CONTENTS
- Pathophysiology
- Epidemiology
- Clinical manifestations
- Diagnosis
- Management
- Podcast
- Questions & discussion
- Pitfalls
mechanism of tumor seeding the meninges
- Tumor cells may reach the meninges via hematogenous spread, or via direct extension (from parenchymal, dural, or bony lesions).
mechanisms of altering neurologic function (28178708)
- Mass effect of tumor nodules.
- Impingement on cranial nerves and/or spinal nerve roots.
- Direct invasion of the leptomeninges and brain parenchyma.
- Hydrocephalus of various types:
- May cause obstructive hydrocephalus due to blocking CSF flow at various levels.
- May cause communicating hydrocephalus due to impaired CSF reabsorption.
- Ischemia secondary to blood vessel involvement.
overall epidemiology
- Leptomeningeal metastasis occurs in ~5-10% of all patients with cancer.
- Leptomeningeal disease may grow increasingly common as new treatments extend the lifespan of cancer patients. Since many medications don't cross the blood-brain barrier, the central nervous system may serve as a sanctuary site for malignant cells.
when leptomeningeal metastasis occurs in the course of cancer
- Range of timing:
- Usually occurs in the context of known malignancy.
- May be presenting feature of malignancy in 5-10% of patients.
- ⚠️ If a thorough search fails to find any primary malignancy (e.g., whole body PET/CT is normal), leptomeningeal metastasis is unlikely.(24198904)
- Solid tumors: Leptomeningeal involvement generally occurs at an advanced disease stage. ~60% of patients with leptomeningeal disease have current or prior parenchymal brain involvement.(29165794)
- Leukemia/lymphoma: Leptomeningeal involvement is often the first site of tumor recurrence, without evidence of systemic disease (due to low penetration of chemotherapy into the nervous system).
common causes of leptomeningeal metastatic disease
- Metastatic solid tumor:
- Melanoma.
- Breast cancer.
- Bronchogenic carcinoma.
- Renal cell carcinoma.
- Germ cell tumors.
- Primary CNS tumors.
- Hematologic malignancies:
- Lymphoma, mostly non-Hodgkin's lymphoma and PCNSL (primary CNS lymphoma).
- Leukemia, mostly ALL (acute lymphoblastic leukemia).
general
- A single large tumor nodule may cause focal signs/symptoms, but most patients have numerous levels of neuraxial involvement.
- Most common symptoms:
- Headache, nausea/vomiting, meningismus.
- Cognitive disorders (lethargy, confusion, memory impairment).
- Gait abnormalities.
elevated intracranial pressure
- Headache is common, frequently related to intracranial pressure elevation.
- Nausea, vomiting may occur.
- 💡 Consider leptomeningeal carcinomatosis in patients with otherwise unexplained hydrocephalus.
cerebrum (15%)
- Cognitive disturbance (which may include rapidly progressive dementia).(29165794)
- Focal weakness and/or numbness.
- Aphasia.
- Seizure.
- Cerebellar dysfunction, ataxia.
- Rarely, pituitary stalk involvement may cause diabetes insipidus or panhypopituitarism.(28178708)
- 💡 Consider leptomeningeal disease in patients with cancer who have neurological symptoms which are unexplained by their brain parenchymal tumor burden.
cranial nerve & brainstem involvement (35%)
- Diplopia, decreased vision.
- Hearing loss.
- Ophthalmoplegia (often an early sign).
- Facial numbness or pain.
- Facial weakness.
- Dysphagia.
- Dysarthria.
- Hypoglossal (tongue) weakness.
- 💡 Consider leptomeningeal disease in patients with multiple cranial neuropathies which are otherwise unexplained.
spinal cord & nerve root involvement (60%)
- Back pain and/or radicular pain.
- Limb weakness.
- Meningeal signs (e.g., nuchal rigidity) in only ~15% of patients.
- Radiculopathy, dermatomal sensory deficit.
- Lhermitte's sign.
- Bowel and bladder dysfunction.
- Cauda equina syndrome.
basic chemistries
- CSF is totally normal in only 3% of cases.
- Protein is elevated (>50 ng/dL) in ~80% of cases.
- If protein levels are very high (>500 mg/dL) then there is probably obstruction of CSF flow or advanced disease.(29069871)
- Pleocytosis (>5 WBC/mm3) occurs in ~60% of cases.(28178708)
- Solid tumors: mostly neutrophils, mononuclear cells, or both.
