Clinical Approach To Cognitive and Neurobehavioral Symptoms: Review Article

REVIEW ARTICLE

Clinical Approach to
CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
Cognitive and
Neurobehavioral
Symptoms
By Meredith Wicklund, MD, FAAN
ABSTRACT
PURPOSE OF REVIEW: This article provides a framework for the approach to
patients with cognitive or neurobehavioral concerns.
RECENT FINDINGS:Recent advances in structural neuroimaging, functional

neuroimaging, and disease biomarkers have greatly expanded knowledge
of brain-behavior relationships, neural networks and functional
connectivity, and pathophysiologic processes leading to cognitive and
neurobehavioral disorders. However, any one of these studies is subject to
misinterpretation if not applied in the appropriate clinical context.
SUMMARY: A systematic approach to the history and examination in patients

CITE AS:
CONTINUUM (MINNEAP MINN) with cognitive and neurobehavioral symptoms is important in marrying
2021;27(6, BEHAVIORAL NEUROLOGY clinical assessments with contemporary diagnostic studies and
AND PSYCHIATRY):1518–1548.
treatments.
Address correspondence to
Dr Meredith Wicklund, Barrow
Neurological Institute, 240 W
Thomas Rd, Ste 301, Phoenix,
AZ 85013, meredith.wicklund@ INTRODUCTION
C
dignityhealth.org. ognitive and neurobehavioral symptoms are common presenting
RELATIONSHIP DISCLOSURE :
chief complaints to a neurologist, whether evaluating an acute
Dr Wicklund has received confusional state in a hospitalized patient, progressive cognitive
research/grant support from decline in an older adult in the outpatient clinic, a focal
Alector, Inc, Barrow Neurological
Foundation, Biogen, F. Hoffman-
neurobehavioral syndrome such as aphasia or apraxia, or the
La Roche Ltd, Functional complex cognitive and behavioral features of many neurologic disorders such as
Neuromodulation Ltd, Green epilepsy, stroke, multiple sclerosis, movement disorders, or traumatic brain
Valley Inc, Janssen Research &
Development, and the National injury (TBI). Recent advances in neuroimaging, including functional MRI
Institutes of Health (fMRI) and positron emission tomography (PET), have provided extraordinary
(5P30AG019610-21).
advances in the understanding of brain-behavior relationships. Likewise,
UNLABELED USE OF developments in structural neuroimaging, including quantitative volumetric
P R O D U C T S/ I N V E S T I G A T I O N A L assessments with MRI and diffusion tensor imaging of white matter tracts,
USE DISCLOSURE:
Dr Wicklund reports no
continue to greatly expand knowledge of neural networks and their functional
disclosure. connectivity.1 Advances in biomarkers of many neurodegenerative disorders,
such as PET imaging with amyloid and tau in Alzheimer disease, have led to
© 2021 American Academy greater understanding of pathophysiologic processes and in vivo diagnosis.
of Neurology. However, these studies are subject to limitations in availability, cost, and
1518 DECEMBER 2021
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

guidelines for appropriate clinical use. Appropriate clinical phenotyping is KEY POINTS
necessary for selection of applicable diagnostic studies. This article provides a
● History should be
practical approach to the clinical assessment of disturbances of cognition obtained from both the
and behaviors encountered in the general neurology practice. patient and a collateral
source who knows the
CLINICAL HISTORY patient well because
patients with cognitive and
Obtaining a good history is paramount in patients presenting with cognitive
behavioral symptoms may
and neurobehavioral concerns. This can be challenging as patients may have not be able to provide an
difficulty attending to the interview because of disorders of attention/ accurate history.
concentration, organizing thoughts effectively because of disorders of executive
function, communicating symptoms because of disorders of language, recalling ● Age at onset of the first
symptom aids in determining
symptoms because of disorders of memory, or recognizing deficits because of the differential diagnosis
anosognosia. It is thus critical to have a conceptual approach and obtain because of varying
additional history from a collateral source who knows the patient well and can prevalence of diseases in
inform on the relevant aspects of the history. different age groups.
● Education, occupational
PATIENT DEMOGRAPHICS history, native language, and
Age at onset of the first symptom aids in determining the differential diagnosis. cultural factors are critical
Although not exclusively so, neurodegenerative and cerebrovascular disorders variables to be obtained for
interpretation of the mental
are increasingly more likely with older age, whereas younger individuals are
status examination.
more likely to have neurometabolic disorders, leukodystrophies, genetic
disorders, or demyelinating, infectious, or inflammatory etiologies.
Furthermore, the neurodevelopmental history of a patient can inform on
phenotypic manifestations of neurodegenerative diseases in later life. For example,
nonlanguage mathematical and visuospatial learning disabilities are more common
in the atypical visual presentation of Alzheimer disease (posterior cortical atrophy),2
whereas dyslexia is more common in the atypical language presentation of
Alzheimer disease (logopenic variant primary progressive aphasia)3 than in the
typical amnestic form of Alzheimer disease.
Education and occupational history provide important information about a
patient’s premorbid intelligence and are critical variables in the interpretation of
the mental status examination. For example, highly educated individuals may be
expected to have average performance or above on assessments; scores in the low
to average range, although not impaired across the spectrum of cognitively intact
adults, may reflect a decline from premorbid abilities for that patient and
indicate a potential emerging cognitive disorder.4 Additionally, the native
language of the individual and cultural factors must be factored into
interpretation of cognitive assessments.5
Handedness provides important information about lateralization of specific
cognitive functions in the cerebral hemispheres. Language is left lateralized in
about 96% of right-handed people and 76% of left-handed people, with
approximately 14% of left-handed people showing bilateral representation and
only 10% of left-handed people showing full lateralization to the right
hemisphere.6 It is important to keep in mind that many older individuals may
have experienced significant pressures to switch handedness because of cultural
and social stigma in their youth. In addition, many environmental constraints
for left-handed people living in a world dominated by those who are right
handed may affect a person’s hand preference.7
Furthermore, it is imperative to inquire about a patient’s lifestyle and daily
routine to understand how they might affect the patient’s health. Important
CONTINUUMJOURNAL.COM 1519

CLINICAL APPROACH TO COGNITIVE AND NEUROBEHAVIORAL SYMPTOMS
CASE 1-1 A 60-year-old right-handed woman presented with a chief complaint of

memory loss that had been slowly progressing over the previous year.
Upon clarification of what was meant by memory loss, her spouse noted
that she had difficulty recalling coworkers, specifically not recognizing
the faces of coworkers that she had worked with daily for many years.
She additionally had difficulty recognizing faces of famous people she
saw on billboards. Her spouse further noted that the patient commented
that her local neighborhood did not seem familiar to her and she had not
recognized familiar objects, such as not recognizing a flamingo lawn
ornament as a flamingo. Her spouse noted more recently that the patient
had seemed less empathetic and had developed compulsive behaviors.
On examination, she scored 28/30 on the Montreal Cognitive
Assessment (MoCA) with one point deducted each for delayed recall and
orientation to date. In a more detailed bedside mental status
examination, attention, memory, and executive functions were intact.
Conversational language, fluency,
repetition, verbal comprehension,
reading, and writing were normal.
She displayed difficulties with visual
but not auditory confrontation naming.
She had difficulty recognizing famous
faces but was able to discriminate
colors. Her performance on a line
bisection task, overlapping figures
task, and copy of a complex figure
was normal. Her general neurologic
examination was normal.
Brain MRI demonstrated focal right
temporal lobar atrophy (FIGURE 1-1).
Brain fludeoxyglucose positron
emission tomography (FDG-PET)
demonstrated right more than left FIGURE 1-1
Axial fluid-attenuated inversion
anterior hypometabolism. A diagnosis recovery (FLAIR) MRI of the patient in
of right temporal variant CASE 1-1 demonstrating right temporal
frontotemporal dementia was made. atrophy.
COMMENT This case highlights that many patients may describe any cognitive
disturbance as memory loss, but the nature of the presenting chief
complaint can be clarified by asking informants to provide examples.
Additionally, although this patient scored well on the screening
neurocognitive test, this test did not adequately assess her presenting
symptoms, and more detailed examination was needed. The cognitive
profile revealed findings of visual agnosia localizing to the right temporal
lobe, which was confirmed with neuroimaging.
1520 DECEMBER 2021

