Chapter 31. Intracranial Neoplasms and Paraneoplastic Disorders

Tumors of the central nervous system (CNS) constitute a bleak but vitally important chapter of neurologic medicine. Their importance derives from their great variety; the numerous neurologic symptoms caused by their size, location, and invasive qualities; the destruction and displacement of tissues in which they are situated; the elevation of intracranial pressure they cause; and, most of all, their lethality. Slowly, this dismal state of affairs is changing as a result of advances in anesthesiology, stereotactic and microneurosurgical techniques, focused radiation therapy, and the use of new chemotherapeutic agents.

For clinicians, the several generalizations should be a matter of general knowledge about brain tumors. First, many types of tumor, both primary and secondary, occur in the cranial cavity and spinal canal but certain ones are much more frequent than others and are prone to occur in particular age groups. Secondary metastatic deposits are more common than primary brain tumors in adults and the opposite is true in children. Furthermore, certain cancers (breast, lung, melanoma, renal cell cancer) display a tendency to metastasize to nervous tissue and many others do not do so. Second, some primary intracranial and spinal tumors, such as craniopharyngioma, meningioma, and schwannoma, have a disposition to grow in particular parts of the cranial cavity, thereby producing characteristic neurologic syndromes. Third, the presence of a state of immunosuppression such as AIDS or cancer chemotherapy, special inherited disorders such as neurofibromatosis, and exposure to radiation each predispose to the development of tumors of the nervous system. Fourth, the growth rates and invasiveness of tumors vary; some, like glioblastoma, are highly malignant, invasive, and rapidly progressive and others, like meningioma, are most often benign, slowly progressive, and compressive. These different qualities have substantial clinical implications, frequently providing the explanation of slowly or rapidly evolving clinical states as well as potential surgical cure and prognosis.

Finally, a special class of disorders result from the production of autoantibodies that are elaborated by systemic, nonneural, tumors and target cerebral and spinal neurons. These remote effects, referred to as paraneoplastic, often constitute the initial or only clinical manifestation of the underlying neoplasm.

A comprehensive reference on brain tumors is the text edited by Kaye and Laws.

Incidence of CNS Tumors and Their Types

Currently, in each year there are an estimated 600,000 deaths from cancer in the United States. Of these, the number of patients who died of primary tumors of the brain seems comparatively small (approximately 20,000, half of them malignant gliomas), but in roughly another 130,000 patients the brain is affected at the time of death by metastases. Thus, in approximately 25 percent of all the patients with cancer, the brain or its coverings are involved by neoplasm at some time in the course of the illness. Among causes of death from intracranial disease in adults, tumor is exceeded in frequency only by stroke, whereas in children primary brain tumors constitute the most common solid tumor and represent 22 percent of all childhood neoplasms, second in frequency only to leukemia. Viewed from another perspective, in the United States, the yearly incidence of all tumors that involve the brain is 46 per 100,000, and of primary brain tumors, 15 per 100,000.

It is difficult to obtain accurate statistics as to the types of intracranial tumors, for most of them have been obtained from university hospitals with specialized cancer and neurosurgical centers. From the figures of Posner and Chernik, one can infer that secondary tumors of the brain greatly outnumber primary ones; yet in the large series reported in the past (those of Cushing [1932], Olivecrona, Zülch, and Zimmerman), only 4 to 8 percent were of this type. In the autopsy statistics of municipal hospitals, where one would expect a more natural selection of cases, the figures for metastatic tumors vary widely, from 20 to 42 percent (Rubinstein, 1972). Even these estimates probably underestimate the incidence, particularly of metastatic disease. With these qualifications, the figures in Table 31-1 may be taken as representative.

Most primary brain tumors are of presumed glia cell origin—i.e., gliomas—a category that includes astrocytomas (which occur in several grades of malignancy), oligodendrogliomas, ependymomas (which may have characteristics of both glia and of epithelium), and a number of rarer types. Other brain tumors arise from ectodermal structures related to the brain (meningioma), from lymphocytes (CNS lymphoma), or from precursor neuronal elements (neuroblastoma, medulloblastoma), germ cells (germinoma, craniopharyngioma, teratoma), or endocrine elements (pituitary adenoma). Table 31-2 provides a detailed tabulation compiled by the Central Brain Tumor Registry. Notable in all series, and emphasized in this table, is the higher frequency of certain tumors during childhood.

The main change since the first edition of this book in 1977 is the increase in incidence of primary CNS lymphomas. At that time, the incidence of this tumor, formerly called reticulum cell sarcoma, was negligible. In the last 25 years, the number in our hospitals has more than tripled; in specialized centers such as the Memorial Sloan-Kettering Cancer Center, the increase has been even more dramatic (DeAngelis). It now represents over 3 percent of all brain tumors. This increase is only partly attributable to the rise in number of immunosuppressed individuals, particularly of those with AIDS, as the tumor appears to be increasing in incidence even in those with normal immune function.

Classification and Grading of Nervous System Tumors

Classifications and grading systems of intracranial tumors abound and are often confusing to the general neurologist. Most classifications have been based on the presumed cell of origin of the neoplasm, while grading systems are meant to be an estimate of the rate of growth and clinical behavior, but the two are often concordant. The most recent World Health Organization (WHO) classification (the fourth revision, 2007) represents the current view of tumor specialists but the entire list is unwieldy for most clinicians. Table 31-3 shows the main items and a discussion of this system can be found in the article by Louis and colleagues (2007). In the past, the numerical grading system of Daumas-Duport and coworkers (also known as the St. Anne–Mayo system) and the three-tiered system of Ringertz (which correlates most closely with clinical survival) were widely used and are cited in the literature. The various classification systems notwithstanding, it is clear that there are practical and prognostic consequences to subclassifying tumors by additional molecular methods that are predictive of outcome and of treatment response (see further on).

The astrocytic tumors, the most common forms of glioma, have been subdivided into diffuse well-differentiated astrocytoma (grade II), anaplastic astrocytoma (grade III), and glioblastoma (glioblastoma multiforme, or "GBM," grade IV). These grades represent a spectrum in terms of growth potential (degree of nuclear atypia, cellularity, mitoses, and vascular proliferation) and prognosis. The glioblastomas are largely defined by the features of necrosis and anaplasia of nonneural elements such as vascular proliferation and are set apart from anaplastic astrocytomas on the basis not only of their histology but also by a later age of onset than astrocytoma and a more rapid course. The grade I classification for astrocytomas is reserved for the relatively benign group that includes pilocytic astrocytomas (well-differentiated tumors mostly of children and young adults); the pleomorphic xanthoastrocytoma (with lipid-filled cells), and the subependymal giant cell astrocytoma (associated with tuberous sclerosis). They have been set apart because of their different growth patterns, pathologic features, and better prognosis.

The ependymomas are subdivided into cellular, myxopapillary, clear cell, and mixed types; the anaplastic ependymoma and the subependymoma are given separate status. The pathologic criteria of malignant astrocytoma do not apply to oligodendroglioma, for reasons elaborated further on. They are subdivided into tumors of pure oligodendroglial composition and those with mixed astrocytes and oligodendroglia.

Meningiomas are classified on the basis of their cytoarchitecture and genetic origin into 4 categories: (1) the common meningothelial or syncytial type, (2) the fibroblastic and (3) angioblastic variants, and (4) the malignant type. Tumors of the pineal gland, which were not included in earlier classifications, comprise germ cell tumors, the rare pineocytomas, and pineoblastomas. The medulloblastoma has been reclassified with other tumors of presumed neuroectodermal origin, namely neuroblastoma, retinoblastoma, neuroepithelioma, and ependymoblastoma. Tumors derived from the choroid plexus are divided into two classes, both rare: papillomas and carcinomas.

Given separate status also are the intracranial midline germ cell tumors, such as germinoma, teratoma, choriocarcinoma, and endodermal sinus carcinoma. A miscellaneous group comprises CNS lymphoma, hemangioblastoma, chordoma, hemangiopericytoma, spongioblastoma, and ganglioneuroma.

Tumors of cranial and peripheral nerves differentiate into three main types: schwannomas, neurofibromas, and neurofibrosarcomas. Most are sporadic but the neurofibromas assume special importance in neurofibromatosis.

Biology of Nervous System Tumors

In considering this subject, one of the first problems is with the definition of neoplasia. It is well known that a number of lesions may simulate brain tumors in their clinical manifestations and histologic appearance but are really hamartomas and not true tumors. A hamartoma is a "tumor-like formation that has its basis in maldevelopment" (Russell) and undergoes little change during the life of the host. The difficulty one encounters in distinguishing it from a true neoplasm, whose constituent cells multiply without restraint, is well illustrated by tuberous sclerosis and von Recklinghausen neurofibromatosis, where hamartomas and neoplasms are both found. Similarly, in a number of mass lesions—such as certain cerebellar astrocytomas, bipolar astrocytomas of the pons and optic nerves, von Hippel-Lindau cerebellar cysts, and pineal teratomas—a clear distinction between neoplasms and hamartomas is often not possible.

Many studies of the pathogenesis of brain tumors have gradually shed light on their origin. Johannes Müller (1838), in his atlas Structure and Function of Neoplasms, first enunciated the appealing idea that tumors might originate in embryonic cells left in the brain during development. This idea was elaborated upon by Cohnheim (1878), who postulated that the source of tumors was an anomaly of the embryonic anlage. Ribbert, in 1904, extended this hypothesis by postulating that the potential for differentiation of these stem cells would favor blastomatous growth.

For many years, thinking about the pathogenesis of primary CNS tumors was dominated by the histogenetic theory of Bailey and Cushing, which was based on the assumed embryology of nerve and glia cells. Although it is not a popular notion today, Bailey and Cushing attached the suffix blastoma to indicate all tumors composed of primitive-looking cells, such as glioblastoma and medulloblastoma. One prominent theory was that most tumors arise from neoplastic transformation of mature adult cells (dedifferentiation). A normal astrocyte, oligodendrocyte, microgliocyte, or ependymocyte is transformed into a neoplastic cell and, as it multiplies, the daughter cells become variably anaplastic, more so as the degree of malignancy increases. (Anaplasia refers to the more primitive undifferentiated state of the constituent cells.)

In fact, the cells of origin of the major types of brain tumors have not been unequivocally identified or, in many cases, they appear to arise from pluripotential stem cells that reside in the brain, a concept not known in Bailey's time. If this is indeed the case, it may be that the apparent dedifferentiation of tumor cells is an artifact of their histologic appearance and not a fundamental property.

The factor of age plays a central role in the biology of brain tumors. Medulloblastomas, polar spongioblastomas, optic nerve gliomas, and pinealomas occur mainly before the age of 20 years, and meningiomas and glioblastomas are most frequent in the sixth decade of life. A number of mutations, only some inherited, also figure greatly in the genesis of certain tumors, particularly retinoblastomas, neurofibromas, and hemangioblastomas. The gliomas associated with neurofibromatosis and tuberous sclerosis and the cerebellar hemangioblastomas of von Hippel-Lindau are the best examples of a genetic determinant. The rare familial disorders of multiple endocrine neoplasia and multiple hamartomas are associated with an increased incidence of anterior pituitary tumors and meningiomas, respectively. Glioblastomas and cerebral astrocytomas have also been reported occasionally in more than one member of a family but the study of such families has not disclosed the operation of an identifiable genetic factor.

Although there is only indirect evidence for an association between viruses and certain primary tumors of the nervous system, epidemiologic and experimental data—drawn from studies of the human papillomavirus and the hepatitis B, Epstein-Barr, and human T-lymphotropic viruses—indicate that they may be involved or act as risk factors in certain human cancers. The genes of Epstein-Barr virus (EBV), for example, are incorporated into the DNA of many cerebral lymphomas. In transgenic mice, certain viruses are capable of inducing olfactory neuroblastomas and neurofibromas. Each of these viruses possesses a small number of genes that are incorporated in a cellular component of the nervous system (usually a dividing cell such as an astrocyte, oligodendrocyte, ependymocyte, endothelial cell, or lymphocyte). The virus is believed to act to force the cell from its normal activity into an unrestrained replicative cycle. Because of this capacity to transform the cellular genome, the virus product is called an oncogene; such oncogenes are capable of immortalizing, so to speak, the stimulated cell to form a tumor. Oncogenes are also found in normal cells and may contain mutations or are capable of being activated by cellular and environmental (epigenetic) events as noted later.

Molecular and Genetic Features of Brain Tumors

The above concepts have been expanded greatly by the identification of certain genetic aberrations that arise in tumor cells of the nervous system. What has emerged from these studies is the view that the biogenesis and progression of brain tumors are a consequence of defects in the control of the cell cycle. Some molecular defects predispose to tumor genesis; others underlie subsequent progression and accelerated malignant transformation and yet others may confer sensitivity or resistance to chemotherapeutic agents. This model presupposes the acquisition of multiple genetic defects over time since, with the exception of special inherited conditions such as neurofibromatosis, ataxia telangectasia, and a few others, these are not germ line mutations but are acquired as somatic events in the course of tumor evolution.

In cases that have an inherited and transmissible germ line defect there may be additional events that also cause somatic genetic mutations. Typically, inherited mutations affect only one of two copies of a tumor suppressor gene that, by itself, does not cause cancer. However, if the second copy of the gene acquires a mutation (e.g., from a chemical toxin or irradiation) the tumor suppression function of the gene is lost and neoplastic transformation of the cell becomes likely. These ideas are consistent with the observation that many of the gene defects that predispose to cancer are dominantly inherited. More recently, single nucleotide polymorphisms have been identified that in combination predispose to certain childhood tumors such as neuroblastoma, or to the more aggressive forms of various tumors.

The above model is illustrated by consideration of the astrocytoma. Among the first detectable changes are mutations acquired in the act of neoplastic cell division that inactivate the tumor suppressor gene p53 on chromosome 17p; over 50 percent of astrocytomas have deletions within this gene. Other early changes include overexpression of genes that control growth factors or their receptors as noted below. After the tumor develops, progression to a more malignant grade of astrocytoma or to a glioblastoma may be triggered by defects in the p16-retinoblastoma gene signaling pathway, loss of chromosome 10 (seen in approximately 90 percent of high-grade gliomas), or overexpression of the epidermal growth factor gene. In fact, it is striking that analysis of the patterns of these defects in some tumors correlates with the staging and aggressive characteristics of these tumors. The events that lead to their accumulation are not clear, as noted below. Also, mutations in the genes that code for isocitrate dehydrogenase(IDH1 and 2) are common in gliomas and oligodendrogliomas and their presence relates to less tumor progression.

Knowledge of the molecular signatures of certain tumors may have considerable clinical value. For example, oligodendrogliomas that have combined deletions in chromosomes 1p and 19q respond well to chemotherapy and this property increases survival (Reifenberger and Louis; Louis et al, 2002). The childhood tumors of neuroectodermal origin would seem to be particularly attractive as models to explore genetic alterations and indeed, various changes such as the amplification of the MYCN oncogene has been associated with an aggressive clinical course and poor outcome in neuroblastoma and medulloblastoma.

Much of the modern genetic understanding of brain tumors is derived from the technical gene microarrays. The patterns of these multiple gene analyses are able to distinguish some types of medulloblastomas from the similar-appearing, primitive neuroectodermal tumors; the medulloblastomas express classes of genes that are characteristic of cerebellar granule cells, suggesting they arise from these cells. Also, gene expression signatures confer useful prognostic information in a more general way than noted above for oligodendroglioma. For example, medulloblastomas that express genes indicative of cerebellar differentiation are associated with longer survival than those expressing genes related to cell division (Pomeroy et al).

As alluded to earlier, in approximately 50 percent of gliomas there is an overexpression or a mutant form of epidermal growth factor receptor (EGFR) and of platelet-derived transforming growth factor receptor (PDGFR), suggesting a role for these in the progression of certain tumor types. Other trophic factors are overexpressed in yet other brain neoplasms and perhaps contribute to their morphology and growth pattern; for example, vascular endothelial growth factor (VEGF) is found in extremely high concentrations in meningiomas, which are highly vascular by nature. These findings, taken together, suggest an autocrine stimulation of growth by these factors and an interaction with some of the aforementioned gene defects. However, having emphasized molecular and chromosomal changes, it is not yet clear that any of them is truly causative or if they simply reflect an aberrant genetic process that accompanies the evolution of tumor growth and progression.

Finally, epigenetic events related to the attachment of histones to various tumor genes alter transcription in ways that may be relevant to growth and treatment effects. The best studied of these is the methylation status of the promoter of MGMT, a methyltransferase that alters sensitivity of the glioma to chemotherapy (see further on).

On the basis of this molecular information, views of the pathogenesis of neoplasia are being cast along new lines. Some of the specifics of these new data are presented in the following discussions of particular tumor types. A more extensive review can be found in the article by Osborne and colleagues, and the text by Kaye and Laws.

Pathophysiology of Brain Tumors

The production of symptoms by tumor growth is governed by certain principles of mechanics and physiology, some of which were discussed in Chaps. 17 and 30. There it was pointed out that the cranial cavity has a restricted volume, and the three elements contained therein—the brain (about 1,200 to 1,400 mL), cerebrospinal fluid (CSF; 70 to 140 mL), and blood (150 mL)—are relatively but not entirely incompressible, particularly the brain substance, and each is subject to displacement by a localized mass lesion. According to the Monro-Kellie doctrine, the total bulk of the three elements is at all times constant, and any increase in the volume of one of them must be at the expense of the others, as discussed in Chap. 30. A tumor growing in one part of the brain therefore compresses the surrounding brain tissue and displaces CSF and blood; once the limit of this accommodation is reached, the intracranial pressure (ICP) rises. The elevation of ICP and perioptic pressure impairs axonal transport in the optic nerve and the venous drainage from the optic nerve head and retina, manifesting in papilledema.

Only some brain tumors cause papilledema and many others—often quite as large—do not. Thus one may question whether the Monro-Kellie doctrine and its simple implied relationships of intracranial volume and CSF pressure fully account for the development of raised ICP and papilledema with brain tumors. This discrepancy is in part because in a slow process, such as tumor growth, brain tissue is to some degree compressible, as one might suspect from the large indentations of brain produced by massive meningiomas.

The slow growth of most tumors permits accommodation of the brain to changes in cerebral blood flow and ICP. Only in the advanced stages of tumor growth do the compensatory mechanisms fail and CSF pressure and ICP rise, with consequences described in Chap. 30. Once pressure is raised in a particular compartment of the cranium, the tumor begins to displace tissue at first locally and at a distance from the tumor, resulting in a number of false localizing signs, including coma, described in Chap. 17. Indeed, the transtentorial herniations, the paradoxical corticospinal signs of Kernohan and Woltman, sixth- and third-nerve palsies, occipital lobe infarcts, midbrain hemorrhages, and secondary hydrocephalus were all originally described in tumor cases (see further on, under "Brain Displacements and Herniations").

Brain Edema

Brain edema is such a prominent feature of cerebral neoplasm that this is a suitable place to summarize what is known about it. With tumor growth, the venules in the cerebral tissue adjacent to the tumor are compressed, with resulting elevation of capillary pressure, particularly in the cerebral white matter where edema is most prominent.

It has been recognized that conditions leading to peripheral edema, such as hypoalbuminemia and increased systemic venous pressure, do not have a similar effect on the brain. By contrast, lesions that alter the blood–brain barrier cause rapid swelling of brain tissue. Klatzo specified two categories of edema: vasogenic and cytotoxic. Fishman added a third, which he called interstitial edema. An example of the latter is the edema that occurs with obstructive hydrocephalus, especially when the ependymal lining is disrupted and CSF seeps into the periventricular tissues in the spaces between cells and myelin. Most neuropathologists use the term interstitial to refer to any increase in the extravascular intercellular compartment of the brain; this would include both vasogenic and interstitial edema.

Vasogenic edema is the type seen in the vicinity of tumor growths and other localized processes as well as in more diffuse injury to the blood vessels (e.g., lead encephalopathy, malignant hypertension). It is practically limited to the white matter and is evidenced by decreased attenuation on CT and by hyperintensity on T2-weighted MRI and elevated diffusivity (reduced anisotropy) on diffusion-weighted MRI. Presumably, there is increased permeability of the capillary endothelial cells so that plasma proteins exude into the extracellular spaces (Fig. 31-1A). This heightened permeability has been attributed to a defect in the tight endothelial cell junctions, but current evidence indicates that active vesicular transport of water across the endothelial cells is a more important factor.

