# 26 - 21 Neurocognitive Disorders

# 01 - 21.1 Introduction and Overview

# 21.1 Introduction and Overview

Neurocognitive Disorders
 21.1 Introduction and Overview
Advances in molecular biology diagnostic techniques and medication management have
significantly improved the ability to recognize and treat cognitive disorders. Cognition
includes 
memory, 
language, 
orientation, 
judgment, 
conducting 
interpersonal
relationships, performing actions (praxis), and problem solving. Cognitive disorders
reflect disruption in one or more of these domains and are frequently complicated by
behavioral symptoms. Cognitive disorders exemplify the complex interface among
neurology, medicine, and psychiatry in that medical or neurological conditions often
lead to cognitive disorders that, in turn, are associated with behavioral symptoms. It can
be argued that of all psychiatric conditions, cognitive disorders best demonstrate how
biological insults result in behavioral symptomatology. The clinician must carefully
assess the history and context of the presentation of these disorders before arriving at a
diagnosis and treatment plan.
This century-old distinction between organic and functional disorders is outdated and
has been deleted from the nomenclature. Every psychiatric disorder has an organic (i.e.,
biological or chemical) component. Because of this reassessment, the concept of
functional disorders has been determined to be misleading, and the term functional and
its historical opposite, organic, are no longer used in the current Diagnostic and Statistical
Manual of Mental Disorders (DSM) nomenclature. A further indication that the dichotomy
is no longer valid is the revival of the term neuropsychiatry, which emphasizes the
somatic substructure on which mental operations and emotions are based; it is
concerned with the psychopathological accompaniments of brain dysfunction as
observed in seizure disorders, for example. Neuropsychiatry focuses on the psychiatric
aspects of neurological disorders and the role of brain dysfunction in psychiatric
disorders.
Cognitive disorders tend to defy Occam’s razor, challenging clinicians and nosologists
with multiplicity, comorbidity, and unclear boundaries. These concerns are most true in
elderly adults, the demographic group most at risk for cognitive disorders. Dementias of
late life are particularly problematic in this regard. Existing, although often
unrecognized, dementia is a major risk factor for superimposed delirium. Moreover,
certain dementias, such as dementia with Lewy bodies or late stages of Alzheimer’s
disease, may have chronic clinical presentations virtually indistinguishable from
delirium except for temporal onset and the lack of an identifiable acute source.
Similarly, the course of nearly all subjects developing a progressive dementia is
complicated by the onset of one or more distinct behavioral syndromes, including

anxiety, depression, sleep problems, psychosis, and aggression. These symptoms can be
as distressing and disabling as the primary cognitive disorder. Some of these behavioral
syndromes, such as psychosis, may themselves result from independent underlying
biologies and may be additive with the primary neurodegenerative process.
The boundaries between types of dementia and between dementia and normal aging
can be similarly diffuse. Neuropathologic studies of both clinical and population samples
have revealed a surprising truth. The most common neuropathologic presentation
associated with dementia reveal mixtures of Alzheimer’s disease, vascular, and Lewy
body pathologies. Pure syndromes are relatively less common, although often the
dementia is ascribed to one of the coexisting pathologies. Strategies regarding how to
understand or reconcile multiple pathologies in the clinic are needed, although they lag
behind.
DEFINITION
Delirium
Delirium is marked by short-term confusion and changes in cognition. There are four
subcategories based on several causes: (1) general medical condition (e.g., infection),
(2) substance induced (e.g., cocaine, opioids, phencyclidine [PCP]), (3) multiple causes
(e.g., head trauma and kidney disease), and (4) other or multiple etiologies (e.g., sleep
deprivation, mediation). Delirium is discussed in Section 21.2.
Dementia (Major Neurocogntive Disorder)
Dementia, also referred to as major neurocognitive disorder in the fifth edition of DSM
(DSM-5), is marked by severe impairment in memory, judgment, orientation, and
cognition. The subcategories are (1) dementia of the Alzheimer’s type, which usually
occurs in persons older than 65 years of age and is manifested by progressive
intellectual disorientation and dementia, delusions, or depression; (2) vascular
dementia, caused by vessel thrombosis or hemorrhage; (3) human immunodeficiency
virus (HIV) disease; (4) head trauma; (5) Pick’s disease or frontotemporal lobar
degeneration; (6) Prion disease such as Creutzfeldt-Jakob disease, which is caused by a
slow-growing transmittable virus); (7) substance induced, caused by toxin or medication
(e.g., gasoline fumes, atropine); (8) multiple etiologies; and (9) not specified (if cause is
unknown).
In DSM-5, a less severe form of dementia called mild neurocognitive disorder is listed.
Dementia is discussed in Section 21.3.
Amnestic Disorder
Amnestic disorders are classified in DSM-5 as major neurocognitive disorders caused by
other medical conditions. They are marked primarily by memory impairment in addition
to other cognitive symptoms. They may be caused by (1) medical conditions (hypoxia),

(2) toxins or medications (e.g., marijuana, diazepam), and (3) unknown causes. These
disorders are discussed in Section 21.4.
CLINICAL EVALUATION
During the history taking, the clinician seeks to elicit the development of the illness.
Subtle cognitive disorders, fluctuating symptoms, and progressing disease processes may
be tracked effectively. The clinician should obtain a detailed rendition of changes in the
patient’s daily routine involving such factors as self-care, job responsibilities, and work
habits; meal preparation; shopping and personal support; interactions with friends;
hobbies and sports; reading interests; religious, social, and recreational activities; and
ability to maintain personal finances. Understanding the past life of each patient
provides an invaluable source of baseline data regarding changes in function, such as
attention and concentration, intellectual abilities, personality, motor skills, and mood
and perception. The examiner seeks to find the particular pursuits that the patient
considers most important, or central, to his or her lifestyle and attempts to discern how
those pursuits have been affected by the emerging clinical condition. Such a method
provides the opportunity to appraise both the impact of the illness and the patientspecific baseline for monitoring the effects of future therapies.
Mental Status Examination
After taking a thorough history, the clinician’s primary tool is the assessment of the
patient’s mental status. As with the physical examination, the mental status examination
is a means of surveying functions and abilities to allow a definition of personal
strengths and weakness. It is a repeatable, structured assessment of symptoms and signs
that promotes effective communication among clinicians. It also establishes the basis for
future comparison, essential for documenting therapeutic effectiveness, and it allows
comparisons between different patients, with a generalization of findings from one
patient to another. Table 21.1-1 lists the components of a comprehensive
neuropsychiatric mental status examination.
Table 21.1-1
Neuropsychiatric Mental Status Examination

Cognition
When testing cognitive functions, the clinician should evaluate memory; visuospatial
and constructional abilities; and reading, writing, and mathematical abilities.
Assessment of abstraction ability is also valuable, although a patient’s performance on
tasks such as proverb interpretation may be a useful bedside projective test in some
patients, the specific interpretation may result from a variety of factors, such as poor
education, low intelligence, and failure to understand the concept of proverbs, as well
as from a broad array of primary and secondary psychopathological disturbances.
PATHOLOGY AND LABORATORY EXAMINATION
As with all medical tests, psychiatric evaluations such as the mental status examination
must be interpreted in the overall context of thorough clinical and laboratory
assessment. Psychiatric and neuropsychiatric patients require careful physical
examination, especially when issues exist that involve etiologically related or comorbid
medical conditions. When consulting internists and other medical specialists, the
clinician must ask specific questions to focus the differential diagnostic process and use
the consultation most effectively. In particular, most systemic medical or primary
cerebral diseases that lead to psychopathological disturbances also manifest with a
variety of peripheral or central abnormalities.
A screening laboratory evaluation is sought initially and may be followed by a variety
of ancillary tests to increase the diagnostic specificity. Table 21.1-2 lists such procedures,

some of which are described below.
Table 21.1-2
Screening Laboratory Tests
ELECTROENCEPHALOGRAPHY
Electroencephalography (EEG) is an easily accessible, noninvasive test of brain dysfunction that has high sensitivity for
many disorders but relatively low specificity. Beyond its recognized uses in epilepsy, EEG’s greatest utility is in detecting
altered electrical rhythms associated with mild delirium, space-occupying lesions, and continuing complex partial seizures
(in which the patient remains conscious, although behaviorally impaired). EEG is also sensitive to metabolic and toxic

states, often showing a diffuse slowing of brain activity. The EEG is discussed in Section 3.4, Electrophysiology.
COMPUTED TOMOGRAPHY AND MAGNETIC RESONANCE IMAGING
Computed tomography (CT) and magnetic resonance imaging (MRI) have proved to be powerful neuropsychiatric
research tools. Recent developments in MRI allow the direct measurement of structures such as the thalamus, basal
ganglia, hippocampus, and amygdala, as well as temporal and apical areas of the brain and the structures of the posterior
fossa. MRI has largely replaced CT as the most utilitarian and cost-effective method of imaging in neuropsychiatry.
Patients with acute cerebral hemorrhages or hematomas must continue to be assessed using CT, but these patients present
infrequently in psychiatric settings. MRI better discriminates the interface between gray and white matter and is useful in
detecting a variety of white matter lesions in the periventricular and subcortical regions. The pathophysiological
significance of such findings remains to be defined. White matter abnormalities are detected in younger patients with
multiple sclerosis or human immunodeficiency virus (HIV) infection and in older patients with hypertension, vascular
dementia, or dementia of the Alzheimer’s type. The prevalence of these abnormalities is also increased in healthy, aging
individuals who have no defined disease process. As with CT, the greatest utility of MRI in the evaluation of patients with
dementia arises from what it may exclude (tumors, vascular disease) rather than what it can demonstrate specifically.
BRAIN BIOPSY
Brain needle biopsy is used to diagnose a variety of disorders: Alzheimers disease,
autoimmune encephalopaties, and tumors. It is conducted stereotactically and indicated
when no other investigative techniques such as MRI or lumbar puncture have been
sufficient to make a diagnosis. The procedure is not without risk in that seizures may
occur if scar tissue forms at the biopsy site.
NEUROPSYCHOLOGICAL TESTING
Neuropsychological testing provides a standardized, quantitative, reproducible
evaluation of a patient’s cognitive abilities. Such procedures may be useful for initial
evaluation and periodic assessment. Tests are available that assess abilities across the
broad array of cognitive domains, and many offer comparative normative groups or
adjusted scores based on normative samples. The clinician seeking neuropsychological
consultation should understand enough about the strengths and weaknesses of selected
procedures to benefit fully from the results obtained.
REFERENCES
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Bugnicourt J-M, Godefroy O, Chillon J-M, Choukroun G, Massy ZA. Cognitive disorders and dementia in CKD: The
neglected kidney-brain axis. J Am Soc Nephrol. 2013;24:353.
Bugnicourt J-M, Guegan-Massardier E, Roussel M, Martinaud O, Canaple S, Triquenot-Bagan A, Wallon D, Lamy C, Leclercq
C, Hannequin D, Godefroy O. Cognitive impairment after cerebral venous thrombosis: A two-center study. J Neurol.
2013;260:1324.

# 02 - 21.2 Delirium

# 21.2 Delirium

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 21.2 Delirium
Delirium is characterized by an acute decline in both the level of consciousness and
cognition with particular impairment in attention. A life threatening, yet potentially
reversible disorder of the central nervous system (CNS), delirium often involves
perceptual disturbances, abnormal psychomotor activity, and sleep cycle impairment.
Delirium is often underrecognized by health care workers. Part of the problem is that the
syndrome has a variety of other names (Table 21.2-1).
Table 21.2-1
Delirium by Other Names

The hallmark symptom of delirium is an impairment of consciousness, usually
occurring in association with global impairments of cognitive functions. Abnormalities
of mood, perception, and behavior are common psychiatric symptoms. Tremor, asterixis,
nystagmus, incoordination, and urinary incontinence are common neurological
symptoms. Classically, delirium has a sudden onset (hours or days), a brief and
fluctuating course, and rapid improvement when the causative factor is identified and
eliminated, but each of these characteristic features can vary in individual patients.
Physicians must recognize delirium to identify and treat the underlying cause and to
avert the development of delirium-related complications such as accidental injury
because of the patient’s clouded consciousness.
EPIDEMIOLOGY
Delirium is a common disorder, with most incidence and prevalence rates reported in
elderly adults. In community studies, 1 percent of elderly persons age 55 years or older
have delirium (13 percent in the age 85 years and older group in the community).
Among elderly emergency department patients, 5 to 10 percent have been reported to
have delirium. At the time of admission to medical wards, between 15 and 21 percent of
older patients meet criteria for delirium-prevalent cases. Of patients free of delirium at
time of hospital admission, 5 to 30 percent reported subsequent incidences of delirium
during hospitalization. Delirium has been reported in 10 to 15 percent of general
surgical patients, 30 percent of open heart surgery patients, and more than 50 percent
of patients treated for hip fractures. Delirium occurs in 70 to 87 percent of those in
intensive care units and in up to 83 percent of all patients at the end of life care. Sixty
percent of patients in nursing homes or postacute care settings have delirium. An
estimated 21 percent of patients with severe burns and 30 to 40 percent of patients with
acquired immune deficiency syndrome (AIDS) have episodes of delirium while they are
hospitalized. Delirium develops in 80 percent of terminally ill patients. The causes of
postoperative delirium include the stress of surgery, postoperative pain, insomnia, pain
medication, electrolyte imbalances, infection, fever, and blood loss. The incidence and
prevalence rates for delirium across settings are shown in Table 21.2-2.
Table 21.2-2
Delirium Incidence and Prevalence in Multiple Settings

Risk for delirium could be conceptualized into two categories, predisposing and
precipitating factors (Tables 21.2-3 and 21.2-4). Current approaches to delirium focus
primarily on the precipitation factors and do little to address the predisposing factors.
Managing predisposing factors for delirium becomes essential in decreasing future
episodes of delirium and the morbidity and mortality associated with it.
Table 21.2-4
Precipitating Factors for Delirium

Table 21.2-3
Predisposing Factors for Delirium

Advanced age is a major risk factor for the development of delirium. Approximately
30 to 40 percent of hospitalized patients older than age 65 years have an episode of
delirium, and another 10 to 15 percent of elderly persons exhibit delirium on admission
to the hospital. Of nursing home residents older than age 75 years, 60 percent have
repeated episodes of delirium. Male gender is also an independent risk factor for
delirium.
Delirium is a poor prognostic sign. Rates of institutionalization are increased threefold
for patients 65 years and older who exhibit delirium while in the hospital. The 3-month
mortality rate of patients who have an episode of delirium is estimated to be 23 to 33
percent. The 1-year mortality rate for patients who have an episode of delirium may be
as high as 50 percent. Elderly patients who experience delirium while hospitalized have
a 21 to 75 percent mortality rate during that hospitalization. After discharge, up to 15
percent of these persons die within a 1-month period, and 25 percent die within
6 months.
ETIOLOGY
The major causes of delirium are CNS disease (e.g., epilepsy), systemic disease (e.g.,
cardiac failure), and either intoxication or withdrawal from pharmacological or toxic

agents (Table 21.2-5). When evaluating patients with delirium, clinicians should assume
that any drug that a patient has taken may be etiologically relevant to the delirium.
Table 21.2-5
Common Causes of Delirium

DIAGNOSIS AND CLINICAL FEATURES
The DSM-5 diagnostic criteria for delirium are listed in Table 21.2-6. The syndrome of
delirium is almost always caused by one or more systemic or cerebral derangements that
affect brain function.
Table 21.2-6
DSM-5 Diagnostic Criteria for Delirium

A 70-year old woman, Mrs. K, was brought to the emergency department by the
police. The police had responded to complaints from neighbors that Mrs. K was
wandering the neighborhood and was not taking care of herself. When the police
found Mrs. K in her apartment, she was dirty, foul smelling, and wearing nothing but
a bra. Her apartment was also filthy with garbage and rotting food everywhere.
When interviewed, Mrs. K would not look at the interviewer and was confused and
unresponsive to most of the questions asked. She knew her name and address but not
the date. She was unable to describe the events that led to her admission.
The next day, the supervising psychiatrist attempted to interview Mrs. K. Her facial
expression was still unresponsive, and she still did not know the month or the name of
the hospital she was in. She explained that the neighbors called the police because she

was “sick” and that she did indeed feel sick and weak, with pains in her shoulder. She
also reported not eating for 3 days. She denied ever being in a psychiatric hospital or
hearing voices but acknowledged seeing a psychiatrist at one point because she had
trouble sleeping. She said the doctor had prescribed medication, but she could not
remember the name.
The core features of delirium include altered consciousness, such as decreased level of
consciousness; altered attention, which can include diminished ability to focus, sustain,
or shift attention; impairment in other realms of cognitive function, which can manifest
as disorientation (especially to time and space) and decreased memory; relatively rapid
onset (usually hours to days); brief duration (usually days to weeks); and often marked,
unpredictable fluctuations in severity and other clinical manifestations during the course
of the day, sometimes worse at night (sundowning), which may range from periods of
lucidity to severe cognitive impairment and disorganization.
Associated clinical features are often present and may be prominent. They can include
disorganization of thought processes (ranging from mild tangentiality to frank
incoherence), perceptual disturbances such as illusions and hallucinations, psychomotor
hyperactivity and hypoactivity, disruption of the sleep–wake cycle (often manifested as
fragmented sleep at night, with or without daytime drowsiness), mood alterations (from
subtle irritability to obvious dysphoria, anxiety, or even euphoria), and other
manifestations of altered neurological function (e.g., autonomic hyperactivity or
instability, myoclonic jerking, and dysarthria). The EEG usually shows diffuse slowing of
background activity, although patients with delirium caused by alcohol or sedative–
hypnotic withdrawal have low-voltage fast activity.
The major neurotransmitter hypothesized to be involved in delirium is acetylcholine,
and the major neuroanatomical area is the reticular formation. The reticular formation
of the brainstem is the principal area regulating attention and arousal; the major
pathway implicated in delirium is the dorsal tegmental pathway, which projects from
the mesencephalic reticular formation to the tectum and thalamus. Several studies have
reported that a variety of delirium-inducing factors result in decreased acetylcholine
activity in the brain. One of the most common causes of delirium is toxicity from too
many prescribed medications with anticholinergic activity. Researchers have suggested
other pathophysiological mechanisms for delirium. In particular, the delirium associated
with alcohol withdrawal has been associated with hyperactivity of the locus ceruleus and
its noradrenergic neurons. Other neurotransmitters that have been implicated are
serotonin and glutamate.
PHYSICAL AND LABORATORY EXAMINATIONS
Delirium is usually diagnosed at the bedside and is characterized by the sudden onset of
symptoms. A bedside mental status examination—such as the Mini-Mental State
Examination, the mental status examination, or neurological signs—can be used to
document the cognitive impairment and to provide a baseline from which to measure

the patient’s clinical course. The physical examination often reveals clues to the cause of
the delirium (Table 21.2-7). The presence of a known physical illness or a history of
head trauma or alcohol or other substance dependence increases the likelihood of the
diagnosis.
Table 21.2-7
Physical Examination of the Delirious Patient

The laboratory workup of a patient with delirium should include standard tests and
additional studies indicated by the clinical situation (Table 21.2-8). In delirium, the EEG
characteristically shows a generalized slowing of activity and may be useful in
differentiating delirium from depression or psychosis. The EEG of a delirious patient

sometimes shows focal areas of hyperactivity. In rare cases, it may be difficult to
differentiate delirium related to epilepsy from delirium related to other causes.
Table 21.2-8
Laboratory Workup of the Patient with Delirium
DIFFERENTIAL DIAGNOSIS
Delirium versus Dementia
A number of clinical features help distinguish delirium from dementia (Table 21.2-9).
The major differential points between dementia and delirium are the time to
development of the condition and the fluctuation in level of attention in delirium
compared with relatively consistent attention in dementia. The time to development of
symptoms is usually short in delirium, and except for vascular dementia caused by
stroke, it is usually gradual and insidious in dementia. Although both conditions include
cognitive impairment, the changes in dementia are more stable over time and, for
example, usually do not fluctuate over the course of a day. A patient with dementia is
usually alert; a patient with delirium has episodes of decreased consciousness.
Occasionally, delirium occurs in a patient with dementia, a condition known as
beclouded dementia. A dual diagnosis of delirium can be made when there is a definite
history of preexisting dementia.
Table 21.2-9
Frequency of Clinical Features of Delirium Contrasted with Dementia

