Leptomeningeal metastases (LM) represent a severe and often terminal complication of cancer, marked by high morbidity and mortality. It can arise at any point during the cancer course—either as an initial symptom or, more commonly, as a manifestation of disease relapse.
LM involves the spread of cancer cells into the subarachnoid space of the central nervous system (CNS), where they multiply. This invasion can result from several mechanisms: hematogenous spread, direct perineural extension (commonly seen in head and neck or gastric cancers), or “drop metastases” descending from a primary tumor located higher up in the neuraxis.
The leptomeninges, composed of the arachnoid and pia mater, enclose the cerebrospinal fluid (CSF). Tumor cells entering the CSF—via direct invasion (as in brain tumors) or through the bloodstream (as seen in leukemia) are dispersed throughout the CNS by CSF circulation. This results in either widespread or patchy infiltration of the leptomeninges. The condition is referred to as leptomeningeal carcinomatosis when caused by solid tumors and as lymphomatous or leukemic meningitis when hematologic cancers are involved. Despite the term “meningitis,” an inflammatory response is not always present.
Originally described by Eberth in 1870, LM has remained underrecognized but is now diagnosed more frequently due to advancements in imaging (notably MRI), improved treatment options, and greater clinical awareness. It presents in diverse pathological forms—sometimes alongside CNS metastases or intraventricular involvement—leading to varied clinical features depending on the pattern and extent of spread.
Epidemiology
LM is identified in approximately 1% to 8% of individuals with cancer. Among patients who exhibit neurological symptoms, LM is found in nearly 19% of autopsy cases, particularly in those with advanced or widespread disease. The prevalence varies by cancer type: LM affects 1–5% of patients with solid tumors, 5–15% with leukemia, and 1–2% with primary brain tumors. In some cases (5–10%), LM may be the initial sign of malignancy, although its true incidence is likely underreported due to challenges in detecting multifocal spread or sampling unaffected CNS regions during autopsy.
Adenocarcinomas are the leading cause of LM, although any systemic cancer can potentially spread to the leptomeninges. Small-cell lung cancer has a leptomeningeal involvement rate between 9–25%, melanoma around 23%, and breast cancer roughly 5%. Due to the high global incidence of breast cancer, it remains the most common primary source of LM, followed by lung cancer.
Rare malignancies like embryonal rhabdomyosarcoma and retinoblastoma also demonstrate a tendency to involve the leptomeninges, while sarcomas generally do not. In head and neck cancers, particularly squamous cell carcinoma, spread to the meninges may occur along cranial nerves. In pediatric populations, LM is uncommon but is a known complication of medulloblastoma.
The likelihood of LM increases with longer cancer duration, and it is frequently accompanied by other CNS metastases—seen in 98% of non-leukemic patients with LM. As cancer treatments improve and patient survival increases, the incidence of LM appears to be rising. Some tumors, such as ALK-positive non-small cell lung cancers treated with crizotinib, have a propensity to relapse in the central nervous system, making the CNS a potential sanctuary site for specific cancer subtypes.
Anatomy
Pathophysiology
LM develop when cancer cells infiltrate the leptomeninges and cerebrospinal fluid (CSF), leading to widespread dissemination throughout the central nervous system. This spread can occur through several proposed pathways, including hematogenous dissemination to the choroid plexus or directly through leptomeningeal vessels, retrograde flow via the Batson venous plexus, extension along perineural lymphatics, centripetal spread from axial lymph nodes through intervertebral or cranial foramina, or direct invasion from adjacent tumors. Once malignant cells enter the CSF, they are distributed by its flow, with accumulation often seen in regions such as the basilar cisterns, dorsal spinal cord, and cauda equina. LM is often accompanied by parenchymal or dural metastases. The resulting clinical manifestations are primarily due to obstruction of CSF pathways, direct tumor infiltration, metabolic disturbances in neural tissue, or vascular occlusion. These pathological changes can lead to increased intracranial pressure, hydrocephalus, cranial nerve palsies, radiculopathies, seizures, encephalopathy, focal neurological deficits, and, in some cases, infarcts due to compromised blood flow in the subarachnoid space.
Etiology
It is also referred to as carcinomatous meningitis or leptomeningeal disease, arise when malignant cells infiltrate the leptomeninges—the pia mater and arachnoid layers—and spread through the cerebrospinal fluid (CSF). This condition typically occurs as a late manifestation of systemic malignancies, most frequently associated with breast cancer, lung cancer, and melanoma. The spread of tumor cells to the leptomeninges can occur through several pathways. One common route is hematogenous dissemination, where cancer cells travel via the bloodstream and invade the leptomeningeal space. Another mechanism involves direct extension, in which tumors situated near the brain or spinal cord grow into the meningeal layers. Additionally, cancer cells may enter the CSF through shedding from the primary tumor and then disseminate widely throughout the central nervous system via CSF flow. These mechanisms collectively contribute to the development of LM in patients with advanced cancer.