features to inquire about include with whom the patient resides and who lives KEY POINTS
nearby, access to transportation, physical activity, and social network. Of
● To develop realistic and
particular importance is inquiring about the physical, financial, and appropriate interventions
psychological impact of the patient’s illness on family and caregivers and the for both the patient and
capacity of those involved to provide practical and psychological support.1 By caregiver, the clinician
being aware of these features, more realistic and appropriate interventions can be should inquire about the
physical, financial, and
devised for both the patient and caregiver.
psychological impact of the
patient’s illness on family
GENERAL MEDICAL HISTORY and caregivers and the
When obtaining the history, it is also imperative to review the general medical capacity of those involved
to provide practical and
history, with particular attention to any medical disorders that may impact
psychological support.
cognition, such as liver and renal failure, endocrinopathies, or chronic
obstructive pulmonary disease. History of any major psychiatric illnesses is ● The clinician should query
likewise relevant. A detailed description of any neurologic disorders, such as about history of other
stroke, multiple sclerosis, or epilepsy is needed. Movement disorders are neurologic disorders (eg,
epilepsy, multiple sclerosis,
particularly common in many cognitive and neurobehavioral disorders, and their stroke), abnormal
presence should be specifically assessed. A screening question about TBI movements, traumatic brain
should be routine, with follow-up questions regarding the mechanism of injury, injury, and cerebrovascular
severity, and associated amnesia as needed.1 Medical history pertaining to risk factors (eg, diabetes,
hypertension, heart disease)
cerebrovascular risk factors such as hypertension, diabetes, coronary artery and supplement with review
disease, dyslipidemia, obesity, and smoking is important. When possible, of the electronic medical
it is helpful to supplement the history obtained from the patient and informant record, when possible.
with review of the general medical record because many patients are
● Many patients are
often unaware of important aspects of the medical history, such as results
unaware of the deleterious
of prior diagnostic studies or specific dosages of medications.8 cognitive effects of many
over-the-counter
FAMILY AND SOCIAL HISTORY medications, particularly
Family history, including history of and age at onset of cognitive and sleep aids, and do not report
use of these medications
neurobehavioral symptoms in relatives, is needed. A detailed pedigree is often unless directly asked.
needed for presentation of any cognitive or neurobehavioral disorders in young
patients (younger than 65). As many genetic disorders can have a wide spectrum
of phenotypes, a broad family history that asks about cerebrovascular diseases,
motor neuron diseases, epilepsy, psychiatric diseases, or any movement
disorders such as parkinsonism, ataxia, or chorea, is important. Social history
should include a review of alcohol, tobacco, and illicit substance use.
MEDICATIONS
A list of prescription and over-the-counter medications and supplements
should be obtained. Many patients are unaware of the deleterious cognitive
effects of many over-the-counter medications, particularly sleep aids, and do not
report use of these medications unless directly queried. Furthermore, patients
should be encouraged to bring pill bottles to the clinic for review. The clinician
should attempt to match the prescribing date on the bottles and the number of
pills in each bottle, as discrepancies may indicate patient noncompliance due
to forgetfulness.
PRESENTING SYMPTOMS
It is often necessary to clarify with patients and informants about the
presenting symptoms, as illustrated in CASE 1-1. Many patients and informants
report any cognitive disturbance as “memory loss.” For example, an

informant may report “memory loss for words” in the patient with an aphasic
disorder, or the informant may report memory loss when describing slips of
everyday actions (eg, forgetting the filter in the coffee pot) in the patient with
primary impairment in attention/working memory. Thus, it is helpful to
obtain specific examples from the informant about the presenting symptoms,
and it is up to the clinician to determine the reason based on the history and
examination. In addition, it is essential to be mindful of subtle, early changes
that may be dismissed by the informant as part of normal aging or due
to “stress.”9
TEMPO OF ILLNESS
Knowledge about the onset, pace, and sequences of events aids in localization
and informs the differential diagnosis, as highlighted in CASE 1-2. The important
aspects to inquire about include the following:
1 First symptom noted. Many cognitive and neurobehavioral disorders, particularly those
due to neurodegenerative diseases, have similar phenotypes in the end stages.10 By knowing
this key feature of the illness, a clearer understanding of localization can be ascertained.
2 Mode of onset (acute, subacute, or chronic) and pace of change (transient, static,
progressive, or fluctuating). This information assists in forming a differential diagnosis and
guiding further investigations, as noted in TABLE 1-1.
REVIEW OF SYMPTOMS PERTAINING TO COGNITIVE DOMAINS

Akin to a general medical review of systems, questions should be posed to query
the functioning of all cognitive domains and behaviors (TABLE 1-2). This is
important because many patients and informants report any cognitive disturbance
as “memory loss,” as noted earlier, and the presence or absence of reported
impairment in different domains provides information about the potential
localization and directs more detailed examination in those domains.9
REVIEW OF NEUROPSYCHIATRIC SYMPTOMS

Neuropsychiatric symptoms are common in cognitive disorders and are a
defining feature of behavioral disorders; they play a large role in the effect on the
patient and burden to the caregiver but yet are potentially amenable to many
nonpharmacologic and pharmacologic interventions.
Neuropsychiatric symptoms can be divided into behavioral domains as shown
in TABLE 1-3.9 A thorough review of each domain, similar to the review of each
cognitive domain, is an important aspect of the clinical history. This can be
accomplished through patient and informant interviews, but the use of
standardized measures allows for greater precision, assessment of severity, and a
means of monitoring evolution and response to treatment. A widely used
measure suitable for clinical practice is the Neuropsychiatric Inventory-Questionnaire
(NPI-Q),11 which can be supplemented with measures for particular neuropsychiatric
symptoms, such as for depression, if more detailed ascertainment of a particular
behavioral domain is needed.
REVIEW OF SLEEP-RELATED SYMPTOMS

Sleep disturbance is a common symptom in many cognitive and neurobehavioral
disorders and represents an important therapeutic target.12 Additionally, the
presence of certain sleep disturbances can aid in the differential diagnosis; rapid
1522 DECEMBER 2021

eye movement (REM) sleep disorder, in particular, is increasingly recognized as KEY POINTS
an important prodromal symptom in disorders of α-synuclein pathology.13
● It is helpful to obtain
When asking about sleep history, it is important to inquire about a patient’s specific examples from the
sleep schedule, including bedtime routine, sleep-onset latency, awakenings at informant about the
night, and daytime naps, to assess for sufficient sleep. Obtaining collateral presenting symptoms
history from a bedtime partner on snoring, noisy breathing, or apnea during because patients and
caregivers may describe any
sleep informs on the risk of obstructive sleep apnea, and asking about abnormal
cognitive symptom as
movements at night can indicate REM and non-REM parasomnias.14 “memory loss” or ascribe
subtle, early changes to
REVIEW OF FUNCTIONAL CAPACITY normal aging or
psychosocial stressors.
Determining a patient’s functional capacity aids in determining the stage of
illness from mild cognitive impairment, in which functional capacity is ● The clinician should
preserved, to mild, moderate, or severe dementia, in which functional capacity obtain history regarding the
is affected in increasing severity. Additionally, this aids in identifying specific first symptom noted, mode
areas for neurorehabilitation, addressing safety concerns such as driving, of onset (acute, subacute, or
chronic), and pace of
medication management, and fall risk, and assessing caregiver burden and change (transient, static,
mitigation strategies. progressive, or fluctuating).
Patients and caregivers should be asked about both instrumental and basic
activities of daily living (ADLs). Instrumental ADLs are the complex skills ● The presence of
symptoms in each cognitive
needed to live independently, such as driving, medication and financial
and neuropsychiatric and
management, preparing meals, shopping, and using devices. Basic ADLs are skills behavioral domain helps
needed for basic daily functioning such as dressing, toileting, bathing, or eating. It define the cognitive profile
is helpful to provide descriptors of the assistance an individual needs for each and aid in the differential
diagnosis.
instrumental and basic ADL, from doing so fully independently, needing
prompting but can do independently, needing some assistance, or fully dependent. ● Obtaining functional
Several standardized scales are available for assessment of ADLs. Some capacity of the patient aids
examples include the Functional Activities Questionnaire (FAQ)15 or the Lawton in defining the stage of
Instrumental Activities of Daily Living (IADL) Scale16 for assessment of illness, identifying needs for
neurorehabilitation,
instrumental ADLs and the Barthel Index17 or Katz Index18 for assessment of addressing safety concerns,
basic ADLs. Although an interview with an informant suffices in many and assessing caregiver
circumstances, the use of standardized scales structures the interview and burden.
provides helpful benchmarks to track changes over time.
EXAMINATION
After obtaining a complete history, the next step in evaluation of cognitive and
neurobehavioral symptoms is general medical and neurologic examinations.
General Medical Examination

A general medical examination can provide important diagnostic clues in
evaluation of cognitive and neurobehavioral disorders. General observations may
include assessment for signs of developmental anomalies, trauma, or physical
signs of substance abuse or withdrawal.1 Auscultation of the carotids and a
cardiac examination are important when considering cerebrovascular diseases.
An eye examination can show signs of retinitis pigmentosa seen in some
spinocerebellar ataxias and mitochondrial disorders, Kayser-Fleischer rings seen
in Wilson disease, or relative afferent pupillary defect seen in disorders affecting
the optic nerves (eg, demyelinating or mitochondrial disorders). An abdominal
examination should evaluate for organomegaly that may indicate liver
dysfunction that can be seen with alcohol use disorder, mitochondrial disorders,
Wilson disease, or neurometabolic disorders such as Gaucher disease.

