Skip to content

Methotrexate Toxicity

Summary

fleuron

  • Methotrexate-induced neurotoxicity presents with acute to subacute neurological symptoms including confusion, seizures, and focal deficits
  • Pathologically characterised by demyelination and white matter injury, particularly affecting periventricular regions
  • MRI demonstrates characteristic symmetric white matter T2/FLAIR hyperintensities with restricted diffusion in acute phase

Pathophysiology

  • Direct toxic effect on oligodendrocytes leading to demyelination
  • Disruption of folate metabolism affecting myelin synthesis and maintenance
  • Accumulation of adenosine and homocysteine causing excitotoxicity
  • Blood-brain barrier disruption with intrathecal administration
  • Two main patterns:
    • Acute/subacute leukoencephalopathy (most common)
    • Chronic mineralizing microangiopathy (rare, in children)

Demographics

  • Higher incidence with intrathecal administration versus systemic therapy
  • Paediatric patients with ALL most commonly affected (5-10% incidence)
  • Adult patients with CNS lymphoma or leptomeningeal disease
  • Risk factors:
    • High cumulative doses
    • Concurrent cranial radiation
    • Young age (<10 years) or elderly (>60 years)
    • Renal insufficiency (impaired clearance)

Diagnosis

  • Clinical presentation:
    • Acute: confusion, somnolence, seizures (within days)
    • Subacute: progressive cognitive decline, ataxia (weeks to months)
    • Stroke-like episodes with focal deficits
    • Transverse myelopathy (with intrathecal administration)
  • Laboratory findings:
    • CSF: elevated protein, mild pleocytosis
    • Serum methotrexate levels (if recent administration)
  • Temporal relationship to methotrexate administration crucial for diagnosis

Imaging

  • T2/FLAIR:
    • Symmetric hyperintense periventricular white matter lesions
    • Centrum semiovale involvement common
    • Corpus callosum may be affected
    • Subcortical U-fibres typically spared
  • T1:
    • Hypointense in affected white matter regions
    • No significant mass effect
  • T1+C:
    • Usually no enhancement (distinguishes from infection/tumour)
    • Rare patchy enhancement in acute phase
  • DWI/ADC:
    • Restricted diffusion (high DWI, low ADC) in acute toxicity
    • Normalization or facilitated diffusion in chronic phase
    • May show "reversal sign" with resolution
  • SWI:
    • Mineralizing microangiopathy: punctate calcifications in basal ganglia and dentate nuclei
    • No haemorrhage typically
  • MR Spectroscopy:
    • Decreased NAA (neuronal loss)
    • Elevated choline (demyelination)
    • Possible lactate peak in acute phase
  • CT:
    • Hypodense white matter changes
    • Calcifications in chronic mineralizing microangiopathy

panels-1

  • A 20-year-old patient having methotrexate as part of treatment for leukaemia presented with bilateral leg weakness.
  • MRI showed symmetrical posterior centrum semiovale diffusion restriction without gadolinium enhancement.

Treatment

  • Immediate discontinuation of methotrexate
  • Supportive care:
    • Seizure management with anticonvulsants
    • Corticosteroids (controversial benefit)
  • Leucovorin (folinic acid) rescue:
    • 10-100 mg IV/IM every 6 hours
    • Continue until methotrexate levels <0.01 μmol/L
  • Aminophylline for acute toxicity (adenosine antagonist)
  • Methylene blue for severe cases (experimental)
  • Dextromethorphan (NMDA receptor antagonist) under investigation
  • Prognosis:
    • Acute toxicity often reversible with prompt treatment
    • Chronic changes may be permanent
    • Imaging abnormalities may persist despite clinical improvement

Differential diagnosis

Differential diagnosis Differentiating feature
Progressive multifocal leukoencephalopathy (PML) Asymmetric scalloped white matter lesions with subcortical U-fibre involvement; restricted DWI at active edge; no contrast enhancement
ADEM Multifocal bilateral white matter and basal ganglia lesions; ring enhancement; juxtacortical involvement
Multiple sclerosis Ovoid periventricular lesions (Dawson's fingers); corpus callosum involvement; calloso-septal interface
Radiation-induced leukoencephalopathy White matter changes confined to the prior radiation field
PRES Posterior predominant vasogenic oedema; elevated ADC values; no corpus callosum involvement
HIV encephalopathy Bilateral symmetric periventricular and subcortical white matter hyperintensities without dominant lesions
Osmotic demyelination syndrome Central pontine T2 signal with trident or bat wing morphology; extrapontine basal ganglia involvement
Other chemotherapy-induced leukoencephalopathy Similar periventricular white matter changes; indistinguishable from methotrexate on imaging alone