Neurosurgery Issue: Volume 36(4), April 1995, p 858-863 Copyright: Copyright (C) by the Congress of Neurological Surgeons Publication Type: [Case Report] ISSN: 0148-396X Accession: 00006123-199504000-00032 Keywords: Aspergillus, Cerebral abscess, Immunosuppression, Itraconazole, Liposomal amphotericin B, Neurosurgery [Case Report] Invasive Central Nervous System Aspergillosis: Cure with Liposomal Amphotericin B, Itraconazole, and Radical Surgery-Case Report and Review of the Literature Coleman, Jacinta M. M.B.B.S., F.R.A.C.P.; Hogg, Geoff G. B.M., B.S.; Rosenfeld, Jeffrey V. M.B., M.S.; Waters, Keith D. M.B.B.S. Author Information Departments of Clinical Microbiology (JMC, GGH), Neurosurgery (JVR), and Hematology (KDW), Royal Children's Hospital, Parkville, Victoria, Australia Reprint requests: Dr. Geoff G. Hogg, Director of Clinical Microbiology and Infectious Diseases, Royal Children's Hospital, Park-ville, Victoria 3052, Australia. Received, September 28, 1993. Accepted, November 11, 1994. ---------------------------------------------- Outline ABSTRACT CASE REPORT DISCUSSION Clinical manifestations of invasive aspergillosis Clinical treatment Surgical procedures Antifungal therapy CONCLUSION ACKNOWLEDGMENTS REFERENCES: () COMMENTS REFERENCES: () COMMENTS ABSTRACT INVASIVE ASPERGILLOSIS OF the central nervous system is a rare but well-described disease. There have been only a few reported survivors, and mortality exceeds 95% in the immunosuppressed host. We present a 2-year-old boy with acute lymphatic leukemia and multiple Aspergillus brain abscesses who was successfully treated with liposomal amphotericin B, itraconazole, and surgical excision of the abscesses. Liposomal amphotericin B is a new preparation that safely allows the attainment of significantly higher tissue levels with less toxicity than standard amphotericin B. The treatment of patients with invasive central nervous system aspergillosis is reviewed. ---------------------------------------------- Invasive aspergillosis is a rare disease that predominantly effects the immunocompromised patient (1,13). It continues to have a high mortality rate >90% in most series, despite the use of antifungal chemotherapy and surgery (1,13,30,40). Liposomal amphotericin B achieves significantly higher tissue levels than conventional amphotericin B. Combining this with an extensive neurosurgical approach and itraconazole achieved a cure in an immunocompromised patient with invasive aspergillosis of the central nervous system (CNS) after 33 months of follow-up. CASE REPORT A 2-year-old boy with acute lymphatic leukemia began induction therapy with intravenous administration of vincristine and daunorubicin, intramuscular administration of L-aspariginase, intrathecal administration of methotrexate, and oral administration of prednisolone. In addition, he received oral cotrimoxazole and nystatin. He was discharged in remission. The patient presented 4 weeks after beginning chemotherapy, with a 10-day history of cough and rhinorrhea, 3 days of fever, and 12 hours of recurrent myoclonic jerking of the left side of his body, involving his arm and face. Neurological and fundal examinations revealed nothing abnormal. A full blood examination showed a white cell count of 1.8 x 109/L, with 3% bands, 30% neutrophils, 65% lymphocytes, and 2% monocytes. A lumbar puncture was not performed. A computerized tomographic (CT) brain scan showed several right-sided frontal lesions with ring enhancement after administration of contrast material. There was no evidence of edema or mass effect (Fig. 1). A chest x-ray and abdominal ultrasound revealed nothing abnormal. A right frontotemporal craniotomy was performed, and two abscesses were located measuring 1.5 cm in diameter. The cortical surface appeared normal. The wall of the abscess cavity was not well formed, and frank pus and necrotic brain were removed. Histology of the specimen showed necrotic brain substance with invasion by polymorphs and fibrin. Blood vessels were cuffed by lymphocytes and occasional polymorphs. Microscopic analysis and culture of this specimen yielded Aspergillus fumigatus. A separate parasagittal frontal craniotomy was performed, but the deep medial frontal abscess was not located. After surgery, conventional amphotericin B was started at 0.5 