Successful treatment of a giant isolated cerebral mucormycotic (zygomycotic) abscess using endoscopic debridement: case report and therapeutic considerations

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Surgical Neurology 69 (2008) 510 – 515 www.surgicalneurology-online.com

Infection

Successful treatment of a giant isolated cerebral mucormycotic (zygomycotic) abscess using endoscopic debridement: case report and therapeutic considerations Philippe Metellus, MDa,4, Mehdi Laghmari, MDa, Ste´phane Fuentes, MDa, Alexandre Eusebio, MDb, Tarek Adetchessi, MDb, Ste´phane Ranque, MDd, Corinne Bouvier, MD, PhDc, Henry Dufour, MDa, Franc¸ois Grisoli, MDa De´partamentes de aNeurochirurgie, bNeurologie, and cNeuropathologie, Hoˆpital Timone, Marseille, France d Laboratoire de Mycologie et Parasitologie, Hoˆpital Timone, Marseille, France Received 7 November 2006; accepted 13 February 2007

Abstract

Background: Cerebral mucormycosis without rhino-orbital or systemic involvement is an extremely rare condition mostly associated with parenteral drug abuse. Case Description: We report the case of a 42-year-old woman who presented with hemiparesis of the left side and altered mental status. Neuroradiologic workup demonstrated an inflammatory lesion involving the right basal ganglia. Proton magnetic resonance spectroscopy demonstrated features consistent with a pyogenic abscess. Computed tomography–guided stereotactic biopsy led to the diagnosis of cerebral mucormycosis. Parenteral AMB-L treatment was conducted, but the patient worsened clinically, presenting with a complete hemiplegia, and cerebral magnetic resonance imaging (MRI) scans demonstrated a voluminous abscess formation. Then, under stereotactic guidance, a surgical endoscopic debridement of the abscess cavity associated with the placement of an Ommaya reservoir was performed. Systemic and intralesional treatment with AmB associated with an adjunctive immune therapy was conducted. At 3-year follow-up, the patient had recovered partially from her left hemiplegia, allowing her to walk without help, and cerebral MRI scans showed complete resorption of the abscess. Conclusion: Our good results suggest that surgical endoscopic debridement associated with intravenous and intracavitary antifungal therapy might be valuable in treating voluminous deepseated mucormycotic lesions. D 2008 Elsevier Inc. All rights reserved.

Keywords:

Mucormycosis; Zygomycosis; Endoscopy; Cerebral abscess; Magnetic resonance spectroscopy; Amphotericin B

1. Introduction The genera Rhizopus, Absidia, and Mucor are the prominent pathogens of the class Mucormycetes causing the uncommon, potentially lethal, opportunistic fungal Abbreviations: AmB, amphotericin-B; AMB-D, deoxycholate amphotericin-B; AMB-L, liposomal amphotericin-B; CSF, cerebrospinal fluid; HPS, hematoxilin phloxin safran. 4 Corresponding author. Timone Hospital, Neurosurgical Department Pr Grisoli, 13385 Marseille Cedex 05, France. Tel.: +33 4 91 38 55 45; fax: +33 4 91 49 25 18. E-mail address: [email protected] (P. Metellus). 0090-3019/$ – see front matter D 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.surneu.2007.02.035

infection of the brain referred to as cerebral mucormycosis (or zygomycosis) [2,31]. Mucormycetes are found in plant debris and soil, as well as being isolated from foods and indoor air environments. In recent years, mucormycosis incidence has increased as a result of the increasing number of immunocompromised patients. Infection is generally acute and rapidly developing in debilitated patients (diabetes mellitus, AIDS, long-term corticotherapy, or malignancy). In most cases, cerebral zygomycosis infection ascends from nasal passages to sinuses or orbits to the brain. Isolated cerebral mucormycosis without rhino-orbital or systemic involvement is mostly associated with parenteral

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2. Case report A 42-year-old right-handed woman presented to an outpatient clinic with a 15-day history of refractory intense headache. Seven days before admission, she had bouts of fever (39.58C) with gait disturbance and complained of weakness of the left arm and the left leg. Her medical history was unremarkable except for an 8-year drug abuse habit. On physical examination, the presence of needle tracks was noted, and no sign of sinusonasal inflammation or infection was present. The patient was mildly lethargic but easily stimulated. A severe left central hemiparesis was noted. Laboratory data including white blood cell count, hemoglobin, natremia, and kaliemia were normal. Creactive protein, fibrinogen, and erythrocyte sedimentation rates were slightly increased. She tested positive for hepatitis C and negative for HIV, B hepatitis B, and toxoplasma. Blood and urine culture were negative. Cerebrospinal fluid analysis was not performed because lumbar punction was considered hazardous with regard to the parenchymal mass effect.

