Neurology India Medknow Publications on behalf of the Neurological Society of India ISSN: 0028-3886 EISSN: 1998-4022 Vol. 58, Num. 2, 2010, pp. 270-276

Neurology India, Vol. 58, No. 2, March-April, 2010, pp. 270-276

Original Article

Invasive rhino-cerebral fungal granuloma

Muralimohan Selvam, Anil Pande, Vasudevan M Chakravarthy, Ravi Ramamurthi

Department of Neurosurgery, Postgraduate Institute of Neurological Surgery, ALNC, VHS Medical Centre, Taramani, Chennai - 600 113, India

Correspondence Address: Muralimohan Selvam, No 51, 3rd cross, Brindavan Layout, Vijinapuram, Bangalore - 560 016, India, drmurali78@gmail.com

Date of Acceptance: 01-Feb-2010

Code Number: ni10068

PMID: 20508348

DOI: 10.4103/0028-3886.63805

Abstract

Background: Increased incidence of fungal infection has been reported globally in the recent years. Fungal infection of the central nervous system remains one of the most difficult diseases to treat and requires multi-modality intensive therapeutic strategies.
Materials and Methods: Retrospective analysis of case records of patients with confirmed skull base fungal granuloma treated at a tertiary hospital between 1988-2008. An attempt was made to stage the extent of skull base fungal granuloma based on neuroimaging, operative findings and course of the disease on serial follow-up.
Results: Thirty-three patients with skull base fungal granuloma were treated surgically during the study period. The mean age at presentation was 33.2 years and diabetes was a major predisposing factor. Eight patients expired in the first two months following surgical intervention due to flare-up of the disease. Eighteen patients who underwent grossly total excision had a mean progression-free survival (PFS) of 43 months and seven patients with subtotal excision had a mean PFS of 23 months. Better survival probability was noted in those patients who underwent total excision at surgery and received complete course of amphotericin.
Conclusion: Total surgical excision with complete course of antimycotic drug therapy increases PFS. A better antimycotic drug with less toxicity and high efficacy with fungicidal property can make a difference in the outcomes of the disease.

Keywords: Aspergillosis, amphotericin, mucor mycosis, paranasal sinus, rhinocerebral mycosis

Introduction

Increased incidence of fungal infection has been reported globally in the recent years. This has been attributed to increased aging population and longer survival of immunocompromised people. Fungal infection of the central nervous system (CNS) remains one of the most difficult diseases to treat and requires multi-modality intensive therapeutic strategies. Mortality often reaches 75-100% despite such and intensive treatment strategies, though occasional long-term survivors have been reported.

Materials and Methods

Retrospective analysis of case records of patients with histopathologically confirmed rhino-cerebral fungal granuloma treated at our Institute between 1988-2008 was performed. Only those patients who underwent surgical procedure were included in the study. Patients presenting with exclusive meningoencephalitis or with abscesses were not included. The histological diagnosis was based on the evidence of branching septated fungi interspersed with evidence of tissue invasion. The data collected included: demographics, clinical and neurological features, histological findings, microbiological studies, radiology, treatment received and outcome. The data were analyzed statistically and an attempt was made to stage the extent of skull base fungal granuloma based on neuroimaging studies, operative findings and course of the disease on serial follow-up. Treatment outcome was divided in to three groups: ′disease progression′ (DP), ′progression-free survival′ (PFS) and ′disease-free′ (DF).

Results

Of the 33 surgically treated patients with rhino-cerebral fungal granuloma, 16 were males and 17 females and the mean age was 33.2 years (range 17 - 68 years). Majority of the infection occurred in the middle age group. Thirty patients had paranasal sinus granuloma extending into the skull base, in 25 of whom there was extension into the base of anterior cranial fossa (ACF). Two patients had sellar-parasellar and three had orbital extension. The remaining three had its origin from the mastoid with extension into the base of middle cranial fossa (MCF). The clinical characteristics have been summarized in [Table - 1].

