Clinical features and diagnosis of leptomeningeal disease from solid tumors

INTRODUCTION — Leptomeningeal disease (LMD; also referred to as leptomeningeal metastases or carcinomatous meningitis) is a rare but frequently devastating complication of advanced cancer from solid tumors, mostly commonly lung cancer, breast cancer, and melanoma. Patients can present with a broad range of signs and symptoms due to simultaneous involvement of multiple areas of the craniospinal axis. Diagnosis often requires a high index of suspicion and is confirmed by neuroimaging and cerebrospinal fluid (CSF) analysis.

The pathophysiology, clinical manifestations, and diagnosis of LMD from solid tumors will be reviewed here. Treatment of LMD and leptomeningeal involvement in hematologic malignancies are discussed separately. (See "Treatment of leptomeningeal disease from solid tumors" and "Secondary central nervous system lymphoma: Clinical features and diagnosis", section on 'Leptomeningeal dissemination' and "Involvement of the central nervous system (CNS) with acute myeloid leukemia (AML)".)

EPIDEMIOLOGY — LMD is diagnosed in approximately 5 percent of patients with metastatic cancer [1-3], but undiagnosed or asymptomatic involvement is more common [4-10]. At autopsy, the frequency of LMD averages 20 percent and is much higher with some tumor types [2,11,12]. Coexisting brain metastases are present in 50 to 80 percent of patients in modern series [13-17].

The most common solid tumors giving rise to LMD are breast cancer (12 to 35 percent), lung cancer (10 to 26 percent), melanoma (5 to 25 percent), gastrointestinal malignancies (4 to 14 percent), and cancers of unknown primary (1 to 7 percent) [1-3,13]. In females with breast cancer, infiltrating lobular carcinoma and human epidermal growth factor receptor 2 (HER2)-positive neoplasms have particular predilections to metastasize to the leptomeninges [18-20]. Similarly, in a large study of patients with non-small cell lung cancer, the percentage of patients with LMD harboring epidermal growth factor receptor (EGFR) mutations was higher than that of patients with wildtype EGFR status (9.4 versus 1.7 percent) [21].

Primary brain tumors, including low- and high-grade astrocytomas, medulloblastomas, ependymomas, pineoblastomas, and oligodendrogliomas, can infiltrate the leptomeninges or disseminate along cerebrospinal fluid (CSF) pathways [22-24]. Pilocytic astrocytomas, a World Health Organization (WHO) grade I malignancy, may also spread this way [25].

The development of LMD may also be influenced by treatment:

●Improved treatment strategies for systemic cancers that lead to longer survival (eg, trastuzumab in HER2-positive breast cancer) may increase the risk of developing central nervous system (CNS) metastases, including LMD [26-29]. In some cases, the blood-CSF barrier likely creates a sanctuary site where malignant cells are shielded from systemic therapy.

●Patients who have undergone surgical resection of a brain metastasis are at increased risk of subsequent LMD compared with those who have not undergone surgery, presumably due to spillage of malignant cells into the CSF [30-32]. The risk appears to be greater after piecemeal resection of metastases compared with en bloc resections for both posterior fossa and supratentorial brain metastases [33-35]. The incidence of LMD as well as pachymeningeal seeding may also be higher in the era of omission of postoperative whole brain radiation therapy [36-38]. The distribution of disease can be a classic, sugarcoating pattern or a nodular pattern of disease with a more limited number of bulky deposits [37,39,40].

PATHOPHYSIOLOGY — There are three membranes surrounding the brain and spinal cord: the dura mater, the arachnoid, and the pia mater. The dura mater is also referred to as the pachymeninges, while the arachnoid and pia mater are collectively called the leptomeninges. The subarachnoid space lies between the arachnoid and pia mater and contains both cerebrospinal fluid (CSF) and arteries penetrating the brain parenchyma. Tumoral involvement of the leptomeninges, which is distinguished from tumor involving the dura/pachymeninges, allows malignant cells to spread throughout the subarachnoid space, travel to distant sites, settle, and grow.