Fig. 1. A: Postcontrast CT scan obtained on hospital day 1, showing right basal ganglia swelling without contrast enhancement consistent with a lowgrade glioma. B: T1-weighted postcontrast coronal images obtained on hospital day 4 showing a mass in the right basal ganglia with a flecked enhancement and mass effect on medial structures.

drug abuse [7,18]. In these particular cases, the fungus is likely to be transmitted hematogenously directly from the venous entry port. Standard cerebral mucormycosis treatment guidelines rely on aggressive complete surgical removal of the fungal abscess associated with the administration of a systemic antifungal regimen. However, surgical resection can be very challenging, especially when the mucormycosis involves basal ganglia that constitute the predominant location. Surgery is then a high-risk procedure plagued with permanent neurologic sequelae. In these cases, less invasive surgical techniques are warranted. We report a case of isolated giant cerebral mucormycosis abscess involving basal ganglia successfully treated, after medical treatment failure, by endoscopic surgical debridement, intralesional AmB, and intravenous AMB-L associated with an adjunctive immune therapy.

Fig. 2. A: The biopsy shows minimal inflammation with epithelioid granuloma (HPS  40). B: Presence of wide nonseptate hyphal fragments in areas of necrosis leading to the diagnosis of mucormycosis (HPS  40).

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and paranasal sinuses failed to show any abnormality. A stereotactic biopsy was decided on. On hospital day 4, temperature normalized, but the patient presented with an impairment of her motor function. Cerebral magnetic resonance imaging (MRI) scans demonstrated an increase in size of the voluminous mass, now showing mass effect on the medial structure. On T2-weighted images and fluidattenuated inversion recovery sequences, the lesion displayed a hypointense signal. Gadolinium intravenous infusion resulted in a faint enhancement of the lesion on MRI T1-weighted sequences consistent with an anaplastic glioma or presuppurative encephalitis (Fig. 1B). A proton magnetic resonance spectroscopy (MRS) was integrated with MRI evaluation. Magnetic resonance spectroscopy demonstrated elevated lipid and lactate and depleted N-acetyl aspartate. Myoinositol and creatine were reduced in level. Choline was elevated as well as valine, leucine, and isoleucine. 2.1. Patient management and clinical course

Fig. 3. T1-weighted postcontrast axial (A), coronal (B), and sagittal (C) images obtained on hospital day 10 demonstrating the organization of a voluminous abscess involving the right basal ganglia with mass effect.

Cerebral computed tomographic (CT) scan performed at admission showed a voluminous nonenhancing mass involving the right basal ganglia and insula that was consistent with a low-grade glioma or an inflammatory lesion (Fig. 1A). Computed tomographic scan of the orbit

The patient underwent a CT-guided stereotactic biopsy of the lesion with the G Leksell stereotactic frame (Elekta Instrument AB, Stockholm, Sweden). Tissue samples were obtained easily and revealed minimal inflammation with epitheloid granulomas; scattered Langherans-type giant cells; lymphocytes and neutrophils; and wide, nonseparate hyphal fragments typical of Zygomycetes (Fig. 2A, B). The patient received intravenous injection of AMB-L (AmBisome; NeXstar Pharmaceuticals/Fujisawa, San Dimas, Calif) 5 days a week for 6 months (average dose, 0.5 mg/kg). On hospital day 10, postcontrast CT scan demonstrated a progressive organization of the lesion with a marked peripheral enhancement. The patient remained conscious and alert but presented with an impairment of her left arm motor function and completion of the left leg palsy. On day 15, MRI scans on follow-up showed an organization of the lesion and strong ring enhancement corresponding to an abscess formation (Fig. 3). Clinically, the patient was impaired, showing evident signs of raised intracranial pressure. Then, a more aggressive therapeutic strategy was decided on. Under stereotactic guidance with a Leksell G frame (Elekta), an endoscope (Storz, Tuttlingen, Germany) was introduced into the brain abscess, enabling abscess debridement and aspiration of 30 cc of yellow pus. Macroscopically, the abscess wall appeared to be made of long filaments. Then, an intracavitary Ommaya reservoir was placed in the cavity (Fig. 4A). Intracavitary injection of AMB-D (Fungizone; Bristol Meyers–Squibb, Princeton, NJ) was started 1 week after catheter placement. Dosages of 0.5 mg of AMB-D in 3 cc of 5% dextrose in water were placed in the abscess cavity every other day for 80 days as recommended by Adler et al [1]. Initially, the patient experienced clinical impairment with a complete left hemiplegia. Continued injection of AMB-D via Ommaya reservoir resulted in progressive decrements in the size of the cavity and eventual neurologic improvement. A total of