Genetics
Prognostic Factors
The prognosis for LM is generally poor, with survival heavily influenced by the primary cancer type and disease extent within and beyond the CNS. Without treatment, survival is just 4–6 weeks, but therapeutic interventions may extend it to 2–4 months. Leukemic and lymphomatous meningitis respond better to agents like methotrexate and cytarabine, whereas solid tumors show variable outcomes. Among them, breast cancer-associated LM has the best response, with 60% stabilizing or improving and median survival of 7 months; 15% may survive over a year.
In contrast, LM from small-cell lung cancer and melanoma have worse outcomes, with median survival of 4 months and 3.6 months, respectively. Prognosis is poorer in patients with low Karnofsky scores, severe neurologic symptoms, extensive systemic disease, impaired CSF flow, or bulky CNS lesions. A Karnofsky score ≥70 is linked to significantly longer survival (313 days vs. 36 days for scores ≤60). Early treatment response within two weeks suggests a better outcome, while rapid deterioration and extensive CNS involvement predict poor survival. A study of 135 older patients found that poor performance status, early LM onset post-cancer diagnosis, and primary lung cancer or melanoma were associated with shorter survival, while systemic chemotherapy was the key factor improving life expectancy.
Clinical History
Age Group:
Leptomeningeal metastases typically occur in adults with advanced-stage cancer, particularly in middle-aged to older individuals. However, LM can also present in children with specific cancers like medulloblastoma, though this is less common.
Physical Examination
Common findings include cranial nerve deficits—particularly involving cranial nerves III through VIII—manifesting as diplopia, facial weakness, ptosis, ophthalmoplegia, or hearing loss. Cerebellar signs such as ataxia, dysmetria, and nystagmus may be present when the posterior fossa is involved. Motor and sensory abnormalities, including asymmetric or symmetric weakness and dermatomal sensory loss, can occur due to infiltration of spinal roots or the spinal cord.
Patients may exhibit features of radiculopathy or myelopathy, such as back pain, loss of reflexes, or spasticity depending on the level of spinal involvement. Meningeal irritation signs like neck stiffness, Kernig’s sign, and Brudzinski’s sign may be noted but are often subtle or absent. Altered mental status, including confusion or personality changes, can result from cortical irritation or increased intracranial pressure (ICP). Gait disturbances, either due to cerebellar dysfunction or sensory ataxia, are also common. Additionally, signs of raised ICP such as papilledema, headache, vomiting, and sixth nerve palsy may be observed on examination. Overall, the clinical picture is frequently multifocal, making LM a diagnostic challenge that requires a high index of suspicion.
Age group
Associated comorbidity
Most patients diagnosed with LM already have a known history of systemic malignancy—commonly breast cancer, lung cancer, melanoma, or hematologic malignancies like leukemia or lymphoma. LM often occurs during advanced disease stages and is frequently associated with widespread metastatic burden. Comorbid conditions such as neurologic dysfunction, previous CNS involvement, or immunosuppression may increase the risk or worsen clinical presentation.
Associated activity
Acuity of presentation
The onset of LM symptoms can be subacute or gradual but may escalate quickly as the disease progresses. Early signs are often subtle and nonspecific, requiring a high index of suspicion for diagnosis. Pain and seizures are among the most common initial complaints. As the disease evolves, symptoms intensify and diversify depending on CNS regions affected.
Differential Diagnoses
Toxic/metabolic encephalopathy
Brain metastasis
Spinal metastasis
Epidural spinal cord compression
Meningococcal meningitis
Tuberculous meningitis
Paraneoplastic syndromes
Fungal meningitis
Sarcoidosis
Laboratory Studies
Imaging Studies
Procedures
Histologic Findings
Staging
Treatment Paradigm
The management of leptomeningeal metastases (LM) typically follows a phased approach to optimize symptom control and prolong survival. The initial phase involves accurate diagnosis through CSF cytology and MRI, followed by stabilization of acute symptoms, such as elevated intracranial pressure (ICP), which may require corticosteroids or surgical intervention like ventriculoperitoneal (VP) shunting. The treatment phase focuses on delivering intrathecal chemotherapy, either via lumbar puncture or an Ommaya reservoir, alongside focal radiotherapy when indicated. In selected cases, surgical resection of parenchymal brain metastases is also considered. Finally, the maintenance and palliative phase emphasizes symptom management, supportive care, and psychosocial support, recognizing the overall poor prognosis associated with LM.