CASE 1-2 A 65-year-old right-handed man presented for a 1-month history of

rapidly progressive confusion. His wife noted that he was having
difficulty with word finding and comprehending others. He had no other
associated neuropsychiatric symptoms. Two months ago, the patient was
successfully managing his own business; he was currently unable to
manage medications or finances but was able to prepare meals, operate
appliances, and complete all basic activities of daily living without
prompting or assistance. His medical history was notable for
hypertension and hyperlipidemia, and he had no family history of any
neurologic disorder.
On examination, he scored 5/30 on the Montreal Cognitive Assessment
(MoCA). His verbal output was characterized by normal grammar, syntax,
and phrase length but with frequent breaks for word retrieval and use of
numerous nonspecific words, such as “thing,” and occasional phonemic
paraphasias. Visual confrontation naming was markedly impaired, but he
was able to correctly match semantically related pictures, match words
with definitions, and answer yes/no questions appropriately.
Comprehension of simple, single-step verbal instructions was intact, but
comprehension for verbal instructions of increasing complexity was
impaired.
Brain MRI with and without contrast demonstrated advanced
subcortical white matter disease, multifocal acute infarcts, superficial
siderosis, and leptomeningeal enhancement of the left greater than right
cerebral hemisphere, most notable in the left temporoparietal and
occipital regions (FIGURE 1-2). CSF analysis showed mildly elevated protein
at 60 mg/dL but normal glucose and cell count and absence of
oligoclonal bands. CSF culture and studies for infectious organisms were
negative. Serum and CSF testing for neuronal antibodies was negative.
Catheter cerebral angiogram was normal. Brain biopsy demonstrated
abundant amyloid-β deposition in blood vessels with surrounding
granulomatous inflammation, diagnostic of amyloid-β related angiitis.
COMMENT The subacute onset and rapid progression of cognitive symptoms aids in
narrowing the differential diagnosis to an infectious, demyelinating,
inflammatory, autoimmune, paraneoplastic, or high-grade malignant
process. The screening neurocognitive test demonstrated severe, global
impairment that was disproportionately affected compared with the
patient’s functional capacity. That, combined with the patient’s presenting
symptoms of predominantly language-based difficulties, warranted more
in-depth assessment of language functions, which showed language
impairment localizing mainly to the temporoparietal region, corresponding
with the area of greatest abnormality on the brain MRI. A precise diagnosis
was made possible only with the combination of history, detailed
examination, and comprehensive diagnostic testing warranted by the rapid
onset.
1524 DECEMBER 2021

FIGURE 1-2
Representative MRI sequences of the patient in CASE 1-2. A, Axial diffusion-weighted images
demonstrating punctate acute infarcts in the left temporoparietal region (arrows). B, Axial
T2-weighted image showing hyperintensities of the white matter, which are advanced for
the age of 65 years. C, Axial susceptibility-weighted image showing diffuse hemosiderin
deposition of the cortical surface, consistent with superficial siderosis, most prominent in
the left temporoparietal region (arrow). D, Coronal postcontrast T1-weighted image showing
leptomeningeal contrast enhancement, most notable in the left temporoparietal region
(arrow).

Neurologic Examination
The neurologic examination helps determine the presence of a neurologic
abnormality and its localization, which may later be confirmed with
investigations. All neurologic systems should be screened, but as the presenting
symptom is a cognitive or neurobehavioral one, the focus is on a detailed
mental status examination.
MENTAL STATUS EXAMINATION. The mental status examination begins with

observation of the patient’s appearance and behavior during the interview with
the patient and caregiver. This includes assessment of arousal, motivation, mood
and affect, thought content and processes, judgment, and insight.
The mental status examination should provide a description of the degree of
arousal; it is more useful to describe arousal in terms of the degree of stimulus
needed to provoke a particular motor response (eg, the patient briefly opened his
eyes with light tactile stimulation) rather than terms such as alert, lethargic, or
obtunded. Assessment of appearance should also include a description of apparent
age, hygiene and grooming, eye contact, demeanor and interpersonal interactions,
and any noteworthy physical characteristics (eg, craniotomy scar, dysmorphic
features).1 Motivation is further noted through the extent to which the patient
expresses goal-directed thoughts and feelings while participating in the interview
and examination. Mood, affect, thought content, insight, and judgment are
TABLE 1-1 Selected Differential Diagnosis of Cognitive and Neurobehavioral

Symptoms Aided by Tempo of Presenting Symptom
Mode of onset
Pace of
change Acute (seconds to days) Subacute (weeks to months) Chronic (years)
Transient Transient ischemic attack Not applicable Not applicable
Migraine
Seizure
Static Stroke Metabolic Not applicable

Traumatic brain injury
Metabolic
Progressive Infection (viral, bacterial) Infection (spirochetal, fungal, prion) Cerebrovascular disease
(chronic small vessel ischemic
Inflammatory and demyelinating Endocrine
disease, multi-infarct dementia)
disorders
Demyelinating disorders
Neurodegenerative
Inflammatory
Genetic
Autoimmune
Tumors
Paraneoplastic
High-grade tumor
Fluctuating Not applicable Metabolic Epilepsy

Autoimmune
Paraneoplastic
1526 DECEMBER 2021

assessed as part of the review of neuropsychiatric symptoms in the history. KEY POINTS
Thought process is observed throughout the history with note of any deviation
● The mental status
from normal, logical, and goal-directed processes, such as tangential, circumstantial, examination begins with
perseverative, or bradyphrenic responses.1 observation of the patient’s
The bulk of the mental status examination centers on cognitive assessment, appearance and behavior,
which can be time-consuming. Thus, standardized screening evaluations, such as including assessment of
arousal, motivation, mood
the Mini-Mental Status Examination (MMSE)19 or Montreal Cognitive
and affect, thought content
Assessment (MoCA),20 are often used to obtain a basic understanding of the and processes, judgment,
patient’s cognitive functioning in a short amount of time. However, these and insight.
screening evaluations have inherent weaknesses, and they should not be used as
the sole basis for assessing cognitive dysfunction. For example, many of these ● Screening neurocognitive
tests are helpful in obtaining
screening tests were developed for assessing cognitive functions in older adults, a basic understanding of the
and they may not be generalizable to other cognitive and neurobehavioral patient’s cognitive
disorders. Many scales also focus largely on memory and orientation and may not functioning in a short
assess some cognitive domains altogether. However, by starting an examination amount of time, but they
have inherent weaknesses
with one of these standardized screening measures, the examiner can detect key and should not be used as
deficits and expand on them and supplement with additional tests for cognitive the sole basis for assessing
domains highlighted by the presenting symptom or that may be lacking in the cognitive dysfunction.
screening measure, as noted in CASE 1-1. The screening measures can also be
● Attention is a necessary
helpful for tracking changes over time.
substrate for intact
A mental status examination often, therefore, needs to be expanded with performance in all other
additional single-domain cognitive tests. These tests typically include assessment cognitive domains; thus,
of attention, memory, language, visual-perceptual-spatial, executive, and praxis interpretation of
performance in other
functions. The American Academy of Neurology Behavioral Neurology Section
cognitive domains is limited
Workgroup reviewed select single-domain tests that are useful in clinical if attention is impaired.
practice, with attention to being standardized, are easy/free to access, and have
short administration time.21 A detailed description of evaluation of each
cognitive domain is provided below with a summary of bedside cognitive tests
and pearls and pitfalls of these tests shown in TABLE 1-4.22-35 Assessment of praxis
is discussed separately in the article “Upper Limb Apraxia” by Kenneth L.
Heilman, MD, FAAN,36 in this issue of Continuum.
ATTENTION. It is helpful to begin assessment of cognitive function by first

assessing attention, as attention is a necessary substrate for intact performance in
all other cognitive domains. If attention is impaired, the examiner may consider
curtailing the remainder of the cognitive examination as interpretation of
performance in the remaining cognitive domains will be severely limited.
Additionally, impaired attention has little localizing value, although it is
classically associated with frontal and right parietal lesions.
Tests of attention can be divided into tests of “basic” and “complex” attention,
where basic attention reflects the ability to sustain focus to perform a certain task
and complex attention reflects the ability to control, shift, and divide attentional
focus.21 Basic attention can be assessed through forward digit span,31 in which the
examiner asks the patient to repeat a string of numbers of increasing length; intact
performance for an adult is 7 ± 2. Trail Making Test Part A22 is another common test
of basic attention (specifically, processing speed) in which the patient is asked to
draw connecting lines between numbers 1 through 25 randomly distributed on a
sheet of paper, sequencing in ascending order. If the paper template is not readily
available, Trail Making Test A can be completed orally as well by asking the patient
to verbally count 1 through 25. Vigilance can further be assessed with letter

cancellation tasks31 in which the patient is asked to signal when a specific letter is
found among other letters distributed on a piece of paper or presented orally.
Complex attention can be assessed through measures such as backward digit
span, in which the patient recites the backward order of digits read aloud; the
average adult can obtain a backward span of 5 ± 2. Alternatively, the examiner
can ask the patient to recite overlearned pieces of information, such as months,
days of the week, or the alphabet in reverse order. Note that subtraction of
serial 7s is a common test of complex attention, but many healthy older adults
TABLE 1-2 Sample Questions to Probe Function of Cognitive Domainsa
Cognitive domain Probing questions
Attention/working memory Does the patient have difficulty with:

Concentrating when reading a book?
Following the plot of a movie?
Maintaining train of thought?
Recalling why they entered a room?
Making frequent slips of everyday action such as forgetting a filter in the coffee pot?
Language Does the patient:

Sound as articulate as before?
Use words with incorrect or distorted sounds?
Have difficulty with correct grammar?
Have word-finding difficulty?
Substitute wrong words?
Have a decline in vocabulary?
Have difficulty understanding the meaning of words?
Have a change in ability to spell?
Read for pleasure?
Follow instructions (oral or written)?
Memory Does the patient:

