The Spectrum of Headache in Leptomeningeal Metastases: A Comprehensive Review with Clinical Management Guidelines

Abstract

Purpose of review: Headaches are a common, oftentimes debilitating symptom in patients with leptomeningeal metastases.

Recent findings: The third edition of the International Classification of Headache Disorders provides a useful diagnostic framework for headaches secondary to leptomeningeal metastases based on the temporal relationship of headache with disease onset, change in headache severity in correlation with leptomeningeal disease burden, and accompanying neurologic signs such as cranial nerve palsies and encephalopathy. However, headaches in patients with leptomeningeal metastases can be further defined by a wide range of varying cancer- and treatment-related pathophysiologies, each requiring a tailored approach. A thorough review of the literature and expert opinion on five observed headache sub-classifications in patients with leptomeningeal metastases is provided, with attention to necessary diagnostic testing, recommended first-line treatments, and prevention strategies.

Keywords: Headache; Intracranial pressure; Intrathecal chemotherapy; Leptomeningeal metastases; Whole-brain radiation therapy.

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

Fig. 2

Clinical algorithm in differentiating headache subtypes in patients with leptomeningeal metastases. When assessing headaches in a patient with leptomeningeal metastases, inquiring about the presence of positional symptoms is an essential first step in the diagnosis of elevated intracranial pressure or intracranial hypotension, in the appropriate clinical setting. If pressure-mediated headache subtypes are sufficiently ruled out on clinical or diagnostic grounds, the clinician should then inquire about any recent leptomeningeal-directed cancer therapies, such as intrathecal chemotherapy or cranial irradiation, which can independently induce inflammation in the subarachnoid space. In the absence of these relevant details, headache secondary to potentially progressive leptomeningeal metastasis and the associated CSF inflammatory response is likely, with other non-cancer-related primary headache disorders, a diagnosis of exclusion