Microvascular transudative factors, such as proteases released by tumor cells, also contribute to vasogenic edema by loosening the blood–brain barrier and allowing passage of blood proteins. The small protein fragments that are generated by this protease activity may exert osmotic effects as they spread through the white matter of the brain. This is the postulated basis of the regional swelling, or localized cerebral edema that surrounds the tumor. Experimentally, the increase in permeability has been shown to vary inversely with the molecular weight of various markers; e.g., inulin (molecular weight: 5,000) enters the intercellular space more readily than albumin (molecular weight: 70,000).

The vulnerability of white matter to vasogenic edema is not well understood; probably its loose structural organization offers less resistance to fluid under pressure than the gray matter. There may also be special morphologic characteristics of white matter capillaries. The accumulation of plasma filtrate, with its high protein content, in the extracellular spaces and between the layers of myelin sheaths would be expected to alter the ionic balance of nerve fibers, impairing their function but this has never been demonstrated satisfactorily.

By contrast, in cytotoxic edema, all the cellular elements (neurons, glia, and endothelial cells) swell with fluid and there is a corresponding reduction in the extracellular fluid space. Because a shift of water occurs from the extracellular to the intracellular compartment, there is relatively little mass effect, the opposite of what occurs with the vascular leak of vasogenic edema. This cellular edema occurs typically with hypoxic–ischemic injury but it may also complicate acute hypoosmolality of the plasma, acute hepatic encephalopathy, inappropriate secretion of antidiuretic hormone, and the osmotic disequilibrium syndrome of hemodialysis (see discussion of hyponatremia and "dialysis disequilibrium syndrome" in Chap. 40). The effect of oxygen deprivation is the cause of failure of the adenosine triphosphate (ATP)-dependent sodium pump within cells; sodium accumulates in the cells, and water follows (Fig. 31-1B). The term cellular edema may be preferable to cytotoxic edema because it emphasizes intracellular ionic movement and not the implication of a toxic factor.

Like vasogenic edema, cytotoxic edema results in decreased attenuation in CT and hyperintensity on T2-weighted MRI. However, it is coupled with reduced diffusivity (increased anisotropy) rather than elevated diffusivity on diffusion-weighted MRI. In the case of cerebral infarction, an initial phase of cytotoxic edema precedes the onset of vasogenic edema, manifest as early reduced diffusivity followed by later elevated diffusivity on diffusion-weighted MRI.

Interstitial (hydrocephalic) edema, as defined by Fishman, is a recognizable condition but is probably of less clinical significance than cytotoxic or cellular edema. In tension hydrocephalus, the edema can extend for up to 2 to 3 mm from the ventricular wall. However, MRI suggests that the periventricular edema is more extensive than what is observed pathologically. There are also experimental data to show that a transependymal or periventricular route is utilized for absorption of CSF in hydrocephalus (Rosenberg et al).

Treatment of Brain Edema and Raised ICP (See "Management of Raised Intracranial Pressure" in Chap. 35)

The treatment of brain edema and elevated ICP is governed by the underlying disease (excision of a tumor, treatment of intracranial infection, placement of a shunt, etc.). Here we consider the therapeutic measures that can be directed against the edema itself and the raised ICP as they apply to brain tumor.

The use of high-potency glucocorticosteroids has a beneficial effect on the vasogenic edema associated with tumors, both primary and metastatic, sometimes beginning within hours. Probably these steroids act directly on the endothelial cells, reducing their permeability. Steroids also shrink normal brain tissue, thus reducing overall intracranial pressure. Drugs such as dexamethasone also reduce the vasogenic edema associated with brain abscess and head injury, but their usefulness in these cases and in large cerebral infarctions, contusions, and hemorrhage is less clear; in fact, most attempts to demonstrate benefit in all conditions but brain tumors have proven negative. The swelling surrounding necrotic tissue is reduced; however, there is no evidence that cytotoxic or cellular edema responds to administration of glucocorticoids.

For patients with brain tumor, it is common practice initially to use doses of dexamethasone of approximately 4 mg q6h, or the equivalent dose of methylprednisolone. Although a few patients require a rigid schedule, a dose with meals and at bedtime usually suffices to suppress headache and focal tumor signs. In patients with large tumors and marked secondary edema, further benefit is sometimes achieved by the administration of extremely high doses of dexamethasone, to a total of 100 mg/d or more for a brief time. An initial dose may be given intravenously. Always to be kept in mind are the potentially serious side effects of sustained steroid administration, even at standard dose levels. Rare complications, such as aseptic necrosis of the hip, are sometimes idiosyncratic; consequently, the schedule should be organized around the desired clinical effect. It is also recognized that these drugs interfere with the metabolism of certain anticonvulsants commonly used in brain tumor patients.

In patients who have brain edema and who require intravenous fluids, one avoids solutions containing water ("free water") not matched by equivalent amounts of sodium. Normal saline (314 mOsm/L) is preferable, and lactated Ringer solution (osmolarity 289 mOsm/L) is acceptable, but dextrose solutions alone, in any concentration (except D5/NS), are avoided because of their hypoosmolar concentration.

The parenteral administration of hypertonic solutions, to which the brain is only partially permeable (mannitol, hypertonic saline, urea, glycerol), by shifting water from brain to plasma, is an effective means of rapidly reducing brain volume and lowering ICP as discussed more extensively in Chap. 35 in relation to trauma as we have summarized elsewhere in a review (Ropper). These agents are useful in urgent circumstances but have a diminishing effect over days. Edema, however, is actually little affected by shrinkage of the remaining normal brain provides most of the internal decompression.

Mannitol is the most widely used osmotic agent; a 25 percent solution is administered parenterally in a dose of 0.5 to 1.0 g/kg body weight over a period of 2 to 10 min. Hypertonic saline solutions (3, 7, or 23 percent) are equally effective. Repeated use on a regular schedule can lead to a reduction in headache and stabilization of some of the deleterious effects of a tumor. Diuretic drugs, notably acetazolamide and furosemide, may be helpful in special instances (interstitial edema, pseudotumor cerebri) by virtue of creating a hyperosmolar state and by reducing the formation of CSF. However, their effects are usually mild and transient.

Highly permeable solutes such as glucose do little to reduce brain volume, as they do not create an osmolar gradient that shifts water from the brain to the vasculature. Furthermore, with repeated administration of hyperosmolar solutions such as mannitol or with diuretics, the brain gradually increases its osmolality—the result of added intracellular solute; thus these agents are not suitable for long-term use. The notion that hyperosmolar agents might exaggerate tissue shifts by shrinking normal brain tissue has not been substantiated. The net effect of hyperosmolar therapy is reflected roughly by the degree of hyperosmolarity and hypernatremia that is attained.

Controlled hyperventilation is another method of rapidly reducing brain volume by producing respiratory alkalosis and cerebral vasoconstriction; it is used mainly in cases of brain trauma with high ICP (see Chap. 35), during intracranial surgery, and in the management of patients who have become acutely comatose from the mass effect of a tumor, but its effect is brief.

Brain Displacements and Herniations (See Also Chap. 17)

An understanding of the effects of elevated intracranial pressure, localized vasogenic edema, and displacements of tissue and herniations are absolutely essential to understanding the clinical behavior of intracranial tumors and mass lesions of any type. Often the symptoms of intracranial tumors are related more to these effects than to invasion or destruction of neurologic structures by the tumor. The several "false localizing" signs (coma, unilateral or bilateral abducens palsy, pupillary changes, ipsilateral or bilateral corticospinal tract signs, etc.) are also attributable to these mechanical changes and tissue displacements. The main aspects of this problem, particularly the coma-producing mechanisms, were considered in Chap. 17. The pressure from a mass within any one dural compartment causes shifts or herniations of brain tissue to an adjacent compartment where the pressure is lower. The three well-known herniations are subfalcial, transtentorial, and cerebellar–foramen magnum (see Fig. 17-1), and there are several less familiar ones (upward cerebellar-tentorial, diencephalic–sella turcica, and orbital frontal–middle cranial fossa [transalar]). Herniation of swollen brain through an acquired defect in the calvarium, in relation to craniocerebral trauma or surgical craniotomy, is yet another (transcalvarial) type.

Subfalcial herniation, in which the cingulate gyrus is pushed under the falx, occurs frequently, but little is known of its clinical manifestations except that there may be occlusion of an anterior cerebral artery and resultant frontal lobe infarction. The cerebellar–foramen magnum herniation or pressure cone described by Cushing in 1917 consists of downward displacement of the inferomedial parts of the cerebellar hemispheres (mainly the ventral paraflocculi or tonsillae) through the foramen magnum, dorsolateral to the cervical cord. The clinical manifestations are less well delineated than those of the temporal lobe–tentorial herniation. Cushing considered the typical signs of cerebellar herniation to be episodic tonic extension and arching of the neck and back and extension and internal rotation of the limbs, with respiratory disturbances, cardiac irregularity (bradycardia or tachycardia), and loss of consciousness.

Other signs with subacutely evolving masses in the posterior fossa include pain in the neck, stiff neck, head tilt, and paresthesias in the shoulders, dysphagia, and loss of tendon reflexes in the arms. Head tilt, stiff neck, arching of the neck, and paresthesias over the shoulders are attributable to the herniation of the cerebellar tonsils into the foramen magnum, and tonic extensor spasms of the limbs and body (so-called cerebellar fits) and coma are caused by the compressive effects of the cerebellar mass on medullary structures or of hydrocephalus on upper brainstem structures. In any case, respiratory arrest is the feared and often fatal effect of medullary compression by a "cerebellar pressure cone." It may occur suddenly, without the aforementioned additional signs. With cerebellar mass lesions there may also be upward herniation of the cerebellum through the incisura of the tentorium. The clinical effects have not been clearly determined, but Cuneo and colleagues have attributed decerebrate posturing and pupillary changes—initially both pupils are miotic but still reactive, progressing to anisocoria and enlargement—to this type of brain displacement.

It should be stated at the outset that tumors of the brain often exist with hardly any symptoms. A slight bewilderment, slowness in comprehension, or loss of capacity for sustained mental activity may be the only deviations from normal, and signs of focal cerebral disease are wholly lacking. In some patients, on the other hand, there is early indication of cerebral disease in the form of a progressive hemiparesis, a seizure occurring in a previously well person, or some other dramatic symptom. In a third group, the existence of a brain tumor can be assumed because of the presence of increased intracranial pressure with or without localizing signs of the tumor. In yet another group, the symptoms are so definite as to make it likely that not only is there an intracranial neoplasm but that it is of a certain type and is located in a particular region. These localized growths create certain syndromes seldom caused by any other disease.

In the further exposition of this subject, intracranial tumors are considered in relation to these common modes of clinical presentation:

1. Patients who present with focal cerebral signs and general impairment of cerebral function, headaches, or seizures

2. Patients who present with evidence of increased intracranial pressure

3. Patients who present with specific intracranial tumor syndromes

Patients Presenting with General Impairment of Cerebral Function, Headaches, and Seizures

Altered mental function, headache, dizziness, and seizures are the usual manifestations in this group of patients. Until the advent of modern imaging procedures, these were the patients who presented the greatest difficulty in diagnosis and about whom decisions were often made with a great degree of uncertainty. Their initial symptoms are vague, and not until some time has elapsed will signs of focal brain disease appear; when they do, they are not always of accurate localizing value.

Changes in Mental Function

A lack of persistent application to everyday tasks, undue irritability, emotional lability, mental inertia, faulty insight, forgetfulness, reduced range of mental activity (judged by inquiring about the patient's introspections and manifested in his conversation), indifference to common social practices, lack of initiative and spontaneity—all of which may be misattributed to anxiety or depression—make up the cognitive and behavioral abnormalities seen in this clinical circumstance. Inordinate drowsiness or apathy may be prominent. We have sought a convenient term for this complex of symptoms, which is perhaps the most common type of mental disturbance encountered with neurologic disease, but none seems entirely appropriate. There is both a reduction in the amount of thought and action and a slowing of reaction time. MacCabe referred to this condition as "mental asthenia," which has the merit of distinguishing it from depression.

Much of this change in behavior is accepted by the patient with forbearance; if any complaint is made, it is of being weak, tired, or dizzy (nonvertiginous). Within a few weeks or months, these symptoms become more prominent. When the patient is questioned, a long pause precedes each reply (abulia); at times the patient may not respond at all. Or, at the moment the examiner decides that the patient has not heard the question and prepares to repeat it, an appropriate answer is given, usually in few words. Moreover, the responses are often more intelligent than one would expect, considering the patient's torpid mental state. Many of these features will be recognized as components of a frontal lobe syndrome, but the tumor is often situated elsewhere, or is diffusely infiltrative. There are, in addition, patients who are overtly confused or demented. If the condition remains untreated, dullness and somnolence increase gradually and, finally, as increased intracranial pressure supervenes, the patient progresses to stupor or coma.

Headaches (See Also "Headaches of Brain Tumor" in Chap. 10)

These are an early symptom in fewer than 25 percent of patients with brain tumor and are variable in nature. In some, the pain is slight, dull, and episodic; in others, it is severe and either dull or sharp but also intermittent. If there are any characteristic features of the headache, they would be its nocturnal occurrence or presence on first awakening and perhaps its deep, nonpulsatile quality. However, these are not specific attributes, as migraine and hypertensive vascular headaches may also begin in the early morning hours or upon awakening. But if vomiting occurs at the peak of the head pain, tumor is more likely, as noted later. Occipitonuchal headache with vomiting is indicative of a tumor in or near the cerebellum and foramen magnum and is one typical presentation in children.

Patients with brain tumors do not always complain of head pain even when it is present, but they may betray its existence by placing their hands to their heads and looking distressed. When headache appears in the course of the psychomotor asthenia syndrome, it serves to clarify the diagnosis, but not nearly as much as does the occurrence of a seizure.

The mechanism of the headache is not fully understood and there may be more than one pathophysiology. In the majority of instances, the CSF pressure is normal during the first weeks when the headache is present, and one can attribute it only to local swelling of tissues and to distortion of blood vessels in the dura overlying the tumor. Later, the headache may be related to increases in intracranial pressure, thus the early morning occurrence after recumbency and vomiting, as discussed in Chap. 10. Tumors above the tentorium cause headache on the side of the tumor and in its vicinity, in the orbitofrontal, temporal, or parietal region; tumors in the posterior fossa usually cause ipsilateral retroauricular or occipital headache. With elevated intracranial pressure, bifrontal or bioccipital headache is the rule regardless of the location of the tumor.

Vomiting and Dizziness

Vomiting appears in a relatively small number of patients with a tumor syndrome and usually accompanies the headache when the latter is severe. It is more frequent with tumors of the posterior fossa. The most persistent vomiting (lasting several weeks) that we have observed has been in patients with low brainstem gliomas, fourth ventricular ependymomas, and subtentorial meningiomas. Some patients may vomit unexpectedly and forcibly without preceding nausea ("projectile vomiting"), a sign that is fairly specific to tumor in children, but others suffer nausea and severe discomfort. Usually the vomiting is not related to the ingestion of food, and, often, it occurs before breakfast.

No less frequent is the complaint of dizziness. As a rule it is not described with accuracy and consists of an unnatural sensation in the head, coupled with feelings of strangeness and insecurity when the position of the head is altered. Positional vertigo can be a symptom of a tumor in the posterior fossa affecting vestibular structures, but has many other more common and benign causes (see Chap. 15).

Seizures

The occurrence of focal or generalized seizures is the other major manifestation of brain tumor besides slowing of mental functions and signs of focal brain damage. Convulsions have been observed in 20 to 50 percent of all patients with cerebral tumors. A first seizure during adulthood is always suggestive of brain tumor and, in the authors' experience, has been the most common initial manifestation of primary and metastatic neoplasm. The localizing significance of seizure patterns was discussed in Chap. 16. Seizures caused by brain tumor most often have a focal onset and may secondarily generalize. There may be one seizure or many, and they may follow the other symptoms or precede them by weeks or months or—exceptionally, in patients with low-grade astrocytoma, oligodendroglioma, or meningioma—by several years. Status epilepticus as an early event from brain tumor is rare but has occurred in a few of our patients. As a rule, the seizures respond to standard antiepileptic medications and may improve after surgery for tumor resection.

Patients Presenting with Regional or Localizing Symptoms and Signs (Glioblastoma Multiforme, Astrocytoma, Oligodendroglioma, Ependymoma, Metastatic Carcinoma, Meningioma, and Primary Lymphoma)

Sooner or later, focal cerebral signs will be discovered in most patients with brain tumors. Most often the focal signs are at first slight and subtle, but some patients present with such signs. In the modern era of ubiquitous imaging for all manner of cerebral complaints, CT or MRI often will have disclosed the presence of a tumor before either focal cerebral signs or the signs of increased intracranial pressure have become evident.

The cerebral tumors that are most likely to produce the syndromes of asthenia, headache, seizures, or focal signs are the ones listed above in the heading. The clinical aspects of these diseases, which happen to be the most common brain tumors in adults, are discussed in the sections below.

Glioblastoma Multiforme and Anaplastic Astrocytoma

These high-grade gliomas account for approximately 20 percent of all intracranial tumors and for more than 80 percent of gliomas of the cerebral hemispheres in adults. Although predominantly cerebral in location, they may also arise in the brainstem, cerebellum, or spinal cord. The peak incidence is in middle adult life (mean age for the occurrence of glioblastoma is approximately 60 years, and 46 years for anaplastic astrocytoma), but no age group is exempt. The incidence is higher in men (ratio of approximately 1.6:1). Almost all of the high-grade gliomas occur sporadically, without a familial predilection.

The glioblastoma, known since the time of Virchow, was definitively recognized as a glioma by Bailey and Cushing and given a place in their histogenetic classification. They are now listed as grade IV glial tumors in the WHO classification. Most arise in the deep white matter as a heterogenous mass and quickly infiltrate the brain extensively, sometimes attaining enormous size before attracting medical attention.

The tumor may extend to the meningeal surface or the ventricular wall, which probably accounts for the increase in CSF protein (more than 100 mg/dL in many cases), as well as for an occasional pleocytosis of 10 to 100 cells or more, mostly lymphocytes. The CSF is usually normal, however. Malignant cells, carried in the CSF, rarely may form distant foci on spinal roots or cause a widespread meningeal gliomatosis. Extraneural metastases, involving bone and lymph nodes, are very rare; usually they occur only after a craniotomy has been performed. Approximately 50 percent of glioblastomas occupy more than one lobe of a hemisphere; between 3 and 6 percent show multicentric foci of growth and thereby simulate metastatic cancer. A legitimate question is whether these tumors can have a multicentric origin or spread via CSF pathways. We have the impression that the first configuration does exist.

The tumor has a variegated appearance, being a mottled gray, red, orange, or brown, depending on the degree of necrosis and presence of hemorrhage, recent or old. The imaging appearance is usually that of an inhomogeneous mass, often with a center that is hypointense and nonenhancing. An irregular rim of enhancement surrounds the core lesion, and is surrounded by nonenhancing edematous brain tissue, consisting of a combination of infiltrating tumor cells and vasogenic edema (Fig. 31-2). It is not uncommon to see small nodular enhancing lesions adjacent to, but distinct from, the primary lesion. Part of one lateral ventricle is often distorted, and both lateral and third ventricles may be displaced.

The characteristic histologic findings of glioblastoma are hypercellularity with pleomorphism of cells and nuclear atypia; identifiable astrocytes with fibrils in combination with primitive forms in many cases; tumor giant cells and cells in mitosis; hyperplasia of endothelial cells of small vessels; and necrosis, hemorrhage, and thrombosis of vessels. This variegated appearance distinguishes glioblastoma from the anaplastic astrocytomas, which show frequent mitoses and atypical cytogenic features but no grossly necrotic or hemorrhagic areas. It is the necrotic and sometimes cystic areas that appear hypointense on imaging studies. An MRI study by Ulmer and colleagues showed that 70 percent of patients show evidence of a small region of infarction immediately surrounding the tumor in the postoperative period; most of the affected areas also demonstrate these cystic encephalomalacic areas. The vasculature and fibroblasts can undergo a sarcomatous transformation giving the tumor a mixed appearance that is termed gliosarcoma.