Use lists or notes more than in the past?
Ask or make repetitive statements?
Forget recent conversations and events?
Frequently misplace objects?
Forget past personal events such as previous surgeries, jobs, or places of residence?
CONTINUED ON PAGE 1529
1528 DECEMBER 2021

make errors on this task, and this should not be interpreted as impairment in
attention when assessed in isolation.
Working memory is the ability to hold pieces of information in mind
for a brief period of time after presentation. Working memory is a function of
the attentional matrix and not the memory systems.25 It is assessed through
tasks mentioned earlier, such as digit span and citing months of the year in
reverse. Note that a patient with severe amnesia can have intact working
memory.
CONTINUED FROM PAGE 1528
Cognitive domain Probing questions
Visual-perceptual-spatial Is the patient able to:

Find places within and outside the immediate neighborhood?
Find objects on a counter/shelf directly in front of them?
Recognize familiar faces?
Recognize everyday objects?
Recognize landmarks?
Drive without acquiring new dents and scratches?
Walk without bumping into walls/doorways (in absence of motor deficit)?
Praxis Does the patient have:

Difficulty with manual skills such as opening a can, drawing the blinds?
Clumsiness, or do they move a limb in a coordinated manner?
Ability to use utensils or tools?
Difficulty knowing how to put on clothes?
Difficulty getting in/out of bed or the car?
Executive Is the patient capable of:

Resisting scams/advertisements?
Using appliances and gadgets?
Planning an outing/errand?
Balancing the checkbook?
Maintaining hobbies and activities (eg, card games, crafts, woodworking)?
Social Does the patient:

Take other people’s feelings into account?
Make inappropriate comments?
Have loss of manners/social decorum?
Show empathy/interpersonal warmth?
Show interest and initiative in activities?
Have compulsive, stereotyped, or ritualistic behaviors?
a
Reprinted with permission from Tang-Wai DF and Freedman M, Continuum (Minneap Minn).4 © 2018 American Academy of Neurology.

LANGUAGE. Bedside assessment of language begins with evaluation of

spontaneous language features during conversation. The examiner should listen
for articulation and note if words are well formed or if the words sound laborious
and distorted. The examiner should also be listening for paraphasias, grammar
and syntax, fluency, and prosody. Paraphasias can be phonemic or semantic,
with the phonemic form consisting of the patient selecting an incorrect sound
(or phoneme) of a syllable of the intended word and creating a nonword (eg, “laise”
for raise) and the semantic form consisting of the patient selecting an incorrect word
for the intended word (eg, “orange” for apple). Agrammatism is noted by simplified
syntax with shorter phrase length, lack of grammatical words such as pronouns or
prepositions, and errors of tense. Patients with agrammatism often sound
telegraphic, which means to be concise and omitting inessential words.
Fluency is a measure of phrase length and not necessarily the number of
breaks to produce verbal output. Thus, assessment of fluency must be separated
from difficulties with word-finding, as this may produce breaks in output.
However, patients with word-finding difficulties may be capable of occasionally
producing longer phrases and thus are not nonfluent.10
When assessing spontaneous verbal output, the examiner should note the
prosody (the melodic tone of the patient). This can be more formally assessed by
asking the patient to mimic the examiner’s affect or inflections. Aprosodia
is seen most often in nondominant hemisphere lesions.
Some patients produce little spontaneous verbal output but do better when
given context. Thus, language function should additionally be assessed by
providing the patient with a complex picture and asking the patient to describe
the picture. A picture from a magazine can serve this purpose.
Evaluation of language should also include assessment of naming, repetition,
comprehension, reading, and writing. Naming can be assessed informally by
TABLE 1-3 Behavioral Domains of Neuropsychiatric Symptomsa
Domain Examples
Disorders of volition and Apathy, impulsions, compulsions (including simple and complex rituals, hoarding)
self-control
Affective states Depression, anxiety, euphoria/jocularity, mania, irritability/agitation
Aggression Impulsive, reactive, premeditated
Abnormal precepts Illusions and pareidolias (imposing meaningful interpretation on nebulous stimuli), hallucinations
Abnormal ideation Preoccupations and ruminations, misinterpretations, delusions
Motor disturbances Restless/fidgeting, rummaging, roaming
Feeding disorders Anorexia, hyperphagia, foraging, pica
Abnormal sexual Asexuality/hyposexuality, misdirected intimacy, hypersexuality (which may include impulsive
behaviors propositions and intrusions)
Disorders of sleep Hyposomnia/insomnia, hypersomnia, sleep-cycle disruptions, rapid eye movement (REM) parasomnias
a
Reprinted with permission from Miller BL, Boeve BF, Cambridge University Press.9 © 2017 Cambridge University Press.
1530 DECEMBER 2021

asking the patient to name various objects on the examiner or within the KEY POINTS
examination room. However, deficits in naming show a marked frequency
● Working memory is a
effect, with even patients who have severe anomia able to name familiar, function of the attentional
high-frequency objects such as a pen. The frequency effect can be overcome by matrix and not the memory
asking the patient to name individual pieces of objects, such as the lapel on a shirt systems. A patient with
or the crystal of a watch. The examiner can also ask the patient to name line severe amnesia can have
intact working memory.
drawings of objects. Several standardized instruments are available, such as the
Boston Naming Test,37 that can be used for tracking changes over time. For ● Assessment of fluency
patients with visual deficits, naming can be assessed by asking the patient to should be distinguished
name objects from verbal, semantic cues provided by the examiner (eg, asking from difficulties with word
the patient to name an animal that roars). finding.
Assessment of repetition should begin with asking the patient to first repeat ● Deficits in naming show
single words and then a string of words of increasing phrase length. Patients with a marked frequency
apraxia of speech or phonologic processing deficits will be unable to repeat single effect; even patients who
multisyllabic words, particularly when asked to repeat the word multiple times have severe anomia are
able to name familiar,
successively. Note that errors of substitution and omission in repeating longer high-frequency objects
phrases can be due to deficits in working memory and not necessarily language such as a pen.
deficits. Additionally, errors can result from social and cultural factors or from
assessing repetition in the non-native language of the patient.1 ● Errors of substitution and
omission in repeating longer
Assessment of comprehension is divided into assessment of semantic and
phrases can be due to
syntactic comprehension. Semantic comprehension can be evaluated by asking deficits in working memory
yes/no questions (eg, “Is the sky blue?” or “Do pigs fly?”), asking the patient and not necessarily
to point to objects in the room of medium to low frequency (which can then language deficits. Errors can
later be used to assess spatial memory; see the following “Memory” section), also result from social and
cultural factors or from
or word-definition matching in which the patient is asked to provide a definition assessing repetition in the
of a word supplied by the examiner. Next, syntactic comprehension is assessed non-native language of the
by asking the patient to complete tasks of increasing syntactic complexity, patient.
such as “Point to your nose after you touch the desk.” Note that errors can be
caused by impaired working memory and not necessarily deficits in
comprehension.
Reading and writing are often neglected in bedside assessment of language
functions but provide important information as to localization, pathology, and
rehabilitation needs. Assessment of reading and writing should begin with
assessment of single letters and then single words, including regular, irregular,
and nonwords, and lastly sentences and paragraphs. Regular words are words
that are pronounced or spelled according to the phonic “rules” of the language,
whereas irregular words do not follow such rules and must be decoded by sight.
Reading errors can include errors in letter identification (as seen in pure alexia),
letter-by-letter reading, neglect, or deep or surface central linguistic errors.10
Deep dyslexia is characterized by semantic errors and the inability to read
nonwords, whereas surface dyslexia is characterized by regularization errors of
irregular words (eg, pronouncing “yatchet” when reading “yacht”).
Writing should be similarly assessed, including writing spontaneously and to
dictation of single words, phrases, and sentences. If a patient has deficits in
spelling, this can be further assessed with assessment of oral spelling, which
should include assessment of regular, irregular, and nonwords.
MEMORY. Assessment of memory focuses on testing of explicit (ie, declarative)

memory and refers to recollection of facts or events. Examination of explicit
memory includes assessment of orientation, awareness of current news, recall

TABLE 1-4 Bedside Assessment of Select Cognitive Domains
Cognitive domain Bedside tests Pearls and pitfalls
Attention/working Digit span (forward and reverse) These tasks are dependent on intact language;
memory consider tests of spatially mediated attention
Months, days of the week, or alphabet in
such as Corsi Block-Tapping Test23 or Spatial
reverse
Span subtest of Wechsler Memory Scale, Third
Spelling backward Edition24 if the patient is aphasic
Serial subtraction
Trail Making Test Parts A and B22
Language
Spontaneous Assess articulation, paraphasias, grammar and Separate word-finding difficulties from fluency;
syntax, fluency, and prosody during normal patients capable of producing longer phrases
conversation (~5 words or longer) are fluent, regardless of
pauses for word retrieval
Picture description Assess articulation, paraphasias, grammar and Subtle deficits in articulation, grammar and
syntax, fluency, and prosody with a narrative syntax, fluency, and prosody may be more
context, such as description of a complex notable within a narrative context
picture from a magazine
Naming Ask the patient to name objects present on Avoid frequency effect by asking the patient to
the examiner (eg, watch, lapel) or within the name objects with lower frequency in everyday
examination room life; provide verbal semantic cues for naming
objects in patients who are visually impaired;
watch for vague superordinate responses in
patients with semantic deficits
Repetition Ask the patient to repeat single words and Deficits of repetition of single, multisyllabic words
phrases of increasing complexity may be due to apraxia of speech or phonologic
processing deficits; deficits of repetition of longer
phrases may be due to deficits of working
memory, or social, cultural, or native language
features in addition to deficits in language function
Comprehension
Semantic Ask the patient to answer simple yes/no Errors can also arise from auditory or visual
questions and to match words and definitions perceptual deficits
Grammatical Ask the patient to perform tasks of increasing Errors can also be seen with deficits in working
syntactic complexity memory in addition to deficits in language function
Reading Ask the patient to read regular and irregular Consider neglect or dyslexia/dysgraphia if other
words, nonwords, and short paragraphs aspects of spoken language are normal
Writing Ask the patient to write spontaneously and to Acutely confused patients may write with
dictation, regular and irregular words, perseverative repetition of letters and careless
nonwords, and sentences penmanship25; deficits in grammar and syntax
may be more notable in the written than verbal
domain
Memory
Orientation Ask the patient for the current date, month, Orientation is also impaired in patients with
year, and location and reason for visit attentional disorders; assess with multiple-
choice in anomic/aphasic patients
1532 DECEMBER 2021

