Leptomeningeal Metastases

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


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.




Meningeal symptoms are the first manifestations of leptomeningeal metastases (LM) in some patients; however, by the time LM is detected, most patients already have widespread and progressive cancer.

A high index of suspicion is necessary, and involvement of multiple anatomic sites in the CNS should raise the suspicion for LM, although multiple metastases are statitically more likely with that presentation.

The symptoms are protean and can include the following:

  • Headaches (usually associated with nausea, vomiting, lightheadedness)

  • Memory problems, confusion (dementia)

  • Double vision, facial numbness and/or facial weakness (cranial neuropathies)

  • Gait difficulties from weakness or ataxia

  • Neck, back, or radicular pain

  • Incontinence

  • Sensory abnormalities

Pain and seizures are the most common presenting complaints.

Physical Examination

Signs of leptomeningeal metastases (LM) generally exceed patient-reported symptoms.

Involvement of the CNS is divided into the following 3 broad anatomical groups:

  • Cerebral involvement results in headache, lethargy, papilledema, behavior changes, and gait disturbance (the latter can be due to either cerebellar or cauda equina involvement). Major dysfunction, such as hemiparesis and hemisensory loss or visual field defects, is rare and more indicative of parenchymal metastasis.

  • Cranial nerve involvement presents with impaired vision, diplopia (most common), hearing loss, and sensory deficits, including vertigo. Palsies of cranial nerves III, V, and VI are most common; palsy of nerve VII is less common. Isolated VII nerve palsies may occur however, and may be hard to differentiate from idiopathic facial nerve (Bell's) palsies.[14]  Solid tumor-derived LM has a greater affinity for the optic and extraocular nerves, while leukemic meningitis preferentially affects the facial nerve. Involvement of multiple cranial nerves is the rule rather than the exception.

  • Spinal root involvement is caused by either meningeal irritation, presenting with nuchal rigidity (15%) and neck and back pain (rare), or invasion of the spinal roots. The latter can cause leg weakness, radiculopathy (usually lumbar, mimicking a herniated disk), reflex asymmetry or loss (most common, noted in 70% of patients), sphincter incontinence (less common), positive Babinski reflexes, paresthesias, and numbness. Asymptomatic bladder enlargement can occur from spinal cord compression. Spinal-root symptoms are usually followed by cranial-nerve symptoms. Nuchal rigidity, positive results on the straight-leg raising test, and decreased rectal tone are rare.

Over the course of the disease, cranial-nerve deficits are the most frequent signs, occurring in 94% of patients. Although these are seldom the presenting complaint (30% of patients), mild cranial-nerve abnormalities are usually present on physical examination; the abnormalities typically include diplopia, dysphagia, dysarthria, and hearing loss. However, most patients do not have isolated cranial-nerve deficits; rather, they have a combination of cranial-nerve, cerebral, and spinal signs.



The most common complication of leptomeningeal metastases (LM) is hydrocephalus, which results when tumor cells occlude the CSF outflow foramina of the fourth ventricle or over the convexities of the brain, decreasing CSF reabsorption.

Hydrocephalus causes ventricular dilatation and increased ICP, occasionally leading to brain herniation and death.

Even in the absence of hydrocephalus, CSF flow abnormalities are present in 70% of patients with LM, and this adversely affects the distribution of intrathecal chemotherapy.

Other complications of the disease

LM may cause seizures or other neurologic dysfunction by invading the parenchyma of the brain or Virchow-Robin spaces or cause areas of ischemia or infarction by interfering with blood supply.

Competition for glucose between malignant cells and neurons can lead to hypofunction in affected areas. For example, in hypothalamic leukemia, weight gain in patients in leukemic remission can signify relapse because hypothalamic hypoglycorrhachia is induced by local competition for glucose by metastatic tumor cells.

LM also causes partial disruption of the blood–brain barrier once the tumor size has increased enough to stimulate growth of its own vasculature.

Treatment-related complications can result from catheter placement, chemotherapy, or radiation.

Catheter placement causes perioperative complications (1% of patients), and after placement, the catheter tip can migrate into the brain tissue, obstruct the shunt, or, more commonly, cause infection (usually Staphylococcus epidermidis, in 5% of patients).

