Posterior leukoencephalopathy following intrathecal chemotherapy with MRA-documented vasospasm

Case report.

A 54-year-old woman was diagnosed with acute lymphoblastic leukemia (ALL). Her medical history included Wolff-Parkinson-White syndrome, which had not required specific treatment. Induction chemotherapy including IV dexamethasone, vincristine, adriamycin, and cyclophosphamide was administered. On day 1, 12 mg of intrathecal methotrexate was given, and on day 8, 100 mg of intrathecal cytarabine was administered. Seven days after the intrathecal cytarabine, the patient was neutropenic and thrombocytopenic and developed fevers requiring treatment with broad-spectrum antibiotics. At this point (day 15), confusion and bilateral visual loss developed and continued to progress over 2 days. Visual fields were peripherally restricted, affecting all quadrants of both eyes. An inability to perform ocular saccades or pursuits was noted. There was left upper limb neglect, astereognosis, and bilateral ataxia of the upper limbs on attempted repetitive finger nose testing. The patient’s blood pressure was within the range of 120 to 170 mm Hg/60 to 90 mm Hg before and throughout the development of clinical symptoms until they reached their maximal extent. No episodes of marked hypertension were noted and no notable change from baseline before the admission or on subsequent admissions was noted. Episodic tachyarrhythmias with heart rate increase up to 160 beats per minute were noted. Systemic hypotension was not documented, and there was no evidence of renal or hepatic dysfunction to suggest hypotension. Seizures were not observed.

MRI performed on the day after symptom onset showed areas of hyperintense signal on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images bilaterally in the white matter of the parieto-occipital border zone regions. Diffusion-weighted images (DWI) showed patchy small hyperintense areas within these regions. The apparent diffusion coefficient (ADC) map of these areas showed restricted diffusion, consistent with cytotoxic edema, in keeping with ischemia. Repeat MRI performed 4 days later, at the time of maximal clinical deficit, showed extension of the abnormalities on FLAIR images, with these new areas being hyperintense on DWI and showing restricted diffusion on ADC maps, again consistent with cytotoxic edema (figure 1). MRA showed abnormalities in the vasculature of both the carotid and vertebrobasilar circulation (figure 2) with extensive areas of narrowing and caliber irregularities. A transesophageal echocardiogram did not identify an embolic source. Antiplatelet therapy was not given because of the patient’s thrombocytopenia.

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Figure 1. MRI performed 5 days after symptom onset shows hyperintensities on fluid-attenuated inversion recovery (left) and diffusion-weighted imaging (center) sequences with restricted diffusion on the apparent diffusion coefficient map (right). The abnormalities were primarily in a posterior cerebral distribution consistent with predominantly cytotoxic edema.

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Figure 2. MR angiography performed 5 days after symptom onset shows irregularities in carotid and vertebrobasilar arteries that were resolved on the repeat study performed 19 days later.

Following the initial progression of the confusion and visual loss, there was gradual but incomplete improvement over the subsequent week. During this time, the leukocyte count recovered and the fever resolved. Two weeks after the onset of symptoms, the patient’s visual fields showed mild peripheral restrictions. Ocular ataxia remained present. On repeat MRA performed 19 days after the first MRA, the vascular changes had resolved (see figure 2). Essentially no improvement was noted on repeat FLAIR and DWI performed 19 days after the second study and, in addition, probable hemorrhage had occurred into the ischemic tissue in the left parieto-occipital lobe (figure 3). An MRI performed 3 months later was largely unchanged. The distribution of MR changes is consistent with the reports of the so-called reversible posterior leukoencephalopathy syndrome1 with areas of superimposed infarction.

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Figure 3. Repeat imaging as shown in figure 1 performed 19 days later. There is now normal diffusion on the apparent diffusion coefficient map without change in the fluid-attenuated inversion recovery or diffusion-weighted imaging sequences. No improvement was noted.

Discussion.

