What is leptomeningeal disease?

Leptomeningeal Disease: Definition, Pathophysiology, and Clinical Impact

Leptomeningeal disease (LMD) is a condition characterized by the dissemination and growth of cancer cells within the leptomeninges (pia and arachnoid membranes) that surround the brain and spinal cord, resulting in significant neurological morbidity and poor survival with median survival of only 2-4 months without treatment. 1

Pathophysiology

Leptomeningeal disease occurs when malignant cells gain entry into the cerebrospinal fluid (CSF) and the leptomeningeal space. The leptomeninges consist of:

• The pia mater (innermost layer)
• The arachnoid membrane (middle layer)
• CSF circulates within the subarachnoid space between these layers

Cancer cells can access the leptomeningeal space through several mechanisms:

• Hematogenous spread via the choroid plexus or arachnoid vessels
• Direct invasion from brain or dural metastases
• Perineural invasion along peripheral nerves
• Retrograde venous extension via Batson's plexus
• Direct seeding during neurosurgical procedures
• Rarely, primary tumors arising within the meninges 1

Once in the leptomeningeal space, cancer cells:

• Circulate freely throughout the neuraxis driven by pulsatile CSF flow
• Form adherent plaques on the surface of the brain, spinal cord, and exiting cranial/spinal nerves
• Exist as free-floating cells or cellular clusters in the CSF
• Preferentially colonize regions of slow CSF flow and gravity-dependent locations (posterior fossa, basilar cisterns, lumbar cistern) 1

Epidemiology

LMD is clinically recognized in approximately 4-7% of all cancer patients, though autopsy studies suggest asymptomatic involvement may be as high as 20% 1. The most common solid tumors associated with LMD include:

• Breast cancer (particularly infiltrating lobular subtype)
• Lung cancer (particularly relapsed small cell lung cancer)
• Melanoma
• Gastrointestinal cancers 1

With improved cancer treatments extending patient survival and better diagnostic techniques, LMD is now being observed in up to 1 in 5 patients with certain high-risk cancer molecular subtypes 1.

Clinical Presentation

Symptoms and signs of LMD are typically multifocal, reflecting involvement of different areas of the central nervous system:

• Cerebral involvement:

  • Headache
  • Nausea and vomiting
  • Mental status changes
  • Seizures
  • Increased intracranial pressure symptoms

• Cranial nerve involvement:

  • Visual disturbances (CN II, III, IV, VI)
  • Hearing loss (CN VIII)
  • Facial numbness or weakness
  • Diplopia
  • Dysphagia

• Spinal involvement:

  • Radicular pain
  • Limb weakness
  • Sensory deficits
  • Voiding difficulties
  • Cauda equina syndrome
  • Neck and back pain 1

Diagnosis

Diagnosis of LMD requires a combination of:

1. Clinical assessment: Detailed neurological examination with attention to multifocal neurological deficits
2. Neuroimaging: Gadolinium-enhanced MRI of the brain and spine
3. CSF analysis: Cytology for malignant cells, biochemical parameters (protein, glucose)
4. Emerging techniques: CSF circulating tumor cells, cell-free DNA assessment 2, 3

Diagnosis is often delayed until fixed neurologic deficits become evident, highlighting the importance of maintaining a high index of suspicion in cancer patients with new neurological symptoms 1.

Prognosis and Treatment

Without treatment, median survival is extremely poor at 4-6 weeks. With LM-directed treatment, survival may be extended to:

• 1.75-4.5 months in breast cancer
• 3-6 months in lung cancer
• 1.7-2.5 months in melanoma 1

Treatment approaches include:

• Radiation therapy:

  • Whole brain radiation
  • Focal spinal radiation
  • Emerging approaches include proton craniospinal irradiation and focal hypofractionated stereotactic radiotherapy 4

• Chemotherapy:

  • Systemic chemotherapy with CNS-penetrant agents
  • Intrathecal chemotherapy (methotrexate, cytarabine, thiotepa)
  • Liposomal cytarabine (Depocyt) 1

• Targeted therapies and immunotherapy:

  • Emerging data shows promise for targeted agents in specific molecular subtypes
  • Ongoing trials evaluating immunotherapy approaches 5, 3

• Supportive care:

  • CSF diversion procedures for increased intracranial pressure
  • Symptom management

Key Considerations and Pitfalls

1. Diagnostic challenges:

   • CSF cytology has limited sensitivity; false negatives are common
   • Multiple CSF samples may be needed
   • Neuroimaging findings can be subtle or absent

2. Treatment limitations:

   • Poor drug penetration into the CSF compartment
   • Toxicity of available treatments
   • Limited evidence base for treatment decisions

3. Prognostic factors:

   • Performance status at diagnosis is the most important prognostic factor
   • Primary tumor type significantly impacts outcomes
   • CSF protein levels correlate with prognosis 1

4. Emerging approaches:

   • Molecular diagnostics are improving detection sensitivity
   • Novel targeted therapies show promise for specific tumor subtypes
   • Clinical trials are essential to advance treatment options 5, 3

LMD represents a devastating complication of cancer with significant impact on quality of life and survival. Early recognition, prompt diagnosis, and appropriate treatment selection are critical to optimize outcomes in this challenging disease.