AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

Leptomeningeal carcinomatosis (LC) is a serious complication of cancer that carries substantial rates of morbidity and mortality. It may occur at any stage in the neoplastic disease, either as the presenting sign or as a late complication, though it is associated frequently with relapse of cancer elsewhere in the body.

First recognized by Eberth in 1870, LC remains underdiagnosed even today. Nevertheless, it has been recognized more frequently in the last 3 decades than before because of improved diagnostic tools, therapy, and awareness.

LC occurs with invasion to and subsequent proliferation of neoplastic cells in the subarachnoid space. Malignancies of diverse origins may spread to this space, which is bound by the leptomeninges. Spread of hematologic cancers to this space and direct CSF seeding of intraparenchymal intraaxial CNS tumors are also well recognized.

The leptomeninges consist of the arachnoid and the pia mater; the space between the 2 contains the CSF. When tumor cells enter the CSF (either by direct extension, as in primary brain tumors, or by hematogenous dissemination, as in leukemia), they are transported throughout the nervous system by CSF flow, causing either multifocal or diffuse infiltration of the leptomeninges in a sheetlike fashion along the surface of the brain and spinal cord. This multifocal seeding of the leptomeninges by malignant cells is called leptomeningeal carcinomatosis if the primary is a solid tumor, and lymphomatous meningitis or leukemic meningitis if the primary is not a solid tumor.

Lymphomatous or leukemic meningitis is somewhat of a misnomer, as meningitis implies an inflammatory response that may or may not be present. It is not a single entity pathologically; it can occur concurrently with CNS invasion or wide dissemination in the intraventricular spaces, or in association with CNS metastases, with the clinical picture differing somewhat in each case.

Pathophysiology

Metastatic seeding of the leptomeninges may be explained by the following five postulated mechanisms: (1) hematogenous spread to choroid plexus and then to leptomeninges, (2) primary hematogenous metastases through the leptomeningeal vessels, (3) metastasis via the Batson venous plexus, (4) retrograde dissemination along perineural lymphatics and sheaths, and (5) centripetal extension along perivascular and perineural lymphatics from axial lymphatic nodes and vessels through the intervertebral and possibly from the cranial foramina to the leptomeninges. CSF flow then seeds the tumor cells widely, with infiltration greatest at the basilar cisterns and dorsal surface of the spinal cord, particularly the cauda equina.

Signs and symptoms usually are attributable to obstruction of CSF flow that leads to increased intracranial pressure (ICP) or hydrocephalus, local tumor infiltration in the brain or spinal cord that causes cranial-nerve palsies or radiculopathies, alterations in the metabolism of nervous tissue that causes seizures, and encephalopathy or focal deficits or occlusion of blood vessels as they cross the subarachnoid that lead to infarcts.

Frequency

United States

Approximately 1-8% of patients with cancer develop LC. However, the exact incidence is difficult to determine as gross inspection at autopsy may miss LC, and microscopic pathologic examination findings may be normal if the seeding is multifocal or if an unaffected area of the CNS is examined. The most frequent origin of such neoplasms is the lungs (30-70%), followed by breast (10-30%), GI tract (2-20%), and malignant melanomas (2-15%).

Adenocarcinomas are the most common tumors to metastasize to the leptomeninges, though any systemic cancer can do so. Small-cell lung cancers spread to the leptomeninges in 9-25% of cases; melanomas, in 23%; and breast cancers, in 5%. However, because of the different relative frequencies of these cancers, most patients with LC have breast cancer.

Uncommon neoplasms, such as embryonal rhabdomyosarcoma and retinoblastoma, also tend to spread to leptomeninges, but sarcomas rarely do. Medulloblastomas are among those tumors that spread to the CSF, as do ependymomas and glioblastomas on occasion. Squamous cell carcinomas of head and neck can spread to the meninges along cranial-nerve paths. Although LC is uncommon in children, it can be seen in those with acute lymphocytic leukemia (ALL) and primary brain tumors, particularly ependymomas, medulloblastomas, and germ-cell tumors.

