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Chemotherapy and the pediatric brain


Survival rates of children with cancer are steadily increasing. This urges our attention to neurocognitive and psychiatric outcomes, as these can markedly influence the quality of life of these children. Neurobehavioral morbidity in childhood cancer survivors affects diverse aspects of cognitive function, which can include attention, memory, processing speed, intellect, academic achievement, and emotional health. Reasons for neurobehavioral morbidity are multiple with one major contributor being chemotherapy-induced central nervous system (CNS) toxicity. Clinical studies investigating the effects of chemotherapy on the CNS in children with cancer have reported causative associations with the development of leukoencephalopathies as well as smaller regional grey and white matter volumes, which have been found to correlate with neurocognitive deficits.

Preclinical work has provided compelling evidence that chemotherapy drugs are potent neuro- and gliotoxins in vitro and in vivo and can cause brain injury via excitotoxic and apoptotic mechanisms. Furthermore, chemotherapy triggers DNA (deoxyribonucleic acid) damage directly or through increased oxidative stress. It can shorten telomeres and accelerate cell aging, cause cytokine deregulation, inhibit hippocampal neurogenesis, and reduce brain vascularization and blood flow. These mechanisms, when allowed to operate on the developing brain of a child, have high potential to not only cause brain injury, but also alter crucial developmental events, such as myelination, synaptogenesis, neurogenesis, cortical thinning, and formation of neuronal networks.

This short review summarizes key publications describing neurotoxicity of chemotherapy in pediatric cancers and potential underlying pathomechanisms.


The 5-year survival rate for childhood cancers exceeds 80%, resulting in a growing population of long-term survivors. One in 570 young adults between ages 20 and 34 years is a childhood cancer survivor [1], and 40% of them have at least one chronic medical condition which include neurocognitive toxicity [2,3,4]. In many cases, especially those from the late 1900s, neurocognitive toxicity is the result of combined polychemotherapy and radiation treatments. However, recent systematic multicenter longitudinal studies of intellectual development of childhood acute lymphoblastic leukemia (ALL) patients treated solely with polychemotherapy also document lower performance IQ (intelligence quotient) scores and worse intellectual outcomes in patients diagnosed and treated prior to the 6th year of life [5]. Given that the tumor burden reflected by low versus increased risk did not affect IQ scores, the investigators attributed this adverse effect to treatment rather than to the disease burden. In another study on pediatric B-cell ALL survivors, the authors described the development of leukoencephalopathies as late as 7.7 years after the end of treatment [6]. In this study, 40% of patients scored < 86 on either Verbal or Performance IQ. Children had significant attention problems and neurocognitive impairments, which were dependent upon treatment protocol. This strongly supports concerns about intensive chemotherapy being a major contributor to CNS late effects [6].

Deficits are consistently reported in visual processing, visual-motor function, attention, concentration, working memory, and executive functions [7,8,9,10,11]. Buizer and colleagues [9] reviewed 21 trials comparing patients with ALL and controls and described long-term deficits in attention and executive function, worse among the younger female patients. There are also studies which did not detect significant neurocognitive deficits in ALL survivors. Von der Weid and coinvestigators [12] found no significant differences between 132 survivors of ALL versus not-CNS solid tumors in global IQ. Jansen and colleagues reported in a prospective longitudinal, sibling-controlled study of children with ALL, treated with chemotherapy only, no major differences between patients and siblings up to 4.5 years from diagnosis except for a significant diminution in complex fine motor functioning in the patients at the last evaluation [13].

Understanding the pathomechanisms via which chemotherapy impacts on central nervous system (CNS) integrity is crucial to the development of cancer therapies that will spare the CNS.

Many studies have been performed in children with brain tumors and leukemia to explore chemotherapy impact on the developing CNS [14,15,16]. Studies of intellectual development of childhood acute lymphoblastic leukemia (ALL) patients treated solely with polychemotherapy document worse intellectual outcomes in patients diagnosed and treated prior to the 6th year of life [5]. Our understanding of how chemotherapy injures the pediatric brain, what the pathomechanisms of this injury are and what accounts for the higher vulnerability of children under 6 years of age remains limited. We know that chemotherapy associates with leukoencephalopathies and low white matter/grey matter volumes in pediatric B-cell ALL survivors, but we know very little about the biochemical and microstructural changes that lead to these states. More systematic research in this area is urgently needed in order to characterize mechanisms of chemotherapy neurotoxicity in children, identify biomarkers which signal critical CNS toxicity, and also design strategies to prevent it.

The great majority of clinical studies addressing neurotoxicity of chemotherapy in children with cancer are cross-sectional studies performed after cancer treatment has been completed. There are few studies focusing on dynamic changes in brain morphology and function and molecular changes in biological fluids during chemotherapy in children, and there is a dearth of longitudinal prospective clinical studies that examine timely progression and potential reversibility of evolving sequelae. This is the type of studies needed to help explore what acute effects cancer and cancer treatment exert on the developing brain, how early they occur, what the earliest indicators and mechanisms are, and whether treatments can be developed to counteract and/or prevent them.

Effects of chemotherapy on the microstructure of the developing brain

The neural structures and circuits affected by chemotherapy treatment are beginning to be explored. Application of neuroimaging tools could help start to uncover a neural basis for the cognitive deficits observed in cancer survivors. With the advances and refinement of imaging technologies, it has become increasingly recognized that CNS-directed chemotherapy for ALL but also polychemotherapy for solid peripheral tumors lead to alterations in white (WM) and grey matter (GM) which are visible with modern imaging techniques.

White matter

A prospective longitudinal study assessing effects of chemotherapy on the WM in the pediatric brain reported on the occurrence of transient and mostly reversible WM changes during chemotherapy in the majority of patients [14]. Some cross-sectional studies provide evidence that chemotherapy alone or combined with radiation in children cause changes in the WM [15, 17,18,19,20]. Carey and colleagues [15] used voxel based morphometry (VBM) analysis in subjects who were treated with systemic and intrathecal chemotherapy only and reported reduced WM volumes in the right frontal lobes compared to healthy individuals. Others [18] used diffusion tensor imaging (DTI) analysis and examined the images of 13 adult survivors, 17–37 years old, who had been treated with total brain radiation and chemotherapy. These authors reported significantly reduced fractional anisotropy values in the temporal lobes, hippocampi and thalami, which were accompanied by significant WM volume loss. Reddick and coinvestigators [19] used voxel-based analysis of T2-weighted imaging of patients during treatment to identify which WM regions are preferentially damaged. Two sets of conventional T2-weighted axial images were acquired from 197 consecutive patients (85 female, 112 male; aged 1.0–18.9 years) enrolled on an institutional ALL treatment protocol. Two highly significant bilateral clusters of T2 signal intensity change were identified in both 1-group and 2-group analyses. Increased T2-weighted signal intensity from these regions both within and between examinations were nonlinear functions of age at examination, and the difference between the examinations was greater for older subjects who received more intense therapy. These analyses identified specific WM tracts involving predominantly the anterior, superior, and posterior corona radiata and superior longitudinal fasciculus, which were at increased risk for the development of T2-weighted hyperintensities during therapy for childhood ALL. The investigators concluded that these vulnerable regions may be the cause of subsequent cognitive difficulties consistently observed in survivors. Another group of investigators [21] aimed to determine if the loss of WM fractional anisotropy (FA), measured by DTI in post-treatment childhood medulloblastoma and acute lymphoblastic leukemia survivors, correlates with IQ scores. This was a cross-sectional study performed at 6.38 years after diagnosis of ALL and 3.25 years after diagnosis of medulloblastoma. Change in FA had a significant effect on full-scale IQ and verbal and performance IQ. It was suggested that WM FA may be a clinically useful biomarker for the assessment of treatment-related neurotoxicity in childhood cancer survivors [21].

