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Neurology_Adams. The methylating agent temozolomide, given in the form of an orally administered prodrug, has lower toxicity and has been shown in several trials to produce slightly superior results to the aforementioned agents. In a large trial conducted by Stupp and colleagues, the median survival was 14.6 months with radiation and temozolomide, compared to 12.1 months with radiation alone, but 2-year survival was more than doubled from 10 to 27 percent. The drug is administered daily (75 mg/m2) concurrently with radiotherapy and, after a hiatus of 4 weeks, given for 5 days every 28 days for 6 cycles. Its main complications are thrombocytopenia or leukopenia in 5 to 10 percent of patients, and rare cases of Pneumocystis carinii pneumonia. Furthermore, high levels of a methyltransferase protein (MGMT) in some glioblastomas lead to resistance to chemotherapy. Hegi and colleagues found a relationship between the epigenetic silencing of the promoter of this gene (“methylation status”) and the response


Neurology_Adams

Neurology_Adams. some glioblastomas lead to resistance to chemotherapy. Hegi and colleagues found a relationship between the epigenetic silencing of the promoter of this gene (“methylation status”) and the response to temozolomide. In fact, almost all the marginal benefit of the drug in their study could be attributed to improved survival in this group who displayed a methylated gene. However, there is still activity of temozolomide in nonmethylated tumors and it is used in almost all cases. Additionally, there may be an interaction between MGMT methylation and mutations in other genes such as IDH1 (Wick et al).


Neurology_Adams

Neurology_Adams. Tyrosine kinase inhibitors (erlotinib, gefitinib) have been developed in response to the upregulation of EGFR mentioned earlier. In a preliminary but provocative study, Mellinghoff and coworkers found that a deletion mutation of the gene for this protein and expression of the tumor suppression protein PTEN predicted responsiveness of recurrent gliomas to treatment with EGFR kinase inhibitors. This represents one example in a growing field of prediction of treatment response in relation to tumor genetics; however, phase III studies of a tyrosine kinase inhibitor failed to improve outcome (Bode et al).


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Neurology_Adams. The treatment of recurrent glioblastoma or anaplastic astrocytoma after surgery and radiation, almost inevitable occurrences, is controversial and must be guided by the location and pattern of tumor growth and the patient’s age and relative state of health. Almost all glioblastomas recur within 2 cm of their original site and 10 percent develop additional lesions at distant locations. Reoperation is sometimes undertaken for local recurrences. The most aggressive approach—a second surgery and chemotherapy—can prove effective and has been generally used in patients younger than age 40 years whose original operation was many months earlier. If the PCV regimen discussed earlier has not already been used, some neurooncologists resort to that combination or the newer and better-tolerated alkylating agent temozolomide (which may be used if the PCV regimen was administered previously). These chemotherapeutic drugs may prolong the symptom-free interval but have little effect on survival. A


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Neurology_Adams. agent temozolomide (which may be used if the PCV regimen was administered previously). These chemotherapeutic drugs may prolong the symptom-free interval but have little effect on survival. A promising approach for recurrent malignant gliomas is the use of drugs that target the tumor’s vasculature. A recent but preliminary provocative observation from retrospective series has been that patients with glioblastoma receiving valganciclovir, ostensibly for concurrent CMV infections, had better survival than those who did not receive the drug (Söderberg-Nauclér and colleagues).


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Neurology_Adams. With aggressive surgical removal and radiotherapy, as described above, median survival for patients with glioblastoma is approximately 12 months, compared to 7 to 9 months without such treatment.


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Neurology_Adams. In the current WHO classification, diffuse astrocytoma is considered grade II and anaplastic astrocytoma, grade III as in Table 30-2. The lower-grade astrocytomas constitute a minority of adult tumors but a larger proportion of (infratentorial) tumors in children. The median survival in cases of anaplastic astrocytoma is considerably longer than for glioblastoma, 2 to 5 years in adults, often longer. Favored sites of occurrence are the cerebrum in adults and in children, are cerebellum, hypothalamus, optic nerve and chiasm, and pons. Astrocytomas of the cerebral hemispheres arise mainly in adults in their third and fourth decades or earlier; astrocytomas in other parts of the nervous system, particularly the posterior fossa and optic nerves, are more frequent in children and adolescents. These tumors had been classified further according to their histologic characteristics: protoplasmic or fibrillary; gemistocytic (enlarged cells distended with hyaline and eosinophilic material);


Neurology_Adams

Neurology_Adams. These tumors had been classified further according to their histologic characteristics: protoplasmic or fibrillary; gemistocytic (enlarged cells distended with hyaline and eosinophilic material); pilocytic (elongated, bipolar cells); and mixed astrocytoma-oligodendroglioma types; the current terminology is in Table 30-2 wherein these are subsumed by the larger category of astrocytoma. The most common type is composed of well-differentiated fibrillary astrocytes. The tumor cells contain glial fibrillary acidic protein (GFAP), which is a useful diagnostic marker in biopsy specimens. Some cerebral astrocytomas present as mixed astrocytomas and glioblastomas. The most common low-grade fibrillary type (grade II) is distinguished from the more benign WHO grade I pilocytic tumor (with a very good prognosis) and the rare pleomorphic xanthoastrocytoma. These distinctions correlate to a degree with the biologic behavior of the astrocytomas and therefore have prognostic importance but are


Neurology_Adams

Neurology_Adams. good prognosis) and the rare pleomorphic xanthoastrocytoma. These distinctions correlate to a degree with the biologic behavior of the astrocytomas and therefore have prognostic importance but are eclipsed by certain genetic characteristics discussed above.


Neurology_Adams

Neurology_Adams. Cerebral astrocytoma is a slowly growing tumor of infiltrative character with a tendency in some cases to form large cavities or pseudocysts. Other astrocytomas are noncavitating and appear grayish white, firm, and relatively avascular, almost indistinguishable from normal white matter, with which they merge imperceptibly. Fine granules of calcium may be deposited in parts of the tumor, but calcium in a slow-growing intracerebral tumor is more characteristic of an oligodendroglioma. The CSF is acellular; the only abnormalities in some cases are the increased pressure and protein content. The tumor may distort the lateral and third ventricles and displace adjacent cerebral vessels (Fig. 30-4). It may not be possible on clinical or imaging grounds to distinguish low-grade gliomas from a number of rare tumors in childhood such as the dysembryoplastic neuroepithelioma (DNET) discussed further on.


Neurology_Adams

Neurology_Adams. In about two-thirds of patients with astrocytoma, the first symptom is a focal or generalized seizure, and between 60 and 75 percent of patients have recurrent seizures in the course of their illness. Other subtle cerebral symptoms follow after months, sometimes after years. Headaches and signs of increased intracranial pressure are relatively late occurrences. On T1-weighted MRI, astrocytomas are isointense or hypointense; on T2 sequences, hyperintense, and there is variable enhancement of the solid portion of the tumor after gadolinium infusion. Cyst formation and small amounts of calcification are common, especially in cerebellar tumors. Other low-grade astrocytomas take the form of a more homogenous T1 hypointense and T2 hyperintense infiltrating mass with poorly defined borders and little or no contrast enhancement.


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Neurology_Adams. In children, astrocytic tumors usually arise in the cerebellum and declare themselves by some combination of gait unsteadiness, unilateral ataxia, and increased intracranial pressure (headaches, vomiting).


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Neurology_Adams. Treatment One of the more interesting developments in the treatment of low-grade cerebral tumors has been the comparison made by Jakola and colleagues between the practices in two Norwegian centers, one which practiced an aggressive approach of removing accessible tumors when they are discovered, and another, of observing the patient by sequential imaging to determine if the tumor has transformed into a more aggressive mode. While a small, and not a randomized trial, surgical excision resulted in longer survival. Excision of part of a cerebral astrocytoma can improve survival in a good functional state for many years. Modern techniques of brain mapping have allowed larger and probably safer resections of these tumors. An example of this has been offered by Sanai and colleagues, who performed mapping of language areas in a large consecutive series of glioma patients.


Neurology_Adams

Neurology_Adams. The cystic astrocytoma of the cerebellum is relatively benign in its overall behavior. In such cases, resection of the tumor nodule is of singular importance in delaying or preventing a recurrence. In clinical series, the rate of survival 5 years after successful surgery has been greater than 90 percent (Pencalet et al). The outcome is less ensured when the tumor also involves the brainstem and cannot be safely resected.


Neurology_Adams

Neurology_Adams. The natural history of the low-grade gliomas is to grow slowly and eventually undergo malignant transformation. The duration of progression before this transformation occurs and the latency to recurrence with modern treatment may extend for many years. A survey of the outcome of these low-grade supratentorial tumors showed that 10-year survival after operation was from 11 to 40 percent provided that conformal therapy (focused on the tumor, in contrast to whole brain radiation) 5,300 cGy was given postoperatively (Shaw et al). This, of course, is quite in contrast to the figures for glioblastoma. Repeated operations prolong life in some patients.


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Neurology_Adams. In younger patients, particularly if the neurologic examination is normal or nearly so, radiation can be delayed, and the status of the tumor can be evaluated by serial imaging. A number of studies have come to the conclusion that delaying radiation in younger patients may avoid the consequences of dementia and hypopituitarism (Peterson and DeAngelis), but others have suggested that the tumor itself and antiepileptic drugs cause more difficulty than high-dose radiation. An extensive randomized trial of early radiotherapy in adults demonstrated that median progression-free survival was extended to 5.3 years by early treatment in comparison to 3.4 years for observation only and radiation treatment that was initiated when signs of progression occurred, but that overall survival was unaffected, averaging just over 7 years in both groups (van den Bent et al). Lacking any clear benefit on survival, it seems to us that radiation may be withheld initially. An increase in seizures or worsening


Neurology_Adams

Neurology_Adams. averaging just over 7 years in both groups (van den Bent et al). Lacking any clear benefit on survival, it seems to us that radiation may be withheld initially. An increase in seizures or worsening neurologic signs then presses one to turn to radiation or further surgery.


