Isolated cerebral mucormycosis: Report of a case and review of the literature
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Transcript of Isolated cerebral mucormycosis: Report of a case and review of the literature
www.elsevier.com/locate/jns
Journal of the Neurological Sc
Isolated cerebral mucormycosis: Report of a case and
review of the literature
Ashok Verma a,*, Branimir Brozman a, Carol K. Petito b
a Department of Neurology, University of Miami School of Medicine, 1150 NW 14 Street, Suite 701, Miami, FL 33136, USAb Department of Pathology (Neuropathology), University of Miami School of Medicine, Miami, FL, USA
Received 1 July 2005; received in revised form 6 September 2005; accepted 8 September 2005
Available online 2 November 2005
Abstract
Isolated cerebral mucormycosis is a rare but life-threatening infection that generally occurs in patients with intravenous drug abuse or
immune deficiency. We report a case of primary cerebral mucormycosis in a healthy adult. Whole body autopsy in this case revealed cerebral
mucormycosis with prominent vascular pathology and hemorrhagic necrosis. No nasal sinus, orbital or other primary locus of fungus
infection was discovered. Review of the previously reported 30 cases of isolated cerebral mucormycosis revealed associated systemic
predisposition in 11 patients and history of intravenous drug abuse in 17 cases. In the remaining two cases, the diagnosis of fungal infection
was made only after surgical exploration. Early tissue diagnosis and the consequent surgical excision of the necrotic tissue and aggressive
antifungal therapy might salvage life in this fatal condition.
D 2005 Elsevier B.V. All rights reserved.
Keywords: Mucormycosis; Fungus; Cerebral; Rhinocerebral; Cerebritis; IVDA
1. Introduction
Cerebral mucormycosis is a rare disorder caused by
several genera of the family Mucoraceae [1]. The genera
Rhizopus, Absidia, and Mucor are the prominent pathogenic
groups. Infection by these organisms usually complicates an
underlying chronic disease, such as diabetes mellitus or
malignancy. Most mucormycosis cases are rhinocerebral in
which the infection ascends from the nasal passage to sinuses
or orbit and then sometimes to the brain. Open head injury
can also implant this ubiquitous fungus directly into the brain.
In patients with malignancy-associated isolated cerebral
mucormycosis (without rhino-orbital focus), the infection
often disseminates hematogenously from the pulmonary
system [2–6]. Patients with isolated cerebral mucormycosis
without predisposing disease mostly have history of intrave-
nous drug abuse (IVDA) ([7–20], Table 1); the fungus is
likely transmitted hematogenously from the venous port.
0022-510X/$ - see front matter D 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jns.2005.09.010
* Corresponding author. Fax: +1 305 243 7525.
E-mail address: [email protected] (A. Verma).
Isolated cerebral mucormycosis in healthy individuals
without history of IVDA or head trauma is rare [21,22].
After extensive review of the medical literature, we report
what we believe is the third case of isolated cerebral
mucormycosis in a patient without a predisposing condition
or disease. In the two other cases, the clinical presentation was
that of meningitis [21] and hydrocephalus [22]. The case
described here presented with progressive cerebritis and
autopsy failed to reveal extracerebral focus of fungal infection.
2. Case report
A previously healthy 49-year-old Caucasian carpenter
had a generalized tonic–clonic seizure during nighttime
sleep. Clinical examination and a contrast-enhanced brain
CT scan were normal. There was no history of recent ravel
or drug abuse.
Over the following 3 days, he developed low-grade fever,
headache and lethargy. A brain MRI scan showed a signal
abnormality in the left frontal lobe, which did not enhance
iences 240 (2006) 65 – 69
Table 1
Isolated cerebral mucormycosis
Reference Sex/age Predisposing factors Initial symptoms Outcome Diagnostic procedure
Kurrien M/1 Uremia Sz, AMS Died Autopsy
Muresan et al. M/8 – HA, Fever Survived Operative
Adelman et al. M/24 IVDA Dead on arrival Died Autopsy
Hameroff et al. M/32 IVDA Dys, Hemi Died Autopsy
Chmel et al. M/32 IVDA Hemi Died Autopsy
Whalen et al W/31 Cirr, Pred HA, Fever Died Autopsy
Sweeney et al. W/37 – Vertigo, Emesis Survived Operative
Jones et al. M/61 DM HA, Men Survived Clivus bone bx
Pierce et al. M/28 IVDA HA, Fever, AMS Died Operative
Masucci et al. M/27 IVDA HA, Hemi Died Autopsy
Welti et al.
