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Clinical features and diagnosis of cognitive impairment and delirium in patients with cancer

Authors: Jacynthe Rivest, MD, Jon Levenson, MD

Section Editors: Jonathan M Silver, MD, Susan D Block, MD
Deputy Editor: David Solomon, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2018. | This topic last updated: Apr 20, 2018.

INTRODUCTION — Cognitive impairment and delirium are common in patients with cancer [1]. Delirium is
distressing for patients and families, can interfere with recognition and management of symptoms such as
pain, and is associated with increased mortality.

This topic reviews the clinical features of cognitive impairment and delirium in patients diagnosed with and
treated for cancer, and also reviews the diagnosis of delirium. Other topics discuss cognitive function after
cancer treatment, the clinical features and diagnosis of other psychiatric disorders in cancer patients, the
clinical features and diagnosis of delirium in palliative care, and the management of delirium in cancer
patients.

● (See "Cognitive function after cancer and cancer treatment".)

● (See "Clinical features and diagnosis of psychiatric disorders in patients with cancer: Overview".)

● (See "Approach to symptom assessment in palliative care", section on 'Delirium'.)

● (See "Management of psychiatric disorders in patients with cancer", section on 'Delirium'.)

COGNITIVE IMPAIRMENT — Patients with cancer, including cancer located outside of the central nervous
system, often manifest cognitive impairment, based upon studies that compared cancer patients prior to
treatment with healthy controls [2,3]. Although the prevalence of cognitive impairment varies due to
differences in study populations and assessments [2,4], reviews estimate that impairment after diagnosis of
cancer but prior to treatment occurs in 20 to 30 percent of patients [2,3].

Cognitive dysfunction can occur in several domains, including [2,3]:

● Attention

● Concentration

● Executive function (eg, planning, problem solving, and response inhibition)

● Information processing speed

● Memory

However, the magnitude of the impairment is typically modest [2,4,5].

In addition, cancer treatments are associated with neuropsychological deficits in up to 75 percent of patients
[2,3]. As an example, a meta-analysis of five cross-sectional studies examined cognition in patients with
breast cancer who were receiving or had received adjuvant chemotherapy (n = 208), as well as controls (eg,
breast cancer patients who did not receive adjuvant chemotherapy; n = 122) [6]. Executive functioning,
language, memory, and spatial ability were each worse in patients treated with chemotherapy than controls,
and the difference was small to moderate. Although many studies have focused upon chemotherapy
(“chemobrain”), patients in these studies often received other treatments that can affect cognition, such as
hormonal therapy, as well as radiation therapy and surgery involving the use of general anesthesia.

There are no established risk factors for cognitive impairment in patients with cancer, but increased age and
decreased baseline cognitive reserve (capacity) may increase the risk [2,3].

Cognitive deficits related to cancer chemotherapy can persist after treatment is finished. (See "Cognitive
function after cancer and cancer treatment".)

In addition to studies that involved the use of clinician administered tests of cognition, self-reported cognitive
impairment is greater in patients with cancer than the general public and may affect patient functioning
(professional or personal) and quality of life. Patient self-reports may provide information about subtle
cognitive changes that are not detected by standard neuropsychological tests, but self-reports are generally
nonspecific and influenced by beliefs and stress [3]. A nationally representative survey identified individuals
with a history of cancer (n >1300) and individuals with no history of cancer; after controlling for potential
confounding factors (eg, age, education, and self-rated general health), the analyses found that self-rated
memory problems were present in more individuals with a history of cancer than controls (14 versus 8
percent) [7].

The neurobiologic mechanisms by which cancer and cancer treatment impact cognitive function have not
been elucidated, but both structural and functional central nervous system changes have been correlated with
cognitive decline contribute. It is likely that many mechanisms contribute and that the observed cognitive
dysfunction in some patients reflects an interaction between multiple factors, including baseline lower
cognitive reserve. (See "Cognitive function after cancer and cancer treatment", section on 'Neurobiologic
basis'.)

Clinicians who want to screen patients with cancer for cognitive impairment can use either the Mini Mental
State Examination or the Montreal Cognitive Assessment. These tests should be interpreted using age- and
education-based normative values; the Montreal Cognitive Assessment in particular is prone to yielding false
positives. A study of patients with brain tumors (n = 58) found that sensitivity was superior with the Montreal
Cognitive Assessment than the Mini Mental State Examination (62 versus 19 percent), and that specificity
was superior with the Mini Mental State Examination (94 versus 56 percent) [8]. The Montreal Cognitive
Assessment is accessible online and in multiple languages at www.mocatest.org. Additional information about
these screening tests is discussed in the context of dementia. (See "Evaluation of cognitive impairment and
dementia", section on 'Cognitive testing'.)

