fever, these presentations make the
diagnosis of cryptococcal disease diffi-
cult. Cranial neuropathies that affect
cranial nerves II through VIII are not
uncommon and may be related to ele-
vated intracranial pressure manifested
by papilledema, direct fungal invasion,
or inflammation. Visual and hearing
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 Fungal Infections
KEY POINTS
h Controlling both
microbiological and
immunologic aspects of
infection is key to
successful management
of cryptococcosis.
h An exuberant
inflammatory response
to cryptococcal antigen
in the setting of
microbiological control
may occur in non-HIV
nontransplant hosts,
reminiscent of the
immune reconstitution
inflammatory syndrome
seen in HIV and solid
organ transplant
patients; it may be
managed successfully
with judicious
corticosteroid use.
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loss as well as cognitive impairment
and gait ataxia with or without urinary
incontinence may accompany obstruc-
tive or nonobstructive hydrocephalus
and may be long- lasting, especially after
delays in diagnosis.15
Diagnosis and management. CSF
examination is essential, both for pri-
mary diagnosis and for staging in the
case of apparently localized skin or lung
disease; it typically demonstrates low
glucose, elevated protein, and high IgG
indices, although cell counts can be quite
low, especially in HIV-related cases. Low
cell count is a poor prognostic sign, as
are persistent fungal growth and ele-
vated intracranial pressure.16 Crypto-
coccal antigen titers from the serum
and CSF via enzyme immunoassay, latex
agglutination, or the novel sensitive and
less expensive lateral flow assay (LFA)
are important in the diagnosis of cryp-
tococcal disease, including culture-
negative cases.17 These simple tests
are highly sensitive and specific, can
be performed on either blood or CSF,
and should be strongly considered as
a screening test in patients with subcor-
tical dementias. In addition, MRI may
reveal focal masslike cryptococcomas
or granulomas, leptomeningeal
enhancement, hydrocephalus with or
without transependymal flow, and di-
lated Virchow-Robin perivascular spaces
with gelatinous pseudocysts.18,19
Successful management can be
tricky and requires a consideration of
both microbiological and immunologic
aspects of the infection. Microbiolog-
ical control is facilitated by the use of
fungicidal drugs such as amphotericin
B for initial therapy with or without
flucytosine, whereas fungistatic drugs
such as fluconazole result in poor initial
outcome and are reserved for subse-
quent therapy to complete a 12- to
18-month course.20 Newer azoles such
as voriconazole (trough level 1 mg/L to
5.5 mg/L) and posaconazole may have a
role in salvage therapy but require level
monitoring, and the latter may have
poor CNS penetration.21,22 A second
important consideration is an apparent
paradoxical immune response (immune
reconstitution inflammatory syndrome
[IRIS] in individuals infected with HIV,
and a postinfectious immune response
syndrome in previously healthy individ-
uals without HIV infection), accompanied
by cerebral edema, resulting in neuro-
logic worsening evident during initial
therapy (Case 6-1) as well as after ini-
tiation of antiretroviral therapy in pa-
tients who are infected with HIV, have
had a reduction in immunosuppression
following solid organ transplantation, or
are postpartum. During initial therapy,
increased intracranial pressures are com-
mon and can be controlled by daily high-
volume lumbar punctures both for
mental status and preservation of vi-
sion.21 These elevations are caused by
a combination of increased cerebral
edema and outflow obstructions due to
arachnoiditis, as illustrated in Case 6-2,
as well as obstructions within the
foramen of Monro or Luschka/
Magendie. Mannitol and acetazolamide
should be avoided because they may
be ineffective or cause worse out-
comes.29,30 Corticosteroids can provide
ancillary improvement in cerebral
edema and other neuroinflammation,
but their use needs to be balanced with
effective microbiological control since
steroids exacerbate cryptococcal infec-
tions. In addition, once inflammation is
controlled with steroids, tapering of the
steroids must be individualized based
on clinical presentation, MRI, and CSF
parameters (eg, glucose, protein, and
cell count), as the process appears to
be driven by fungal antigen load and
individual host responses. Careful atten-
tion must be paid to microbiological
control and secondary infections while
on immunosuppressants such as ste-
roids, and frequent CSF monitoring is
required. Surgical shunting of refractory
December 2015
 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
h Central nervous system
candidiasis may present
as embolic brain
microabscesses
following hematogenous
dissemination in
neutropenic and other
susceptible hosts.
