Chapter 21. Dementia, the Amnesic Syndrome, and the Neurology of Intelligence and Memory

Increasingly, as the number of elderly in our population rises, the neurologist is consulted because an otherwise healthy person begins to fail mentally and loses his capacity to function effectively at work or in the home. This may indicate the development of a degenerative brain disease, a brain tumor, multiple strokes, chronic subdural hematomas, drug intoxication, chronic meningoencephalitis (such as caused by HIV or syphilis), normal-pressure hydrocephalus, or a depressive illness. Formerly, when there was little that could be done about these clinical states, no great premium was attached to diagnosis. But there are now effective means of treating several of these conditions, and in some instances, of restoring the patient to normal mental competence. Moreover, diagnostic technologies allow earlier recognition of the underlying pathologic process, thus improving the chances of recovery or of preventing the disease's progression.

The definitions of normal and abnormal states of mind were considered in Chap. 20, where it was pointed out that the term dementia denotes a persistent deterioration of intellectual or cognitive function with little or no disturbance of consciousness or perception. In current neurologic parlance, the term is used to designate a syndrome of failing memory and impairment of other intellectual functions as a result of chronic progressive degenerative disease of the brain. Such a definition may be too narrow. The term more accurately includes a number of closely related syndromes characterized not only by intellectual deterioration but also by certain behavioral abnormalities and changes in personality. Furthermore, dementia can be the result of a static encephalopathy such as head trauma or cerebral anoxia or of a progressive degenerative disease, but it differs from "encephalopathy" in its chronicity. Thus, it is not possible to determine if a confused, amnestic person is demented until some time has passed and the deficits have perished. Encephalopathies, by contrast, are largely reversible.

Beyond the need to properly define these terms, the two entities have different causes. There are several states of dementia of differing causes and mechanisms and that a degeneration of certain systems of cerebral neurons, albeit common, is only one of the many types. Thus, it is more correct to speak of the dementias or the dementing diseases.

To understand the phenomenon of intellectual deterioration, it is helpful to have some idea of how intellectual functions, particularly intelligence and memory, are normally organized and sustained, and the manner in which deficits in these functions relate to diffuse and focal cerebral lesions. The neurology of intelligence is considered in this chapter as a prelude to a discussion of the dementias and the neurology of memory.

Intelligence, or intelligent behavior, has been variously defined as a "general mental efficiency," as "innate cognitive ability," or as "the aggregate or global capacity of an individual to act purposefully, to think rationally, and to deal effectively with his environment" (Wechsler) in other words, the capacity to have ideas and reason about them. It is global because it characterizes an individual's behavior as a whole; it is an aggregate in the sense that it is composed of a number of independent and qualitatively distinguishable cognitive abilities. This topic should be of interest to neurologists because intelligence is disturbed by many disorders of the brain but cannot be easily attributed to any cerebral region or particular cognitive function. In the dementias and in developmental delays, intelligence is affected in a way that cannot be explained except by some global aspect of brain function.

As every educated person knows, intelligence has something to do with normal cerebral function. It is also apparent that the level of intelligence differs widely from one person to another, and members of certain families are exceptionally bright and intellectually accomplished, whereas members of other families are just the opposite. If properly motivated, intelligent children excel in school and score high on intelligence tests. Indeed, the first intelligence tests, devised by Binet and Simon in 1905, were for the purpose of predicting scholastic success. The term intelligence quotient, or IQ, was introduced by the German psychologist Stern and used by Terman in 1916 for the development of intelligence testing. It denotes the figure that is obtained by dividing the subject's mental age (as determined by the Binet-Simon scale) by his chronologic age (up to the 14th year) and multiplying the result by 100. The IQ correlates, but only broadly, with achievement in school and eventual success in professional work. IQ increases with age up to the 14th to 16th years and then remains stable, at least until late adult life. At any given age, a large sample of normal children attains test scores of a normal, or gaussian, distribution.

The original studies of pedigrees of highly intelligent and mentally less-able families, which revealed a striking concordance between parent and child, lent support to the idea that intelligence is to a large extent inherited. However, it became evident that the tests were also greatly influenced by the environment in which the child was reared. Moreover, tests were less reliable in identifying talented children who were not offered optimal opportunities. This led to the widespread belief that intelligence tests are only achievement tests and that environmental factors fostering high performance are the important factors determining intelligence.

Neither of these views is likely to be entirely correct. Studies of monozygotic and dizygotic twins raised in the same or different families have put the matter in a clearer light. Identical twins reared together or apart are more alike in intelligence than nonidentical twins brought up in the same home (see reviews of Willerman, of Shields, and of Slater and Cowie). A study of elderly twins by McClearn and colleagues has shed further light on the issue; even in twins who were older than 80 years of age, a substantial part (an estimated 62 percent) of cognitive performance could be accounted for by genetic traits. These findings suggest that life experience alters intelligence, but in only a limited way. There can be little doubt, therefore, that genetic endowment is the more important factor—a view that was championed by Piercy and more recently by Herrnstein and Murray. However, there is also evidence that early learning modifies the level of ability that is finally attained. The latter should be looked upon not as the sum of genetic and environmental factors but as the product of the two. More importantly, it is generally appreciated that nonscholastic achievement or success is governed by factors other than intellectual ones, such as curiosity, a readiness to learn, interest, persistence, sociability, and ambition or motivation—factors that vary considerably from person to person and are not measured by tests of intelligence.

As to the genetic mechanisms involved in the inheritance of intelligence, a limited amount is known. There is an excess of males with mental retardation, and there are several well-characterized syndromes in which the inheritance of mental retardation is X-linked as described in Chaps. 28 and 38. Also notable is the somewhat different patterns of subtest performance between males and females (males perform better on subtests of spatial ability and certain mathematical tasks). Males may be more likely to be affected by advantageous or aberrant genes on a single X chromosome, whereas females benefit from the mosaic provided by two X chromosomes. In some families, high intelligence segregates to certain individuals through an X-linked pattern. Further study will determine the validity of this view and its contribution to our understanding of what will certainly prove to be a polygenic inheritance of intellectual traits.

One would think that neurologic structure and function would correlate in some way with intelligence, but with the exception of the pathologically developmentally delayed (Chaps. 28 and 38), such an association has been difficult to document. Brain weight and the complexity of the convolutional pattern are not correlated with intelligence—despite popular notions to the contrary, including a widely criticized analysis of the brain of Albert Einstein. (In regard to Einstein's brain, Witelson and colleagues proposed that an enlarged inferior parietal lobule, a crossmodal association area, accounted for his visuospatial and mathematical genius, but this has been disputed.) Only laboratory measures of vigilance and facility of sensory registration (speed of motor responses/reaction time and rapid recognition of differences between lines, shapes, or pictures) have a definite but still modest correlation with IQ. However, it is of interest that morphometric features of the regions of the cortex that are presumed to underlie IQ and verbal skills, such as the frontal and language areas, show a heritable component when measured on high-resolution MRI scans in twins (see Thompson et al).

As to psychologic theories of intelligence, several have traditionally been held at different historical periods. One is the two-factor theory of Spearman, who noted that all the separate tests of cognitive abilities correlated with each other, suggesting that a general factor (g factor) enters into all performance. Because none of the correlations between subtests approached unity, he postulated that each test measures not only this general ability (commonly identified with intelligence) but also a subsidiary factors specific to the individual tests, which he designated the s factors. A second theory, the multifactorial theory of Thurstone, proposed that intelligence consists of a number of primary mental abilities, such as memory, verbal facility, numerical ability, visuospatial perception, and capacity for problem solving, all of them more or less equivalent. These primary abilities, although correlated, are not subordinate to a more general ability. For Eysenck, intelligence exists in three forms: biologic (the genetic component), social (development of the genetic component in relation to personal relationships), and a number of specific abilities subject to measurement by psychometric tests.

Thurstone's multifactorial theory of intelligence has been periodically resurrected, most recently by Gardner who recognizes six categories of high-order cerebral ability but restates them in more modern terms: linguistic (encompassing all language functions); musical (including composition and performance); logical–mathematical (the ideas and works of mathematicians); spatial (including artistic talent and the creation of visual impressions); bodily–kinesthetic (including dance and athletic performance); and the personal (consciousness of self and others in social interactions). He refers to each of these as intelligences, defined as the ability to solve problems or resolve difficulties and to be creative within the particular field. Several lines of evidence are marshaled in support of this parceling of separable skills and abilities: (1) each may be developed to an exceptionally high level in certain individuals, constituting virtuosity or genius; (2) each can be destroyed or spared in isolation as a consequence of a lesion in a certain part of the nervous system; (3) in certain individuals, i.e., in prodigies, special competence in one of these abilities is evident at an unusually early age; (4) in the autism spectrum, one or more of these abilities may be selectively spared or developed to an abnormally high degree (idiot savant). Each of these entities appears to have a genetic basis in so far as musical, artistic, mathematical, and athletic ability often runs in families, but their full development is influenced by environmental factors.

