196 PART 2 Cardinal Manifestations and Presentation of Diseases

and behavioral functions (domains) are coordinated by intersecting

large-scale neural networks that contain interconnected cortical and

subcortical components. Five anatomically defined large-scale networks

are most relevant to clinical practice: (1) a left-dominant perisylvian

network for language, (2) a right-dominant parietofrontal network for

spatial orientation, (3) an occipitotemporal network for face and object

recognition, (4) a limbic network for episodic memory and emotional

modulation, and (5) a prefrontal network for the executive control

of cognition and comportment. Investigations based on functional

imaging have also identified a default mode network, which becomes

activated when the person is not engaged in a specific task requiring

attention to external events. The clinical consequences of damage to

this network are not yet fully defined.

THE LEFT PERISYLVIAN NETWORK FOR

LANGUAGE AND APHASIAS

The production and comprehension of words and sentences is dependent on the integrity of a distributed network located along the perisylvian region of the language-dominant (usually left) hemisphere. One

hub, situated in the inferior frontal gyrus, is known as Broca’s area.

Damage to this region impairs fluency of verbal output and the grammatical structure of sentences. The location of a second hub, critical

for language comprehension, is less clearly settled. Accounts of patients

with focal cerebrovascular lesions identified Wernicke’s area, located at

the parietotemporal junction, as a critical hub for word and sentence

comprehension. Occlusive or embolic strokes involving this area interfere with the ability to understand spoken or written language as well

as the ability to express thoughts through meaningful words and statements. However, investigations of patients with the neurodegenerative

syndrome of primary progressive aphasia (PPA) have shown that sentence comprehension is a widely distributed faculty jointly subserved

by Broca’s and Wernicke’s areas, and that the areas critical for word

comprehension are more closely associated with the anterior temporal

lobe than with Wernicke’s area. All components of the language network are interconnected with each other and with surrounding parts

of the frontal, parietal, and temporal lobes. Damage to this network

gives rise to language impairments known as aphasia. Aphasia should

be diagnosed only when there are deficits in the formal aspects of language, such as word finding, word choice, comprehension, spelling, or

grammar. Dysarthria, apraxia of speech, and mutism do not by themselves lead to a diagnosis of aphasia. In ~90% of right-handers and 60%

of left-handers, aphasia occurs only after lesions of the left hemisphere.

■ CLINICAL EXAMINATION

The clinical examination of language should include the assessment

of naming, spontaneous speech, comprehension, repetition, reading,

and writing. A deficit of naming (anomia) is the single most common

finding in aphasic patients. When asked to name a common object, the

patient may fail to come up with the appropriate word, may provide a

circumlocutious description of the object (“the thing for writing”), or

may come up with the wrong word (paraphasia). If the patient offers

TABLE 30-1 Clinical Features of Aphasias and Related Conditions Commonly Seen in Cerebrovascular Accidents

COMPREHENSION

REPETITION OF SPOKEN

LANGUAGE NAMING FLUENCY

Wernicke’s Impaired Impaired Impaired Preserved or increased

Broca’s Preserved (except grammar) Impaired Impaired Decreased

Global Impaired Impaired Impaired Decreased

Conduction Preserved Impaired Impaired Preserved

Nonfluent (anterior) transcortical Preserved Preserved Impaired Impaired

Fluent (posterior) transcortical Impaired Preserved Impaired Preserved

Isolation Impaired Echolalia Impaired No purposeful speech

Anomic Preserved Preserved Impaired Preserved except for wordfinding pauses

Pure word deafness Impaired only for spoken language Impaired Preserved Preserved

Pure alexia Impaired only for reading Preserved Preserved Preserved

an incorrect but related word (“pen” for “pencil”), the naming error

is known as a semantic paraphasia; if the word approximates the correct answer but is phonetically inaccurate (“plentil” for “pencil”), it is

known as a phonemic paraphasia. In most anomias, the patient cannot

retrieve the appropriate name when shown an object but can point to

the appropriate object when the name is provided by the examiner.

This is known as a one-way (or retrieval-based) naming deficit. A

two-way (comprehension-based or semantic) naming deficit exists

if the patient can neither provide nor recognize the correct name.

Spontaneous speech is described as “fluent” if it maintains appropriate

output volume, phrase length, and melody or as “nonfluent” if it is

sparse and halting and average utterance length is below four words.

The examiner also should note the integrity of grammar as manifested

by word order (syntax), tenses, suffixes, prefixes, plurals, and possessives. Comprehension can be tested by assessing the patient’s ability to

follow conversation, asking yes-no questions (“Can a dog fly?” “Does it

snow in summer?”), asking the patient to point to appropriate objects

(“Where is the source of illumination in this room?”), or asking for

verbal definitions of single words. Repetition is assessed by asking the

patient to repeat single words, short sentences, or strings of words such

as “No ifs, ands, or buts.” The testing of repetition with tongue twisters

such as “hippopotamus” and “Irish constabulary” provides a better

assessment of dysarthria and apraxia of speech than of aphasia. It is

important to make sure that the number of words does not exceed the

patient’s attention span. Otherwise, the failure of repetition becomes a

reflection of the narrowed attention span (auditory working memory)

rather than an indication of an aphasic deficit caused by dysfunction

of a hypothetical phonological loop in the language network. Reading

should be assessed for deficits in reading aloud as well as comprehension. Alexia describes an inability to either read aloud or comprehend

written words and sentences; agraphia (or dysgraphia) is used to

describe an acquired deficit in spelling.

Aphasias can arise acutely in cerebrovascular accidents (CVAs) or

gradually in neurodegenerative diseases. In CVAs, damage encompasses cerebral cortex as well as deep white matter pathways interconnecting otherwise unaffected cortical areas. The syndromes listed

in Table 30-1 are most applicable to this group, where gray matter

and white matter at the lesion site are abruptly and jointly destroyed.

Progressive neurodegenerative diseases can have cellular, laminar, and

regional specificity for the cerebral cortex, giving rise to a different set

of aphasias that will be described separately.

Wernicke’s Aphasia Comprehension is impaired for spoken and

written words and sentences. Language output is fluent but is highly

paraphasic and circumlocutious. Paraphasic errors may lead to strings

of neologisms, which lead to “jargon aphasia.” Speech contains few substantive nouns. The output is therefore voluminous but uninformative.

For example, a patient attempts to describe how his wife accidentally

threw away something important, perhaps his dentures: “We don’t

need it anymore, she says. And with it when that was downstairs was

my teeth-tick … a … den … dentith … my dentist. And they happened

197Aphasia, Memory Loss, and Other Cognitive Disorders CHAPTER 30

to be in that bag … see? …Where my two … two little pieces of dentist

that I use … that I … all gone. If she throws the whole thing away …

visit some friends of hers and she can’t throw them away.”

Gestures and pantomime do not improve communication. The

patient may not realize that his or her language is incomprehensible

and may appear angry and impatient when the examiner fails to

decipher the meaning of a severely paraphasic statement. In some

patients, this type of aphasia can be associated with severe agitation

and paranoia. The ability to follow commands aimed at axial musculature may be preserved. The dissociation between the failure to

understand simple questions (“What is your name?”) in a patient who

rapidly closes his or her eyes, sits up, or rolls over when asked to do so

is characteristic of Wernicke’s aphasia and helps differentiate it from

deafness, psychiatric disease, or malingering. Patients with Wernicke’s

aphasia cannot express their thoughts in meaning-appropriate words

and cannot decode the meaning of words in any modality of input.

