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: averma@med.miami.edu (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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