The main syndromes are listed in Table 15-1 (page 254) and have been summarized here in order to increase awareness of the large number of hereditary-degenerative neurologic diseases for which the clue is provided by the detection of impaired hearing and labyrinthine functions anxiety symptoms to get xanax cheap venlor 75mg mastercard. Increasing daily clozapine doses suppress dyskinesias and improve Parkinsonism symptoms anxiety xanax cheap venlor 75 mg fast delivery. Relationships of this type anxiety or depression venlor 75 mg on line, between an acquired disease of some thoracic anxiety symptoms 5 year old buy generic venlor 75 mg online, abdominal anxiety videos purchase venlor 75mg online, or endocrine organ and the brain anxiety symptoms vs pregnancy symptoms buy discount venlor 75mg online, have rather interesting implications. In the first place, recognition of the neurologic syndrome may be a guide to the diagnosis of the systemic disease; indeed, the neurologic symptoms may be more informative and significant than the symptoms referable to the organ primarily involved. Moreover, these encephalopathies are often reversible if the systemic dysfunction is brought under control. Neurologists must therefore have an understanding of the underlying medical disorder, for this may provide the means of controlling the neurologic part of the disease. In other words, the therapy for what appears to be a neurologic disease lies squarely in the field of internal medicine- a clear reason why every neurologist should be well trained in internal medicine. Of more theoretical importance, the investigation of the acquired metabolic diseases may provide new insights into the chemistry and pathology of the brain. To select a single example, the discovery of an episodic encephalopathy that is associated with advanced liver disease and portocaval shunts opened a vast new area in brain chemistry, pertaining to the effect of ammonia on glutamine metabolism, and has brought to light an intriguing histopathologic change- a relatively pure hyperplasia of protoplasmic astrocytes. Each visceral disease affects the brain in a somewhat different way, and since the pathogenic mechanism is not completely understood in any of them, the study of these metabolic diseases promises rich rewards to the scientist. In Table 40-1 the acquired metabolic diseases of the nervous system are classified according to their most common modes of clinical expression. Not included are the diseases due to nutritional deficiencies and those due to exogenous drugs and toxins, which can be considered metabolic in the broad sense; these are presented in the following chapters. Intoxication with alcohol and other drugs figures prominently in the differential diagnosis. The main features of the reversible metabolic encephalopathies are mental confusion, typified by disorientation and inattentiveness and accompanied in certain special instances by asterixis, tremor, and myoclonus, but usually without signs of focal cerebral disease. With few exceptions, usually pertaining to cerebral edema, imaging studies are normal. Laboratory examinations are highly informative in the investigation of the acquired metabolic diseases. Most often they are derived from an exogenous toxin or drug such as mannitol, but renal failure, ketonemia, and an increase of serum lactate may also result in the accumulation of small molecules that contribute to the serum osmolality. Where an exogenous toxin is suspected of causing an encephalopathy and in all cases where the cause is unknown, a "toxic screen" of blood and urine, using high-pressure liquid chromatography, should be obtained. A point to be remembered is that the brain may be damaged, even to an irreparable degree, by a disturbance of blood chemistry. Other metabolic encephalopathies: acidosis due to diabetes mellitus or renal failure (see also inherited forms of acidosis, in Chap. This is the product of hemoglobin concentration and the percentage of oxygen saturation of the hemoglobin molecule. At normal temperature and pH, hemoglobin is 90% saturated at an oxygen partial pressure of 60 mmHg and still 75% saturated at 40 mmHg; i. The product of the oxygen content and the cardiac output is the ultimate determinant of the adequacy of oxygen supply to the organs. Reduced to the simplest formulation, a deficient supply of oxygen to the brain is due either to a failure of cerebral perfusion (ischemia) or to a reduced amount of circulating arterial oxygen, the result of diminished oxygen saturation, or insufficiency of hemoglobin (hypoxia). Although they are often combined, the neurologic effects of ischemia and hypoxia are subtly different. Physiology of Ischemic and Hypoxic Damage A number of physiologic mechanisms of a homeostatic nature protect the brain under conditions of both ischemia and hypoxia. Through a mechanism termed autoregulation, there is a compensatory dilatation of resistance vessels in response to a reduction in cerebral perfusion, which maintains blood flow at a constant rate, as noted in Chap. When the cerebral blood pressure falls below 60 to 70 mmHg, an additional compensation in the form of increased oxygen extraction allows normal energy metabolism to continue. In total cerebral ischemia, the tissue is depleted of its sources of energy in about 5 min, although longer periods are tolerated under conditions of hypothermia. A similar increase in flow occurs with a decrease in hemoglobin to 20 percent of normal. In most clinical situations in which the brain is deprived of adequate oxygen, as already commented, there is a combination of ischemia and hypoxia, with one or the other predominating. The pathologic effects of ischemic brain injury from systemic hypotension differ from those due to pure anoxia. Under conditions of ischemia, the main damage takes the form of incomplete infarctions in the border zones between major cerebral arteries. With anoxia, neurons in portions of the hippocampus and the deep folia of the cerebellum are particularly vulnerable. More severe degrees of either ischemia or hypoxia lead to selective damage to certain layers of cortical neurons, and if more profound, to generalized damage of all the cerebral cortex, deep nuclei, and cerebellum. The nuclear structures of the brainstem and spinal cord are relatively resistant to anoxia and hypotension and stop functioning only after the cortex has been badly damaged. The cellular pathophysiology of neuronal damage under conditions of ischemia is discussed in Chap. Essentially, the mechanism of injury is an arrest of the aerobic metabolic processes necessary to sustain the Krebs (tricarboxylic acid) cycle and the electron transport system. Neurons, if completely deprived of their source of energy, proceed to catabolize themselves in an attempt to maintain their activity and in so doing are damaged to a degree that does not permit their survival- i. The accumulation of catabolic products (particularly lactic acid) in the interstitial tissue contributes to the parenchymal damage. Ultimately, the accumulated injury leads to cell death, probably through more than one mechanism. The most acute forms of cell death are characterized by massive swelling and necrosis of neuronal and nonneuronal cells (cytotoxic edema). Short of immediate piratory failure" and in neurologic notations to "ischemic-hypoxic" encephalopathy. Ischemic-hypoxic encephalopathy in various forms and degrees of severity is one of the most frequent and disastrous cerebral disorders encountered in the emergency departments and recovery rooms of every general hospital. There is experimental evidence that certain excitatory neurotransmitters, particularly glutamate, contribute to the rapid destruction of neurons under conditions of anoxia and ischemia (Choi and Rothman); the pertinence of these effects to clinical situations is uncertain. Ultimately, this process