h The possibility of Candida
endophthalmitis should
be evaluated in any
patient with candidemia.
obstructions is useful to preserve cor-
tical and visual function; cryptococcal
infection alone should not be a con-
traindication for surgery as this fungus
does not typically form biofilms on
CNS catheters, although recurrent
obstruction from infected debris may
require revision.31
Candida
Risk factors and clinical manifesta-
tions. Despite candidemia being the
fourth leading cause of positive blood
cultures, with a crude mortality of 40%
despite therapy,32 Candida CNS infec-
tion is uncommon. However, its impor-
tance is suggested by autopsy studies
showing that patients dying of invasive
candidiasis have a high percentage of
CNS involvement, nearly 50%, with most
having antecedent cardiac involvement
suggesting an embolic pathogenesis.33 A
primary risk factor for disseminated
candidiasis is neutropenia; interestingly,
while mucosal infections in HIV/acquired
immunodeficiency syndrome (AIDS) are
extremely common, disseminated dis-
ease in the absence of neutropenia is
uncommon. However, inherited dis-
orders including autosomal recessive
CARD9 immunodeficiency may lead to
spontaneous relapsing meningoence-
phalitis.34 Other risk factors include
extremes of age, indwelling catheters,
injectable drug use, total parenteral nu-
trition, malignancy, immunosuppressive
drugs, broad-spectrum antibiotics, and
mucosal disruption.32 Thus, the source
of candidemia seeding the CNS may be
exogenous or endogenous. Impor-
tantly, Candida endophthalmitis is
a frequent and debilitating sequela
of bloodstream infections; all patients
with candidemia should have oph-
thalmologic examination as this entity
requires prolonged therapy and verifi-
cation of cure.35 Other than neurosur-
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
on prosthetic material), or wound, the
majority of CNS candidiasis cases are
associated with disseminated candidia-
sis. In adults, the disease is the second
most common cause of scattered brain
microabscesses after Staphylococcus
aureus36 with little involvement of the
meninges and is chronic, whereas, in
neonates, it presents as an acute men-
ingitis.37 Rarely, CNS Candida can pres-
ent as a brain abscess with vascular
involvement and basilar artery throm-
rupture of mycotic aneurysms or vascu- h Cryptococcal spinal
lar invasion.38 arachnoiditis may be an
underrecognized entity
Diagnosis and management. Men-
that can present as
ingeal infection produces changes similar
cauda equina or conus
to those seen in other fungal meningit- medullaris syndromes.
ides with a CSF pleocytosis characterized
by a neutrophilic or monocytic predom-
inance, reductions in glucose, and eleva-
tions in protein. However, few CSF
parameter changes may be seen in more
immunosuppressed individuals. CSF
Gram stain is positive in only a minority
of cases; negative cultures have been

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 Fungal Infections
KEY POINTS
h Liposomal amphotericin
B and fluconazole are
the treatments of choice
in susceptible central
nervous system
candidiasis cases.
h Cerebral aspergillosis
may present as a focal
mass resulting in
hemiparesis or seizures,
or invade blood vessels
to cause hemorrhage or
thrombosis as in the
cavernous sinus
syndrome, which is a
neurosurgical emergency.
