Neurosurgery Issue: Volume 31(3), September 1992, p 575-579 Copyright: Copyright (C) by the Congress of Neurological Surgeons Publication Type: [Case Report] ISSN: 0148-396X Accession: 00006123-199209000-00023 Keywords: Amphotericin B, Aspergillus, Brain abscess, Intracavitary antibiotics, Transplant [Case Report] Continual Intracavitary Administration of Amphotericin B as an Adjunct in the Treatment of Aspergillus Brain Abscess: Case Report and Review of the Literature Camarata, Paul J. M.D.; Dunn, David L. M.D., Ph.D.; Farney, Alan C. M.D.; Parker, Richard G. M.D.; Seljeskog, Edward L. M.D., Ph.D. Author Information Departments of Neurosurgery (PJC, RGP, ELS) and Surgery (DLD, ACF), University of Minnesota, Minneapolis, Minnesota Reprint requests: Paul J. Camarata, M.D., Department of Neurosurgery, University of Minnesota, Box 96 UMHC, 420 Delaware St. S.E., Minneapolis, MN 55455. Received, April 8, 1991. Accepted, March 20, 1992. ---------------------------------------------- Outline ABSTRACT CASE REPORT DISCUSSION ACKNOWLEDGMENTS REFERENCES:() COMMENTS COMMENTS ABSTRACT ASPERGILLUS BRAIN ABSCESS is often a fatal disease, regardless of the mode of therapy. Most often seen in the compromised host, it is notoriously refractory to systemic antifungal agents and intrathecal antimycotics. Even with radical surgical debridement, only 13 patients, including the present case, have survived longer than 3 months after being treated for aspergillus brain abscess or granuloma. Studies have shown poor penetration of amphotericin B into the brain and cerebrospinal fluid. One way to achieve therapeutic levels of the agent near the abscess is through the direct introduction of the agent into the abscess site via an indwelling catheter. In the present case, a woman with an aspergillus abscess of the left temporal lobe was treated by a combination of systemic agents, radical debridement, and local therapy, resulting in a cure with a follow-up of 6 years. This is the first reported instance of the use of long-term, local antifungal therapy delivered to the area of the abscess cavity, using a closed reservoir system, and this patient is only the second renal transplant patient reported to have survived aspergillus brain abscess. This form of treatment produced no untoward long-term side effects or neurological sequelae. Local irrigation with antifungal agents should be considered in conjunction with systemic antifungal drugs and drainage and/or debridement in cases of fungal intracerebral aspergilloma. This technique may also prove useful with other fungal brain lesions. ---------------------------------------------- Aspergillosis of the central nervous system (CNS) is a rare but deadly complication of immunosuppressive therapy 3,6,15,30,32,33. As the second most common fungal infection in the immunocompromised host, it can manifest as a disabling meningitis, cerebritis, abscess, granuloma, or vasculitis 30. In organ transplant patients, it most often appears within 6 months of grafting, when the net state of immunosuppression is at its peak, especially in those patients whose immunosuppression has been acutely increased to combat graft rejection 6. Treatment of this fungal infection is most often ineffective and usually requires multiple therapeutic strategies, including systemic antifungal agents, surgery (either open or stereotactic) for drainage and treatment of mass effect, and intrathecal or intraventricular administration of amphotericin B in the case of aspergillus meningitis 30. Even with the most aggressive surgery and antifungal therapy, most cases of aspergillus abscess or granuloma are fatal, with only a rarely reported long-term survivor in the literature 1,2,5,7,10,12,13,16,17,21-23,29. We report a patient with aspergillus abscess treated not only with surgical drainage and debridement and antifungal agents, but also with the continual administration of an intracavitary antifungal agent. She is alive and well 6 years after treatment. The efficacy and the therapeutic potential of continual local antifungal therapy as an adjunct in treating this and other infectious lesions are discussed. CASE REPORT A 20-year-old woman underwent a cadaveric renal transplant in April 1984 for chronic renal failure secondary to damage from Epstein's syndrome. Her immunosuppression regimen consisted of azathioprine, prednisone, and cyclosporine A. Cyclosporine A was eventually discontinued because of toxicity. The patient experienced several episodes of acute rejection in June 1984, September 1984, and in September 1985, each of which was treated with an increase in prednisone, followed by a standard taper. She was admitted to the hospital on October 27, 1985, after complaining of a 3-week history of headache on the left side, decreased visual acuity, neck pain, and more recently, nausea and vomiting. One day before admission, she experienced intermittent blurred vision, arm pain, dizziness, and increasing lethargy. Her physical examination was remarkable for gross bilateral papilledema. She was disoriented and lethargic, but she moved all extremities well. Computed tomography (CT) of the brain revealed a large ring enhancing mass lesion, measuring 3 x 3 x 4 cm, in the left posterior temporoparietal region, with a large amount of surrounding edema, compression of the lateral ventricle, and significant midline shift (Fig. 1A). The lesion was aspirated under CT guidance, and 14 ml of grossly purulent material was removed after the firm abscess wall was penetrated, with significant relief of the mass effect. Potassium hydroxide preparation revealed the presence of numerous septated hyphae, and the patient began receiving amphotericin B