Cognitive impairment may be a symptom of a depressive syndrome, such as major depression (table 1) or
minor depression (table 2), if the impairment occurs in conjunction with other depressive symptoms like
dysphoria, anhedonia, and suicidal ideation or behavior. Impairment may also be a symptom of fatigue. (See
"Clinical features, assessment, and diagnosis of unipolar depressive disorders in patients with cancer".)

DELIRIUM — Delirium is common in patients with cancer and is associated with distress in patients and
families, prolonged hospitalizations, and increased morbidity and mortality [1]. As an example, a study of
hospitalized cancer patients who developed delirium (n = 140) found that 30-day mortality was 25 percent [9].
The subsections below discuss delirium in patients with cancer. The clinical features, causes, assessment,
diagnosis, and differential diagnosis of delirium in general clinical settings are discussed in detail separately,
and delirium in patients approaching the end of life is also discussed separately. (See "Diagnosis of delirium
and confusional states" and "Overview of managing common non-pain symptoms in palliative care", section
on 'Delirium'.)

Prevalence — Delirium is a common complication of cancer and its treatment, especially in patients who are
hospitalized and patients with advanced disease [10]. Reviews suggest that at a minimum, the prevalence of
delirium in hospitalized patients is approximately 10 to 30 percent [1]. However, higher rates have been
reported; as an example, a prospective study of 90 patients undergoing hematopoietic stem cell
transplantation found that during five weeks of hospitalization, delirium occurred in 50 percent [11].

Pathogenesis — Delirium is due to a physiologic disturbance and often involves multiple etiologies [1,12].
Among patients with cancer, delirium is often due to medications used for chemotherapy (eg, corticosteroids,
fluorouracil, ifosfamide, methotrexate, and vincristine), immunotherapy (eg, interferon), and/or control of pain,
anxiety, and agitation (eg, opioids and benzodiazepines). In addition, the direct or indirect effects of cancer
can cause delirium, including primary brain tumors, brain metastases (common with breast and lung cancer),
dehydration, electrolyte imbalance, infection, major organ failure, paraneoplastic syndromes, and vascular
complications. Substance intoxication or withdrawal can also contribute to delirium.

Clinical features — The clinical features of delirium in patients with cancer include the following [1]:

● Sudden onset of symptoms that typically fluctuate in severity during the day

● Decreased level of consciousness (alertness or arousal)

● Attentional disturbances and cognitive impairment in other domains

• Apraxia

• Agnosia

• Executive functioning (eg, planning)

• Language disturbances

• Memory impairment

• Visuospatial dysfunction

• Disorientation

● Delusions

● Mood symptoms (eg, dysphoria and lability)

● Neurologic findings (eg, asterixis, myoclonus, and tremor)

● Perceptual disturbances (illusions or hallucinations)

● Psychomotor activity increased or decreased

● Sleep-wake cycle disturbances

● Speech is incoherent
 ● Thought process is disorganized

Screening — Screening tools can help clinicians diagnose delirium. Among the instruments that have been
validated in patients with cancer, we suggest the Confusion Assessment Method (table 3) [1]. However,
reasonable alternatives include the Memorial Delirium Assessment Scale (form 1A-B) and the Delirium Rating
Scale-Revised 98. Delirium in cancer patients is frequently missed and is often misdiagnosed as akathisia,
anxiety, dementia, depression, or psychosis [12,13].

Diagnosis — According to the American Psychiatric Association's Diagnostic and Statistical Manual of
Mental Disorders, Fifth Edition (DSM-5), the diagnosis of delirium requires each of the following criteria [14]:

● Disturbance in attention and awareness that develops quickly (usually hours to days) and tends to
fluctuate each day.

● Disturbance in cognition (eg, memory, orientation, language, visual spatial ability, and/or perception).

● The disturbances in attention, awareness, and cognition are not better explained by another
neurocognitive disorder and do not occur in the context of coma.

● Evidence from the history, physical examination, or laboratory findings indicate that the disturbances are
caused by a general medical condition, substance intoxication or withdrawal, and/or medication side
effect.

