Case Report
Abstract
MTX is used in the treatment of several childhood cancers and is a main
component of the treatment regimen for osteosarcoma. MTX has been linked
with side effects of varying severity; Headaches, nausea, emesis,
lethargy, blurred vision, aphasia, hemiparesis, paresis, convulsions,
leucoencephalopathy, and arachnoiditis are symptoms of MTX toxicity
[1]. MTX-induced neurotoxicity can occur in up to 15% of patients
receiving high-dose MTX [2, 3]. The effects may be transient but can
have life-threatening implications, sometimes requiring intubation for
respiratory support.
Elevated homocysteine levels in the CSF are documented in cases of
MTX-induced neurotoxicity; Dextromethorphan is used as an initial
treatment for MTX-induced neurotoxicity as it works as a non-competitive
antagonist for the NMDA receptors and suppresses homocysteine activity.
In severe cases requiring intubation, medications for sedation are
utilized. Ketamine is also an NMDA receptor antagonist, and as such, may
be considered as an optimal treatment choice when sedation is required.
We describe the use of ketamine in a pediatric patient with
methotrexate-induced neurotoxicity. The use of ketamine in the treatment
of MTX-induced neurotoxicity has not been described in the literature.
A 15 -year -old male patient undergoing treatment for a distal femur
osteosarcoma, status post ten weeks of chemotherapy with a regimen
containing adriamycin, cisplatin, and Methotrexate (MTX), presented to
the Emergency Department (ED) reporting left upper extremity weakness.
He was discharged from the hospital after clearing high-dose MTX two
days prior to presentation. The day prior to ED presentation, he felt
weakness in his left hand when playing videogames, which progressed the
next day to involve his left arm. Upon arrival to the ED, his
neurological exam was significant for left upper extremity strength 1/5
with all other extremities 5/5 strength. Sensation in the left upper
extremity was intact. He was alert and interactive and in no apparent
distress, with stable vital signs.
CT scan of the head and CT angiogram of brain and neck did not show any
abnormalities. MRI of the brain showed hazy signal abnormality within
the fronto-parietal white matter (right side greater than left),
demonstrating restricted diffusion on DWI sequence. Diagnostic concerns
for demyelination and leukoencephalopathy were noted. While still in the
ED, patient developed a left-sided facial droop and was unable to
swallow liquid medication. He soon become somnolent with respiratory
distress and was intubated.
The patient was sedated with dexmedetomidine and fentanyl infusions and
was started on levetiracetam for seizure prophylaxis. Dextromethorphan
was initiated through an orogastric tube to treat presumed MTX-induced
neurotoxicity and was continued throughout hospital stay. Within 12
hours of initial treatment, a slight improvement in strength was noted
and treatment with aminophylline was discussed but not given at that
time. The dexmedetomidine and fentanyl infusions were replaced by a
ketamine infusion for its NMDA receptor antagonist properties and was
dosed at 30mcg/kg/min, in consultation with toxicology recommendations.
While on ketamine, the patient was able to communicate by shaking or
nodding his head. He also was able to demonstrate improved strength in
his left hand as he was able to squeeze when requested.
36 hours after admission, the patient was extubated and the ketamine was
discontinued at this time and the patient regained all bulbar function.
While all bulbar nerves were intact, the patient was sleepy and did not
initiate communication but was responsive to questions. The patient
received his normal morning medications, and after his levetiracetam
dose had a change in mental status with depressed mood, minimal
responsiveness to commands, responding only to noxious stimuli.
Aminophylline 2.5mg/kg was administered and during the infusion the
patient returned to his baseline mental status with normal
musculoskeletal strength exam. VEEG was initiated and showed
intermittent semi-rhythmic short runs of bisynchronous frontal
hemispheric slowing, consistent with cerebral electrophysiological
dysfunction that resolved the following day. No seizure activity was
noted. Patient was discharged 4 days after admission with no focal
neurological deficit and back to baseline behavior.
Discussion
Elevated homocysteine and elevated adenosine levels in the cerebrospinal
fluid have both been implicated in MTX-induced neurotoxicity. MTX
inhibits dihydrofolate reductase (DHFR), which results in decreased
folate and cobalamin, and increased homocysteine levels. Elevated
homocysteine levels has been reported in the cerebrospinal fluid (CSF)
of patients with MTX toxicity and can cause seizures and vascular
disease. An analogue of glutamate, homocysteine is an NMDA receptor
agonist; thus, accumulation of large quantities of homocysteine in the
CNS can cause neuronal damage and apoptosis via excitotoxicity [1, 4,
5]. Dextromethorphan is a non-competitive antagonist for the NMDA
receptors and suppresses homocysteine activity, so is often used as the
first line treatment for MTX-induced neurotoxicity [6]. MTX
treatment is reported to lead to high levels of adenosine in the CSF.
Adenosine interferes with neurotransmitter synthesis and release,
further contributing to MTX-induced neurotoxicity [7]. Aminophylline
is a competitive agonist of adenosine receptors and therefore is used in
treatment of MTX-induced neurotoxicity [8]. Ketamine has
historically been used for sedation however, more recently, studies have
proven that sub-anesthetic doses of ketamine have immediate effects in
treatment resistant major depressive disorder and bipolar depression
[9]. An NMDA receptor antagonist and synaptic glutamatergic
modulator, ketamine exerts antidepressant effects as rapidly as 24 hours
after administration. The behavioral changes seen in response to the
rapid-acting antidepressant effects associated with ketamine may be more
directly linked to direct modulation of glutamate in affected brain
regions [10]. Apart from its competitive antagonistic properties at
the NMDA receptor to counter the effects of MTX, the immediate mood
changes in our patient after withdrawal of ketamine may be explained
through the mechanism discussed above. This case highlights the clinical
benefits of using ketamine for patients with MTX-induced neurotoxicity.
Once the ketamine infusion was started, in conjunction with the
continued dextromethorphan, our patient’s clinical condition improved
with increased strength on the left side of his body and improved mental
status. Once the ketamine was discontinued, and after the levetiracetam
was administered, the patient clinically regressed. However, it is
important to note that the regression was most likely attributed
secondary to the ketamine withdrawal as opposed to the levetiracetam,
and that the timing was coincidental. He displayed mood changes and
appeared agitated as demonstrated by facial grimacing. He was also
unresponsive to commands unless he was firmly addressed, which was
different from his demeanor while on ketamine. However, after
administering aminophylline, these symptoms quickly reversed back to
baseline. Patients with MTX-induced neurotoxicity may require intubation
for rapidly declining mental status and airway compromise, thus
requiring sedation. Ketamine is an NMDA receptor antagonist and should
be strongly considered for sedation as it may lower the toxic effects of
homocysteine at the receptor level. This report describes the effect of
ketamine as a choice of sedative in a teenage patient with osteosarcoma
intubated due to MTX-induced neurotoxicity and also highlights the
potential side effects of abrupt withdrawal of this medication which
could be weaned more slowly peri-extubaiton
Conclusion
While dextromethorphan and aminophylline are known treatments for
MTX-induced neurotoxicity, ketamine may be a useful adjunct if the
patient requires sedation, as it contributes to NMDA receptor
antagonism. We present a case of MTX-induced neurotoxicity in a
pediatric patient treated with dextromethorphan, aminophylline and
ketamine. We are not aware of any other documented cases of MTX-induced
neurotoxicity treated with ketamine.
Conflict of Interest
We have no conflicts of interest to disclose.
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