may be affected by massive calcium influx through a number of different membrane channels, which activates various kinases that participate in the process of gradual cellular destruction. There is also a poorly understood phenomenon of delayed neurologic deterioration after anoxia; this may be due to the blockage or exhaustion of some enzymatic process during the period when brain metabolism is restored. Clinical Features of Anoxic Encephalopathy Mild degrees of hypoxia without loss of consciousness induce only inattentiveness, poor judgment, and motor incoordination; in our experience there have been no lasting clinical effects in such cases, though Hornbein and colleagues found, on psychologic testing, a slight decline in visual and verbal long-term memory and mild aphasic errors in Himalayan mountaineers who had earlier ascended to altitudes of 18,000 to 29,000 ft. These observations make the point that profound anoxia may be well tolerated if arrived at gradually. For example, we have seen several patients with advanced pulmonary disease who were fully awake when their arterial oxygen pressure was in the range of 30 mmHg. An important derivative rule is that degrees of hypoxia that at no time abolish consciousness rarely if ever cause permanent damage to the nervous system. In the circumstances of severe global ischemia with prolonged loss of consciousness, the clinical effects can be quite variable. Following cardiac arrest, for example, consciousness is lost within seconds, but recovery will be complete if breathing, oxygenation of blood, and cardiac action are restored within 3 to 5 min. As shown in experimental models, one of the reasons for the irreversibility of the lesion may be swelling of the endothelium and blockage of circulation into the ischemic cerebral tissues, the so-called no-reflow phenomenon described by Ames and colleagues. Clinically, however, it is often difficult to judge the precise degree and duration of ischemia, since slight heart action or an imperceptible blood pressure may have served to maintain the circulation to some extent. Hence some individuals have made an excellent recovery after cerebral ischemia that apparently lasted 8 to 10 min or longer. Subnormal body temperatures, as might occur when the body is immersed in ice-cold water, greatly prolong the tolerable period of hypoxia. This has led to the successful application of moderate cooling after cardiac arrest as a technique to limit cerebral damage (see further on). Conversely, the absence of these brainstem reflexes even after circulation and oxygenation have been restored, particularly pupils that are unchanged to light, implies a grave outlook in most circumstances, as elaborated further on. If the damage is almost total, coma persists, decerebrate postures may be present spontaneously or in response to painful stimuli, and bilateral Babinski signs can be evoked. In the first 24 to 48 h, death may terminate this state in a setting of rising temperature, deepening coma, and circulatory collapse, or the syndrome of brain death intervenes, as discussed below. Most patients who have suffered severe but lesser degrees of hypoxia will have stabilized their breathing and cardiac activity by the time they are first examined; yet they may be comatose, with the eyes slightly divergent and motionless but with reactive pupils, the limbs inert and flaccid or intensely rigid, and the tendon reflexes diminished. Within a few minutes after cardiac action and breathing have been restored, generalized convulsions and isolated or grouped myoclonic twitches of muscles may supervene. The seizures, if severe and recurrent, double or treble the oxygen need of cerebral tissues. With severe degrees of injury, the cerebral and cerebellar cortices and parts of the thalami are partly or completely destroyed but the brainstem-spinal structures survive. Tragically, the individual may survive for an indefinite period in a state that is variously referred to as cortical death, irreversible coma, or persistent vegetative state (see page 304). Some patients remain mute, unresponsive, and unaware of their environment for weeks, months, or years. Long survival is usually attended by some degree of improvement, but the patient appears to know nothing of his present situation and to have lost all past memories, power of reasoning, and capacity for meaningful social interaction and independent existence (a so-called minimally responsive state, actually a severe dementia, page 305). With lesser degrees of anoxic-ischemic injury, the patient improves after a period of coma lasting hours or less. Some of these patients quickly pass through this acute posthypoxic phase and proceed to make a full recovery; others are left with varying degrees of permanent disability. The most common early change in cases of severe injury is a loss of the distinction between the cerebral gray and white matter. Patient with this finding are invariably comatose and few awaken with a good neurologic outcome. With less severe and predominantly hypotensive-ischemic events such as cardiac arrest, watershed infarctions become evident in the border zones between the anterior, middle, and posterior cerebral arteries. Natural respiration cannot be sustained; only cardiac action and blood pressure are maintained. At autopsy one finds that most if not all the gray matter of cerebral, cerebellar, and brainstem structures- and in some instances even the upper cervical spinal cord- has been severely damaged. These patients are able to walk, but their arms dangle and their hips may be weak. The interested reader may consult the appropriate chapter in the text on neurologic intensive care by Ropper and associates for further details. Myoclonus is a grave sign in most cases, but it generally recedes after several hours or a few days. Delayed Postanoxic Encephalopathy this is a relatively uncommon and unexplained phenomenon. Initial improvement, which appears to be complete, is followed after a variable period of time (1 to 4 weeks in most instances) by a relapse, characterized by apathy, confusion, irritability, and occasionally agitation or mania. Most patients survive this second episode, but some are left with serious mental and motor disturbances (Choi; Plum et al). In still other cases, there appears to be progression of the initial neurologic syndrome with additional weakness, shuffling gait, diffuse rigidity and spasticity, sphincteric incontinence, coma, and death after 1 to 2 weeks. Exceptionally, there is yet another syndrome in which an episode of hypoxia is followed by slow deterioration, which progresses for weeks to months until the patient is mute, rigid, and helpless. In such cases the basal ganglia are affected more than the cerebral cortex and white matter as in the case studied by our colleagues Dooling and Richardson. Instances have followed cardiac arrest, drowning, asphyxiation, and carbon monoxide poisoning. In exceptional cases, however, the provision of adequate fluid, vasopressor, and respiratory support allows preservation of the somatic organism in a comatose state for longer periods. Posthypoxic Neurologic Syndromes the permanent neurologic sequelae or posthypoxic syndromes observed most frequently are as follows: 1. With lesser degrees of cerebral injury, dementia with or without extrapyramidal signs 3. Extrapyramidal (parkinsonian) syndrome with cognitive impairment (discussed in relation to carbon monoxide poisoning) 4. A Korsakoff amnesic state If ischemic hypoperfusion dominates, the patient may also display the manifestations of watershed infarctions, situated between the end territories of the major cerebral vessels. Visual agnosias including Balint syndrome and cortical blindness (page 406), representing infarctions of the watershed between the middle and posterior cerebral arteries. Watershed infarction between the middle and posterior cerebral arteries after brief cardiac arrest. All of them incorporate several simple clinical features involving loss of motor, verbal, and pupillary functions in various combinations. The most often cited and extensive study of the prognostic aspects of coma following cardiac arrest is the one by Levy and colleagues of 150 patients who remained in coma for at least 6 h after cardiac arrest. It has provided the following guidelines: mortality from this state is high: 20 percent died on the first day and 64 percent by the end of 1 week. In terms of recovery, 17 percent of the patients who awakened had done so by 3 days, and only an additional 2 percent did so by 2 days. At the other extreme of the 31 percent of patients who were in a vegetative state at 1 day, 70 percent survived for 1 week, and only 3 patients recovered. We have never observed deep coma of this type lasting 5 days in an adult or more to be attended by full recovery.
