Fig. 1
Pathophysiologic representation of five headache subtypes in patients with leptomeningeal metastases. In the setting of leptomeningeal metastases, cancer cells can be found free-floating in the CSF or adherent to the leptomeninges, transitioning between the adherent and floating states. a In disease-related meningeal irritation, sensory nerves embedded in the dura mater are theorized to experience innate-mediated activation. Myeloid cells (e.g., macrophage) and lymphoid cells (e.g., T cells) outnumber cancer cells, and higher levels of inflammatory cytokines (IL-6, IL-8, IL-1β) are observed. b Post-dural puncture headaches result from persistent CSF leakage incident to the dural hole and intracranial hypotension. On contrast-enhanced MRI brain, pachymeningeal thickening and enhancement are observed; a proposed explanation is compensatory dural vein engorgement. c Elevated intracranial pressure arises as cancer cells fill arachnoid granulations, disrupting the normal drainage of CSF from the subarachnoid space into dural venous sinuses. Brain imaging reveals communicating hydrocephalus or “ballooning” of the ventricles. d Intrathecal chemotherapy delivered via Ommaya reservoir causes a chemical arachnoiditis in the subarachnoid space, marked by increased leukocytes (T cells and macrophages), granulocytes (neutrophils), and inflammatory cytokines. e Ionizing radiation activates resident microglia, releasing pro-inflammatory cytokines (IL-6, IL-8, IL-1β, TNFα), chemokines (CCL2, CXCL2), and reactive oxygen and nitrogen species into the CSF. With increased blood-brain and blood-CSF barrier permeability, additional T lymphocytes and macrophages infiltrate the subarachnoid space and add to the inflammatory milieu