There are only limited data regarding the highest levels of intelligence identified as genius. Terman and Ogden's longitudinal study of 1,500 California school children who were initially tested in 1921 supported the idea that an extremely high IQ predicted future scholastic accomplishments (though not necessarily occupational and life success). On the other hand, most individuals recognized as geniuses have been especially skilled in one domain—such as painting, linguistics, music, chess, or mathematics—and such "domain genius" is not necessarily predicated on high IQ scores, although certain individuals display crossmodal superiorities—particularly in mathematics and music.

Chapter 28 discusses the developmental aspects of intelligence in detail. One of the leading theories has been that of Piaget, who proposed that this is accomplished in discrete stages related to age: sensorimotor, from 0 to 2 years; preconceptual thought, from 2 to 4 years; intuitive thought, from 4 to 7 years; concrete operations (conceptualization), from 7 to 11 years; and, finally, the period of "formal operations" (logical or abstract thought), from 11 years on. This scheme implies that the capacity for logical thought, developing as it does according to an orderly timetable, is coded in the genes. Surely, one can recognize these states of intellectual development in the child, but Piaget's theory has been criticized as being too anecdotal and lacking the quantitative validation that could be derived only from studies of a large normal population. Furthermore, it does not take into account an individual's special abilities, which do not usually develop and reach their maximum at the same time as the more general intellectual capacities.

One would suppose that in neurology, where one is exposed to so many diseases affecting the cerebrum, it might be possible to verify one of these several theories of intelligence and to determine the anatomy of this cognitive entity. Presumably, the g factor of intelligence would be maximally impaired, by diffuse lesions, in proportion to the mass of brain involved, an idea expressed by Lashley as the "mass-action principle." Indeed, according to Chapman and Wolff, there is a correlation between the volume of brain tissue lost and a general deficit of cerebral function. Others disagree, claiming that no universal psychologic deficit can be linked to lesions affecting particular parts of the brain. Probably the truth lies between these two divergent points of view. According to Tomlinson and colleagues, who studied the effects of vascular lesions in the aging brain, lesions that involve more than 50 mL of tissue cause some general reduction in performance, especially in speed and capacity to solve problems. Piercy, on the other hand, found correlations only between specific intellectual deficits and lesions of particular parts of the left and right hemispheres. These problems are discussed in Chap. 22. It is surprising that lesions of the frontal lobes, and particularly the prefrontal regions, which so profoundly disorder planning and "executive" functions, do not measurably affect IQ except in subtests specific to these skills.

The authors conclude from experience and from evidence provided by neurologic studies that intelligence is a combination of multiple primary abilities, each of which seems to be inherited and each of which has a separate but as yet poorly delineated anatomy. Yet we would disagree with both Thurstone and Gardner that these special abilities are of equivalent weight with regard to what is generally considered as "intelligence." When viewed in the light of the classics of literature, history, and science, we attach a disproportionate importance to some of them, namely linguistic and mathematical, and perhaps spatial–dimensional, abilities. These are integral to ideation and problem solving and are largely absent in the developmentally delayed and lost early in dementing diseases. To the extent that facility with general mental performance, that requiring the manipulation of abstract symbols and thoughts, marks an individual as "intelligent" and that these correlate with each other, we find Spearman's g factor to be a credible but not completely satisfying concept for intelligence.

Neurologic data certainly do not exclude the possibility of a general factor for intelligence—one that is unavoidably measured in many different tests of cerebral functions. It is expressed in thinking and abstract reasoning and is operative only if the connections between the frontal lobes and other parts of the brain are intact. Attention, drive, and motivation are noncognitive psychologic attributes of fundamental importance, the precise anatomy and physiology of which remain to be identified but are largely generated in the frontal and prefrontal region. It is also possible, if not likely, that the associative areas of the cerebrum are engaged in the apperception of sensory experiences and their manipulation in symbolic form. This applies equally to the ability to relate thoughts to each other and to stored concepts, but here, memory plays a central role. We view memory and capacity to learn as a separate cognitive entity, with its own neuroanatomic localizations. The interrelationships between some of these special abilities had been thoughtfully analyzed by Luria (see the section on frontal lobes in Chap. 22). An account of the subject of IQ and intelligence can also be found in the monograph by Mackintosh.

An even more complex problem arises in the neurologic analysis of the highest human achievement and the method of human advancement, namely creativity. In some ways, creativity is tied to special skills along the lines of Gardner's modality-based intelligence, particularly as it relates to artistic work, but the brain structures involved in aesthetics and abstraction are entirely obscure, as Zeki points out. Some insight is gained from the fact that intelligence and problem-solving ability are innately but only roughly tied to creativity and that there are congenital absences and deficiencies of appreciation of visual, artistic, or mathematical skills. The capacity to be creative may be inhibited by other functions of the brain, as exposed in the case described by Seeley and colleagues of a woman with frontotemporal dementia whose artistic abilities emerged as her facility with language deteriorated. But, as pointed out in the following chapter, traits such as creativity almost certainly do not reside in a particular lobe or structure of the brain and may depend on the overdevelopment of certain associative areas, as well as on frontal lobe drive and, of course, are fully manifest only by educational exposure.

Dementia is a syndrome consisting of a loss of several separable but overlapping intellectual abilities and presents in a number of different combinations. These constellations of intellectual deficits constitute the preeminent clinical abnormalities in several cerebral diseases and are sometimes virtually the only abnormalities. Table 21-1 lists the most common types of dementing diseases and their relative frequency.

What is noteworthy about the figures in this table is the apparently high level of accuracy of diagnosis. Rather consistently, postmortem examination confirms that the accuracy of the clinical diagnosis of Alzheimer disease is in excess of 80 percent when rigid research criteria are used (Table 21-2). Of course, the high frequency of this disease in the older population makes the likelihood of correct diagnosis higher. In most cases, the degenerative diseases can be differentiated by one or two characteristic clinical features, but these distinctions may be difficult to discern early in the disease process. In particular, a proportion of patients thought to have Alzheimer disease are found to have another type of degenerative cerebral atrophy, such as Lewy-body disease, progressive supranuclear palsy, Huntington disease, Parkinson disease, corticobasal degeneration, Pick disease, or one of the frontotemporal lobar degenerative diseases (all described in Chap. 39). Or such patients have one of a variety of other processes, such as multiinfarct dementia or hydrocephalus alone or in combination with one of the other disorders. Of special importance is the fact that approximately 10 percent of patients who are referred to a neurologic center with a question of dementia prove to have a potentially reversible psychiatric or metabolic disorder. Emphasized again are the group of nonprogressive dementias that are the lasting result of a monophasic injury to the brain and do not appear in Table 21-2.

In the following pages, we consider the prototypic dementing syndromes. They are observed most frequently with degenerative diseases of the brain (Chap. 39) and less often as part of other categories of disease (vascular, traumatic, infectious, demyelinating), which are considered in their appropriate chapters.

Mild Cognitive Impairment and Early Dementia

It has become apparent that many individuals have memory complaints that are mild and do not interfere with daily functioning but are still disproportionate for the patient's age and education. It is often difficult to differentiate this less-intrusive problem, which may be a result of the normal process of aging, from dementia. The former condition has been called mild cognitive impairment, age-associated memory impairment, and, in the past, benign senescent forgetfulness, as discussed in Chap. 29. When other aspects of mental functioning are affected, terms such as aging-associated cognitive decline are used. Defining the boundaries of such a condition has proved problematic, and determining the risk of progression to a dementing illness that does interfere with daily function, even more so. There is a further problem introduced by the premise that highly intelligent individuals would have to decline considerably on intelligence and memory tests to be identified as being below certain age-adjusted norms. However, a notion has evolved in which Alzheimer disease and mild cognitive impairment exist in a spectrum (see Petersen), 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 with mild cognitive decline will be found to have later acquired Alzheimer disease. A number of factors have been identified as associated with a progression to a state of indisputable dementia. These include elevated blood pressure, changes in the cerebral white matter on MRI, abnormality of gait, and—perhaps not surprisingly—certain biologic markers that are connected to Alzheimer disease. Other factors for the development of dementia, particularly the level of prior education and maintenance of an active mental life, have been studied in relation to Alzheimer disease (C.F. Willis et al) and are discussed in that section of Chap. 39.

At the moment, the clinician must simply counsel caution and reassurance in advising patients with mild memory impairment, and exclude treatable causes. Nonetheless, if the symptoms are progressive or begin to interfere in any consistent way with other mental functions or with the performance of daily activities, a dementing illness is likely.