Subtypes of delirium have been delineated, based upon the patient’s psychomotor behavior and level of
arousal [1,14]:

● Hypoactive subtype – Psychomotor retardation, lethargy, and decreased level of arousal.

● Hyperactive subtype – Restlessness, agitation, and hypervigilance. Mood lability, failure to cooperate
with care, and psychotic features may also be present.

Some patients may display alternating (mixed) features of each subtype.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics”
and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want
in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail
these topics to your patients. (You can also locate patient education articles on a variety of subjects by
searching on “patient info” and the keyword(s) of interest.)

● Basics topic (see "Patient education: Delirium (confusion) (The Basics)")

● Beyond the Basics topic (see "Patient education: Delirium (Beyond the Basics)")

SUMMARY

● Patients with cancer often manifest acute and long-term cognitive impairment, the magnitude of which is
typically modest. Cognitive dysfunction has been observed in attention, concentration, executive function,
 information processing speed, and memory. The prevalence of cognitive impairment in patients with
cancer is high, reaching up to 75 percent of patients during treatment. Both cancer itself and cancer
treatment are associated with cognitive impairment. Cognitive impairment in cancer patients may be
temporary or permanent. (See 'Cognitive impairment' above.)

● Delirium is common in patients with cancer and is associated with increased morbidity and mortality.
(See 'Delirium' above.)

● Delirium is a common complication of cancer and its treatment; at a minimum, the prevalence of delirium
in patients hospitalized with cancer is approximately 10 to 30 percent. (See 'Prevalence' above.)

● Delirium is due to a physiologic disturbance and often involves multiple etiologies. Among patients with
cancer, delirium is often due to medications used for chemotherapy, immunotherapy, and/or control of
pain, anxiety, and agitation. In addition, the direct or indirect effects of cancer can cause delirium,
including primary brain tumors, brain metastases, dehydration, electrolyte imbalance, infection, major
organ failure, paraneoplastic syndromes, and vascular complications. Substance intoxication or
withdrawal can also contribute to delirium. (See 'Pathogenesis' above.)

● The clinical features of delirium in patients with cancer include sudden onset of symptoms that typically
fluctuate in severity during the day, decreased level of consciousness, attentional disturbances and
cognitive impairment in other domains, neurologic findings, perceptual disturbances, sleep-wake cycle
disturbances, incoherent speech, and disorganized thought process. (See 'Clinical features' above.)

● Screening tools can help clinicians diagnose delirium. Among the instruments that have been validated in
patients with cancer, we suggest the Confusion Assessment Method (table 3). (See 'Screening' above.)

● The diagnosis of delirium requires each of the following criteria:

• Disturbance in attention and awareness that develops quickly (usually hours to days) and tends to
fluctuate each day.

• Disturbance in cognition (eg, memory and/or orientation).

• The disturbances in attention, awareness, and cognition are not better explained by another
neurocognitive disorder and do not occur in the context of coma.

• Evidence from the history, physical examination, or laboratory findings indicate that the disturbances
are caused by a general medical condition, substance intoxication or withdrawal, and/or medication
side effect.

(See 'Diagnosis' above.)

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Topic 109994 Version 1.0

GRAPHICS

DSM-5 diagnostic criteria for a major depressive episode

A. Five (or more) of the following symptoms have been present during the same two-week period and represent a
change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest
or pleasure.

NOTE: Do not include symptoms that are clearly attributable to another medical condition.

1) Depressed mood most of the day, nearly every day, as indicated by either subjective report (eg, feels sad,
empty, hopeless) or observations made by others (eg, appears tearful). (NOTE: In children and adolescents, can
be irritable mood.)

2) Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as
indicated by either subjective account or observation)

3) Significant weight loss when not dieting or weight gain (eg, a change of more than 5% of body weight in a
month), or decrease or increase in appetite nearly every day. (NOTE: In children, consider failure to make
expected weight gain.)

4) Insomnia or hypersomnia nearly every day

5) Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of
restlessness or being slowed down)

6) Fatigue or loss of energy nearly every day

7) Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not
merely self-reproach or guilt about being sick)

8) Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by their subjective
account or as observed by others)

9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a
suicide attempt or a specific plan for committing suicide

B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas
of functioning.

C. The episode is not attributable to the direct physiological effects of a substance or to another medical condition.

NOTE: Criteria A through C represent a major depressive episode.