Neurology_Adams

Neurology_Adams. Although chemotherapy has an ambiguous place in the treatment of low-grade pure astrocytomas, tumors with an oligodendroglial component respond well to combination chemotherapy used for the treatment of anaplastic oligodendroglioma. One randomized trial has shown a modest benefit in overall survival by adding chemotherapy (procarbazine, CCNU, vincristine; termed PCV) to radiation therapy of the brain (13.8 years median survival vs 7.8 years; see Buckner et al). Temozolomide has replaced PCV in many centers. The special features of astrocytomas of the pons, hypothalamus, optic nerves, and chiasm, which produce highly characteristic clinical syndromes and do not behave like a cerebral mass, are discussed further on in this chapter.


Neurology_Adams

Neurology_Adams. This interesting variant of high-grade glioma is no longer part of the WHO 2016 classification. However, its behavior and its appearance on imaging, as well as the property of diffuse infiltration of neoplastic glial cells, involving much of one or both cerebral hemispheres without a discrete tumor mass, establishes it as a useful conceptualization for clinical purposes. Whether this type of “gliomatosis” represents neoplastic transformation of multicentric origin or direct spread from one or more small neoplastic foci is not known. For these and other reasons, the tumor is impossible to classify (or to grade) using the conventional brain tumor schemes. The genetic and molecular alterations found in high-grade gliomas, as described earlier, are seen in some cases of gliomatosis cerebri as well.


Neurology_Adams

Neurology_Adams. Many small series of gliomatosis cerebri have been reported since Nevin introduced the term in 1938, but no truly distinctive clinical picture has emerged (Dunn and Kernohan). Impairment of intellect, headache, seizures, and papilledema are the major manifestations and do not set these cases apart on a clinical basis from the malignant astrocytoma, in which the tumor may also be more widespread than the macroscopic picture suggests. If there is a syndrome that can be associated early on with gliomatosis, in our experience it has been a nondescript frontal lobe behavioral syndrome sometimes mistaken for depression or a subacute dementia, or pseudobulbar palsy may be the first manifestation. The prognosis is variable but generally poor, measured in months to a few years from the time of diagnosis.


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Neurology_Adams. CT and MRI reveal small ventricles and one or more large confluent areas of signal change (Fig. 30-5). Imaging studies characteristically show the tumor crossing and thickening the corpus callosum. Contrast enhancement is scant, differentiating the tumor from cerebral lymphoma, which otherwise may have a similar appearance. As the tumor advances, enhancing nodules may appear, suggesting the emergence of foci of high-grade glioma.


Neurology_Adams

Neurology_Adams. Treatment These tumors are too infrequent for categorical assessments of therapy, but the overall response to all antitumor treatments has been disappointing and the prognosis, as mentioned, is poor, survival usually being measured in months. Corticosteroids have little clinical effect, probably because of a paucity of vasogenic edema. Most trials suggest a benefit to radiation treatment, but the absolute prolongation of life has been only several weeks (Leibel et al). The addition of chemotherapy may confer a marginal further benefit when survival at 1 year is considered. Small series of patients treated with temozolomide suggest it may be a promising agent for this tumor but it will be difficult to conduct a randomized trial given its rarity. When a large region is infiltrated, particularly in the temporal lobe, surgical debulking may prolong life, but otherwise surgery is futile except to obtain a diagnosis. Stereotactic biopsy is usually undertaken.


Neurology_Adams

Neurology_Adams. This tumor was first identified by Bailey and Cushing in 1926 and described more fully by Bailey and Bucy in 1929. It is derived from oligodendrocytes or their precursor cells and may occur at any age, most often in the third and fourth decades, with an earlier peak at 6 to 12 years. It is relatively infrequent, constituting approximately 5 to 7 percent of all intracranial gliomas. From the time of its original descriptions, it was recognized as being more benign than the malignant astrocytoma. The incidence in men is twice that in women. In some cases, the tumor may be recognized at surgery by its pink-gray color and multilobular form, its relative avascularity and firmness (slightly tougher than surrounding brain), and its tendency to encapsulate and form calcium and small cysts. Most oligodendrogliomas, however, are grossly indistinguishable from other gliomas, and a proportion—up to half in some series—are mixed oligoastrocytomas, suggesting that the precursor cell is


Neurology_Adams

Neurology_Adams. Most oligodendrogliomas, however, are grossly indistinguishable from other gliomas, and a proportion—up to half in some series—are mixed oligoastrocytomas, suggesting that the precursor cell is pluripotential.


Neurology_Adams

Neurology_Adams. The neoplastic oligodendrocyte has a small round nucleus and a halo of unstained cytoplasm (“fried egg” appearance). The cell processes are few and stubby, visualized only with silver carbonate stains. Some of the oligodendrocytes have intense immunoreactivity to GFAP, similar to normal myelin-forming oligodendrocytes. Microscopic calcifications are observed frequently, both within the tumor and in immediately adjacent brain tissue.


Neurology_Adams

Neurology_Adams. Genetics A remarkable degree of progress has been made in understanding the genetic aberrations that occur as acquired somatic mutation within these tumors and the relationship of these changes to the prognosis and response to therapy. Specifically, loss of certain alleles on chromosome 1p has been predictive of a high degree of responsiveness to the below-described PCV chemotherapy regimen, and a similar loss on chromosome 19q has been associated with longer survival. The current schemes for classification require that there be a mutation in the IDH gene family (see Yan et al) and a codeletion of 1p and 19q (1p/19q) but some tumors in childhood do not have these changes. What is more important as mentioned, these genetic alterations predict responsiveness to treatment and longer survival (see in the following text).


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Neurology_Adams. The most common sites of this tumor are the frontal and temporal lobes (40 to 70 percent), often deep in the white matter, with one or more streaks of calcium but little or no surrounding edema. It is rarely found in other parts of the nervous system. By extending to the pial surface or ependymal wall, the tumor may metastasize distantly in ventricular and subarachnoid spaces, accounting for 11 percent of the series of gliomas with meningeal dissemination reported by Polmeteer and Kernohan (less frequent than medulloblastoma and glioblastoma; see also Yung et al). The tumor does not lend itself easily to any of the grading scales, but a distinction is made between low grade (grade II) and a anaplastic type with degeneration, evidenced by greater cellularity and by numerous and abnormal mitoses (grade III); necrosis may occur in small regions of the tumor in about one-third of cases. In the oligoastrocytomas, either cell type may be anaplastic.


Neurology_Adams

Neurology_Adams. The typical oligodendroglioma grows slowly. As with astrocytomas, the first symptom in more than half of patients is a focal or generalized seizure; seizures often persist for many years before other symptoms develop. Approximately 15 percent of patients have early symptoms and signs of increased intracranial pressure; an even smaller number have focal cerebral signs (hemiparesis). Much less frequent are unilateral extrapyramidal rigidity, cerebellar ataxia, Parinaud syndrome, intratumoral hemorrhage, and meningeal oligodendrogliosis (cranial–spinal nerve palsies, hydrocephalus, lymphocytes, and tumor cells in CSF).


Neurology_Adams

Neurology_Adams. The appearance on imaging studies is variable, but the most typical is a hypodense (on CT) or T2 hyperintense (on MRI) heterogenous mass near the cortical surface with relatively well-defined borders (Fig. 30-6). Intratumoral calcification can be seen in more than half the cases and is a helpful diagnostic sign, but in the context of seizures, this finding also raises the possibility of an arteriovenous malformation or a low-grade astrocytoma. Approximately half of oligodendrogliomas demonstrate some contrast enhancement, and leptomeningeal enhancement adjacent to the tumor can be seen but is rare.


Neurology_Adams

Neurology_Adams. Treatment Surgical excision followed by radiation therapy has been the conventional treatment for oligodendroglioma. However, because of uncertainty as to the histologic classification of many of the reported cases, it is not clear whether radiation therapy is attended by longer survival. Well-differentiated oligodendrogliomas should probably not receive radiation if seizures are well controlled and there are no neurologic deficits. As mentioned earlier, in the discovery by Cairncross and MacDonald of considerable importance is that many oligodendrogliomas, especially anaplastic ones and those with IDH mutations and 1p/19q codeletion, respond impressively to chemotherapeutic agents. This has been studied with the PCV regimen (procarbazine, cyclophosphamide, and vincristine) given in approximately 6 cycles, but also applies to the better-tolerated temozolomide, which has become the preferred treatment.


Neurology_Adams

Neurology_Adams. Mixed oligodendrogliomas and astrocytomas should generally be treated like astrocytomas, but temozolomide probably suffice to treat both components. An adequate direct comparison between temozolomide and PCV is awaited. Ependymoma (See Also “Patients Who Present Primarily With Signs of Increased Intracranial Pressure” Further on)


Neurology_Adams

Neurology_Adams. Ependymoma (See Also “Patients Who Present Primarily With Signs of Increased Intracranial Pressure” Further on) Correctly diagnosed by Virchow as early as 1863, the origin of this tumor from ependymal cells was first suggested by Mallory, who found the typical blepharoplasts (small, darkly staining cytoplasmic dots that are the basal bodies of the cilia as seen by electron microscopy). Two types were recognized by Bailey and Cushing: one was the ependymoma, and the other, with more malignant and invasive properties, the ependymoblastoma, now recognized as an anaplastic ependymoma. Fewer than 10 percent of all intracranial gliomas are ependymomas, the percentage being slightly higher in children. Approximately 40 percent of the infratentorial ependymomas occur in the first decade of life, a few as early as the first year. The supratentorial ones are more evenly distributed among all age groups, but in general the age incidence is lower than that of other malignant gliomas.


Neurology_Adams

Neurology_Adams. There is also a myxopapillomatous type of ependymoma, localized exclusively in the filum terminale of the spinal cord as discussed further on. The latter gives rise to a special syndrome that variably combines symptoms and signs of the conus medullaris and the cauda equina such as sciatica or femoral pain, bladder difficulty, saddle anesthesia, and spastic leg weakness.


Neurology_Adams

Neurology_Adams. Ependymomas are derived from ependymal cells, that is, the cells lining the ventricles of the brain and the central canal of the spinal cord; this is the most common glioma of the spinal cord. These cells have both glial and epithelial characteristics. As one might expect, the tumors grow either into the ventricle or adjacent brain tissue. The most common cerebral site is the fourth ventricle; less often they occur in the lateral or third ventricles. Grossly, those in the fourth ventricle are grayish pink, firm, cauliflower-like growths; those in the cerebrum, arising from the wall of the lateral ventricle, may be large (several centimeters in diameter), reddish gray, and softer and more clearly demarcated from adjacent tissue than astrocytomas, but they are not encapsulated. The tumor cells tend to form rosettes with central lumens or, more often, circular arrangements around blood vessels (pseudorosettes). Some ependymomas are densely cellular; others form papillae. Some of the


Neurology_Adams

Neurology_Adams. cells tend to form rosettes with central lumens or, more often, circular arrangements around blood vessels (pseudorosettes). Some ependymomas are densely cellular; others form papillae. Some of the well-differentiated fourth ventricular tumors are probably derived from subependymal astrocytes (see later in this chapter).