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reported frequently39 and may be op-
timized by use of large-volume CSF
culture (30 mL). A fungal cell wall com-
ponent in the CSF, 1,3-$-D-glucan, has
been used in diagnosis, although its
presence is not specific for Candida,
and it has been used in iatrogenic men-
ingitis outbreaks due to other fungi (see
the section on diagnosis and manage-
ment of Aspergillus species).40,41 MRI
has been useful in visualizing micro-
abscesses that can identify biopsy tar-
gets and help monitor therapy. Etiologies
can be grouped as C. albicans versus
non-albicans species; the former cate-
gory usually responds to azoles, whereas
the latter may not. Despite its apparent
poor CNS penetration, amphotericin B
has a long history of clinical use and
is the preferred agent.35 Fluconazole
achieves good CSF penetration42 but
has generally been shown to have less
efficacy than amphotericin B products
in CNS candidiasis, especially liposomal
compounds; liposomal amphotericin B
shows the best CNS delivery com-
pared with the other formulations,35,43,44
while flucytosine may show synergy.44
Cross-azole resistance may occur in
some cases.45 Although echinocandins
(such as caspofungin, micafungin, and
anidulafungin) have excellent activity
against Candida species, their levels
are undetectable in the CSF and only
10% to 20% in the brain parenchyma,
making them substandard choices in
CNS candidiasis.44 This is an important
point, as echinocandins have become
the standard initial therapy in dissemi-
nated Candida infections, highlighting
the need to diagnose CNS and optic
involvement during fungemia. A related
point is that echinocandins are inactive
against other neurologic fungal infec-
tions, such as cryptococcosis, empha-
sizing the need for definitive fungal
identification. In situations of neurosur-
gical device infection, hardware must be
removed as Candida biofilms are diffi-
cult to eradicate.
MOLDS
Aspergillus
Risk factors and clinical manifesta-
tions. Aspergillus species are ubiqui-
tous septated molds that have a
higher propensity to invade the tissue
and vasculature with increasing immu-
nosuppression (Table 6-1), particularly
from quantitative and qualitative neutro-
penia, hematologic malignancies, chronic
granulomatous disease, end-stage AIDS,
transplantation, and autoimmune dis-
eases requiring corticosteroids.46 In-
tracranial spread may occur in 10% to
20% of cases, with focal masses being
more common than meningoencephali-
tis. The lungs and paranasal sinuses are
the primary routes of infection. Fever,
headache, changes in mental status,
cranial nerve deficits due to cavernous
venous thrombosis, and focal neuro-
logic signs including hemiparesis and
seizures may occur. Nasal stuffiness, ear
discharge, and periorbital pain may
occur in the trans-sinus route with sub-
sequent proptosis, ophthalmoplegia,
chemosis, and visual loss. Skull base
involvement may lead to multiple cranial
nerve palsies and other syndromes that
present indolently over months. The
anterior and middle cerebral arteries are
most usually involved, resulting in stroke
syndromes that present acutely. Rela-
tively immunocompetent hosts dem-
onstrate a contained fibrous capsule. In
such patients, immune workup should
include assays for neutrophil function-
ality such as the dihydrorhodamine flow
cytometryYbased assay.47 Spinal syn-
dromes such as epidural abscess are rare.
The case fatality proportion was 50% to
100% in some series but less in others.48,49
Another important syndrome is cav-
ernous sinus thrombosis, characterized
by orbital pain, ophthalmoplegia, ptosis,
and proptosis. This is a neurosurgical
emergency, requiring astute assessment
December 2015
 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
syndromes from fungal infectionYrelated
vasculitis and thrombosis are rare, these
can occur as a consequence of angio-
invasive molds, including Aspergil-
lus and Mucor, more commonly than
yeasts like Candida and Cryptococcus.
Brain parenchymal aspergillosis may
cause strokelike syndromes via cerebral
infarction, mycotic aneurysms, or hem-
orrhage; ring lesions with abscess forma-
tion via hematogenous dissemination;
and direct tissue plane invasion from the
paranasal sinuses. The latter is the pre-
dominant pathogenesis in rhinocerebral
Mucorales infections (discussed later in
this article). Sinocranial aspergillosis may
result in focal intracranial granulomas
with consequent skull-base syndromes,
such as orbital apex, that affect cranial
nerves II to V and lead to blindness,
cavernous sinus syndrome.1
Diagnosis and management. The
differential diagnosis includes gliomas
and other brain tumors, metastasis,
lymphoma, dural-based meningiomas,
tuberculomas, toxoplasmosis, pyogenic
abscess, and other mycoses. Diagnosis
is made via tissue biopsy culture and
histopathology, but biomarkers such
as serum galactomannan and 1,3-$-D-
glucan or polymerase chain reaction
(PCR) are becoming increasingly used
with high negative predictive values.
