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102.1 Clinical Features

and Laboratory Investigations In the treatment of malignancies three modalities play a major role: surgery, radiotherapy, and chemotherapy. Other treatment modalities such as hyper- thermia and laser coagulation, often image-guided, are of some, but lesser importance. Radiotherapy and chemotherapy are not only applied in the treatment of primary brain tumors and metastases, but intrathecal and intravenous administration of chemo- therapeutic drugs, together with cranial or total neu- raxis irradiation, are also widely used in the prophy- laxis of cerebral involvement in extracerebral malignancies.

For many years the brain was considered to be relatively resistant to therapeutic doses of irradiation and chemotherapy, because neurons do not multiply and the turnover of glial cells is relatively slow. Also, the blood–brain barrier may prevent the penetration of chemotherapeutics into the brain. These concepts have to be modified, because it has become clear that adverse effects are not exceptional.

In the classical description of the effects of radiotherapy three types of damage are distinguished ac- cording to their time of occurrence: acute reactions, which occur during the time of treatment and may change the treatment schedule; early delayed reactions, which are usually transient and appear from a few weeks to a few months after treatment; and late delayed reactions, with onset from several months to several years after treatment.

Acute reactions are usually mild and of little consequence, but severe reactions may occur. Clinically they may present as mild signs of increased intracra- nial pressure. The patient may become confused, in- coherent, and disoriented. In more severe cases the patient suffers from headaches, nausea, vomiting, and sometimes elevation of body temperature. Seizures occasionally occur, and the patient may lapse into co- ma. Discontinuation of the treatment and corticos- teroid administration may be necessary and life-sav- ing.

Early delayed reactions are usually transient and disappear without treatment. Various clinical symptoms have been reported: somnolence, nausea, vomiting, dysarthria, dysphagia, cerebellar ataxia, and nys- tagmus.

Late delayed reactions are generally irreversible.

The process begins insidiously with personality changes, gradually progressing over several months.

Initially there is excessive drowsiness and loss of initiative and interest. In the course of time there is a decrease of cognitive functioning, confusion, irri- tability, and memory loss, eventually leading to global dementia.

This classical description is used to describe time- linked reactions after radio- and chemotherapy. In addition, the “focal radiation injury” and “focal white matter injury” resulting from stereotactic radiosurgery, gamma knife surgery, or intensity-modulat- ed radiotherapy may be seen as fitting within the classical concept. Clinically some of these injuries have important consequences. Focal radiation injury caused by irradiation of extracranial structures, e.g.

of nasopharyngeal squamous cell tumors or pituitary tumors, may lead to damage of the brain – in these cases, damage to both temporal lobes, resulting in a complex behavioral change, the Klüver–Bucy syndrome.

There are a number of irradiation- and chemotherapy-related patterns that need special considera- tion because of their consequences for the prognosis and sometimes the need for therapeutic management. This holds especially for multifocal inflammatory leukoencephalopathy (MIL), and the posterior reversible encephalopathy syndrome (PRES). MIL and PRES are addressed separately in Chaps. 88 and 92.

102.2 Pathology

Neuropathological changes in acute reactions after radiotherapy are primarily characterized by cerebral edema, with flattening of gyri, obliteration of sulci, and signs of tentorial herniation. The lateral ventri- cles are narrowed. Vascular changes are present and consist of fibrinoid necrosis and thickening of the endothelium with extravasation of fibrinous material and perivascular lymphocytic infiltration.

Because the early delayed reaction is usually transient and nonlethal in nature, the amount of informa- tion available on the histopathological features is lim- ited. Foci of demyelination with central necrosis and petechial hemorrhages have been described. Lym- phocytes and plasma cells are found in the perivascu-

Leukoencephalopathy After Radiotherapy and Chemotherapy

Chapter 102

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lar spaces, and there is pronounced microglial and as- trocytic proliferation in the affected areas. Vascular changes are not prominent in the affected areas, but occasionally the lesions are more marked and show fibrinoid necrosis, fibroproliferative vessel thickening, enlargement of endothelial cells, and capillary proliferation. The cytoarchitecture of the gray matter is usually intact.