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Neurology_Adams. Anaplastic ependymomas are identified by their high mitotic activity and endothelial proliferation, nuclear atypia, and necrosis. However, correlations between histopathologic features and clinical outcomes have not been well defined. A genetic aberration in which the RELA gene becomes fused to an open reading frame of chromosome 11 (RELA-fusion positive) occurs in the majority of supratentorial tumors in children. The symptomatology depends on the location of the neoplasm. The clinical manifestations of fourth ventricular tumors are described further on; the point to be made here is the frequent occurrence of hydrocephalus and signs of raised intracranial pressure (manifest in children by lethargy, nausea, vomiting, and papilledema). Cerebral ependymomas otherwise resemble the other gliomas in their clinical expression in that seizures occur in approximately one-third of the cases.


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Neurology_Adams. The imaging characteristics are rather different from those of other tumors. With CT one observes a well-demarcated heterogeneous hyperdense mass with fairly uniform contrast enhancement. Calcification and some degree of cystic change are common in supratentorial tumors, but less so in infratentorial ones. There are mixed signal characteristics on MRI, generally hypointense on T1 sequences and hyperintense on T2. An intraventricular location supports the diagnosis of ependymoma, but meningioma and a number of other tumors may be found in this location. In keeping with the variability of anaplasia, the interval between the first symptom and the diagnosis ranges from 4 weeks in the most malignant types, to 7 to 8 years.


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Neurology_Adams. Treatment and outcome In a follow-up study of 101 cases in Norway, where ependymomas made up 1.2 percent of all primary intracranial tumors (and 32 percent of intraspinal tumors), the postoperative survival was poor. Within a year, 47 percent of the patients had died, although 13 percent were alive after 10 years. Doubtless the prognosis depends on the degree of anaplasia (Mørk and Løken), the location of the tumor, and whether it is operable but the lack of certainty of these dicta have been alluded to earlier. Surgical removal is supplemented by radiation therapy, particularly to address the high rate of seeding of the ventricles and spinal axis. In the treatment of anaplastic ependymomas, antineoplastic drugs are often used in combination with radiation therapy.


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Neurology_Adams. This tumor, first illustrated by Matthew Bailie in his Morbid Anatomy (1787) and first identified properly by Bright, in 1831, originates from the dura mater or arachnoid. It was analyzed from every point of view by Harvey Cushing and was the subject of one of his most important monographs (Cushing, 1962). The tumor is discussed again further on in relation to particular sites of origin.


Neurology_Adams

Neurology_Adams. Meningiomas represent approximately one-third of all primary intracranial tumors; they are more common in women than in men (2:1) and have their highest incidence in the sixth and seventh decades of life. Some are familial. There is evidence that persons who have undergone radiation therapy to the scalp or cranium are vulnerable to the development of meningiomas and that the tumors appear at an earlier age in such individuals (Rubinstein et al). Radiofrequency energy exposure from portable cellular devices has failed to be linked to elevated incidence of meningiomas (or gliomas). There are also a number of reports of a meningioma developing at the site of previous trauma, such as a cranial fracture line, but the association is uncertain.


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Neurology_Adams. The most frequent acquired genetic defects of meningiomas are truncating (inactivating) mutations in the neurofibromatosis 2 gene (merlin) on chromosome 22q. These are present in the great majority of certain meningiomas (e.g., fibroblastic and transitional types), but not others. Merlin deletions probably also play a role in those instances in which there is a loss of the long arm of chromosome 22. In meningiomas of both the sporadic and neurofibromatosis type 2 (NF2)–associated types, other somatic genetic defects are found, including deletions on chromosomes 1p, 6q, 9p, 10q, 14q, and 18q.


Neurology_Adams

Neurology_Adams. Meningiomas also elaborate a variety of soluble proteins, some of which (VEGF) are angiogenic and probably relate to both the highly vascularized nature of these tumors and their prominent surrounding edema (see Lamszus for further details). Some meningiomas contain estrogen and progesterone receptors. These findings may relate to the increased incidence of the tumor in women, its tendency to enlarge during pregnancy, and an association with breast cancer. The precise cellular origin of meningiomas is still not settled. According to Rubinstein, they may arise from dural fibroblasts, but it was the opinion of our colleague


Neurology_Adams

Neurology_Adams. R.D. Adams that, they are more clearly derived from arachnoidal (meningothelial) cells, in particular from those forming the arachnoid villi. Because the clusters of arachnoidal cells penetrate the dura in largest number in the vicinity of venous sinuses, these are the sites of predilection for the tumor. Grossly, the tumor is firm, gray, and sharply circumscribed, taking the shape of the space in which it grows; thus, some tumors are flat and plaque-like, others round and lobulated. They may indent the brain and acquire a pia-arachnoid covering as part of their capsule, but they are clearly demarcated from the brain tissue (extraaxial) except in the unusual circumstance of a malignant invasive meningioma. Infrequently, they arise from arachnoidal cells within the choroid plexus, forming an intraventricular meningioma.


Neurology_Adams

Neurology_Adams. The cells of meningiomas are relatively uniform, with round or elongated nuclei, visible cytoplasmic membrane, and a characteristic tendency to encircle one another, forming whorls and psammoma bodies (laminated calcific concretions). A notable electron microscopic characteristic is the formation of very complex interdigitations between cells and the presence of desmosomes (Kepes). Cushing and Eisenhardt and, more recently, the World Health Organization (Lopes et al) have divided meningiomas into many subtypes depending on their mesenchymal variations, the character of the stroma, and their relative vascularity, but the value of such classifications is debatable. Currently neuropathologists recognize a meningothelial (syncytial) form as being the most common. It is readily distinguished from other similar but nonmeningothelial tumors such as hemangiopericytomas, fibroblastomas, and chondrosarcomas.


Neurology_Adams

Neurology_Adams. Meningiomas occur at sites of dural folds, most commonly the frontoparietal parasagittal convexities, falx, tentorium cerebelli, sphenoid wings, olfactory groove, and tuberculum sellae. Ninety percent of meningiomas are supratentorial, and the majority of infratentorial meningiomas occur at the cerebellopontine angle. Some meningiomas—such as those of the olfactory groove, sphenoid wing, and tuberculum sellae—express themselves by highly distinctive syndromes that are almost diagnostic; these are described further on in this chapter. Rarely, the tumors are multiple. Inasmuch as the meningioma extends from the dural surface, it commonly incites hyperostosis of adjacent bone and can, in more malignant cases, invade and erode the cranial bones or excite an osteoblastic reaction, giving rise to an exostosis on the external surface of the skull. Most of the following remarks apply to meningiomas of the parasagittal, sylvian, and other surface areas of the cerebrum.


Neurology_Adams

Neurology_Adams. Small meningiomas, less than 2.0 cm in diameter, are often found at autopsy in middle-aged and elderly persons without having caused symptoms. Only when they exceed a certain size and indent the brain or cause a seizure do they alter function. The size that must be reached before symptoms appear varies with the size of the space in which the tumor grows and the surrounding anatomic arrangements. Focal seizures are an early sign of meningiomas that overlie the cerebrum. The parasagittal frontoparietal meningioma may cause a slowly progressive spastic weakness or numbness of one leg and later of both legs, and incontinence in the late stages. The larger sylvian tumors are manifest by a variety of motor, sensory, and aphasic disturbances in accord with their location, and by seizures.


Neurology_Adams

Neurology_Adams. Before brain imaging became widely available, a meningioma often gave rise to neurologic signs for many years before the diagnosis was established, attesting to its slow rate of growth. Even now some tumors reach enormous size, to the point of causing papilledema, before the patient comes to medical attention. Many are detected on CT in individuals with unrelated neurologic diseases. The diagnosis of meningioma is greatly facilitated by their ready visualization with contrast-enhanced CT and MRI (Figs. 30-7 and 30-8), which reveal their tendency to calcify as well as their prominent vascularity. These changes are reflected by homogeneous contrast enhancement and by “tumor blush” on angiography. Typically the tumor takes the form of a smoothly contoured mass sometimes lobulated, with one edge abutting the inner surface of the skull, along the dura. On CT performed without contrast they are isodense or slightly hyperdense; calcification at the outer surface or heterogeneously throughout


Neurology_Adams

Neurology_Adams. abutting the inner surface of the skull, along the dura. On CT performed without contrast they are isodense or slightly hyperdense; calcification at the outer surface or heterogeneously throughout the mass is common. The amount of edema surrounding the tumor is highly variable and may relate to the extent of local brain symptoms. The CSF protein is usually elevated.


Neurology_Adams

Neurology_Adams. Treatment Surgical excision should afford long-term or permanent cure in most symptomatic and accessible tumors. Recurrence is likely if removal is incomplete, as is often the case, but for some the growth rate is so slow that there may be a latency of many years or decades. A few tumors show malignant qualities; that is, a high mitotic index, nuclear atypia, marked nuclear and cellular pleomorphism, and invasiveness of brain. Their regrowth is then rapid if they are not completely excised. Tumors that lie beneath the hypothalamus, along the medial part of the sphenoid bone and parasellar region, or anterior to the brainstem are the most difficult to remove surgically. By invading adjacent bone, they may become impossible to remove totally. Carefully planned radiation therapy, including various forms of stereotactic treatment, is beneficial in cases that are inoperable and when the tumor is incompletely removed or shows malignant characteristics.


Neurology_Adams

Neurology_Adams. Smaller tumors at the base of the skull can be obliterated or reduced in size by focused radiation, probably with comparable or less risk than posed by surgery (see discussion by Chang and Alder). Conventional chemotherapy and hormonal therapy are probably ineffective, but the latter has been a subject of interest. Investigations are being undertaken with antiangiogenic antibodies for recurrent tumors. This tumor has assumed increasing significance in the last few decades because of its increased incidence in patients with AIDS and other immunosuppressed states. There is a peak incidence in the fifth through seventh decades of life, or in the third and fourth decades in patients with AIDS and the incidence is increasing independent of this form of immunosuppression.


