Leptomeningeal Metastases

Updated: Oct 27, 2021
  • Author: Herbert H Engelhard, III, MD, PhD, FACS, FAANS; Chief Editor: Stephen A Berman, MD, PhD, MBA  more...
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Practice Essentials

The occurrence of leptomeningeal metastases (LM) is a rare complication of cancer in which the disease spreads to the membranes (meninges) surrounding the brain and/or spinal cord. LM occurs in approximately 5–8% of people with solid tumors and is usually terminal. If left untreated, median survival is 4–6 weeks. [1]  If treated, median survival is 2–4 months. [2, 3] However, some new opportunities for therapies and for predicting therapeutic response have recently become available. [3, 4]

LM can be divided into three different categories based on the origin of the primary tumor: 1) carcinoma or solid tumor, 2) hematological malignancy, such as leukemia or lymphoma, and 3) primary CNS tumors, notably medulloblastoma. [5, 6] LM has sometimes been termed "carcinomatous meningitis" or "neoplastic meningitis."

Signs and symptoms

Pain and seizures are the most common presenting complaints of patients with LM, although neurolgic deficits may already be present. Meningeal symptoms are the first manifestations in some patients. Symptoms may include:

  • Headaches (which may be associated with nausea, vomiting, light-headedness)

  • Gait difficulties from weakness or ataxia

  • Memory problems

  • Incontinence

  • Sensory abnormalities

CNS symptoms can be divided into four anatomic categories:

  • Cerebral involvement: Headache, lethargy, seizure, papilledema, behavioral changes, and gait disturbance. These may be the result of hydrocephalus and increased intracranial pressure from obstruction of CSF drainage.

  • Cranial nerve involvement: Impaired vision, diplopia, hearing loss, sensory deficits, and/or vertigo. Cranial nerve palsies commonly involve CN III, IV, VI, VII, and/or VIII.

  • Spinal root involvement: Nuchal rigidity; neck and/or back pain; radiculopathy.

  • Spinal cord compression: Weakness, numbness, gait disturbance, incontinence.

Symptoms of LM may be seen concurrently with symptoms from other manifestations of cancer that has spread to the CNS, such as solid tissue metastases and epidural spinal cord compression. Generalized symptoms from LC (such as an alteration in mental status) may be caused by a secondary event, such as hydrocephalus resulting from the obstruction of CSF drainage.


Diagnosis of LM is made with positive CSF cytologic results, subarachnoid metastases identified on radiologic studies, or a history and physical examination highly suggestive of LM along with abnormal CSF findings (e.g. elevated protein).

Lumbar puncture

  • The standard diagnostic procedure.

  • Positive CSF cytology is found on initial lumbar puncture in 50–70% of cases.

  • Increased CSF pressure and elevated CSF protein are also commonly found.

Imaging studies - Brain and entire spinal canal

  • Gadolinium-enhanced multiplanar MRI is the preferred imaging modality over CT because of its sensitivity and specificity.

  • MRI findings considered diagnostic of LC include leptomeningeal enhancement of the brain, spinal cord, cauda equina, or subependymal areas, which extend into the sulci of the cerebrum or folia of the cerebellum.

  • MRI of the spinal cord can show nerve-root thickening, cord enlargement, intraparenchymal and subarachnoid nodules, or epidural compression.

  • The differential diagnosis for leptomeningeal enhancement on MRI is broad and can include infectious, autoimmune, inflammatory and traumatic etiologies, sometimes confounding the diagnosis of LM. [7]


Currently, the condition of leptomeningeal metastases is not curable and is difficult to treat. Treatment goals include improvement or stabilization of the patient's neurologic status, prolongation of survival, and palliation. Most patients are offered a combination of surgery, radiation, and/or chemotherapy.

The standard therapies are: (1) radiation therapy to symptomatic sites and regions where imaging has demonstrated bulk disease, and (2) intrathecal chemotherapy. Systemic chemotherapy to further treat the underlying cancer may also be used.

Radiation may palliate local symptoms, relieve CSF flow obstruction, and treat areas such as nerve-root sleeves, Virchow-Robin spaces, and the interior of bulky lesions that chemotherapy does not reach.

Intrathecal chemotherapy treats subclinical leptomeningeal deposits and tumor cells floating in the CSF, helping to prevent further seeding. [8] Cytarabine (Ara-C), methotrexate (MTX), and thiotepa are 3 agents that have often been administered for LM.

