Intrathecal Methotrexate Toxicity Resulting in Brain Death due to Generalized Cerebral Edema Case Report

Abstract

Intrathecal methotrexate (IT MTX) resulting in severe adverse events including life-threatening cerebral edema is not well described. We report a rare case of death in a 37-year-old BRCA1+ woman with metastatic triple-negative breast cancer status post mastectomy following administration of IT MTX for leptomeningeal carcinomatosis. Within the 24 hours after intraoperative IT MTX delivery, she developed neurologically devastating diffuse cerebral edema leading to uncal and cerebellar tonsillar herniation. This case report highlights a rare but devastating side effect of IT MTX.

Introduction

IT MTX is used to treat central nervous system (CNS) malignancies, including both hematologic malignancies such as leukemias and lymphomas, as well as solid tumors that have undergone leptomeningeal metastasis. Of these, primary breast cancer is a solid tumor malignancy associated with leptomeningeal carcinomatosis. ¹ Leptomeningeal carcinomatosis occurs when cancerous cells seed the leptomeninges and is a serious sequalae occurring in 5% of patients with breast cancer. ² This advanced stage of primary breast cancer often results in a high mortality rate with a median survival time of 4 to 6 weeks without therapy. ³ IT MTX is a therapeutic option for leptomeningeal metastasis and is recommended by the European Association of Neuro-Oncology (EANO) and European Society for Medical Oncology (ESMO) as a consideration for patients with cytologically or histologically verified leptomeningeal metastasis without bulky leptomeningeal disease or hydrocephalus. ⁴ This route of administration allows for chemotherapy to bypass the blood-brain barrier and directly treat subclinical leptomeningeal deposits and tumor cells in the cerebral spinal fluid (CSF) ³ and as such provides an alternative delivery and mechanism for chemotherapy treatment in aggressive cases.

While adverse events such as headaches, leukoencephalopathy, and aseptic meningitis may occur and are typically self-limiting, ⁵ there are only a handful of cases where a patient suffered the most severe IT MTX effects of cerebral edema resulting in rapid neurologic deterioration, and ultimately death. ⁶ To our knowledge, this is the first reported case of rapid diffuse cerebral edema resulting from IT MTX within 24 hours of administration in a patient with leptomeningeal carcinomatosis from breast adenocarcinoma.

Case Presentation

A 37-year-old BRCA1+ woman with a history of metastatic triple-negative ductal carcinoma in situ presented after a lengthy and progressive clinical course. Her prior management included bilateral mastectomy and salpingo-oophorectomy, immunotherapy, radiotherapy, and chemotherapy. Following this extensive treatment course, she then presented with 2 weeks of headaches and confusion. Magnetic resonance imaging (MRI) demonstrated widespread leptomeningeal enhancement along the right temporal cortex, insula, and cerebellum suggestive of leptomeningeal carcinomatosis (Figure 1). CSF cytology confirmed the presence of malignant cells.

Figure 1.

Post-gadolinium MRI of the brain and spine. A, Axial preoperative post-gadolinium T1 weighted brain MRI demonstrated widespread leptomeningeal enhancement along the cerebellum and right temporal cortex (B) with extension throughout the CNS involving the surface of the spinal cord and associated diffuse osseus metastatic disease (C).

The patient underwent placement of an Ommaya reservoir with subsequent intra-operative administration of 12mg of IT MTX without any immediate complications noted. Postoperative head computed tomography (CT) revealed good placement of the Ommaya reservoir (Figure 2A). Twelve hours postoperatively, she became agitated, and went from a Glasgow Coma Score (GCS) 15 to a GCS 13. She was started on levetiracetam 500 mg twice daily empirically for potential seizure and an electroencephalogram (EEG) was requested.

Figure 2.

Non-contrast head CT Findings. A, Immediate postoperative non-contrast head CT with good placement of the Ommaya catheter. B, Repeat non-contrast head CT 19 hours after Ommaya placement and IT MTX administration.

Over the next sixteen hours, she became lethargic, ultimately becoming unresponsive with loss of all brainstem reflexes. Brain edema was suspected, and mannitol and dexamethasone were administered with no improvement in exam. Subsequent head CT nineteen hours after the initial postoperative imaging revealed diffuse cerebral edema with uncal and tonsillar herniation (Figure 2B). MRI was notable for absence of gadolinium in the post-contrast sequences, suggesting lack of intracerebral blood flow.

During the patient’s 5-day course in the neuroscience intensive care unit (NSICU), she developed diabetes insipidus and was treated accordingly. Continuous EEG revealed severely attenuated background <10 μV in amplitude and there were no significant changes in her neurologic exam over this period. Given this neurologic picture, formal declaration of death by neurologic criteria was discussed, however family elected for palliative extubation, and the patient died shortly thereafter.

