5-fluoruracil ( 5-fu ) , pyrimidine antimetabolite , is a chemotherapeutic agent widely used for various tumors . neurotoxicites of 5-fu with manifestations of somnolence , upper motor neuronal signs , cerebellar ataxia and a cluster of symptoms and signs of organic brain syndrome have rarely been reported . we report a case of serious neurotoxicity following 5-fu infusion for malignant gastrointestinal stromal tumor ( gist ) and also briefly review 5-fu related neurotoxicity . a 44-year - old male patient received his first cycle of palliative 5-day chemotherapy containing 5-fu ( 800 mg / m ) , adriamycin ( 40 mg / m ) and mitomycin- c ( 8 mg / m ) for a recurrent , massive , malignant gastrointestinal stromal tumor ( gist ) which developed at 3 years after surgery . his tumor was about 20 cm in diameter and invaded the urinary bladder and sigmoid colon ( figure 1 ) . about 1 week after the completion of his first cycle of chemotherapy , he displayed slurred speech and inappropriate behavior for 35 days at home . such abnormal symptoms improved spontaneously . on the beginning of the second cycle of chemotherapy , he appeared well and no remarkable abnormality was found on physical examination and laboratory test . he received the second cycle of chemotherapy with the same regimen as the first and was discharged without any complaint . on the 7 day after the completion of his second chemotherapy , his mental status deteriorated with slurred speech , inappropriate language , hyperventilation , insomnia , disorientation and incontinence of stool and urine . the er , his vital signs were as follows : blood pressure 120/70 mmhg , pulse rate 92/minute , respiration rate 24 /minute and body temperature 36.8c . on physical examination neurological examination revealed confused mental status , bizarre behavior , lethargy , slurred speech and somnolence . light reflex was prompt with symmetric , isocoric pupils . orientation to time , person and place however , he showed neither focal neurological sign nor pathological reflex . on the laboratory findings , white blood cell count was 3,020/ul , bun and creatinine were 24.0 mg / dl and 1.4 mg / dl , respectively , serum natrium 135.0 meq / l , serum pottasium 4.3 meq / l , ionized calcium 4.25 mg / dl and serum albumin 2.9 g / dl . on arterial blood gas analysis ( abga ) , respiratory alkalosis pattern was found with ph 7.546 , pco2 19.3 mmhg , po2 133.3 mmhg , bicarbonate 16.8 meq / l and o2 saturation 99.4 % at room air . his serum ammonia level was at 326 ug / dl , higher than the upper limit of normal range ( 0150 ug / dl ) . chest x - ray was normal , abdominal simple x - ray showed mild paralytic ileus pattern . brain computed tomography at the er was normal without evidence of metastasis or cerebral vascular accident . after a few sessions of lactulose enema , his mental status recovered somewhat with intact orientation to persons . during the admission period for 15 days , his mental status and general condition gradually recovered . he complained of intermittent abdominal pain and gastric distension due to partial obstruction of the proximal small bowel by the mass . cerebellar function tests , such as finger to nose , rapid alternative test , heel to shin test and romberg test , were all negative . brain magnetic resonance imaging revealed no abnormal lesion in brain parenchyma . his mental status and general condition recovered , so that we changed the chemotheapeutic regimen to adriamycin ( 60 mg / m ) and cisplatin ( 60 mg / m ) for 1 day , omitting 5-fu . on the 5 day of postchemotherapy , he was in stuporous mentality and lethargic condition . at er , he was found to have neutropenic fever and sepsis syndrome with pancytopenia , respiratory alkalosis and hypokalemia . cerebrospinal fluid ( csf ) study was normal in pressure , cell count and chemistry . on blood culture , after treatment with intravenous fluids and broad - spectrum antibiotics , his mental status and general condition rapidly improved for 23 days . on the 17 day after the 3 chemotherapy , he was discharged since he completely recovered from sepsis syndrome . after discharge , he intermittently experienced altered mentality which developed after constipation and abdominal distention . his neurological symptoms were relieved after repeated lactulose enema at a local hospital . on the last visit after 2 months of 5-fu administration , he still displayed slightly slurred speech and slowly progressive cachexia . brain magnetic resonance imaging revealed newly developed hyperintense lesions in the bilateral cerebellar hemisphere , thalami and midbrain on t2wi without mass effect . on t1wi , hypertensive lesion was developed in bilateral basal ganglia ( figure 3 ) . there are many reports on serious neurotoxicity of 5-fu in patients with dihydropyrimidine dehydrogenase ( dpd ) deficiency . dpd is the rate - limiting enzyme of 5-fu catabolism and is encoded by the human dihydropyrimidine dehydrogenase gene ( dpyd ) . so far , about 20 different mutations of dpyd have been reported in dpd deficient subjects . g to a point mutation within the 5-splicing site ( gt to at ) , also known as dpyd2a ( intron 14 g1a ) , is one of the common