20
Dementia, the Amnesic Syndrome, and the
Neurology of Intelligence and Memory
Increasingly, as the population of elderly rises, the
neurologist is consulted because an otherwise healthy per-
son begins to fail mentally and loses his capacity to func-
tion 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 hydrocepha-
lus, or a depressive illness. Formerly, there was little that
could be done about these clinical states, but there are
now effective means of treating several of these conditions,
and in some instances, of restoring the patient to normal
competence. Moreover, diagnostic technologies allow ear-
lier 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. 19, where it was pointed out that
the term dementia denotes a persistent deterioration of
intellectual or cognitive function with little or no distur-
bance of consciousness or perception. In current medi-
cal parlance, the term is used to designate a syndrome of
failing memory and 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 dif-
fers from the global confusional state, or 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 persisted, mark-
ing a dementia, or abated, signifying an encephalopathy.
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 degen-
eration of systems of cerebral neurons, albeit common,
is only one of the many causes. Similarly, as discussed in
previous chapters, there are myriad intrinsic (metabolic)
and extrinsic (toxic) causes of encephalopathy.
To understand the phenomenon of intellectual dete-
rioration, it is helpful to have some idea of how intellectual
452
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functions, particularly intelligence and memory, are nor-
mally organized and sustained, and the manner in which
diffuse and focal cerebral lesions cause deficits in these
functions. The neurology of intelligence is considered in
this chapter as a prelude to a discussion of the dementias
and the neurology of memory.
INTELLIGENCE
Intelligence, or intelligent behavior, has been variously
defined as a “general mental efficiency,” as “innate cog-
nitive 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 attrib-
uted to any cerebral region or particular cognitive func-
tion. Indeed, the dementias and developmental delays,
affect intelligence in a way that cannot be explained except
by some widely distributed aspect of brain function.
As every educated person recognizes, intelligence has
something to do with normal cerebral function. It is also
apparent that the level of intelligence differs from one per-
son to another, and members of certain families are excep-
tionally 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, although this may be tautologic
as the tests are designed specially to measure certain
aspects of performance. Furthermore, the first intelligence
tests, devised by Binet and Simon in 1905, were for the pur-
pose of predicting scholastic success. The term intelligence
quotient, or IQ, was introduced by the German psycholo-
gist 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 to a
 CHAPTER 20 Dementia, the Amnesic Syndrome, and the Neurology of Intelligence and Memory
lesser extent with eventual success in professional work.
An individual IQ increases with age up to the 14th to 16th
years and then remains stable, at least until late adult life.
At any 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 strik-
ing 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 used 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 opportuni-
ties. This led to the equally polarized but 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.
Past studies of monozygotic and dizygotic twins raised in
the same or different families 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 is further instructive; 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 shared genetic traits. These findings sug-
gest that life experience alters intelligence, but in a modest
way. There is therefore a strong suggestion 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 equally valid evidence that
early learning modifies the level of ability that is finally
attained. In this way, intelligence may 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 at all mea-
sured by tests of intelligence.
As to the genetic mechanisms involved in the inheri-
tance of intelligence, a limited amount is known. There is
an excess of males with what was previously called men-
tal retardation, and now less pejoratively “developmental
delay,” and there are several well-characterized syndromes
in which the inheritance of mental retardation is X-linked
as described in Chaps. 27 and 37. Also notable are the some-
what different patterns of performance between males and
females on subtests of the various intelligence tests (males
perform better in spatial ability and certain mathematical
tasks). Males are more likely to be affected by advanta-
geous or by aberrant genes on their single X chromosome,
whereas females benefit from the mosaic provided by two
X chromosomes. In some families, high intelligence seg-
regates to certain individuals through an X-linked pattern.
Further study will determine the validity of these views and
of what will certainly prove to be a polygenic inheritance of
intelligence and intellectual traits.
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453
One would think that neurologic structure and func-
tion would correlate in some way with intelligence, but
with the exception of the pathologically developmentally
delayed (see Chaps. 27 and 37), such an association has
been difficult to document. Brain weight and the com-
plexity of the convolutional pattern are not correlated
with intelligence—despite popular notions to the con-
trary, including a widely criticized analysis of the brain of
Albert Einstein. (Witelson and colleagues proposed that an
enlarged inferior parietal lobule, a crossmodal association
area, accounted for Einstein’s visuospatial and mathemati-
cal genius, but this is certainly an oversimplification). 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 consistent but still modest correla-
tion 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 lan-
guage areas, show a heritable component when measured
on high-resolution MRI scans (see Thompson et al).
As to psychologic theories of intelligence, several have
traditionally been influential 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 num-
ber of entirely separable primary mental abilities, such
as memory, verbal facility, numerical ability, visuospatial
perception, and capacity for problem solving, all of them
more or less equivalent. He proposed that 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 reframed, for example by Gardner, who
separated six categories of high-order cerebral ability but
restated them in more modern terms: linguistic (encom-
passing all language functions); musical (including com-
position 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 perfor-
mance); and the personal (consciousness of self and oth-
ers in social interactions). He referred 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 skills and abilities: (1) each may be
developed to an exceptionally high level in certain indi-
viduals, constituting virtuosity or genius; (2) each can be
destroyed or spared in isolation as a consequence of a
454 Part 2 CARDINAL MANIFESTATIONS OF NEUROLOGIC DISEASE
lesion in a certain part of the nervous system; (3) in certain
individuals, that is, 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, mathe-
matical, 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 schoolchildren who
were initially tested in 1921 supported the idea that an
extremely high IQ predicted future scholastic accomplish-
ments (though not occupational or life success). On the
other hand, most individuals recognized as geniuses have
been especially skilled in one domain—such as paint-
ing, 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 27 discusses the developmental aspects of
intelligence in more detail. One of the leading theories
had been that of Piaget, who proposed that the emergence
of intelligence 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 opera-
tions” (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 anecdotal and lack-
ing 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 neurology, embodying an
understanding of so many diseases affecting the cere-
brum, might make it possible to verify one of these several
theories of intelligence and to determine the anatomy
of this cognitive entity. Presumably, Spearman’s 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 corre-
lation 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 involved
more than 50 mL of tissue caused a moderate general
reduction in performance, especially in speed and capac-
ity 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.
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It is important to acknowledge, for example, that lesions of
the frontal lobes, and particularly the prefrontal regions,
which disorder planning and “executive” functions, do not
measurably affect overall IQ but do, of course, slow mental
processing and degrade subtests specific to these skills.
These problems are discussed in Chap. 21 on the localized
functions of the cerebral cortex.
The authors conclude from experience and from evi-
dence provided by neurologic studies that intelligence
consists of a combination of multiple primary abilities,
each of which may be inherited and each of which has a
separate but poorly delineated anatomical representation.
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, his-
tory, and science, some of them, namely linguistic and
mathematical, and perhaps spatial–dimensional abilities,
are more closely integral to ideation and problem solving.
Furthermore, they are affected most 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 still not satisfying concept for
intelligence.
Neurologic data, while unable to locate the sources of
a general factor for intelligence certainly does not exclude
its possibility—one that is unavoidably measured in many
different tests of cerebral functions. It is expressed if the
connections between the frontal lobes and other parts
of the brain are intact as attention, drive, and motivation
are noncognitive psychologic attributes of fundamental
importance to performance reside in this lobe. It is also
possible, if not likely, that the parietal lobe associative areas
of the cerebrum are engaged in the processing 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, symbols, and
names, requiring the full function of the temporal lobes,
play a central role. The interrelationships between some
of these special abilities had been thoughtfully analyzed
by Luria (see also the section on frontal lobes in Chap. 21).
An account of the subject of IQ and intelligence can also be
found in the monograph by Mackintosh.
An equivalently complex problem arises in the neu-
rologic 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 obscure, as Zeki points out.