This aphasia therefore has expressive as well as receptive components.

Repetition, naming, reading, and writing also are impaired.

The lesion site most commonly associated with Wernicke’s aphasia

caused by CVAs is the posterior portion of the language network.

An embolus to the inferior division of the middle cerebral artery

(MCA), to the posterior temporal or angular branches in particular,

is the most common etiology (Chap. 426). Intracerebral hemorrhage,

head trauma, and neoplasm are other causes of Wernicke’s aphasia. A

coexisting right hemianopia or superior quadrantanopia is common,

and mild right nasolabial flattening may be found, but otherwise, the

examination is often unrevealing. The paraphasic, neologistic speech in

an agitated patient with an otherwise unremarkable neurologic examination may lead to the suspicion of a primary psychiatric disorder such

as schizophrenia or mania, but the other components characteristic of

acquired aphasia and the absence of prior psychiatric disease usually

settle the issue. Prognosis for recovery of language function is guarded.

Broca’s Aphasia Speech is nonfluent, labored, interrupted by many

word-finding pauses, and usually dysarthric. It is impoverished in

function words but enriched in meaning-appropriate nouns. Abnormal

word order and the inappropriate deployment of bound morphemes

(word endings used to denote tenses, possessives, or plurals) lead to a

characteristic agrammatism. Speech is telegraphic and pithy but quite

informative. In the following passage, a patient with Broca’s aphasia

describes his medical history: “I see … the dotor, dotor sent me …

Bosson. Go to hospital. Dotor … kept me beside. Two, tee days, doctor

send me home.”

Output may be reduced to a grunt or single word (“yes” or “no”),

which is emitted with different intonations in an attempt to express

approval or disapproval. In addition to fluency, naming and repetition

are impaired. Comprehension of spoken language is intact except

for syntactically difficult sentences with a passive voice structure

or embedded clauses, indicating that Broca’s aphasia is not just an

“expressive” or “motor” disorder and that it also may involve a comprehension deficit in decoding syntax. Patients with Broca’s aphasia can be

tearful, easily frustrated, and profoundly depressed. Insight into their

condition is preserved, in contrast to Wernicke’s aphasia. Even when

spontaneous speech is severely dysarthric, the patient may be able to

display a relatively normal articulation of words when singing. This

dissociation has been used to develop specific therapeutic approaches

(melodic intonation therapy) for Broca’s aphasia. Additional neurologic

deficits include right facial weakness, hemiparesis or hemiplegia, and

a buccofacial apraxia characterized by an inability to carry out motor

commands involving oropharyngeal and facial musculature (e.g.,

patients are unable to demonstrate how to blow out a match or suck

through a straw). The cause is most often infarction of Broca’s area (the

inferior frontal convolution; “B” in Fig. 30-1) and surrounding anterior

perisylvian and insular cortex due to occlusion of the superior division

of the MCA (Chap. 426). Mass lesions, including tumor, intracerebral

hemorrhage, and abscess, also may be responsible. When the cause of

Broca’s aphasia is stroke, recovery of language function generally peaks

within 2–6 months, after which time further progress is limited. Speech

therapy is more successful than in Wernicke’s aphasia.

Conduction Aphasia Speech output is fluent but contains many

phonemic paraphasias, comprehension of spoken language is intact,

and repetition is severely impaired. Naming elicits phonemic paraphasias, and spelling is impaired. Reading aloud is impaired, but reading

comprehension is preserved. The responsible lesion, usually a CVA in

the temporoparietal or dorsal perisylvian region, interferes with the

function of the phonological loop interconnecting Broca’s area with

Wernicke’s area. Occasionally, a transient Wernicke’s aphasia may rapidly resolve into a conduction aphasia. The paraphasic and circumlocutious output in conduction aphasia interferes with the ability to express

meaning, but this deficit is not nearly as severe as the one displayed by

patients with Wernicke’s aphasia. Associated neurologic signs in conduction aphasia vary according to the primary lesion site.

Transcortical Aphasias: Fluent and Nonfluent Clinical features of fluent (posterior) transcortical aphasia are similar to those of

Wernicke’s aphasia, but repetition is intact. The lesion site disconnects

the intact core of the language network from other temporoparietal

association areas. Associated neurologic findings may include hemianopia. Cerebrovascular lesions (e.g., infarctions in the posterior

watershed zone) and neoplasms that involve the temporoparietal cortex posterior to Wernicke’s area are common causes. The features of

nonfluent (anterior) transcortical aphasia are similar to those of Broca’s

aphasia, but repetition is intact and agrammatism is less pronounced.

The neurologic examination may be otherwise intact, but a right hemiparesis also can exist. The lesion site disconnects the intact language

network from prefrontal areas of the brain and usually involves the

anterior watershed zone between anterior and MCA territories or the

supplementary motor cortex in the territory of the anterior cerebral

artery.

Global and Isolation Aphasias Global aphasia represents the

combined dysfunction of Broca’s and Wernicke’s areas and usually

results from strokes that involve the entire MCA distribution in the

left hemisphere. Speech output is nonfluent, and comprehension of

language is severely impaired. Related signs include right hemiplegia,

hemisensory loss, and homonymous hemianopia. Isolation aphasia

represents a combination of the two transcortical aphasias. Comprehension is severely impaired, and there is no purposeful speech output.

The patient may parrot fragments of heard conversations (echolalia),

indicating that the neural mechanisms for repetition are at least partially intact. This condition represents the pathologic function of the

language network when it is isolated from other regions of the brain.

Broca’s and Wernicke’s areas tend to be spared, but there is damage

to the surrounding frontal, parietal, and temporal cortex. Lesions are

patchy and can be associated with anoxia, carbon monoxide poisoning,

or complete watershed zone infarctions.

Anomic Aphasia This form of aphasia may be considered the

“minimal dysfunction” syndrome of the language network. Articulation, comprehension, and repetition are intact, but confrontation

naming, word finding, and spelling are impaired. Word-finding

pauses are uncommon, so language output is fluent but paraphasic,

circumlocutious, and uninformative. The lesion sites can be anywhere

within the left hemisphere language network, including the middle

and inferior temporal gyri. Anomic aphasia is the single most common

language disturbance seen in head trauma, metabolic encephalopathy,

and Alzheimer’s disease.

Pure Word Deafness The most common causes are either bilateral or left-sided MCA strokes affecting the superior temporal gyrus.

The net effect of the underlying lesion is to interrupt the flow of

information from the auditory association cortex to the language

network. Patients have no difficulty understanding written language

and can express themselves well in spoken or written language. They

have no difficulty interpreting and reacting to environmental sounds

if the primary auditory cortex and auditory association areas of the

right hemisphere are spared. Because auditory information cannot

be conveyed to the language network, however, it cannot be decoded

into neural word representations, and the patient reacts to speech as if

it were in an alien tongue that cannot be deciphered. Patients cannot

198 PART 2 Cardinal Manifestations and Presentation of Diseases

repeat spoken language but have no difficulty naming objects. In time,

patients with pure word deafness teach themselves lipreading and may

appear to have improved. There may be no additional neurologic findings, but agitated paranoid reactions are common in the acute stages.

