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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 causes

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

  • Immediate discontinuation of pembrolizumab
  • High-dose corticosteroids:
    • Methylprednisolone 1g IV daily for 3-5 days, followed by oral prednisone taper
  • Additional immunosuppression if needed:
    • IVIG or plasmapheresis
    • Rituximab or cyclophosphamide for refractory cases
  • Supportive care:
    • Management of neurological deficits
    • Rehabilitation and physical therapy
  • Monitoring:
    • Serial neurological examinations
    • Follow-up MRI to assess treatment response
  • Prognosis:
    • Variable, ranging from complete recovery to persistent neurological deficits
    • Early recognition and prompt treatment associated with better outcomes

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