Neurology_Adams

Neurology_Adams. For many years, the cell of origin of this tumor was attributed to the reticulum cell, a histiocytic component of the germinal center of lymph nodes that produces the reticulum stroma of the nodes, and the tumor was termed “reticulum cell sarcoma.” The meningeal histiocyte and microgliacytes are the equivalent cells in the brain to the reticulum cell and considered then the origin of the tumor. Later, it was recognized that the malignant cells were lymphocytes and lymphoblasts, leading to its reclassification as a lymphoma (diffuse large cell type). It has been appreciated, on the basis of immunocytochemical studies, that the tumor cells are B lymphocytes. There is a fine reticulum reaction between the reticulum cells derived from fibroblasts and microglia or histiocytes. The disproportionate emphasis on this reticular stroma was in part the result of staining methods that brought it into relief with the lymphocytes. The B lymphocyte or lymphoblast is the tumor cell, whereas the fine


Neurology_Adams

Neurology_Adams. emphasis on this reticular stroma was in part the result of staining methods that brought it into relief with the lymphocytes. The B lymphocyte or lymphoblast is the tumor cell, whereas the fine reticulum and “microgliacytes” are secondary interstitial reactions.


Neurology_Adams

Neurology_Adams. In contrast, T-cell lymphomas of the nervous system are rare but do occur in both immunocompetent and immunosuppressed patients. Because the brain is devoid of lymphatic tissue, it is uncertain how this tumor arises; one theory holds that it represents a systemic lymphoma with a particular propensity to metastasize to the nervous system. This seems unlikely to the authors; systemic lymphomas of the usual kind rarely metastasize, as discussed further on, under “Involvement of the Nervous System in Systemic Lymphoma.”


Neurology_Adams

Neurology_Adams. Primary CNS lymphoma may arise in any part of the cerebrum, cerebellum, or brainstem, with 60 percent being in the cerebral hemispheres; they may be solitary or multifocal. A periventricular localization is common. Vitreous, uveal, and retinal (ocular) involvement occurs in 10 to 20 percent of cases; here vitreous biopsy may be diagnostic, but it is not often performed. (Two-thirds of patients with ocular lymphoma will have cerebral involvement within a year.) Lai and colleagues have presented evidence that, in advanced cases that were autopsied, microscopic deposits of tumor found their way to many regions of the brain and not solely in areas indicated by nodular enhancement on MRI. Whether this indicates a widespread or multifocal origin of brain lymphoma is not clear.


Neurology_Adams

Neurology_Adams. The pia and arachnoid may be infiltrated, and a meningeal form of B-cell lymphoma that involves peripheral and cranial nerves is also known. Cases of what has been termed neurolymphomatosis may or may not arise from systemic lymphoma (hence, primary neurolymphomatosis) and present with variably painful, predominantly motor polyradiculopathies. Lymphomatous metastases to the same regions are probably more common than the isolated peripheral nerve and meningeal form but give rise to a similar syndrome of multiple radiculopathies. One such patient of ours had a flaccid paraparesis and back and sciatic pain; MRI showed tumor infiltrating the cauda equina nerve roots and contiguous meninges.


Neurology_Adams

Neurology_Adams. The tumor forms a pinkish gray, soft, ill-defined, infiltrative mass in the brain, difficult at times to distinguish from an astrocytoma. Perivascular and meningeal spread results in shedding of cells into the CSF, accounting perhaps for the multifocal appearance of the tumor in many cases. The neoplasm is highly cellular and grows around and into blood vessels (“angiocentric” pattern) but elicits no tendency to necrosis. The nuclei are oval or bean-shaped with scant cytoplasm, and mitotic figures are numerous. B-cell markers applied to fixed tissue define the lymphoblastic cell population as monoclonal and identify the tumor cell type. The stainability of reticulum and microglial cells also serves to distinguish this tumor microscopically. There is no tumor tissue outside the brain.


Neurology_Adams

Neurology_Adams. Several of our cases of meningeal and cranial nerve lymphoma with similar histologic characteristics to primary CNS lymphoma were complications of chronic lymphatic leukemia, a type of so-called Richter transformation. Primary lymphoma involving the cerebral hemispheres initially pursues a clinical course somewhat similar to that of the gliomas but with a vastly different response to treatment. Behavioral and personality changes, confusion, dizziness, and focal cerebral signs predominate over headache and other signs of increased intracranial pressure as presenting manifestations. Seizures may occur but are less common, in our experience, than they are as the introductory feature of gliomas. Most cases occur in adult life, but some have been observed in children, in whom the tumor may simulate the cerebellar symptomatology of medulloblastoma.


Neurology_Adams

Neurology_Adams. The finding on CT and MRI of one or several dense (hypercellular), homogeneous, enhancing, infiltrating, nonnecrotic, nonhemorrhagic, periventricular masses is characteristic (Fig. 30-9). However, rim enhancement also occurs, and any part of the brain may be involved. There is often restriction of diffusion on MRI because of the tumor’s dense cellularity. The radiologic appearance in the immunosuppressed patient is less predictable and may be difficult to distinguish from that of toxoplasmosis, progressive multifocal leukoencephalopathy (PML), or another process with which lymphoma may coexist.


Neurology_Adams

Neurology_Adams. In some cases, a multitude of deep cerebral white matter lesions, some radially oriented and thereby simulating multiple sclerosis, are seen. Tumor enhancement with contrast agents tends to be more prominent and homogeneous than with the acute lesions of multiple sclerosis. A similar multinodular appearance occurs with intravascular lymphoma discussed in a later section. Characteristic of primary CNS lymphoma is the disappearance on imaging of the lesions or complete but transient resolution of contrast enhancement in response to corticosteroids.


Neurology_Adams

Neurology_Adams. Lymphocytic and mononuclear pleocytosis of CSF is more frequent than with gliomas and metastatic tumors, occurring in up to half of cases. The immunohistochemical demonstration in CSF of monoclonal lymphocytes or an elevated beta-2 microglobulin points to leptomeningeal spread of the tumor (Li et al), but frequently the diagnosis is not possible from CSF cytologic examination. Gene rearrangements within the monoclonal cell populations, especially of the immunoglobulin heavy chain gene (IGH) are used a diagnostic test that is more sensitive than cytology of the spinal fluid. These findings occur in approximately one-quarter of patients with proved CNS lymphoma; as noted, it reflects the monoclonality of the lymphocytes.


Neurology_Adams

Neurology_Adams. Patients with AIDS and less-common immunodeficiency states, such as the Wiskott-Aldrich syndrome and ataxia-telangiectasia, and those who are receiving immunosuppressive drugs for long periods, as for example, in renal transplantation, are particularly liable to develop this type of lymphoma. Many of the tumors in immunosuppressed patients contain the EBV genome, suggesting a pathogenetic role for the virus (Bashir et al); however, the EBV genome has also been found in the tumors of a few immunocompetent patients (Hochberg and Miller). Sometimes this tumor appears as a complication of an obscure medical condition such as salivary and lacrimal gland enlargement (Mikulicz syndrome) and the related Sjögren syndrome. Another disorder, lymphomatoid granulomatosis (called by several different names), is also driven by EBV virus and has similarities to CNS lymphoma, as outlined in a later section.


Neurology_Adams

Neurology_Adams. Stereotactic needle biopsy is the preferred method of establishing the histologic diagnosis in sporadic cases. In immunosuppressed patients, the differential diagnosis of a solitary brain nodule that is suspected to be lymphoma is aided by the response, or lack thereof, to treatment for toxoplasmosis, the main alternative diagnosis (see “Toxoplasmosis” in Chap. 31). Reduction in the size of the lesion with antimicrobial drugs makes biopsy unnecessary.


Neurology_Adams

Neurology_Adams. Treatment Because the tumors are deep and often multicentric, surgical resection is ineffective. Treatment with cranial irradiation and corticosteroids often produces a partial or, transiently, a complete response, but the tumor recurs in greater than 90 percent of patients. At times, the response to corticosteroids can be striking, even eliminating imaging and histopathologic evidence of the tumor and making the diagnosis difficult. Paradoxically, clinicians use this dramatic disappearance as implicit evidence of the existence of CNS lymphoma, although other disorders such as demyelinating disease may do the same.


Neurology_Adams

Neurology_Adams. Until decades ago, the median survival of patients had been 10 to 18 months, and less in those with AIDS and in individuals who were otherwise immunocompromised. The treatment of CNS lymphoma is different in patients with AIDS than in patients who are immunocompetent in that chemotherapy creates an additional risk for infection. Restoring immune competence is advisable but, in contrast to the opportunistic infection that may be associated with immunosuppression, PML, there is little evidence that this restoration improves CNS lymphoma. While methotrexate, for example, had been eschewed, it has been tried in AIDS patients who also start antiretroviral treatment. Cranial irradiation is the predominant treatment.


Neurology_Adams

Neurology_Adams. There is currently no consensus on the optimal treatment of CNS lymphoma but methotrexate-based regimens are most effective. Single high dose intravenous therapy is widely used but multiple dose regimens in combination with whole brain radiation is also employed. Cranial irradiation has been studied heterogeneously as part of the initial treatment. More recently, methotrexate plus either cytarabine or a combination of rituximab and temozolomide has been assessed but not uniformly implemented. With these various regimens, despite high initial response rates, survival rates have been, at best near 50 percent. Survival in AIDS patients is far shorter but may be improved with the inception of aggressive antiretroviral treatment.


Neurology_Adams

Neurology_Adams. Ocular lymphoma is eradicated only by radiation therapy. Corticosteroids are added at any point to control neurologic symptoms. The median survival time with this approach in the non-AIDS patient is in the range of 3.5 years with intravenous methotrexate alone and 4 years or more if radiation is given subsequently. Some patients are alive at 10 years.