Cerebrovascular lesions are the most common cause.

Pure Alexia Without Agraphia This is the visual equivalent of

pure word deafness. The lesions (usually a combination of damage

to the left occipital cortex and to a posterior sector of the corpus

callosum—the splenium) interrupt the flow of visual input into the

language network. There is usually a right hemianopia, but the core

language network remains unaffected. The patient can understand and

produce spoken language, name objects in the left visual hemifield,

repeat, and write. However, the patient acts as if illiterate when asked

to read even the simplest sentence because the visual information

from the written words (presented to the intact left visual hemifield)

cannot reach the language network. Objects in the left hemifield may

be named accurately because they activate nonvisual associations in

the right hemisphere, which in turn can access the language network

through transcallosal pathways anterior to the splenium. Patients with

this syndrome also may lose the ability to name colors, although they

can match colors. This is known as a color anomia. The most common

etiology of pure alexia is a vascular lesion in the territory of the posterior cerebral artery or an infiltrating neoplasm in the left occipital cortex that involves the optic radiations as well as the crossing fibers of the

splenium. Because the posterior cerebral artery also supplies medial

temporal components of the limbic system, a patient with pure alexia

also may experience an amnesia, but this is usually transient because

the limbic lesion is unilateral.

Apraxia and Aphemia Apraxia designates a complex motor deficit that cannot be attributed to pyramidal, extrapyramidal, cerebellar,

or sensory dysfunction and that does not arise from the patient’s

failure to understand the nature of the task. Apraxia of speech is used

to designate articulatory abnormalities in the duration, fluidity, and

stress of syllables that make up words. It can arise with CVAs in the

posterior part of Broca’s area or in the course of frontotemporal lobar

degeneration (FTLD) with tauopathy. Aphemia is a severe form of

acute speech apraxia that presents with severely impaired fluency

(often mutism). Recovery is the rule and involves an intermediate

stage of hoarse whispering. Writing, reading, and comprehension are

intact, and so this is not a true aphasic syndrome. CVAs in parts of

Broca’s area or subcortical lesions that undercut its connections with

other parts of the brain may be present. Occasionally, the lesion site

is on the medial aspects of the frontal lobes and may involve the supplementary motor cortex of the left hemisphere. Ideomotor apraxia is

diagnosed when commands to perform a specific motor act (“cough,”

“blow out a match”) or pantomime the use of a common tool (a comb,

hammer, straw, or toothbrush) in the absence of the real object cannot

be followed. The patient’s ability to comprehend the command is ascertained by demonstrating multiple movements and establishing that the

correct one can be recognized. Some patients with this type of apraxia

can imitate the appropriate movement when it is demonstrated by the

examiner and show no impairment when handed the real object, indicating that the sensorimotor mechanisms necessary for the movement

are intact. Some forms of ideomotor apraxia represent a disconnection

of the language network from pyramidal motor systems so that commands to execute complex movements are understood but cannot be

conveyed to the appropriate motor areas. Buccofacial apraxia involves

apraxic deficits in movements of the face and mouth. Ideomotor limb

apraxia encompasses apraxic deficits in movements of the arms and

legs. Ideomotor apraxia almost always is caused by lesions in the left

hemisphere and is commonly associated with aphasic syndromes, especially Broca’s aphasia and conduction aphasia. Because the handling of

real objects is not impaired, ideomotor apraxia by itself causes no major

limitation of daily living activities. Patients with lesions of the anterior

corpus callosum can display ideomotor apraxia confined to the left

side of the body, a sign known as sympathetic dyspraxia. A severe

form of sympathetic dyspraxia, known as the alien hand syndrome, is

characterized by additional features of motor disinhibition on the left

hand. Ideational apraxia refers to a deficit in the sequencing of goaldirected movements in patients who have no difficulty executing the

individual components of the sequence. For example, when the patient

is asked to pick up a pen and write, the sequence of uncapping the pen,

placing the cap at the opposite end, turning the point toward the writing surface, and writing may be disrupted, and the patient may be seen

trying to write with the wrong end of the pen or even with the removed

cap. These motor sequencing problems usually are seen in the context

of confusional states and dementias rather than focal lesions associated

with aphasic conditions. Limb-kinetic apraxia involves clumsiness in

the use of tools or objects that cannot be attributed to sensory, pyramidal, extrapyramidal, or cerebellar dysfunction. This condition can

emerge in the context of focal premotor cortex lesions or corticobasal

degeneration and can interfere with the use of tools and utensils.

Gerstmann’s Syndrome The combination of acalculia (impairment of simple arithmetic), dysgraphia (impaired writing), finger

anomia (an inability to name individual fingers such as the index and

thumb), and right-left confusion (an inability to tell whether a hand,

foot, or arm of the patient or examiner is on the right or left side of the

body) is known as Gerstmann’s syndrome. In making this diagnosis, it

is important to establish that the finger and left-right naming deficits

are not part of a more generalized anomia and that the patient is not

otherwise aphasic. When Gerstmann’s syndrome arises acutely and in

isolation, it is commonly associated with damage to the inferior parietal lobule (especially the angular gyrus) in the left hemisphere.

Pragmatics and Prosody Pragmatics refers to aspects of language

that communicate attitude, affect, and the figurative rather than literal

aspects of a message (e.g., “green thumb” does not refer to the actual

color of the finger). One component of pragmatics, prosody, refers

to variations of melodic stress and intonation that influence attitude

and the inferential aspect of verbal messages. For example, the two

statements “He is clever.” and “He is clever?” contain an identical word

choice and syntax but convey vastly different messages because of differences in the intonation with which the statements are uttered. Damage to right hemisphere regions corresponding to Broca’s area impairs

the ability to introduce meaning-appropriate prosody into spoken

language. The patient produces grammatically correct language with

accurate word choice, but the statements are uttered in a monotone

that interferes with the ability to convey the intended stress and effect.

Patients with this type of aprosodia give the mistaken impression of

being depressed or indifferent. Other aspects of pragmatics, especially

the ability to infer the figurative aspect of a message, become impaired

by damage to the right hemisphere or frontal lobes.

Subcortical Aphasia Damage to subcortical components of the

language network (e.g., the striatum and thalamus of the left hemisphere) also can lead to aphasia. The resulting syndromes contain

combinations of deficits in the various aspects of language but rarely fit

the specific patterns described in Table 30-1. In a patient with a CVA,

an anomic aphasia accompanied by dysarthria or a fluent aphasia with

hemiparesis should raise the suspicion of a subcortical lesion site.

CLINICAL PRESENTATION AND DIAGNOSIS OF PPA Aphasias caused

by CVAs start suddenly and display maximal deficits at the onset.

These are the “classic” aphasias described above. Aphasias caused by

neurodegenerative diseases have an insidious onset and relentless progression. The neuropathology can be selective not only for gray matter

but also for specific layers and cell types. The clinico-anatomic patterns

are therefore different from those described in Table 30-1.

Several neurodegenerative syndromes, such as typical Alzheimertype (amnestic; Chap. 431) and frontotemporal (behavioral; Chap.