Retrograde memory Query patient about details of life in chronologic Look for a temporal gradient in retrograde
order and knowledge of major news events memory
Anterograde verbal Query patient about a recent holiday, journey Anterograde amnesia will have intact acquisition
memory to the clinic, or recent viewing of a television of a word list or story due to spared working
program; assess acquisition, recall, and memory, with impaired delayed free and
recognition of a word list or story recognition memory; impaired free delayed recall
with intact recognition implies deficit of memory
retrieval from frontal-subcortical dysfunction
Anterograde Walk the patient around clinic and ask to

nonverbal memory repeat the route alone; show the patient 3
objects in the room and later ask the patient to
point to the objects; ad hoc face recognition
from magazine pictures; copy and recall of
complex figures or shapes such as
Rey-Osterrieth Complex Figure Test26,27 or
Three Words–Three Shapes Test25
Visual-perceptual-spatial
Construction Cube copy Watch for stimulus-bound behavior of drawing

on top of or connected to the original, often seen
Copy of interlocking pentagons
in frontal lobe dysfunction
Clock drawing
Rey-Osterrieth Complex Figure Test
Visuoperception Judgment of Line Orientation28

Hooper Visual Organization Test29
Navon figure30
Overlapping figures31
Face Recognition Ask the patient to identify pictures in a

magazine or facial features of the examiner
Benton Facial Recognition Test32
Object Recognition Ask the patient to name objects by sight, and if

unable then ask the patient to name by sound
or touch
Spatial attention Double simultaneous stimulation

Line bisection33,34
Letter or shape cancellation tasks25,31
Executive function
Abstraction/reasoning Similarities Use unfamiliar similarities and proverbs, as some

can be overlearned
Proverbs
Motor sequencing Luria fist-edge-palm35
Set-shifting Tail Making Test Part B22 Use the oral version for patients who are visually
impaired

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35
Response inhibition Go/no-go test These tests are insensitive, but abnormalities are
25
pathologic
Alternating sequences
Verbal initiation/ Letter and semantic category fluency tasks Look for poor retrieval strategies, perseverative
planning responses, and difficulty switching between
tasks; category fluency is often better than letter
fluency unless there is a semantic memory deficit
Visual initiation/ Clock drawing

planning
Rey-Osterrieth Complex Figure Test
of past events, and ability to learn and retain new verbal and nonverbal
information.
Assessment of orientation includes person, place, time, and situation. Note
that even in severe amnestic disorders, it is unusual for patients to not be oriented
to name, except in functional cognitive impairment. Additionally, orientation to
place and orientation to the exact date are not very sensitive measures of
memory. Likewise, orientation requires intact attention, and patients with acute
confusional states are typically disoriented.
Retrograde memory is next assessed through inquiring with the patient about
culturally sensitive knowledge of public events, popular television shows, and
autobiographical information. An informant is needed to corroborate this
information. Individuals with a typical amnestic syndrome display retrograde
memory loss with a temporal gradient; that is, events that occurred closer in time
to the onset of the memory loss are recalled least well, whereas more remote
events are better recalled, presumably to the less extensive consolidation of more
recent memories.25 For example, an individual with an amnestic disorder is less
likely to recall events of September 11, 2001, than the assassination of President
John F. Kennedy or less likely to recall faces and names of grandchildren
than children.
The bulk of the bedside assessment of memory focuses on anterograde
memory, which refers to the learning, retention, and retrieval of newly presented
information. This should be assessed in both verbal and nonverbal domains
because of differing localizing values, as selective verbal memory deficits are
seen with unilateral left hippocampal lesions, and selective nonverbal memory
deficits are seen in unilateral right hippocampal lesions.
Anterograde verbal memory is routinely assessed with word lists in which the
patient is asked to learn a list of words over one or more trials and then recall
those words after a delay. Most screening cognitive tests incorporate lists of 3 to 5
words, but more robust lists of 10 to 15 words in length may be needed to fully
assess verbal memory function. In assessing delayed recall, it is helpful to assess
both freely recalled words as well as recognition or cued recall. Individuals who
are truly amnestic are impaired on both free and recognition recall, whereas
individuals with disorders of memory retrieval, which is classically seen in
1534 DECEMBER 2021

individuals with frontal-subcortical dysfunction, have impairment with free KEY POINTS
recall but no impairment with recognition or cued recall. Note also that the initial
● Individuals with a typical
portion of the task assesses learning, or acquisition, of the word list, and is a amnestic syndrome display
function of working memory. An individual with a pure anterograde amnesia has retrograde memory loss with
intact initial learning but impaired delayed recall. a temporal gradient; events
Anterograde verbal memory can also be assessed with learning and delayed that occurred closer in time
to the onset of the memory
recall of stories, also referred to as logical memory. A discrepancy between more
loss are recalled least well,
severely impaired word-list learning and relatively intact logical memory can be whereas more remote
seen in individuals with executive dysfunction, in which the context and events are better recalled.
organization of the story aid in recall.
Nonverbal domains of anterograde memory, such as spatial and face memory, ● In assessing delayed
recall, the clinician should
should also be examined. Nonverbal anterograde memory can be casually assess both freely recalled
examined by walking the patient around a route in the clinic and asking the words as well as recognition
patient to repeat that route or by pointing out objects in the examination room to or cued recall. Individuals
the patient and later asking the patient to point to those same objects. More who are truly amnestic are
impaired on both free and
formal tests of nonverbal anterograde memory incorporate asking the patient to recognition recall, whereas
copy a complex design, such as the Rey-Osterrieth Complex Figure Test individuals with disorders of
(FIGURE 1-3),26,27 or shape(s) and later draw the same design or shape(s). memory retrieval have
impairment with free recall
VISUAL-PERCEPTUAL-SPATIAL FUNCTION. Bedside tests of visual-perceptual-spatial but no impairment with
recognition or cued recall.
function typically involve asking the patient to copy a complex figure, such as a
cube or interlocking pentagons, or to draw a clock. Attention should be given to a
disorganized approach, which may suggest executive dysfunction, or an
impoverished half of the design that may reflect neglect due to nondominant
FIGURE 1-3
The Rey-Osterrieth Complex Figure.

hemispheric lesions. Standardized assessment can include the use of the

Rey-Osterrieth Complex Figure Test.
Visual-perceptual function can further be assessed through tasks such as
Judgment of Line Orientation,28 in which the patient is asked to match lines
drawn at specific angles, and the Hooper Visual Organization Task,29 in which
the patient is asked to conceptually rearrange fragments of line-drawing pictures
into unified objects. Part-whole discrimination, a feature of simultagnosia, can be
further assessed with the Navon figure,30 in which many small letters are used to
form a larger letter; an individual with simultagnosia can perceive the small
letters but not the larger one. Another common test of visual-perceptual function
involves the use of overlapping figures, in which a patient is asked to identify line
drawings of objects overlapping with one another.31
Visual agnosia is the most common of the agnosias and is, thus, discussed here.
Visual agnosia is the inability to recognize objects that are visually presented, despite
intact elementary visual processes. Visual agnosia is divided into apperceptive and
associative visual agnosia. Apperceptive visual agnosia is the inability to form a
complete percept of an object and can be assessed by asking the patient to copy a
complex figure, identify incomplete letters, or discriminate shapes. Associative
visual agnosia is the inability to access stored knowledge of the percept and can be
category specific (eg, faces, landmarks, objects), as noted in CASE 1-1. Recognition of
faces (prosopagnosia) can be assessed at the bedside by asking the patient to name
faces in a magazine or asking the patient to describe facial features (eg, hair or eye
color) of the examiner. Several standardized assessments of facial recognition exist,
such as the Benton Facial Recognition Test.32 Individuals can have the inability to
recognize written words despite preservation of other aspects of language function,
a condition known as pure word blindness or pure alexia. Furthermore, individuals
can have difficulty identifying and discriminating colors (achromatopsia), which
can be assessed by asking a patient to name and identify a color and asking to
match hues of colors. Visual object agnosia can be assessed with visual
confrontational naming tasks and then asking the patient to name the same
object by sound or touch. An individual with visual object agnosia will be unable
to identify an object when shown a picture of the object but may be able to do so
when the object is presented in other sensory modalities.
Spatial attention can be assessed through recognition of double simultaneous
stimulation in visual or tactile domains. Standardized assessment can include a
line bisection task33,34 or letter or shape cancellation tasks, in which the patient is
asked to cross out a specified letter or shape from a page full of random letters or
shapes.25,31 An individual with impaired spatial attention may selectively cross
out letters or shapes from a select portion of the full page.
EXECUTIVE FUNCTION. Often, the history obtained from the informant regarding
functional abilities to plan events and outings, operate appliances and gadgets,
multitask, etc, can be as informative, or more so, about the patient’s executive
function than a formal examination can be.10 Abstraction and reasoning can be
assessed at the bedside with use of similarities (eg, “How are an apple and a
banana similar?”) and proverbs (eg, “What does it mean, ‘Rome was not built in
a day’?”), although one should note the heavy influence of education and culture
on responses. Complex motor sequencing can be assessed with the Luria
fist-edge-palm test35 in which the patient is shown the sequence of three gestures
of the hand and then asked to demonstrate over six trials.
1536 DECEMBER 2021

