Clinical Presentation, Diagnosis, and Radiological Findings of Neoplastic Meningitis

Georgios Rigakos, MD; Chrysoula I. Liakou, MD; Naillid Felipe, Dennis Orkoulas-Razis, MHS; Evangelia Razis, MD, PhD


Cancer Control. 2017;24(1):9-21. 

In This Article

Differential Diagnosis

The clinical presentation of neoplastic meningitis can be mimicked by a variety of conditions. The differential diagnosis of patients with symptoms suggestive of neoplastic meningitis is less laborious in patients with a diagnosed malignancy than in those without a diagnosis of cancer because a wide range of infectious and noninfectious causes of meningitis-like symptoms will need to be vetted.

In patients with cancer, metastatic disease in compartments of the CNS adjacent to the meninges may provoke clinical features similar to those seen in neoplastic meningitis. The bone structures surrounding the CNS, with special attention paid to the base of skull as well as the dura and brain parenchyma, must be evaluated for metastatic disease that may or may not coexist with neoplastic meningitis.[21]

Paraneoplastic syndromes are a group of disorders that can present in patients with cancer; many of these syndromes have symptoms resembling neoplastic meningitis. Cerebellar degeneration, sensory neuropathy, limbic encephalitis, myasthenia gravis, and Eaton-Lambert myasthenic syndrome are the most common paraneoplastic neurological syndromes, and their manifestation can precede a cancer diagnosis by years.[22]

A list of infectious agents should be included in the differential diagnosis of meningitis, with special interest paid to those causing more chronic forms of meningitis. This is because acute infections are generally less difficult to rule out based on their typical clinical and laboratory findings. However, the clinician must keep in mind that patients with leptomeningeal disease can also have acute infectious meningitis.

Bacteria that can cause chronic meningitis include Listeria monocytogenes, Rickettsia rickettsii, Tropheryma whippelii, and species of Actinomyces, Brucella, Ehrlichia, and Nocardia. Tuberculosis and spirochetal infections due to Borrelia burgdorferi, Treponema pallidum, and Leptospira species are also included in the differential diagnosis of chronic meningitis, as are many viral infections (HIV, cytomegalovirus, Epstein-Barr virus, human T-cell lymphotropic virus types 1 and 2, herpes simplex virus [HSV; typically type 2 because type 1 causes encephalitis], varicella zoster virus, Enterovirus, paramyxovirus, West Nile virus, St Louis encephalitis virus, and lymphocytic choriomeningitis virus).[23] Fungal infections should be acknowledged in the differential diagnosis and include the fungi Cryptococcus neoformans, Blastomyces dermatiditis, and Coccidioides immitis, as well as parasitic infections with Taenia solium, Angiostrongylus schistosoma, Toxoplasma gondii, and Acanthamoeba species.[23]

Viral encephalitis or partially treated bacterial meningitis may have persistent symptoms that may be misleading. Recurrent meningeal inflammation (usually related to HSV type 2 infection) has also been described as Mollaret meningitis, with more than 3 episodes of fever and meningismus lasting less than 1 week and spontaneously resolving.[24] Noninfectious, recurrent meningeal irritation may be related to an epidermoid cyst or other intracranial cystic abnormalities, because they can lead to the intermittent leakage of irritating squamous material into the CSF.[25]

Infection of structures adjacent to the meninges, such as an epidural or subdural abscess, sinusitis, or otitis, should be ruled out. Occasionally, systemic infections may have CNS complications such as brain microabscesses in bacterial endocarditis.

Autoimmune diseases are important to the differential diagnosis of neoplastic meningitis. Sarcoidosis, systemic lupus erythematosus, granulomatosis with polyangiitis, Behçet disease, CNS vasculitis, and Vogt-Koyanagi-Harada syndrome can all present similarly to neoplastic meningitis.[26] The same is true for multiple sclerosis, Creutzfeldt-Jakob disease, and other neurodegenerative diseases with a protracted clinical course.[27]

Drug-induced meningitis is another entity to rule out in the differential diagnosis. Symptoms and signs of aseptic meningitis can be induced by a number of medications, including nonsteroidal anti-inflammatory drugs, certain antibiotics (eg, trimethoprim/sulfamethoxazole), intravenous immunoglobulin, cetuximab, and antiepileptic drugs.[28–31] In addition to drug-related symptoms and findings that mimic neoplastic meningitis, a neoplastic meningitis–like presentation can occur as a complication of treatment (radiation-induced nerve root dysfunction with thickening).