The total CSF volume in adults is approximately 140 mL, and the entire volume is replaced more than five times daily. The physiology of CSF formation and flow is discussed in detail elsewhere. (See "Cerebrospinal fluid: Physiology and utility of an examination in disease states".)

Tumor cells can gain access to the CSF in several ways (figure 1). Hematogenous spread via the arachnoid vessels or direct extension from the brain parenchyma are probably the most common means. Other possible routes include spread from choroid plexus metastases into the CSF; direct extension from vertebral, subdural, or epidural metastases; retrograde invasion along peripheral or cranial nerves to the subarachnoid space; and rare de novo tumors arising in the meninges, including lymphoma, melanoma, and several sarcomas (eg, malignant peripheral nerve sheath tumors).

Several different pathophysiologic mechanisms may cause characteristic clinical symptoms:

●Increased intracranial pressure, whether due to mass effect from bulky tumor following neoplastic invasion of the leptomeninges with associated inflammation, or CSF flow obstruction causing hydrocephalus, or, less often, obstruction without hydrocephalus.

●Cranial nerve and spinal nerve root dysfunction, caused by direct tumor involvement.

●Diffuse cerebral dysfunction. Invasion of the brain parenchyma by tumor cells, usually via the Virchow-Robin spaces, may lead to interference with cerebrovascular circulation or competition with brain cells for essential metabolites, including glucose and oxygen, producing symptoms.

●Cerebral edema (disruption of the blood-brain barrier).

Gross tumor involvement is commonly seen at the base of the brain (basilar cisterns or posterior fossa), the sylvian fissures, and the cauda equina. Tumor cells may also invade the spinal or cranial nerves, cerebral cortex, or spinal cord (picture 1).

CLINICAL FEATURES — Patients with LMD develop symptoms over days to weeks. Multifocal neurologic signs and symptoms are common and indicate multilevel involvement. Neuroimaging findings are highly sensitive, showing linear and/or nodular enhancement of the leptomeninges, cranial nerves, and spinal nerve roots, especially the cauda equina. Cerebrospinal fluid (CSF) is usually abnormal, with elevated protein, increased numbers of nucleated cells, and decreased glucose. While positive cytology is highly specific, it is not as sensitive as neuroimaging abnormalities. Moreover, both neuroimaging and CSF may be unrevealing, especially in patients with hematologic malignancies.

Clinical manifestations — Multifocal involvement is a hallmark of LMD. Although patients may present with a single symptom, careful neurologic evaluation often reveals additional sites of neurologic dysfunction. As an example, a patient complaining of diplopia may have an absent Achilles tendon reflex. The specific clinical symptoms and signs vary, depending upon the site(s) of leptomeningeal invasion and the underlying pathophysiology (eg, hydrocephalus).

In a series of 150 patients with solid tumor LMD, the most common presenting signs and symptoms were headache (39 percent), nausea and vomiting (25 percent), leg weakness (21 percent), cerebellar dysfunction (17 percent), altered mental status (16 percent), diplopia (14 percent), and facial weakness (13 percent) [13,41]. In the same series, 34 percent of patients presented with symptoms localized to one compartment (cerebral, posterior fossa, or spine), 39 percent to two compartments, and 25 percent to all three. Only two patients (1 percent) with solid tumor LMD were asymptomatic at the time of diagnosis.

Headache — Headache is the most common initial symptom of LMD, present in 30 to 50 percent of patients [1,13]. Headache can be caused by increased intracranial pressure (ICP) or meningeal irritation, and it is sometimes difficult to distinguish the two. Asking about other symptoms associated with the headache can help:

●Nausea, vomiting, and dizziness accompanying headache suggest increased ICP, with or without associated hydrocephalus. The symptoms may worsen episodically in association with the development of plateau waves, often triggered by changes in body position (eg, sitting to standing), which may even precipitate loss of consciousness. Funduscopic exam may show papilledema. (See "Evaluation and management of elevated intracranial pressure in adults".)

