Systemic chemotherapy, often with multidrug combinations, is a treatment of choice for oncological malignancy, especially for patients with hematopoietic cell malignancy. “Chemotherapy-induced toxic leukoencephalopathy” is currently a rising clinical syndrome characterized by progressive cognitive disorder and detrimental effects on the quality of life, which may lead to sudden death. However, a few data have been accumulated and most are methotrexate-induced leukoencephalopathy.
Here, two cases of autopsy-proven toxic leukoencephalopathy caused by chemotherapy regimens other than methotrexate were reported. In this way, we are able to share distinctive clinicopathologic findings and caution other physicians to make accurate diagnosis and treatment when meeting similar patients. Both patients were administered multiple courses of various chemotherapy regimens, in which fludarabine was included. Clinically, both patients presented with a neurological disorder, including cognitive disorder and motor and sensory loss, which rapidly progressed to coma and death. Brain autopsies depicted cerebral white matter spongiform change, axonal spheroids, and foamy macrophage infiltration. Infiltrating macrophages were CD68-positive but TMEM119-negative in both cases. CD3, CD8, and CD20 stains revealed no lymphocytic infiltration in both cases. No apoptotic cells were identified. Pathologic findings of these two cases were consistent with Chemotherapy-induced toxic leukoencephalopathy.[4–10]
Methotrexate is the most common drug associated with chemo brain, characterized by acute (reversible) encephalopathy, subacute encephalopathy, chronic encephalopathy, cerebral infarctions, seizure, or aseptic meningitis. However, other chemotherapy drugs are also associated with toxic encephalopathy symptoms that present with the above-mentioned symptoms. Chronic encephalopathy and PRES are related to high dose multi-chemotherapies, including cyclophosphamide, Ara-C, cis-platinum, ifosfamide, vincristine, gemcitabine, and other immunosuppressants.[9, 11] Chronic encephalopathy usually develops after a latency of some months to years, often presenting progressive and irreversible clinical manifestations. PRES is clinically characterized by headaches, visual disturbances, confusion, seizures, and eventually coma.
In 2004, Lai et al. reported an autopsy-proven, methotrexate-based, chemotherapy-induced leukoencephalopathy in primary CNS lymphoma . Unfortunately, treatment-related leukoencephalopathy is the leading brain pathology after the successful treatment of primary CNS lymphoma (PCNSL). Lai et al. reviewed five more autopsied patients who died of leukoencephalopathy . Neurological symptoms developed at a median of 1 month after treatment completion. The median survival was 30 months (range, 22–68 months) after neurotoxicity onset. All had hyperintensity on T2-weighted MRI, and two patients presented with enhancing lesions that were observed 5 and 14 months after the treatment, respectively. The autopsy revealed no residual PCNSL. Common pathologies were myelin and axonal loss, reactive gliosis, spongiosis, and rarefaction of the white matter. Two patients had brain necrosis, which correlated to the enhancing lesions seen on MRI. Interestingly, all had small vessel disease, and four had atherosclerosis of large cerebral vessels in the circle of Willis; two had recent strokes that were discovered during autopsy. The authors concluded that Chemotherapy-induced toxic leukoencephalopathy is not always a late or delayed consequence of chemoradiation therapy but also can develop very early in some patients. They also suggested that vascular disease may be a component of this injury .
Our cases might be due to fludarabine, Ara-C, busulfan, and cytarabine treatment. High dose fludarabine may cause cortical blindness, which has been associated with the administration of immunosuppressive drugs, antibodies, and other substances . Ara-C can induce cerebellar dysfunction and aseptic meningitis [9, 12]. Busulfan, cyclosporine, vincristine, cis-platinum, methotrexate, and paclitaxel may cause seizures . The frequency and severity of CNS toxicity depend on the drug, cumulative doses, the duration of treatment, and additional risk factors such as coexisting neurological morbidity . Well-known factors that increase the risk are dose escalation, combination therapy, stem cell transplantation, and irradiation of the brain .
In 1994, Cheson et al. reviewed the neurotoxicity of purine analogs that are widely used in indolent lymphoid malignancies, including fludarabine, cladribine, and pentostatin . They compared the adverse drug effects of fludarabine in chronic lymphocytic leukemia and cladribine and pentostatin in hairy cell leukemia. The neurotoxicity spectrum of these drugs was similar, which include myelosuppression, immunosuppression, and sporadic neurotoxicity . All three drugs lead to life-threatening or fatal neurotoxicity at higher-than-recommended doses. Each agent-induced neurologic complication occurs in approximately 15% of patients at the recommended doses, mostly mild and reversible. However, severe neurologic deficits were encountered. They were occasionally delayed, often at least partially reversible, or sometimes fatal .
In 1994, Zabernigg first reported about late-onset fatal neurotoxicity induced by low dose fludarabine monotherapy in patients with B-cell chronic lymphocytic leukemia (CLL) . A 55-year-old man developed a severe neurological disorder six months after finishing six cycles of fludarabine monotherapy. He presented with aphasia, apraxia, acalculia, hemihypesthesia, and spastic hemiparesis. A computed tomography scan of the brain showed multiple low-density areas involving the subcortical white matter. MRI showed subcortical white-matter abnormalities compatible with demyelination. Bizarre astrocytes and swollen oligodendrocytes were noted in the subcortical area. Multinuclear inclusion bodies were identified in some oligodendrocyte nuclei. The pathologic diagnosis was progressive multifocal leukoencephalopathy. Finally, he succumbed to coma and death . Although a low dose of fludarabine was used, the spectrum and severity of neurotoxicity were not different from that of a high dose.
The underlying cellular mechanism is still unclear. However, some models based on clinical and animal experiments help us speculate the possible mechanism of chemo brain. Peripheral cytokines initiate the development of chemo brain [15–17]. This cytokine-mediated signaling cascade induces persistent epigenetic alterations. These epigenetic changes alter gene expression, metabolic activity, and neuronal transmission that ultimately affect cognitive function. Chemotherapy drugs cause cellular stress and injury [15–17]. This induces an inflammatory response in the periphery, releasing cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-8, IL-10, and monocyte chemoattractant protein-1 (MCP-1). Peripheral cytokines can access the brain through leaky lesions in the blood-brain-barrier or can be transported via active mechanisms.[18, 19]
It is assumed that peripheral cytokines communicate with the cytokines of the CNS through the local inflammatory network. Peripheral cytokines stimulate endothelial cells and perivascular macrophages, monocytes, and T cells in the brain to produce similar local cytokines and chemokines. Microglia, astrocytes, oligodendrocytes, and neurons respond by releasing additional cytokines and chemokines in the brain. As a consequence of this cascade, oxidative stress increases, neurogenesis and neuroplasticity decreases, and neuronal excitotoxicity increases. These factors ultimately influence neurotransmitters and neuronal alteration [16, 21, 22]. Cytokines in the CNS are known to be mainly derived from microglia.[16, 19] Along with the strong evidence of correlating peripheral cytokines and cognitive dysfunction, microglial activation has been identified as a key factor in the reactivation of astrocytes and dysfunctional oligodendrocyte precursor cells in the previous work. TMEM119 is a reliable microglial marker, as it distinguishes microglia from circulating macrophages that flow into the brain . Recently, neuroimaging studies have broadened our understanding of the structural and functional changes in progressive cognitive dysfunction, showing a reduction in the frontoparietal white and gray matter [13, 25].