A more recent study by Edelmann and colleagues [22] in survivors of childhood ALL treated with chemotherapy alone (n = 36), cranial radiation (n = 39), and healthy controls (n = 23) revealed that survivors of ALL treated with chemotherapy alone performed worse in processing speed, verbal selective reminding and academics compared to population norms. They also measured higher fractional anisotropy in fiber tracts within the left hemisphere and a lower ratio of WM to intracranial volume in frontal and temporal lobes. There were significant associations between neurocognitive performance and brain imaging, particularly for frontal and temporal WM and GM volumes. The predictive value of FA within the frontal lobe for neurotoxicity in childhood ALL survivors has been suggested [23]. Finally, atypical structural connectome organization in young survivors of ALL was described [24]. Clustered connectivity in the parietal, frontal, hippocampal, amygdalar, thalamic, and occipital regions was altered in the ALL group compared to control subjects and could underlie impaired local information processing, hub connectivity, and cognitive reserve [24].

Sleurs and colleagues [25] conducted magnetic resonance (MR) diffusion imaging in survivors of childhood bone and soft tissue sarcoma. This is the first study to show extensive regions with lower fractional anisotropy and fixel-based measures of apparent fiber density in survivors of solid peripheral tumors (non-ALL, non-CNS). The authors demonstrated global chemotherapy-related changes with particular vulnerability of centrally located WM bundles.

Grey matter

There are few studies examining GM changes during chemotherapy in cancer patients, mainly adults. McDonald and coinvestigators [26, 27] evaluated GM alterations in a cross-sectional MRI study in breast cancer patients with (n = 17) and without (n = 12) chemotherapy and in healthy controls (n = 18). The chemotherapy groups had decreased GM volumes in the bilateral frontal, temporal, and cerebellar regions and right thalamus at 1 month with some recovery seen at 1 year.

Genschaft and colleagues [16] performed a cross-sectional study of brain morphology and neurocognitive function in adolescent and young adult survivors of childhood ALL (n = 27), treated with chemotherapy only, and healthy controls (n = 27). Volumes of GM, WM, and olfactory bulbs were measured using FMRIB’s Integrated Registration and Segmentation Tool (FIRST) and voxel-based morphometry (VBM). The authors found smaller mean GM volumes of the left hippocampus, amygdala, thalamus, and nucleus accumbens in the ALL group. VBM analysis revealed significantly smaller volumes of the left calcarine gyrus, both lingual gyri and the left precuneus. Lower scores in hippocampus-dependent memory were measured in ALL subjects, while lower figural memory correlated with smaller hippocampal volumes. These findings demonstrate that childhood ALL treated with chemotherapy associates with smaller volumes of neocortical and subcortical GM and lower hippocampal memory performance in adolescence and adulthood [16].

Tamnes and colleagues [28] reported smaller surface area in several cortical regions including prefrontal regions, which associated with problems in executive functioning in childhood ALL survivors (ages 18–46 years; age at diagnosis 0–16 years; years since diagnosis 7–40). The pathomechanisms of these differences remain unclear, i.e., it is unknown whether the smaller GM volumes in the ALL groups are caused by destruction of neuronal tissue, impaired neuro- and gliogenesis or disturbance of structural refinements (cortical thinning) that occur naturally during development.

Neurochemical biomarkers in body fluids in cancer patients

Few studies have focused on analysis of chemical and molecular biomarkers indicative of chemotherapy-induced CNS toxicity in cancer patients. Oesterlundh and colleagues [29] analyzed neurochemical markers of brain injury in cerebrospinal fluid (CSF) during induction treatment for acute ALL in children (n = 121; mean age 6.4 years/1.3–16.8 years) on days 0, 8, 15, and 29. They reported significant increases in the levels of neuron-specific-enolase, glial fibrillary acidic protein, and neurofilament protein light chain which suggest that cell injury, involving both neurons and astroglia, occurs during induction chemotherapy in children. Elevation of homocysteine and excitatory amino acid neurotransmitters in the CSF of children who receive methotrexate for cancer treatment has been reported [30] as well as increased beta-glucuronidase activity in the CSF of children with ALL undergoing treatment with high-dose methotrexate [31]. Beta glucuronidase levels correlated with plasma methotrexate levels. The authors concluded that increased beta-glucuronidase activity was due to enzyme leakage through the cell membranes caused by the toxic effect of methotrexate on the cells of the CNS [31].

In a small prospective study, it was shown that neuron-specific enolase CSF levels increase during induction chemotherapy for ALL and remain elevated during consolidation [32]. The authors also reported increased levels of nerve growth factor and brain-derived neurotrophic factor in the CSF during induction and consolidation therapy for ALL, which were interpreted as indicating activation of neuroprotective mechanisms.

Van Gool and colleagues [33] described increase in CSF-Tau, CSF-P-Tau, and CSF-neuromodulin after induction chemotherapy and one intrathecal injection of methotrexate followed by 7 days of systemic corticosteroids. CSF-Tau remained high during induction treatment whereas CSF-P-Tau and CSF-neuromodulin decreased suggesting different mechanisms of neurotoxicity in the course of induction chemotherapy. Similary, Krawzuk-Rybak and coinvestigators [34] measured elevated tau protein levels in the CSF of ALL patients. A negative correlation was found between Tau protein levels obtained from the last CSF (during last routine lumbar puncture) with total and verbal IQ, performance IQ, and perceptual organization index. They concluded that WM injury occurs during chemotherapy and that elevated Tau protein levels in the CSF at the end of treatment indicate future neurocognitive difficulties.

Higher degrees of oxidative stress in the CNS, as measured by levels of oxidized CSF phospholipids in 88 children undergoing chemotherapy for ALL, correlated with higher degree of cognitive dysfunction [35]. Elevated CSF levels of F2 isoprostanes (oxidative marker) and caspase 3/7 (apoptosis markers) were reported in three patients with methotrexate toxicity following intrathecal chemotherapy and high-dose methotrexate [36].

Finally, CSF folate and homocysteine levels were studied in patients with ALL [37]. CSF folate dropped during the first month of therapy and remained low throughout treatment. CSF homocysteine was inversely related to cognitive function prior to treatment and increased during treatment. Of 36 patients who had imaging after completion of chemotherapy, 9 had periventricular or subcortical white matter abnormalities consistent with leukoencephalopathy. In these patients, CSF peak tau concentrations were the highest suggesting that these biomarkers may have predictive value for neurologic outcomes in long-term survivors of childhood ALL [37].