Surgery

Thirty-one patients underwent craniotomy and two underwent transethmosphenoidal (TES) approach. One patient who underwent the TES approach underwent second-stage craniotomy. Conventional craniotomy was performed in all except two patients. Craniofacial resection was performed in one patient and extended frontal approach in the other to attain total excision. Gross total resection was possible in 23 patients. Ten patients underwent subtotal excision as the lesion was extending into the cavernous sinus in seven [Figure - 1] and into the orbital apex in three patients. The lesion at the surgery was firm, grayish white, avascular with areas of soft necrotic material. There was evidence of bone erosion with bony spicules within the lesion. The dura, though thickened with inflammatory changes, was intact and identifiable as a separate layer preventing further intracranial extension in five patients. In the remaining patients with intracranial extension, the granuloma had a definite plane of cleavage with the surrounding brain. Thrombotic vessels were found on and in the substance of the granuloma.

Etiology

Twenty-three were aspergillus, eight mucormycosis and in two the fungus could not be identified specifically. The major predisposing factor was uncontrolled diabetes in 27 patients. None of the patients was immunocompromised.

Medications

Perioperative diagnosis of tubercular granuloma was considered in 21 patients and the patients were started on empirical Anti-Tubercular Treatment (ATT). Subsequent to histological diagnosis ATT was discontinued in all these patients. Amphotericin was administered in 32 patients. In addition, three patients received fluconazole, one Itraconazole and one ketoconazole. One patient received only flucytosine. Twenty-eight patients received plain formulation of amphotericin and four liposomal. Seven patients on amphotericin developed renal impairment and the drug had to be discontinued.

Postoperative course

Eight patients developed Cerebro-Spinal Fluid (CSF) rhinorrhea, of which six were managed with repeated drainage lumbar punctures, while two underwent transethmoidal repair. Three patients developed ophthalmoplegia, four diabetes insipidus and three scalp infection. There was flare-up of the disease process in eight patients, of which two succumbed in the immediate postoperative period and the remaining six died within the first two months, all these patients developed fulminant meningoencephalitis [Table - 2].

Staging of the disease

Based on the clinical presentation, imaging and surgical anatomy, an effort was made to stage the disease progression [Table - 3]. Purely rhino-sino-orbital infection was taken as Stage I [Figure - 2]. Bone is a poor defense barrier as the infection can spread across it through the emissary veins. In addition, they are prone for erosion and destruction, especially when their blood supply is compromised by the disease process. However, the dura forms a definitive protective barrier against infection. It is composed of tough fibrous tissue and has a rich blood supply. Hence the involvement of the skull base (bone) with an intact dural barrier was staged separately as Stage II [Figure - 3]. Breach of the dural barrier marks further progression of the disease, opening the corridor to intracranial contents. This was staged as Stage III a [Figure - 4] and the involvement of the brain parenchyma was taken as Stage III b [Figure - 5]. The further course of the disease depended upon the host defense and the nature of treatment given. A variable period of progression-free survival (PFS) was noted in our study which largely depended upon the extent of the surgical excision, following which further progression occurred in the form of development of fulminant meningoencephalitis. Angioinvasion is a commonly noted histological hallmark; however, larger arteries are also known to get involved with subsequent thrombosis resulting in large areas of infarcts, which further aid in the spread of the disease process (Stage IV).

Three patients were in Stage I, two in Stage II, three in Stage IIIa and 25 in Stage IIIb at presentation. Patients in Stage I, II and IIIa presented with skull base syndromes, whereas those in Stage IIIb in addition presented with features of raised intracranial pressure. Twenty-eight patients progressed to Stage IV with development of fulminant meningoencephalitis after a variable interval of time. Two of these patients also developed large infarcts following involvement of the major intracranial arteries.

Follow-up

After an interval period, in all but one patient, the lesion recurred despite surgery and regular medications. Three patients with exclusive orbital granuloma (Stage I), who underwent transcranial excision had disease progression to Stage IV and succumbed. Two patients with sellar granuloma (Stage II) were operated by the TES approach. One patient with subtotal removal succumbed to disease progression. The other patient underwent craniotomy and total excision, followed by flucytosine therapy. He had initial disease control, but at one year he developed recurrence with disease progression. He expired at two years follow-up. Three patients with sino-orbital disease with dural involvement (Stage III a) were operated transcranially. Subtotal removal was done in one patient; he had disease progression to Stage IV and expired in a month′s time. Total excision was possible in another two patients, who also received full course of amphotericin. Disease control was achieved in them for 23 and 31 months respectively before they presented with recurrence. Twenty-five patients with parenchymal granuloma (Stage III b) underwent craniotomy. Nineteen were total removal and six subtotal. In seven patients (five subtotal and two total excision), there was disease progression and in another three patients, though initial disease control was achieved, they subsequently progressed and expired within the first year of treatment. Thirteen patients received full course of Amphotericin. At three years follow-up, there were 11 survivors and seven at five years. Eighteen patients who underwent grossly total excision had a mean PFS of 43 months and seven patients with subtotal excision had a mean PFS of 23 months. On long-term follow-up only four are surviving, of whom, one patient has been declared ′disease-free′ at 94 months follow-up. The remaining three patients are on antifungal medications.