Originally, glioblastoma was thought to be derived from and composed of primitive embryonal cells, or, in the late decades of the twentieth century, to arise through anaplasia of maturing astrocytes. However, these views have been called into question because models of malignant transformation of neural stem cells or of glial progenitor cells explain many of the characteristics and behavior of gliomas. The location, cellular and genetic heterogeneity, and manner of growth and spread of these tumors are consistent with an origin in a primitive cell. Sanai and colleagues have summarized the case for stem cell origin, but this notion is not universally accepted and potential deficiencies in this theory are noted by Reid and coworkers. The genetic or epigenetic events that putatively lead to a malignant evolution of these progenitor cells are not known. Ironically, this is a reversion to the idea of the early last century that posited an embryonal origin of glioma.

The histologic grade may vary from site to site within a tumor and it is common for sites of low-grade astrocytoma and glioblastoma to coexist; in some high-grade tumors there are even sites of well-differentiated astrocytoma. This relates to a problem that arises in interpreting single small biopsy samples taken for diagnosis. It is a fair statement that the most aggressive component (e.g., glioblast elements) determines the tumor's behavior.

To some extent, this behavior is also related to the genetic changes described earlier under "Molecular and Genetic Features of Brain Tumors." Amplification of the EGFR gene is characteristic in older patients with tumors that begin entirely as glioblastomas, whereas acquired mutations of the p53 gene tend to occur in younger individuals whose tumors progress from an astrocytoma to a glioblastoma. More recently, the progression of astrocytomas and oligodendrogliomas to more malignant forms has been related to the enzyme isocitrate dehydrogenase, encoded by the genes IDH1 and IDH2. Patients with mutations in these genes had better outcomes and slower tumor progression as presented by Yan and colleagues. The change in EGFR, a receptor tyrosine kinase that is implicated in the growth of a number of solid tumors, and other acquired mutations and epigenetic alterations, such as in the MGMT promoter gene discussed further on, are proving to be predictors of responsiveness to chemotherapeutic agents and of prognosis, as noted later in the chapter. Other tumors display underexpression of the tumor suppressor gene PTEN. It is likely that genetic analyses of tumor material from individual patients will become an increasingly important part of therapeutic decisions.

The natural history of untreated glioblastoma is well characterized. Fewer than 20 percent of patients survive for 1 year after the onset of symptoms and only about 10 percent live beyond 2 years (Shapiro). Age is an important prognostic factor; fewer than 10 percent of patients older than age 60 years survive for 18 months, in comparison to two-thirds of patients younger than age 40 years. Survival with anaplastic astrocytoma is somewhat better, typically 3 to 5 years. Cerebral edema and increased intracranial pressure are usually the causes of death. Survival rates with treatment are discussed below.

The diagnosis must be confirmed by a stereotactic biopsy or by a craniotomy that aims to remove as much tumor as is feasible at the same time.

Treatment

At operation, usually only part of the tumor can be removed; its multicentricity and diffusely infiltrative character defy the scalpel. Partial resection of the tumor ("debulking"), however, seems to prolong survival as noted below. Neurosurgeons have developed a number of cortical electrophysiologic mapping and imaging techniques to facilitate maximal resection without injuring adjacent brain tissue.

Except for palliation, little can be done to alter the course of glioblastoma. For a brief period, corticosteroids, usually dexamethasone in doses of 4 to 10 mg q6–12h, are helpful if there are symptoms of mass effect, such as headache or drowsiness; local signs and surrounding edema tend to improve as well. Antiepileptic medications are not required unless there have been seizures. Although some neurologists and neurosurgeons still administer them in order to preempt a convulsion, several series have found antiepileptic medications to be unnecessary for this purpose. Serious skin reactions (erythema multiforme and Stevens-Johnson syndrome) may occur in patients receiving phenytoin at the same time as cranial radiation (Delattre et al). A maximally feasible resection, the debulking described above, is combined with radiation and chemotherapy. Cranial irradiation to a total dose of 6,000 cGy increases survival by 5 months on average (see below). This is true even in the elderly who have had only a biopsy without resection according to a trial conducted by Keime-Guibert and colleagues.

It had been considered for several decades that the addition of chemotherapeutic nitrosourea agents such as carmustine (BCNU) or lomustine (CCNU) increase survival slightly. Cisplatin and carboplatin have provided similar small marginal improvements in survival beyond that obtained by debulking and radiation therapy. Several randomized trials, however, have failed to show substantial benefit of chemotherapy but the Glioma Meta-analysis Trialists (GMT) Group had concluded in 2002 that there was a clear but quite small benefit of chemotherapy.

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 d every 28 d 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 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 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).

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.

Brachytherapy (implantation of iodine-125 or iridium-193 beads or needles) and high-dose focused radiation (stereotactic radiosurgery) have so far not significantly altered survival times but continue to be studied.

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 promising approach for recurrent malignant gliomas is the use of drugs that target the tumor's vasculature. Antiangiogenic agents such as bevacizumab, a VEGF inhibitor, sometimes given in combination with chemotherapy, may delay progression and greatly reduce cerebral edema, therefore diminishing the requirement for corticosteroids, but also do not prolong survival. 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).

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

Low- and Intermediate-Grade Astrocytoma

The lower-grade astrocytomas (grade II in the WHO classification), which constitute between 25 and 30 percent of cerebral gliomas, may occur anywhere in the brain or spinal cord. The median survival in cases of anaplastic astrocytoma is considerably longer than for glioblastoma, 2 to 5 years, often longer. Favored sites of occurrence are the cerebrum, cerebellum, hypothalamus, optic nerve and chiasm, and pons. In general, the location of the tumor appears to be influenced by the age of the patient. 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 are 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 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 and the rare pleomorphic xanthoastrocytoma. These distinctions correlate to a degree with the biologic behavior of the astrocytomas and therefore have prognostic importance.

Cerebral astrocytoma is a slowly growing tumor of infiltrative character with a tendency in some cases to form large cavities or pseudocysts. Other tumors of this category 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. 31-3). 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.

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.

MRI may be helpful in distinguishing the more frequent fibrillary type of tumor under discussion from pilocytic astrocytomas. Pilocytic types are sharply demarcated, with smooth borders and little edema. On T1-weighted MRI, they are isointense or hypointense; on T2 sequences, hyperintense, and there tends to be marked enhancement of the nodular solid portion of the tumor after gadolinium infusion. Cyst formation and small amounts of calcification are common, especially in cerebellar tumors. The fibrillary tumors have a less-stereotyped appearance, generally taking the form of a more homogenous T1 hypointense and T2 hyperintense infiltrating mass with less well-defined borders and little or no contrast enhancement.

In children, astrocytic tumors usually arise in the cerebellum (Fig. 31-4) and declare themselves by some combination of gait unsteadiness, unilateral ataxia, and increased intracranial pressure (headaches, vomiting).

Treatment

One of the more interesting developments in the treatment of low-grade 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. 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 recent series, the rate of survival 5 years after successful surgery has been greater than 90 percent (Pencalet et al). The outcome is less assured when the tumor also involves the brainstem and cannot be safely resected.

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 5,300 cGy was given postoperatively (Shaw et al). This, of course, is quite in contrast to the figures for glioblastoma.

In younger patients, particularly if the neurologic examination is normal or nearly so, radiation can be delayed and the course of the tumor 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 neurologic signs then presses one to turn to radiation or further surgery. Repeated operations prolong life in some patients. Although chemotherapy has as yet no established 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, as described later.

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.

Gliomatosis Cerebri

In this variant of high-grade glioma there is a diffuse infiltration of neoplastic glial cells, involving much of one or both cerebral hemispheres with sparing of neuronal elements but without a discrete tumor mass. 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, though the genetic and molecular alterations found in high-grade gliomas, as described earlier, are seen in some cases of gliomatosis cerebri as well.

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.

CT and MRI reveal small ventricles and one or more large confluent areas of signal change (Fig. 31-5). 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.

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.

Oligodendroglioma

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 pluripotential.

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.

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 malignant type with degeneration, evidenced by greater cellularity and by numerous and abnormal mitoses; necrosis may occur in small regions of the tumor in about one-third of cases. In the oligoastrocytomas, either cell type may be anaplastic.

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).

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. 31-6). 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.

In recent years, 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.

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, 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.

The identification by Cairncross and others of genetic markers has been of great interest. For example, of 50 patients who had loss of regions on 1p, median survival was over 10 years. These findings have been variably adopted into general clinical practice and it is likely that refinements in this approach will be forthcoming (see Louis et al [2007] and Reifenberger and Louis for discussion). Mutations in IDH1 also appear to confer survival benefit. 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 "Ependymoma and Papilloma of the Fourth Ventricle" Further on)

This tumor proves to be more complex and variable than other gliomas. Correctly diagnosed by Virchow as early as 1863, its origin 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. Approximately 6 percent of all intracranial gliomas are ependymomas, the percentage being slightly higher in children (8 percent). 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.

There is also a myxopapillomatous type of ependymoma, localized exclusively in the filum terminale of the spinal cord as discussed further on in the chapter. 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.

Ependymomas are derived from ependymal cells, i.e., 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, called epithelial, 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 and also Fig. 31-12).

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.

The symptomatology depends on the location of the neoplasm. The clinical manifestations of fourth ventricular tumors are described further on in this chapter; 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.

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.

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.

Meningioma (See Also "Meningioma of the Sphenoid Ridge" Further on)

This is a tumor, first illustrated by Matthew Bailie in his Morbid Anatomy (1787) and first identified properly by Bright, in 1831, originating 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).

Meningiomas represent approximately 15 percent 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), however due to some inconclusive data, and mainly social pressure, the International Agency for Research on Cancer has classified radiofrequency electromagnetic fields as "possibly carcinogenic." 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.

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. 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. The implications of these findings are not yet clear, but 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 origin of meningiomas is still not settled. According to Rubinstein, they may arise from dural fibroblasts, but it was the opinion of our colleague 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.

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.

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.

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.

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. 31-7 and 31-8), 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 isointense or slightly hyperintense; 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.

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; i.e., 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.

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.

Primary Central Nervous System Lymphoma

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 preponderance of men, with the peak incidence in the fifth through seventh decades of life, or in the third and fourth decades in patients with AIDS.

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 reticulum and "microgliacytes" are secondary interstitial reactions.

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."

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.

The pia and arachnoid may be infiltrated, and a purely meningeal form of B-cell lymphoma that involves peripheral and cranial nerves is also known. Most such cases of what has been termed neurolymphomatosis present with painful, predominantly motor polyradiculopathies. 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.

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.

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.

The finding on CT and MRI of one or several dense (hypercellular), homogeneous, enhancing, infiltrating, nonnecrotic, nonhemorrhagic, periventricular masses is characteristic (Fig. 31-9). However, rim enhancement also occurs, and any part of the brain may be involved. The radiologic appearance in the immunosuppressed patient is less predictable and may be difficult to distinguish from that of toxoplasmosis or another process with which lymphoma may coexist.

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. Lymphocytic and mononuclear pleocytosis of CSF is more frequent than with gliomas and metastatic tumors. The immunohistochemical demonstration in CSF of monoclonal lymphocytes or an elevated beta microglobulin points to leptomeningeal spread of the tumor (Li et al), but frequently the diagnosis is not possible from CSF cytologic examination.

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) or Sjögren syndrome.

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. 32). Reduction in the size of the lesion with antimicrobial drugs makes biopsy unnecessary.

Treatment

Because the tumors are deep and often multicentric, surgical resection is ineffective except in rare instances. 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. Until recently, the median survival of patients treated in this way has been 10 to 18 months and less in those with AIDS and in individuals who are otherwise immunocompromised. In immunocompetent patients, the addition of intrathecal methotrexate and intravenous cytosine arabinoside has increased median survival to more than 3 years (DeAngelis), and apparent cure is not unknown. However, this combined treatment is associated with a high risk of a leukoencephalopathy (see further on and Fig. 31-25) and causes considerable systemic side effects.

Glass and colleagues (1994) recommended a treatment regimen consisting of several cycles of intravenous methotrexate (3.5 g/m2) and citrovorum, administered at 2- to 3-week intervals and at times continued indefinitely if the treatment is tolerated. More recently, methotrexate plus either cytarabine or a combination of rituximab and temozolomide has been favored. Cranial irradiation is not typically part of the initial treatment. 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.

Intracranial Metastatic Carcinoma

These are far more common than are primary brain tumors. Among secondary intracranial tumors, only metastatic carcinoma occurs with high frequency. 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 a number of other cellular events participate in the implantation of what is essentially a neoplastic embolus.

Autopsy studies disclose intracranial metastases in approximately 25 percent of patients who die of cancer (Posner, 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. Cancers of the pelvis and colon are exceptional in this respect, having a somewhat higher tendency than this to spread to the posterior fossa. 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 (meningeal carcinomatosis). As common as intracranial metastases are, metastases to the vertebral column, which eventually cause compression of the spinal cord and nerve roots. This separate problem is discussed in Chap. 44. Metastatic deposits in 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 further on).

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 radionuclide bone and CT scans and most are evident in plain films. 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.

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 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.

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. 31-10).

Metastases from melanoma and chorioepithelioma are often hemorrhagic, but some from the lung, thyroid, and kidney exhibit this characteristic as well. 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.

The usual clinical picture of metastatic carcinoma of the brain is much like that of glioma. Seizures, headache, focal weakness, mental and behavioral abnormalities, ataxia, aphasia, and signs of increased intracranial pressure—all inexorably progressive over a few weeks or months—are the common clinical manifestations. 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.

The onset of symptoms from brain metastases is infrequently 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.

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 and without contrast, will detect practically all sizable (1 cm) metastases though MRI is 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.

Solitary metastatic disease must be distinguished from a primary tumor of the brain and from infective abscess. Multiple brain metastases must not be confused with the neurologic syndromes that sometimes accompany carcinoma but are not caused by the invasion or compression of the nervous system by tumor. The latter, referred to as paraneoplastic disorders, 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)."

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.

Treatment

The treatment of secondary (metastatic) tumors of the nervous system is undergoing a change. Current programs utilize various combinations of corticosteroids, brain irradiation, surgical intervention, and chemotherapy. 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 also temporarily benefit from the use of whole-brain irradiation, usually administered over a 2-week period, in 10 doses of 300 cGy each. High-dose focused radiotherapy is a suitable alternative for single or several cerebral metastases.

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 greater numbers.

The issue of prophylactic radiation of the entire cranium in the case of certain tumors is more controversial. The best current information is from a trial by Slotman and colleagues and an older one by Aupérin and coworkers in patients with chemotherapy-responsive small cell lung cancer. Prophylactic radiation prolonged survival by 1.5 months and reduced the later emergence of metastasis to the brain.

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, sometimes repeatedly.

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.

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. 16.

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. Patients with bone metastases tend to live longer than those with brain and meningeal metastases.

Carcinomatous Meningitis

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.

Headache and backache, often 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 (always 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.

The diagnosis can be established in most cases by identifying tumor cells in the CSF using cytology and flow cytometry techniques. 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 may also be altered in some cases of intracranial infection and parenchymal metastases (Kaplan et al). In a few of the cases of meningeal carcinomatosis, there are also parenchymal brain metastases.

Also known is a rare primary malignant melanoma of the meninges that acts in a similar way to carcinomatous meningitis 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 Carcinomatous Meningitis

This consists of radiation therapy to the symptomatic areas (cranium, posterior fossa, or spine) followed in selected cases by the intraventricular administration of methotrexate, but these measures rarely stabilize neurologic symptoms for more than a few weeks. The methotrexate is administered into the lateral ventricle via an Ommaya reservoir (12 mg diluted in preservative-free saline) or into the lumbar subarachnoid space through a lumbar puncture needle (12 to 15 mg). Several regimens have been devised, including daily instillation for 3 to 4 days followed by radiation, or methotrexate doses on days 1, 4, 8, 11, and 15. Involvement of the cranial nerves or an encephalopathy 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.

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. An encephalopathy caused by widespread tumor infiltration is a highly concerning and usually preterminal sign. The leukoencephalopathy that follows the combined use of intrathecal methotrexate and radiation therapy is described later. 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 most poorly.

Involvement of the Nervous System in Leukemia

Almost one-third of all leukemic patients 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 far more frequent in children than in adults. The highest incidence is in children with acute lymphocytic (lymphoblastic) leukemia who relapse after treatment with combination chemotherapy (60 to 70 percent at time of death). The clinical and CSF picture of meningeal leukemia is much the same as that of meningeal carcinomatosis discussed 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.

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.

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 necrotizing leukoencephalopathy within several days to months after the last administration of methotrexate and several months after completion of radiotherapy (Robain et al). The leukoencephalopathy occurs most frequently and is most severe when all three modalities of treatment, i.e., cranial irradiation and intrathecal and intravenous methotrexate, are used. The initial symptoms—consisting of apathy, drowsiness, depression of consciousness, and behavioral disorders—evolve over a few weeks to include cerebellar ataxia, spasticity, pseudobulbar palsy, extrapyramidal motor abnormalities, and akinetic mutism. Large hypodense areas of varying size appear on CT but—unlike the case with tumor metastases—there is no contrast enhancement. On MRI these lesions appear T2 hyperintense, but compared with pure radiation necrosis (see further on), they have poorly demarcated borders and like on CT, do not enhance. In some patients the condition stabilizes or improves, with corresponding radiographic resolution of the lesions. More often the patient is left with severe persistent sequelae; in most, death occurs within several weeks or months of onset but a few survive for years. Radiation injury seems to be the most important factor, coupled with the age of the patient (most are younger than 5 years old). In an attempt to reduce the 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

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 a tissue diagnosis is lacking, 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.

Much more common is meningeal dissemination of non-Hodgkin lymphoma (the earlier mentioned neurolymphomatosis), the clinical and CSF pictures being 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.

Intravascular Lymphoma and Related Disorders (Malignant Angioendotheliomatosis, Angiotropic or Angioblastic Lymphoma, Lymphomatoid Granulomatosis, Castleman Disease)

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 term, lymphomatoid granulomatosis (also known as Castleman disease), is not equivalent to the more recently elucidated process of intravascular lymphoma; it is more accurate to consider the former a prelymphomatous process. 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, but others have noted this transformation in a considerably higher number. The genomic sequences of EBV, HHV-6, or HHV-8 have been found in most of these lesions.

The angioblastic or 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) or grow intravascularly and cause occlusion of small and moderate-sized vessels, hence the several alternative designations for the same process. 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 the brain and spinal cord there are lesions of various sizes that represent the combined effects of occlusion of small vessels and concentric infiltration of the adjacent tissue by neoplastic cells. 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.

Although the lymphoid origin of the intravascular anaplastic cells is clear, not all are T cells as was at one time believed; an equal number are B cells. As in some cases of primary CNS lymphoma, portions of the genome of EBV have been isolated from the malignant B cells in a few cases. It has been proposed that the disorder in some cases represents an EBV-induced proliferation of B cells with a prominent inflammatory T-cell reaction (Guinee et al).

Because of the inconsistent location and size of the nervous system lesions there is no uniform 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 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.

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 only through a biopsy of radiographically involved lung or nervous tissue that includes tissue with numerous intrinsic blood vessels. A helpful diagnostic 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. 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 not found. The sedimentation rate and serum lactate dehydrogenase (LDH) are said to be elevated in most patients, but this has not been consistently so in our experience.

Similar to demyelinating and lymphomatous lesions, these abnormalities may recede temporarily in response to treatment with corticosteroids and there is corresponding clinical improvement. 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 Behçet disease, but intravascular lymphoma is more rapidly progressive than most of these conditions.

Sarcomas of the Brain

These are malignant tumors 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.

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 in this group (see below). Occasionally one or more 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 of which we are aware, 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 two intracranial lesions that simulated meningiomas and two others that arose in the high cervical spinal cord and caused subacute quadriparesis initially misdiagnosed as a polyneuropathy.

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.

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 Rarer Related Tumors)

Upon first presentation, a number of patients show the characteristic symptoms and signs of increased intracranial pressure: 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. Most of these symptoms and the increased ICP are the result of hydrocephalus.

The diagnostic problem is resolved by CT or MRI, which should be obtained in all patients with symptoms of increased intracranial pressure with or without focal signs. In addition to the tumors listed in the heading above, other tumors that may present in this way are central neurocytoma, craniopharyngioma, and a high spinal cord 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).

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) that have been prevented from maturing to their normal growth-arrested state. For this reason, newer classifications include it among the primitive neuroectodermal tumors (PNETs).