The incidence of LC increases the longer a patient has the primary cancer; LC is accompanied by other intracranial metastases in 98% of patients with a nonleukemic primary cancer.

Mortality/Morbidity

The median survival is 7 months for patients with LC from breast cancers, 4 months for patients with LC from small-cell lung carcinomas, and 3.6 months for patients with LC from melanomas.

• Without therapy, most patients survive 4-6 weeks, with death occurring because of progressive neurologic dysfunction.
• With therapy, most patients die from the systemic complications of their cancer rather than the neurologic complications of LC.
• Fixed focal neurologic deficits (eg, cranial-nerve palsies) generally do not improve, but encephalopathies can improve dramatically with treatment.

Race

There is no evidence that races are differentially affected.

Sex

Men and women are equally affected.

Age

The incidence of most forms of cancer that lead to LC increases with age.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

• Meningeal symptoms are the first manifestations in some patients; however, most patients already have widespread and progressive cancer with few therapeutic options left.
• A high index of suspicion is necessary, and involvement of multiple anatomic sites in the CNS should raise the suspicion for LC, although multiple metastases are more likely with that presentation.
• The symptoms are protean and can include the following:
• • Headaches (usually associated with nausea, vomiting, lightheadedness)
  • Gait difficulties from weakness or ataxia
  • Memory problems
  • Incontinence
  • Sensory abnormalities
• Pain and seizures are the most common presenting complaints.

Physical

• Signs generally exceed patient-reported symptoms.
• Involvement of CNS is divided into the following three broad anatomical groups:
• • Cerebral involvement results in headache, lethargy, papilledema, behavior changes, and gait disturbance (the latter can be due to either cerebellar or cauda equina involvement). Major dysfunction, such as hemiparesis and hemisensory loss of visual field defects, is rare and more indicative of parenchymal metastasis.
  • Cranial-nerve involvement presents with impaired vision, diplopia (most common), hearing loss, and sensory deficits, including vertigo. Palsies of cranial nerves III, V, and VI are most common; palsy of nerve VII is less common. Solid tumor-derived LC has a higher affinity for the optic and extraocular nerves, while leukemic meningitis preferentially affects the facial nerve. Involvement of multiple cranial nerves is the rule rather than the exception.
  • Spinal-root involvement is caused by either meningeal irritation, presenting with nuchal rigidity (15%) and neck and back pain (rare), or invasion of the spinal roots. The latter can cause leg weakness, radiculopathy (usually lumbar, mimicking a herniated disk), reflex asymmetry or loss (most common, noted in 70% of patients), sphincter incontinence (less common), positive Babinski reflexes, paresthesias, and numbness. Asymptomatic bladder enlargement can occur from spinal cord compression. Spinal-root symptoms are usually followed by cranial-nerve symptoms. Nuchal rigidity, positive results on the straight-leg raising test, and decreased rectal tone are rare.
• Over the course of the disease, cranial-nerve deficits are the most frequent signs, occurring in 94% of patients. Although these are seldom the presenting complaint (30% of patients), mild cranial-nerve abnormalities are usually present on physical examination; the abnormalities typically include diplopia, dysphagia, dysarthria, and hearing loss. However, most patients do not have isolated cranial-nerve deficits; rather, they have a combination of cranial-nerve, cerebral, and spinal signs.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Other Problems to be Considered

New signs or symptoms may represent LC progression, but must be distinguished from parenchymal disease, because 30-40% of those with LC also have brain metastases also, paraneoplastic syndromes, or the adverse effects of chemotherapy or radiation. Multifocal neurologic signs can also be characteristic signs of multiple brain or epidural metastases, and signs of meningeal irritation can also be caused by infection.

LC can be difficult to distinguish from subacute or chronic meningoencephalitis caused by tuberculosis or fungus, as CSF findings in both show moderate mononuclear pleocytosis and decreased glucose. However, patients with LC usually are afebrile, and their neurologic symptoms appear early in the course with a preserved level of consciousness, rather than late with depressed mental status as in tubercular or fungal meningoencephalitis.