Survival analysis

Survival analysis was performed using Kaplan Meier curves. Analysis was performed for four groups of patients (total excision with amphotericin, total excision without Amphotericin, subtotal excision with amphotericin and subtotal excision without amphotericin) [Figure - 6]. The Kaplan Meier curves demonstrated better survival probability in patients who underwent total excision at surgery and received a complete course of Amphotericin.

Discussion

Fungal infections of the CNS have been recognized since the beginning of this century. They are being encountered more frequently as opportunistic infections in patients, whose host defense mechanisms have been compromised due to disease or due to immune-suppression and immune-modulation used for managing malignant and autoimmune diseases ^[1],[2],[3] and for organ transplantation. ^[4] Cases of CNS mycoses in apparently immunocompetent and healthy individuals have also been reported, mostly from India. ^{[5],[6],[7],[8],[9],[10],[11]}

Rhino/sino-orbito-cerebral mycosis is a disease entity most often caused by the saprophytic moulds aspergillus and mucorales. ^{[12],[13],[14],[15]} These fungi are found worldwide in a variety of habitats-in soil, on decaying vegetation, in the air, and in water supplies. Their thermo-tolerance permits a wide range of suitable host conditions. ^{[1],[8],[12],[16],[17]} Involvement of the nasal passages or sinuses (acute invasive rhino-sinusitis) is relatively the typical manifestation of invasive aspergillosis. ^{[13],[18],[19]} The clinical manifestations are initially nonspecific and consist of fever, cough, epistaxis, sinus discharge, and headaches. ^[19] Clinical examination is usually non-diagnostic. Frequently, the disease spreads to adjacent areas ^[20] including the CNS and the mortality in these cases is high. ^[16],[21] Computed tomography (CT) scans of sinus are useful for establishing extent of infection and determining local invasion of bone and soft tissues. Diagnosis is established presumptively from culture of sinus or nasal material but requires tissue to document invasiveness. ^{[1],[17],[22]} The source of mucormycosis is exogenous and the organism usually gains entry into the host through the respiratory tract. ^[12] Spores can also be introduced directly through abraded skin to cause primary cutaneous mucormycosis that can further proliferate and disseminate to other body organs. ^[8] Patients with diabetic ketoacidosis are at high risk of developing rhinocerebral mucormycosis. ^{[1],[19],[23],[24],[25]} The clinical hallmark of mucormycosis is the rapid onset of tissue necrosis, with or without fever. This necrosis is the result of invasion of blood vessels and subsequent thrombosis. ^[26],[27] Mucormycosis is frequently rapidly progressive and antifungal therapy alone is often inadequate to control the infection. Surgical debridement of the infected and necrotic tissue should be performed on an urgent basis. ^[21],[26]

Rhinocerebral mycosis is associated with high mortality in spite of aggressive therapy. Intracranial extension with focal neurological deficits is a major predictor of mortality in rhinocerebral mycosis. It carries a high residual morbidity and mortality due to the angioinvasive property of fungi, causing vascular occlusion and extensive tissue necrosis. Impaired delivery of the antifungal drugs to the site of infection because of vascular thrombosis and limited aggressive surgery because of the complex anatomy of the rhinoorbitocerebral region cautions for early diagnosis and aggressive management in these patients. ^[28] It has been observed that radical surgery done early and as a first procedure is better than repeated attempts at sub-radical resection. ^[29] A peculiar response to surgery has been reported in the literature, which was also noted in our series. The disease process which may have been present for some time flares up postoperatively assuming a rapidly fulminant course. The hallmark of this unusual response is high-grade fever, tachycardia and rapidly increasing diffuse cerebral edema causing a potentially fatal rise in intracranial pressure refractory to medical management. The reason for this unique stormy postoperative course is incompletely understood but may be explained on the basis of either the patient becoming immunocompromised secondary to surgery or due to the manipulation of organism catalyzing the stimulation of previously quiescent fungi. Another possibility is that of acute aspergillus meningo-encephalitis which may also lead to diffuse cerebral edema. ^[30]

