Video Upload Options

1. Introduction

The incidence of invasive fungal disease (IFD) has significantly increased over the last decades, as it was shown in two sequential autopsy studies performed in a large University hospital in Germany covering the time period of 1977–2005 ^[1][2]. Corroborating an analysis of 11 autopsy reports, these autopsy studies identified Aspergillus spp. as the most common pathogen, followed by Candida spp. and mucorales ^[3]. The clinical impact of invasive aspergillosis was demonstrated by a retrospective cohort study in the US analyzing 666 cases of invasive aspergillosis among 152,231 immunocompromised children ^[4]. Invasive aspergillosis not only significantly increased the length of hospital stay and costs, but was also associated with higher mortality independently from the underlying malignancy.

Invasive mold infections mainly affect the lung, but may also occur in other sites such as liver, kidney, bones, or the central nervous system (CNS). The CNS involvement is a particularly severe form of fungal infection, which is not only difficult to diagnose but also difficult to treat. Mortality of invasive mold disease of the CNS (CNS IMD) is unacceptably high, and those patients who survive often suffer from significant and permanent neurological sequelae.

2. Epidemiology and Risk Groups

Both epidemiology of and risk factors for IFD in general have been analyzed in a number of studies. In a retrospective pediatric analysis, highest incidence rates for IFD were found for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) (13.9%), de novo (10%) and relapsed (17.9%) acute myeloid leukemia (AML), which corroborate the data of a 2-year prospective analysis in three major pediatric centers ^[5][6]. A systematic review including 22 studies found that the underlying disease (e.g., AML, high risk acute lymphoblastic leukemia (ALL), relapsed acute leukemia), allogeneic HSCT (in particular with acute and chronic graft-versus-host-disease), prolonged neutropenia (>10 days), high-dose steroids, and increasing age were the most relevant risk factors for IFD in children ^[7]. Outside the clinical setting of cancer patients, diabetes, low birth weight, malnutrition, and liver diseases are well described risk factors for mucormycosis ^[8].

Whereas incidence rates of IFD are quite consistent across most of the studies, the incidence of CNS IFD is less clear ^[9]. In a prospective surveillance study in adults (median age, 40 years), 232 IFDs were identified, 113 in patients with hematological malignancies and 119 in patients without hematological malignancies ^[10]. Among the patients with hematological malignancies and IFD, invasive aspergillosis occurred in 86 patients (76.1%; 18 patients suffered from Aspergillus fumigatus, 14 from A. flavus, two from A. terreus, and one each from A. niger, A. flavipes, A. nidulans, or from more than one species; in 48 patients, the species of Aspergillus could not be identified). In 11patients (9.7%), Fusarium spp. was isolated (Fusarium solani in three patients, Fusarium proliferatum and Fusarium verticilloides in one patient each), and mucormycosis was diagnosed in seven patients (6.2%; Rhizopus oryzae in three patients, and Absidia corymbifera, Rhizomucor pusillus, Mucor spp., and Rhizopus spp. in one patient each). In the 113 patients with hematological malignancies, 16 patients with CNS IMD (14.1%) were observed, whereas this was the case in 13 out of the 119 patients without hematological malignancies (10.9%). Unfortunately, the authors did not report on the pathogens identified in the patients with CNS IMD. In a multicenter retrospective study analyzing pediatric patients (median age, 9.3 years), 127 IFDs were diagnosed in 123 out of 2183 patients (5.6%), and the CNS was involved in only four of the 123 patients (3.3%) ^[5]. The pathogens in these children have not been reported. In an analysis of 25 cases of mucormycosis occurring in 1136 prospectively registered children with acute leukemia (2.2%), 23 patients (59%) had a rhinocerebral pattern of infection, eight of them with adjacent spread to the CNS ^[11]. Rhizopus spp. was the most common causative pathogen (46% of patients). Whereas in a large case series of 89 proven or probable CNS IFD in mostly adult patients (median age, 40 years) Aspergillus spp. was the most common pathogen (69%), followed by mucormycetes (22%), Cryptococcus spp. (4%) and Fusarium spp. (2%), data in the pediatric setting are lacking ^[12].

3. Pathogenesis

Molds are ubiquitous organisms which can be found in soil, water, and decaying vegetation ^[13]. The portal of entry of these pathogens is usually the respiratory tract, with subsequent hematogenous dissemination to the CNS. Direct inoculation of CNS or paraspinal tissue as a result of surgery or trauma may occur, or fungi may affect sinuses or mastoids and directly expand to the CNS (Figure 1) ^[14][15]. Whereas yeast are able to enter the CNS directly through the blood–brain barrier either trans-cellularly, para-cellularly or inside infected phagocytes (“Trojan horse mechanism”), the exact mechanism of the blood–brain barrier penetration of molds is not well understood to date ^{[14][15][16][17]}. It was speculated that mycotoxins such as gliotoxin produced by A. fumigatus exhibit various effects which ultimately lead to intracerebral invasion of the fungus. For example, mycotoxins are immunosuppressive and reduce the opsonization of the conidia and inhibit phagocytosis. Mycotoxins also damage microglia, which exhibits phagocytic abilities and is the major surveillance of the CNS against the fungus ^{[14][16][18][19]}. Similarly, fumonisin B1, a mycotoxin produced by Fusarium spp., damages the microglia and leads to neuronal axon demyelination ^[20]. However, a better understanding of the exact pathomechanisms is urgently needed which might also help to develop new approaches in preventing and treating CNS IMD.

4. Clinical Presentation

The clinical symptoms of CNS IMD depend on the site of involvement and are often unspecific (e.g., fever refractory to antibiotic treatment), so that early diagnosis is difficult. First signs of rhino-cerebral IMD are commonly headache, periorbital redness and tenderness, and protrusion of the eye ^[21]. Depending on the extent and the localization, intracerebral lesions may result in cranial nerve palsy, seizures, hallucination, and somnolence.

An analysis in 89 adult patients (median age, 40 years) reported that the most common presenting symptom of CNS IFD was fever (65%) followed by headache (26%) ^[21]. Focal neurological symptoms (e.g., aphasia, diplopia) were seen in 48%, and seizures occurred in 18%. Interestingly, in a study on CNS IMD in 29 children, 21 (72%) presented with CNS related symptoms, whereas eight (28%) were neurologically asymptomatic and CNS IFD was detected by diagnostic work-up for pulmonary or liver fungal infection or during routine CNS imaging for assessing tumor response ^[22]. Common neurological symptoms were somnolence and cerebral palsy (each 24%), followed by headache (21%). In one patient each, impaired vision, aphasia, ataxia, hallucination, paresthesia, and seizures were reported. These data indicate that in patients at risk for IFD, further diagnostic work-up including imaging studies with magnetic resonance imaging (MRI) of the brain should be considered in patients with any CNS related symptom or in those with proven or probable IMD outside the CNS ^[23].