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Neuroaspergillosis is mostly reported in immunocompromised patients with a mortality rate near 100%.1 Only 16 cases have been reported in immunocompetent patients with a low mortality rate (two of 16).1 2 Tuberculomas of the brain constitute 0.15% of all intracranial space occupying lesions in western countries. We describe the first known case of neuroaspergillosis associated with neurotuberculosis in an immunocompetent patient successfully treated with itraconazole and antituberculous therapy.
A 42 year old Djiboutian woman, living in France since 1973, was admitted to hospital for partial seizures after a one month history of fatigue and 5 kg weight loss (42 kg). She had no previous history of immunodeficiency, transplantation, cancer, long term chemotherapy, or other chronic illness. The patient had no identifiable risk factors for AIDS. On admission, physical examination disclosed fever (⩾38°C), a left sided hemiparesis, and a nystagmus. Routine laboratory tests were normal, as were serum globulin, rheumatoid factor, antinuclear antibodies, anti-native DNA antibodies, anti-SS-A and anti-SS-B antibodies, anti-Sm antigen, antineutrophil cytoplasmic antibodies, circulating immune complexes, serum complement, and antithyroid antibodies. Although she had never received BCG vaccination, the tuberculin skin test showed an induration of 14 mm. A serological test for human immunodeficiency virus (HIV1 and HIV2) was negative. The contrast enhanced brain CT showed multiple low density lesions with a ring enhancement consistent with cerebral abscesses and others lesions with homogenous enhancement consistent with granulomas, located in the cerebellum and hemispheric lobes, confirmed by the MRI (figure). A chest radiograph and CT showed bilateral nodular diffuse infiltrate syndrome suggesting miliary tuberculosis, and cavitary process in the upper right pulmonary lobe. Microscopical examination of the bronchoalveolar lavage fluid was negative and the CD4/CD8 index was normal (2.923). Lumbar puncture was not performed because of a lesion near the fourth ventricle. Craniofacial and ophthalmological examination, a sinus radiograph, and an echocardiogram were normal (excepting the existence of the nystagmus). Five days after admission, chemotherapy was given with isoniazid (300 mg daily), rifampicin (600 mg daily), ethambutol (1200 mg daily) and pyrazinamide (1800 mg daily). After 15 days, it was interrupted because of severe hepatic cytolysis with hepatic insufficiency (prothrombin time 30%). Brain biopsy (granuloma formation) was performed and microscopical examination disclosed branching septate hyphae. Histopathology showed granuloma with epithelioïd cells and Langhans giant cells and a necrotic centre without caseation. Ziehl-Nielsen, periodic acid Schiff, and Grocott stains were negative. Löwenstein and Sabouraud cultures of the cerebral tissue grew Mycobacterium tuberculosis andAspergillus fumigatus. Bronchoalveolar lavage fluid culture grew Mycobacterium tuberculosis. Aspergillusserology by counter-immunoelectrophoresis was negative. The patient was treated orally with a combination of itraconazole (600 mg daily) and the same antituberculous agents at lower doses (150, 400, 1000, and 1500 mg daily respectively). There was a complicated course with jaundice and mild hepatic necrosis with antituberculous agents, itraconazole and valproate, agranulocytosis with carbamazepine and phenytoin, and encephalopathy with vigabatrin. After five weeks and eight weeks respectively, pyrazinamide and isoniazid were stopped. After eight weeks, itraconazole was stopped. There was a favourable clinical outcome with rare focal seizures. After four months, white blood cell count was normal, a second serological test for HIV and P24 antigenemia was negative. No HIV virus culture was performed. Lymphocyte proliferation tests with phenylalanine, concanavaline A, and poke weed were normal. Control of humoral immunity was normal, as were a chest radiograph and encephalic MRI. After nine months with rifampicin and ethambutol antituberculous therapy and primidone antiepileptic drug therapy, the patient was clinically asymptomatic; red and white blood cell counts were normal. There was an isolated mild increase in γ-glutamyltransferase. Routine chest radiography was normal.
Aspergillosis is an infrequent fungal infection of the CNS. Neuroaspergillosis is an opportunistic infection and usually occurs in disseminated aspergillosis complicating an underlying malignancy or other cause of chronic immunosuppression with a mortality rate near 100%.1 Most cases are due to Aspergillus fumigatus.3 Definite diagnosis of neuroaspergillosis requires isolation of Aspergillus fumigatus from a biopsy specimen of the cerebral tissue or from CSF.4 In our case, Löwenstein culture of the brain biopsy was positive for Aspergillus fumigatus and microscopical examination disclosed branching septate hyphae excluding accidental direct cerebral contamination. Definite diagnosis of brain tuberculosis generally requires isolation of Mycobacterium tuberculosis from a biopsy specimen of the cerebral tissue or typical granuloma. Granuloma formation is the most frequent form of parenchymal brain tuberculosis with central solid caseation with few or no bacilli. Tuberculous abscesses with central pus with numerousTubercle bacilli are uncommon and more often found in patients with AIDs. The morphological changes in aspergillosis of the CNS tend to be acute and necrotising or purulent when the infection is the result of haematogenous dissemination.3 In our patient granulomas and abscesses were found on brain CT and brain biopsy confirmed the granulomatous character of one formation. In both infectious diseases, brain involvement is usually the result of haematogenous dissemination from the lung. No pulmonary aspergillosis was identified in our case, but it could have been limited to the cavitary process of the upper lobe, explaining the negativity of the aspergillus serology. A transient cellular immunodeficiency, due to the pulmonary tuberculosis or to an unknown factor could have been a predisposing factor for brain involvement by Aspergillus fumigatus. There was a good outcome with antituberculous agents and with itraconazole therapy. For invasive aspergillosis, response to itraconazole therapy is sometimes superior to conventional amphotericin B.1 2 The clinical response to itraconazole therapy is correlated with serum antifungeal concentrations.4 5Although concurrent administration of rifampicin may lead to a reduction in serum itraconazole concentrations,5 there was a good outcome in our patient. Our finding suggests that neuroaspergillosis and neurotuberculosis may be associated and seems to confirm the relative mildness of neuroaspergillosis and the efficacy of itraconazole therapy in immunocompetent patients
We thank Mr Richard Medeiros for his advice in editing the manuscript.
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