The most common symptom of LM is headaches. The majority of affected individuals also claims nausea and vomiting. Furthermore, patients may experience neurological symptoms consistent with cranial nerve palsies, cerebellar dysfunction, and spinal neuropathies. In this context, visual impairment (diplopia, visual field defects), limb weakness, blunted reflexes, ataxia, hemiparesis, radicular pain, urinary incontinence or retention, fecal incontinence or constipation, among others, may be observed. Because most affected individuals suffer from multiple LM, they may show neurological symptoms seemingly unrelated to each other. For instance, a single patient may present with diplopia and urinary incontinence. Stroke-like episodes have also been described in LM patients. Patients may present with an altered mental status. Additionally, focal or generalized seizures, as well as meningism, may be reported. Neither of the aforementioned symptoms is specific for LM [11].

• Weakness

  A patient with uvular cancer presented with lower limb weakness and paresthesiae, headache, neck stiffness and multiple cranial palsies. No malignant cells were found on lumbar puncture. CT, and MRI were normal. [ncbi.nlm.nih.gov]

  Cranial nerve symptoms including visual loss, diplopia, hearing loss, dysphagia, ocular muscle weakness, facial weakness and facial pain are also seen. [adventhealthcancerinstitute.com]

  Irradiation can be an important part of treatment if the pressure is very high or if signs or symptoms of pain, numbness, or weakness are significant. [jamanetwork.com]

  Facial weakness. Dysphagia. Dysarthria. Hypoglossal (tongue) weakness. [emcrit.org]

  Symptoms Cancer cells in the covering of the brain can cause a range of symptoms, including: headaches changes to your sight, such as double vision or loss of sight confusion weakness seizures (fits) feeling sick (nausea) vomiting hearing changes facial [cancerresearchuk.org]

• Difficulty Walking

  This increased pressure can cause vague but uncomfortable symptoms including headaches (often worse in the morning), nausea, vision changes, and difficulty walking. [jamanetwork.com]

  One of the most common symptoms of cerebral dysfunction due to LM is back pain. anorexia. difficulty walking. [journals.lww.com]

  For example, if the patient has difficulty walking, a hiking pole, cane, walker, or wheelchair may be indicated. [nursingcenter.com]

  The patient eventually developed significant difficulty walking, lower extremity neuropathic pain and numbness, constipation, and urinary retention. In the emergency department, he was nonambulatory and was diagnosed with cauda equina syndrome. [appliedradiationoncology.com]

• Pallor

  Figure 3: Visual field in automated perimetry test showed a cecocentral scotoma after 6 months of treatment Click here to view Figure 4: After 6 months of treatment, he had a temporal pallor of optic disc and optical coherence tomography showed an atrophy [e-tjo.org]

  There was no pallor, icterus, or pedal edema but mild nonpitting edema of the right upper limb. Right axillary lymph node, nontender, firm to hard in consistency measuring 2 cm × 3 cm was palpable. [mjdrdypu.org]

• Nausea

  A 60-year-old woman with a history of ovarian carcinoma and complaining of gait instability, dizziness, nausea, and a right temporal headache visited a neurologist. [ncbi.nlm.nih.gov]

  Most common AEs were skin effects (n = 20), diarrhea (n = 13), nausea (n = 11) and paronychia (n = 9). All were grade (G) 1/2 except 1 case each of diarrhea and nausea (both G3). 9 pts had dose interruptions and 4 had dose reductions to 80 mg qd. [ascopubs.org]

• Vomiting

  When LM occurs, signs and symptoms include headache, nausea, vomiting, lumbar back pain, and stiff or painful neck; LM also may lead to mental disturbances and seizures. [ncbi.nlm.nih.gov]

  […] year-old Caucasian woman with a history of BRCA-positive stage IIIC ovarian carcinoma who was treated with cytoreduction and multiple rounds of intravenous and intraperitoneal chemotherapy presented to the emergency room with progressive headaches, vomiting [academic.oup.com]

  She was suffering from intractable headaches, severe nausea and vomiting, and cerebellar ataxia. [surgicalneurologyint.com]

