Completely normal profile
The low initial sensitivity of cytologic examination may be attributed to the fact that tumor cells adhere to the meninges with few free-floating cells resulting in negative cytology. Increasing the CSF volume (10-20 cc), examining the specimen as soon as possible, and performing serial lumbar punctures (LP) may increase the diagnostic yield. If the specimen is delivered within minutes it may be examined without fixation, but routinely it is fixed in an equal volume of fixate. A recent review suggests that two LPs may be sufficient to achieve a sensitivity of 90 %.48
The CSF cytology results may vary if the sample is obtained from Ommaya reservoir as opposed to LP.55'90 The sensitivity may be dependent upon the localization of clinical symptoms. When only cranial signs or symptoms are present, the ventricular CSF is nearly three times more likely to be positive than lumbar, whereas when only spinal signs or symptoms were present, the lumbar CSF is nearly three times more likely to be positive than the ventricular CSF.27 CSF is also more likely to be positive when LM is more disseminated than when it is focal.51 Cisternal puncture is an alternative way to collect CSF and may be positive even when the fluid is negative.97 This is done by a lateral cervical puncture at the C2 level under fluoroscopic visualization. It may be more likely to yield a positive cytology when cranial signs and symptoms present. When CSF remains negative, other abnormalities of the CSF may aid in the diagnosis of LM.
Elevated CSF pressure is seen in approximately 50 % of patients with LM. Obstruction of the arachnoid granulations by malignant cells is the likely cause of increased pressure which can ultimately lead to hydrocephalus. However, there are other etiologies that can elevate CSF pressure in cancer patients including cerebral sinus thrombosis,94 or an increase in systemic venous pressure due to compression or obstruction of superior vena cava or jugular vein.
The white blood cell count is elevated in approximately 50% of patients. Red blood cells or xanthochromia can be seen from bleeding due to LM, especially with melanoma.90 Elevated CSF protein is seen in approximately 70-85% of patients with LM but is a non-specific finding. Low glucose is seen in 40% of patients with LM; it is a relatively specific finding for this condition, especially when less than 10. Tuberculous and bacterial meningitis can have a low glucose and need to be excluded. A normal CSF glucose level in a diabetic patient may indicate hypoglycorrhachia. The mechanism of hypoglycorrhachia is unclear but may be due to diminished carrier-mediated transport of glucose across the BBB or glucose metabolism by malignant and reactive cells.90
Used in the appropriate clinical setting, certain biochemical markers in the CSF can aid in the diagnosis of LM. Metastases outside the leptomeninges, such as parenchyma brain metastases, do not usually elevate these markers.133 They can also be helpful in monitoring disease activity or response to treatment.103 Unfortunately, the sensitivity of these markers is generally low, the normal values for certain markers are unknown, and some are investigational.
Specific markers include carcinoembryonic antigen (CEA) found in adenocarcinomas of the lung, breast, colon and bladder cancer,39' 103' 133 alpha-fetoprotein (AFP) found in teratocarcinoma, yolk sac tumor, endodermal sinus tumor and embryonal carcinoma, and beta-human chorionic gonadotropin (b-HCG) found in choriocarcinoma, embryonal carcinoma and germ-cell tumors.  Five- hydroxyindole acetic acid (5-HIAA) is a substance found in normal CSF, but if grossly elevated may be helpful in making the diagnosis of carcinoid.79 Other specific markers include prostate specific antigen (PSA) in prostate cancer,74 alkaline phosphatase level and CA 19-9 in lung cancer,66'102 CA 125 in ovarian cancer,90 CA 15-3 in breast cancer, 90 and gastrin releasing peptide in small cell carcinoma.21
In order to interpret the results of these markers in CSF, serum levels should be obtained simultaneously because high serum levels can diffuse into the CSF. In the case of CEA, levels greater than 1 % of serum CEA in the spinal fluid suggests LM.103
Nonspecific markers include beta-glucuronidase, ' LDH
isoenzyme-5,39' 126' 127 beta 2-microglobulin,126' 127 myelin basic protein,107 ferritin,140 an epithelial glycoprotein HMFG1 antigen,76 and tumor necrosis factor-alpha81. These nonspecific markers can be elevated in CNS processes other than LM including bacterial meningitis and stroke, but in combination may increase diagnostic accuracy of LM.127. Recently, vascular endothelial growth factor (VEGF), a potent promoter of tumor angiogenesis, was found to be significantly elevated in patients with LM but not in the CSF of patients in the control group.113 Certain matrix metalloproteinase (MMP) profiles have been shown to correlate with LM compared to patients with brain metastases, primary brain tumors, and controls; patients with LM have activation of MMP-2 and -9.42 Elevation of cathepsin B and H and decreased cystatin C in CSF was found in the CSF of patients with LM but not in controls, suggesting that this may be another diagnostic marker.78 In general, levels of all of these markers are lower in ventricular than in lumbar fluid.103
