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MAJOR CATEGORIES OF NEUROLOGIC DISEASE
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equina), multiple cranial nerve palsies, and a confusional state have been the principal manifestations, and many cases are restricted to one of these subsyndromes Only a small number have an uncomplicated menigneal syndrome of headache, nausea, and meningismus, but these features develop late in the course of many cases Delirium, stupor, and coma follow in the pure meningeal syndrome Focal neurologic signs and seizures may be associated, and somewhat fewer than half the patients develop hydrocephalus This is among the most deceptive of neurologic diagnoses It may cause a painful or painless polyradiculopathy and simulate a polyneuropathy; it has several times deceived us into considering the diagnosis of an in ammatory polyneuropathy The combination of a cranial neuropathy, such as unilateral facial weakness, hearing loss or ocular motor palsy, with bilateral asymmetrical limb weakness is particularly suggestive The evolution in all these syndromes is generally subacute over weeks with a more rapid phase as the illness progresses The diagnosis can be established in most cases by identifying tumor cells in the CSF using ow cytometry, cytospin, centrifugation, or Millipore ltering More than one examination, using generous quantities of CSF, may be needed Increased pressure, elevation of protein and low glucose levels, and lymphocytic pleocytosis (up to a hundred but typically much fewer) are other common CSF ndings Nevertheless, in a few patients, the CSF remains persistently normal Measuring the CSF for certain biochemical markers of cancer such as lactate dehydrogenase, -glucuronidase, 2-microglobulin, and carcinoembryonic antigen (CEA) offers another means of making the diagnosis and following the response to therapy These markers are most likely to be abnormal in hematologic malignancies but may also be altered in some cases of intracranial infection and parenchymal metastases (Kaplan et al) In a few of the cases of meningeal carcinomatosis, there are also parenchymal brain metastases Also known is a rare primary malignant melanoma of the meninges that acts in a similar way to carcinomatous meningitis Bloody CSF is a characteristic feature The prognosis is as bleak as it is for metastatic carcinomatous meningitis The prognosis for this condition is quite poor (lymphomatous in ltration is an exception); seldom does the patient survive more than 1 to 3 months, perhaps longer by several weeks if treatment is successful An encephalopathy due to widespread in ltration of the cerebral meninges is a particularly malevolent sign Treatment This consists of radiation therapy to the symptomatic areas (cranium, posterior fossa, or spine), followed in selected cases by the intraventricular administration of methotrexate; but these measures rarely stabilize neurologic symptoms for more than a few weeks The methotrexate is administered into the lateral ventricle via an Ommaya reservoir (10 mg diluted in water) or into the lumbar subarachnoid space through a lumbar puncture needle (12 to 15 mg) Several regimens have been devised, including daily instillation for 3 to 4 days followed by radiation, or methotrexate doses on days 1, 4, 8, 11, and 15 Involvement of the cranial nerves or an encephalopathy due to widespread in ltration of the cranial meninges is treated with whole-brain radiation, 3000 cGy, given in fractions of 300 cGy per day for 10 days Spinal root in ltration responds to spinal radiation, and regional treatments are helpful temporarily for local seeding of the lumbar roots The median duration of survival after diagnosis of meningeal carcinomatosis was 6 months in the large series reported by Wasserstrom and colleagues but only 43 days in the series of Sorenson and coworkers The leukoencephalopathy that may follow the combined use of
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intrathecal methotrexate and radiation therapy is described below The best response to treatment occurs in patients with lymphoma and breast and small-cell lung cancers; cases of meningeal in ltration by other lung cancers, melanoma, and adenocarcinoma do poorly Involvement of the Nervous System in Leukemia Almost onethird of all leukemic patients have evidence of diffuse in ltration of the leptomeninges and cranial and spinal nerve roots at autopsy (Barcos et al) The incidence is greater in acute than in chronic leukemia and greater in lymphocytic than in myelocytic leukemia; it is also far more frequent in children than in adults The highest incidence is in children with acute lymphocytic (lymphoblastic) leukemia who relapse after treatment with combination chemotherapy (60 to 70 percent at time of death) The clinical and CSF picture of meningeal leukemia is much the same as that of meningeal carcinomatosis, discussed above, with the quali cation that leukemic cells are more likely to be found by cytologic examination of the spinal uid The treatment of the two disorders is also similar The studies of Price and Johnson demonstrated that CNS leukemia is primarily a pial disease The earliest evidence of leukemia is detected in the walls of pial veins, with or without cells lying freely in the CSF The leukemic in ltrate in our pathologic material has extended to the deep perivascular spaces, where the pial-glial membrane often con nes it; at this stage the CSF consistently contains leukemic cells Depending on the severity of meningeal involvement, transgression of the pial-glial membrane eventually occurs, with varying degrees of super cial parenchymal in ltration by collections of leukemic cells Hemorrhages of varying sizes are another common complication and are sometimes lethal Chloroma, a solid green-colored mass of myelogenous leukemic cells, may affect the dura or, less often the brain, but it is distinctly uncommon Cranial irradiation, combined with methotrexate given intrathecally or intravenously, has been effective in the prevention and treatment of meningeal involvement in childhood leukemia However, in a signi cant number of patients, it has given rise to a distinctive necrotizing leukoencephalopathy This neurologic complication may appear within several days to months after the last administration of methotrexate and several months after completion of radiotherapy (Robain et al) The leukoencephalopathy occurs most frequently and is most severe when all three modalities of treatment, ie, cranial irradiation and intrathecal and intravenous methotrexate, are used The initial symptoms consisting of apathy, drowsiness, depression of consciousness, and behavioral disorders evolve over a few weeks to include cerebellar ataxia, spasticity, pseudobulbar palsy, extrapyramidal motor abnormalities, and akinetic mutism Hypodense areas of varying size appear in the CT scan but unlike the case with tumor metastases there is no contrast enhancement By MRI these methotrexate lesions are hyperintense in T2-weighted images, but compared with pure radiation necrosis (see further on), they have poorly demarcated borders In some patients the condition stabilizes or improves, with corresponding resolution of the lesions More often the patient is left with severe persistent sequelae; in most, death occurs within several weeks or months of onset Throughout the cerebral white matter and to a lesser extent in the brainstem, there are foci of coagulation necrosis of varying size and severity In the smaller lesions, a perivascular topography of tissue disintegration is evident The pathogenesis of this disorder is unclear Radiation injury
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