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Year : 2015  |  Volume : 5  |  Issue : 1  |  Page : 37-39

An oral methotrexate may cause intracerebral hemorrhage

Department of Neurology, Dr. Sampurnanand Medical College and Mahatma Gandhi Hospital, Jodhpur, Rajasthan, India

Date of Web Publication27-Jan-2015

Correspondence Address:
Bharat Bhushan
H. No. 21/267, Chopasani Housing Board, Jodhpur - 340 008, Rajasthan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2231-0738.150075

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The neurotoxicity of methotrexate (MTX) is a well-documented issue but the development of an intracerebral hematoma following the administration of oral MTX is extremely rare. A 25-year-old female with a history of hydatidiform mole underwent dilatation and curettage 2 months earlier. She was put on oral MTX regimen 7.5 mg thrice weekly. Mistakenly she was taking 22.5 mg daily for the past 2 months. She presented to us with skin rashes and seizures. Later, she developed a deteriorating state of consciousness, with a clinical diagnosis of stroke. Magnetic resonance imaging (MRI) of the brain demonstrated a large left parietal hematoma. We failed to prove brain or lung metastasis due to choriocarcinoma, vasculitis syndrome, antiphospholipid syndrome, demyelination, and infective etiology.We used the Naranjo Adverse Drug Reaction (ADR) Probability Scale and stopped MTX, and treated the patient successfully with leucovorin, dexamethasone, aminophylline, and other measures. She was discharged after 25 days of hospital stay. We concluded that an high dose oral MTX may cause intracerebral hemorrhage.

Keywords: Cerebral hemorrhage, methotrexate, neurotoxicity, oral

How to cite this article:
Bhushan B, Bhargava A, Kasundra GM, Shubhakaran K. An oral methotrexate may cause intracerebral hemorrhage. Int J Nutr Pharmacol Neurol Dis 2015;5:37-9

How to cite this URL:
Bhushan B, Bhargava A, Kasundra GM, Shubhakaran K. An oral methotrexate may cause intracerebral hemorrhage. Int J Nutr Pharmacol Neurol Dis [serial online] 2015 [cited 2022 Dec 8];5:37-9. Available from:

   Introduction Top

Methotrexate (MTX) is classified as an antimetabolite drug, which means it is capable of blocking the metabolism of cells. This drug itself and its active metabolites compete for the folate binding site of the enzyme dihydrofolatereductase. Owing to their poor ability to cross the blood-brain barrier, injectable and intrathecal regimens are used for intracranial therapeutic purposes like cerebral metastasis in gestational trophoblastic disease (GTD).MTX toxicity develops due to increased patient susceptibility during treatment, excessive parenteral or intrathecal administration, and therapeutic errors by patients. Protean manifestations of adverse drug reactions (ADRs) from short-term and long-term oral as well as intrathecal MTX were reported. It included skin lesions, hepatic fibrosis, bone marrow suppression and the spectrum of neurotoxicity. The most important problem in assessing ADRs is whether there is a causal relationship between the drug and the untoward clinical event. We used the Naranjo ADR scale to endorse our observations regarding the adverse effects of MTX. [1]

   Case report Top

A 25-year-old female (gravida 4, para 1) visited us with a poor obstetric history of three missed abortions within 7 years of marriage. Two months ago she received a consultation for 5 months amenorrhea. Her ultrasonography suggested complete hydatidiform mole and in serum, high beta human chorionic gonadotropin (23,200 mIU/ml). The case being considered one of gestational trophoblastic disease (GTD), dilatation and curettage was done. After 5 days on intramuscular MTX, she was discharged with MTX regimen (7.5 mg thrice weekly). Mistakenly she was taking 22.5 mg daily for the past 2 months. During MTX treatment, she developed skin rashes and three episodes of seizures over a 1-month period. She came to us for the evaluation of seizures, with prior investigation in view of metastasis including normal serum beta human chorionic gonadotropin (βHCG) and brain and whole body positron emission tomography (PET) scan [Figure 1]. Due to skin lesions, seizures, lack of cerebral metastasis evidence on PET, and a background of high dose-MTX, we considered the ADR of MTX. We used the Naranjo ADR Probability Scale (reintroduction of the drug caused a reappearance of symptoms, and the serum level was 2.1 μmol/L, normal <1 μmol/L), which indicated a probable (the score was 7) relationship between skin lesions with seizure and MTX therapy for ADR. [2] We stopped MTX, treated the patient with levetiracetam, and investigated further. We failed to prove brain and lung metastasis of GTD, vasculitis syndrome and infective etiology. Other positive investigations revealed anemia, thrombocytopenia, eosinophilia, and high homocysteine (67 μmol/L in blood and 38 μmol/L in spinal fluid).Cerebral spinal fluid (CSF) examination showed 66 proteins, 43 mg/dL glucose, 6 cells, all lymphocytes. On day 3, the patient again developed one episode seizure. Her brain magnetic resonance imaging (MRI) showed enhancing lesions [Figure 2]a and b. Other investigations were normal including βHCG in serum and spinal tap and MRI pelvis. After 4 days of the last seizure she developed sudden onset vomiting and altered sensorium, with a clinical diagnosis of right hemiplegia. MRI brain showed left parietal lobe hemorrhage in a preexisting lesion [Figure 2]c. MR venogram and angio gram of the brain and large intracranial vessels did not reveal any vascular abnormality or tumor circulation. With the help of decompressive measure, leucovorin, dexamethasone, aminophylline, folic acid, and dextromethorphan, she improved over a 24-day period of hospital stay and was discharged on the 25 th day on modified Rankin Scale 2.
Figure 1: (a and b) PET-CT Brain and whole-body reveal absence of obvious fluorodeoxyglucose (FDG)-avid lesion