Complications of treatment

MTX administration can cause acute arachnoiditis (nausea, vomiting, mental status changes), seizures, mucositis, or myelosuppression (mitigated with folinic acid coadministration, 10 mg q6h for 24 h).

Meningeal irritation, characterized by headache, fever, stiff neck (sometimes), confusion, and disorientation, often develops several hours following intrathecal MTX administration but is self-limiting and resolves within 24–72 hours. This can be treated on an outpatient basis with antipyretics, antiemetics, and corticosteroids.

Transverse myelitis is a rare idiosyncratic reaction to MTX that begins 30 min to 48 h after intrathecal treatment and presents with paraplegia, leg pains, and development of a sensory level and bladder dysfunction; it should be distinguished from traumatic spinal subdural hematoma. Again, no specific treatment is available but some improvement can occur over days to months.

Leukoencephalopathy is the most serious complication; it appears a year after treatment and is more likely in those who have also undergone cranial radiation. It presents as a progressive encephalopathy, often with ataxia, dysarthria, and focal findings.

Cytarabine, like MTX, also may cause meningism, headache, and fever.

Thiotepa causes less neurologic toxicity than MTX; the most common effect is transient limb paresthesias. Unlike MTX, there is no way of mitigating the resultant myelosuppression.

Radiation can cause myelosuppression and increase the neurotoxicity of intrathecal chemotherapy. Necrotizing leukoencephalopathy is most common after a combination of MTX and cranial irradiation. Initial findings are changes in the white matter on neuroimaging after 6 months of therapy; progressive dementia and other neurologic complications develop later. Other complications are delayed cerebral radiation necrosis, acute transverse myelopathy, chronic progressive myelopathy, and acute brachial plexus lesions.

The syndrome of inappropriate diuretic hormone secretion (SIADH) may occur with LM.[3]



Diagnostic Considerations

New signs or symptoms (particularly when multifocal) may represent progression of leptomeningeal metastases (LM) but may need to be distinguished from parenchymal disease (primarily brain) and or epidural metastases. Of patients with LM, 30–40% will also have brain metastases.

LM may also coexist with paraneoplastic syndromes or the adverse effects of chemotherapy or radiation. Signs of meningeal irritation may also be caused by infection. LM can be difficult to distinguish from subacute or chronic meningoencephalitis caused by tuberculosis or fungus. In these diseases, CSF findings may also show moderate mononuclear pleocytosis, elevated protein and decreased glucose (as described below). However, patients with LM usually are afebrile, and their neurologic symptoms appear earlier in the disease course with a preserved level of consciousness, rather than later with depressed mental status as in tubercular or fungal meningoencephalitis.

Intradural extramedullary spinal metastases (IESM) may be a separate phenomenon from LM. Proposed diagnostic criteria for IESM include: solid tumors located within the intradural extramedullary space, the absence of other leptomeningeal lesions seen on full-spine injected magnetic resonance imaging, and the absence of malignant cells in CSF. According to one study, the median overall survival was significantly higher for IESM patients (732 days) than for patients with LM (53 days).[15]

Differential Diagnoses



Approach Considerations

In a patient with known cancer (especially with a lung, breast, lymphoma, or melanoma primary), the index of suspicion for leptomeningeal metastases (LM) should be high. CNS symptoms or signs usually trigger diagnostic imaging, typically by MRI with and without gadolinium contrast, which may include the brain and/or entire spine depending on the individual patient. Cytological evaluation of the CSF is still the "gold" standard for diagnosing LM, and also helps assess treatment response.[16]

CSF cytology, when positive for malignant cells, is definitive for disease confirmation. However, false negatives are common and can occur in up to 50% of a single CSF analysis even with a large sample volume (> 10 ml).[17]

Laboratory Studies

Diagnosis of leptomeningeal metastases (LM) is typically made with positive CSF cytologic results (the most useful test), subarachnoid metastases identified on MRI, or a history and physical examination suggestive of LM along with abnormal CSF findings (typically mild pleocytosis, elevated protein and decreased glucose).[3]

Evaluation for LM is considered for patients presenting with:

  • Neurologic signs and symptoms at more than 1 level of the neuraxis (present in 75% of patients with LM).