NOTE: Responses to a significant loss (eg, bereavement, financial ruin, losses from a natural disaster, a serious
medical illness or disability) may include the feelings of intense sadness, rumination about the loss, insomnia, poor
appetite, and weight loss noted in Criterion A, which may resemble a depressive episode. Although such symptoms
may be understandable or considered appropriate to the loss, the presence of a major depressive episode in addition
to the normal response to a significant loss should also be carefully considered. This decision inevitably requires the
exercise of clinical judgement based on the individual's history and the cultural norms for the expression of distress
in the context of loss.

D. The occurence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia,
schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other
psychotic disorders.

E. There has never been a manic or hypomanic episode.

NOTE: This exclusion does not apply if all of the manic-like or hypomanic-like epsidoes are substance-induced or
are attributable to the physiological effects of another medical condition.

Specify:

With anxious distress

With mixed features

With melancholic features

With atypical features

 With psychotic features

With catatonia

With peripartum onset

With seasonal pattern

Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright ©
2013). American Psychiatric Association. All Rights Reserved.

Graphic 89994 Version 12.0

Diagnostic criteria for minor depression

We suggest diagnosing minor depressive episodes according to all of the following

criteria (A through F).
A. Two to four of the following symptoms have been present during the same two-week period:

1. Dysphoria – Depressed mood most of the day, nearly every day

2. Anhedonia – Markedly diminished interest or pleasure most of the day, nearly every day
3. Significant appetite or weight change
4. Insomnia or hypersomnia nearly every day
5. Psychomotor agitation or retardation (observable by others)
6. Anergia – Fatigue nearly every day
7. Thoughts of worthlessness or inappropriate guilt nearly every day
8. Impaired concentration or memory nearly every day
9. Recurrent thoughts of death or suicide, or suicide attempt

B. At least one of the symptoms includes dysphoria or anhedonia

C. The symptoms cause clinically significant distress of psychosocial impairment

D. The symptoms are not due to the physiologic effects of a substance, medication, or general medical condition

E. Persistent depressive disorder (dysthymia) and cyclothymic disorder are not present

F. The mood disturbance does not occur exclusively during a psychotic disorder

These criteria for minor depression are similar to the criteria that are used in the American Psychiatric
Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) for the diagnosis, "Other
specified depressive disorder, depressive episode with insufficient symptoms" (ie, the depressive episode is
characterized by an insufficient number of symptoms to meet criteria for major depression).

Reference:
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5),
American Psychiatric Association, Arlington 2013.

Graphic 106958 Version 1.0

Confusion assessment method (CAM) for the diagnosis of delirium*

Feature Assessment

1. Acute onset and Usually obtained from a family member or nurse and shown by positive responses to the
fluctuating course following questions:
"Is there evidence of an acute change in mental status from the patient's baseline?";
"Did the abnormal behavior fluctuate during the day, that is, tend to come and go, or
increase and decrease in severity?"

2. Inattention Shown by a positive response to the following:

"Did the patient have difficulty focusing attention, for example, being easily distractible or
having difficulty keeping track of what was being said?"

3. Disorganized Shown by a positive response to the following:

thinking "Was the patient's thinking disorganized or incoherent, such as rambling or irrelevant
conversation, unclear or illogical flow of ideas, or unpredictable switching from subject to
subject?"

4. Altered level of Shown by any answer other than "alert" to the following:
consciousness
"Overall, how would you rate this patient's level ofconsciousness?"

Normal = alert

Hyperalert = vigilant

Drowsy, easily aroused = lethargic

Difficult to arouse = stupor

Unarousable = coma

*The diagnosis of delirium requires the presence of features 1 AND 2 plus either 3 OR 4.

Graphic 69489 Version 1.0

Memorial Delirium Assessment Scale (MDAS)

Reproduced with permission from: Breitbart, W, Rosenfield, B, Roth, A, Smith, M, Cohen, K, Passik, S. The
memorial delirium assessment scale. J Pain Symptom Manage 1997; 13:128. Copyright ©1997 The US Cancer
Pain Relief Committee.

Graphic 56787 Version 2.0

Memorial Delirium Assessment Scale (MDAS) cont.

Reproduced with permission from: Breitbart, W, Rosenfield, B, Roth, A, Smith, M, Cohen, K, Passik, S. The
memorial delirium assessment scale. J Pain Symptom Manage 1997; 13:128. Copyright ©1997 The US Cancer
Pain Relief Committee.

Graphic 69509 Version 2.0