Supportive care for patients includes analgesia with opioids, anticonvulsants for seizures, antidepressants, and anxiolytics. Attention problems and somnolence from whole-brain radiation can be treated with psychostimulants or modafinil.



Leptomeningeal metastases (LM) is a devastating complication of cancer that carries substantial rates of morbidity and mortality. It may occur at any stage in the neoplastic disease, either as the presenting sign or as a late complication, though it is associated frequently with relapse of cancer elsewhere in the body.

In this disease, neoplastic cells invade (and subsequently  proliferate in) the subarachnoid spaces of the central nervous system (CNS). Infiltration of the meningeal space may occur from "drop" metastases that have spread from a more cephalad location, hematogenous seeding, or local perineural invasion. Perineural invasion is not infrequently seen in the context of gastric cancer or head and neck cancers.

The leptomeninges consist of the arachnoid and the pia mater; the space between the 2 contains the CSF. [9] When tumor cells enter the CSF (either by direct extension, as in primary brain tumors, or by hematogenous dissemination, as in leukemia), they are transported throughout the nervous system by CSF flow, causing either multifocal or diffuse infiltration of the leptomeninges in a sheetlike fashion along the surface of the brain and spinal cord. This multifocal seeding of the leptomeninges by malignant cells is called leptomeningeal carcinomatosis if the primary is a solid tumor, and lymphomatous meningitis or leukemic meningitis if the primary is not a solid tumor. "Meningitis" is somewhat of a misnomer, as meningitis implies an inflammatory response that may or may not be present.

First recognized by Eberth in 1870, LM remains underdiagnosed even today. Nevertheless, it has been recognized more frequently in the last 3 decades than before because of improved diagnostic tools (such as MRI), the availability of therapy, and awareness. It is not a single entity pathologically; it can occur concurrently with CNS invasion or wide dissemination in the intraventricular spaces, or in association with CNS metastases, with the clinical picture differing somewhat in each case.



The anatomy and physiology of the cerebrospinal fluid and leptomeninges have been described. [9]

Metastatic seeding of the leptomeninges may be explained by 6 postulated mechanisms: (1) hematogenous spread to choroid plexus and then to leptomeninges, (2) primary hematogenous metastases through the leptomeningeal vessels, (3) metastasis via the Batson venous plexus, (4) retrograde dissemination along perineural lymphatics and sheaths, (5) centripetal extension along perivascular and perineural lymphatics from axial lymphatic nodes and vessels through the intervertebral and possibly from the cranial foramina to the leptomeninges, and (6) direct extension from contiguous tumor deposits. CSF flow then seeds the tumor cells widely, with infiltration greatest at the basilar cisterns and dorsal surface of the spinal cord, particularly the cauda equina. [1, 3]

Leptomeningeal tumor seeding is often seen concurrently with parenchymal and dural disease. [3]

Signs and symptoms are usually attributable to obstruction of CSF flow by tumor adhesions that leads to one of the following:

  • Increased intracranial pressure (ICP) or hydrocephalus

  • Local tumor infiltration in the brain or spinal cord that causes cranial-nerve palsies or radiculopathies

  • Alterations in the metabolism of nervous tissue that cause seizures, encephalopathy, or focal deficits

  • Occlusion of blood vessels as they cross the subarachnoid, leading to infarcts




Approximately 1–8% of patients with cancer are diagnosed with leptomeningeal metastases (LM), and it is present in 19% of those with cancer and neurologic signs and symptoms on autopsy, usually in those with disseminated systemic disease. LM is present in 1–5% of patients with solid tumors, 5–15% of patients with leukemia, and 1–2% of patients with primary brain tumors. LM can be the presenting symptom 5–10% of the time; however, the exact incidence is difficult to determine. Gross inspection at autopsy may miss LM, and microscopic pathologic examination findings may be normal if the seeding is multifocal or if an unaffected area of the CNS is examined.

Adenocarcinomas are the most common tumors to metastasize to the leptomeninges, although any systemic cancer may do so. Small-cell lung cancers spread to the leptomeninges in 9–25% of cases; melanomas, in 23%; and breast cancers, in 5%. However, because of the different relative frequencies of these cancers, most patients with LM have breast cancer. [10]  Lung cancer is the second most common tumor associated with LM.