Trail Making Test Part B consists of asking the patient to connect numbers KEY POINTS
and letters in alternating consecutive sequence, is a good assessment of
● Often, the history
set-shifting (as well as response inhibition), and can also be done orally for obtained from the informant
patients who have a visual impairment. Response inhibition can be further regarding functional abilities
assessed with the go/no-go task,35 in which the patient is asked to tap once in such as to plan events and
response to the examiner tapping once and asked to not tap when the outings, operate appliances
and gadgets, and multitask
examiner taps twice. Another bedside measure of response inhibition is the
can be as informative, or
alternating sequences task, in which the patient is asked to write or draw more so, about the patient’s
alternating sequences of letters (eg, alternating m-n-m-n) or shapes (eg, executive function than a
alternating triangle-square-triangle-square).25 formal examination can be.
Executive control of language functioning can be assessed with fluency tasks,
● Semantic fluency is often
in which the patient is asked to name words beginning with a target letter (eg, F) better than letter fluency
or belonging to a semantic category (eg, animals), with the total number of because of the contextual
responses calculated in 60 seconds. Often, in intact individuals a notable strategy organization offered by the
to a fluency task can be observed (eg, naming zoo animals then farm animals). semantic category that is
lacking in letter fluency, but
Individuals with poor executive function may show poor retrieval strategies, semantic fluency will be
perseverative responses, or difficulty switching between tasks. Note that disproportionately impaired
semantic fluency is often better than letter fluency because of the contextual in individuals with semantic
organization offered by the semantic category that is lacking in letter fluency, but naming deficits.
semantic fluency will be disproportionately impaired in individuals with
● The cognitive profile is
semantic naming deficits, as is often seen in early Alzheimer dementia. determined by contrasting
Executive control of visual functions can be assessed with the domains of primary
visual-construction tasks discussed earlier, such as the clock drawing, or the impairment with those in
which test failure is
Rey-Osterrieth Complex Figure Test.
secondary to another factor
A composite of frontal-executive bedside tests has been developed into and those in which
standardized batteries. One such common measure is the Frontal Assessment performance is normal.
Battery,38 comprising six tests of frontal executive function that can be calculated
into a total score up to 18, which can be tracked over time for change.
INTERPRETATION. After obtaining a complete mental status examination, one can

provide an interpretation of the elements into a cognitive profile, which aids in
localization and determination of potential etiology. The cognitive profile is
determined by contrasting domains of primary impairment with those in which
test failure is secondary to another factor and those in which performance is
normal.10 Performance may be affected by internal patient factors such as
education, occupation, age, native language, or culture or by external factors
such as poor sleep, anxiety/depression, or side effects of medications.39 In
interpreting the cognitive profile, it is important to keep in mind that no test is
perfectly selective for a single cognitive domain; thus the clinician must factor
in whether failure on a particular test was due to failure in the cognitive domain
for which the test was selected versus impairment in another cognitive domain.
For example, memory tests based on word lists also require attention,
motivation, and language processes for performance.25
In determining the primary cognitive domains of impairment, often one
domain is more impaired than others, and the profile is then labeled accordingly.
Common profiles are amnestic, language impairment, predominant
visual-perceptual-spatial impairment, or dysexecutive.4
The amnestic profile is characterized by intact learning of newly presented
verbal and visual material with rapid forgetting on delayed recall. Classic
amnestic syndromes localize to the limbic system or diencephalon or both.

Because much of the mental status examination relies on verbal presentation

of instructions and verbal responses, individuals with primary language
impairment tend to show widespread impairment across many cognitive
domains, with a discrepancy noted for relative preservation of tasks that are less
heavily influenced by verbal instructions and responses, such as tests of spatial
attention or visual memory tests. The heavy language influence is particularly
notable on screening measures such as MMSE or MoCA, in which patients who
are aphasic often score in severely impaired ranges, which is illustrated in
CASE 1-2. However, the examiner can be alerted that the patient may have
predominant language dysfunction by the discrepancy between the cognitive
screening measure and functional capacity of the patient, in which function is
typically more preserved than would be expected for the degree of impairment
on the screening measure. Language disorders classically localize to the
dominant hemisphere.
Individuals with a predominant visual-perceptual-spatial profile will show
impairment in tests of those domains as well as any tests of other cognitive
domains that are presented visually, such as Trail-Making Test Parts A and B,
spatial memory tests, or visual naming tests. Examining verbal memory,
auditory naming, and Trail Making Tests orally can help differentiate if
deficits are primarily due to visual-perceptual-spatial impairment and not
impairment in other cognitive domains. Visual-perceptual-spatial
impairment classically localizes to parieto-occipital and temporo-occipital
regions.
The dysexecutive cognitive profile classically localizes to prefrontal regions
and its subcortical basal ganglial-thalamic and cerebellar connections. In addition
to impairment on tests of executive function noted earlier, individuals with
dysexecutive impairment may show deficiency in the executive control of other
cognitive domains, as noted with impairment in lexical fluency and
visual-construction tests discussed earlier.
After interpreting the cognitive profile, the clinician can begin to refine the
differential diagnosis with the aid of the history already obtained. For example,
an amnestic profile but a reported abrupt onset with stable deficits suggests a
likely vascular etiology in the Papez circuit (eg, posterior cerebral artery
infarctions involving the hippocampus), whereas an insidious onset with
progression may suggest a neurodegenerative etiology involving mesial temporal
structures, such as Alzheimer disease.
COMPUTERIZED ASSESSMENTS. In an era of increasing demands on clinicians’ time

and poor reimbursement for detailed mental status testing, computerized
assessment of cognitive functioning is an increasingly attractive option. Indeed,
computerized assessments have potential advantages of improved efficiency,
cost, and accessibility; the ability to more precisely assess certain cognitive
features such as reaction times; ease of administration in different languages; and
automated interpretive algorithms.40
Although computerized assessments can be an additional tool to evaluate a
patient’s mental status, they cannot replace the clinician’s examination in its
entirety as computerized assessments lack the examiner’s observation of
behaviors and comportment; those observations, as well as the additional
information obtained from the history such as education and occupation, disease
course, comorbid illness, and functional capacity, are imperative for accurate
1538 DECEMBER 2021

interpretation of test results, regardless of any automated interpretation that may KEY POINTS
be provided.
● Individuals with primary
Additionally, increased anxiety can be associated with computer use, language impairment tend to
especially among older adults,41 as well as differing levels of familiarity with show widespread
computer interfaces,42 and changes in vision, hearing, and motor functions can impairment across many
confound results.43 Furthermore, it should be noted that although the landscape cognitive domains, with a
discrepancy noted for
of computerized assessments is rapidly evolving, normative data and
relative preservation of
psychometric properties of these assessments are limited. Careful attention must tasks that are less heavily
also be paid to the conditions in which the assessment is to be used (eg, for influenced by verbal
screening versus more detailed assessment of cognitive performance), age range, instructions and responses.
diagnoses, cultural and ethnic backgrounds, and ensuring that the platform is
● Although computerized
appropriately qualified for each unique patient encounter. assessments can be an
additional tool to evaluate a
GENERAL NEUROLOGIC EXAMINATION. Beyond the mental status examination, patient’s mental status, they
features of the general neurologic examination can provide important clues as to cannot replace the
clinician’s examination in its
the etiology of the presenting cognitive or neurobehavioral symptoms, as noted entirety.
in TABLE 1-544 and exemplified in CASE 1-3. In the cranial nerve examination,
assessment of smell is particularly helpful when considering TBI or ● Features of the general
neurodegenerative disorders involving mesial temporal structures neurologic examination can
provide important clues as
(eg, Alzheimer disease). Visual field assessment can provide important localizing
to the etiology of the
value to corroborate with the mental status examination; hemianopia indicates presenting cognitive or
contralateral occipital lobe dysfunction, whereas inferior quadrantanopia neurobehavioral symptoms.
signifies dysfunction of the contralateral parietal lobe and superior
quadrantanopia of the contralateral temporal lobe. Careful assessment of ● Parkinsonism is present in
many cognitive and
extraocular movements can provide signs of certain neurodegenerative, neurobehavioral disorders,
infectious, inflammatory, and inherited disorders. Many of these signs can be but the clinician should not
subtle, with greater sensitivity for detection of abnormal extraocular movements overinterpret subtle
when assessing saccades in addition to pursuits. Hearing loss can be indicative of findings, such as stooped
posture and general
certain disease processes (TABLE 1-5) but also is a risk factor for dementia.45 slowness of movement, that
The motor examination can provide many important clues to the diagnostic can be seen in aging
etiology. Upper motor neuron findings include pyramidal distribution weakness individuals.
(extensor greater than flexor weakness in the upper limbs, flexor greater than
extensor weakness in the lower limbs), spasticity, and hyperreflexia. Unilateral
upper motor neuron signs may signal space-occupying lesions whereas
asymmetric but not strictly unilateral upper motor neuron findings may indicate
cerebrovascular, demyelinating, or mitochondrial disorders; symmetric findings
are more typical of many inherited disorders. A combination of upper motor
neuron and lower motor neuron findings (flaccid tone, fasciculations,
hyporeflexia) on motor examination reflects motor neuron disease, indicative of
frontotemporal dementia with motor neuron disease.
Observation for involuntary movements including myoclonus, tremor, and
chorea also can narrow the differential diagnosis. Parkinsonism (tremor, rigidity,
bradykinesia, postural instability) is present in many cognitive and
neurobehavioral disorders and can be subtle, although clinicians should pay
careful attention to not overinterpret subtle findings, such as stooped posture
and general slowness of movement, that can be seen in aging individuals.
Likewise, mild parkinsonism is common in moderate to advanced stages of many
neurodegenerative disorders, including Alzheimer disease.
Many patients with cognitive and neurobehavioral disorders exhibit paratonia,
which is the inability to relax the muscles during muscle tone assessment.