The temporal association of the encephalopathy with the intrathecal chemotherapy agents in our case is suggestive of a causative role; however, we cannot discount the contribution of acute medical illness.1,2⇓ Neurotoxicity has been documented in association with both intrathecal cytarabine (cytosine arabinoside or ARA-C) (see supplementary reference 2 at www.neurology.org)5 and intrathecal methotrexate (see supplementary references 3 and 4 at www.neurology.org), as well as the combination.6 Clinical and radiologic reversibility is usually noted in the delayed leukoencephalopathy following intrathecal chemotherapy (see supplementary references 2 and 3 at www.neurology.org),5,6⇓ although persistent neuroimaging changes or cerebral infarction have been noted in children (see supplementary reference 4 at www.neurology.org). The clinical features in our case differ from the leukoencephalopathy associated with hypertension or immunosuppression, where reversibility is usually noted (see supplementary reference 6 at www.neurology.org)1,3,4,7,8⇓⇓⇓⇓; however, residual neuroimaging changes or hemorrhage (see supplementary reference 5 at www.neurology.org) have previously been documented, particularly in patients with acute medical illness.2 With respect to cytarabine, posterior encephalopathy is generally reported with intrathecal administration rather than the IV route, although cytarabine rapidly distributes into the CSF and high-dose IV regimens could potentially cause cytotoxicity (see supplementary reference 6 at www.neurology.org). The CSF administration may suggest that vasospasm is occurring in the smooth muscle of the outer layers of the arterial wall directly exposed to the agent rather than from a bloodborne route. Hypertension appears to be an important feature of PLES, but it is not always present1,2⇓ and was not documented in previous cases with intrathecal cytarabine neurotoxicity.5

In our case, the encephalopathy was temporally associated with MRA findings of reversible irregular narrowing of large and medium-sized arteries, consistent with vasospasm. Cerebral vasospasm has been documented previously in hypertension with eclampsia and pre-eclampsia and there is usually reversibility on neuroimaging (see supplementary reference 7 at www.neurology.org).3,4⇓ Vasospasm is thought to impair normal cerebral autoregulation with dilatation of arterioles leading to interstitial edema through a pressure effect.3

The MR findings described with hypertension typically are those of vasogenic edema, with hyperintense T2 and FLAIR changes together with hyperintense DWI and normal to increased ADC (unrestricted diffusion).7,8⇓ In our case with vasospasm and without hypertension, the MR findings with T2 and FLAIR sequences are similar; however, the hyperintense DWI occurred with reduced ADC (restricted diffusion) indicating that cytotoxic edema was the predominant feature. As recently reported, the ADC map may be particularly useful in determining the balance of vasogenic and cytotoxic edema.8

The presence of ischemia in normotensive patients2 raises the possibility that hypertension may play a protective autoregulatory role against cerebral hypoperfusion in the setting of vasospasm, similar to the theory of vasospasm therapy following subarachnoid hemorrhage. However, it is likely that other factors, such as the causative stimulus, patient characteristics, and concomitant metabolic or infectious disturbances, determine the nature of the cerebral involvement.

Similar to previously reported PLES cases where angiography or MRA was performed (see supplementary reference 1 at www.neurology.org),3,4⇓ the vasospasm in our case was present in anterior and posterior regions. A probable explanation for the posterior distribution of lesions is the relatively reduced sympathetic innervation in the posterior cerebral vasculature with a reduced ability of already impaired cerebral autoregulation to compensate in these regions.9 Posterior watershed regions may be particularly prone to ischemia superimposed on leukoencephalopathy when reduced cerebral perfusion is an additional factor. Reduced cerebral perfusion in posterior regions has been documented in patients with hypertensive leukoencephalopathy.10

This case suggests that intrathecal chemotherapy is another potential cause of posterior leukoencephalopathy that may not necessarily be associated with hypertension or reversibility. The vasospasm seen in this case is a feature that may be of pathophysiologic importance but does not, of itself, explain the posterior predominance.