432) dementias, can also include language impairments as the disease

progresses. In these cases, the aphasia is an ancillary component of the

overall syndrome. A diagnosis of primary progressive aphasia (PPA)

is justified only if the language disorder (i.e., aphasia) arises in relative

isolation, becomes the primary concern that brings the patient to medical attention, and remains the most salient deficit for 1–2 years. PPA

199Aphasia, Memory Loss, and Other Cognitive Disorders CHAPTER 30

can be caused by either FTLD or Alzheimer’s disease (AD) pathology.

Rarely, an identical syndrome can be caused by Creutzfeldt-Jacob disease (CJD) but with a more rapid progression (Chap. 438).

LANGUAGE IN PPA The impairments of language in PPA have slightly

different patterns from those seen in CVA-caused aphasias. For example, the full syndrome of Wernicke’s aphasia is almost never seen in

PPA, confirming the view that sentence comprehension and word comprehension are controlled by different regions of the language network.

Three major subtypes of PPA can be recognized.

Agrammatic PPA The agrammatic variant is characterized by

consistently low fluency and impaired grammar but intact word

comprehension. It most closely resembles Broca’s aphasia or anterior

transcortical aphasia but usually lacks the right hemiparesis or dysarthria and may have more profound impairments of grammar. Peak

sites of neuronal loss (gray matter atrophy) include the left inferior

frontal gyrus where Broca’s area is located. The neuropathology is

usually a FTLD with tauopathy but can also be an atypical form of AD

pathology.

Semantic PPA The semantic variant is characterized by preserved

fluency and syntax but poor single-word comprehension and profound

two-way naming impairments. This kind of aphasia is not seen with

CVAs. It differs from Wernicke’s aphasia or posterior transcortical

aphasia because speech is usually informative and repetition is intact.

Comprehension of sentences is relatively preserved if the meaning is

not too dependent on words that fail to be understood allowing the

patient to surmise the gist of the conversation through contextual

cues. Such patients may appear unimpaired in the course of casual

small talk but become puzzled upon encountering an undecipherable

word such as “pumpkin” or “umbrella.” Peak atrophy sites are located

in the left anterior temporal lobe, indicating that this part of the brain

plays a critical role in the comprehension of words, especially words

that denote concrete objects. This is a part of the brain that was not

included within the classic language network, probably because it is

not a common site for focal CVAs. The neuropathology is frequently an

FTLD with abnormal precipitates of the 43-kDa transactive response

DNA-binding protein TDP-43 of type C.

Logopenic PPA The logopenic variant is characterized by preserved

syntax and comprehension but frequent and severe word-finding

pauses, anomia, circumlocutions, and simplifications during spontaneous speech. Repetition is usually impaired. Peak atrophy sites are

located in the temporoparietal junction and posterior temporal lobe,

partially overlapping with traditional location of Wernicke’s area.

However, the comprehension impairment of Wernicke’s aphasia is

absent probably because the underlying deep white matter, frequently

damaged by CVAs, remains relatively intact in PPA. The repetition

impairment suggests that parts of Wernicke’s area are critical for phonological loop functionality. In contrast to Broca’s aphasia or agrammatic PPA, the interruption of fluency is variable so that speech may

appear entirely normal if the patient is allowed to engage in small talk.

Logopenic PPA resembles the anomic aphasia of Table 30-1 but usually

has longer and more frequent word-finding pauses. When repetition is

impaired, the aphasia resembles the conduction aphasia in Table 30-1.

Of all PPA subtypes, this is the one most commonly associated with the

pathology of AD, but FTLD can also be the cause. In addition to these

three major subtypes, there is also a mixed type of PPA where grammar,

fluency, and word comprehension are jointly impaired. This is most

like the global aphasia of Table 30-1. Rarely, PPA can present with

patterns reminiscent of pure word deafness or Gerstmann’s syndrome.

THE PARIETOFRONTAL NETWORK FOR

SPATIAL ORIENTATION

Adaptive spatial orientation is subserved by a large-scale network containing three major cortical components. The cingulate cortex provides

access to a motivational mapping of the extrapersonal space, the posterior parietal cortex to a sensorimotor representation of salient extrapersonal events, and the frontal eye fields to motor strategies for attentional

behaviors (Fig. 30-2). Subcortical components of this network include

the striatum and the thalamus. Damage to this network can undermine

the distribution of attention within the extrapersonal space, giving rise

to hemispatial neglect, simultanagnosia, and object finding failures.

The integration of egocentric (self-centered) with allocentric (objectcentered) coordinates can also be disrupted, giving rise to impairments

in route finding, the ability to avoid obstacles, and the ability to dress.

■ HEMISPATIAL NEGLECT

Contralesional hemispatial neglect represents one outcome of damage to the cortical or subcortical components of this network. The

traditional view that hemispatial neglect always denotes a parietal lobe

lesion is inaccurate. According to one model of spatial cognition, the

right hemisphere directs attention within the entire extrapersonal

space, whereas the left hemisphere directs attention mostly within the

contralateral right hemispace. Consequently, left hemisphere lesions

do not give rise to much contralesional neglect because the global

attentional mechanisms of the right hemisphere can compensate for

the loss of the contralaterally directed attentional functions of the left

hemisphere. Right hemisphere lesions, however, give rise to severe contralesional left hemispatial neglect because the unaffected left hemisphere does not contain ipsilateral attentional mechanisms. This model

is consistent with clinical experience, which shows that contralesional

neglect is more common, more severe, and longer lasting after damage to the right hemisphere than after damage to the left hemisphere.

Severe neglect for the right hemispace is rare, even in left-handers with

left hemisphere lesions.

FIGURE 30-2 Functional magnetic resonance imaging of language and spatial

attention in neurologically intact subjects. The red and black areas show regions

of task-related significant activation. (Top) The subjects were asked to determine if

two words were synonymous. This language task led to the simultaneous activation

of the two components of the language network, Broca’s area (B) and Wernicke’s

area (W). The activations are exclusively in the left hemisphere. (Bottom) The

subjects were asked to shift spatial attention to a peripheral target. This task led

to the simultaneous activation of the three epicenters of the attentional network:

the posterior parietal cortex (P), the frontal eye fields (F), and the cingulate gyrus

(CG). The activations are predominantly in the right hemisphere. (Courtesy of Darren

Gitelman, MD.)

200 PART 2 Cardinal Manifestations and Presentation of Diseases

Clinical Examination Patients with severe neglect may fail to

dress, shave, or groom the left side of the body; fail to eat food placed

on the left side of the tray; and fail to read the left half of sentences.

When asked to copy a simple line drawing, the patient fails to copy

detail on the left, and when the patient is asked to write, there is a tendency to leave an unusually wide margin on the left. Two bedside tests

that are useful in assessing neglect are simultaneous bilateral stimulation and visual target cancellation. In the former, the examiner provides

either unilateral or simultaneous bilateral stimulation in the visual,

auditory, and tactile modalities. After right hemisphere injury, patients

who have no difficulty detecting unilateral stimuli on either side

experience the bilaterally presented stimulus as coming only from the

right. This phenomenon is known as extinction and is a manifestation

of the sensory-representational aspect of hemispatial neglect. In the

target detection task, targets (e.g., A’s) are interspersed with foils (e.g.,

other letters of the alphabet) on a 21.5- to 28.0-cm (8.5–11 in.) sheet

of paper, and the patient is asked to circle all the targets. A failure to

detect targets on the left is a manifestation of the exploratory (motor)

deficit in hemispatial neglect (Fig. 30-3A). Hemianopia is not by itself

sufficient to cause the target detection failure because the patient is free

to turn the head and eyes to the left. Target detection failures therefore

reflect a distortion of spatial attention, not just of sensory input. Some

patients with neglect also may deny the existence of hemiparesis and

may even deny ownership of the paralyzed limb, a condition known as

anosognosia.

