to blindness within a matter of 48 h. MRI in this setting may be unrevealing and, as such, leptomeningeal optic neuropathy remains a clinical diagnosis. Even in the acute setting, treatment with radiation therapy and intravenous steroids has been largely disappointing [44, 45].

32.5 Treatment

Treatment of LMD is aimed at preventing neurologic deterioration and improving patient survival. The National Comprehensive Cancer Network clinical practice guidelines stratify patients with LMD for treatment purposes into good-risk and poor-risk groups. The good-risk group comprises patients with minimal neurologic deficits and minimal systemic disease as evidenced by a high Karnofsky performance status score (60 or above). The poor-risk group is characterized by multiple, serious neurologic deficits, extensive systemic disease, bulky CNS disease, encephalopathy, and a low Karnofsky performance status score. Patients in the good-risk group may proceed to a CSF flow study followed by initial intrathecal or intraventricular chemotherapy along with fractionated external-beam radiation therapy. The CSF flow study identifies areas of poor CSF distribution or obstruction that may resolve with focused radiation therapy, thus allowing for a more homogeneous distribution of subsequent intrathecal chemotherapy. Patients in the poor-risk group may benefit from more targeted fractionated externalbeam radiation therapy delivered to symptomatic sites only, along with supportive care [41].

Chemotherapy regimens for LMD have focused on four drugs: methotrexate, cytarabine, sustained-release cytarabine (depo-Cyt), and thiotepa. These agents have classically been administered intrathecally through a subcutaneous reservoir and ventricular catheter (i.e., Ommaya reservoir) or by lumbar puncture. They are highly effective for small leptomeningeal deposits or tumor cells suspended in CSF and have decreased penetration in bulky disease or sequestered deposits in perineural and Virchow–Robin spaces. Given the fragile neurologic status of patients with LMD, care must be taken to remove isovolumetric amounts of CSF prior to infusing chemotherapy to avoid increasing the total CSF volume. These samples can be sent for cytologic and other studies. Side effects of the four drugs commonly used to treat LMD include leukoencephalopathy and myelosuppression. In addition, increased intracranial pressure has been associated with the use of cytarabine and depo-Cyt [32].

Treatment strategies on the horizon include the use of other chemotherapeutic agents (dacarbazine, diaziquone, mafosfamide, nitrosoureas, busulfan, trimetrexate, melphalan, and topotecan), immunomodulatory drugs (intrathecal interleukin-2 and interferon-α), monoclonal antibody therapy (intravenous rituximab or radiolabeled monoclonal antibodies), and gene therapy (adenoviral vector delivery of herpes simplex virus-thymidine kinase to leptomeningeal metastases followed by systemic administration of ganciclovir) [2, 33].

32.6 Prognosis

Despite aggressive treatment protocols, the overall prognosis of patients with LMD remains poor; most studies report a median survival of 2 months (range, 2–3 months) [2, 46, 47]. Survival appears to be dependent on the primary tumor type. Reported median survival rates for breast cancer-related LMD range from 2.6 to 7.2 months, while those for lung cancer-related LMD range from 1 to 3 months. For the hematogenous tumors, survival after a diagnosis of LMD has likewise been dismal—median survival times of 6.0 and 2.3 months have been reported for the leukemias and lymphomas, respectively [4]. Interestingly, in one study patients with primary brain tumor-related LMD were diagnosed at a younger age and had a slightly longer median survival (not statistically significant, however) than patients with primary brain tumors without leptomeningeal involvement [25, 27].

In a study of 85 patients with solid tumors, the following predictors of good prognosis were identified on univariate analysis: female gender, LMD as the first relapse site, an interval of more than 1 year between diagnosis of the primary tumor and diagnosis of LMD, and good performance status. However, on multivariate regression analysis, only performance status and the extent of leptomeningeal involvement on CT or MRI achieved statistical significance [47].

Another commonly cited prognostic factor is CSF flow status, which, as mentioned previously, also guides treatment decisions. In a study of 31 patients with solid tumor-, hematologic tumor-, or primary brain tumor-related LMD, survival was significantly longer among patients with initially normal and abnormal but correctable CSF flow than among those with uncorrectable CSF flow (6.9, 13.0, and 0.7 months, respectively; P < 0.001) [48].

Finally, neurologic status at presentation and the extent of systemic cancer play an important role in determining clinical outcomes. In this regard, patients with encephalopathy secondary to hydrocephalus may respond well to symptomatic measures, while those with more focal neurologic deficits may be more resistant to treatment [17].

32.7 Conclusion

LMD currently complicates the management of approximately 5–8% of cancer patients, and the incidence of LMD is expected to continue to increase in the future as a result of new diagnostic modalities, improved therapies for systemic cancer, and increased clinical awareness. Recognizing LMD requires a high index of suspicion for new neurologic complaints, a comprehensive neurologic and neuro-ophthalmic examination with attention to the three domains of involvement (the cerebral hemispheres, the cranial nerves, and the spinal cord and roots), and a multidisciplinary approach. An excellent history and physical examination are instrumental in guiding imaging, particularly in cases with negative CSF cytology. Patient stratification based on Karnofsky performance status score, radiographic extent of disease,

and CSF flow studies allows for the implementation of more compassionate and cost-effective treatment strategies. Treatment is aimed at preventing neurologic deterioration and improving patient survival. Unfortunately, despite aggressive treatment, prognosis remains poor in most cases. New therapies may allow for extended survival in patients with LMD.