Autopsy was completed and revealed widely metastatic disease involving bilateral lungs with visceral extension, deposits on the anterior surface of pericardium, in the parietal pleura, liver, peripancreatic lymph node, and multiple bony lesions involving ribs, sternum and vertebrae. Brain was normal in weight (1190g) but showed effacement of sulci, was soft, brown-gray, extensively macerated and friable, consistent with "non-perfused/respirator brain" with superimposed delayed postmortem interval (3 days). There was bilateral uncal and cerebellar tonsillar prominence, consistent with herniation. The ventricles were compressed. There was a Duret-type hemorrhage extending from the midbrain to the pons and middle cerebellar peduncle. The spinal cord contained extensive deposits of necrotic and hemorrhagic debris filling up the subarachnoid space (Figure 3A and B).

Figure 3.

Autopsy and histopathological findings. , Ventral surface of the thoracic-lumbar spinal cord with dura opened longitudinally and pinned down. B, Close-up of hemorrhagic and partially necrotic deposits underneath arachnoid membrane. C, Hematoxylin and eosin (H&E) 100X magnification showing a stained section of cerebellum with extensive meningeal spread. D, 100X magnification H&E section of spinal cord (arrow indicates central canal) showing carcinoma extending through the ventral fissure.

Microscopy showed extensive leptomeningeal carcinomatosis. Additionally, wide-spread deep parenchymal cancerous deposits extending from the leptomeninges along the Virchow-robin spaces were seen (Figure 3C and D) with predominantly viable tumor cells in the midst of anoxic/ischemic neuronal alterations of non-perfused brain. The white matter showed edema but no demyelination or necrotizing leukoencephalopathy. Pituitary showed global infarction and metastatic disease.

Discussion

The patient reported here suffered from a severe complication of IT MTX resulting in diffuse cerebral edema with an examination that was concerning for death by neurologic criteria. Severe complications of IT MTX can occur in 36% of patients and include blindness, cerebral infarctions, coma, necrotizing leukoencephalopathy, seizures, cerebral edema, hemorrhage, and death. ⁷ Literature review at the time of this manuscript demonstrates only 1 other case of acute fatal encephalopathy from IT MTX in a patient with leptomeningeal metastasis from breast cancer who died within 24 hours of Ommaya reservoir placement and subsequent IT injection of 10mg MTX. ⁷ Several other case reports describe the complications of IT MTX in patients with hematologic cancers including diffuse large B-cell lymphomas, acute myeloid leukemias, and acute lymphoblastic leukemias. These reports describe patients who developed cerebral edema 36-48 hours after administration of IT MTX and improved clinically and radiographically after administration of a steroid regimen. ⁸ MTX specific rescue therapies such as leucovorin have also been used in other cases after MTX administration to decrease its toxic effects, ⁹ although it was not used in our case. Additional reports describe fatal encephalopathies resulting in fulminant brain edema and herniation as late as 28 days post administration (Table 1).

Table 1.

Select cases reporting adverse effects of IT MTX.

Author(s)	Year	Type	Presentation	Events
Pavlidou et al. PMID 27942481	2016	Case Report	13-year-old boy with Burkitt lymphoma/leukemia	Posterior reversible encephalopathy syndrome (PRES)
Bachegowda et al. PMID 19847678	2010	Case Report	54-year-old with large B-cell lymphoma	Seizures and diffuse cerebral edema
Aradillas et al. PMID 21210832	2010	Case Report	55-year-old woman with diffuse large B-cell type lymphoma	PRES
Weigel et al. PMID 15003295	2004	Case Series	Three patients with diffuse large B-cell lymphomas (mean age 52, range 30-70 years)	Two patients died secondary to fulminant brain edema; a third patient developed leukoencephalopathy
Boogerd et al. PMID 15571954	2004	Randomized study	Patients with leptomeningeal metastasis from breast cancer randomized to receive IT chemotherapy	One patient became comatose and died within 24 h after placement of the reservoir and the subsequent administration 10 mg IT MTX
Sandoval et al. PMID 14561622	2003	Case Report	13-year-old girl with Pre-B acute lymphoblastic leukemia	Cytotoxic cerebral edema
Weid et al. PMID 2023567	1991	Case Report	12-year-old girl with acute lymphoblastic leukemia	Fatal toxic encephalomyelopathy
Shore et al. PMID 2304423	1990	Case Report	21-year-old male with T-cell acute lymphoblastic leukemia	Leukoencephalopathy resulting in brain death
Hughes et al. PMID 2500219	1989	Case Report	23-year-old woman with acute myeloid leukemia	Cerebral edema which resolved after 7 days
Boogerd et al. PMID 3225584	1988	Case Series	14 patients with leptomeningeal carcinomatosis from breast carcinoma (age range 39-72)	9 out of 14 patients developed disseminated necrotizing leukoencephalopathy