■ BÁLINT’S SYNDROME, SIMULTANAGNOSIA,

DRESSING APRAXIA, CONSTRUCTION APRAXIA,

AND ROUTE-FINDING IMPAIRMENTS

Bilateral involvement of the network for spatial attention, especially

its parietal components, leads to a state of severe spatial disorientation

known as Bálint’s syndrome. Bálint’s syndrome involves deficits in the

FIGURE 30-3 A. A 47-year-old man with a large frontoparietal lesion in the right hemisphere was asked to circle all the A’s. Only targets on the right are circled. This is a

manifestation of left hemispatial neglect. B. A 70-year-old woman with a 2-year history of degenerative dementia was able to circle most of the small targets but ignored the

larger ones. This is a manifestation of simultanagnosia.

A

B

201Aphasia, Memory Loss, and Other Cognitive Disorders CHAPTER 30

orderly visuomotor scanning of the environment (oculomotor apraxia),

accurate manual reaching toward visual targets (optic ataxia), and the

ability to integrate visual information in the center of gaze with more

peripheral information (simultanagnosia). A patient with simultanagnosia “misses the forest for the trees.” For example, a patient who

is shown a table lamp and asked to name the object may look at its

circular base and call it an ashtray. Some patients with simultanagnosia

report that objects they look at may vanish suddenly, probably indicating an inability to compute the oculomotor return to the original point

of gaze after brief saccadic displacements. Movement and distracting

stimuli greatly exacerbate the difficulties of visual perception. Simultanagnosia can occur without the other two components of Bálint’s

syndrome, especially in association with AD.

A modification of the letter cancellation task described above can

be used for the bedside diagnosis of simultanagnosia. In this modification, some of the targets (e.g., A’s) are made to be much larger than the

others (7.5–10 cm vs 2.5 cm [3–4 in. vs 1 in.] in height), and all targets

are embedded among foils. Patients with simultanagnosia display a

counterintuitive but characteristic tendency to miss the larger targets

(Fig. 30-3B). This occurs because the information needed for the

identification of the larger targets cannot be confined to the immediate

line of gaze and requires the integration of visual information across

multiple fixation points. The greater difficulty in the detection of the

larger targets also indicates that poor acuity is not responsible for the

impairment of visual function and that the problem is central rather

than peripheral. The test shown in Fig. 30-3B is not by itself sufficient

to diagnose simultanagnosia as some patients with a frontal network

syndrome may omit the letters that appear incongruous for the size of

the paper. This may happen because they lack the mental flexibility to

realize that the two types of targets are symbolically identical despite

being superficially different.

Bilateral parietal lesions can impair the integration of egocentric

with allocentric spatial coordinates. One manifestation is dressing

apraxia. A patient with this condition is unable to align the body axis

with the axis of the garment and can be seen struggling as he or she

holds a coat from its bottom or extends his or her arm into a fold of

the garment rather than into its sleeve. Lesions that involve the posterior parietal cortex also lead to severe difficulties in copying simple

line drawings. This is known as a construction apraxia and is much

more severe if the lesion is in the right hemisphere. In some patients

with right hemisphere lesions, the drawing difficulties are confined to

the left side of the figure and represent a manifestation of hemispatial

neglect; in others, there is a more universal deficit in reproducing contours and three-dimensional perspective. Impairments of route finding

can be included in this group of disorders, which reflect an inability to

orient the self with respect to external objects and landmarks.

Causes of Spatial Disorientation and the Posterior Cortical

Atrophy Syndrome Cerebrovascular lesions and neoplasms in the

right hemisphere are common causes of hemispatial neglect. Depending on the site of the lesion, a patient with neglect also may have hemiparesis, hemihypesthesia, and hemianopia on the left, but these are not

invariant findings. The majority of these patients display considerable

improvement of hemispatial neglect, usually within the first several

weeks. Bálint’s syndrome, dressing apraxia, and route-finding impairments are more likely to result from bilateral dorsal parietal lesions;

common settings for acute onset include watershed infarction between

the middle and posterior cerebral artery territories, hypoglycemia, and

sagittal sinus thrombosis.

A progressive form of spatial disorientation, known as the posterior

cortical atrophy (PCA) syndrome, most commonly represents a variant

of AD with unusual concentrations of neurofibrillary degeneration

in the parieto-occipital cortex and the superior colliculus (Fig. 30-4).

Lewy body disease (LBD), CJD, and FTLD (corticobasal degeneration

type) are other possible causes. The patient displays progressive hemispatial neglect, Bálint’s syndrome, and route-finding impairments, usually accompanied by dressing and construction apraxia.

THE OCCIPITOTEMPORAL NETWORK FOR

FACE AND OBJECT RECOGNITION

A patient with prosopagnosia cannot recognize familiar faces, including, sometimes, the reflection of their own face in the mirror. This is

not a perceptual deficit because prosopagnosic patients easily can tell

whether two faces are identical. Furthermore, a prosopagnosic patient

who cannot recognize a familiar face by visual inspection alone can use

auditory cues to reach appropriate recognition if allowed to listen to

the person’s voice. The deficit in prosopagnosia is therefore modalityspecific and reflects the existence of a lesion that prevents the activation of otherwise intact multimodal associative templates by relevant

visual input. Prosopagnosic patients characteristically have no difficulty with the generic identification of a face as a face or a car as a car,

but may not recognize the identity of an individual face or the make of

an individual car. This reflects a visual recognition deficit for proprietary features that characterize individual members of an object class.

When recognition problems become more generalized and extend to

the generic identification of common objects, the condition is known

as visual object agnosia. A patient with anomia cannot name the object

but can describe its use. In contrast, a patient with visual agnosia is

unable either to name a visually presented object or to describe its

use. Face and object recognition disorders also can result from the

simultanagnosia of Bálint’s syndrome, in which case they are known as

apperceptive agnosias as opposed to the associative agnosias that result

from inferior temporal lobe lesions.

AMNESTIC

(Dementia of the Alzheimer-type-DAT)

AD>>>FTLD

VISUO-SPATIAL

(Posterior cortical atrophy-PCA)

AD>>LBD>FTLD

APHASIC

(Primary progressive aphasia- PPA)

FTLD>AD

BEHAVIORAL

(Frontotemporal dementia- bvFTD)

FTLD>>AD

LATERAL VIEW MEDIAL VIEW

FIGURE 30-4 Four focal dementia syndromes and their most likely neuropathologic correlates. AD, Alzheimer’s disease; bvFTD, behavioral variant frontotemporal

dementia; DAT, amnestic dementia of the Alzheimer type; FTLD, frontotemporal lobar degeneration (tau or TDP-43 type); LBD, Lewy body disease; PCA, posterior cortical

atrophy syndrome; PPA, primary progressive aphasia.