Mechanisms of chemotherapy-induced neurotoxicity and gliotoxicity

Cytostatic drugs utilize various mechanisms via which they attack cancers. Alkylating agents alkylate electron-rich atoms, form covalent bonds, and react with DNA bases. This reaction prevents cells from replicating (39). Cisplatin and analogues form monofunctional and bifunctional adducts which lead to intrastrand or interstrand DNA cross-links interrupting separation, replication and transcription of the DNA (39). Antimetabolites disturb the biosynthesis and function of nucleic acids and impair formation of new DNA and RNA, which leads to cell cycle arrest. Finally, DNA topoisomerase inhibitors form single- or double-strand breaks in the DNA double helix, which relaxes the torsional stress that occurs when the DNA double helix unwinds. Accumulation of torsionally strained and supercoiled DNA interferes with vital cell processes leading to cytotoxic DNA damage causing cell arrest, apoptosis, or necrosis [38].

There has been considerable preclinical research, which demonstrated that cytostatic drugs can produce cognitive impairment in small animal models (for review, see [39,40,41]). The pathomechanisms of this toxicity have been explored in vivo and in vitro.

It appears that toxicity induced by cytostatic drugs within the central nervous system utilizes pathways which are also involved in other brain injury syndromes such as hypoxia/ischemia, traumatic injury, and neuroinflammation.

Oxidative stress is attributed to disruption of mitochondrial DNA leading to formation of reactive oxygen species (ROS). Production of ROS has been demonstrated for various agents, including cyclophosphamide, cytarabin, doxorubicin, methotrexate, and carboplatin [42,43,44,45,46,47,48,49,50,51].

Disruption of neurogenesis has been shown to occur within the hippocampus following treatment with carmustine, cyclophosphamide, 5-fluorouracil, or cisplatin [40, 41, 53,54,55,56,57,58].

Excitotoxicity and apoptosis

In many acute and chronic brain injury syndromes, such as hypoxia-ischemia, trauma, status epilepticus, and neurodegeneration in the context of mitochondrial dysfunction [59,60,61,62], toxic stimuli operate via two well-characterized mechanisms to cause neuronal death. Excitotoxicity is a form of passive neuronal death caused by excessive stimulation of excitatory amino acid (EAA) receptors [60,61,62]. Three subtypes of EAA receptors, N-methyl-d-aspartate, alpha-amino-3-hydroxyl-5-methyl-isoxazol-4-propionic acid, and kainate receptors, are coupled to ion channels and are called ionotropic. Excessive stimulation of ionotropic glutamate receptors causes excitotoxic neuronal death in vitro and in vivo [63]. Active caspase-mediated cell death or apoptosis represents a form of slower degeneration that occurs in hypoxic and traumatic brain injury as well as in the context of mitochondrial dysfunction [59, 60, 62, 64]. Caspase-mediated cell death can be triggered by a primary excitotoxic stimulus of low intensity [65].

In the developing brain, active cell death that occurs after hypoxic or traumatic brain injury markedly resembles morphologically physiological apoptosis [59, 66, 67]. Rzeski and colleagues undertook a series of studies aimed to evaluate whether anticancer agents may exert direct neurotoxic effects and also explored whether excitotoxic and caspase-mediated death comprise components of this toxicity. They investigated neurotoxic effects of common cytotoxic drugs in vitro in neuronal and glial cultures and in vivo in the developing rat brain [68]. When neurons and astroglia were exposed to cisplatin, cyclophosphamide, methotrexate, vinblastin, or thiotepa, a concentration-dependent neurotoxic effect was observed. Neurotoxicity was potentiated by nontoxic glutamate concentrations and blocked by ionotropic glutamate receptor antagonists and a pancaspase inhibitor. To investigate neurotoxicity in vivo, Rzeski and colleagues administered to infant rats cisplatin, cyclophosphamide, thiotepa, or ifosfamide and analyzed their brains. All tested compounds produced widespread lesions within cortex, thalamus, hippocampal dentate gyrus, and caudate nucleus in a dose-dependent fashion [68]. Early histological analysis demonstrated dendritic swelling and relative preservation of axonal terminals, which are morphological features indicating excitotoxicity. After longer survival periods, degenerating neurons displayed morphological features consistent with active, caspase-mediated cell death. These results demonstrate that anticancer drugs are potent neurotoxins in vitro and in vivo; they activate excitotoxic mechanisms but also trigger active, caspase-mediated neuronal death. Other investigators have reported similar findings [46, 69, 70].

A direct toxic effect of some cytostatic drugs on oligodendrocytes and their precursors has been described [52, 54, 71] and likely contributes to white matter pathology seen in pediatric cancer survivors.


Systemic inflammation with cytokine release, which may occur in cancer patients as a response to mucositis and systemic infections, may facilitate a process of neuroinflammation, microglial activation, and suppression of neurogenesis [72,73,74,75,76,77].

Brain perfusion

A reduction by chemotherapy of regional blood flow, possibly due to a reduction in blood vessel density, has also been reported [78,79,80], including more recently a clinical study in pediatric cancer survivors [81]. Using positron emission tomography/magnetic resonance imaging (PET/MR), these investigators measured significantly lower cerebral blood flow and metabolic activity in key brain areas compared to control subjects.

The role of the blood–brain barrier

The brain is protected against potentially harmful medications by the blood–brain barrier, which consist of capillary endothelial unfenestrated cells, linked by tight junctions. Efflux transporters such as P-glycoprotein control and limit invasion of cytotoxic drugs [39]. Moreover, pericytes inhibit the expression of molecules that increase vascular permeability and CNS immune cell infiltration [82]. Multiple studies suggest that the blood–brain barrier is already mature and effective in the fetal brain [83, 84].

To penetrate the blood–brain barrier, drug molecules need to be small (< 500 Da) and lipophilic so they can passively diffuse. Drugs that can use inward transport systems but remain unrecognized by efflux transporters, can also enter the brain [85]. The blood–brain barrier can be disrupted in the proximity to brain tumors and brain metastases, posterior reversible encephalopathy syndrome, following radiation and when brain disruptors are used [86]. In these cases, chemotherapeutic agents can easily penetrate into the central nervous system. Furthermore, in a number of pediatric malignancies, intrathecal chemotherapy is administered which increases the risk for neurologic complications.

Chemotherapy-induced neuropathology

Some cancer chemotherapeutics have been studied in rodents. The studies have focused on methotrexate, alkylating agents (ifosfamide, cyclophosphamide, cisplatin), and vincristine (see reviews [5, 39]). Neuropathological and neurophysiological correlates of CNS toxicity in infant, young, and adult rodents have included marked increase of apoptosis, decline in neurogenesis, impairment of long-term potentiation (LTP), synaptic remodeling, increased blood–brain barrier permeability, impaired cell division and migration, and increased markers for oxidative stress [5, 39]. Table 1 summarizes the types of CNS toxicity described in rodent models at different ages.

Table 1 Neurotoxic effects of chemotherapeutic agents in rodent models [25]

In humans, brain pathology can be studied using MRI techniques. Assigning a particular type of toxicity to one medication is very difficult, given the fact that multidrug regimen are used to treat pediatric malignancies. In addition, radiotherapy is often coadministered.