Newer techniques may assist the diagnosis of LM from solid tumors. In flow cytometry, molecular markers and chromosomal analysis may detect abnormalities suggesting tumor cells. Polymerase chain reaction (PCR) analysis of known genetic alterations may increase the diagnostic yield of CSF studies.29, 44,117 Florescence in situ hybridization (FISH) detects the chromosomal aberrations in the interphase nucleus.130' 132 One study tested the aneusomy of chromosome 1, which is frequently involved in carcinogenesis of solid tumors, and found a better correlation with neurologic status and accurate diagnosis of LM.132
5.2 Computed tomography scan (CT) and magnetic resonance imaging (MRI)
MRI has dramatically increased the diagnostic yield of LM.41 The sensitivity of MRI is approximately 75% with a specificity of 77 %.31'114
Linear or nodular enhancement can be seen on the surface of the cerebrum or within the cerebellar folia, basal cisterns, cranial or spinal nerves and nerve roots after administration of gadolinium. Diffuse leptomeningeal enhancement can be seen, but is not as sensitive as focal dural enhancement which may be reactive from base of skull metastasis or from intracranial hypotension, typically after LP.96 Therefore, contrast enhanced MRI should be performed before LP. Other processes that may mimic LM include neurosarcoidosis,2 chronic meningitis or Guillain-Barre syndrome.52
Fluid-attenuated inversion recovery (FLAIR) sequences are somewhat less sensitive than Ti gadolinium images, but may detect small abnormalities as bright signals within the subarachnoid space often missed with gadolinium.109 Contrast-enhanced FLAIR may further improve the sensitivity.71 A comparison of these three techniques suggests that contrast enhanced Tl images remain the most accurate with a sensitivity of 59% and specificity of 93%, compared to unenhanced FLAIR of 12% and 93%, enhanced FLAIR of 41% and 88%, respectively. Using all three sequences the sensitivity is 65%.110
CT is not as sensitive as MRI, although nodular enhancement may be seen in some cases. In one study, CT with contrast was normal in 40 %, and LM was mistaken for parenchymal disease in 24 %, making the sensitivity less than one-third.31
Although a nonspecific finding, hydrocephalus seen on CT or MRI of the brain should raise the suspicion of LM.
Patients with LM can have abnormal CSF flow dynamics without evidence of hydrocephalus or any other abnormality on neurologic imaging. Radioisotope ventriculography can evaluate CSF flow dynamics by measuring the distribution of the isotope throughout the subarachnoid space by gamma counter. Fifty to seventy percent of patients have evidence of CSF flow disturbance demonstrated on indium or technecium lO AH ^^
ventriculography. ' ' Common sites of abnormal flow were ventricular outlet obstructions, spinal canal, and over the cortical convexities. Flow abnormality correlates with prognosis.47'53 Patients with abnormal flow who were treated with intrathecal (IT) chemotherapy experienced significant drug toxicity and had a significantly lower survival. Patients whose flow was restored to normal after focal radiation had a better outcome. Mason et al. measured the ventricular methotrexate levels in these patients, and showed that patients with a partial spinal block who achieved a therapeutic level still had a poor prognosis.70 They suggested that inadequate drug distribution is not the sole cause of chemotherapeutic failure; impaired flow may be an indirect measure of tumor burden within the subarachnoid space which is associated with more extensive disease and a worse prognosis.
The sensitivity of CT myelography for detecting LM is about 26 % 135 and similar to an MRI of the spine.22 Small nodules seen along nerve roots can suggest the diagnosis of LM. Given the noninvasive nature of MRI, CT myelography does not have a primary role in the diagnosis of LM.
Electrophysiological tests are nonspecific but may help assist the diagnosis in some cases. For example, electroencephalography (EEG) may be able to differentiate seizure activity versus pressure waves. Nerve conduction study/electromyography may be able to differentiate root disease versus peripheral neuropathy and the finding of polyradiculopathy on EMG/NCS in a cancer patient is suggestive of LM. The diagnosis may also to be established by leptomeningeal biopsy.9'90
6. TREATMENT (Table 4)
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