immediately. The next day, a catheter was inserted into the abscess cavity under CT guidance, and daily irrigation of the cavity with amphotericin B was begun. Simultaneously, the patient began receiving intravenous administrations of 5-FC and rifampin for synergistic activity against Aspergillus fumigatus, which was now growing from initial cultures. On November 5, a new catheter (Scott cannula, Baxter V. Mueller, Chicago, IL) was repositioned into the abscess cavity, and an additional 12 ml of purulent material was aspirated. Irrigation and intracavitary administration of 5 [mu]g of amphotericin B in 1 ml of sodium chloride solution was performed daily for 4 weeks. Cultures aspirated from the cavity were positive for fungus 3 weeks later. The catheter was removed after 4 weeks. The patient had developed transient numbness in her right lower extremity that had now resolved, and a CT scan showed resolution of most of the abscess and mass effect. The patient was maintained on systemic amphotericin B therapy for about 6 months and was doing well. Her immunosuppressive therapy was continued throughout this time period. The antifungal therapy was discontinued when a biopsy of the abscess cavity was negative for fungus. She was readmitted, however, in July 1986 complaining of severe headache, and CT showed a large recurrent abscess cavity (Fig. 1B). She was taken to the operating room, the abscess cavity was drained and debrided of necrotic material, and a catheter attached to an Ommaya reservoir (Codman and Shurtleff, Inc., Randolph, MA) was placed and used for intracavitary instillation of amphotericin B on a daily basis, postoperatively. A similar system has been described previously in the aspiration of intracranial cysts 9. Beginning initially at 5 [mu]g, the intracavitary dose was increased slowly to 25 [mu]g/d. The administration of systemic amphotericin B was also started again at this time, and her immunosuppressive therapy was continued. She did well for 2 months, but then she returned with increasing visual complaints and was found to have a right 6th nerve palsy and a right homonymous hemianopsia. CT showed a large recurrent mass. A craniotomy was performed, the cavity was drained, and the surrounding granulomatous mass was excised. The Ommaya reservoir and catheter were removed, and a new assembly was placed. Material excised at this operation showed fungus infiltrating brain parenchyma and septated hyphae with hematoxylin and eosin staining (Fig. 2). Postoperatively, the right homonymous hemianopsia remained. The azathioprine was discontinued at this time; the prednisone was continued on a low maintenance dose (10 mg/d). She was treated as an outpatient, receiving daily administrations of systemic amphotericin B and intracavitary amphotericin B at a dose of 40 [mu]g/d. After 3 months, the dosage was decreased to 40 [mu]g every other day and was eventually discontinued after 6 months, as it was becoming increasingly difficult to instill the medication into the reservoir. This was probably caused by scarring around the catheter. The systemic antifungal therapy was continued for another 2 months. The patient was subsequently readmitted with what proved to be a Staphylococcus epidermidis sepsis and meningitis, with a concomitant infection of the reservoir; CT showed no parenchymal changes. Both the Ommaya reservoir and catheter were removed as well as her Hickman catheter, and she was treated with a 2-week course of intravenously administered antibiotics. She remains disease free 5 years later with no further radiographic or neurological progression. Her most recent magnetic resonance imaging scan is seen in Figure 1C. DISCUSSION There is no routinely effective treatment of aspergillus brain abscess. The surgical treatment of fungal brain lesions is varied and is determined by the nature of the infection 35. Abscesses with well-formed capsules are often drained or excised depending on the size and location of the lesion, yet this is rarely curative. Medical treatment of aspergillus CNS infections is most often ineffective, mainly because of the problems in delivering sufficient doses of amphotericin B to the brain. Indeed, recent studies have provided evidence that after systemic administration only extremely low concentrations of amphotericin B occur in the cerebrospinal fluid 28 and brain parenchyma 24. The poor success of traditional medical and surgical treatment modalities led us to attempt long-term intracavitary administration of amphotericin B in this patient. Although CT-guided drainage and administrations of systemic amphotericin B were initially effective in controlling the disease, a subsequent recurrence required open surgical drainage and debridement. Despite this surgery, the abscess recurred, requiring an additional surgical debridement, with a cure being effected only after long-term intracavitary and systemic amphotericin B. Surgical drainage and intravenous administrations of antimycotics have only rarely been successful in treating aspergillus brain abscess. In a review of the literature, Goodman and Coffey 12 found only 5 patients who survived, with follow-up ranging from 3 months to 3 1/2 years. Including the present report, we have found an additional 11 cases of biopsy-proven intracerebral aspergillosis, with survival after treatment (Table 1). There was 1 other case of survival after aspergillus abscess in a renal transplant patient 5. In 2 of these cases, the length of follow-up was not stated 14,26. Three additional cases of patients with presumptive aspergillosis who survived were reported by Lemarie et al. 25, Jinkins et al. 20, and Mohandas et al. 27. All of the biopsy-proven cases