Neurology_Adams

Neurology_Adams. These are far more common than are primary brain tumors. The presence of multiple intracranial lesions is also more suggestive of metastases compared to primary tumor. Among secondary intracranial tumors, only metastatic carcinoma occurs with high frequency. Lymphoma and leukemia are less frequent than carcinoma and they have far less proclivity to spread to the brain or its coverings. Occasionally one encounters a rhabdomyosarcoma, Ewing tumor, carcinoid, and others that have metastasized, but these have such low incidence that cerebral metastases seldom become a matter of diagnostic concern. The interesting pathobiology of metastatic carcinoma—the complex biologic mechanisms that govern the detachment of tumor cells from the primary growth, their transport to distant tissues, and their implantation on the capillary endothelium of the particular organ in which they will eventually grow is of research interest. Suffice it to say that tumor cell adhesion molecules, the vasculature, and


Neurology_Adams

Neurology_Adams. on the capillary endothelium of the particular organ in which they will eventually grow is of research interest. Suffice it to say that tumor cell adhesion molecules, the vasculature, and a number of other cellular events participate in the implantation of what is essentially a neoplastic embolus.


Neurology_Adams

Neurology_Adams. Autopsy studies disclose intracranial metastases in approximately 25 percent of patients who die of cancer (Posner and Chernik 1978). Approximately 80 percent are in the cerebral hemispheres and 20 percent in posterior fossa structures, corresponding roughly to the relative size and weights of these portions of the brain and their blood flow. Intracranial metastases assume three main patterns—those to the skull and dura, those to the brain itself, and those spreading diffusely through the craniospinal meninges (leptomeningeal metastases, which includes carcinomatous meningitis [meningeal carcinomatosis] and lymphomatous meningitis). As common as intracranial metastases are metastases to the vertebral column, which eventually cause compression of the spinal cord and nerve roots are more frequent. This separate problem is discussed in Chap. 42. Metastatic deposits within the spinal cord itself are infrequent but are seen from time to time; they are more common, however, than another


Neurology_Adams

Neurology_Adams. frequent. This separate problem is discussed in Chap. 42. Metastatic deposits within the spinal cord itself are infrequent but are seen from time to time; they are more common, however, than another cancer-associated spinal cord lesion, paraneoplastic necrotic myelopathy (see in the following text).


Neurology_Adams

Neurology_Adams. Metastases to the skull and dura occur with any tumor that metastasizes to bone, but they are particularly common with carcinoma of the breast and prostate and in the special case of multiple myeloma. Secondary deposits usually occur without metastases to the brain itself and reach the skull either via the systemic circulation (as in carcinoma of the breast) or via the Batson vertebral venous plexus—a valveless system of veins that runs the length of the vertebral column from the pelvic veins to the large venous sinuses of the skull, bypassing the systemic circulation (the route presumably taken by carcinoma of the prostate). Metastatic tumors of the convexity of the skull are usually asymptomatic but those at the base may implicate the cranial nerve roots or the pituitary gland. Bony metastases are readily recognized on various imaging techniques. Occasionally, a carcinoma metastasizes to the subdural surface dura and compresses the brain, comparable to a subdural hematoma. Many


Neurology_Adams

Neurology_Adams. metastases are readily recognized on various imaging techniques. Occasionally, a carcinoma metastasizes to the subdural surface dura and compresses the brain, comparable to a subdural hematoma. Many metastases in the skull and dura, perhaps most, are asymptomatic.


Neurology_Adams

Neurology_Adams. Apart from the above, most carcinomas reach the brain by hematogenous spread. Almost one-third of metastases to the brain originate in the lung and half this number in the breast; melanoma is the third most frequent source in most series, and the gastrointestinal tract (particularly the colon and rectum) and kidney are the next most common, in part reflecting the prevalence of each of these tumors but also because of a tropism for the nervous system, as noted below. Carcinomas of the gallbladder, liver, thyroid, testicle, uterus, ovary, pancreas, etc., account for the remainder. Tumors originating in the prostate, esophagus, oropharynx, and skin (except for melanoma) only rarely metastasize to the substance of the brain. From a different perspective, certain neoplasms are particularly prone to metastasize to the brain—75 percent of melanomas do so, 55 percent of testicular tumors, and 35 percent of bronchial carcinomas, of which 40 percent are small cell tumors according to Posner and


Neurology_Adams

Neurology_Adams. to metastasize to the brain—75 percent of melanomas do so, 55 percent of testicular tumors, and 35 percent of bronchial carcinomas, of which 40 percent are small cell tumors according to Posner and Chernik. They describe a solitary metastasis in 47 percent of cases, a somewhat higher figure than that observed in our practice and reported by others (see Henson and Urich). The metastatic tumors most likely to be single come from kidney, breast, thyroid, and adenocarcinoma of the lung. Small cell carcinomas and melanomas more often tend to be multiple, but exceptions abound. All of these comments relating to the proportion of metastases from various origins and the propensity for a given tumor to metastasize to the brain are similar to more recent surveys.


Neurology_Adams

Neurology_Adams. Generally, the cerebral metastasis forms a circumscribed mass, usually solid but sometimes in the form of a ring (i.e., cystic), that excites little glial reaction but much regional vasogenic edema. Edema alone is often evident on imaging studies until the administration of contrast exposes small tumor nodules (Fig. 30-10). Metastases from melanoma and chorioepithelioma are often hemorrhagic, but it is not unusual for tumors originating in lung, thyroid, and kidney to exhibit this characteristic. In a number of these cases, one-quarter in some series, the first manifestation of the metastasis is an intratumoral hemorrhage. The relative frequency of lung cancer makes it the most common metastatic tumor to bleed, even though only a small proportion does so.


Neurology_Adams

Neurology_Adams. The usual clinical picture of metastatic carcinoma of the brain is of seizures, headache, focal weakness, mental and behavioral abnormalities, ataxia, aphasia, or signs of increased intracranial pressure—all inexorably progressive over a few weeks or months. In addition, a number of unusual syndromes may occur. One that presents particular difficulty in diagnosis is a diffuse cerebral disturbance with headache, nervousness, depressed mood, trembling, confusion, and forgetfulness, resembling a relatively rapid dementia from degenerative disease. Cerebellar metastasis, with headache, dizziness, and ataxia (the latter being brought out only by having the patient walk) is another condition that may be difficult to diagnose. Brainstem metastases, most often originating in the lung, are rare but distinctive, giving rise to diplopia, imbalance, and facial palsy, as in the characteristic case described by Weiss and Richardson.


Neurology_Adams

Neurology_Adams. The onset of symptoms from brain metastases may occasionally be abrupt or even “stroke-like” rather than insidious. Some cases of sudden onset can be explained by bleeding into the tumor and others perhaps by tumor embolism that occludes a cerebral vessel. In most cases, the explanation for this temporal profile is not known. Also, non-bacterial thrombotic (marantic) endocarditis with cerebral embolism must be suspected when a stroke-like event occurs in a cancer patient. It is not unusual for one or other of these neurologic manifestations to precede the discovery of a pancreatic, bowel, gastric, breast, or lung carcinoma.


Neurology_Adams

Neurology_Adams. When any of the several clinical syndromes caused by metastatic tumor is fully developed, diagnosis is relatively easy. If only headache and vomiting are present, a common problem is to attribute them to migraine or tension headache. One should invoke such explanations only if the patient has the standard symptoms of one of these conditions. CT with contrast will detect practically all sizable (1 cm) metastases though MRI with gadolinium is much more sensitive especially for cerebellar and subcentimeter lesions, and will expose associated leptomeningeal disease. Multiple nodular deposits of tumor in the brain on imaging studies most clearly distinguish metastatic cancer from other tumors but this pattern may also occur with brain abscesses, brain lymphoma, and glioblastoma.


Neurology_Adams

Neurology_Adams. Solitary metastatic disease must be distinguished from a primary tumor of the brain, CNS lymphoma, tumefactive demyelination (see Chap. 35), and from infective abscess. Multiple brain metastases must not be confused with the syndromes associated paraneoplastic neurologic syndromes that sometimes accompany carcinoma. The latter include sensory neuronopathies and the Lambert-Eaton myasthenic syndrome (usually with carcinoma of the lung), cerebellar degeneration (ovarian and other carcinomas and Hodgkin disease), necrotizing myelopathy (rare), limbic encephalitis, and the opsoclonus–myoclonus syndrome. These paraneoplastic syndromes are discussed further on, under “Remote Effects of Neoplasia on the Nervous System (Paraneoplastic Disorders).”


Neurology_Adams

Neurology_Adams. In addition to the aforementioned conditions, there are many patients with cancer who exhibit symptoms of an altered mental state without evidence of metastases or a recognizable paraneoplastic disorder. These symptoms usually have their basis in systemic metabolic disturbances (hypercalcemia in particular), drugs, and psychologic reactions, some of which have yet to be clearly delineated. Problems of this type were noted in a high percentage of cancer patients seen in consultation at the Memorial Sloan-Kettering Cancer Center (Clouston et al) and are seen almost daily on the wards of our hospital. Once chemotherapy or brain radiation has been administered, the secondary effects of these treatments further cloud the picture.


Neurology_Adams

Neurology_Adams. Treatment The treatment of metastatic tumors of the nervous system undergoes frequent change. Current programs utilize various combinations of corticosteroids, radiation therapy (focal or whole brain treatment), surgical removal, and chemotherapy and immune modulating treatment. Corticosteroids produce prompt improvement, probably on the basis of a reduction in the edema surrounding the lesion(s), but sustained use is restricted by side effects and eventual loss of efficacy. Most patients with multiple metastases also temporarily benefit from the use of whole-brain irradiation, usually administered over approximately a 2-week period, in multiple doses. Various studies report a response rate, albeit temporary, in 50 to 70 percent of patients with multiple metastases but the type of tumor also determines the likelihood of response. High-dose and focused radiotherapy (radiosurgery) is now considered the main alternative for single or several cerebral metastases.


Neurology_Adams

Neurology_Adams. One randomized trial comparing stereotactic radiotherapy alone, or combined with whole-brain radiation for 1 to 4 metastases, found no difference in survival but there was a reduction in the frequency of recurrence at other sites in the brain when whole-brain treatment was added (Aoyama et al). Several other studies have suggested that control of local symptoms related to a metastasis is better with focused radiotherapy. However, with the exception of a single lesion from small cell lung cancer, there does not seem to be an advantage to either approach. If focused treatment has been used, whole-brain radiation can still be instituted at the time of a recurrence. Whether there is evidence to justify the routine implementation of this approach is not clear, especially as overall measures of the quality of life are not generally improved. An arbitrary limit of stereotactic treatment of four metastases arose as the field evolved but it appears that the results are similar with even


Neurology_Adams

Neurology_Adams. of the quality of life are not generally improved. An arbitrary limit of stereotactic treatment of four metastases arose as the field evolved but it appears that the results are similar with even greater numbers.