TABLE 1-5 Selected Differential Diagnosis of Cognitive and Neurobehavioral

Symptoms Aided by Additional Neurologic Findingsa
Neurologic finding Differential diagnosis
Extraocular movements
Oculomasticatory myorhythmia Whipple disease
Oculomotor apraxia Corticobasal syndrome, posterior cortical atrophy
Supranuclear gaze palsy Vertical: Progressive supranuclear palsy, Niemann-Pick Type C

Horizontal: Gaucher disease
Dysconjugate gaze and/or nystagmus Mitochondrial disorders, spinocerebellar ataxias, paraneoplastic
Opsoclonus Paraneoplastic
Pyramidal signs Cerebrovascular disease

Leukodystrophies
Demyelinating disorders
Space-occupying lesions (abscess, tumor)
Frontotemporal dementia with motor neuron disease
Spinocerebellar ataxias
Autosomal dominant Alzheimer disease (some presenilin mutations)
Parkinsonism Lewy body diseases

Corticobasal syndrome
Progressive supranuclear palsy
Multiple system atrophy
Huntington disease
Frontotemporal lobar degeneration with parkinsonism-17
Cerebrovascular disease
Antipsychotic use
Chronic traumatic encephalopathy
Wilson disease
Fahr disease
Anoxic brain injury
Dystonia/chorea Huntington disease

Wilson disease
Neuroacanthocytosis
Neurodegeneration with brain iron accumulation
Neuroferritinopathy
Neuronal ceroid lipofuscinosis
Lesch-Nyhan syndrome
Dentatorubral-pallidoluysian atrophy
Anti–N-methyl-D-aspartate (NMDA)-receptor encephalitis
1540 DECEMBER 2021

Ataxia Alcohol use disorder

Thiamine deficiency
Anoxic brain injury
Paraneoplastic
Multiple system atrophy
Alexander disease
Fahr disease
Niemann-Pick type C disease
Neuronal ceroid lipofuscinosis
Fragile X tremor ataxia syndrome
Prion diseases
Superficial siderosis
Mitochondrial disorders
Myoclonus Prion diseases

Anoxic brain injury
Epileptic encephalopathies
Metabolic disturbances
Medications
Toxic disturbances (eg, bismuth toxicity)
Paraneoplastic
Subacute sclerosing panencephalitis
Systemic or central infection
Late stage of Alzheimer disease
Lewy body diseases
Huntington disease
Sialidosis

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PAGE 1541
Peripheral neuropathy Human immunodeficiency virus (HIV)

Alcohol
Leukodystrophies
Porphyria
Heavy metal toxicity
Fabry disease
Neuroacanthocytosis
Cerebrotendinous xanthomatosis
Sialidosis
Lafora body disease
Rheumatologic disorders
Myopathy Alcohol use disorder

Rheumatologic disorders
Hypothyroidism
Metabolic disturbances
Deafness Superficial siderosis

Sialidosis
a
Reprinted with permission from Rossor MN, et al, Lancet Neurol.44 © 2010 Elsevier Ltd.
Paratonia can suggest frontal-subcortical dysfunction but otherwise is of limited

diagnostic value. Paratonia occurs in two forms: (1) mitgehen, in which the
patient facilitates passive movements, and (2) gegenhalten, in which the patient
resists passive movements.1
Assessment of deep tendon reflexes is an important part of the motor
examination, largely to aid in assessment of upper and lower motor neuron
features. Frontal release signs, or primitive reflexes, are often performed as
part of the reflex examination in assessment of cognitive and neurobehavioral
disorders. Frontal release signs are reflexes that are present in a newborn
but become inhibited as the brain matures, causing the reflex to disappear.
Any brain disease that affects these inhibitory pathways can cause the
reflexes to be “released” and elicited on examination.46 Frontal release signs
include grasp, pout, snout, suck, palmomental, and glabellar tap responses.
Although traditionally thought to signify frontal lobe dysfunction, frontal
1542 DECEMBER 2021

release signs have little diagnostic value and can be seen in healthy older
adults.
Sensory examination should include examination of both large (vibration,
proprioception) and small (pain, temperature) fiber modalities. Abnormalities
may signify peripheral neuropathy, which is associated with several cognitive
and neurobehavioral disorders, including human immunodeficiency virus
(HIV), alcohol use disorder, and mitochondrial disorders, among others.
Reduced large fiber sensation in the toes should be recognized as a normal
feature of aging. If the basic large and small fiber sensations are intact, then the
sensory examination should also include assessment for cortical sensory loss. The
contralateral parietal cortex is largely responsible for discriminative sensation,
which can manifest with the inability to correctly discriminate two points,
identify traced fingers in the palm (graphesthesia), identify objects by touch
(stereognosis), or distinguish double simultaneous stimulation.
Examination of coordination should include tests of the limbs (eg, finger-nose
and heel-shin) and the trunk (posture and gait coordination), given their
separate localizing value (cerebellar hemispheres and vermis, respectively).
Many cognitive and neurobehavioral disorders are associated with ataxia,
including spinocerebellar ataxias, multiple system atrophy cerebellar type,
alcohol use disorder, paraneoplastic disorders, and mitochondrial disorders.
No neurologic examination is complete without watching a patient rise and walk.
Features of the gait can highlight dysfunction of many of the neurologic systems
described earlier. For example, individuals with parkinsonism may be noted to have
a stooped posture, lack of arm swing, and short, shuffling steps, whereas individuals
A 25-year-old left-handed man presented with insidious decline in CASE 1-3

cognitive, behavioral, and motoric functions over the preceding 7 years.
His family noted that he had difficulty making decisions and following
steps of instructions and was forgetful of recent events. He additionally
developed disinhibition, apathy, and compulsive behaviors. He also had
difficulty swallowing liquids, was slurring his words, and stumbled as he
walked. He had no family history of any neurologic disorders.
On examination, he was noted to be thin, had infrequent eye contact
with the examiner, and made inappropriate remarks. Cognitive testing
revealed impairment in attention, memory, and executive domains.
Neurologic examination showed a vertical supranuclear gaze palsy,
dysarthria, and ataxia. Brain MRI demonstrated generalized cerebral and
cerebellar atrophy. Cultured fibroblasts obtained from a skin biopsy
showed abnormal filipin staining, and molecular sequencing of the NPC1
gene revealed a pathologic mutation, confirming the diagnosis of
Niemann-Pick C1 disease.
Abnormalities of the neurologic examination aid in refining the differential COMMENT

diagnosis. In this case, Niemann-Pick C1 disease was suspected because of
the presence of vertical supranuclear gaze palsy and ataxia, which was
confirmed with biochemical testing and genetic sequencing.

