What is Leptomeningeal Disease?
Leptomeningeal diseases (LMD), also known as leptomeningeal metastasis, meningeal carcinomatosis, or neoplastic meningitis, is a severe and often fatal complication of systemic malignancies, primary brain tumors, or hematologic cancers. It occurs when malignant cells disseminate to the leptomeninges—the pia and arachnoid mater—through cerebrospinal fluid (CSF) pathways. Tumor cells may adhere to the pia, float in the subarachnoid space, or spread along the neuraxis via CSF flow. Without timely diagnosis and management, neurological deterioration progresses rapidly.
Common Causes and Risk Factors
LMD is most frequently associated with:
Solid tumors: Breast cancer, lung cancer (particularly non-small cell lung cancer), melanoma, gastrointestinal malignancies.
Hematologic cancers: Leukemias and lymphomas, particularly in aggressive lymphoproliferative disorders.
Primary CNS tumors: Especially high-risk pediatric tumors such as medulloblastoma.
Risk factors include:
Advanced systemic disease
Prior CNS metastases or neurosurgical procedures
Specific molecular subtypes (e.g., HER2+ breast cancer, EGFR-mutant lung adenocarcinoma)
Leptomeningeal Disease Symptoms:
Leptomeningeal disease produces multifocal neurological symptoms due to involvement of the brain, cranial nerves, and spinal roots. Common symptoms of leptomeningeal disease:
Signs of raised intracranial pressure: Headache, nausea, vomiting
Cranial nerve dysfunctions: Diplopia, visual disturbances, facial weakness, hearing loss, trigeminal sensory changes
Motor and sensory deficits: Weakness, gait disturbance, paresthesia, dermatomal sensory loss
Cognitive changes and mental confusion
Seizures (focal or generalized)
Spinal/radicular symptoms: Pain radiating along nerve roots, limb weakness, sphincter dysfunction, incontinence
Diagnostic Workup
Diagnosing LMD requires a multimodal approach combining clinical assessment, imaging, and CSF analysis.
Clinical Evaluation
Comprehensive neurological examination (cranial nerves, motor-sensory testing, cognitive assessment).
Recognizing multilevel involvement (brain, cranial nerves, and spine) raises clinical suspicion.
Neuroimaging
Contrast-enhanced brain and complete spine MRI (whole neuraxis imaging): Reveals linear or nodular leptomeningeal enhancement along cortical sulci, cranial nerves, or spinal roots.
PET (including amino acid PET): Helpful in ambiguous cases or when MRI is equivocal.
CSF Analysis
Cytology: Gold standard; direct detection of malignant cells. Sensitivity increases with repeated sampling (up to 3 lumbar punctures).
Biochemistry: Elevated protein, low glucose, and pleocytosis may support the diagnosis.
Emerging biomarkers: Cell-free tumor DNA (cfDNA) and molecular mutation profiling are increasingly valuable for early and precise detection.
Treatment Strategies
Management aims to stabilize neurological function, control symptoms, and prolong survival, as cure is rarely achievable. A multidisciplinary approach is essential.
1. Radiotherapy
Focal radiotherapy: Used for symptomatic or bulky leptomeningeal lesions, cranial nerve involvement, or CSF flow obstruction.
Goal: Relieve mass effect, restore CSF flow, and enhance the efficacy of intrathecal therapy.
2. Intrathecal Chemotherapy
Delivery: Lumbar puncture or via Ommaya reservoir directly into CSF.
Common agents: Methotrexate (MTX), liposomal cytarabine (DepoCyt), and occasionally thiotepa.
Toxicity management: Includes corticosteroids, hydration, and leucovorin rescue for MTX.
3. Systemic Therapy / Targeted Therapy
Drugs with CNS penetration may be effective: EGFR inhibitors (e.g., osimertinib) for EGFR-mutant NSCLC
HER2-targeted therapy for HER2+ breast cancer
Immunotherapy and targeted therapy for melanoma and other molecularly driven tumors show promise in ongoing clinical trials.
4. Supportive and Symptomatic Care
Hydrocephalus management: Ventriculoperitoneal shunting if needed.
Seizure control: Antiepileptic therapy.
Corticosteroids and rehabilitation: To reduce edema and improve functional status.