mg/kg. (The child weighed 13.4 kg.) A repeat CT scan 3 days after commencement showed development of a new enhancing lesion in the lower lateral right frontal lobe (Fig. 2), and a decision was made to start liposomal amphotericin B (AmBisome, Faulding) at 3 mg/kg/day. The patient remained well clinically, despite occasional seizures while receiving treatment with phenytoin. A second CT scan showed progression in the number and size of the right frontal lobe abscesses and development of new abscesses in the left parietal region, the right cerebellum, and the left thalamus. At this stage, because of the patient's excellent tolerance of liposomal amphotericin B, the dose was increased from 3 to 5 mg/kg after 6 days of therapy. After an additional 7 days at this dose, and continuing high tolerance of the drug, it was increased to 10 mg/kg and, finally, to a maximal dose of 15 mg/kg/day after 4 days. It was only then that he became hypokalemic. Further CT scans showed that the frontal abscesses had continued to enlarge (Fig. 3). Twenty-one days after admission, a right frontal craniotomy, a frontal lobectomy, and a left parietal craniotomy were performed. During the right-sided procedure, an intraoperative ultrasound examination identified the posterior and medial extent of the right frontal abscess, which was carefully excised. The latter area was seen to have a clearly abnormal section of cortex, which was contiguous with an underlying abscess measuring approximately 2.5 cm in diameter. This entire complex was excised. A. fumigatus was reisolated from the right frontal extradural tissue but not from the brain substance. After surgery, the patient had a dense left hemiplegia, which resolved almost completely during a 2-week period. Oral itraconazole, 50 mg daily, was added to his antifungal regimen, and antileukemic therapy was reinstituted 5 weeks after admission. One month later, another brain CT scan showed a residual abscess in the right frontotemporal region in the posterior aspect of the previous resection (Fig. 4). This remaining abscess was excised but was culture negative. A full blood examination now demonstrated a white cell count of 10 x 109/L with 73% neutrophils. The patient had a residual, slowly resolving, dense left-sided hemiplegia. In total, he received 40 days of daily liposomal amphotericin B at 15 mg/kg, in addition to 21 days of varying dosages, as previously described, to a total dose of 11.45 g of liposomal amphotericin B. He had a further 20 days of alternate-day conventional amphotericin B, making a total combined dose of 11.75 g of amphotericin B. He remained on itraconazole for 15 weeks. Currently, 29 months after cessation of liposomal amphotericin B and itraconazole and extensive surgery, he remains in leukemic remission, and additional CT brain scans show no evidence of residual abscesses. His postoperative course was complicated by the development of hydrocephalus requiring insertion of a ventriculoperitoneal shunt. Neurologically, he has a moderate paresis of the left arm and a mild hemiplegic gait. He has not had any psychometric evaluations at this stage. DISCUSSION Clinical manifestations of invasive aspergillosis The most common clinical pattern of invasive aspergillosis is the development of unremitting fever, despite broad-spectrum antibiotics, and the appearance of pulmonary infiltrates on chest x-ray (12,30). Pulmonary involvement occurs in the majority of patients (1,12,30). In patients who develop CNS involvement, it is rare to find isolated disease (30,38,40). A postmortem analysis of 17 patients with invasive aspergillosis of the CNS concluded that immunosuppressed patients were less likely to present with neurological symptoms than immunocompetent hosts (38). Headache was usually absent in both immunosuppressed and immunocompetent patients, and the presenting symptoms were predominantly focal neurological deficits, particularly hemiparesis, consistent with the underlying anatomical site of the disease. Seizures were uncommon, particularly in the immunosuppressed patients, and meningeal symptoms occurred in only one patient with sarcoidosis, who also had a subarachnoid hemorrhage. Clinical treatment An extensive review of the literature revealed 25 survivors of invasive CNS aspergillosis in addition to our