Article Text

Download PDFPDF

Delayed leukoencephalopathy with stroke-like presentation in chemotherapy recipients
  1. J M Baehring1,
  2. R K Fulbright2
  1. 1
    Departments of Neurology and Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA
  2. 2
    Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA
  1. Dr J M Baehring, Departments of Neurology and Neurosurgery, Yale University School of Medicine, 333 Cedar Street, TMP 412, New Haven, CT 06510, USA; joachim.baehring{at}


Background: A transient leukoencephalopathy mimicking cerebrovascular accident has been described as a complication of chemotherapy, most commonly in recipients of intrathecal methotrexate for childhood leukaemia. Recently published neuroimaging data suggest a common pathophysiology associated with a variety of chemotherapy agents and modes of administration.

Methods: We reviewed the medical literature for single reports and case series of patients presenting with stroke-like episodes while receiving systemic or intrathecal chemotherapy. We only included studies providing detailed neuroimaging data. Patients with cerebrovascular accidents were excluded.

Results: We identified 27 reports of toxic leukoencephalopathy in patients treated with methotrexate (intrathecal, systemic), 5-fluorouracil and its derivative carmofur, and capecitabine. Diffusion weighted imaging (DWI) of all patients revealed well demarcated hyperintense lesions within the subcortical white matter of the cerebral hemispheres and the corpus callosum, corresponding to areas of decreased proton diffusion on apparent diffusion coefficient (ADC) maps (available in 21/27 patients). Lesions exceeded the confines of adjacent vascular territories. Complete resolution of symptoms within 1–4 days was accompanied by normalisation of ADC abnormalities. However, fluid attenuated inversion recovery (FLAIR) sequences frequently revealed persistent white matter abnormalities.

Conclusions: Several pathophysiological models of delayed leukoencephalopathy after exposure to intrathecal or systemic chemotherapy have been proposed. DWI findings in this cohort are indicative of cytotoxic oedema within cerebral white matter and lend support to an at least partially reversible metabolic derangement as the basis for this syndrome.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Structural alterations affecting the cerebral white matter infrequently complicate chemotherapy with cytotoxic agents. Clinical syndromes associated with these leukoencephalopathies (LEPs) are variable and can be acute, delayed acute, subacute or late in onset. Based on recent observations of toxic LEPs related to various chemotherapeutic agents,13 we have become particularly interested in a clinically distinct form of delayed acute LEP, characterised by peculiar findings on diffusion weighted MRI (DWI). Symptoms resembling cerebrovascular accident typically start within days to a couple of weeks after chemotherapy. Complete neurological recovery is the rule although chronic radiographic sequelae occur. The pathophysiology of the syndrome has not been elucidated. In the absence of histopathological data, current knowledge is based on neuroimaging techniques and spinal fluid analysis.4 5

We conducted a literature search for chemotherapy recipients with acute LEP in whom diffusion MRI data were available. We will refer to the syndrome as delayed LEP with stroke-like presentation (DLEPS).


We reviewed the PubMed database and the registry of the Yale Brain Tumor Center using the following search terms: diffusion weighted MRI, DWI, apparent diffusion coefficient map, ADC, leukoencephalopathy, methotrexate, capecitabine, 5-fluorouracil, carmofur, tegafur. In order to be included, patients had to have a clinical syndrome characterised by acute onset of focal or diffuse central neurological deficits in combination with new onset of LEP displaying decreased proton diffusion on DWI. Numerical apparent diffusion coefficient (ADC) values were available in five of our patients.


The results are summarised in table 1. Figure 1 shows a representative MRI of DLEPS.