●Headache accompanied by neck pain or stiffness and exacerbated by head movements is more characteristic of meningeal irritation. In addition, pain with straight leg raising can also suggest spinal meningeal irritation. Nuchal rigidity may be present with or without headache.

Altered mental status — Symptoms of confusion, forgetfulness, disorientation, subtle personality changes, and/or lethargy, collectively referred to as encephalopathy or altered mental status, are common in patients with LMD and can be secondary to diffuse cerebral dysfunction, hydrocephalus, seizures, or a combination. Encephalopathy in isolation, without other focal signs or symptoms, is uncommon.

Cranial neuropathies — Cranial neuropathies are caused by invasion of the cranial nerves within the subarachnoid space [11,42].

●Diplopia is the most common cranial nerve symptom of LMD [4,14,41]. Dysfunction of any cranial nerve supplying the extraocular muscles (ie, the oculomotor [III], trochlear [IV], or abducens [VI] nerves) can cause it. The history and exam can help localize diplopia to one or more cranial nerves. (See "Overview of diplopia", section on 'Clinical presentation'.)

●Facial pain, paresthesias, and numbness may indicate involvement of the trigeminal nerve. One classic form of facial numbness, the "numb chin syndrome," can be a presenting symptom of LMD, although it was more frequently due to bony mandibular metastases [11] in one series of 42 patients. Numb chin syndrome was the presenting symptom of LMD in 22 percent of those cases and often preceded the diagnosis of recurrent cancer [43].

●Facial weakness secondary to involvement of the facial nerve is manifested by weakness of both the upper face (ie, difficulty closing the eye completely, decreased eyebrow raise) and the lower face. Confusion with Bell's palsy is frequent, as both conditions may demonstrate enhancement of cranial nerve VII. (See "Bell's palsy: Pathogenesis, clinical features, and diagnosis in adults".)

●Unilateral or bilateral sensorineural hearing loss from involvement of the vestibulocochlear cranial nerves is an infrequent presenting symptom of LMD (<5 percent) but becomes more common as the disease progresses.

●Dysarthria, dysphagia, or hoarseness can be symptoms of lower cranial nerve dysfunction.

Cerebellar dysfunction — Gait instability, difficulty walking, dizziness, and falls referable to cerebellar dysfunction are present in approximately 20 percent of patients at diagnosis [1,13]. Both midline cerebellar symptoms (eg, gait ataxia) and lateral cerebellar symptoms (eg, limb dysmetria) can be seen.

Radiculopathy and cauda equina syndrome — Spinal nerve root involvement may cause radicular pain, numbness, or muscle weakness in the anatomic distribution of the involved level (figure 2 and figure 3). Most commonly, the roots of the cauda equina supplying the lower extremities, bowel, and bladder are affected, but roots in the thoracic and cervical spinal cord can also be involved. Cauda equina involvement can be manifested as leg pain, leg weakness or numbness, urinary incontinence or retention, and/or an asymmetry of deep tendon reflexes. (See "Anatomy and localization of spinal cord disorders", section on 'Cauda equina syndrome' and "Polyradiculopathy: Spinal stenosis, infectious, carcinomatous, and inflammatory nerve root syndromes".)

Seizures — Partial seizures with or without secondary generalization can be caused by cortical irritation from adjacent leptomeningeal deposits, invasion of brain parenchyma, or local edema. Seizures have been reported in up to 25 percent of patients with LMD [1,14].

Plateau waves — Dizziness, lightheadedness, presyncope, or even frank syncope, typically associated with positional changes (eg, sitting to standing), can be symptomatic of plateau waves in the setting of increased ICP or venous obstruction, even in the absence of headache. Evidence of increased ICP (eg, papilledema, hydrocephalus on imaging studies) should be sought. Frequently, ventricular enlargement is absent [44,45].

