Herbert B. Newton, MD, FAAN
DESCRIPTION 
Carcinomatous meningitis (CAM) is a common neurological complication of systemic cancer that is associated with a high mortality and morbidity. CAM is caused by the spread of cancer cells into the subarachnoid space and CSF, with subsequent access to the entire neuraxis. CAM has the capacity to affect every component of the CNS, including the brain, cranial nerves, spinal cord, spinal nerve roots, and cauda equine. It can develop in virtually any malignancy, but is most common in leukemia, lymphoma, and solid tumors such as melanoma, breast carcinoma, and small cell lung carcinoma.
EPIDEMIOLOGY
Incidence/Prevalence
- The estimated incidence of CAM is 4–15% of patients with solid tumors, 7–15% of patients with lymphoma, 5–15% of patients with leukemia, and 1–2% of patients with primary brain tumors.
- All races and ethnic groups equally affected. Typical presentation is between 45 and 60 years of age. Females have a higher incidence than males—1.6:1.
RISK FACTORS
Risk factors that increase the probability of CAM include tumor type (e.g., melanoma) and aggressive, wide-spread systemic disease.
Genetics
CAM is a sporadic process without any specific genetic influence.
GENERAL PREVENTION
No preventive measures are known.
PATHOPHYSIOLOGY/ETIOLOGY
- Systemic tumor cells gain access to the subarachnoid space and CSF through hematogenous spread to arachnoidal vessels, choroid plexus, or Batson's vertebral venous plexus; by direct extension from superficial regions of brain parenchyma, periventricular, or epidural metastases; and by perineural spread along spinal or cranial nerves. CAM is histologically similar to the primary neoplasm.
- Neurological function is disrupted by CAM through several mechanisms, including elevation of intracranial pressure by the presence of diffuse tumor burden, direct invasion of neural tissues (brain, spinal cord, cranial and spinal nerves), ischemia due to obstruction of arterial blood flow, and regional metabolic alterations (e.g., lactic acidosis, low glucose concentration).
- Tumor cells most likely to metastasize to the CNS have a more aggressive and motile phenotype. These changes are mediated by scatter factor, autocrine motility factor, amplification of oncogenes, and mutation of metastasis-suppressor genes (e.g., nm23).
COMMONLY ASSOCIATED CONDITIONS
Commonly associated conditions include other common, general, and neurological complications of cancer patients such as infection and sepsis, metabolic encephalopathy, brain metastasis, and epidural spinal cord compression.
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HISTORY
Symptoms and signs of CAM can involve any region of the neuraxis, including the brain, cranial nerves, and spine. The symptoms are usually progressive over days to weeks. In 30–40% of patients, more than one region of the neuraxis will be involved. Cerebral signs and symptoms include headache (60%), mental status changes (50%), gait alterations (25%), nausea and emesis (22%), seizures (11%), and hemiparesis (3%). Cranial nerve signs and symptoms include diplopia and ocular motor pareses of III, IV, and VI (30%), facial weakness (27%), impaired hearing (13%), facial numbness (8%), visual loss and optic neuropathy (8%), and tongue weakness (8%); spinal signs and symptoms include reflex asymmetry (85%), leg weakness (70%), paresthesias (40%), sensory loss (30%), back/neck pain (30%), radicular pain (26%), and bowel/bladder dysfunction (15%).
PHYSICAL EXAM
Stepwise loss of function affecting some or all levels of the neuraxis, as noted above.
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
The single most useful diagnostic test is examination of the CSF by lumbar puncture (LP); the CSF is always abnormal, even when the cytology is negative; in most patients, there is a mild to moderate pleocytosis, elevated protein, reduced glucose level, and elevated lactate level; tumor markers (e.g., β-glucuronidase, β-2-microglobulin, carcinoembryonic antigen) are adjunctive tests that can improve diagnostic accuracy if elevated; 50% of patients with CAM will have a positive cytology after one LP and 90% will be positive after the third LP; CSF cytology can remain negative in some patients.
Follow-Up & Special Considerations
Brain imaging should occur before LP to rule out focal mass lesion and potential risk of herniation.
Imaging
Initial Approach
Magnetic resonance imaging of the brain and/or spinal cord, with or without gadolinium contrast, is the most sensitive imaging test. Axial, coronal, and midsagittal-enhanced images should be obtained. Abnormal enhancement is noted in 70% of patients with CAM, along the surface of the brain, ventricular ependyma, cranial nerves, spinal cord, and cauda equina. Nodules of enhancement and hydrocephalus are noted in 38% and 7% of patients, respectively. CT reveals similar enhancement patterns, but in only 40% of patients with CAM. MRI or CT evidence of CAM can be diagnostic if CSF cytology is negative; however, a negative MRI or CT does not rule out CAM. Myelography, with or without CT follow-through, can also be diagnostic if MRI is unavailable.