own patient. The survivors include 12 immunocompetent and 13 immunosuppressed patients (Table 1). Treatment of the surviving patients involved a combination of antifungal chemotherapy and neurosurgery. To our knowledge, this is the first such patient to be described in whom a combination of liposomal amphotericin B, itraconazole, and aggressive neurosurgery has been used. Surgical procedures Neurosurgical procedures were performed in 20 of the 25 survivors. Only two patients with no underlying immunodeficiency had surgery alone (11,37). Fifteen patients had craniotomies with aspiration and resection of brain abscesses. In addition, two patients had intracavitary (8,23) and two had intraventricular (18,20) catheters inserted for the administration of local amphotericin B. Three additional patients underwent computed tomography-guided stereotactic aspiration and drainage procedures of their cerebral abscesses (6,17,36). Our patient initially had a craniotomy and resection of the abscess present in the right frontal lobe. In view of its position, close to the motor cortex, as limited a resection as possible was undertaken to preserve brain function. On the CT scan, a residual abscess was present in the posterior part of his previous resection, and a subsequent craniotomy was performed. Culture of this tissue proved negative. Antifungal therapy Antifungal therapy was instituted in the majority of survivors. This was administered either intravenously or locally into the site of infection. (Table 1). Our patient began therapy with conventional amphotericin B but showed progression of the existing lesions and development of new abscesses in the right cerebellum and left parietal and thalamic regions on CT scan. Liposomal amphotericin B was introduced and was rapidly increased to a dose of 15 mg/kg, a level that would be unattainable with conventional amphotericin B because of its nephrotoxicity (32,34,39). Inasmuch as liposomal amphotericin B is better tolerated, higher doses can be administered with resulting increased concentrations in infected tissues (9,29,34,38). Most patients are able to tolerate only 0.5-1.0 mg/kg conventional amphotericin B (39). Our patient was able to tolerate 15 to 30 times the maximally tolerated dose of conventional amphotericin B by using liposomal amphotericin B without developing significant renal function abnormalities. Studies in animals comparing the toxicity of liposomal amphotericin B to conventional amphotericin B demonstrate that the former is much better tolerated. Concentrations of amphotericin B in liver and splenic tissue are two- to threefold greater after administration of 1 mg/kg liposomal than the same dose of conventional amphotericin B. In brain tissue, the same dose of liposomal amphotericin B results in half the concentration of amphotericin B. However, a 5-mg/kg dose of liposomal amphotericin B results in a 10-fold rise in the concentration of amphotericin B in reticuloendothelial tissues and a 4-fold rise in brain tissue when compared with 1 mg/kg conventional amphotericin B (32). No controlled trials comparing tissue concentration of amphotericin B after administration of either liposomal or conventional amphotericin B in humans have been done. Itraconazole (Sporanox, Janssen-Cilag) is a triazole derivative and is an orally administered preparation with a broad antifungal spectrum of activity including Aspergillus species (3,19). The role of itraconazole in treating invasive aspergillosis has not yet been fully defined (14). Itraconazole was added to our patient's regimen to increase the antifungal treatment administered and to enable a longer period of treatment to be given. Its major advantage is that it can be given orally. The role of combining itraconazole and liposomal amphotericin B is not known. There have been two reported case histories of patients with invasive CNS aspergillosis who were treated with oral itraconazole and survived (5,26). CONCLUSION Invasive aspergillosis of the CNS is a serious complication in the immunosuppressed host, and early detection is mandatory for survival. Mortality of invasive disease is exceedingly high in such patients. 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Ramos-Gabatin A, Jordan RM: Primary pituitary aspergillosis responding to transphenoidal surgery and combined therapy with amphotericin B and 5-fluorocytosine. J Neurosurg 54:839-841, 1981. 