The neuropathological findings of the late delayed leukoencephalopathy are rather specific. The changes consist of demyelination, astrogliosis, multifocal co- agulative necrosis, and cavitation. The periventricular white matter and the centrum semiovale are involved bilaterally, whereas the subcortical arcuate fibers, the cerebral cortex, and deep gray matter structures are usually spared. Within and around the necrotizing lesions conspicuous swelling of axons occurs. An inflammatory response is usually absent. There are marked vascular lesions, characterized by hyaliniza- tion, fibrosis, and necrosis of vessel walls and vascular thrombosis. Areas of endothelial proliferation and various degrees of adventitial fibroblast proliferation are found. Obliteration of the lumen may result. De- position of iron salts and calcium in the vessel walls may occur. Calcifications may be extensive and be present in the subcortical areas, the basal ganglia, and, less commonly, in the pons. It is noteworthy that mineralizing angiopathy is more often seen in children than in adults.

The installment of prophylactic irradiation and radiotherapy for acute lymphatic leukemia and the treatment of genetic disorders with bone marrow transplantation have focused attention on the side effects of these therapies. In most patients these reactions are transient and have the nature of temporary white matter edema, as has been confirmed by an occasional biopsy, and more recently by quantitative MR data. Multifocal white matter necrosis has the same neuropathological features as the radiation necrosis described above for late delayed post-irradiation reactions.

102.3 Pathogenetic Considerations

Cranial irradiation and systemic, intracarotid, intravenous, and intrathecal chemotherapy, alone or in combination, may result in lesions of the CNS, of either the white matter, the gray matter, or both. In cases of combined therapy it is impossible to delin- eate the relative contributions of radiation and chemotherapy to the development of cerebral lesions.

The total radiation dose and possible overdosage on specific targets, as well as the dose of systemic intravenously or intrathecally administered chemotherapeutics all influence the outcome. Some chemothera- peutic agents are radiosensitizers, for example bis-

chloroethyl-nitrosourea (BCNU), methotrexate, and cisplatin. They enhance the effect of radiation-induced changes. On the other hand, radiation may in- duce changes in the permeability of the blood–brain barrier and thus affect the delivery of potentially toxic agents. Other factors in the patient, such as nutri- tional status, type of primary malignancy, or pre- transplant status, and the presence of a paraneoplas- tic syndrome, may well contribute to the development and severity of cerebral lesions.

The acute post-therapy syndrome is thought to be due to vasogenic edema resulting from damage to the capillary endothelium.

Early delayed reactions are believed to be due to demyelination and may be reversible to some degree.

There are suggestions that they may be the result of an autoimmune reaction following sensitization for some myelin antigen that has become exposed by therapy-induced tissue necrosis. Antigens are re- leased in the intracellular spaces by damaged myelin and glial cells, and may evoke hypersensitivity reactions. This hypothesis has never been proven, but the perivascular inflammatory reaction may be an argu- ment. Another mechanism which may account for the marked demyelination in the absence of vascular changes in early delayed post-treatment leukoencephalopathy is primary damage to glial cells, in particular oligodendrocytes. Sometimes striking glial proliferations are noticed, associated with bizarre cells and giant multinuclear astrocytes, supporting this hypothesis.

In the late delayed reactions vascular changes with secondary ischemic changes form the most likely ex- planation for the tissue damage. The endothelium of blood vessels is one of the most sensitive tissues of the brain. Damage to the endothelium leads to endothelial proliferation and changes in the vessel wall, with subsequent obliteration of the lumen and ischemia.

Small vessels are usually most affected, but larger ar- teries may also suffer, and may be partially or totally occluded, possibly with formation of moyamoya-like collaterals.

It is important to realize that the adverse consequences of irradiation of the brain, in particular in combination with chemotherapy, may be more severe in infants and children than in adults. The consequences for the immature brain may differ from those for the more mature brain. From the management of medulloblastomas in young children it has become clear that aggressive treatment approaches, especially craniospinal irradiation, can harm the developing brain. It is hard to predict what dose of radiotherapy will be harmful in each individual child. It is well known that very young children will have significant learning problems after full-dose radiotherapy, and that even older children may develop difficulties in school. However, a reduction in dosage may also re-

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duce efficacy on the tumor. Hence, approaches using reduced-dose craniospinal irradiation and chemotherapy, in order to reduce cognitive, endocrine, and psychological deficits, may decrease late effects, but carry with them the risk of having more treatment failures.