Case 1 M/20 IVDA HA, Hemi Died Autopsy
Case 2 F/33 IVDA HA, Hyd Died Autopsy
Case 3 M/32 IVDA Fever, Hemi Survived Brain bx
Woods et al. W/24 IVDA HA, Hyd Survived Operative
Parfrey et al.
Case 8 F/46 DM, Pan HA, Hemi Died Autopsy
Case 10 M/47 Cirr, Pred Fever, Sz Died Autopsy
Kesantikul et al.
Case 1 M/28 IVDA Men, Hyd Survived Operative
Case 2 M/40 IVDA AMS, Hemi Died Autopsy
Cook et al. F/13 ALL (new) HA, Fever, AMS Died Brain bx
Stave et al. M/44 IVDA Fever, AMS Survived Brain bx
Escobar et al. F/33 SLE, Pred, Cyc HA, Fever, AMS Died Autopsy
Case 52-1990 W/31 IVDA, HIV HA, Hemi Survived Operative
Gollard et al. M/28 IVDA HA, Hemi Survived Brain bx
Siddiqi et al. F/29 IVDA HA, Fever Survived Brain bx
Blazquez et al. F/30 IVDA HA, Fever Survived Brain bx
Birchall et al. M/48 ALL Fever, Men Survived Operative
Zarei et al. M/57 NHL, BMT Hemi Died Autopsy
Eucker et al. M/18 ALL Fever, Hemi Died Autopsy
Oliveri et al. M/25 IVDA Hemi Died Operative
Rumboldt et al. M/16 ALL, BMT Fever, AMS Died Operative
Current case M/49 – Sz, Fever, Hemi Died Autopsy
ALL, acute lymphocytic leukemia; AMS, altered mental status; BMT, bone-marrow transplant; Bx, biopsy; Cirr, liver cirrhosis; Cyc, cyclophosphamide; DM,
diabetes mellitus; Dys, dysphagia; HA, headache; HIV, human immunodeficiency virus infection; Hemi, hemiparesis; Hyd, hydrocephalus; IVDA, intravenous
drug abuse; Men, meningitis; NHL, non-Hodgkin lymphoma; Pan, pancreatitis; Pred, prednisone; SLE, systemic lupus erythematosus; Sz, seizure
A. Verma et al. / Journal of the Neurological Sciences 240 (2006) 65–6966
with gadolinium. Cerebrospinal fluid analysis revealed 181
cells/mm3 (45% neutrophils, 50% lymphocytes, 5% mono-
cytes), protein 111 mg/mm3 and glucose 58 mg/mm3
(plasma glucose 110 mg/mm3). CSF stains and culture for
microorganisms were negative. Electroencephalographic
examination showed asymmetric slowing, greater on left,
in the frontal region. With presumed CNS infection, he
received a combination of intravenous Ceftriaxone, Vanco-
mycin and Acyclovir, in addition to phenytoin, and was
transferred to our facility.
General physical examination, including eyes, nasal and
pharyngeal mucosa, paranasal sinuses, orbit, and chest were
normal. He was intermittently drowsy but without focal
lateralizing neurological deficit. Following investigations
were normal or negative: complete blood counts, urinalysis,
blood chemistry, serial blood cultures, chest X-ray, electro-
cardiogram, echocardiogram, liver enzymes, thyroid and
renal function tests, serology for HIV-1, Lyme and syphilis,
antibody panel for collagen vascular diseases, angiotensin-
converting enzyme level, and CSF cytology. Sedimentation
rate was at 6 mm/first hour (Westgren). Screening assay for
T cell subsets, B cells, NK cells and monocytes; serum
protein electrophoresis; components of the complement
system; and delayed hypersensitivity skin tests (PPD,
candida and mumps antigen) revealed no abnormality.