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

• The diagnosis is made with positive CSF cytologic results, subarachnoid metastases identified on radiologic studies, or a history and physical examination suggestive of LC along with abnormal CSF findings. Order a workup for LC in patients presenting with the following:
• • Neurologic signs and symptoms at more than 1 level of the neuraxis (present in 75% of patients with LC).
  • Neurologic signs and symptoms consistent with a single lesion but with no mass evident on imaging.
  • Neurologic signs and symptoms consistent with inflammatory meningitis but without fever.
  • Imaging showing leptomeningeal enhancement or CSF-flow obstruction.
  • Elevated CSF protein level in a patient with cancer but without known cerebral metastases.
• The first step in diagnostic workup should be gadolinium-enhanced MRI of the area of maximal symptomatology, followed by a lumbar puncture (LP) if the patient has no evidence of increased ICP, repeated as many as 3 times or until findings are positive.

Imaging Studies

• In general, imaging findings are consistent with or suggestive rather than diagnostic of LC, and they are most useful in detecting secondary complications of LC, such as hydrocephalus, periventricular edema, and gyral effacement.
• • About 50% of patients with LC have abnormal imaging findings, most commonly contrast enhancement of the basilar cisterns, cortical convexities, cauda equina, or hydrocephalus without a mass legion. However, this enhancement usually follows positive cytologic findings by 6 months.
  • MRI of the spinal cord involvement can show nerve-root thickening, cord enlargement, intraparenchymal and subarachnoid nodules, or epidural compression.
  • Meningeal enhancement, which reflects either a blood supply outside the blood-brain barrier or a disturbed blood-brain barrier, is also seen in infections, inflammatory diseases, trauma, or subdural hematomas; after craniotomy; and sometimes after LP. Nevertheless, delineation of the extent of leptomeningeal disease through imaging is important because radiotherapy then can be effectively targeted to these regions rather than to the entire neuraxis.
• Perform contrast-enhanced brain CT or gadolinium-enhanced MRI in patients with cancer and neurologic symptoms to look for metastases and to determine the risk of herniation from LP. However, these tests are relatively insensitive for LC itself. As many as 60% of CT scans appear normal; MRI is more sensitive.
• CT results will most likely be normal. Scans may reveal unexplained communicating hydrocephalus or abnormal enhancement of the tentorium, sylvian fissures and basal cisterns, cortical subarachnoid space, and ventricular walls.
• MRI is the imaging study of choice and slightly more sensitive than CT (66%) because of the use of paramagnetic contrast agents.
• Although seldom indicated, myelography may show nodularities or thickening of the nerve roots in approximately 25% of patients with LC, with similar findings apparent on MRI. Myelography can show intra-arachnoid nodular filling defects, longitudinal striations, prominent and crowded nerve roots of the cauda equina, or scalloping of the subarachnoid space.

Other Tests

• Radionuclide studies using either ¹¹¹indium-diethylenetriamine penta-acetic acid or ⁹⁹Tc macroaggregated albumin can be used to assess CSF flow, which is abnormal in 30-40% of patients with LC. Abnormal CSF flow must be addressed prior to the administration of intrathecal chemotherapy, as it can prevent homogenous delivery.
• Myelography, cerebral arteriography, and other tests, such as EEG, seldom are indicated.
• Electromyography (EMG) can assist with diagnosis, but it is rarely necessary.
• Monoclonal antibodies can be useful in diagnosing CSF lymphoma, particularly if cytologic examination cannot distinguish between reactive lymphocytes and malignant lymphocytes.