Other symptoms — Focal cortical signs and symptoms such as hemiparesis, aphasia, or visual field defects are very unusual in LMD, but can be caused rarely by invasion of brain parenchyma or focal ischemia [46]. Panhypopituitarism, arginine vasopressin deficiency (AVP-D, previously called central diabetes insipidus), or paradoxical weight gain can result from leptomeningeal invasion of the pituitary stalk, although this is more common in leukemic than solid tumor LMD.

Neuroimaging studies — Gadolinium-enhanced magnetic resonance imaging (MRI) of the brain and spine often provides important evidence of LMD. Although MRI probably is more sensitive (76 to 87 percent in multiple studies) than a single CSF specimen for cytology, it is less specific because a false-positive cytologic examination is rare [47-50]. (See 'Cytology' below.)

In patients who cannot undergo MRI, computed tomography (CT) with contrast can demonstrate similar findings, albeit with lower sensitivity than MRI. Another imaging option for those who cannot undergo MRI is 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) [51].

Brain MRI — The typical brain MRI findings of LMD include diffuse linear or nodular enhancing foci within cerebral and cerebellar sulci, cisterns, or both (image 1). Common sites of abnormal leptomeningeal enhancement are the cerebellar folia (often best visualized on coronal postcontrast images) (image 2), the cortical surface, and the basal cisterns, particularly along the ventral surface of the brainstem (image 3). In addition, the cisternal segments of the cranial nerves may be abnormally thickened and enhancing (image 4). High-resolution contrast-enhanced MRI through the skull base and brainstem often shows cranial nerve abnormalities that are not seen on routine MRI. Fluid-attenuated inversion recovery (FLAIR) images may show hyperintensity within the subarachnoid space, indicative of high protein content in the CSF [52].

Any or all of these findings may be accompanied by ventriculomegaly in the absence of, or out of proportion to, the degree of sulcal enlargement (ie, hydrocephalus). In older adults and in patients previously treated with whole brain radiation, it can sometimes be difficult to distinguish hydrocephalus from ex vacuo enlargement of the ventricles. Imaging findings that suggest true hydrocephalus include abnormal periventricular T2 hyperintensity (suggesting transependymal CSF absorption) and sulcal effacement (image 5).

Occasionally, frank leptomeningeal enhancement is not seen on MRI, but the presence of bulky subependymal disease or multiple small sulcal metastases suggests the diagnosis (image 6).

In patients who are being treated with the antiangiogenic agent bevacizumab, the diagnosis may be more difficult because neuroimaging features may be altered [53]. Leptomeningeal enhancement may be minimal or absent, and the observed abnormalities may suggest vasculitis or small vessel vasculopathy.

Spine MRI — MRI can show linear or nodular enhancement along the surface of the spinal cord, cauda equina, or both (image 7). Occasionally, clumping of nerve roots at the cauda equina, mimicking arachnoiditis, may suggest the diagnosis even if contrast enhancement is not seen. Rarely, a leptomeningeal spinal tumor may obstruct CSF flow, resulting in hydrocephalus without any discrete tumor masses in the leptomeninges of the brain.

Cerebrospinal fluid — The classic CSF findings of LMD include a high protein concentration, low glucose concentration, lymphocytic pleocytosis, and positive cytology for malignant cells. Although most patients do not have all of these features, an entirely normal CSF examination is uncommon [1,4,54,55]. As an example, in one large series, only 5 of 104 patients with LMD had completely normal basic CSF parameters; of these, four had breast cancer and one had leukemia. The most common CSF profile is a combination of high protein concentration and lymphocytic pleocytosis. (See "Cerebrospinal fluid: Physiology and utility of an examination in disease states".)

Basic parameters — Each one of the four basic CSF parameters (opening pressure, cell count with differential, total protein, and glucose) can be affected by the presence of LMD.

●An elevated opening pressure above 16 cm H₂O is common when measured, but selection bias may be present in observational studies, as the decision to assess the pressure may be affected by the patient symptoms. In a study of 187 patients with LMD at a single center over a two-year period, opening pressure was only measured in 32 patients, of whom 50 percent had values >20 cm H₂O [13].

