INTRODUCTION
Methotrexate (MTX) is a cornerstone treatment of children
oncohematological diseases1. For acute lymphoblastic
leukaemia (ALL) its intrathecal administration is essential to avoid
central nervous system (CNS) recurrences. After its use associated or
not with other chemotherapeutic agents the CNS recurrences has decreased
from 25% to 5% 2.
Methotrexate, a folic acid antagonist, blocks the synthesis of the
purine by inhibiting regulatory enzymes. Its administration is
associated with multiple side effects: myelosuppression, mucositis,
liver damage, kidney failure or neurotoxicity. This toxicity can lead to
acute, subacute and chronic syndromes. The symptoms and the severity of
them will depend on the route of administration, dose and association
with other chemotherapies.
Regarding MTX neurotoxicity, it takes place in days or weeks after
intrathecal or intravenous administration. It can be associated with
hemiparesis, sensory deficit, aphasia, dysarthria, dysphagia or
diplopia. There is no precise pathophysiological description, but a
delay in MTX elimination could be related to it. Therefore, clinical
suspicion is essential to avoid inappropriate approaches in a clinical
event that may remind an ischemic episode.
We present a fifteen-year-old female with a large-cell B lymphoma
diagnosis after the accidental discovery of a mediastinal mass. She had
pleural and pericardial effusion, bilateral multiple pulmonary nodules,
right lateral cervical and supraclavicular adenopathies, mesenteric and
retroperitoneal, hepatic, pancreatic, renal and intestinal adenopathy
conglomerate (stage IIIB). She received chemotherapeutic and
radiotherapy according to the group B of high-risk protocol (“Inter B
NHL RTX 2010”). She suffered delayed MTX elimination, acute renal
failure, vincristine neurotoxicity and grade four myelosuppression.
On the eighteenth day of the second COPADM cycle (Vincristine,
Cyclophosphamide, Prednisone, Adriamycin and Methotrexate), she
presented left facial palsy and left upper limb weakness. The
sensitivity was preserved. Two hours later, she showed left arm
paralysis without other symptomatology. A magnetic resonance (MRI) was
done and described as compatible with stroke (Figure 1). She was
transferred to the pediatric intensive care unit (PICU). The patient did
not meet fibrinolysis criteria, so it was maintained a conservative
treatment. The cranial doppler was symmetrical. It was impossible to
perform a lumbar puncture (low platelet count). Therapy with acyclovir
was started. Two hours after PICU admission, the clinical deficiencies
disappeared.
On the second day of PICU admission, the patient repeats the symptoms
previously described adding a left lower limb paresis. Like the previous
day, the clinic was fully solved in less than 12 hours. On the third day
of admission, she started again with self-limited peribucal paresthesias
without other neurological signs. In this context, and with the
suspicion of a possible link to MTX, oral theophylline was started. This
treatment was continued for three days. The patient showed complete
recovery. Before PICU discharge, a new MRI did not show changes. The
patient did not suffer other neurological symptoms.
As seen, we present a case of MTX neurotoxicity treated with supportive
therapies and antiviral drugs. After clinical suspicion, theophylline
was started. The clinical and imaging tests observed were similar to the
described in cerebral ischemic events. The link between MTX and
neurotoxicity was critical to avoid nor indicated therapies that could
lead to severe complications.
The MTX is a folic acid antagonist that interrupts cell replication by
inhibiting dihydrofolate reductase. It prevents the folic acid
conversion to tetrahydrofolic acid. The pathophysiology that induces
neurotoxicity is not entirely understood. A hypothesis is based on the
elevation of homocysteine levels in the blood and cerebrospinal fluid.
This conversion can be carried out by betaine-homocysteine
methyltransferase, an enzyme found in the liver or the kidney but not
in the CNS. So, the homocysteine accumulated in the CNS could generate
vascular endothelium damage. Also, its metabolites may activate the NMDA
receptors, which contribute to neurological symptoms.
We reviewed the MTX neurotoxicity cases in our centre between 2010 and
2018 (Table 1). We also made a literature review of previously published
cases. According to the literature, the MTX neurotoxicity incidence is
around 4%. The only risk factor described is age older than ten years
old 1,3-5. The interval from the MTX administration to
the symptom varies from 3 to 29 days (Table 1)1,6. The
occurrence of this event is linked to the chemotherapy intensification
or consolidation phases1,3,7. Also, the concomitant
administration of cytarabine and cyclophosphamide may facilitate
it1,7. In our centre, one of the children was in the
high-risk protocol for large-cell B lymphoma, and the other was in the
consolidation phase (Table 1).
The symptoms, such as palsy, loss of strength or paresis, are described
and observed in most cases. Also, psychomotor agitation or
aggressiveness are described. Regarding the complimentary tests, MRI
brain alterations are commonly observed. Focal images with restriction
to diffusion are generally described1,4,5,8. Two main
therapeutics approaches are described to treat MTX neurotoxicity. First,
dextromethorphan, a non-competitive NMDA receptor antagonist. It has
been indicated to improve the cognitive deficit5,9,10.
In our experience, this drug has been prophylactically used with slight
efficacy. Also, theophylline, an adenosine antagonist, can be used. This
drug decreases the toxicity of vascular endothelium. However, digestive
and cardiac side effects should be monitored. In the case reported, this
drug was administered after 48 hours of symptoms. We do not know if the
clinical improvement could be related to this drug or just to the MTX
clearance.
In conclusion, neurotoxicity is a described but little known
complication related to MTX. It should be considered in children with
cancer and stroke-like symptoms or image findings. The treatment should
be based on a supportive approach with drugs aimed to antagonise or
minimise the effect of MTX metabolites on the endothelium. The evolution
is usually towards a complete recovery without neurological sequelae.