  • Neurologic signs and symptoms consistent with a single lesion but with no mass evident on imaging.

  • Neurologic signs and symptoms consistent with inflammatory meningitis but without fever.

  • Imaging showing leptomeningeal enhancement or CSF flow obstruction.

  • Elevated CSF protein level in a patient with cancer but without known cerebral metastases.

The first step in the diagnostic workup should be gadolinium-enhanced MRI of the area of maximal symptomatology, followed by a lumbar puncture (LP) if the patient has no evidence of increased ICP, repeated as many as 3 times or until findings are positive.

Imaging Studies

In general, imaging findings are consistent with or suggestive rather than diagnostic of leptomeningeal metastases (LM). They are also useful in detecting secondary complications of LM, such as hydrocephalus, periventricular edema, gyral effacement, and spinal cord compression.

About 50% of patients with LM have abnormal imaging findings, most commonly contrast enhancement of the basilar cisterns, cortical convexities, Sylvian fissure, tentorium, ventricles, or cauda equina, or preence of hydrocephalus even without a discrete obstructive lesion. Identification of enhancing lesions usually follows positive cytologic findings, by up to 6 months.

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


Gadolinium-enhanced MRI of the entire CNS is used in patients with cancer and neurologic symptoms to look for metastases and to determine the risk of possibly catastrophic brain herniation from LP. 

MRI (1.5T) has been reported to be similar in sensitivity to CSF cytology in the diagnosis of LM for patients with solid tumors but less sensitive than CSF cytology for patients with LM from leukemia or lymphoma.[18]  Normal MR imaging does not exclude the diagnosis of LM.

Meningeal enhancement can also be seen in infections, inflammatory diseases, trauma, or subdural hematoma; after craniotomy; and sometimes after LP.

Delineation of the extent of enhancement on MRI may be used to discriminate LM (in addition to cytology) from metastases and/or epidural compression, and might therefore be used to inform decisions regarding radiation therapy and/or radiosurgery.

CT scan

Brain CT with and without contrast may also be useful to look for metastases, hemorrhage and hydrocephalus, and to determine the risk of herniation from LP. While enhancement of structures may sometimes be seen, this test is even less sensitive (than MRI) for detecting LM itself. As with MRI, normal CT imaging does not exclude the diagnosis of LM.


Although seldom indicated, myelography may show nodularities or thickening of the nerve roots in approximately 25% of patients with LM. Myelography can show intra-arachnoid nodular filling defects, longitudinal striations, prominent and crowded nerve roots of the cauda equina, or scalloping of the subarachnoid space.

CSF flow studies

Radionuclide studies using either111 indium-diethylenetriamine penta-acetic acid or99 Tc macroaggregated albumin can be used to assess CSF flow, which is abnormal in 30–40% of patients with LM. Abnormal CSF flow must be addressed prior to the administration of intrathecal chemotherapy, as it can prevent delivery throughout the CSF space.

Other Tests

Cerebral arteriography, MRA, EEG, and electromyography (EMG) are rarely indicated for leptomeningeal metastases (LM) itself but may be needed according to individual patient circumstances.

Monoclonal antibodies can be useful in diagnosing CSF lymphoma, particularly if cytologic examination cannot distinguish between reactive lymphocytes and malignant lymphocytes.

Hormonal status is an important prognostic factor in patients with breast cancer-related LM. Patients with positive hormone receptor status have been shown to have a longer time from diagnosis to development of LM and a greater chance of survival.


Lumbar puncture and CSF cytology

If safe to perform, lumbar puncture is the most useful test.

Analysis of CSF obtained by lumbar spinal puncture is more accurate than that obtained by using a ventricular catheter, as ventricular fluid usually has higher glucose and lower protein levels and is less likely to yield positive cytologic findings. For this reason, periodic LP is recommended, even in patients with catheters.

