Brain abscesses are a challenging emergency and any delay in diagnosis or treatment may result in poor health outcomes for affected patients. The incidence of this infectious disease is approximately 0.4–0.9 per 100,000 individuals worldwide, with much higher rates among immunocompromised patients.1 Brain abscesses can be caused by bacteria, fungi or parasites.1 Aspergillus sp. is an opportunistic ubiquitous fungus that usually enters the body by inhalation of airborne spores; it can then invade the central nervous system (CNS) via the haematogenous route, from direct extension through the paranasal sinuses or by direct inoculation during trauma or surgical procedures.2,3 Invasive intracranial aspergillosis is unusual, accounting for 10–20% of all cases of invasive aspergillosis.4 Most patients with this condition have immune defects, usually in the form of neutrophil or macrophage dysfunction.5,6 Invasive intracranial aspergillosis is associated with high morbidity and mortality rates; the latter can be as high as 88% in bone marrow transplant recipients and for those with disseminated or cerebral aspergillosis.2,7,8 CNS-invasive aspergillosis may present with meningitis, cerebritis, infarctions, abscesses, granulomas or mycotic aneurysms.9 The exact pathology depends upon the disease pathway and the host’s immunity. The most frequent pathological findings are haemorrhage, infarctions and abscesses.10 Rarely, Aspergillus infections present as space- occupying lesions in immunocompetent patients.3,10 1Department of Paediatric Infectious Disease, Royal Hospital, Muscat, Oman; Departments of 2Child Health, 3Paediatric Infectious Disease and 4Neurosurgery, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia *Corresponding Author e-mail: nawal.almaskari@gmail.com ارشاشيات فالفس املستحثة للخراج يف دماغ طفل ذو كفاءة مناعية تقرير احلالة نوال امل�سكرية، ابراهيم بن ح�سني، �سليمان جمعه، ع�سام ال�سهيل abstract: Intracranial aspergillosis is an extremely rare manifestation of invasive aspergillosis in immuno- competent children and is associated with high morbidity and mortality. We report a 12-year-old immunocompetent male child who was referred to the King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia, in May 2010 after a sudden-onset headache and loss of consciousness. Brain imaging revealed a large right space-occupying occipital lesion and the patient underwent a craniotomy and resection. Histopathology of the lesion revealed necrotising granulomatous fungal encephalitis with many hyphae engulfed by multinucleated giant histiocytes. Two days later, a computed tomography scan showed debulking of the fungal mass and the patient was discharged on oral voriconazole. However, imaging at a six-week follow-up showed progression of the abnormality. A residual or persistent fungal brain lesion was suspected. Further neurosurgical resection of the lesion was performed and cultures showed growth of Aspergillus flavus. The patient was treated successfully with antifungal therapy over the following two years. Keywords: Brain Abscess; Fungus Disease; Aspergillus flavus; Antifungal Agents; Immunocompetence; Case Report; Saudi Arabia. وتكون املناعية الكفاءة ذوي الأطفال يف الجتياحية الر�سا�سيات من للغاية نادر مظهر الدماغي القحف داخل الر�سا�سيات امللخ�ص: التخ�س�سي في�سل امللك م�ست�سفى اإىل اأحيل عاما 12 العمر من بالغ طفل باأن نفيدكم مرتفعة. لذلك نتيجة والوفيات العتالل معدلت ومركز الأبحاث يف مايو 2010 حيث اأن املري�س اأ�سيب ب�سداع مفاجئ وفقدان للوعي. ك�سف ت�سوير الدماغ الأمين اآفة قذايل حتتل م�ساحة من العديد مع تقرحي حبيبي فطري دماغ التهاب بوجود امل�ستاأ�سل الن�سيج درا�سة وك�سفت الآفة. ل�ستئ�سال املري�س وخ�سع كبرية اخليوط املحاطة مبن�سجات عمالقة متعددة النوى. بعد يومني، اأظهر امل�سح املقطعي املحو�سب خلو املخ من الكتلة الفطرية وخرج املري�س على دواء فوريكونازول. ومع ذلك، اأظهر الت�سوير املغناطي�سي خالل �ستة اأ�سابيع تطور الفطريات يف الدماغ مرة اأخرى. مت تنفيذ مزيد من البرت لالآفة يف جراحة الأع�ساب واأظهرت زارعة الن�سجه منو فطريات الفالف�س.