Radiation therapy: Focal or craniospinal irradiation is used to reduce tumor burden, particularly in symptomatic areas like the spine or brain.
Surgical interventions: Ventriculoperitoneal (VP) shunting can relieve raised intracranial pressure caused by hydrocephalus.
Supportive care: Includes physical therapy, occupational therapy, and psychosocial support to manage neurological deficits and improve functional status.
Palliative care: Focuses on symptom control (e.g., pain, weakness, incontinence) and end-of-life care planning.
Role of Chemotherapeutic agents
Methotrexate: It is the primary drug used for treatment. However, its clearance from the cerebrospinal fluid (CSF) can be unpredictable due to meningeal involvement. To maintain therapeutic levels (around 10⁻⁶ M), monitoring is essential. Folinic acid and hydrocortisone may be co-administered to reduce side effects.
Cytarabine: It serves as a second-line agent when methotrexate is not suitable or fails to work. Although ineffective for solid tumors, it is beneficial in leukemic and lymphomatous meningitis. Its sustained-release formulation extends its CSF half-life significantly.
Thiotepa: It is a third-line alkylating agent, is used intrathecally off-label in the U.S. It clears rapidly from CSF and provides survival outcomes comparable to methotrexate, with fewer neurological side effects. However, it lacks an antidote for the myelosuppression it may cause.
Trastuzumab: It is an anti-HER2 monoclonal antibody, has been administered intrathecally off-label in cases of leptomeningeal disease from HER2-positive breast cancer. Though supported mainly by case reports, it has shown improved prognosis and slowed disease progression in such settings.
Procedural interventions play a critical role in managing leptomeningeal metastases, particularly when symptoms arise from increased intracranial pressure (ICP) or require targeted drug delivery. Intraventricular or subgaleal catheter placement enables effective administration of intrathecal chemotherapy. For patients with elevated ICP unresponsive to corticosteroids, a ventriculoperitoneal (VP) shunt may be required to relieve symptoms, even though it carries a risk of peritoneal seeding. VP shunting remains a palliative option due to the poor prognosis associated with hydrocephalus in LM. Advanced systems combining a reservoir, valve, and shunt can allow for both symptom relief and intrathecal drug delivery. If a VP shunt is present, chemotherapy should be given via lumbar puncture to ensure adequate drug distribution. Intrathecal administration may be preferable to lumbar routes for short-acting drugs like methotrexate, while the route is less critical for longer-acting agents. Additionally, surgical resection of any parenchymal brain metastases may be considered when appropriate.
Management of leptomeningeal metastases (LM) can be approached in three key phases:
Induction phase aims to rapidly reduce tumor burden in the cerebrospinal fluid (CSF) through intensive treatment, typically using intrathecal chemotherapy or systemic agents. Consolidation phase follows, stabilizing the disease with continued but less intensive therapy to maintain control over CSF tumor cells. Maintenance phase focuses on sustaining remission, minimizing recurrence, and managing symptoms with ongoing surveillance and supportive care. This phased approach allows for a structured, goal-oriented strategy tailored to patient response and disease progression.
Leptomeningeal metastases (LM) represent a severe and often terminal complication of cancer, marked by high morbidity and mortality. It can arise at any point during the cancer course—either as an initial symptom or, more commonly, as a manifestation of disease relapse.
LM involves the spread of cancer cells into the subarachnoid space of the central nervous system (CNS), where they multiply. This invasion can result from several mechanisms: hematogenous spread, direct perineural extension (commonly seen in head and neck or gastric cancers), or “drop metastases” descending from a primary tumor located higher up in the neuraxis.
The leptomeninges, composed of the arachnoid and pia mater, enclose the cerebrospinal fluid (CSF). Tumor cells entering the CSF—via direct invasion (as in brain tumors) or through the bloodstream (as seen in leukemia) are dispersed throughout the CNS by CSF circulation. This results in either widespread or patchy infiltration of the leptomeninges. The condition is referred to as leptomeningeal carcinomatosis when caused by solid tumors and as lymphomatous or leukemic meningitis when hematologic cancers are involved. Despite the term “meningitis,” an inflammatory response is not always present.
Originally described by Eberth in 1870, LM has remained underrecognized but is now diagnosed more frequently due to advancements in imaging (notably MRI), improved treatment options, and greater clinical awareness. It presents in diverse pathological forms—sometimes alongside CNS metastases or intraventricular involvement—leading to varied clinical features depending on the pattern and extent of spread.