202 PART 2 Cardinal Manifestations and Presentation of Diseases

■ CAUSES AND RELATION TO SEMANTIC

DEMENTIA

The characteristic lesions in prosopagnosia and visual object agnosia

of acute onset consist of bilateral infarctions in the territory of the

posterior cerebral arteries that involve the fusiform gyrus. Associated

deficits can include visual field defects (especially superior quadrantanopias) and a centrally based color blindness known as achromatopsia.

Rarely, the responsible lesion is unilateral. In such cases, prosopagnosia

is associated with lesions in the right hemisphere, and object agnosia

with lesions in the left. Degenerative diseases of anterior and inferior

temporal cortex can cause progressive associative prosopagnosia and

object agnosia. The combination of progressive associative agnosia

and a fluent aphasia with word comprehension impairment is known

as semantic dementia. Patients with semantic dementia fail to recognize faces and objects and cannot understand the meaning of words

denoting objects. This needs to be differentiated from the semantic

type of PPA where there is severe impairment in understanding words

that denote objects and in naming faces and objects but a relative

preservation of face and object recognition. The anterior temporal lobe

atrophy is usually bilateral in semantic dementia whereas it tends to

affect mostly the left hemisphere in semantic PPA. Acute onset of the

semantic dementia syndrome can be associated with herpes simplex

encephalitis.

LIMBIC NETWORK FOR EXPLICIT MEMORY

AND AMNESIA

Limbic areas (e.g., the hippocampus, amygdala, and entorhinal cortex), paralimbic areas (e.g., the cingulate gyrus, insula, temporopolar

cortex, and parts of orbitofrontal regions), the anterior and medial

nuclei of the thalamus, the medial and basal parts of the striatum, and

the hypothalamus collectively constitute a distributed network known

as the limbic system. The behavioral affiliations of this network can

be classified into two groups. One includes the coordination of emotion, motivation, affiliative behaviors, autonomic tone, and endocrine

function. These functions are under the influence of the amygdala and

anterior paralimbic areas. They make up the salience network. The two

neurologic conditions that most frequently interfere with this group

of limbic functions are temporal lobe epilepsy and behavioral variant

frontotemporal dementia (bvFTD). An additional area of specialization

for the limbic network and the one that is of most relevance to clinical

practice is that of declarative (explicit) memory for recent episodes and

experiences. This function is under the influence of the hippocampus,

entorhinal cortex, posterior paralimbic areas, and limbic nuclei of the

thalamus. This part of the limbic system is also known as the Papez

circuit. A disturbance of explicit memory is known as an amnestic

state. In the absence of deficits in motivation, attention, language,

or visuospatial function, the clinical diagnosis of a persistent global

amnestic state is always associated with bilateral damage to the limbic

network, usually within the hippocampo-entorhinal complex or the

thalamus. Damage to the limbic network does not necessarily destroy

memories but interferes with their conscious recall in coherent form.

The individual fragments of information remain preserved despite the

limbic lesions and can sustain what is known as implicit memory. For

example, patients with amnestic states can acquire new motor or perceptual skills even though they may have no conscious knowledge of

the experiences that led to the acquisition of these skills.

The memory disturbance in the amnestic state is multimodal and

includes retrograde and anterograde components. The retrograde

amnesia involves an inability to recall experiences that occurred before

the onset of the amnestic state. Relatively recent events are more vulnerable to retrograde amnesia than are more remote and more extensively consolidated events. A patient who comes to the emergency

room complaining that he cannot remember his or her identity but

can remember the events of the previous day almost certainly does

not have a neurologic cause of memory disturbance. The second and

most important component of the amnestic state is the anterograde

amnesia, which indicates an inability to store, retain, and recall new

knowledge. Patients with amnestic states cannot remember what they

ate a few hours ago or the details of an important event they may have

experienced in the recent past. In the acute stages, there also may be a

tendency to fill in memory gaps with inaccurate, fabricated, and often

implausible information. This is known as confabulation. Patients with

the amnestic syndrome forget that they forget and tend to deny the

existence of a memory problem when questioned. Confabulation is

more common in cases where the underlying lesion also interferes with

parts of the frontal network, as in the case of the Wernicke-Korsakoff

syndrome or traumatic head injury.

■ CLINICAL EXAMINATION

A patient with an amnestic state is almost always disoriented, especially

to time, and has little knowledge of current news. The anterograde

component of an amnestic state can be tested with a list of four to five

words read aloud by the examiner up to five times or until the patient

can immediately repeat the entire list without an intervening delay. The

next phase of the recall occurs after a period of 5–10 min during which

the patient is engaged in other tasks. Amnestic patients fail this phase

of the task and may even forget that they were given a list of words to

remember. Accurate recognition of the words by multiple choice in a

patient who cannot recall them indicates a less severe memory disturbance that affects mostly the retrieval stage of memory. The retrograde

component of an amnesia can be assessed with questions related to

autobiographical or historic events. The anterograde component of

amnestic states is usually much more prominent than the retrograde

component. In rare instances, occasionally associated with temporal

lobe epilepsy or herpes simplex encephalitis, the retrograde component may dominate. Confusional states caused by toxic-metabolic

encephalopathies and some types of frontal lobe damage lead to secondary memory impairments, especially at the stages of encoding and

retrieval, even in the absence of limbic lesions. This sort of memory

impairment can be differentiated from the amnestic state by the presence of additional impairments in the attention-related tasks described

below in the section on the frontal lobes.

■ CAUSES, INCLUDING ALZHEIMER’S DISEASE

Neurologic diseases that give rise to an amnestic state include tumors

(of the sphenoid wing, posterior corpus callosum, thalamus, or medial

temporal lobe), infarctions (in the territories of the anterior or posterior cerebral arteries), head trauma, herpes simplex encephalitis,

Wernicke-Korsakoff encephalopathy, autoimmune limbic encephalitis,

and degenerative dementias such as AD and Pick’s disease. The one

common denominator of all these diseases is the presence of bilateral lesions within one or more components in the limbic network.

Occasionally, unilateral left-sided hippocampal lesions can give rise

to an amnestic state, but the memory disorder tends to be transient.

Depending on the nature and distribution of the underlying neurologic

disease, the patient also may have visual field deficits, eye movement

limitations, or cerebellar findings.

The most common cause of progressive memory impairments in the

elderly is AD. This is why a predominantly amnestic dementia is also

known as a dementia of the Alzheimer type (DAT). A prodromal stage

of DAT, when daily living activities are generally preserved, is known

as amnestic mild cognitive impairment (MCI). The predilection of the

entorhinal cortex and hippocampus for early neurofibrillary degeneration by typical AD pathology is responsible for the initially selective

impairment of episodic memory. In time, additional impairments in

language, attention, and visuospatial skills emerge as the neurofibrillary degeneration spreads to additional neocortical areas. Less frequently, amnestic dementias can also be caused by FTLD.