with dystonia or chorea may have their abnormal movements become more
apparent during gait. Spasticity can often be seen with abnormal circumduction of
the lower limbs, and asking a patient to perform tandem (heel-toe) walking
provides a good opportunity for assessment of cerebellar vermis function.
INVESTIGATIONS
The history and examination mentioned earlier help determine further
investigations based on the localization and differential diagnosis formulated thus
far. For patients with a typical insidious onset and progression of a cognitive
syndrome suggesting a neurodegenerative dementia, often a minimal workup with
structural neuroimaging and a few serum laboratory tests is needed. However, with
CASE 1-4 A 67-year-old right-handed woman presented with a 1-year history of

progressive memory loss. Her family noted that she had been forgetful of
recent events and conversations. For example, she was unable to recall
many details of a recent family vacation and often forgot she had spoken
via telephone with family members when asked later the same day about
the conversations. In addition, her family noted that she was having
episodes of behavioral arrest, lasting minutes at a time. She also
developed bed-wetting at night, although she had no urinary
incontinence when awake. Instrumental and basic activities of daily living
(ADLs) were intact. She had no significant past medical history and did
not take any routine medications.
General neurologic examination was normal. She scored 26/30 on the
Montreal Cognitive Assessment (MoCA), with all points lost for delayed
recall. Neuropsychological examination revealed deficits in verbal but
not visual delayed recall and relative weakness in visual confrontation
naming and semantic fluency. Brain MRI was normal. EEG demonstrated
frequent left temporal sharp waves. CSF was normal, and no neuronal
antibodies were detected in serum or CSF.
Based on the clinical history, examination, and diagnostic studies, she
was diagnosed with transient epileptic amnesia. One month after
institution of levetiracetam, her family noted she was no longer forgetful,
she had no further episodes of behavioral arrest, and her
neuropsychological profile normalized.
COMMENT Insidious progression of memory loss with intact ADLs and

neuropsychological profile of impairment in delayed recall and relative
weakness in semantic fluency and visual confrontation naming is commonly
seen in mild cognitive impairment due to Alzheimer disease. In such cases,
limited diagnostic testing with serum laboratory tests and structural
neuroimaging is warranted. However, the reported behavioral arrests in
this patient are atypical of Alzheimer disease and merited further
diagnostic assessment with EEG, which revealed findings of left temporal
epileptogenicity. While EEG is not always abnormal in transient epileptic
amnesia, it was supportive in this case.
1544 DECEMBER 2021

a more acute-subacute onset, rapid course, atypical mental status or neurologic KEY POINTS
examination findings, or young age at onset, more detailed workup as discussed
● Although traditionally
may be needed. thought to signify frontal
lobe dysfunction, frontal
Neuropsychological Evaluation release signs have little
Neuropsychological evaluation represents an extension of the examiner’s mental diagnostic value and can be
seen in healthy older adults.
status examination. The goal is to support or refute the hypotheses generated by
the examiner thus far to aid in refining the differential diagnosis.47 ● Neuropsychological
Neuropsychological evaluation is particularly helpful in individuals with young- evaluation represents an
onset cognitive or behavioral impairment, in those with atypical features or extension of the examiner’s
significant confounding features in the mental status examination such as mental status examination.
The goal is to support, or
psychiatric disturbances, and when clarity is needed because of discrepancies refute, the hypotheses
among subjective concerns, functional capacity, and bedside mental status generated by the examiner
examination. The neuropsychological evaluation can also assess for performance thus far to aid in refining the
validity, that is, that the performance obtained during the course of evaluation is differential diagnosis.
a true indication of cognitive function. Performance can be invalid if the patient ● Structural brain imaging
is unable to effectively engage in the tasks, which can occur for a variety of with either head CT or MRI is
reasons, such as psychiatric illness or medicolegal reasons, but is not necessarily needed in evaluation of
an indicator of malingering, as impaired validity testing may occur in the cognitive and
neurobehavioral disorders.
presence of some health conditions (eg, untreated sleep apnea), dementia, low
Brain MRI is generally
intelligence, low education, or English as a second language. The preferred given the greater
neuropsychological evaluation can be helpful to elucidate areas of cognitive sensitivity for detection of
strength and weaknesses that are important for rehabilitation needs and atrophy patterns, white
matter diseases, lacunes,
providing resources and referrals to support patient and caregiver needs.
and microhemorrhages.
However, when the bedside mental status examination demonstrates severe or
global cognitive deficits, a neuropsychological evaluation may be taxing and
burdensome for the patient and may not provide any further diagnostic clarity.
Additional Testing
The American Academy of Neurology practice parameter recommends routine
testing of vitamin B12 and thyroid function in patients being evaluated for
dementia.48 Additionally, a basic metabolic panel, calcium, and liver and renal
function tests provide valuable information on factors that can cause or
worsen cognitive or neurobehavioral symptoms. In individuals with risk
factors, screening with HIV and syphilis serology is also needed.48
Structural brain imaging with either head CT or MRI is needed in evaluation of
cognitive and neurobehavioral disorders. Although structural brain imaging is often
unremarkable in routine evaluation of many cognitive and neurobehavioral disorders, it
is essential not to miss important structural changes that are potentially treatable, such
as subdural hematomas, tumors, or hydrocephalus. A brain MRI is generally preferred
given the greater sensitivity for detection of atrophy patterns, white matter diseases
(eg, small vessel ischemic disease, leukodystrophies), lacunes, and microhemorrhages.
In atypical cases, such as young onset or rapid progression of cognitive/
behavioral symptoms, further testing is guided by additional features in the
history regarding the tempo of onset (TABLE 1-1), neurologic examination
(TABLE 1-5), and structural imaging that aid in refining the differential diagnosis.
For example, an acute or subacute onset warrants additional serologic and CSF
testing for infectious, autoimmune, and paraneoplastic disorders. EEGs are
useful when considering prion diseases or when fluctuating symptoms
concerning for seizures are present (CASE 1-4). Advanced neuroimaging

techniques, such as brain FDG-PET or amyloid PET, or CSF analysis of amyloid-

β and tau can provide useful information in the evaluation of young-onset mild
cognitive impairment or dementia in which routine evaluations have not
suggested an etiology, but this is not routinely recommended because of a lack of
standard use criteria for biomarkers, limited standardization of biomarkers from
one locale to another, limited availability, and limited insurance coverage49,50;
however, a clinician may discuss with patients referral for biomarker research in
such instances.51 Imaging findings concerning for leukodystrophy warrant
neurometabolic screening such as serum very long chain fatty acids, arylsulfatase
A, hexosaminidase A, galactocerebrosidase, and β-galactosidase. Furthermore,
genetic testing may be considered in select cases where inherited etiologies are
being considered, but it is an individualized decision influenced by such factors
as the presence of other affected or at-risk family members and cost and
insurance coverage.
CONCLUSION
The clinical approach to cognitive and neurobehavioral symptoms involves first
obtaining a history from the patient and a collateral source that includes
demographic data, tempo of the presenting symptoms, associated cognitive and
behavioral impairments in other domains, functional capacity, and review of the
general medical, family, and social history and medications that may contribute
to the presenting symptoms. The history is then synthesized with the neurologic
examination, which focuses on the mental status examination. The mental status
examination encompasses selection of appropriate screening measures and
additional examination into attention, language, memory, visuospatial,
executive, and praxis functions as needed to expand on the presenting symptoms
and overcome weaknesses in the selected screening measure. A cognitive/
behavioral profile is then obtained, which aids in refining the localization. The
history and examination can then be combined to narrow the differential
diagnosis and select appropriate further diagnostic studies. In approaching
cognitive and behavioral symptoms in such a systematic manner, the clinician
can be confident in the diagnosis and develop a relevant therapeutic program
that can include disease-specific treatments, as well as neurorehabilitation of
cognitive and focal neurobehavioral symptoms, identification and management
of associated neuropsychiatric symptoms, and alleviation of caregiver burden.
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1548 DECEMBER 2021

Clinical Approach To Cognitive and Neurobehavioral Symptoms: Review Article

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RECENT FINDINGS:Recent advances in structural neuroimaging, functional

SUMMARY: A systematic approach to the history and examination in patients

1518 DECEMBER 2021

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CASE 1-1 A 60-year-old right-handed woman presented with a chief complaint of

1520 DECEMBER 2021

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

REVIEW OF SYMPTOMS PERTAINING TO COGNITIVE DOMAINS

REVIEW OF NEUROPSYCHIATRIC SYMPTOMS

REVIEW OF SLEEP-RELATED SYMPTOMS

1522 DECEMBER 2021

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General Medical Examination

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CASE 1-2 A 65-year-old right-handed man presented for a 1-month history of

1524 DECEMBER 2021

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MENTAL STATUS EXAMINATION. The mental status examination begins with

TABLE 1-1 Selected Differential Diagnosis of Cognitive and Neurobehavioral

Static Stroke Metabolic Not applicable

Fluctuating Not applicable Metabolic Epilepsy

1526 DECEMBER 2021

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ATTENTION. It is helpful to begin assessment of cognitive function by first

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TABLE 1-2 Sample Questions to Probe Function of Cognitive Domainsa

Cognitive domain Probing questions

Attention/working memory Does the patient have difficulty with:

Language Does the patient:

Memory Does the patient:

CONTINUED ON PAGE 1529

1528 DECEMBER 2021

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CONTINUED FROM PAGE 1528

Cognitive domain Probing questions

Visual-perceptual-spatial Is the patient able to:

Praxis Does the patient have:

Executive Is the patient capable of:

Social Does the patient:

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LANGUAGE. Bedside assessment of language begins with evaluation of

TABLE 1-3 Behavioral Domains of Neuropsychiatric Symptomsa

Affective states Depression, anxiety, euphoria/jocularity, mania, irritability/agitation

Aggression Impulsive, reactive, premeditated

Abnormal ideation Preoccupations and ruminations, misinterpretations, delusions

Motor disturbances Restless/fidgeting, rummaging, roaming

Feeding disorders Anorexia, hyperphagia, foraging, pica

1530 DECEMBER 2021

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MEMORY. Assessment of memory focuses on testing of explicit (ie, declarative)

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TABLE 1-4 Bedside Assessment of Select Cognitive Domains

Cognitive domain Bedside tests Pearls and pitfalls

CONTINUED ON PAGE 1533

1532 DECEMBER 2021