Leptomeningeal cancer is a rare complication of cancer in which the disease spreads from the original tumor site to the meninges surrounding the brain and spinal cord. This leads to an inflammatory response, hence the alternative names neoplastic meningitis (NM), malignant meningitis, or carcinomatous meningitis. The term leptomeningeal (from the Greek lepto, meaning 'fine' or 'slight') describes the thin meninges, the arachnoid and the pia mater, between which the cerebrospinal fluid is located. The disorder was originally reported by Eberth in 1870. It is also known as leptomeningeal carcinomatosis, leptomeningeal disease (LMD), leptomeningeal metastasis, meningeal metastasis and meningeal carcinomatosis.
It occurs with cancers that are most likely to spread to the central nervous system. The most common cancers that spread to the leptomeninges are breast cancer, lung cancer, and melanomas because they can metastasize to the subarachnoid space in the brain which offers a hospitable environment for the growth of metastatic tumor cells. Individuals whose cancer has spread to an area of the brain known as the posterior fossa have a greater risk of developing a leptomeningeal cancer. The condition can also arise from primary brain tumor like medulloblastoma.
Leptomeningeal disease is becoming more evident because cancer patients are living longer and many chemotherapies cannot reach sufficient concentrations in the spinal fluid to kill the tumor cells.
Signs and symptoms Depending on where the tumor cells settle, leptomeningeal cancer can cause almost any neurological problem.
The most common symptoms of leptomeningeal cancer are pain and seizures. The other symptoms may include headaches (usually associated with nausea, vomiting, light-headedness), gait difficulties from weakness or ataxia, memory problems, incontinence, and sensory abnormalities. In some cases, symptoms may include double vision, vision loss, numb chin, back pain, leg weakness, sphincter-related problems, hydrocephalus, loss of urine control, and difficulty walking.
Other symptoms that are less common cranial nerve abnormalities, spinal symptoms such as limb weakness and paresthesia, and bowel and bladder dysfunction.
Diplopia is the most common symptom of cranial nerve dysfunction. Trigeminal sensory or motor loss, cochlear dysfunction, and optic neuropathy are also common findings.
Spinal signs and symptoms include weakness, dermatomal or segmental sensory loss, and pain in the neck, back, or following radicular patterns.
3 affected domains of neurological function: Cerebral hemisphere (15%) Cranial nerves (35%) Spinal cord and roots (60%)
Signs reported: Headache Mental status change Confusion Cognitive impairment Seizures Hemiparesis Gait instability
Related diseases Parenchymal disease occurs in 30% to 40% of those diagnosed with NM. The disease associated with the main functioning body of an organ, in this case the brain. Acute cerebellar ataxia is a rare initial presenting feature of NM, particularly in gastric cancer. Paraneoplastic cerebellar degeneration (PCD) is a well-known cause of cerebellar ataxia associated with neoplastic disorders, and commonly, with positivity for various anti-neuronal antibodies.Seok, H., Eun, M., Yoo, J., & Jung, K. (2011). Neoplastic meningitis presenting with acute cerebellar ataxia. Journal of Clinical Neuroscience, 18(3), 441-442. Bilateral sensorineural hearing loss caused by complications with the vestibulocochlear nerves from onset of NM Jeffs, G., Lee, G., & Wong, G. (2006). Leptomeningeal carcinomatosis: an unusual cause of sudden onset bilateral sensorineural hearing loss. Journal of Clinical Neuroscience, 13(1), 116-118. Subacute confusion: when functioning of the brain such as cognition deteriorates but at a less rapid rate than that of acute confusionKim, P., Ashton, D., & Pollard, J. (2005). Isolated hypoglycorrachia: leptomeningeal carcinomatosis causing subacute confusion. Journal of Clinical Neuroscience, 12(7), 841-843.
Causes Leptomeningeal carcinomatosis occurs when the cancer cells invade the cerebrospinal fluid and spread throughout the central nervous system. The metastatic tumor cells grow either attached to the pia mater covering the brain and spinal cord or floating unattached to the subarachnoid space. Tumors of diverse origins and hematologic cancers may spread to this space.
Some patients may develop leptomeningeal cancer while receiving chemotherapy for their primary tumour, partly because the blood-brain barrier serves as a protective filter that shields the central nervous system from toxins and pathogens circulating in the blood. While essential for protection, this barrier also complicates treatment, as many chemotherapy agents and biopharmaceuticals struggle to cross into the brain and spinal cord.
Pathology There are three anatomic patterns by which the tumor can spread in the subarachnoid space. More than one pattern may coexist in the same patient.
First, there may be plaque-like deposits of cells in the leptomeninges with invasion of Virchow-Robin spaces and, usually, the shedding of tumor cells into the cerebrospinal fluid.
Second, there may only be a thin coating of meninges, in some cases with only a single cell layer, but also with shedding of tumor cells into the cerebrospinal fluid. Third, there may be a pattern of nodular deposits of tumor on cranial and spinal nerve roots, frequently without tumor cells being shed into the cerebrospinal fluid.
The first and third patterns are common in solid tumors whereas the second occurs most frequently with leukemia and lymphoma.