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Figure 2: (a) Time course MRI images showing hyperintense at right frontal and left parietal on diffusion sequence, (b) gadolinium enhancement in left parietal lobe, (c) blooming on gradient echo at left parietal lobe

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   Discussion Top

The protean effects of MTX on the central nervous system (CNS) are the least well understood. MTX may acutely cause somnolence, seizures, confusion, dysarthria, aphasia, and focal neurologic defects such as hemiparesis and intracerebral hemorrhage (ICH). Cognitive and developmental impairment, stroke-like lesions in the white matter, and leukoencephalopathy characterize chronic MTX neurotoxicity (MNT). [2]

ICH is particularly common with few intravenous or intrathecal antineoplastic drugs. MTX induced various presentations of neurotoxicity, and ICH was reported after a few days to week of intrathecal therapy. [3] Recently, Boran et al., reported intracerebral hematoma as a complication of intrathecal MTX administration after the 6 th day of the last intrathecal (12mg) therapy. [4] Metabolic alterations are responsible for both the therapeutic and the toxic effects of MTX. The possible mechanisms for MNT have been proposed by various studies. These include increased adenosine accumulation, homocysteine elevation, excitatory effects on the N-methyl-D-aspartate (NMDA) receptor, and alterations of biopterin metabolism. [3],[4] Both the degree and the sites of MNT are difficult to determine. There is no clear correlation either between findings on ancillary tests (MRI study) and the clinical manifestations that prompted their performance, or among the findings themselves on the different modalities.

The possibility of oral MTX-induced ICH is conditional, as with our case of the patient who consumed a daily high oral dose. The possible pathophysiology of MNT is by aforementioned mechanisms due to the cumulative effect of MTX. Oral MTX-induced neurotoxicity was considered in view of the following:

  • The patient's erroneous consumption of a high daily oral dose
  • Evidence of MTX toxicity features (skin lesion, anemia, thrombocytopenia, eosinophila, hyperhomocysteinemia, and seizure)
  • The possibility of ICH having been described by injectable MTX
  • Naranjo ADR Probability Scale indicating a probable (the score was 7) relationship between symptoms and MTX therapy and
  • Good outcome after management according to the relevant offending drug.

Brain hemorrhage associated with GTD may be the presenting feature of the disease; it tends to occur in multiple sites and may be associated with surrounding edema. [5] Metastasis should be suspected in case of plateau or rising βHCG. In this case, abnormalities in neither whole-body PET-CT, serum/CSF βHCG nor MRI suggested metastasis of GTD pelvis. Therefore, the ICH in our patient was not attributed to the metastasis of GTD and other possibilities.

Treatment attempts for MNT have included aminophylline, an adenosine antagonist, and dextromethorphan, an antagonist of the NMDA receptor. [4],[5] Some anecdotal success has been reported but no large series have confirmed the efficacy of either agent. In GTD it is especially important to monitor HCG levels during treatment and follow-up to make sure the disease is cured and there is no recurrence. We conclude that oral MTX may lead to ICH being presented, though it may be conditional as in our case.

   Acknowledgments Top

The author would like to thank Dr. Janardan Sharma, Dr. Mohamad Yasin.Registrar, D.M. Neurology. Dr. S.N. Medical College and M.G. Hospital, Jodhpur, Rajasthan, India and Dr. Isha Sood; Senior Registrar, Department of Medicine. Dr. S.N. Medical College and M.G. Hospital, Jodhpur, Rajasthan, India.

   References Top

Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 1
Huang CY, Chen CA, HsiehCY, Cheng WF. Intracerebralhemorrhage as initial presentation of gestational choriocarcinoma: A case report and literature review. Int J Gynecol Cancer 2007;17:1166-71.  Back to cited text no. 2
Peyriere H, Poiree M, Cociglio M, Margueritte G, Hansel S, Hillaire-Buys D. Reversal of neurologic disturbances related to high-dose methotrexate by aminophylline. Med Pediatr Oncol 2001;36:662-4.  Back to cited text no. 3
Boran P, Tokuc G, Boran BO, Oktem S. Intracerebral hematoma as a complication of intrathecal methotrexate administration. Pediatr Blood Cancer 2008;50:152-4.  Back to cited text no. 4
Shuper A, Stark B, Kornreich L, Cohen IJ, Aviner S, Steinmetz A, et al. Methotrexate treatment protocols and the central nervous system: Significant cure with significant neurotoxicity. J Child Neurol 2000;15:573-80.  Back to cited text no. 5


  [Figure 1], [Figure 2]


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