Discussion
Invasive CNS mucormycosis (CNS-M) is a rare but often deadly invasive fungal infection in the pediatric population (4)(5). The acute and rapidly progressive evolution generally causes unfavorable outcomes with very high mortality rates of up to 65% despite appropriate treatment (5).
CNS-M can manifest in three distinct clinical forms: as rhinocerebral mucormycosis (RCM), disseminated mucormycosis with CNS involvement, or as ICM(6). The latter is the least frequent form, accounting for only 8% of CNS-M cases (7, 8)
Isolated cerebral mucormycosis has been described in the literature as having an exceedingly poor prognosis(7, 9-11){Kerezoudis, 2019 #143;Kerezoudis, 2019 #143}. The pooled mortality rate in a meta-analysis by the Mayo clinic was noted at 65%in adults(12), Rhizopus has been shown to be the most common isolated organism (59%)(13). Cases of isolated cerebral mucormycosis usually involve the basal ganglia or thalamus(7). Lesions are usually deep-seated with common basal ganglia involvement which is thought to be due to seeding from the middle cerebral artery, especially in intravenous drug users(6). However, interestingly, it has been shown that in immunocompromised patients, cortical lesions are more common like our case(6, 14)
Our case outlines the major obstacles in diagnosis of ICM as the clinical symptoms were initially fairly subtle, conventional stains and cultures were negative, and obtaining a CNS biopsy specimen is not always feasible in vulnerable populations such as pediatric cancer patients (9). There are currently no clinically available circulating biomarkers of mucormycosis (9). Serum tests such as the 1,3-β-D-glucan assay and the aspergillus galactomannan assay are typically negative in invasive mucormycosis (10). Therefore, definitive diagnosis requires microbiological analysis of tissue obtained by biopsy or surgical debridement (11), high degree of clinical suspicion and prompt intervention (9, 12). The inclusion of PCR based testing for infectious organisms was critical in this cryptogenic presentation as the first finding to indicate the correct diagnosis(11, 15).
There are limited prospective clinical data on optimal therapies for CNS-M in children(10, 12, 16). A combined medical and surgical approach has repeatedly been shown to lead to the best outcomes(17), though aggressive surgical debridement is not always feasible depending on location of the infection, such as the CNS, where severe sequelae may result from attempting to surgically remove all fungal disease(12, 18). It has been widely accepted that early and aggressive surgical debridement in rhinosinus mucormycosis is essential to survival but this has not been established for isolated cerebral mucormycosis(13). Some studies have shown decreased mortality with stereotactic aspiration/debridement, but others have shown no differences in outcome(14). In our case, an aggressive debridement of all radiologically involved tissue would have conferred a neurological deficit that was not acceptable to the patient or family. The positive outcome in this case from a more limited debridement in combination with a salvage medical regimen supports a measured approach(15, 18).
Until recently, amphotericin B and the triazole antifungals (Posaconazole and ISAV) were the only systemic antifungals available with good activity against Mucorales species (18, 19). Posaconazole has been used in invasive mucormycosis in adults and adolescents as salvage therapy; however, CNS penetration has been reported to be poor (20), and Posaconazole monotherapy in CNS-M has not been adequately studied(20). Furthermore, there are concerns about the oral bioavailability of Posaconazole oral suspension in younger children who can’t swallow the extended-release tablet(21).
ISAV, a second-generation triazole, was approved for the treatment of invasive aspergillosis (IA) or invasive mucormycosis(22). There is limited information on the CNS penetration of ISAV, however, a few studies demonstrated efficacy with ISAV treatment for CNS infections caused by a wide range of different fungi(9, 23). More recently, ISAV was assessed prospectively in a single-arm study of patients with mucormycosis and other rare fungal infections (the VITAL trial) (16, 24). In this study, ISAV showed promising results against mucormycosis with efficacy and outcomes similar to amphotericin B, these results turn light in horizon for ISAV not only as salvage but also as first-line agent of mucormycosis treatment(22). VITAL trial didn’t look specifically effectiveness of ISAV in CNS-M, but 29% of cases had CNS involvement. Meanwhile, the pediatric dosing regimen of this drug has not been established. Desai et al. extrapolated an adult population pharmacokinetic model to determine the appropriate dose of ISAV for children(16). Accordingly, our patient received 10mg/kg of the prodrug isavuconazonium sulfate (equivalent to 5.4mg/kg of isavuconazole) every 8 hours for the first 2 days and once daily thereafter. Duration of therapy is always a question. Although our patient achieved radiographic resolution(10), we would continue ISAV suppressive treatment until the patient completes chemotherapy, is no longer in an immunosuppressive state and has reconstitution of the immune system.
In summary, our case is noteworthy in highlighting several challenges encountered in the diagnostics and management of ICM with eventually successful salvage treatment with monotherapy ISAV with complete clinical and radiologic responses. We hope that our case adds to the growing evidence supporting of ISAV as well-tolerated, safe, and efficacious therapy in ICM and promising therapy for salvage treatment and could be hope in horizon in children with ICM. The availability of an IV and oral of ISAV makes an attractive oral step-down therapy for with invasive or disseminated mucormycosis. Prospective clinical trials are needed to evaluate the established pediatric dose, safety, and efficacy of ISAV in children and its role as first-line treatment for ICM.
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