References

1.Eberth C. Zur entwicklung des epitheliomas dur pia under der lung. Virchows Arch 1870;49:51–63.

2.Grossman SA, Krabak MJ. Leptomeningeal carcinomatosis. Cancer Treat Rev 1999;25: 103–19.

3.DeAngelis L. Current diagnosis and treatment of leptomeningeal metastasis. J Neurooncol 1998;38:245–52.

4.Chamberlain MC, Nolan C, Abrey LE. Leukemic and lymphomatous meningitis: incidence, prognosis and treatment. J Neurooncol 2005;75(1):71–83.

5.Olson M, Chernik N, Posner J. Infiltration of the leptomeninges by systemic cancer. A clinical and pathologic study. Arch Neurol 1974;30:122–37.

6.Little J, Dale A, Okazaki H. Meningeal carcinomatosis clinical manifestations. Arch Neurol 1974;30:138–43.

7.Shapiro WR, Posner JB, Ushio Y, Chemik NL, Young DF. Treatment of meningeal neoplasms. Cancer Treat Rep 1977;61(4):733–43.

8.Theodore W, Gendelman S. Meningeal carcinomatosis. Arch Neurol 1981;38:696–9.

9.Wasserstrom W, Glass J, Posner J. Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer 1982;49:759–72.

10.Kaplan JG, DeSouza TG, Farkash A, Shafran B, Pack D, Rehman F, Fuks J, Portenoy R. Leptomeningeal metastases: comparison of clinical features and laboratory data of solid tumors, lymphomas and leukemias. J Neurooncol 1990;9(3):225–9.

11.Chamberlain M. Leptomeningeal metastases: 111indium-DTPA CSF flow studies. Neurology 1991;41:1765–9.

12. Chamberlain M. Leptomeningeal metastases: a review of evaluation and treatment. J Neurooncol 1998;37:271–84.

13.Posner JB, Chernik NL. Intracranial metastases from systemic cancer. Adv Neurol 1978;19:579–92.

14.Rosen ST, Aisner J, Makuch RW, Matthews MJ, Ihde DC, Whitacre M, Glatstein EJ, Wiernik PH, Lichter AS, Bunn PA, Jr. Carcinomatous leptomeningitis in small cell lung cancer: a clinicopathologic review of the National Cancer Institute experience. Medicine (Baltimore) 1982;61(1):45–53.

15.van Oostenbrugge R, Twijnstra A. Presenting features and value of diagnostic procedures in leptomeningeal metastases. Neurology 1999;53:382–5.

16.Maroldi R, Ambrosi C, Farina D. Metastatic disease of the brain: extra-axial metastases (skull, dural, leptomeningeal) and tumor spread. Eur J Radiol 2004;15:617–26.

17.Taillibert S, Laigle-Donadey F, Chodkiewicz C, Sanson M, Hoang-Xuan K, Delattre JY. Leptomeningeal metastases from solid malignancy: a review. J Neurooncol 2005;75(1):85–99.

18.Balm M, Hammack J. Leptomeningeal carcinomatosis. Presenting features and prognostic factors. Arch Neurol 1996;53:626–32.

19.Law IP, Dick FR, Blom J, Bergevin PR. Involvement of the central nervous system in nonHodgkin’s lymphoma. Cancer 1975;36(1):225–31.

20.Levitt LJ, Dawson DM, Rosenthal DS, Moloney WC. CNS involvement in the non Hodgkin’s lymphomas. Cancer 1980;45(3):545–52.

21.Bhatti M, Schmalfuss I, Eskin T. Isolated cranial nerve III palsy as the presenting manifestation of HIV-related large B-cell lymphoma: clinical, radiological, and postmortem observations: report of a case and review of the literature. Surv Ophthalmol 2005;50: 598–606.

22.Lange CP, Brouwer RE, Brooimans R, Vecht Ch J. Leptomeningeal disease in chronic lymphocytic leukemia. Clin Neurol Neurosurg 2007;109(10):896–901.

23.Levin N, Soffer D, Grissaru S, Aizikovich N, Gomori JM, Siegal T. Primary T-cell CNS lymphoma presenting with leptomeningeal spread and neurolymphomatosis. J Neurooncol 2008;90(1):77–83.

24.Shenkier TN, Blay JY, O’Neill BP, Poortmans P, Thiel E, Jahnke K, Abrey LE, Neuwelt E, Tsang R, Batchelor T, et al. Primary CNS lymphoma of T-cell origin: a descriptive analysis from the international primary CNS lymphoma collaborative group. J Clin Oncol 2005;23(10):2233–9.

