Lupine Publishers | Journal paediatrics and neonatology
Abstract
Ifosfamide encephalopathy is a fatal toxicity of Ifosfamide therapy. 13 cases have been reported till the year of 2018 worldwide
in children and none among Ewing’s sarcoma cases. Here we are discussing a unique case of Ifosfamide encephalopathy during
the course of treatment of Ewing’s sarcoma and was on Ifosfamide therapy and developed encephalopathy. Child improved
symptomatically with MESNA and mannitol. Child was found to be normal on follow up and chemotherapy treatment was continued..
Keywords:Encephalopathy; Ewing’s Sarcoma; Ifosfamide; Mesna
Introduction
Encephalopathy is a potentially fatal toxicity of Ifosfamide.
Clinical manifestation of encephalopathy range from fatigue and
confusion to coma and death. Early identification of this toxicity and
prompt cessation of Ifosfamide are the essential elements in the
management of Ifosfamide encephalopathy. Neurotoxicity has been
reported in about 5% children treated with Ifosfamide for tumour
not involving the CNS [1]. The entity of Ifosfamide neurotoxicity
can be of different degree, from very light and transient to fatal.
Neurotoxicity occurring during or immediately after Ifosfamide
infusion were recorded in children with both solid tumours or
leukemia. The drug was administered in different chemotherapeutic
association and dosage. Concomitant clinical conditions possibly
playing a role as risk factors were the administration of other
neurotoxic drugs, the presence of cerebral metastasis, a subclinical
lysis syndrome, and altered respiratory function. Symptoms were
transient and consisted in most cases, but some had partial or
generalised seizures. In some cases, the treatment was continued
substituting Ifosfamide with cyclophosphamide. Particularly in
patients presenting risk factors, attention has to be paid to the
risk of Ifosfamide neurotoxicity and rapidly suspend the drug
administration to avoid irreparable damage to the CNS [2-8].
Thereafter the treatment can be reassessed. If Ifosfamide is
considered the best option for the given case, it could be safely
re-administered in association with methylene blue or thiamine.
If encephalopathy re-appears, substitution of Ifosfamide with
cyclophosphamide could offer the same oppurtunities of cure of
the patient. Ifosfamide is an oxazaphosphorine antienoplastic
agent (a nitrogen mustard derivative) and is a structural
analog of cyclophosphamide [5,9]. Ifosfamide is a prodrug that
requires hepatic activation to its cytotoxic metabolite, ifosfamide
mustard [9,10]. The latter is metabolized by cytochrome p450 to
generate the active alkylating agents, 4-hydroxy-ifosfamide and
isophosphoramide mustard [10]. Ifosfamide and its metabolites
can penetrate the blood brain barrier, with CNS toxicity occurring in
10-40% of patients receiving high doses of the drug [4-8]. The exact
pathophysiological mechanisms responsible for the development
of ifosfamide-induced encephalopathy are unclear, but one of the
causes is thought to be the dechloroethylation of Ifosfamide to form
chloroacetaldehyde (CAA) [10-12]. The neurotoxic effects of CAA
maybe due to
a. A direct neurotoxic effect,
b. Depletion from the CNS of Glutathion, and/or
c. The inhibition of mitochondrial oxidative phosphorylation
resulting in impaired fatty acid metabolism.
Case Summary
A 4 yr old, male child presented with H/O swelling of right
arm noticed in 1st week of march. Father has developed a bone
tumour about 3 years back and was on treatment. O/E: Ht: 94cms,
Wt:12.1 Kgs, Pulse: 100/min, RR: 24/min, BP:100/70mm Hg Initial
Systemic examination: WNL, Local examination: tenderness around
right humerus and elbow, with bony swelling of right humerus and
right elbow. INVESTIGATION: RFT, LFT: WNL, Ca:9.2P:4.5LDH:863,
PS: mild neutrophilia Hb: 11.5gm%, TC:12900cells/mm. Plain
X-ray: Right humerus with shoulder and elbow joint. Radiological
features: Signs of Ewing’s Sarcoma, Chest X-ray: W.N.L, no evidence
of metastasis [13-15].