34. Ringden O, Meunier F, Tollemar J, Ricci P, Tura S, Kuse EE, Viviani MA, Gorin NC, Klastersky J, Fenaux P, Prentice HG, Ksionski G: Efficacy of amphotericin B encapsulated in liposomes (AmBisome) in the treatment of invasive fungal infections in immunocompromised patients. J Antimicrob Chemother 28[Suppl B]:73-82, 1991. 35. Seres JL, Hirohisa O, Benner EJ: Aspergillosis presenting as spinal cord compression. J Neurosurg 36:221-224, 1972. Full text via Find It Bibliographic Links 36. Shuper A, Levitsky HI, Cornblath DR: Early invasive CNS aspergillosis: An easily missed diagnosis. Neuroradiology 33:183-185, 1991. Full text via Find It Bibliographic Links 37. Venugopal PV, Venugopal TV, Thiruneelakantan K, Subramanian S, Shetty MV: Cerebral aspergillosis: Report of two cases. Sabouraudia 15:225-230, 1977. Full text via Find It Bibliographic Links 38. Walsh TJ, Hier DB, Caplan LR: Aspergillosis of the central nervous system: Clinicopathological analysis of 17 patients. Ann Neurol 18:574-582, 1985. 39. Warnock DW: Amphotericin B: An introduction. J Antimicrob Chemother 28[Suppl B]:27-38, 1991. 40. Young RC, Bennett JE, Vogel CL, Carbone PP, DeVita VT: Aspergillosis: The spectrum of the disease in 98 patients. Medicine 49:147-172, 1970. Ovid Full Text Full text via Find It Bibliographic Links COMMENTS In patients with cancer, Aspergillus fumigatus has been reported to be the most common single organism causing brain abscess (1), with infection occurring within the first 2 weeks of neutropenia associated with acute leukemia and its therapy (2). The authors present a young child with multiple Aspergillus abscesses after receiving chemotherapy for leukemia, whose cure was effected by a rigorous multimodal approach, including multiple surgeries and administration of liposomal amphotericin B and itraconazole. The authors further review the literature with respect to survivors of invasive central nervous system aspergillosis. In light of the high mortality associated with fungal abscesses, especially in the setting of cancer, in which it may be as high as 95% (3), an aggressive approach combining surgical therapy with such newly developed antifungal chemotherapeutic agents is indicated to offer patients the greatest possibility of a successful outcome. Robert M. Levy Chicago, Illinois REFERENCES: (1-3) 1. Chernik NL, Armstrong D, Posner JB: Central nervous system infections in patients with cancer. Medicine 52:563-581, 1973. Ovid Full Text Full text via Find It Bibliographic Links 2. Hall WB: Neurosurgical infections in the compromised host. Neurosurg Clin North Am 3:435-442, 1992. Full text via Find It Bibliographic Links 3. Denning DW, Stevens DA: Antifungal and surgical treatment of invasive aspergillosis: Review of 2121 published cases. Rev Infect Dis 12:1147-1201, 1990. Full text via Find It Bibliographic Links COMMENTS Central nervous system aspergillosis in the immunocompromised patient is not necessarily fatal. Nonetheless, it carries an extremely grave prognosis, and even with the most aggressive therapy, most patients will die. The authors point out that aggressive surgical and chemotherapeutic efforts sometimes can be successful. We certainly hope that subsequent work will demonstrate the increased efficacy of liposomal amphotericin B, so that it becomes more widely available. The occasional success of very aggressive treatment of a disease that usually appears in the setting of a patient who already has a poor prognosis for other reasons creates a terrible therapeutic dilemma for the patient, the family, and the physician. This report will give comfort and support in those circumstances when extremely aggressive treatment seems justified by some reasonable chance of an ultimately good and functional outcome. However, in those situations in which the original underlying disease carries nearly as grave a prognosis as this complication, a decision not to pursue such a high risk of noncertain therapy may be viewed as medically and ethically appropriate. Stephen J. Haines Minneapolis, Minnesota KEY WORDS: Aspergillus; Cerebral abscess; Immunosuppression; Itraconazole; Liposomal amphotericin B; Neurosurgery ----------------------------------------------