Measure the opening pressure (elevated in 50% of patients) and send the CSF for an analysis of cytology, flow cytometry, cell counts, and protein and glucose levels.

Carcinoma cells in the CSF are diagnostic, with the exception of a few false-positive results in patients who have reactive lymphocytes (which are difficult to distinguish from malignant lymphomatous cells) because of an infectious or inflammatory process in the CSF. However, negative cytologic findings do not rule out the diagnosis, as 50% of patients with LC have a negative cytologic result on the first LP. This percentage drops to 20% after 2 high-volume LPs and 15% after 3.

Cytologic findings are more likely to be positive in patients with extensive leptomeningeal involvement than in patients with focal involvement because CSF obtained from a site distant to the pathology is more likely to yield negative pathology.

Other causes of false negatives can include not obtaining CSF from a site of symptomatic or radiographically demonstrated disease, withdrawing < 10.5 mL CSF, delayed processing of samples, and obtaining only 1 sample.

CSF pleocytosis and modest protein elevations are consistent with but not indicative of the diagnosis, but reduced glucose levels usually are seen only with LM (ie, abnormal glucose transport) or infection (ie, increased glucose utilization).

The lymphocyte count is elevated in more than 50% of patients with LC, and the presence of eosinophils should raise the suspicion of lymphomatous infiltration (except patients who are given ibuprofen).

CSF samples in LM patients with solid tumors have a greater number of inflammatory cells and a different leukocyte distribution than CSF samples from patients with lymphomatous LM. CSF polymorphic neutrophils (PMN) are more likely to be present in patients with LC than in patients with LM or patients with brain metastases due to solid tumors without LM.[19]

Flow cytometry immunophenotyping (FCI) may be helpful in identifying epithelial cell cancers. Compared with routine cytology, FCI had greater sensitivity (79.79% vs. 50%) and negative predictive value with lower specificity (84% vs. 100%) and positive predictive value. Patients with 8% or more epithelial cell adhesion molecule positive cells had statistically worse survival.[20]

Xanthochromia can occur from leptomeningeal bleeding, which is most likely in LM from a melanoma.

Biochemical markers in the CSF

Most biochemical markers in CSF have poor sensitivity and specificity, but when present, levels decline with successful therapy. Their reelevation can thus signal a relapse before any other findings become apparent. Useful markers include carcinoembryonic antigen (CEA) from adenocarcinomas, alpha-fetoprotein and beta-human chorionic gonadotropin from testicular cancers, 5-hydroxyindoleacetic acid (5-HIAA) from carcinoid tumors, and immunoglobulins from multiple myeloma; their presence in CSF is virtually diagnostic. Nonspecific markers such as endothelial growth factor can be strong indirect indicators of LM, but none are sensitive enough to improve the cytological diagnosis.

Epithelial-associated glycoprotein (HMFGI antigen) has been reported to be present in 90% of LM patients.

Cytokeratins measured by tissue polypeptide antigen (TPA) and tissue polypeptide-specific antigen (TPS) have 80% sensitivity to LM from breast cancer.

Neither CEA nor beta-glucuronidase is helpful in detecting solid tumors or metastases, nor are they useful in detecting leptomeningeal lymphomatosis. However, if their levels are elevated, a return to normal levels of both markers signifies successful treatment.

Elevated CSF CEA is specific, unless serum levels are unusually high (ie, >100 ng/mL). The combination of CEA with a second tumor marker CYFRA 21-1 in lung cancer patients increased specficities to 100%, and elevations of either CEA or CYFRA 21-1 were associated with a 100% sensitivity.[21]

CSF beta-glucuronidase values are frequently elevated, but wide fluctuations make it unreliable as a marker, and elevations also occur with bacterial, viral, fungal, or tubercular meningitis. In association with elevated lactate dehydrogenase (LDH), however, high CSF beta-glucuronidase levels can indicate LM from a breast primary tumor with a high sensitivity and specificity.

CSF fibronectin values are elevated in LM but also in bacterial meningitis and tick-borne encephalitis.

Myelin basic protein can indicate disease activity, particularly if values are measured longitudinally.