  Most patients were admitted to hospital with increased intracranial pressure symptoms such as headache, nausea and vomit. [nnjournal.net]

• Constipation

  A twenty-five-year-old Moroccan man came to the Emergency Department presenting with abdominal pain and constipation of a four day duration. The patient also reported rectal bleeding and weight loss. [scielo.isciii.es]

  Symptoms of leptomeningeal metastases may include: Headache Backache Loss of sensation in the face Mental confusion Dizziness Weakness or loss of sensation in the legs and inner thighs Loss of control of the bladder or bowel Constipation Vision and hearing [brainmetsbc.org]

  In this context, visual impairment (diplopia, visual field defects), limb weakness, blunted reflexes, ataxia, hemiparesis, radicular pain, urinary incontinence or retention, fecal incontinence or constipation, among others, may be observed. [symptoma.com]

  The patient eventually developed significant difficulty walking, lower extremity neuropathic pain and numbness, constipation, and urinary retention. In the emergency department, he was nonambulatory and was diagnosed with cauda equina syndrome. [appliedradiationoncology.com]

• Fecal Incontinence

  In this context, visual impairment (diplopia, visual field defects), limb weakness, blunted reflexes, ataxia, hemiparesis, radicular pain, urinary incontinence or retention, fecal incontinence or constipation, among others, may be observed. [symptoma.com]

• Diplopia

  Nine months after the allogeneic SCT, she presented with oculomotor and trochlear nerve palsy (diplopia, ptosis of the right upper eye lid, and dilated right pupil). [bloodjournal.org]

  Cranial nerve symptoms including visual loss, diplopia, hearing loss, dysphagia, ocular muscle weakness, facial weakness and facial pain are also seen. [adventhealthcancerinstitute.com]

  For instance, a single patient may present with diplopia and urinary incontinence. Stroke-like episodes have also been described in LM patients. Patients may present with an altered mental status. [symptoma.com]

  After two months of neoadjuvant therapy the patient returned to the Emergency Department due to headaches, vomiting, diplopia and a limited abduction in the right eye. A brain MRI showed protein content in the parietal sulci. [scielo.isciii.es]

  Patient B suffered from radicular pain in both legs and diplopia. The clinically suspected LMM initially could not be confirmed by cytological examination of the CSF. [clinchem.aaccjnls.org]

• Visual Impairment

  In this context, visual impairment (diplopia, visual field defects), limb weakness, blunted reflexes, ataxia, hemiparesis, radicular pain, urinary incontinence or retention, fecal incontinence or constipation, among others, may be observed. [symptoma.com]

  Most common neurological findings, present in 60% of patients, were cranial nerve disorders (cranial nerve palsy, cauda equina syndrome), followed by radicular pain (53.3%), headache (33.3%), visual impairment such as diplopia (40%), vomiting, nausea, [dovepress.com]

  impairment (II), ophthalmoparesis (III-IV-VI), hearing loss (VIII), facial weakness (VII), trigeminal sensory impairment (V), dysphagia (XI-X) Impaired consciousness Mood and mental changes (especially in case of encephalopathy), seizures Gait disturbances [jcmtjournal.com]

• Muscle Weakness

  Cranial nerve symptoms including visual loss, diplopia, hearing loss, dysphagia, ocular muscle weakness, facial weakness and facial pain are also seen. [adventhealthcancerinstitute.com]

  weakness Vestibulocochlear: Hearing loss and vertigo Glossopharyngeal: Hearing loss and vertigo Vagus: Difficulty swallowing and/or speaking Spinal accessory: Shoulder weakness Hypoglossal: Difficulty speaking because of trouble moving the tongue Encephalopathy [verywellhealth.com]

• Incontinence

  A case of leptomeningeal metastasis from an unknown primary source presenting with urinary incontinence as the sole complaint is reported. [ncbi.nlm.nih.gov]

  In this context, visual impairment (diplopia, visual field defects), limb weakness, blunted reflexes, ataxia, hemiparesis, radicular pain, urinary incontinence or retention, fecal incontinence or constipation, among others, may be observed. [symptoma.com]

