Neurotoxicity: Changes in the Brains of Children with Brain Tumors of the Central Nervous System

Kathy Warren, M.D., pediatric oncologist, National Cancer Institute

Neurotoxicity is a significant tumor-and treatment-related complication for a number of childhood cancer survivors. It is particularly relevant for children with brain tumors who require therapy specifically directed at the central nervous system. Despite its significance, relatively little is known about the etiology, diagnosis, prevention, or treatment of neurotoxicity. As more children with cancer are surviving longer, the importance of determining the long-term effects of treatment becomes paramount. Clinical studies to investigate these issues are becoming more prevalent.

Neurotoxicity is defined as a detrimental effect on the nervous system caused by a biological, chemical or physical agent. It can manifest in a variety of ways, which include headache, seizures, a decrease in IQ, new learning disabilities, difficulty with concentration and memory, and personality changes. The degree of neurological impairment varies from clinically undetectable to severe. Injury to the brain tissue may be due to the primary tumor itself, a neurological intervention, radiation therapy, systemic chemotherapy or intrathecal (administered directly into the spinal fluid) chemotherapy. Neurotoxicity may occur immediately after a treatment, weeks, months after a treatment, or even years after treatment. Some effects may be partially or completely reversible, but for others, the extent of clinical impairment can worsen over time even after the treatment has been completed. (1) Research to identify patients who are at risk for neurotoxicity is ongoing. Young age, radiation to the whole brain, tumor location within the brain, and the rate of tumor growth are factors that appear to have a direct impact on the level of cognitive decline. (2)

Neurotoxicity can be classified functionally (behavioral, chemical or electrophysiologic) or structurally (anatomic location of the brain injury). There is uncertainty about how best to objectively classify functional information about brain function, but there are methodology problems associated with testing children while they are being treated on a clinical trial. (3) For example, different testing instruments are used depending on the patient's age. A child may receive one battery of tests at the beginning of the study, but may cross over to another test battery as they get older. Comparing scores among different tests that measure the same neurological function (e.g., I.Q.) over time may not be valid. Children may also demonstrate a "practice" effect with repeated testing. Furthermore, correlation of MRI changes with clinical symptoms and neurological testing has been inconsistent (4) and the clinical implications of abnormalities on MRI or CT scans are unclear. (5) We are still searching for early objective predictive tests of early neurotoxicity. At present, neurotoxicity is best classified as structural changes within the brain.

The medical terms for the structural changes that occur within the brain and that have been associated with neurotoxicity are 1) subacute leukoencephalopathy, 2) mineralizing microangiopathy, and 3) cortical atrophy. Subacute leukoencephalopathy is damage of the white matter (nerve fibers) of the brain and is manifested by loss of neuronal processes and the myelin sheaths that coat nerve fibers and enhance the transmission of signals through these fibers. This can occur in several discreet areas of the brain or be confluent throughout the brain and is commonly seen around the ventricles (fluid containing compartments within the brain). Patients may be asymptomatic, or exhibit a range of neurologic deficits. Mineralizing microangiopathy is degeneration of the wall and lining of the small blood vessels. (6) Although this results in permanent destructive changes to the surrounding brain, its effect on neuropsychologic functioning is not clearly defined. (6) Cortical atrophy is a gray matter (nerve cell) disorder with irregular loss of neurons. The exact relationship between treatments and development of these structural lesions has been difficult to define.

New techniques in brain imaging may provide better, non-invasive tools for detecting and characterizing changes associated with the development of neurotoxicity. Proton Nuclear Magnetic Resonance Spectroscopy (1H-NMRS) is a non-invasive imaging technique currently being studied at the National Cancer Institute. It is performed in a MRI scanner, at the same time that a standard MRI is obtained. Whereas the standard MRI gives a picture of a section of the brain, 1H-NMRS provides a profile of chemical make-up within a section of brain tissue. The chemicals that are measured include: 1) N-Acetyl Aspartate (NAA), 2) Choline, 3) Creatine, and 4) Lactate. NAA is found only in normal nerve cells and their processes (fibers). (7) Brain tumors are thought to replace or destroy the normal NAA-containing cells, thereby causing a decrease in NAA levels on 1H-NMRS. Increased choline levels have been associated with an increased number of cells, a greater rate of cell membrane synthesis, and increased cell turnover, which are processes associated with tumor cell division. (8,9) Creatine is a marker of cell energy, which lactate is an indicator of oxygen deficiency, which is typical of dead or dying tissue. Ratios of these chemicals within parts of the brain can be measured before treatment and followed over time.

At the National Institutes of Health, a method for measuring these chemicals in contiguous small areas of the brain was developed. (9) This method allows investigators to look at these chemicals in a large portion of the brain, rather than in one specific area. This method has been applied to the study of children with a variety of disorders. In children with metabolic disorders, areas of abnormal white matter on MRI images correspond to abnormalities in NAA, Choline and Lactate by 1H-NMRS. Other studies have shown NAA to be altered in disease states that involve neuronal damage. In children with brain tumors, the patterns of chemicals may help distinguish active tumor from brain swelling and dead tumor, and may also be predictive of outcome. (11)

Because both subacute leukoencephalopathy and cortical atrophy involve damage or loss of neurons, determination of changes in brain tissue chemicals, particularly NAA, by 1H-NMRS imaging may be helpful in characterizing and predicting neurotoxicity. In the Neuro-Oncology Branch of the National Cancer Institute, we are currently studying patterns of metabolites from 1H-NMRS imaging of patients with brain tumors in both normal and abnormal appearing areas of the MRI. We are comparing these results with results of neuropsychological testing to determine if any correlation exists. We hope to use this information to objectively determine when patients are developing neurotoxicity, and potentially avert further damage by changing therapy.

Kathy Warren, M.D. is a Pediatric Oncologist in the recently formed Neuro-Oncology Branch of the National Cancer Institute and National Institute for Neurologic Disorders and Stroke. This program is under the direction of Howard Fine, M.D. Its mission is to develop an integrated clinical, translational and basic research program for the purpose of developing novel experimental therapeutics for children and adults with tumors of the Central Nervous System. Investigators in the branch conduct both laboratory and clinical research aimed at improving the prognosis and management of patients with brain tumors.

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This article was written for the Childhood Brain Tumor Foundation, Germantown, MD,

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