PCR for Herpes simplex and mycobacterium tuberculosis
from CSF sample were negative. Chest, abdominal and
pelvic CT scans were unremarkable.
On the eighth day, he developed mild right hemiparesis
and left gaze preference. Repeat brain MRI confirmed
worsening of the lesion. Stereotactic biopsy from the left
frontal lesion revealed perivascular monocytic cell infil-
trates. Histology or tissue culture did not reveal a pathogen.
Intravenous corticosteroids and amphotericin-B (1 mg/kg
daily) were added to the antimicrobial regimen.
The fever subsided on the ninth day, but he became
increasingly lethargic and developed bilateral pyramidal
tract signs, along with worsening of the right-side weakness.
Another brain MRI showed extension of the lesion through
corpus callosum to the right frontal lobe and basal ganglia
(Fig. 1). No sinus, paranasal, nasopharyngeal or orbital
disease was noted in MRI images.
Fig. 1. Axial FLAIR magnetic resonance image showing mixed intensity
bilateral deep cerebral lesions.
A. Verma et al. / Journal of the Neurological Sciences 240 (2006) 65–69 67
On the eleventh day, the patient became stuporous and
his temperature rose to 38.5 -C. A new brain CT scan
showed a bifrontal lesion and bilateral basal ganglia
hemorrhage, and evidence of transtentorial herniation. He
was intubated, hyperventilated, and intravenous mannitol
was given. He continued to receive broad-spectrum anti-
bacterial antibiotics, amphotericin-B, and corticosteroids.
No clinical improvement occurred and he became deeply
comatose and began losing brainstem reflexes. The family
decided to withdraw the ventilatory support and he expired
13 days after the onset of the first neurologic symptom.
3. Post-mortem report
Whole body autopsy was performed after an informed
consent. Gross brain examination showed bilateral poorly
circumscribed regions of softening and petechiae and basal
ganglia hematomas extending to the ventricles (Fig. 2A).
Microscopic examination revealed thin-walled non-septated
fungal hyphae, more than 10 Am in diameter, branching at
right angles (Fig. 2B). These were in continuity with large
round spore-like fungal forms of more than 25 Am in
diameter. Extensive vascular necrosis was noted. The fungal
morphology suggested mucormycosis. Tissue was preserved
in formalin and culture from this specimen for fungus was
unsuccessful. No involvement of the orbit, nasal and
paranasal cavities, lungs, intestines or other organs was
identified.
Fig. 2. (A) Coronal section of brain reveals hemorrhagic necrosis in the
basal ganglia and periventricular white matter, with massive right basal
ganglionic and intraventricular hemorrhage. (B) Brain with microabscess
which is composed of mixed inflammatory cells and numerous large fungal
hyphae (arrows). Hematoxylin–eosin; original magnification �400.
4. Discussion
Mucormycosis is a saprophytic fungal disease which
mostly occurs in compromised hosts with suppressed
resistance or immunodeficiency [1,5,6,20,23–25]. Classi-
cally, these patients have (1) predisposing conditions, most
commonly diabetic ketoacidosis; and (2) rhinosinusitis with
or without orbital complication. Other debilitating illnesses
associated with the occurrence of mucormycosis include
hematologic malignancy [1,2,3,5,6], other cancers [4], liver
cirrhosis [23,24], connective tissue disease [25], renal
disease [26], and hemochromatosis [27]. States of immune
incompetence, such as radiation and chemotherapy, pro-
longed corticosteroid use, and acquired immunodeficiency
syndrome, are also known to predispose to this disease
process [1,20,23–25]. In children, mucormycosis has been
described in association with malnutrition and severe
dehydration secondary to diarrhea [26].