  Physical findings: Clinical features of this disease include: • Headaches; • Nausea; • Vomiting; • Light-headedness; • Gait difficulties; • Ataxia; • Memory problems; • Incontinence; and • Sensory abnormalities. [secure.ssa.gov]

  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 [emedicine.medscape.com]

• Urinary Retention

  About 2 weeks after completing whole-brain radiation, the patient presented to the hospital with left lower extremity weakness, urinary retention, bowel incontinence, saddle anesthesia, and malaise. [mdedge.com]

  The patient eventually developed significant difficulty walking, lower extremity neuropathic pain and numbness, constipation, and urinary retention. In the emergency department, he was nonambulatory and was diagnosed with cauda equina syndrome. [appliedradiationoncology.com]

  Autonomic dysfunction manifests in most patients as painless urinary retention, with urinary and bowel incontinence less frequently noted. Sensory complaints develop concomitantly with weakness. [aafp.org]

  retention being a very early sign of LMC (9,15,29)]. [jgo.amegroups.com]

• Urinary Incontinence

  A case of leptomeningeal metastasis from an unknown primary source presenting with urinary incontinence as the sole complaint is reported. [ncbi.nlm.nih.gov]

  In this context, visual impairment (diplopia, visual field defects), limb weakness, blunted reflexes, ataxia, hemiparesis, radicular pain, urinary incontinence or retention, fecal incontinence or constipation, among others, may be observed. [symptoma.com]

   A 60 year-old man presented with progressive right facial palsy, followed by bilateral lower extremities weakness and urinary incontinence for 3 weeks. [slideshare.net]

• Meningism

  The cancer may cause the meninges to be inflamed. Also called carcinomatous meningitis, leptomeningeal carcinoma, leptomeningeal carcinomatosis, meningeal carcinomatosis, meningeal metastasis, and neoplastic meningitis. [cancer.gov]

  This article includes discussion of leptomeningeal metastasis, carcinomatous meningitis, leptomeningeal carcinoma, meningeal carcinoma, meningeal carcinomatosis, neoplastic meningitis, drop metastases, meningeal lymphomatosis, meningeal gliomatosis, and [medlink.com]

  The brain and the spinal cord are enveloped by distinct tissues referred to as meninges. The inner meninges, pia mater and arachnoid mater, may also be designated leptomeninges. [symptoma.com]

• Headache

  Leptomeningeal metastasis-related hydrocephalus causes distress to patients with end-stage cancer through headache and other symptoms by elevating intracranial pressure, thus reducing quality of life. [ncbi.nlm.nih.gov]

  M was discharged from the ED with an oral opioid for his headache and referred to his oncologist for next-day evaluation and follow up. [nursingcenter.com]

• Seizure

  When LM occurs, signs and symptoms include headache, nausea, vomiting, lumbar back pain, and stiff or painful neck; LM also may lead to mental disturbances and seizures. [ncbi.nlm.nih.gov]

  Symptoms including confusion, seizures, pain and paralysis may be a result of either metastases to the nervous system or one of several nonmetastatic complications of cancer. [books.google.com]

  Seizures are another commonly encountered symptom of brain metastases. [aafp.org]

  For his seizures, the patient was treated with a higher dose of levetiracetam and lacosamide, later titrated to phenytoin. [appliedradiationoncology.com]

  Symptoms Cancer cells in the covering of the brain can cause a range of symptoms, including: headaches changes to your sight, such as double vision or loss of sight confusion weakness seizures (fits) feeling sick (nausea) vomiting hearing changes facial [cancerresearchuk.org]

• Paresthesia

  A patient with uvular cancer presented with lower limb weakness and paresthesiae, headache, neck stiffness and multiple cranial palsies. No malignant cells were found on lumbar puncture. CT, and MRI were normal. [ncbi.nlm.nih.gov]

  For patients with spinal LMD, radicular pain, weakness and paresthesias are also common, Risk Factors Leptomeningeal disease occurs when tumor cells infiltrate the cerebrospinal fluid pathways and travel various parts of the brain and spinal cord and [adventhealthcancerinstitute.com]