When other aspects of mental functioning are affected anxiety symptoms checklist pdf purchase 75 mg venlor otc, terms such as aging-associated cognitive decline are used anxiety network buy discount venlor 75mg online. Defining the boundaries of such a condition has proved problematic anxiety killing me cheap venlor 75 mg with mastercard, and determining the risk of progression to a dementing illness even more so anxiety videos proven 75mg venlor. There is a further problem introduced by the premise that highly intelligent individuals would have to drop considerably on intelligence and memory tests to be identified as below certain age-adjusted norms anxiety symptoms list 75mg venlor amex. However anxiety girl meme discount 75 mg venlor otc, a notion has evolved in which Alzheimer disease and mild cognitive impairment exist in a spectrum (see Burns and Zaudig), and one of the main values to identifying such patients in a presymptomatic period of Alzheimer disease is the potential for early institution of treatment. In most studies, 10 to 20 percent per year of such affected patients will be found to have acquired Alzheimer disease. Loss of social graces and indifference to social customs occur, but usually later in the course of illness. Although more typical of advanced cases, on occasion the first indication of an oncoming dementia is the expression of paranoia- for example, relating to being robbed by cleaning help or to the infidelity of a spouse. Also more typical of late disease but an early feature of certain degenerative dementias, visual and auditory hallucinations, sometimes quite vivid in nature, may be added. Wandering, pacing, and other aimless activities are common in the intermediate stage of the illness, while other patients sit placidly for hours. As a rule, these patients have little or no realization of the changes occurring within themselves; i. As the condition progresses, all intellectual faculties are impaired; but in the most common degenerative diseases, memory is most affected. Eventually patients also fail to retain remote memories, to recognize their relatives, and even to recall the names of their children. Apraxias and agnosias are early and prominent in certain degenerative conditions, occurring only later in Alzheimer disease, and these defects may alter the performance of the simplest tasks, such as preparing a meal, setting the table, or even using the telephone or a knife and fork, dressing, or walking. Or, language functions may be impaired almost from the beginning of certain forms of dementia. Lost is the capacity to understand nuances of the spoken and written word, as are the suppleness and spontaneity of verbal expression. The patient gropes for proper names and common nouns and no longer formulates ideas with well-constructed phrases or sentences. Instead, there is a tendency to resort to cliches, stereotyped phrases, and exclamations, which may hide the underlying defect during conversation. Paraphasias and difficulty in comprehending complex conversations are almost universal abnormalities. Subsequently, more severe degrees of aphasia, dysarthria, palilalia, and echolalia may be added to the clinical picture. As pointed out by Chapman and Wolff, there is loss also of the capacity to express feelings, to suppress impulses, and to tolerate frustration and restrictions. If the patient is restrained, disagreeable behavior, petulance, agitation, shouting, and whining may occur. Well known to physicians is nighttime confusion and inversion of the normal sleep pattern, as well as increased confusion and restlessness in the early evening ("sundowning"), as described in Chap. Any febrile illness, drug intoxication, surgery, or metabolic upset is poorly tolerated, leading to severe confusion and even stupor- an indication of the precarious state of cerebral compensation (see "Beclouded Dementia," page 363). It would be an error to think that the abnormalities in the atrophic-degenerative dementing diseases are confined to the intellectual sphere. He may look bewildered, as though lost, or his expression may be vacant, and he does not maintain a lively interest or participate in the interview. All movements are slightly slow, sometimes suggesting an oncoming parkinsonian syndrome. Sooner or later gait is characteristically altered to a greater or lesser degree (Chap. Passive movements of the limbs encounter a fluctuating resistance or paratonia (gegenhalten). Mouthing movements and a number of abnormal reflexes- grasping and sucking (in response to visual as well as tactile stimuli), inability to inhibit blink on tapping the glabella, snout reflex (protrusion of the lips in response to perioral tapping), biting or jaw clamping (bulldog) reflex, corneomandibular reflex (jaw clenching when the cornea is touched), and palmomental reflex (retraction of one side of the mouth and chin caused by contraction of the mentalis muscle when the thenar eminence of the palm is stroked)- all occur with increasing frequency in the advanced stages of the dementia. Many of these abnormalities are considered to be motor disinhibitions that appear when the premotor areas of the brain are involved. Food intake, which may be increased at the onset of the illness, sometimes to the point of gluttony, is in the end reduced, with resulting emaciation. Finally, these patients remain in bed most of the time, oblivious of their surroundings, and succumb at this stage to pneumonia or some other intercurrent infection. Some patients, should they not die in this way, become virtually decorticate- totally unaware of their environment, unresponsive, mute, incontinent, and, in the end, adopting a posture of paraplegia in flexion. The term persistent vegetative state is appropriately applied to these patients, although it was originally devised to describe patients in this same state after cardiac arrest or head injury, as described in Chap. Occasionally, diffuse choreoathetotic movements or random myoclonic jerking can be observed, and seizures occur in a few advanced cases. The course of the prototype of dementia, Alzheimer disease, extends for 5 to 10 years or more from the time that the memory defect becomes evident. Not infrequently, a patient is brought to the physician because of an impaired facility with language. In other patients, impairment of retentive memory with relatively intact reasoning power may be the dominant clinical feature in the first months or even years of the disease; or low impulsivity (apathy and abulia) may be the most conspicuous feature, resulting in obscuration of all the more specialized higher cerebral functions. Gait disorder, though usually a late development, may occur early, particularly in patients in whom the dementia is associated with or superimposed on frontal lobe degeneration, Parkinson disease, normalpressure hydrocephalus, cerebellar ataxia, or progressive supranuclear palsy. Insofar as the several types of degenerative disease