Leptomeningeal Disease

Leptomeningeal disease (LMD) is a rare form of central nervous system (CNS) metastasis that occurs when cancerous cells spread to the leptomeninges—the delicate layers of tissue that envelop the brain and spinal cord—and enter the cerebrospinal fluid (CSF). The condition is distinct from brain metastasis, which involves the infiltration of cancer into the brain tissues.

LMD is relatively uncommon and tends to develop in individuals with certain advanced-stage primary tumors. Because it can progress quickly and significantly affect neurological function, early detection and timely intervention are critical to preserving quality of life and improving the outcome.

What types of cancer are most likely to progress into leptomeningeal disease?

Certain cancers have a higher propensity to spread to the CNS, leading to LMD. These include:

• Lung cancer – Small cell lung cancer (SCLC) in particular has a high likelihood of spreading to the brain and leptomeninges.
• Breast cancer – HER2-positive and triple-negative breast cancer tend to be aggressive and more likely to invade the CNS than other cancers.
• Melanoma – Due to its ability to travel easily through the bloodstream and lymphatic system, this serious form of skin cancer has a strong tendency to metastasize to the brain and CSF.
• Leukemia and lymphoma – Certain blood cancers, such as acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), and some types of non-Hodgkin lymphoma frequently spread to the CNS, including the leptomeninges.

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What causes leptomeningeal disease?

Researchers believe cancer cells can metastasize from a primary tumor to the leptomeninges and CSF through one of the following mechanisms:

• Hematogenous spread – Tumor cells enter the bloodstream, circulate throughout the body and invade the leptomeninges.
• Direct invasion – A tumor situated near the brain or spinal cord progresses and grows into the meninges.
• Seeding from the CSF – Cancer cells shed from the primary tumor, circulate within the cerebrospinal fluid and spread within the CNS.

Because the leptomeninges lack a strong immune defense, cancer cells tend to multiply and migrate more easily once they reach this area of the body.

What are the risk factors for leptomeningeal disease?

Several factors can increase the likelihood of developing LMD, particularly in individuals with advanced cancer. Known risk factors include:

• Primary cancer type – LMD is most commonly associated with lung cancer, breast cancer, melanoma and hematologic malignancies, such as leukemia and lymphoma.
• Advanced or metastatic cancer – A patient with a tumor that has already spread to another part of the body, especially the brain or spinal cord, is at heightened risk of developing leptomeningeal disease.
• High tumor burden – A large number of cancer cells in the bloodstream increases the likelihood of cancer spreading to the leptomeninges.
• Previous cancer spread to the brain – Prior brain metastasis may indicate an increased ability of the cancer cells to infiltrate the CNS, raising the risk of LMD.
• Aggressive tumor biology – Some cancers are more prone to spreading through the CSF due to their rapid growth and invasive nature.
• Treatment history – A patient who has undergone radiation therapy or systemic treatment that does not effectively reach the CSF may be at risk for leptomeningeal disease because the cancer cells may persist or evolve resistance.

Understanding these risk factors can help physicians closely monitor at-risk patients for early signs of LMD and adjust treatment strategies accordingly.

What are the symptoms of leptomeningeal disease?

LMD symptoms can vary depending on which areas of the brain and spinal cord are affected. As cancerous cells circulate within the CSF, a range of neurological symptoms may develop, including:

• Cognitive and behavioral changes – Confusion, memory loss, difficulty concentrating or personality changes
• Headaches – Persistent or worsening headaches, often accompanied by nausea and vomiting due to increased intracranial pressure
• Seizures – New-onset seizures or worsening seizure activity in individuals with a prior history
• Vision and hearing problems – Blurred or double vision, sensitivity to light, hearing loss or ringing in the ears (tinnitus)
• Weakness and numbness – Muscle weakness, numbness or tingling in the arms or legs, which may progress over time
• Balance and coordination issues – Dizziness, difficulty walking or unsteady gait
• Speech and swallowing difficulties – Slurred speech, vocal hoarseness or trouble swallowing
• Bladder and bowel dysfunction – Loss of bladder or bowel control, or difficulty urinating or defecating

How can I manage the symptoms of leptomeningeal disease?