  […] patients CNS involvement symptoms and signs Number of cases (%) Cranial nerve involvement Number of cases (%) Spinal and PNS involvement Number of cases (%) Headache, nausea and vomiting 54 (70.1) Abducens nerve palsy 10 (13.0) Bilateral limbs weakness or paresthesia [nnjournal.net]

  The pain becomes progressively more severe and later is often accompanied by numbness, paresthesias and weakness of the arm or hand. [aafp.org]

  […] disturbances * cranial nerve palsies * diplopia * facial numbness/paresis * hearing impairment or loss * sensory deficits * vertigo * vision impairment or loss Spinal cord * back pain * bladder and bowel dysfunction * lower motor weakness * neck pain * paresthesias [nursingcenter.com]

• Communicating Hydrocephalus

  It is noteworthy that LM generally causes communicating hydrocephalus. [ncbi.nlm.nih.gov]

  Communicating hydrocephalus in cancer patients should be considered to be related to leptomeningeal metastasis until proven otherwise. [ajronline.org]

  Hydrocephalus At Memorial Sloan-Kettering Cancer Center (MSKCC), approximately 10% of patients referred for placement of Ommaya reservoirs have or develop hydrocephalus.6 This is typically communicating hydrocephalus, resulting from occlusion of the arachnoid [78stepshealth.us]

  Hydrocephalus of various types: May cause obstructive hydrocephalus due to blocking CSF flow at various levels. May cause communicating hydrocephalus due to impaired CSF reabsorption. [emcrit.org]

  Repeat cisternogram demonstrated communicating hydrocephalus, and a ventriculoperitoneal shunt was placed. Despite short-lived improvement after the shunt, her mental status continued to deteriorate. [acgcasereports.gi.org]

LM are typically associated with high tumor grades and other metastases. Thus, in patients previously diagnosed with advanced-stage cancer, clinical findings may prompt a suspicion of parenchymal brain tumors or neoplastic meningitis. Rarely, symptoms related to LM constitute the first manifestation of cancer. Diagnosis of LM is based on gadolinium-enhanced magnetic resonance imaging and cytological analyses of CSF specimens, and the former technique may also be employed to visualize parenchymal brain lesions [12]. Neuroimaging is preferentially performed before lumbar puncture to obtain CSF samples since the latter procedure may provoke misleading meningeal enhancement.

Indeed, enhancement of the outer meninges is a very common, yet unspecific finding in LM patients. Enhancement of the pia mater and nodular lesions are less frequently observed, but are considered to be more specific for neoplastic meningitis. Imaging procedures should encompass the entire neuroaxis because the majority of individuals who develop LM present with multiple metastases unevenly distributed throughout the subarachnoidal space. Besides LM, affected individuals may present parenchymal brain tumors and hydrocephalus. While hydrocephalus is readily observed in computed tomography scans, this technique does often yield unaltered images with regards to the meninges.

At least 10 ml of CSF should be examined for tumor cells to avoid false-negative results. Furthermore, a second sample may be obtained and analyzed in the case of the first specimen yields negative results. Morphological features of tumor cells largely depend on the origin of the primary tumor and it may be a challenge to distinguish malignant cells from merely atypical ones, particularly in the case of lymphoma or leukemia. Here, flow cytometric analyses may be necessary to identify a monoclonal population of immune cells. Immunohistochemical and molecular analyses may also aid to relate LM with a determined solid primary tumor and set the basis for target-oriented therapy. Finally, it has to be noted that LM is frequently associated with pleocytosis, enhanced protein levels, and low glucose concentrations in CSF.