LM is identified in approximately 1% to 8% of individuals with cancer. Among patients who exhibit neurological symptoms, LM is found in nearly 19% of autopsy cases, particularly in those with advanced or widespread disease. The prevalence varies by cancer type: LM affects 1–5% of patients with solid tumors, 5–15% with leukemia, and 1–2% with primary brain tumors. In some cases (5–10%), LM may be the initial sign of malignancy, although its true incidence is likely underreported due to challenges in detecting multifocal spread or sampling unaffected CNS regions during autopsy.
Adenocarcinomas are the leading cause of LM, although any systemic cancer can potentially spread to the leptomeninges. Small-cell lung cancer has a leptomeningeal involvement rate between 9–25%, melanoma around 23%, and breast cancer roughly 5%. Due to the high global incidence of breast cancer, it remains the most common primary source of LM, followed by lung cancer.
Rare malignancies like embryonal rhabdomyosarcoma and retinoblastoma also demonstrate a tendency to involve the leptomeninges, while sarcomas generally do not. In head and neck cancers, particularly squamous cell carcinoma, spread to the meninges may occur along cranial nerves. In pediatric populations, LM is uncommon but is a known complication of medulloblastoma.
The likelihood of LM increases with longer cancer duration, and it is frequently accompanied by other CNS metastases—seen in 98% of non-leukemic patients with LM. As cancer treatments improve and patient survival increases, the incidence of LM appears to be rising. Some tumors, such as ALK-positive non-small cell lung cancers treated with crizotinib, have a propensity to relapse in the central nervous system, making the CNS a potential sanctuary site for specific cancer subtypes.
LM develop when cancer cells infiltrate the leptomeninges and cerebrospinal fluid (CSF), leading to widespread dissemination throughout the central nervous system. This spread can occur through several proposed pathways, including hematogenous dissemination to the choroid plexus or directly through leptomeningeal vessels, retrograde flow via the Batson venous plexus, extension along perineural lymphatics, centripetal spread from axial lymph nodes through intervertebral or cranial foramina, or direct invasion from adjacent tumors. Once malignant cells enter the CSF, they are distributed by its flow, with accumulation often seen in regions such as the basilar cisterns, dorsal spinal cord, and cauda equina. LM is often accompanied by parenchymal or dural metastases. The resulting clinical manifestations are primarily due to obstruction of CSF pathways, direct tumor infiltration, metabolic disturbances in neural tissue, or vascular occlusion. These pathological changes can lead to increased intracranial pressure, hydrocephalus, cranial nerve palsies, radiculopathies, seizures, encephalopathy, focal neurological deficits, and, in some cases, infarcts due to compromised blood flow in the subarachnoid space.
It is also referred to as carcinomatous meningitis or leptomeningeal disease, arise when malignant cells infiltrate the leptomeninges—the pia mater and arachnoid layers—and spread through the cerebrospinal fluid (CSF). This condition typically occurs as a late manifestation of systemic malignancies, most frequently associated with breast cancer, lung cancer, and melanoma. The spread of tumor cells to the leptomeninges can occur through several pathways. One common route is hematogenous dissemination, where cancer cells travel via the bloodstream and invade the leptomeningeal space. Another mechanism involves direct extension, in which tumors situated near the brain or spinal cord grow into the meningeal layers. Additionally, cancer cells may enter the CSF through shedding from the primary tumor and then disseminate widely throughout the central nervous system via CSF flow. These mechanisms collectively contribute to the development of LM in patients with advanced cancer.
The prognosis for LM is generally poor, with survival heavily influenced by the primary cancer type and disease extent within and beyond the CNS. Without treatment, survival is just 4–6 weeks, but therapeutic interventions may extend it to 2–4 months. Leukemic and lymphomatous meningitis respond better to agents like methotrexate and cytarabine, whereas solid tumors show variable outcomes. Among them, breast cancer-associated LM has the best response, with 60% stabilizing or improving and median survival of 7 months; 15% may survive over a year.
In contrast, LM from small-cell lung cancer and melanoma have worse outcomes, with median survival of 4 months and 3.6 months, respectively. Prognosis is poorer in patients with low Karnofsky scores, severe neurologic symptoms, extensive systemic disease, impaired CSF flow, or bulky CNS lesions. A Karnofsky score ≥70 is linked to significantly longer survival (313 days vs. 36 days for scores ≤60). Early treatment response within two weeks suggests a better outcome, while rapid deterioration and extensive CNS involvement predict poor survival. A study of 135 older patients found that poor performance status, early LM onset post-cancer diagnosis, and primary lung cancer or melanoma were associated with shorter survival, while systemic chemotherapy was the key factor improving life expectancy.