Delirium versus Schizophrenia or Depression
Delirium must also be differentiated from schizophrenia and depressive disorder. Some
patients with psychotic disorders, usually schizophrenia or manic episodes, can have
periods of extremely disorganized behavior difficult to distinguish from delirium. In
general, however, the hallucinations and delusions of patients with schizophrenia are
more constant and better organized than those of patients with delirium. Patients with
schizophrenia usually experience no change in their level of consciousness or in their
orientation. Patients with hypoactive symptoms of delirium may appear somewhat
similar to severely depressed patients, but they can be distinguished on the basis of an
EEG. Other psychiatric diagnoses to consider in the differential diagnosis of delirium are
brief psychotic disorder, schizophreniform disorder, and dissociative disorders. Patients
with factitious disorders may attempt to simulate the symptoms of delirium but usually
reveal the factitious nature of their symptoms by inconsistencies on their mental status
examinations, and an EEG can easily separate the two diagnoses.
COURSE AND PROGNOSIS
Although the onset of delirium is usually sudden, prodromal symptoms (e.g., restlessness
and fearfulness) can occur in the days preceding the onset of florid symptoms. The
symptoms of delirium usually persist as long as the causally relevant factors are present,
although delirium generally lasts less than 1 week. After identification and removal of
the causative factors, the symptoms of delirium usually recede over a 3- to 7-day period,
although some symptoms may take up to 2 weeks to resolve completely. The older the
patient and the longer the patient has been delirious, the longer the delirium takes to
resolve. Recall of what transpired during a delirium, once it is over, is characteristically
spotty; a patient may refer to the episode as a bad dream or a nightmare only vaguely
remembered. As stated in the discussion on epidemiology, the occurrence of delirium is
associated with a high mortality rate in the ensuing year, primarily because of the
serious nature of the associated medical conditions that lead to delirium.
Whether delirium progresses to dementia has not been demonstrated in carefully
controlled studies, although many clinicians believe that they have seen such a

progression. A clinical observation that has been validated by some studies, however, is
that periods of delirium are sometimes followed by depression or posttraumatic stress
disorder.
TREATMENT
In treating delirium, the primary goal is to treat the underlying cause. When the
underlying condition is anticholinergic toxicity, the use of physostigmine salicylate
(Antilirium), 1 to 2 mg intravenously or intramuscularly, with repeated doses in 15 to
30 minutes may be indicated. The other important goal of treatment is to provide
physical, sensory, and environmental support. Physical support is necessary so that
delirious patients do not get into situations in which they may have accidents. Patients
with delirium should be neither sensory deprived nor overly stimulated by the
environment. They are usually helped by having a friend or relative in the room or by
the presence of a regular sitter. Familiar pictures and decorations; the presence of a
clock or a calendar; and regular orientations to person, place, and time help make
patients with delirium comfortable. Delirium can sometimes occur in older patients
wearing eye patches after cataract surgery (“black-patch delirium”). Such patients can
be helped by placing pinholes in the patches to let in some stimuli or by occasionally
removing one patch at a time during recovery.
Pharmacotherapy
The two major symptoms of delirium that may require pharmacological treatment are
psychosis and insomnia. A commonly used drug for psychosis is haloperidol (Haldol), a
butyrophenone antipsychotic drug. Depending on a patient’s age, weight, and physical
condition, the initial dose may range from 2 to 6 mg intramuscularly, repeated in an
hour if the patient remains agitated. As soon as the patient is calm, oral medication in
liquid concentrate or tablet form should begin. Two daily oral doses should suffice, with
two-thirds of the dose being given at bedtime. To achieve the same therapeutic effect,
the oral dose should be approximately 1.5 times the parenteral dose. The effective total
daily dose of haloperidol may range from 5 to 40 mg for most patients with delirium.
Haloperidol has been associated with prolongation of QT interval. Clinicians should
evaluate baseline and periodic electrocardiograms as well as monitor cardiac status of
the patient. Droperidol (Inapsine) is a butyrophenone available as an alternative
intravenous (IV) formulation, although careful monitoring of the electrocardiogram may
be prudent with this treatment. The U.S. Food and Drug Administration (FDA) has issued
a Black Box Warning because cases of QT prolongation and torsades de pointes have
been reported in patients receiving droperidol. Because of its potential for serious
proarrhythmic effects and death, it should be used only in patients who do not respond
well to other treatments. Phenothiazines should be avoided in delirious patients because
these drugs are associated with significant anticholinergic activity.
Use of second-generation antipsychotics, such as risperidone (Risperdal), clozapine,
olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), and aripiprazole

(Abilify), may be considered for delirium management, but clinical trial experience with
these agents for delirium is limited. Ziprasidone appears to have an activating effect
and may not be appropriate in delirium management. Olanzapine is available for
intramuscular (IM) use and as a rapidly disintegrating oral preparation. These routes of
administration may be preferable for some patients with delirium who are poorly
compliant with medications or who are too sedated to safely swallow medications.
Insomnia is best treated with benzodiazepines with short or intermediate half-lives
(e.g., lorazepam [Ativan] 1 to 2 mg at bedtime). Benzodiazepines with long half-lives
and barbiturates should be avoided unless they are being used as part of the treatment
for the underlying disorder (e.g., alcohol withdrawal). Clinicians should be aware that
there is no conclusive evidence to support the use of benzodiazepines in non–alcoholrelated delirium. There have been case reports of improvement in or remission of
delirious states caused by intractable medical illnesses with electroconvulsive therapy
(ECT); however, routine consideration of ECT for delirium is not advised. If delirium is
caused by severe pain or dyspnea, a physician should not hesitate to prescribe opioids
for both their analgesic and sedative effects (Table 21.2-10).
Table 21.2-10
Pharmacological Treatment
Current trials are ongoing to see if dexmedetomidine (Precedex) is a more effective
medication than haloperidol in the treatment of agitation and delirium in patients
receiving mechanical ventilation in an intensive care unit.
Treatment in Special Populations
Parkinson’s Disease.
 In Parkinson’s disease, the antiparkinsonian agents are
frequently implicated in causing delirium. If a coexistent dementia is present, delirium is
twice as likely to develop in patients with Parkinson’s disease with dementia receiving
antiparkinsonian agents than in those without dementia. Decreasing the dosage of the
antiparkinsonian agent has to be weighed against a worsening of motor symptoms. If
the antiparkinsonian agents cannot be further reduced, or if the delirium persists after
attenuation of the antiparkinsonian agents, clozapine is recommended. If a patient is

not able to tolerate clozapine or the required blood monitoring, alternative
antipsychotic agents should be considered. Quetiapine has not been as rigorously studied
as clozapine and may have parkinsonian side effects, but it is used in clinical practice to
treat psychosis in Parkinson’s disease.
Terminally Ill Patients.
 When delirium occurs in the context of a terminal illness,
issues about advanced directives and the existence of a health care proxy become more
significant. This scenario emphasizes the importance of early development of advance
directives for health care decision making while a person has the capacity to
communicate the wishes regarding the extent of aggressive diagnostic tests at life’s end.
The focus may change from an aggressive search for the etiology of the delirium to one
of palliation, comfort, and assistance with dying.
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# 03 - 21.3 Dementia (Major Neurocognitive Disorder)

# 21.3 Dementia (Major Neurocognitive Disorder)

Yang FM, Marcantonio ER, Inouye SK, Kiely DK, Rudolph JL, Fearing MA, Jones RN. Phenomenological subtypes of
delirium in older persons: Patterns, prevalence, and prognosis. Psychosomatics. 2109;50:248.
 21.3 Dementia (Major Neurocognitive Disorder)
Dementia refers to a disease process marked by progressive cognitive impairment in
clear consciousness. Dementia does not refer to low intellectual functioning or mental
retardation because these are developmental and static conditions, and the cognitive
deficits in dementia represent a decline from a previous level of functioning. Dementia
involves multiple cognitive domains and cognitive deficits cause significant impairment
in social and occupational functioning. There are four types of dementias based on
etiology: Alzheimer’s disease, dementia of Lewy bodies, vascular dementia,
frontotemporal dementia, traumatic brain injury (TBI), HIV, prion disease, Parkinson’s
disease, and Huntington’s disease. Dementia can also be caused by other medical and
neurological conditions or can be caused by various substances. (See Section 21.4:
Amnestic Disorders.)
The critical clinical points of dementia are the identification of the syndrome and the
clinical workup of its cause. The disorder can be progressive or static; permanent or
reversible. An underlying cause is always assumed, although, in rare cases, it is
impossible to determine a specific cause. The potential reversibility of dementia is
related to the underlying pathological condition and to the availability and application
of effective treatment. Approximately 15 percent of people with dementia have
reversible illnesses if treatment is initiated before irreversible damage takes place.
EPIDEMIOLOGY
With the aging population, the prevalence of dementia is rising. The prevalence of
moderate to severe dementia in different population groups is approximately 5 percent
in the general population older than 65 years of age, 20 to 40 percent in the general
population older than 85 years of age, 15 to 20 percent in outpatient general medical
practices, and 50 percent in chronic care facilities.
Of all patients with dementia, 50 to 60 percent have the most common type of
dementia, dementia of the Alzheimer’s type (Alzheimer’s disease). Dementia of the
Alzheimer’s type increases in prevalence with increasing age. For persons age 65 years,
men have a prevalence rate of 0.6 percent and women of 0.8 percent. At age 90, rates
are 21 percent. For all of these figures, 40 to 60 percent of cases are moderate to severe.
The rates of prevalence (men to women) are 11 and 14 percent at age 85, 21 and 25
percent at age 90 years and 36 and 41 percent at age 95 years. Patients with dementia
of the Alzheimer’s type occupy more than 50 percent of nursing home beds. More than
2 million persons with dementia are cared for in these homes. By 2050, current
predictions suggest that there will be 14 million Americans with Alzheimer’s disease and
therefore more than 18 million people with dementia.
The second most common type of dementia is vascular dementia, which is causally

related to cerebrovascular diseases. Hypertension predisposes a person to the disease.
Vascular dementias account for 15 to 30 percent of all dementia cases. Vascular
dementia is most common in persons between the ages of 60 and 70 and is more
common in men than in women. Approximately 10 to 15 percent of patients have
coexisting vascular dementia and dementia of the Alzheimer’s type.
Other common causes of dementia, each representing 1 to 5 percent of all cases,
include head trauma; alcohol-related dementias; and various movement disorder-related
dementias, such as Huntington’s disease and Parkinson’s disease. Because dementia is a
fairly general syndrome, it has many causes, and clinicians must embark on a careful
clinical workup of a patient with dementia to establish its cause.
ETIOLOGY
The most common causes of dementia in individuals older than 65 years of age are (1)
Alzheimer’s disease, (2) vascular dementia, and (3) mixed vascular and Alzheimer’s
dementia. Other illnesses that account for approximately 10 percent include Lewy body
dementia; Pick’s disease; frontotemporal dementias; normal-pressure hydrocephalus
(NPH); alcoholic dementia; infectious dementia, such as HIV or syphilis; and Parkinson’s
disease. Many types of dementias evaluated in clinical settings can be attributable to
reversible causes, such as metabolic abnormalities (e.g., hypothyroidism), nutritional
deficiencies (e.g., vitamin B12 or folate deficiencies), or dementia syndrome caused by
depression. See Table 21.3-1 for a review of possible etiologies of dementia.
Table 21.3-1
Possible Etiologies of Dementia

Dementia of the Alzheimer’s Type
In 1907, Alois Alzheimer (Fig. 21.3-1) first described the condition that later assumed his
name. He described a 51-year-old woman with a 4½-year course of progressive
dementia. The final diagnosis of Alzheimer’s disease requires a neuropathological
examination of the brain; nevertheless, dementia of the Alzheimer’s type is commonly
diagnosed in the clinical setting after other causes of dementia have been excluded from
diagnostic consideration.

FIGURE 21.3-1
Alois Alzheimer (1864–1915), a German psychiatrist, described a type of senile dementia
that bears his name
Genetic Factors.
 Although the cause of dementia of the Alzheimer’s type remains
unknown, progress has been made in understanding the molecular basis of the amyloid
deposits that are a hallmark of the disorder’s neuropathology. Some studies have
indicated that as many as 40 percent of patients have a family history of dementia of
the Alzheimer’s type; thus, genetic factors are presumed to play a part in the
development of the disorder, at least in some cases. Additional support for a genetic
influence is the concordance rate for monozygotic twins, which is higher than the rate
for dizygotic twins (43 percent vs. 8 percent, respectively). In several well-documented
cases, the disorder has been transmitted in families through an autosomal dominant
gene, although such transmission is rare. Alzheimer’s type dementia has shown linkage
to chromosomes 1, 14, and 21.
AMYLOID PRECURSOR PROTEIN. The gene for amyloid precursor protein is on the long arm
of chromosome 21. The process of differential splicing yields four forms of amyloid
precursor protein. The β/A4 protein, the major constituent of senile plaques, is a 42amino acid peptide that is a breakdown product of amyloid precursor protein. In Down
syndrome (trisomy 21) are found three copies of the amyloid precursor protein gene,
and in a disease in which a mutation is found at codon 717 in the amyloid precursor
protein gene, a pathological process results in the excessive deposition of β/A4 protein.
Whether the processing of abnormal amyloid precursor protein is of primary causative
significance in Alzheimer’s disease is unknown, but many research groups are studying
both the normal metabolic processing of amyloid precursor protein and its processing in
patients with dementia of the Alzheimer’s type in an attempt to answer this question.
MULTIPLE E4 GENES. One study implicated gene E4 in the origin of Alzheimer’s disease.

People with one copy of the gene have Alzheimer’s disease three times more frequently
than do those with no E4 gene, and people with two E4 genes have the disease eight
times more frequently than do those with no E4 gene. Diagnostic testing for this gene is
not currently recommended because it is found in persons without dementia and not
found in all cases of dementia.
Neuropathology.
 The classic gross neuroanatomical observation of a brain from a
patient with Alzheimer’s disease is diffuse atrophy with flattened cortical sulci and
enlarged cerebral ventricles. The classic and pathognomonic microscopic findings are
senile plaques, neurofibrillary tangles, neuronal loss (particularly in the cortex and the
hippocampus), synaptic loss (perhaps as much as 50 percent in the cortex), and
granulovascular degeneration of the neurons. Neurofibrillary tangles (Fig. 21.3-2) are
composed of cytoskeletal elements, primarily phosphorylated tau protein, although
other cytoskeletal proteins are also present. Neurofibrillary tangles are not unique to
Alzheimer’s disease; they also occur in Down syndrome, dementia pugilistica (punchdrunk syndrome), Parkinson-dementia complex of Guam, Hallervorden-Spatz disease,
and the brains of normal people as they age. Neurofibrillary tangles are commonly
found in the cortex, the hippocampus, the substantia nigra, and the locus ceruleus.

FIGURE 21.3-2
Photomicrographs of Alzheimer’s disease neuropathology. (A) Deposition of insoluble
fibrillar Aβ into plaques begins in the neocortex, labeled here using an antibody against
Aβ and appearing as reddish-brown deposits (arrows). (B) Bielchowsky stain of
neocortex from an individual who died in advanced stages of Alzheimer’s disease (Braak
stage VI). The Aβ plaques appear as dark brown in this preparation (arrows) and can be
seen to be associated with dystrophic neuronal processes (arrowheads) in which insoluble
microtubule-associate protein τ (MAPT) aggregates appear as black deposits. This
neurofibrillary pathology also appears extensively throughout the neuropil, and several
neurofibrillary tangles can be seen (open arrowheads). (C) Bielchowsky stain of

neocortex from an individual who died in a less advanced disease stage (Braak stage
IV). Although some neurofibrillary tangles are still evident (open arrowheads), the degree
of neurofibrillary pathology in the neuropil is substantially diminished. (D) Isolated
neurofibrillary tangles (open arrowheads) in entorhinal cortex that can be seen in normal
aging (Bielchowsky stain). Notice the lack of Aβ plaques and limited neuropil
involvement. (All images obtained at 200× magnification and provided courtesy of Dr.
Ronald L. Hamilton, Department of Pathology, Division of Neuropathology, University
of Pittsburgh School of Medicine.)
Senile plaques, also referred to as amyloid plaques, more strongly indicate Alzheimer’s
disease, although they are also seen in Down syndrome and, to some extent, in normal
aging. Senile plaques are composed of a particular protein, β/A4, and astrocytes,
dystrophic neuronal processes, and microglia. The number and the density of senile
plaques present in postmortem brains have been correlated with the severity of the
disease that affected the persons.
Neurotransmitters.
 The neurotransmitters that are most often implicated in the
pathophysiological condition of Alzheimer’s disease are acetylcholine and
norepinephrine, both of which are hypothesized to be hypoactive in Alzheimer’s disease.
Several studies have reported data consistent with the hypothesis that specific
degeneration of cholinergic neurons is present in the nucleus basalis of Meynert in
persons with Alzheimer’s disease. Other data supporting a cholinergic deficit in
Alzheimer’s disease demonstrate decreased acetylcholine and choline acetyltransferase
concentrations in the brain. Choline acetyltransferase is the key enzyme for the
synthesis of acetylcholine, and a reduction in choline acetyltransferase concentration
suggests a decrease in the number of cholinergic neurons present. Additional support for
the cholinergic deficit hypothesis comes from the observation that cholinergic
antagonists, such as scopolamine and atropine, impair cognitive abilities, whereas
cholinergic agonists, such as physostigmine and arecoline, enhance cognitive abilities.
Decreased norepinephrine activity in Alzheimer’s disease is suggested by the decrease in
norepinephrine-containing neurons in the locus ceruleus found in some pathological
examinations of brains from persons with Alzheimer’s disease. Two other
neurotransmitters implicated in the pathophysiological condition of Alzheimer’s disease
are the neuroactive peptides somatostatin and corticotropin; decreased concentrations
of both have been reported in persons with Alzheimer’s disease.
Other Causes.
 Another theory to explain the development of Alzheimer’s disease is
that an abnormality in the regulation of membrane phospholipid metabolism results in
membranes that are less fluid—that is, more rigid—than normal. Several investigators
are using molecular resonance spectroscopic imaging to assess this hypothesis directly in
patients with dementia of the Alzheimer’s type. Aluminum toxicity has also been
hypothesized to be a causative factor because high levels of aluminum have been found
in the brains of some patients with Alzheimer’s disease, but this is no longer considered

a significant etiological factor. Excessive stimulation by the transmitter glutamate that
may damage neurons is another theory of causation.
Familial Multiple System Taupathy with Presenile Dementia.
 A recently
discovered type of dementia, familial multiple system taupathy, shares some brain
abnormalities found in people with Alzheimer’s disease. The gene that causes the
disorder is thought to be carried on chromosome 17. The symptoms of the disorder
include short-term memory problems and difficulty maintaining balance and walking.
The onset of disease occurs in the 40s and 50s, and persons with the disease live an
average of 11 years after the onset of symptoms.
As in patients with Alzheimer’s disease, tau protein builds up in neurons and glial cells
of persons with familial multiple system taupathy. Eventually, the protein buildup kills
brain cells. The disorder is not associated with the senile plaques seen with Alzheimer’s
disease.
Mr. J, a 70-year-old retired businessman, was brought to psychiatric services on
referral by the family physician. His wife claimed that Mr. J had become so forgetful
that she was afraid to leave him alone, even at home. Mr. J retired at age 62 years
after experiencing a decline in work performance during the previous 5 years. He also
slowly gave up hobbies he once enjoyed (photography, reading, golf) and became
increasingly quiet. However, his growing forgetfulness went basically unnoticed at
home. Then one day while walking in an area he knew well, he could not find his way
home. From then on his memory failure began to increase. He would forget
appointments, misplace things, and lose his way around the neighborhood he resided
in for 40 years. He failed to recognize people, even those he knew for many years.
His wife had to start bathing and dressing him because he forgot how to do so himself.
On examination, Mr. J was disoriented in time and place. He was only able to
recall his name and place of birth. Mr. J seemed lost during the interview, only
responding to questions with an occasional shrug of his shoulders. When asked to
name objects or to recall words or numbers, Mr. J appeared tense and distressed. Mr.
J had difficulty following instructions and was unable to dress or undress himself. His
general medical condition was good. Laboratory examinations showed abnormalities
on Mr. J’s EEG and CT scans.
Vascular Dementia
The primary cause of vascular dementia, formerly referred to as multi-infarct dementia, is
presumed to be multiple areas of cerebral vascular disease, resulting in a symptom
pattern of dementia. Vascular dementia most commonly is seen in men, especially those
with preexisting hypertension or other cardiovascular risk factors. The disorder affects
primarily small- and medium-sized cerebral vessels, which undergo infarction and
produce multiple parenchymal lesions spread over wide areas of the brain (Fig. 21.3-3).