• Cerebrospinal Fluid Abnormality

  Cerebrospinal fluid abnormalities in meningeosis neoplastica: a retrospective 12-year analysis. Fluids Barriers CNS. (2017) 14:7. doi: 10.1186/s12987-017-0057-2 PubMed Abstract | CrossRef Full Text | Google Scholar 35. [frontiersin.org]

A thorough workup including an analysis for further metastases, an association of LM with a primary tumor, and a pathohistological classification of both is the basis of therapy. Determined molecular properties, e.g., hormone receptor expression and enzymatic activity, may render neoplasms susceptible to certain therapeutics, but they may differ between the primary tumor and LM [13]. While systemic chemotherapy is generally indicated to treat malignancies and metastases in peripheral tissues, an alternative route of administration has to be chosen to deliver drugs to the subarachnoid space. Intrathecal drug application via an intraventricular reservoir is preferred, but mechanical obstruction of the subarachnoid space by metastases may prevent compounds from reaching the entire neuroaxis. Lumbar punctures may be required to deliver active agents to the leptomeninges surrounding the inferior segments of the central nervous system. Of note, certain chemotherapeutics are neurotoxic and cannot be applied as described above. This is the case for vincristine; methotrexate, cytarabine, liposomal ara-C, and thiotepa, and are rather well-tolerated, though, and are most commonly used in LM patients. Pharmacodynamic and pharmacokinetic properties of those drugs have been reviewed elsewhere [1].

In patients with a high-performance status, craniospinal axis irradiation is recommended to target the entire neuroaxis. In contrast, a low-performance status indicates irradiation of symptomatic sites or sole palliative care.

Additional measures may be taken to relieve symptoms, e.g., the positioning of a ventriculoperitoneal shunt to lower intracranial pressure and application of corticosteroids to reduce spinal cord compression.

Despite diagnostic advances that allow for an earlier recognition of LM, they are still associated with a poor prognosis. In general, patients suffering from hematological malignancies that spread to the leptomeninges have a better outcome than those diagnosed with solid primary tumors. Median survival times of few months and two months have been reported, respectively [10].

LM may arise after the spread of malignant cells originating from solid tumors, lymphoma or leukemia [3]. While the possibility of spread to the leptomeninges cannot be ruled out in any cancer, most cases of LM are associated with the following primary tumors [1]:

• Carcinoma of the breast (up to a third of all cases)
• Carcinoma of the lung (about a fourth of all cases)
• Malignant melanoma (about a fourth of all cases)
• Malignancies of the gastrointestinal tract
• Adenocarcinoma of unknown origin

Although reported incidences of LM are increasing, this complication of cancer is still assumed to be largely underdiagnosed. Epidemiological data provided should thus be interpreted with care.

As has been indicated in the previous section, certain malignancies are associated with an increased risk of LM. According to current knowledge, the individual risk of cancer patients for developing LM is as follows [4]:

• About 3% of patients suffering from carcinoma of the breast develop LM. Negativity for estrogen and progesterone receptors may predispose for LM, while highest incidence rates have been reported for triple-negative breast carcinoma (negativity for estrogen and progesterone receptors and lack of overexpression of human epidermal growth factor receptor 2 HER2/neu) and tumors of the lobular subtype [5]. Of note, prognostic factors for brain parenchymal metastases and LM don't necessarily coincide.
• Small cell carcinoma of the lung spreads to the leptomeninges in about 6% of cases, while other malignancies of the lung are associated with LM in only about 1% of affected individuals.
• The likelihood of LM in malignant melanoma patients is less than 2%.
• Malignancies of the gastrointestinal tract spread through the CSF in less than 1% of patients.
• Adenocarcinomas of unknown origin metastasize to the leptomeninges in approximately 3% of cases.

Infiltration of the subarachnoid space allows for an extensive distribution of tumor cells along the entire neuroaxis. Considerable research efforts have been undertaken to clarify how degenerated cells reach this privileged area, and the following routes of metastatic spread have been identified [6]:

• Hematogenous spread of tumor cells, adherence to the endothelium of vessels supplying the leptomeninges and subsequent infiltration of those tissues and the subarachnoid space is assumed to be the most common form of spread to the leptomeninges in the case of solid primary tumors.
• LM may also arise after spread via perivascular lymph vessels [7].
• The leptomeninges envelops the roots of cranial and spinal nerves, while peripheral segments of those nerves are sheathed by the perineurium. The continuity between leptomeninges and perineurium, between the subarachnoid and perineural spaces facilitates the perineural spread of tumor cells [8].
• Brain tumors may infiltrate the leptomeninges and the subarachnoid space and spread along the neuroaxis. Of note, tumor cells originating from carcinoma of the breast or lung have been shown to invade and degrade the leptomeninges, while cells stemming from glioma may not be able to do so [9].
• Finally, surgical interventions may result in the iatrogenic spread of tumor cells to the CSF.