The tumor may differentiate uni- or pluripotentially, varying from case to case, and accounting for the recognized histologic variants, ranging from the undifferentiated medulloblastoma 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 the distal part of chromosome 17 distal to the p53 region. Schmidek has 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 ligand, and in Turcot syndrome, as a consequence of mutations in DNA repair genes (Louis et al). Gene expression profiling has given preliminary 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 implicated the JC virus, the same agent that causes progressive multifocal leukoencephalopathy (Chap. 33). Genomic sequences from this virus have been found in 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.

The majority of the 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 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.

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.

The radiologic appearance is also distinctive: high signal intensity on both T1- 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. 31-11). 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.

Treatment

Maximal resection of the tumor is 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.

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. Rutkowski and colleagues have reported some promising results, especially in those who had gross total tumor resection, but a large number nonetheless acquired a leukoencephalopathy that 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, and more so those with metastases, have a much poorer prognosis. Any of the features of brainstem invasion, spinal subarachnoid metastases, incomplete removal, 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 in medulloblastoma cells had a marked effect in one adult patient (Rudin et al).

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).

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.

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.

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 and Papilloma of the Fourth Ventricle

Ependymomas, as pointed out earlier in this chapter, arise from the lining cells in the walls of the ventricles. Approximately 70 percent of them originate in the fourth ventricle, according to Fokes and Earle (Fig. 31-12). Postmortem, some of these tumors, if small, are found protruding into the fourth ventricle, never having produced local symptoms. Whereas the supratentorial ependymoma occurs at all ages, fourth ventricular ependymomas appear mostly in childhood. In the large series of Fokes and Earle (83 cases), 33 developed in the first decade of life, 6 in the second decade, and 44 after the age of 20 years. Males have been affected almost twice as often as females.

Cerebral ependymomas usually arise from the floor of the fourth ventricle and extend through the foramina of Luschka and Magendie. They may later invade the medulla. These tumors produce a clinical syndrome much like that of the medulloblastoma except for their more protracted course and lack of early cerebellar signs. The histologic features of this tumor were described earlier in this chapter. The degree of anaplastic change varies and has prognostic significance. The most anaplastic form is the ependymoblastoma, a highly aggressive tumor that falls within the spectrum of primitive neuroectodermal tumors (see later).

Symptoms may be present for 1 or 2 years before diagnosis and operation. About two-thirds of the patients come to notice because of increased intracranial pressure; in the remainder, vomiting, difficulty in swallowing, paresthesia of the extremities, abdominal pain, vertigo, and neck flexion or head tilt are prominent manifestations. Some patients with impending cerebellar–tonsillar herniation are disinclined to sit and have vertical downbeating nystagmus. Surgical removal offers the only hope of survival. The addition of radiation therapy and sometimes ventriculoperitoneal shunting of CSF may prolong life. Myxopapillary ependymomas of the spinal cord and filum are discussed with the spinal cord tumors.

Papillomas of the choroid plexus are about one-fifth as frequent as ependymomas. They arise mainly in the lateral and fourth ventricles, occasionally in the third. Two authoritative studies (Laurence et al; Matson and Crofton) give the ratios of lateral/third/fourth ventricular locations as 50:10:40. The tumor, which takes the form of a giant choroid plexus, has as its cellular element the cuboidal epithelium of the plexus, which is closely related embryologically to the ependyma. An oncogene T (tumor) antigen of the SV40 virus is possibly involved in tumor induction (see Schmidek). Essentially, these are tumors of childhood. Fully 50 percent cause symptoms in the first year of life and 75 percent in the first decade. In the younger patient, hydrocephalus is usually the presenting syndrome, sometimes aggravated acutely by hemorrhage; there may be papilledema, an unusual finding in a hydrocephalic infant with enlarging head. Headaches, lethargy, stupor, spastic weakness of the legs, unsteadiness of gait, and diplopia are more frequent in the older child. Tumors that arise from the choroid plexus and project into the lateral recess of the fourth ventricle may present with a syndrome of the cerebellopontine angle (see further on). One consequence of the tumor (rather uncertain or inconsistent) may be increased CSF formation, which contributes to the hydrocephalus. Some of the tumors acquire more malignant attributes (mitoses, atypia of nuclei) and invade surrounding brain. They have the appearance of a carcinoma and may be mistaken for an epithelial metastasis from an extracranial site.

Treatment by surgical excision is usually curative, but palliative ventricular shunting may be needed first if the patient's condition does not permit surgery. The prognosis of the rare choroid plexus carcinomas is poor.

Primitive Neuroectodermal Tumor

This term was introduced by Hart and Earle in 1973 to describe tumors that have the histologic features of medulloblastoma but occur supratentorially. Various poorly differentiated or embryonal tumors of infancy and childhood were in the past included in this group: medulloblastoma, neuroblastoma, retinoblastoma, ependymoblastoma, and pineoblastoma (described further on). Subsequent authors have broadened the category of PNETs to include all CNS neoplasms of neuroectodermal origin. With the advent of immunohistochemical techniques, many of these poorly differentiated neoplasms of infancy came to be recognized as small cell gliomas (Friede et al); others, after ultrastructural study, could be classified as other types of primitive neoplasms. To some pathologists, the term primitive neuroectodermal tumors has appeal but has added little to our understanding of their undifferentiated embryonal origin. In practical terms, the prognosis and treatment of all these tumors are much the same, regardless of what they are called (see Duffner et al). Certain patterns of gene expression are used to distinguish this group of tumors from histologically similar medulloblastomas.

Hemangioblastoma of the Cerebellum

This tumor is referred to most often in connection with von Hippel-Lindau disease. Dizziness, ataxia of gait or of the limbs on one side, symptoms and signs of increased ICP from compression of the fourth ventricle, and in some instances an associated retinal angioma or hepatic and pancreatic cysts (disclosed by CT or MRI) constitute the syndrome. There is a tendency later for the development of malignant renal or adrenal tumors. Many patients have polycythemia as a result of elaboration of an erythropoietic factor by the tumor.

The age of onset is usually between 15 and 50 years. Blacks, whites, and Asians are equally affected. Dominant inheritance of von Hippel-Lindau disease is well known. Seizinger and coworkers, in cases associated with renal cell carcinoma and pheochromocytoma, localized a defect in a tumor suppressor gene (termed VHL; see Chap. 38).

The diagnosis can be deduced from the appearance on CT or MRI of a cerebellar cyst containing an enhancing nodular lesion on its wall. Often the associated retinal hemangioma will be disclosed by the same imaging procedure. The angiographic picture is also characteristic: a cluster of small vessels forming a mass 1.0 to 2.0 cm in diameter (Fig. 31-13). Craniotomy with opening of the cerebellar cyst and excision of the mural hemangioblastomatous nodule is usually curative, but there is a high rate of recurrence if the entire tumor, including the nodule, is not completely removed. In the series of Boughey and colleagues, the lesion was successfully excised in 80 percent of patients; 15 percent of patients, who had only partial resection of an isolated cerebellar lesion, developed recurrent tumors. More recently, several groups have used endovascular embolization of the vascular nodule prior to surgery, but it is not clear if this reduces the incidence of recurrence. Treatment with focused radiation is also being undertaken, particularly for multifocal or surgically inaccessible lesions, and several modern case series using either stereotactic radiosurgery, or external or proton beam radiation indicate results that may be comparable to conventional treatment.

Hemangioblastomas of the spinal cord are frequently associated with a syringomyelic lesion (greater than 70 percent of cases); such lesions may be multiple and are located mainly in the posterior columns. A retinal hemangioblastoma may be the initial finding and leads to blindness if not treated by laser. New lesions continue to be formed over a period of years while the patient is under observation. The children of a parent with a hemangioblastoma of the cerebellum should be examined regularly for an ocular lesion and renal cell carcinoma.

Pineal Tumors

There has been much uncertainty as to the proper classification of pineal tumors. Originally they were all thought to be composed of pineal cells; hence they were classified as true pinealomas, a term suggested by Krabbe. Globus and Silbert believed that these originated from embryonic pineal cells but Russell later pointed out that some tumors in the pineal region are really atypical teratomas resembling the seminoma of the testicle. Four types of pineal tumors are now recognized: germinoma, nongerminatous germ cell tumors, pinealoma (pineocytoma, atypical pineocytoma, and pineoblastoma), and a glioma originating in astroglial cells of the pineal body. Some would include teratomas in this group.

The germinoma is a firm, discrete mass that usually reaches 3 to 4 cm in greatest diameter. It compresses the superior colliculi and sometimes the superior surface of the cerebellum and narrows the aqueduct of Sylvius. Often it extends anteriorly into the third ventricle and may then compress the hypothalamus. A germinoma may also arise in the suprasellar area. Microscopically, these tumors are composed of large, spherical epithelial cells separated by a network of reticular connective tissue and containing many lymphocytes.

Of the four groups of pineal tumors, approximately 50 percent are germinomas. Pinealomas, pineoblastomas, and gliomas are infrequent. Children, adolescents, and young adults—males more than females—are affected. Only rarely does one see a patient with a pineal tumor that has developed after the thirtieth year of life.

The pineocytoma, atypical pineocytoma, and pineoblastoma reproduce the normal structure of the pineal gland. These tumors enlarge the gland, are locally invasive, and may extend into the third ventricle and seed along the neuraxis. Cytologically, the pineocytoma is a moderately cellular tumor with none of the histologic attributes of anaplasia. The tumor cells tend to form circular arrangements, so-called pineocytomatous rosettes. Pinealocytes may be impregnated by silver carbonate methods, and some contain the retinal S antigen of photoreceptor cells. Pineoblastomas are highly cellular and composed of small, undifferentiated cells bearing some resemblance to medulloblasts. The teratoma and dermoid and epidermoid cysts of the pineal body have no special features—some are quite benign. The gliomas have the usual morphologic characteristics of an astrocytoma of varying degrees of malignancy. In some cases, the clinical syndrome of the several types of pineal tumors consists solely of symptoms and signs of increased intracranial pressure. Beyond this, the most characteristic localizing signs are an inability to look upward and slightly dilated pupils that react on accommodation but not to light (Parinaud syndrome). Sometimes ataxia of the limbs, choreic movements, or spastic weakness appears in the later stages of the illness. It is uncertain whether the ocular and motor signs are caused by neoplastic compression of the brachia conjunctivae and other tegmental structures of the upper midbrain or to hydrocephalus (dilatation of the posterior part of the third ventricle). Probably both mechanisms are operative. Precocious puberty occurs in males who harbor a germinoma. Although the pineal gland is the source of melatonin, sleep is not affected to an important degree in patients with these tumors, as discussed in "The Pineal Gland and Melatonin" in Chap. 27. Measurement of CSF or serum melatonin is useful mainly in the detection of tumor recurrence after surgical extirpation. In patients with a germ cell tumor, the CSF or serum may show elevations of β-human choriogonadotropin or alpha-fetoprotein. The diagnosis is made by neuroimaging (Fig. 31-14). The CSF may contain tumor cells and lymphocytes but may also be entirely normal.

Treatment

These lesions were formerly judged to be inoperable. However, the use of the operating microscope now makes it possible to excise them by a supracerebellar or transtentorial approach. Operation for purposes of excision and histologic diagnosis is advised because each type of pineal tumor must be managed differently. Moreover, one may occasionally find an arachnoidal cyst that needs only excision. The germ cell tumors should be removed insofar as possible and the ventricular region radiated for germinomas, and the whole neuraxis is treated in the case of nongerminomatous lesions. The use of chemotherapy in addition to or instead of cranial irradiation is still being evaluated. Several of our patients have survived more than 5 years after the removal of a pineal glioma.

Neuroepithelial Tumors (DNET), Germinomas, Gangliocytomas, Mixed Neuronal-Glial Tumors, and Lhermitte-Duclos Disease

Malignant germ cell tumors occurring in locations other than the pineal body are usually found in the suprasellar space and rarely in the roof of the third. Germinoma is the most common of this rare group of neoplasms, which also includes choriocarcinoma, embryonal cell carcinoma, endodermal sinus tumors, and malignant teratomas. Certain biochemical markers of these tumors are of interest and of clinical utility, because they may be detected in samples of the blood and CSF. The beta subunit of human chorionic gonadotropin (hCG) is elaborated by choriocarcinoma and alpha-fetoprotein, and by endodermal sinus tumors and immature teratomas. Typical germinomas have shown little elevation of either. Most often these markers indicate the presence of complex mixed germ cell tumors.

Gangliogliomas and mixed neuronal–glial tumors are special tumor types, more frequent in the young and of variable but usually low-grade malignancy. They are composed both of differentiated glial cells, usually astrocytes, and of neurons in various degrees of differentiation. The latter, which may resemble glial cells, can be identified by Nissl stains, silver stains, and immunochemical reactions for cytoskeletal proteins. Inflammation is common in the parenchyma and adjacent to these tumors; this has led to the erroneous diagnosis of a nonneoplastic inflammatory condition if only limited biopsy samples are taken.

Some of these developmental tumors are difficult to separate from hamartomas or from the tubers of tuberous sclerosis. In the case of hamartomas, it may be difficult to determine if the tumor or the associated developmental abnormality is the cause of seizures. Some of these tumors take the form of large, slowly growing cystic lesions.

The best characterized, albeit rare, type in this group is the gangliocytoma, a tumor that occurs in the adrenal gland, retroperitoneal and thoracic sympathetic chain, internal auditory canal, and in the spinal cord. One form is the dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). This is a slowly evolving lesion that forms a mass in the cerebellum; it is composed of granule, Purkinje, and glia cells. Reproduced therein, in a disorganized fashion, is the architecture of the cerebellum with no clear plane from normally structured cerebellar tissue. The importance of distinguishing this disease from other cerebellar tumors is its lack of growth potential and favorable prognosis. It should, however, be excised if symptomatic. The appearance on imaging is highly characteristic; a cerebellar hemisphere is occupied with an indistinct mass of "tiger stripe" appearance as a result of alternating layers of dysmorphic cerebellar cells (Fig. 31-15). Interest in this entity derives from its association with a germ line mutation in the PTEN gene that relates the disease to other gangliocytomas and to Cowden syndrome of multiple skin hamartomas and cancers of the gynecologic, breast, and thyroid glands (and which may include Lhermitte-Duclos as a component). Mice with the PTEN gene knocked-out have abnormal synaptic structure and dysplasia of the cerebellar granule cells.

Other forms of gangliogliomas include the desmoplastic infantile ganglioglioma, some of the xanthoastrocytomas, and the dysembryoplastic neuroepithelioma tumor (DNET).

This last of these tumors, DNET, is worthy of comment as it often causes seizures that may be difficult to control in children. We have encountered them mostly in young adults after a single seizure or as an incidental finding on MRI. Although the tumors may be located in any part of the brain, there is a proclivity for the superficial (juxtacortical or intracortical) lateral or medial temporal lobe. The radiologic appearance is usually of a nodule or small cyst, or more specific to this entity, a cluster of several adjacent small cystic lesions, generally not enhancing and hyperintense on T2-weighted MRI (Fig. 31-16). The lesion is very slow growing and, if appropriately situated, may remodel the bone of the orbital roof or calvarium. The tumors originate from dysplastic cells in the germinal matrix that become arrested during migration toward the cortex; they are often associated with an adjacent region of cortical heterotopia. The histologic appearance varies but has as its main element a collection of neuroepithelial cells and clusters of oligodendrocytes with multinodular architecture that create mucinous cysts in some cases. When the lesion is single and has a nonspecific radiologic appearance, a biopsy or resection is required to differentiate it from a low-grade glioma or oligodendroglioma. Biopsy alone may be misleading in showing only the adjacent inflammation, at times prominent enough to appear almost granulomatous. Resection is curative and often eliminates the seizures but it is not clear what the best course of action is for asymptomatic lesions.

Another tumor that may be considered in this group is the subependymal giant cell astrocytoma that is found in up to 20 percent of patients with tuberous sclerosis. These are very slowly growing tumors that arise mostly near the foramen of Munro. Repeated resection is sometimes required to treat hydrocephalus. Krueger and colleagues have reported that everolimus, an inhibitor of the mTOR complex, which is disrupted in this phakomatosis, reduces the size of the tumor and ameliorates seizures. The remaining tumors mentioned earlier are rare and affect children mostly; therefore, they are not discussed further here. Good descriptions are to be found in the monographs of Russell, of Rubinstein (1972), of Levine (both articles from 1993), and of Schmidek, and in the article by Zentner and coworkers.

Colloid (Paraphysial) Cyst and Other Tumors of the Third Ventricle

The most important of these is the colloid tumor, which is derived from ependymal cells of a vestigial third ventricular structure known as the paraphysis. The cysts formed in this structure are always situated in the anterior portion of the third ventricle between the interventricular foramina and are attached to the roof of the ventricle (Fig. 31-17). They vary from 1 to 4 cm in diameter, are oval or round with a smooth external surface, and are filled with a gelatinous material containing a variety of mucopolysaccharides. The wall is composed of a layer of epithelial cells, some ciliated, surrounded by a capsule of fibrous connective tissue. Although congenital, the cysts practically never declare themselves clinically until adult life, when they block CSF outflow through the foramen of Monro and produce an obstructive hydrocephalus.

Suspicion of this tumor is occasioned by intermittent, severe bifrontal–bioccipital headaches, sometimes modified by posture ("ball valve" obstruction) or with crises of headache and obtundation, incontinence, unsteadiness of gait, bilateral paresthesias, dim vision, and weakness of the legs, with sudden falls but no loss of consciousness ("drop attacks"). Stooping may result in an increase or onset of headache and loss of balance. However, this intermittent obstructive syndrome has been infrequent in our experience. More often the patient has no headache and presents with the symptoms comparable to those of normal-pressure hydrocephalus or, as frequently, the tumor is found incidentally on CT or MRI. On CT and MRI, the lesion density depends on the hydration state of the mucopolysaccharides. These lesions do not restrict diffusion or enhance with contrast. Subtle behavioral changes are common and a few patients, as emphasized by Lobosky and colleagues, experience mild confusion and changes in personality that may reach the extreme of psychotic behavior. In our experience, chronic headache or gait difficulty is usually present by that time.

The treatment for many years has been surgical excision, which always carries some risk, but satisfactory results have also been obtained by ventriculoperitoneal shunting of the CSF, leaving the benign growth untouched. Decompression of the cyst by aspiration under stereotactic control has also become an increasingly popular procedure.

Other tumors found in the third ventricle and giving rise mainly to obstructive symptoms are craniopharyngiomas (see later), papillomas of the choroid plexus, and ependymomas (discussed earlier).

Arachnoid Cyst

This CSF-filled lesion, which is probably congenital, presents clinically at all ages but may become evident only in adult life, when it gives rise to symptoms of increased intracranial pressure and sometimes to focal cerebral or cerebellar signs, simulating intracranial neoplasm. Seizures may occur but are not characteristic. In infants and young children, macrocrania and extensive unilateral transillumination are characteristic features. Usually these cysts overlie the sylvian fissure or temporal pole; occasionally they are interhemispheric under the frontal lobes or lie in the pineal region or under the cerebellum. They may attain a large size, to the point of enlarging the middle cranial fossa and remodeling and elevating the lesser wing of the sphenoid, but they do not communicate with the ventricles. Rarely, one of these cysts may cover the entire surface of both cerebral hemispheres and create a so-called external hydrocephalus.

The cysts are readily recognized (often accidentally) on unenhanced CT or MRI, showing a circumscribed tissue defect filled with fluid that has the density of CSF (Gandy and Heier). If these cysts are completely asymptomatic, they should be left alone; if symptomatic, additional MRI studies are indicated, so as not to overlook a chronic subdural hematoma, which is often associated and may not be visualized on the unenhanced CT. Suprasellar arachnoid cysts are discussed further on, under "Empty Sella Syndrome."

The treatment of enlarging and symptomatic cysts is marsupialization or, less preferably, by shunting from the cyst to the subarachnoid space.

Skull Base and Other Regional Intracranial Tumor Syndromes (Vestibular Schwannoma, Other Tumors of the Cerebellopontine Angle, Craniopharyngioma, Pituitary, Meningioma of the Sphenoid Ridge and Olfactory Groove, Glioma of the Optic Nerve, Pontine Glioma, Chordoma Chondrosarcoma, Glomus Jugulare and Carotid Body Tumors, Nasopharyngeal Carcinoma)

In this group of tumors, symptoms and signs of general cerebral impairment and increased pressure occur late or not at all. Instead, special syndromes referable to particular intracranial loci arise and progress slowly. One arrives at the correct diagnosis by localizing the lesion accurately from the neurologic findings and by reasoning that the etiology must be neoplastic because of an afebrile and steadily progressive nature. Investigation by CT, MRI, and other special studies will usually confirm the clinical impression.