CSF vascular growth factor has recently been suggested as a useful biomarker.[22]

Antithrombin III has been suggested as a useful biomarker in patients with primary CNS lymphoma but has not been evaluated in patients with LM.

For lymphoma and leukemia, the weight of the evidence (as well as recent National Comprehensive Cancer Network guidelines) suggests that flow cytometry is more sensitive than cytology and should be used instead.[5, 23]

Monoclonal antibodies are not more sensitive than cytology but can be used to distinguish between reactive and neoplastic lymphocytes in the case of LM from lymphoma.

Creatine-kinase BB isoenzyme (CK-BB), tissue polypeptide antigen (TPA), b2- microglobulin, β -glucuronidase, LDH isoenzyme-5, and vascular endothelial growth factor (VEGF) are strong indirect indicators of LM, but are not sensitive enough to improve on cytology.

LDH concentrations are elevated in cases of stroke, bacterial meningitis, CSF pleocytosis, head injury, primary CNS tumors, and some metastases. Levels are also elevated in 80% of patients; therefore, they can be useful in confirming the diagnosis. LDH isoenzyme-5 levels are elevated in LM from breast or lung primary tumors and melanoma, as well as bacterial meningitis, but they are sometimes normal even when cytologic findings are positive

Levels of CSF β 2 -microglobulin may be useful in detecting LM caused by hematologic spread but not in LM from solid tumors. levels may be elevated after treatment with intrathecal methotrexate (MTX).

Ferritin levels are sensitive to inflammatory changes in the CSF, but they are nonspecific for early LM.

CSF alkaline phosphatase levels may be elevated in an LM from a lung primary tumor.

CSF prostate-specific antigen (PSA) may be elevated in an LM from a prostate primary tumor.

PCR is not useful as the precise genetic alteration of the neoplasia is usually not known.

An NMR metabolomics approach to LM diagnosis has been proposed. In a pilot study, a combination of specific CSF biometabolites was associated with a higher likelihood of LM.

Histologic Findings

Leptomeningeal biopsy may be necessary if the patient has no evidence of a primary tumor. The findings can be diagnostic if results of all other tests are negative, especially if taken from an enhancing region identified on MRI. Macroscopic pathology shows diffuse fibrotic thickening of the brain and spinal cord, as well as layering of the nerve roots with tumor tissue. Microscopic examination shows local fibrosis with tumor cells covering the blood vessels and nerve roots, either as a single layer or as aggregates.


Staging varies by primary cancer, but LM represents metastatic disease that, by definition, is a stage IV malignancy.



Approach Considerations

Treatment of leptomeningeal metastases (LM) is individualized based on factors including histology, prognosis, presence of bulky CNS disease, and the state of systemic disease.[16]  Treatment modalities may include systemic chemotherapy, radiation therapy, use of targeted agents, intrathecal therapy, and immunotherapy.

Treatment goals for patients with LM include improvement or stabilization of the patient's neurologic status, prolongation of survival, and palliation. Maintaining quality of life (QOL) is a major consideration (as well as a distinct challenge) for patients with this disease. Decisions are made on a case-by-case basis. Some clinicians are hesitant to treat LM, given the previously reported short duration of survival and risk of neurotoxicity. In some cases, a high index of suspicion (ie, early diagnosis) and prompt treatment can prevent or delay neurologic damage and act to prolong QOL. Given the lack of large randomized controlled trials, the choices for treatment are usually options rather than according to established guidelines. Multimodality treatment is often pursued.

Assessing the response to treatment in LM is difficult for a variety of reasons, and therefore utilizes three elements: standardized neurologic examination, CSF cytology or flow cytometry, and radiographic evaluation. Progressive disease is defined by worsening neurologic examination as a result of LM or worsening neuroradiographic assessment.[24]

Medical Care

The intensity of treatment for leptomeningeal metastases (LM) is based on the presence of a systemic cancer that is responsive to treatment and preexisting neurologic damage and relatively preserved functionality.

Treat the systemic cancer, as the patient is likely to die from systemic disease.