Dementia Caused by Degenerative Diseases

The earliest signs of dementia caused by degenerative disease may be so subtle as to escape the notice of the most discerning physician. An observant relative of the patient or an employer may become aware of a certain lack of initiative or lack of interest in work, a neglect of routine tasks, or an abandonment of pleasurable pursuits. Initially, these changes may be attributed to depression, fatigue, or boredom in retirement. More often, gradual development of forgetfulness is the most prominent early symptom. Proper names are no longer remembered and cannot be recalled with time, to a far greater extent than can be attributed to "mild cognitive impairment." Difficulty in balancing a checkbook and making change becomes evident. The purpose of an errand is forgotten, appointments are not kept, and recent conversations or social events have been overlooked. The patient may ask the same question repeatedly over the course of a day, having failed to retain the answers that were previously given.

Later, it becomes evident that the patient is easily distracted by every passing incident. He no longer finds it possible to think about or discuss a problem with customary clarity or to comprehend all aspects of complex situations. The ability to make proper deductions and inferences from given premises are greatly reduced. One feature of a situation or some relatively unimportant event may become a source of unreasonable concern or worry. Tasks that require several steps cannot be accomplished, and all but the simplest directions cannot be followed. The patient may get lost, even along habitual routes of travel. Day-to-day events are not recalled, and perseveration or impersistence in speech, action, and thought becomes evident.

In yet other instances, an early abnormality may be in the nature of emotional instability, taking the form of unreasonable outbursts of anger, easy tearfulness, or aggressiveness. A change in mood becomes apparent, deviating more toward depression than elation. Apathy is common. Some patients are irascible; a few are cheerful and facetious. The direction of the mood change is said to depend on the patient's previous personality rather than on the character of the disease, but one can think of glaring exceptions from clinical experience. Excessive lability of affect may also be observed—for example, easy fluctuation from laughter to tears on slight provocation.

A considerable group of patients come to the physician with physical complaints, the most common being dizziness, a vague mental "fogginess," and nondescript headaches. The patient's inability to give a coherent account of his symptoms bears witness to the presence of dementia. Sleep disturbances, especially insomnia, are prominent in some cases and a particular disorder relating to the acting out of dreams during REM sleep marks some of the degenerative dementia. Sometimes the mental failure is brought to light more dramatically by a severe confusional state attending a febrile illness, a concussive head injury, an operative procedure, or the administration of some new medicine, as discussed below and in Chap. 20. As noted there, the family almost uniformly, but mistakenly, dates an abrupt onset of dementia to the time of the intercurrent illness.

Loss of social graces and indifference to social customs may occur, but usually later in the course of illness. Judgment becomes impaired, early in some, late in others. At certain phases of the illness, suspiciousness or frank paranoia may develop. 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 employees or to the infidelity of a spouse. When the patient's condition is probed by an examination, there are no signs of depression, hallucinations, or illogical ideas, but memory and problem solving are found to be deficient. The troublesome paranoid ideas then persist throughout the illness. 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. By this point, these patients have little or no realization of the changes occurring within themselves; i.e., they lack insight into the problem.

As the condition progresses, all intellectual faculties become impaired; but in the most common degenerative diseases, memory is most affected. Deference to a spouse or child when the patient is unable to answer the examiner's questions is characteristic. Up to a certain point in the illness, memories of the distant past are relatively well retained at a time when more recently acquired information has been lost (Ribot's law). 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 one special group of degenerative conditions, occurring only later in Alzheimer disease. 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 are impaired almost from the beginning of certain forms of dementia. Lost in these cases is the capacity to understand nuances of the spoken and written word, as are the suppleness and spontaneity of verbal expression. Vocabulary becomes restricted and conversation is rambling and repetitious. 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 clichés, stereotyped phrases, and exclamations, which hide the underlying defect during conversation. Paraphasias and difficulty in comprehending complex conversations become prominent. 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.

However, several clinical variants of dementia in which memory is relatively spared have long been recognized, and in recent years three of them—frontotemporal dementia (Pick disease), primary progressive aphasia, and semantic dementia—have been subsumed under the summary term frontotemporal lobar degeneration. 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 degeneration of the frontal lobes: early personality changes, particularly apathy or disinhibition, euphoria, perseveration in motor and cognitive tasks, ritualistic and repetitive behaviors, and laconic speech leading to mutism—all with relative preservation of memory, orientation, and visuospatial capability. 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. These are subsumed under the term disorders of "executive functions." To these features in some patients is added a parkinsonian syndrome.

In the advanced stages of some dementias, restraining the patient leads to disagreeable behavior, petulance, agitation, shouting, and whining. 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. 20. Any febrile illness, drug intoxication, anesthesia, surgery, or metabolic upset is poorly tolerated, leading to severe confusion and even stupor—an indication of the precarious state of cerebral compensation.

It would be an error to think that the abnormalities in the degenerative dementing diseases are confined to the intellectual sphere. The patient's appearance and the physical examination yield highly informative data. The first impression is often revealing; the patient may be unkempt and unbathed. 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. There is a kind of psychic inertia. Movements may be slightly slow, sometimes suggesting an oncoming parkinsonian syndrome.

Sooner or later, gait is characteristically altered in many of the dementias (Chap. 7). 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.

In the very later stages, physical deterioration is inexorable. 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 adopting a posture of flexion. They lie with their eyes open but do not look about. Food and drink are no longer requested but are swallowed if placed in the patient's mouth. The term persistent vegetative state is appropriately applied to these patients, although it was originally devised to describe patients in this inert state after cardiac arrest or head injury. Occasionally, diffuse choreoathetotic movements or random myoclonic jerking can be observed, and seizures occur in a few advanced cases. Pain or an uncomfortable posture goes unheeded. 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. The clinical course of advanced dementia has been studied by Mitchell and colleagues in nursing homes. Those who acquired pneumonia, a febrile episode or an eating disorder, not surprisingly, had high rates of mortality, approaching half, in the subsequent 6 months.

Naturally, every case does not follow the exact sequence outlined here. Often, a patient is brought to the physician because of an impaired facility with language. In other patients, impairment of 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, although 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, normal pressure hydrocephalus, cerebellar ataxia, or progressive supranuclear palsy. Insofar as the 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. Chapter 39 discusses these variations and others more fully.

The aforementioned alterations of intellect and behavior are the direct consequence of neuronal loss in certain parts of the cerebrum. In other words, the symptoms are the primary manifestations of neurologic disease. However, some symptoms are secondary; i.e., they may represent the patient's reactions to his mental incapacity. 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 calls 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 neuropsychologic tests aid in the quantitation of some of these abnormalities, as indicated in the later part of this chapter.

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—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 mild forgetfulness, slowed thought processes, lack of initiative, and depression of mood. Relatively spared, however, are vocabulary, naming, and praxis. 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 mostly, in the ill-defined projections in the white matter 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 almost 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 both 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. They argue that the distinctions between cortical and subcortical dementias are not fundamental and that any differences between them are probably attributable to differences in the relative severity of the dementing processes. 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 earlier (see Pillon et al). And, the clinical distinction between cortical and subcortical dementia based on a relative sparing of core cortical functions is very useful.

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. Lashley's concept of loss of intelligence in proportion to brain damage has already been mentioned. 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. Two types of difficulty have obstructed progress in this field. First, there is the problem of defining and analyzing the nature of the intellectual functions as already discussed. Second, the pathologic anatomy of the dementing diseases is often so diffuse and complex that it cannot be fully localized and quantitated.

As described in Chap. 22, certain portions of the intellectual ensemble are controlled by circumscribed regions of the cerebrum. Memory impairment, which is a central feature of some dementias, may occur with extensive disease in several different parts of the cerebrum, but the integrity of certain discrete parts of the diencephalon and inferomedial parts of the temporal lobes is fundamental to memory. 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., is observed with parietal lobe lesions, more often with right-sided (nondominant) than with left-sided ones. 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.e., the amount of cerebral tissue destroyed, and in part on the region of the brain that bears the brunt of the pathologic change.

Dementia of the degenerative types is related to obvious structural diseases of the cerebral cortex but the diencephalon and, as mentioned earlier, the basal ganglia are also implicated. 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. There is no evidence, however, that arteriosclerosis per se, without vascular occlusion and infarction, is a cause of progressive dementia as was thought in previous decades. Undoubtedly, the cumulative effects of recurrent strokes impair the intellect. Usually, but not always, the stroke-by-stroke advance of the disease is apparent in such patients (multi-infarct dementia). More uncertain in our opinion is the notion that a decline in mental function can be attributed to periventricular white matter changes (leukoaraiosis), which are observed on CT and MRI scans of many elderly patients and are presumed to be ischemic in nature (see review of van Gijn). Also, the construct that small strokes exaggerate or in some way biologically produce an Alzheimer neuropathologic process has been uncritically accepted in some quarters. The two processes do seem to coincide more often than chance. The special problem of arteriosclerotic or multi-infarct dementia is discussed in Chap. 34 on cerebrovascular disease.