The causes of the infarctions can include occlusion of the vessels by arteriosclerotic
plaques or thromobemboli from distant origins (e.g., heart valves). An examination of a
patient may reveal carotid bruits, funduscopic abnormalities, or enlarged cardiac
chambers (Fig. 21.3-4).
FIGURE 21.3-4
Patients with chronic dementia usually requires custodial care in their declining years.
Regressive behavior, such as finger sucking, is typical in this state. (Courtesy of Bill
Stanton for Magnum Photos, Inc.)
FIGURE 21.3-3
Gross appearance of the cerebral cortex on coronal section from a patient with vascular
dementia. The multiple bilateral lacunar infarcts involve the thalamus, the internal
capsule, and the globus pallidus. (Courtesy of Daniel P. Perl, M.D.)
Binswanger’s Disease.
 Binswanger’s disease (Fig. 21.3-5), also known as

subcortical arteriosclerotic encephalopathy, is characterized by the presence of many small
infarctions of the white matter that spare the cortical regions (Fig. 21.3-6). Although
Binswanger’s disease was previously considered a rare condition, the advent of
sophisticated and powerful imaging techniques, such as MRI, has revealed that the
condition is more common than previously thought.
FIGURE 21.3-5
Otto Binswanger (1852–1929), a Swiss psychiatrist who described a condition he call
“encephalitis subcorticalis chronica progressive,” now known as Binswanger’s disease.
FIGURE 21.3-6

Binswanger’s disease. Cross-section demonstrating extensive subcortical white matter
infarction, with sparing of the overlying gray matter. (Courtesy of Dushyant Purohit,
M.D., Neuropathology Division, Mount Sinai School of Medicine, New York, NY.)
Frontotemporal Dementia (Pick’s Disease)
In contrast to the parietal-temporal distribution of pathological findings in Alzheimer’s
disease, Pick’s disease (Fig. 21.3-7) is characterized by a preponderance of atrophy in
the frontotemporal regions. These regions also have neuronal loss; gliosis; and neuronal
Pick’s bodies, which are masses of cytoskeletal elements. Pick’s bodies are seen in some
postmortem specimens but are not necessary for the diagnosis. The cause of Pick’s
disease is unknown, but the disease constitutes approximately 5 percent of all
irreversible dementias. It is most common in men, especially those who have a firstdegree relative with the condition. Pick’s disease is difficult to distinguish from dementia
of the Alzheimer’s type, although the early stages of Pick’s disease are more often
characterized by personality and behavioral changes, with relative preservation of other
cognitive functions, and it typically begins before 75 years of age. Familial cases may
have an earlier onset, and some studies have shown that approximately half of the cases
of Pick’s disease are familial (Fig. 21.3-8). Features of Klüver-Bucy syndrome
(e.g., hypersexuality, placidity, and hyperorality) are much more common in Pick’s
disease than in Alzheimer’s disease.
FIGURE 21.3-7
Arnold Pick (1851–1924), a Czech neurologist and psychiatrist who described
frontotemporal dementia and the Pick bodies that are characteristic of the disorder.

FIGURE 21.3-8
Pick’s disease gross pathology. This demonstrates the marked frontal and temporal
atrophy seen in frontotemporal dementias, such as Pick’s disease. (Courtesy of Dushyant
Purohit, M.D., Neuropathology Division, Mount Sinai School of Medicine, New York,
NY.)
Lewy Body Disease
Lewy body disease is a dementia clinically similar to Alzheimer’s disease and often
characterized by hallucinations, parkinsonian features, and extrapyramidal signs (Table
21.3-2). Lewy inclusion bodies are found in the cerebral cortex (Fig. 21.3-9). The exact
incidence is unknown. These patients often have Capgras syndrome (reduplicative
paramnesia) as party of the clinical picture.
FIGURE 21.3-9
Photomicrographs of Lewy body pathology. (A) Abnormal accumulation of α-synuclein
aggregates demonstrated by immunocytochemistry in the amygdala of a subject with
dementia. Lewy bodies appear as dense intracellular inclusions (arrows), but staining of
neuronal processes can be seen throughout the neuropil (arrowheads). In individuals in
whom Lewy body pathology occurs concurrently with Alzheimer’s disease, the amygdala
is often the only region affected. (B) Classic appearance of a Lewy body (arrow) in a
large pigmented neuron of the substantia nigra. (C) Lewy body pathology in the
neocortex. Both Lewy bodies (arrows) and substantial labeling of neuronal processes in

the neuropil (arrowheads) are evident. (Magnification for [A] and [B] 200×, for [C]
400×. All images provided courtesy of Dr. Ronald L. Hamilton, Department of
Pathology, Division of Neuropathology, University of Pittsburgh School of Medicine.)
Table 21.3-2
Clinical Criteria for Dementia with Lewy Bodies (DLB)
Huntington’s Disease
Huntington’s disease (Fig. 21.3-10) is classically associated with the development of
dementia. The dementia seen in this disease is the subcortical type of dementia,
characterized by more motor abnormalities and fewer language abnormalities than in
the cortical type of dementia (Table 21.3-3). The dementia of Huntington’s disease
exhibits psychomotor slowing and difficulty with complex tasks, but memory, language,
and insight remain relatively intact in the early and middle stages of the illness. As the
disease progresses, however, the dementia becomes complete; the features distinguishing
it from dementia of the Alzheimer’s type are the high incidence of depression and
psychosis in addition to the classic choreoathetoid movement disorder.

FIGURE 21.3-10
George Huntington (1850–1916), an American physician who first described the disease
that bears his name, Huntington’s disease.
Table 21.3-3
Distinguishing Features of Subcortical and Cortical Dementias

Parkinson’s Disease
As with Huntington’s disease, parkinsonism is a disease of the basal ganglia, commonly
associated with dementia and depression. An estimated 20 to 30 percent of patients with
Parkinson’s disease have dementia, and an additional 30 to 40 percent have measurable
impairment in cognitive abilities. The slow movements of persons with Parkinson’s
disease are paralleled in the slow thinking of some affected patients, a feature that
clinicians may refer to as bradyphrenia.
Mr. M, 77 years of age, came for a neurological examination because he noticed his
memory was slipping and he was having difficulty concentrating, which interfered
with his work. He complained of slowness and losing his train of thought. His wife
stated that he was becoming withdrawn and was more reluctant to participate in
activities he usually enjoyed. He denied symptoms of depression other than feeling
mildly depressed about his disabilities. Two years prior, Mr. M developed an
intermittent resting tremor in his right hand and a shuffling gait. Although a
psychiatrist considered a diagnosis of Parkinson’s disease, it was not confirmed by a
neurologist and therefore was never treated.
During an initial neurological examination, Mr. M’s spontaneous speech was
hesitant and unclear (dysarthric). Cranial nerve examination was normal. Motor tone
was increased slightly in the neck and all limbs. He performed alternating movements
in his hands slowly. He had a slight intermittent tremor of his right arm at rest.

Reflexes were symmetrical. A neuropsychological examination was performed three
weeks later. It was found that Mr. M showed impairment of memory, naming, and
constructional abilities.
HIV-Related Dementia
Encephalopathy in HIV infection is associated with dementia and is termed acquired
immune deficiency syndrome (AIDS) dementia complex, or HIV dementia. Patients infected
with HIV experience dementia at an annual rate of approximately 14 percent. An
estimated 75 percent of patients with AIDS have involvement of the CNS at the time of
autopsy. The development of dementia in people infected with HIV is often paralleled
by the appearance of parenchymal abnormalities in MRI scans. Other infectious
dementias are caused by Cryptococcus or Treponema pallidum.
The diagnosis of AIDS dementia complex is made by confirmation of HIV infection and exclusion of alternative
pathology to explain cognitive impairment. The American Academy of Neurology AIDS Task Force developed research
criteria for the clinical diagnosis of CNS disorders in adults and adolescents (Table 21.3-4). The AIDS Task Force criteria for
AIDS dementia complex require laboratory evidence for systemic HIV, at least two cognitive deficits, and the presence of
motor abnormalities or personality changes. Personality changes may be manifested by apathy, emotional lability, or
behavioral disinhibition. The AIDS Task Force criteria also require the absence of clouding of consciousness or evidence of
another etiology that could produce the cognitive impairment. Cognitive, motor, and behavioral changes are assessed using
physical, neurological, and psychiatric examinations, in addition to neuropsychological testing.
Table 21.3-4
Criteria for Clinical Diagnosis of HIV Type 1-Associated Dementia Complex

Head Trauma-Related Dementia
Dementia can be a sequela of head trauma. The so-called punch-drunk syndrome
(dementia pugilistica) occurs in boxers after repeated head trauma over many years. It
is characterized by emotional lability, dysarthria, and impulsivity. It has also been
observed in professional football players who developed dementia after repeated
concussions over many years.
Mrs. S, 75 years of age, was brought to the emergency department after being
found wandering her neighborhood in a confused and disoriented state. She was in
good health until a few months prior when her husband was hospitalized for 10 days
for minor surgery. About a month after her husband returned home, he and their two
adult children, who do not reside with them, reported a noticeable change in Mrs. S’s
mental status. Mrs. S became hyperactive and appeared to have excessive energy, was
agitated and irritable, and had difficulty sleeping at night.
At examination, Mrs. S was disoriented to time and place, agitated, and confused.
Her husband revealed upon interview that Mrs. S has for many years suffered from
dizziness and lightheadedness upon standing and occasionally suffered from falls,
none of which caused any major damage. Not long before her confused symptoms
began, Mrs. S had apparently suffered a fall one night, and her husband found her the
next morning lying next to the bed in a confused state. Because of her history of falls,

neither Mr. S nor Mrs. S thought much of the incident. A CT scan revealed the
presence of a subdural hematoma, which was then evacuated. Afterward, Mrs. S’s
confusion and disorientation cleared and she returned to her normal state of
functioning.
DIAGNOSIS AND CLINICAL FEATURES
The DSM-5 diagnostic criteria are listed in Tables 21.3-5 and 21.3-6. DSM-5 makes a
distinction between major and minor cognitive disorder based upon levels of
functioning, but the underlying etiology is similar.
Table 21.3-5
DSM-5 Diagnostic Criteria for Major Neurocognitive Disorder (Dementia)
Table 21.3-6
DSM-5 Diagnostic Criteria for Major or Mild Neurocognitive Disorder Due to
Alzheimer’s Disease

The diagnosis of dementia is based on the clinical examination, including a mental
status examination, and on information from the patient’s family, friends, and
employers. Complaints of a personality change in a patient older than age 40 years
suggest that a diagnosis of dementia should be carefully considered.
Clinicians should note patients’ complaints about intellectual impairment and
forgetfulness as well as evidence of patients’ evasion, denial, or rationalization aimed at
concealing cognitive deficits. Excessive orderliness, social withdrawal, or a tendency to
relate events in minute detail can be characteristic, and sudden outbursts of anger or
sarcasm can occur. Patients’ appearance and behavior should be observed. Lability of
emotions; sloppy grooming; uninhibited remarks; silly jokes; or a dull, apathetic, or
vacuous facial expression and manner suggest the presence of dementia, especially
when coupled with memory impairment.
Memory impairment is typically an early and prominent feature in dementia,
especially in dementias involving the cortex, such as dementia of the Alzheimer’s type.
Early in the course of dementia, memory impairment is mild and usually most marked
for recent events; people forget telephone numbers, conversations, and events of the
day. As the course of dementia progresses, memory impairment becomes severe, and
only the earliest learned information (e.g., a person’s place of birth) is retained.
Inasmuch as memory is important for orientation to person, place, and time,
orientation can be progressively affected during the course of a dementing illness. For

example, patients with dementia may forget how to get back to their rooms after going
to the bathroom. No matter how severe the disorientation seems, however, patients
show no impairment in their level of consciousness.
Dementing processes that affect the cortex, primarily dementia of the Alzheimer’s type
and vascular dementia, can affect patients’ language abilities.
Psychiatric and Neurological Changes
Personality.
 Changes in the personality of a person with dementia are especially
disturbing for their families. Preexisting personality traits may be accentuated during
the development of a dementia. Patients with dementia may also become introverted
and seem to be less concerned than they previously were about the effects of their
behavior on others. Persons with dementia who have paranoid delusions are generally
hostile to family members and caretakers. Patients with frontal and temporal
involvement are likely to have marked personality changes and may be irritable and
explosive.
Hallucinations and Delusions.
 An estimated 20 to 30 percent of patients with
dementia (primarily patients with dementia of the Alzheimer’s type) have
hallucinations, and 30 to 40 percent have delusions, primarily of a paranoid or
persecutory and unsystematized nature, although complex, sustained, and wellsystematized delusions are also reported by these patients. Physical aggression and
other forms of violence are common in demented patients who also have psychotic
symptoms.
Mood.
 In addition to psychosis and personality changes, depression and anxiety are
major symptoms in an estimated 40 to 50 percent of patients with dementia, although
the full syndrome of depressive disorder may be present in only 10 to 20 percent.
Patients with dementia also may exhibit pathological laughter or crying—that is,
extremes of emotions—with no apparent provocation.
Cognitive Change.
 In addition to the aphasias in patients with dementia, apraxias
and agnosias are common. Other neurological signs that can be associated with
dementia are seizures, seen in approximately 10 percent of patients with dementia of
the Alzheimer’s type and in 20 percent of patients with vascular dementia, and atypical
neurological presentations, such as nondominant parietal lobe syndromes. Primitive
reflexes, such as the grasp, snout, suck, tonic-foot, and palmomental reflexes, may be
present on neurological examination, and myoclonic jerks are present in 5 to 10 percent
of patients.
Patients with vascular dementia may have additional neurological symptoms, such as
headaches, dizziness, faintness, weakness, focal neurological signs, and sleep
disturbances, possibly attributable to the location of the cerebrovascular disease.
Pseudobulbar palsy, dysarthria, and dysphagia are also more common in vascular

dementia than in other dementing conditions.
Catastrophic Reaction.
 Patients with dementia also exhibit a reduced ability to
apply what Kurt Goldstein called the “abstract attitude.” Patients have difficulty
generalizing from a single instance, forming concepts, and grasping similarities and
differences among concepts. Furthermore, the ability to solve problems, to reason
logically, and to make sound judgments is compromised. Goldstein also described a
catastrophic reaction marked by agitation secondary to the subjective awareness of
intellectual deficits under stressful circumstances. Persons usually attempt to
compensate for defects by using strategies to avoid demonstrating failures in intellectual
performance; they may change the subject, make jokes, or otherwise divert the
interviewer. Lack of judgment and poor impulse control appear commonly, particularly
in dementias that primarily affect the frontal lobes. Examples of these impairments
include coarse language, inappropriate jokes, neglect of personal appearance and
hygiene, and a general disregard for the conventional rules of social conduct.
Sundowner Syndrome.
 Sundowner syndrome is characterized by drowsiness,
confusion, ataxia, and accidental falls. It occurs in older people who are overly sedated
and in patients with dementia who react adversely to even a small dose of a
psychoactive drug. The syndrome also occurs in demented patients when external
stimuli, such as light and interpersonal orienting cues, are diminished.
Vascular Dementia
The general symptoms of vascular dementia are the same as those for dementia of the
Alzheimer’s type, but the diagnosis of vascular dementia requires either clinical or
laboratory evidence in support of a vascular cause of the dementia. Vascular dementia is
more likely to show a decremental, stepwise deterioration than is Alzheimer’s disease.
Substance-Induced Persisting Dementia
To facilitate the clinician’s thinking about differential diagnosis, substance-induced
persisting dementia is listed in two places, with the dementias and with the substancerelated disorders. The specific substances that cross references are alcohol, inhalants,
sedatives, hypnotics, or anxiolytics, and other or unknown substances.
Alcohol-Induced Persisting Dementia.
 To make the diagnosis of alcoholinduced persisting dementia, the criteria for dementia must be met. Because amnesia
can also occur in the context of Korsakoff’s psychosis, it is important to distinguish
between memory impairment accompanied by other cognitive deficits (i.e., dementia)
and amnesia caused by thiamine deficiency. To complicate matters, however, evidence
also suggests that other cognitive functions, such as attention and concentration, may
also be impaired in Wernicke-Korsakoff syndrome. In addition, alcohol abuse is
frequently associated with mood changes, so poor concentration and other cognitive

symptoms often observed in the context of a major depression must also be ruled out.
Prevalence rates differ considerably according to the population studied and the
diagnostic criteria used, although alcohol-related dementia has been estimated to
account for approximately 4 percent of dementias.
PATHOLOGY, PHYSICAL FINDINGS, AND LABORATORY EXAMINATION
A comprehensive laboratory workup must be performed when evaluating a patient with
dementia. The purposes of the workup are to detect reversible causes of dementia and to
provide the patient and family with a definitive diagnosis. The range of possible causes
of dementia mandates selective use of laboratory tests. The evaluation should follow
informed clinical suspicion based on the history and physical and mental status
examination results. The continued improvements in brain imaging techniques,
particularly MRI, have made differentiation between dementia of the Alzheimer’s type
and vascular dementia, in some cases, somewhat more straightforward than in the past.
An active area of research is the use of single-photon emission computed tomography
(SPECT) to detect patterns of brain metabolism in various types of dementias; the use of
SPECT images may soon help in the clinical differential diagnosis of dementing
illnesses.
A general physical examination is a routine component of the workup for dementia. It
may reveal evidence of systemic disease causing brain dysfunction, such as an enlarged
liver and hepatic encephalopathy, or it may demonstrate systemic disease related to
particular CNS processes. The detection of Kaposi’s sarcoma, for example, should alert
the clinician to the probable presence of AIDS and the associated possibility of AIDS
dementia complex. Focal neurological findings, such as asymmetrical hyperreflexia or
weakness, are seen more often in vascular than in degenerative disease. Frontal lobe
signs and primitive reflexes occur in many disorders and often point to greater
progression.
DIFFERENTIAL DIAGNOSIS
Dementia of the Alzheimer’s Type versus Vascular Dementia
Classically, vascular dementia has been distinguished from dementia of the Alzheimer’s
type by the decremental deterioration that can accompany cerebrovascular disease over
time. Although the discrete, stepwise deterioration may not be apparent in all cases,
focal neurological symptoms are more common in vascular dementia than in dementia
of the Alzheimer’s type, as are the standard risk factors for cerebrovascular disease.
Vascular Dementia versus Transient Ischemic Attacks
Transient ischemic attacks (TIAs) are brief episodes of focal neurological dysfunction
lasting less than 24 hours (usually 5 to 15 minutes). Although a variety of mechanisms
may be responsible, the episodes are frequently the result of microembolization from a

proximal intracranial arterial lesion that produces transient brain ischemia, and the
episodes usually resolve without significant pathological alteration of the parenchymal
tissue. Approximately one-third of persons with untreated TIAs experience a brain
infarction later; therefore, recognition of TIAs is an important clinical strategy to
prevent brain infarction.
Clinicians should distinguish episodes involving the vertebrobasilar system from those
involving the carotid arterial system. In general, symptoms of vertebrobasilar disease
reflect a transient functional disturbance in either the brainstem or the occipital lobe;
carotid distribution symptoms reflect unilateral retinal or hemispheric abnormality.
Anticoagulant therapy, antiplatelet agglutinating drugs such as aspirin, and extracranial
and intracranial reconstructive vascular surgery are effective in reducing the risk of
infarction in patients with TIAs.
Delirium
In general, delirium is distinguished by rapid onset, brief duration, cognitive
impairment fluctuation during the course of the day; nocturnal exacerbation of
symptoms; marked disturbance of the sleep–wake cycle; and prominent disturbances in
attention and perception.
Depression
Some patients with depression have symptoms of cognitive impairment difficult to
distinguish from symptoms of dementia. The clinical picture is sometimes referred to as
pseudodementia, although the term depression-related cognitive dysfunction is preferable
and more descriptive (Table 21.3-7). Patients with depression-related cognitive
dysfunction generally have prominent depressive symptoms, more insight into their
symptoms than do demented patients, and often a history of depressive episodes.
Table 21.3-7
Major Clinical Features Differentiating Pseudodementia from Dementia

Factitious Disorder
Persons who attempt to simulate memory loss, as in factitious disorder, do so in an
erratic and inconsistent manner. In true dementia, memory for time and place is lost
before memory for person, and recent memory is lost before remote memory.
Schizophrenia
Although schizophrenia can be associated with some acquired intellectual impairment,
its symptoms are much less severe than are the related symptoms of psychosis and
thought disorder seen in dementia.
Normal Aging
Aging is not necessarily associated with any significant cognitive decline, but minor
memory problems can occur as a normal part of aging. These normal occurrences are
sometimes referred to as benign senescent forgetfulness, age-associated memory impairment,
or normal benign age-related senescence. They are distinguished from dementia by their
minor severity and because they do not interfere significantly with a person’s social or
occupational behavior. See Section 21.6 for a discussion of mild cognitive impairment.
Other Disorders