A most recent study by van der Plas and colleagues in survivors of childhood B-cell ALL who received no radiotherapy describes smaller volumes of both grey and white matter structures, indicating that there has been cell loss in these areas and/or their development was compromised [99]. Nevertheless, there are distinct forms of brain toxicity that have been associated with certain chemotherapeutic drugs.

Leukoencephalopathy is a known complication of chemotherapy, in children and adults, in particular for regimens that include methotrexate, BCNU, melphalan, fludarabine, cytarabine, 5-fluorouracil, levamisole, and cisplatin [100,101,102,103,104]. In many cases, a mild and reversible form of injury occurs. When methotrexate is combined with radiation therapy, the degree of white matter injury increases dramatically and, in such cases, leukoencephalopathy may be irreversible. Determining the relative contributions of each treatment modality to brain injury is practically impossible under such circumstances [101, 102, 105,106,107,108,109].

However, methotrexate has been shown to cause the same type of toxic leukoencephalopathy in the absence of radiation, in cases with intrathecal or intraventricular administration [110,111,112,113]. The greatest injury is seen surrounding a leaky or misplaced ventriculostomy tube used to administer methotrexate via an Ommaya reservoir [100, 109, 114,115,116]. Risk factors for toxicity are also not well understood, but appear to relate to dosages of methotrexate and radiation, modes of administration, types of diluent, preexisting folate deficiency, and idiosyncratic predispositions [86, 101].

An early asymptomatic form of leukoencephalopathy has been reported in children with medulloblastoma and supratentorial primary neuroectodermal tumors receiving combination chemotherapy, with or without concomitant radiation [117,118,119]. In most cases, these lesions were transient and reversible, but there was an increased risk of subsequent neurocognitive deficits. An acute and transient form of encephalopathy has been reported in children receiving high-dose methotrexate for acute lymphoblastic leukemia or osteosarcoma [120]. It has been postulated that under such circumstances a disruption of the blood–brain barrier occurs. In biopsies of such lesions, myelin pallor, vacuolation, axonal spheroids, modest macrophage infiltrates, and gliosis have been reported [86].

Disseminated necrotizing leukoencephalopathy (DNL) presents with a miliary distribution of lesions, ranging from small rounded foci to large confluent zones of non-inflammatory demyelination or white matter necrosis [86, 108, 121, 122]. This disease was first described in children with metastatic meningeal acute lymphoblastic lymphoma (ALL) treated with high-dose methotrexate-based chemotherapy and whole brain irradiation [108, 123]. In adults, DNL has been described in patients with other tumor types, primary CNS and systemic lymphomas, carcinomas, sarcomas, and primitive/embryonal neoplasms [100, 106, 107, 111, 124,125,126,127], and in high-grade gliomas treated with intra-arterial BCNU, both with and without irradiation [128,129,130,131].

Clinical presentation of DNL is that of a rapidly progressive subcortical dementia. Symptoms present after completion of therapy to many months later and may progress to dementia, seizures, coma, and death within months [86].

Reversible posterior leukoencephalopathy syndrome

Reversible posterior leukoencephalopathy syndrome (RPLES) or posterior reversible encephalopathy syndrome (PRES) presents with acute cortical blindness, headache, mental status changes, and sometimes seizures [132]. Malignant hypertension and T2-weighted/FLAIR MRI signal abnormalities in the occipital and posterior temporo-parietal regions are the hallmarks of this disease entity. Lesions may affect grey matter [133,134,135,136,137,138,139,140]. High-dose corticosteroids and various single or combination chemotherapeutic regimens, including cisplatin, cytarabine, cyclophosphamide, and methotrexate, have been identified as triggers.

Symptoms may develop at initiation of therapy or may be delayed for days to weeks. The mechanism of toxicity is poorly understood, although radiologic studies suggest vasogenic edema as the main pathology. Proposed mechanisms have included endothelial damage with blood–brain barrier disruption, transient episodes of hypertension overloading the autoregulatory capabilities of the posterior circulation, and electrolyte imbalances, such as hypomagnesemia [133,134,135,136,137,138,139,140]. In rarely obtained biopsies, vasogenic edema without vascular damage or infarct was detected [137]. In some patients, permanent deficits were encountered suggesting that ischemic damage is possible in severe cases or delays in making the diagnosis and instituting blood pressure control.

Future challenges

There is increasing knowledge from preclinical studies about the effects of cancer chemotherapeutic agents on the mammalian brain, but little information is available on how such findings from various animal models translate and apply to the human pediatric brain.

Advanced neuroimaging studies in cancer patients have started to shed light on the structural and functional impact of chemotherapy on the pediatric and adult brain. There are few studies focusing on dynamic changes in brain morphology and function during chemotherapy in children, and there is a dearth of longitudinal prospective clinical studies that examine step by step their progression and potential reversibility. This is the type of studies needed to help explore what acute effects cancer and cancer treatment exert on the developing brain, how early they occur, what the earliest indicators and mechanisms are, and whether treatments can be developed to counteract and/or prevent them.

Better understanding of pathomechanisms and identification of biomarkers which can trace neurotoxicity risk in individual patients will allow for timely modifications of treatment to minimize toxicity.





Acute lymphoblastic leukemia


Blood–brain barrier


Central nervous system


Cerebrospinal fluid


Deoxyribonucleic acid


Disseminated necrotizing leukoencephalopathy


Diffusion tensor imaging


Excitatory amino acid


Fractional anisotropy


FMRIB’s Integrated Registration and Segmentation Tool


Grey matter


Intelligence quotient


Magnetic resonance


Positron emission tomography


Posterior reversible encephalopathy syndrome


Reactive oxygen species


Reversible posterior leukoencephalopathy syndrome


Voxel based morphometry


White matter


  1. 1.

    Henderson TO, Friedman DL, Meadows AT (2010) Childhood cancer survivors: transition to adult-focused risk-based care. Pediatrics 126:129–136

  2. 2.

    Kadan-Lottick NS, Zeltzer LK, Liu Q et al (2010) Neurocognitive functioning in adult survivors of childhood noncentral nervous system cancers. J Natl Cancer Inst 102:881–893

  3. 3.

    Oeffinger KC, Nathan PC, Kremer LC (2010) Challenges after curative treatment for childhood cancer and long-term follow up of survivors. Hematol Oncol Clin North Am 24:129–149

  4. 4.

    Zeltzer LK, Recklitis C, Buchbinder D et al (2009) Psychological status in childhood cancer survivors: a report from the Childhood Cancer Survivor Study. J Clin Oncol 27:2396–2404

  5. 5.

    Sleurs C, Lemiere J, Vercruysse T et al (2017) Intellectual development of childhood ALL patients: a multicenter longitudinal study. Psycho-Oncology 26:508–514

  6. 6.

    Duffner PK, Armstrong FD, Chen L et al (2014) Neurocognitive and neuroradiologic central nervous system late effects in children treated on Pediatric Oncology Group (POG) P9605 (standard risk) and P9201 (lesser risk) acute lymphoblastic leukemia protocols (ACCL0131): a methotrexate consequence? A report from the Children’s Oncology Group. J Pediatr Hematol Oncol 36:8–15

  7. 7.