Procedures

• Lumbar puncture
• • LP is the most useful test. Analysis of CSF obtained is more accurate than that obtained by using a ventricular catheter, as ventricular fluid usually has higher glucose and lower protein levels and is less likely to yield positive cytologic findings. For this reason, periodic LP is recommended, even in patients with catheters.
  • Measure the opening pressure (elevated in 50% of patients) and send the CSF for an analysis of cytology, cell counts, and protein and glucose levels.
  • Carcinoma cells in the CSF is diagnostic, with the exception of a few false-positive results in patients who have reactive lymphocytes (which are difficult to distinguish from malignant lymphomatous cells) because of an infectious or inflammatory process in the CSF. However, negative cytologic findings do not rule out the diagnosis, as 50% of patients with LC have a negative cytologic result on the first LP. This percentage drops to 15% after 3 high-volume LPs.
  • Cytologic findings are more likely to be positive in patients with extensive leptomeningeal involvement than in patients with focal involvement because CSF obtained from a site distant to the pathology is more likely to yield negative pathology.
  • CSF pleocytosis and modest protein elevations are consistent with but not indicative of the diagnosis, but reduced glucose levels usually are seen only with LC (ie, abnormal glucose transport) or infection (ie, increased glucose utilization).
  • The lymphocyte count is elevated in more than 50% of patients with LC, and the presence of eosinophils should raise the suspicion of lymphomatous infiltration (except patients who are given ibuprofen).
  • Xanthochromia can occur from leptomeningeal bleeding, which is most likely in LC from a melanoma.
  • Most biochemical markers in CSF have poor sensitivity and specificity, but when present, levels decline with successful therapy. Their reelevation can thus signal a relapse before any other findings become apparent. Useful markers include carcinoembryonic antigen (CEA) from adenocarcinomas, alpha-fetoprotein and beta-human chorionic gonadotropin from testicular cancers, 5-hydroxyindoleacetic acid (5-HIAA) from carcinoid tumors, and immunoglobulins from multiple myeloma; their presence in CSF is virtually diagnostic.
  • • Epithelial-associated glycoprotein (HMFGI antigen) is present in 90% of LCs.
    • Cytokeratins measured by tissue polypeptide antigen (TPA) and tissue polypeptide-specific antigen (TPS) have 80% sensitivity to LC from breast cancer.
    • Neither CEA nor beta-glucuronidase is helpful in detecting solid tumors or metastases, nor are they useful in detecting leptomeningeal lymphomatosis. However, if their levels are elevated, a return to normal levels of both markers signifies successful treatment.
    • CSF fibronectin values are elevated in LC but also in bacterial meningitis and tick-borne encephalitis.
    • Myelin basic protein can indicate disease activity, particularly if values are measured longitudinally.
    • Elevated CSF CEA is specific, unless serum levels are unusually high (ie, >100 ng/mL).
    • CSF beta-glucuronidase values are frequently elevated, but wide fluctuations make it unreliable as a marker, and elevations also occur with bacterial, viral, fungal, or tubercular meningitis. In association with elevated lactate dehydrogenase (LDH), however, high CSF beta-glucuronidase levels can indicate LC from a breast primary tumor with a high sensitivity and specificity.
  • Monoclonal antibodies are also not more sensitive than cytology, but can be used to distinguish between reactive and neoplastic lymphocytes in the case of LC from lymphoma.
  • Creatine-kinase BB isoenzyme (CK-BB), tissue polypeptide antigen (TPA), b_2-microglobulin, b-glucuronidase, LDH isoenzyme-5, and vascular endothelial growth factor (VEGF) are strong indirect indicators of LC, but are not sensitive enough to improve on cytology.
• • LDH concentrations are elevated in cases of stroke, bacterial meningitis, CSF pleocytosis, head injury, primary CNS tumors, and some metastases. Levels are also elevated in 80% of LCs; therefore, they can be useful in confirming the diagnosis. LDH isoenzyme-5 levels are elevated in LCs from breast or lung primary tumors and melanoma, as well as bacterial meningitis, but they are sometimes normal even when cytologic findings are positive
  • Levels of CSF b₂-microglobulin may be useful in detecting LC caused by hematologic spread but not in LC from solid tumors. Levels may be elevated after treatment with intrathecal methotrexate (MTX).
• • Ferritin levels are sensitive to inflammatory changes in the CSF, but they are nonspecific for early LC.
  • CSF alkaline phosphatase levels may be elevated in an LC from a lung primary tumor.
  • CSF prostate-specific antigen (PSA) may be elevated in an LC from a prostate primary tumor.
  • PCR is not useful as the precise genetic alteration of the neoplasia is usually not known.