Some insight is gained from the fact that intelligence and
problem-solving ability are 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
 CHAPTER 20 Dementia, the Amnesic Syndrome, and the Neurology of Intelligence and Memory 455

with language deteriorated. As pointed out in the following Table 20-2

chapter, like intelligence, traits such as creativity almost
certainly do not reside in a particular lobe or structure NEUROPATHOLOGIC DIAGNOSES FOR 261 CASES WITH A
of the brain and may depend on the overdevelopment of CLINICAL DIAGNOSIS OF ALZHEIMER DISEASE: DATA FROM
certain associative areas, as well as on frontal lobe drive THE MASSACHUSETTS ADRC BRAIN REGISTRY, 19841993
and, of course, are fully manifest only by exposure and NEUROPATHOLOGIC
encouragement. DIAGNOSIS NUMBER OF CASES PERCENT
Alzheimer disease 218 83.5
Parkinson and 16 6.1
Alzheimer
THE NEUROLOGY OF DEMENTIA diseases
Lewy-body disease 8 3.1
Dementia is a syndrome comprising the loss of several Pick disease 6 2.3
separable but overlapping intellectual abilities. It therefore
Multiple infarcts 5 1.9
presents in a number of different combinations. These
constellations of intellectual deficits constitute the preem- Binswanger disease 1 0.4
inent clinical abnormalities of a large number of cerebral Corticobasal 1 0.4
diseases and are sometimes virtually the only abnormali- ganglionic
degeneration
ties. Table 20-1 lists the most common types of dementing
diseases and their relative frequency. Mixed dementia 1 0.4
What is noteworthy to us about the figures in this table Other 5 1.9
is the apparently high level of accuracy of diagnosis based Total 261 100
on clinical assessment. Certainly, specialized testing that
Source: Courtesy of Dr. John Growdon.
is now available improves the diagnostic accuracy but

Table 20-1 rather consistently, postmortem examination confirms the

THE COMMON TYPES OF DEMENTING DISEASES AND THEIR
APPROXIMATE FREQUENCIES
DEMENTING DISEASE
Cerebral atrophy, mainly
Alzheimer but including
Lewy body, Parkinson,
frontotemporal, and Pick
diseases
Multi-infarct dementia
Alcoholic dementia
Intracranial tumors
Normal-pressure
hydrocephalus
Huntington chorea
Chronic drug intoxications
Miscellaneous diseases
(hepatic failure; pernicious
anemia; hypo- or hyper-
thyroidism; dementias with
amyotrophic lateral sclerosis,
amyloid angiopathy, neuro-
syphilis; Creutzfeldt-Jakob
disease; multiple sclerosis;
chronic epilepsy)
Cerebral trauma
AIDS dementia
Pseudodementias (depression,
hypomania, schizophrenia,
hysteria, undiagnosed)
Source: Adapted from Van Horn, from Mayeux et al, and from Cummings JL,
Benson DF: Dementia: A Clinical Approach, 2nd ed. Boston, Butterworth,
1992.
(See also Table 20-2.)
clinical diagnosis of Alzheimer disease is in excess of 80
percent when rigid research criteria are used (Table 20-2).
RELATIVE FREQUENCY, % (The high frequency of this disease in the older popula-
tion makes the likelihood of correct diagnosis high). In
50
most cases, the degenerative dementias can be differen-
tiated by one or two characteristic clinical features, but
these distinctions may be difficult to discern early in the
process. In particular, a proportion of patients thought
10 to have Alzheimer disease are ultimately found to have
7 another type of degenerative cerebral atrophy, such as
Lewy-body disease, progressive supranuclear palsy, Hun-
5
tington disease, Parkinson disease, corticobasal degen-
5 eration, Pick disease, or one of the frontotemporal lobar
degenerative diseases (see Chap. 38). Or such patients
2 have a non-degenerative processes, such as multiinfarct
3 dementia or hydrocephalus alone or in combination with
6 one of the degenerative disorders. Of special importance
is that approximately 10 percent of patients who are
referred to a neurologic center with a question of demen-
tia prove to have a potentially reversible psychiatric or
metabolic disorder. There are also the earlier mentioned
groups of nonprogressive dementias that are the lasting
result of a single injury to the brain and do not appear in
Table 20-2.
2 In the following pages, we consider the prototypic
2
dementing syndromes. As has been emphasized, they are
most frequently due to degenerative diseases of the brain
8 (see Chap. 38) and less often occur as a component of
other categories of disease (vascular, traumatic, infectious,
demyelinating), which are considered in their appropriate
chapters. The discussion of dementing diseases is pre-
ceded by a description of a syndrome of incipient demen-
tia currently called mild cognitive impairment.

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456 Part 2 CARDINAL MANIFESTATIONS OF NEUROLOGIC DISEASE
Mild Cognitive Impairment and Early Dementia
It has become apparent that many individuals have mem-
ory 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
very troubling but less-intrusive problem, which may be a
result of the normal process of aging, from dementia. The
condition has been called mild cognitive impairment, and
in the past, age-associated memory impairment, or benign
senescent forgetfulness, as discussed in Chap. 28. When
other aspects of mental functioning are affected, terms
such as aging-associated cognitive decline had been 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.
It must be stated, however, that worry over occasionally
forgetting one’s keys or recalling another person’s name as
one ages, common complaints in the neurology practice
setting, generally do not indicate cognitive decline, mild
or otherwise. Many factors including poor sleep and sleep
apnea, depression, medications, systemic endocrine and
infectious disorders, and general distractibility contribute
greatly to these complaints in the normal population.
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 fac-
tors 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 the
later development of Alzheimer disease, much of which
has reached the popular consciousness in diluted form,
and are discussed in Chap. 38.
At the moment, the clinician must simply counsel
caution and reassurance in advising patients with mild
memory impairment, and exclude treatable causes. None-
theless, if the symptoms are progressive or begin to inter-
fere 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
Despite what has been said in the section above, the earli-
est signs of dementia caused by degenerative disease may
be so subtle as to escape the notice of the most discern-
ing physician. An observant relative of the patient or an
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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 bore-
dom 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 pur-
pose of an errand is forgotten, appointments are not kept,
and recent conversations or social events have been over-
looked. 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 cus-
tomary 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. Diminished capacity for abstraction, attention,
planning, and problem solving may be observed as the
degenerative process continues. The last of these is sub-
sumed under the term disorder of “executive functions.”
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 to this statement from clinical experi-
ence. 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 dizzi-
ness, a vague mental “fogginess,” and nondescript head-
aches. 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 act-
ing 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 in the following text and in Chap. 19.
As noted there, the family almost uniformly, but mistakenly,
dates an abrupt onset of dementia to the time of the inter-
current illness, a fall, or an operation.
 CHAPTER 20 Dementia, the Amnesic Syndrome, and the Neurology of Intelligence and Memory
Loss of social graces and indifference to social customs
may occur, but usually much 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, hallucina-
tions, 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 intermedi-
ate stage of the illness, while other patients sit placidly for
hours. By this point, these patients have little or no realiza-
tion of the changes occurring within themselves; that is,
they lack insight into the problem.
As the condition progresses, all intellectual facul-
ties become impaired; but in the most common degen-
erative diseases, as stated earlier, 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 (the earlier mentioned
Ribot’s law). Eventually, patients also fail to retain remote
memories, to recognize their relatives, and even to recall
the names of their children.
Language functions are impaired almost from the
beginning of certain forms of dementia, the primary pro-
gressive aphasias discussed in the following text and in
Chap. 38, but fragments of this problem are apparent in
nondescript and amnestic forms of dementia as well.
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 per-
formance 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.
Furthermore, several clinical variants of dementia in
which memory is relatively spared have long been recog-
nized, 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).
Lost in some aphasic cases is the capacity to under-
stand nuances of the spoken and written word, as are the
suppleness and spontaneity of verbal expression. Or, vocab-
ulary becomes restricted and conversation may become
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
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457
conversation. Paraphasias and difficulty in comprehending
complex conversations later become prominent. Subse-
quently, more severe degrees of aphasia, dysarthria, pali-
lalia, and echolalia may be added to the clinical picture. As
pointed out by Chapman and Wolff, there may be loss also
of the capacity to express feelings, to suppress impulses,
and to tolerate frustration and restrictions.