do not affect certain parts of the brain equally, it is not surprising that their symptomatology varies. Moreover, frank psychosis with delusions and hallucinations may be woven into the dementia and are particularly characteristic of certain diseases such as Lewy-body dementia. In other words, the symptoms are the primary manifestations of neurologic disease. For example, a demented person may seek solitude to hide his affliction and thus may appear to be asocial or apathetic. Again, excessive orderliness may be an attempt to compensate for failing memory; apprehension, gloom, and irritability may reflect a general dissatisfaction with a necessarily restricted life. According to Goldstein, who has written about these "catastrophic reactions," as he called them, even patients in a state of fairly advanced deterioration are still capable of reacting to their illness and to persons who care for them. In the early and intermediate stages of the illness, special psychologic tests aid in the quantitation of some of these abnormalities, as indicated in the later part of this chapter. Frontotemporal Dementia As indicated above, not all degenerative dementias have a uniform mode of onset and clinical course. Loss of memery function stands out in most descriptions of dementia because it is the core feature of Alzheimer disease, by far the most common cause of the condition. However, several clinical variants of dementia in which memory is not disproportionately affected have long been recognized, and in recent years three of them- frontotemporal dementia, primary progressive aphasia, and semantic dementia- have been subsumed under the newly minted term frontotemporal dementia. Several consensus statements on the clinical diagnostic criteria for these syndromes have been published, although not all writings on this subject are in agreement (see Morris). The most common clinical syndrome in this group is characterized by features that would be expected of diffuse cortical degeneration of the frontal lobes: early personality changes, particularly apathy or disinhibition, euphoria, perseveration in motor and cognitive tasks, ritualistic and repetitive behaviors, laconic speech leading to mutism- all with relative preservation of memory and orientation. With anterior temporal lobe involvement, hyperorality, excessive smoking, or overeating occur, and there may be added anxiety, depression, and anomia. Diminished capacity for abstraction, attention, planning, and problem solving may be observed as the degenerative process continues. Primary progressive (nonfluent) aphasia is a more highly circumscribed frontal syndrome, characterized by effortful speech, agrammatism, and impairment of reading and writing, with relative preservation of the understanding of the meaning of words. Such aphasic syndromes may persist in isolation for several years before other features of cognitive decline become evident. Semantic dementia is the least common and most poorly defined of the three syndromes. It is characterized by a fluent aphasia in which impaired semantic memory causes severe anomia and impaired word comprehension. Certainly, frontotemporal dementia, however it is defined, does not have a unique pathology; the same degenerative diseases that cause primary dementia can also at times underlie so-called frontotemporal dementia. Furthermore, dementias in which language problems are early and pre-eminent have long been known to result from Pick or Alzheimer disease and at other times to have an ambiguous pathology, i. It is to this type of nondescript pathologic change without the characteristic neurofibrillary tangles and amyloid plaques of Alzheimer disease or special intracellular inclusions that the term frontotemporal dementia is now being applied by some authors, and this at least has the advantage of separating one category of cerebral degeneration on clinical and pathologic grounds from Alzheimer disease. Current opinion also supports the separation of this subgroup of cases on the basis of a heritable type of frontotemporal dementia; these and the sporadic cases share the pathologic features of cell loss, microvacuolation of the frontal and temporal cortex, gliosis, and the deposition of tau protein. A separate group is similar in clinical presentation but displays Pick bodies as well as deposition of tau, and yet others, as mentioned, have none of these changes. Subcortical Dementia and Dementias Associated with Diseases of the Basal Ganglia McHugh, who introduced the concept of subcortical dementia, pointed out that the cognitive decline of certain predominantly basal ganglionic diseases- such as progressive supranuclear palsy, Huntington chorea, and Parkinson disease- though similar, is different in several respects from the cortical dementia of Alzheimer disease. In addition to the obvious disorders of motility and involuntary movements, there are degrees of forgetfulness, slowed thought processes, lack of initiative, and depression of mood. By contrast, the "cortical dementias" (exemplified by Alzheimer disease) are distinguished by more severe disturbances of memory, language, and calculation, prominent signs of apraxia and agnosia, and impaired capacity for abstract thought. The pathologic changes underlying the subcortical dementias predominate in the basal ganglia, thalamus, rostral brainstem nuclei, and the ill-defined projections from these regions to the cortex, particularly of the frontal lobes; however, it would be overly simplistic to attribute the dementia to changes in these areas. One of the problems with the concept of subcortical dementia is the name itself, implying as it does that symptoms of dementia are ascribed to lesions confined to subcortical structures. Anatomically, none of the neurodegenerative dementias is strictly cortical or subcortical. The attribution of dementia to subcortical gliosis, for example, has always proved to be incorrect; invariably there are cortical neuronal changes as well. In a similar way, the changes of Alzheimer disease may extend well beyond the cerebral cortex, involving the striatum, thalamus, and even cerebellum. Also, functionally, these lesions produce their effects by interrupting neural links to the frontal and other parts of the cerebral cortex. Similar ambiguity arises when one considers the dementias caused by Lewy-body disease (probably second in frequency only to Alzheimer disease) and by normal-pressure hydrocephalus; here there are parkinsonism and dementing features that could be construed as cortical and subcortical in nature. Certain authors, notably Mayeux and Stern and their colleagues as well as Tierney and coworkers, have been critical of the concept of subcortical dementia. Nonetheless, a number of studies do indeed indicate that the constellations of cognitive impairments in the two groups of dementias differ along the lines indicated above (see Brandt et al; Pillon et al). Pathogenesis of Dementia Attempts to relate the impairment of general intellectual function to lesions in certain parts of the brain or a particular pathologic change have been largely unsuccessful. This is not to say that certain parts of the cognitive apparatus are not localizable. It is the integrated capacity to think that defies easy attribution to a part of the brain. First, there is the problem of defining and analyzing the nature of the so-called intellectual functions. Second, the pathologic anatomy of the dementing diseases is often so diffuse and complex that it cannot be fully localized and quantitated. In a similar way, impairment of language function is associated specifically with disease of the dominant cerebral hemisphere, particularly the perisylvian parts of the frontal, temporal, and parietal lobes. Loss of capacity for reading and calculation is related to lesions in the posterior part of the left (dominant) cerebral hemisphere; loss of use