Spinal cord Neoplastic meningitis (NM) shows diffuse infiltration of tumor cells into the subarachnoid space which may be associated with increased intracranial pressure, signs of meningeal irritation, and damage to the cranial and spinal nerve roots. Pathological feature include: Circular necrosis of the white matter in the periphery of the spinal cord was also noted which probably resulted from circulatory disturbance secondary to tumor infiltration. Dorsal radiculopathy which is secondary ascending degeneration of the posterior funiculus may also occur due to malignant cells collecting or a presence of tumor which cause compression of the nerve. Tumor cell proliferation is observed around nerve roots as well as loss of myelinated nerve fibers and axonal swelling. In areas of tumor cells, infiltration of macrophages is observed. Nerve root infiltration has shown positive correlation with meningeal dissemination. Infiltration of the spinal cord parenchyma is found with destruction of the pia mater. Tumor cell infiltration is associated with spongy changes in the white matter of the spinal cord beneath the pia mater with demyelination, axonal swelling, and macrophage infiltration. Transverse necrosis of the spinal cord is usually marked with bleeding from tumor growth in the subarachnoid space and is the result of compression by the hematoma in the subarachnoid space.
From primary cancer to the meninges NM is a secondary cancer meaning that it is the result of neoplastic cells that have metastasized from a primary cancer site. These cancers develop an enzyme that is able to break down blood vessels at a microscopic level. These cells enter the blood vessels and travel across the body. Once the brain is reached, they break down the blood–brain barrier to enter the Cerebrospinal Fluid (CSF). There the cancerous cells seed and disseminate into the leptomeninges which are composed of the arachnoid and the pia. The CSF continues to carry neoplastic cells through the brain tracts and spreads the cancerous cells.
Lung cancer, breast cancer, and melanoma comprise the majority of solid tumors spreading to the leptomeninges. Although rare, meningeal carcinomatosis can arise from cervical cancer. Only eight cases of MC arising from squamous cell carcinoma of the uterine cervix are previously reported in the literature.
Since NM is a result of primary cancer metastasis and can develop from primary brain tumors or parenchymal metastasis when tumor cells are lodged in small central nervous system (CNS) vasculature, causing local ischemia and vessel damage which result in tumor spillage into the Virchow-Robin spaces and providing access to the subarachnoid space.
Invasion routes Hematogenous spread, or spread through blood vessels, occurs either through the venous plexus of Batson or by arterial dissemination. This occurs with arterioles as a result of tumor cells being lodged in vessels that feed the meninges and later causing leakage into the meninges and CSF. This same situation also appear with spinal arteries where leakage of tumor cells is into the nerve roots. More regarding the effects of NM on spinal cord is discussed later. Tumor cells may also seed the choroid plexus, where CSF is produced, and ultimately gaining direct access to the CSF. Seeding of the choroid plexus is most common in patients with third and lateral ventricular hydrocephalus. Venous spread may occur when intra-abdominal or thoracic pressure increases and venous flow is retrograde which then allows tumor cells in the systemic venous system to enter the vertebral venous system. Centripetal migration from systemic tumors along perineural, invasion of nerve space, or perivascular spaces.Chamberlain, Marc C. (2008). Neoplastic meningitis. The Oncologist, 13(9), 967-977. Malignant cells can migrate along spinal or cranial nerve epineurium-perineurium, invade the subpial space, and travel along blood vessels into the endoneurial space, or invade the nerve parenchyma.
Infiltration happens most often at the base of the brain, dorsal surface, and especially at the cauda equina, which is largely due to the effect of gravity. Once in the CSF, malignant cells can extend along the membrane surfaces or spread freely in the CSF and attach to other locations. These cells have the ability to penetrate the pial membrane and invade the spinal cord and cranial nerves.Mammoser, A., & Groves, M. (2010). Biology and therapy of neoplastic meningitis. Current Oncology Reports, 12(1), 41-49.
Infiltration to spinal cord Infiltration from the subarachnoid space into the spinal cord occurs primarily along the perivascular tissues that surround blood vessels at the brain entrance. Infiltration from the anterior median fissure, a 3mm deep furrow on the anterior side of the spinal cord, to the anterior horn of the spinal cord, the ventral grey matter of the spinal cord, is found along the central artery. Direct infiltration of the nerve roots is also observed, mostly from the dorsal roots (the afferent sensory root of the spinal nerve) than the ventral roots (the efferent motor root of a spinal nerve).
With mild infiltration, tumor cells are found diffusely in the subarachnoid space from the cervical to sacral levels. In some cases however there are no differences between spine levels. Infiltration from the subarachnoid space into the spinal cord occurs mainly along the perivascular space of the white matter. However, in some cases, direct infiltration into the spinal cord parenchyma is found together with destruction of the pia mater.Kizawa, M., Mori, N., Hashizume, Y., & Yoshida, M. (2008). Pathological examination of spinal lesions in meningeal carcinomatosis. Neuropathology, 28(3), 295-302.
Diagnosis Screening involves an MRI scan to identify and diagnose tumors in the subarachnoid region of the brain. MRI can make a diagnosis even without an analysis of the cerebrospinal fluid but it can sometimes be difficult to detect because MRI scans cannot always pick up the problem.
Diagnosis is most commonly made by lumbar puncture to detect malignant cells in the CSF, although the tests may be negative in roughly 10% of patients. Diagnosis often requires a high index of suspicion and is confirmed by neuroimaging and cerebrospinal fluid analysis.