A common clinical syndrome in this group is charac-
terized 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.
In the advanced stages of some dementias, restrain-
ing the patient leads to disagreeable behavior, petulance,
agitation, shouting, and whining. Well known to physi-
cians is nighttime confusion and inversion of the normal
sleep pattern, as well as increased confusion and restless-
ness in the early evening (“sundowning”), as described in
Chap. 19. 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.
Physical Deterioration in Dementing Illnesses
It would be an error to think that the abnormalities in
the degenerative dementing diseases are confined to the
intellectual sphere. In advancing stages, the patient’s
appearance and the physical examination yield highly
informative data. The first impression is often reveal-
ing; 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 par-
ticipate 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 (see Chap. 6). Passive movements
of the limbs encounter a fluctuating resistance or parato-
nia (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
(slight retraction of one side of the chin caused by contrac-
tion of the mentalis muscle when 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 inexo-
rable. 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
458 Part 2 CARDINAL MANIFESTATIONS OF NEUROLOGIC DISEASE
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 pneu-
monia, a febrile episode or an eating disorder, not surpris-
ingly, 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, par-
ticularly in patients in whom the dementia is associated
with or superimposed on frontal lobe degeneration, Par-
kinson disease, normal pressure hydrocephalus, cerebel-
lar 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 symptom-
atology 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 38 discusses these varia-
tions 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 symp-
toms are the primary manifestations of neurologic disease.
However, some symptoms are secondary; that is, they may
represent the patient’s reactions to his mental incapac-
ity. For example, a demented person may seek solitude
to hide his affliction and thus may appear to be asocial or
apathetic. Again, excessive orderliness may be an attempt
to compensate for failing memory; apprehension, gloom,
and irritability may reflect a general dissatisfaction with a
necessarily restricted life. According to Goldstein, who has
written about these “catastrophic reactions,” as he called
them, even patients in a state of fairly advanced deteriora-
tion are still capable of reacting to their illness and to per-
sons who care for them.
In the early and intermediate stages of the illness,
neuropsychologic tests aid in the quantitation of some of
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these abnormalities, as indicated in the later part of this
chapter.
Subcortical Dementia Associated With Diseases
of the Basal Ganglia and White Matter
McHugh, who introduced the concept of subcortical
dementia, pointed out that the cognitive decline of cer-
tain 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” (exempli-
fied 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 subcortical
dementia predominates in the basal ganglia, thalamus,
rostral brainstem nuclei, and in the ill-defined projections
in the white matter from these regions to the cortex, par-
ticularly to 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 subcorti-
cal dementia is the name itself, implying as it does that
symptoms of dementia are due to lesions confined to sub-
cortical structures (non-cortical dementia may be more
apt). None of the neurodegenerative dementias is strictly
cortical or subcortical. In a similar way, the changes of
Alzheimer disease may extend well beyond the cerebral
cortex, involving the striatum, thalamus, and even cer-
ebellum. Also, functionally, these lesions produce their
effects by interrupting neural links to the frontal and other
parts of the cerebral cortex. Further 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 con-
strued as both cortical and subcortical in nature.
Certain authors, notably Mayeux and Stern and May-
eux and 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 pathologic pro-
cesses. Nevertheless, many clinical studies 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 corti-
cal and subcortical dementia based on a relative sparing of
cortical functions is very useful.
Pathogenesis of Dementia
Attempts to relate the impairment of general intellec-
tual function to lesions in certain parts of the brain or a
 CHAPTER 20 Dementia, the Amnesic Syndrome, and the Neurology of Intelligence and Memory
particular pathologic change have been largely unsuccess-
ful as discussed earlier. Lashley’s concept of loss of intelli-
gence in proportion to brain damage has been mentioned.
This is not to say that components of the cognitive appa-
ratus, particularly memory, 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 localized and quantitated.
Memory impairment, which is a central feature of
many dementias, occurs with extensive disease in several
different parts of the cerebrum, but the integrity of discrete
parts of the diencephalon and of the medial temporal
lobes is fundamental to memory. Also, impairment of
language function is associated specifically with disease of
the dominant cerebral hemisphere, particularly the peri-
sylvian 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 pari-
etal region. Impairment in drawing or constructing simple
and complex figures with blocks, sticks, picture arrange-
ments, 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 large part on the location as
well as the extent of the lesion.
Dementia of the degenerative types is related to obvi-
ous 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, par-
ticularly as regards memory. Even when a particular dis-
ease 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 hip-
pocampus, greatly augments the deterioration in memory
function. Indeed, replacement of this lost cholinergic
influence is one of the current approaches to the treatment
of the disease.
Arteriosclerotic cerebrovascular disease, which pur-
sues a different course than the neurodegenerative dis-
eases, results in multiple foci of infarction throughout the
thalami, basal ganglia, brainstem, and cerebrum, includ-
ing the motor, sensory, and visual projection areas as well
as the association areas. However, arteriosclerosis per se,
without vascular occlusion and infarction, is not 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
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459
(multi-infarct, or vascular dementia). Also, the construct
that small strokes exaggerate or in some way biologically
induce an Alzheimer neuropathologic process has been
advanced. The two processes seem to coincide more often
than chance. The special problem of multi-infarct, vascu-
lar dementia is discussed in Chap. 33 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 thala-
mus. In some cases, there is widespread degeneration of
the deep cerebral hemispheres, because of a mechanical
disruption of the deep white matter termed axonal shear-
ing. Most traumatic lesions that produce dementia are
quite extensive, making localization difficult. Our experi-
ence suggests that the thalamic lesions are important, but
many authorities view the diffuse axonal shearing lesions
in cerebral white matter as the primary cause of trau-
matic dementia. The special problem of chronic traumatic
encephalopathy is addressed in Chap. 34.
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. Compres-
sion of the cerebral white matter is probably a 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 inflam-
matory 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 neurons and an inflamma-
tory derangement of function in the neurons that remain.
The prion diseases (e.g., Creutzfeldt-Jakob disease) cause
a widespread loss of cortical neurons, replacement gliosis,
and spongiform change and produce special patterns of
cognitive dysfunction.
The adult forms of leukodystrophy (see Chap. 36) also
give rise to a dementing state, generally a “subcortical”
dementia syndrome with prominent frontal lobe features.
Or extensive lesions in the white matter may be the result
of advanced multiple sclerosis, progressive multifocal leu-
koencephalitis, or some of the vascular dementias already
mentioned (Binswanger disease and CADASIL [cerebral
autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy; Chap. 33]). Last, several of the
metabolic and toxic disorders discussed in later chapters,
for example, vitamin B12 deficiency, may interfere with
nervous function over a period of time and create a clini-
cal picture similar, if not identical, to that of the demen-
tias. One must suppose in those cases that the altered
biochemical environment has affected neuronal function
in critical areas.
Classification of the Dementing Diseases
Conventionally, the dementing diseases have been classi-
fied according to cause, to the specific pathologic changes,
or by the most prominent clinical feature, for exam-
ple, memory loss in Alzheimer disease. Another practical
460 Part 2 CARDINAL MANIFESTATIONS OF NEUROLOGIC DISEASE
approach, which follows from the method by which much of
the subject matter is presented in this book, is to divide the
diseases into categories on the basis of the neurologic signs
and associated clinical and laboratory features of medical
disease: (1) dementia with medical disease, (2) dementia
that is accompanied by other principal neurologic signs,
and (3) dementia as the sole or predominant feature of the
illness (Table 20-3). Once it has been determined that the
patient suffers from a dementing illness, the illness may be
characterized from these medical, neurologic, and ancil-
lary data discussed in the following text. This classification
may seem somewhat dated and less based on genetic and
molecular models of degenerative disease, but it is likely
to be more useful to the physician who must confront the
many processes that cause dementia.