    Anderson FS, Kunin-Batson AS (2009) Neurocognitive late effects of chemotherapy in children: the past 10 years of research on brain structure and function. Pediatr Blood Cancer 52:159–164

  8. 8.

    Ashford J, Schoffstall C, Reddick WE et al (2010) Attention and working memory abilities in children treated for acute lymphoblastic leukemia. Cancer 116:1173–1186

  9. 9.

    Buizer AI, de Sonneville LM, Veerman AJ (2009) Effects of chemotherapy on neurocognitive function in children with acute lymphoblastic leukemia: a critical review of the literature. Pediatr Blood Cancer 52:447–454

  10. 10.

    Lofstad GE, Reinfjell T, Hestad K et al (2009) Cognitive outcome in children and adolescents treated for acute lymphoblastic leukaemia with chemotherapy only. Acta Paediatr 98:180–186

  11. 11.

    Moleski M (2000) Neuropsychological, neuroanatomical, and neurophysiological consequences of CNS chemotherapy for acute lymphoblastic leukemia. Arch Clin Neuropsychol 15:603–630

  12. 12.

    von der Weid N, Mosimann I, Hirt A et al (2003) Intellectual outcome in children and adolescents with acute lymphoblastic leukaemia treated with chemotherapy alone: age- and sex-related differences. Eur J Cancer 39:359–365

  13. 13.

    Jansen NC, Kingma A, Schuitema A et al (2008) Neuropsychological outcome in chemotherapy-only-treated children with acute lymphoblastic leukemia. J Clin Oncol 26:3025–3030

  14. 14.

    Bhojwani D, Sabin ND, Pei D et al (2014) Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. J Clin Oncol 32:949–959

  15. 15.

    Carey ME, Haut MW, Reminger SL et al (2008) Reduced frontal white matter volume in long-term childhood leukemia survivors: a voxel-based morphometry study. AJNR Am J Neuroradiol 29:792–797

  16. 16.

    Genschaft M, Huebner T, Plessow F et al (2013) Impact of chemotherapy for childhood leukemia on brain morphology and function. PLOS One 8(11):e78599.

  17. 17.

    Asato R, Akiyama Y, Ito M et al (1992) Nuclear magnetic resonance abnormalities of the cerebral white matter in children with acute lymphoblastic leukemia and malignant lymphoma during and after central nervous system prophylactic treatment with intrathecal methotrexate. Cancer 70:1997–2004

  18. 18.

    Dellani PR, Eder S, Gawehn J et al (2008) Late structural alterations of cerebral white matter in long-term survivors of childhood leukemia. J Magn Reson Imaging 27:1250–1255

  19. 19.

    Reddick WE, Glass JO, Johnson DP, Laningham FH, Pui C-H (2009) Voxel-based analysis of T2 hyperintensities in white matter during treatment of childhood leukemia. Am J Neuroradiol 30:1947–1954

  20. 20.

    Deprez S, Amant F, Smeets A et al (2012) Longitudinal assessment of chemotherapy-induced changes in cerebral white matter and its correlation with impaired cognitive functioning. J Clin Oncol 30:274–281

  21. 21.

    Khong P-L, Leung LHT, Fung ASM et al (2006) White matter anisotropy in post-treatment childhood cancer survivors: preliminary evidence of association with neurocognitive function. J Clin Oncol 24:884–890

  22. 22.

    Edelmann MN, Krull KR, Liu W et al (2014) Diffusion tenson imaging and neurocognition in survivors of childhood acute lymphoblastic leukaemia. Brain 137:2973–2983

  23. 23.

    ElAlfy M, Ragab I, Azab I, Amin S, Abdel-Maguid M (2014) Neurocognitive outcome and white matter anisotropy in childhood acute lymphoblastic leukemia survivors treated with different protocols. Pediatr Hematol Oncol 31:194–204

  24. 24.

    Kesler SR, Gugel M, Huston-Warren E, Watson C (2016) Atypical structural connectome organization and cognitive impairment in young survivors of acute lymphoblastic leukemia. Brain Connect 6:273–282

  25. 25.

    Sleurs C, Lemiere J, Christiaens D et al (2018) Advanced MR diffusion imaging and chemotherapy-related changes in cerebral white matter microstructure of survivors of childhood bone and soft tissue sarcoma. Hum Brain Mapp:1–13

  26. 26.

    McDonald BC, Conroy SK, Ahles TA, West JD, Saykin AJ (2010) Gray matter reduction associated with systemic chemotherapy for breast cancer: a prospective MRI study. Breast Canc Res Treat 123:819–828

  27. 27.

    McDonald BC, Conroy SK, Smith DJ, West JD, Saykin AJ (2013) Frontal gray matter reduction after breast cancer chemotherapy and association with executive symptoms: a replication and extension study. Brain Behav Immun 30:S117–S125

  28. 28.

    Tamnes CT, Zeller B, Amlien IK et al (2015) Cortical surface area and thickness in adult survivors of pediatric acute lymphoblastic leukemia. Pediatr Blood Cancer 62:1027–1034

  29. 29.

    Oesterlundh G, Kjellmer I, Lannering B et al (2008) Neurochemical markers of brain damage in cerebrospinal fluid during induction treatment of acute lymphoblastic leukemia in children. Pediatr Blood Cancer 50:793–798

  30. 30.

    Quinn CT, Griener JC, Bottiglieri T et al (1997) Elevation of homocysteine and excitatory amino acid neurotransmitters in the CSF of children who receive methotrexate for the treatment of cancer. J Clin Oncol 15:2800–2806

  31. 31.

    Viacha V, Eliopoulou M, Haidas S, Beratis NG (2004) Correlation of cerebrospinal fluid betal-glucuronidase activity with plasma methotrexate concentrations in leukemic children receiving high-dose methotrexate. Pediatr Blood Cancer 42:350–356

  32. 32.

    Chiaretti A, Ruggiero A, Coccia P et al (2011) Expression of liquoral neuroprotection markers in children with acute lymphoblastic leukemia. Leukemia Res 35:1467–1471

  33. 33.

    Van Gool SW, De Meyer G, van de Voorde A, Vanmechelen E, Vanderstichele H (2004) Neurotoxicity marker profiles in the CSF are not age-dependent but show variation in children treated for acute lymphoblastic leukemia. Neurotoxicology 25:471–480

  34. 34.

    Krawczuk-Rybak M, Grabowska A, Protal PT, Muszynska-Roslan K, Braszko J (2012) Intellectual functioning of childhood leukemia survivors – relation to Tau protein – a marker of white matter injury. Adv Med Sci 57:266–272

  35. 35.

    Caron JE, Krull KR, Hockenberry M et al (2009) Oxidative stress and executive function in children receiving chemotherapy for acute lymphoblastic leukemia. Pediatr Blood Cancer 53:551–556

  36. 36.

    Taylor OA, Hockenberry MJ, McCarthy K et al (2015) Evaluation of biomarkers of oxidative stress and apoptosis in patients with severe methotrexate neurotoxicity: a case series. J Pediatr Oncol Nurs 32:320–325

  37. 37.

    Cole PD, Beckwith KA, Vijayanathan V et al (2009) Folate homeostasis in cerebrospinal fluid during therapy for acute lymphoblastic leukemia. Pediatr Neurol 40:34–41

  38. 38.

