Leptomeningeal Disease

1 Leptomeningeal Disease

Leptomeningeal carcinomatosis is a serious complication of cancer. It is also known as neoplastic meningitis. It causes substantial morbidity and mortality. It can occur at any time. Leptomeningeal disease is mostly associated with a relapse of cancer elsewhere in the body. In the neoplastic disease, leptomeningeal carcinomatosis can occur at any stage; it can occur either as a late complication or as a present sign.

Leptomeningeal carcinomatosis spreads to the surrounding membrane of the brain and spinal cord. The neoplastic cells in the subarachnoid space invade and proliferate. Intra-axial CNS tumors of different origin and hematologic cancers may also spread to this space. Due to drop, metastases through the spread of extra-axial space, local perineural invasion, hematogenous seeding, and infiltration of the meningeal space may occur. However, in cases of gastric cancer or cancer of the head and neck, perineural invasion is not frequently seen.

Leptomeningeal actually consists of the arachnoid and pia matter, and between the spaces is the CSF. Tumor cells may enter this space with the flow of cerebrospinal fluid, or CSF, and get transported throughout the entire nervous system. This results in multifocal seeding or diffuse infiltration of the leptomeningeal. It also spreads on the surface of the brain and spinal cord in a sheet-like fashion. Leptomeningeal carcinomatosis is the multifocal seeding of the leptomeningeal by the tumor cells if the primary cells are solid tumor cells. If the primary cells are not solid tumor, it is known as leukemic meningitis.

Leukemic meningitis is also known as lymphomatous meningitis. It was first recognized by Eberth in 1870. Until today, it remained undetected. However, due to improved diagnostic tools, awareness, and therapy, in the last three decades, it has been frequently diagnosed.

When the tumor cells infiltrate the CSF and travel through various paths of brain and spinal cord, it results in leptomeningeal disease. Even though this disease is fatal, the patient can benefit greatly from a combination of treatments, such as radiation, chemotherapy, and surgery.

Leptomeningeal Disease

2 How it occurs

When the cancer cells from the breast, lung, or other part of the body migrate to the CSF, leptomeningeal disease occurs. CSF is a fluid that circulates nutrients and chemicals to the brain and spinal cord. If the malignant/cancer cells reach the CSF, they settle there and grow. This condition has various names, such as neoplastic meningitis, carcinomatous meningitis, leukemic meningitis, and lymphomatous meningitis.

Leptomeningeal disease is thought to occur in 3%–5% of cancer cases. Cancer of the breast or lungs are the most likely to develop into leptomeningeal disease. It may cause cauda equina nerve deficit or radiculopathy when the tumor cells surround the cranial nerves, or cauda equina syndrome.

3 Symptoms

The signs and symptoms are associated with brain pressure. These include changes in mental status, headache, vomiting, nausea, seizures, difficulty balancing, and papilledema.

The symptoms of leptomeningeal disease include:

  • Headache accompanied by nausea, lightheadedness, and vomiting
  • Difference in gait due to weakness and ataxia
  • Memory problems
  • Sensory abnormalities
  • Incontinence

Even the central nervous system is affected. The symptoms have been divided into three regions depending on whether or not muscle weakness, dysphagia, facial weakness, and facial pain are present:

  • Involvement of the cerebrum: Symptoms include papilledema, gait disturbances, changes in behavior, headache, and lethargy.
  • Involvement of the cranial nerve: Symptoms include diplopia, hearing loss, impaired vision, sensory deficits, vertigo, and cranial nerve palsies. This especially involves nerves CN III, IV, VI, VII, and VIII.
  • Involvement of the spinal root: Symptoms include neck pain, back pain, nuchal rigidity, invasion of spinal roots, radicular pain, and paresthesia.