Rhinocerebral mucormycosis clinically presents as an
acute fungal infection and despite optimal surgical inter-
vention and antifungal therapy it carries a very high
mortality [1]. Survival has mostly occurred in cases in
which the diagnosis was established early and the disease
was confined to the rhino-orbital structures leading to
surgical debridement of the necrotic tissue. Extension to
the central nervous system carries a uniformly poor
A. Verma et al. / Journal of the Neurological Sciences 240 (2006) 65–6968
prognosis; in one report all 11 cases of rhinocerebral
mucormycosis ended in fatality [28]. In a review of 48
patients with central nervous system mucormycosis, Berg-
strom et al. [29] recorded 14 cases involving the cavernous
sinus, with only six of these cases based on ante mortem
clinical diagnosis. The diagnosis of CNS disease was made
at autopsy in 33 of the 48 patients [29], indicating both the
ante-mortem diagnostic difficulty and high fatality with this
form of mucormycosis. The clinical diagnosis is particu-
larly daunting in isolated cerebral mucormycosis when
rhino-orbital structures are not involved and a systemic
predisposition does not exist [21,22]. The case reported
herein is unusual and deserves attention on several
accounts.
First, the patient had been in good health before the
onset of the present illness; extensive investigation did not
reveal a systemic disease or predisposing condition.
However, unknown subtle humoral or cellular immunode-
ficiency cannot be entirely ruled out in this case. Of the 31
cases of isolated cerebral mucormycosis (our case includ-
ed), 17 were intravenous drug abusers (Table 1). Four had
acute lymphocytic leukemia [2,3,5,6] and two each had
diabetes mellitus [24,30], and liver cirrhosis [23,24].
Isolated cerebral mucormycosis occurred in two apparently
healthy individuals [21,22]. Sweeney et al. [22] reported a
37-year-old woman who presented with vertigo and
obstructive hydrocephalus. CSF exudates collected from
the posterior fossa at craniotomy revealed mucormycosis.
She improved following CSF shunt and antifungal therapy.
Prominent initial positional vertigo at presentation suggests
possible spread of infection from the ear cavity or mastoid
sinus in this patient. The other patient had subacute
meningitis [21] and, again, the infection might have spread
from the juxta-meningeal extracerebral focus. Both these
cases survived.
Second, no primary focus, other than cerebrum, was
discovered at autopsy in this case. It remains unclear how
the infection was acquired, although the absence of rhino-
orbital focus and the presence of deep cerebral site of initial
lesion suggest hematogenous route of infection. There is
experimental evidence to support hematogenous route for
deep isolated cerebral mucormycosis. Following intrave-
nous inoculation of spores of Absidia ramosa, localized
infection was demonstrated in the mouse brain [31].
Third, fungal infections, including mucormycosis, are
becoming increasingly common in recent years [32]. The
reasons for increasing incidence of fungal infections include
widespread use of antibiotics, corticosteroides and chemo-
therapeutic agents; more aggressive immunosuppressive
regimen in cancer chemotherapy and for bone marrow and
solid organ transplants; the acquired immunodeficiency
syndrome; increasing elderly and diabetic population; and
increasing survival of the debilitated patients. It is possible
that the diagnosis of isolated cerebral mucormycosis is
probably missed in some cases. Among 31 cases of isolated
cerebral mucormycosis, the correct diagnosis was made at
autopsy in 16 and following surgical exploration in 9 other
cases (Table 1).
Finally, limited tissue sample obtained by stereotactic
approach may fail to yield the diagnosis of focal cerebral
mucormycosis. Open surgical biopsy is advisable in
appropriate clinical setting and negative stereotactic biopsy.
When mucormycosis is suspected, laboratory personnel
should be alerted so that optimum mycotic procedure can be
used. Direct inoculation of the tissue into the media without
excessive specimen chopping or grinding may be important,
as hyphae damage can render the fungi nonviable, resulting
in false-negative culture.
In conclusion, focal isolated cerebral mucormycosis
should be recognized as a clinical entity. This entity is
different from the rhinocerebral mucormycosis seen with
diabetes mellitus and other diseases, as it occurs mostly in
patients with IVDA and it presents as deep focal cerebral
infection, meningitis, or CSF pathway obstruction. Despite
increasing awareness of possible CNS fungal disease, the
diagnosis of isolated cerebral mucormycosis during life
remains difficult. High suspicion with the attendant early
diagnosis, surgical removal of devitalized infected tissue,
and aggressive antifungal therapy could represent the only
hope for this lethal disease.
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