Figure 1 Representative MRI of delayed leukoencephalopathy with stroke-like presentation (DLEPS). Upper row: diffusion weighted imaging (DWI) and apparent diffusion coefficient map (ADC) of this 13-year-old patient (see table 1, Haykin1 13 M) who developed DLEPS 10 days after intrathecal methotrexate administration demonstrates large areas of restricted proton diffusion affecting the centrum semiovale of both cerebral hemispheres (hyperintense on DWI (left), hypointense on ADC (middle)). Fluid attenuated inversion recovery (FLAIR) MRI reveals slightly hyperintense signal in corresponding areas (right). Lower row: a 41-year-old woman (see table 1, Baehring (unpublished) 41 F) suffered DLEPS shortly after initiating capecitabine salvage chemotherapy for metastatic breast cancer. DWI and ADC reveal areas of restricted proton diffusion within the centrum semiovale of both hemispheres and the corpus callosum. FLAIR sequences show a subtle increase in signal intensity in corresponding areas.
Table 1 Summary of patients with delayed leukoencephalopathy with stroke-like presentation

The vast majority of patients presented with focal neurological signs and symptoms (hemiparesis (n = 15), dysphasia (n = 9), hemihypaesthesia or hemidysaesthesia (n = 3), cerebellar dysfunction (n = 4), subcortical and brainstem signs (dysarthria (n = 5), dysphagia (n = 1), dysphonia (n = 1), pseudobulbar affect (n = 1)). Two patients displayed bilateral weakness and one patient bilateral dysmetria. Alteration of consciousness was observed in three patients (somnolence (n = 1), coma (n = 1), undefined (n = 1)). One patient suffered a generalised convulsion. Non-specific, descriptive and other uncommon signs or symptoms were reported in 14 patients (confusion (n = 2), agitation (n = 2), headache (n = 5), fatigue (n = 1), dizziness (n = 1), absence of pupillary response (n = 1), “inability to speak” (n = 1), central facial weakness (n = 1)).

We identified 18 reports of DLEPS in recipients of intrathecal methotrexate. Median age was 14 years (range 6–20). Female to male ratio was 1:1. The tumour spectrum of these patients included acute leukaemias and lymphoma. DLEPS occurred between 6 h and 11 days after administration of chemotherapy. A fluctuating clinical course over 20 h to 6 days was described in four individuals. Two patients had a second episode on re-exposure to methotrexate, one a week and the other 5 months after the first episode. All patients recovered within hours to 1 month (nine patients within 36 h; 15 patients within 1 week; time course of clinical recovery unknown in two). One patient had received systemic high dose methotrexate (5 g/m2) for pre-T-cell lymphoblastic leukaemia 7 days prior to DLEPS.

We found two publications of 5-fluorouracil (5-FU) related DLEPS documented with diffusion MRI. Both patients had received 5-FU as a continuous infusion and recovered within days of cessation of therapy. The 5-FU derivative carmofur was associated with DLEPS in one case in whom DWI and ADC were obtained. Neurological follow-up data were not provided for this patient. The case stands out as it is the only one in which DWI abnormalities persisted for at least 3 months. Five reports are available of patients who developed DLEPS on capecitabine chemotherapy between 3 and 7 days of treatment initiation (age range 40–74 years). All patients were female, suffered from breast (n = 4) or pancreatic cancer, and recovered within days of discontinuation of capecitabine.

Reduced water diffusion rates (hyperintense lesions on DWI, hypointense lesions on ADC maps) were found in 21/27 patients. ADC maps were not reported in six patients and thus “T2-shine through” (hyperintense appearance on DWI in spite of increased water diffusion rates) could not be excluded with certainty in these cases. Diffusion abnormalities almost invariably involved the white matter of the cerebral hemispheres. Gray matter involvement was seen in only two cases (cortex, thalamus). MRI abnormalities were unilateral in five and bilateral in 21 (one unknown). The corpus callosum was affected in six individuals and the brainstem in one. MRI scans obtained between 2 weeks and 6 months in six patients after DLEPS revealed residual fluid attenuated inversion recovery (FLAIR)/T2 signal abnormalities in five and normalisation in one.

A region of interest analysis compared ADC values in lesions and in normal brains in five patients studied at our institution (Haykin and colleagues1 17 F (studied twice), 13 M, 15 F; Baehring (unpublished) 13 M; 16 M). In each subject, a circular region of interest (ranging from 45 to 185 mm2) was placed in the lesion and in contralateral normal appearing brain. The mean ADC in lesions (0.47 (0.2) × 10−3 mm2/s) was significantly different (p<0.0001) from the mean ADC in normal appearing brain (0.83 (0.17) × 10−3 mm2/s).