Intellectual disability, which does not include memory impairment, occurs in childhood.
Amnestic disorder is characterized by circumscribed loss of memory and no
deterioration. Major depression in which memory is impaired responds to
antidepressant medication. Malingering and pituitary disorder must be ruled out, but
they are unlikely.
COURSE AND PROGNOSIS
The classic course of dementia is an onset in the patient’s 50s or 60s, with gradual
deterioration over 5 to 10 years, leading eventually to death. The age of onset and the
rapidity of deterioration vary among different types of dementia and within individual
diagnostic categories. The average survival expectation for patients with dementia of
the Alzheimer’s type is approximately 8 years, with a range of 1 to 20 years. Data
suggest that in persons with an early onset of dementia or with a family history of
dementia, the disease is likely to have a rapid course. In a recent study of 821 persons
with Alzheimer’s disease, the median survival time was 3.5 years. After dementia is
diagnosed, patients must have a complete medical and neurological workup because 10
to 15 percent of all patients with dementia have a potentially reversible condition if
treatment is initiated before permanent brain damage occurs.
The most common course of dementia begins with a number of subtle signs that may,
at first, be ignored by both the patient and the people closest to the patient. A gradual
onset of symptoms is most commonly associated with dementia of the Alzheimer’s type,
vascular dementia, endocrinopathies, brain tumors, and metabolic disorders.
Conversely, the onset of dementia resulting from head trauma, cardiac arrest with
cerebral hypoxia, or encephalitis can be sudden. Although the symptoms of the early
phase of dementia are subtle, they become conspicuous as the dementia progresses, and
family members may then bring a patient to a physician’s attention. People with
dementia may be sensitive to the use of benzodiazepines or alcohol, which can
precipitate agitated, aggressive, or psychotic behavior. In the terminal stages of
dementia, patients become empty shells of their former selves—profoundly disoriented,
incoherent, amnestic, and incontinent of urine and feces.
With psychosocial and pharmacological treatment and possibly because of the selfhealing properties of the brain, the symptoms of dementia may progress slowly for a
time or may even recede somewhat. Symptom regression is certainly a possibility in
reversible dementias (dementias caused by hypothyroidism, NPH, and brain tumors)
after treatment is initiated. The course of the dementia varies from a steady progression
(commonly seen with dementia of the Alzheimer’s type) to an incrementally worsening
dementia (commonly seen with vascular dementia) to a stable dementia (as may be
seen in dementia related to head trauma).
Psychosocial Determinants
The severity and course of dementia can be affected by psychosocial factors. The greater
a person’s premorbid intelligence and education, the better the ability to compensate for

intellectual deficits. People who have a rapid onset of dementia use fewer defenses than
do those who experience an insidious onset. Anxiety and depression can intensify and
aggravate the symptoms. Pseudodementia occurs in depressed people who complain of
impaired memory but, in fact, have a depressive disorder. When the depression is
treated, the cognitive defects disappear.
TREATMENT
The first step in the treatment of dementia is verification of the diagnosis. Accurate
diagnosis is imperative because the progression may be halted or even reversed if
appropriate therapy is provided. Preventive measures are important, particularly in
vascular dementia. Such measures might include changes in diet, exercise, and control of
diabetes and hypertension. Pharmacological agents might include antihypertensive,
anticoagulant, or antiplatelet agents. Blood pressure control should aim for the higher
end of the normal range because that has been demonstrated to improve cognitive
function in patients with vascular dementia. Blood pressure below the normal range has
been demonstrated to further impair cognitive function in patients with dementia. The
choice of antihypertensive agent can be significant in that β-adrenergic receptor
antagonists have been associated with exaggeration of cognitive impairment.
Angiotensin-converting enzyme (ACE) inhibitors and diuretics have not been linked to
exaggeration of cognitive impairment and are thought to lower blood pressure without
affecting cerebral blood flow, which is presumed to be correlated with cognitive
function. Surgical removal of carotid plaques may prevent subsequent vascular events in
carefully selected patients. The general treatment approach to patients with dementia is
to provide supportive medical care; emotional support for the patients and their
families; and pharmacological treatment for specific symptoms, including disruptive
behavior.
Psychosocial Therapies
The deterioration of mental faculties has significant psychological meaning for patients
with dementia. The experience of a sense of continuity over time depends on memory.
Recent memory is lost before remote memory in most cases of dementia, and many
patients are highly distressed by clearly recalling how they used to function while
observing their obvious deterioration. At the most fundamental level, the self is a
product of brain functioning. Patients’ identities begin to fade as the illness progresses,
and they can recall less and less of their past. Emotional reactions ranging from
depression to severe anxiety to catastrophic terror can stem from the realization that the
sense of self is disappearing.
Patients often benefit from a supportive and educational psychotherapy in which the
nature and course of their illness are clearly explained. They may also benefit from
assistance in grieving and accepting the extent of their disability and from attention to
self-esteem issues. Any areas of intact functioning should be maximized by helping
patients identify activities in which successful functioning is possible. A psychodynamic

assessment of defective ego functions and cognitive limitations can also be useful.
Clinicians can help patients find ways to deal with the defective ego functions, such as
keeping calendars for orientation problems, making schedules to help structure
activities, and taking notes for memory problems.
Psychodynamic interventions with family members of patients with dementia may be
of great assistance. Those who take care of a patient struggle with feelings of guilt,
grief, anger, and exhaustion as they watch a family member gradually deteriorate. A
common problem that develops among caregivers involves their self-sacrifice in caring
for a patient. The gradually developing resentment from this self-sacrifice is often
suppressed because of the guilt feelings it produces. Clinicians can help caregivers
understand the complex mixture of feelings associated with seeing a loved one decline
and can provide understanding as well as permission to express these feelings.
Clinicians must also be aware of the caregivers’ tendencies to blame themselves or
others for patients’ illnesses and must appreciate the role that patients with dementia
play in the lives of family members.
Pharmacotherapy
Clinicians may prescribe benzodiazepines for insomnia and anxiety, antidepressants for
depression, and antipsychotic drugs for delusions and hallucinations, but they should be
aware of possible idiosyncratic drug effects in older people (e.g., paradoxical
excitement, confusion, and increased sedation). In general, drugs with high
anticholinergic activity should be avoided.
Donepezil (Aricept), rivastigmine (Exelon), galantamine (Remiryl), and tacrine
(Cognex) are cholinesterase inhibitors used to treat mild to moderate cognitive
impairment in Alzheimer’s disease. They reduce the inactivation of the neurotransmitter
acetylcholine and thus potentiate the cholinergic neurotransmitter, which in turn
produces a modest improvement in memory and goal-directed thought. These drugs are
most useful for persons with mild to moderate memory loss who have sufficient
preservation of their basal forebrain cholinergic neurons to benefit from augmentation
of cholinergic neurotransmission.
Donepezil is well tolerated and widely used. Tacrine is rarely used because of its
potential for hepatotoxicity. Fewer clinical data are available for rivastigmine and
galantamine, which appear more likely to cause gastrointestinal (GI) and
neuropsychiatric adverse effects than does donepezil. None of these medications
prevents the progressive neuronal degeneration of the disorder. Prescribing information
for anticholinesterase inhibitors can be found in Section 36.14.
Memantine (Namenda) protects neurons from excessive amounts of glutamate, which
may be neurotoxic. The drug is sometimes combined with donepezil. It has been known
to improve dementia.
Other Treatment Approaches.
 Other drugs being tested for cognitive-enhancing
activity include general cerebral metabolic enhancers, calcium channel inhibitors, and

serotonergic agents. Some studies have shown that selegiline (Eldepryl), a selective type
B monoamine oxidase (MAOB) inhibitor, may slow the advance of this disease.
Ondansetron (Zofran), a 5-HT3 receptor antagonist, is under investigation.
Estrogen replacement therapy may reduce the risk of cognitive decline in
postmenopausal women; however, more studies are needed to confirm this effect.
Complementary and alternative medicine studies of ginkgo biloba and other
phytomedicinals are required to see if they have a positive effect on cognition. Reports
have appeared of patients using nonsteroidal antiinflammatory agents having a lower
risk of developing Alzheimer’s disease. Vitamin E has not been shown to be of value in
preventing the disease.
REFERENCES
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Assessment of Neuropsychiatric and Neuromedical Disorders. 3rd ed. New York: Oxford University Press; 2009:159.
Brand BL, Stadnik R. What contributes to predicting change in the treatment of dissociation: Initial levels of dissociation,
PTSD, or overall distress? J Trauma Dissociation. 2013;14:328.
Clare L, Whitaker CJ, Nelis SM, et al. Self-concept in early stage dementia: Profile, course, correlates, predictors and
implications for quality of life. Int J Geriatr Psychiatry. 2013;28(5):494–503.
Craft S. The role of metabolic disorders in Alzheimer disease and vascular dementia. Arch Neurol. 2009;66(3):300.
Elvish R, Lever S-J, Johnstone J, Cawley R, Keady J. Psychological interventions for carers of people with dementia: A
systematic review of quantitative and qualitative evidence. Counsel Psychother Res. 2013;13(2):106–125.
Goldman J, Stebbins G, Merkitch D, Dinh V, Bernard B, DeToledo-Morrell L, Goetz C. Hallucinations and dementia in
Parkinson’s disease: clinically related but structurally distinct (P5. 257). Neurology. 2014;82(10 Supplement):P5-257.
Graff-Radford NR, Woodruff BK. Frontotemporal dementia. Semin Neurol. 2007; 27:48.
Hansen KF, Karenlina K, Sakamoto K, Wayman GA, Impey S, Obrietan K. miRNA-132: A dynamic regulator of cognitive
capacity. Brain Structure Function. 2013;218:817.
Insausti R, Annese J, Amaral DG, Squire LR. Human amnesia and the medial temporal lobe illuminated by
neuropsychological and neurohistological findings for patient E.P. Proc Natl Acad Sci U S A. 2013;110:E1953.
Kemp PM, Holmes C. Imaging in dementia with Lewy bodies: A review. Nucl Med Commun. 2007;28:511.
McLaren AN, LaMantia MA, Callahan CM. Systematic review of non-pharmacologic interventions to delay functional
decline in community-dwelling patients with dementia. Aging & Ment Health. 2013;17(6):655–666.
Mitchell SL, Teno JM, Kiely DK, Shaffer ML, Jones RN, Prigerson HG, Volicer L, Given JL, Hamel MB. The clinical course
of advanced dementia. N Engl J Med. 2009;361:1529.
Nervi A, Reitz C, Tang MX, Santana V, Piriz A, Reyes D, Lantigua R, Medrano M, Jiménez-Velázquez IZ, Lee, JH, Mayeux
M. Familial aggregation of dementia with Lewy bodies. Arch Neurol. 2011;68(1):90.
Nguyen TP, Soukup VM, Gelman BB. Persistent hijacking of brain proteasomes in HIV-associated dementia. Am J Pathol.
2010;176:893.
Panza F, Frisardi V, Capurso C, D’Introno A, Colacicco AM, Imbimbo BP, Santamato A, Vendemiale G, Seripa D, Pilotto A,
Capurso A, Solfrizzi V. Late-life depression, mild cognitive impairment, and dementia: Possible continuum? Am J
Geriatr Psychiatry. 2010;18(2):98.
Richards SS, Sweet RA. Dementia. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s Comprehensive Textbook of
Psychiatry. 9th edition. Philadelphia: Lippincott Williams & Wilkins; 2009: 1167.

# 04 - 21.4 Major or Minor Neurocognitive Disorder D

# 21.4 Major or Minor Neurocognitive Disorder Due to Another Medical Condition (Amnestic Disorders)

Watson PD, Voss JL, Warren DE, Tranel D, Cohen NJ. Spatial reconstruction by patients with hippocampal damage is
dominated by relational memory errors. Hippocampus. 2013;23:570.
 21.4 Major or Minor Neurocognitive Disorder Due to
Another Medical Condition (Amnestic Disorders)
The amnestic disorders are coded in the DSM-5 as “major or minor neurocognitive
disorders due to another medical condition.” All of these disorders cause impairment in
memory as the major sign and symptom, although other signs of cognitive decline may
coexist. The authors of Synopsis believe amnestic disorder to be a clinically useful
descriptive category of illness, but they are coded in DSM-5 as a neurocognitive disorder
due to another medical condition with the specific medical condition noted.
The amnestic disorders are a broad category that results from a variety of diseases
and conditions that have amnesia as the major complaint. The syndrome is defined
primarily by impairment in the ability to create new memories. Three different
etiologies exist: amnestic disorder caused by a general medical condition (e.g., head
trauma), substance-induced persisting amnestic disorder (e.g., caused by carbon
monoxide poisoning or chronic alcohol consumption), and amnestic disorder not
otherwise specified for cases in which the etiology is unclear.
EPIDEMIOLOGY
No adequate studies have reported on the incidence or prevalence of amnestic disorders.
Amnesia is most commonly found in alcohol use disorders and in head injury. In general
practice and hospital settings, the frequency of amnesia related to chronic alcohol abuse
has decreased, and the frequency of amnesia related to head trauma has increased.
ETIOLOGY
The major neuroanatomical structures involved in memory and in the development of
an amnestic disorder are particular diencephalic structures such as the dorsomedial and
midline nuclei of the thalamus and midtemporal lobe structures such as the
hippocampus, the mamillary bodies, and the amygdala. Although amnesia is usually the
result of bilateral damage to these structures, some cases of unilateral damage result in
an amnestic disorder, and evidence indicates that the left hemisphere may be more
critical than the right hemisphere in the development of memory disorders. Many
studies of memory and amnesia in animals have suggested that other brain areas may
also be involved in the symptoms accompanying amnesia. Frontal lobe involvement can
result in such symptoms as confabulation and apathy, which can be seen in patients
with amnestic disorders.
Amnestic disorders have many potential causes (Table 21.4-1). Thiamine deficiency,
hypoglycemia, hypoxia (including carbon monoxide poisoning), and herpes simplex
encephalitis all have a predilection to damage the temporal lobes, particularly the

hippocampi, and thus can be associated with the development of amnestic disorders.
Similarly, when tumors, cerebrovascular diseases, surgical procedures, or multiple
sclerosis plaques involve the diencephalic or temporal regions of the brain, the
symptoms of an amnestic disorder may develop. General insults to the brain, such as
seizures, ECT, and head trauma, can also result in memory impairment. Transient global
amnesia is presumed to be a cerebrovascular disorder involving transient impairment in
blood flow through the vertebrobasilar arteries.
Table 21.4-1
Major Causes of Amnestic Disorders
Many drugs have been associated with the development of amnesia, and clinicians
should review all drugs taken, including nonprescription drugs, in the diagnostic
workup of a patient with amnesia. The benzodiazepines are the most commonly used
prescription drugs associated with amnesia. All benzodiazepines can be associated with
amnesia, especially if combined with alcohol. When triazolam (Halcion) is used in doses
of 0.25 mg or less, which are generally equivalent to standard doses of other
benzodiazepines, amnesia is no more often associated with triazolam than with other
benzodiazepines. With alcohol and higher doses, anterograde amnesia has been
reported.
DIAGNOSIS
The recognition of amnestic disorder occurs when impairment in the ability to learn new
information or the inability to recall previously learned information, as a result of
which there is significant impairment in social or occupational functioning and which is
caused by a general medical condition (including physical trauma). Amnestic disorder
may be transient, lasting for hours or days or chronic lasting weeks or months. A
diagnosis of substance-induced persisting amnestic disorder is made when evidence

suggests that the symptoms are causatively related to the use of a substance. The DSM-5
refers clinicians to specific diagnoses within substance-related disorders: alcohol-induced
disorder; sedative, hypnotic, or anxiolytic-induced disorder; and other (or unknown)
substance-induced disorder.
CLINICAL FEATURES AND SUBTYPES
The central symptom of amnestic disorders is the development of a memory disorder
characterized by an impairment in the ability to learn new information (anterograde
amnesia) and an inability to recall previously remembered knowledge (retrograde
amnesia). The symptom must result in significant problems for patients in their social or
occupational functioning. The time in which a patient is amnestic can begin directly at
the point of trauma or include a period before the trauma. Memory for the time during
the physical insult (e.g., during a cerebrovascular event) may also be lost.
Short-term and recent memory are usually impaired. Patients cannot remember what
they had for breakfast or lunch, the name of the hospital, or their doctors. In some
patients, the amnesia is so profound that the patient cannot orient himself or herself to
city and time, although orientation to person is seldom lost in amnestic disorders.
Memory for overlearned information or events from the remote past, such as childhood
experiences, is good, but memory for events from the less remote past (over the past
decade) is impaired. Immediate memory (tested, for example, by asking a patient to
repeat six numbers) remains intact. With improvement, patients may experience a
gradual shrinking of the time for which memory has been lost, although some patients
experience a gradual improvement in memory for the entire period.
The onset of symptoms can be sudden, as in trauma, cerebrovascular events, and
neurotoxic chemical assaults, or gradual, as in nutritional deficiency and cerebral
tumors. The amnesia can be of short duration.
A variety of other symptoms can be associated with amnestic disorders. For patients
with other cognitive impairments, a diagnosis of dementia or delirium is more
appropriate than a diagnosis of an amnestic disorder. Both subtle and gross changes in
personality can accompany the symptoms of memory impairment in amnestic disorders.
Patients may be apathetic, lack initiative, have unprovoked episodes of agitation, or
appear to be overly friendly or agreeable. Patients with amnestic disorders can also
appear bewildered and confused and may attempt to cover their confusion with
confabulatory answers to questions. Characteristically, patients with amnestic disorders
do not have good insight into their neuropsychiatric conditions.
A 73-year-old survivor of the Holocaust was admitted to the psychiatric unit from a
local nursing home. She was born in Germany to a middle-class family. Her education
was truncated because of internment in a concentration camp. She immigrated to
Israel after liberation from the concentration camp and later to the United States,
where she married and raised a family. Premorbidly, she was described as a quiet,

intelligent, and loving woman who spoke several languages. At 55 years of age, she
had a significant carbon monoxide exposure when a gas line leaked while she and her
husband slept. Her husband died of carbon monoxide poisoning, but the patient
survived after a period of coma. After being stabilized, she displayed significant
cognitive and behavioral problems. She had difficulty with learning new information
and making appropriate plans. She retained the ability to perform activities of daily
living but could not be relied on to pay bills, buy food, cook, or clean, despite
appearing to have retained the intellectual ability to do these tasks. She was admitted
to a nursing home after several difficult years at home and in the homes of relatives.
In the nursing home, she was able to learn her way about the facility. She displayed
little interest in scheduled group activities, hobbies, reading, or television. She had
frequent behavioral problems. She repeatedly pressed staff to get her sweets and
snacks and cursed them vociferously with racial epithets and disparaging comments
on their weight and dress. On one occasion, she scratched the cars of several staff with
a key. Neuropsychological testing demonstrated severe deficits in delayed recall;
intact performance on language and general knowledge measures; and moderate
deficits on domains of executive function, such as concept formation and cognitive
flexibility. She was noted to respond immediately to firmly set limits and rewards, but
deficits in memory prevented long-term incorporation of these boundaries.
Management involved development of a behavioral plan that could be implemented
at the nursing home and empirical trials of medications aimed at amelioration of
irritability.
Cerebrovascular Diseases
Cerebrovascular diseases affecting the hippocampus involve the posterior cerebral and
basilar arteries and their branches. Infarctions are rarely limited to the hippocampus;
they often involve the occipital or parietal lobes. Thus, common accompanying
symptoms of cerebrovascular diseases in this region are focal neurological signs
involving vision or sensory modalities. Cerebrovascular diseases affecting the bilateral
medial thalamus, particularly the anterior portions, are often associated with symptoms
of amnestic disorders. A few case studies report amnestic disorders from rupture of an
aneurysm of the anterior communicating artery, resulting in infarction of the basal
forebrain region.
Multiple Sclerosis
The pathophysiological process of multiple sclerosis involves the seemingly random
formation of plaques within the brain parenchyma. When the plaques occur in the
temporal lobe and the diencephalic regions, symptoms of memory impairment can
occur. In fact, the most common cognitive complaints in patients with multiple sclerosis
involve impaired memory, which occurs in 40 to 60 percent of patients.
Characteristically, digit span memory is normal, but immediate recall and delayed recall

of information are impaired. The memory impairment can affect both verbal and
nonverbal material.
Korsakoff’s Syndrome
Korsakoff’s syndrome is an amnestic syndrome caused by thiamine deficiency, most
commonly associated with the poor nutritional habits of people with chronic alcohol
abuse. Other causes of poor nutrition (e.g., starvation), gastric carcinoma, hemodialysis,
hyperemesis gravidarum, prolonged IV hyperalimentation, and gastric plication can
also result in thiamine deficiency. Korsakoff’s syndrome is often associated with
Wernicke’s encephalopathy, which is the associated syndrome of confusion, ataxia, and
ophthalmoplegia. In patients with these thiamine deficiency–related symptoms, the
neuropathological findings include hyperplasia of the small blood vessels with
occasional hemorrhages, hypertrophy of astrocytes, and subtle changes in neuronal
axons. Although the delirium clears up within a month or so, the amnestic syndrome
either accompanies or follows untreated Wernicke’s encephalopathy in approximately
85 percent of all cases.
Patients with Korsakoff’s syndrome typically demonstrate a change in personality as
well, such that they display a lack of initiative, diminished spontaneity, and a lack of
interest or concern. These changes appear frontal lobe–like, similar to the personality
change ascribed to patients with frontal lobe lesions or degeneration. Indeed, such
patients often demonstrate executive function deficits on neuropsychological tasks
involving attention, planning, set shifting, and inferential reasoning consistent with
frontal pattern injuries. For this reason, Korsakoff’s syndrome is not a pure memory
disorder, although it certainly is a good paradigm of the more common clinical
presentations for the amnestic syndrome.
The onset of Korsakoff’s syndrome can be gradual. Recent memory tends to be
affected more than is remote memory, but this feature is variable. Confabulation,
apathy, and passivity are often prominent symptoms in the syndrome. With treatment,
patients may remain amnestic for up to 3 months and then gradually improve over the
ensuing year. Administration of thiamine may prevent the development of additional
amnestic symptoms, but the treatment seldom reverses severe amnestic symptoms when
they are present. Approximately one-third to one-fourth of all patients recover
completely, and approximately one-fourth of all patients have no improvement of their
symptoms.
Alcoholic Blackouts
Some persons with severe alcohol abuse may exhibit the syndrome commonly referred to
as an alcoholic blackout. Characteristically, these persons awake in the morning with a
conscious awareness of being unable to remember a period the night before during
which they were intoxicated. Sometimes specific behaviors (hiding money in a secret
place and provoking fights) are associated with the blackouts.