Age Group:
Leptomeningeal metastases typically occur in adults with advanced-stage cancer, particularly in middle-aged to older individuals. However, LM can also present in children with specific cancers like medulloblastoma, though this is less common.
Common findings include cranial nerve deficits—particularly involving cranial nerves III through VIII—manifesting as diplopia, facial weakness, ptosis, ophthalmoplegia, or hearing loss. Cerebellar signs such as ataxia, dysmetria, and nystagmus may be present when the posterior fossa is involved. Motor and sensory abnormalities, including asymmetric or symmetric weakness and dermatomal sensory loss, can occur due to infiltration of spinal roots or the spinal cord.
Patients may exhibit features of radiculopathy or myelopathy, such as back pain, loss of reflexes, or spasticity depending on the level of spinal involvement. Meningeal irritation signs like neck stiffness, Kernig’s sign, and Brudzinski’s sign may be noted but are often subtle or absent. Altered mental status, including confusion or personality changes, can result from cortical irritation or increased intracranial pressure (ICP). Gait disturbances, either due to cerebellar dysfunction or sensory ataxia, are also common. Additionally, signs of raised ICP such as papilledema, headache, vomiting, and sixth nerve palsy may be observed on examination. Overall, the clinical picture is frequently multifocal, making LM a diagnostic challenge that requires a high index of suspicion.
Most patients diagnosed with LM already have a known history of systemic malignancy—commonly breast cancer, lung cancer, melanoma, or hematologic malignancies like leukemia or lymphoma. LM often occurs during advanced disease stages and is frequently associated with widespread metastatic burden. Comorbid conditions such as neurologic dysfunction, previous CNS involvement, or immunosuppression may increase the risk or worsen clinical presentation.
The onset of LM symptoms can be subacute or gradual but may escalate quickly as the disease progresses. Early signs are often subtle and nonspecific, requiring a high index of suspicion for diagnosis. Pain and seizures are among the most common initial complaints. As the disease evolves, symptoms intensify and diversify depending on CNS regions affected.
Toxic/metabolic encephalopathy
Brain metastasis
Spinal metastasis
Epidural spinal cord compression
Meningococcal meningitis
Tuberculous meningitis
Paraneoplastic syndromes
Fungal meningitis
Sarcoidosis
The management of leptomeningeal metastases (LM) typically follows a phased approach to optimize symptom control and prolong survival. The initial phase involves accurate diagnosis through CSF cytology and MRI, followed by stabilization of acute symptoms, such as elevated intracranial pressure (ICP), which may require corticosteroids or surgical intervention like ventriculoperitoneal (VP) shunting. The treatment phase focuses on delivering intrathecal chemotherapy, either via lumbar puncture or an Ommaya reservoir, alongside focal radiotherapy when indicated. In selected cases, surgical resection of parenchymal brain metastases is also considered. Finally, the maintenance and palliative phase emphasizes symptom management, supportive care, and psychosocial support, recognizing the overall poor prognosis associated with LM.
Neurology
Radiation therapy: Focal or craniospinal irradiation is used to reduce tumor burden, particularly in symptomatic areas like the spine or brain.
Surgical interventions: Ventriculoperitoneal (VP) shunting can relieve raised intracranial pressure caused by hydrocephalus.
Supportive care: Includes physical therapy, occupational therapy, and psychosocial support to manage neurological deficits and improve functional status.
Palliative care: Focuses on symptom control (e.g., pain, weakness, incontinence) and end-of-life care planning.
Neurology
Methotrexate: It is the primary drug used for treatment. However, its clearance from the cerebrospinal fluid (CSF) can be unpredictable due to meningeal involvement. To maintain therapeutic levels (around 10⁻⁶ M), monitoring is essential. Folinic acid and hydrocortisone may be co-administered to reduce side effects.
Cytarabine: It serves as a second-line agent when methotrexate is not suitable or fails to work. Although ineffective for solid tumors, it is beneficial in leukemic and lymphomatous meningitis. Its sustained-release formulation extends its CSF half-life significantly.
Thiotepa: It is a third-line alkylating agent, is used intrathecally off-label in the U.S. It clears rapidly from CSF and provides survival outcomes comparable to methotrexate, with fewer neurological side effects. However, it lacks an antidote for the myelosuppression it may cause.