The tumors that most often produce these unique intracranial syndromes are the ones listed above as well as a number of other erosive tumors at the base of the skull. The aforementioned medulloblastoma, hemangioblastoma, and ependymoma of the fourth ventricle may have a similar regional clinical signature.

Vestibular Schwannoma (Acoustic Neuroma)

This tumor was first described as a pathologic entity by Sandifort in 1777, diagnosed clinically by Oppenheim in 1890, and recognized as a surgically treatable disease in the early 1900s. Cushing's monograph (1917) was a milestone, and the papers of House and Hitselberger and of Ojemann and colleagues provide valuable descriptions of diagnostic tests and surgical treatment in the era before modern imaging.

Approximately 3,000 new cases of acoustic neuroma are diagnosed each year in the United States (incidence rate of 1 per 100,000 per year). The tumor occurs occasionally as part of von Recklinghausen neurofibromatosis, in which case it takes one of two forms. In classic von Recklinghausen disease (peripheral or type 1 neurofibromatosis), a schwannoma may sporadically involve the eighth nerve, usually in adult life, but it may involve any other cranial (particularly trigeminal) or spinal nerve root. Rarely, if ever, do bilateral acoustic neuromas occur in this form of the disease. However, bilateral acoustic neuromas are the hallmark of the genetically distinct neurofibromatosis type 2 (NF2), in which they practically always occur before the age of 21 and show a strong (autosomal dominant) heredity (Fig. 31-18). Schwannomas are distinguished from neurofibromas (composed of both Schwann cells and fibroblasts) found in peripheral nerves of type 1 von Recklinghausen disease. A small percentage of neurofibromas become malignant, a phenomenon that is highly unusual in schwannomas.

In this context, a rare form of familial schwannomatosis should be mentioned, characterized by multiple schwannomas without vestibular tumors, which maps genetically to chromosome 22 but is distinct from NF2. The primary gene defect in this familial schwannomatosis has not been defined (MacCollin et al), although mutations in the SMARCB1 gene on chromosome 22 locus have been identified in some patients.

The typical vestibular schwannoma in adults presents as a solitary tumor. Being a schwannoma, it originates in nerve. The examination of small tumors reveals that they practically always arise from the vestibular rather than the cochlear division of the eighth nerve, just within the internal auditory canal (Fig. 31-19). As the eighth nerve schwannoma grows, it extends into the posterior fossa to occupy the angle between the cerebellum and pons (cerebellopontine angle). In this lateral position, it is so situated as to compress the seventh, fifth, and less often the ninth and tenth cranial nerves, which are implicated in various combinations. Later it displaces and compresses the pons and lateral medulla and obstructs the CSF circulation; very rarely, it is a source of subarachnoid hemorrhage.

Certain biologic and clinical data assume clinical importance. The highest incidence is in the fifth and sixth decades of life, and the sexes are equally affected. Familial occurrence is a mark, usually, of von Recklinghausen disease. The earliest symptom reported by the 46 patients in the decades-old but instructive series of Ojemann and coworkers was loss of hearing (33 of 46 patients); headache (4 patients); disturbed sense of balance (3 patients); unsteadiness of gait (3 patients); and facial pain, tinnitus, and facial weakness, each in a single case. Some patients sought medical advice soon after the appearance of the initial symptom, some later, after other symptoms had occurred. One-third of the patients were troubled by vertigo associated with nausea, vomiting, and pressure in the ear. The vertiginous symptoms differed from those of Ménière disease in that discrete attacks separated by periods of normalcy were rare. The vertigo coincided more or less with hearing loss and tinnitus (most often a unilateral high-pitched ringing, sometimes a machinery-like roaring or hissing sound, like that of a steam kettle). Some of our patients ignored their deafness for many months or years; often the first indication of the tumor in such patients is a shift to the unaccustomed ear (usually right to left) in the use of the telephone. Others neglected these symptoms to a point where they presented with impaired mentation, imbalance, and sphincteric incontinence because of brainstem compression and secondary hydrocephalus.

The neurologic findings at the time of examination in the series mentioned above were as follows: eighth nerve involvement (auditory and vestibular; 45 of 46 patients), facial weakness including disturbance of taste (26 patients), sensory loss over the face (26 patients), gait abnormality (19 patients), and unilateral ataxia of the limbs (9 patients). Inequality of reflexes and eleventh- and twelfth-nerve palsies were present in only a few patients. Signs of increased intracranial pressure appear late and have been present in fewer than 25 percent of our patients. These findings are comparable to those reported by House and Hitselberger and by Harner and Laws. With the shift in recent years to fairly routine investigation of unilateral hearing loss by cerebral imaging, it is common to find these tumors at a far earlier stage, if as an incidental finding on cerebral imaging, well before the tumor becomes symptomatic.

The contrast-enhanced CT will detect practically all vestibular schwannomas that are larger than 2.0 cm in diameter and project further than 1.5 cm into the cerebellopontine angle. Much smaller intracanalicular tumors (i.e., restricted to within the internal acoustic canal) can be detected reliably by MRI with gadolinium (see Fig. 31-19). Specialized thin-slice MRI sequences such as steady-state free precession can accurately define anatomic relationships between the tumor and adjacent cranial nerves and vessels with high resolution.

Audiologic and vestibular evaluation includes the various tests described in Chap. 15, the brainstem auditory evoked response probably being the most sensitive to the presence of acoustic schwannoma. In combination, they permit localization of the deafness and vestibular disturbance to the cochlear and vestibular nerves rather than to their end organs. The CSF protein is raised in two-thirds of the patients (greater than 100 mg/dL in one-third); a clinically inevident acoustic schwannoma is one of the causes of an unexpectedly elevated CSF protein when a lumbar puncture is performed for other reasons.

Treatment

The preferred treatment in most symptomatic cases has been surgical excision. Neurosurgeons who have had a lot of experience with these tumors favor a microsurgical suboccipital transmeatal approach (Martuza and Ojemann). The facial nerve can usually be preserved by intraoperative monitoring of brainstem auditory responses and facial nerve electromyography (EMG); in experienced hands, hearing can be preserved in approximately one-third of patients with tumors smaller than 2.5 cm in diameter. If no attempt is to be made to save hearing, small tumors can be removed safely by the translabyrinthine approach.

An alternative to surgery is focused radiation, which controls the growth of many of the smaller tumors. In a large series of patients treated with radiosurgery, facial motor and sensory functions were preserved in 75 percent of cases and, after 28 months of observation, no new neurologic deficits were detected (Kondziolka et al). This approach is favored in older patients with few symptoms but is being adopted increasingly for others. The rates of hearing loss and facial numbness and weakness are comparable or lower than with surgery, but the follow-up period in most series is less than 5 years (Flickinger et al). Focused radiation with the gamma Knife or proton beam also appears to be preferable to surgery in cases of recurrent tumor. The antiangiogenic agent, bevacizumab, in preliminary reports has reduced the size of these tumors in patients with NF2 (Plotkin et al).

There is no consensus on the management of an incidentally identified tumors but it is reasonable to follow these with audiograms and serial imaging. Some sources suggest that half of lesion smaller than 2 cm in diameter will not progress, or do so slowly enough that hearing and balance are not impaired. However, lesions larger than this size are associated with more surgical complications and make sparing of hearing less likely.

Other Tumors of the Cerebellopontine Angle

Neurinoma or schwannoma of the trigeminal (gasserian) ganglion or neighboring cranial nerves and meningioma of the cerebellopontine angle may, in some instances, be indistinguishable from a vestibular schwannoma. Fifth cranial nerve tumors should always be considered if deafness, tinnitus, and lack of response to caloric stimulation ("dead labyrinth") are not the initial symptoms of a cerebellopontine angle syndrome. A true cholesteatoma (epidermoid cyst) is a relatively rare tumor that is most often located in the cerebellopontine angle where it may simulate an acoustic neuroma but usually causes more severe facial weakness. Spillage of the contents of the cyst may produce intense chemical meningitis. Other disorders that enter into the differential diagnosis are glomus jugulare tumor (see later), metastatic cancer, neoplastic meningitis (especially lymphomatous), syphilitic meningitis, arachnoid cyst, and epidural plasmacytoma of the petrous bone. All these disorders may produce a cerebellopontine angle syndrome consisting of imbalance and unilateral hearing loss, but they are more likely to cause multiple lower cranial neuropathies and their temporal course differs from that of vestibular schwannoma. Occasionally, a tumor that originates in the pons or in the fourth ventricle (ependymoma, astrocytoma, papilloma, medulloblastoma) or a nasopharyngeal carcinoma may present as a cerebellopontine angle syndrome.

Craniopharyngioma (Suprasellar Epidermoid Cyst, Rathke Pouch or Hypophyseal Duct Tumor, Adamantinoma)

This is a histologically benign epithelioid tumor, generally assumed to originate from cell rests (remnants of the Rathke pouch [or adenohypophyseal diverticulum]) at the junction of the infundibular stem and pituitary gland. By the time the tumor has attained a diameter of 3 to 4 cm, it is almost always cystic and partly calcified. Usually it lies above the sella turcica, compressing and elevating the optic chiasm and extending up into the third ventricle. Less often it is subdiaphragmatic, i.e., within the sella, where it compresses the pituitary body and erodes one part of the wall of the sella or a clinoid process; seldom it balloons the sella like a pituitary adenoma. Large tumors may obstruct the flow of CSF.

The tumor is oval, round, or lobulated and has a smooth surface. The wall of the cyst and the solid parts of the tumor consist of cords and whorls of epithelial cells (often with intercellular bridges and keratohyalin) separated by a loose network of stellate cells. If there are bridges between tumor cells, which have an epithelial origin, the tumor is classed as an adamantinoma. The cyst contains dark albuminous fluid, cholesterol crystals, and calcium deposits; the calcium can be seen in plain films or CT of the suprasellar region in 70 to 80 percent of cases. The sella beneath the tumor tends to be flattened and enlarged. The majority of the patients are children, but the tumor is not infrequent in adults, and we have encountered patients up to 60 years of age.

The presenting syndrome may be one of increased intracranial pressure, but more often it takes the form of a combined pituitary-hypothalamic-chiasmal derangement. The symptoms are often subtle and long standing. In children, visual loss and diabetes insipidus are the most frequent findings, followed in a few cases by adiposity, delayed physical and mental development, headaches, and vomiting. The visual disorder takes the form of dim vision, chiasmal field defects, optic atrophy, or papilledema, as emphasized long ago by Kennedy and Smith. In adults, waning libido, amenorrhea, slight spastic weakness of one or both legs, headache without papilledema, failing vision, and mental dullness and confusion are the usual manifestations. One of the most remarkable cases in our experience was a middle-aged nurse who became distractible and ineffective at work and was thought for many months to be simply depressed. Often it is observed that drowsiness, ocular palsies, diabetes insipidus, and disturbance of temperature regulation (indicating hypothalamic involvement) occur later. Spontaneous rupture of the cystic lesion can incite severe aseptic meningitis, at times with depressed glucose in the CSF, a syndrome similar to that caused by rupture of the earlier described cholesteatoma.

In the differential diagnosis of the several craniopharyngioma syndromes, a careful clinical analysis is often more informative than laboratory procedures. Among the latter, MRI is likely to give the most useful information. Often, because of the cholesterol content, the tumor gives an increased signal on T1-weighted images. Usually, the cyst itself is isointense, like CSF, but occasionally it may give a decreased T2 signal.

Treatment

Modern microsurgical techniques, reinforced by corticosteroid therapy before and after surgery and careful control of temperature and water balance postoperatively, permit successful excision of all or part of the tumor in the majority of cases. Although smaller tumors can be removed by a transsphenoidal approach, attempts at total removal require craniotomy and remain a challenge because of frequent adherence of the mass to surrounding structures (Fahlsbusch et al), as well as the potential for postoperative chemical meningitis from cyst contents. Partial removal practically ensures recurrence of the tumor, usually within 3 years, and the surgical risks of reoperation are considerable (10 percent mortality in large series). In 21 of our 35 patients, only partial removal was possible; of these, 8 died, most in the first postoperative year. Stereotactic aspiration is sometimes a useful palliative procedure, as are focused radiation therapy and ventricular shunting in patients with solid, nonresectable tumors. Endocrine replacement is necessary for an indefinite time. We have several times seen a syndrome of prolonged but reversible delirium after tumor resection.

Glomus Jugulare Tumor

This tumor is relatively rare but of interest to neurologists nonetheless. It is a purplish red, highly vascular tumor composed of large epithelioid cells, arranged in an alveolar pattern and possessing an abundant capillary network. The tumor is thought to be derived from minute clusters of nonchromaffin paraganglioma cells (glomus bodies) found mainly in the adventitia of the dome of the jugular bulb (glomus jugulare) immediately below the floor of the middle ear, as well as in multiple other sites in and around the temporal bone. These clusters of cells are part of the chemoreceptor system that also includes the carotid, vagal, ciliary, and aortic bodies.

The fully developed syndrome consists of partial deafness, facial palsy, dysphagia, and unilateral atrophy of the tongue combined with a vascular polyp in the external auditory meatus and a palpable mass below and anterior to the mastoid eminence, occasionally with a bruit that may be audible to the patient ("self-audible bruit"). Other neurologic manifestations are phrenic nerve palsy, numbness of the face, a Horner syndrome, cerebellar ataxia, and temporal lobe epilepsy. As with vestibular schwannoma, the availability of MRI has led to the earlier discovery of these tumors.

The jugular foramen is eroded and CSF protein may be elevated. Women are affected more than men, and the peak incidence is during middle adult life. The tumor grows slowly over a period of many years, sometimes 10 to 20 or more. Treatment in the past has consisted of radical mastoidectomy and removal of as much tumor as possible, followed by radiation. The combined intracranial and extracranial two-stage operation has resulted in the cure of many cases (Gardner et al). Embolization prior to resection is now also employed. A detailed account of this tumor can be found in the article by Kramer.

Carotid Body Tumor (Paraganglioma)

This is a generally benign but potentially malignant tumor originating in a small aggregate of paraganglioma cells of neuroectodermal type. The normal carotid body is small (4 mm in greatest diameter and 10 mg in weight) and is located at the bifurcation of the common carotid artery. The cells are of uniform size, have an abundant cytoplasm, are rich in substance P, and are sensitive to changes in PO2, Pco2, and pH (i.e., they are chemoreceptors, not to be confused with baroreceptors). The tumors that arise from these cells are identical in appearance to tumors of other chemoreceptor organs such as the glomus jugulare neoplasm described in the preceding section (paragangliomas). Interestingly, they are many times more frequent in individuals living at high altitudes.

The usual presentation is of a painless mass at the side of the neck below the angle of the jaw; thus it must be differentiated from the branchial cleft cyst, mixed tumor of the salivary gland, and carcinomas and aneurysms in this region. As the tumor grows (at an estimated rate of 2.0 cm in diameter every 5 years) it may implicate the sympathetic, glossopharyngeal, vagus, spinal accessory, and hypoglossal nerves (syndrome of the retroparotid space; see Chap. 47). Hearing loss, tinnitus, and vertigo are present in some cases. Tumors of the carotid body have been a source of transient ischemic attacks in 5 to 15 percent of the 600 or more reported cases. One of the most interesting presentations has been with sleep apnea, particularly with bilateral tumors (see later); respiratory depression as well as lability of blood pressure are common postoperative problems. Malignant transformation occurs in 5 percent of cases.

A similar paraganglioma of the vagus nerve has been reported; it occurs typically in the jugular or nodose ganglion but may arise anywhere along the course of the nerve. These tumors may also undergo malignant transformation in about 5 percent of cases, metastasize, or invade the base of the skull.

Carotid body tumor has been seen in combination with von Recklinghausen neurofibromatosis type 1 (NF1) and in von Hippel-Lindau disease. Familial cases are known, especially with bilateral carotid body tumors (about 5 percent of these tumors are bilateral). The treatment is surgical excision with or without prior intravascular embolization; radiation therapy has not been advised.

Pituitary Adenoma (See Also "Pituitary Insufficiency" in Chap. 27)

Tumors arising in the anterior pituitary are of considerable interest to neurologists because they often cause visual and other symptoms related to involvement of structures bordering upon the sella turcica, before an endocrine disorder becomes apparent. Pituitary tumors are age-linked; they become increasingly numerous with each decade. By the eightieth year, small adenomas are found in more than 20 percent of pituitary glands. In some cases, an apparent stimulus to adenoma formation is endocrine end-organ failure, as occurs, for example, with ovarian atrophy that induces a basophilic adenoma. Only a small proportion (6 to 8 percent) enlarge the sella, i.e., most are "microadenomas," as discussed below.

On the basis of conventional hematoxylin-eosin- staining methods, cells of the normal pituitary gland were for many years classified as chromophobe, acidophil, and basophil, these types being present in a ratio of 5:4:1. Adenomas of the pituitary are most often composed of chromophobe cells (4 to 20 times as common as acidophil cell adenomas); the incidence of basophil cell adenomas is uncertain. Histologic study is now based on immunoperoxidase-staining techniques that define the nature of the hormones within the pituitary cells—both of the normal gland and of pituitary adenomas. These methods have shown that either a chromophobe or an acidophil cell may produce prolactin, growth hormone (GH), and thyroid-stimulating hormone (TSH), whereas the basophil cells produce adrenocorticotropic hormone (ACTH), β-lipotropin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH).

The development of sensitive methods for the measurement of pituitary hormones in the serum has made possible the detection of adenomas at an early stage of their development and the designation of several types of pituitary adenomas on the basis of the endocrine disturbance. Hormonal tests for the detection of pituitary adenomas, preferably carried out in an endocrine clinic, are listed in Table 31-4. Between 60 and 70 percent of tumors in both men and women are prolactin secreting. About 10 to 15 percent secrete growth hormone, and a smaller number secrete ACTH. Tumors that secrete gonadotropins and TSH are quite rare. These tumors may be monohormonal or plurihormonal and approximately one-third are composed of nonfunctional (null) cells.

Pituitary tumors usually arise as discrete nodules in the anterior part of the gland (adenohypophysis). They are reddish gray, soft (almost gelatinous), and often partly cystic, with a rim of calcium in some instances. The adenomatous cells are arranged diffusely or in various patterns, with little stroma and few blood vessels; less frequently the architecture is sinusoidal or papillary in type. Variability of nuclear structure, hyperchromatism, cellular pleomorphism, and mitotic figures are interpreted as signs of malignancy, which is exceedingly rare. Tumors less than 1 cm in diameter are referred to as microadenomas and are at first confined to the sella. As the tumor grows, it first compresses the pituitary gland; then, as it extends upward and out of the sella, it compresses the optic chiasm; later, with continued growth, it may extend into the cavernous sinus, third ventricle, temporal lobes, or posterior fossa. Recognition of an adenoma when it is still confined to the sella is of considerable practical importance, since total removal of the tumor by transsphenoidal excision or some form of stereotactic radiosurgery is possible at this stage with prevention of further damage to normal glandular structure and the optic chiasm. Penetration of the diaphragm sellae by the tumor and invasion of the surrounding structures make treatment more difficult.

Pituitary adenomas come to medical attention because of endocrine or visual abnormalities. Headaches are reported by nearly half of patients with macroadenomas but are not clearly part of the syndrome. The visual disorder usually proves to be a complete or partial bitemporal hemianopia, which has developed gradually and may not be evident to the patient (see the description of the chiasmatic syndromes in "Neurologic Causes of Reduced Vision" in Chap. 13). Early on, the upper parts of the visual fields may be affected predominantly, since those fibers run along the inferior optic nerve and chiasm. A small number of patients will be almost blind in one eye and have a temporal hemianopia in the other. Bitemporal central hemianopic scotomata are a less-frequent finding. A postfixed (situated relatively posteriorly) chiasm may be compressed in such a way that there is an interruption of some of the nasal retinal fibers, which, as they decussate, project into the base of the opposite optic nerve (Wilbrand knee); the controversy regarding the validity of this projection in humans is mentioned in Chap. 13. This results in a central scotoma on one or both sides (junctional syndrome) in addition to the classic temporal field defect (see Fig. 13-2).