included craniotomy and excision and drainage of the mass with the exception of those reported by Goodman and Coffey 12, Bradley et al. 2, Burton et al. 5, and Green et al. 13, whose patients were cured by stereotactic drainage and the administration of systemic and/or intraventricular 2,12,13 and intraocular 5 antifungal agents alone. Intracavitary antibiotics have routinely been used to treat fungal abscesses elsewhere in the body, most notably the chest 19,31. Broggi et al. 4 reported the successful treatment of four patients with brain abscesses treated with stereotactic aspiration, followed by irrigation with antibiotics through a closed system (Rickham reservoir). There were no untoward effects of this treatment. Henze et al. 17 described the successful treat-ment of a young, immunosuppressed child with aspergillosis, using postsurgical local antimycotic treatment for 4 days, followed by removal of the catheter. Direct CNS administration of amphotericin B has been limited because of associated neurotoxic symptoms, including psychosis, quadriparesis, seizures, visual disturbances, myelinolysis 18, and leukoencephalopathy 8. It has proven useful in some cases of fungal meningitis 11,34,35. There has been no apparent CNS injury in our patient, who is alive, well, and disease free some 6 years after her initial presentation. Medical and surgical therapy using systemic amphotericin B and drainage or debridement has rarely been effective in eradicating aspergillus abscess. We believe that the addition of continual intracavitary administration of amphotericin B through a closed system might be a useful adjunct to long-term systemic antifungal agents, local drainage, and debridement in treating aspergillus brain abscess, which has historically been an invariably lethal infection. Additional experience in using intracavitary antimycotics will be needed to assess the efficacy of this modality in the treatment of fungal brain abscess. ACKNOWLEDGMENTS The authors would like to acknowledge the help of Dr. Josephine Lo in the translation of reference number 10. REFERENCES:(1-35) 1. 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Monji N, Bonner DP, Hashimoto Y, Schaffner CP: Studies on the absorption, distribution and excretion of radioactivity after intravenous and intraperitoneal administration of 14C-labeled methyl ester of amphotericin. B J Antibiot (Tokyo) 28:317-324, 1975. 29. Ramos-Gabatin A, Jordan RM: Primary pituitary aspergillosis responding to transsphenoidal surgery and combined therapy with amphotericin-B and 5-fluorocytosine. J Neurosurg 54:839-841, 1981. 30. Salaki JS, Louria DB, Chmel H: Fungal and yeast infections of the central nervous system. A clinical review. Medicine 63:108-132, 1984. Ovid Full Text Full text via Find It Bibliographic Links 31. Schmitt GS, Ohar JM, Kanter KR, Naunheim KS: Indwelling transbronchial catheter drainage of pulmonary abscess. Ann Thorac Surg 45:43-47, 1988. Full text via Find It Bibliographic Links 32. Walsh TJ, Hier DB, Caplan LR: Aspergillosis of the central nervous system: Clincopathological analysis of 17 patients. Ann Neurol 18:574-582, 1985. 33. Walsh TJ, Hier DB, Caplan LR: Fungal infections of the central nervous system: Comparative analysis of risk factors and clinical signs in 57 patients. Neurology 35:1654-1657, 1985. Full text via Find It Bibliographic Links 34. Winn WA: The treatment of coccidioidal meningitis. The use of amphotericin B in a group of 25 patients. Calif Med 101:78-89, 1964. Full text via Find It Bibliographic Links 35. Young RF, Gade G, Grinnell V: Surgical treatment for fungal infections in the central nervous system. J Neurosurg 63:371-381, 1985. Full text via Find It Bibliographic Links COMMENTS The physicians caring for the patient in this Case Report were tenacious in effecting what probably is a cure. The value of this report is that it demonstrates that one can use local therapy with amphotericin B in combating this fungal disease of the brain. However, it is possible that systemic therapy combined with a reduction in the immunotherapy necessary to support the renal transplant was also essential in providing suppression of the disease process. In dealing with patients whose immune systems are not normal, the medical practitioner is faced with an enormous challenge to balance the agents that are needed to suppress immune rejection as well as infective agents. The authors have shown that local therapy probably played an important role in that balance. It would be interesting to question the authors as to whether, if faced with another similar patient, they would wait so long to excise the abscess. A cure really was not assured until the time-honored treatment of surgical excision was performed, although one has to factor in the information that immunosuppressive therapy also was decreased before effecting what appears to be a cure. It would be of added interest to know whether or not the authors think that their initial course of therapy with systemic amphotericin B, which was stopped at the end of 6 months, should have been continued for a longer period of time. Frances K. Conley Stanford, California COMMENTS An innovative treatment method is introduced for very a recalcitrant disease: Fungal abscess of the brain. The method deserves a more wide-spread trial, and a final determination of its efficacy will require results from a significantly larger number of cases. In this one reported case, the authors have achieved a long survival for their patient. Howard A. Richter Wynnewood, Pennsylvania KEY WORDS: Amphotericin B; Aspergillus; Brain abscess; Intracavitary antibiotics; Transplant ----------------------------------------------