Differential Diagnosis
Although dementia does not indicate a particular dis-
ease, certain combinations of symptoms and neurologic
signs are more or less characteristic and aid greatly in
diagnosis. The age of the patient, the mode of onset of
the dementia, its clinical course and time span, any asso-
ciated neurologic signs, and accessory laboratory data
constitute the basis for differential diagnosis. It must
be acknowledged, 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 intoxi-
cation, normal-pressure hydrocephalus, HIV (reversible
to some extent), neurosyphilis, cryptococcosis, pellagra,
vitamin B12 and thiamine deficiency states, hypothyroid-
ism, 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. Also, progressive deafness or
loss of sight in an elderly person may sometimes be misin-
terpreted as dementia. In the future, when effective means
for treatment of degenerative dementias are established,
refined methods, mentioned further on, will be used to
differentiate the fundamental causes of neuronal damage.
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 should 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. The abrupt onset of mental symptoms
usually points to a delirium or other type of acute confu-
sional state or to a stroke; inattention, perceptual distur-
bances, and often drowsiness are conjoined (see Chap. 19).
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
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Table 20-3
BEDSIDE CLASSIFICATION OF THE DEMENTIAS
I. Diseases in which dementia is associated with clinical and
laboratory signs of other medical diseases
A. AIDS–HIV infection
B. Endocrine disorders: hypothyroidism, Cushing syndrome,
rarely hypopituitarism, Hashimoto encephalopathy
C. Nutritional deficiency states: Wernicke-Korsakoff syn-
drome, subacute combined degeneration (vitamin B12
deficiency), pellagra
D. Chronic meningoencephalitis: general paresis, meningo-
vascular syphilis, cryptococcosis
E. Hepatolenticular degeneration—familial (Wilson disease)
and acquired
F. Chronic drug and environmental intoxications (including
CO poisoning)
G. Prolonged hypoglycemia or hypoxia
H. Paraneoplastic “limbic” encephalitis
I. Heavy metal exposure: arsenic, bismuth, gold, manga-
nese, mercury
J. Dialysis dementia (now rare)
II. Diseases in which dementia is associated with other neuro-
logic signs but not with obvious medical diseases
A. Invariably associated with other neurologic signs
1. Huntington chorea (choreoathetosis)
2. Multiple sclerosis, Schilder disease, adrenal leukodys-
trophy, and related demyelinative diseases (spastic
weakness, pseudobulbar palsy, blindness)
3. Lipid-storage diseases (myoclonic seizures, blindness,
spasticity, cerebellar ataxia)
4. Myoclonic epilepsy (diffuse myoclonus, generalized
seizures, cerebellar ataxia)
5. Subacute spongiform encephalopathy; Creutzfeldt-
Jakob disease; Gerstmann-Sträussler-Scheinker dis-
ease (prion, myoclonic dementias)
6. Cerebrocerebellar degeneration (cerebellar ataxia)
7. Cerebrobasal ganglionic degenerations
(apraxia-rigidity)
8. Dementia with spastic paraplegia
9. Progressive supranuclear palsy (falls, vertical gaze palsy)
10. Parkinson disease
11. Amyotrophic lateral sclerosis (ALS) and ALS-
Parkinson-dementia complex
12. Other rare metabolic diseases, including polyglucosan
disease and leukodystrophies
B. Often associated with other neurologic signs
1. Multiple thrombotic or embolic cerebral infarctions
and Binswanger disease
2. Brain tumor (primary or metastatic) or abscess
3. Brain trauma, such as cerebral contusions, midbrain
hemorrhages, chronic subdural hematoma
4. Lewy-body disease (parkinsonian features)
5. Communicating, normal pressure, or obstructive
hydrocephalus (usually with ataxia of gait)
6. Progressive multifocal leukoencephalitis
7. Marchiafava-Bignami disease (often with apraxia and
other frontal lobe signs)
8. Granulomatous and other vasculitides of the brain
III. Diseases in which dementia is usually the only evidence of
neurologic or medical diseases
A. Alzheimer disease
B. Pick disease
C. Some cases of AIDS
D. Progressive aphasia syndromes
E. Frontotemporal and “frontal lobe” dementias associated
with tau deposition, Alzheimer change, or with no specific
pathologic alteration
F. Degenerative disease of unspecified type
Note: The special clinical features and morbid anatomy of these many
dementing diseases are discussed in appropriate chapters throughout this
book, particularly Chap. 38 on degenerative disorders, Chaps. 39 and 40 on
metabolic and nutritional disturbances, and Chap. 32 on chronic infections.
 CHAPTER 20 Dementia, the Amnesic Syndrome, and the Neurology of Intelligence and Memory
label the patient as anxious. This will be avoided if one
keeps in mind that these psychiatric 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, psychomo-
tor underactivity or its opposite, agitation with pacing,
persecutory delusions, hypochondriasis, and a history
of depression in the past and in the family. Although
depressed patients may complain of memory failure, scru-
tiny 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 anxi-
ety, 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. When such patients are calmed by reas-
surance and encouraged to try harder, their mental func-
tion improves, indicating that intellectual deterioration
has not occurred. Conversely, it is helpful to remember
that demented patients in the mid-stages of the process
infrequently have sufficient insight to complain of men-
tal 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 fam-
ily 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, e.g., in Huntington disease)
may precede or mask early intellectual deterioration.
The neuropsychiatric symptoms associated with met-
abolic, endocrine, or toxic disorders (e.g., Cushing syn-
drome, vitamin B12 deficiency, hypercalcemia, uremia)
may present difficulties in diagnosis because of the 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 exog-
enously caused confusional state, with the exception that
Lewy-body dementia also has these characteristics. When-
ever 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 pro-
duce an apparent dementia or worsen a structurally based
dementia, as discussed in Chap. 19. 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 whether
there are other neurologic signs or indications of a medical
disease. This enables the physician to place the case in one
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461
of the three aforementioned categories in the bedside clas-
sification (see above and Table 20-3).
Experienced neurologists recognize that certain lead-
ing neurologic features are indicative of particular degen-
erative dementias. Foremost among these are disorders
of movement, for example, prominent and early parkin-
sonian signs such as bradykinesia, tremor, and shortened
step are characteristic 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. Frequent falls and a disorder of
vertical eye movements are the core components of pro-
gressive supranuclear palsy that often has an attendant
dementia. Involuntary movements such as choreoath-
etosis, dystonia, ataxia, and myoclonus are each signs
of particular disorders that include Huntington disease,
acquired and inherited hepatocerebral degenerations, and
prion disease, all of which are discussed in later chapters.
In the nondegenerative categories of dementia, spasticity
and Babinski signs are typical of vascular dementias.
Ancillary examinations—such as CT, MRI, lumbar
puncture, measurement of blood urea nitrogen, calcium,
electrolytes, and liver function tests—should be carried
out in appropriate cases. Brain MRI and CT are of major
importance in objectifying hydrocephalus, lobar atro-
phy, cerebrovascular disease, tumor, and subdural hema-
toma. Functional imaging, particularly with PET, including
with the use of radioligands to amyloid, tau and other
substances is assuming great importance in identifying
Alzheimer, Lew body and corticobasal degeneration. Test-
ing for syphilis, vitamin B12 deficiency, and thyroid func-
tion is also undertaken 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 indi-
vidual circumstances by serologic testing for HIV infec-
tion, measurement of copper and ceruloplasmin levels
(Wilson disease), heavy metal concentrations in serum,
urine or tissues, autoantibodies including anti-Hu for
paraneoplastic encephalitis, and drug toxicology screen-
ing. The final step is to determine, from the total clinical
picture, the particular disease within each category.