Biopsy Diagnosis
Showing bony speckles with a neoplastic infiltrate in the
marrow cavity. Infiltrate is composed of cohesive sheets of small
round cells with hyperchromic round nuclei. Interstitium have
mild fibrosis. Fragments of necrotic bone are also seen. Peripheral
reactive new bone formation is also seen, suggestive of Ewing’s
Sarcoma. The child was put on the following Chemotherapy:
Inj. Ifosfamide 1.6g/m2 dissolve in 540 ml N.S. over 3 hours, Inj.
MESNA 400mg/m2/dose–3doses at 3 hr interval after Ifosfamide,
Inj. Etoposide 100mg/m2 in 540ml N.S. over 1 hour, 2 weeks
later child developed fever with convulsions and oropharyngeal
Bacterial and candidly infection with a patch [16]. Child has
altered sensorium, had a right UMN facial palsy and right ear
discharge. the child was investigated ,Hb: 7.8g%,TC: 5900cells/
mm3,N: 44%,L:54%,E:2%,ESR: 90mm/hour, RFT: W.N.L.,S.
electrolytes: W.N.L., Urine: 3-4 WBCs, Protein: +,Throat swab:
Gram stain: Gram–ve bacilli and Gram +ve cocci are seen Culture
and sensitivity report: Pseudomonas spp and Staphylococci have
grown. No fungus has grown. CT chest and right humerus and right
elbow: no evidence of metastasis, EEG was suggestive of metabolic
encephalopathy. Right Ewing’s sarcoma of humerus and elbow. Ear
swab: Pseudomonas saprophyticus resistant to first line antibiotics.
Meningitis and CNS secondaries were ruled out and a diagnosis of
Ifosfamide induced encephalopathy was made. Child improved
with Mannitol, Anticonvulsants, Antibiotics and antifungals. Child
started on alternative chemotherapy (CUA regimen) and was found
to be normal on follow-up.
Discussion
Child had presented with c/o swelling in the right arm and
was diagnosed to have Ewing’s sarcoma, which was confirmed
on biopsy. Child was started on Inj Ifosfamide, Inj Mesna and Inj
Etoposide.2 weeks later child developed fever with convulsions
and oropharyngeal Bacterial or candidial infection with a patch.
Child has altered sensorium. Had a right UMN facial palsy and ear
discharge. A diagnosis of Ifosfamide induced encephalopathy was
made. Child improved with mannitol, anticonvulsants, antibiotics
and antifungals. CNS toxicity of Ifosfamide displays a wide
spectrum of signs and symptoms. Manifestations of Ifosfamide
induced encephalopathy include cerebellar ataxia, mental
confusion, complex visual hallucinations, extrapyramidal signs,
seizures and/or mutism. Less common manifestations include
asterixis, non-convulsive status epilepticus, manic episodes and
cerebellar and temperofrontal cortical degeneration. Ifosfamide
induced encephalopathy is a clinical diagnosis [17]. The differential
diagnoses of Ifosfamide induced encephalopathy include
infection, metabolic abnormalities and concomitant drug induced
syndromes. It is supported by normal brain imaging, EEG findings
of metabolic encephalopathy and the absence of other causes. EEG
characteristics have been correlated with the clinical grading of
Ifosfamide induced encephalopathy. Methylene blue was found to
be useful in managing cases of Ifosfamide induced encephalopathy
For more Lupine Publishers Open Access Journals Please visit our website:
For more journal paediatrics and neonatology articles Please Click Here:
Follow on Linkedin : https://www.linkedin.com/company/lupinepublishers
Follow on Twitter : https://twitter.com/lupine_online
No comments:
Post a Comment