These biomarkers have not yet been
sufficiently validated for the CSF, although
reports supporting their successful use
exist.51 Nonetheless, CSF sampling may
be difficult when a mass effect is present.
The main brain MRI findings include in-
farction, abscesslike ring-enhancing
lesions following infarction, dural or
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-
alized using MRI diffusion-weighted
imaging. Irregular space-occupying le-
sions that are hypointense or isointense
on T1 but bright on postgadolinium T1
and dim on T2 correlate with brain tis-
sue coagulative necrosis.49,52 Voricona-
zole has good CNS penetration and is
the treatment of choice in the majority
of cases that are due to Aspergillus fumi-
gatus, with 35% to 47% response and
31% to 43% overall 1-year survival that
were differential by host type.53,54
Higher-dose liposomal amphotericin B,
posaconazole, and itraconazole may be
alternatives, although the latter two have
poor CNS penetration but should be
taken with fatty meals to increase ab-
sorption with a target trough between
0.5 to 1.5 mcg/mL.55 Adjunctive surgery
may decrease mortality from approxi-
mately 50% to 25%.48,53
Mucorales
Risk factors and clinical manifestations.
Mucormycosis is a disease caused by a
molds that infect the same patient pop-
ulations as Aspergillus. Mucormycosis
must be distinguished from aspergil-
losis because of its aggressive course,
requirement for surgical debridement,
and poor response to voriconazole ther-
apy often used against Aspergillus. An
older term for mucormycosis was zygo-
mycosis, but this has recently been dis-
carded because of reclassification using
sequence-based DNA phylogeny.56 De-
layed diagnosis results in significantly
higher mortality,57 emphasizing the need
for all consulting physicians to be aware
of this important differential. Indeed,
84% of patients who had leukemia or
received stem cell transplantation were
receiving ineffective therapy for mucor-
mycosis at the time of diagnosis.58 Mu-
cormycosis should rise in the differential
in patients with prolonged neutropenia,
especially in the setting of leukemia,
high-risk hematopoietic stem cell trans-
plantation (eg, recipients of matched
unrelated and haploidentical donors or

1670 www.ContinuumJournal.com December 2015

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


cord blood, or who are T-cell depleted),
or exposure to voriconazole. Diabetic
ketoacidosis and corticosteroid-associated
hyperglycemia, IV drug use, and iron
overload states (eg, massive transfusions
following major trauma) as well as de-
feroxamine chelation are also unique risk
factors for mucormycosis.59,60 Rhino-
cerebral disease is the major CNS mani-
festation, especially in uncontrolled
diabetes mellitus or stem cell transplant
recipients. The mold traverses tissue
planes inferiorly to the palate and sphe-
noid sinus, laterally to the cavernous
sinus and orbits, and cranially via the
orbital apex or cribriform plate to the
brain. Sinusitis, periorbital cellulitis, and
facial numbness or pain with or without
associated ocular cranial neuropathies
in a susceptible host should trigger a
high index of suspicion and early inter-
vention.60 Several anatomic findings on
imaging include rhinoorbital disease,
with or without cerebral invasion,
accompanied by bony destruction.61
A strong tropism for invasion of blood
vessels also results in a propensity for
infarction and necrosis in both neuro-
logic and pulmonary lesions.62 All such
immunosuppressed patients should
have rapid evaluation by otolaryngolo-
gy and biopsy of suspicious lesions.