In patients presenting with symptoms suggestive of neoplastic meningitis, particularly if a diagnosis of cancer has not been established, the clinician must obtain the patient's medical history. A travel history should also be taken, which could indicate an endemic infection such as coccidiomycosis if the patient has recently traveled to the southwestern United States or Mexico. Animal or arthropod exposure can lead the clinician to suspect conditions such as Lyme disease or lymphocytic choriomeningitis, and a history of unpasteurized dairy product consumption, contact with cattle, or both may point to brucellosis.

Involvement in risky sexual behaviors and intravenous drug use could suggest infection with HSV type 2, HIV, or syphilis, and a history of contact with other individuals with suspect symptoms or conditions (eg, enterovirus infection, tuberculosis) can be helpful for the differential diagnosis. A medication list must also be obtained (eg, nonsteroidal anti-inflammatory drugs, immunoglobulin).

Scrutiny in the review of systems may reveal symptoms indicative of an etiology other than neoplastic meningitis. Patients who are acutely ill with fever are more likely to have bacterial meningitis or a form of aseptic meningitis than neoplastic meningitis, which, in turn, would be expected to have a more insidious presentation. If the non-neurological systemic symptoms present are not related to a known cancer diagnosis, the likelihood of neoplastic meningitis is low. Uveitis, iritis, or both are suggestive of sarcoidosis, Behçet disease, or Vogt-Koyanagi-Harada syndrome (as well as vitiligo and poliosis for the latter). Diabetes insipidus and peripheral facial nerve palsy are also indicative of sarcoidosis. Recurrent genital ulcers related to Behçet disease and herpetic skin and genital lesions may precede neurological signs in herpetic meningoencephalitis. Skin rash and purpura are typical skin findings in Neisseria meningitides infection. Enteroviral infection, primary HIV infection, or syphilis may present with a diffuse maculopapular rash. Salivary gland inflammation is seen in mumps, and pharyngeal inflammation in conjunction with sores and encephalopathy are signs of primary HIV infection.

Laboratory Tests

CSF cytology is the diagnostic cornerstone of neoplastic meningitis because it has a high rate of specificity.[32] In rare cases, viral infections can cause false-positive results when a patient is evaluated for neoplastic meningitis as a result of a hematological malignancy, but not for solid tumor–related neoplastic meningitis.[33] A negative finding on cytology does not exclude neoplastic meningitis if the clinical presentation and findings on imaging are suggestive of the disease, but it is unusual to have neoplastic meningitis in conjunction with a normal CSF cell count and normal findings on biochemistry.[34]

Pleocytosis in CSF has been observed in many clinical entities resembling neoplastic meningitis. In 1 study, a CSF neutrophilic white blood cell count of 1180 cells/μL, a protein level above 220 mg/dL, and a glucose level below 34 mg/dL were suggestive of bacterial meningitis in the appropriate clinical setting.[35] It is possible that different white blood cell populations could indicate the diagnosis without being a hallmark for it. Fungal infections (eg, nocardiosis, actinomycosis, aspergillosis), autoimmune disease (eg, systemic lupus erythematosus), and chemical or drug-induced meningitis are related to predominantly neutrophilic CSF pleocytosis. In 1 study using flow cytometry immunophenotyping to describe the distribution of the main leukocyte populations in patients with neoplastic meningitis, solid tumor–related neoplastic meningitis showed prominent neutrophilic pleocytosis when compared with lymphoma-associated neoplastic meningitis.[36]

A high CSF lymphocyte count can be seen within 24 hours of enteroviral infection.[37] Eosinophils increase when the following are present: parasitic and bacterial infestations (eg, Mycobacterium tuberculosis, Mycoplasma pneumoniae, Rickettsia rickettsii), hematological malignancies (acute lymphocytic leukemia, Hodgkin lymphoma), subarachnoid hemorrhage, and obstructive hydrocephalus.[38] Mononuclear pleocytosis can be seen in tuberculosis, cryptococcal infections (with a low CSF white blood cell count), and coccidiomycosis. Traumatic lumbar puncture or subarachnoid bleeding can cause generalized transient seizures and an increase in the white blood cell count.