Trastuzumab: It is an anti-HER2 monoclonal antibody, has been administered intrathecally off-label in cases of leptomeningeal disease from HER2-positive breast cancer. Though supported mainly by case reports, it has shown improved prognosis and slowed disease progression in such settings.
Neurology
Procedural interventions play a critical role in managing leptomeningeal metastases, particularly when symptoms arise from increased intracranial pressure (ICP) or require targeted drug delivery. Intraventricular or subgaleal catheter placement enables effective administration of intrathecal chemotherapy. For patients with elevated ICP unresponsive to corticosteroids, a ventriculoperitoneal (VP) shunt may be required to relieve symptoms, even though it carries a risk of peritoneal seeding. VP shunting remains a palliative option due to the poor prognosis associated with hydrocephalus in LM. Advanced systems combining a reservoir, valve, and shunt can allow for both symptom relief and intrathecal drug delivery. If a VP shunt is present, chemotherapy should be given via lumbar puncture to ensure adequate drug distribution. Intrathecal administration may be preferable to lumbar routes for short-acting drugs like methotrexate, while the route is less critical for longer-acting agents. Additionally, surgical resection of any parenchymal brain metastases may be considered when appropriate.
Management of leptomeningeal metastases (LM) can be approached in three key phases:
Induction phase aims to rapidly reduce tumor burden in the cerebrospinal fluid (CSF) through intensive treatment, typically using intrathecal chemotherapy or systemic agents. Consolidation phase follows, stabilizing the disease with continued but less intensive therapy to maintain control over CSF tumor cells. Maintenance phase focuses on sustaining remission, minimizing recurrence, and managing symptoms with ongoing surveillance and supportive care. This phased approach allows for a structured, goal-oriented strategy tailored to patient response and disease progression.
Leptomeningeal metastases (LM) represent a severe and often terminal complication of cancer, marked by high morbidity and mortality. It can arise at any point during the cancer course—either as an initial symptom or, more commonly, as a manifestation of disease relapse.
LM involves the spread of cancer cells into the subarachnoid space of the central nervous system (CNS), where they multiply. This invasion can result from several mechanisms: hematogenous spread, direct perineural extension (commonly seen in head and neck or gastric cancers), or “drop metastases” descending from a primary tumor located higher up in the neuraxis.
The leptomeninges, composed of the arachnoid and pia mater, enclose the cerebrospinal fluid (CSF). Tumor cells entering the CSF—via direct invasion (as in brain tumors) or through the bloodstream (as seen in leukemia) are dispersed throughout the CNS by CSF circulation. This results in either widespread or patchy infiltration of the leptomeninges. The condition is referred to as leptomeningeal carcinomatosis when caused by solid tumors and as lymphomatous or leukemic meningitis when hematologic cancers are involved. Despite the term “meningitis,” an inflammatory response is not always present.
Originally described by Eberth in 1870, LM has remained underrecognized but is now diagnosed more frequently due to advancements in imaging (notably MRI), improved treatment options, and greater clinical awareness. It presents in diverse pathological forms—sometimes alongside CNS metastases or intraventricular involvement—leading to varied clinical features depending on the pattern and extent of spread.
LM is identified in approximately 1% to 8% of individuals with cancer. Among patients who exhibit neurological symptoms, LM is found in nearly 19% of autopsy cases, particularly in those with advanced or widespread disease. The prevalence varies by cancer type: LM affects 1–5% of patients with solid tumors, 5–15% with leukemia, and 1–2% with primary brain tumors. In some cases (5–10%), LM may be the initial sign of malignancy, although its true incidence is likely underreported due to challenges in detecting multifocal spread or sampling unaffected CNS regions during autopsy.
Adenocarcinomas are the leading cause of LM, although any systemic cancer can potentially spread to the leptomeninges. Small-cell lung cancer has a leptomeningeal involvement rate between 9–25%, melanoma around 23%, and breast cancer roughly 5%. Due to the high global incidence of breast cancer, it remains the most common primary source of LM, followed by lung cancer.
Rare malignancies like embryonal rhabdomyosarcoma and retinoblastoma also demonstrate a tendency to involve the leptomeninges, while sarcomas generally do not. In head and neck cancers, particularly squamous cell carcinoma, spread to the meninges may occur along cranial nerves. In pediatric populations, LM is uncommon but is a known complication of medulloblastoma.
The likelihood of LM increases with longer cancer duration, and it is frequently accompanied by other CNS metastases—seen in 98% of non-leukemic patients with LM. As cancer treatments improve and patient survival increases, the incidence of LM appears to be rising. Some tumors, such as ALK-positive non-small cell lung cancers treated with crizotinib, have a propensity to relapse in the central nervous system, making the CNS a potential sanctuary site for specific cancer subtypes.