The combination of radiotherapy and chemotherapy leads to synergistic inhibition of the synthesis of macromolecules and DNA repair, possibly further contributing to the damage. In a postmortem study of children with childhood leukemia treated with different modes of application of this combined therapy, comparing those who showed leukoencephalopathy and those who did not show leukoencephalopathy, it became clear that the development of white matter damage did not correlate with age, despite the different stages of myelination and neuronal differentia- tion in the pediatric age group. Nor was there a rela- tionship with intercurrent infections, nutrition, or the presence of CNS leukemia. There was a clear relation- ship with the radiation dose the child had received in combination with intrathecal methotrexate. The total amount of intrathecally administered methotrexate seemed less important. The dose of methotrexate was important when given intravenously: the incidence of leukoencephalopathy increased with the total dose of intravenously administered methotrexate.

To add substance to this discussion, the multicen- ter study of the German Late Effects (of acute lymphatic leukemia treatment) Working Group, summa- rizes findings in a large population treated with stan- dard protocols (Hertzberg et al. 1997). In this study 118 former patients with acute lymphatic leukemia in first continuous remission underwent CT and/or MRI. The group was subdivided into: group A (39 patients), receiving intrathecal methotrexate and systemic medium–high dose methotrexate; group B (41 patients), receiving cranial irradiation (16.8 Gy) and intrathecal methotrexate or systemic methotrexate;

and group C (38 patients), receiving irradiation (17.1 Gy) and intrathecal methotrexate. Abnormal MRI and CT scans were found in 61 of the 118 patients, consisting of white matter changes (diffuse or focal), brain atrophy, and calcifications. Of these 61 patients, 15 were from group A (38.5%), 23 from group B (56.1%), and 23 from group C (60.5%). Pa- tients with definite CNS changes showed impaired neuropsychological function. It is clear from this re- port that methotrexate without irradiation can also lead to serious CNS changes, both of gray and white matter. This has been reported in more detail by Lövblad et al. (1998). They describe the cases of four children treated with high-dose intravenous and intrathecal methotrexate without irradiation. In all these cases the cure was prolonged, lasting for more than 1 year. These children developed serious CNS abnormalities with diffuse hyperintense white matter

changes on T2-weighted images and subcortical hy- perdensities on CT, consistent with calcifications. The authors attribute these changes to a mineralizing angiopathy, commonly thought to be the result of cranial irradiation in combination with chemotherapy.

From this and other reports it has become clear that chemotherapy without irradiation may also lead to leukoencephalopathy and mineralizing angiopathy.

102.4 Therapy

In acute reactions corticosteroids are useful in allevi- ating cerebral vasogenic edema and may be life-sav- ing in patients with imminent tentorial herniation.

The importance of recognizing early delayed reactions is the fact that they are usually transient and do not necessarily require intervention or indicate a fail- ure of therapy. In the late delayed reaction corticosteroids play a minor role. In cases with focal radiation necrosis, surgery is an option. In patients with neuro- logical syndromes caused by toxic effects of cytostatic or immunosuppressive drugs that may be reversible, abortion of the therapy or a switch to other drugs may have a beneficial effect. Psychiatric syndromes, especially when caused by more permanent damage of both temporal lobes, as happens in the irradiation of nasopharyngeal and pituitary tumors, are difficult to treat and may require special mea- sures.

102.5 Magnetic Resonance Imaging

MRI is generally the first choice of imaging modalities in the follow-up of patients treated with cranial irradiation and/or chemotherapy, because its sensi- tivity is much better than that of CT. Only in the detection of microcalcifications, such as occur in mineralizing angiopathy, does CT have an advantage.

All stages of radiation and chemotherapy injuries

Chapter 102 Leukoencephalopathy After Radiotherapy and Chemotherapy 810

Fig. 102.1. A 62-year-old woman treated with chemotherapy and irradiation for a right frontal glioma. The initial tumor is barely visible on the FLAIR images (first three rows) within a now much larger area of high signal involving the periventricular and deep frontal white matter, right more than left, and the corpus callosum.T1-weighted images after contrast (fourth row) show a rim of a few millimeters’ thickness along the wall of the left lateral ventricle as well as an enhancing dot in the right frontal area. The white matter changes can be attributed to the irradiation and chemotherapy.The enhancement, which did not change during further follow-up, probably represents either inactivated tumor tissue, or, more probably, radiation-induced changes

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Fig. 102.1.