THE AMNESIC KORSAKOFF SYNDROME
SEE ALSO CHAP. 40
The two terms listed previously are used interchangeably
to designate a unique and disorder of cognitive function in
which memory and learning are greatly impaired almost
in isolation from all other components of mentation and
behavior. The amnesic state, as defined by Ribot, pos-
sesses 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
462 Part 2 CARDINAL MANIFESTATIONS OF NEUROLOGIC DISEASE
before the onset of the illness (retrograde amnesia) and
(2) an the inability to acquire new information, that is,
to learn or to form new memories (anterograde amne-
sia). 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 experi-
ence. 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 deduc-
tions 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—for example,
impairment in attention and perception (as in the deliri-
ous, 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, respon-
sive individual is often included in the definition of the
Korsakoff amnesic state but is not a requisite for diag-
nosis. It can be provoked by questions as to the patient’s
recent activities. The replies may be recognized as par-
tially remembered events and personal experiences that
Memory
Short term, intermediate
Long term
(working memory)
Explicit Implicit
Episodic Semantic Classical Procedural (physical
(autobiographical) (factual) conditioning and similar skills)
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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 sponta-
neous 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 Agamanolis, 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 mem-
ory 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 expe-
rienced 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 syn-
drome, 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. 20-1 and Table 20-4. An
initial distinction 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 in order to be
able to walk across a room and dial the phone; or, perform-
ing a series of mental calculations that require holding
Figure 20-1. Schematic definitions of memory systems (see
text). (From Budson and Price with permission.)
 CHAPTER 20 Dementia, the Amnesic Syndrome, and the Neurology of Intelligence and Memory 463

Table 20-4
NEUROPSYCHOLOGIC CATEGORIES OF MEMORY
LONG-TERM MEMORY

IMMEDIATE WORKING EXPLICIT IMPLICIT

RECALL MEMORY SEMANTIC EPISODIC PROCEDURAL VISUAL
Function Repetition Short-term recall Recall for facts Recall for tempo- Operational recall Recall of visual
of objects, and their rally organized (“how to do”) representations
plans, names, relationships events
sequencing
Conscious Yes Yes Yes Yes Usually No
access
Anatomic Perisylvian Prefrontal Anterior, infe- Association cortex Premotor and Occipital lobes
regions cortex of cortex, medial rior temporal motor cortex,
involved dominant temporal lobes, lobes; frontal basal ganglia,
hemisphere dorsomedial lobes cerebellum
thalamus
Conditions Agitation, Wernicke- AD, fronto- Hippocampal AD and other AD, other CNS
that disturb confusion Korsakoff syn- temporal infarction, alco- CNS degenera- degenerative
memory (impaired drome, herpes dementia, holic Korsakoff tive disorders, disorders,
attention) encephalitis, encephalitis, syndrome, AD encephalitis, encephalitis,
infarction of chronic toxins, and other CNS chronic toxic tumors
hippocampi, tumors degenerative dis- exposure,
dorsomedial orders, encepha- tumors
thalamus litis, chronic toxic
exposure, tumors
AD, Alzheimer disease; CNS, central nervous system.

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 that
are termed procedural memory. Classic conditioning is
considered another type of implicit memory.
Explicit memory subsumes what most persons con-
sider 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 envi-
ronment 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. More-
over, 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 bilateral hippocampal
damage from hypoxic-ischemic injury sustained early in
life. Here, again, the subject matter most affected in this
type of amnesia involved episodic, or autobiographical,
memory. The same occurs in early Alzheimer disease in
paraneoplastic and herpes simplex encephalitis.
A pervasive problem with these descriptive terms
for various types of memory is the lack of uniformity in
defining them. 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 per-
ceptual and factual knowledge, which makes it possible to
comprehend language and make inferences. This hardly
constitutes a novel concept; Korsakoff himself clearly rec-
ognized that certain aspects of mental function (among
them those now being defined as semantic memory) are
retained, despite profound impairment of episodic mem-
ory. 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 syn-
drome, 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 the fol-
lowing text). Further interesting derivative issues regard-
ing the neuropsychology of memory in relation to brain
diseases can be found in the review by Kopelman. Among

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464 Part 2 CARDINAL MANIFESTATIONS OF NEUROLOGIC DISEASE
these is the degree to which a disparity between retrograde
and anterograde memory can be detected in certain dis-
eases. He also points out the subtle distinctions between
recall and memory by recognition.
Neuropsychologists have further subdivided mem-
ory and suggested that there are corresponding anatomic
regions for specific categories (see Table 20-4). Some of
these more complex subtypes have been alluded to above
and others are simply restatements of the act of registra-
tion. Furthermore, it is not surprising that the participa-
tion of certain areas of the brain not primarily involved in
memory function, particularly the language and visuospa-
tial areas, is required for the performance of most 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 hippo-
campi 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 dis-
cussion of the mechanisms that underlie working memory.
Finally, there are reasons, based mainly on the neuro-
anatomic and functional imaging studies discussed later,
to view episodic memory for spatial and topographic infor-
mation 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 degra-
dation of learned topographic and directional information
compared to learned semantic material; such a dissocia-
tion 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 hippo-
campus (see later).
Anatomic Basis of the Amnesic Syndrome
Two anatomic structures are of central importance in
memory function: the thalamus (specifically the medial
portions of the dorsomedial and adjacent midline nuclei)
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 dispropor-
tionate to all other cognitive functions, and even a unilat-
eral lesion of these structures, especially of the dominant
hemisphere, can produce a lesser degree of the same effect.
These two main structures are linked by the mammillotha-
lamic tract (tract of Vicq d’Azyr) with a single synapse in
the mamillary bodies. The clinical–anatomic relationships
that bear on this subject are discussed 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
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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 syn-
drome 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 thalamic–hippocampal
structures in all memory function. The difficulty of evalu-
ating memory function in monkeys has been overcome to
some extent by the use of the “delayed nonmatching-to-
sample task,” which is essentially a refined test of recog-
nition 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 tem-
poral 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 forma-
tion 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 corti-
ces) 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 hippocam-
pus. Experimental lesions of the anteromedial parts of the
thalamus, which receive and send fibers to the amygdala
and hippocampus, similarly abolished memory function.
Regarding specifically thalamic lesions and memory
dysfunction in man, a clinical-MRI correlative study by
Danet and coworkers demonstrated that isolated infarc-
tions of the left mammillothalamic tract most consistently
affected memory, particularly in verbal memory tasks, and
isolated lesions of the medial dorsal nucleus of the thala-
mus caused consistent but less severe memory defects.
Thus, the primacy of these two structures in moderate or
severe and lasting memory defects is affirmed.
There may be subtle differences in memory distur-
bance based on the specific location of a lesion in the mem-
ory pathways. Graff-Radford and colleagues have found
that with purely thalamic lesions, as appreciated by imaging
studies, anterograde learning is more affected than retro-
grade recall; but comparing these functions quantitatively
is difficult. Kopelman, in reviewing his own studies and
those of others, concludes that the differences are subtle
 CHAPTER 20 Dementia, the Amnesic Syndrome, and the Neurology of Intelligence and Memory
and pertain mostly to temporal ordering and the modality
of information, which is degraded more with diencephalic–
temporal lesions than with frontal lobe damage.
A body of work using functional neuroimaging also
addresses the anatomic mechanisms of memory func-
tion. It has been found that the hippocampal forma-
tions are consistently engaged during memory acquisition
and retrieval tasks. In addition, Maguire’s group found
differential activation of the right side during recall of
topographic spatial information and the left side for auto-
biographical memory. Their clever use of London taxi
drivers as subjects for imaging studies has further sug-
gested 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 func-
tion, as emphasized, involves many parts of the brain in
addition to diencephalic–hippocampal structures. The
aforementioned basal frontal nuclei that project to the hip-
pocampi are an example.
It is also clear that particular lesions of the neocor-
tex may cause impairment of specific forms of memory
and learning. Perhaps these high-order cortical functions
should not be considered in the same context as what is
colloquially called memory because they involve skills that
are partly learned but partly innate such as language. 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 abil-
ity 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 acquir-
ing 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.
