lymphomatous meningitis, leukemic meningitis, leptomeningeal carcinomatosis, and leptomeningeal metastasis. To avoid confusion, we will refer to these entities collectively as LMD.

32.2 Epidemiology

The first reported case of LMD was reported by Eberth [1] in 1870. At that time, the condition was considered rare and was uncommonly diagnosed before death. Over the past four decades, the incidence of LMD has increased, largely as a result of new diagnostic modalities, improved therapies for systemic cancer, and increased clinical awareness [2]. LMD currently complicates the management of approximately 5% of patients with cancer [3, 4]. Several clinical series have estimated LMD to occur in 7–15% of patients with lymphoma, 5–15% of patients with leukemia, 4–15% of patients with solid tumors, 1–7% of patients with an unknown primary tumor, and 1–2% of patients with primary brain tumors [5–11]. The high incidence of LMD seen with solid tumors may reflect reporting bias rather than a true predisposition for leptomeningeal involvement, as solid tumors occur more frequently than hematologic malignancies [12].

32.3 Clinical Presentation

Three domains of leptomeningeal involvement have been described: the cerebral hemispheres, the cranial nerves, and the spinal cord and roots. Hemispheric symptoms may include headache and mental status change with attendant signs such as cognitive deficits, confusion, dementia, seizures, and hemiparesis. Patients may also develop stroke-like symptoms from tumor occlusion of the small pial blood vessels or symptoms of increased intracranial pressure with or without frank hydrocephalus [12]. Cranial nerve symptoms may include loss of vision, diplopia, facial weakness or numbness, and hearing loss. Signs of cranial nerve dysfunction include disc edema, extraocular muscle palsies, trigeminal and facial nerve palsies, and neurosensory hearing loss. Spinal symptoms and signs may include weakness (lower extremity more often than upper), dermatomal numbness, and radicular pain. In advanced cases, patients may also develop cauda equina syndrome or conus medullaris involvement [2, 3, 6, 10, 12–15].

Cancers can reach the leptomeninges by direct extension, migration along perivascular or perineural spaces, vascular extension (i.e., through the choroid plexus or Batson’s venous plexus), or hematogenous spread [2]. Two growth patterns have been observed: sheet-like diffusion along the pial surface, sometimes associated with inflammation; and development of multiple nodules on the surface of the brain, ventricles, and cranial nerves [16]. Despite these limited routes of dissemination, LMD is a protean disease with multiple clinical manifestations arising from differences in tropism of the inciting cancer. In order to better understand these

differences in clinical behavior, it is appropriate to divide LMD into three categories: LMD resulting from solid tumors, LMD resulting from hematogenous tumors, and LMD resulting from primary brain tumors.

32.3.1 LMD due to Solid Tumors

The solid tumors that most commonly spread to the leptomeninges are breast, lung, and head and neck cancers, melanoma, and gastric cancer. In the case of breast and lung cancers, the incidence of LMD appears to be increasing. However, this is likely due to better systemic therapies and increased survival in these patients. In addition, many of the first-line chemotherapeutic agents used to treat breast and lung cancers have poor penetration of the blood–brain barrier and are not effective against leptomeningeal disease [2, 17].

Patients with LMD due to solid tumors usually present with a random and highly asymmetric distribution of symptoms. This presentation is far more common than meningeal irritation; only 15% of patients have positive Kernig and Brudzinski signs [17]. In a series of 90 patients with solid tumor leptomeningeal metastases, the overall prevalence of cerebral and spinal symptoms and signs was higher than that of cranial neuropathies. The cranial neuropathies observed included ophthalmoplegia (30% of patients, with abducens more common than oculomotor and oculomotor more common than trochlear palsies), facial weakness (27%), hearing loss (13%), optic neuropathy (8%), trigeminal neuropathy (8%), and diminished gag reflex (5%) [5, 17, 18]. Hence, there should be a high index of suspicion of LMD in cancer patients who present with new onset of neurologic symptoms, including cerebral, spinal, and cranial neuropathies.

LMD generally presents late in the disease course in patients with solid tumor metastases; up to 90% of patients with LMD have advanced disease burden at diagnosis [10]. Approximately two-thirds of these patients have multifocal symptoms at presentation. Patients with LMD who present with unifocal and/or nonlocalizing symptoms or signs represent a diagnostic challenge and often experience delays in diagnosis [15, 18].

32.3.2 LMD due to Hematogenous Tumors

With the notable exception of primary central nervous system (CNS) lymphoma, the leukemias and lymphomas reach the leptomeninges almost exclusively by hematogenous spread. As opposed to LMD due to solid tumors, LMD due to hematogenous cancers is often identified during periods of remission or systemic disease inactivity and typically presents with a higher frequency of cranial nerve signs [10, 12, 15, 19–23].

In a series of 37 patients with chronic lymphocytic leukemia and leptomeningeal involvement compiled from cases reported over the past three decades, the most frequent presenting signs were cranial nerve abnormalities (54% of patients),