The most important inciting cause leading to our patient’s fatal outcome was the rapidly metastasizing tumor. In addition, we speculate if the initiation of chemotherapy contributed to severe acute changes in the CNS compartment, including possible CNS tumor lysis syndrome. In order to validate our speculation, we performed thorough literature review using PubMed database, focusing on CNS neurotoxicity from doxorubicin chemotherapy and more specifically drug induced CNS tumor lysis.

Upon thorough literature review, we confirmed that doxorubicin was not associated with acute-onset SIADH or cerebral edema in cancer patients undergoing active therapy, outside of cases in which it was prescribed as a part of combined chemotherapy with agents associated with SIADH [5, 6]. Animal studies have described acute neurotoxic effect of doxorubicin on rodent despite of its known poor CNS penetration [7]. Very few cases have been reported in the literature describing malignant cerebral edema in conjunction with therapy for CNS tumors. Zhu et al described the case of a 10-year-old girl with glioblastoma, treated with Nivolumab, wherein the malignant cerebral edema took place after each infusion of Nivolumab, with evidence of severe tumor necrosis on CT scans [8]. As in our case, signs of trans tentorial herniation accompanied the edema, in their case requiring dexamethasone initially and ultimately a decompressive craniectomy. Zhu had speculated that augmented T-cell responsiveness due to the immunomodulator effects of nivolumab may have caused an inflammatory response resulting in the cerebral edema. However, subsequent pathology findings did not demonstrate signs of extensive inflammation, but rather evidence of tumor necrosis with localized inflammation. Hodi et al also reported a case with symptomatic cerebral edema around melanoma metastases following ipilimumab therapy [9]. Unlike our patient, both patients responded favorably to dexamethasone therapy and cessation of chemotherapy. Ahmed et al found 6 of 26 patients (23%) with metastatic melanoma with greater than 20% increase in tumor volume due to cerebral edema, hemorrhage, or both following ipilimumab therapy [10].

Most literature on tumor lysis syndrome describes it in peripheral blood compartment, typically in the setting of leukemias and lymphomas. There are rare cases reporting drug induced CNS tumor lysis syndrome involving solid tumors [11]. In their report, Bachegowda et al described the CNS neurotoxicity of seizures within 48 hours of administration of intrathecal methotrexate for management of diffuse large B-cell lymphoma with known CNS metastasis [12]. They associated the development of cerebral edema and disappearance of CNS metastasis (both on MRI and on CSF flow cytometry) as an effect of methotrexate and speculate if CNS tumor lysis could be the pathogenetic mechanism for this effect. We did not find any report elucidating drug induced CNS tumor lysis syndrome involving primary CNS tumors.

This case report highlights the fatality from a highly aggressive CNS ATRT and prompts future research focusing on acute doxorubicin neurotoxicity and understanding the pathophysiology of CNS tumor lysis syndrome.

Funding Disclosure: No funding was received for this manuscript. This manuscript was not generated as part of the employment of authors.

Conflicts of Interest: None of the authors listed has any conflicts of interest. All the authors have contributed significantly to this manuscript and have reviewed the manuscript and agree with the contents.

Acknowledgements: None.