In the last decades more aggressive treatment meth- ods have been used to control otherwise fatal dis- eases. This kind of treatment has a considerable im- pact on the temporary improvement, cure, and sur- vival rate of patients with life-threatening conditions.
It has been known for a long time that radiation ther- apy of the brain, either for prophylaxis as in acute lymphoblastic leukemia (ALL) of childhood, or for therapeutic reasons as in tumors of the brain, can lead to radiation damage of the brain, either as radiation necrosis or leukoencephalopathy, focal or diffuse (see Chap. 102). When radiation therapy is used in combi- nation with intravenous or intrathecal methotrexate, the lesions can be even more pronounced. The intro- duction of bone marrow and organ transplantation in the treatment of a number of disorders has increased the numbers both of reversible and of permanent le- sions in the central and/or peripheral nervous system related to the medical treatment before and after the intervention. This means that radiologists are in- creasingly being confronted with lesions of the brain that are therapy-related, either during the period of intervention, during the months following it, or even after an intervention that took place many years pre- viously
The list of compounds that can be responsible for brain lesions is long, and for many of them the nature of the damage they may cause is known. Table 88.1 shows where the pharmaceutical compound has its place in present treatment plans. Notice that for some interventions an aggressive pretreatment is neces- sary. This pretreatment may cause lesions of the brain, but it has also been shown that the choice of pretreatment medication can influence the later out- come of drugs used after the intervention.
In this chapter we will discuss the side effects of drugs used in modern therapeutic strategies. Fortu- nately most of these side effects are reversible or, de- spite their visibility on MRI, do not lead to permanent major neurological dysfunction. An early clinical and radiological diagnosis is important. The therapeutic regimen should be modified or aborted and, if neces- sary and possible, replaced by a therapy with similar effect. This will in most cases lead to disappearance of the clinical symptoms and MR manifestations, but not in all.
The reported reactions to the drugs cited in the Table 88.1 may be divided in two groups of abnormal- ities:
88.1 Multifocal Inflammatory Leukoencephalopathy
In the patients with multifocal inflammatory leuko- encephalopathy (MIL) the lesions may appear multi- ple sclerosis-like (Fig. 88.1). There are multiple le- sions in the centrum semiovale, some with the ap- pearance of Dawson’s fingers. Many lesions may en- hance after contrast injection. The enhancement may be ring-like. In other cases the lesions have the appearance of progressive multifocal leukoen- cephalopathy, with larger confluent lesions extending into the arcuate fibers. Sometimes the multiple en- hancing lesions are taken for cerebral metastases and brain biopsy may be performed. The latter is also prompted by the clinical presentation of a multifocal neurological syndrome with subacute confusion, ataxia, dysarthria, diplopia, seizures, and other neuro- logical signs. Neuropathology of MIL shows marked
Iatrogenic Toxic Encephalopathies
Chapter 88
Table 88.1. Schematic overview of the most common drugs used before and after the central intervention.
The list of drugs is incomplete
Pretreatment Treatment Post-treatment
Immunosuppression Radiotherapy Anti-GVHD
Chemotherapy Bone marrow transplant Cyclosporine Cyclophosphamide Organ transplant Tacrolimus (FK506)
Doxorubicin Cytostatics Corticosteroids
Vincristine Chemotherapy Prednisone 5-Fluorouracil
L-Asparaginase Levamisole Cytosine arabinoside Pegaspargase
Cisplatin Progenitor stem cell support BCNU
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Fig. 88.1. Multifocal inflammatory leukoencephalopathy in a 57-year-old woman during adjuvant therapy with levamisole for malignant melanoma. Over a period of 3 weeks the patient became progressively confused and ataxic. The proton densi- ty image (left) shows multifocal white matter lesions, which enhance after contrast (contrast-enhanced T1-weighted im-
age on the right). After discontinuation of levamisole and un- der treatment with steroids, the clinical picture improved dra- matically. The MRI improved too. From Kimmel et al. (1995), with permission, and courtesy of Dr. E.F.M. Wijdicks, Depart- ment of Neurology, Mayo Clinic, Rochester Minnesota, USA
Fig. 88.2. The T2-weighted images show the classical pattern of the posterior reversible encephalopathy syndrome with in- volvement of the border zones between the middle and pos-
terior cerebral artery and the middle and anterior cerebral artery
focal cellularity of the white matter, with mononu- clear cells scattered throughout the white matter and around the blood vessels. The mononuclear cells are mainly macrophages. Knowledge of the drugs the pa- tient is taking will, of course, lead to the correct diag- nosis and treatment. MIL is mostly seen in patients with colon cancer treated with a combination of 5- fluorouracil (5-FU) and levamisole, the latter proba- bly playing the dominant role and 5-fluorouracil act- ing as potentiator of the immunostimulatory actions of levamisole (Fig. 88.1). A patient has been reported who developed MIL after treatment with 5-fluo- rouracil alone. This patient, however, had a deficiency of dihydropyrimidine dehydrogenase, an enzyme necessary for 5-fluorouracil catabolism. MIL has also been described in patients treated with 5-fluorouracil derivatives, such as tegafur [1-(2-tetrahydrofuryl)-5- fluoro-uracil] and carmofur (1-hexylcarbamoyl-5- fluoro-uracil).After discontinuing the therapy the en- cephalopathy usually still progresses for 1 or 2 months, and then gradually clinical and radiological improvement occurs, although often incomplete.