Typically, sinus lesions are necrotic, but
this sign is unreliable, especially early in
the disease; thus, absence of tissue ne-
crosis in the appropriate host should
not preclude tissue biopsy.
Diagnosis and management. Sinus
CT may show fluid-filled sinuses; bony
destruction is a late finding. MRI is
more sensitive and can identify cavern-
ous sinus thrombosis and perineural
intradural spread.60 On biopsy, lack of
septa in the hyphae, with irregular
diameters, is an important histologic
feature that distinguishes Mucorales
from Aspergillus, evident on Grocott-
Gomori methenamine-silver stain (GMS)
Continuum (Minneap Minn) 2015;21(6):16621678
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
as well as by Calcofluor white fluores- h Rhinocerebral disease is
cent stain. However, lack of septae (that the major manifestation
protect other hyphal molds such as of central nervous system
Aspergillus from injury during biopsy) mucormycosis that must
results in leakage of cellular material and be diagnosed early in
rapid death after hyphae breakage, re- at-risk hosts, such as those
sulting in poor microbiological recovery with poorly controlled
diabetes mellitus with
of Mucorales after biopsy (40% to 50%).
sinus pain, to
CSF offers poorer yield. Therapy nor-
improve outcomes.
mally includes aggressive debridement
with clean surgical edges and high-dose h High-dose liposomal
amphotericin B and
liposomal amphotericin BYbased regi-
aggressive surgical
mens accompanied by reductions in
debridement, with or
immunosuppression with or without without adjunctive
adjunctive therapy such as cytokine granulocyte infusions or
support, granulocyte transfusions, or cytokine therapy, is the
hyperbaric oxygen.63 Posaconazole has major management
activity against certain species and strategy for central
may be used effectively as salvage or nervous system
in combination with liposomal ampho- mucormycosis.
tericin B but has poor CNS penetration; h Central nervous system
serum levels must be monitored. Mor- disease caused by
tality remains high at 25% to 40%.61 dark-pigmented molds
(eg, Cladophialophora
bantiana and
Dematiaceous Fungi (Focus on Exserohilum rostratum)
Exserohilum rostratum) carries high mortality
Risk factors and clinical manifestations. regardless of host
Dematiaceous fungi are soil-based and immune status.
darkly pigmented, being melanized,
and classified as phaeohyphomycosis.
Cladophialophora bantiana has his-
torically caused CNS disease in half
of the cases; in three-quarters of these,
patients had no known immunodefi-
ciency, but mortality was nondifferential
by immune status (71% to 74%). This
was followed by Rhinocladiella
mackenziei in the Middle East, but
Ochroconis, Wangiella, and Bipolaris
have also been reported pathogens.
Single-lesion brain abscess via hema-
togenous dissemination after inhala-
tion was the primary manifestation.64
However, more recently, Exserohilum
rostratum was identified as the major
pathogen (20% or more) in the largest
recorded fungal outbreak to date. This
was the consequence of contamination
www.ContinuumJournal.com 1671
 Fungal Infections
KEY POINTS
h An iatrogenic outbreak
in 2013 of Exserohilum
rostratumYcontaminated
methylprednisolone
lots for musculoskeletal
injection resulted in
meningitis, vertebrobasilar
stroke, and
spinal syndromes.
h Central nervous system
scedosporiosis may
present shortly after
near drowning or
aspiration of
polluted water.
1672 www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
of compounding pharmacy lots of
preservative-free methylprednisolone
acetate for epidural, spinal, or para-
spinal injections to treat chronic mus-
culoskeletal pain.3 As of October 23,
2013, 751 iatrogenic cases were iden-
tified by the Centers for Disease Control
and Prevention (CDC) with 64 deaths
(case fatality ratio = 8.5%).65 Symptoms
began approximately 40 days follow-
ing exposure. One-third of those af-
fected developed meningitis, while 5%
had posterior circulation strokes (ische-
mic more often than hemorrhagic). Al-
though the majority of cerebrovascular
events affected the vertebrobasilar sys-
tem, many affected the basal ganglia,
and 85% of deaths were associated with
stroke. Forty-three percent had spinal
or paraspinal infections presenting as
epidural abscess, vertebral osteomyelitis/
diskitis, arachnoiditis, and cauda equina
syndrome. Accordingly, fever, head-
ache, and back pain were the most com-
mon symptoms.66,67
Diagnosis and management.