For patients with lung cancer, systemic therapy with modern chemotherapeutic agents prolongs survival. In a study from Stanford University, a systemic regimen containing pemetrexed, bevacizumab, or a tyrosine kinase inhibitor was associated with mean survival of six months and a statistically significant decreased hazard of death (hazard ratio [HR], 0.24; P = .007).[25]

Treat the entire neuraxis, as tumor cells are disseminated widely by CSF flow. The standard therapies are (1) radiation therapy to symptomatic sites and regions where imaging has demonstrated bulk disease and (2) intrathecal chemotherapy.

Radiation palliates local symptoms, relieves CSF flow obstruction, and treats areas such as nerve-root sleeves, Virchow-Robin spaces, and the interior of bulky lesions that chemotherapy does not reach. Even without evidence of bulky disease, patients may benefit from radiation. Radiation therapy typically consists of 2400 rads given in 8 doses over 10–14 days. Radiation is directed to the site of major clinical involvement and planned so that myelosuppression is acceptable and does not compromise efforts to eliminate malignant cells from the CSF. Dosages can range from 20 Gy in 1 week to 30 Gy over 3–4 weeks. The dosage for lymphomatous and leukemic meningitis is usually 30 Gy given over 10 doses.

Intrathecal chemotherapy treats subclinical leptomeningeal deposits and tumor cells floating in the CSF, preventing further seeding.[8]

Three agents are routinely given; methotrexate (MTX), cytarabine (Ara-C), and thiotepa.

Cytararabine is the first-choice agent (in its liposomal form only); it is not effective for solid tumors but is useful in leukemic and lymphomatous meningitis. It has been available in liposome-encapsulated form (DepoCyt) that can be administered every 2 weeks rather than 2–3 times a week and results in a longer time to disease progression and higher quality of life than therapy with MTX.

Thiotepa, the second-line agent after MTX and cytarabine, is cleared from CSF within minutes and has survival curves similar to those of MTX with less neurologic toxicity than MTX.

The superiority of combination intrathecal therapies over single agents is controversial. Six randomized trials have shown no difference between single-agent methotrexate and combined therapy, and combination treatments may be more neurotoxic than single agents.

For patients who respond well to treatment, start treatment with radiation to bulky tumors and symptomatic sites, and place a ventricular catheter if possible. Scan CSF flow, and follow this with intrathecal chemotherapy if CSF flow is not obstructed. Also, optimally manage any systemic cancers.

Additional chemotherapeutic regimens have been associated with prolonged survival in systemic cancers and are discussed below.

For patients with a fair response to treatment, local radiation therapy and intrathecal chemotherapy delivered by means of LP may be appropriate.

For patients who are classified as poor risk, offer radiation therapy to symptomatic sites or supportive measures only (eg, analgesics, anticonvulsants, and steroids). Treatment is difficult and primarily palliative, and results are generally poor because of the presence of many metastases.

Therapies in development

A number of other therapies are under development or experimental.

  • Mafosfamide is a form of cyclophosphamide that is active intrathecally and has little neurotoxicity aside from headaches, but only phase II trials have been conducted.

  • Trastuzumab has been given intrathecally to treat LM from breast cancer.[26, 27, 28, 29]

  • Diaziquone is effective in hematologic tumors. Adverse effects include headaches and immunosuppression. It can be given at a dosage of 2 mg twice weekly.

  • Temozolomide, in combination with Ara-C, has completed Phase I/II trials.

  • Another drug, 4-hydroperoxycyclophosphamide (4-HC) is in phase I trials and is apparently effective in treating medulloblastoma.

  • Topotecan, a topoisomerase I inhibitor, has completed phase II trials.

  • A drug available for high-dose systemic administration, 6-mercaptopurine (6-MP), has shown efficacy in some patients.

  • There are case reports of LM from non-small cell lung cancer (NSCLC) or breast cancer responding to intrathecal gemcitabine, trastuzumab, letrozole, and tamoxifen.

  • Epidermal growth factor receptor inhibitors (EGRG) as monotherapy or in combnation may be beneficial in treatment of LM due to non-small cell lung cancer. Example of these agents include afatinib, cetuximab, erlotinib, afatinib, pemetrexed, bevacizumab,  and orbevacizumab.