Neurology_Adams

Neurology_Adams. There remains a controversial issue of prophylactic radiation of the entire cranium in the case of certain tumors, particularly small cell lung cancer. Information from a trial by Slotman and colleagues and an older one by Aupérin and coworkers in patients with chemotherapy-responsive small cell lung cancer suggests that prophylactic radiation prolonged survival by 1.5 months and markedly reduced the later emergence of metastasis to the brain. Critics have noted that, with recently improving survival rates, the later cognitive effects of brain radiation may become evident.


Neurology_Adams

Neurology_Adams. In patients with a single parenchymatous metastasis (shown to be solitary by gadolinium-enhanced MRI), surgical extirpation may be undertaken provided that growth of the primary tumor and its systemic metastases is under good control and the metastasis is accessible to the surgeon and not located in a strategic motor or language area of the brain. Usually, excision is followed by radiation therapy to the entire brain. Patchell and coworkers have shown that survival and the interval between treatment and recurrence are longer and that the quality of life is better in patients treated in this way than in comparable patients treated with whole-brain radiation alone. Single or dual metastases from renal cell cancer, melanoma, and adenocarcinoma of the gastrointestinal tract lend themselves best to surgical removal, as implemented in the matched cohort study by Bindal and colleagues.


Neurology_Adams

Neurology_Adams. There is increasing evidence that some metastatic brain tumors are sensitive to chemotherapeutic agents, especially if the primary tumor is similarly responsive. Intrathecal and intraventricular chemotherapy are not thought to be of value in the treatment of parenchymal metastases. Immunotherapy has not yet been widely employed for brain metastases but this is rapidly changing, for example with melanoma and lung cancer. Prophylactic antiepileptic drugs are generally not employed as they do not appear to prevent a first seizure, as mentioned earlier. Several studies, some well controlled, corroborate this as discussed in Chap. 15.


Neurology_Adams

Neurology_Adams. Despite all of these measures, survival is only slightly prolonged by treatment. The average period of survival in cases of brain metastases, even with therapy, is about 6 months, but it varies widely and is dominated by the extent of other systemic metastases. Between 15 and 30 percent of patients live for a year and 5 to 10 percent for 2 years; with certain radiosensitive tumors (lymphoma, testicular carcinoma, choriocarcinoma, some breast cancers), however, survival can be much longer. It has been stated, without strong corroboration, that patients with bone metastases tend to live longer than those with brain and meningeal metastases.


Neurology_Adams

Neurology_Adams. Widespread dissemination of tumor cells throughout the meninges and ventricles, a special form of metastatic cancer, is the pattern in approximately 5 percent of cases of adenocarcinoma of breast, lung, and gastrointestinal tract, melanoma, childhood leukemia, and systemic lymphoma. This is among the most deceptive of neurologic diagnoses. With certain carcinomas, notably gastric, it may be the first manifestation of a neoplastic illness, although more often the primary tumor has been present and is under treatment.


Neurology_Adams

Neurology_Adams. Headache and backache, sometimes with sciatica, are common but not invariable. Polyradiculopathies (particularly of the cauda equina), multiple cranial nerve palsies, and a confusional state have been the principal manifestations, and many cases are restricted to one of these features. Only a small number have an uncomplicated meningeal syndrome of headache, nausea, and meningismus, but these features develop within weeks in many cases. Delirium, stupor, and coma follow. Focal neurologic signs and seizures may be associated, and somewhat fewer than half the patients develop hydrocephalus. The combination of a cranial neuropathy, such as unilateral facial weakness, hearing loss (suggestive of lymphoma), or ocular motor palsy, with bilateral asymmetrical limb weakness is particularly characteristic. The evolution in all these syndromes is generally subacute over weeks with a more rapid phase as the illness progresses.


Neurology_Adams

Neurology_Adams. Neoplastic meningitis presents a characteristic pattern on imaging studies, particularly with gadolinium enhanced MRI of the brain or spine. The leptomeninges are found to be thickened and variably enhancing, sometimes with nodular appearing lesions but as often with smooth contiguous areas of involvement. The basilar portions of the brain, around the cisternal segments of the cranial nerves and overlying the cerebellar folia are preferred regions for appearance of these findings (Fig. 30-11). There may be hydrocephalus but it is surprisingly infrequent.


Neurology_Adams

Neurology_Adams. The diagnosis is established by identifying tumor cells in the CSF using cytology and flow cytometry techniques. We generally undertake an examination of the CSF with the exception of cases with noncommunicating hydrocephalus. In the latter instance, a ventricular drain may have been placed and CSF can be obtained from that source. More than one examination, using generous quantities of CSF, may be needed. Increased pressure in the subarachnoid space, elevation of CSF protein and low glucose levels, and lymphocytic pleocytosis (up to 100 cells but typically much fewer) are other common findings. Nevertheless, in a few patients, the CSF remains persistently normal. Measurement of certain biochemical markers of cancer in the CSF—such as lactate dehydrogenase, β-glucuronidase, β2-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


Neurology_Adams

Neurology_Adams. 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 many of the cases of meningeal carcinomatosis, there are also parenchymal brain metastases.


Neurology_Adams

Neurology_Adams. Also known is a rare primary malignant melanoma of the meninges that acts in a similar way to carcinomatous meningitis but has the striking feature of bloody CSF (1,000 to 10,000 red blood cells per mm3). The origin of the neoplasm is from native melanotic cells in the meninges. The prognosis is as bleak as it is for metastatic carcinomatous meningitis as discussed by Liubinas et al. Treatment and outcome of malignant meningitis


Neurology_Adams

Neurology_Adams. Treatment and outcome of malignant meningitis This consists mainly 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 or months. The methotrexate is typically administered into the lateral ventricle via an Ommaya reservoir (12 mg diluted in preservative-free saline) or into the lumbar subarachnoid space through a lumbar puncture needle. 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.


Neurology_Adams

Neurology_Adams. Involvement of the cranial nerves or an encephalopathy caused by widespread infiltration of the cranial meninges has been treated with whole-brain radiation, 3,000 cGy, given in fractions of 300 cGy per day for 10 days. Spinal root infiltration responds to spinal radiation, and regional treatments are helpful temporarily for local seeding of the lumbar roots. A study of CSF flow by the injection of a radionuclide agent may be useful to determine if there is impeded flow that prevents circulation of the methotrexate or exposes one region to excessive toxicity. In tumors that are sensitive to a specific chemotherapy, systemic administration may be effective depending on the permeability of the blood–brain barrier to these agents, for example, in some forms of breast cancer, and the systemic use of check point (cell-cycle, e.g., PD-1) inhibitors is being investigated.


Neurology_Adams

Neurology_Adams. 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. We have experience, however, with individuals who have survived with stable deficits for over a year with breast cancer metastatic to the meninges and lumbar roots. An encephalopathy caused by widespread tumor infiltration or hydrocephalus is a highly concerning and usually preterminal sign. The leukoencephalopathy that follows the combined use of intrathecal methotrexate and radiation therapy is described later. Some patients do not survive long enough for the problem to be manifest. The best response to treatment occurs in patients with lymphoma and breast and small cell lung cancers; cases of meningeal infiltration by other lung cancers, melanoma, and adenocarcinoma do less well. Involvement of the Nervous System in Leukemia


Neurology_Adams

Neurology_Adams. Involvement of the Nervous System in Leukemia Almost one-third of all leukemic patients, especially with childhood leukemia, have evidence of diffuse infiltration 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 as mentioned 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). In those cases, the disease in the meninges may be fulminant. The clinical and CSF picture of meningeal leukemia has many similarities to that of meningeal carcinomatosis discussed earlier, with the qualification that leukemic cells are more likely to be found by cytologic examination of the spinal fluid. The treatment of the two disorders is also similar.


Neurology_Adams

Neurology_Adams. 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 infiltrate in our pathologic material has extended to the deep perivascular spaces, where the pial-glial membrane often confines 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 superficial parenchymal infiltration 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 infiltrate the dura or, less often, the brain, but it is distinctly uncommon.


Neurology_Adams

Neurology_Adams. Leukoencephalopathy following combined intrathecal methotrexate and cranial irradiation (see further on, under “Radiation Toxicity”) Cranial radiation, combined with methotrexate given intrathecally or intravenously, has been effective in the prevention and treatment of meningeal involvement in childhood leukemia. However, in a significant number of patients this combination gives rise to a distinctive acute necrotizing leukoencephalopathy within several days to weeks after the last administration of methotrexate (Robain et al). This condition has been distinguished from the more conventional form of cerebral radiation necrosis discussed later. The leukoencephalopathy occurs most frequently and is most severe when all three modalities of treatment, that is, cranial irradiation and intrathecal and intravenous methotrexate, are used in children. The age differentiation may explain the infrequency of this condition in adults. The initial symptoms—consisting of apathy, drowsiness,


Neurology_Adams

Neurology_Adams. intrathecal and intravenous methotrexate, are used in children. The age differentiation may explain the infrequency of this condition in adults. 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.


Neurology_Adams

Neurology_Adams. In the acute and fulminant form of the disorder, large hypodense areas of varying size appear on CT and there can be contrast enhancement and edema that may simulate a tumor. This is distinct from the common occurrence of regional radiation change surrounding a tumor or sometimes distant to it. On MRI these lesions appear T2 hyperintense and can have poorly demarcated borders. In a few patients this aggressive form of the condition stabilizes or improves, with corresponding resolution of enhancement and edema. (The concept of “pseudoprogression” of a brain tumor has been introduced to denote radiation change that simulates tumor growth). More often, the patient is left with severe persistent sequelae or rarely the edema may progress and lead to death.