●Mild elevation of the white blood cell count is seen in 50 to 60 percent of patients. The white cells are usually lymphocytes, although eosinophilia is seen with recurrent acute lymphoblastic leukemia and Hodgkin lymphoma [56].

●Xanthochromia is a result of bleeding into the CSF or elevation of the CSF protein >150 mg/dL; hemorrhage from LMD is common with melanoma but rare in other tumors [57].

●The CSF protein concentration is elevated (>38 mg/dL) in 60 to 80 percent of cases, mainly as the result of blood-brain barrier breakdown, although tumor protein production may also contribute [1,13]. Very high protein levels suggest blockage of CSF flow and may be associated with a paucity of CSF obtained during the procedure ("dry tap"). Normal range levels for CSF protein are different between ventricular, cervical, and lumbar sites, increasing more caudally.

●The CSF glucose concentration is decreased (CSF:serum ratio <0.6) in approximately 30 percent of cases, the result of either impaired transport [58] or increased metabolism by reactive pia, lymphocytes, or tumors [1,13].

Cytology — The definitive diagnostic finding for LMD is the cytologic identification of malignant cells within the CSF (picture 2) [9,54]. The specificity of CSF cytology is very high, since false-positive results are rare in the hands of experienced cytopathologists [54].

By contrast, the sensitivity of cytology is only between 80 and 95 percent, and false-negative results can be a source of frustration for clinicians and patients, necessitating repeat lumbar punctures (LPs) and delaying therapy [4,54,59]. Specific recommendations to minimize false-negative results include the following [54,55]:

●A minimum of 10 mL of CSF should be reserved solely for cytologic analysis. CSF samples for cell count and chemistry (protein, glucose, tumor markers, if applicable) require only 1 and 3 mL, respectively. In hematologic malignancies, flow cytometric analysis requires more fluid if the lymphocyte cell count is low.

●Specimens must be processed promptly, including immediate fixation in a 1:1 ratio of CSF to ethanol-based fixative for cytology. Specimens should not sit overnight before being fixed, even if refrigerated. Flow cytometry specimens should not be placed in fixative.

●LP should be repeated if the initial cytology is negative but clinical suspicion is high, particularly if basic indices are abnormal (eg, low glucose, high protein, or pleocytosis).

●CSF obtained closest to the site of symptoms (ie, intraventricularly or by cervical spine puncture under fluoroscopic guidance for cranial symptoms and LP for spinal root dysfunction) may have the highest yield [55]. CSF drawn from an indwelling ventricular access device (eg, an Ommaya catheter) may yield very different results than CSF drawn from an LP.

The optimal number of samples is uncertain. In most cases, a positive cytology can be obtained with two separate samplings totaling at least 30 mL, with little if any benefit gained from additional specimens.

Despite these measures, CSF cytology is persistently negative in as much as 20 percent of patients with clinically or radiographically unequivocal LMD [13,54]. The reason for negative CSF cytology in such patients is unclear; presumably, the malignant cells adhere to the leptomeninges rather than float in the CSF. In these cases, the diagnosis can be made in the appropriate clinical context by neuroimaging alone [47]. (See 'Diagnostic evaluation' below.)

Immunohistochemical staining of cells in the cytologic specimen is sometimes possible and may provide diagnostic information or suggest the primary site in a patient with an unknown primary [60].

Flow cytometry — CSF flow cytometry or other molecular studies may be particularly valuable in diagnosing LMD from hematologic malignancies. Flow cytometry is not generally informative for the evaluation of suspected LMD from solid tumors. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis", section on 'Leptomeningeal dissemination' and "Involvement of the central nervous system (CNS) with acute myeloid leukemia (AML)".)