Histologic Findings

Leptomeningeal biopsy may be necessary if the patient has no evidence of a primary tumor. The findings can be diagnostic if results of all other tests are negative. Macroscopic pathology shows diffuse fibrotic thickening of the brain and spinal cord, as well as layering of the nerve roots with tumor tissue. Microscopic examination shows local fibrosis with tumor cells covering the blood vessels and nerves, either as a single layer or as aggregates.

Staging

Staging varies by primary cancer, but metastatic disease is stage IV by definition.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Medical Care

Treatment goals include improvement or stabilization of the patient's neurologic status and prolongation of survival. Some clinicians are hesitant to even treat LC, given the short duration of survival and risk of neurotoxicity, but a high index of suspicion and prompt treatment can prevent serious and irreversible neurologic damage. The lack of large randomized controlled trials has made the correct choice of treatment controversial.

• The intensity of treatment is decided on the basis of the presence of a systemic cancer that is responsive to treatment and preexisting neurologic damage and relatively preserved functionality.
• The entire neuraxis must be treated, as tumor cells are disseminated widely by CSF flow. The standard therapies are (1) radiation therapy to symptomatic sites and regions where imaging has demonstrated bulk disease and (2) intrathecal chemotherapy.
• • Radiation palliates local symptoms, relieves CSF flow obstruction, and treats areas such as nerve-root sleeves, Virchow-Robin spaces, and the interior of bulky lesions that chemotherapy does not reach. Radiation therapy typically consists of 2400 rads given in 8 doses over 10-14 days. Radiation is directed to the site of major clinical involvement and planned so that myelosuppression is acceptable and does not compromise efforts to eliminate malignant cells from the CSF. Dosages can range from 20 Gy in 1 week to 30 Gy over 3-4 weeks. The dosage for lymphomatous and leukemic meningitis is usually 30 Gy given over 10 doses.
  • Intrathecal chemotherapy treats subclinical leptomeningeal deposits and tumor cells floating in the CSF, preventing further seeding.
  • • Three agents are routinely given; methotrexate (MTX), cytarabine (Ara-C), and thiotepa.
    • Cytararabine is the first-choice agent; it is not effective for solid tumors but is useful in leukemic and lymphomatous meningitis. It is now available in liposome-encapsulated form (DepoCyt) that can be administered every 2 weeks rather than 2-3 times a week and results in a longer time to disease progression and higher quality of life than therapy with MTX.
    • Thiotepa, the second-line agent after MTX and cytarabine, is cleared from CSF within minutes and has survival curves similar to those of MTX with less neurologic toxicity than MTX.
    • The superiority of combination intrathecal therapies over single agents is controversial, but there is evidence that the combination of MTX, cytarabine, and hydrocortisone leads to increased cytologic response and longer median survival time than MTX alone. Combination treatments may be more neurotoxic than single agents, however.
  • Treat the systemic cancer, as the patient is likely to die from that.
• For patients who respond well to treatment, start treatment with radiation to bulky tumors and symptomatic sites, and place a ventricular catheter if possible. Scan CSF flow, and follow this with intrathecal chemotherapy if CSF flow is not obstructed. Also, optimally manage any systemic cancers.
• For patients with a fair response to treatment, local radiation therapy and intrathecal chemotherapy delivered by means of LP may be appropriate.
• Patients who are classified as poor risk may be offered radiation therapy to symptomatic sites or supportive measures only (eg, analgesics, anticonvulsants, steroids). Treatment is difficult and primarily palliative, and results are generally poor because of the presence of many metastases.
• A number of other therapies are under development.
• • Mafosfamide is a form of cyclophosphamide that is active intrathecally and has little neurotoxicity aside from headaches, but only phase II trials have been conducted.
  • Diaziquone is effective in hematologic tumors. Adverse effects include headaches and immunosuppression. It can be given at a dosage of 2 mg twice weekly.
  • Another drug, 4-hydroperoxycyclophosphamide (4-HC) is in phase I trials and is apparently effective in treating medulloblastoma.
  • Topotecan, a topoisomerase I inhibitor, is in phase I trials.
  • A drug available for high-dose systemic administration, 6-mercaptopurine (6-MP), has shown efficacy in some patients.
  • There are case reports of LC from non—small cell lung cancer (NSCLC) or breast cancer responding to intrathecal gemcitabine, trastuzumab, letrozole, and tamoxifen.
  • One patient with LC from prostate cancer responded to hormonal manipulation.
  • Intrathecal busulfan, currently in phase I trials, may be active against cyclophosphamide-resistant neoplasms and other tumors.
  • Another drug, 3-(4-amino-2-methyl-5-pyrimidinyl) methyl-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU) is modestly effective in animal studies; however, it is neurotoxic and not yet available for use in humans.
  • Immunotoxins, such as monoclonal antibodies coupled with a protein toxin or radioisotope, seem effective and are being studied.
  • Gene therapy based on the herpes simplex virus thymidine kinase gene combined with ganciclovir is under study but not yet available.
• Supportive care: Analgesia with opioids, anticonvulsants for seizures, antidepressants, and anxiolytics should be offered to all patients as needed. Attention problems and somnolence from whole-brain radiation can be treated with psychostimulants or modafinil.