4 Diagnosis

Diagnoses can be made with the help of the following:

  • Positive CSF cytological test results
  • Radiology studies: If subarachnoid metastasis is identified, the disease can be diagnosed.
  • Physical examination
  • History of the patient
  • Physical examination/medical history: The physician looks for signs such as lumps or anything else abnormal. The doctor will ask about the patient’s health habits, any illnesses in the past, and treatment given for the illness.
  • Lumbar puncture: This is a standard diagnostic procedure. In 50%–70% of cases on initial lumbar puncture, the CSY cytology test is found to be positive. In nearly all cases, after three attempts, the result is positive. In this diagnostic procedure, the CSF pressure and CSF protein are also found to be greater. If CSF is obtained by performing a cisternal puncture rather than a lumbar puncture, it may improve the yield of positive cytology, especially in patients with predominant cerebral symptoms. Sometimes, when a lumbar CSG is negative, cytology of ventricular fluid obtained from intraventricular reservoir is found to be positive. CSF markers and raised tumor markers may indicate the presence of disease. CSF markers include raised cell count, raised protein, low glucose, and raised opening pressure. Although these markers are not diagnostic tools, they may be abnormal in other conditions, too. In some patients with intracranial pressure and a coagulopathy, it may be difficult to obtain CSF.
  • Imaging studies: An MRI includes the use of a magnet, radio waves, and a computer. It gives images of the brain and spinal cord. Imaging modality is preferred over a CT scan. A gadolinium-enhanced multiplanar MRI is done because of its sensitivity and specificity. The findings of an MRI show leptomeningeal enhancement of the spinal cord, brain, cauda equina, and subependymal areas, which may reach into the sulci or folia of the cerebrum of the brain. The MRI may also show nerve root thickening of the spinal cord, enlargement of the cord, intraparenchymal nodules, subarachnoid nodules, or compressed epidural.
  • Neurological exam: In order to check the function of the brain and spinal cord, the doctor will ask some simple questions or may ask to perform certain tests. This is to check a person’s coordination, if the person is able to walk normally, and determine the patient’s mental status. Neuroimaging may be helpful in excluding other neurological symptoms and signs, as well as confirm the clinical suspicion of leptomeningeal disease. In patients with leptomeningeal disease, an MRI may be abnormal. It may be either a positive scan, suggestive scan, or negative scan.
    • Positive scan: Clear leptomeningeal enhancement in the brain, spinal cord, or cauda equina, or subependymal enhancement.
    • Suggestive scan: Dural enhancement, superior cerebral lesion in close proximity to the subarachnoid space, enhancement of cranial nerves, slight leptomeningeal enhancement in the brain, spinal cord, or cauda equina, communicating hydrocephalus.

In almost 79% of patients with positive cytology, neuroimaging was abnormal. In patients with solid tumors rather than hematological tumors, 90% showed abnormal neuroimaging. This may be due to adhesion properties of neoplasm. The neuroimaging becomes enhanced due to bulky leptomeningeal masses. This enhancement forms cerebral lesions and communication hydrocephalus.

The prognosis can be improved through a combination of treatments, such as surgery, radiation, and chemotherapy. Some tumor cells show sensitivity when chemo is injected directly, either by lumbar puncture or Ommaya. Some respond well to oral chemotherapy, such as lung cancer in non-smoking Asian women.

Ommaya is a surgical device implanted under the skin. This implant is connected to a thin, plastic tube that passes deep within the brain into the ventricles where the body makes CSF. With the help of this device, the spinal fluid can be easily assessed. There is no need for a lumbar puncture in order to test the presence of tumor cells and to administer the medication. Many neuro-oncologists believe it is better to instill chemotherapy than to inject it, because it is less painful, easier, and the delivery of the drugs is quicker and more accurate.

CSF is produced by the ventricles. It travels from the center to the back of the brain and then down to the spinal cord. It then goes to the brain surface and again to the blood stream from where it came. Several times a day, our bodies replace this CSF. If the tumor cells reach the CSF, they will travel and cause neurological problems throughout the entire nervous system. Commonly occurring problems include headache, vomiting, weakness, double vision, nausea, difficulty walking, and loss of urine control. Depending on where the cancer lands, leptomeningeal disease can cause various neurological problems. More and more, leptomeningeal disease is being seen by doctors since cancer patients live longer and because chemotherapies are not able to kill the tumor cells due to the fact they are not able to reach the spinal fluid in sufficient amounts. Also, because the MRI cannot pick up the problems in certain areas, detecting the disease becomes difficult.

5 Management

Leptomeningeal disease cannot be cured. Moreover, it is difficult to treat. The main objective of treatment includes stabilizing the patient’s neurological status and prolonging their survival and palliation.

Sometimes, combinations of treatments are needed, such as radiation, surgery, and/or chemotherapy.