    DeVita V, Hellman S, Rosenberg S (2005) Cancer: principles&practice of oncology, 7th edn, pp 332–422

  39. 39.

    Seigers R, Fardell JE (2011) Neurobiological basis of chemotherapy-induced cognitive impairment: a review of rodent research. Neurosci Biobehav Rev 35:729–741

  40. 40.

    Seigers R, Schagen SB, Beerling W et al (2008) Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat. Behav Brain Res 186:168–175

  41. 41.

    Seigers R, Schagen SB, Coppens CM et al (2009) Methotrexate decreases hippocampal cell proliferation and induces memory deficits in rats. Behav Brain Res 2:279–284

  42. 42.

    Geller HM, Cheng KY, Goldsmith NK et al (2001) Oxidative stress mediates neuronal DNA damage and apoptosis in response to cytosine arabinoside. J Neurochem 78:265–275

  43. 43.

    Husain K, Whitworth C, Hazelrigg S, Rybak L (2003) Carboplatin-induced oxidative injury in rat inferior colliculus. Int J Toxicol 22:335–342

  44. 44.

    Husain K, Whitworth C, Somani SM, Rybak LP (2001) Carboplatin-induced oxidative stress in rat cochlea. Hear Res 159:14–22

  45. 45.

    Oboh G, Ogunruku OO (2010) Cyclophosphamide-induced oxidative stress in brain: protective effect of hot short pepper (Capsicum frutescens L. var. abbreviatum). Exp Toxicol Pathol 63:227–233

  46. 46.

    Koros C, Kitraki E (2009) Neurofilament isoform alterations in the rat cerebellum following cytosine arabinoside administration. Toxicol Lett 189:215–218

  47. 47.

    Joshi G, Sultana R, Tangpong J et al (2005) Free radical mediated oxidative stress and toxic side effects in brain induced by the anti cancer drug adriamycin: insight into chemobrain. Free Radic Res 39:1147–1154

  48. 48.

    Montilla P, Tunez I, Munoz MC, Soria JV, Lopez A (1997) Antioxidative effect of melatonin in rat brain oxidative stress induced by Adriamycin. Rev Esp Fisiol 53:301–305

  49. 49.

    Öz E, Ilhan MN (2006) Effects of melatonin in reducing the toxic effects of doxorubicin. Mol Cell Biochem 286:11–15

  50. 50.

    Rajamani R, Muthuvel A, Senthilvelan M, Sheeladevi R (2006) Oxidative stress induced by methotrexate alone and in the presence of methanol in discrete regions of the rodent brain, retina and optic nerve. Toxicol Lett 165:265–273

  51. 51.

    Uzar E, Koyuncuoglu HR, Uz E et al (2006) The activities of antioxidant enzymes and the level of malondialdehyde in cerebellum of rats subjected to methotrexate: protective effect of caffeic acid phenethyl ester. Mol Cell Biochem 291:63–68

  52. 52.

    Dietrich J, Han R, Yang Y, Mayer-Proschel M, Noble M (2006) CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. J Biol 5:22.1–22.23

  53. 53.

    Dietrich J, Prust M, Kaiser J (2015) Chemotherapy, cognitive impairment and hippocampal toxicity. Neuroscience 308:224–232

  54. 54.

    Han R, Yang YM, Dietrich J et al (2008) Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system. J Biol 7:12.1–12.22

  55. 55.

    Mignone RG, Weber ET (2006) Potent inhibition of cell proliferation in the hippocampal dentate gyrus of mice by the chemotherapeutic drug thioTEPA. Brain Res 1111:26–29

  56. 56.

    Mondie CM, Vandergrift KA, Wilson CL, Gulinello ME, Weber ET (2010) The chemotherapy agent, thioTEPA, yields long-term impairment of hippocampal cell proliferation and memory deficits but not depression-related behaviors in mice. Behav Brain Res 209:66–72

  57. 57.

    Mustafa S, Walker A, Bennett G, Wigmore PM (2008) 5-Fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus. Eur J Neurosci 28:323–330

  58. 58.

    Yang M, Kim JS, Song MS et al (2010) Cyclophosphamide impairs hippocampus-dependent learning and memory in adult mice: possible involvement of hippocampal neurogenesis in chemotherapy-induced memory deficits. Neurobiol Learn Mem 93:487–494

  59. 59.

    Bittigau P, Sifringer M, Pohl D (1999) Apoptotic neurodegeneration following trauma is markedly enhanced in the immature brain. Ann Neurol 45:724–735

  60. 60.

    Bossy-Wetzel E, Barsoum MJ, Godzik A et al (2003) Mitochondrial function in apoptosis, neurodegeneration and aging. Curr Opin Cell Biol 15:706–716

  61. 61.

    Lipton SA, Rosenberg PA (1994) Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 330:613–622

  62. 62.

    Murphy AN, Fiskum G, Beal MF (1999) Mitochondria in neurodegeneration: bioenergetic function in cell life and death. J Cereb Blood Flow Metab 19:231–245

  63. 63.

    Rothman SM, Olney JW (1995) Excitotoxicity and the NMDA receptor—still lethal after eight years. Trends Neurosci 18:57–58

  64. 64.

    Lee JM, Zipfel GJ, Choi DW (1999) The changing landscape of ischaemic brain injury mechanisms. Nature 399(suppl):A7–A14

  65. 65.

    Bonfoco E, Krainc D, Ankarcrona M et al (1995) Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci U S A 92:7162–7166

  66. 66.

    Northington FJ, Ferriero DM, Graham EM et al (2001) Early neurodegeneration after hypoxia-ischemia in neonatal rat is necrosis while delayed neuronal death is apoptosis. Neurobiol Dis 8:207–219

  67. 67.

    Pohl D, Bittigau P, Ishimaru MJ et al (1999) NMDA antagonists and apoptotic cell death triggered by head trauma in developing rat brain. Proc Natl Acad Sci U S A 96:2508–2513

  68. 68.

    Rzeski W, Pruskil S, Macke A et al (2004) Anticancer agents are potent neurotoxins in vitro and in vivo. Ann Neurol 56:351–360

  69. 69.

    Courtney MJ, Coffey ET (1999) The mechanism of Ara-C-induced apoptosis of differentiating cerebellar granule neurons. Eur J Neurosci 11:1073–1084

  70. 70.

    Wick A, Wick W, Hirrlinger J et al (2004) Chemotherapy-induced cell death in primary cerebellar granule neurons but not in astrocytes: in vitro paradigm of differential neurotoxicity. J Neurochem 91:1067–1074

  71. 71.

    Gregorios JB, Gregorios AB, Mora J et al (1989) Morphologic alterations in rat brain following systemic and intraventricular methotrexate injection: light and electron microscopic studies. J Neuropathol Exp Neurol 48:33–47

  72. 72.

    Das S, Basu A (2008) Inflammation: a new candidate in modulating adult neurogenesis. J Neurosci Res 86:1199–1208

  73. 73.

    de Koning BA, van Dieren JM, Lindenbergh-Kortleve DJ et al (2006) Contributions of mucosal immune cells to methotrexate-induced mucositis. Int Immunol 18:941–949

  74. 74.

