Isolated cerebral mucormycosis: Report of a case and review of the literature

Journal of the Neurological Sciences 240 (2006) 65 – 69 www.elsevier.com/locate/jns

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, USA b 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 intravenous drug abuse (IVDA) ([7– 20], Table 1); the fungus is likely transmitted hematogenously from the venous port. * Corresponding author. Fax: +1 305 243 7525. E-mail address: [email protected] (A. Verma). 0022-510X/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2005.09.010

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

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A. Verma et al. / Journal of the Neurological Sciences 240 (2006) 65 – 69

Table 1 Isolated cerebral mucormycosis Reference

Sex/age

Predisposing factors

Initial symptoms

Outcome

Diagnostic procedure

Kurrien Muresan et al. Adelman et al. Hameroff et al. Chmel et al. Whalen et al Sweeney et al. Jones et al. Pierce et al. Masucci et al. Welti et al. Case 1 Case 2 Case 3 Woods et al. Parfrey et al. Case 8 Case 10 Kesantikul et al. Case 1 Case 2 Cook et al. Stave et al. Escobar et al. Case 52-1990 Gollard et al. Siddiqi et al. Blazquez et al. Birchall et al. Zarei et al. Eucker et al. Oliveri et al. Rumboldt et al. Current case

M/1 M/8 M/24 M/32 M/32 W/31 W/37 M/61 M/28 M/27

Uremia – IVDA IVDA IVDA Cirr, Pred – DM IVDA IVDA

Sz, AMS HA, Fever Dead on arrival Dys, Hemi Hemi HA, Fever Vertigo, Emesis HA, Men HA, Fever, AMS HA, Hemi

Died Survived Died Died Died Died Survived Survived Died Died

Autopsy Operative Autopsy Autopsy Autopsy Autopsy Operative Clivus bone bx Operative Autopsy

M/20 F/33 M/32 W/24

IVDA IVDA IVDA IVDA

HA, Hemi HA, Hyd Fever, Hemi HA, Hyd

Died Died Survived Survived

Autopsy Autopsy Brain bx Operative

F/46 M/47

DM, Pan Cirr, Pred

HA, Hemi Fever, Sz

Died Died

Autopsy Autopsy

M/28 M/40 F/13 M/44 F/33 W/31 M/28 F/29 F/30 M/48 M/57 M/18 M/25 M/16 M/49

IVDA IVDA ALL (new) IVDA SLE, Pred, Cyc IVDA, HIV IVDA IVDA IVDA ALL NHL, BMT ALL IVDA ALL, BMT –

Men, Hyd AMS, Hemi HA, Fever, AMS Fever, AMS HA, Fever, AMS HA, Hemi HA, Hemi HA, Fever HA, Fever Fever, Men Hemi Fever, Hemi Hemi Fever, AMS Sz, Fever, Hemi

Survived Died Died Survived Died Survived Survived Survived Survived Survived Died Died Died Died Died

Operative Autopsy Brain bx Brain bx Autopsy Operative Brain bx Brain bx Brain bx Operative Autopsy Autopsy Operative Operative 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

with gadolinium. Cerebrospinal fluid analysis revealed 181 cells/mm3 (45% neutrophils, 50% lymphocytes, 5% monocytes), 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, Vancomycin 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, electrocardiogram, echocardiogram, liver enzymes, thyroid and renal function tests, serology for HIV-1, Lyme and syphilis, antibody panel for collagen vascular diseases, angiotensinconverting 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 infiltrates. 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.

A. Verma et al. / Journal of the Neurological Sciences 240 (2006) 65 – 69

Fig. 1. Axial FLAIR magnetic resonance image showing mixed intensity bilateral deep cerebral lesions.

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 antibacterial 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.

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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, prolonged 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 intervention 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

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.

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-

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.

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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, Bergstrom 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 particularly 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 immunodeficiency cannot be entirely ruled out in this case. Of the 31 cases of isolated cerebral mucormycosis (our case included), 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 rhinoorbital 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 intravenous 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 chemotherapeutic 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. References [1] Venezio FR, Tucker P. Zygomycosis (mucormycosis). Harris AA, editor. Handbook of clinical neurology, vol. 8 (52). Amsterdam’ Elsevier; 1988. p. 467 – 77. [2] Cook BA, White CB, Blaney SM, Bass JW. Survival after cerebral mucormycosis. Am J Pediatr Hematol Oncol 1989;11:330 – 3. [3] Birchall D, Leong WK, McAuliffe W. Cerebral mucormycosis. J Neurol Neurosurg Psychiatry 1999;66:404 – 5. [4] Zarei M, Morris J, Aachi V, Gregory R, Meanock C, Brito-Babapulle F. Acute isolated cerebral mucormycosis in a patient with high grade non-Hodgkin’s lymphoma. Eur J Neurol 2000;7:443 – 7. [5] Rumboldt Z, Kalousek M, Castillo M. Hyperacute subarachnoid hemorrhage on T2-weighted MR images. Am J Neuroradiol 2003; 24:472 – 5. [6] Eucker J, Sezer O, Lehmann R, Weber JR, Graf B, Denkert C, et al. Disseminated mucormycosis caused by Absidia corymbifera leading to cerebral vasculitis. Infection 2000;28:246 – 50. [7] Adelman LS, Aronson SM. The neuropathologic complications of narcotics addiction. Bull N Y Acad Med 1969;45:225 – 34. [8] Hameroff SB, Eckholdt JW, Lindenberg R. Cerebral phycomycosis in a heroin addict. Neurology 1970;20:261 – 5. [9] Chmel H, Grieco MH. Cerebral mucormycosis and renal aspergillosis in heroin addicts without endocarditis. Am J Med Sci 1973;266: 225 – 31. [10] Pierce Jr PF, Solomon SL, Kaufman L, Garagusi VF, Parker RH, Ajello L. Zygomycetes brain abscesses in narcotic addicts with serological diagnosis. JAMA 1982;248:2881 – 2. [11] Masucci EF, Fabara JA, Saini N, Kurtzke JF. Cerebral mucormycosis (phycomycosis) in a heroin addict. Arch Neurol 1982;39:304 – 6. [12] Welti C, Weiss C, Cleary T, Gyori E. Fungal cerebritis from intravenous drug abuse. J Forensic Sci 1984;29:260 – 8. [13] Kasantikul V, Shuangshoti S, Taecholarn C. Primary phycomycosis of the brain in heroin addicts. Surg Neurol 1987;28:468 – 72. [14] Stave GM, Heimberger T, Kerkering TM. Zygomycosis of the basal ganglia in intravenous drug users. Am J Med 1989;86:115 – 7.

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