Surgical Care

• Place an intraventricular or subgaleal catheter if necessary for the administration of cytotoxic drugs.
• In patients with symptomatic increased ICP (ie, severe intractable headache, papilledema, stupor, and repetitive plateau waves on EEG), placement of a ventriculoperitoneal shunt may be necessary if the increased ICP is not ameliorated by steroids.
• Administer intrathecal chemotherapy by means of LP rather than an Ommaya device if a shunt is present to ensure that the medication reaches the basal cisterns and spinal leptomeninges.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Chemotherapy is best administered intrathecally so that chemotherapeutic agents, which are usually hydrophilic, do not encounter the blood-brain barrier and easily reach tumor cells in the CSF or leptomeninges. The preferred route of administration is through an implanted subcutaneous reservoir (eg, Rickham or Ommaya reservoir) and ventricular catheter rather than LP, for 4 reasons. First, intraventricular injection through an Ommaya reservoir is easy and ensures entry into the CSF. Second, when injected into the ventricle, the drug follows normal CSF flow and thus reaches all parts of the CSF space. Third, repetitive LPs are arduous and painful for the patient. Fourth, about 10-15% of LPs do not deliver all of the drug intended to reach the subarachnoid space.

CSF flow abnormalities are common in patients with increased ICP and hydrocephalus, and 70% of patients with LC have ventricular outlet obstructions, abnormal spinal canal flow, or impaired flow over the cortical convexities, but these can be reversed with local radiation therapy. A CSF-flow study is recommended for all patients at the initiation of intrathecal chemotherapy, and such therapy should be deferred if an obstruction is noted. Systemic therapy can be useful if the blood-brain barrier already has been disrupted or if the chemotherapeutic agent is lipid soluble.

Drug Category: Chemotherapeutic agents

These agents inhibit cell growth and proliferation.

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Further Inpatient Care

• Once intrathecal chemotherapy has been initiated, check CSF cytology every 4 weeks.
• • If the cytologic result is negative, continue chemotherapy at the same rate of twice a week for 2 more weeks, then decrease the frequency to twice a week for 1 week a month, followed by further CSF monitoring every two months.
  • If the CSF cytologic results remain positive, continue the chemotherapy at the same rate, change the chemotherapeutic agent, or reclassify patient as poor risk and administer palliative treatment.

