Prevalence of leukoencephalopathy and its potential cognitive sequelae in cancer patients

Abstract

Due to the rising use of chemotherapy in cancer patients and growing survival rates, therapy-induced neurotoxic side effects are increasingly reported. Given the ambiguity about the prevalence and severity of leukoencephalopathy, one of such toxic side effects, in non-central nervous system (CNS) cancer patients, we performed a systematic literature search using the PubMed/Medline database to summarize existing literature regarding leukoencephalopathy epidemiology in non-CNS cancer patients and its potential cognitive sequelae. The search was based on the following terms: ('MRI' OR 'T2-weighted MRI' OR 'FLAIR') AND ('cancer' OR 'tumor' OR 'leukemia' OR 'neoplasms') AND ('chemotherapy' OR 'radiotherapy') AND ('posterior reversible encephalopathy' OR 'leukoencephalopathy' OR 'cerebral ischemia' OR 'stroke'). Thirtytwo studies discussing the occurrence of leukoencephalopathy in cancer patients were included, of which the majority investigated Acute Lymphoblastic Leukemia (ALL) patients (n=22).Regularly scanned ALL patients showed a prevalence of leukoencephalopathy between 17 -87%, and 15 -83% of patients presented with leukoencephalopathy when only scanned after a CNS event. When diagnosed with posterior reversible encephalopathy syndrome, 100% of patients showed leukoencephalopathy because its diagnosis is based in part on observable lesions. An increased prevalence was observed in ALL patients treated with higher doses of methotrexate (5 g/m2 MTX, 42 -87%) when compared to lower doses (< 5 g/m2, 32 -67%). By contrast, in breast cancer patients, white matter lesions were mainly detected in case of neurological symptoms, but not (yet) clearly associated with chemotherapy administration in general. However, chemotherapy treatment was associated with more infratentorial microbleeds in breast cancer patients. Up to 50% of other (neurologically asymptomatic) solid tumor patients presented white matter lesions, even years after treatment. When cognitive data were investigated, lesioned patients showed lower scores on neurocognitive tests in 50% of studies, years after ending therapy.In conclusion, leukoencephalopathy is well-documented for ALL patients (with a focus on methotrexate), but there is a lack of knowledge for other intravenous chemotherapeutics, other oncological populations, wider age ranges and risk factors (e.g. history of CNS event). Furthermore, the long-term neuropsychological impact and potential risk for neurodegenerative processes due to leukoencephalopathy remains inconclusive.Hence, large international databanks, epidemiological and prospective case-control studies are necessary to stratify risk groups for CNS-related side effects.

An observational MRI study of methotrexate-treated children with acute lymphoblastic leukemia in remission and subtle cognitive decline

“…Secondly, the first MR examination for the children with ALL was scheduled for 1 to 3 days after complete remission was confirmed. The second MR examination was scheduled for at least 46 days after the completion of MTX treatment, by which point some asymptomatic children may have recovered from MTXrelated leukoencephalopathy and become negative on T1 WI and T2 WI (3,35). After intensive treatment, there might have impacted on the children's energy levels or psychological state, the effect of this on their cognitive scores cannot be overlooked.…”

“…Neurotoxic side effects of MTX include leukoencephalopathy, which appears as transient, hyperintense regions on T2-weighted imaging (T2WI). In previous research, regularly scanning of patients with acute lymphoblastic leukemia (ALL) showed that leukoencephalopathy had a prevalence of between 17% and 87%, and 15% to 83% of patients presented with leukoencephalopathy when scanned only after a central nervous system event (3). Survivors of childhood ALL have been shown to experience treatment-related complications, such as secondary malignancies or neurocognitive impairment, which impact their quality of life after remission (4).…”

Neuroinflammation as potential precursor of leukoencephalopathy in early-stage breast cancer patients: A cross-sectional PET-MRI study

“…Only few studies have examined the prevalence of leukoencephalopathy in early-stage breast cancer patients. These studies either did not encounter treatment-associated leukoencephalopathy at all or only observed higher lesion load in patients showing neurologic symptoms [7,20]. This could partly be explained by different cancer types or stages and consequently other treatment regimens, as well as the heterogeneity in forms of observed lesions (for instance multifocal punctuate lesions are less easily detected).…”

“…MS], T2-weighted-Fluid-Attenuated Inversion Recovery (FLAIR) imaging is most often used, which shows white matter lesions (WMLs) as hyperintense regions [12]. High-dose chemotherapy is known to potentially cause MS-mimicking WMLs observable via FLAIR, or so-called leukoencephalopathy [20,21]. Additionally, post-mortem brain autopsies of former (metastatic) cancer patients treated with high-dose chemotherapy revealed demyelination in areas that showed WMLs on T2-weighted scans in vivo [22].…”

Structural Neuroimaging Findings Related to Adult Non-CNS Cancer and Treatment: Review, Integration, and Implications for Treatment of Cognitive Dysfunction

“…Functional neuroimaging approaches are incorporated as utilized in studies implementing multimodal neuroimaging approaches; however, a comprehensive review of functional neuroimaging studies in CRCD is beyond the scope of this review. Case studies [26][27][28] and reports on specific neurological effects such as leukoencephalopathy [29] are also not reviewed, and pediatric cancer populations are not discussed, given other recent reviews [e.g. , 30].…”