Melanin-binding Masson-Fontana stain
can be used to identify these molds in
tissue. In the iatrogenic fungal menin-
gitis outbreak, although most had pleo-
cytosis, glucose was lower and protein
was slightly high in the CSF in stroke
compared to nonstroke CNS cases, al-
though hypoglycorrhachia was uncom-
mon overall. Higher CSF white blood
count was an independent risk factor
for mortality. Most diagnoses were con-
firmed by PCR using internal transcribed
spacer (ITS) sequence comparison and
culture of CSF or tissue.68 MRI identi-
fied several asymptomatic cases. High-
dose voriconazole 6 mg/kg 2 times a day
and liposomal amphotericin B 5 mg/kg/d
to 6 mg/kg/d for at least 6 months
has been advocated in complicated
E. rostratum disease. Nonetheless, flu-
cytosine, posaconazole, itraconazole,
and isavuconazole have activity against
this and many other etiologies. Com-
plete surgical resection of mass lesions
may lead to better outcomes than
partial resection.64
Other Molds
Scedosporium apiospermum (sexual
or perfect stage: Pseudallescheria
boydii) can form brain abscesses
(mostly in the frontal lobe followed
by the parietal area) in immunocom-
promised hosts and after near drown-
ing (with aspiration of polluted water)
or trauma. Meningitis and spinal cord
involvement are less common. The
incubation period may be 1 to 3 weeks
in near-drowning victims and more var-
iable in the transplant host, up to 1 year.
The clinical presentation can vary and
may include headache, altered mental
status, and focal neurologic signs. As
with Aspergillus and Mucorales, angio-
invasive sequelae may occur. Diagnosis
can be made antemortem in up to two-
thirds of cases via histopathology or
culture of tissue or occasionally CSF
(especially with the presence of heavy
neutrophilic pleocytosis), and their
hyphal appearance resembles acute-
angle septated Aspergillus. Mortality
may exceed 70% regardless of immune
status.69 Despite the often histologic
diagnostic confusion with Aspergillus,
voriconazole with or without adjunc-
tive surgery is also the treatment of
choice, with 56% clinical response.54
In general, combining antifungals with
surgery may improve survival.54,69 Ocu-
lar infections including keratitis and end-
ophthalmitis may occur after trauma
and less commonly endogenously. Sce-
dosporium prolificans is an even more
virulent species that is a rare cause of
CNS disease via hematogenous dis-
semination in immunocompromised
hosts (including hematopoietic stem
cell transplant recipients or those with
chronic granulomatous disease). The
December 2015

prognosis is dismal and may require
voriconazole and surgery in combina-
tion with terbinafine.70
DIMORPHIC ENDEMIC FUNGI
(FOCUS ON NORTH AMERICA)
These fungi are geographically restricted
and exist as tissue-invasive yeast forms
at human body temperature but as
molds in the environment. Therefore,
a careful travel and exposure history
must be taken to anticipate diagnosis.
The main etiologies in North America
include Blastomyces dermatitidis in
the US midwestern states and Canadian
provinces that border the Great Lakes
and St. Lawrence River, as well as
southeastern and south central states;
Histoplasma capsulatum around the
Ohio and Mississippi River basins; and
Coccidioides immitis and Coccidioides
posadasii in the arid southwestern
United States. The use of tumor necro-
sis factor (TNF)-" antagonists in-
creases the risk for disseminated disease
in all three following inhalation of
the fungus. 71
Disseminated coccidioidomycosis
occurs after exposure to dust from
endemic areas, especially among high-
risk groups such as African Americans,
Filipinos, Hispanics, those in late preg-
nancy, and those who are immunocom-
promised because of AIDS or transplant
conditioning or genetic mutations. CNS
involvement may occur in up to half,
presenting as a chronic basilar meningitis
with headache, low-grade fever, weight
loss, and mental status changes, but one-
third of patients may lack meningismus.