Transient global amnesia is a distinctive syndrome usually seen

in late middle age. Patients become acutely disoriented and repeatedly ask who they are, where they are, and what they are doing. The

spell is characterized by anterograde amnesia (inability to retain new

information) and a retrograde amnesia for relatively recent events

that occurred before the onset. The syndrome usually resolves within

24–48 h and is followed by the filling in of the period affected by the

retrograde amnesia, although there is persistent loss of memory for

the events that occurred during the ictus. Recurrences are noted in

203Aphasia, Memory Loss, and Other Cognitive Disorders CHAPTER 30

~20% of patients. Migraine, temporal lobe seizures, and perfusion

abnormalities in the posterior cerebral territory have been postulated

as causes of transient global amnesia. The absence of associated neurologic findings occasionally may lead to the incorrect diagnosis of a

psychiatric disorder.

THE PREFRONTAL NETWORK FOR

EXECUTIVE FUNCTION AND BEHAVIOR

The frontal lobes can be subdivided into motor-premotor, dorsolateral prefrontal, medial prefrontal, and orbitofrontal components. The

terms frontal lobe syndrome and prefrontal cortex refer only to the last

three of these four components. These are the parts of the cerebral

cortex that show the greatest phylogenetic expansion in primates,

especially in humans. The dorsolateral prefrontal, medial prefrontal,

and orbitofrontal areas, along with the subcortical structures with

which they are interconnected (i.e., the head of the caudate and the

dorsomedial nucleus of the thalamus), collectively make up a largescale network that coordinates exceedingly complex aspects of human

cognition and behavior. The prefrontal network overlaps with the

salience network through the anterior cingulate gyrus and parts of the

orbitofrontal region. Impairments of social conduct and empathy seen

in neurodegenerative frontal dementias (such as bvFTD) are attributed

to pathology of the prefrontal and salience networks.

The prefrontal network plays an important role in behaviors that

require multitasking and the integration of thought with emotion.

Cognitive operations impaired by prefrontal cortex lesions often are

referred to as “executive functions.” The most common clinical manifestations of damage to the prefrontal network take the form of two

relatively distinct syndromes. In the frontal abulic syndrome, the patient

shows a loss of initiative, creativity, and curiosity and displays a pervasive emotional blandness, apathy, and lack of empathy. In the frontal

disinhibition syndrome, the patient becomes socially disinhibited and

shows severe impairments of judgment, insight, foresight, and the

ability to mind rules of conduct. The dissociation between intact intellectual function and a total lack of even rudimentary common sense

is striking. Despite the preservation of all essential memory functions,

the patient cannot learn from experience and continues to display inappropriate behaviors without appearing to feel emotional pain, guilt,

or regret when those behaviors repeatedly lead to disastrous consequences. The impairments may emerge only in real-life situations when

behavior is under minimal external control and may not be apparent

within the structured environment of the medical office. Testing judgment by asking patients what they would do if they detected a fire in a

theater or found a stamped and addressed envelope on the road is not

very informative because patients who answer these questions wisely in

the office may still act very foolishly in real-life settings. The physician

must therefore be prepared to make a diagnosis of frontal lobe disease

based on historic information alone even when the mental state is quite

intact in the office examination.

■ CLINICAL EXAMINATION

The emergence of developmentally primitive reflexes, also known as

frontal release signs, such as grasping (elicited by stroking the palm)

and sucking (elicited by stroking the lips) are seen primarily in patients

with large structural lesions that extend into the premotor components

of the frontal lobes or in the context of metabolic encephalopathies.

The vast majority of patients with prefrontal lesions and frontal lobe

behavioral syndromes do not display these reflexes. Damage to the

frontal lobe disrupts a variety of attention-related functions, including

working memory (the transient online holding and manipulation of

information), concentration span, the effortful scanning and retrieval

of stored information, the inhibition of immediate but inappropriate

responses, and mental flexibility. Digit span (which should be seven

forward and five reverse) is decreased, reflecting poor working memory; the recitation of the months of the year in reverse order (which

should take <15 s) is slowed as another indication of poor working

memory; and the fluency in producing words starting with the letter

a, f, or s that can be generated in 1 min (normally ≥12 per letter) is

diminished even in nonaphasic patients, indicating an impairment in

the ability to search and retrieve information from long-term stores. In

“go–no go” tasks (where the instruction is to raise the finger upon hearing one tap but keep it still upon hearing two taps), the patient shows a

characteristic inability to inhibit the response to the “no go” stimulus.

Mental flexibility (tested by the ability to shift from one criterion to

another in sorting or matching tasks) is impoverished; distractibility by

irrelevant stimuli is increased; and there is a pronounced tendency for

impersistence and perseveration. The ability for abstracting similarities

and interpreting proverbs is also undermined.

The attentional deficits disrupt the orderly registration and retrieval

of new information and lead to secondary deficits of explicit memory.

The distinction of the underlying neural mechanisms is illustrated by

the observation that severely amnestic patients who cannot remember

events that occurred a few minutes ago may have intact if not superior

working memory capacity as shown in tests of digit span. The use of the

term memory to designate two completely different mental faculties is

confusing. Working memory depends on the on-line holding of information for brief periods of time, whereas explicit memory depends on

the off-line storage and subsequent retrieval of the information.

■ CAUSES: TRAUMA, NEOPLASM, AND

FRONTOTEMPORAL DEMENTIA

The abulic syndrome tends to be associated with damage in dorsolateral or dorsomedial prefrontal cortex, and the disinhibition syndrome

with damage in orbitofrontal or ventromedial cortex. These syndromes

tend to arise almost exclusively after bilateral lesions. Unilateral lesions

confined to the prefrontal cortex may remain silent until the pathology

spreads to the other side; this explains why thromboembolic CVA

is an unusual cause of the frontal lobe syndrome. When behavioral

syndromes of the frontal network arise in conjunction with asymmetric disease, the lesion tends to be predominantly on the right side

of the brain. Common settings for frontal lobe syndromes include

head trauma, ruptured aneurysms, hydrocephalus, tumors (including

metastases, glioblastoma, and falx or olfactory groove meningiomas),

and focal degenerative diseases, especially FTLD. The most prominent

neurodegenerative frontal syndrome is bvFTD. In many patients with

bvFTD, the atrophy includes orbitofrontal cortex and also extends

into the anterior temporal lobes, insula, and anterior cingulate cortex.

Occasionally, atrophy predominantly in the right anterior temporal

lobe presents with the bvFTD syndrome. The behavioral changes in

these patients can range from apathy to shoplifting, compulsive gambling, sexual indiscretions, remarkable lack of common sense, new

ritualistic behaviors, and alterations in dietary preferences, usually

leading to increased taste for sweets or rigid attachment to specific

food items. In many patients with AD, neurofibrillary degeneration

eventually spreads to prefrontal cortex and gives rise to components

of the frontal lobe syndrome, but almost always on a background of

severe memory impairment. Rarely, the bvFTD syndrome can arise in

isolation in the context of an atypical form of AD pathology.

Lesions in the caudate nucleus or in the dorsomedial nucleus of the

thalamus (subcortical components of the prefrontal network) also can

produce a frontal lobe syndrome affecting mostly executive functions.

This is one reason why the changes in mental state associated with

degenerative basal ganglia diseases such as Parkinson’s disease and

Huntington’s disease display components of the frontal lobe syndrome.