Standard therapies include:

  • Radiation therapy: This is done in symptomatic areas and in those areas where bulk disease has shown up in imaging. It helps in palliating local symptoms, relieving CSF flow obstruction, treating nerve root sleeve-like areas, and treating areas  at cannot be reached by chemotherapy, such as Virchow-Roin spaces and the interiors of bulky lesions.
  • Intrathecal chemotherapy: Sometimes, in order to treat the underlying cancer, systemic therapy may also be helpful. It aids in treating sub-clinical deposits of leptomeningeal and any floating in the CSF, if there are any tumor cells. It then treats them as well as prevents any further seeding. The three agents routinely administered are cytarabine, methotrexate, and thiotepa.

If leptomeningeal metastases are not treated, the person may have a poor prognosis and, usually, within a few months, may succumb to the disease. With treatment, the patient’s survival can extend up to six to ten months. Treatment includes radiotherapy and intrathecal chemotherapy. Chemotherapy is the commonly adopted treatment.

Some drugs can be delivered intrathecally, but some, such as vincristine, if delivered intrathecally, may become neurotoxic. With a methotrexate regimen, the drug can be routinely administered in 12mg twice a week in five does. The frequency of treatment is then educed. Later, it is administered monthly. Before administering chemotherapy, the patient cytology on CSF is checked by taking it from the intraventricular reservoir, and the patient is also monitored clinically.

Side effects associated with methotrexate include aseptic meningitis, transverse myelopathy, encephalopathy, chronic leukoencephalopathy (which can further lead to dementia), quadriparesis, and hemiparesis. A patient who receives intrathecal methotrexate should also be given oral leucovorin; this will help prevent systemic toxicity. If patients have raised intracranial pressure, a ventricular peritoneal shunt may be needed.

Supportive care includes:

  • Anticonvulsants for seizures
  • Analgesia with opioids
  • Antidepressants
  • Anxiolytics
  • Pyschostimulants for attention problems

6 Pathophysiology

The seeding of metastases can be postulated by the following mechanisms:

  • Hematogenous spread to choroid plexus, and then to leptomeningeal
  • Through leptomeningeal vessels, it causes primary hematogenous metastases
  • Through the Batson venous plexus, it may cause metastasis
  • Along perineural lymphatic and sheath, it may cause retrograde dissemination
  • It may extend centripetally along perivascular and perineural lymphatic through the intervertebral from axial lymphatic vessels and reach the leptomeningeal from the cranial foramina.
  • From contiguous tumor deposits, it may extend directly. The seeding of the tumor cells happens through the CSF flow; the greatest infiltration occurs at the basilar cisterns, the dorsal surface of the spinal cord, and particularly at the cauda equina.

Signs and symptoms are experienced due to the obstruction of CSF flow that happens because of the adhesion of tumor cells. The obstruction of CSF flow causes the following:

  • Hydrocephalus or increased intracranial pressure
  • In the brain or spinal cord, local tumor infiltration may occur and cause radiculopathies or cranial nerve palsies.
  • The metabolism of nervous tissue becomes altered, which then causes encephalopathy, focal deficits, and seizures.
  • As they cross the subarachnoid, occlusion of blood vessels occurs and leads to infarcts.

7 Morbidity/mortality

For patients with leptomeningeal carcinomatosis due to breast cancer, the reported median survival time is seven months; leptomeningeal carcinomatosis from small cell lung carcinoma is four months; and for patients with leptomeningeal carcinomatosis from melanomas, the reported median survival is 3.6 months. However, the survival rates may increase due to new chemotherapeutic regimens. If no therapy is done, the patient survives only four to six weeks. Death may occur due to a progressive neurological disorder. Patients die mostly from systemic complications of cancer, not the neurological complications. Generally, if there is a fixed focal neurologic deficit, the patient may not show any improvement, but with treatment, encephalopathy can improve dramatically.

There have been no reports of leptomeningeal carcinomatosis affecting a particular race, and both sexes are equally affected.

Leptomeningeal carcinomatosis may seed diffusely or multi-focally. In autopsies of cancer patients, 8% of patients had leptomeningeal disease. It is common in hematological malignancies and in solid tumors. Also, it is common in adenocarcinoma. The sanctuary site can be CSF in the central nervous system.