Hydrocephalus and ischemic vasculitis
may complicate up to 40% of cases
months later.72 MRI may reveal pre-
dominantly leptomeningeal enhance-
ment of the basilar cisterns and middle
cerebral artery cisterns. Hydrocephalus
with transependymal flow may require
shunting. Spinal nerve root enhancement
and clumping that may be asymptom-
Continuum (Minneap Minn) 2015;21(6):16621678
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
atic occurs in one-third of cases.73 CSF h A careful travel and
may occasionally reveal an eosinophilic exposure history is
pleocytosis with elevated protein and necessary when a
low glucose, but culture is positive in clinical suspicion for
only about 15%, requiring complement central nervous system
fixation titers that may have a diagnostic disease due to the
yield of greater than 70%.72 The clinical endemic mycoses
microbiology laboratory should be no- coccidioidomycosis,
tified if this diagnosis is suspected so histoplasmosis, and
that appropriate specimen handling blastomycosis exists.
may be performed. Fluconazole is the h While Coccidioides may
drug of choice, affording nearly 80% cause an eosinophilic
clinical response,74 but intrathecal am- meningitis, both
photericin B has also been advocated.75 Coccidioides and
Histoplasma can also
Lifelong suppressive therapy may be
cause a chronic basilar
needed, as relapse can occur.76 None-
meningitis with clinical
theless, 40% mortality has remained in features that resemble
the postazole era.72 cryptococcosis.
Progressive disseminated histoplas-
mosis may occur after exposure to soil
contaminated by avian droppings or
bat guano from endemic areas, or
among patients with AIDS or other
cellular immune deficits, the latter of
which may be subclinical. Among those
with disseminated histoplasmosis, CNS
disease may occur in 5% to 10% as
manifested by focal parenchymal le-
sions of the brain or spinal cord and
chronic meningoencephalitis with or
without ischemic strokes due to em-
boli or small vessel vasculitis, as can be
seen in cryptococcosis and the other
endemic mycoses. CSF reveals high
protein and hypoglycorrhachia with
a myeloid pleocytosis. Urine, serum,
and CSF Histoplasma galactomannan
antigen (quantitative enzyme immu-
noassay) may be positive, but cross-
reaction with Blastomyces is frequent.
CSF culture requires multiple high-
volume sampling to increase yield.77
Biopsy of mass lesions may be positive
by culture and histopathology.78 Cor-
ticosteroids may be inadvertently
given rather than antifungal therapy
for presumed noninfectious vasculitis,
which can lead to clinical deteriora-
tion. 79 Liposomal amphotericin B
www.ContinuumJournal.com 1673
 Fungal Infections
KEY POINTS
h Lifelong suppressive
azole therapy following
initial treatment may be
necessary to avoid
relapses due to central
nervous system infection
from endemic fungi,
particularly among
immunocompromised
hosts.
h Syndromic diagnosis of
central nervous system
fungal infections may
permit earlier
implementation of
effective therapy
pending confirmatory
diagnosis, with broad
initial antifungal
coverage for a spectrum
of potential etiologies
followed by narrowing
the spectrum once
definitive diagnosis is
established. Such an
approach may
improve outcomes.
1674 www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
(5.0 mg/kg/d for a total of 175 mg/kg
given over 4 to 6 weeks) followed by
itraconazole (200 mg 2 or 3 times a day)
for at least 1 year is the suggested
treatment for CNS histoplasmosis,
with monitoring of itraconazole trough
serum levels and CSF Histoplasma
antigen. Voriconazole or posaconazole
may be effective step-down alterna-
tives.80 Lifelong suppressive therapy
with such triazoles may be necessary
in those for whom effective immune re-
constitution is not possible, as relapse
may occur.81
Of extrapulmonary blastomycosis
cases, 5% to 10% involve the CNS.