The lesions of severe cerebral trauma, if they result in dementia, are found in the cerebral convolutions (mainly frontal and temporal poles), corpus callosum, and thalamus. In some cases, there is widespread degeneration of the deep cerebral hemispheres, because of 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 critical, but many authorities view the axonal shearing lesions as the primary cause of traumatic dementia. The special problem of chronic traumatic encephalopathy is addressed in Chap. 35.

Mechanisms other than the overt destruction of brain tissue may operate in some cases of dementia. Chronic hydrocephalus, regardless of cause, is often associated with a general impairment of mental function. Compression of the cerebral white matter is probably the main factor, but this has not been settled. The extrinsic compression of one or both of the cerebral hemispheres by chronic subdural hematomas may have the same effect. A diffuse inflammatory process is at least in part the basis of dementia in syphilis, cryptococcosis, other chronic meningitides, and viral infections such as HIV encephalitis, herpes simplex encephalitis, and subacute sclerosing panencephalitis; presumably, there is a loss of some neurons and an inflammatory derangement of function in the neurons that remain. The prion diseases (e.g., Creutzfeldt–Jakob disease) cause a diffuse loss of cortical neurons, replacement gliosis, and spongiform change and produce special patterns of cognitive dysfunction.

The adult forms of leukodystrophy (Chap. 37) also give rise to a dementing state, generally a "subcortical" syndrome with prominent frontal lobe features. Or extensive lesions in the white matter may be the result of advanced multiple sclerosis, progressive multifocal leukoencephalitis, or some of the vascular dementias already mentioned (Binswanger disease and CADASIL [cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy]). Last, several of the metabolic and toxic disorders discussed in Chaps. 37, 40, and 43 may interfere with nervous function over a period of time and create a clinical picture similar, if not identical, to that of one of the dementias. One must suppose in those cases that the altered biochemical environment has affected neuronal function.

Classification of the Dementing Diseases

Conventionally, the dementing diseases have been classified according to cause if known, to the pathologic changes, or more recently, to a genetic mutation. Another, more practical approach, which follows logically from the method by which much of the subject matter is presented in this book, is to divide the diseases into three categories on the basis of the neurologic signs and associated clinical and laboratory signs of medical disease: (1) dementia with medical disease, (2) dementia that is accompanied by other prominent neurologic signs, and (3) dementia as the sole or predominant feature of the illness (Table 21-3). Once it has been determined that the patient suffers from a dementing illness, it must then be decided from the medical, neurologic, and ancillary data into which category the case fits. This classification may at first seem somewhat dated and not based on newer genetic and molecular models, but it is likely to be more useful to the student or physician who must confront the many diseases that cause dementia.

Differential Diagnosis

Although dementia per se does not indicate a particular disease, certain combinations of symptoms and neurologic signs are more or less characteristic and may aid in diagnosis. The age of the patient, the mode of onset of the dementia, its clinical course and time span, the associated neurologic signs, and the accessory laboratory data constitute the basis of differential diagnosis. It must be admitted, however, that some of the rarer types of degenerative brain disease are at present recognized mainly by pathologic examination or genetic testing. The correct diagnosis of treatable forms of dementia—subdural hematoma, certain brain tumors, chronic drug intoxication, normal-pressure hydrocephalus, HIV (reversible to some extent), neurosyphilis, cryptococcosis, pellagra, vitamin B12 and thiamine deficiency states, hypothyroidism, and other metabolic and endocrine disorders—is, of course, of greater practical importance than the diagnosis of the untreatable ones. Also important is the detection of a depressive illness, which may masquerade as dementia, and chronic intoxication with drugs or chemical agents, both of which are treatable.

The first task in dealing with this class of patients is to verify the presence of intellectual deterioration and personality change. It may be necessary to examine the patient serially before one is confident of the clinical findings and their chronicity. A mild aphasia from a focal brain lesion must not be mistaken for dementia. Aphasic patients appear uncertain of themselves, and their speech may be incoherent. Careful attention to the patient's language performance will lead to the correct diagnosis in most instances. It is a clinical truism that the abrupt onset of mental symptoms points to a delirium or other type of acute confusional state or to a stroke; inattention, perceptual disturbances, and often drowsiness are conjoined (Chap. 20). Also, progressive deafness or loss of sight in an elderly person may sometimes be misinterpreted as dementia.

There is always a tendency to assume that mental function is normal if a patient complains only of anxiety, fatigue, insomnia, or vague somatic symptoms, and to label the patient as anxious. This will be avoided if one keeps in mind that these disorders rarely have their onset in middle or late adult life.

Clues to the diagnosis of depression are the presence of frequent sighing, crying, loss of energy, psychomotor underactivity or its opposite, agitation with pacing, persecutory delusions, persistent hypochondriasis, and a history of depression in the past and in the family. Although depressed patients may complain of memory failure, scrutiny of their complaints will show that they can usually remember the details of their illness and that little or no qualitative change in other intellectual functions has taken place. Their difficulty is either a lack of energy and interest or preoccupation with personal worries and anxiety, which prevents the focusing of attention on anything except their own problems. Even during mental tests, their performance may be impaired by "emotional blocking," in much the same way as the worried student blocks during an examination ("experiential confusion"). When such patients are calmed by reassurance and encouraged to try harder, their mental function improves, indicating that intellectual deterioration has not occurred. Conversely, it is helpful to remember that demented patients rarely have sufficient insight to complain of mental deterioration; if they admit to poor memory, they do so without conviction or full appreciation of the degree of their disability. The physician must not rely on the patient's statements alone in gauging the efficiency of mental function and should seek corroboration from family members. Yet another problem is that of the impulsive, cantankerous, and quarrelsome patient who is a constant source of distress to employer and family. Such changes in personality and behavior (as, for example, in Huntington disease) may precede or mask early intellectual deterioration.

The neuropsychiatric symptoms associated with metabolic, endocrine, or toxic disorders (e.g., Cushing syndrome, vitamin B12 deficiency, hypercalcemia, uremia) may present difficulties in diagnosis because of the wide variety of clinical pictures by which they manifest themselves. Drowsiness or stupor and asterixis are the surest signs of a metabolic or drug-induced encephalopathy, but they are not always present. Psychosis with hallucinations and a great deal of fluctuation in behavior also bespeak an exogenously caused confusional state, with the exception that Lewy-body dementia also has these characteristics. Whenever any such metabolic or toxic disorder is suspected, a thorough review of the patient's medications is crucial. Medications with atropinic activity, for example, can produce an apparent dementia or worsen a structurally based dementia, as discussed in Chap. 20. Occupational exposure to toxins and heavy metals should also be explored, but this is an infrequent cause of dementia; therefore, slight or even moderately elevated levels of these chemicals in the blood should be interpreted cautiously. It is also useful to keep in mind that seizures are not a usual component of the degenerative dementias; when they are present, they generally do not appear until a very late stage.

Once it is decided that the patient suffers from a dementing condition, the next step is to determine by careful physical examination, whether there are other neurologic signs or indications of a particular medical disease. This enables the physician to place the case in one of the three aforementioned categories in the bedside classification (see above and Table 21-3).

Experienced neurologists recognize that certain leading neurologic features are indicative of particular degenerative dementias. For example, prominent and early parkinsonian signs such as bradykinesia, tremor, and shortened gait step are parts of the subcortical dementias of Lewy body and Parkinson diseases. Rigidity of the limbs and apraxia may have a similar clinical appearance but point to corticobasal degeneration as the cause of mental decline. An early aphasia or visuospatial difficulty that is manifest as either geographic confusion or difficulty with drawing, copying, and recognizing faces and objects are characteristic of a focal degeneration of the parietal or inferior temporal lobes. Involuntary movements such as choreoathetosis, dystonia, ataxia, and myoclonus are each signs of particular degenerative disorders that include Huntington disease, acquired and inherited hepatocerebral degenerations, and prion disorder, all of which are discussed in later chapter. Frequent falls and a disorder of vertical eye movements are the core components of progressive supranuclear palsy that often has an attendant dementia. In the nondegenerative categories of dementia, spasticity and Babinski signs are typical of vascular dementias.

Ancillary examinations—such as CT, MRI, electroencephalography (EEG), lumbar puncture, measurement of blood urea nitrogen, as well as serum concentrations of calcium and electrolytes, and liver function tests—should be carried out in appropriate cases. Brain MRI and CT are of major importance in objectifying hydrocephalus, lobar atrophy, cerebrovascular disease, tumor, and subdural hematoma. Testing for syphilis, vitamin B12 deficiency, and thyroid function is also done in many clinics almost as a matter of routine because the tests are simple and the dementias they cause are reversible. These are supplemented in individual circumstances by serologic testing for HIV infection, measurement of copper and ceruloplasmin levels (Wilson disease), heavy metal concentrations in urine or tissues, serum cortisol levels, and drug toxicology screening. The final step is to determine, from the total clinical picture, the particular disease within any one category.

