Keywords
Chemotherapy - drug-induced encephalopathy - encephalopathy - 5-fluorouracil
Introduction
Colon cancer is the 4th most common malignancy among women and 3rd most common among men in India and is one of the leading cause of cancer-related
mortality. Colon cancer is well known for its excellent responsiveness to chemotherapy
compared with the other gastrointestinal tract cancer and chemotherapy has been given
to patients with advanced colon cancer as an adjuvant or palliative treatment modality.
Fluorouracil (5-FU), a pyrimidine antimetabolite has been widely used in the chemotherapy
of colon cancer since its introduction in 1957. Very few cases of neurological adverse
events of 5-FU have been reported till date. Among them, encephalopathy is rare and
may present as disorientation, confusion, agitation, neurosensory hearing impairment,
seizure, stupor, and even deep coma. We report here a patient who developed acute
neurotoxicity after systemic chemotherapy with continuous infusion of 5-FU and was
diagnosed and managed successfully.
Case
A 43-year-old female, known case of hypothyroidism presented with h/o bleeding per
rectum and increased frequency of stools for 1 month. Colonoscopy revealed 5 cm ×
7 cm ulceroproliferative growth in rectum 2 cm above the anal verge. A rectal biopsy
was suggestive of adenocarcinoma. She was planned for neoadjuvant chemotherapy with
FOLFOXIRI after discussion in a multidisciplinary tumor board. This regimen consisted
of irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, and 5-FU 400
mg/m2 bolus on day 1, followed by 5-FU 3200 mg/m2 by continuous infusion over the
next 46 hours. She was discharged with an ambulatory 5-FU pump. After 24 hours of
infusion, patient presented with complaints of diarrhea, palpitations, and vomiting.
She was started on IV fluids and supportive measures. On day 3, she was agitated and
developed an acute confusional state. On examination, she was disoriented and GCS
was 9/15. Meningeal signs were negative and there were no focal neurologic deficits.
She had urinary incontinence, pupils were reactive, and plantar extensors signs were
positive. Blood pressure was normal throughout her presentation. Her initial lab investigations
showed normal complete blood cell count, liver function tests, kidney function tests,
electrolytes, and thyroid function. non-contrast CT head was normal [[Figure 1]]. Her 5-FU infusion was completed by this time. Over the next few hours, the patient’s
mental status progressively deteriorated to a comatose state. Subsequently performed
contrast-enhanced MRI brain showed focal hypointensity in the splenium of the corpus
callosum on T1, which was hyperintense on T2/FLAIR and showed restriction on diffusion-weighted
image (DWI) with ADC value of 308 mm2/sec. A similar finding was found in the bilateral
middle cerebellar peduncle where ADC was approximately 523 mm2/sec. Ill-defined hyper
intensity at bilateral parieto-occiptal white matter was also present [[Figures 2] and [3]]. None of these lesions show contrast enhancement. With due consideration to this
detailed clinical findings and correlation. The final diagnosis of drug-induced encephalopathy
was made and further 5FU-based therapy was withheld. She gradually improved with supportive
measures and was discharged after a week. She was started on IROX + Bevacizumab (irinotecan
200 mg/m2, oxaliplatin 65mg/m2, bevacizumab 7.5 mg/kg). She tolerated her 1st cycle
well without any immediate side effects. She was asymptomatic and neurological examination
was normal after one month of her presentation to an emergency. Follow-up non contrast
MRI after 1 month showed persistent T2 hyperintensity at splenium and middle cerebellar
peduncle but with an increase in ADC value (540 mm2/sec and 600 mm2/sec, respectively).
As hyperintensity in the T2 weighted image takes a longer time for a resolution than
that in DWI, findings were indicative of improvement [[Figures 4] and [5]]. In view of 5 FU toxicity, she was started on a regimen containing irinotecan,
oxaliplatin, and bevacizumab. She tolerated the subsequent chemotherapy without any
significant adverse effects. She attained partial response and underwent surgery successfully.