Diagnostic Procedures/Other
Flow cytometry of the CSF may be diagnostic of CAM from leukemia and lymphoma if able to demonstrate a monoclonal population of cells; it may also demonstrate the presence of neoplastic aneuploid DNA populations. For CAM patients with diffuse, bulky disease, a radionuclide CSF flow study may be necessary to demonstrate patency of the CSF pathways before intrathecal (IT) chemotherapy is administered through an Ommaya reservoir.
Pathological Findings
Patches and nodules of tumor cells, with same histology as the primary tumor, along the surface of the cranial meninges, cranial nerves, spinal cord, and spinal nerve roots.
DIFFERENTIAL DIAGNOSIS
Differential diagnosis includes other diseases that can involve the subarachnoid space, induce CSF inflammation, and cause enhancement of the leptomeninges on MRI, such as chronic bacterial or fungal meningitis, neurosarcoidosis, Guillain–Barre syndrome, and vasculitis.
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MEDICATION
First Line
Dexamethasone (2–8 mg/day) may be of benefit to reduce edema and swelling, or to improve transient symptoms of pressure and swelling after RT. Seizures may be a problem in patients with CAM. Appropriate anticonvulsant choices (e.g., phenytoin, carbamazepine, levetiracetam) and management will be critical. Narcotic analgesics may be necessary for adequate amelioration of pain.
ADDITIONAL TREATMENT
General Measures
General measures should include symptomatic treatment and consultation by radiation oncology, neuro-oncology, and neurosurgery for treatment evaluation.
Additional Therapies
- Conventional radiotherapy (RT) is of benefit to stabilize or palliate symptomatic regions of CAM. It is most often administered to the whole brain or to involved regions of the spinal axis with bulky disease. RT is more effective than IT chemotherapy for bulky disease, due to poor penetration of drug deeper than 2–3 mm. Pain-related symptoms are often improved with RT. Spinal neuraxis RT is generally avoided due to severe myelosuppression. The recommended dose to the brain or involved spine is 30 Gy in 10 fractions over 2 weeks. Patients with leukemic or lymphomatous CAM may improve neurologically after RT. Improvement is uncommon with CAM from solid tumors.
- Chemotherapy is the only therapeutic modality that can treat the whole neuraxis. It is best administered by the IT route, either by LP or Ommaya reservoir. Drug distribution is more even throughout the neuraxis when using the intraventricular route. Drugs that are approved for IT chemotherapy (usually once or twice weekly) include methotrexate, cytarabine, thiotepa, and depofoam cytarabine. Systemic chemotherapy has not been as effective as IT, due to poor CSF penetration and low drug concentrations. High-dose intravenous methotrexate, cytarabine, and thiotepa have had modest efficacy in some patients.
SURGERY/OTHER PROCEDURES
Surgical intervention is rarely necessary for treatment of CAM. Leptomeningeal biopsy may be of benefit in clinically suspicious patients with negative CSF and MRI testing. Ommaya reservoir placement should be considered for all patients receiving IT chemotherapy. Patients that develop hydrocephalus will require placement of a ventriculoperitoneal shunt. The shunt should contain an on–off valve to allow IT chemotherapy.
IN-PATIENT CONSIDERATIONS
Initial Stabilization
Initial stabilization consists of dexamethasone to control symptoms of intracranial pressure, anticonvulsants as required to control seizures, and pain control.
Admission Criteria
Admission is usually for progression of neurological dysfunction and/or seizure activity.
Discharge Criteria
Maximizing anticonvulsant doses and resolving metabolic disturbances will be required before discharge; new modes of treatment may be required (e.g., RT, IT chemotherapy).
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FOLLOW-UP RECOMMENDATIONS
Follow-up recommendations will vary depending on the acute issues involved, and on the extent of further active treatment.
Patient Monitoring
Patients are followed with assessment of neurological function and CSF evaluation every 4–8 weeks. MRI follow-up is required every 2–4 months; patients receiving chemotherapy may need more frequent monitoring of clinical and hematological status. Anticonvulsant levels need to be monitored carefully.
PATIENT EDUCATION
PROGNOSIS
- CAM is a virulent complication of cancer with a natural history of death in 4–8 weeks without treatment. Median overall survival is poor and ranges from 4 to 6 months with treatment. Survival is most limited for patients with solid tumors, except for those with breast cancer, who may survive 6–12 months. Patients with leukemia and lymphoma may respond well to therapy.
- The most important factors for extended survival are early diagnosis with low subarachnoid tumor burden, good performance status, mild neurological dysfunction, female sex, longer duration of symptoms, and treatment with IT chemotherapy; factors contributing to brief survival include high CSF protein levels, severe neurological dysfunction, male sex, poor performance status, and clinical involvement of the supratentorial leptomeninges.
COMPLICATIONS
Complications involve the potential loss of neurological function if leptomeningeal tumor is allowed to damage the brain, cranial nerves, spinal cord, or spinal nerve roots.
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