What remains clear is that the integrity of both the hip-
pocampal–thalamic system and the appropriate cortical
region is required for memory as we refer to it in this chap-
ter, 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
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465
be, it is never complete. Certain past memories can be
recalled, but imperfectly and with no regard for their nor-
mal temporal relationships, giving them a fictional quality
and explaining many instances of confabulation. Another
noteworthy fact is that long-standing social habits, auto-
matic motor skills, and memory for words (language) and
visual impressions (visual or pictorial attributes of per-
sons, 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 habitu-
ation, come to be stored or filed in other regions of the
brain; that is, they acquire a separate and autonomous
anatomy that may be regional, cellular, or subcellular.
Several fundamental questions concerning the amne-
sic syndrome remain unanswered. Not known is how, or
better stated, why a disease process not only impairs future
learning but also wipes out portions of a vast reservoir of
past memories that had been firmly established before
the onset of the illness. Most likely, it is not the memo-
ries themselves that are obliterated but the mechanism
required to both encode and access them.
One provocative observation regarding memory has
been the enhancement of performance by electrical stimu-
lation of the entorhinal area. The study by Suthana and
colleagues in individuals with epilepsy is one of several
demonstrating this effect as an improved ability to retain
topographic-spatial landmarks in a simulated exercise. At
a minimum, these findings confirm the role of parahip-
pocampal regions (perforant pathways) in forming and
stabilizing memories, in these cases, the major source of
afferent input to the hippocampus.
This begs the essential question of “what is a memory?”
Current understanding suggests that no single hippocampal
neuron, for example, embodies a memory but that the per-
haps the connections between an ensemble of neurons in
the medial temporal lobes and modality-specific neurons
in the associative cortices are, in fact, the source of 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 shown in
experimental models. It is not clear if a hippocampal neu-
ron is the trigger to the memory ensemble or the entirety of
hippocampal system serves a generic role in cohering all
memories. These 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 ana-
tomic 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.
466 Part 2 CARDINAL MANIFESTATIONS OF NEUROLOGIC DISEASE
Table 20-5
CLASSIFICATION OF THE AMNESIC STATES
I. Amnesic syndrome of sudden onset—usually with gradual
but incomplete recovery
A. Bilateral or left (dominant) hippocampal infarction
because of atherosclerotic-thrombotic or embolic occlu-
sion of the posterior cerebral arteries or their inferior
temporal branches
B. Bilateral or left (dominant) infarction of anteromedial
thalamic nuclei
C. Infarction of the basal forebrain due to occlusion of
anterior cerebral–anterior communicating arteries
D. Subarachnoid hemorrhage (usually rupture of anterior
communicating artery aneurysm)
E. Trauma to the diencephalic, inferomedial temporal, or
orbitofrontal regions
F. Cardiac arrest, carbon monoxide poisoning, and other
hypoxic states (hippocampal damage)
G. Following prolonged status epilepticus
H. Following delirium tremens
II. Amnesia of sudden onset and short duration
A. Temporal lobe seizures
B. Postconcussive states
C. Transient global amnesia
D. Hysteria
III. Amnesic syndrome of subacute onset with varying degrees of
recovery, usually leaving permanent residua
A. Alcoholic Wernicke-Korsakoff syndrome
B. Herpes simplex encephalitis
C. Tuberculous and other forms of meningitis characterized
by a granulomatous exudate at the base of the brain
IV. Slowly progressive amnesic states
A. Tumors involving the floor and walls of the third ventricle
and limbic cortical structures
B. Alzheimer disease (early stage) and other degenerative
disorders with disproportionate affection of the temporal
lobes
C. Paraneoplastic and other forms of immune “limbic”
encephalitis
Certain 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 recollec-
tion, 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).
Each of the amnesic states listed in Table 20-5 is con-
sidered 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 cer-
tain. 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.
TRANSIENT GLOBAL AMNESIA
This was the name applied by Fisher and Adams to a
transient disturbance of memory they observed in more
than 20 middle-aged and elderly persons. The condition is
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characterized by an episode of amnesia and bewilderment
lasting for several hours. The syndrome has its basis in
amnesia for events of the recent past coupled with ongo-
ing anterograde amnesia. During the attack, there is no
impairment in the state of consciousness, no other sign of
confusion, and no seizure activity; personal identification
is intact, as are motor, sensory, and reflex functions. The
patient’s behavior is normal except for a very characteris-
tic incessant, repetitive questioning about his immediate
circumstances—usually of the identical question over and
over at intervals of 20 to 60 s after a response to the query
has already been given by the examiner (e.g., “What am
I doing here?”; “How did we get here?”). Curiously, even
the inflection used in questioning is repeated. Unlike psy-
chomotor epilepsy, the patient is alert, in contact with his
surroundings, and capable of high-level intellectual activ-
ity 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 a
large part of the period of the attack and for a brief period
(hours or days) preceding it. The patient may be left with a
mild headache. It is possible there are incomplete or mild
attacks as brief as 1 h in duration but they are not common
(we have observed three such patients) and a typical epi-
sode is longer. It is difficult to determine when precisely a
given attack began and when it ends is difficult. The con-
dition is among the most curious in medicine and may be
mistaken for a psychiatric episode.
Hodges and Ward have made detailed psychologic
observations in 5 patients during an episode. The psycho-
logic deficit, except for its transience, was much the same
as that in a permanent amnesia syndrome. Personality,
cognition involving high-level functioning, semantic lan-
guage, and visuospatial discrimination were all preserved.
So-called immediate memory—that is, registration (see
earlier)—was likewise operating normally, but memory
was essentially obliterated. The duration of retrograde
amnesia was 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 identi-
fied, but certain ones—such as a highly emotional experi-
ence like hearing of the death of a family member, pain,
exposure to cold water, sexual activity, and mild head
 CHAPTER 20 Dementia, the Amnesic Syndrome, and the Neurology of Intelligence and Memory
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 climb-
ers and have created difficulty in distinguishing TGA from
altitude sickness.
The main concern in differential diagnosis is a tempo-
ral lobe seizure (see in the following text). Transient isch-
emic attack involving the same posterior regions is another.
Whether migrainous episodes can produce a clinical syn-
drome 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
determined. It has been suggested that typical case repre-
sents an unusual form of temporal lobe epilepsy (transient
epileptic amnesia [TEA]), but this seems an unlikely unify-
ing hypothesis. A number of patients have been studied
with EEGs during an attack or shortly thereafter and have
not shown seizure activity (Miller et al). Moreover, amne-
sic 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 envi-
ronment. Using EEG and nasopharyngeal leads, Rowan
and Protass found mesiotemporal spike discharges in 5
of 7 patients. They attributed the discharges to ischemic
lesions during drug-induced sleep, which we do not find
entirely plausible. 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.
An interesting functional correlate has been identified
by Peer and coworkers using functional MRI. Several of the
structures that were identified as participating in episodic
memory retrieval showed reduced activity during TGA; the
effect was bilateral, waned as the spell progressed, was and
reversible. However, many other regions besides the hippo-
campus and its immediate connections were also affected.
Transient global amnesia may be ischemic or perhaps
migrainous in nature, though not of the usual atheroscle-
rotic-thrombotic, and rarely (if ever) do the attacks prog-
ress to stroke. There are certainly comparable memory
deficits with ischemia in the territory of the posterior
cerebral artery branches to the medial temporal lobe and
thalamus but they lack many of the characteristic aspects
of TGA including completely normal functioning other-
wise. We have, however, cared for several patients with
unusual basilar artery ischemic syndromes who displayed
the repetitive questioning typical of TGA at longer intervals
than customary for the latter. Regarding cerebrovascu-
lar 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 cerebro-
vascular disease; there was, however, an increased his-
tory 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
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467
internal jugular arteries during the Valsalva maneuver
(the maneuver occasionally precipitates an attack), Sander
and colleagues and Chung and coworkers have suggested
that venous congestion of the temporal lobes was opera-
tive. 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.