If the visual disorder is longstanding, the optic nerve heads are atrophic. In 5 to 10 percent of cases, the pituitary adenoma extends into the cavernous sinus, causing some combination of ocular motor palsies as well as potential compression of the cavernous segment of the internal carotid artery. Other neurologic abnormalities, rare to be sure, are seizures from indentation of the medial temporal lobe, CSF rhinorrhea from erosion of the sella, and diabetes insipidus, hypothermia, and somnolence from hypothalamic compression.

With regard to differential diagnosis, bitemporal hemianopia with a normal-size sella indicates that the causative lesion is probably a saccular aneurysm of the circle of Willis or a meningioma of the tuberculum sellae; multiple sclerosis may simulate this pattern and eventration of a greatly hydrocephalic third ventricle is an uncertain cause (see Chap. 13). The idiopathic syndrome of an "empty sella" also can cause bitemporal hemianopia and is discussed further on.

The major endocrine syndromes associated with pituitary adenomas are described briefly in the following pages. Their functional classification can be found in the monograph edited by Kovacs and Asa. A detailed discussion of the diagnosis and management of hormone-secreting pituitary adenomas is given in the reviews of Klibanski and Zervas and of Pappas and colleagues; recommended also is an article that details the neurologic features of pituitary tumors by Anderson and colleagues. Worthy of emphasis is the catastrophic syndrome of pituitary apoplexy discussed further on.

Amenorrhea-Galactorrhea Syndrome

As a rule, this syndrome becomes manifest during the childbearing years. The history usually discloses that menarche had occurred at the appropriate age; primary amenorrhea is rare. A common history is that the patient took birth control pills, only to find, when she stopped, that the menstrual cycle did not reestablish itself. On examination, there may be no abnormalities other than galactorrhea. Serum prolactin concentrations are increased (usually in excess of 100 ng/mL). In general, the longer the duration of amenorrhea and the higher the serum prolactin level, the larger the tumor (prolactinoma). The elevated prolactin levels distinguish this disorder from idiopathic galactorrhea, in which the serum prolactin concentration is normal.

Males with prolactin-secreting tumors rarely have galactorrhea and usually present with a larger tumor and complaints such as headache, impotence, and visual abnormalities. In normal persons, the serum prolactin rises markedly in response to the administration of chlorpromazine or thyrotropin-releasing hormone (TRH); patients with a prolactin-secreting tumor fail to show such a response. With large tumors that compress normal pituitary tissue, thyroid and adrenal function will also be impaired. It should be emphasized that large, nonfunctioning pituitary adenomas also cause modest hyperprolactinemia by distorting the pituitary stalk and reducing dopamine delivery to prolactin-producing cells.

Acromegaly

This disorder consists of acral growth and prognathism in combination with visceromegaly, headache, and several endocrine disorders (hypermetabolism, diabetes mellitus). The highly characteristic facial and bodily appearance, well known to all physicians, is caused by an overproduction of GH after puberty; prior to puberty, an oversecretion of GH leads to gigantism. In a small number of acromegalic patients, there is an excess secretion of both GH and prolactin, derived apparently from two distinct populations of tumor cells. The diagnosis of this disorder, which is often long delayed, is made on the basis of the characteristic clinical changes, the finding of elevated serum GH values (0.10 ng/mL), and the failure of the serum GH concentration to rise in response to the administration of glucose or TRH. The new growth hormone-receptor antagonist pegvisomant was introduced to reduce many of the manifestations of acromegaly (see the review by Melmed).

Cushing Disease

Described in 1932 by Cushing, this condition is only about one-fourth as frequent as acromegaly. A distinction is made between Cushing disease and Cushing syndrome, as indicated in Chap. 27. The former term is reserved for cases that are caused by the excessive secretion of pituitary ACTH, which, in turn, causes adrenal hyperplasia; the usual basis is a pituitary adenoma. Cushing syndrome refers to the effects of cortisol excess from any one of several sources—excessive administration of steroids (the most common cause), adenoma of the adrenal cortex, ACTH-producing bronchial carcinoma, and, very rarely, other carcinomas that produce ACTH. The clinical effects are the same in all of these disorders and include truncal obesity, hypertension, proximal muscle weakness, amenorrhea, hirsutism, abdominal striae, hyperglycemia, osteoporosis, and in some cases a characteristic mental disorder (see "Cushing Disease and Corticosteroid Psychoses" in Chap. 53).

Although Cushing originally referred to the disease as pituitary basophilism and attributed it to a basophil adenoma, the pathologic change may consist only of hyperplasia of basophilic cells or of a nonbasophilic microadenoma. Seldom is the sella turcica enlarged: Consequently, visual symptoms or signs as a result of involvement of the optic chiasm or nerves and extension to the cavernous sinus are rare. The diagnosis of Cushing disease is made by demonstrating increased concentration of plasma and urinary cortisol; these levels are not suppressed by the administration of relatively small doses of dexamethasone (0.5 mg qid), but they are suppressed by high doses (8 mg daily). A low level of ACTH and a high level of cortisol in the blood, increased free cortisol in the urine, and nonsuppression of adrenal function after administration of high doses of dexamethasone are evidence of an adrenal source of the Cushing syndrome—usually a tumor and less often a micronodular hyperplasia of the adrenal gland.

Diagnosis of Pituitary Adenoma

This is virtually certain when a chiasmal syndrome is combined with an endocrine syndrome of either hypopituitary or hyperpituitary type. Laboratory data that are confirmatory of an endocrine disorder, as described above, and sometimes a ballooned sella turcica on plain films of the skull are occasionally found. Patients who are suspected of having a pituitary adenoma should be examined by MRI with gadolinium; this procedure will visualize pituitary adenomas as small as 3 mm in diameter and show the relationship of the tumor to the optic chiasm (Fig. 31-20). This also provides the means of following the tumor's response to therapy. It should be kept in mind that pituitary tissue normally enhances on CT and MRI, revealing small tumors as relatively hypoenhancing nodules.

Tumors and lesions other than pituitary adenomas may sometimes expand the sella. Enlargement may be the result of an intrasellar craniopharyngioma, meningioma, carotid aneurysm, or cyst of the pituitary gland. Intrasellar epithelium-lined cysts are rare lesions. They originate from the apex of the Rathke pouch, which may persist as a cleft between the anterior and posterior lobes of the hypophysis. Rarer still are intrasellar cysts that have no epithelial lining and contain thick, dark brown fluid, the product of intermittent hemorrhages. Both types of intrasellar cysts may compress the pituitary gland and mimic the endocrine-suppressive effects of pituitary adenomas. Neoplasms originating in the nasopharynx or sinuses may invade the sella and pituitary gland, and sarcoid lesions at the base of the brain may do the same. Also, the pituitary gland and the infundibulum (and the chiasm) may be the site of metastases, most of them from the lung and breast (Morita et al); they give rise to diabetes insipidus, pituitary insufficiency, or orbital pain, and rarely may be the first indication of a systemic tumor.

Empty Sella Syndrome

More common than the aforementioned conditions is a nontumorous enlargement of the sella ("empty sella"). This results from a defect in the dural diaphragm, which may occur without obvious cause or with states of raised intracranial pressure, such as pseudotumor cerebri (see Chap. 30) or hydrocephalus, or may follow surgical excision of a pituitary adenoma or meningioma of the tuberculum sellae or pituitary apoplexy (see later). The arachnoid covering the diaphragm sellae will bulge downward through the dural defect, and the sella then enlarges gradually, presumably because of the pressure and pulsations of the CSF acting on its walls. In the process, the pituitary gland becomes flattened, sometimes to an extreme degree; however, the functions of the gland are usually unimpaired. Flattening of the pituitary gland precedes bony expansion of the sella in many cases. Erosion or dishiscence of the sellar floor does not occur and the appearance of these changes implicates another type of lesion. Downward herniation of the optic chiasm occurs occasionally and may cause visual disturbances simulating those of a pituitary adenoma (Kaufman et al). As mentioned earlier, a bitemporal hemianopia with a normal-sized sella is usually caused by a primary suprasellar lesion (saccular aneurysm of the distal carotid artery, meningioma, or craniopharyngioma).

Treatment

This varies with the type and size of the pituitary tumor, the status of the endocrine and visual systems, and the age and childbearing plans of the patient. The administration of the dopamine agonist bromocriptine (which inhibits prolactin) in a beginning dosage of 0.5 to 1.25 mg daily (taken with food) may be the only therapy needed for small or even large prolactinomas, and is a useful adjunct in the treatment of the amenorrhea–galactorrhea syndrome. The dose should be slowly increased by 2.5 mg or less every several days until a therapeutic response is obtained. Under the influence of bromocriptine, the tumor decreases in size within days, the prolactin level falls, and the visual field defect improves.

Some cases of acromegaly also respond to the administration of bromocriptine but even better to octreotide, an analogue of somatostatin. The initial dose of octreotide is 200 mg/d, increased in divided doses to 1,600 mg by increments of 200 mg weekly. In Lamberts' series of acromegaly patients, the growth hormone levels returned to normal and tumor size was reduced in 12 of 15 cases. Treatment with bromocriptine and octreotide must be continuous to prevent relapse. Newer slow-release somatostatin analogues and long-acting dopamine agonists such as cabergoline have been developed for use in patients who do not respond to the conventional agents (Colao and Lombardi).

If the patient is intolerant of medication (or, in the case of acromegaly, to octreotide and newer drugs), the treatment is surgical, using a transsphenoidal microsurgical approach, with an attempt at total removal of the tumor and preservation of normal pituitary function. Unfortunately, approximately 15 percent of GH-secreting tumors and prolactinomas will recur at 1 year. For this reason, incomplete removal or recurrence of the tumor (or tumors that are unresponsive to hormonal therapy) should be followed by radiation therapy.

Alternative primary treatment for intrasellar tumors is forms of stereotactic radiosurgery, provided that vision is not being threatened and there is no other urgent need for surgery. These forms of radiation can be focused precisely on the tumor and will destroy it. Kjellberg and colleagues and Chapman, using proton beam radiation, in the past treated more than 1,100 pituitary adenomas without a fatality and with few complications (Kliman et al). A single brief exposure was all that was necessary. An endocrine deficit will follow in most instances and must be corrected by hormone replacement therapy. Several equivalent methods (gamma Knife, Cyberknife) are more accessible and have become widely used. The advantage of these radiotherapeutic methods is that tumor recurrence is rare. A disadvantage is that the radiation effect is obtained only after several months. Estrada and colleagues have also reported that external beam-radiation therapy may be employed after unsuccessful transsphenoidal surgery for Cushing disease. After approximately 3.5 years following radiation, 83 percent of their patients showed no signs of tumor growth. There are a few reports, however, of a decline in memory ability after radiation treatment of all types.

Large extrasellar extensions of a pituitary growth must be removed by craniotomy, usually with a transfrontal approach, followed by radiation therapy. Visual field defects often remain, but some improvement in vision can be anticipated.

Pituitary Apoplexy

This syndrome, described originally by Brougham, Heusner, and Adams, occurs as a result of infarction of an adenoma that has outgrown its blood supply. It is characterized by the acute onset of severe headache that may be retro-orbital, frontal, bitemporal, or generalized ophthalmoplegia; bilateral visual loss; and in severe cases, drowsiness or coma, with either subarachnoid hemorrhage or pleocytosis and elevated protein in the CSF. The CT or MRI shows infarction of tumor, often with hemorrhage in and above an enlarged sella. Pituitary apoplexy may threaten life unless the acute addisonian state is treated by hydrocortisone. Blindness is the other dreaded complication. If there is no improvement after 24 to 48 h, or if vision is markedly affected, transsphenoidal decompression of the sella is indicated. Factors that may precipitate the necrosis or hemorrhage of a pituitary tumor are anticoagulation, pituitary function testing, radiation, bromocriptine treatment, and head trauma; most cases, however, occur spontaneously. Some pituitary adenomas have been cured by this accident.

Ischemic necrosis of the pituitary, without the presence of a tumor followed by hypopituitarism, occurs under a variety of circumstances, the most common being in the partum or postpartum period (Sheehan syndrome).

Meningioma of the Sphenoid Ridge

This tumor, mentioned earlier in the chapter, is situated over the lesser wing of the sphenoid bone. As it grows, it may expand medially to involve structures in the wall of the cavernous sinus, anteriorly into the orbit, or laterally into the temporal bone. Fully 75 percent of such tumors occur in women, and the average age at onset is 50 years. Most prominent among the symptoms are a slowly developing unilateral exophthalmos, slight bulging of the bone in the temporal region, and radiologic evidence of thickening or erosion of the lesser wing of the sphenoid bone. Variants of the clinical syndrome include anosmia; oculomotor palsies; painful ophthalmoplegia (sphenoidal fissure and Tolosa-Hunt syndromes; see Table 47-2); blindness and optic atrophy in one eye, sometimes with papilledema of the other eye (Foster Kennedy syndrome); mental changes; seizures ("uncinate fits"); and increased intracranial pressure. Rarely, a skull bruit can be heard over a highly vascular tumor. Sarcomas arising from skull bones, metastatic carcinoma, orbitoethmoidal osteoma, benign giant cell bone cyst, tumors of the optic nerve, and angiomas of the orbit must be considered in the differential diagnosis. Neuroimaging with contrast provides the definitive diagnosis. The tumor is resectable without further injury to the optic nerve if the bone has not been invaded.

Meningioma of the Olfactory Groove

This tumor originates in arachnoidal cells along the cribriform plate. The diagnosis depends on the finding of ipsilateral or bilateral anosmia or ipsilateral or bilateral blindness—often with optic atrophy and mental changes. The tumors may reach enormous size before coming to the attention of the physician but as many are small and found incidentally with cerebral imaging (see Fig. 31-7B). If the anosmia is unilateral, it is rarely if ever reported by the patient. The unilateral visual disturbance may consist of a slowly developing central scotoma. Abulia, confusion, forgetfulness, and inappropriate jocularity (witzelsucht) are the usual psychic disturbances from compression of the inferior frontal lobes (see Chap. 22). The patient may be indifferent to or joke about his blindness. Usually there are radiographic changes along the cribriform plate. MRI with gadolinium is diagnostic. Except for the largest and most invasive tumors, surgical removal is possible.

Meningioma of the Tuberculum Sella

Cushing was the first to delineate the syndrome caused by this tumor. All of his 23 patients were female. The presenting symptoms were visual failure—a slowly advancing bitemporal hemianopia with a sella of normal size. Often the field defects are asymmetrical, indicating a combined chiasmal–optic nerve involvement. Usually there are no hypothalamic or pituitary deficits. If the tumor is not too large, complete excision is possible. If removal is incomplete or the tumor recurs or undergoes malignant changes, radiation therapy of one type or another is indicated. The outlook is then guarded; several of our patients succumbed within a few years.

Glioma of the Brainstem

Astrocytomas of the brainstem are relatively slow-growing tumors that infiltrate tracts and nuclei. They produce a variable clinical picture depending on their location in the medulla, pons, or midbrain. Most often, this tumor begins in childhood (peak age of onset is 7 years), and 80 percent appear before the twenty-first year. Symptoms have usually been present for 3 to 5 months before coming to medical notice. In most patients the initial manifestation is a palsy of one or more cranial nerves, usually the sixth and seventh on one side, followed by long tract signs—hemiparesis, unilateral ataxia, ataxia of gait, paraparesis, and hemisensory and gaze disorders in addition to pseudobulbar dysarthria and palsy. In the remaining patients the symptoms occur in the reverse order—i.e., long tract signs precede the cranial nerve abnormalities. Patients in the latter group survive longer than those whose illness begins with cranial nerve palsies. Headache, vomiting, and papilledema may occur, usually late in the illness. The course is slowly progressive over several years unless some part of the tumor becomes more malignant (anaplastic astrocytoma or glioblastoma multiforme) or, as rarely happens, spreads to the meninges (meningeal gliomatosis), in which instance the illness may terminate fatally within months.

The main problem in diagnosis is to differentiate this disease from a pontine form of multiple sclerosis, a vascular malformation of the pons (usually a cavernous hemangioma), or brainstem encephalitis, and to distinguish the focal from the diffuse type of glioma (see below). The most helpful procedure in diagnosis and prognosis is contrast-enhanced MRI (Fig. 31-21).

A study of 87 patients by Barkovich and coworkers emphasized the importance of distinguishing between diffusely infiltrating and focal nodular tumors. In the more common diffuse type, there is mass effect with hypointense signal on T1-weighted MRI and heterogeneously increased T2 signal, which reflects edema and tumor infiltration. These diffusely infiltrating tumors, usually showing an asymmetrical enlargement of the pons, have a poorer prognosis than the focal or nodular tumors, which tend to occur in the dorsal brainstem and often protrude in an exophytic manner. In a few instances of diffuse brainstem glioma, surgical exploration is necessary to establish the diagnosis (inspection and possibly biopsy). However, the histologic characteristics of a minute biopsy specimen of the tumor are not particularly helpful in determining prognosis or treatment and the general practice is to avoid surgery unless the tumor exhibits unusual clinical behavior or does not conform to the typical MRI appearance of the diffuse type.

Treatment

The treatment of the diffuse infiltrative type is radiation, and if increased intracranial pressure develops as a result of hydrocephalus, ventricular shunting of CSF becomes necessary. Adjuvant chemotherapy has not been helpful. A series of 16 patients treated by Pollack and colleagues emphasizes that the focal and exophytic brainstem tumors are almost all low-grade astrocytomas; these tumors, in contrast to the more diffuse type, usually respond well to partial resection and permit long-term survival because they recur only slowly and do not undergo malignant transformation. Gangliocytomas or mixed astrogangliocytomas are rare imitators of nodular glioma in the brainstem. The rarer cystic glioma of the brainstem (see Fig. 31-19), a pilocytic tumor like its counterpart in the cerebellum, is treated by resection of the mural nodule and, as mentioned earlier, has an excellent prognosis. Landolfi and colleagues emphasized the longer survival in adults with pontine glioma (median 54 months) as compared to children. Most of the patients with pontine tumors with which we are familiar proved to have malignant gliomas.

Glioma of the Optic Nerves and Chiasm

This tumor, like the brainstem glioma, occurs most frequently during childhood and adolescence. In 85 percent of cases, it appears before the age of 15 years (average 3.5 years), and it is twice as frequent in girls as in boys (Cogan). The initial symptoms are dimness of vision with constricted fields, followed by bilateral field defects of homonymous, heteronymous, and sometimes bitemporal type and progressing to blindness and optic atrophy with or without papilledema. Ocular proptosis from the orbital mass is the other main feature. Hypothalamic signs (adiposity, polyuria, somnolence, and genital atrophy) occur occasionally as a result of proximal tumor extension. CT, MRI, and ultrasonography will usually reveal the tumor, and radiographs will show an enlargement of the optic foramen (greater than 7.0 mm). This finding and the lack of ballooning of the sella or of suprasellar calcification will exclude pituitary adenoma, craniopharyngioma, Hand-Schüller-Christian disease, and sarcoidosis. In adolescents and young adults, the medial sphenoid, olfactory groove, and intraorbital meningiomas (optic nerve sheath meningioma) are other tumors that cause monocular blindness and proptosis. If the entire tumor is prechiasmatic (the less-common configuration), surgical extirpation can be curative. For tumors that have infiltrated the chiasm or are causing regional symptoms and hydrocephalus, partial excision followed by radiation is all that can be offered. Both gliomas and nontumorous gliotic (hamartomatous) lesions of the optic nerves may occur in von Recklinghausen disease; the latter are sometimes impossible to distinguish from optic nerve gliomas and should be followed closely.

Chordoma

This is a soft, jelly-like, gray-pink growth that arises from remnants of the primitive notochord. It is located most often within the clivus (from dorsum sellae to foramen magnum) and in the sacrococcygeal region. It affects males more than females, usually in early or middle adult years and is one of the rare causes of syndromes involving multiple cranial nerves or the cauda equina. Approximately 40 percent of chordomas occur at each of these two ends of the neuraxis; the rest are found at any point in the vertebral bodies in between. The tumor is made up of cords or masses of large cells with granules of glycogen in their cytoplasm and often with multiple nuclei and intracellular mucoid material. Chordomas are locally invasive, especially of surrounding bone, but they do not metastasize.

