Chemotherapy and the pediatric brain

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, 17‐20]. 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.

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.

In many acute and chronic brain injury syndromes, such as hypoxia-ischemia, trauma, status epilepticus, and neurodegeneration in the context of mitochondrial dysfunction [59‐62], 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 [60‐62]. 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 [72‐77].

A reduction by chemotherapy of regional blood flow, possibly due to a reduction in blood vessel density, has also been reported [78‐80], 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 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.

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 [133‐140]. 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 [133‐140]. 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.