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18 mg of AMB-D was administrated over 80 days (average dose, 0.5 mg every other day). A total dose of 3488 mg of AMB-L was administered intravenously (111 injections) over 180 days. Concomitantly with antifungal therapy, a systemic adjunctive immune treatment was conducted using subcutaneous injection of granulocyte-monocyte colonystimulation factor at a dose of 250 lg 3 times per week for 6 months as recommended by Garcia-Diaz et al [15]. No adverse effect was noted. At a 3-year follow-up, the patient had completely recovered from the left leg but only partially from the left arm paralysis. Cerebral MRI showed the complete disparition of the abscess (Fig. 4B, C). Given the hemorrhagic risk of removing the Ommaya catheter, it has been decided to let it remain in place. 3. Discussion 3.1. Epidemiology Cerebral mucormycosis isolated or associated with rhinoorbital involvement is a life-threatening disease that requires prompt intervention and multimodal therapy. It is important to identify risk factors for this pathology. Classically, such patients typically have an underlying disease. Seventy percent of patients have poorly controlled diabetes with ketoacidosis, and other conditions, such as uremia, cirrhosis, and administration of cytotoxic drugs, can also predispose to infection [24,25]. Cerebral mucormycosis can be consecutive to 2 main pathophysiologic mechanisms. The most common mechanism is a direct extension from paranasal sinuses and orbits to the brain, responsible for the rhinocerebral form of the disease. Survival occurs in cases in which the diagnosis is established early, and the disease is confined to the rhinoorbital structures, making the surgical removal of the necrotic tissue possible [1,3,5,6,9,11,16,17,20,22,26,28]. The second mechanism is a hematogenous spread from direct intravenous inoculation of spores or from a primary pulmonary focus that causes the rare isolated cerebral form associated with intravenous drug abuse such as in the case reported here [13,14,18,19,23,33,37]. In the rhino-cerebral form, extension to the brain carries a uniformly poor prognosis. 3.2. Diagnosis Although very rare, isolated cerebral mucormycosis should be considered in the differential diagnosis of any cerebral mass lesion in an intravenous drug abuser. The presence of basal ganglia lesions in intravenous drug users Fig. 4. Nonenhanced cerebral CT scan performed after surgical endoscopic debridement of the abscess showing the Ommaya reservoir in the abscess cavity and a little thalamic hemorrhage (A). Postcontrast CT scan performed at 6 months postoperatively showing a significant narrowing of the abscess and the Ommaya catheter position (B). T1-weighted postcontrast axial images performed at 3-year follow-up demonstrating the disappearance of the abscess (C).

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should suggest the possibility of mucormycosis regardless of the patient’s HIV status. Intravenous drug use is more important than immunosuppression in the etiology of isolated cerebral mucormycosis. In fact, this disease has not been described in patients with AIDS who were not intravenous drug abusers. The clinical presentation is extremely varied, and there is no clinical syndrome that suggests a diagnosis. Furthermore, no direct serologic test is available, although an immunodiffusion test has been evaluated, and even CSF examination is usually nonspecific [1]. For these reasons, clinicians and radiologists need to maintain a high index of suspicion of cerebral mucormycosis, which must be timely diagnosed to increase the probability of a successful treatment. On MRI examination, cerebral mucormycosis abscess is frequently located in the basal ganglia but does not display specific features. Even with proton MRS, we were not able to distinguish the zygomicotic abscess from a classical bacterial abscess. Siegal et al [29] reported the first case of MRS evaluation of a zygomicotic abscess and found that MRS features were consistent with a bacterial abscess but without the commonly seen resonances of the amino acids valine, leucine, and isoleucine. In our case, the amino acid resonances were found as in a typical bacterial abscess. The diagnosis of cerebral mucormycosis relies essentially on histologic examination, which typically shows broad, nonseptate hyphae that branch at right angles, with or without subsequent culture confirmation. Stereotactic biopsy remains the diagnostic method of choice because surgical debridement of the abscess is not always warranted. However, when stereotactic biopsy fails to yield to the diagnosis, open surgical biopsy is warranted. 3.3. Treatment The key factor in successful treatment is instituting prompt treatment with adequate systemic antifungal agents. In one series reported, all 11 cases of rhino-cerebral mucormycosis ended in fatality [31]. In a review of 48 patients with central nervous involvement, Bergstrom et al [4] reported that the diagnosis was made at autopsy in 33 of 48 patients, stressing the difficulty of antemortem diagnosis and the high mortality rate of this disease. The diagnosis in isolated mucormycosis with neither rhino-orbital involvement nor systemic predisposition is particularly daunting [32,34]. Including our case, 32 cases of isolated cerebral mucormycosis have been diagnosed to date [34]; 18 occurred in intravenous drug users, 4 had acute lymphocytic leukemia, 2 had diabetes mellitus, and 2 had liver cirrhosis [6,10,12,25,27,30,35]. Isolated cerebral mucormycosis occurred in 3 apparently healthy individuals [21,32,34]. Among these 32 patients, diagnosis was made at autopsy in 16 cases, and 3 patients died during hospitalization time. The antifungal treatment of choice for invasive mucormycosis is AmB. Because the fungus is relatively resistant to AmB, high doses are required. The toxicity of AmB, manifested as electrolyte abnormalities, phlebitis, anemia, fever, nausea, and vomiting, is well known [4,38]. It has