The cranial neurologic syndrome caused by this tumor is remarkable in that all or any combination of cranial nerves from the second to twelfth on one or both sides may be involved. Associated signs in the series of Kendall and Lee were facial pain, conductive deafness, and cerebellar ataxia, the result of pontomedullary and cerebellar compression. A characteristic feature is neck pain radiating to the vertex of the skull on neck flexion. The tumors at the base of the skull may destroy the clivus and bulge into the nasopharynx, causing nasal obstruction and discharge and sometimes dysphagia. Extension to the cervical epidural space may result in cord compression. Thus, chordoma is one of the lesions that may present both as an intracranial and extracranial mass, the others being meningioma, neurofibroma, glomus jugulare tumor, and carcinoma of the sinuses or pharynx. CT of the skull base is useful for defining the bony margins of the tumor, and MRI can identify involved and adjacent neural and vascular structures. Midline (Wegener) granulomas, histiocytosis, Erdheim-Chester disease, and sarcoidosis also figure in the differential diagnosis. Chondrosarcoma of the clivus produces a similar syndrome.

Treatment of the chordoma is surgical excision and radiation (focused radiation). This form of treatment has effected a 5-year survival without recurrence in approximately 80 percent of patients.

Nasopharyngeal Growths that Erode the Base of the Skull (Nasopharyngeal Transitional Cell Carcinoma, Schmincke Tumor)

These are seen regularly in a general hospital; they arise from the mucous membrane of the paranasal sinuses or the nasopharynx near the eustachian tube, i.e., the fossa of Rosenmüller. In addition to symptoms of nasopharyngeal or sinus disease, which may not be prominent, facial pain and numbness, abducens, and other cranial nerve palsies may occur. Diagnosis depends on inspection and biopsy of a nasopharyngeal mass or an involved cervical lymph node and radiologic evidence of erosion of the base of the skull. Bone scans and CT are helpful in diagnosis (see Fig. 47-5). The treatment is surgical resection and radiation but chemotherapy is increasingly being included. Carcinoma of the ethmoid or sphenoid sinuses and postradiation neuropathy, coming on years after the treatment of a nasopharyngeal tumor, may produce similar clinical pictures and are difficult to differentiate. The syndromes resulting from nasopharyngeal tumors are discussed in Chap. 47, under "Diseases of the Cranial Nerves."

Other Tumors of the Base of the Skull

In addition to meningioma, nasopharyngeal tumors, and the other tumors enumerated earlier, there are a large variety of tumors, rare to be sure, that derive from tissues at the base of the skull and paranasal sinuses, ears, and other structures and give rise to distinctive syndromes. Included in this category are osteomas, chondromas, ossifying fibromas, giant cell tumors of bone, lipomas, epidermoids, teratomas, mixed tumors of the parotid gland, and hemangiomas and cylindromas (adenoid cystic carcinomas of salivary gland origin) of the sinuses and orbit; sarcoid granulomas may produce the same effect. Most of these tumors are benign, but some have a potential for malignant change. To the group must be added the esthesioneuroblastoma (of the nasal cavity) with anterior fossa extension and, perhaps most common of all of these, the systemic malignant tumors that metastasize to basal skull bones (prostate, lung, and breast being the most common sources), or involve them as part of a multicentric neoplastic process, e.g., primary lymphoma, multiple myeloma, plasmacytoma, and lymphocytic leukemia.

Suprasellar arachnoid cysts also occur in this region. CSF flows upward from the interpeduncular cistern but is trapped above the sella by thickened arachnoid (membrane of Liliequist). As the CSF accumulates, it forms a cyst that invaginates the third ventricle; the dome of the cyst may intermittently block the foramina of Monro and cause hydrocephalus (see Fox and Al-Mefty). Children with this condition exhibit a curious to-and-fro bobbing and nodding of the head, like a doll with a weighted head resting on a coiled spring. This has been referred to as the "bobble-head doll syndrome" by Benton and colleagues; it can be cured by emptying the cyst. Seesaw and other pendular and jerk types of nystagmus may also result from these suprasellar lesions.

Tables 31-5 and 47-1, adapted from Bingas' large neurosurgical service in Berlin, summarizes the facts about the focal syndromes of the skull base; his authoritative article and the more recent one by Morita and Piepgras, both in the Handbook of Clinical Neurology, are recommended references.

Modern imaging techniques now serve to clarify many of the diagnostic problems posed by these tumors. MRI is particularly helpful in delineating structures at the base of the brain and in the upper cervical region. CT is also capable of determining the absorptive values of the tumor itself and the sites of bone erosion. When the lesion is analyzed in this way, an etiologic diagnosis often becomes possible. For example, the absorptive value of lipomatous tissue is different from that of brain tissue, glioma, blood, and calcium. Bone scans (technetium and gallium) display active destructive lesions with remarkable fidelity, but in some cases, even when the tumor is seen with various studies, it may be difficult to obtain a satisfactory biopsy.

Tumors of the Foramen Magnum

Tumors in the region of the foramen magnum are of particular importance because of the need to differentiate them from diseases such as multiple sclerosis, Chiari malformation, syringomyelia, and bony abnormalities of the craniocervical junction. Failure to recognize these tumors is a consequential matter because the majority are benign and extramedullary, i.e., potentially resectable and curable. If unrecognized, they terminate fatally by causing medullary and high spinal cord compression.

Although these tumors are not common (approximately 1 percent of all intracranial and intraspinal tumors) sizable series have been collected by several clinicians (see Meyer et al for a complete bibliography). In all series, meningiomas, schwannomas, neurofibromas, and dermoid cysts are the most common types; others, all rare, are teratomas, dermoids, granulomas, cavernous hemangiomas, hemangioblastomas, hemangiopericytomas, lipomas, and epidural carcinomas.

Pain in the suboccipital or posterior cervical region, mostly on the side of the tumor, is usually the first and by far the most prominent complaint. In some instances the pain may extend into the shoulder and even the arm. The latter distribution is more frequent with tumors arising in the spinal canal and extending intracranially than the reverse. For uncertain reasons, the pain may radiate down the back, even to the lower spine. Both spine and root pain can be recognized, the latter because of involvement of either the C2 or C3 root or both.

One pattern is weakness of a shoulder and arm progressing to the ipsilateral leg and then to the opposite leg and arm ("around-the-clock" paralysis) as discussed in Chap. 3. Another configuration is triplegia that is a characteristic but not invariable sequence of events, caused by the encroachment of tumor upon the decussating corticospinal tracts at the foramen magnum. Occasionally, both upper limbs are involved alone; surprisingly, there may be atrophic weakness of the hand or forearm or even intercostal muscles with diminished tendon reflexes well below the level of the tumor, an observation made originally by Oppenheim. Involvement of sensory tracts also occurs; more often it is posterior column sensibility that is impaired on one or both sides, with patterns of progression similar to those of the motor paralysis. Sensation of intense cold in the neck and shoulders has been another unexpected complaint, and also "bands" of hyperesthesia around the neck and back of the head. Segmental bibrachial sensory loss has been demonstrated in a few of the cases and a Lhermitte sign (really a symptom) of electric-like sensations down the spine and limbs upon flexing the neck has been reported frequently. The cranial nerve signs most frequently conjoined and indicative of intracranial extension of a foramen magnum tumor are dysphagia, dysphonia, dysarthria, and drooping shoulder (because of vagal, hypoglossal, and spinal accessory involvement); included less often are nystagmus and episodic diplopia, sensory loss over the face and unilateral or bilateral facial weakness, and a Horner syndrome.

The clinical course of such lesions often extends for years, with deceptive and unexplained fluctuations. The important diagnostic procedure is contrast-enhanced MRI (Fig. 31-22). With dermoid cysts of the upper cervical region, as in the case reported by Adams and Wegner, complete and prolonged remissions from quadriparesis may occur.

Tumors of the foramen magnum, as mentioned, should be differentiated from spinal or brainstem-cerebellar multiple sclerosis, Chiari malformation with syrinx, and bony compression. Persistent occipital neuralgia with a foramen magnum syndrome is particularly suggestive of a tumor at that site. The early occipitonuchal pain must be differentiated from mundane crucial osteoarthritis. Treatment is surgical excision (Hakuba et al) followed by focused radiation if the resection is incomplete and the tumor is known to be radiosensitive.

See Table 31-6.

In the past 50 years a group of neurologic disorders has been delineated that occur in patients with systemic neoplasia even though the nervous system is not the site of metastases or direct invasion or compression by the tumor. These so-called paraneoplastic disorders are not specific or confined to cancer, but the conditions are linked far more frequently than could be accounted for by chance. They assume special importance because in many cases the neurologic syndrome becomes apparent before the underlying tumor is found. The great variety of clinical presentations of paraneoplastic encephalitis disease can be appreciated from early series reported by Graus and colleagues of 200 patients: sensory neuropathy, 54 percent; cerebellar ataxia, 10 percent; limbic encephalitis, 9 percent; and others, including multiple sites, in 11 percent. Some of the paraneoplastic disorders that involve nerve and muscle—namely, polyneuropathy, polymyositis, and the myasthenic-myopathic syndrome of Lambert-Eaton—are described in later chapters on these subjects. Here we present the paraneoplastic processes that involve the spinal cord, cerebellum, brainstem, and cerebral hemispheres.

Comprehensive accounts of the paraneoplastic disorders may be found in the writings of Posner (1995), Darnell and Posner, and Dalmau and Rosenfeld. Some are associated with immunoglobulin G (IgG) autoantibodies (see Table 31-5), but it should be remarked that although certain antibodies are associated with specific syndromes, they are not invariably linked to particular cancers and vice versa. Furthermore, the same syndromes and antibodies occur sometimes without an evident tumor. This was emphasized in the survey by Pittock and colleagues at the Mayo Clinic, who found that one-third of sera from patients with paraneoplastic neurologic disorders had more than one antibody. They have suggested that this reflects the numerous immunogenic onconeural proteins that are expressed by tumors. Consequently, the relationships between particular antibodies and a clinical syndromes listed in Table 31-6 should be taken as approximate, or nonexclusive. Nonetheless, certain syndromes seem to occur disproportionately often with particular antibodies. Small cell cancer of the lung, adenocarcinoma of the breast and ovary, and Hodgkin disease are the tumors most often associated with these disorders, but the paraneoplastic neurologic syndromes occur in only a very small proportion of patients with these tumors.

The mechanisms by which carcinomas produce their remote effects are incompletely understood. Perhaps the most plausible theory, as intimated above, is that they have an autoimmune basis. According to this theory, antigenic molecules are shared by certain tumors and central or peripheral neurons. The immune response is then directed to the shared antigen in both the tumor and the nervous system. The evidence for such an autoimmune mechanism is most clearly exemplified by the Lambert-Eaton syndrome, in which an antibody derived from a tumor binds to voltage-gated calcium channels at neuromuscular junctions (see Chap. 49).

Furthermore, in some types of paraneoplastic disorders, there is provocative evidence that the inciting tumor has antigen on its surface and self-binding of the antibody may inhibit tumor growth. This may account for the difficulty in detecting diminutive small cell lung cancers that underlie some of the paraneoplastic syndromes. It should be noted, however, that there is no evidence that suppressing or removing the antibody leads to growth of the tumor.

Encephalomyelitis Associated with Carcinoma and "Limbic Encephalitis"

The occurrence of regional and bilateral encephalomyelitic changes in association with carcinoma has been described by several authors (Corsellis et al; Henson and Urich; Posner, 1995). In most of the reported cases, the encephalitic process has been associated with carcinoma of the bronchus, usually of the small cell type, but all types of neoplasms, including Hodgkin disease, have been implicated. Histologically, this group of paraneoplastic disorders is characterized by extensive loss of neurons, accompanied by microglial proliferation, small patches of necrosis, and marked perivascular cuffing by lymphocytes and monocytes. Foci of lymphocytic infiltration have been observed in the leptomeninges as well. These pathologic changes may involve the brain and spinal cord diffusely, but more often they predominate in a particular part of the nervous system, notably in the medial temporal lobes and adjacent nuclei ("limbic encephalitis," Fig. 31-23), the brainstem, the cerebellum (see earlier), or the gray matter of the spinal cord. The symptoms will, of course, depend on the location and severity of the inflammatory changes and may overlap. Most cases are subacute, meaning specifically a progression over a few weeks or months, but often the main symptoms in mild form become apparent in a matter of days. Rare instances of remission have been reported.

The most distinctive features of paraneoplastic limbic encephalitis consists of a confusional–agitated state, memory defect (Korsakoff syndrome), seizures, sometimes focal, hallucinations, and dementia—singly or in various combinations and evolving subacutely (Gultekin et al); an amnestic component is almost universal and the central feature in most cases.

Vertigo, nystagmus, ataxia, nausea and vomiting, and a variety of ocular and gaze palsies reflect a different process of paraneoplastic brainstem encephalitis. As indicated above, these symptoms may be joined with cerebellar ataxia, and another group has an additional sensory neuropathy. We have seen instances of this condition involving only the midbrain and others involving only the medulla, the latter with unusual breathing patterns including gasping, inspiratory breathholding, and vocal–respiratory incoordination, and yet others with chorea and additional basal ganglionic features. Pathologic studies have partially clarified this form of paraneoplastic disorder. In some cases, few changes were demonstrable in the brain, even though there had been a prominent dementia during life. Contrariwise, widespread inflammatory changes may be found without clinical abnormalities having been recorded during life.

In most of these cases, MRI shows abnormal T2 hyperintensity and edema in affected regions; in severe cases, zones of focal necrosis may be seen. Odd seizures, including epilepsia partialis continua, have been observed with this disorder, but they must be uncommon. Sensory symptoms may be related to neuronal loss in the posterior horns, traced to the commonly associated loss of neurons in the dorsal root ganglia (sensory neuronopathy and sensory neuropathy) as mentioned earlier and discussed further on.

Most patients with small cell lung cancer and any of the types of paraneoplastic encephalomyelitis have been found to harbor circulating polyclonal IgG antibodies (anti-Hu, or antineuronal antibody type 1) that bind to the nuclei of neurons in many regions of the brain and spinal cord, dorsal root ganglion cells, and peripheral autonomic neurons. The antibodies are reactive with certain nuclear RNA-binding proteins. Cancers of the prostate and breast and neuroblastoma may rarely produce a similar antibody. The antibody titer is higher in the CSF than in the serum (as it is for anti-Yo with cerebellar degeneration), indicating production of antibody within the nervous system. Low titers of anti-Hu are found in approximately 15 percent of patients with small cell cancer who are neurologically normal, probably because these tumors have expressed only low levels of antigens that are recognized by anti-Hu. Antibodies to voltage-gated potassium channels (VGKC) have been identified in patients with limbic encephalitis without, or less often with, cancer (Vincent et al). A number of these cases respond to plasma exchange. The anti-VGKC disorders tend to be slower in evolution and less severe than the typical paraneoplastic neurologic syndromes.

Treatment

Despite a few reports of improvement with plasma exchange or intravenous gamma globulin, the results of treatment have been disappointing. However, those few patients who did improve had treatment from the onset of symptoms, and this is possibly a way of limiting the neuronal loss.

Anti-NMDA Encephalitis

A special form of paraneoplastic encephalitis presents itself as an acute or subacute psychiatric syndrome consisting of some combination of hallucinations, panic, delusions, and incoherence, coupled with seizures, memory disturbance and hypoventilation has been described by Vitaliani and colleagues in four women with ovarian teratoma. Many patients have a non-descript prodrome of malaise, fatigue, headache excessive sleepiness, or low fever. Dalmau and coworkers (2007) demonstrated that this syndrome is associated with antibodies against a component of the NMDA receptor. The teratoma in one of their patients was located in the mediastinum instead of the ovary and rare cases have occurred with small cell lung cancer, including in men. Dalmau's series of 100 patients (2008) is instructive in that they were very predominantly women in their twenties with presentations or psychiatric or memory deterioration but a large number had dyskinesias, seizures, or hypoventilation. Almost all had several or dozens of white blood cells in the CSF, a majority had oligoclonal bands and the MRI showed abnormal T2 hyperintensity in the medial temporal lobes, similar to those of the anti-Hu type of limbic encephalitis.

We have been impressed with the autonomic overactivity in the patients under our care with this syndrome. Episodes of hypertension, tachycardia and diaphoresis can be pronounced, as is excessive salivation, pupillary dilation, and other signs of sympathetic dysfunction, individually or concurrently.

Dalmau and colleagues have identified the target of the antibody as the subunit of the NMDA receptor, NR1. There is a reasonable degree of certainty that the antibody is pathogenic.

Another peculiar syndrome associated with prostate cancer, which we have encountered once, was described by Baloh and colleagues prior to the discovery of most of the currently known paraneoplastic antibodies. These patients display brainstem signs, particularly loss of horizontal gaze, and facial and pharyngeal spasms or abdominal myoclonus. Whether this process will be subsumed under one or another of the known antibody syndromes is not known but it is notable because prostate cancer otherwise rarely gives rise to paraneoplastic disease.

Treatment

A premium is attached to early identification of this disorder and rapid removal of the ovary containing the teratoma or resection of another inciting tumor. Vaginal ultrasound may be necessary for the demonstration of the ovarian lesion but a more extensive examination such as CT or PET is needed for the detection of other tumors. Improvement after tumor removal is associated with subsidence of the antibody titer over many weeks and a good outcome occurs in a majority of cases. Decisions regarding oophorectomy are difficult in view of reducing fertility in young women.

It has become apparent that a fair proportion of cases with circulating anti-NMDA antibody do not have a tumor that is detectable and immune treatments such as intravenous gamma globulin may then be used. It is reasonable to start these same immune treatments while awaiting surgery in cases that are highly symptomatic.

Paraneoplastic Sensory Neuronopathy (See also Chap. 46)

This is a distinctive syndrome that is associated in most cases with the anti-Hu antibody. It should be emphasized that a nondescript, mainly sensory neuropathy is a more common accompaniment of systemic cancer, and it may or may not be associated with the anti-Hu antibody. As discussed further in Chap. 46, a sensory polyneuropathy from chemotherapeutic agents, notably the platinum-based ones and vincristine, also needs to be distinguished from the anti-Hu neuropathy syndrome.

The sensory neuronopathy and neuropathy were first described by Denny-Brown in 1948 and are notable because they served to introduce the modern-day concept of paraneoplastic neurologic disease. The initial symptoms in both processes are numbness or paresthesia, sometimes painful, in a limb or in both feet. There may be lancinating pains at the onset. Over a period of days in some cases, but more typically over weeks, the initially focal symptoms become bilateral and may spread to all limbs and their proximal portions and then to the trunk. It is this widespread and proximal distribution and the involvement of the face, scalp, and often the oral and genital mucosa that mark the process as a sensory ganglionitis and radiculitis and when subacute are highly suggestive of a paraneoplastic process.

As the illness progresses, all forms of sensation are greatly reduced, resulting in disabling ataxia and pseudoathetoid movements of the outstretched hands. The reflexes are lost, but not always at the outset, and strength is relatively preserved. Autonomic dysfunction—including constipation or ileus, sicca syndrome, pupillary areflexia, and orthostatic hypotension—is sometimes associated. Also, a virtually pure form of peripheral autonomic failure has been recorded as a paraneoplastic phenomenon (paraneoplastic dysautonomia). One of our patients with sensory neuronopathy had gastric atony with fatal aspiration after vomiting and another died of unexpected cardiac arrhythmia. Very early in the illness, the electrophysiologic studies may be normal, but this soon gives way to a loss of all sensory potentials, sometimes with indications of a mild motor neuropathy.

The spinal fluid usually contains an elevated protein and a few lymphocytes. As with paraneoplastic encephalomyelitis, most of the cases associated with small cell lung cancer demonstrate the anti-Hu antibody. As mentioned, neuropathy and encephalomyelitis often occur together. The sensory neuronopathy–ganglionopathy that is related to Sjögren disease and an idiopathic variety do not have this antibody, making its presence a reliable marker for lung cancer in patients with sensory neuronopathy. The polyneuropathy is refractory to almost all forms of treatment, or there is a transient benefit, and most patients die within months of onset, but there have been reports of brief remissions with plasma exchange and intravenous gamma globulin applied early in the illness. Resection of the lung tumor may halt progression of the neurologic illness.

Paraneoplastic Cerebellar Degeneration

For many years, this disorder was considered to be quite uncommon, but it is perhaps the most characteristic of the paraneoplastic syndromes. In reviewing this subject in 1970, Adams and Victor were able to find only 41 pathologically verified cases; in a subsequent review (Henson and Urich), only a few more cases were added. The actual incidence is much higher than these figures would indicate. At the Cleveland Metropolitan General Hospital, in a series of 1,700 consecutive autopsies in adults, there were 5 instances of cerebellar degeneration associated with neoplasm. In the experience of Henson and Urich, about half of all patients with nonfamilial, late-onset cerebellar degeneration proved sooner or later to be harboring a neoplasm. Large series of cases have been reported from the Mayo Clinic and the Memorial Sloan-Kettering Cancer Center (Hammock et al and N.E. Anderson et al, respectively). We see several such cases yearly, but have also encountered numerous instances of an identical syndrome with no cancer evident and no antibodies that are probably a result of diverse causes summarized in Chap. 5 and Table 5-1.