Neurology_Adams

Neurology_Adams. In addition to radiation injury, important factors in the development of the fulminant syndrome are the age of the patient (many are younger than 5 years old). In an attempt to address the long-term cognitive sequela of cranial radiation in children with leukemia, Pui and coworkers conducted a study and found that it could be safely omitted if all other aspects of therapy have been optimized. Involvement of the Nervous System in Systemic Lymphoma


Neurology_Adams

Neurology_Adams. Involvement of the Nervous System in Systemic Lymphoma Extradural compression of the spinal cord or cauda equina is the most common neurologic complication of all types of lymphoma, the result of extension from vertebrae or paravertebral lymph nodes. Treatment is with radiation to the affected portion of the neuraxis or, if the compression is very acute and causing serious myelopathy, surgical decompression. Systemic lymphoma rarely metastasizes to the brain. In a review of more than 100 autopsies at the Mallory Institute of Pathology, our colleague R.D. Adams observed only a half-dozen instances where patients with lymphomas had deposits of tumor cells in the brain and in none of these cases were they from multiple myeloma (Sparling et al). In the series of Levitt and associates, comprising 592 patients with non-Hodgkin lymphoma, there were only 8 with intracerebral metastases.


Neurology_Adams

Neurology_Adams. The appearance of non-Hodgkin lymphoma in the meninges and adjacent roots or peripheral nerves (a form of the earlier mentioned neurolymphomatosis) is distinct from primary CNS lymphoma, in which there are parenchymal lesions and no systemic disease. The clinical and CSF pictures are similar to those of meningeal leukemia and carcinomatosis described earlier. In the rare cases of meningeal involvement with Hodgkin lymphoma, there may be an eosinophilic pleocytosis. Leptomeningeal dissemination occurs almost exclusively in high-grade lymphomas with diffuse (rather than nodular) changes in the lymph nodes. Cranial nerve palsies are common, with a predilection for the eighth nerve; the cauda equina is involved eventually in most cases. The optimal treatment has not yet been ascertained. Radiotherapy and systemic and intraventricular chemotherapy have all met with some degree of success in small series.


Neurology_Adams

Neurology_Adams. Intravascular Lymphoma and Related Disorders (including Lymphomatoid Granulomatosis, Castleman Disease)


Neurology_Adams

Neurology_Adams. These conditions are presented here with other forms of lymphoma, although their clinical behavior is as much in keeping with a vasculitic or prelymphomatous process. Although considered rare, we encounter several new cases yearly in our service. The nomenclature is confusing and the original terms, lymphomatoid granulomatosis and Castleman disease are not equivalent to the more recently elucidated process of intravascular lymphoma; it is more accurate to consider the first two as prelymphomatous processes. As described by Liebow and colleagues, lymphomatoid granulomatosis is a systemic disease with prominent nodular pulmonary lesions, dermal, and lymph node changes and, in approximately 30 percent of cases, involvement of the CNS. In a small proportion, the changes are confined to the nervous system. According to Katzenstein and associates, a systemic malignant lymphoma develops in 12 percent of such patients. Castleman disease is precipitated by constituent HHV-8 virus infection in


Neurology_Adams

Neurology_Adams. system. According to Katzenstein and associates, a systemic malignant lymphoma develops in 12 percent of such patients. Castleman disease is precipitated by constituent HHV-8 virus infection in about half of cases and lymphomatoid granulomatosis has a similar viral origin, but mainly from EBV.


Neurology_Adams

Neurology_Adams. The intravascular lymphoma, on the other hand, is regarded as a multifocal neoplasm of large anaplastic monoclonal lymphocytes that infiltrate the walls of blood vessels and surrounding areas (Sheibani et al). The tumor cells grow intravascularly and cause occlusion of small and moderate-sized vessels and may cause small cerebral or spinal infarctions, as well as of other organs. The disease can be distinguished from primary CNS lymphoma, which is also typically “angiocentric,” meaning centered around vessels, but does not selectively invade and occlude vascular structures. In half of the cases, meningeal vessels are involved and in a few, the peripheral nerves, or more particularly the endoneurial vessels within spinal roots, have been involved by the neoplasm and we have seen two cases with a flaccid paraplegia on this basis.


Neurology_Adams

Neurology_Adams. The lymphoid origin of the intravascular anaplastic cells is clear, and the predominant species is of monoclonal B cells with a T-cell reactive component. As in some cases of primary CNS lymphoma, portions of the genome of EBV have occasionally been isolated from the malignant B cells. It has been proposed that the disorder in those cases represents an EBV-induced proliferation of B cells with a prominent inflammatory T-cell reaction (Guinee et al).


Neurology_Adams

Neurology_Adams. Because of the inconsistent location and size of the nervous system lesions there is no uniform clinical syndrome, but intravascular lymphoma should be suspected in patients with a subacute encephalopathy and indications of focal brain and spinal cord or nerve root lesions. Headache is a prominent early component in some cases. One of our patients had intermittent seizures 3 months before confusion and progressive encephalopathy. The variety of clinical presentations is emphasized in the reviews of cases by Beristain and Azzarelli and the article by Glass and associates (1993). All had focal cerebral signs, 7 had dementia, 5 had seizures, and 2 had myelopathy. Some of our own patients, as mentioned above, have also had a flaccid paraplegia as a result of infiltration of the cauda roots; this peripheral involvement has been commented on by other authors. Only a few patients will have nodular or multiple infiltrative pulmonary lesions, skin lesions, or adenopathy; almost all of our


Neurology_Adams

Neurology_Adams. this peripheral involvement has been commented on by other authors. Only a few patients will have nodular or multiple infiltrative pulmonary lesions, skin lesions, or adenopathy; almost all of our cases were restricted to the brain and spinal cord, but other reports suggest systemic disease in a high proportion, including infiltration of the adrenal glands.


Neurology_Adams

Neurology_Adams. MRI shows multiple nodular or variegated abnormalities on T2-weighted images throughout the white matter of the brain; most lesions are enhanced by gadolinium, and some demonstrate restricted diffusion resulting from microvascular occlusion and infarction. In one of the cases we studied there were numerous hemorrhagic lesions. Definitive diagnosis is possible through a biopsy of involved lung, skin, kidney, or nervous tissue that contains an adequate number of intrinsic blood vessels. A feature may be the presence of antibodies to nuclear cytoplasmic antigens (c-ANCA), in some cases, as they are in a number of other vasculitic and granulomatous processes. We are uncertain of the frequency of this finding. A small number of our patients have also had adrenal or renal enlargement, as mentioned earlier, presumably because of infiltration of the vessels of these organs by the neoplasm. The spinal fluid has a variable lymphocytic pleocytosis and protein elevation, but malignant cells are


Neurology_Adams

Neurology_Adams. earlier, presumably because of infiltration of the vessels of these organs by the neoplasm. The spinal fluid has a variable lymphocytic pleocytosis and protein elevation, but malignant cells are not found. The sedimentation rate and serum lactate dehydrogenase (LDH) are reported to be elevated in most patients, but this has not been consistently so in our experience.


Neurology_Adams

Neurology_Adams. Similar to demyelinating and lymphomatous lesions, these abnormalities in the brain may recede temporarily on imaging in response to treatment with corticosteroids and there is corresponding clinical improvement. Furthermore, some lesions may follow the temporal course expected of small strokes. The course tends to be fluctuating over months, although one of our patients died within weeks despite treatment. In a few cases, whole-brain irradiation has been successful in prolonging survival, but the outlook in most instances is poor. An uncertain number of these patients have AIDS, although we have not encountered this combination. The illness must be distinguished from multiple sclerosis, primary CNS lymphoma, gliomatosis cerebri, and a process that simulates it closely, sarcoidosis (which produces brain and lung lesions) as well as from the cerebral vasculitides and Beh¸et disease, but intravascular lymphoma is more rapidly progressive than most of these conditions.


Neurology_Adams

Neurology_Adams. Sarcomas of the Cranium and Brain These tumors are composed of cells derived from connective tissue elements (fibroblasts, rhabdomyocytes, lipocytes, osteoblasts, smooth muscle cells). They take their names from their histogenetic derivation—namely, fibrosarcoma, rhabdomyosarcoma, osteogenic sarcoma, and chondrosarcoma—and sometimes from the tissue of which the cells are a part, such as adventitial sarcomas and hemangiopericytoma.


Neurology_Adams

Neurology_Adams. All these tumors are rare. They constitute from 1 to 3 percent of intracranial tumors, depending on how wide a range of neoplasms one chooses to include (see in the following text). Occasionally, cerebral deposits of these types of tumors will occur as a metastasis from a sarcoma in another organ. Almost all others are primary in the cranial cavity and exhibit as one of their unique properties a tendency to metastasize to nonneural tissues—a decidedly rare occurrence with primary glial tumors. It is a disturbing fact that a few sarcomas have developed 5 to 10 years after cranial irradiation or, in one instance among 3,000 patients related to us by R.D. Adams, after proton beam irradiation of the brain. Fibrosarcomas have occurred after radiation of pituitary adenomas and osteogenic sarcoma, after other types of radiation, all localized to bone or meninges. Our experience with hemangiopericytoma has included to three intracranial lesions that simulated meningiomas and two others that


Neurology_Adams

Neurology_Adams. after other types of radiation, all localized to bone or meninges. Our experience with hemangiopericytoma has included to three intracranial lesions that simulated meningiomas and two others that arose in the high cervical spinal cord and caused subacute quadriparesis, initially misdiagnosed as an acute polyneuropathy.


Neurology_Adams

Neurology_Adams. A number of other cerebral tumors, described in the literature as sarcomas, are probably tumors of other types. The rapidly growing, highly malignant “monstrocellular sarcoma” of Zülch or “giant cell fibrosarcoma” of Kernohan and Uihlein, so named for their multinucleated giant cells, were reinterpreted by Rubinstein (1972) as a form of giant cell glioblastoma or mixed glioblastoma and fibrosarcoma. The “hemangiopericytoma of the leptomeninges,” also classified by Kernohan and Uihlein as a form of cerebral sarcoma, is considered by Rubinstein (1972) to be a variant of the angioblastic meningioma. In the WHO classification, a gliosarcoma is categorized with other gliomas and a granulocytic sarcoma is listed under the hematopoetic tumors but restricting the term to these does not fully capture the range and unusual behaviors of most cranial sarcomas.


Neurology_Adams

Neurology_Adams. Patients Who Present Primarily With Signs of Increased Intracranial Pressure (Medulloblastoma, Ependymoma of the Fourth Ventricle, Hemangioblastoma of the Cerebellum, Pinealoma, Colloid Cyst of the Third Ventricle and Rare Related Tumors) Upon first presentation, a number of patients with brain tumors show the characteristic symptoms and signs of increased intracranial pressure, namely periodic bifrontal and bioccipital headaches that awaken the patient during the night or are present upon awakening, projectile vomiting, mental torpor, unsteady gait, sphincteric incontinence, and papilledema. In the tumors listed above, most of the symptoms and the associated increase in ICP are the result of hydrocephalus rather than being attributable to the tumor mass.