    De Visser KE, Eichten A, Coussens LM (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6:24–37

  75. 75.

    Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O (2003) Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A 100:13632–13637

  76. 76.

    Seruga B, Zhang H, Bernstein LJ, Tannock IF (2008) Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer 8:887–899

  77. 77.

    Wilson CJ, Finch CE, Cohen HJ (2002) Cytokines and cognition—the case for a head-to-toe inflammatory paradigm. J Am Geriatr Soc 50:2041–2056

  78. 78.

    de Vos FY, Willemse PH, De Vries EG, Gietema JA (2004) Endothelial cell effects of cytotoxics: balance between desired and unwanted effects. Cancer Treat Rev 30:495–513

  79. 79.

    Mizusawa S, Kondoh Y, Murakami M et al (1988) Effect of methotrexate on local cerebral blood flow in conscious rats. Jpn J Pharmacol 48:499–501

  80. 80.

    Seigers R, Timmermans J, van der Horn HJ et al (2010) Methotrexate reduces hippocampal blood vessel density and activates microglia in rats but does not elevate central cytokine release. Behav Brain Res 207:265–272

  81. 81.

    Theruvath AJ, Ilivitzki A, Muehe A et al (2017) A PET/MRI imaging approach for the integrated assessment of chemotherapy-induced brain, heart, and bone injuries in pediatric cancer survivors: a pilot study. Radiology 285:971–979

  82. 82.

    Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468:562–566

  83. 83.

    Saunders NR, Knott GW, Dziegielewska KM (2000) Barriers in the immature brain. Cell Mol Neurobiol 20:29–40

  84. 84.

    Virgintino D, Errede M, Girolamo F et al (2008) Fetal blood-brain barrier P-glycoprotein contributes to brain protection during human development. J Neuropathol Exp Neurol 67:50–61

  85. 85.

    de Vries NA, Beijnen JH, Boogerd W, van Tellingen O (2006) Blood–brain barrier and chemotherapeutic treatment of brain tumors. Expert Rev Neurother 6:1199–1209

  86. 86.

    Perry A, Schmidt RE (2006) Cancer therapy-associated CNS neuropathology: an update and review of the literature. Acta Neuropathol 111:197–212

  87. 87.

    Briones TL, Woods J (2011) Chemotherapy-induced cognitive impairment is associated with decreases in cell proliferation and histone modifications. BMC Neurosci 12:124

  88. 88.

    Briones TL, Woods J (2013) Dysregulation in myelination mediated by persistent neuroinflammation: possible mechanisms in chemotherapy-related cognitive impairment. Brain Behav Immun 35:23–32

  89. 89.

    Lyons L, Elbeltagy M, Bennett G, Wigmore P (2011) The effects of cyclophosphamide on hippocampal cell proliferation and spatial working memory in rat. PLoS One 6:e21445

  90. 90.

    Lee GD, Longo DI, Wang Y et al (2006) Transient improvement in cognitive function and synaptic plasticity in rats following cancer chemotherapy. Clin Cancer Res 12:198–205

  91. 91.

    Xiao R, Yu HL, Zhao HF et al (2007) Developmental neurotoxicity role of cyclophosphamide onpost-neural tube closure of rodents in vitro and in vivo. Int J Dev Neurosci 25:531–537

  92. 92.

    Avella D, Pisu MB, Roda E, Gravati M, Bernocchi G (2006) Reorganization of the rat cerebellar cortex during postnatal development following cisplatin treatment. Exp Neurol 201:131–143

  93. 93.

    Andres AL, Gong C, Di K, Bota DA (2014) Low-doses of cisplatin injure hippocampal synapses: a mechanism for ‘chemo’ brain? Exp Neurol 255:137–144

  94. 94.

    Cerri S, Piccolini VM, Santin G et al (2011) The developmental neurotoxicity study of platinum compounds: effects of cisplatin versus a novel Pt(II) complex on rat cerebellum. Neurotoxicol Teratol 33:273–281

  95. 95.

    Gopal KV, Wu C, Shrestha B et al (2012) D-Methionine protects against cisplatin-induced neurotoxicity in cortical networks. Neurotoxicol Teratol 34:495–504

  96. 96.

    Sugimoto S, Yamamoto YL, Nagahiro S, Diksic M (1995) Permeability change and brain tissue damage after intracarotid administration of cisplatin studied by double-tracer autoradiography in rats. J Neuro-Oncol 24:229–240

  97. 97.

    Piccolini VM, Cerri S, Romanelli E, Bernocchi G (2012) Interactions of neurotransmitter systems duringpostnatal development of the rat hippocampal formation: effects of cisplatin. Exp Neurol 234:239–252

  98. 98.

    Turan MI, Cayir A, Cetin N et al (2014) An investigation of the effect of thiamine pyrophosphateon cisplatin-induced oxidative stress and DNA damage in rat brain tissue compared with thiamine: thiamine and thiamine pyrophosphate effects on cisplatin neurotoxicity. Hum Exp Toxicol 33:14–21

  99. 99.

    van der Plas E, Schachar RJ, Hitzler J et al (2016) Brain structure, working memory and response inhibition in childhood leukemia survivors. Brain Behav 7:e00621

  100. 100.

    Cossaart N, SantaCruz KS, Preston D, Johnson P, Skikne BS (2003) Fatal chemotherapy-induced encephalopathy following high-dose therapy for metastatic breast cancer: a case report and review of the literature. Bone Marrow Transplant 31:57–60

  101. 101.

    Cruz-Sanchez FF, Artigas J, Cervos-Navarro J, Rossi ML, Ferszt R (1991) Brain lesions following combined treatment with methotrexate and craniospinal irradiation. J Neuro-Oncol 10:165–171

  102. 102.

    Fassas AB, Gattani AM, Morgello S (1994) Cerebral demyelination with 5-fluorouracil and levamisole. Cancer Investig 12:379–383

  103. 103.

    Liu HM, Maurer HS, Vongsvivut S, Conway JJ (1978) Methotrexate encephalopathy. A neuropathologic study. Hum Pathol 9:635–648

  104. 104.

    Moore-Maxwell CA, Datto MB, Hulette CM (2004) Chemotherapy-induced toxic leukoencephalopathy causes a wide range of symptoms: a series of four autopsies. Mod Pathol 17:241–247

  105. 105.

    Antunes NL, Souweidane MM, Lis E, Rosenblum MK, Steinherz PG (2002) Methotrexate leukoencephalopathy presenting as Kluver–Bucy syndrome and uncinate seizures. Pediatr Neurol 26:305–308

  106. 106.

    DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ (2002) Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: radiation therapy oncology group study 93–10. J Clin Oncol 20:4643–4648

  107. 107.

    Lai R, Abrey LE, Rosenblum MK, DeAngelis LM (2004) Treatment-induced leukoencephalopathy in primary CNS lymphoma: a clinical and autopsy study. Neurology 62:451–456

  108. 108.

    Rubinstein LJ, Herman MM, Long TF, Wilbur JR (1975) Disseminated necrotizing leukoencephalopathy: a complication of treated central nervous system leukemia and lymphoma. Cancer 35:291–305

  109. 109.