Bilateral multifocal lesions of the cerebral hemispheres, none of which

are individually large enough to cause specific cognitive deficits such as

aphasia and neglect, can collectively interfere with the connectivity and

therefore integrating (executive) function of the prefrontal cortex. A

frontal lobe syndrome, usually of the abulic form, is therefore the single

most common behavioral profile associated with a variety of bilateral

multifocal brain diseases, including metabolic encephalopathy, multiple sclerosis, and vitamin B12 deficiency, among others. Many patients

with the clinical diagnosis of a frontal lobe syndrome tend to have

lesions that do not involve prefrontal cortex but involve either the subcortical components of the prefrontal network or its connections with

other parts of the brain. To avoid making a diagnosis of “frontal lobe

syndrome” in a patient with no evidence of frontal cortex disease, it is

advisable to use the diagnostic term frontal network syndrome, with the

204 PART 2 Cardinal Manifestations and Presentation of Diseases

understanding that the responsible lesions can lie anywhere within this

distributed network. A patient with frontal lobe disease raises potential

dilemmas in differential diagnosis: the abulia and blandness may be

misinterpreted as depression, and the disinhibition as idiopathic mania

or acting out. Appropriate intervention may be delayed while a treatable tumor keeps expanding.

CARING FOR PATIENTS WITH DEFICITS OF

HIGHER CEREBRAL FUNCTION

Spontaneous improvement of cognitive deficits following stroke or

trauma is common. It is most rapid in the first few weeks but may

continue for up to 2 years, especially in young individuals with single

brain lesions. Some of the initial deficits in such cases appear to arise

from remote dysfunction (diaschisis) in brain regions that are interconnected with the site of initial injury. Improvement in these patients

may reflect, at least in part, a normalization of the remote dysfunction.

Other mechanisms may involve functional reorganization in surviving

neurons adjacent to the injury or the compensatory use of homologous

structures, e.g., the right superior temporal gyrus with recovery from

Wernicke’s aphasia. In contrast, neurodegenerative diseases show a

progression of impairment but at rates that vary greatly from patient

to patient.

Pharmacologic and Nonpharmacologic Interventions Some

of the deficits described in this chapter are so complex that they may

bewilder not only the patient and family but also the physician. The

care of patients with such deficits requires a careful evaluation of the

history, cognitive test results, and diagnostic procedures. Each piece of

information needs to be interpreted cautiously and placed in context.

A complaint of “poor memory,” for example, may reflect an anomia;

poor scores on a learning task may reflect a weakness of attention

rather than explicit memory; a report of depression or indifference

may reflect impaired prosody rather than a change in mood or empathy; jocularity may arise from poor insight rather than good mood.

Although there are few well-controlled studies, several nonpharmacologic interventions have been used to treat higher cortical deficits.

These include speech therapy for aphasias, behavioral modification

for compartmental disorders, and cognitive training for visuospatial

disorientation and amnestic syndromes. More practical interventions,

usually delivered through occupational therapy, aim to improve daily

living activities through assistive devices and modifications of the

home environment. Determining driving competence is challenging,

especially in the early stages of dementing diseases. An on-the-road

driving test and reports from family members may help time decisions

related to this very important activity. In neurodegenerative conditions

such as PPA, transcranial magnetic (or direct current) stimulation has

had mixed success in eliciting symptomatic improvement. The goal

is to activate remaining neurons at sites of atrophy or in unaffected

regions of the contralateral hemisphere. Depression and sleep disorders can intensify the cognitive disorders and should be treated with

appropriate modalities. If neuroleptics become absolutely necessary for

the control of agitation, atypical neuroleptics are preferable because of

their lower extrapyramidal side effects. Treatment with neuroleptics in

elderly patients with dementia requires weighing the potential benefits

against the potentially serious side effects. This is especially relevant to

the case of patients with Lewy body dementia, who can be unusually

sensitive to side effects.

As in all other branches of medicine, a crucial step in patient care is

to identify the underlying cause of the impairment. This is easily done

in cases of CVA, head trauma, or encephalitis but becomes particularly

challenging in the dementias because the same progressive clinical

syndrome can be caused by one of several neuropathologic entities.

The advent of imaging, blood, and cerebrospinal fluid biomarkers now

makes it possible to address this question with reasonable success and

to make specific diagnoses of AD, LBD, CJD, and FTLD. A specific

etiologic diagnosis allows the physician to recommend medications or

clinical trials that are the most appropriate for the underlying disease

process. A clinical assessment that identifies the principal domain of

behavioral and cognitive impairment followed by the judicious use of

biomarker information to surmise the nature of the underlying disease allows a personalized approach to patients with higher cognitive

impairment.

■ FURTHER READING

Ghetti B et al: Frontotemporal Dementias: Emerging Milestones of the

21st Century. New York, Springer, 2021.

Henry ML et al: Retraining speech production and fluency in nonfluent/agrammatic primary progressive aphasia. Brain 141:1799,

2018.

Mesulam M-M: Behavioral neuroanatomy: Large-scale networks,

association cortex, frontal syndromes, the limbic system and hemispheric specialization, in Principles of Behavioral and Cognitive

Neurology, M-M Mesulam (ed). New York, Oxford University Press,

2000, pp 1–120.

Mesulam M-M et al: Word comprehension in temporal cortex and

Wernicke area: A PPA perspective. Neurology 92:e224, 2019.

Miller BL, Boeve BF (eds): The Behavioral Neurology of Dementia,

2nd ed. Cambridge, Cambridge University Press, 2017.

Disturbed sleep is one of the most common health complaints that

physicians encounter. More than one-half of adults in the United States

experience at least intermittent sleep disturbance, and only 30% of

adult Americans report consistently obtaining a sufficient amount of

sleep. The National Academy of Medicine has estimated that 50–70

million Americans suffer from a chronic disorder of sleep and wakefulness, which can adversely affect daytime functioning as well as

physical and mental health. A high prevalence of sleep disorders across

all cultures is also now increasingly recognized, and these problems are

expected to further increase in the years ahead as the global population

ages. Over the last 30 years, the field of sleep medicine has emerged as a

distinct specialty in response to the impact of sleep disorders and sleep

deficiency on overall health. Nonetheless, over 80% of patients with

sleep disorders remain undiagnosed and untreated—costing the U.S.

economy over $400 billion annually in increased health care costs, lost

productivity, accidents and injuries, and leading to the development of

workplace-based sleep health education and sleep disorders screening

programs designed to address this unmet medical need.

PHYSIOLOGY OF SLEEP AND

WAKEFULNESS

Most adults need 7–9 h of sleep per night to promote optimal health,

although the timing, duration, and internal structure of sleep vary

among individuals. In the United States, adults tend to have one consolidated sleep episode each night, although in some cultures sleep may

be divided into a mid-afternoon nap and a shortened night sleep. This

pattern changes considerably over the life span, as infants and young

children sleep considerably more than older people, while individuals

>70 years of age sleep on average about an hour less than young adults.

The stages of human sleep are defined on the basis of characteristic

patterns in the electroencephalogram (EEG), the electrooculogram

(EOG—a measure of eye-movement activity), and the surface electromyogram (EMG) measured on the chin, neck, and legs. The continuous recording of these electrophysiologic parameters to define sleep

and wakefulness is termed polysomnography.

Polysomnographic profiles define two basic states of sleep: (1) rapid

eye movement (REM) sleep and (2) non–rapid eye movement (NREM)

31 Sleep Disorders

Thomas E. Scammell, Clifford B. Saper,

Charles A. Czeisler