(See also Chap. 41)

The terms listed above are used interchangeably to designate a unique disorder of cognitive function in which memory and learning are deranged almost in isolation from all other components of mentation and behavior. The amnesic state, as originally defined by Ribot, possesses two salient features that may vary in severity but are always conjoined: (1) an impaired ability to recall events and other information that had been firmly established before the onset of the illness (retrograde amnesia) and (2) an impaired ability to acquire new information, i.e., to learn or to form new memories (anterograde amnesia). This duality inspired the White Queen, one of Lewis Carroll's characters, to quip, "It's a poor sort of memory that works only backwards." In other words, the functions of memory and learning are inseparable. A third feature of the Korsakoff syndrome, contingent upon retrograde amnesia, is impaired temporal localization of past experience. Other cognitive functions, particularly the capacity for concentration, spatial organization, and visual and verbal abstraction, which depend little or not at all on memory, are usually not affected. Equally important in the definition of the Korsakoff syndrome, or amnesic state (these terms are preferable to the older term, Korsakoff psychosis), is this integrity of certain aspects of behavior and mental function.

In order to establish the presence of the Korsakoff syndrome, the patient must be awake, attentive, and responsive—capable of perceiving and understanding the written and spoken word, of making appropriate deductions from given premises, and of solving such problems as can be included within his forward memory span. These features are of particular diagnostic importance because they help to distinguish the Korsakoff amnesic state from a number of other disorders in which the basic defect is not in memory but in some other abnormality—e.g., impairment in attention and perception (as in the delirious, confused, or stuporous patient), in loss of personal identity (as in the hysterical patient), or in volition (as in the apathetic or abulic patient with frontal lobe disease or depression).

Immediate recall, a function of working memory, allows the patient with Korsakoff syndrome to repeat a string of digits, but this is more a measure of attention and registration. Remote memory is relatively less affected than recent memory (the Ribot rule, as discussed later).

Confabulation

The creative falsification of memory in an alert, responsive individual is often included in the definition of the Korsakoff amnesic state but is not a requisite for diagnosis. It can be provoked by questions as to the patient's recent activities. The replies may be recognized as partially remembered events and personal experiences that are inaccurately localized in the past and related with no regard to their proper temporal sequence. Less frequent in Korsakoff syndrome, but more dramatic, is a spontaneous recital of personal experiences, many of which are fantasies. These two forms of confabulation have been referred to as "momentary" and "fantastic". In the patients with the alcoholic Korsakoff syndrome studied by Victor and Adams, fantastic confabulation was observed mainly in the initial phase of the illness, in which it could be related to a state of profound general confusion. In the chronic, stable stage of the illness, confabulation was rarely elicitable irrespective of how broadly this symptom was defined. Confabulation therefore is not an obligate feature of the Korsakoff syndrome.

Neuropsychology of Memory

Memory function obeys certain neurologic laws. As memory fails, it first loses its hold on recent events. The extent in time of retrograde amnesia is generally proportionate to the magnitude of the underlying neurologic disorder. Early life memories are better preserved and often have been integrated into habitual responses; nevertheless, with natural aging, there is also a gradual loss of early life memories. In transitory amnesias (e.g., concussive head injury), memories are recovered in reverse order: first the remote and then the more recent. The enduring aspect of early life memories in contrast to more recently experienced and learned material, a restatement of the Ribot law, is apparent in both normal adults and in demented patients. As quoted by Kopelman, Ribot in 1882 stated: "The progressive destruction of memory follows a logical order—a law—it begins at the most recent recollections which, being rarely repeated and having no permanent associations, represent organization in its feeblest form."

In the further analysis of the Korsakoff amnesic syndrome, it is necessary to consider the proposition that memory is not a unitary function, but takes several forms. One practical classification that adheres broadly to current ideas in the field is shown in Fig. 21-1 and Table 21-4. An initial separation is made between the aforementioned immediate recall and the other types of memory. Short-term memory is exemplified by the common daily acts of hearing a phone number and retaining it to be able to walk across a room and dial the phone; or, performing a series of mental calculations that requires holding an intermediate sum briefly in mind; all the numbers are soon forgotten. Long–term memory can be viewed from the perspective the individual's awareness of the learning of new material (explicit memory), or not being conscious of the event of acquiring memory (implicit memory). Functions such the acquisition of physical skills (such as driving a car or playing tennis) are implicit memories termed procedural memory. Classic conditioning is considered another type of implicit memory.

Explicit memory subsumes what most persons consider to be memory and learning, that is, the ability to retain and recount events that were consciously experienced by the person, including the time and general circumstances of the acquisition (episodic, or autobiographical memory). Semantic memory, the learning of the nature of the environment and factual knowledge (such as the shape and color of a lion) is also a type of explicit memory but the event of acquiring the memory cannot be recalled. A patient with virtually no capacity to learn any newly presented information can nonetheless still acquire some simple manual and pattern-analyzing skills. Moreover, having acquired these skills, the patient may have no memory of the circumstances in which they were acquired. The learning of simple mechanical skills has been referred to as procedural memory, in distinction to learning new data information. Cohen and Squire have described this dichotomy as "knowing how" as opposed to "knowing that."

As confirmation of the separation of episodic from semantic memory functions, Gadian and colleagues have described young patients who showed severe impairments of episodic memory with relative preservation of semantic memory that was attributable to hypoxic-ischemic injury (bilateral hippocampal atrophy) sustained early in life. Here, again, the subject matter most relevant to amnesia involves episodic, or autobiographical, memory. The same occurs in early Alzheimer disease and herpes simplex encephalitis.

A pervasive problem with these terms is the lack of uniformity in defining the terms of memory. To Tulving, whose writings on this subject are recommended, the term episodic denotes a memory system for dating personal experiences and their temporal relationships; semantic memory is one's repository of perceptual and factual knowledge, which makes it possible to comprehend language and make inferences. This hardly constitutes a novel concept; Korsakoff himself clearly recognized that certain aspects of mental function (among them those now being defined as semantic memory) remain intact, despite the profound impairment of episodic memory. Damasio has introduced yet another set of terms—generic in place of semantic and contextual for episodic. To Damasio, generic memory denotes the basic properties of acquired information, such as its class membership and function; he makes the point that in the amnesic syndrome, this component of declarative memory remains intact and only the contextual component is impaired.

The full significance of these categorizations is still being explored. The categorical purity of semantic memory is open to question, as is the notion of a strict dichotomy between semantic and episodic memory. Most importantly, a separate anatomic basis for these systems of memory has not been clearly established (see below). Further interesting derivative issues regarding the neuropsychology of memory in relation to brain diseases can be found in the review by Kopelman. Among these is the degree to which a disparity between retrograde and anterograde memory can be detected in certain diseases. He also points out nicely the subtle distinctions between recall and memory by recognition.

Neuropsychologists have further subdivided memory and suggested that there are corresponding anatomic regions for specific categories (see Table 21-4). Some of these more complex subtypes have been alluded to above and others are simply restatements of the act of registration. Furthermore, it is not surprising that the participation of certain areas of the brain not primarily involved in memory function, particularly the language and visuospatial areas, is required for the performance of certain memory tasks. Among the special modules of memory, the notion of a working memory has both clinical and neuropsychologic credibility. This relates to the capacity to register and attend to a task, and there is little question that it is a measurable form of memory. Several regions of the brain must be active during tasks of working memory, including the hippocampi and dorsal thalamus, but lesions of the dorsolateral prefrontal cortex most specifically impair the skill. The original work of Goldman-Rakic may be referred to for discussion of the mechanisms that underlie working memory.

Finally, there are reasons, based mainly on the neuroanatomic and functional imaging studies discussed later, to view episodic memory for spatial and topographic information in a particular way. Certainly the recollection of personally experienced events can be dissociated to some degree from the memory of the topographic arrangement of the scene in which these memories were formed, but often these two elements are inextricably bound in one experience. More salient may be a disproportionate degradation of learned topographic and directional information compared to learned semantic material; such a dissociation can be found, but only in relative terms, in patients who have injuries to their right hippocampus, whereas semantic material is dependent more on the left hippocampus (see later).