Electroconvulsive Therapy
Electroconvulsive therapy treatments are usually associated with retrograde amnesia for
a period of several minutes before the treatment and anterograde amnesia after the
treatment. The anterograde amnesia usually resolves within 5 hours. Mild memory
deficits may remain for 1 to 2 months after a course of ECT treatments, but the
symptoms are completely resolved 6 to 9 months after treatment.
Head Injury
Head injuries (both closed and penetrating) can result in a wide range of
neuropsychiatric symptoms, including dementia, depression, personality changes, and
amnestic disorders. Amnestic disorders caused by head injuries are commonly associated
with a period of retrograde amnesia leading up to the traumatic incident and amnesia
for the traumatic incident itself. The severity of the brain injury correlates somewhat
with the duration and severity of the amnestic syndrome, but the best correlate of
eventual improvement is the degree of clinical improvement in the amnesia during the
first week after the patient regains consciousness.
Transient Global Amnesia
Transient global amnesia is characterized by the abrupt loss of the ability to recall
recent events or to remember new information. The syndrome is often characterized by
mild confusion and a lack of insight into the problem; a clear sensorium; and,
occasionally, the inability to perform some well-learned complex tasks. Episodes last
from 6 to 24 hours. Studies suggest that transient global amnesia occurs in 5 to 10 cases
per 100,000 persons per year, although, for patients older than age 50 years, the rate
may be as high as 30 cases per 100,000 persons per year. The pathophysiology is
unknown, but it likely involves ischemia of the temporal lobe and the diencephalic brain
regions. Several studies of patients with SPECT have shown decreased blood flow in the
temporal and parietotemporal regions, particularly in the left hemisphere. Patients with
transient global amnesia almost universally experience complete improvement,
although one study found that approximately 20 percent of patients may have
recurrence of the episode, and another study found that approximately 7 percent of
patients may have epilepsy. Patients with transient global amnesia have been
differentiated from patients with transient ischemic attacks in that fewer patients have
diabetes, hypercholesterolemia, and hypertriglyceridemia, but more have hypertension
and migrainous episodes.
PATHOLOGY AND LABORATORY EXAMINATION
Laboratory findings diagnostic of amnestic disorder may be obtained using quantitative
neuropsychological testing. Standardized tests also are available to assess recall of wellknown historical events or public figures to characterize an individual’s inability to

remember previously learned information. Performance on such tests varies among
individuals with amnestic disorder. Subtle deficits in other cognitive functions may be
noted in individuals with amnestic disorder. Memory deficits, however, constitute the
predominant feature of the mental status examination and account largely for any
functional deficits. No specific or diagnostic features are detectable on imaging studies
such as MRI or CT. Damage of midtemporal lobe structures is common, however, and
may be reflected in enlargement of third ventricle or temporal horns or in structural
atrophy detected by MRI.
DIFFERENTIAL DIAGNOSIS
Table 21.4-1 lists the major causes of amnestic disorders. To make the diagnosis,
clinicians must obtain a patient’s history, conduct a complete physical examination, and
order all appropriate laboratory tests. Other diagnoses, however, can be confused with
the amnestic disorders.
Dementia and Delirium
Amnestic disorders can be distinguished from delirium because they occur in the absence
of a disturbance of consciousness and are striking for the relative preservation of other
cognitive domains.
Table 21.4-2 outlines the key distinctions between Alzheimer’s dementia and the
amnestic disorders. Both disorders can have an insidious onset with slow progression, as
in a Korsakoff’s psychosis in a chronic drinker. Amnestic disorders, however, can also
develop precipitously, as in Wernicke’s encephalopathy, transient global amnesia, or
anoxic insults. Although Alzheimer’s dementia progresses relentlessly, amnestic disorders
tend to remain static or even improve after the offending cause has been removed. In
terms of the actual memory deficits, the amnestic disorder and Alzheimer’s disease still
differ. Alzheimer’s disease has an impact on retrieval in addition to encoding and
consolidation. The deficits in Alzheimer’s disease extend beyond memory to general
knowledge (semantic memory), language, praxis, and general function. These are
spared in amnestic disorders. The dementias associated with Parkinson’s disease, AIDS,
and other subcortical disorders demonstrate disproportionate impairment of retrieval,
but relatively intact encoding and consolidation and thus can be distinguished from
amnestic disorders. The subcortical pattern dementias are also likely to display motor
symptoms, such as bradykinesia, chorea, or tremor, that are not components of the
amnestic disorders.
Table 21.4-2
Comparison of Syndrome Characteristics in Alzheimer’s Disease and Amnestic
Disorder

Normal Aging
Some minor impairment in memory may accompany normal aging, but the requirement
that the memory impairment cause significant impairment in social or occupational
functioning should exclude normal aging from the diagnosis.
Dissociative Disorders
The dissociative disorders can sometimes be difficult to differentiate from the amnestic
disorders. Patients with dissociative disorders, however, are more likely to have lost
their orientation to self and may have more selective memory deficits than do patients
with amnestic disorders. For example, patients with dissociative disorders may not know
their names or home addresses, but they are still able to learn new information and
remember selected past memories. Dissociative disorders are also often associated with
emotionally stressful life events involving money, the legal system, or troubled
relationships.
Factitious Disorders
Patients with factitious disorders who are mimicking an amnestic disorder often have
inconsistent results on memory tests and have no evidence of an identifiable cause.
These findings, coupled with evidence of primary or secondary gain for a patient,
should suggest a factitious disorder.
COURSE AND PROGNOSIS
The course of an amnestic disorder depends on its etiology and treatment, particularly
acute treatment. Generally, the amnestic disorder has a static course. Little
improvement is seen over time, but also no progression of the disorder occurs. The
exceptions are the acute amnesias, such as transient global amnesia, which resolves
entirely over hours to days, and the amnestic disorder associated with head trauma,
which improves steadily in the months subsequent to the trauma. Amnesia secondary to
processes that destroy brain tissue, such as stroke, tumor, and infection, are irreversible,
although, again, static, after the acute infection or ischemia has been staunched.
TREATMENT

The primary approach to treating amnestic disorders is to treat the underlying cause.
Although a patient is amnestic, supportive prompts about the date, the time, and the
patient’s location can be helpful and can reduce the patient’s anxiety. After resolution of
the amnestic episode, psychotherapy of some type (cognitive, psychodynamic, or
supportive) may help patients incorporate the amnestic experience into their lives.
Psychotherapy
Psychodynamic interventions may be of considerable value for patients who have
amnestic disorders that result from insults to the brain. Understanding the course of
recovery in such patients helps clinicians to be sensitive to the narcissistic injury
inherent in damage to the CNS.
The first phase of recovery, in which patients are incapable of processing what
happened because the ego defenses are overwhelmed, requires clinicians to serve as a
supportive auxiliary ego who explains to a patient what is happening and provides
missing ego functions. In the second phase of recovery, as the realization of the injury
sets in, patients may become angry and feel victimized by the malevolent hand of fate.
They may view others, including the clinician, as bad or destructive, and clinicians must
contain these projections without becoming punitive or retaliatory. Clinicians can build
a therapeutic alliance with patients by explaining slowly and clearly what happened
and by offering an explanation for a patient’s internal experience. The third phase of
recovery is integrative. As a patient accepts what has happened, a clinician can help the
patient form a new identity by connecting current experiences of the self with past
experiences. Grieving over the lost faculties may be an important feature of the third
phase.
Most patients who are amnestic because of brain injury engage in denial. Clinicians
must respect and empathize with the patient’s need to deny the reality of what has
happened. Insensitive and blunt confrontations destroy any developing therapeutic
alliance and can cause patients to feel attacked. In a sensitive approach, clinicians help
patients accept their cognitive limitations by exposing them to these deficits bit by bit
over time. When patients fully accept what has happened, they may need assistance in
forgiving themselves and any others involved, so that they can get on with their lives.
Clinicians must also be wary of being seduced into thinking that all of the patient’s
symptoms are directly related to the brain insult. An evaluation of preexisting
personality disorders, such as borderline, antisocial, and narcissistic personality
disorders, must be part of the overall assessment; many patients with personality
disorders place themselves in situations that predispose them to injuries. These
personality features may become a crucial part of the psychodynamic psychotherapy.
Recently, centers for cognitive rehabilitation have been established whose
rehabilitation-oriented therapeutic milieu is intended to promote recovery from brain
injury, especially that from traumatic causes. Despite the high cost of extended care at
these sites, which provide both long-term institutional and daytime services, no data
have been developed to define therapeutic effectiveness for the heterogeneous groups of

# 05 - 21.5 Neurocognitive and Other Disorders Due t

# 21.5 Neurocognitive and Other Disorders Due to a General Medical Condition

patients who participate in such tasks as memory retaining.
REFERENCES
Andreescu C, Aizenstein HJ. Amnestic disorders and mild cognitive impairment. In: Sadock BJ, Sadock VA, Ruiz P, eds.
Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins;
2009:1198.
Auyeunga M, Tsoi TH, Cheung CM, Fong DYT, Li R, Chan JKW, Lau KY. Association of diffusion weighted imaging
abnormalities and recurrence in transient global amnesia. J Clin Neurosci. 2011;18:531.
Gerridzen IJ, Goossensen MA. Patients with Korsakoff syndrome in nursing homes: characteristics, comorbidity, and use of
psychotropic drugs. Int Psychogeriatr. 2014;26(1):115–121.
Kearney H, Mallon P, Kavanagh E, Lawler L, Kelly P, O’Rourke K. Amnestic syndrome due to meningovascular
neurosyphilis. J Neurol. 2010;257:669.
McLaren AN, LaMantia MA, Callahan CM. Systematic review of non-pharmacologic interventions to delay functional
decline in community-dwelling patients with dementia. Aging Mental Health. 2013;17:655.
Purohit V, Rapaka R, Frankenheim J, Avila A, Sorensen R, Rutter J. National Institute on Drug Abuse symposium report:
Drug of abuse, dopamine, and HIV-associated neurocognitive disorders/HIV-associated dementia. J Neurovirol.
2013;19:119.
Race E, Verfaellie M. Remote memory function and dysfunction in Korsakoff’s syndrome. Neuropsychol Rev. 2012;22:105.
Rogalski EJ, Rademaker A, Harrison TM, Helenowski I, Johnson N, Bigio E, Mishra M, Weintraub S, Mesulam MM. ApoE
E4 is a susceptibility factor in amnestic but not aphasic dementias. Alzheimer Dis Assoc Disord. 2011;25:159.
Tannenbaum C, Paquette A, Hilmer S, Holroyd-Leduc J, Carnahan R. A systematic review of amnestic and non-amnestic
mild cognitive impairment induced by anticholinergic, antihistamine, GABAergic and opioid drugs. Drug Aging.
2012;29:639.
van Geldorp B, Bergmann HC, Robertson J, Wester AJ, Kessels RPC. The interaction of working memory performance and
episodic memory formation in patients with Korsakoff’s amnesia. Brain Res. 2012;1433:98.
 21.5 Neurocognitive and Other Disorders Due to a
General Medical Condition
Increasingly, scientific views of mental illness recognize that, whether caused by an
identifiable anomaly (e.g., brain tumor), a neurotransmitter disturbance of unclear
origin (e.g., schizophrenia), or a consequence of deranged upbringing or environment
(e.g., personality disorder), all mental disorders ultimately share one common
underlying theme: aberration in brain function. Treatments for those conditions,
whether psychological or biological, attempt to restore normal brain chemistry.
The differential diagnosis for a mental syndrome in a patient should always include
consideration of (1) any general medical condition that a patient may have and (2) any
prescription, nonprescription, or illegal substances that a patient may be taking.
Although some specific medical conditions have classically been associated with mental
syndromes, a much larger number of general medical conditions have been associated
with mental syndromes in case reports and small studies.
The mental disorders caused by a general medical condition span the entire spectrum

of diagnostic categories. Thus, one can have a cognitive disorder, mood disorder, sleep
disorder, anxiety disorder, and psychotic disorder to mention but a few that are caused
or aggravated by a medical condition. In this section, neurocognitive disorders due to a
general medical condition are described, including epilepsy, autoimmune disorders and
AIDS, of which psychiatrists should be aware.
SPECIFIC DISORDERS
Epilepsy
Epilepsy is the most common chronic neurological disease in the general population and
affects approximately 1 percent of the population in the United States. For psychiatrists,
the major concerns about epilepsy are consideration of an epileptic diagnosis in
psychiatric patients, the psychosocial ramifications of a diagnosis of epilepsy for a
patient, and the psychological and cognitive effects of commonly used anticonvulsant
drugs. With regard to the first of these concerns, 30 to 50 percent of all persons with
epilepsy have psychiatric difficulties sometime during the course of their illness. The
most common behavioral symptom of epilepsy is a change in personality. Psychosis and
violence occur much less commonly than was previously believed.
Definitions.
 A seizure is a transient paroxysmal pathophysiological disturbance of
cerebral function caused by a spontaneous, excessive discharge of neurons. Patients are
said to have epilepsy if they have a chronic condition characterized by recurrent seizure.
The ictus, or ictal event, is the seizure itself. The nonictal periods are categorized as
preictal, postictal, and interictal. The symptoms during the ictal event are determined
primarily by the site of origin in the brain for the seizure and by the pattern of the
spread of seizure activity through the brain. Interictal symptoms are influenced by the
ictal event and other neuropsychiatric and psychosocial factors, such as coexisting
psychiatric or neurological disorders, the presence of psychosocial stressors, and
premorbid personality traits.
Classification.
 The two major categories of seizures are partial and generalized.
Partial seizures involve epileptiform activity in localized brain regions. Generalized
seizures involve the entire brain (Fig. 21.5-1). A classification system for seizures is
outlined in Table 21.5-1.

FIGURE 21.5-1
Electroencephalographic recording during generalized tonic-clonic seizure showing
rhythmic sharp waves and muscles artifact during tonic phase, spike and wave
discharges during clonic phase, and attenuation of activity during postictal state.
(Courtesy of Barbara F. Westmoreland, M.D.)
Table 21.5-1
International Classification of Epileptic Seizures

GENERALIZED SEIZURES. Generalized tonic-clonic seizures exhibit the classic symptoms of
loss of consciousness, generalized tonic-clonic movements of the limbs, tongue biting,
and incontinence. Although the diagnosis of the ictal events of the seizure is relatively
straightforward, the postictal state, characterized by a slow, gradual recovery of
consciousness and cognition, occasionally presents a diagnostic dilemma for a
psychiatrist in an emergency department. The recovery period from a generalized tonicclonic seizure ranges from a few minutes to many hours, and the clinical picture is that
of a gradually clearing delirium. The most common psychiatric problems associated with
generalized seizures involve helping patients adjust to a chronic neurological disorder
and assessing the cognitive or behavioral effects of anticonvulsant drugs.
Absence Seizure (Petit Mal).
 A difficult type of generalized seizure for a psychiatrist to
diagnose is an absence, or petit mal, seizure. The epileptic nature of the episodes may
go unrecognized because the characteristic motor or sensory manifestations of epilepsy
may be absent or so slight that they do not arouse suspicion. Petit mal epilepsy usually
begins in childhood between the ages of 5 and 7 years and ceases by puberty. Brief
disruptions of consciousness, during which the patient suddenly loses contact with the
environment, are characteristic of petit mal epilepsy, but the patient has no true loss of
consciousness and no convulsive movements during the episodes. The EEG produces a
characteristic pattern of three-per-second spike-and-wave activity (Fig. 21.5-2). In rare
instances, petit mal epilepsy begins in adulthood. Adult-onset petit mal epilepsy can be
characterized by sudden, recurrent psychotic episodes or deliriums that appear and
disappear abruptly. The symptoms may be accompanied by a history of falling or
fainting spells.

FIGURE 21.5-2
Petit mal epilepsy characterized by bilaterally synchronous, 3-Hz spike and slow-wave
activity.
PARTIAL SEIZURES. Partial seizures are classified as either simple (without alterations in
consciousness) or complex (with an alteration in consciousness). Somewhat more than
half of all patients with partial seizures have complex partial seizures. Other terms used
for complex partial seizures are temporal lobe epilepsy, psychomotor seizures, and
limbic epilepsy; these terms, however, are not accurate descriptions of the clinical
situation. Complex partial epilepsy, the most common form of epilepsy in adults, affects
approximately three of 1,000 persons. About 30 percent of patients with complex partial
seizures have major mental illness such as depression.
SYMPTOMS
PREICTAL SYMPTOMS. Preictal events (auras) in complex partial epilepsy include
autonomic sensations (e.g., fullness in the stomach, blushing, and changes in
respiration); cognitive sensations (e.g., déjá vu, jamais vu, forced thinking, dreamy
states); affective states (e.g., fear, panic, depression, elation); and, classically,
automatisms (e.g., lip smacking, rubbing, chewing).
ICTAL SYMPTOMS. Brief, disorganized, and uninhibited behavior characterizes the ictal
event. Although some defense attorneys may claim otherwise, rarely does a person
exhibit organized, directed violent behavior during an epileptic episode. The cognitive
symptoms include amnesia for the time during the seizure and a period of resolving
delirium after the seizure. A seizure focus can be found on an EEG in 25 to 50 percent of
all patients with complex partial epilepsy (Fig. 21.5-3). The use of sphenoidal or
anterior temporal electrodes and sleep-deprived EEGs may increase the likelihood of
finding an EEG abnormality. Multiple normal EEGs are often obtained for a patient
with complex partial epilepsy; therefore, normal EEGs cannot be used to exclude a

diagnosis of complex partial epilepsy. The use of long-term EEG recordings (usually 24
to 72 hours) can help clinicians detect a seizure focus in some patients. Most studies
show that the use of nasopharyngeal leads does not add much to the sensitivity of an
EEG, but they do add to the discomfort of the procedure for the patient.
FIGURE 21.5-3
An interictal encephalograph in a patient with complex partial seizures reveals frequent
left temporal spike discharges and rare, independent right temporal sharp-wave
activity. (From Cascino GD. Complex partial seizures: clinical features and differential
diagnosis. Psychiatr Clin North Am. 1992;15:377, with permission.)
INTERICTAL SYMPTOMS
Personality Disturbances.
 The most frequent psychiatric abnormalities reported in
patients with epilepsy are personality disorders, and they are especially likely to occur
in patients with epilepsy of temporal lobe origin. The most common features are
religiosity, a heightened experience of emotions—a quality usually called viscosity of
personality—and changes in sexual behavior. The syndrome in its complete form is
relatively rare even in those with complex partial seizures of temporal lobe origin.
Many patients are not affected by personality disturbances; others have a variety of
disturbances that differ strikingly from the classic syndrome.
A striking religiosity may be manifested not only by increased participation in overtly religious activities but also by
unusual concern for moral and ethical issues, preoccupation with right and wrong, and heightened interest in global and
philosophical concerns. The hyperreligious features can sometimes seem like the prodromal symptoms of schizophrenia
and can result in a diagnostic problem in an adolescent or a young adult.