25.Yung W, Horten C, Shapiro W. Meningeal gliomatosis: a review of 12 cases. Ann Neurol 1980;8:605–8.

26.Reifenberger G, Bostrom J, Bettag M, Bock WJ, Wechsler W, Kepes JJ. Primary glioblastoma multiforme of the oculomotor nerve. Case report. J Neurosurg 1996;84(6):1062–6.

27.Trivedi RA, Nichols P, Coley S, Cadoux-Hudson TA, Donaghy M. Leptomeningeal glioblastoma presenting with multiple cranial neuropathies and confusion. Clin Neurol Neurosurg 2000;102(4):223–6.

28.Glass JP, Melamed M, Chernik NL, Posner JB. Malignant cells in cerebrospinal fluid (CSF): the meaning of a positive CSF cytology. Neurology 1979;29(10):1369–75.

29.Murray JJ, Greco FA, Wolff SN, Hainsworth JD. Neoplastic meningitis. Marked variations of cerebrospinal fluid composition in the absence of extradural block. Am J Med 1983;75(2):289–94.

30.Glantz MJ, Cole BF, Glantz LK, Cobb J, Mills P, Lekos A, Walters BC, Recht LD. Cerebrospinal fluid cytology in patients with cancer: minimizing false-negative results. Cancer 1998;82(4):733–9.

31.Reuler J, Meier D. Leptomeningeal carcinomatosis with normal CSF features. Arch Intern Med 1979;139:237–8.

32.Chowdhary S, Chamberlain M. Leptomeningeal metastases: current concepts and management guidelines. J Natl Compr Canc Netw 2005;3:693–703.

33.Kara I, Sahin B, Gunesacar R. Levels of serum and cerebrospinal fluid soluble CD27 in the diagnosis of leptomeningeal involvement of hematolymphoid malignancies. Adv Ther 2007;24:741–7.

34.Schold SC, Wasserstrom WR, Fleisher M, Schwartz MK, Posner JB. Cerebrospinal fluid biochemical markers of central nervous system metastases. Ann Neurol 1980;8(6):597–604.

35.Ernerudh J, Olsson T, Berlin G, von Schenck H. Cerebrospinal fluid immunoglobulins and beta 2-microglobulin in lymphoproliferative and other neoplastic diseases of the central nervous system. Arch Neurol 1987;44(9):915–20.

36.Klee GG, Tallman RD, Goellner JR, Yanagihara T. Elevation of carcinoembryonic antigen in cerebrospinal fluid among patients with meningeal carcinomatosis. Mayo Clin Proc 1986;61(1):9–13.

37.Schipper HI, Bardosi A, Jacobi C, Felgenhauer K. Meningeal carcinomatosis: origin of local IgG production in the CSF. Neurology 1988;38(3):413–6.

38.Newton HB, Fleisher M, Schwartz MK, Malkin MG. Glucosephosphate isomerase as a CSF marker for leptomeningeal metastasis. Neurology 1991;41(3):395–8.

39.Freilich R, Krol G, Deangelis L. Neuroimaging and cerebral spinal fluid cytology in the diagnosis of leptomeningeal metastasis. Ann Neurol 1995;38:51–7.

40.Saremi F, Helmy M, Farzin S, Zee CS, Go JL. MRI of cranial nerve enhancement. AJR Am J Roentgenol 2005;185(6):1487–97.

41.Network NCC. NCCN Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network, Vol 1, Jenkintown, PA, 2008:23–6.

42.Shapiro W, Young D, Mehta B. Methotrexate: distribution in CSF fluid after intravenous, ventricular, and lumbar injections. N Engl J Med 1975;293:161–6.

43.Katz J, Valsamins M, Jampel R. Ocular signs in diffuse carcinomatous meningitis. Am J Ophthalmol 1961;76:672–9.

44.McFadzean R, Brosnahan D, Doyle D, Going J, Hadley D, Lee W. A diagnostic quartet in leptomeningeal infiltration of the optic nerve sheath. J Neuroophthalmol 1994;14(3):175–82.

45.Losa F, Montes A, Arruga J, Mesía R, Cardenal F. Meningeal carcinomatosis as a cause of partially reversible blindness. Clin Transl Oncol 2000;2(6):320–1.

46.Jayson G, Howell A. Carcinomatous meningitis in solid tumors. Ann Oncol 1996;7:773–86.

47.Waki F, Ando M, Takashima A, Yonemori K, Nokihara H, Miyake M, Tateishi U, Tsuta K, Shimada Y, Fujiwara Y, et al. Prognostic factors and clinical outcomes in patients with leptomeningeal metastasis from solid tumors. J Neurooncol 2009;93(2):205–12.

48.Glantz MJ, Hall WA, Cole BF, Chozick BS, Shannon CM, Wahlberg L, Akerley W, Marin L, Choy H. Diagnosis, management, and survival of patients with leptomeningeal cancer based on cerebrospinal fluid-flow status. Cancer 1995;75(12):2919–31.