Anatomic Basis of the Amnesic Syndrome

Two anatomic structures are of central importance in memory function: the diencephalon (specifically the medial portions of the dorsomedial and adjacent midline nuclei of the thalamus) and the hippocampal formations of the medial temporal lobes including their associated structures (dentate gyrus, hippocampus, parahippocampal gyrus, subiculum, and entorhinal cortex). Discrete bilateral lesions in these two main regions derange memory and learning disproportionate to all other cognitive functions, and even a unilateral lesion of these structures, especially of the dominant hemisphere, can produce a lesser degree of the same effect. The clinical–anatomic relationships that bear on this subject are discussed in detail by Aggleton and Saunders and in the monograph on Wernicke–Korsakoff syndrome by Victor et al.

While central to memory function, these are not the only regions engaged in the formation and retrieval of memory. A severe but less-enduring defect in memory is observed with damage of the anterior septal gray matter; a cluster of midline nuclei at the base of the frontal lobes, just below the interventricular septum and including the septal nucleus, nucleus accumbens, diagonal band of Broca; and paraventricular hypothalamic gray matter. The case of infarction of this region reported by Phillips and colleagues confirms the participation of this region in memory formation and retrieval. The amnesic syndrome, usually not permanent, that follows a ruptured anterior communicating aneurysm is a consequence of disruption of these nuclei. These septal nuclei have connections with the hippocampus through the precommissural fornix and with the amygdala through the diagonal band. Again, what is most remarkable about this basal frontal amnesic syndrome is its initial severity lasting for weeks to months and the potential for almost complete recovery.

Observations of human disease have confirmed the fundamental importance of the diencephalic–hippocampal structures in all memory function. The difficulty of evaluating memory function in monkeys has been largely overcome by use of the "delayed nonmatching-to-sample task," which is essentially a refined test of recognition memory and is impaired both in patients with the amnesic syndrome and in monkeys with lesions of the mediodorsal nuclei of the thalamus and inferomedial temporal cortical regions (Mishkin and Delacour). Using this method and several others that simulate a restricted form of human amnesia, Zola-Morgan and colleagues have shown that bilateral lesions of the hippocampal formation cause an enduring impairment of memory function. Lesions confined to the fornices or mammillary bodies and stereotaxic lesions of the amygdala that spared the adjacent cortical regions (entorhinal and perirhinal cortices) failed to produce a memory defect. However, lesions that were restricted to the perirhinal and entorhinal cortex (Brodmann areas 35 and 36) and the closely associated parahippocampal cortex did cause a persistent memory defect, presumably by interrupting the major afferent pathways conveying cortical information to the hippocampus. Lesions of the anteromedial parts of the diencephalon, which receive and send fibers to the amygdala and hippocampus, similarly abolished memory function.

A body of work using functional neuroimaging also addresses the anatomic mechanisms of memory function. It has been found that the hippocampal formations are consistently engaged during memory acquisition and retrieval tasks. In addition, Maguire's group found a differential activation of the right side during recall of topographic spatial information and the left side for autobiographical memory. Their clever use of London taxi drivers as subjects for imaging studies has further suggested that the volume of the right hippocampus is larger in subjects who have more experience navigating the arcane streets of London. An asymmetrical representation of certain modalities of memory is in keeping with limited clinicopathologic studies of patients who have undergone temporal lobectomy on one side.

These observations in aggregate confirm that integrity of the hippocampal formations and the medial-dorsal nuclei of the thalamus are essential for normal memory and learning. Interestingly, there are only sparse direct anatomic connections between these two regions. The importance assigned to the hippocampal formations and medial thalamic nuclei in memory function does not mean that the mechanisms governing this function are confined to these structures or that these parts of the brain form a "memory center." It informs us only that these are the sites where the smallest lesions have the most devastating effects on memory and learning. Normal memory function, as emphasized, involves many parts of the brain in addition to diencephalic–hippocampal structures. The aforementioned basal frontal nuclei that project to the hippocampi are an example.

It is also clear that particular lesions of the neocortex may cause impairment of specific forms of memory and learning. Thus, a lesion of the dominant temporal lobe impairs the ability to remember words (loss of explicit semantic memory), and a lesion of the inferior parietal lobule undermines the recognition of written or printed words as well as the ability to relearn them (alexia). The dominant parietal lobe is related to recollection of geometric figures and numbers; the nondominant parietal lobe, to visuospatial relations; the inferoposterior temporal lobes, to the recognition of faces; and the dominant posterofrontal region, to acquiring and remembering motor skills and their affective associations. Whether these are truly forms of memory, or whether these regions of cortex must be entrained in order to retrieve and "experience" the memory, is philosophical. Taken to its extremes, aphasia from a left temporal perisylvian lesion (Wernicke's aphasia) could be viewed as an amnesia for language, and parietal lesions that cause ideomotor apraxia could be taken to represent a loss of memory for these previously learned acts. What remains inviolate is that the integrity of both the hippocampal–thalamic system and the appropriate cortical region is required for memory as we refer to it in this chapter, but only the former is integrated into all modalities of learning and retrieval.

It is a remarkable feature of the Korsakoff amnesic state that no matter how severe the defect in memory may be, it is never complete. Certain past memories can be recalled, but imperfectly and with no regard for their normal temporal relationships, giving them a fictional quality and explaining many instances of confabulation. Another noteworthy fact is that long-standing social habits, automatic motor skills, and memory for words (language) and visual impressions (visual or pictorial attributes of persons, objects, and places) are unimpaired. Long periods of repetition and usage may have made these implicit or procedural memories virtually automatic; they no longer require the participation of the diencephalic–hippocampal structures that were necessary to learn them originally. All of this suggests that these special memories, or coded forms of them, through a process of relearning and habituation, come to be stored or filed in other regions of the brain; i.e., they acquire a separate and autonomous anatomy that may be regional, cellular, or subcellular.

Several fundamental questions concerning the amnesic syndrome remain unanswered. Not known is how a disease process, acting over a brief period of time, not only impairs all future learning but also wipes out portions of a vast reservoir of past memories that had been firmly established for many years before the onset of the illness. Most likely, it is not the memories themselves that are obliterated but the mechanism required to access them.

One of the most provocative new observations regarding memory has been the enhancement of performance by electrical stimulation of the entorhinal area in individuals with epilepsy. The study by Suthana and colleagues is one of several demonstrating this effect in an improved ability to retain topographic-spatial landmarks in a simulated exercise. At a minimum, these findings confirm the critical role of parahippocampal regions (perforant pathways) in forming and stabilizing memories, in these cases, the major source of afferent input to the hippocampus.

This begs the fascinating question of "what is a memory?" Current notions suggest that no single hippocampal neuron, for example, embodies a memory but that the connections between an ensemble of neurons in the medial temporal lobes and modality-specific neurons in the associative cortices are, in fact, the memory. Strengthening synaptic connections among this network serves to establish the memory. This may occur through long-term potentiation, as the work of Kandel has emphasized in experimental models. It is not clear if a hippocampal neuron is the trigger to the memory ensemble or the entirety of hippocampal system serves a generic role in cohering all memories. The cellular mechanisms involved in learning and the formation of memories are only beginning to be understood. Whether physiologic phenomena such as long-term potentiation or anatomic changes in the dendritic structure of neurons are at the center of memory storage is not known; certainly both are likely to be involved. The neurochemical systems that are activated during formation and recall of memory are also obscure. Kandel has provided a detailed review of information on this subject. The anatomic and physiologic mechanisms that govern immediate registration, which remains intact in even the most severely damaged patients with the Korsakoff amnesic syndrome has not been fully deciphered.

Other psychologic features of human memory that must be accounted for by any model purporting to explain this function are the importance of cueing in eliciting learned material and the imprecision of past memories, allowing for unwitting embellishment and false recollection, to the point of fabrication. The latter aspect has been a topic of considerable importance in children who have (or have not) been subjected to sexual abuse and in adults and children whose memories of past abuse have been suggested by the examiners (see Schacter).

The separate roles of the thalamus, the hippocampi, and the frontal lobes in memory and the differences in the nature of the amnesia resulting from damage at each site remain to be clarified. That isolated thalamic lesions, without implicating medial temporal areas, can cause a Korsakoff syndrome is evident from the experience with alcoholism and stroke. Graff-Radford and colleagues have found that with purely thalamic lesions, as appreciated by imaging studies, anterograde learning is more affected than retrograde recall; but comparing these functions quantitatively is difficult. Kopelman, in reviewing his own studies and those of others, concludes that the differences are subtle and pertain mostly to temporal ordering and the modality of information, which is degraded more with diencephalic–temporal lesions than with frontal lobe damage.

Each of the amnesic states listed in Table 21-5 is considered at an appropriate point in subsequent chapters of this book. The only exception is the striking syndrome of transient global amnesia, the nature of which is not certain. It cannot be included with any assurance with the epilepsies or the cerebrovascular diseases or any other category of disease and is therefore considered here.