Complications

• The most common complication is hydrocephalus, which results when tumor occludes the CSF outflow foramina of the fourth ventricle and the inflammatory response decreases CSF reabsorption.
• • A rapidly developing hydrocephalus causes increased ICP, occasionally leading to herniation of the tentorium and cerebellum, while a slowly developing hydrocephalus can cause dilatation of the ventricles without an increase in ICP, confusing the diagnostician if this is the presenting sign.
  • Even in the absence of hydrocephalus, flow abnormalities are present in 70% of patients with LC, adversely affecting the distribution of intrathecal chemotherapy.
• Other complications are frequent.
• • LC may invade the parenchyma of the brain or Virchow-Robin spaces to cause seizures or other neurologic dysfunction, and interference with blood supply causes areas of ischemia or infarction.
  • Competition for glucose between malignant cells and neurons can lead to hypofunction in affected areas. For example, in hypothalamic leukemia, weight gain in patients in leukemic remission can signify relapse because hypothalamic hypoglycorrhachia is induced by local competition for glucose by metastatic tumor cells.
  • LC also causes partial disruption of the blood-brain barrier once the tumor size has increased enough to stimulate growth of its own vasculature.
• Treatment-related complications can result from catheter placement, chemotherapy, or radiation.
• • Catheter placement causes perioperative complications (1% of patients), and after placement, the catheter tip can migrate into the brain tissue, obstruct the shunt, or, more commonly, cause infection (usually Staphylococcus epidermidis, in 5% of patients).
  • MTX administration can cause acute arachnoiditis (nausea, vomiting, mental status changes), seizures, mucositis, or myelosuppression (mitigated with folinic acid coadministration, 10 mg q6h for 24 h).
  • • Meningeal irritation, characterized by headache, fever, stiff neck (sometimes), confusion, and disorientation, often develops several hours following intrathecal MTX administration but is self-limiting and resolves within 24-72 hours. This can be treated on an outpatient basis with antipyretics, antiemetics, and corticosteroids.
    • Transverse myelitis is a rare idiosyncratic reaction to MTX that begins 30 min to 48 h after intrathecal treatment and presents with paraplegia, leg pains, and development of a sensory level and bladder dysfunction; it should be distinguished from traumatic spinal subdural hematoma. Again, no specific treatment is available but some improvement can occur over days to months.
    • Leukoencephalopathy is the most serious complication; it appears a year after treatment and is more likely in those who have also undergone cranial radiation. It presents as a progressive encephalopathy, often with ataxia, dysarthria, and focal findings.
  • Cytarabine, like MTX, also may cause meningism, headache, and fever.
  • Thiotepa causes less neurologic toxicity than MTX; the most common effect is transient limb paresthesias. Unlike MTX, there is no way of mitigating the resultant myelosuppression.
  • Radiation can cause myelosuppression and increase the neurotoxicity of intrathecal chemotherapy. Necrotizing leukoencephalopathy is most common after a combination of MTX and cranial irradiation. Initial findings are changes in the white matter on neuroimaging after 6 months of therapy; progressive dementia and other neurologic complications develop later. Other complications are delayed cerebral radiation necrosis, acute transverse myelopathy, chronic progressive myelopathy, and acute brachial plexus lesions.