DLEPS is an uncommon complication after administration of various chemotherapeutic agents. It is estimated to occur in less than 2% of recipients of MTX12 and has been associated with intrathecal as well as intermediate to high dose intravenous administration.1317 Mimicking cerebrovascular accident at onset, symptoms may fluctuate over a few days and spread to involve both hemispheres but generally resolve without clinical residual. The clinical syndromes associated with 5-FU, carmofur or capecitabine seem to be more difficult to localise. DLEPS should not be confused with early acute or chronic MTX toxicity or multifocal inflammatory leukoencephalopathy, a disorder described in recipients of 5-FU, in which diffusion weighted MRI abnormalities have not been reported. “Successful” therapy with dextromethorphan, aminophylline, intravenous immunoglobulin and folinic acid has been described although most patients seem to recover spontaneously.13 18 Methotrexate was frequently eliminated from the therapeutic regimen after DLEPS but re-exposure seems possible without symptom recurrence.1 6 17

Diffusion weighted MRI data in DLEPS remain scarce. Diffusion MRI provides image contrast dependent on the molecular motion of water. It has proven most useful in the diagnosis of cytotoxic oedema secondary to acute ischaemia.19 Normalisation of ADC occurs within 1–4 weeks after the ischaemic event. In ischaemic stroke, profoundly decreased ADC values are correlated with irreversible brain damage. In DLEPS on the contrary, brain regions with marked hypointensity on ADC maps had rapid normalisation of ADC hypointensity in almost all cases. Relative and absolute ADC reduction, as measured in five patients seen at our institution, were within the range of acute ischaemia.

DLEPS involving the periventricular white matter is not limited to recipients of chemotherapy. A variety of metabolic derangements and toxin exposures have been described to result in a similar clinical syndrome and MRI findings, such as carbon monoxide poisoning or hypoglycaemia.

The histopathological correlate of DLEPS and its pathophysiology are currently unknown. Diffusion MRI data do not support a vasculopathic aetiology of DLEPS, as lesions exceed the confines of vascular territories. Our data and that of others are consistent with a transient and at least partially reversible metabolic encephalopathy leading to cytotoxic oedema in cerebral white matter. In an animal model, vacuolation secondary to splitting of the myelin intraperiod line or separation between the axon and the innermost layer of myelin was observed after prolonged daily oral administration of 5-FU, tegafur and carmofur,20 and intraventricular infusion of two toxic 5-FU metabolites.21 The same metabolites were shown to cause segmental splitting of the myelinic intraperiod line with subsequent vacuolation and myelin swelling at the early stage of exposure in tissue culture; later stages were characterised by fragmentation, granularity and myelin loss.22 In humans, splitting of intraperiod lines and vacuole formation has been described in spongiform leukoencephalopathy after inhalation of pyrolysated heroin,23 a condition characterised by restricted water diffusion.24 It is conceivable that accumulation of water molecules between the myelin lamellae might give rise to restricted diffusivity and thus decreased signal on ADC. The notion that intramyelinic sheath oedema represents an early, rapidly reversible stage and vacuolation a later stage that may slowly resolve or progress to irreversible myelin destruction remains speculative.

It is likely that the various clinical manifestations of chemotherapy related neurotoxicity are a complex function of dose, exposure time and the genetic background of the affected individual. It has been proposed that polymorphisms in the enzyme 5, 10-methylenetetrahydrofolate reductase may lead to increased susceptibility to DLEPS after methotrexate exposure.16


DLEPS has been described after chemotherapy with methotrexate, 5-FU, capecitabine and carmofur. It is characterised by an acute stage defined by decreased water diffusion rates on MRI. It remains unknown if there is a unifying neuropathological correlate. Such has been described in animal models of 5-FU neurotoxicity and consists of intramyelinic sheath oedema and formation of vacuoles. DLEPS seems to be reversible. Reversibility of markedly decreased ADC values without clinically apparent permanent deficit is in striking contrast with findings in acute ischaemia. Recognition of the clinical syndrome supported by a comprehensive neuroimaging evaluation can spare the patient from unnecessary invasive procedures or therapies. Interruption of exposure to the suspected toxin may be crucial in order to prevent permanent neurological injury.



  • Competing interests: None.