of tools and imitation of gestures (apraxias) is related to loss of tissue in the dominant parietal region. Impairment in drawing or constructing simple and complex figures with blocks, sticks, picture arrangements, etc. And problems with modulation of behavior and stability of personality are generally related to frontal lobe degeneration. Thus, the clinical picture resulting from cerebral disease depends in part on the extent of the lesion, i. Dementia of the degenerative type is usually related to obvious structural diseases mainly of the cerebral cortex but also of the diencephalon and possibly, as mentioned earlier under "Subcortical Dementia," to the basal ganglia. In some pathologic entities, such as Alzheimer disease, the main process is a degeneration and loss of nerve cells in the cortical association areas and medial temporal lobes. In Pick disease and the primary frontotemporal dementia group discussed earlier, the atrophy is mainly frontal, temporal, or both; sometimes it is quite asymmetrical. In other diseases, such as Huntington chorea, the neuronal degeneration predominates in the caudate nuclei, putamens, and other parts of the basal ganglia. Rarely, purely thalamic degenerations may be the basis of a dementia because of the integral relationship of the thalamus to the cerebral cortex, particularly as regards memory. Even when a particular disease disproportionately affects one part of the cerebrum, additional areas are often implicated and contribute to the mental decline. One such important example is found in Alzheimer disease, in which the main site of damage is in the hippocampus, but degeneration of the cholinergic nuclei of the basal frontal region, which project to the hippocampus, greatly augments the deterioration in memory function. Indeed, replacement of this lost cholinergic influence is one of the main approaches to the treatment of the disease. Arteriosclerotic cerebrovascular disease, which pursues a different course than the neurodegenerative diseases, results in multiple foci of infarction throughout the thalami, basal ganglia, brainstem, and cerebrum, including the motor, sensory, and visual projection areas as well as the association areas. Also, the notion that small strokes exaggerate or in some way produce an Alzheimer neuropathologic process has been uncritically accepted in some quarters. The special problem of arteriosclerotic or multi-infarct dementia and our bias that it is overdiagnosed are discussed further in Chap. The lesions of severe cerebral trauma, if they result in dementia, are to be found in the cerebral convolutions (mainly frontal and temporal poles), corpus callosum, and thalamus; there is in some cases a widespread degeneration of the deep cerebral hemispheres, from a mechanical disruption of the deep white matter, termed axonal shearing. Most traumatic lesions that produce dementia are quite extensive, making localization difficult. Our own experience suggests that the thalamic lesions are central, but many authorities view the axonal shearing lesions as the primary cause of traumatic dementia (see Chap. Mechanisms other than the overt destruction of brain tissue may operate in some cases.
The inflammation may be in the anterior part of the eye or in the posterior part anxiety symptoms lasting all day generic 75mg venlor, behind the iris and extending to the retina and choroid anxiety symptoms vs heart attack venlor 75 mg low cost. Visual stimuli entering the eye traverse the inner layers of the retina to reach its outer (posterior) layer anxiety symptoms red blotches buy generic venlor 75mg, which contains two classes of photoreceptor cells- the flask-shaped cones and the slender rods anxiety after eating venlor 75mg online. The photoreceptors rest on a single layer of pigmented epithelial cells anxiety symptoms go away when distracted cheap 75mg venlor with amex, which form the outermost surface of the retina anxiety loss of appetite generic 75 mg venlor with amex. The rods and cones and pigmentary epithelium receive their blood supply from the capillaries of the choroid and, to a smaller extent, from the retinal arterioles. The rod cells contain rhodopsin, a conjugated protein in which the chromophore group is a carotenoid akin to vitamin A. The rods function in the perception of visual stimuli in subdued light (twilight or scotopic vision), and the cones are responsible for color discrimination and the perception of stimuli in bright light (photopic vision). Most of the cones are concentrated in the macular region, particularly in its central part, the fovea, and are responsible for the highest level of visual acuity. Specialized pigments in the rods and cones absorb light energy and transform it into electrical signals, which are transmitted to the bipolar cells of the retina and then, in turn, to the superficially (anteriorly) placed neurons, or ganglion cells. The axons of the retinal ganglion cells, as they stream across the inner surface of the retina, pursue an arcuate course. Being unmyelinated, they are not visible, although fluorescein retinography shows a trace of their outlines; an experienced examiner, using a bright light and deep green filter, can visualize them through direct ophthalmoscopy. The axons of ganglion cells are collected in the optic discs and then pass uninterruptedly through the optic nerves, optic chiasm, and optic tracts to synapse in the lateral geniculate nuclei, the superior colliculi, and the midbrain pretectum. The optic chiasm lies just above the pituiInternal limiting tary body and also forms part of the Anterior membrane anterior wall of the third ventricle; Nerve fiber layer hence the crossing fibers may be compressed from below by a pituiGanglion cell tary tumor, a meningioma of the tublayer erculum sellae, or an aneurysm and from above by a dilated third ventriInner plexiform cle or craniopharyngioma. Optic Bipolar cells Inner nuclear tract lesions, in comparison with chiHorizontal cell layer asmatic and nerve lesions, are relatively rare. Surprisingly, in albinism, Outer plexiform there is an abnormality of chiasmatic layer decussation, in which a majority of the fibers, including many that would Outer nuclear not normally cross to the other side, layer decussate. How this relates to the albinic defect in the pigment epitheExternal limiting lium is not known. Three of these laminae (1, 4, 6), Pigmented layer which constitute the large dorsal nucleus, receive crossed (nasal) fibers Posterior Figure 13-1. Light entering the eye anteriorly passes through from the contralateral eye, and three the full thickness of the retina to reach the rods and cones (first system of retinal neurons). Impulses arising (2, 3, 5) receive uncrossed (temporal) in these cells are transmitted by the bipolar cells (second system of retinal neurons) to the ganglion cell layer. The the third system of visual neurons consists of the ganglion cells and their axons, which run uninterruptedly geniculate cells project to the visual through the optic nerve, chiasm, and optic tracts, synapsing with cells in the lateral geniculate body. Other optic tract fibers terminate in the pretectum and innervate both Edinger-Westphal nuclei, which subserve pupillary constriction cells form a discrete bundle that first occupies the temporal side of and accommodation (see. A small group of fibers terthe disc and optic nerve and then assumes a more central position minate in the suprachiasmatic nuclei in animals and presumably within the nerve (papillomacular bundle). These anatomic details explain several useful clinsmaller caliber than the peripheral optic nerve fibers. If there is a lesion in one optic nerve, a light stimulus to keep in mind that the retinal ganglion cells and their axonic to the affected eye will have no effect on the pupil of either eye, extensions are, properly speaking, an exteriorized part of the brain although