Risk factors include diabetes mellitus
and cellular immune deficits conferred
by corticosteroids, AIDS, or transplan-
tation. In the pre-HAART era, as many
as 40% of patients with AIDS who had
blastomycosis had CNS disease.82 As
with the other mycoses, nonspecific
headache, focal neurologic deficits, al-
tered mental status, vision changes,
and seizures predominate. However,
dissemination to the CNS from the
lung is accompanied by spread to
more common sites, such as the skin,
bone, and genitourinary tract, in ap-
proximately 75%; concomitant puru-
lent vertebral osteomyelitis may occur.
MRI may reveal diffuse meningeal en-
hancement or mass lesions in the basal
ganglia or cerebellum more commonly
than other areas.83 While serum immu-
nodiffusion tests are highly specific,
false negatives may occur in 20% to
35%. Unfortunately, CSF findings may
be variable, and high cross-reactivity
with the Histoplasma antigen enzyme
immunoassay may make the Blastomyces
antigen test result not definitive, given
the overlapping areas of endemicity.
Thus, culture of serial high-volume CSF
sampling is the gold standard, and ven-
tricular fluid sampling may be more
sensitive than lumbar fluid sampling.
Nonetheless, histopathologic differences
in appearance from tissue biopsies using
GMS, hematoxylin and eosin (H&E), or
periodic acidYSchiff (PAS) staining, in
which Blastomyces appears larger with
a double refractile wall and broad-based
bud compared to Histoplasma, can be
made, even from concomitant alterna-
tively infected sites.84 Fortunately, the
recommended treatment regimen is the
same as for CNS histoplasmosis except
that step-down therapy may also include
fluconazole 800 mg/d or voriconazole
200 mg to 400 mg 2 times a day to com-
plete at least 12 months of therapy, deter-
mined by CSF abnormality resolution
and being off immunosuppression.82,83
CONCLUSION
CNS mycoses carry a tremendous mor-
bidity and mortality such that early
recognition of neurologic syndromes
with implementation of efficacious
management is paramount. Cryptococ-
cus may cause focal masses in the basal
ganglia, meningitis, vasculitis, and spi-
nal arachnoiditis. Even with therapy,
IRIS-like syndromes with consequent
neurologic sequelae may occur in the
setting of microbiological control of
this neurotrophic fungus. Candida
may cause multiple microabscesses in
the brain via hematogenous spread
in a susceptible, usually neutropenic,
host; endophthalmitis; or neurosurgi-
cal hardware-associated disease with
meningitis. Angioinvasive molds such
as Aspergillus, Scedosporium, and Mu-
corales may cause mass lesions that
erode into blood vessels to cause
ischemic or hemorrhagic stroke syn-
dromes and cavernous sinus thrombo-
sis syndrome, which is a neurosurgical
emergency. The iatrogenic fungal men-
ingitis and spinal syndrome outbreak
primarily caused by E. rostratum
heightened clinician awareness to con-
sider medical vehicles for CNS fungal
infections. Finally, a careful travel and
exposure history is particularly critical
December 2015
when considering the US endemic my-
coses (coccidioidomycosis, histoplasmo-
sis, and blastomycosis) as a cause of
CNS disease.
ACKNOWLEDGMENTS
The authors would like to thank Sarah
Kranick, MD, formerly from the Na-
tional Institute of Neurological Disor-
ders and Stroke (NINDS) at the NIH,
for her contribution to the case findings
for Case 6-2 and Dima Hammoud, MD,
of Radiology and Imaging Sciences at
NIH Clinical Center, for supplying the
images for Figure 6-1 and Figure 6-2.
This research was supported in part by
the Intramural Research Program of the
NIH/National Institute of Allergy and
Infectious Diseases/Division of Intramu-
ral Research/Laboratory of Clinical Infec-
tious Diseases. The views herein do not
reflect the official opinions of the
Uniformed Services University of Health
Sciences or the Department of Defense.
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