  • Bevacizumab has also demonstrated activity in CNS choroidal metastases and is used to treat radiation necrosis of the brain and glioblastoma multiforme.

  • Tyrosine kinase inhibitiors such as crizotinib, erlotinib, or gefitinib may also be helpful in patients with LM in the context of NSLC.

  • The survival benefit for NSLC patients with LM was also greater for patients treated with pemetrexed, an inhibitor of thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are involved in purine and pyrimidine synthesis necessary for formation of new DNA and RNA.

  • One patient with LM from prostate cancer responded to hormonal manipulation.

  • Intrathecal busulfan, currently in phase I trials, may be active against cyclophosphamide-resistant neoplasms and other tumors.

  • Another drug, 3-(4-amino-2-methyl-5-pyrimidinyl) methyl-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU) is modestly effective in animal studies; however, it is neurotoxic and not yet available for use in humans.

  • Immunotoxins, such as monoclonal antibodies coupled with a protein toxin or radioisotope, seem effective and are being studied.

  • Gene therapy based on the herpes simplex virus thymidine kinase gene combined with ganciclovir is under study but not yet available.

Supportive care: Offer analgesia with opioids, anticonvulsants for seizures, antidepressants, and anxiolytics to all patients as needed. Treat attention problems and somnolence from whole-brain radiation with psychostimulants or modafinil.

Surgical Care

Placement of an intraventricular or subgaleal catheter is necessary for the administration of cytotoxic drugs.

In patients with symptomatic increased intracranial pressure (ICP) (ie, severe intractable headache, papilledema, stupor, and repetitive plateau waves on EEG), placement of a ventriculoperitoneal (VP) shunt may be necessary if the increased ICP is not ameliorated by steroids. This should be done even with the risk of peritoneal seeding as the presence of LC in the context of systemic cancer implies that diffuse spread of the cancer has already occurred. Placment of a VP shunt is typically a palliative procedure however, because the presence of hydrocephalus portends poor survival.

In patients with leptomeningeal metastases (LM) and hydrocephalus, Lin et al found that placement of a combined reservoir-on/off valve-ventriculoperitoneal shunt system was safe, resulted in symptomatic improvement in most patients, and could effectively administer intrathecal chemotherapy.[30]

Administer intrathecal chemotherapy by means of LP rather than an Ommaya device if a shunt is present to ensure that the medication reaches the basal cisterns and spinal leptomeninges.

Intrathecal (IT) administrations may be preferable to lumbar puncture (LP) for short half-life drugs such as methotrexate; for drugs with longer half-lives, route of administration (IT or LP) may be less critical.[31]

Resect parenchymal brain metastases, if present.

Outpatient Care

As has been pointed out, management goals for patients with leptomeningeal metastases (LM) include improving or stabilizing neurologic function, prolonging survival, and preserving quality of life whenever possible.[16]  Hospice care is often eventually required, either as an outpatient or on an inpatient basis.

Once intrathecal chemotherapy has been initiated, CSF cytology is typically checked every 4 weeks (ie, with each additional intrathecal dose).[32, 2]

If CSF cytology result is negative, chemotherapy is continued at the same rate of twice a week for 2 more weeks, then decreased to twice a week for 1 week per month, followed by further CSF monitoring every two months.

If CSF cytology results remain positive, chemotherapy is continued at the same rate, the chemotherapeutic agent is changed, or the patient is reclassified as having a poor prognosis with the administration of palliative care.

Supportive care also may include anticonvulsants for seizure control, analgesia with opioids, antiemetics, and antidepressants and anxiolytics as needed. Corticosteroids may help vasogenic edema associated with metastases, although they may have limited effect on the neurologic symptoms associated with LM. Psychostimulants may help with inattention and somnolence secondary to whole-brain radiation.


In addition to hematology–oncology care, consultations to radiation therapy, neurology and neurosurgery may be extremely helpful in cases of leptomeningeal metastases (LM).


No special diet has been known to be useful in the treatment of leptomeningeal metastases (LM), but nutritional support is always useful in the treatment of cancer patients.