ومت عالج املري�س بنجاح بالأدوية امل�سادة للفطريات على مدى العامني التاليني. كلمات مفتاحية: خراج الدماغ؛ الأمرا�س الفطرية؛ ار�سا�سيات فالف�س؛ الأدوية امل�سادة للفطريات؛ الكفاءة املناعية؛ تقرير حالة؛ العربية ال�سعودية. Aspergillus flavus-Induced Brain Abscess in an Immunocompetent Child Case report *Nawal Al-Maskari,1 Ibrahim Hussain,2 Suleiman Jumaa,3 Essam A. Al-Shail4 Sultan Qaboos University Med J, May 2016, Vol. 16, Iss. 2, pp. 246–249, Epub. 15 May 16 Submitted 9 Jun 15 Revisions Req. 26 Jul & 27 Sep 15; Revisions Recd. 31 Aug & 6 Oct 15 Accepted 29 Oct 15 case report doi: 10.18295/squmj.2016.16.02.019 Nawal Al-Maskari, Ibrahim Hussain, Suleiman Jumaa and Essam A. Al-Shail Case Report | e247 were requested as the lesion was believed to be a tumour. The patient was prescribed daily intravenous liposomal amphotericin B (5 mg/kg/dose). Two days after the surgery, a brain CT scan showed debulking of the right-sided occipital fungal mass. The extent of the perilesional reactive changes had regressed with a persistent mild midline shift to the left and regression of the right trigone effacement [Figure 1B]. Blood assays showed high (1,3)-beta-D-glucan levels (272 picogrammes [pg]/mL; normal range: 0‒60 pg/mL) and non-reactive Aspergillus galactomannan. An eye examination, abdominal ultrasound and echocar- diogram were unremarkable. The results of an immun- ological work-up were normal, including serum immunoglobulin levels, lymphocyte markers, blasto- genic response, complement deficiency, oxida-tive burst and polymorphonuclear chemotaxis. A human immunodeficiency virus infection test was negative. The patient was discharged on oral voriconazole (6 mg/kg every 12 hours). At a six-week follow-up appointment, the patient underwent CT and MRI scans of the brain which showed a progression of the dense solid marginal tissue abnormality. The enhancement was consistent with a granulomatous tissue abnormality [Figure 2A]. A residual or persistent fungal brain lesion was suspected and the patient subsequently underwent surgical exploration with further resection of the lesion. The histopathology remained consistent with that of the first resected brain lesion; however, cultures showed A. flavus growth. Oral administration of voriconazole was substituted for intravenous administration (6 mg/kg every 12 hours). Two days later, a postoperative CT scan showed a slight nonspecific enhancement in the periphery of the resected area. The patient was discharged with a prescription for oral voriconazole (6 mg/kg every 12 hours). This report describes an invasive Aspergillus-induced brain abscess in an immunocompetent patient with no history of trauma. Case Report A previously healthy 12-year-old male child was referred to the King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia, in May 2010 after a sudden-onset headache and loss of consciousness for 15 minutes. He had no convulsions, abnormal movements, eye abnormalities, vision impairment, fever, vomiting or skin rashes. In addition, he had no history of trauma. On examination, the patient was stable and interactive with no obvious neurological deficits. Computed tomography (CT) of the brain showed a right occipital space-occupying lesion, suspected to be a tumour. The nasal sinuses were clear. His complete blood count (haemoglobin: 135 g/L; white blood cell count: 6.4 x 109/L; neutrophil count: 2.51 x 109/L; eosinophils: 0.47 x 109/L; platelet count: 333 x 109/L) and erythrocyte sedimentation rate (3 mm/hour) were normal. Magnetic resonance imaging (MRI) of the brain revealed a large right occipital mass with heterogeneous enhancement and perifocal oedema in the right temporal and parietal lobes. The right occipital horn was compressed and there was a midline shift to the left [Figure 1A]. A preoperative diagnosis of a brain tumour was made. The patient underwent a craniotomy and resection of the brain lesion. Histopathology examination of the lesion revealed necrotising granulomatous fungal encephalitis with