In approximately one-third of the cases, the underlying neoplasm has been in the lung (most often a small cell carcinoma)—a figure reflecting the high incidence of this tumor. However, the association of ovarian carcinoma and lymphoma, particularly Hodgkin disease, accounting for approximately 25 and 15 percent, respectively, is considerably higher than would be expected on the basis of the frequency of these malignancies. Carcinomas of the breast, bowel, uterus, and other viscera have accounted for most of the remaining cases (Posner, 1995).

The cerebellar symptoms have a subacute onset and steady progression over a period of weeks to months; in more than half the cases, the cerebellar signs are recognized before those of the associated neoplasm. Symmetrical ataxia of gait and limbs—affecting arms and legs more or less equally—dysarthria, and nystagmus are the usual manifestations; some have vertigo. Striking in fully developed cases has been the severity of the ataxia, matched by few other diseases. Occasionally, myoclonus and opsoclonus or a fast-frequency myoclonic tremor may be associated ("dancing eyes–dancing feet," as noted later). In addition, there are quite often symptoms and signs not strictly cerebellar in nature, notably diplopia, vertigo, Babinski signs (common in our cases), sensorineural hearing loss, disorders of ocular motility, and alteration of affect and mentation—findings that serve to distinguish paraneoplastic from alcoholic and other varieties of cerebellar degeneration. Lambert-Eaton syndrome is known to occur with cerebellar degeneration as paraneoplastic illnesses. These are well emphasized in the series of 47 patients collected by Anderson and colleagues and the 55 cases by Peterson et al, who tabulated these noncerebellar neurologic features.

The CSF may show a mild pleocytosis (up to 50 cells/mm3 in a few of our patients) and increased protein, or it may be entirely normal. Early in the course of the disease, CT and MRI show no abnormality, but after a few months, atrophy of the brainstem and cerebellum may appear. In a few cases, T2-weighted MRI discloses increased signal of the cerebellar white matter (Hammock et al), but this has not been uniform in our experience, and furthermore does not correlate well to the degree of Purkinje cell loss (Fig. 31-23).

Pathologically, there are diffuse degenerative changes of the cerebellar cortex and deep cerebellar nuclei. Purkinje cells are affected prominently and all parts of the cerebellar cortex are involved. Degenerative changes in the spinal cord, involving the posterior columns and spinocerebellar tracts, have been found rarely. The cerebellar neuronal degeneration is frequently associated with perivascular and meningeal clusters of inflammatory cells. Henson and Urich regard the inflammatory changes as an independent process, part of a subacute paraneoplastic encephalomyelitis (see below). This view is supported by the finding that the specific antibodies linked to cerebellar degeneration differ from those found in paraneoplastic inflammatory lesions in other parts of the nervous system.

Anti-Purkinje cell antibodies (termed "anti-Yo") can be found in the sera of about half of patients with paraneoplastic cerebellar degeneration and in the large majority of those related to carcinoma of the breast or female genital tract, linking the clinical syndrome and this antibody closely. Antibodies against a nuclear antigen, termed anti-Hu, may also be present; they are more closely linked to the paraneoplastic encephalomyelitis discussed further on. (Hu and Yo are taken from the names of patients in whom the antibody was first found.) In the Mayo Clinic series of 32 patients with paraneoplastic cerebellar degeneration, 16 had such antibodies; all were women and most of them had breast or ovarian cancers. Anderson and colleagues report a similar proportion but point out that several anti-Purkinje antibodies besides the highly characteristic one may be found by special techniques. Death occurred in 4 to 18 months. In an equal number of cases without antibodies, half are men with lung cancer, some of whom display the anti-Hu antibody. This leaves a proportion who have no circulating antibody but who are nonetheless found to have a concealed tumor that must be sought by other ancillary tests including positron emission tomography (PET) of the entire body. In another small group, it must be conceded that no underlying tumor can be found despite extensive examinations and even at autopsy. The death rate in these cases has varied widely from 6 months to several years and depends on the behavior of the underlying tumor.

Whether the anti-Yo antibodies are merely markers of an underlying tumor or the agents of destruction of the Purkinje cells is not clear. They bind to a C-myc protein that initiates a degeneration of Purkinje cells. Regardless of the pathogenic significance of the antibodies, their presence in a patient with the typical neurologic disorder has considerable diagnostic significance. As mentioned above, they usually indicate that there is an underlying breast or ovarian cancer, which may be asymptomatic and small enough to be resected successfully. Other antibodies besides anti-Yo and anti-Hu are found on occasion, such as those against a glutamate receptor in patients with Hodgkin disease (Smitt et al). The differential diagnosis of subacute cerebellar ataxia is broad, as indicated in Table 5-1. The main considerations are a variant of Creutzfeldt-Jakob disease, postinfectious cerebellitis, and various intoxications.

Treatment

Reports of aggressive plasma exchange or intravenous immunoglobulin treatment early in the course suggest some benefit, but it should not be assumed that this approach will succeed in most patients, and our own experience has been discouraging in this regard. There are also on record several cases in which there was a partial or complete remission of symptoms after removal of the primary tumor (Paone and Jeyasingham). Furthermore, in some cases associated with Hodgkin disease, there has been spontaneous improvement of the cerebellar symptoms.

Opsoclonus–Myoclonus–Ataxia Syndrome

In children, this syndrome is usually a manifestation of neuroblastoma, but it is more common and occurs in adults in relation to breast cancer and small cell lung cancer. The unique feature of the neuroblastoma is a response of this syndrome to corticosteroids and ACTH in most children and in some adults, and resolution of the neurologic signs when the neuroblastoma is removed. A subgroup of breast cancers produce an antineuronal antibody directed against a different RNA-binding antigen from the anti-Hu antibody; thus it has been termed "anti-Ri" (antineuronal antibody type 2). This antibody is not found in the opsoclonus–ataxic syndrome of neuroblastoma and is present only rarely with small cell lung cancer. There have also been a limited number of positive serologic tests in children with opsoclonus, apparently without an underlying tumor. A few such patients have had a mild pleocytosis in the CSF; the MRI is usually normal. More complex syndromes have been reported with the anti-Ri antibody, manifest by rigidity and intense stimulus-sensitive myoclonus in addition to the core features of opsoclonus and ataxia.

The neuropathologic findings have not been distinctive; mild cell loss has been described in the Purkinje cell layer, inferior olives, and brainstem, with mild inflammatory changes (Luque et al).

Besides breast cancer, we have observed the opsoclonus–myoclonus syndrome in a middle-aged woman with bronchial carcinoma and in a man with gastric carcinoma. Similar cases occur with both cerebellar ataxia and an irregular tremor, which we have interpreted as myoclonic in character. These patients were found to have marked degeneration of the dentate nuclei. The prognosis in this syndrome is somewhat better than that for the other paraneoplastic diseases, but besides a trial of ACTH, there is little that can be done but search for the tumor and resect it if possible.

Carcinomatous Myelopathy and Motor Neuronopathy

In addition to subacute degeneration of spinal cord tracts that may be associated with paraneoplastic cerebellar degeneration (see earlier), there has been described a rapidly progressive form of more widespread degeneration of the spinal cord (Mancall and Rosales). The myelopathy is characterized by a rapidly ascending sensorimotor deficit that terminates fatally in a matter of weeks. There is a roughly symmetrical necrosis of both the gray and white matter of most of the cord. This necrotizing myelopathy is distinctly rare, being far less common than compression of the spinal cord from cancer and even less frequent than intramedullary spinal cord metastases. Flanagan and colleagues have summarized a large series of their cases and described a variety of presentations including longitudinally extensive involvement on imaging studies that simulate the pattern seen with anti-aquaproin antibodies of Devic disease as described in Chaps. 36 and 44. It can therefore be said that there is a paraneoplastic type of neuromyelitis optica. Most of their cases had a CSF pleocytosis, half had oligoclonal bands, and one of the known paraneoplastic autoantibodies was found the majority.

Better defined is subacute motor neuronopathy that occurs as a remote effect of bronchogenic carcinoma, Hodgkin disease, and other lymphomas as mentioned earlier in the discussion of encephalomyelitis (Schold et al). Some cases take the form of a relatively benign, purely motor weakness of the limbs, the course and severity of which are independent of the underlying neoplasm. Other cases are severe and progressive, causing respiratory failure and death, thus simulating amyotrophic lateral sclerosis (ALS); some of these will have the anti-Hu antibody (Verma et al; Forsyth et al). The basic neuropathologic change is a depletion of anterior horn cells; also seen are inflammatory changes and neuronophagia as in chronic poliomyelitis. The few autopsied cases have shown gliosis of the posterior columns, pointing to an asymptomatic affection of the primary sensory neuron, as well as a reduction in the number of Purkinje cells.

Forsyth and colleagues subdivided their cases of paraneoplastic motor neuron syndromes into three groups: (1) rapidly progressive amyotrophy and fasciculations with or without brisk reflexes—all of their 3 patients displayed anti-Hu antibodies, 2 with small cell lung cancer and 1 with prostate cancer; (2) a predominantly corticospinal syndrome that affected the oropharyngeal or limb musculature, without definite evidence of denervation, thus resembling primary lateral sclerosis—all were breast cancer patients and none showed antineuronal antibodies; and (3) a syndrome indistinguishable from ALS in 6 patients with breast or small cell lung cancer, Hodgkin disease, or ovarian cancer, none of whom had antineuronal antibodies. In the latter two groups one cannot be certain that the condition was not a chance occurrence of the idiopathic variety of motor neuron disease. Nevertheless, this is such a rare cause of motor neuron disease that an evaluation for tumor is not required in the typical case of ALS.

A rare paraneoplastic syndrome of spinal myoclonus with tonic spasms can occur and is assumed to be from inflammation of the spinal cord gray matter as discussed in Chaps. 6 and 44.

Other Paraneoplastic Disorders

Several more recently discovered antibodies, such as CRMP-5 (collapsin-responsive mediator protein) and anti-Ma1 and -Ma2, have been detected in cases of brainstem encephalitis including with ophthalmoplegia but there have been associations with limbic and diencephalic syndromes as well and a hypokinetic parkinsonian appearance (Dalmau et al 2004). The anti-Ma antibodies cross-react with testicular antigens and a search for a testicular tumor is undertaken (Voltz et al). Although rare, the clinical syndromes associated with the anti-Ma antibody and testicular tumors are diverse: limbic, brainstem, or hypothalamic inflammation and an ataxic–opsoclonic syndrome that is more typical of anti-Ri antibody (see earlier).

The antibody to CRMP-5 is reported in some series to be second in frequency only to anti-Hu. Lung carcinoma has been the most common source in the series of Yu and colleagues, with thymoma, renal cell, and other neoplasms accounting for a few of the cases. The clinical features have been as diverse as for anti-Hu, including seizures, dementia, confusion, depression, as well as a variety of peripheral and cranial neuropathies and, surprisingly, the Lambert-Eaton syndrome.

An illness similar to the one caused by anti-NMDA antibodies, under the name of Ophelia syndrome, has been reported as a paraneoplastic syndrome that is due to antibodies directed against the metabotropic glutamate receptor, mGluR5 (see Lancaster et al).

Paraneoplastic Optic Neuropathy

An optic neuropathy is probably the most specific associated syndrome with the CRMP-5 antibody, as described by Cross and colleagues. There is subacute visual loss, disc swelling, and a cellular reaction in the vitreous. Most patients have features of another paraneoplastic syndrome. Several authors have remarked on the occurrence of chorea as a presenting symptom along with basal ganglionic changes on MRI. It is difficult for us to make sense of the clinical features aside from the optic neuropathy (really an optic neuritis), but they seem comparable to the perivenous inflammatory encephalitis and neuritis of the anti-Hu syndromes. Presumably this antibody accounts for some of the odd subacutely progressive syndromes previously thought to be antibody-negative; testing for this antibody might be included when an unusual paraneoplastic syndrome is suspected. The heterogeneity of antibody response to these expressed proteins may account for different clinical manifestations of the immune process but there is no certain evidence yet of their pathogenetic role.

Paraneoplastic Retinopathy

In recent years, there have been reports of retinopathy as a paraneoplastic syndrome that is distinct from the above-described optic neuropathy. Small cell carcinoma of the lung has been the most common underlying malignancy. In about half of the reported cases, retinal symptoms preceded the discovery of the tumor by several months. The lesion is in the photoreceptor cells, and antiretinal antibodies (directed against a calcium-binding protein, recoverin) have been identified in the serum. Photosensitivity, ring scotomas, and attenuation of the retinal arterioles are the main clinical features; Jacobson and coworkers suggested that they constitute a diagnostic triad.

Paraneoplastic Stiff Man Syndrome and Related Neuromuscular Disorders (see Chap. 48)

Occasionally this disorder (stiff man syndrome) occurs as a paraneoplastic disease. Lesser degrees of unexplained mild rigidity are seen from time to time, perhaps as a consequence of loss of spinal cord interneurons. In what might be called "stiff woman syndrome," Folli and associates described 3 female patients with breast cancer who developed a state of generalized motor hyperexcitability and rigidity. These patients generally have no antibodies to glutamic acid decarboxylase (GAD), as in the sporadic cases of "stiff man syndrome"; probably there are antibodies to other synaptic proteins.

The "chorée fibrillaire" of Morvan is an extraordinary disorder of continuous muscle fiber activity, insomnia, and hallucinosis that may be caused by a paraneoplastic antibody to voltage-gated potassium channels, as discussed in Chap. 48 and 50s. This same antibody, as well as acetylcholine receptor antibodies, has been associated with neuromyotonia of Isaac syndrome, seen in cases of lung cancer, lymphoma, and thymoma.

The Lambert-Eaton syndrome is perhaps the most common paraneoplastic neurologic syndrome; it is associated with antibodies directed against calcium channels, as mentioned earlier. This disorder, which may occur concurrently with other paraneoplastic syndromes such as cerebellar ataxia, is discussed in Chap. 53. Basal ganglia syndromes, chorea in particular, are associated with the anti-Hu and CRMP-5 antibodies as already noted. A myoclonus syndrome without ataxia or opsoclonus is reported from time to time in the literature and probably is a derivative of one of the better-characterized antibody diseases.

Radiation Injury of the Brain

Injury to the CNS from radiation is appropriately discussed here, since it occurs mainly in relation to therapy of brain tumors. Three syndromes of radiation damage have been delineated: acute, early delayed, and late delayed, although these syndromes often blend into one another. The acute reaction may begin during the latter part of a series of fractionated treatments or soon thereafter. There may be a seizure, a transitory worsening of the tumor symptoms, or signs of increased intracranial pressure. Although the condition has been attributed to brain edema, this is not always visible on MRI and its basis is unknown. The symptoms subside in days to weeks. Corticosteroids are usually administered, but with the exception of cases with demonstrable edema, their effect is uncertain. A novel syndrome of migraine-like headache and focal neurologic deficits, developing many years after cranial radiation, has also been described and is referred to below.

The early radiation syndrome has been more troublesome in our experience that has the very acute form. As with the acute syndrome, focal tumor symptoms may increase, and as seen on MRI (Fig. 31-25), the tumor mass enlarges, raising the possibility of further tumor growth, but again the symptoms usually reflect extensive demyelination, loss of oligodendrocytes beyond the confines of the tumor, and varying degrees of tissue necrosis. Possibly the administration of dexamethasone or a similar corticosteroid hastens resolution of this condition.

The late-delayed process is the most serious of radiation complications. Here one finds—in structures adjacent to a cerebral neoplasm, the pituitary gland, or other structures of the head and neck—necrosis of the white matter of the brain and, occasionally, of the brainstem. In some areas, the tissue undergoes softening and liquefaction, with cavitation. With lesser degrees of injury, the process is predominantly a demyelinating one, with partial preservation of axons. Later reactions are thought to be caused by diffuse vascular changes as a result of radiation energy. Endothelial cells frequently multiply and, because ionization injures dividing cells, the vessels are most vulnerable. The result is hyaline thickening of vessels with fibrinoid necrosis and widespread microthrombosis. There is a lesser degree of damage to glial cells. Neurons are relatively resistant though they can be secondarily affected by loss of glial support as well as reduced tissue perfusion.

The symptoms of delayed injury, coming on 3 months to many years after radiation therapy, are either those of a subacutely evolving mass, difficult to separate from those of tumor growth, or of a subacute dementia. The clinical pattern varies with the site of the lesion: focal or generalized seizures, impairment of mental function, and, sometimes, increased ICP. Whole-brain radiation for metastatic tumor or acute lymphoblastic leukemia can lead to multifocal zones of necrosis and holohemispheric spongiform changes in the white matter, with diffuse cerebral atrophy and enlarged ventricles. Progressive dementia, ataxia, and urinary incontinence are the main clinical features of this state (DeAngelis et al). In its mildest form there are no radiographic changes aside from the tumor, but the patient becomes mentally dull, slightly disinhibited, and often sleepy for large parts of the day. Panhypopituitarism is another complication of whole-brain radiotherapy, particularly in children, who may also suffer growth retardation. Radiation necrosis of the spinal cord is described in Chap. 44.

In the production of radiation necrosis, the total and fractional doses of radiation and the time over which treatment is administered are obviously important factors, but the exact amounts that produce such damage cannot be stated. Accepted levels of large-field radiation are tolerated in amounts approaching 6,000 cGy, provided it is given in small daily doses (200 to 300 cGy) 5 days per week over a period of 6 weeks. Other factors, still undefined, must play a part, as similar courses of radiation treatment may damage one patient and leave another unaffected. The severe necrotizing encephalopathy that has followed the combined use of methotrexate (intrathecally but also intravenously) was discussed earlier, under "Involvement of the Nervous System in Leukemia," the condition in which it was first described and formerly was most prevalent.

CT and MRI show a contrast-enhancing lesion, and by angiography there is an avascular mass. Small calcifications may appear many years after the radiation. MRI is somewhat more sensitive in distinguishing radiation necrosis from tumor and peritumor products, but PET is the most reliable way of differentiating the two, perhaps obviating the need for biopsy (Glantz et al, 1991). Single-photon emission tomography (SPECT) can be useful for this purpose as well (Carvalho et al). CT or MRI perfusion imaging can also be used to differentiate radiation necrosis from tumor progression; cerebral blood volume is reduced in the former and most often elevated in the latter.

Treatment has consisted of the administration of corticosteroids, which may cause regression of symptoms and of edema surrounding the lesion. Very high doses may be necessary, 40 mg or more of dexamethasone (or its equivalent) daily. Rarely, surgical resection of a necrotic mass has been attempted, with uncertain results.

A difficult to classify migraine-like syndrome following cranial irradiation has been described by Partap and colleagues and by Pruitt and coworkers. This syndrome has been given the acronym SMART, for stroke-like migraine attacks after radiation therapy. The typical case is of a young adult who, years or decades after receiving radiation as a child for an intracranial neoplasm, develops episodes of severe headache and simultaneous symptoms such as aphasia, hemiparesis, or hemianopia, sometimes lasting days. There may be an independent headache suggestive of migraine. The CSF protein is often elevated. In some cases there is diffuse gyriform enhancement over a large region of cortex spanning several arterial territories, and focal narrowing of intracranial vessels or capillary telangiectasias can be seen as well, both interpreted by the above authors as radiation-induced change. Corticosteroids seemed helpful in some cases.

It is also known that tumors, usually sarcomas, can be induced by radiation, as mentioned earlier (Cavin et al). While well documented, this occurs rarely and only after an interval of many years. We have also seen two cases of fibrosarcoma of the brachial plexus region in the radiation field for breast tumors (Gorson et al). These lesions appeared more than 10 years after the initial treatment, and many cases of even longer latency are on record.

Tumors of the spinal cord and peripheral nerves are discussed in Chaps. 44 and 46, respectively. The various neurologic effects of chemotherapy for systemic tumors, especially polyneuropathy, are discussed in Chaps. 43 and 46. The interesting problem of the effects on the nervous system of graft-versus-host disease are taken up in Chap. 36 with other inflammatory conditions (Figs. 31-24 and 31-25).