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Pembrolizumab Associated Brainstem Encephalitis

Summary

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  • Rare but serious neurological adverse event associated with pembrolizumab immunotherapy
  • Characterised by inflammation of the brainstem, leading to various neurological deficits
  • Diagnosis based on clinical presentation, MRI findings, and exclusion of other causes1

Pathophysiology

  • Immune-mediated inflammation of the brainstem triggered by pembrolizumab
  • Exact mechanism not fully understood, but likely involves:
    • T-cell activation and infiltration of the brainstem
    • Cytokine release and local inflammation
    • Potential cross-reactivity between tumour antigens and neural tissue

Demographics

  • Incidence: Rare, estimated at <1% of patients receiving pembrolizumab
  • Risk factors:
    • Prior history of autoimmune disorders
    • Concurrent use of other immunotherapies
    • Longer duration of pembrolizumab treatment

Diagnosis

  • Clinical presentation:
    • Acute or subacute onset of neurological symptoms
    • Cranial nerve deficits (e.g., diplopia, facial weakness)
    • Ataxia and gait disturbances
    • Altered mental status
  • Laboratory findings:
    • CSF analysis: Elevated protein, lymphocytic pleocytosis
    • Serum and CSF autoantibody panels (to rule out other causes)
  • Exclusion of other etiologies:
    • Infectious causes (e.g., viral encephalitis)
    • Metastatic disease
    • Paraneoplastic syndromes

Imaging

  • MRI brain with contrast:
    • T2/FLAIR hyperintensities in the brainstem
    • Potential enhancement on T1 post-contrast images
    • Diffusion restriction may be present in acute stages
  • PET-CT:
    • May show hypermetabolism in affected areas of the brainstem
  • Differential diagnosis on imaging:
    • Brainstem glioma
    • Demyelinating disorders (e.g., multiple sclerosis)
    • Vascular lesions (e.g., infarction, vasculitis)

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Treatment

  • Stop the checkpoint inhibitor and give high-dose corticosteroids (± IVIG/plasma exchange). Recognising it as an immune-related adverse event, rather than metastatic or infectious disease, is the key

Differential diagnosis

Differential Diagnosis Distinguishing Feature
Brainstem glioma Expansile infiltrative T2 signal in pons or medulla with mass effect; no associated cerebral hemisphere lesions
Brainstem infarction DWI restriction conforming to vascular territory (basilar perforator, PICA, AICA); associated vessel occlusion on MRA
Multiple sclerosis Focal ovoid demyelinating plaques without mass effect; periventricular and juxtacortical lesions elsewhere
Wernicke's encephalopathy Symmetric T2 hyperintensity in mammillary bodies, periaqueductal grey, and medial thalami
CLIPPERS Punctate and curvilinear perivascular enhancement ("pepper-like") centred on pons and cerebellum
Leptomeningeal or parenchymal metastases Nodular or ring-enhancing lesions with mass effect; other metastatic lesions elsewhere

  1. Buckley et al. Immune-related encephalitis after immune checkpoint inhibitor therapy. 2025. The oncologist - Open in new tab. ↩