CSF should be sent for routine Gram stain, which has rates of sensitivity and specificity of 97% and 80%, respectively, for bacterial meningitis; cultures should be obtained for aerobic, anaerobic, and fungal infections; blood cultures and other samples should also be collected as clinically indicated.[39] Additional CSF tests to consider include ®-D-glucan for Candida meningitis, mycobacterial cultures with acid-fast bacilli smear, and other tests based on the differential diagnosis (eg, polymerase chain reaction), fungal and parasitic assays (eg, Cryptococcus, Toxoplasma, Taenia), and serology and virus-detection assays.[40,41]

Biochemistry of the CSF can also be helpful. CSF lactate concentration may differentiate bacterial from viral meningitis better than white blood cell count, glucose level, and protein concentration, although CSF lactate may be elevated in patients with other CNS diseases.[42,43] The level of protein can be elevated in many infectious and noninfectious diseases as well as in traumatic lumbar puncture and subarachnoid bleeding. Creatinine kinase and lactate dehydrogenase (LDH) CSF levels are also high in pyogenic or tubercular meningitis.[44]

Typically, the presence of xanthochromia is assessed to distinguish a traumatic tap from subarachnoid hemorrhage, but it can also be found in neoplastic meningitis from malignant melanoma.[45]

Oligoclonal bands may suggest multiple sclerosis, although they are also present in other conditions (eg, Lyme disease, autoimmune diseases, brain malignancies, lymphoproliferative diseases).[46] CSF Tau proteins and 14–3-3 protein levels can help in the diagnosis of Creutzfeldt-Jakob disease.[27] Detection of paraneoplastic syndrome–related antibodies in the serum or CSF may help reach a diagnosis. Anti-Yo, anti-Hu, anti-Ri, anti-N-methyl-D-aspartate receptor antibody, anti-Musk, or antibodies against acetylcholine receptors or voltage-gated calcium channels may also be helpful.

The level of CSF glucose is typically low in neoplastic meningitis, similar to other pathological conditions (bacterial meningitis and mycobacterial, mycoplasma and fungal CNS infections, meningoencephalitis due to mumps, infection with enteroviruses, lymphocytic choriomeningitis virus, HSV, or varicella zoster virus, subarachnoid hemorrhage, and neurosarcoidosis).

Although it is not routinely recommended, meningeal biopsy can be performed for diagnostic purposes if findings on both cytology and imaging are negative in a patient with a strongly suggestive clinical syndrome.[47,48] The findings can be diagnostic, especially if taken from an area of contrast enhancement on magnetic resonance imaging (MRI). Pathology will show macroscopically diffuse, fibrotic thickening of the affected area 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.

Imaging in Differential Diagnosis

MRI of the craniospinal axis with paramagnetic contrast is useful in detecting neoplastic meningitis and has a sensitivity rate of up to 88% in solid tumors.[10]

Findings on MRI do not confer a definitive diagnosis because they are nonspecific. Neurosarcoidosis, chronic meningitis, Guillain-Barre syndrome, and many infectious cases of meningitides can cause the linear leptomeningeal enhancement seen on MRI.[49] Bacterial and viral meningeal inflammation tends to appear as linear enhancement, whereas fungal inflammation is generally nodular.[50] Primary nerve sheath tumors in the subarachnoid space may also appear as areas of nodular enhancement.[50] In addition, lumbar puncture can indicate false-positive meningeal enhancement seen at the level of puncture and at higher levels and can persist for months, so it is important to obtain MRI prior to performing lumbar puncture.[51] Dural metastases, intracranial hypotension, granulomas, and meningiomas can appear as pachymeningeal linear or nodular enhancement that can be falsely interpreted as neoplastic meningitis.[50]