the ipsilateral pupil will still constrict consensually, i. The vascular supply of the lateral geIn the optic chiasm, the fibers derived from the nasal half of niculate body is from both the posterior and anterior choroidal and each retina decussate and continue in the optic tract with uncrossed thalamogeniculate arteries; it is therefore rarely infarcted. Thus, interIn their course through the temporal lobes, the fibers from the ruption of the left optic tract causes a right hemianopic defect in lower and upper quadrants of each retina diverge. In partial tract lesions, the visual defects in the ventricle before turning posteriorly; the upper ones follow a more two eyes are not exactly congruent, since the tract fibers are not direct path through the white matter of the uppermost part of the evenly admixed. For these reasons, incomplete lesions of the geniculocalcarine tional" point of the optic nerve and the chiasm, generally compathways cause visual field defects that are partial and often not pressive in nature, may therefore cause a contralateral quadrantic fully congruent. The receptive neurons are arranged in columns, some of which are activated by form and others by moving stimuli or by color. The neurons for each eye are grouped together and have concentric, center-surround receptive fields. The deep neurons of area 17 project to the secA ondary and tertiary visual areas of the occipitotemporal cortex of the same and opposite cerebral hemispheres and also to other multisensory parietal and temporal cortices. Separate visual A C systems are utilized in the perception of motion, color, stereopsis, contour, and depth perception. The B C classic studies of Hubel and Wiesel have elucidated much of this visual cortical physiology. The normal development of the connections deD scribed above requires that the visual system be acD tivated at each of several critical periods of development. The early deprivation of vision in one eye causes a failure of development of the geniculate and E cortical receptive fields of that eye. Moreover, the corF tical receptive fields of the seeing eye become abnormally large and usurp the monocular dominance colE umns of the blind eye (Hubel and Wiesel). In children F with congenital cataracts, the eye will remain amblyopic if the opacity is removed after a critical period of development. A severe strabismus in early life, esG G pecially an esotropia, will have the same effect (amblyopia exanopia). H In regard to the vascular supply of the eye, the H ophthalmic branch of the internal carotid artery supplies the retina, posterior coats of the eye, and optic Figure 13-2. Diagram showing the effects on the fields of vision produced by lesions at nerve head. This artery gives origin to the posterior various points along the optic pathway: A. Complete blindness in left eye from an optic ciliary arteries; the latter form a rich circumferential nerve lesion. The usual effect is a left-junction scotoma in association with a right upper plexus of vessels (arterial circle of Zinn-Haller) lo- quadrantanopia. The latter results from interruption of right retinal nasal fibers that project cated deep to the lamina cribrosa. A left nasal hemianopia could occur supplies the optic disc and adjacent part of the distal from a lesion at this point but is rare. Right superior and astamoses with the pial arterial plexus that surrounds inferior quadrant hemianopia from interruption of visual radiations. A short distance from the disc, these vessels lose in cases of visual loss are failure to carefully inspect the macular their internal elastic lamina and the media (muscularis) becomes zone (which is located 3 to 4 mm lateral to the optic disc and thin; they are properly classed as arterioles. The inner layers of the provides for 95 percent of visual acuity) and to search the periphery retina, including the ganglion and bipolar cells, receive their blood of the retina through a dilated pupil. There are variations in the supply from these arterioles and their capillaries, whereas the appearance of the normal macula and optic disc, and these may deeper photoreceptor elements and the fovea are nourished by the prove troublesome. This is most often helpful in detecting demyelinative lesions of the optic nerve, which produce Abnormalities of the Retina a loss of discrete bundles of the radially arranged and arching retinal fibers as they converge to the disc. There may be associated congestive heart failure and kidney failure; the elevated blood pressure Optic radiation must, of course, be controlled rapidly, but too preOptic tract cipitous a drop can result in retinal hypoperfusion and blindness. Calcarine area the ophthalmoscopic appearance of retinal hemorrhages is determined by the structural arChiasm rangements of the particular tissue in which they Optic occur. The geniculocalcarine projection, showing the detour of lower fibers around the rhages usually overlie and obscure the retinal vestemporal horn. Round or oval ("dot-and-blot") hemorrhages lie behind the vessels, in the outer plexiform layer of the retina (synaptic layer between bipolar cells and nuclei of and in blond individuals, and the prominence of the lamina cribrosa rods and cones-. Rupture of arterioles on the inner surface of the retina- as of receptive elements in the optic disc, or papilla, accounts for the occurs with ruptured intracranial saccular aneurysms, arteriovenous normal blind spot. The ganglion-cell axons normally acquire their malformations, and other conditions causing sudden severe elevamyelin sheaths after penetration of the lamina cribrosa, but they tion of intracranial pressure- permits the accumulation of a sometimes do so in their intraretinal course, as they approach the sharply outlined lake of blood between the internal limiting memdisc. These myelinated fibers adjacent to the disc appear as white patches with fine-feathered edges and are a normal variant, not to be confused with exudates. Nasal half of Temporal half of In evaluating changes in the retinal vessels, one must rememleft retina right retina ber that these are arterioles and not arteries. Since the walls of retinal arterioles are transparent, what is seen with the ophthalmoscope is the column of blood within them. The central light streak of many normal arterioles is thought to represent the reflection of light from the ophthalmoscope as it strikes the interface of the column of blood and the concave vascular wall. In arteriolosclerosis (usually coexistent with hypertension), the lumina of the vessels are segmentally narrowed because of fibrous tissue replacement of the media and thickening of the basement membrane. Straightening of the arterioles and arteriolar-venous compression are other signs of hypertension and arteriolosclerosis. In this cirRight lateral cumstance the vein is compressed by the thickened arteriole within geniculate nucleus the adventitial envelope shared by both vessels at the site of crossing; this compression may rarely lead to occlusion of branches of the retinal veins. Progressive arteriolar disease, to the point of occlusion of the lumen, results in a narrow, white ("silver-wire") vessel with no visible blood column. This change is associated most often with severe hypertension but may follow other types of Visual area occlusion of the central retinal artery or its branches (see descripof right tions and retinal illustrations further on). Sheathing of the venules, hemisphere probably representing focal leakage of cells from the vessels, is reportedly observed in up to 25 percent of patients with multiple sclerosis, but we have only rarely been able to detect it. Similar alterations are also seen in leukemia, malignant hypertension, sarcoid, Behcet disease, and other forms of vasculitis. Diagrammatic depiction of the retinal projections, showing of the optic nerve head and the retinal arteriolar changes noted