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Fusarium Meningoencepbalitis in a Cbild witb Acute Leukemia By D. P. Agamanolis1, D. K. Kalwinskr, C. E. Krill]r. 1, Sarada Dasu l , B. Halasa l and Pamela G. Gallowayl

Abstract A 15-year-old boy with acute lymphoblastic leukemia (ALL) developed disseminated fusarium infection with meningoencephalitis following a contaminated skin wound. With antifungal therapy, the cutaneous lesions cleared but central nervous system (CNS) infection persisted causing a fibrosing meningitis and a brain granuloma. Fusaria are soil saprophytes that are more commonly associated with superficial eye and skin lesions, but mayaIso cause severe systemic infections with CNS involvement in immunocompromised patients. The organism may be confused with Aspergillus in tissue sections, and can only be diagnosed by culture.

Keywords Fusarium - Fungal infections - Acute lymphoblastic leukemia - Opportunistic infections - Meningitis

Fusarium, a ubiquitous soil saprophyte, can cause superficial corneal and cutaneous infections, but systemic infections are very rare. The following case, involving a child with ALL and fusarium meningoencephalitis, is unique. Fusarium brain abscess has been described in a child with burns but to our knowledge CNS infection in a child with a neoplasm has not been previously reported.

Case report A 15-year-old boy with a two-year history of ALL was on reinduction chemotherapy for bone marrow relapse when he had a motorcycle accident, during which he sustained a dirt-contaminated wound of the elbow.

Reeeived Oetober 18,1989; aeeepted November 13,1990 Neuropediatries 22 (1991) 110-112 © Hippokrates Verlag Stuttgart

The laceration healed weIl without evidence of infection and chemotherapy was continued. Blood and skin cultures were negative. After removal of the sutures, the healed laceration became indurated. Red, tender nodules appeared on the trunk and extremities. Aspirates of these grew fusarium oxysporum and biopsies revealed branching septate hyphae with vascular invasion. Treatment with granulocyte transfusions, miconazole, flucytosine and amphotericin B was begun. More skin lesions appeared, presenting as tender macules which progressed to bullae, underwent central necrosis, dried, shelledout, and healed. At the peak of this illness the patient had approximately 80 skin lesions. Twenty-five days after the first appearance of skin lesions, while still on amphotericin, a lumbar puncture showed a polymorphonuclear pleocytosis and cultures of CSF yielded fusarium. A repeat lumbar puncture three days later showed 5000 leukocytes/cu mm (92 % polys), and a CSF protein of 383 mg/dl. Fusarium cultures were now negative. Meningeal symptoms subsided and CSF protein decreased over the ensuing ten days. Serial CT scans revealed no evidence of parenchymal CNS or deep organ involvement and echocardiography showed no valvular vegetations. The skin lesions healed gradually. Chest x-rays and liver function tests remained normal through this period. No intrathecal antifungal therapy was given and after 40 days of systemic amphotericin B treatment, CSF, blood, and skin cultures were negative and antifungal therapy was discontinued. In the ensuing three months the patient remained in remission, but developed intermittent headaches and progressive neurologie deterioration with marked confusion. A lumbar puncture yielded xanthochromic CSF with 168 leukocytes/cu mm, glucose of 19 mg/dl and protein 188 mg/dl. Cultures for fusarium were negative. Several other lumbar punctures preceding and following this showed similar findings. Despite continued chemotherapy and antibiotics, the patient expired.

Pathological findings At autopsy, there was bronchopneumonia and no residualleukemia was found. The basalleptomeninges were cloudy and the subarachnoid space contained multiple 1 mrn, miliary yellowish nodules along blood vessels. A similar yellow granular coagulum was noted around the infundibulum, and small nodules or plaques of similar material were seen in the spinal subarachnoid (Fig. 1) and subdural space. Coronal seetions

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IDepartment of Pathology and Pediatries (Hematology-Oneology), Children's Hospital Medieal Center of Akron, Akron, Ohio, and Northeastern Ohio Universities College of Medieine, Rootstown, Ohio, and 2St. Jude Children's Hospital, Division of Leukemia/ Lymphoma, Memphis, Tennessee

Neuropediatrics 22 (1991)

Fig. 1 Multiple foci of purulent material are scattered along the spinal subarachnoid space. Fig. 2 Septate hyphae and chlamydospores in the spinal leptomeninges. Gomori methenamine silver, x 220.

of the brain revealed a one cm circumscribed yellow necrotic lesion in the left putamen. Multiple similar lesions measuring from 0.5 to 0.8 cm were seen in the spleen and kidneys. Microscopic examination of the meningeal lesions revealed masses of 5 to 7 micra-thick septate hyphae with moderate branching and with frequent chlamydospores in a background of degenerating acute and chronic inflammatory ceIls (Fig. 2). In other areas, organisms were fewer and the inflammatory reaction consisted of diffuse masses of epithelioid ceIls with numerous giant cells. There was diffuse fibrosing arachnoiditis and radiculitis. Small arteries showed inflammation, intimal proliferation, and narrowing of their lumina, but DO fungi were seen in their walls. A wide zone of CNS tissue around the lesions showed chronic inflammation, gliosis and hemosiderin deposition. The lesions of the kidneys and spleen were similar. Sections of skeletal muscle revealed severe denervation atrophy. Necrotic and purulent material from spinal cord and brain stern leptomeninges grew rapidlyon Sabouraud's glucose agar producing, in three to four days, white velvety colonies with a pink-violet center and a brightyellow colored reverse side. Slide cultures revealed septate hyphae and numerous characteristic sickle-shaped multiseptate mac.roconidia diagnostic of fusarium (Fig. 3). No other fungi were isolated from the CNS.