Perhaps the most persuasive cases for an ischemic
basis, 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 dem-
onstrated 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. 20-2). The precipitation, rarely, of attacks by vertebro-
basilar 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 pro-
vides 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 explana-
tion 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
Figure 20-2. MRI showing a tiny area of restricted diffusion in the left
hippocampus, 36 hours after an episode of transient global amnesia.
468 Part 2 CARDINAL MANIFESTATIONS OF NEUROLOGIC DISEASE
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 retro-
grade and complete anterograde amnesia.
APPROACH TO THE PATIENT WITH DEMENTIA
AND THE AMNESIC STATE
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 syn-
dromes; 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 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 circum-
stances. 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. Many practitioners favor the
formal assessment and scoring provided by the paper and
pencil formalized testing of MMSE or MoCA because they
are quicker and allow for quantified serial measurement as
described in the following text. A perplexed or slowed indi-
vidual may ultimately perform adequately but nonetheless
have seriously flawed cortical or subcortical function.
Each of the categories in the following text is an abstrac-
tion but ones that separate particular functions of the brain.
Examples are given for each group but practitioners often
adopt their own based on background and training. 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.
booksmedicos.org
1. Immediate recall (attention, short-term working mem-
ory): This is necessary as a prelude to subsequent test-
ing. Repeat these numbers after me (give series of 3, 4,
5, 6, 7, 8 digits at a speed of 1 per second). 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 back-
ward; 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-…).
2. Insight (patient’s replies to questions about the chief
symptoms): What is your difficulty? Are you ill? When
did your illness begin?
3. Orientation (knowledge of personal identity and pres-
ent situation): What is your name, address, telephone
number? What is your occupation? Are you married?
a. 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?
b. 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?
4. Memory:
a. 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.
b. Recent past: Tell me about your recent illness (com-
pare 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?
c. 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.
d. 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 individu-
als can list at least 12 items in each category.
e. Visual facility: Show the patient a picture of several
objects; then ask him to name the objects.
5. Capacity for calculation, construction, and abstraction:
a. Calculation: Test ability to add, subtract, multi-
ply, and divide. Subtraction of serial 3s and 7s
from 100 is a good test of calculation as well as of
concentration.
 CHAPTER 20 Dementia, the Amnesic Syndrome, and the Neurology of Intelligence and Memory
b. 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.
c. 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”).
6. General behavior: Attitudes, general bearing, evidence
of hallucinosis, stream of coherent thought and atten-
tiveness (ability to maintain a sequence of mental
operations), mood, manner of dress, etc.
7. 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 physi-
cian 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 individu-
als 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. A high level of performance on all tests
eliminates the possibility of dementia in almost all cases
and accords well with scores on the more formal paper
and pencil tests mentioned earlier. 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 psycho-
logic tests is certain to arise. Such tests yield quantitative
data of comparative value but perhaps may be less valu-
able for diagnostic purposes. The Mini-Mental Status
Examination (MMSE) devised by Folstein and cowork-
ers, and the Montreal Cognitive Assessment (MoCA)
(Fig. 20-3) are popularly used. A score above 24/30 on the
“mini-mental” is considered normal and scores below 21
indicate cognitive impairment (but in our practices, most
educated adults in an office setting can exceed a score of
25). 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). The MoCA has been validated for
adults ages 55 to 85 and also has a maximum score of 30.
For patients who cannot finish the written portion because
of physical disability, the test can be scored with 25 as the
maximum and proportionately converted to 30. Several
versions of the MoCA are available for use to avoid a learn-
ing effect if testing is done at 3 month intervals or less.
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469
Patients with mid cognitive impairment usually score in
the range of 19 to 25 and those with confirmed Alzheimer
disease, below 22.
A number of other tests that measure the degree of
dementia (usually carrying the names of their originators:
Roth, Pfeiffer, Blessed, Mattis) rely essentially on the points
mentioned previously 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. For serial measurement
specifically for those with Alzheimer disease, a number of
systems have been devised as reviewed in Chap. 38. Among
the most commonly used is the Alzheimer Disease Assess-
ment Scale-Cognitive (ADAS-Cog). It is more comprehen-
sive than the others and takes longer to administer.
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 intel-
ligence 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 (dis-
crepancy 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.
MANAGEMENT OF THE DEMENTED PATIENT
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. 38) can be car-
ried 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 diag-
nose 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
470 Part 2 CARDINAL MANIFESTATIONS OF NEUROLOGIC DISEASE

Figure 20-3. Montreal Cognitive Assessment (MoCA). (Copyright Z. Nasreddine, MD. Reproduced by permission. Copies available at www.
mocatest.org.)

booksmedicos.org
 CHAPTER 20 Dementia, the Amnesic Syndrome, and the Neurology of Intelligence and Memory
disease. To this query, we usually respond that they may,
but that more time is required to be certain. Some intel-
ligent 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.
In the advanced stages of dementia, as reviewed by
Mitchell, feeding tubes are probably not a wise choice
and hospice and palliative care may be employed to good
benefit.
The value of centrally acting cholinergic agents and
glutamate antagonists in the treatment of Alzheimer dis-
ease is modest but clear and should be weighed against the
need for blood testing and side effects. These medications,
however, may offer psychologic benefit to the patient and
family if they do not worsen behavior or increase halluci-
nations; they are not appropriate for advanced stages of
disease. Chapter 38 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. Randomized trials
and observational studies of these drugs show no benefit
and may increase overall mortality rates (see the meta-
analysis by Schneider and colleagues), in many circum-
stances there are few other options. Experts recommend
behavioral approaches to these problems. Nevertheless,
References
Aggleton JP, Saunders RC: The relationships between temporal
lobe and diencephalic structures implicated in anterograde
amnesia. Memory 5:49, 1997.
Budson AE, Price BH: Memory: Clinical disorders. Encyclopedia of
Life Sciences. London, McMillan Ltd. Nature Publishing Group,
2001, p 1.
Caplan L, Chedru F, Lhermitte F, Mayman G: Transient global
amnesia and migraine. Neurology 31:1167, 1981.
Chapman LF, Wolff HF: The cerebral hemispheres and the highest
integrative functions. Arch Neurol 1:357, 1959.
Chung CP, Hsu HY, Chao AC, et al: Detection of intracranial
venous reflux in patients of transient global amnesia.
Neurology 66:1873, 2006.
Cohen NJ, Squire LR: Personal learning and retention of pattern-
analyzing skill in amnesia: Dissociation of knowing how and
knowing that. Science 210:207, 1980.
booksmedicos.org
471
if reorientation, calming environmental changes, reassur-
ance, and presence of family members and staff do not
reduce anxiety, emotional lability and paranoid tenden-
cies, there may be a need for the judicious use of low doses
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. Com-
mon 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 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?” (Medica-
tion 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 web-
site, 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.
Crum RM, Anthony JC, Bassett SS, Folstein MF: Population-based
norms for the Mini-Mental State Examination by age and
educational level. JAMA 269:2386, 1993.
Danet L, Barbeau EJ, Eustache P, et al: Thalamic amnesia after
infarct. Neurology 85:2107, 2015.
Eysenck HJ: Revolution in the theory and measurement of intel-
ligence. Eval Psicol 1:99, 1985.
Fisher CM: Transient global amnesia: Precipitating activities and
other observations. Arch Neurol 39:605, 1982.
Fisher CM, Adams RD: Transient global amnesia. Acta Neurol
Scand 40(Suppl 9):1, 1964.
Folstein MF, Folstein SE, McHugh PR: “Mini-mental status”: A
practical method for grading the cognitive state of patients for
the clinician. J Psychiatr Res 12:189, 1975.
Gadian DG, Aicardi J, Watkins KE, et al: Developmental amnesia asso-
ciated with early hypoxic-ischaemic injury. Brain 123:499, 2000.
472 Part 2 CARDINAL MANIFESTATIONS OF NEUROLOGIC DISEASE
Gardner H: Multiple Intelligences: The Theory in Practice.
New York, Basic Books, 1993.
Goldman-Rakic PS: Working memory and the mind. Sci Am
267:110, 1992.