- Lymphomas: mostly lymphocytes.
- Glucose is decreased (e.g., <40 mg/dL) in ~30% of cases.(28178708)
- Opening pressure is elevated in most patients.
cytology
- Yield depends on the number of lumbar punctures:
- 1 lumbar puncture: Yield ~60%.
- 2 lumbar punctures: Yield ~80%.
- 3 lumbar punctures: Yield ~90%.(28178708)
- Yield may vary depending on malignancy type:
- Highest for leukemias.
- Lower for metastatic carcinoma or primary CNS malignancy.
- Flow cytometry may be helpful in patients with hematological malignancy.
- Samples should be transported promptly to the laboratory and handled carefully, as cancer cells may deteriorate rapidly. Refrigeration for two days may decrease the yield by 36%.(29165794)
overall approach
- Contrast-enhanced MRI is the test of choice, with a sensitivity of ~80%. However, performance may be lower in leptomeningeal metastases due to leukemia or lymphoma.(28178708)
- Brain and/or spinal cord may be involved. It's ideal to image the entire brain and spinal cord, if possible.
potential findings include:
- Contrast enhancement of subarachnoid space.
- Obliteration of cisterns or sulci.
- Nodules (subarachnoid and/or intraventricular).
- Communicating hydrocephalus (with bilateral transependymal edema in the periventricular white matter of the cerebral hemispheres).(Wijdicks, 2019)
Differential diagnosis will vary widely depending on the clinical findings in any specific patient. More common considerations include the following:
- Malignant spinal cord compression.
- Paraneoplastic neurological syndromes.
- Chronic infectious meningitis (e.g., Listeria monocytogenes, Lyme, syphilis, Cryptococcus neoformans, coccidiomycosis, tuberculosis, brucellosis).
- Chronic inflammatory processes (e.g., neurosarcoid, lupus, granulomatosis with polyangiitis).
- Iatrogenic:
- Chemotherapy side effect (especially intrathecal chemotherapy).
- Radiation side effects.
- Drug-induced meningitis (e.g., NSAIDs, trimethoprim/sulfamethoxazole, intravenous immunoglobulin).
- Treatment will vary depending on the type of malignancy, its sensitivity to chemotherapy/radiotherapy/biologics, and the patient's performance status. For most adults with leptomeningeal metastasis, treatment is provided with palliative intent (i.e., cure is not possible). However, in some situations newer biologic therapies may lead to sustained responses.
- Focused radiotherapy may be helpful to alleviate blockage of CSF flow or compressive lesions that are causing radiculopathy.
- Hydrocephalus may be managed with placement of a ventriculoperitoneal shunt, or palliated with acetazolamide.(Pruitt 2022)
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- The main pitfall is not considering the possibility that the patient has leptomeningeal carcinomatosis. For patients without a pre-existing cancer diagnosis, presentation is often insidious and complex – which may defy many diagnostic algorithms.
Guide to emoji hyperlinks
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References
- 28178708 Rigakos G, Liakou CI, Felipe N, Orkoulas-Razis D, Razis E. Clinical Presentation, Diagnosis, and Radiological Findings of Neoplastic Meningitis. Cancer Control. 2017 Jan;24(1):9-21. doi: 10.1177/107327481702400103 [PubMed]
- 29069871 Nayar G, Ejikeme T, Chongsathidkiet P, Elsamadicy AA, Blackwell KL, Clarke JM, Lad SP, Fecci PE. Leptomeningeal disease: current diagnostic and therapeutic strategies. Oncotarget. 2017 Aug 16;8(42):73312-73328. doi: 10.18632/oncotarget.20272 [PubMed]
- 29165794 Wang N, Bertalan MS, Brastianos PK. Leptomeningeal metastasis from systemic cancer: Review and update on management. Cancer. 2018 Jan 1;124(1):21-35. doi: 10.1002/cncr.30911 [PubMed]
- Wijdicks E.F.M., Findlay, J. Y., Freeman, W. D., Sen A. (2019). Mayo Clinic critical and Neurocritical Care Board Review. Oxford University Press.
- Strowd RE, Pruitt AA, Porter AB (2022): Neurologic consultations in cancer patients. Presentation at the American Academy of Neurology Conference, Seattle 2022.
Suggested search terminology: “neoplastic meningitis,” “leptomeningeal carcinomatosis” and “carcinomatous meningitis” and “leptomeningeal metastasis.”