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have in common an increase in free tissue and, sometimes, intracellular water. The consequence of this is a higher signal intensity on T2-weighted and lower signal intensity on T1-weighted images. This signal be- havior may, however, reflect many forms of underlying pathology, such as impairment of the blood–brain barrier due to endothelial damage and vasogenic edema, demyelination, gliosis, ischemia, and tissue necrosis. Newer techniques, such as diffusion-weighted imaging, perfusion imaging, and proton MRS, have been of considerable help in the determination of the structural tissue changes. Diffusion-weighted imaging, in combination with calculated ADC maps, or diffusion tensor imaging with the calculation of frac- tional anisotropy, have made it possible to differenti- ate between vasogenic edema and cytotoxic edema, and permits a better estimation of the prognosis of the abnormalities found. Contrast administration plays an important role, even though it does not dif-

ferentiate radiation necrosis from tumor recurrence.

Perfusion imaging and MRS have a prominent role in distinguishing tumor recurrence from radiation necrosis. In necrotizing tissue perfusion is low, whereas in tumor recurrence it is usually high. MRS – if possible, chemical shift imaging to cover the whole area – shows in tumor recurrence high choline, lactate, and often the presence of some residual brain metabolites, for instance N-acetylaspartate in re- duced concentration. In necrotic tissue N-acetylas- partate is usually absent, as is choline, whereas lactate is present. It is, however, not rare that both tissue necrosis and tumor recurrence are present at the same time. Microbleeds can be made visible on MR images with gradient echo or hybrid spin-echo–gradient-echo techniques.

In the acute reaction MR findings are nonspecific.

The images may be completely normal or subtly abnormal with poorly defined multifocal areas of hy-

Fig. 102.2. A 52-year-old male patient presented with a par- tial seizure. He had been treated previously for a right-sided nasopharyngeal squamous cell carcinoma with partial exci- sion and radiotherapy.The right temporal lobe was included in

the irradiation field. Coronal T2-weighted images show the im- pact of the radiation on the right temporal lobe, involving both white and gray matter

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perintensity on T2-weighted images, most often in both hemispheres. The abnormalities usually disappear spontaneously, given an uneventful clinical course.

In early delayed reactions, occurring a few weeks to months after treatment, the white matter changes are also usually transient. Changes on MRI include high signal intensity on T2-weighted or FLAIR images in the basal ganglia, the cerebral peduncles, and the deep white matter. Diffusion-weighted imaging also shows high signal intensity in these areas, with also a high ADC value. The term “T2 shine-through” is sometimes used for this phenomenon, but seems not quite correct, because the combination of high signal on diffusion-weighted imaging and high diffusivity may reflect an underlying condition, most probably, but not only, vasogenic edema. It is in general an indi- cation of a benign nature of the lesion. In some patients who develop a diffuse leukoencephalopathy a few weeks to a few months after treatment, the course is not benign and the white matter abnormalities are

not reversible. Enhancing lesions within the white matter correlate with tissue necrosis at autopsy.

Transient white matter abnormalities are often found in patients treated for acute lymphocytic leukemia with prophylactic cranial irradiation, chemotherapy, and bone marrow transplantation.

The lesions are located in the periventricular area and may be more or less extensive. There is no clear rela- tionship between the severity of the lesions on MRI and the clinical condition and outcome. Diffusion- weighted imaging and ADC maps may be helpful by showing the nature of the lesions. The lesions may remain visible for a long time after the clinical disap- pearance of symptoms.

Late delayed reactions occur months to years after the initial treatment. Depending on the field of irradiation the lesions are more focal (Figs. 102.1–102.3) or more generalized (Figs. 102.4 and 102.5). So-called

“diffuse radiation injury” can be caused by irradiation, by combined irradiation and chemotherapy, and by chemotherapy alone. The white matter lesions,

Fig. 102.3. A 4-year-old boy was treated prophylactically with irradiation and intrathecal methotrexate because of acute lymphocytic leukemia. The T2-weighted images (upper row) show involvement of the basal ganglia, internal capsule, and

cerebral peduncles in the midbrain. The T1-weighted images (second row) reveal cysts in the basal ganglia, indicating that cystic necrosis has developed. With contrast, an enhancing recurrent tumor is seen in the third ventricle