been shown that administration of AMB-L significantly decreases toxicity while retaining and perhaps increasing efficacy [36]. In our case, at the early stage of the disease, corresponding to presuppurative cerebritis, stereotaxic biopsy allowed a histologic examination yielding a timely diagnosis and a prompt introduction of an antifungal treatment. However, despite prompt intravenous AMB-L treatment, which presumably enhances the efficacy of AmB by facilitating its intracellular delivery to the phagocyte, the clinical status of the patient worsened, and, radiologically, an abscess formed. Careful clinical and cerebral imaging follow-up is very important once the diagnosis is made. If an abscess has formed or if clinical status worsened, surgical evacuation is mandatory. Indeed, delivering this drugphagocyte complex to necrotic tissues and obtaining effective tissue concentrations is a key issue. The surgery aims at removing infracted tissue and reestablishing blood supply to the infected area [1]. However, radical surgical treatment is hazardous, with a high risk of neurologic sequelae, if the abscess is located in the vicinity of vital structures such as basal ganglia and the midbrain. In our case, endoscopic surgery under stereotactic guidance allows us to efficiently remove the abscess contents under visual control and to place preoperatively an Ommaya reservoir for an intracavitary AMB-D treatment. Given the important volume of the abscess (greater axis, 6 cm) and the absence of response to parenteral AMB-L treatment, we decided to adjunct an immune therapy as reported in the literature [8,15]. We cannot assert that the adjunction of the immune therapy was essential in this case; however, the treatment was well tolerated, and our result corroborates those of other teams. In the authors’ opinion, more studies are needed to elucidate the full potential of granulocyte-monocyte colony-stimulation factor therapy. 4. Conclusion The favorable outcome of our case after 3 years of follow-up suggests that surgical endoscopic debridement associated with intravenous and intracavitary antifungal therapy might be valuable in treating voluminous and deepseated zygomycotic abscess. The role of adjunct immune therapy in this disease remains to be evaluated further. References [1] Adler DE, Milhorat TH, Miller JI. Treatment of rhinocerebral mucormycosis with intravenous interstitial, and cerebrospinal fluid administration of amphotericin B: case report. Neurosurgery 1998; 42:644 - 8 [discussion 648-649]. [2] Baker RD. The phycomycoses. Ann N Y Acad Sci 1970;174:592 - 605. [3] Bendet E, Talmi YP, Kronenberg J. Rhino-orbito-cerebral mucormycosis. Otolaryngol Head Neck Surg 1996;114:830 - 2. [4] Bergstrom L, Hemenway WG, Barnhart RA. Rhinocerebral mucormycosis. Ann Otol Rhinol Laryngol 1970;79:70 - 81. [5] Betharia SM, Wagh VB, Pathak H, Sharma V. Rhino-orbital-cerebral mucormycosis. A retrospective analysis and treatment option. Indian J Ophthalmol 2004;52:82 [author reply 82-83].

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Commentary Mucormycosis affecting the skull base and/or the brain poses a difficult problem for neurosurgeons. Certainly, in the skull base, the principles of extensive debridement and long-term antifungal treatment are well established. Intracerebral abscesses in superficial position are probably best treated in a similar manner. However, the occurrence of a deep intracerebral abscess poses a difficult problem that the authors have managed with endoscopic debridement and with antifungal and immunotherapy. Endoscopic debridement has a very reasonable rational basis, although whether it has a better outcome than repeated aspiration alone cannot be known at this stage. John D. Laidlaw, MD Department of Neurosurgery Royal Melbourne Hospital Parkville, Victoria 3050, Australia