Académique Documents
Professionnel Documents
Culture Documents
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
1664 www.ContinuumJournal.com December 2015
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.
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
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
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.
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.
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
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
1674 www.ContinuumJournal.com December 2015
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