Tumor markers — Tumor markers (eg, CEA, PSA, CA-15-3, CA-125, and MART-1 and MAGE-3 in melanoma) may provide evidence for CSF dissemination of disease, even when serial cytologic evaluations are negative (table 1) [2,59,61-71]. Concentrations of CSF tumor markers that are more than 2 to 3 percent of simultaneous serum values are unlikely to be due to serum contamination or simple diffusion across the blood-brain barrier, unless the CSF albumin concentration is also very high (>100 mg/dL), indicating disruption of the blood-brain barrier. If the concentration of biochemical tumor markers within the CSF is greater than the serum concentration, then neoplastic meningitis is almost certain, even in the face of negative cytology.

Novel biochemical markers implicated in tumor invasion, angiogenesis, and metastasis (eg, vascular endothelial growth factor, matrix metalloproteinases, and lipid-associated sialic acid) are promising diagnostically but more data are needed, and they are not available for routine clinical care [71-76].

Circulating tumor cells or DNA — Techniques for identifying circulating tumor cells (CTCs) and cell-free deoxyribonucleic acid (DNA) in peripheral blood can be modified for CSF samples with high sensitivity and specificity for epithelial tumors [77-83]. In a study of 51 patients with solid tumors undergoing LP for clinical suspicion of LMD, CTCs were detected in all 15 patients who were diagnosed with LMD by CSF cytology and/or typical MRI findings, as well as in one additional patient with negative cytology and nondiagnostic MRI who went on to develop typical MRI findings of LMD six months later [80]. In a larger study from the same institution, a threshold of >1 CTC in CSF had a sensitivity and specificity of 93 and 95 percent for the diagnosis of LMD compared with an integrated clinical diagnosis (requiring clinical suspicion, positive CSF cytology, and/or unequivocal MRI findings) [84]. In newly diagnosed patients, a correlation between increased number of CTCs and worse prognosis has been described [85,86].

DIAGNOSTIC EVALUATION

Evaluation — Patients suspected of having LMD should initially undergo a complete history and physical examination. The history should pay specific attention to subtle symptoms suggestive of multifocal involvement. The physical examination should include a detailed neurologic examination, which may reveal findings not suggested by the history.

Contrast-enhanced MRI of the brain and spine should be performed in all patients with suspected LMD. Brain MRI should include high-resolution, contrast-enhanced images through the skull base and brainstem to detect metastases of the cranial nerves or to diagnose an alternative explanation for cranial neuropathies (eg, extensive bony disease within the skull base). Particular attention should also be given to ventricular size. MRIs should ideally be obtained prior to lumbar puncture (LP), thereby avoiding post-LP imaging artifacts that might be confused with LMD. (See 'Differential diagnosis' below.)

LP is not always necessary when there are definitive findings on imaging that establish the diagnosis. LP is essential when imaging is negative or there are concerns that the patient has elevated intracranial pressure (ICP), regardless of imaging findings. LP should be deferred in patients with large intracranial or spinal masses due to the risk of causing herniation.

Cerebrospinal fluid (CSF) should be routinely sent for cell count, differential, total protein, glucose, and cytology. CSF analysis of circulating tumor cells (CTCs) is a useful complement to cytology where available. In addition, an opening pressure should be measured to screen for elevated ICP, which may be relevant for treatment. (See "Treatment of leptomeningeal disease from solid tumors", section on 'Hydrocephalus and increased intracranial pressure'.)

Diagnosis — The diagnosis of LMD should be considered in patients presenting with multifocal neurologic signs and symptoms. As described above, the results of MRI and analysis of CSF are complementary, and the use of both increases diagnostic accuracy [13,47]. (See 'Neuroimaging studies' above and 'Cerebrospinal fluid' above.)

In patients without a known cancer diagnosis, the diagnosis can be more difficult, and repeated LPs and sometimes open biopsy of the leptomeninges may be required to secure a diagnosis. (See "Approach to the patient with chronic meningitis", section on 'Role of meningeal or brain biopsy'.)