Fig. 3 Hyphae and characteristic banana-shaped septate macroconidia of fusarium in slide culture. Toluidine blue, x 440.

definitive diagnosis can onIy be made by culture; it is suspected by the gross morphology of the colonies, and confirmed by the presence of the diagnostic banana-shaped multiseptate macroDiscussion conidia in slide cultures. As demonstrated by the present case, This unusual and interesting case underlines CSF cultures may be negative in the presence of chronic the importance of this saprophytic organism as a potential op- meningoencephalitis and only cultures of infected tissue may portunistic pathogen in immunocompromised patients. It may yield reliable growth. produce chronic smoldering infection despite treatment with Fungi of the genus fusarium (class Deuteroantifungal agents, and invade the central nervous system. mycetes or fungi imperfecti, order Moniliales) have a worldIn tissues, fusarium appears as septate hyphae wide distribution in soil and have been found in plants and aniwith rare branching and is easily confused with aspergillus. A mals (5, 11). Fusarium secretes a mycotoxin that can result in

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D. P. Agamanolis et al

References

an illness called "alimentary toxic aleukia" when contaminated grain is ingested (11).

Our patient probably acquired the infection by contamination of skin wounds he suffered in the course of the motorcycle accident. With intensive amphotericin treatment, the skin lesions healed but the organism was apparently not eradicated and, following the initial phase of hematogenous dissemination, multiple foci of infection persisted in the spleen, kidneys, and brain. CSF pleocytosis and elevated protein suggested a chronic infection but repeated blood and CSF cultures were negative, and at autopsy the organism was isolated only from cultures of infected tissue.

Acknowledgment

We thank Terrie Hnat for assistance in photography and Vicki Parisi for typing the manuscript.

Abramowsky, C. R., et al: Systemic infection with fusarium in a bumed child. The emergence of a saprophytic strain. J. Pediatr. 84 (1974) 561564 2 Annaissie, E., et al: Fungal infection caused by fusarium in cancer patients. Am J. Clin. Oncol. (CCT) 10 (1987) 86-88 3 Benjamin, R. P., et al: Facial granuloma associated with fusarium infection. Arch. Dermatol. 101 (1970) 598-600 4 Blazer, B. R., et al: Invasive fusarium infections in bone marrow transplant recipients. Am J. Med. 77 (1984) 645-651 5 Booth, C.: The genus fusarium. Commonwealth Mycology Institute, Surrey, England, 1971 6 Bourguignon, R. L., et al: Fusarium species osteomyelitis., Case report. J. BoneJointSurg. 58 (1976) 722-723 7 Cho, C. T, et al: Fusarium solani infection during treatment for acute leukemia. J. Pediatr. 83 (1973) 1028-1031 8 Gutman, L., et al: Fusariosis, myasthenic syndrome, and aplastic anemia. Neurology 25 (1975) 922-926 9 iones, B. R., et al: Corneal and intraocular infection due to fusarium solani. Trans. Ophthalmol. Soc. UK 89 (1979) 757-779 10 Mutton, K.]., et al: Disseminated fusarium infection. Med. J. Austr.2 (1980) 1980-1981 11 Parker,]. C., Klintworth, G. K.: Fusariosis. In: Baker, R. D., ed.: Human Infections with Fungi, Actinomycetes and Algae. New York: SpringerVerlag (1971) 982-985 12 Steinberg, G. K., et al: Fusarium brain abscess. Case report. J. Neurosurg. 56(1983)598-601 13 Tackle, C., et al: Septic arthritis due to fusarium solani. J. Rheumatol. 10 (1983) 151-153 14 Wheeler, M. 5., et al: Fusarium infection in burned patients. Am. J. Clin. Path.75(1981)304-311 15 Young, N. A., et al: Disseminated infection by fusarium moniliforme during treatment for malignant lymphoma. J. Clin. Microbiol. 7 (1978) 589594 1

D. P. Agamanolis, M.D. Children's Hospital Medical Center of Akron Dept. of Pathology 281 Locust Street Akron, Ohio 44308, U.S.A.

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Human diseases due to direct invasion by fusaria, include superficial dermatoses, nail infections, and keratitis (11). Deep infections such as endophthalmitis (9), facial granuloma (3), osteomyelitis (6), and arthritis (13) have been reported following trauma or contamination of surgical wounds, especially in immunosuppressed patients, and fusarium peritonitis has been described in patients with continuous ambulatory peritoneal dialysis (14). Invasive fusarium infection has been described in bone marrow transplant recipients (4) and an increase in the incidence of mycoses, including infections by fusarium and other saprophytic organisms has been reported in burned patients (1, 14). Systemic fusariosis has been reported previously in eight patients, two with burns (1, 14), four with lymphoma-Ieukemia (2, 7, 10), one with aplastic anemia (8), and one with chronic infectious mononucleosis and immunodeficiency (12). Two of these patients had brain abscesses (1, 12), and one had, in addition, meningitis (12). As demonstrated by the present case and other reports (4, 14), the organism is difficult to eradicate being resistant to 5-fluorocytosine and relatively insensitive to amphotericin B.

Fusarium meningoencephalitis in a child with acute leukemia.

A 15-year-old boy with acute lymphoblastic leukemia (ALL) developed disseminated fusarium infection with meningoencephalitis following a contaminated ...
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