Amphotericin B remains the only antifungal agent approved for the treatment of this infection. ^{[9],[31],[32],[33]} Because many Mucorales isolates are either relatively or highly resistant to amphotericin B, high doses of this drug are required. ^[26],[34] However, this dose frequently causes nephrotoxicity. ^[33] The lipid formulations of amphotericin B are significantly less nephrotoxic than amphotericin B deoxycholate and can be administered at higher doses for a longer period of time. ^[35] Several case reports of patients with mucormycosis document successful treatment with up to 15 mg/kg/day of a lipid formulation of amphotericin B. ^{[16],[36],[37]} The utility of liposomal amphotericin B at 5 mg/kg/day was compared to standard amphotericin B at 1.0 mg/kg/day for proven or suspected invasive mycoses. ^[24],[38] Overall outcomes of both groups in this small study were equivalent; however, analysis of outcomes in those patients with proven invasive aspergillosis favored therapy with the liposomal preparation. ^[39] Itraconazole is the only marketed azole drug that has in vitro activity against Mucorales. ^[40] However, itraconazole has not been found to be effective for treating mucormycosis. Voriconazole, a recently approved second-generation broad-spectrum triazole, is not active against Mucorales in vitro. ^[40] However, it has been found to be more efficacious then amphotericin B in cases of invasive aspergillosis. ^[6],[2] Combination of suboptimal doses of liposomal amphotericin B and voriconazole given concurrently had a significantly better efficacy in comparison with either monotherapy. ^[41] In addition, liposomal amphotericin B in combination with caspofungin and micafungin also showed strong trends towards improved efficacy. ^[30] The efficacy, dosages and spectrum of the antimycotic drugs have been summarized in [Table - 4].

In our series, we analyzed the granulomatous fungal lesions affecting the skull base. Good host immunity is a prerequisite for granuloma formation whereas patients with poor immunity often develop meningitis or meningoencephalitis. ^[17] This probably explains the apparent increase in occurrence of infection in immunocompetent individuals in our series. The proposed staging is based on the natural course of the disease entity. The invasiveness of the disease should be confirmed by tissue sampling in Stage I before initiating aggressive therapy, as there are noninvasive fungal infections such as skull base allergic fungal sinusitis, ^[42] which incorporate the histologic diagnostic criteria of allergic fungal sinusitis with the CT criteria of bone erosion. Once the invasiveness is proved with tissue sampling, a thorough debridement followed by antifungal therapy is a must even in Stage I. If the disease process has not breached the dura (Stage II), a transcranial procedure has to be avoided as the iatrogenic dural breach and contamination of the CNS can result in rapid progression of the disease to terminal stages. ^[43] To avoid such a disaster, a high degree of clinical suspicion of the diagnosis is required, and a trans-nasal biopsy is performed to diagnose tissue invasiveness. In Stage III, once the diagnosis is confirmed, aggressive surgical debridement of infected tissue with total excision of the granuloma, and appropriate antifungal therapy has to be administered. All efforts to attain gross total excision should be made at surgery, followed by a complete course of antifungal therapy, as longer PFS has been attained with this strategy. The prognosis is very poor when the disease progresses to Stage IV. ^{[17],[43],[44],[45]} Patients at this stage are often not candidates for surgery, and are managed with antimycotic therapy and supportive care.

To conclude, invasive rhino-cerebral mycosis has a poor prognosis. Sinocranial aspergillosis is a rare entity and the mass lesions can be intracranial extracerebral (mostly in anterior cranial fossae), intracerebral or both. These patients need surgical procedures that combine otolaryngological and neurosurgical expertise. ^[46] A high degree of clinical suspicion is required for diagnosis, as the critical factor in treatment is the rapidity of diagnosis and early administration of antimycotic therapy. At times radical surgical excision may not be possible and radical surgery may be associated with significant morbidity. Some of these patients may have a stormy course or rapid progression following surgery. ^[46] Total surgical excision with complete course of antimycotic therapy increases the PFS period. A better antimycotic drug with less toxicity and high efficacy with fungicidal property can make a difference in the prognosis of the disease.

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