Goldstein K: The Organism: A Holistic Approach to Biology.
New York, American Book Company, 1939, pp 35–61.
Graff-Radford NR, Tranel D, van Hoesen GW, Brandt JP:
Diencephalic amnesia. Brain 113:1, 1990.
Haas DC, Ross GS: Transient global amnesia triggered by mild
head trauma. Brain 109:251, 1986.
Herrnstein RJ, Murray C: The Bell Curve: Intelligence and Class
Structure in American Life. New York, Free Press, 1994.
Hinge HH, Jensen TS, Kjaer M, et al: The prognosis of transient
global amnesia. Arch Neurol 43:673, 1986.
Hodges JR, Ward CD: Observations during transient global amne-
sia: A behavioral and neuropsychological study of five cases.
Brain 112:595, 1989.
Hodges JR, Warlow CP: The aetiology of transient global amnesia:
A case-control study of 114 cases with prospective follow-up.
Brain 113:639, 1990.
Kandel ER: Cellular mechanisms of learning and the biological
basis of individuality. In: Kandel ER, Schwartz JH, Jessel TM
(eds): Principles of Neural Science, 4th ed. New York, McGraw-
Hill, 2000, pp 1247–1279.
Kopelman MD: Disorders of memory. Brain 125:2152, 2002.
Lashley KS: Brain Mechanisms and Intelligence. Chicago,
University of Chicago Press, 1929.
Luria AR: The Working Brain. London. Penguin Books Ltd. 1973.
Mackintosh NJ: IQ and Human Intelligence. Oxford, Oxford
University Press, 1998.
Maguire EA: Neuroimaging, memory and the human hippocampus.
Rev Neurol 157:791, 2001.
Maguire EA, Frackowiak RSJ, Frith CD: Recalling routes around
London: Activation of the right hippocampus in taxi drivers.
J Neurosci 17:7013, 1997.
Mayeux R, Foster NL, Rossor MN, Whitehouse PJ: The clinical
evaluation of patients with dementia. In: Whitehouse PJ (ed):
Dementia. Philadelphia, Davis, 1993, pp 92–129.
Mayeux R, Stern Y: Subcortical dementia. Arch Neurol 44:129,
1987.
McClearn GE, Johansson B, Berg S, et al: Substantial genetic
influence on cognitive abilities in twins 80 or more years old.
Science 276:1560, 1997.
McHugh PR: The basal ganglia: The region, the integration of its
symptoms and implications for psychiatry and neurology. In:
Franks AJ, Ironside JW, Mindham RHS, et al (eds): Function
and Dysfunction in the Basal Ganglia. New York, Manchester
Press, 1990, pp 259–268.
McHugh PR, Folstein MF: Psychiatric syndromes of Huntington’s
chorea: A clinical and phenomenologic study. In: Benson DF,
Blumer D (eds): Psychiatric Aspects of Neurologic Disease.
New York, Grune & Stratton, 1975, pp 267–286.
Miller JW, Peterson RC, Metter EJ, et al: Transient global amne-
sia: Clinical characteristics and prognosis. Neurology 37:733,
1987.
Miller JW, Yanagihara T, Peterson RC, Klass DW: Transient global
amnesia and epilepsy. Arch Neurol 44:629, 1987.
Mishkin M: A memory system in the monkey. Philos Trans R Soc
Lond B Biol Sci 298:85, 1982.
Mishkin M, Delacour J: An analysis of short-term visual memory
in the monkey. J Exp Psychol Anim Behav Proc 1:326, 1975.
Mitchell SL: Advanced dementia. N Engl J Med 372:2533, 2015.
Mitchell SL, Teno JM, Kisly DK, et al: The clinical course of
advanced dementia. New Engl J Med 361:1529, 2009.
Morris JC: Frontotemporal dementias. In: Clark CM, Trojanowski
JQ (eds): Neurodegenerative Dementias. New York, McGraw-
Hill, 2000, pp 279–290.
booksmedicos.org
Palmini AL, Gloor P, Jones-Gotman M: Pure amnestic seizures in
temporal lobe epilepsy. Brain 115:749, 1992.
Peer M, Nitzan M, Goldberg I, et al: Reversible functional con-
nectivity disturbances during transient global amnesia. Ann
Neurol 75:634, 2014.
Petersen RC: Clinical practice. Mild cognitive impairment. N Engl
J Med 364:2227, 2011.
Phillips S, Sangelang V, Sterns G: Basal forebrain infarction. Arch
Neurol 44:1134, 1987.
Piaget J: The Psychology of Intelligence. London, Routledge &
Kegan Paul, 1950.
Piercy M: Neurological aspects of intelligence. In: Vinken PJ,
Bruyn GW (eds): Handbook of Clinical Neurology. Vol 3: Disor-
ders of Higher Nervous Activity. Amsterdam, North-Holland,
1969, pp 296–315.
Pillon B, DuBois B, Ploska A, Agid Y: Severity and specificity of
cognitive impairment in Alzheimer’s, Huntington’s, and
Parkinson’s diseases and progressive supranuclear palsy.
Neurology 41:634, 1991.
Ribot TH: Diseases of Memory: An Essay in Positive Psychology.
New York, Appleton, 1882.
Rowan AJ, Protass LM: Transient global amnesia: Clinical and
electroencephalographic findings in 10 cases. Neurology
29:869, 1979.
Sander D, Winbeck K, Eigen T, et al: Disturbance of venous flow
patterns in patients with transient global amnesia. Lancet
356:1982, 2000.
Schacter DL: Searching for Memory. New York, Basic Books, 1996.
Schneider LS, Dagerman KS, Insel P. Risk of death with atypical
antipsychotic drug treatment for dementia: Meta-analysis of
randomized placebo-controlled trials. JAMA 294:1934, 2005.
Schreiber SJ, Doepp F, Klingebiel R, Valdueza JM: Internal jugular
vein valve incompetence and intracranial venous anatomy
in transient global amnesia. J Neurol Neurosurg Psychiatry
76:509, 2005.
Sedlaczek O, Hirsch JG, Grips G, et al: Detection of delayed focal
MR changes in the lateral hippocampus in transient global
amnesia. Neurology 62:2165, 2004.
Seeley WW, Matthews BR, Crawford RK, et al: Unravelling Boléro:
Progressive aphasia, transmodal creativity and the right poste-
rior neocortex. Brain 131:39, 2008.
Shields J: Heredity and psychological abnormality. In: Eysenck HJ
(ed): Handbook of Abnormal Psychology, 2nd ed. London,
Pitman, 1973, pp 173–192.
Shields J: Monozygotic Twins Brought Up Apart and Brought Up
Together: An Investigation Into the Genetic and Environmental
Causes of Variation in Personality. Oxford, Oxford University
Press, 1962.
Slater E, Cowie V: The Genetics of Mental Disorders. Oxford,
Oxford University Press, 1971, pp 196–200.
Spearman CE: The Abilities of Man. London, Macmillan, 1927.
Stillhard G, Landis T, Schiess R, et al: Bitemporal hypoperfusion
in transient global amnesia: 99m-Tc-HM-PAO SPECT and neu-
ropsychological findings during and after an attack. J Neurol
Neurosurg Psychiatry 53:339, 1990.
Strupp M, Ning R, Hua R, et al: Diffusion-weighted MRI in tran-
sient global amnesia: Elevated signal intensity in the left
mesial temporal lobe in 7 of 10 patients. Ann Neurol 43:164,
1998.
Suthana N, Haneef Z, Stern J, et al: Memory enhancement and
deep-brain stimulation of the entorhinal area. New Engl J Med
366:502, 2012.
Terman LM, Ogden MH: The Gifted Group at Mid-life: Genetic
Studies of Genius. Vol IV. Stanford, CA, Stanford University
Press, 1959.
Thompson PM, Cannon TD, Narr KL, et al: Genetic influences on
brain structure. Nat Neurosci 4:1253, 2001.