The symptom of viscosity of personality is usually most noticeable in a patient’s conversation, which is likely to be
slow, serious, ponderous, pedantic, overly replete with nonessential details, and often circumstantial. The listener may
grow bored but be unable to find a courteous and successful way to disengage from the conversation. The speech
tendencies, often mirrored in the patient’s writing, result in a symptom known as hypergraphia, which some clinicians
consider virtually pathognomonic for complex partial epilepsy.
Changes in sexual behavior may be manifested by hypersexuality; deviations in sexual interest, such as fetishism and
transvestism; and, most commonly, hyposexuality. The hyposexuality is characterized both by a lack of interest in sexual
matters and by reduced sexual arousal. Some patients with the onset of complex partial epilepsy before puberty may fail
to reach a normal level of sexual interest after puberty, although this characteristic may not disturb the patient. For
patients with the onset of complex partial epilepsy after puberty, the change in sexual interest may be bothersome and
worrisome.
Psychotic Symptoms.
 Interictal psychotic states are more common than ictal psychoses.
Schizophrenia-like interictal episodes can occur in patients with epilepsy, particularly
those with temporal lobe origins. An estimated 10 percent of all patients with complex
partial epilepsy have psychotic symptoms. Risk factors for the symptoms include female
gender, left-handedness, the onset of seizures during puberty, and a left-sided lesion.
The onset of psychotic symptoms in epilepsy is variable. Classically, psychotic symptoms appear in patients who have
had epilepsy for a long time, and the onset of psychotic symptoms is preceded by the development of personality changes
related to the epileptic brain activity. The most characteristic symptoms of the psychoses are hallucinations and paranoid
delusions. Patients usually remain warm and appropriate in affect, in contrast to the abnormalities of affect commonly
seen in patients with schizophrenia. The thought disorder symptoms in patients with psychotic epilepsy are most
commonly those involving conceptualization and circumstantiality rather than the classic schizophrenic symptoms of
blocking and looseness.
Violence.
 Episodic violence has been a problem in some patients with epilepsy,
especially epilepsy of temporal and frontal lobe origin. Whether the violence is a
manifestation of the seizure itself or is of interictal psychopathological origin is
uncertain. Most evidence points to the extreme rarity of violence as an ictal
phenomenon. Only in rare cases should violence in the patient with epilepsy be
attributed to the seizure itself.
Mood Disorder Symptoms.
 Mood disorder symptoms, such as depression and mania, are
seen less often in epilepsy than are schizophrenia-like symptoms. The mood disorder
symptoms that do occur tend to be episodic and appear most often when the epileptic
foci affect the temporal lobe of the nondominant cerebral hemisphere. The importance
of mood disorder symptoms may be attested to by the increased incidence of attempted
suicide in people with epilepsy.
Diagnosis.
 A correct diagnosis of epilepsy can be particularly difficult when the
ictal and interictal symptoms of epilepsy are severe manifestations of psychiatric
symptoms in the absence of significant changes in consciousness and cognitive abilities.
Psychiatrists, therefore, must maintain a high level of suspicion during the evaluation of

a new patient and must consider the possibility of an epileptic disorder even in the
absence of the classic signs and symptoms. Another differential diagnosis to consider is
pseudoseizure, in which a patient has some conscious control over mimicking the
symptoms of a seizure (Table 21.5-2).
Table 21.5-2
Differentiating Features of Pseudoseizures and Epileptic Seizures
For patients who have previously received a diagnosis of epilepsy, the appearance of
new psychiatric symptoms should be considered as possibly representing an evolution in
their epileptic symptoms. The appearance of psychotic symptoms, mood disorder
symptoms, personality changes, or symptoms of anxiety (e.g., panic attacks) should
cause a clinician to evaluate the control of the patient’s epilepsy and to assess the
patient for the presence of an independent mental disorder. In such circumstances, the
clinician should evaluate the patient’s compliance with the anticonvulsant drug regimen
and should consider whether the psychiatric symptoms could be adverse effects from the
antiepileptic drugs themselves. When psychiatric symptoms appear in a patient who has
had epilepsy diagnosed or considered as a diagnosis in the past, the clinician should
obtain results of one or more EEG examinations.
In patients who have not previously received a diagnosis of epilepsy, four
characteristics should cause a clinician to be suspicious of the possibility: the abrupt
onset of psychosis in a person previously regarded as psychologically healthy, the
abrupt onset of delirium without a recognized cause, a history of similar episodes with
abrupt onset and spontaneous recovery, and a history of previous unexplained falling or
fainting spells.
Treatment.
 First-line drugs for generalized tonic-clonic seizures are valproate and

phenytoin (Dilantin). First-line drugs for partial seizures include carbamazepine,
oxcarbazepine (Trileptal), and phenytoin. Ethosuximide (Zarontin) and valproate are
first-line drugs for absence (petit mal) seizures. The drugs used for various types of
seizures are listed in Table 21.5-3. Carbamazepine and valproic acid may be helpful in
controlling the symptoms of irritability and outbursts of aggression, as are the typical
antipsychotic drugs. Psychotherapy, family counseling, and group therapy may be useful
in addressing the psychosocial issues associated with epilepsy. In addition, clinicians
should be aware that many antiepileptic drugs cause mild to moderate cognitive
impairment, and an adjustment of the dosage or a change in medications should be
considered if symptoms of cognitive impairment are a problem in a patient.
Table 21.5-3
Commonly Used Anticonvulsant Drugs
Brain Tumors
Brain tumors and cerebrovascular diseases can cause virtually any psychiatric symptom
or syndrome, but cerebrovascular diseases, by the nature of their onset and symptom
pattern, are rarely misdiagnosed as mental disorders. In general, tumors are associated
with fewer psychopathological signs and symptoms than are cerebrovascular diseases
affecting a similar volume of brain tissue. The two key approaches to the diagnosis of
either condition are a comprehensive clinical history and a complete neurological
examination. Performance of the appropriate brain imaging technique is usually the
final diagnostic procedure; the imaging should confirm the clinical diagnosis.
Clinical Features, Course, and Prognosis.
 Mental symptoms are experienced
at some time during the course of illness in approximately 50 percent of patients with
brain tumors. In approximately 80 percent of these patients with mental symptoms, the
tumors are located in frontal or limbic brain regions rather than in parietal or temporal
regions. Whereas meningiomas are likely to cause focal symptoms by compressing a
limited region of the cortex, gliomas are likely to cause diffuse symptoms. Delirium is
most often a component of rapidly growing, large, or metastatic tumors. If a patient’s

history and a physical examination reveal bowel or bladder incontinence, a frontal lobe
tumor should be suspected; if the history and examination reveal abnormalities in
memory and speech, a temporal lobe tumor should be suspected.
COGNITION. Impaired intellectual functioning often accompanies the presence of a brain
tumor, regardless of its type or location.
LANGUAGE SKILLS. Disorders of language function may be severe, particularly if tumor
growth is rapid. In fact, defects of language function often obscure all other mental
symptoms.
MEMORY. Loss of memory is a frequent symptom of brain tumors. Patients with brain
tumors exhibit Korsakoff’s syndrome and retain no memory of events that occurred since
the illness began. Events of the immediate past, even painful ones, are lost. Patients,
however, retain old memories and are unaware of their loss of recent memory.
PERCEPTION. Prominent perceptual defects are often associated with behavioral
disorders, especially because patients must integrate tactile, auditory, and visual
perceptions to function normally.
AWARENESS. Alterations of consciousness are common late symptoms of increased
intracranial pressure caused by a brain tumor. Tumors arising in the upper part of the
brainstem can produce a unique symptom called akinetic mutism, or vigilant coma. The
patient is immobile and mute yet alert.
Colloid Cysts.
 Although they are not brain tumors, colloid cysts located in the third
ventricle can exert physical pressure on structures within the diencephalon and produce
such mental symptoms as depression, emotional lability, psychotic symptoms, and
personality changes. The classic associated neurological symptoms are positiondependent intermittent headaches.
Head Trauma
Head trauma can result in an array of mental symptoms and lead to a diagnosis of
dementia due to head trauma or to mental disorder not otherwise specified due to a
general medical condition (e.g., postconcussional disorder). The postconcussive
syndrome remains controversial because it focuses on the wide range of psychiatric
symptoms, some serious, that can follow what seems to be minor head trauma.
Pathophysiology.
 Head trauma is a common clinical situation; an estimated 2
million incidents involve head trauma each year. Head trauma most commonly occurs in
people 15 to 25 years of age and has a male-to-female predominance of approximately
3 to 1. Gross estimates based on the severity of the head trauma suggest that virtually
all patients with serious head trauma, more than half of patients with moderate head
trauma, and about 10 percent of patients with mild head trauma have ongoing
neuropsychiatric sequelae resulting from the head trauma. Head trauma can be divided

grossly into penetrating head trauma (e.g., trauma produced by a bullet) and blunt
trauma, in which there is no physical penetration of the skull. Blunt trauma is far more
common than penetrating head trauma. Motor vehicle accidents account for more than
half of all the incidents of blunt CNS trauma; falls, violence, and sports-related head
trauma account for most of the remaining cases (Fig. 21.5-4).
FIGURE 21.5-4
Severe contusion of the frontal poles has resulted in their atrophy and distortion.
(Courtesy of Dr. H. M. Zimmerman.)
Whereas brain injury from penetrating wounds is usually localized to the areas
directly affected by the missile, brain injury from blunt trauma involves several
mechanisms. During the actual head trauma, the head usually moves back and forth
violently, so that the brain hits repeatedly against the skull as it and the skull are
mismatched in their rapid deceleration and acceleration. This crashing results in focal
contusions, and the stretching of the brain parenchyma produces diffuse axonal injury.
Later developing processes, such as edema and hemorrhaging, can result in further
damage to the brain.
Symptoms.
 The two major clusters of symptoms related to head trauma are those of
cognitive impairment and of behavioral sequelae. After a period of posttraumatic
amnesia, there is usually a 6- to 12-month period of recovery, after which the remaining

symptoms are likely to be permanent. The most common cognitive problems are
decreased speed in information processing, decreased attention, increased distractibility,
deficits in problem-solving and in the ability to sustain effort, and problems with
memory and learning new information. A variety of language disabilities can also
occur.
Behaviorally, the major symptoms involve depression, increased impulsivity,
increased aggression, and changes in personality. These symptoms can be further
exacerbated by the use of alcohol, which is often involved in the head trauma event
itself. A debate has ensued about how preexisting character and personality traits affect
the development of behavioral symptoms after head trauma. The critical studies needed
to answer the question definitively have not yet been done, but the weight of opinion is
leaning toward a biologically and neuroanatomically based association between the
head trauma and the behavioral sequelae.
Treatment.
 The treatment of the cognitive and behavioral disorders in patients with
head trauma is basically similar to the treatment approaches used in other patients with
these symptoms. One difference is that patients with head trauma may be particularly
susceptible to the side effects associated with psychotropic drugs; therefore, treatment
with these agents should be initiated in lower dosages than usual, and they should be
titrated upward more slowly than usual. Standard antidepressants can be used to treat
depression, and either anticonvulsants or antipsychotics can be used to treat aggression
and impulsivity. Other approaches to the symptoms include lithium, calcium channel
blockers, and β-adrenergic receptor antagonists.
Clinicians must support patients through individual or group psychotherapy and
should support the major caretakers through couples and family therapy. Patients with
minor and moderate head trauma often rejoin their families and restart their jobs;
therefore, all involved parties need help to adjust to any changes in the patient’s
personality and mental abilities.
Demyelinating Disorders
Multiple sclerosis (MS) is the major demyelinating disorder. Other demyelinating
disorders include amyotrophic lateral sclerosis (ALS), metachromatic leukodystrophy,
adrenoleukodystrophy, gangliosidoses, subacute sclerosing panencephalitis, and Kufs’
disease. All of these disorders can be associated with neurological, cognitive, and
behavioral symptoms.
Multiple Sclerosis.
 MS is characterized by multiple episodes of symptoms,
pathophysiologically related to multifocal lesions in the white matter of the CNS (Fig.
21.5-5). The cause remains unknown, but studies have focused on slow viral infections
and disturbances in the immune system. The estimated prevalence of MS in the Western
Hemisphere is 50 per 100,000 people. The disease is much more frequent in cold and
temperate climates than in the tropics and subtropics and more common in women than

in men; it is predominantly a disease of young adults. In most patients, the onset occurs
between the ages of 20 and 40 years.
FIGURE 21.5-5
Multiple sclerosis. Irregular, seemingly punched out zones of demyelination are evident
in this section through the level of the fourth ventricle. Myelin stain. 2.6×. (Courtesy of
Dr. H. M. Zimmerman.)
The neuropsychiatric symptoms of MS can be divided into cognitive and behavioral
types. Research reports have found that 30 to 50 percent of patients with MS have mild
cognitive impairment and that 20 to 30 percent of them have serious cognitive
impairments. Although evidence indicates that patients with MS experience a decline in
their general intelligence, memory is the most commonly affected cognitive function.
The severity of the memory impairment does not seem to be correlated with the severity
of the neurological symptoms or the duration of the illness.
The behavioral symptoms associated with MS are varied and can include euphoria,
depression, and personality changes. Psychosis is a rare complication. Approximately 25
percent of persons with MS exhibit a euphoric mood that is not hypomanic but
somewhat more cheerful than their situation warrants and not necessarily in character
with their disposition before the onset of MS. Only 10 percent of patients with MS have
a sustained and elevated mood, although it is still not truly hypomanic. Depression,
however, is common; it affects 25 to 50 percent of patients with MS and results in a
higher rate of suicide than is seen in the general population. Risk factors for suicide in
patients with MS are male sex, onset of MS before age 30 years, and a relatively recent
diagnosis of the disorder. Personality changes are also common in patients with MS;
they affect 20 to 40 percent of patients and are often characterized by increased
irritability or apathy.
Amyotrophic Lateral Sclerosis.
 ALS is a progressive, noninherited disease of
asymmetrical muscle atrophy. It begins in adult life and progresses over months or years
to involve all the striated muscles except the cardiac and ocular muscles. In addition to
muscle atrophy, patients have signs of pyramidal tract involvement. The illness is rare
and occurs in approximately 1.6 persons per 100,000 annually. A few patients have
concomitant dementia. The disease progresses rapidly, and death generally occurs

within 4 years of onset.
Infectious Diseases
Herpes Simplex Encephalitis.
 Herpes simplex encephalitis, the most common
type of focal encephalitis, most commonly affects the frontal and temporal lobes. The
symptoms often include anosmia, olfactory and gustatory hallucinations, and
personality changes and can also involve bizarre or psychotic behaviors. Complex
partial epilepsy may also develop in patients with herpes simplex encephalitis. Although
the mortality rate for the infection has decreased, many patients exhibit personality
changes, symptoms of memory loss, and psychotic symptoms.
Rabies Encephalitis.
 The incubation period for rabies ranges from 10 days to 1
year, after which symptoms of restlessness, overactivity, and agitation can develop.
Hydrophobia, present in up to 50 percent of patients, is characterized by an intense fear
of drinking water. The fear develops from the severe laryngeal and diaphragmatic
spasms that the patients experience when they drink water. When rabies encephalitis
develops, the disease is fatal within days or weeks.
Neurosyphilis.
 Neurosyphilis (also known as general paresis) appears 10 to 15
years after the primary Treponema infection. Since the advent of penicillin,
neurosyphilis has become a rare disorder, although AIDS is associated with reintroducing
neurosyphilis into medical practice in some urban settings. Neurosyphilis generally
affects the frontal lobes and results in personality changes, development of poor
judgment, irritability, and decreased care for self. Delusions of grandeur develop in 10
to 20 percent of affected patients. The disease progresses with the development of
dementia and tremor until patients are paretic. The neurological symptoms include
Argyll-Robertson pupils, which are small, irregular, and unequal and have light-near
reflex dissociation, tremor, dysarthria, and hyperreflexia. Cerebrospinal fluid (CSF)
examination shows lymphocytosis, increased protein, and a positive result on a
Venereal Disease Research Laboratory (VDRL) test.
Chronic Meningitis.
 Chronic meningitis is now seen more often than in the recent
past because of the immunocompromised condition of people with AIDS. The usual
causative agents are Mycobacterium tuberculosis, Cryptococcus spp., and Coccidioides spp.
The usual symptoms are headache, memory impairment, confusion, and fever.
Subacute Sclerosing Panencephalitis.
 Subacute sclerosing panencephalitis is a
disease of childhood and early adolescence, with a 3-to-1 male-to-female ratio. The onset
usually follows either an infection with measles or a vaccination for measles. The initial
symptoms may be behavioral change, temper tantrums, sleepiness, and hallucinations,
but the classic symptoms of myoclonus, ataxia, seizures, and intellectual deterioration
eventually develop. The disease progresses relentlessly to coma and death in 1 to 2

years.
Lyme Disease.
 Lyme disease is caused by infection with the spirochete Borrelia
burgdorferi transmitted through the bite of the deer tick (Ixodes scapularis), which feeds
on infected deer and mice. About 16,000 cases are reported annually in the United
States.
A characteristic bull’s-eye rash (Fig. 21.5-6) is found at the site of the tick bite
followed shortly thereafter by flulike symptoms. Impaired cognitive functioning and
mood changes are associated with the illness and may be the presenting complaint.
These include memory lapses, difficulty concentrating, irritability, and depression.
FIGURE 21.5-6
Erythema migrans (“bull’s-eye” rash) on the thigh. (From Barbour R. Lyme disease. In:
Hoeprich PD, Jordan MC, Ronald AR, eds. Infectious Diseases: A Treatise of Infectious
Processes. Philadelphia: JB Lippincott; 1994:1329, with permission.)
No clear-cut diagnostic test is available. About 50 percent of patients become
seropositive to B. burgdorferi. Prophylaxis vaccine is not always effective and is
controversial. Treatment consists of a 14- to 21-day course of doxycycline (Vibramycin),
which results in a 90 percent cure rate. Specific psychotropic drugs can be targeted to
treat the psychiatric sign or symptom (e.g., diazepam [Valium] for anxiety). Left
untreated, about 60 percent of persons develop a chronic condition. Such patients may

be given an erroneous diagnosis of a primary depression rather than one secondary to
the medical condition. Support groups for patients with chronic Lyme disease are
important. Group members provide each other with emotional support that helps
improve their quality of life.
Prion Disease.
 Prion disease is a group of related disorders caused by a
transmissible infectious protein known as a prion. Included in this group are CreutzfeldtJakob disease (CJD), Gerstmann-Straussler-Scheinker disorder (GSS), fatal familial
insomnia (FFI), and kuru. A variant of CJD (vCJD), also called “mad cow disease,”
appeared in 1995 in the United Kingdom and is attributed to the transmission of bovine
spongiform encephalopathy (BSE) from cattle to humans. Collectively, these disorders
are also known as subacute spongiform encephalopathy because of shared
neuropathological changes that consist of (1) spongiform vacuolization, (2) neuronal
loss, and (3) astrocyte proliferation in the cerebral cortex. Amyloid plaques may or may
not be present.
ETIOLOGY. Prions are transmissible agents but differ from viruses in that they lack
nucleic acid. Prions are mutated proteins generated from the human prion protein gene
(PrP), which is located on the short arm of chromosome 20. No direct link exists between
prion disease and Alzheimer’s disease, which has been traced to chromosome 21.
The PrP mutates into a disease-related isoform PrP-Super-C (PrPSc), which can
replicate and is infectious. The neuropathological changes that occur in prion disease
are presumed to be caused by direct neurotoxic effects of PrPSc.
The specific prion disease that develops depends on the mutation of PrP that occurs.
Mutations at PrP 178N/129V cause CJD, mutations at 178N/129M cause FFI, and
mutations at 102L/129M cause GSS and kuru. Other mutations of PrP have been
described, and research continues in this important area of genomic identification. Some
mutations are both fully penetrant and autosomal dominant and account for inherited
forms of prion disease. For example, both GSS and FFI are inherited disorders, and about
10 percent of cases of CJD are also inherited. Prenatal testing for the abnormal PrP
gene is available; whether or not such testing should be routinely done is open to
question at this time.
CREUTZFELDT-JAKOB DISEASE. First described in 1920, CJD is an invariably fatal, rapidly
progressive disorder that occurs mainly in middle-aged or older adults. It manifests
initially with fatigue, flulike symptoms, and cognitive impairment. As the disease
progresses, focal neurological findings such as aphasia and apraxia occur. Psychiatric
manifestations are protean and include emotional lability, anxiety, euphoria,
depression, delusions, hallucinations, or marked personality changes. The disease
progresses over months, leading to dementia, akinetic mutism, coma, and death.
The rates of CJD range from one to two cases per 1 million persons a year worldwide.
The infectious agent self-replicates and can be transmitted to humans by inoculation
with infected tissue and sometimes by ingestion of contaminated food. Iatrogenic

