Central Nervous System Mold Infections in Children with Hematological Malignancies: Advances in Diagnosis and Treatment

Abstract

The incidence of invasive mold disease (IMD) has significantly increased over the last decades, and IMD of the central nervous system (CNS) is a particularly severe form of this infection. Solid data on the incidence of CNS IMD in the pediatric setting are lacking, in which Aspergillus spp. is the most prevalent pathogen, followed by mucorales. CNS IMD is difficult to diagnose, and although imaging tools such as magnetic resonance imaging have considerably improved, these techniques are still unspecific. As microscopy and culture have a low sensitivity, non-culture-based assays such as the detection of fungal antigens (e.g., galactomannan or beta-D-glucan) or the detection of fungal nucleic acids by molecular assays need to be validated in children with suspected CNS IMD. New and potent antifungal compounds helped to improve outcome of CNS IMD, but not all agents are approved for children and a pediatric dosage has not been established. Therefore, studies have to rapidly evaluate dosage, safety and efficacy of antifungal compounds in the pediatric setting. This review will summarize the current knowledge on diagnostic tools and on the management of CNS IMD with a focus on pediatric patients.

Keywords: Aspergillus; central nervous system; child; invasive fungal disease; mold; mucormycetes.

Figure 1

A 7-year-old girl with relapse of acute lymphoblastic leukemia (ALL) and biopsy-proven aspergillosis of paranasal sinuses. The patient has deceased. Axial T2-weighted magnetic resonance images (MRI) (A and B) show abnormal soft tissue filling the ethmoidal cells and in maxillary sinus on the right with T2-hypointensity (straight arrows). Coronal computerized tomography (CT) (C) shows destruction of the sinus walls and the cribriform plate (star) with extension into the anterior cranial fossa. Follow-up images (not shown) showed multiple parenchymal bleedings on the frontal lobes.

Figure 2

A 12-year-old boy with acute lymphoblastic leukemia with frontal cerebritis in the right and left frontal lobe and probable central nervous system (CNS) invasive mold infection. Aspergillus fumigatus and Rhizopus arrhizus were isolated outside the CNS. The patient is alive with residual left-sided hemiparesis. A, B and C: Imaging performed during the early stage of frontal cerebritis, mainly on the right side. Fluid-attenuated inversion recovery (FLAIR) image shows hyperintense white matter of frontal lobe (A). Diffusion-weighted image (DWI), b = 1000 s/mm², shows diffusion restriction in the area of frontal cerebritis (B). T2* image (C) shows an ill-defined hypointense area (arrow). No enhancement was seen. After 20 days, magnetic resonance imaging was performed after clinical worsening and suspected vascular involvement (D). Susceptibility-weighted image (SWI; D) shows marked decreased signal intensity and blooming with mass effect. Findings were consistent with major secondary hemorrhage (D, arrow) and intraventricular bleeding.

Figure 3

Fungal abscess in a 3-year-old girl with acute lymphoblastic leukemia and proven central nervous system invasive mold infection. The patient is alive with residual right-sided weakness. Axial T2-weighted (A) shows a mass in the left central region, which is predominantly of low T2 signal intensity, centrally with hyperintense perilesional edema and a well-defined ring-like hypointense area (arrow). Diffusion-weighted image (DWI), b = 1000 s/mm², shows mainly restriction within the hypointense rim (B, arrow). Axial unenhanced T1-weighted shows a slight rim-like high signal intensity probably due to the presence of iron, manganese or methemoglobin (C, arrow). T1 after contrast shows a strong ring enhancement (D, arrow).

Figure 4

Vascular involvement in a 3-year-old girl with acute lymphoblastic leukemia (ALL) and proven central nervous system invasive mold infection (CNS IMD). The patient is alive but is a wheelchair user. Immunocompromised children have an impaired host immune system to fight against fungi (Figure 4A, curved arrow), which often results in an infiltration of the vascular structures (Figure 4A, straight arrow). Susceptibility-weighted image (SWI) (A) shows ring-like fungal infection on the left side (curved arrow) and thrombosis of the deep medullary veins (straight arrow), which are visualized as low signal intensity at SWI. Enhanced T1W (B) shows multiple ring-enhancing fungal abscesses on the right (star), but no enhancement on the left side. Diffusion-weighted image (DWI) (C) shows restricted diffusion within multiple ring-enhancing fungal abscesses on the right (star). The infarct with diffusion restriction (C) on the left involves the nonenhancing ring-like structure shown in the SWI (A, curved arrow).

Figure 5

Vascular involvement in a 5-year-old boy with acute lymphoblastic leukemia (ALL) and probable central nervous system invasive mold infection. The patient is alive with residual right-sided hemiparesis. Magnetic resonance imaging (MRI) shows a large hemispheric infarction on the left side and cortical necrosis (arrow) on T1-W images without contrast (A). Time-of-flight magnetic resonance angiography (TOF-MRA) (B) shows only weak flow of the left internal cerebral artery.

Figure 6

Diagnostic tools for brain biopsy specimens and for cerebrospinal fluid.