The exact mechanism of methotrexate neurotoxicity is unclear but is believed to be multifactorial. In addition to inhibiting cell replication as a result of its inhibition of dihydrofolate reductase (DHFR), methotrexate causes a relative excess of homocysteine, which is thought to induce a small vessel vasculopathy. Methotrexate may also disturb myelin metabolism and maintenance of the myelin sheath by way of S-adenosylmethionine deficiency due to inhibition of DHFR. Others have suggested chronic folate depletion, increased excitatory amino acids, excess alterations of biopterin and adenosine metabolisms as putative mechanisms. Tumor lysis within the CNS resulting in axonal swelling may play a role as well. ¹⁰

Additional consideration in this case is the potential interactions between intraoperative anesthetics and methotrexate given that IT MTX was administered intra-operatively. Our patient’s intraoperative anesthetic medications were desflurane, nitrous oxide, and propofol. Nitrous oxide and propofol have been examined as possible contributors to MTX toxicity. ¹¹ Nitrous oxide is proposed to contribute to methotrexate toxicity via depletion of active vitamin B₁₂. Depletion of active vitamin B₁₂ results in accumulation of homocysteine and depletion of methionine as vitamin B₁₂ is a co-factor in the pathway synthesizing methionine from homocysteine. Neurotoxicity occurs as a downstream effect of this altered metabolism. This neurotoxic effect may be potentiated in those with already low vitamin B₁₂ levels prior to receiving MTX. ¹¹ Unfortunately, we did not have a recent vitamin B₁₂ level for our patient. Her vitamin B₁₂ level was assessed 10 months prior and was within normal limits at 498 ng/L (normal range 200-1100 ng/L).

Potential neurotoxic effects of propofol and flurane anesthetics have been examined as well. In 1 study examining a pediatric cancer population that were routinely treated with IV and/or IT MTX, anesthesia administration resulted in dose and duration dependent adverse effects on white matter integrity in the corpus callosum. These adverse effects are thought to be mediated via capase-3 induced apoptotic pathway and neuroinflammation based on animal studies. The adverse neurocognitive outcomes in this study were seen as a cumulative effect in long-term survivors. ¹² It is unclear if these medication interactions contributed to the acute neurotoxicity seen in our case.

Evidence suggests that the degree of neurotoxicity from IT MTX is also related to exposure time to excessive drug concentrations in the CNS. When methotrexate is administered through an Ommaya reservoir, it distributes passively with the flow of CSF. ¹³ However, abnormalities with CSF flow are often present in those with leptomeningeal carcinomatosis. This may impact the distribution and clearance of intrathecal chemotherapies such as methotrexate ¹⁴ and lead to localized areas of high drug concentration which can increase the risk of neurotoxicity. ⁶ Although there are no studies to our knowledge which compare the toxicity of methotrexate in leptomeningeal carcinomatosis with parenchymal oncologic brain involvement, this may be a potential area of future research. It is important to note that, while not performed in this case, CSF flow abnormalities can be detected with radionuclide flow studies prior to intrathecal chemotherapy ¹⁵ and such knowledge might allow for consideration of alternate treatment approaches. One such approach is opting for a treatment schedule of lower doses of intrathecal methotrexate spread out over days rather than all in 1 day. This approach may attenuate toxic peak-doses and reduce the cumulative dose significantly. ¹⁶ Avoiding close association between use of intrathecal methotrexate and radiotherapy may also minimize neurotoxicity as there may be vascular injury caused by the interaction of methotrexate with tissue altered by irradiation. ¹⁷ A maximally conservative strategy may be to avoid intrathecal administration all-together, opting for high dose intravenous MTX, which may provide therapeutic CSF concentrations while minimizing neurotoxicity. ¹⁸

In summary, we present a severe case of IT MTX toxicity leading to diffuse cerebral edema and brain herniation in a patient with leptomeningeal carcinomatosis due to breast adenocarcinoma. While this is a somewhat rare complication of IT MTX, we nevertheless want to raise awareness of this entity given the severe consequences. We hope knowledge of this case will prompt clinicians to consider alternate treatment regimens and methods of chemotherapeutic administration in similar patients when appropriate. This case further highlights the need for continued research to develop effective, non-toxic treatments for patients with widespread leptomeningeal metastases.

ORCID iDs

Haoming Pang https://orcid.org/0000-0003-0553-6720

Julie L. Chan https://orcid.org/0000-0002-0782-6548