Our series of five patients illustrates the clinical presentation, radiological features, and treatment of 5-FU-induced acute toxic leukoencephalopathy. This is a rare complication reported in less than 5% of patients receiving 5-FU-based chemotherapy [10]. Also known as toxic spongiform leukoencephalopathy, it happens due to progressive structural damage of white matter tracts involved in higher mental function [2]. Other chemotherapeutic agents implicated in toxic leukoencephalopathy include methotrexate, vincristine, ifosfamide, fludarabine, cytarabine, cisplatin, and interferons [11]. The commonest presenting symptoms for toxic leukoencephalopathy are confusion, agitation, ataxia, seizures, or even coma.
The exact mechanism of 5-FU-related neurotoxicity is poorly understood. Koenig et al. attribute the accumulation of fluoroacetate, a product of 5-FU catabolism, leading to the inhibition of the thymidylate synthetase in Krebs’s cycle with impairment of urea cycle, leading to accumulation of ammonia in the blood, which in turn is responsible for the encephalopathy [12].. This accumulation of ammonia in the blood is aggravated by factors like concomitant infection, dehydration, and renal dysfunction [13]. An alternative theory attributed the neurologic adverse effects of 5-FU is the deficiency of thiamine [14]. Exposure to 5-FU increases thiamine pyrophosphate (TPP) level, the active form of thiamine [14, 15]. It leads to an increase in the cellular thiamine metabolism, which in turn exacerbates thiamine deficiency [14]. The similarities in the clinical presentation between 5-FU leukoencephalopathy and Wernicke-Korsakoff syndrome, including ataxia, nystagmus, mental confusion, and cognitive changes, are supportive of this theory.
All our five patients had clinical and radiological findings suggestive of 5-FU-induced encephalopathy (Table 1). This was supported by the presence of hyperammonaemia in all patients (Fig. 2). The median time to onset of symptoms from initiation of 5-FU was 3 days (range: 2–4 days), consistent with earlier reports [13, 16]. The criteria to diagnose 5-FU-related encephalopathy include the following features [7, 9, 17]:
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a)
Development of encephalopathic features during (or) after completion of 5-FU therapy
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b)
Exclusion of other metabolic or physical features causing altered conscious level
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c)
Exclusion of other drugs or concomitant medications
Contrast-enhanced MRI brain with diffusion-weighted imaging (DWI) is the gold standard for radiological diagnosis of toxic leukoencephalopathy [2, 18, 19]. MRI features aiding the diagnosis are diffuse bilateral symmetrical hyperintensities in the T2W flair images with corresponding areas of diffusion restriction in periventricular, deep white matter and corpus callosum with sparing of cortex and subcortical white matter as well as basal ganglia [20]. Two of our patients had focal neurological deficits mimicking a stroke; this entity has been described earlier in a case report, where the patient was treated with thrombolysis [21]. Ideally, reversibility of these findings on MRI can be demonstrated after 4–8 weeks. However, none of our patients underwent a repeat MRI imaging.
Dihydropyrimidine dehydrogenase (DPD) is an enzyme that mediates breakdown of 80% of the administered 5-FU and is distributed in the liver, gastrointestinal mucosa, and peripheral lymphocytes (Fig. 1). Thus, a complete deficiency of this enzyme is known to cause life-threatening or fatal toxicity when a patient is treated with fluoropyrimidine-based chemotherapy [4]. The incidence of DPD deficiency overall among cancer patients has been estimated to be 2.7% and 27% among the largest prior cohort of 30 patients with fluoropyrimidine-related encephalopathy [16, 22]. In our cohort, 3 patients underwent DPYD testing, and one (33%) showed a pathogenic heterozygous mutation.
The dosing of 5-FU also plays a contributory role towards predisposition to 5-FU-induced leukoencephalopathy, with patients receiving doses higher than 1800–2600 mg/m2/day, being more susceptible for the same [13]. Kim et al. demonstrated elevated levels of DPD enzyme, among a cohort of patients following treatment with an “intermediate-dose” 5FU and suggested that the transient stagnation of catabolites of 5-FU would play an important role in the development of neurotoxicity [15]. In our cohort, one patient on FLOT chemotherapy for gastric cancer received this “high-dose” 5-FU (2600 mg/m2/day), while the rest (n = 4) received a lower dose of infusional 5-FU while on the m-FOLFOX 6 (1200 mg/m2/day).
There is no current definitive treatment for acute toxic leukoencephalopathy. Prompt identification and withdrawal of the offending agent are the most crucial step, followed by supportive measures like plasma exchange and thiamine infusion (20). Although there is no role for prophylactic steroids, some reports support the use of steroids in the setting of severe encephalopathy and florid MRI changes (20). Three of our patients were given methylprednisolone and responded to the same. All our patients had complete neurological recovery within a week. Though early initiation (within 96 h) of uridine triacetate following life-threatening fluoropyrimidine toxicity has been approved, the access to this drug is difficult [23, 24]. None of our patients underwent a 5-FU rechallenge. Though this is described as an option, the risk of relapse of 5FU encephalopathy is as high as 57%, even if the rechallenge is done in a monitored setting, with lower doses of 5-FU, DPYD testing, and stringent monitoring [16]. We treated four patients with another fluoropyrimidine (capecitabine), and they all successfully completed subsequent treatment without any major toxicity. Our study is limited by its small numbers, lack of information of DPYD status among two patients, and lack of uniformity among treatment approaches and its retrospective nature, which does not account for an accurate assessment of neurological status and hence may lead to underestimation of mild neurological toxicity. Nevertheless, considering the rarity, severity of this entity, and the differences in the pharmacogenomics between Caucasians and Asians, this first series from the Indian subcontinent will increase awareness of fluoropyrimidine-related neurotoxicity and aid early diagnosis and treatment, thus reducing morbidity and mortality.