Neurology_Adams

Neurology_Adams. The diagnostic problem is resolved by CT or MRI, which is obtained in patients with symptoms of increased intracranial pressure, with or without focal signs. In addition to the tumors listed in the heading above, others that may present in this way are central neurocytoma, craniopharyngioma, and a high spinal cord, cervicomedullary junction tumor. In addition, with some of the gliomas discussed in the preceding section, increased intracranial pressure may occasionally precede the first focal cerebral signs. Medulloblastoma, Neuroblastoma, and Retinoblastoma Medulloblastoma Medulloblastoma is an invasive and rapidly growing tumor, mainly of childhood, that arises in the posterior part of the cerebellar vermis and neuroepithelial roof of the fourth ventricle in children. It accounts for 20 percent of childhood brain tumors. Rarely, it presents elsewhere in the cerebellum or other parts of the brain in adults (Peterson and Walker).


Neurology_Adams

Neurology_Adams. The origin of this tumor remained in doubt for a long time and is still not entirely settled, but some recent insights are notable. Bailey and Cushing introduced the name medulloblastoma, although medulloblasts have never been identified in the fetal or adult human brain; nevertheless the term has been retained for no reason other than its familiarity. The current view of the tumor is that it originates from pluripotential stem cells that can differentiate into neuronal or glial elements and have been prevented from maturing to their normal growth-arrested state. For this reason, newer (WHO) classifications include it with the primitive neuroectodermal tumors (PNETs).


Neurology_Adams

Neurology_Adams. The tumor may differentiate unior pluripotentially, varying from case to case, and accounting for the recognized histologic variants, ranging from an undifferentiated medulloblastoma and extending to medulloblastoma with glial, neuronal, or even myoblastic components. Rosette formation, highly characteristic of the below-described neuroblastoma is seen in half of medulloblastomas. Certain molecular, genetic similarities relate the medulloblastoma to retinoblastomas and pineal cell tumors, and, rarely, to autosomal dominant diseases such as nevoid basal cell carcinoma. Chromosomal studies of medulloblastomas reveal a deletion on chromosome 17 distal to the p53 region. Schmidek proposed that this accounts for the neoplastic transformation of cerebellar stem cells at various stages of their differentiation into tumor cells. It is also notable that medulloblastomas are encountered in Gorlin syndrome, caused by mutations in the gene encoding “patched,” the receptor for sonic hedgehog


Neurology_Adams

Neurology_Adams. differentiation into tumor cells. It is also notable that medulloblastomas are encountered in Gorlin syndrome, caused by mutations in the gene encoding “patched,” the receptor for sonic hedgehog ligand, and in Turcot syndrome, as a consequence of mutations in DNA repair genes (Louis et al). Gene expression profiling has given evidence that amplification or overexpression of the transcription factor MYCN (N-MYC) is associated with a poorer prognosis (as it is in neuroblastoma). Aberrations in the copy number of chromosomes 6q and 17q also appear to have predictive value for the behavior of the tumor. Maris has reviewed the complex genetic aspects of the tumor and has introduced the possibility that a combination of common variants may be a risk factor for its development. Another line of research has tentatively implicated the JC virus, the same agent that causes progressive multifocal leukoencephalopathy (see Chap. 32). Genomic sequences from this virus have been found in up to 72


Neurology_Adams

Neurology_Adams. research has tentatively implicated the JC virus, the same agent that causes progressive multifocal leukoencephalopathy (see Chap. 32). Genomic sequences from this virus have been found in up to 72 percent of tumors in some series (Khalili et al), and an experimental transgenic model in which the JC protein is expressed is characterized by a cerebellar tumor that resembles the medulloblastoma.


Neurology_Adams

Neurology_Adams. The majority of affected patients are children 4 to 8 years of age, and males outnumber females 3:2 or 3:1 in most reported series. As a rule, symptoms have been present for 1 to 5 months before the diagnosis is made. The clinical picture is fairly distinctive and derives from secondary hydrocephalus and raised intracranial pressure as a result of blockage of the fourth ventricle. Typically, the child becomes listless, vomits repeatedly, and has a morning headache. The first diagnosis that suggests itself may be gastrointestinal disease or abdominal migraine. Soon, however, a stumbling gait, frequent falls, and diplopia as well as strabismus lead to a neurologic examination and the discovery of papilledema or sixth nerve palsies. However, when the tumor is located in the lateral cerebellum or in the cerebrum, as it usually is in adults, signs of raised intracranial pressure may be delayed. Dizziness (positional) and nystagmus are then frequent. A small proportion of children have a


Neurology_Adams

Neurology_Adams. or in the cerebrum, as it usually is in adults, signs of raised intracranial pressure may be delayed. Dizziness (positional) and nystagmus are then frequent. A small proportion of children have a slight sensory loss on one side of the face and a mild facial weakness. Head tilt, the occiput being tilted back and away from the side of the tumor, indicates a developing cerebellar-foraminal herniation. Rarely, signs of spinal root and subarachnoid metastases precede cerebellar signs.


Neurology_Adams

Neurology_Adams. Extraneural metastases (cervical lymph nodes, lung, liver, and particularly bone) may occur, but usually only after craniotomy, which may allow tumor cells to reach scalp lymphatics. In rare instances the tumor cells may be spontaneously blood-borne and become metastatic to lung or liver. Decerebrate attacks (“cerebellar fits”) appear in the late stages of the disease.


Neurology_Adams

Neurology_Adams. The radiologic appearance of this tumor is distinctive: high signal intensity on both T1-enhanced and T2-weighted MRIs, heterogeneous enhancement, and, of course, the typical location adjacent to and extending into the fourth ventricle. The tumor frequently fills the fourth ventricle and infiltrates its floor (Fig. 30-12). Seeding of the tumor may occur on the ependymal and meningeal surfaces of the cisterna magna and around the spinal cord. The tumor is solid, gray-pink in color, and fairly well demarcated from the adjacent brain tissue. It is very cellular, and the cells are small and closely packed with hyperchromatic nuclei, little cytoplasm, many mitoses, and a tendency to form clusters and pseudorosettes. The interstitial tissue is sparse.


Neurology_Adams

Neurology_Adams. Treatment Maximal resection of the tumor is currently recommended. The addition of chemotherapy and radiotherapy of the entire neuraxis improves the rate and length of disease-free survival even for those children with the most extensive tumors at the time of diagnosis (Packer). The combination of surgery, radiation of the entire neuraxis, and chemotherapy permits a 5-year survival in more than 80 percent of cases.


Neurology_Adams

Neurology_Adams. Fear of radiation-induced cognitive deficits in the young children most often affected by this tumor has led to exploration of postoperative chemotherapy without radiation as an alternative. Rutkowski and colleagues have reported some promising results, especially after gross total tumor resection, but a large number of children nevertheless acquired a leukoencephalopathy, which was said to be asymptomatic. The presence of desmoplastic features (i.e., connective tissue formations) is associated with a better prognosis independent of the type or treatment. Children who have residual tumor after surgery, and more so those with metastases, have a much poorer prognosis. Any of the features of brainstem invasion, spinal subarachnoid metastases, and very early age of onset (younger than 3 years) greatly reduce the period of survival. Acquired genetic alterations in the tumor cells that have prognostic influence have been summarized earlier. A novel inhibitor of the abnormal hedgehog pathway


Neurology_Adams

Neurology_Adams. greatly reduce the period of survival. Acquired genetic alterations in the tumor cells that have prognostic influence have been summarized earlier. A novel inhibitor of the abnormal hedgehog pathway in medulloblastoma cells had a marked therapeutic effect in one adult patient (Rudin et al).


Neurology_Adams

Neurology_Adams. Neuroblastoma This, the most common solid tumor of childhood, is a different entity from medulloblastoma but of nearly identical histologic appearance, arising in the adrenal medulla and sometimes metastasizing widely. Usually it remains extradural even if it invades the cranial and spinal cavities. The main neurologic interest is a syndrome of polymyoclonus with opsoclonus and ataxia that occurs as a paraneoplastic complication as discussed further on. A rare form of neuroblastic medulloblastoma in adults tends to be more benign (Rubinstein, 1985).


Neurology_Adams

Neurology_Adams. In keeping with the genetic determinants of prognosis in this broad class of tumors, a loss of heterozygosity of certain sites on chromosomes 1 and 11 has been associated with somewhat poorer outcomes by Attiyeh and colleagues. MYCN amplification or overexpression is a poor prognostic factor, as it is in medulloblastoma. Various acquired chromosomal deletions and gains may also have predictive importance. More provocative are findings that suggest the emergence of an aggressive tumor based on polymorphisms in chromosome 6p. Maris has provided a review of the interesting genetic aspects of the tumor. Several staging systems have evolved for neuroblastoma and The Children’s Oncology Group has produced a risk-based system that includes the status of chromosomal changes (17q, 1p, 11q), but these approaches are under frequent revision.


Neurology_Adams

Neurology_Adams. Treatment is predicated on clinical staging, with the lowest risk category allowing observation because some lesions regress spontaneously. Those patients who are at intermediate risk are treated with chemotherapy and high-risk children have surgical resection and receive intensive chemotherapy, radiation, and in selected cases, hematopoietic stem cell transplantation. The two better-risk strata have survival rates exceeding 90 percent, but the highest risk group has a 30 percent survival rate.


Neurology_Adams

Neurology_Adams. Retinoblastoma Another closely related tumor is retinoblastoma. This proves to be one of the most frequent extracranial malignant tumors of infancy and childhood. Eighty percent develop before the fifth year of life. It is a small cell tumor with neurofibrils and, like neuroblastoma, has a tendency to form rosettes. The tumor develops within the eye and the blindness that it induces may be overlooked in an infant or small child. It is easily seen ophthalmoscopically, because it arises from cells of the developing retina. An abnormal protein encoded by a growth-suppressor or antioncogenic gene (Rb), mentioned earlier in relation to the genetics of brain tumors, has been identified. It is postulated that an inherited mutation affects one allele of the normal gene, and only if this is accompanied by a mutation that eliminates the function of the second allele will the tumor develop. Early recognition and radiation or surgery effect cure. Ependymoma of the Fourth Ventricle