LM develop when cancer cells infiltrate the leptomeninges and cerebrospinal fluid (CSF), leading to widespread dissemination throughout the central nervous system. This spread can occur through several proposed pathways, including hematogenous dissemination to the choroid plexus or directly through leptomeningeal vessels, retrograde flow via the Batson venous plexus, extension along perineural lymphatics, centripetal spread from axial lymph nodes through intervertebral or cranial foramina, or direct invasion from adjacent tumors. Once malignant cells enter the CSF, they are distributed by its flow, with accumulation often seen in regions such as the basilar cisterns, dorsal spinal cord, and cauda equina. LM is often accompanied by parenchymal or dural metastases. The resulting clinical manifestations are primarily due to obstruction of CSF pathways, direct tumor infiltration, metabolic disturbances in neural tissue, or vascular occlusion. These pathological changes can lead to increased intracranial pressure, hydrocephalus, cranial nerve palsies, radiculopathies, seizures, encephalopathy, focal neurological deficits, and, in some cases, infarcts due to compromised blood flow in the subarachnoid space.
It is also referred to as carcinomatous meningitis or leptomeningeal disease, arise when malignant cells infiltrate the leptomeninges—the pia mater and arachnoid layers—and spread through the cerebrospinal fluid (CSF). This condition typically occurs as a late manifestation of systemic malignancies, most frequently associated with breast cancer, lung cancer, and melanoma. The spread of tumor cells to the leptomeninges can occur through several pathways. One common route is hematogenous dissemination, where cancer cells travel via the bloodstream and invade the leptomeningeal space. Another mechanism involves direct extension, in which tumors situated near the brain or spinal cord grow into the meningeal layers. Additionally, cancer cells may enter the CSF through shedding from the primary tumor and then disseminate widely throughout the central nervous system via CSF flow. These mechanisms collectively contribute to the development of LM in patients with advanced cancer.
The prognosis for LM is generally poor, with survival heavily influenced by the primary cancer type and disease extent within and beyond the CNS. Without treatment, survival is just 4–6 weeks, but therapeutic interventions may extend it to 2–4 months. Leukemic and lymphomatous meningitis respond better to agents like methotrexate and cytarabine, whereas solid tumors show variable outcomes. Among them, breast cancer-associated LM has the best response, with 60% stabilizing or improving and median survival of 7 months; 15% may survive over a year.
In contrast, LM from small-cell lung cancer and melanoma have worse outcomes, with median survival of 4 months and 3.6 months, respectively. Prognosis is poorer in patients with low Karnofsky scores, severe neurologic symptoms, extensive systemic disease, impaired CSF flow, or bulky CNS lesions. A Karnofsky score ≥70 is linked to significantly longer survival (313 days vs. 36 days for scores ≤60). Early treatment response within two weeks suggests a better outcome, while rapid deterioration and extensive CNS involvement predict poor survival. A study of 135 older patients found that poor performance status, early LM onset post-cancer diagnosis, and primary lung cancer or melanoma were associated with shorter survival, while systemic chemotherapy was the key factor improving life expectancy.
Age Group:
Leptomeningeal metastases typically occur in adults with advanced-stage cancer, particularly in middle-aged to older individuals. However, LM can also present in children with specific cancers like medulloblastoma, though this is less common.
Common findings include cranial nerve deficits—particularly involving cranial nerves III through VIII—manifesting as diplopia, facial weakness, ptosis, ophthalmoplegia, or hearing loss. Cerebellar signs such as ataxia, dysmetria, and nystagmus may be present when the posterior fossa is involved. Motor and sensory abnormalities, including asymmetric or symmetric weakness and dermatomal sensory loss, can occur due to infiltration of spinal roots or the spinal cord.
Patients may exhibit features of radiculopathy or myelopathy, such as back pain, loss of reflexes, or spasticity depending on the level of spinal involvement. Meningeal irritation signs like neck stiffness, Kernig’s sign, and Brudzinski’s sign may be noted but are often subtle or absent. Altered mental status, including confusion or personality changes, can result from cortical irritation or increased intracranial pressure (ICP). Gait disturbances, either due to cerebellar dysfunction or sensory ataxia, are also common. Additionally, signs of raised ICP such as papilledema, headache, vomiting, and sixth nerve palsy may be observed on examination. Overall, the clinical picture is frequently multifocal, making LM a diagnostic challenge that requires a high index of suspicion.