transmission has been reported via transplantation of contaminated cornea or dura
mater or to children via contaminated supplies of human growth hormone derived from
infected persons. Neurosurgical transmission has also been reported. Household contacts
are not at greater risk for developing the disease than the general population unless
there is direct inoculation.
Diagnosis requires pathological examination of the cortex, which reveals the classic
triad of spongiform vacuolation, loss of neurons, and astrocyte cell proliferation. The
cortex and basal ganglia are most affected. An immunoassay test for CJD in the CSF
shows promise in supporting the diagnosis; however, this needs to be tested more
extensively. Although not specific for CJD, EEG abnormalities are present in nearly all
patients, consisting of a slow and irregular background rhythm with periodic complex
discharges. CT and MRI studies may reveal cortical atrophy later in the course of
disease. SPECT and positron emission tomography (PET) reveal heterogeneously
decreased uptake throughout the cortex.
No known treatment exists for CJD. Death usually occurs within 6 months after
diagnosis.
VARIANT CJD. In 1995, a variant of CJD (vCJD) appeared in the United Kingdom. The
patients affected all died; they were young (younger than age 40 years), and none had
risk factors of CJD. At autopsy, prion disease was found. The disease was attributed to
the transmission in the United Kingdom of BSE between cattle and from cattle to
humans in the 1980s. BSE appears to have originated from sheep scrapie–contaminated
feed given to cattle. Scrapie is a spongiform encephalopathy found in sheep and goats
that has not been shown to cause human disease; however, it is transmissible to other
animal species.
The mean age of onset is 29 years, and about 150 people worldwide had been infected
as of 2006. Clinicians must be alert to the diagnosis in young people with behavioral
and psychiatric abnormalities in association with cerebellar signs such as ataxia or
myoclonus. The psychiatric presentation of vCJD is not specific. Most patients have
reported depression, withdrawal, anxiety, and sleep disturbance. Paranoid delusions
have occurred. Neuropathological changes are similar to those in vCJD, with the
addition of amyloid plaques.
Epidemiological data are still being gathered. The incubation period for vCJD and the
amount of infected meat product required to cause infection are unknown. One patient
was reported to have been a vegetarian for 5 years before his disease was diagnosed.
vCJD can be diagnosed antemortem by examining the tonsils with Western blot
immunostains to detect PrPSc in lymphoid tissue. Diagnosis relies on the development of
progressive neurodegenerative features in persons who have ingested contaminated
meat or brains. No cure exists, and death usually occurs within 2 to 3 years after
diagnosis. Prevention is dependent on careful monitoring of cattle for disease and
feeding them grain instead of meat byproducts.
KURU. Kuru is an epidemic prion disease found in New Guinea that is caused by
cannibalistic funeral rituals in which the brains of the deceased are eaten. Women are

more affected by the disorder than men, presumably because they participate in the
ceremony to a greater extent. Death usually occurs within 2 years after symptoms
develop. Neuropsychiatric signs and symptoms consist of ataxia, chorea, strabismus,
delirium, and dementia. Pathological changes are similar to those with other prion
disease: neuronal loss, spongiform lesions, and astrocytic proliferation. The cerebellum
is most affected. Iatrogenic transmission of kuru has occurred when cadaveric material
such as dura mater and corneas were transplanted into normal recipients. Since the
cessation of cannibalism in New Guinea, the incidence of the disease has decreased
drastically.
GERSTMANN-STRAUSSLER-SCHEINKER DISEASE. First described in 1928, GSS is a
neurodegenerative syndrome characterized by ataxia, chorea, and cognitive decline
leading to dementia. It is caused by a mutation in the PrP gene that is fully penetrant
and autosomal dominant; thus, the disease is inherited, and affected families have been
identified over several generations. Genetic testing can confirm the presence of the
abnormal genes before onset. Pathological changes characteristic of prion disease are
present: spongiform lesions, neuronal loss, and astrocyte proliferation. Amyloid plaques
have been found in the cerebellum. Onset of the disease occurs between 30 and 40 years
of age. The disease is fatal within 5 years of onset.
FATAL FAMILIAL INSOMNIA. FFI is an inherited prion disease that primarily affects the
thalamus. A syndrome of insomnia and autonomic nervous system dysfunction
consisting of fever, sweating, labile blood pressure, and tachycardia occurs that is
debilitating. Onset is in middle adulthood, and death usually occurs in 1 year. No
treatment currently exists.
FUTURE DIRECTIONS. Determining how prions mutate to produce disease phenotypes and
determining how they are transmitted between different mammalian species are major
areas of research. Public health measures to prevent transmission of animal disease to
humans are ongoing and must be relentless, especially because these disorders are
invariably fatal within a few years of onset. Developing genetic interventions that
prevent or repair damage to the normal prion gene offers the best hope of cure.
Psychiatrists are faced with having to manage cases of persons who actually have the
disease and those with hypochondriacal fears of having contracted the disease. In some
patients, such fears can reach delusional proportions. Treatment is symptomatic and
involves anxiolytics, antidepressants, and psychostimulants, depending on symptoms.
Supportive psychotherapy may be of use in early stages to help patients and family
cope with the illness.
Preventing unintentional human-to-human or animal-to-human transmission of prions
remains the best way to limit the scope of these diseases. Sporadic cases of CJD will still
appear, however, because of the rare spontaneous mutation of the normal prion protein
into the abnormal form. At present, little exists to offer patients with prion disease other
than supportive treatment and emotional support.

Immune Disorders
The major immune disorders in contemporary society is HIV and AIDS, but other
immune disorders such as lupus erythematosus and autoimmune disorders that affect
brain neurotransmitters (discussed below) can also present diagnostic and treatment
challenges to mental health clinicians.
HIV Infection and AIDS
HIV is a retrovirus related to the human T-cell leukemia viruses (HTLV) and to
retroviruses that infect animals, including nonhuman primates. At least two types of
HIV have been identified, HIV-1 and HIV-2. HIV-1 is the causative agent for most HIVrelated diseases; HIV-2, however seems to be causing an increasing number of infections
in Africa. Other types of HIV may exist, which are now classified as HIV-O. HIV is
present in blood; semen; cervical and vaginal secretions; and, to a lesser extent, in
saliva, tears, breast milk, and the CSF of those who are infected. HIV is most often
transmitted through sexual intercourse or the transfer of contaminated blood from one
person to another. Health providers should be aware of the guidelines for safe sexual
practices and should advise their patients to practice safe sex (Table 21.5-4). The
Centers for Disease Control and Prevention guidelines for the prevention of HIV from
infected to uninfected persons is listed in Table 21.5-5.
Table 21.5-5
Centers for Disease Control and Prevention Guidelines for the Prevention of
HIV Transmission from Infected to Uninfected Persons

Table 21.5-4
AIDS Safe-Sex Guidelines

After infection with HIV, AIDS is estimated to develop in 8 to 11 years, although this time is gradually increasing
because of early treatment. When a person is infected with HIV, the virus primarily targets T4 (helper) lymphocytes, socalled CD4+ lymphocytes, to which the virus binds because of a glycoprotein (gp120) on the viral surface has a high
affinity for the CD4 receptor on T4 lymphocytes. After binding, the virus can inject its ribonucleic acid (RNA) into the
infected lymphocyte, where the RNA is transcribed into deoxyribonucleic acid (DNA) by the action of reverse
transcriptase. The resultant DNA can then be incorporated ino the host cell’s genome and translated and eventually
transcribed when the lymphocyte is stimulated to divide. After viral proteins have been produced by lymphocytes, the
various components of the virus assemble, and new mature viruses bud off from the host cell.
Diagnosis
SERUM TESTING. Techniques are now widely available to detect the presence of anti-HIV
antibodies in human. The conventional test uses blood (time to result, 3 to 10 days) and
the rapid test uses an oral swab (time to result, 20 minutes). Both tests are 99.9 percent
sensitive and specific. Health care workers and their patients must understand that the
presence of HIV antibodies indicate infection, not immunity to infection. Those who test
positive have been exposed to the virus, have the virus within their bodies, have the
potential to transmit the virus to another person, and will almost certainly eventually
develop AIDS. Those who test negative have either not been exposed to the HIV virus
and are not infected or were exposed to the HIV virus but have not yet developed the
antibodies, which is a possibility if the exposure occurred less than 1 year before testing.
Seroconversion most commonly occurs 6 to 12 weeks after infection, although in rare

cases seroconversion can take 6 to 12 months.
COUNSELING. Although specific groups of persons are at high risk for contracting HIV
and should be tested, any person who wants to be tested should probably be tested. The
reason for requesting a test should be ascertained to detect unspoken concerns and
motivations that may merit psychotherapeutic intervention.
Past practices that may have put the testee at risk for HIV infection and safe sexual
practices should be discussed. During posttest counseling, counselors should explain that
a negative test finding implies that safe sexual behavior and the avoidance of shared
hypodermic needles are recommended for the person to remain free of HIV infection.
Those with positive results must receive counseling about safe practices and potential
treatment options. They may need additional psychotherapeutic interventions if anxiety
or depressive disorders develop after they discover that they are infected. A person may
react to a positive HIV test finding with a syndrome similar to posttraumatic stress
disorder. Adjustment disorder with anxiety or depressed mood may develop in as many
as 25 percent of those informed of a positive HIV test result.
CONFIDENTIALITY. No one should be given an HIV test without previous knowledge and
consent, although various jurisdictions and organizations, such as the military, now
require HIV testing for all inhabitants or members. The results of an HIV test can be
shared with other members of a medical team, although the information should be
provided to no one else except for special circumstances. The patient should be advised
against disclosing the result of HIV testing too readily to employers, friends, and family
members; the information could result in discrimination in employment, housing, and
insurance.
The major exception to restriction of disclosure is the need to notify potential and past sexual or IV substance use
partners. If a treating physician knows that a patient who is HIV infected is putting another person at risk of becoming
infected, the physician may try either to hospitalize the infected person involuntarily (to prevent danger to others) or to
notify the potential victim. Clinicians should be aware of the laws about such issues, which vary among the states. These
guidelines also apply to inpatient psychiatric wards when a patient with HIV infection is believed to be sexually active
with other patients.
Clinical Features
NON-NEUROLOGICAL FACTORS. About 30 percent of persons infected with HIV experience a
flulike syndrome 3 to 6 weeks after becoming infected; most never notice any symptoms
immediately or shortly after their infection. The flulike syndrome includes fever,
myalgia, headaches, fatigue, GI symptoms, and sometimes a rash. The syndrome may be
accompanied by splenomegaly and lymphadenopathy.
The most common infection in persons affected with HIV who have AIDS is
Pneumocystis carinii pneumonia, which is characterized by a chronic, nonproductive
cough, and dyspnea, sometimes sufficiently severe to result in hypoxemia and its
resultant cognitive effects. For psychiatrists, the importance of these non-neurological,

nonpsychiatric complications lies in their biological effects on patients’ brain function
(e.g., hypoxia in P. carinii pneumonia) and their psychological effects on patients’ moods
and anxiety states.
NEUROLOGICAL FACTORS. An extensive array of disease processes can affect the brain of a
patient infected with HIV (Table 21.5-6). The most important diseases for mental health
workers to be aware of are HIV mild neurocognitive disorder and HIV-associated dementia.
Table 21.5-6
Conditions Associated with Human Immunodeficiency Virus (HIV) Infection
PSYCHIATRIC SYNDROMES. HIV-associated dementia presents with the typical triad of
symptoms seen in other subcortical dementias—memory and psychomotor speed
impairments, depressive symptoms, and movement disorders. Patients may initially
notice slight problems with reading, comprehension, memory, and mathematical skills,
but these symptoms are subtle and may be overlooked or discounted as fatigue and
illness. The Modified HIV Dementia Scale is a useful bedside screen and can be

administered serially to document disease progression. The development of dementia in
HIV-infected patients is generally a poor prognostic sign, and 50 to 75 percent of
patients with dementia die within 6 months.
HIV-associated neurocognitive disorder (also known as HIV encephalopathy) is
characterized by impaired cognitive functioning and reduced mental activity that
interferes with work, domestic, and social functioning. No laboratory findings are
specific to the disorder, and it occurs independently of depression and anxiety.
Progression to HIV-associated dementia usually occurs but may be prevented by early
treatment.
Delirium can result from the same causes that lead to dementia in patients with HIV.
Clinicians have classified delirious states characterized by both increased and decreased
activity. Delirium in patients infected with HIV is probably underdiagnosed, but it
should always precipitate a medical workup of a patient infected with HIV to determine
whether a new CNS-related process has begun.
Patients with HIV infection may have any of the anxiety disorders, but generalized
anxiety disorder, posttraumatic stress disorder, and obsessive-compulsive disorder (OCD)
are particularly common.
Adjustment disorder with anxiety or depressed mood has been reported in 5 to 20
percent of HIV-infected patients. The incidence of adjustment disorder in HIV-infected
patients is higher than usual in some special populations, such as military recruits and
prison inmates.
Depression is a significant problem in HIV and AIDS. Approximately 4 to 40 percent
of HIV-infected patients meet the criteria for depressive disorders. Major depression is a
risk factor for HIV infection by virtue of its impact on behavior, intensification of
substance abuse, exacerbation of self-destructive behaviors, and promotion for poor
partner choice in relationships. The pre-HIV infection prevalence of depressive disorders
may be higher than usual in some groups who are at risk for contracting HIV.
Depression has been shown to hinder effective treatment in infected persons. Patients
with major depression are at increased risk for disease progression and death. HIV
increases the risk of developing major depression through a variety of mechanisms,
including direct injury to subcortical areas of the brain, chronic stress, worsening social
isolation, and intense demoralization. Depression is higher in women than in men.
Mania can occur at any stage of HIV infection for individuals with preexisting bipolar
disorder. AIDS mania is a type of mania that most commonly occurs in late-stage HIV
infections and is associated with cognitive impairment. AIDS mania has a somewhat
different clinical profile than bipolar mania. Patients tend to have cognitive slowing or
dementia, and irritability is more characteristic than euphoria. AIDS mania is usually
quite severe in its presentation and malignant in its course. It seems to be more chronic
than episodic, has infrequent spontaneous remissions, and usually relapses with
cessation of treatment. One clinically significant presentation is the delusional belief
that one has discovered the cure for HIV or has been cured, which may result in high-risk
behaviors and the spread of the HIV infection.
Substance abuse is a primary vector for the spread of HIV. This impact is directed not

only at those who use IV drugs and their sexual partners but also at those who are
disinhibited or cognitively impaired by intoxication and are driven by addiction to
impulsive behaviors and unsafe sexual practices. Ongoing substance abuse has grave
medical implications for HIV-infected patients. The accumulation of medical sequelae
from chronic substance abuse can accelerate the process of immunocompromise and
amplify the progressive burdens of the HIV infection itself. In addition to the direct
physical effects cause by drugs, active substance use is highly associated with both
nonadherence and reduced access to antiretroviral medication. Suicidal ideation and
suicide attempts may increase in patients with HIV infection and AIDS. The risk factors
for suicide among persons infected with HIV are having friends who died from AIDS,
recent notification of HIV seropositivity, relapses, difficult social issues relating to
homosexuality, inadequate social and financial support, and the presence of dementia
or delirium.
Psychotic symptoms are usually later-stage complications of HIV infection. They
require immediate medical and neurological evaluation and often require management
with antipsychotic medications.
The worried well are persons in high-risk groups who, although they tested negative
and are disease free, are anxious about contracting the virus. Some are reassured by
repeated negative test results, but others cannot be reassured. Their worry well status
can progress quickly to generalized anxiety disorder, panic attacks, OCD, and
hypochondriasis.
Treatment.
 Prevention is the primary approach to HIV infection. Primary
prevention involves protecting persons from getting the disease; secondary prevention
involves modification of the disease’s course. All persons with any risk of HIV infection
should be informed about safe-sex practices and about the necessity to avoid sharing
contaminated hypodermic needles. The assessment of patients infected with HIV should
include a complete sexual and substance-abuse history, a psychiatric history, and an
evaluation of the support systems available to them.
PHARMACOTHERAPY. A growing list of agents that act at different points in viral
replication has raised the hope that HIV might be permanently suppressed or actually
eradicated from the body. These agents are divided into five major drug classes. Reverse
transcriptase inhibitors (RTIs) interfere with the critical step during the HIV life cycle
known as reverse transcription. There are two types of RTIs: nucleoside/nucleotide RTIs
(NRTIs), which are faulty DNA building blocks, and non-nucleoside RTIs (NNRTIs),
which bind to RT, interfering with its ability to convert the HIV RNA into HIV DNA.
Protease inhibitors interfere with the protease enzyme that HIV uses to produce
infectious viral particles. Fusion or entry inhibitors interfere with the virus’ ability to
fuse with the cellular membrane, thereby blocking entry into the host cell. Integrase
inhibitors block integrase, the enzyme HIV uses to integrate genetic material of the virus
into its target host cell. Multidrug combination products combine drugs from more than
one class into a single product. The most common of this class of drugs is the highly

active antiretroviral therapy (HAART). Table 21.5-7 lists the available agents in each of
these categories.
Table 21.5-7
Antiretroviral Agents
The antiretroviral agents have many adverse effects. Of importance to psychiatrists is
that protease inhibitors can increase levels of certain psychotropic drugs such as
bupropion (Wellbutrin), meperidine (Demerol), various benzodiazepines, and selective
serotonin reuptake inhibitors (SSRIs). Caution must be taken in prescribing psychotropic
drugs to persons taking protease inhibitors.

PSYCHOTHERAPY. Major psychodynamic themes for patients infected with HIV involved
self-blame, self-esteem, and issues regarding death. The entire range of
psychotherapeutic approaches may be appropriate for patients with HIV-related
disorders. Both individual and group therapy can be effective. Individual therapy may
be either short term or long term and may be supportive, cognitive, behavioral, or
psychodynamic. Group therapy techniques can range from psychodynamic to completely
supportive in nature. Direct counseling regarding substance use and its potential
adverse effects on health of the patient who is HIV infected is indicated. Specific
treatments for particular substance-related disorders should be initiated if necessary for
the total well-being of the patient.
Systemic Lupus Erythematosus.
 Systemic lupus erythematosus (SLE) is an
autoimmune disease that involves inflammation of multiple organ systems. The
officially accepted diagnosis of SLE requires a patient to have four of 11 criteria that
have been defined by the American Rheumatism Association. Between 5 and 50 percent
of patients with SLE have mental symptoms at the initial presentation, and
approximately 50 percent eventually show neuropsychiatric manifestations. The major
symptoms are depression, insomnia, emotional lability, nervousness, and confusion.
Treatment with steroids commonly induces further psychiatric complications, including
mania and psychosis.
Autoimmune Disorders Affecting Brain Neurotransmitters
A group of autoimmune receptor-seeking disorders have been identified that cause an
encephalitis that mimics schizophrenia. Among those is anti-NMDA(N-methyl Daspartate)-receptor encephalitis that causes dissociative symptoms, amnesia and vivid
hallucinations. The disorder occurs mostly in women and was described in a memoir
entitled Brain on Fire. There is no treatment although intravenous immunogloblins have
proved useful. Recovery does occur but some patients might require prolonged intensive
care.
Endocrine Disorders
Thyroid Disorders.
 Hyperthyroidism is characterized by confusion; anxiety; and
an agitated, depressive syndrome. Patients may also complain of being easily fatigued
and of feeling generally weak. Insomnia, weight loss despite increased appetite,
tremulousness, palpitations, and increased perspiration are also common symptoms.
Serious psychiatric symptoms include impairments in memory, orientation, and
judgment; manic excitement; delusions; and hallucinations.
In 1949, Irvin Asher named hypothyroidism “myxedema madness.” In its most severe
form, hypothyroidism is characterized by paranoia, depression, hypomania, and
hallucinations. Slowed thinking and delirium can also be symptoms. The physical
symptoms include weight gain, a deep voice, thin and dry hair, loss of the lateral

eyebrow, facial puffiness, cold intolerance, and impaired hearing. Approximately 10
percent of all patients have residual neuropsychiatric symptoms after hormone
replacement therapy.
Parathyroid Disorders.
 Dysfunction of the parathyroid gland results in the
abnormal regulation of calcium metabolism. Excessive secretion of parathyroid hormone
causes hypercalcemia, which can result in delirium, personality changes, and apathy in
50 to 60 percent of patients and cognitive impairments in approximately 25 percent of
patients. Neuromuscular excitability, which depends on proper calcium ion
concentration, is reduced, and muscle weakness may appear.
Hypocalcemia can occur with hypoparathyroid disorders and can result in
neuropsychiatric symptoms of delirium and personality changes. If the calcium level
decreases gradually, clinicians may see the psychiatric symptoms without the
characteristic tetany of hypocalcemia. Other symptoms of hypocalcemia are cataract
formation, seizures, extrapyramidal symptoms, and increased intracranial pressure.
Adrenal Disorders.
 Adrenal disorders disturb the normal secretion of hormones
from the adrenal cortex and produce significant neurological and psychological changes.
Patients with chronic adrenocortical insufficiency (Addison’s disease), which is most
frequently the result of adrenocortical atrophy or granulomatous invasion caused by
tuberculous or fungal infection, exhibit mild mental symptoms, such as apathy, easy
fatigability, irritability, and depression. Occasionally, confusion or psychotic reactions
develop. Cortisone or one of its synthetic derivatives is effective in correcting such
abnormalities.
Excessive quantities of cortisol produced endogenously by an adrenocortical tumor or
hyperplasia (Cushing’s syndrome) lead to a secondary mood disorder, a syndrome of
agitated depression, and often suicide. Decreased concentration and memory deficits
may also be present. Psychotic reactions, with schizophrenia-like symptoms, are seen in
a few patients. The administration of high doses of exogenous corticosteroids typically
leads to a secondary mood disorder similar to mania. Severe depression can follow the
termination of steroid therapy.
Pituitary Disorders.
 Patients with total pituitary failure can exhibit psychiatric
symptoms, particularly postpartum women who have hemorrhaged into the pituitary, a
condition known as Sheehan’s syndrome. Patients have a combination of symptoms,
especially of thyroid and adrenal disorders, and can show virtually any psychiatric
symptom.
Metabolic Disorders
A common cause of organic brain dysfunction, metabolic encephalopathy can produce alterations in mental processes,
behavior, and neurological functions. The diagnosis should be considered whenever recent and rapid changes in behavior,
thinking, and consciousness have occurred. The earliest signals are likely to be impairment of memory, particularly recent

memory, and impairment of orientation. Some patients become agitated, anxious, and hyperactive; others become quiet,
withdrawn, and inactive. As metabolic encephalopathies progress, confusion or delirium gives way to decreased
responsiveness; stupor; and, eventually, death.
Hepatic Encephalopathy.
 Severe hepatic failure can result in hepatic
encephalopathy, characterized by asterixis, hyperventilation, EEG abnormalities, and
alterations in consciousness. The alterations in consciousness can range from apathy to
drowsiness to coma. Associated psychiatric symptoms are changes in memory, general
intellectual skills, and personality.
Uremic Encephalopathy.
 Renal failure is associated with alterations in memory,
orientation, and consciousness. Restlessness, crawling sensations on the limbs, muscle
twitching, and persistent hiccups are associated symptoms. In young people with brief
episodes of uremia, the neuropsychiatric symptoms tend to be reversible; in elderly
people with long episodes of uremia, the neuropsychiatric symptoms can be irreversible.
Hypoglycemic Encephalopathy.
 Hypoglycemic encephalopathy can be caused
either by excessive endogenous production of insulin or by excessive exogenous insulin
administration. The premonitory symptoms, which do not occur in every patient,
include nausea, sweating, tachycardia, and feelings of hunger, apprehension, and
restlessness. As the disorder progresses, disorientation, confusion, and hallucinations, as
well as other neurological and medical symptoms, can develop. Stupor and coma can
occur, and a residual and persistent dementia can sometimes be a serious
neuropsychiatric sequela of the disorder.
Diabetic Ketoacidosis.
 Diabetic ketoacidosis begins with feelings of weakness,
easy fatigability, and listlessness and increasing polyuria and polydipsia. Headache and
sometimes nausea and vomiting appear. Patients with diabetes mellitus have an
increased likelihood of chronic dementia with general arteriosclerosis.
Acute Intermittent Porphyria.
 The porphyrias are disorders of heme
biosynthesis that result in excessive accumulation of porphyrins. The triad of symptoms
is acute, colicky abdominal pain; motor polyneuropathy; and psychosis. Acute
intermittent porphyria is an autosomal dominant disorder that affects more women than
men and has its onset between ages 20 and 50 years. The psychiatric symptoms include
anxiety, insomnia, lability of mood, depression, and psychosis. Some studies have found
that between 0.2 and 0.5 percent of chronic psychiatric patients may have undiagnosed
porphyrias. Barbiturates precipitate or aggravate the attacks of acute porphyria, and
the use of barbiturates for any reason is absolutely contraindicated in a person with
acute intermittent porphyria and in anyone who has a relative with the disease.
Nutritional Disorders