There are currently no known preventative measures for stopping spread to the leptomeninges, other than preventing or treating the primary cancer. Early treatment of leptomeningeal metastases (LM) would seem to be advantageous.[4]



Guidelines Summary






Medication Summary

Chemotherapy is best administered intrathecally so that chemotherapeutic agents, which are usually hydrophilic, do not encounter the blood–brain barrier and easily reach tumor cells in the CSF or leptomeninges. The preferred route of administration is through an implanted subcutaneous reservoir (eg, Rickham or Ommaya reservoir) and ventricular catheter rather than LP, for 4 reasons. First, intraventricular injection through an Ommaya reservoir is easy and ensures entry into the CSF. Second, when injected into the ventricle, the drug follows normal CSF flow and thus reaches all parts of the CSF space. Third, repetitive LPs are arduous and painful for the patient. Fourth, about 10–15% of LPs do not deliver all of the drug intended to reach the subarachnoid space.

CSF flow abnormalities are common in patients with increased ICP and hydrocephalus, and 70% of patients with leptomeningeal metastases (LM) have ventricular outlet obstructions, abnormal spinal canal flow, or impaired flow over the cortical convexities, but these can be reversed with local radiation therapy. A CSF-flow study is recommended for all patients at the initiation of intrathecal chemotherapy, and such therapy should be deferred if an obstruction is noted. Systemic therapy can be useful if the blood–brain barrier already has been disrupted or if the chemotherapeutic agent is lipid soluble.

Methotrexate (MTX), cytarabine (Ara-C), and thiotepa are administered intrathecally for LM. Additionally, several case reports have shown improved prognosis and decreased progression of LM following intrathecal trastuzumab.[26, 27, 28, 29]

Chemotherapeutic agents

Class Summary

These agents inhibit cell growth and proliferation.

Methotrexate (Folex PFS, Rheumatrex)

Mainstay of treatment. Because meningeal infiltration interferes with drug clearance, CSF concentrations can be unpredictable. Monitor and maintain concentration near 10-6 M, and coadminister with folinic acid and hydrocortisone if necessary.

Cytarabine (Cytosar-U)

Second-line agent used if MTX not tolerated or ineffective. Not effective for solid tumors but useful in leukemic and lymphomatous meningitis. Half-life longer in CSF than serum. Sustained-release form available in United States; extends half-life to >140 h.


Third-line agent that acts as an alkylating agent. Intrathecal administration is an off-label use in the United States. It is cleared from CSF within minutes and has survival curves similar to those of methotrexate (MTX) with less neurologic toxicity (most common being transient limb paresthesias). Unlike MTX, no antidote for resulting myelosuppression is available. Causes cross-linking of DNA strands, inhibition of RNA, DNA, and protein synthesis, and thus cell proliferation.

Trastuzumab (Herceptin)

Off-label intrathecal (IT) administration of trastuzumab has been described in several case reports. Trastuzumab is a monoclonal antibody that inhibits growth of tumor of tumor cells that overexpress HER2. It is an effective systemic treatment of breast cancer, and as such, the potential use of IT administration for LC secondary to breast cancer has shown improved prognosis and decreased progression in several case reports.


Questions & Answers


Which studies are performed in the workup of leptomeningeal carcinomatosis (LC)?

How common is leptomeningeal carcinomatosis (LC)?

What are the signs and symptoms of leptomeningeal carcinomatosis (LC)?

How is leptomeningeal carcinomatosis (LC) treated?

What is leptomeningeal carcinomatosis (LC)?

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Which clinical history findings are characteristic of leptomeningeal carcinomatosis (LC)?

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What are the differential diagnoses for Leptomeningeal Metastases?


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Which chemotherapy agents are used in the treatment of leptomeningeal carcinomatosis (LC)?

What is the treatment for leptomeningeal carcinomatosis (LC) in patients with a fair response to treatment?

What is the treatment for poor-risk patients with leptomeningeal carcinomatosis (LC)?

Which therapies are under investigation for the treatment of leptomeningeal carcinomatosis (LC)?

What is included in supportive care for leptomeningeal carcinomatosis (LC)?

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