This was the name applied by Fisher and Adams to a particular transient type of memory disorder that they observed in more than 20 middle-aged and elderly persons. The condition was characterized by an episode of amnesia and bewilderment lasting for several hours. The symptoms had their basis in an amnesia for events of the recent past coupled with an ongoing anterograde amnesia. During the attack, there is no impairment in the state of consciousness, no other sign of confusion, and no overt seizure activity; personal identification is intact, as are motor, sensory, and reflex functions. The patient's behavior is normal except for a very characteristic incessant, repetitive questioning about his immediate circumstances—usually of the identical question over and over at intervals of 20 to 60 seconds after a response to the query has been given by the examiner (e.g., "What am I doing here?"; "How did we get here?"). Unlike psychomotor epilepsy, the patient is alert, in contact with his surroundings, and capable of high-level intellectual activity and language function during the attack. As soon as the episode has ended, no abnormality of mental function is apparent except for a permanent gap in memory for the period of the attack itself and for a brief period (hours or days) preceding it. The patient may be left with a mild headache. Incomplete or mild attacks are infrequent, and they may be as brief as 1 h, but are typically longer. The condition is among the most curious in neurology and may be mistaken for a psychiatric episode.

Hodges and Ward have made detailed psychologic observations in 5 patients during an episode. The psychologic deficit, except for its transience, was much the same as that in a permanent amnesia syndrome. Personality, cognition involving high-level functioning, semantic language, and visuospatial discrimination were all preserved. So-called immediate memory—i.e., registration (see earlier)—was likewise operating normally, but memory was essentially obliterated. The duration of retrograde amnesia was highly variable, but characteristically it shrank after the attack, leaving a permanent retrograde gap of about 1 h. However, subtle impairment of new learning persisted for up to a week after the acute attack insofar as this defect could be detected by special testing.

In a survey conducted in the Rochester, Minnesota, area, transient global amnesia (TGA) occurred at an annual rate of 5.2 cases per 100,000 population. The recurrence of such attacks is not uncommon, having been noted in 66 of 277 older adults who were observed for an average period of 80 months (Miller et al) and in 16 of 74 patients followed for 7 to 210 months (Hinge et al). Hinge and colleagues estimate the mean annual recurrence rate to be so low (4.7 percent) that most patients are likely to experience only one attack. One of our patients had more than 50 attacks, but among all the rest (more than 100 cases), 5 was the maximum. It seems children are not susceptible to the condition; however, a 13-year-old and 16-year-old with migraine were reported to have had similar attacks during participation in sports (Tosi and Righetti).

No consistent antecedent events have been identified, but certain ones—such as a highly emotional experience like hearing of the death of a family member, pain, exposure to cold water, sexual activity, and mild head trauma—have been reported in some cases (Haas and Ross; Fisher). The similarity to postconcussive amnesia is notable; this is always a concern if the patient was not under observation at the onset of the attack. We have also seen several patients in whom the attacks appeared after minor diagnostic procedures such as colonoscopy, but the residual effects of sedation are suspect in some of these. Several cases have been reported in high-altitude climbers and have created difficulty in distinguishing TGA from altitude sickness.

One can conceive of TGA as a syndrome that has several non idiopathic causes. The main concern is a focal temporal lobe seizure that can simulate the syndrome. Transient ischemic attack involving the same posterior regions is another. Whether migrainous episodes can produce a clinical syndrome is uncertain, as noted later, but by far the largest number of cases are idiopathic after extensive evaluation.

The pathogenesis of idiopathic TGA has not been settled. It has been suggested that typical case represents an unusual form of temporal lobe epilepsy (transient epileptic amnesia [TEA]), but this seems an unlikely unifying hypothesis. A large number of patients have been studied with EEGs during an attack or shortly thereafter and have not shown seizure activity (Miller et al). Moreover, amnesic episodes caused by seizures are usually much briefer than those of TGA, and most or all temporal lobe seizures are associated with impairment of consciousness and an inability to interact fully with the social and physical environment. Using EEG and nasopharyngeal leads, Rowan and Protass found mesiotemporal spike discharges in 5 of 7 patients. Curiously, they attributed the discharges to ischemic lesions during drug-induced sleep. Palmini and coworkers cite exceptional cases of pure amnesic seizures in temporal lobe epilepsy, but even in their best examples, ictal and postictal function was not normal.

Transient global amnesia may be ischemic or perhaps migrainous in nature, though not atherosclerotic-thrombotic, but rarely (if ever) do the attacks progress to stroke. Regarding cerebrovascular disease and TGA, Hinge and associates and Hodges and Warlow, in a case-control study of 114 patients with TGA, found no evidence of an association with cerebrovascular disease; there was, however, a significantly increased history of migraine, as there was in the series of Miller and coworkers (14 percent) and of Caplan and colleagues. From indirect evidence of retrograde blood flow in the internal jugular arteries during the Valsalva maneuver (occasionally reported to precipitate an attack), Sander and colleagues and Chung and coworkers have suggested that venous congestion of the temporal lobes was operative. Other studies suggest that the draining veins in the neck lack valves in patients who have had TGA, which permits venous ischemia in the temporal lobes (Schreiber et al); rare cases associated with lateral sinus thrombosis also implicate derangements in venous blood flow in the genesis of TGA. None of these is definitive and they are mentioned here for completeness.

The most compelling cases for an ischemic basis of TGA, perhaps most relevant to migraine, come from Stillhard and colleagues, who demonstrated bitemporal hypoperfusion during an attack of TGA, and from Strupp and associates and Sedlaczek and colleagues, who demonstrated hippocampal and peri-hippocampal lesions (interpreted as cellular edema) with diffusion-weighted MRI, but only 2 days following an attack, not acutely. Like the clinical syndrome, the MRI findings are reversible (Fig. 21-2). The precipitation of identical attacks by vertebrobasilar and coronary angiography is also suggestive of an ischemic or migrainous causation.

A hypothesis generated by the authors of studies on delayed MRI lesions is of a mismatch between cerebral blood supply and demand in the limbic regions. This provides a potential explanation for the association of highly emotional events prior to an episode.

The benignity of transient global amnesia in most patients is noteworthy. Once the history and examination have excluded vertebrobasilar ischemia and temporal lobe epilepsy, no treatment is required other than an explanation of the nature of the attack and reassurance, although we often hospitalize such patients briefly to be certain that the episode clears without further incident. The diagnosis of TGA should not be accepted if there has been ataxia, vertigo, diplopia, or other visual complaints, or if there are deficits in cognition that extend beyond the limited retrograde and complete anterograde amnesia.

The physician presented with a patient suffering from dementia must adopt an examination technique designed to expose the intellectual defect fully. Abnormalities of posture, movement, sensation, and reflexes cannot be relied on to disclose the disease process. Suspicion of a dementing disease is aroused when the patient presents multiple complaints that seem totally unrelated to one another and to any known syndrome; when symptoms of irritability, nervousness, and anxiety are vaguely described and do not fit exactly into one of the major psychiatric syndromes; and when the patient is incoherent in describing the illness and the reasons for consulting a physician.

Three categories of data are useful for the recognition and differential diagnosis of dementing brain disease:

1. A reliable history of the illness and its impact on daily life

2. Findings on mental examination

3. Ancillary examinations: CT, MRI, functional imaging, sometimes lumbar puncture, EEG, and appropriate laboratory procedures, as described in Chap. 2

The history should always be supplemented by information obtained from a person other than the patient, because, through lack of insight, the patient will have limited and variable grasp of his illness or its gravity; indeed, he may be unaware even of his chief complaint. Special inquiry should be made about the patient's general behavior, capacity for work, personality changes, language, mood, special preoccupations and concerns, delusional ideas, hallucinatory experiences, personal habits and care in hygiene, and such faculties as memory and judgment.

The examination of the mental status should include some of the following general categories with suggested examples for testing as modified for each patient's circumstances. In addition, the mode of answering and solving problems gives invaluable information about the mental operations of the subject and must be incorporated into any analysis of cognition. A perplexed or slowed individual may ultimately perform adequately but nonetheless have seriously flawed cortical or subcortical function. Each of the tests below is necessarily an abstraction but ones that separate particular functions of the brain. As already emphasized, the patient must have normal, or nearly so, attentiveness to carry out these tasks and a deficiency in any one of them may disrupt the performance of others.

1. Insight (patient's replies to questions about the chief symptoms): What is your difficulty? Are you ill? When did your illness begin?

2. Orientation (knowledge of personal identity and present situation): What is your name, address, telephone number? What is your occupation? Are you married?

   1. Place: What is the name of the place where you are now (building, city, state)? How did you get here? What floor is it on? Where is the bathroom?

   2. Time: What is the date today (day of week and of month, year)? What time of the day is it? What meals have you had? When was the last holiday?