mechanisms for dpd deficiency171 . therefore we examined the presence of dpyd2a ( intron 14 g1a ) by polymerase chain reaction - restriction fragment length polymorphism ( pcr - rflp ) . when a pcr - rflp based genotyping was performed , fragments of 278 and 131 bp were produced by the restriction endonuclease mae ii in the wild type allele . however , the mutant allele had no restriction site and remained undigested ( 409 bp ) . therefore , as shown in figure 4 , this patient had a wild - type pattern . although both acute and delayed forms have been reported , fluorouracil - induced neurotoxicity is rare . the acute form consists of cerebellar syndrome and encephalopathy , whereas the delayed variety takes the form of subacute multifocal ieukoencephalopathy . about 5% ( 0.67% ) of the patients who received 5-fu have been reported to experience neurotoxic symptoms . the clinical manifestations of acute cerebellar syndrome , such as ataxia , slurred speech and nystagmus , were first described by riehl and brown in 1964 . encephalopathy or organic brain syndrome following 5-fu treatment is a less commonly observed neurotoxicity with confusion , disorientation and other cognitive disorders . subacute multifocal leukoencephalopathy with typical brain magnetic resonance imaging findings of multifocal , enhancing white matter lesions and biopsy findings of demyelination has been reported as a 5-fu sequela . we reported a case of delayed form of 5-fu neurotoxicity characterized by subacute multifocal leukoencephalopathy . our case initially showed moderate diffuse cerebral dysfunction on electroencephalography ( figure 2 ) without abnormality in brain magnetic resonance imaging . during the 2 months after the last administration of 5-fu , the neurological symptoms waxed and waned depending on the partial obstruction of the bowel and did not fully recover . however , we could not find any relevant papers on the neurotoxicities of adriamycin and mitomycin . 5-fu is a pyrimidine antimetabolite which has to be metabolically activated within the cells and incorporated into both dna and rna , which results in dna strand breakage and abnormal processing and function of rna . 5-fu itself seems to be relatively nontoxic to the nervous system in laboratory animals when administered intrathecally . koenig et al . proposed that fluorocitrate , the major catabolite of 5-fu , inhibited krebs cycle and a blockade of krebs cycle impaired the activity of the urea cycle . reported that , in animal experiments , direct toxic effect on myelin with splitting of the intraperiodline and vacuole formation was not due to 5-fu itself , but to monofluoroacetic acid and -fluoro--alanine ( the major catabolites of 5-fu ) . the other explanations for 5-fu neurotoxicity , such as induction of thiamine deficiency and inherited deficiency of the enzyme dihydropyrimidine dehydrogenase ( dpd ) , have also been presented . the frequency of low and deficient dpd activity in the general population is estimated to be 35% and 0.1% , respectively . recent efforts to explain the relationship between genotype and phenotype in patients with dpd deficiency have brought much progress . dpd protein is encoded by dpyd , which is a large gene ( > 950 kb ) containing 23 exons with approximately 3 kb of coding region . to date , about 20 variant dpyd alleles , containing single amino acid substitutions , nucleotide deletions or a donor splice site mutation resulting in exon skipping , have been described . among them , g to a point mutation within the 5-splicing site ( intron 14 g1a ) is the most common ( 2.2% out of 90 alleles in finnish and 2.7% out of 72 alleles in taiwanese general population ) and analytical methods for this mutation are well established . although this mutant allele was not found in our case , a possibility of decreased dpd activity by other dpyp mutations could not be excluded . as a chemotherapeutic agent , 5-fu is active against a wide variety of solid tumor , including cancers of gastrointestinal tract , ovary and breast . , there are many possible differential diagnoses , such as brain metastasis , infection of brain or meninges , sepsis syndrome , metabolic abnormality . based on our present case , we emphasize that 5-fu - induced neurotoxicity should also be an important category of differential diagnosis in these patients . the treatment of 5-fu neurotoxicity is recommended as supportive care . in the literature , several treatments , such as thiamine infusion , glucocorticosteroid , uridine infusion , charcoal hemoperfusion or hemodialysis , were recommended . however , their efficiency has not been proven . to understand the mechanism of neurological manifestation of 5-fu ,
5-fluorouracil ( 5-fu ) is a commonly used chemotherapeutic agent . however , its neurotoxicity is rare and not well recognized . 
 we report a case of 5-fu neurotoxicity with organic brain syndrome and progression to multifocal leukoencephalopathy in a 44-year - old male patient having malignant gastrointestinal stromal tumor . 
 5-fu - induced neurotoxicity should , therefore , be considered as an important differential diagnosis in cancer patients with neurological abnormality and history of chemotherapy .