Can methotrexate (MTX) cause raised intracranial pressure (ICP) in patients, particularly those with pre-existing neurological conditions or impaired renal (kidney) or liver function?

Can Methotrexate Cause Raised Intracranial Pressure?

Yes, methotrexate can cause raised intracranial pressure, particularly with intrathecal administration and in patients with high tumor burden or pre-existing cerebral edema, though this is an uncommon complication that requires vigilant monitoring in high-risk scenarios.

Mechanism and Clinical Context

Methotrexate-induced raised ICP occurs through several mechanisms:

• Intrathecal administration can lead to high drug levels in cerebrospinal fluid for at least 24 hours, potentially causing aseptic meningitis with meningeal irritation symptoms in 10-50% of patients receiving IT methotrexate 1
• Tumor lysis and biochemical disruptions following high-dose methotrexate can increase cerebral edema and ICP in predisposed patients, particularly those with ring-enhancing lesions and significant mass effect 2
• Fatal outcomes have been documented with intrathecal overdose, including cerebellar herniation associated with increased intracranial pressure and acute toxic encephalopathy 3

High-Risk Patient Populations

Patients requiring heightened vigilance include:

• Those with high tumor burden primary CNS lymphoma receiving methotrexate-based induction chemotherapy, where real-time ICP monitoring may be necessary to prevent cerebral herniation 2
• Patients with pre-existing cerebral edema or mass effect from CNS lesions, where initiation of methotrexate can prove challenging due to impending herniation risk 2
• Individuals with renal impairment, as methotrexate is 85% renally excreted and renal dysfunction is the single most critical risk factor for life-threatening toxicity 4
• Older patients (>50 years) with mild renal insufficiency (baseline creatinine 1.3 mg/dL), who demonstrate higher rates of CNS toxicity including cranial sensations and cognitive symptoms 5

Clinical Presentation and Monitoring

Symptoms of methotrexate-induced raised ICP include:

• Headache, nausea, and vomiting 3
• Seizures or convulsions 3
• Acute toxic encephalopathy 3
• Back or leg pain (with myelopathy) 1
• Altered consciousness and focal neurological signs 1

For patients with significant mass effect receiving high-dose methotrexate:

• Consider real-time ICP monitoring to allow early recognition and aggressive medical management of ICP elevations that could lead to fatal herniation 2
• Monitor for signs of aseptic meningitis, particularly with intrathecal administration 1

Risk Factors Amplifying Toxicity

Critical risk factors that exponentially increase methotrexate neurotoxicity:

• Renal impairment (most critical factor) - requires mandatory test dose of 2.5-5 mg with CBC evaluation 5-6 days later before full dosing 1, 4
• Advanced age (>40-50 years) 1, 5
• Concurrent craniospinal radiotherapy with intrathecal administration 1
• Frequent intrathecal injections via lumbar route 1
• Hepatic impairment 1
• Hypoalbuminemia 1, 4
• Drug interactions affecting renal elimination 1, 4

Management Algorithm

When raised ICP is suspected or documented:

1. Immediately discontinue methotrexate 3
2. Initiate leucovorin (folinic acid) rescue as promptly as possible, with effectiveness decreasing as time interval from methotrexate administration increases 3
3. Monitor serum methotrexate concentrations to determine optimal leucovorin dose and duration 3
4. For massive overdose or intrathecal complications: implement hydration, urinary alkalinization, high-dose systemic leucovorin, alkaline diuresis, rapid CSF drainage, and ventriculolumbar perfusion 3
5. Consider glucarpidase for toxic methotrexate concentrations with delayed clearance due to impaired renal function (do not administer leucovorin within 2 hours before or after glucarpidase) 3
6. Treat elevated ICP aggressively with medical therapy to prevent worsening cerebral edema and herniation 2

Prevention Strategies

To minimize risk of methotrexate-induced raised ICP:

• Verify adequate renal function (GFR >60 mL/min preferred; avoid if <30 mL/min) before initiating therapy 4
• Ensure folic acid supplementation 1-5 mg daily (except on methotrexate dosing day) 4
• Use lowest effective methotrexate dose to minimize cumulative toxicity 4
• Avoid concurrent hepatotoxic agents when possible, as both acitretin and tetracyclines combined with methotrexate increase toxicity risk 1, 6
• Monitor CBC with differential every 2-4 weeks and liver function tests every 2-4 weeks when risk factors present 4

Important Caveats

• While CNS toxicity from low-dose weekly methotrexate is more common than previously recognized (20% in one series), symptoms typically consist of dizziness, headache, cranial sensations, and cognitive changes rather than frank raised ICP 5
• Rechallenge after neurotoxicity is possible: 76% of pediatric patients rechallenged with intrathecal methotrexate after neurotoxic events had no recurrence, with particularly good safety during maintenance therapy 7
• Recovery from methotrexate-induced myelopathy is variable, with the majority showing clinical improvement, though high-dose folate metabolites may be beneficial 1
• Renal dysfunction of CTC grade 2-4 occurs in 40% of high-dose methotrexate cycles for PCNSL and persists at least 4 months post-therapy in 30% of patients, with males >50 years at greatest risk 8