Effective management of LMD symptoms often requires a combination of treatments aimed at alleviating discomfort, reducing inflammation and controlling cancer progression. The specific management plan should be precisely tailored to the patient after taking into consideration their unique diagnosis, primary cancer type and overall health. Common approaches include chemotherapy, radiation treatment, corticosteroids, pain management and symptom-specific therapies, such as anticonvulsant drugs to control seizures.

How is leptomeningeal disease diagnosed?

LMD is typically diagnosed through a clinical evaluation combined with imaging tests and laboratory procedures. Given its aggressive nature, early detection is crucial for effective management. The primary tools used to diagnose leptomeningeal disease are:

Medical history and physical examination

The first step in diagnosing LMD involves a thorough medical history review and physical examination. The physician will assess the patient’s symptoms, particularly any headaches, nausea, neurological deficits or seizures, and inquire about the patient’s history of cancer, which is a key consideration because certain types of cancer are more likely to cause leptomeningeal disease.

Imaging tests

Imaging often plays an important role in the diagnostic process for LMD. Common techniques include:

• Magnetic resonance imaging (MRI) – MRI with contrast dye can help the physician visualize the brain and spinal cord and identify swelling, fluid accumulation (hydrocephalus), changes in the shape of the brain and areas where cancer may have spread to the leptomeninges.
• Computed tomography (CT) – Though less sensitive than MRI for detecting leptomeningeal disease, CT scans can help the physician assess the brain and spinal cord when MRI is unavailable or additional views are needed.
• Positron emission tomography (PET) – Sometimes combined with a CT scan (PET/CT), this imaging technique can help the physician detect areas of high metabolic activity, which could indicate cancer activity related to LMD.

Lumbar puncture (spinal tap)

A key diagnostic procedure for LMD, a spinal tap involves collecting a small sample of cerebrospinal fluid for evaluation in a lab. The presence of cancer cells in the CSF strongly suggests leptomeningeal disease. The laboratory analysis may include:

• Cytology – A pathologist will examine the sample under a microscope. If cancer cells are found, a diagnosis of LMD can be confirmed.
• Flow cytometry – A laser-based lab test that can detect chemical and physical differences of cells, flow cytometry can be used to further analyze the cancer cells in the CSF and identify the specific type of cancer that has spread to the leptomeninges.

Magnetic resonance spectroscopy (MRS)

Sometimes performed as an adjunct to MRI, MRS is a noninvasive test used to analyze the biochemical composition of certain tissues, particularly in the brain, allowing the physician to detect chemical changes that could be indicative of cancer or metastasis.

Biopsy

In rare cases, if the diagnosis is unclear, a biopsy may be performed to remove a tissue sample from the brain or spinal cord to check for the presence of cancer. Typically, this invasive test is considered only when other diagnostic methods do not provide definitive results.

Blood work

Blood tests can help the physician assess the patient’s overall health and identify signs of infection or inflammation. Although blood testing is not used to directly diagnose leptomeningeal disease, it can be useful in ruling out other conditions and ensuring the patient’s body can tolerate certain LMD treatments.

Electroencephalogram (EEG)

If the patient is experiencing seizures, the physician may order an EEG to monitor the electrical activity in the brain. While an electroencephalogram is not typically used to diagnose leptomeningeal disease, the physician may use the results to inform treatment decisions and develop strategies for managing symptoms.

Tumor marker testing

Tumor markers are substances, such as proteins or genes, that may be found in the blood, CSF or other bodily fluids and tissues when cancer is present. To identify the type of primary cancer that has metastasized to the leptomeninges, the physician may order testing for specific tumor markers.

What is the prognosis for leptomeningeal disease?

The prognosis for LMD can vary depending on several factors, including the type of primary tumor, the extent of cancer spread and the patient’s overall health. Often, the condition is associated with advanced-stage cancer and its treatment is complex due to the delicate nature of the leptomeninges. However, several options may be available to help manage the symptoms and potentially improve the patient’s outcome and quality of life. Early diagnosis and individualized treatment are essential.