Uncommon neoplasms, such as embryonal rhabdomyosarcoma and retinoblastoma, also tend to spread to the leptomeninges, but sarcomas rarely do. Squamous cell carcinomas of head and neck can spread to the meninges along cranial nerve pathways. LM is uncommon in children, but notoriously occurs in medulloblastoma. [4, 6]

The incidence of LM increases the longer a patient has the primary cancer. LM is accompanied by other intracranial metastases in 98% of patients with a nonleukemic primary cancer. [11]  LM is becoming more common, with increasing survival from systemic cancers. [2]

The CNS may be a repository for certain cancer subtypes. For example, anaplastic lymphoma kinase (ALK) gene rearrangements represent a NSLC subtype responsive to crizotinib, but the brain is a frequent site of relapse in patients treated with this agent. [12]


The reported median survival is 7 months for patients with LM from breast cancers, 4 months for patients with LM from small-cell lung carcinomas, and 3.6 months for patients with LM from melanomas. However, with new chemotherapeutic regimens longer survival rates have been reported.

Without therapy, most patients survive 4–6 weeks, with death occurring because of progressive neurologic dysfunction.

With therapy, most patients die from the systemic complications of their cancer rather than the neurologic complications of LM.

Fixed focal neurologic deficits (eg, cranial-nerve palsies) generally do not improve, but encephalopathies can improve dramatically with treatment.

Race-, gender-, and age-related demographics

While the underlying cancers may display varying demographics, there is no evidence that LM itself is differentially affected by race or gender.

The incidence of most forms of cancer (that may lead to LM) increases with age. An exception to this may be medulloblastoma, which predominantly affects children and young adults.



The prognosis for patients with leptomeningeal metastases (LM) is generally poor but depends on the type of cancer and extent of disease (both inside and outside the CNS) at the time of diagnosis. [12] If left untreated, median survival is about 4–6 weeks. [1] If treated, median survival is 2–4 months. [2, 3]  Research is important for improving outcomes with this disease, and some new opportunities for therapies and for predicting therapeutic response have recently become available. [3, 4]

A small case series has suggested prolonged survival with newer chemotherapeutic regimens for diseases such as breast and lung cancers. The most notable exception is leukemic or lymphomatous meningitis, which is sensitive to both MTX and Ara-C and often can be eradicated completely from the CNS. Poor prognostic indicators include the following:

  • Poor (Karnofsky) performance status

  • Multiple, serious neurologic deficits

  • Extensive systemic disease with few treatment options

  • Coexistent carcinomatous encephalopathy

  • CSF flow abnormalities on radionuclide ventriculography

  • Bulky CNS disease

Among patients with LM from solid tumors, the best response to chemotherapy and radiation occurs in those with LM from breast cancer, with 60% improving or stabilizing and a median survival of 7 months; 15% survive for a year, a survival rate rare in patients with LM with a primary tumor other than breast.

Only 40% of LM from small-cell lung carcinoma improve or stabilize, and patients with this disease have a median survival of only 4 months.

Melanoma-derived LM carries a 3.6-month median survival, and only 20% of these patients stabilize or improve with treatment.

Nonresponders to chemotherapy seldom survive longer than a month. This prognosis has not improved measurably in the last 20 years despite an increase in incidence and diagnosis.

The most useful prognostic indicator is the Karnofsky scale (KS) score. Patients with a KS score of 70 or higher survive for a mean of 313 days, whereas those with a score of 60 or lower survive for a mean of only 36 days.

Tumor response 2 weeks after the initiation of treatment is a good portent.

Progressive multilevel involvement or rapid progression in 1 or more CNS lesions is ominous.

In a single-center study of 135 patients older than 50 years assessed between 1989 and 2005, with Karnofsky performance status ≤ 70%, and an interval between diagnosis of primary tumor and LM ≤ 12 months, presence of either lung cancer or malignant melanoma were negative prognostic factors. Only treatment with systemic chemotherapy was associated with longer survival consistent with the principle that better outcomes are reached with systemic disease. [13]


Patient Education

As always, education of the patient and their family is of the highest importance so that they may make informed choices about treatment, including end-of-life financial and visitaton decisions and palliative care. Such education encompasses the nature of the disease process, potential complications, and various treatments, such as chemotherapy, radiation therapy, intrathecal drug administration, and procedures such as LP, Ommaya Reservoir placement, and ventriculoperitoneal shunt placement for hydrocephalus.