    Stone JA, Castillo M, Mukherji SK (1999) Leukoencephalopathy complicating an Ommaya reservoir and chemotherapy. Neuroradiology 41:134–136

  110. 110.

    Abelson HT (1978) Methotrexate and central nervous system toxicity. Cancer Treat Rep 2:1999–2001

  111. 111.

    Allen JC, Rosen G, Mehta BM, Horten B (1980) Leukoencephalopathy following high-dose iv methotrexate chemotherapy with leucovorin rescue. Cancer Treat Rep 64:1261–1273

  112. 112.

    Omuro AM, DeAngelis LM, Yahalom J, Abrey LE (2005) Chemotherapy for primary CNS lymphoma: an intent-to-treat analysis with complete follow-up. Neurology 64:69-74

  113. 113.

    Lovblad K, Kelkar P, Ozdoba C et al (1998) Pure methotrexate encephalopathy presenting with seizures: CT and MRI features. Pediatr Radiol 28:86–91

  114. 114.

    de Waal R, Algra PR, Heimans JJ, Wolbers JG, Scheltens P (1993) Methotrexate induced brain necrosis and severe leukoencephalopathy due to disconnection of an Ommaya device. J Neuro-Oncol 15:269–273

  115. 115.

    Packer RJ, Zimmerman RA, Rosenstock J et al (1981) Focal encephalopathy following methotrexate therapy. Administration via a misplaced intraventricular catheter. Arch Neurol 38:450–452

  116. 116.

    Colamaria V, Caraballo R, Borgna-Pignatti C et al (1990) Transient focal leukoencephalopathy following intraventricular methotrexate and cytarabine. A complication of the Ommaya reservoir: case report and review of the literature. Childs Nerv Syst 6:231–235

  117. 117.

    Fouladi M, Chintagumpala M, Laningham FH et al (2004) White matter lesions detected by magnetic resonance imaging after radiotherapy and high-dose chemotherapy in children with medulloblastoma or primitive neuroectodermal tumor. J Clin Oncol 22:4551–4560

  118. 118.

    Rutkowski S, Bode U, Deinlein F et al (2005) Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 352:978–986

  119. 119.

    Fouladi M, Langston J, Mulhern R et al (2000) Silent lacunar lesions detected by magnetic resonance imaging in children with brain tumors: a late sequela of therapy. J Clin Oncol 18:824-831

  120. 120.

    Rubnitz JE, Relling MV, Harrison PL et al (1998) Transient encephalopathy following high-dose methotrexate treatment in childhood acute lymphoblastic leukemia. Leukemia 12:1176–1181

  121. 121.

    Price RA, Jamieson PA (1975) The central nervous system in childhood leukemia. II. Subacute leukoencephalopathy. Cancer 35:306–318

  122. 122.

    Smith B (1975) Brain damage after intrathecal methotrexate. J Neurol Neurosurg Psychiatry 38:810–815

  123. 123.

    Rubinstein JL, Herman MM, Long TF, Wilbur JR (1975) Leukoencephalopathy following combined therapy of central nervous system leukemia and lymphoma. Acta Neuropathol Suppl (Berl) Suppl 6:251–255

  124. 124.

    Atlas SW, Grossman RI, Packer RJ et al (1987) Magnetic resonance imaging diagnosis of disseminated necrotizing leukoencephalopathy. J Comput Tomogr 11:39–43

  125. 125.

    Batara JF, Grossman SA (2003) Primary central nervous system lymphomas. Curr Opin Neurol 16:671–675

  126. 126.

    Sindwahni G, Arora M, Thakker VD, Jain A (2017) MRI in chemotherapy induced leukoencephalopathy: report of two cases and radiologist's perspective. J Clin Diagn Res TD08-TD09.

  127. 127.

    Omuro AM, Ben-Porat LS, Panageas KS et al (2005) Delayed neurotoxicity in primary central nervous system lymphoma. Arch Neurol 62:1595–1600

  128. 128.

    Bashir R, Hochberg FH, Linggood RM, Hottleman K (1988) Pre-irradiation internal carotid artery BCNU in treatment of glioblastoma multiforme. J Neurosurg 68:917–919

  129. 129.

    Kleinschmidt-DeMasters BK (1986) Intracarotid BCNU leukoencephalopathy. Cancer 57:1276–1280

  130. 130.

    Kleinschmidt-DeMasters BK, Geier JM (1989) Pathology of high-dose intra-arterial BCNU. Surg Neurol 31:435–443

  131. 131.

    Rosenblum MK, Delattre JY, Walker RW, Shapiro WR (1989) Fatal necrotizing encephalopathy complicating treatment of malignant gliomas with intra-arterial BCNU and irradiation: a pathological study. J Neuro-Oncol 7:269–281

  132. 132.

    Hinchey J, Chaves C, Appignani B et al (1996) A reversible posterior leukoencephalopathy syndrome. N Engl J Med 334:494–500

  133. 133.

    Kahana A, Rowley HA, Weinstein JM (2005) Cortical blindness: clinical and radiologic findings in reversible posterior leukoencephalopathy syndrome: case report and review of the literature. Ophthalmology 112:e7–e11

  134. 134.

    Pavlakis SG, Frank Y, Chusid R (1999) Hypertensive encephalopathy, reversible occipitoparietal encephalopathy, or reversible posterior leukoencephalopathy: three names for an old syndrome. J Child Neurol 14:277–281

  135. 135.

    Rangi PS, Partridge WJ, Newlands ES, Waldman AD (2005) Posterior reversible encephalopathy syndrome: a possible late interaction between cytotoxic agents and general anaesthesia. Neuroradiology 47:586–590

  136. 136.

    Sanchez-Carpintero R, Narbona J, Lopez de Mesa R, Arbizu J, Sierrasesumaga L (2001) Transient posterior encephalopathy induced by chemotherapy in children. Pediatr Neurol 24:145–148

  137. 137.

    Schiff D, Lopes MB (2005) Neuropathological correlates of reversible posterior leukoencephalopathy. Neurocrit Care 2:303–305

  138. 138.

    Shin RK, Stern JW, Janss AJ, Hunter JV, Liu GT (2001) Reversible posterior leukoencephalopathy during the treatment of acute lymphoblastic leukemia. Neurology 56:388–391

  139. 139.

    Stott VL, Hurrell MA, Anderson TJ (2005) Reversible posterior leukoencephalopathy syndrome: a misnomer reviewed. Intern Med J 35:83–90

  140. 140.

    Tam CS, Galanos J, Seymour JF et al (2004) Reversible posterior leukoencephalopathy syndrome complicating cytotoxic chemotherapy for hematologic malignancies. Am J Hematol 77:72–76

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CI is tenured Professor of Child Neurology in the Department of Neurology at the University of Wisconsin Madison. Her basic and translational research interests lie in studying mechanisms of injury to the developing brain caused by hypoxia, trauma, anesthetic and antiepileptic drugs, drugs of abuse, and cancer chemotherapeutics.

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Ikonomidou, C. Chemotherapy and the pediatric brain. Mol Cell Pediatr 5, 8 (2018).

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  • Neurotoxicity
  • Cognition
  • Brain injury
  • Disease mechanisms