many hyphae engulfed by multinucleated giant histiocytes. No cultures Figure 1A&B: A: Magnetic resonance imaging of the brain of a 12-year-old immunocompetent child showing a large right occipital mass (arrow) with heterogeneous enhancement, perifocal oedema in the right temporal and parietal lobes and a midline shift to the left. The nasal sinuses were clear. B: Post-resection computed tomography showing debulking of the right- sided occipital fungal mass (arrow) two days later. Note the regression of the perilesional reactive changes with a persistent mild midline shift to the left and regression of the right trigone effacement. Figure 2A&B: A: Magnetic resonance imaging (MRI) of the brain of a 12-year-old immunocompetent child six weeks after an initial resection of a right occipital fungal mass showing progression of the dense solid marginal tissue abnormality (arrow) and enhancement consistent with a granulomatous tissue abnormality. B: Brain MRI one month after the second resection showing partial resolution of the solid parenchymal abnormality (arrow). Aspergillus flavus-Induced Brain Abscess in an Immunocompetent Child Case report e248 | SQU Medical Journal, May 2016, Volume 16, Issue 2 In the current case, the patient had invasive CNS aspergillosis without paranasal sinus involvement and with no identifiable immune defects. Although he had negative Aspergillus serum galactomannan antigens, this negative result does not exclude a diagnosis of invasive aspergillosis.13 Culture supernatants of A. flavus have demonstrated lower reactivity, with lower galactomannan concentrations.14 Negative results could be due to factors related to the host, the assay or the fungus itself. One of the blood investigations which can be used to detect Aspergillus is the enzyme-linked immunosorbent assay Platelia™ Aspergillus EIA (Bio-Rad Laboratories, California, USA); this assay is most favourable in patients with haematological malignancies, especially those who have undergone a haematopoietic stem cell transplant and are neutropaenic.15 It is not clear how the patient in the present case developed the brain abscess. Although no immune defects were identified, he may nevertheless have been suffering from a rare form of immunodeficiency, such as an interleukin (IL)-4 or IL-6 deficiency; suppression of monocytes and T helper cells and interferon-gamma (IFN-γ) responses can lead to severe Aspergillus infections.13,16 A previous case report has indicated the beneficial role of IFN-γ treatment in combination with antifungal drugs in managing a patient with an A. fumigatus-induced brain abscess.17 Conclusion Persistent cerebral Aspergillus-induced abscesses in immunocompetent patients are extremely rare and the clinical and radiological features of these cases may be similar to primary or secondary neoplasms or other forms of infection. Health professionals should therefore be aware of the symptoms of Aspergillus- induced brain abscesses, as early detection and appropriate treatment is necessary to ensure positive patient outcomes. References 1. Brouwer MC, Tunkel AR, McKhann GM 2nd, van de Beek D. Brain abscess. N Engl J Med 2014; 371:447–56. doi: 10.1056/ NEJMra1301635. 2. Chen S, Pu JL, Yu J, Zhang JM. Multiple Aspergillus cerebellar abscesses in a middle-aged female: Case report and literature review. Int J Med Sci 2011; 8:635–9. doi: 10.7150/ijms.8.635. 3. Köse S, Çavdar G, Senger SS, Akkoçlu G. Central nervous system aspergillosis in an immunocompetent patient. J Infect Dev Ctries 2011; 5:313–15. doi: 10.3855/jidc.1461. 