Most patients diagnosed with LM already have a known history of systemic malignancy—commonly breast cancer, lung cancer, melanoma, or hematologic malignancies like leukemia or lymphoma. LM often occurs during advanced disease stages and is frequently associated with widespread metastatic burden. Comorbid conditions such as neurologic dysfunction, previous CNS involvement, or immunosuppression may increase the risk or worsen clinical presentation.
The onset of LM symptoms can be subacute or gradual but may escalate quickly as the disease progresses. Early signs are often subtle and nonspecific, requiring a high index of suspicion for diagnosis. Pain and seizures are among the most common initial complaints. As the disease evolves, symptoms intensify and diversify depending on CNS regions affected.
Toxic/metabolic encephalopathy
Brain metastasis
Spinal metastasis
Epidural spinal cord compression
Meningococcal meningitis
Tuberculous meningitis
Paraneoplastic syndromes
Fungal meningitis
Sarcoidosis
The management of leptomeningeal metastases (LM) typically follows a phased approach to optimize symptom control and prolong survival. The initial phase involves accurate diagnosis through CSF cytology and MRI, followed by stabilization of acute symptoms, such as elevated intracranial pressure (ICP), which may require corticosteroids or surgical intervention like ventriculoperitoneal (VP) shunting. The treatment phase focuses on delivering intrathecal chemotherapy, either via lumbar puncture or an Ommaya reservoir, alongside focal radiotherapy when indicated. In selected cases, surgical resection of parenchymal brain metastases is also considered. Finally, the maintenance and palliative phase emphasizes symptom management, supportive care, and psychosocial support, recognizing the overall poor prognosis associated with LM.
Neurology
Radiation therapy: Focal or craniospinal irradiation is used to reduce tumor burden, particularly in symptomatic areas like the spine or brain.
Surgical interventions: Ventriculoperitoneal (VP) shunting can relieve raised intracranial pressure caused by hydrocephalus.
Supportive care: Includes physical therapy, occupational therapy, and psychosocial support to manage neurological deficits and improve functional status.
Palliative care: Focuses on symptom control (e.g., pain, weakness, incontinence) and end-of-life care planning.
Neurology
Methotrexate: It is the primary drug used for treatment. However, its clearance from the cerebrospinal fluid (CSF) can be unpredictable due to meningeal involvement. To maintain therapeutic levels (around 10⁻⁶ M), monitoring is essential. Folinic acid and hydrocortisone may be co-administered to reduce side effects.
Cytarabine: It serves as a second-line agent when methotrexate is not suitable or fails to work. Although ineffective for solid tumors, it is beneficial in leukemic and lymphomatous meningitis. Its sustained-release formulation extends its CSF half-life significantly.
Thiotepa: It is a third-line alkylating agent, is used intrathecally off-label in the U.S. It clears rapidly from CSF and provides survival outcomes comparable to methotrexate, with fewer neurological side effects. However, it lacks an antidote for the myelosuppression it may cause.
Trastuzumab: It is an anti-HER2 monoclonal antibody, has been administered intrathecally off-label in cases of leptomeningeal disease from HER2-positive breast cancer. Though supported mainly by case reports, it has shown improved prognosis and slowed disease progression in such settings.
Neurology
Procedural interventions play a critical role in managing leptomeningeal metastases, particularly when symptoms arise from increased intracranial pressure (ICP) or require targeted drug delivery. Intraventricular or subgaleal catheter placement enables effective administration of intrathecal chemotherapy. For patients with elevated ICP unresponsive to corticosteroids, a ventriculoperitoneal (VP) shunt may be required to relieve symptoms, even though it carries a risk of peritoneal seeding. VP shunting remains a palliative option due to the poor prognosis associated with hydrocephalus in LM. Advanced systems combining a reservoir, valve, and shunt can allow for both symptom relief and intrathecal drug delivery. If a VP shunt is present, chemotherapy should be given via lumbar puncture to ensure adequate drug distribution. Intrathecal administration may be preferable to lumbar routes for short-acting drugs like methotrexate, while the route is less critical for longer-acting agents. Additionally, surgical resection of any parenchymal brain metastases may be considered when appropriate.
Management of leptomeningeal metastases (LM) can be approached in three key phases:
Induction phase aims to rapidly reduce tumor burden in the cerebrospinal fluid (CSF) through intensive treatment, typically using intrathecal chemotherapy or systemic agents. Consolidation phase follows, stabilizing the disease with continued but less intensive therapy to maintain control over CSF tumor cells. Maintenance phase focuses on sustaining remission, minimizing recurrence, and managing symptoms with ongoing surveillance and supportive care. This phased approach allows for a structured, goal-oriented strategy tailored to patient response and disease progression.
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