What treatment options are available for leptomeningeal disease?

Currently, there is no cure for LMD. Instead, treatment focuses on managing symptoms, slowing cancer progression and enhancing the patient's quality of life. Options may include:

• Intrathecal chemotherapy – This targeted treatment involves delivering chemo medications directly into the CSF, allowing powerful cancer-fighting drugs to reach tumor cells in the brain and spinal cord.
• Systemic chemotherapy – When cancer cells spread to the leptomeninges, chemotherapy may be delivered through the bloodstream to treat the primary cancer and control the spread of LMD. However, systemic therapy may have limited effectiveness in the CSF due to the blood-brain barrier.
• Targeted therapy – For certain primary cancers, targeted therapies that focus on specific genetic mutations or abnormal proteins in the cancer cells may be used to manage leptomeningeal disease.
• Radiation therapy – Whole-brain or spinal radiation therapy can help reduce the tumor burden in the brain and spinal cord, alleviate symptoms and improve the outcome and quality of life for some patients with LMD.
• Steroids – Corticosteroids are often prescribed to reduce inflammation and swelling in the brain and spinal cord, which can alleviate symptoms such as headaches, nausea and neurological issues.
• Surgical intervention – In rare cases, surgery may be considered to remove an accessible tumor or relieve pressure in the brain or spinal cord; however, it is infrequently used to address LMD due to the diffuse nature of the disease.
• Supportive care – In addition to specific medical treatments for cancer, supportive care such as pain management, physical therapy and psychological support can be key to improving the patient’s quality of life.

What is intrathecal chemotherapy?

Intrathecal chemotherapy is a method of delivering powerful cancer-fighting drugs directly into the cerebrospinal fluid. This targeted treatment approach allows the medication to bypass the blood-brain barrier, which can sometimes limit the effectiveness of standard chemotherapy in treating cancer in the brain or spinal cord. The chemo drugs are administered through a needle inserted into the space around the spinal cord, typically in the lower back (lumbar region) or via a catheter. A common treatment for leukemia, lymphoma and some types of brain metastases that affect the CNS, including leptomeningeal disease, intrathecal chemotherapy can help control cancer cells in the CSF, reduce the risk of recurrence and improve the chance of remission.

How effective is treatment for leptomeningeal disease?

LMD treatment can help slow the progression of the cancer and manage the symptoms. However, the process can be challenging and complete remission is rare. The effectiveness of treatment can vary depending on factors such as the type of primary cancer, how early metastasis was detected and the patient's overall health.

Are there clinical trials available for leptomeningeal disease?

Yes, clinical trials are available for LMD, offering participants unique opportunities to benefit from emerging therapies that are not yet available in other settings. These important research studies may involve novel chemotherapy agents, targeted therapies, immunotherapies or drug delivery methods. Because the eligibility criteria and treatment options can vary, it is essential for an interested patient to discuss clinical trial opportunities with their physician.

What are the potential side effects of treatment for leptomeningeal disease?

LMD treatment is associated with a wide range of potential side effects depending on the specific approach used. For example, intrathecal chemotherapy may cause headaches, nausea, fatigue or neurological effects, such as confusion. Radiation therapy can result in hair loss, skin irritation and fatigue. Systemic treatment can cause weakened immunity or gastrointestinal issues. These side effects can vary from patient to patient and must be carefully managed by the medical team to maintain quality of life during treatment.

How often will I need to come in for treatment?

The frequency of LMD treatment can vary depending on the type of therapy prescribed and the patient’s overall health. Intrathecal chemotherapy may be administered several times a week initially and then tapered as appropriate. Radiation therapy is typically given over several sessions across one to two weeks. Through follow-up visits and ongoing monitoring, the physician will assess the patient’s response to treatment and adjust the care plan as needed.

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If you would like to learn more about leptomeningeal disease, you can request an appointment with a specialist in Moffitt’s Neuro-Oncology Program by calling 1-888-663-3488 or submitting a new patient registration form online. We do not require referrals.