Figure 1: Axial scan NCCT Head at the level splenium of the corpus callosum is normal
Figure 2 (A-D): Magnetic resonance imaging (Brain) axial images-showing hyperintense signals in bilateral
parieto-occipital white matter (thick arrow) and splenium of corpus callosum (linear
arrow) on axial T2-weighted image (A), and FLAIR (B). DWI (C) and ADCmap (D) are evident
of diffusion restriction
Figure 3 (A-D): Magnetic resonance imaging (Brain) axial images-showing hyperintense signals in bilateral
middle cerebral peduncles (linear arrow) on axial T2-weighted image (A), and FLAIR
(B). DWI (C) and ADC map (D) is evident of diffusion restriction
Figure 4 (A-D): Repeat magnetic resonance imaging (Brain) -showing persistent hyperintense signals
in the splenium of corpus callosum (linear arrow) on axial FLAIR (A), and diffusion-weighted
image (B), Similar findings at the level of MCP (thick arrow) on FLAIR (C) and diffusion-weighted
image (D)
Figure 5 (A and B): ADC maps at splenium (A) and MCP (B) showing persistent restriction with increased
values
Discussion
5-FU is a relatively safe drug approved for the management of carcinoma colon with
side effects ranging from nausea, vomiting, and diarrhea. CNS toxicity is uncommon
and is limited to very few case reports.[[1], [2], [3]] CNS toxicity occurs in the form of sudden onset of slurred speech, confusion, cognitive
disturbances, and paranoia. These symptoms usually develop within 7 days from the
beginning of the chemotherapy cycle as seen in our patient (on Day 3) and resolve
on discontinuation of the drug.
Imaging plays a significant role in depicting the lesions, their location, and extent.
CT may be normal or inconclusive but MRI owing to its better resolution demonstrates
lesions well. DWIs and ADC maps can show these lesions due to edema within intramyelenic
cleft, which is a potential extracellular space and is reversible when toxicity is
withdrawn. Deep white matter and corpus callosum are the reported sites of involvement.[[2], [3]] However, the aforementioned patient also had involvement of the middle cerebral
peduncle.
The reversible lesion in the splenium of the corpus callosum and middle cerebral peduncle
has a vast differential diagnosis and has been reported in a variety of neurologic
and non-neurologic conditions. Such uncommon case emphasizes the importance of clinico-radiological
correlation to rule out differentials like infection, demyelination, epilepsy, vascular
(hypertensive encephalopathy, PRES, Preeclampsia), metabolic (hypoglycaemia, hypo/hypernatremia),
axonal injury, and drugs.[[4]]
Amongst drugs, cyclosporine, 5FU, and metronidazole are known to cause such imaging
features in the splenium and cerebral peduncle.[[4]] The disease mechanism of 5-FU encephalopathy is unclear. The toxicity of 5-FU is
strongly influenced by the dosage used and the rate and duration of drug administration.
Some researchers believe that accumulated fluoroacetate, which is a product of 5-FU
catabolism, inhibits the Krebs cycle enzyme leading to impairment of the urea cycle
and accumulation of ammonia leading to encephalopathy.
The diagnosis of 5-FU-related encephalopathy is a diagnosis of exclusion. The development
of encephalopathy during or shortly after the completion of 5-FU administration and
exclusion of other metabolic factors that may affect a patient’s consciousness and
mental functioning, such as hypoglycemia, organ failure, electrolyte imbalance, sepsis,
central nervous system involvement by cancer, adverse effect by concomitant medications
is needed before its diagnosis. Serumdihydropyrimidine dehydrogenase (DPD) level can
be assessed in patients before starting 5-FU as DPD is an important catalyst in amino
acids—thiamine and uracil (i.e., ingredient of 5 FU) metabolism and its deficiency
leads to the accumulation of fluoropyrimidine causing neurological and GIT symptoms.
In our patient, serum DPD and ammonia levels were normal. After exclusion of all common
metabolic causes and based on radiology we made a final diagnosis of 5 FU-induced
encephalopathy. Our case highlights the rare but important complication of 5FU-containing
chemotherapy and also describes the unique finding in MRI of our patient. To our knowledge,
this is a first reported case where curative surgical resection of the tumour was
done afteririnote can-based regimen following an episode of 5 FU-induced encephalopathy
in the neoadjuvant setting.
Conclusions
Encephalopathy due to 5FU is very rare. Early recognition and withdrawal of the culprit
drug lead to clinical improvement. Imaging plays a vital role in the demonstration
of lesions in neuroparenchyma. Awareness of this entity amongst reporting radiologist
and clinicians along with clinico-radiological correlation is essential for the successful
management of these patients.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
In the form the patient(s) has/have given his/her/their consent for his/her/their
images and other clinical information to be reported in the journal. The patients
understand that their names and initials will not be published and due efforts will
be made to conceal their identity, but anonymity cannot be guaranteed.