88.2 Posterior Reversible Encephalopathy Syndrome
Drugs used in the prevention of graft-versus-host disease (GVHD) may lead to a reversible encephalo- pathy syndrome, posterior reversible encephalopathy syndrome (PRES), that bears resemblance to what is seen in acute hypertensive encephalopathy (Figs.
88.2–88.4; see also Chap. 92). In fact, the reaction may be mediated by hypertension, but there are excep- tions. Clinically the presentation of the syndrome consists of altered mental status, headaches, seizures, and cerebral blindness. Drugs most often used in GVHD are cyclosporine and tacrolimus. Cyclosporine is of great importance in organ and bone marrow transplantation. The activity of cyclosporine is T-cell- mediated and inhibits calcineurin, which plays a role in calcium-mediated cell death. Cyclosporine is also used in autoimmune disorders, insulin-dependent di- abetes mellitus, inflammatory bowel disease, chronic asthma, rheumatoid arthritis, aplastic anemia, and psoriasis. Tacrolimus (FK 506) suppresses both the cell-mediated and humoral immune responses by se- lectively inhibiting the expression of T lymphocytes of a subset of early-phase activation genes, including interleukin (IL)-2, IL-3, IL-4, interferon-g, tumor necrosis factor, and granulocyte colony-stimulating factor. Tacrolimus binds, as cyclosporine, to specific intracellular protein ligands, which play a role in maintaining the stability of intracellular structures.
Tacrolimus and cyclosporine inhibit the activity of calcineurin, but it is unclear how this relates to the de- velopment of leukoencephalopathy. The PRES reac-
tion is only one of the possible neurological side ef- fects of these drugs, and effects on other organs are also known. In PRES there is, as in hypertensive en- cephalopathy, preferential involvement of the occipi- tal lobes, but other locations – the frontal lobes, bor- der zones, mesencephalon, and pons and cerebellum – have also been reported. The preference for areas in the vertebrobasilar arterial territory is considered to be due to the lack of sympathetic–parasympathetic fibers around these vessels, with poorer autoregula- tion as a result. There are many other suggestions for how to explain the selective damage: for example, lo- cal endothelial damage with the release of vasoactive peptides leading to labile blood pressure and va- sospasm, and thrombotic microangiopathy leading to microvascular damage. None of these theories is com- pletely satisfactory. In some cases only the subcortical white matter is involved, the gray matter being spared. In other cases the cortex is also involved.
There is evidence for a relation between the condi- tioning regimens used before allogeneic bone mar- row transplant and the type of lesions observed under post-treatment medication. Patients under post- treatment medication who were pretreated with cy- clophosphamide and a chemotherapeutic agent, such as busulfan or thiotepa, develop cortical abnormali- ties with various degrees of subcortical white matter involvement. Nontransplant and transplant patients treated with cyclophosphamide and total body irradi- ation have lesions in the subcortical and deep white matter, without cortical involvement. This exempli- fies how the final result is the last stage of a complex process. Cyclosporine-related toxicity is more often seen in liver transplantation than in cardiac or renal transplantation. The elimination of cyclosporine is through hepatic metabolism via the P-450 cyto- chrome oxidase system, and the concentration of bio- logically active cyclosporine depends on the blood cholesterol level. For this reason, cyclosporine toxici- ty occurs especially in the period shortly after liver transplantation, when the new liver has not regained its full functional capability. It is also clear that the pre-existing condition of the patient, which necessi- tated the liver transplant and may have included a he- patocerebral syndrome, alcoholic liver cirrhosis, and a severe degree of alcohol-related neurological dis- ease, may obscure the symptoms of cyclosporine or tacrolimus toxicity. In these potentially reversible tox- ic disorders diffusion-weighted images and ADC maps are important. They help to differentiate be- tween cytotoxic edema and vacuolating myelinopa- thy on one hand, and vasogenic edema on the other.
As a rule, increased diffusivity is seen in reversible conditions and is helpful in the initial diagnosis, whereas decreased diffusivity usually predicts a poorer prognosis.
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In the last years it has become clear that toxic ef- fects may appear a long time, even many years, after the intervention, and the link between the interven- tion and the brain abnormalities may not be obvious.
We have just started to learn that even many years
after bone marrow transplant, which involves the use of total body irradiation and immunosuppressive and chemotherapy, severe, fatal leukoencephalopathy may occur.
Fig. 88.3. Images of a 14-year-old girl with Henoch–Schönlein purpura treated with cyclosporine. T2-weighted images did not show abnormalities, despite neurological symptoms.
FLAIR images show some minor lesions in the typical spots in the posterior parts of the hemispheres
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Fig. 88.4. A 45-year-old woman underwent lung transplantation and treatment with cyclosporine to pre- vent graft-versus-host disease. The sagittal T2-weighted images (first row) show a lesion selectively located in the mesencephalon and upper pons.
The FLAIR images (second row) show this lesion even more clearly. The contrast-enhanced T1-weighted images (third row) demonstrate that the core of the lesion enhances. After the medication was changed, the lesion disappeared within 2 weeks
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