the disproportionately large representation of the macula in the lateral geabove, a number of extravascular lesions: the so-called soft exuniculate nucleus and visual (striate) cortex. Either the small superficial or deep retinal hemorrhage may show a central or eccentric pale (Roth) spot, which is caused by an accumulation of white blood cells, fibrin, histiocytes, or amorphous material between the vessel and the hemorrhage. This lesion is said to be characteristic of bacterial endocarditis, but it is also seen in leukemia and in embolic retinopathy due to carotid disease. Cotton-wool patches, or soft exudates, like splinter hemorrhages, overlie and tend to obscure the retinal blood vessels. These patches, even large ones, rarely cause serious disturbances of vision unless they involve the macula. Soft exudates are in reality infarcts of the nerve fiber layer, due to occlusion of precapillary arterioles; they are composed of clusters of ovoid structures called cytoid bodies, representing the terminal swellings of interrupted axons. Hard exudates appear as punctate white or yellow bodies; they lie in the outer plexiform layer, behind the retinal vessels, like the punctate hemorrhages. If present in the macular region, they are arranged in lines radiating toward the fovea (macular star). Hard exudates consist of lipid and other serum precipitants due to abnormal vascular permeability of a type that is not completely understood. They are observed most often in cases of diabetes mellitus and chronic hypertension. Drusen (colloid bodies) appear ophthalmoscopically as pale yellow spots and are difficult to distinguish from hard exudates except when they occur alone; as a rule, hard exudates are accompanied by other funduscopic abnormalities. Hyaline bodies, located on or near the optic disc, are also referred to as drusen but must be distinguished from those occurring peripherally. Their main significance for neurologists is that they are often associated with anomalous elevation of the disc and can be mistaken for papilledema (Table 13-1). Microaneurysms of retinal vessels appear as small, discrete red dots and are located in largest number in the paracentral region. They are most often a sign of diabetes mellitus, sometimes appearing before the usual clinical manifestations of that disease have become obvious. The use of the red-free (green) light on the ophthalmoscope helps to pick out microaneurysms from the background. Microscopically, the aneurysms take the form of small (20to 90-mm) saccular outpouchings from the walls of capillaries, venules, or arterioles. The vessels of origin of the aneurysms are invariably abnormal, being either acellular branches of occluded vessels or themselves occluded by fat or fibrin. Finally, the periphery of the retina may harbor a hemangioblastoma, which may appear during adolescence, before the more characteristic cerebellar lesion. Occasionally, retinal examination discloses the presence of a vascular malformation that may be coextensive with a much larger malformation of the optic nerve and basilar portions of the brain. Fortuitous inspection of the retina during an attack usually shows stagnation of arterial blood flow, which returns within seconds or minutes as vision is restored (Fisher). One or a hundred attacks may precede infarction of a cerebral hemisphere in the territory of the anterior or middle cerebral artery. In one series of 80 such patients followed by Marshall and Meadows for 4 years, 16 percent developed permanent unilateral blindness, a completed hemispheral stroke, or both. If one eye is affected, there is one chance in four that the other will be involved, usually within the first year according to Sawle et al, but this involvement of the contralateral eye has occurred far less often in our patients (unless the underlying cause is temporal arteritis; see further on). Occlusion of the internal carotid artery may cause no disturbance of vision whatsoever provided that there are adequate anastomotic branches from the external carotid artery in the orbit. Rarely, carotid occlusion with inadequate collateralization is associated with a chronic ischemic oculopathy, which may predominantly affect the anterior or posterior segment or both. Insufficient circulation to the anterior segment is manifest by episcleral vascular congestion, cloudiness of the cornea, anterior chamber flare, rubeosis and iris atrophy (rubeosis iridis), and an abnormally low or high intraocular pressure. Ischemia of the posterior segment is manifest by circulatory changes in the retina and optic nerve and by venous stasis. Other neurologic signs of carotid disease may be present, for example, a local bruit (page 669). The retina becomes opaque and has a gray-yellow appearance; the arterioles are narrowed, with segmentation of columns of blood and a cherry-red appearance of the fovea. Most frequently observed are so-called Hollenhorst plaques- glistening, white-yellow atheromatous particles. The remainder are white calcium particles, from calcified aortic or mitral valves or atheroma of the great vessels, and red or white fibrin-platelet emboli from a number of sources, mostly undefined. In addition to the paucity of blood flow in retinal vessels, the retina has a creamy gray appearance and there is a "cherry-red spot" at the fovea. Glistening "Hollenhorst plaque" occlusion of a superior retinal artery branch (arrow). These occlusions represent atheromatous particles or, less often, platelet-fibrin emboli. Some are asymptomatic and others are associated with segmental visual loss or are seen after central retinal artery occlusion.
This variegated appearance distinguishes glioblastoma from the anaplastic astrocytomas anxiety 3rd trimester trusted 75 mg venlor, which show frequent mitoses and atypical cytogenic features but no grossly necrotic or hemorrhagic areas anxiety 9-5 buy cheap venlor 75 mg on-line. It is the necrotic and sometimes cystic areas that appear hypointense on imaging studies anxiety lost night buy cheap venlor 75mg. The vasculature and fibroblasts undergo a sarcomatous transformation with prominent reticulin and collagen in surrounding tissue anxiety symptoms urination cheap venlor 75mg with mastercard. The vascular and connective tissue changes suggest the elaboration of a growth factor by the tumor tissue anxiety tumblr buy discount venlor 75 mg on line. Originally anxiety symptoms kids buy generic venlor 75mg online, the glioblastoma was thought to be derived from and composed of primitive embryonal cells, but it is now generally thought to arise through anaplasia of maturing astrocytes. It should be emphasized that the histologic grade may vary from site to site within a tumor and it is common for sites of anaplastic astrocytoma and glioblastoma to coexist; in some tumors there are even sites of well-differentiated astrocytoma. To some extent, this behavior is related to some of the aforementioned genetic changes. Less than one-fifth of all patients survive for 1 year after the onset of symptoms, and only about 10 percent live beyond 2 years (Shapiro). Age is the most important prognostic factor in this group of tumors; fewer than 10 percent of patients over age 60 survive for 18 months, in comparison to two-thirds of patients under age 40. Cerebral edema and increased intracranial pressure are usually the immediate causes of death. The diagnosis must usually be confirmed by a stereotactic biopsy or by a craniotomy that aims to remove as much tumor as is feasible at the same time. At operation, 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 slightly. Treatment 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 every 4 to 6 h, are helpful if there are symptoms of mass effect such as headache or drowsiness; local signs and surrounding edema tend to improve as well. Anticonvulsants are not required unless there have been seizures, but some neurologists and neurosurgeons administer them in order to pre-empt a convulsion. 