Prognosis

• The prognosis is generally poor because LC usually signifies the presence of metastases elsewhere, and the course of the systemic cancer is the major determinant of the patient's survival. The exception is leukemic or lymphomatous meningitis, which is sensitive to both MTX and Ara-C and often can be eradicated completely from the CNS. Poor prognostic indicators include the following:
• • Poor performance status
  • Multiple fixed neurologic deficits
  • Bulky CNS disease
  • Coexistent carcinomatous encephalopathy
  • CSF flow abnormalities on radionuclide ventriculography
• Among patients with LC from solid tumors, the best response to chemotherapy and radiation occurs in those with LC from breast cancer, with 60% improving or stabilizing and a median survival of 7 months; 15% survive for a year, a survival rate rare in patients with LC with a primary tumor other than breast.
• Only 40% of LCs from small-cell lung carcinoma improve or stabilize, and patients with this disease have a median survival of only four months.
• Melanoma-derived LC carries a 3.6-month median survival, and only 20% of these patients stabilize or improve with treatment.
• Nonresponders to chemotherapy seldom survive longer than a month. This prognosis has not improved measurably in the last 20 years despite an increase in incidence and diagnosis.
• The most useful prognostic indicator is the Karnofsky scale (KS) score. Patients with a KS score of 70 or higher survive for a mean of 313 days, whereas those with a score of 60 or lower survive for a mean of only 36 days.
• Tumor response 2 weeks after the initiation of treatment is a good portent.
• Progressive multilevel involvement or rapid progression in 1 or more CNS lesions is ominous.

Patient Education

• For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education article Brain Cancer.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

• Balm M, Hammack J. Leptomeningeal carcinomatosis: presenting features and prognostic factors. Arch Neurol. Jul 1996;53(7):626-32. [Medline].
• Bradley WG. Leptomeningeal metastases in primary and secondary tumors of the nervous system. In: Neurology in Clinical Practice. Stoneham, MA: Butterworth-Heinemann; 1991.
• Chamberlain MC. Meoplastic meningitis. J Clin Oncol. May 2005;23:3605-3613.
• Chamberlain MC. Neoplastic meningitis: a guide to diagnosis and treatment. Curr Opin Neurol. Dec 2000;13(6):641-8. [Medline].
• Chamberlain MC, Kormanik PA, Glantz MJ. A comparison between ventricular and lumbar cerebrospinal fluid cytology in adult patients with leptomeningeal metastases. Neuro-oncol. Jan 2001;3(1):42-5. [Medline].
• Cokgor I, Friedman AH, Friedman HS. Current options for the treatment of neoplastic meningitis. J Neurooncol. Oct 2002;60(1):79-88. [Medline].
• Gasecki AP, Bashir RM, Foley J. Leptomeningeal carcinomatosis: a report of 3 cases and review of the literature. Eur Neurol. 1992;32(2):74-8. [Medline].
• Glantz MJ, Cole BF, Glantz LK, et al. Cerebrospinal fluid cytology in patients with cancer: minimizing false- negative results. Cancer. Feb 15 1998;82(4):733-9. [Medline].
• Grossman SA, Krabak MJ. Leptomeningeal carcinomatosis. Cancer Treat Rev. Apr 1999;25(2):103-19. [Medline].
• Hildebrand J. Prophylaxis and treatment of leptomeningeal carcinomatosis in solid tumors of adulthood. J Neurooncol. Jun-Jul 1998;38(2-3):193-8. [Medline].
• Pavlidis N. The diagnostic and therapeutic management of leptomeningeal carcinomatosis. Ann Oncol. 2004;15 Suppl 4:iv285-91. [Medline].
• Posner JB. Leptomeningeal metastases. In: Neurologic Complications of Cancer. Oxford, England: Oxford University Press; 1995.
• Recht L, Phuphanich S. Treatment of neoplastic meningitis: what is the standard of care?. Expert Rev Neurother. Jul 2004;4(4 Suppl):S11-7. [Medline].
• Soletormos G, Bach F. Cerebrospinal Fluid Cytokeratins for Diagnosis of Patients with Central Nervous System Metastases from Breast Cancer. Clinical Chemistry. 2001;47:948-950.
• Tetef ML, Margolin KA, Doroshow JH, et al. Pharmacokinetics and toxicity of high-dose intravenous methotrexate in the treatment of leptomeningeal carcinomatosis. Cancer Chemother Pharmacol. 2000;46(1):19-26. [Medline].
• Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer. Feb 15 1982;49(4):759-72. [Medline].
• Wolfgang G, Marcus D, Ulrike S. LC: clinical syndrome in different primaries. J Neurooncol. Jun-Jul 1998;38(2-3):103-10. [Medline].

Article Last Updated: Aug 30, 2007