Advancements in cancer treatment, particularly with immunotherapy and targeted agents, have significantly improved outcomes across a range of malignancies. However, these therapies bring with them a spectrum of neurotoxic complications that challenge timely recognition and management. Traditional treatments such as chemotherapy and radiotherapy remain key contributors to neurotoxicity, while newer modalities including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T-cell therapies introduce distinct and often unpredictable effects. Neurotoxicities can impact both the central and peripheral nervous systems, presenting with nonspecific neurological symptoms that are frequently reversible if identified early. Neuroimaging serves as an essential tool for detecting and differentiating treatment-related neurotoxicities from disease progression or unrelated pathology, enabling appropriate and timely clinical intervention.
Neurotoxicities Associated with Conventional Therapies
Chemotherapy-induced encephalopathy is one of the most frequently encountered central neurotoxic effects, particularly with methotrexate. Depending on the dosage and route of administration, methotrexate may lead to acute, subacute or delayed encephalopathy, with manifestations including headaches, seizures and stroke-like episodes. Imaging findings commonly show restricted diffusion in deep white matter, particularly in the centrum semiovale. These changes are often reversible, although delayed cases may cause permanent deficits. Other agents such as fluorouracil and capecitabine can also produce reversible white matter abnormalities.
Posterior reversible encephalopathy syndrome (PRES) is a notable complication associated with various oncological therapies, including platinum-based agents and tyrosine kinase inhibitors. Its pathophysiology is complex, involving cerebral autoregulation failure, endothelial dysfunction and inflammation. Imaging typically reveals vasogenic oedema in posterior white matter, though patterns can vary widely. Early diagnosis is critical as PRES is generally reversible but may lead to haemorrhage or infarction if untreated.
Neurovascular complications, including arterial ischaemia, venous thrombosis and haemorrhage, may occur due to malignancy-related hypercoagulability or specific chemotherapeutic agents. Platinum-based drugs and high-dose methotrexate elevate stroke risk, while L-asparaginase is linked to cerebral venous thrombosis. Reversible cerebral vasoconstriction syndrome (RCVS), associated with agents like cyclophosphamide and cytarabine, presents with distinctive imaging features, including nonaneurysmal subarachnoid haemorrhage and the characteristic “string-of-beads” appearance on vascular imaging.
Radiation therapy remains integral to cancer management but carries significant neurotoxic potential. Radiation-induced leukoencephalopathy (RIL) typically arises months to years post-treatment and is associated with diffuse white matter changes. Concurrent use of methotrexate exacerbates risk. Radiation necrosis (RN), another delayed effect, often overlaps radiologically with tumour recurrence. Advanced imaging such as perfusion MRI and amino acid PET helps distinguish between RN and progressive disease. Other complications include radiation-induced cavernous malformations, intravascular papillary endothelial hyperplasia and SMART syndrome, all of which have distinct imaging signatures. Vascular abnormalities like radiation-induced arteritis and Moyamoya-like vasculopathy also occur, particularly in young patients or those treated near the circle of Willis.
Immune-Related Neurological Toxicities
Immune checkpoint inhibitors act by enhancing T-cell activity but may provoke immune-related adverse events (irAEs) affecting the nervous system. These toxicities occur in a minority of patients yet may be severe or fatal. They include encephalitis, aseptic meningitis, cranial neuropathies and myelitis, among others. Peripheral nervous system involvement is more common and presents with various neuropathies. Radiological findings are variable and may include leptomeningeal enhancement or demyelinating lesions. PML, caused by JC virus reactivation, is another rare yet serious complication of immunosuppressive therapy, typically involving subcortical white matter on MRI.
ICI-induced hypophysitis is most commonly linked to CTLA-4 inhibitors, although it also occurs with PD-1/PD-L1 therapies. Imaging reveals pituitary enlargement and possible stalk thickening. Neuroophthalmologic effects such as optic neuropathy and thyroid eye disease have also been reported, typically in patients on pembrolizumab.
CAR T-Cell Therapy and Novel Syndromes
CAR T-cell therapy, a transformative immunotherapy for haematological malignancies, introduces new neurotoxic risks. Cytokine release syndrome (CRS) is the most frequent, followed by immune effector cell-associated neurotoxicity syndrome (ICANS). ICANS presents with varied neurological and psychiatric symptoms. Imaging may be unremarkable in mild cases but can show cerebral oedema, splenial lesions or PRES-like changes in severe forms. Diagnosis relies on clinical criteria, supported by neuroimaging to exclude other causes.
Tumour inflammation-associated neurotoxicity (TIAN) represents a localised inflammatory response at the tumour site, typically following CAR T-cell therapy in primary CNS tumours. It may exacerbate focal neurological deficits or cause mechanical effects such as hydrocephalus. Imaging in type 1 TIAN reveals obstructive features, while type 2 TIAN may show peritumoural signal changes without obstruction. Early recognition and differentiation from pseudoprogression are essential, especially as management differs between TIAN subtypes.
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Targeted agents like bevacizumab, though beneficial in reducing oedema and stabilising the blood-brain barrier, pose diagnostic challenges. They may mask progression due to reduced contrast enhancement and, in rare cases, cause PRES, cerebral microhaemorrhages or stroke. Recognising patterns such as stable regions of low ADC helps differentiate these effects from infarction or tumour growth.
The increasing complexity of oncological therapies has expanded the range of potential neurotoxicities, underscoring the vital role of neuroimaging in patient care. Radiologists must remain vigilant and informed about the evolving spectrum of imaging findings associated with both conventional and novel cancer treatments. Through early detection and accurate differentiation of neurotoxicity patterns, imaging enables prompt and appropriate clinical intervention. In doing so, radiologists contribute significantly to safe, high-quality and patient-centred oncological care.
Source: American Journal of Roentgenology
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