DIFFERENTIAL DIAGNOSIS — Various conditions can mimic the clinical presentation or MRI enhancement patterns seen in patients with LMD (table 2). These include metastatic disease in adjacent compartments of the nervous system (eg, base of skull, dura, or superficial brain parenchyma), infectious and autoimmune diseases affecting the leptomeninges and/or nerve roots, late effects of prior treatment (eg, radiation-induced nerve root thickening and/or enhancement), viral meningitides, and imaging artifacts such as prominent meningeal vascular enhancement or postlumbar puncture (LP) changes (although this is typically dural, not leptomeningeal, enhancement) [87-91].

In a patient with widespread cancer, the differential diagnosis is fairly narrow, and the primary tasks are to localize the disease to the leptomeninges (as opposed to skull base or dura) and exclude infection in patients who are febrile and/or immunocompromised by their disease or its treatment. Patients with acute bacterial meningitis are typically quite ill, rapidly symptomatic, and febrile, and it is not difficult to distinguish them from patients with LMD. Similarly, patients with aseptic meningitis usually present more acutely than patients with LMD and will have one or more systemic symptoms such as fever, rash, diarrhea, or malaise. If infection is suspected, cerebrospinal fluid (CSF) should be sent for routine Gram stain and culture. Additional CSF tests to consider include fungal and mycobacterial cultures, acid-fast bacilli (AFB) smear, cryptococcal antigen, and virus detection assays. (See "Clinical features and diagnosis of acute bacterial meningitis in adults", section on 'Clinical features'.)

In a patient without cancer, a broader range of infectious and noninfectious meningitides must be considered (table 3). (See "Approach to the patient with chronic meningitis".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Leptomeningeal disease (LMD) is diagnosed in approximately 5 percent of patients with advanced cancer. The most common primary tumors associated with the development of LMD are breast, lung, and melanoma. The incidence of LMD may be increasing in cancers with improved systemic therapy options. (See 'Epidemiology' above.)

●Clinical features

•Signs and symptoms – Multifocal neurologic signs and symptoms are a hallmark of the presentation of LMD. Among the most common presenting symptoms are headache, nausea and vomiting, leg weakness, ataxia, altered mental status, diplopia, and facial weakness. Seizures occur in up to a quarter of patients. (See 'Clinical manifestations' above.)

•Neuroimaging – Contrast-enhanced MRI of the brain and spine should be performed in all patients suspected of having LMD prior to lumbar puncture (LP). Typical findings on MRI that suggest a diagnosis of LMD include linear and nodular leptomeningeal enhancement (image 1 and image 3); thickening and enhancement of cranial nerves (image 4) or nerve roots, including the cauda equina (image 7); and hydrocephalus (image 5). A typical MRI in the appropriate clinical setting is sufficient for establishing the diagnosis without LP. (See 'Neuroimaging studies' above.)

•Cerebrospinal fluid (CSF) – Most patients with LMD will have abnormal CSF parameters, such as mild pleocytosis, elevated total protein, decreased glucose, and elevated opening pressure. (See 'Basic parameters' above.)

The identification of malignant cells in the CSF (picture 2) definitively establishes the diagnosis of LMD, even if the typical clinical or radiographic features are not present. However, cytology is negative in up to 20 percent of patients. Detection of circulating tumor cells (CTCs) in CSF is technically feasible at some institutions and increases sensitivity for the diagnosis of LMD when combined with other tests. (See 'Cytology' above and 'Circulating tumor cells or DNA' above.)

Elevated tumor marker concentrations in the CSF may be helpful in selected patients (table 1), but we do not routinely do this except in cases where the clinical suspicion is high and multiple cytologic samples are negative. (See 'Tumor markers' above.)

●Diagnosis – A positive CSF cytology is the traditional gold standard and establishes the diagnosis of LMD in the majority of patients. A typical MRI in the appropriate clinical setting is also sufficient for diagnosis. (See 'Diagnostic evaluation' above.)

In exceptional cases with a negative cytology and without evidence of disseminated cancer, an open leptomeningeal biopsy may be required. (See 'Diagnosis' above.)