Predilection sites of tumor cell accumulation and metastatic growth are determined by CSF flow and gravity and comprise basal cisterns, cerebellopontine angle, posterior fossa and lumbar cistern. Here, LM exert local mass effects and interfere with the brain, spinal cord, and nerve function. At the same time, tumor cells may form mechanical obstacles that hinder CSF drainage, and this condition may result in hydrocephalus.

General measures to reduce carcinogen exposure may lower the individual risk of developing malignancies; detection of cancer during early stages may prevent metastatic spread. In this context, patients should be advised to refrain from tobacco consumption, to put safety measures into practice, and to regularly undergo preventive medical check-ups. Treatment of certain subtypes of cancer (e.g., T-cell lymphoblastic lymphoma) comprises prophylactic brain irradiation or intrathecal application of chemotherapeutics.

Brain and spinal cord are surrounded by the meninges, namely by pia mater, arachnoid mater and dura mater. The former two are also referred to as leptomeninges. The subarachnoid space, i.e., the more or less extensive space between pia mater and arachnoid mater, is filled with cerebrospinal fluid (CSF). Tumor cells may infiltrate this space by crossing the boundaries of vessels or adjacent tissues and may then be distributed within the CSF. Accordingly, patients may develop a single leptomeningeal metastasis (LM) or present with multiple secondary tumors to be encountered in pia mater and arachnoid mater.

For a long time, LM have been considered uncommon. Most types of cancer are expected to spread through hematogenous route or through lymphogenic route, and metastases most frequently form in regional lymph nodes, lungs, liver, and spleen. However, the incidence of LM is increasing [1], possibly due to prolonged survival times and improvements of therapeutic regimens directed against neoplasms in the aforementioned tissues. Chemotherapeutic drugs differ with regards to their pharmacokinetic properties and may or may not reach certain compartments. To date, most chemotherapeutics are unable to penetrate into privileged areas because they cannot overcome physiological and functional barriers like the blood-brain barrier and the blood-CSF barrier [2]. Consequently, tumors may proliferate in these regions despite otherwise effective systemic chemotherapy. Tumor growth may be associated with secondary inflammation and this fact that has lead to using the terms carcinomatous and neoplastic meningitis to refer to LM.

Although those barriers may display increased permeability in close proximity to tumors, they do pose a major obstacle to LM treatment. In general, chemotherapeutics have to be administered intrathecally. Furthermore, affected individuals may be subjected to radiotherapy. Despite all efforts, LM are associated with a poor prognosis and median survival times of less than half a year.

The brain and the spinal cord are enveloped by distinct tissues referred to as meninges. The inner meninges, pia mater and arachnoid mater, may also be designated leptomeninges. They enclose the subarachnoid space, which is filled with cerebrospinal fluid (CSF). If tumor cells reach the leptomeninges and the CSF, they may easily spread to multiple sites along the neuroaxis. Consequently, few patients present with a single leptomeningeal metastasis (LM) - the majority of affected individuals suffer from several metastases that interfere with brain and spinal cord function. Common symptoms are headaches, nausea, and vomiting, neurological deficits like visual impairment, limb weakness, back pain, urinary and fecal incontinence, as well as confusion, nuchal rigidity, and seizures.

Tumor cells that spread to the leptomeninges may originate from any type of cancer but are most commonly detected in patients previously diagnosed with carcinoma of the breast or lung, malignant melanoma, malignancies of the gastrointestinal tract and adenocarcinoma of unknown origin. These are aggressive neoplasms, and LM generally develop during advanced stages of these diseases. At this time, metastases may already affect other tissues, too. Thus, any therapeutic regimen should target the primary tumor as well as leptomeningeal and other metastases. In most cases, only palliative care can be offered. Patients may be administered chemotherapeutics, may undergo radiotherapy and additional measures to relieve symptoms in order to maintain life quality during the following months. To date, there is no cure for LM.

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