3. Memory:

   1. Long-term: Tell me the names of your children (or grandchildren) and their birth dates. When were you married? What was your mother's maiden name? What was the name of your first school-teacher? What jobs have you held? These must be corroborated by a spouse or other family member. We also find it useful to quiz the patient about cultural icons of the past that are appropriate to his age. Most patients should be able to name the recent presidents in reverse order.

   2. Recent past: Tell me about your recent illness (compare with previous statements). What is my name (or the nurse's name)? When did you see me for the first time? What tests were done yesterday? What were the headlines of the newspaper today?

   3. Immediate recall (attention, short-term working memory): Repeat these numbers after me (give series of 3, 4, 5, 6, 7, 8 digits at a speed of 1 per second). Now when I give a series of numbers, repeat them in reverse order. Cross out all the a's on a printed page; count forward and backward; say the months of the year forward and backward; spell world forward and then backward. Verbal trail making (reciting alternating letters of the alphabet and their ordinal place, i.e., A-1, B-2, C-3, D-…)

   4. Memorization (learning): The patient is given three or four simple data (examiner's name, date, time of day, and a fruit, structure, or trait, such as honesty—we use "a red ball, Beacon Street, and an envelope") and is asked to repeat them after a minute; or is given a brief story containing several facts and is asked to recount the main facts as soon as the story is over. The capacity to reproduce them at intervals after committing them to memory is a test of memory span.

   5. Another test of memory and verbal fluency we have found useful is the generation of a list of objects in a category; ask the patient to give the names of animals, vegetables, or makes of cars, as many as come to mind in 30 s or so; most individuals can list at least 12 items in each category.

   6. Visual facility: Show the patient a picture of several objects; then ask him to name the objects.

4. Capacity for calculation, construction, and abstraction:

   1. Calculation: Test ability to add, subtract, multiply, and divide. Subtraction of serial 3s and 7s from 100 is a good test of calculation as well as of concentration.

   2. Constructions: Ask the patient to draw a clock and place the hands at 7:45, a map of the United States, a floor plan of her house; ask the patient to copy a cube and other figures.

   3. Abstract thinking: See if the patient can describe the similarities and differences between classes of objects (orange and apple, horse and dog, desk and bookcase, newspaper and radio) or explain a proverb or fable ("People who live in glass houses shouldn't throw stones"; "A stitch in time saves nine"; "A rolling stone gathers no moss"; "Idle hands are the devil's workshop").

5. General behavior: Attitudes, general bearing, evidence of hallucinosis, stream of coherent thought and attentiveness (ability to maintain a sequence of mental operations), mood, manner of dress, etc.

6. Special tests of localized cerebral functions: Grasping, sucking, aphasia battery, praxis with both hands, and corticosensory function.

To enlist the full cooperation of the patient, the physician must prepare him for questions of this type. Otherwise, the patient's first reaction will be one of embarrassment or anger because of the implication that his mind is unsound. It could be pointed out to the patient that some individuals are rather forgetful or have difficulty in concentrating, or that it is necessary to ask specific questions in order to form some impression about his degree of nervousness when being examined. Reassurance that these are not tests of intelligence or of sanity is helpful. If the patient is agitated, suspicious, or belligerent, intellectual functions must be inferred from his remarks and from information supplied by the family.

This type of mental status survey can be accomplished in about 10 min. In our experience, a high level of performance on all tests eliminates the possibility of dementia in almost all cases. It may fail to identify a dementing disease in an uncooperative patient and in a highly intelligent individual in the earliest stages of disease.

The question of whether to resort to formal psychologic tests is certain to arise. Such tests yield quantitative data of comparative value but cannot of themselves be used for diagnostic purposes. The Mini-Mental Status Examination (MMSE) devised by Folstein and coworkers (Table 21-6), and the Montreal Cognitive Assessment (MOCA) are popularly used. A score of 24 on the widely used "mini-mental" is considered normal and scores below 21 generally indicate cognitive impairment. Patients with lower levels of education and older age have lower normative scores, but even individuals in their eighties with a high school education score 23 or above if not demented (see Crum et al for age and education adjusted normal score). A number of other tests that measure the degree of dementia (carrying the names of their originators: Roth, Pfeiffer, Blessed, Mattis) rely essentially on the points mentioned above and a brief assessment of the patient's ability to accomplish the activities of daily living, which is lost in the later stages of disease.

Probably the Wechsler Adult Intelligence Scale (WAIS) is also accurate in detecting dementia. In this test, an index of deterioration is provided by the discrepancy between the vocabulary, picture-completion, and object-assembly tests as a group (these correlate well with premorbid intelligence and are relatively insensitive to dementing brain disease) and other measures of general performance, namely arithmetic, block-design, digit-span, and digit-symbol tests. The Wechsler Memory Scale estimates the degree of memory failure and can be used to distinguish the amnesic state from a more general dementia (discrepancy of more than 25 points between the WAIS and the memory scale). Questions that measure spatial and temporal orientation and memory are the key items in most of these abbreviated scales of dementia. All of the aforementioned clinical and psychologic tests, and several others as well, measure the same aspects of behavior and intellectual function. The WAIS, MOCA, and the MMSE of Folstein and associates are the most widely used clinically in our experience and serve the clinician well.

Dementia is a clinical state of the most serious nature. The physician can see the patient serially over a period of weeks, during which the appropriate laboratory tests (blood, cerebrospinal fluid analysis, and CT, MRI and functional imaging as discussed in Chap. 39) can be carried out. The management of demented patients in the hospital may be relatively simple if they are quiet and cooperative. If the disorder of mental function is severe, it is helpful if a nurse, attendant, or member of the family can stay with the patient at all times.

The primary responsibility of the physician is to diagnose the treatable forms of dementia and to institute appropriate therapy. If it is established that the patient has an untreatable dementing brain disease and the diagnosis is sufficiently certain, a responsible member of the family should be informed of the medical facts and prognosis and assisted in the initiation of social and support services. In the past, it was considered that patients themselves need be told only that they have a condition for which they are to be given rest and treatment. Most physicians (and patients) find this too patronizing; certainly, in the current social environment, patients ask directly if they have Alzheimer disease. To this query we usually respond that they may, but that more time is required to be certain. Some intelligent patients have insisted on knowing the details and implications of this statement, and we have felt obliged to give as much useful information as required by them.

Reassurance that the physician will be available to help the patient and family manage the situation is of utmost value. Crises should be preempted by regular contact with a general physician. If the dementia is slight and circumstances are suitable, patients should remain at home for the first years, continuing to engage in those accustomed activities of which they are capable. They should be spared responsibility and guarded against injury that might result from imprudent action, such as leaving a stove turned on or driving and getting lost—or worse. If they are still at work, plans for occupational retirement should be carried out. In more advanced stages of the disease, when mental and physical enfeeblement become pronounced, a skilled nursing facility or supervised home care should be arranged.

The value of centrally acting cholinergic agents and glutamate antagonists in the treatment of Alzheimer disease is modest but clear and should be weighed against the need for blood testing and side effects. These medications, however, offer psychologic benefit to the patient and family; Chap. 39 discusses the use of these medications.

Undesirable restlessness, nocturnal wandering, and belligerency may be reduced by administration of one of the antipsychotic or benzodiazepine drugs (see Chaps. 20, 43, and 48). Although randomized trials of these drugs have failed to show benefit in extreme circumstances, partly as a result of poor tolerance, there are few other options. Emotional lability and paranoid tendencies may be managed by the judicious use of quetiapine, olanzapine, risperidone, or haloperidol. Some patients are helped by short-acting sedatives such as lorazepam without any worsening of the mental condition, but all these drugs must be given with caution and some may be particularly problematic in patients with combined parkinsonism and dementia syndromes.

Questions asked by the patient's family must be answered patiently and sensitively by the physician. Common questions are "Should I correct or argue with the patient?" (No.) Orientation as to date, circumstances, and planned appointments is, however, helpful in preparing the patient for the day's activities. "Can the patient be left alone?" "Must I be there constantly?" (Depends on specific circumstances and the severity of dementia.) "Should the patient manage his own money?" (Generally not.) "Will a change of environment or a trip help?" (Generally not; often the disruption in daily routine worsens behavior and orientation.) "Can he drive?" (Best to advise against driving in most instances.) "What shall we do about the patient's fears at night and his hallucinations?" (Medication under supervision may help.) "When is a nursing home appropriate?" "How will the condition worsen? What should the family expect, and when?" (Uncertain, but usually a 5- to 10-year course.) Many families have found the information on the Alzheimer Association website, http://www.Alz.org, helpful, but physician guidance is required to make the material applicable to individual circumstances.

Visiting nurses, social agencies, live-in healthcare aides, day care settings, and respite care to relieve families from the constant burden of caring for the patient should all be used to advantage. Some of the inevitable practical problems accompanying the dissolution of personal life caused by dementia can be ameliorated by judicious use of powers of attorney or guardianship and similar legal vehicles.