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when irradiation has covered the whole brain, are located in the white matter of both hemispheres and are symmetrical and confluent. Combinations of diffuse radiation injury and recurrent tumor may occur (Fig. 102.3). The lesions of late delayed reactions have a high signal intensity on proton density, T2-weight-

ed, and FLAIR images. ADC values are usually only slightly above those of normal cerebral tissue. Despite the sometimes extensive white matter lesions, patients may be asymptomatic. In more severe cases there may be slowing down of mental activity and cognitive impairment. The most severe form of late

Fig. 102.4. A 29-year-old woman with disseminated breast carcinoma. Metastases in the brain were treated with radiotherapy and systemic cytostatic treatment. The T2-weighted transverse series 6 months after radiotherapy (upper two rows) shows diffuse symmetrical deep white matter hyperintensity,

also involving the external capsule and the temporal lobes. In the cerebellum there are multiple, asymmetrical lesions and linear high-signal bands in the cerebellar foliae. T1-weighted images after contrast (third row) show multiple metastases and leptomeningeal carcinomatosis

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delayed reaction is necrotizing encephalopathy with areas of focal necrosis (Fig. 102.3). The borders of these lesions may enhance. To verify this diagnosis, perfusion studies may be performed, showing reduced perfusion, or MRS, showing loss of metabolites without a rise in choline concentration and with various amounts of lactate.

A disseminated necrotizing leukoencephalopathy with characteristic contrast enhancement of the white matter has been reported in patients with acute lymphoblastic leukemia after intense chemotherapy with methotrexate and prophylactic cranial irradiation, with either a fulminant or a less fulminant course. In these cases methotrexate was delivered both intra-

Fig. 102.5. A 24-year-old man was treated for acute lympho- cytic leukemia with chemotherapy and intrathecal methotrexate.Two months later he developed progressive encephalopathy. The T2-weighted images show extensive involvement of

arcuate fibers in parietal, frontal, and temporal lobes, as well as bilateral involvement of the posterior limb of the internal capsule, thalamus, corticospinal tracts in the midbrain, and both middle cerebellar peduncles

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Fig. 102.6.

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venously and intrathecally. MRI initially shows extensive white matter abnormalities, with focal but symmetrical enhancement. On follow-up studies the

enhancement disappears but atrophy sets in, leading to death within a few years. The MR pattern differs from that seen in autoimmune suppressive therapy- related MIL.

Severe late delayed reactions may also develop after treatment with a combination of irradiation, chemotherapy, and bone marrow transplantation.

Years after treatment, and following an initially good response, a progressive encephalopathy may develop with loss of mental faculties and an array of neurolog- ical symptoms and ending in death. MRI shows white matter abnormalities predominantly involving the arcuate fibers and progressive atrophy (Figs. 102.6 and 102.7).

Mineralizing angiopathy is more often seen in children than in adults. In children it is the most common abnormality seen on MRI and/or CT. Calcifications are found in the subcortical white matter and sometimes in the basal ganglia, in particular in the puta- men.

Lesions after gamma-knife therapy, stereotactic radiosurgery, and localized overdosage are not funda- mentally different from the classic description. Here, too, the whole gamut of reactions is possible: from vasogenic transient edema, to severe white and/or gray matter lesions, to a cavitating (leuko)encephalopathy.

Fig. 102.6. An 18-year-old girl was treated 7 years ago with chemotherapy, irradiation, and autologous bone marrow transplantation for a non-Hodgkin lymphoma. She has been tumor-free since the treatment. However, since 1.5 years after the treatment she has developed slowly progressive encephalopathy with recently more rapid decline. The encephalopathy was characterized by concentration and memory problems, personality changes, subsequent global cognitive impairment, and finally increasing ataxia and spasticity. The T2-weighted images (first three rows) show extensive white matter changes,especially involving the arcuate fibers.There is some cerebral atrophy with ventriculomegaly, including the temporal horns, and widening of the subarachnoid spaces.

There are bilateral lesions in the thalamus. Diffusion-weighted images (fourth row) at different b values and an ADC map show increased ADC values in the abnormal white matter areas (ADC values in the affected region 1.24–1.55). These values, unfortunately, only reflect the final phase of the process. Because of the insidious start and progress of the encephalopathy, initial ADC values are not available

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Fig. 102.7. The T1-weighted images of the same patient as illustrated in Fig. 102.6, without (first row) and with contrast (second row), reveal multiple small punctate areas of contrast uptake, suggesting perivascular enhancement. These findings suggest an underlying angiitis or vasculopathy