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). Usually a maximally feasible resection, the debulking described above, is combined with external beam radiation and chemotherapy. Cisplatin and carboplatin provide similar marginal improvement in survival beyond that obtained by debulking and radiation therapy. 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. 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, as is brachytherapy, both with uncertain results. The most aggressive approach, a second surgery and chemotherapy, has been generally utilized in patients under age 40 whose original operation was many months earlier. In general, these chemotherapeutic drugs prolong the symptom-free interval but have little effect on survival. 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. The median survival in cases of anaplastic astrocytoma is considerably longer, 2 to 4 years. Viewed from another perspective, in a recent large series, the 18-month postoperative survival was 15 percent in patients with glioblastoma and 62 percent in those with anaplastic astrocytoma. Favored sites 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. Some cerebral astrocytomas, as already noted, present as mixed astrocytomas and glioblastomas. These distinctions correlate to a large 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 this finding in a slow-growing intracerebral tumor is more characteristic of an oligodendroglioma. In about half of patients with astrocytoma, the opening symptom is a focal or generalized seizure, and between 60 and 75 percent of patients have recurrent seizures in the course of their illness. Headaches and signs of increased intracranial pressure are relatively late occurrences. Cyst formation and small amounts of calcium are common, especially in cerebellar tumors. The fibrillary tumors have a less stereotyped appearance, generally taking the form of a hypodense mass with less well defined borders and little or no contrast enhancement. 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. In contrast to glioblastoma, the average survival period after the first symptom is 5 to 6 years in cerebral astrocytomas and 8 years or more in cerebellar ones. Excision of part of a cerebral astrocytoma, particularly the cystic part, may allow survival in a functional state for many years. The cystic astrocytoma of the cerebellum is particularly benign in its overall behavior. In such cases, resection of the tumor nodule is of singular importance in preventing a recurrence. In recent series, the rate of survival 5 years after successful surgery has been over 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 and the latency of recurrence with modern treatment may extend for many years. A survey of the outcome of these lowgrade supratentorial tumors showed that 10-year survival after operation was from 11 to 40 percent provided that 5300 cGy was given postoperatively (Shaw et al). 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 frequent imaging procedures. A number of studies have come to the conclusion that delaying radiation in younger patients may avoid the consequences of dementia and hypopituitarism (see editorial by Peterson and DeAngelis), but others have suggested that the tumor itself and anticonvulsant drugs cause more difficulty than high-dose radiation. Lacking any clear benefit on survival, it seems to us that radiation should be withheld initially. Nevertheless, 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; chemotherapy has as yet no established place in the treatment of low-grade pure astrocytomas. However, tumors with an oligodendroglial component may respond well to combination 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 being identified. 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 reasons, the tumor is impossible to classify (or to grade) using the conventional brain tumor schemes. 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 abnormality, sometimes mistaken for depression or a subacute dementia, or pseudobulbar palsy may be the first manifestation. Imaging studies characteristically show the tumor crossing and thickening the corpus callosum. There is slight enhancement at the edges of the lesions after gadolinium infusion, and the corpus callosum is thickened. Treatment these tumors are too infrequent for categorical judgments to be made regarding therapy, but the overall response to any treatment has been disappointing and the prognosis, as mentioned, is very poor. Corticosteroids have little clinical effect, possibly because of a paucity of edema. Most trials have suggested a benefit of 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 one year is considered. When a large region is infiltrated, particularly in the temporal lobe, surgical debulking may prolong life, but otherwise surgery is futile. Oligodendroglioma this tumor was first identified by Bailey and Cushing in 1926 and described more fully by Bailey and Bucy in 1929. The tumor 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 about 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. 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 their 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. 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. Sometimes the tumor presents in a lateral ventricle; 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 Polmeteer and Kernohan series of gliomas with meningeal dissemination (less frequent than medulloblastoma and glioblastoma; see also Yung et al). The tumor does not lend itself to the glioma grading scale, but malignant degeneration, evidenced by greater cellularity and by numerous and abnormal mitoses, and necrosis occur in about one-third of the cases. As with astrocytomas, the first symptom in more than half the patients is a focal or generalized seizure; seizures often persist for many years before other symptoms develop. Approximately 15 percent of patients enter the hospital with early symptoms and signs of increased intracranial pressure; an even smaller number have focal cerebral signs (hemiparesis). The appearance on imaging studies is variable, but the most typical is a hypodense mass near the cortical surface with relatively well-defined borders. Oligodendrogliomas generally do not demonstrate contrast enhancement, but anaplastic ones and the mixed tumors may do so. In recent years, a remarkable degree of progress has been made in understanding the genetic aberrations within these tumors and the relationship of these genes to the prognosis and response to therapy. 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. Mixed oligodendrogliomas and astrocytomas should generally be treated like astrocytomas, with the addition of chemotherapy to manage the oligodendroglial component. For example, of 50 patients who had loss of these regions on 19p but no other genetic aberrations, the median survival was over 10 years. These findings are just being adopted into general clinical practice, and it is likely that refinements of them will be soon (see Louis et al and Reifenberger and Louis). Ependymoma (See also page 567) 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. More recently a myxopapillomatous type, localized exclusively in the filum terminale of the spinal cord, has been identified (see Chap. 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 (page 567). In the spinal cord, most ependymomas originate in the lumbosacral regions, from the conus medullaris or filum terminale. 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 of the well-differentiated fourth ventricular tumors are probably derived from subependymal astrocytes (see later in this chapter and also. Anaplastic ependymomas are identified by their high mitotic activity and endothelial proliferation, nuclear atypia, and necrosis.