Niacin Deficiency.
 Dietary insufficiency of niacin (nicotinic acid) and its
precursor tryptophan is associated with pellagra, a globally occurring nutritional
deficiency disease seen in association with alcohol abuse, vegetarian diets, and extreme
poverty and starvation. The neuropsychiatric symptoms of pellagra include apathy,
irritability, insomnia, depression, and delirium; the medical symptoms include
dermatitis, peripheral neuropathies, and diarrhea. The course of pellagra has
traditionally been described as “five Ds”: dermatitis, diarrhea, delirium, dementia, and
death. The response to treatment with nicotinic acid is rapid, but dementia from
prolonged illness may improve only slowly and incompletely.
Thiamine Deficiency.
 Thiamine (vitamin B1) deficiency leads to beriberi,
characterized chiefly by cardiovascular and neurological changes, and to WernickeKorsakoff syndrome, which is most often associated with chronic alcohol abuse. Beriberi
occurs primarily in Asia and in areas of famine and poverty. The psychiatric symptoms
include apathy, depression, irritability, nervousness, and poor concentration; severe
memory disorders can develop with prolonged deficiencies.
Cobalamin Deficiency.
 Deficiencies in cobalamin (vitamin B12) arise because of
the failure of the gastric mucosal cells to secrete a specific substance, intrinsic factor,
required for the normal absorption of vitamin B12 in the ileum. The deficiency state is
characterized by the development of a chronic macrocytic megaloblastic anemia
(pernicious anemia) and by neurological manifestations resulting from degenerative
changes in the peripheral nerves, the spinal cord, and the brain. Neurological changes
are seen in approximately 80 percent of all patients. These changes are commonly
associated with megaloblastic anemia, but they occasionally precede the onset of
hematological abnormalities.
Mental changes, such as apathy, depression, irritability, and moodiness, are common. In a few patients, encephalopathy
and its associated delirium, delusions, hallucinations, dementia, and sometimes paranoid features are prominent and are
sometimes called megaloblastic madness. The neurological manifestations of vitamin B12 deficiency can be rapidly and
completely arrested by early and continued administration of parenteral vitamin therapy.
Toxins
Environmental toxins are becoming an increasingly serious threat to physical and mental health in contemporary society.
Mercury.
 Mercury poisoning can be caused by either inorganic or organic mercury.
Inorganic mercury poisoning results in the “mad hatter” syndrome (previously seen in
workers in the hat industry who softened felt by putting it in their mouths), with
depression, irritability, and psychosis. Associated neurological symptoms are headache,
tremor, and weakness. Organic mercury poisoning can be caused by contaminated fish
or grain and can result in depression, irritability, and cognitive impairment. Associated
symptoms are sensory neuropathies, cerebellar ataxia, dysarthria, paresthesias, and

visual field defects. Mercury poisoning in pregnant women causes abnormal fetal
development. No specific therapy is available, although chelation therapy with
dimercaprol has been used in acute poisoning.
Lead.
 Lead poisoning occurs when the amount of lead ingested exceeds the body’s
ability to eliminate it. It takes several months for toxic symptoms to appear.
The signs and symptoms of lead poisoning depend on the level of lead in the blood. When lead reaches levels above 200
mg/L, symptoms of severe lead encephalopathy occur, with dizziness, clumsiness, ataxia, irritability, restlessness,
headache, and insomnia. Later, an excited delirium occurs, with associated vomiting and visual disturbances, and
progresses to convulsions, lethargy, and coma.
Treatment of lead encephalopathy should be instituted as rapidly as possible, even without laboratory confirmation,
because of the high mortality rate. The treatment of choice to facilitate lead excretion is intravenous administration of
calcium disodium edetate (calcium disodium versenate) daily for 5 days.
Manganese.
 Early manganese poisoning (sometimes called manganese madness)
causes symptoms of headache, irritability, joint pains, and somnolence. An eventual
picture appears of emotional lability, pathological laughter, nightmares, hallucinations,
and compulsive and impulsive acts associated with periods of confusion and
aggressiveness. Lesions involving the basal ganglia and pyramidal system result in gait
impairment, rigidity, monotonous or whispering speech, tremors of the extremities and
tongue, masked facies (manganese mask), micrographia, dystonia, dysarthria, and loss
of equilibrium. The psychological effects tend to clear 3 or 4 months after the patient’s
removal from the site of exposure, but neurological symptoms tend to remain stationary
or to progress. No specific treatment exists for manganese poisoning, other than
removal from the source of poisoning. The disorder is found in persons working in
refining ore, brick workers, and those making steel casings.
Arsenic.
 Chronic arsenic poisoning most commonly results from prolonged exposure
to herbicides containing arsenic or from drinking water contaminated with arsenic.
Arsenic is also used in the manufacture of silicon-based computer chips. Early signs of
toxicity are skin pigmentation, GI complaints, renal and hepatic dysfunction, hair loss,
and a characteristic garlic odor to the breath. Encephalopathy eventually occurs, with
generalized sensory and motor loss. Chelation therapy with dimercaprol has been used
successfully to treat arsenic poisoning.
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Clare L, Whitaker CJ, Nelis SM. Self-concept in early stage dementia: Profile, course, correlates, predictors and implications
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# 06 - 21.6 Mild Cognitive Impairment

# 21.6 Mild Cognitive Impairment

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 21.6 Mild Cognitive Impairment
The past decade has seen the emergence of a new concept, mild cognitive impairment
(MCI), which is defined as the presence of mild cognitive decline not warranting the
diagnosis of dementia but with preserved basic activities of daily living.
In the DSM-5, MCI is classified as mild neurocognitive disorder due to multiple etiologies
or unspecified neurocognitive disorder. It will most likely receive more attention in future
revisions of the DSM.
DEFINITION

Although the term mild cognitive impairment has been in use for more than 25 years, it
was suggested as a diagnostic category designed to fill the gap between cognitive
changes associated with aging and cognitive impairment suggestive of dementia. The
criteria proposed by the Mayo Clinic Alzheimer’s Disease Research Center (MCADRC)
are (1) memory complaint, preferably qualified by an informant; (2) objective memory
impairment for age and education; (3) preserved general cognitive function; (4) intact
activities of daily living; and (5) not demented (Table 21.6-1). However, at this time
there are no international diagnostic criteria for MCI.
Table 21.6-1
Mild Cognitive Impairment Original Criteria
Historical Perspective
The imprecise border between normal aging-related cognitive decline and dementia-related cognitive impairment has been
described for several decades. Thus, in 1962, Kral introduced the terms benign senescent forgetfulness (forgetfulness for less
important facts and awareness of problems) and malignant senescent forgetfulness (memory problems for recent events and
lack of awareness). In 1986, the National Institutes of Mental Health (NIMH) recommended the term age associated
memory impairment for age-related normal memory changes. In 1994, the International Psychogeriatrics Association
presented the concept of age-associated cognitive decline, which described cognitive deficits including but not limited to
memory impairment in the absence of dementia or other affecting cognitive conditions. Cognitive impairment no dementia
was introduced in 1997 by the Canadian Study of Health and Aging to describe the presence of nondemented cognitive
impairment regardless of the underlying process (neurological, psychiatric, medical). Several other classifications,
including age-consistent memory impairment and late life forgetfulness, are defined on the bases of performance on various
cognitive tests.
The exact place of MCI in the psychiatric nosology will be challenging. Based on the
current definition of MCI, functional impairment is an exclusion criterion for MCI, but
the same “functional impairment” is one of the standard criteria for defining psychiatric
disorders. Further developments in finding biological markers for MCI will probably
contribute to a more solid conceptualization and, hopefully, treatment of patients with
prodromal dementia (Table 21.6-2).
Table 21.6-2
Terms Related to Mild Cognitive Impairment

EPIDEMIOLOGY AND ETIOLOGY OF MCI
The recognition that Alzheimer’s disease pathology may exist in the brain long before
the presence of clinical symptoms led to the focus on preclinical stages, with the purpose
of characterizing initial impairments that are associated with an increased risk of
progression to Alzheimer’s disease.
The clinical expression of MCI can be viewed as a result of the interaction among
several risk factors and several protective factors. The most significant risk factors are
related to the different types of neurodegeneration witnessed in dementias. These are
clinically expressed in different subtypes of MCI, especially those associated with
amnesia. Other risk factors include the APOE4 allele status and cerebrovascular events
in the form of either cerebrovascular accident or lacunar disease. The role of chronic
exposure to high levels of cortisol, as seen in late life depression, is also hypothesized to
increase the risk for cognitive impairment through hippocampal volume reduction. The
notion of “brain reserve” suggests that effects of brain size and neuron density may be
protective against dementia despite the presence of neurodegeneration (a larger number
of neurons and a bigger brain volume would protect against clinical manifestations of
Alzheimer’s disease despite the presence of neurodegeneration) (Fig. 21.6-1).

FIGURE 21.6-1
Outcome of clinical phenotypes of mild cognitive impairment (MCI) according to
presumed etiology. AD, Alzheimer’s disease; Depr, depression; DLB, dementia with Lewy
bodies; FRD, frontotemporal dementia; VaD, vascular dementia. (Adapted with
permission from Petersen RC, ed. Mild Cognitive Impairment: Aging to Alzheimer’s Disease.
New York: Oxford University Press; 2003.)
CLINICAL PRESENTATION
The clinical picture of MCI is a function of the criteria used to define it. Memory
impairment is necessary but has been difficult to quantify. One measure has been
objective loss of memory or other cognitive domain that is more than 1.5 standard
deviations below the mean for individuals of similar age and education. Some have
suggested subjective complaints of memory loss be used as a marker, but this runs the
risk of many false-positive diagnoses.
Assessment
Neuropsychological Assessment.
 Most experts agree that earlier deficits are
noted in episodic (vs. semantic) memory. There is no consensus among experts with
regard to which memory tests and which cutoffs to use. There is a lack of norms, test
scores do not have normal distributions, and test performance is influenced by multiple
demographic characteristics. Several experts have proposed that a scale such as the
delayed recall task from the Consortium to Establish a Registry for Alzheimer’s Disease
might be useful in detecting Alzheimer’s disease in the earliest stages. Brief mental status
instruments (e.g., the Mini-Mental State Examination) are relatively insensitive for the
detection of memory problems in MCI.
Biomarkers.
 Several markers of progression from MCI to Alzheimer’s disease have
been studies in the past decade. Among these, apolipoprotein E4 (ApoE4) allele carrier
status has been one of the most prominent variables. For the amnestic MCI, ApoE4 has
been shown to be a risk factor for a more rapid progression to Alzheimer’s disease.
Several CSF markers have also been identified as possible predictors of disease
progression: Pathological low concentrations of Aβ42 (the 42 amino acid form of βamyloid) as well as pathological high concentrations of total tau (t-tau) and phospho
tau (p-tau) may differentiate early Alzheimer’s disease from normal aging. Locating
alterations in the expression of proteins involved in the pathogenetic pathways of
Alzheimer’s disease (proteomic approach) is another approach used to help early
detection of Alzheimer’s disease. Several proteins (cystatin C, β-2 microglobulin, and
BEGF polypeptides) have been detected through new techniques, and currently there are
a number of proteins from both CSF and blood that are implicated in Alzheimer’s disease
pathology.

Genetics.
 Because MCI is regarded as the prodromal stage for several disorders
(Alzheimer’s disease, frontotemporal or vascular dementia), different genes are
probably related to MCI. Four genes have been described in relationship with
Alzheimer’s disease: the amyloid precursor protein (APP) gene, presenilin-1 (PSEN1),
presenilin-2 (PSEN2), and the apolipoprotein E (APOE) gene. Because the first three
genes are involved in rare autosomal dominant forms of Alzheimer’s disease, screening
for each of these mutations will have very limited value for the diagnosis of MCI in the
general population. The APOE gene, a common genetic risk factor for early as well as
for late-onset Alzheimer’s disease, has been studied more thoroughly in relationship to
MCI, but the results have been inconsistent. Because the etiology of MCI is
heterogenous, it is likely that a very large number of different genes underlie the
pathology of MCI. Most of these genes are yet to be discovered.
Neuroimaging.
 Advances in neuroimaging studies aim to develop measures
allowing the differentiation between MCI and healthy aging as well as within MCI
among subjects who will convert to Alzheimer’s disease or will remain stable over time.
Structural studies of volumetric MCI showed early changes in the medial temporal
structures, including neuronal atrophy, decreased synaptic density, and overall neuronal
loss. Atrophy of the hippocampal volume and entorhinal cortex has been described in
MCI. Atrophy of the hippocampal formation was also reported to predict the rate of
progression from MCI to Alzheimer’s disease. Three-dimensional modeling techniques
have localized shape alteration and specific regions of atrophy within the hippocampus.
Other methods such as tensor-based morphometry allow tracking brain changes in
detail, quantifying tissue growth or atrophy throughout the brain and indicating the
local rate at which tissue is being lost. Other innovations in neuroimaging include MR
relaxometry, imaging of iron deposition, diffusion tensor imaging, and high-field MRI
scanning.
Perhaps the most promising development has been the advent of PET tracer
compounds that visualize amyloid plaques and neurofibrillary tangles. These new
compounds—Pittsburgh Compound B (carbon-11-PIB) and fluorine-18-FDDNP—track
pathology changes in the preclinical stages of Alzheimer’s disease. These specific tracers
allow investigators to visualize the pathological process and are also used to monitor
progression from MCI to Alzheimer’s disease. However, the burden of β-amyloid plaques
does not always correlate with the clinical stages because some MCI subjects can present
with minimal burden similar to healthy control participants, but others have amyloid
burden comparable to Alzheimer’s disease participants. A single biomarker will probably
be insufficient to identify incipient Alzheimer’s disease. Thus, the combination of several
markers further increases the accuracy of the prediction and will probably become the
norm as described by recent studies (combination of decreased parietal rCBF and CSF
biomarkers as Aβ42, t-tau, and p-tau) (Fig. 21.6-2).

FIGURE 21.6-2
Positron emission tomography images obtained with the amyloid-imaging agent
Pittsburgh Compound-B ([carbon-11]-PIB) in a normal individual with mild cognitive
impairment (MCI; center images) and a patient with mild Alzheimer’s disease (AD) (far
right).
Some MCI patients have control-like levels of amyloid, some have Alzheimer’s disease–
like levels of amyloid, and some have intermediate levels. (Courtesy of William E.
Klunk, M.D., University of Pittsburgh, Department of Psychiatry, Pittsburgh, PA. All
rights retained.)
Diagnostic Differential
The Cognitive Continuum.
 The cognitive continuum describes the subtle
pathway from age-related cognitive decline to MCI to dementia. Per this model, there is
an overlap at both ends of MCI, which indicates that it can be quite challenging to
identify the transition points (Figure 21.6-3). In practice, differentiating MCI from agerelated cognitive decline resides mainly on neuropsychological testing, showing a
cognitive decline more severe for age and less education. The main differentiation
between MCI and Alzheimer’s disease resides in the lack of functional impairment in
MCI.
FIGURE 21.6-3
Cognitive continuum showing the overlap in the boundary between normal aging and
the mild cognitive impairment and Alzheimer’s disease. (Reprinted with permission from
Petersen RC, ed. Mild Cognitive Impairment: Aging to Alzheimer’s Disease. New York:

Oxford University Press, 2003.)
COURSE AND PROGNOSIS
The typical rate at which MCI patients progress to Alzheimer’s disease is 10 to 15
percent per year and is associated with progressive loss of function. However, several
studies have indicated that the diagnosis is not stable in both directions; patients can
either convert to Alzheimer’s disease or revert back to normal. This variability in course
is related to the heterogeneous source of the subjects (clinical vs. community) as well as
to the heterogeneous definition criteria used by different studies. Amnestic MCI has been
associated with increased morbidity compared with reference subjects.
TREATMENT
There are no FDA-approved treatments for MCI at this time. MCI treatment involves
adequate screening and diagnosis. Ideally, MCI treatment would also include
improvement of memory loss together with prevention of further cognitive decline to
dementia. Cognitive training programs have been reported as mildly beneficial for
compensating memory difficulties in MCI. Controlling for vascular risk factors (high
blood pressure, hypercholesterolemia, diabetes mellitus) may be a benefit preventive
method for those MCI cases underlying vascular pathology. Currently, sensitive tools
(imaging techniques or biomarkers) are not available for MCI screening in the general
population.
In primary care setting, clinicians should maintain a high suspicion for subjective
cognitive complaints and should corroborate these complaints with collateral
information whenever possible. Also, identifying reversible causes of cognitive
impairment (hypothyroidism, vitamin B12 deficiency, medication-induced cognitive
impairment, depression) can further benefit some of the prodromal dementia MCI cases.
Currently, there is no evidence for long-term efficacy of pharmacotherapies in
reversing MCI. Several epidemiological studies indicated a reduced risk of dementia in
persons taking antihypertensive medications, cholesterol-lowering drugs, antioxidants,
and anti-inflammatory and estrogen therapy, but no randomized controlled trials verify
these data. With regard to cognitive enhancers, as of 2007, there have been seven trials
designed for amnestic MCI, with ambiguous results (Table 21.6-3). Most of these studies
were confronted with several problems, including (1) obtaining homogeneous samples
and identifying potential beneficiaries of treatment; (2) treating a wider population,
which led to large percentages of negative responses and problematic side effects; and
(3) translation of the MCI construct into multiple cultures and languages and using
Alzheimer’s disease diagnosis as the primary outcome, given the variability of this
diagnosis in different countries.
Table 21.6-3
Treatment Trials for Mild Cognitive Impairment

Advances in MCI detection will be paramount for early detection and treatment of
patients with Alzheimer’s disease; experts agree that disease-modifying treatments for
Alzheimer’s disease will focus on cognitively intact individuals at increased risk. The
field of identifying sensitive and specific biomarkers (biological and neuroimaging
markers) will probably witness exponential development in the coming years.
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