4. Wannasirikul V, Chayakulkeeree M. Multiple brain abscesses caused by Aspergillus fumigatus in a patient with systemic lupus erythematous. J Infect Dis Antimicrob Agents 2012; 29:17–20. A one-month follow-up MRI scan of the patient showed resolution of the solid enhancing parenchymal abnormality [Figure 2B]. Subsequent MRI scans were performed at regular intervals, including four, six, 18 and 24 months after the second resection. After eight months of oral voriconazole treatment, (1,3)-beta-D-glucan levels were undetectable. Repeated assays for Aspergillus galactomannan also revealed undetectable levels. Antifungal treatment was discontinued after two years as there was on-going evidence of the complete resolution of the brain lesion by May 2013. Discussion In general, CNS aspergillosis—particularly invasive aspergillosis—is rarely observed in immunocompetent patients.2 The brain is remarkably resistant to fungal infections due to its abundant blood supply and the relatively impermeable blood-brain barrier. Nevertheless, despite the existence of anatomical and functional barriers which protect the brain and subarachnoid space, fungal pathogens can breach these barriers under certain conditions.2 Persistent cerebral Aspergillus abscesses in immunocompetent patients may exhibit clinical and radiological features similar to primary or secondary neoplasms or other forms of infection.10 Only a few cases of invasive Aspergillus brain abscesses have been reported; of these, most involved adult rather than paedia- tric patients.11 The management of cerebral fungal abscesses remains controversial. Antifungal therapy alone reportedly has a poor outcome for patients with CNS aspergillosis, with a high mortality rate of >90%; this is likely due to the poor penetration of the CNS by the antifungal drugs.2 Other research has indicated that surgical resection of focal CNS aspergillosis lesions reduces the mortality rate from 64% to 39%.2 Overall, voriconazole seems to be the drug of choice for the treatment of aspergillosis.2 In the current case, the patient showed clinical and radiological improvement with intravenous voriconazole administration and surgical resection. However, imaging scans at a six-week follow-up revealed that the lesion had progressed despite the continued administration of oral voriconazole; this is unusual due to the high bioavailability level (82.6%) of oral voriconazole.12 This uncommon occurrence may have been due to poor medication compliance on the part of the patient or incomplete resection which resulted in the slow progression of the remnant lesion. 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Shuper A, Levitsky HI, Cornblath DR. Early invasive CNS aspergillosis: An easily missed diagnosis. Neuroradiology 1991; 33:183–5. doi: 10.1007/BF00588266. 10. Sidani C, Freiser ME, Saigal G, Sklar E. Unusual case of cerebral aspergillosis with clinical and imaging findings mimicking lymphoma. Neuroradiol J 2013; 26:290–6. doi: 10.1177/197140091302600306. 11. Dotis J, Iosifidis E, Roilides E. Central nervous system aspergillosis in children: A systematic review of reported cases. Int J Infect Dis 2007; 11:381–93. doi: 10.1016/j.ijid.2007.01.013. 12. Scholz I, Oberwittler H, Riedel KD, Burhenne J, Weiss J, Haefeli WE, et al. Pharmacokinetics, metabolism and bioavail- ability of the triazole antifungal agent voriconazole in relation to CYP2C19 genotype. Br J Clin Pharmacol 2009; 68:906–15. doi: 10.1111/j.1365-2125.2009.03534.x. 13. Cenci E, Mencacci A, Casagrande A, Mosci P, Bistoni F, Romani L. Impaired antifungal effector activity but not inflammatory cell recruitment in interleukin-6-deficient mice with invasive pulmonary aspergillosis. J Infect Dis 2001; 184:610–17. doi: 10.1086 /322793. 14. Verweija PE, Mennink-Kerstena MA. Issues with galacto- mannan testing. Med Mycol 2006; 44:179–83. doi: 10.1080/1369 3780600904918. 15. Dutkiewicz R, Hage CA. Aspergillus infections in the critically ill. Proc Am Thorac Soc 2010; 7:204–9. doi: 10.1513/ pats.200906-050AL. 16. Monneret G, Venet F, Kullberg BJ, Netea MG. ICU- acquired immunosuppression and the risk for secondary fungal infections. Med Mycol 2011; 49:S17–23. doi: 10.3109 /13693786.2010.509744. 17. Saulsbury FT. Successful treatment of Aspergillus brain abscess with itraconazole and interferon-gamma in a patient with chronic granulomatous disease. 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