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The Impact of Medical Illness on Executive Function

Received Aug. 2, 2004; revision received Nov. 30, 2004; accepted Dec. 16, 2004. From the Departments of Psychiatry, Medicine, and Pharmacology, University of Texas Health Science Center at San Antonio; and the Geriatric Research Education and Clinical Center, Audie L. Murphy Division, South Texas Veterans Health Administration. Address correspondence and reprint requests to Dr. Schillerstrom, Department of Psychiatry, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229; schillerstr{at}uthscsa.edu (e-mail).

ABSTRACT

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Executive function can be defined as one’s ability to plan, initiate, sequence, monitor, and inhibit complex goal-directed behaviors. Although executive impairment is generally associated with dementia, recent studies have suggested that patients with chronic diseases, such as hypertension, chronic obstructive pulmonary disease, and diabetes, may also have executive deficits independent of psychiatric comorbidities. Because executive function is associated with functional outcomes, medication compliance, and the capacity to give informed consent, it is important that it be assessed. However, it is the authors’ impression that executive function is not adequately assessed in medical settings, despite the availability of reliable measures. This article reviews the impact of medical illness on executive function and discusses practical diagnostic instruments and treatment strategies. The changes in functional status associated with executive impairment as well as pathophysiology and treatment strategies are also discussed.

INTRODUCTION

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The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV),¹ defines executive function as one’s ability to plan, initiate, sequence, monitor, and inhibit complex behavior. Royall et al.² described two central conceptual themes for defining executive function. The first associates executive function with "higher" cognitive functions, such as insight, will, abstraction, and judgment, that are mostly dependent on functioning of the frontal lobe. The second emphasizes behavioral regulation of nonexecutive processes by frontal control systems.

Although DSM-IV includes executive impairment only as a subcriterion for dementia, executive impairment is common in other psychiatric disorders. For example, patients with schizophrenia and depression have executive deficits similar to those with dementia.^3,4 A growing literature also suggests that executive impairment is common in patients with medical illness. It is our impression that nonpsychiatric clinicians are largely unaware of the relevance of executive impairment in medical conditions. Harrison’s Principles of Internal Medicine did not index "executive function" until the 16th edition (2005). Furthermore, a MEDLINE search from 1966 to October 2004, combining the Journal of the American Medical Association, the New England Journal of Medicine, and the Annals of Internal Medicine, yielded 119,009 responses. When we combined this search with the key word "executive function," it yielded only one result, and it was an article discussing dementia. Most commonly used cognitive screening instruments, including the Mini-Mental State Examination (MMSE), are insensitive to executive function.⁵ Explicit executive measures are seldom employed by medical and surgical services.

This article discusses the relationship between medical illness and executive impairment, as well as potential functional consequences of executive impairment. We also discuss potential causes and treatments of executive impairment and methods for assessing executive function at the bedside or in routine clinical settings. We hope to raise awareness of this common cognitive impairment and increase clinicians’ understanding of its impact on functional outcome.

EXECUTIVE IMPAIRMENT IN MEDICALLY ILL PATIENTS

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The prevalence of executive impairment in medical inpatient services is high. With the use of published cutoff points, 72% of hospitalized inpatients (mean age=44.9 years, SD=16.7) in medical or surgical services seen by a psychiatric consultation service failed to do well on either of two validated bedside executive function tests, i.e., the Executive Interview or the CLOX, an executive clock-drawing task.⁶ The Executive Interview is a 25-item multitask assessment of executive function.⁷ It correlates significantly with other executive measures, including the Trail Making test part B⁸ (r=0.64) and the Wisconsin Card Sorting Test⁹ (r=0.54). Moreover, it is more strongly associated with functional outcomes than the Wisconsin Card Sorting Test.¹⁰ The CLOX is an executive task based on clock drawing.¹¹ It is more sensitive to executive impairment than similar clock-drawing tasks.¹² In contrast, only 30% of the patients seen by this psychiatry consultation service failed to do well on the MMSE (cutoff point 24). When nondelirious direct admissions to a general medical service (mean age=47.8 years, SD=14) were administered these same tests, 52% failed to do well on either the Executive Interview or the CLOX, whereas only 9% failed to do well on the MMSE.¹³

Although the literature has not yet matured enough to do a systematic review of the association between medical illness and executive function, we believe much can be learned from currently available studies. Despite modest group sizes, several medical illnesses have been associated with executive impairment (Table 1). Patients with common conditions, such as hypertension, chronic obstructive pulmonary disease, and diabetes, perform significantly worse on executive measures compared to normal comparison subjects.^16,20,28 Furthermore, executive deficits persisted in patients with hypertension or diabetes even after covarying for depression and alcohol use, two psychiatric comorbidities commonly associated with executive impairment.^17,28

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TABLE 1. Medical Illnesses Associated With Impairment of Executive Function

The association between medical illness and executive function has not been systematically studied. Thus, the conditions listed in Table 1 may not be comprehensive. In theory, the differential of medical disorders capable of affecting executive control is broad and might include both structural and functional disruptions of frontal circuits. Structural lesions might include stroke and ischemic lesions to frontal system structures, primary and secondary (metastatic) lesions, infectious abscesses (e.g., toxoplasmosis in HIV), "autoimmune" processes (e.g., multiple sclerosis), etc. Functional disruptions might include metabolic dysfunctions (e.g., hypoglycemia, hypoperfusion, or hypoxia), some of which may be iatrogenic (e.g., hypoglycemia in the setting of diabetic treatment, intrasurgical hypotension, or dialysis-related hypovolemia); nutritional or vitamin deficiencies; cytokine-mediated behavioral changes in the setting of infectious, cancerous, inflammatory, or autoimmune diatheses; or direct CNS drug effects. It is important to note that many of these processes may be irreversible, iatrogenic, and/or reversible.

Although several of these studies also detected other cognitive impairments, such as memory problems, it is not likely that these contributed significantly to functional outcomes independent of executive function.^35,36 Furthermore, it is our impression that executive impairment is less likely to be reported than memory loss and more likely to be reported as "memory loss" in clinical practice and therefore unlikely to be specifically assessed. This is unfortunate given the functional losses associated with executive impairment.

FUNCTIONAL IMPACT OF IMPAIRMENT

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Executive function is associated with multiple aspects of patient care. In one study, executive function explained 48% of the variance in the level of care received by older retirees when the authors discriminated between adults living independently in the community, adults living independently in a retirement community, adults requiring assistive living, and adults requiring a skilled nursing unit.³⁷ Similarly, executive function discriminates between independent patients, patients requiring moderate supervision, and patients requiring heavy supervision after traumatic brain injury.³⁸

Executively impaired patients are more likely to resist care and are less likely to comply with medication regimens, including the proper use of an inhaler.^39–41 Among noninstitutionalized elderly retirees, executive function makes a significant independent contribution to both instrumental activities of daily living and the longitudinal rates of change in the performance of those activities.^35,42 In one study, executive impairment explained 28% of the variance in the performance of activities of daily living in patients with Alzheimer’s disease,⁴³ whereas in another study,³⁵ the rate of change in executive function explained 32% of the variance in the rate of change in the performance of instrumental activities of daily living associated with normal aging. Executive measures also predict functional outcome in hospitalized rehabilitation patients.⁴⁴

It has recently been suggested by Cooney et al.⁴⁵ that executive function may be the primary basis for substantiating the argument that community residence is no longer safe, particularly when the alleged incapacitated person is alert and highly verbal. They suggested that executive function is intimately associated with a person’s ability to make decisions, their capacity to carry out a plan to live alone, and behaviors that might indicate a safety hazard to themselves or others when they live alone. They further state that impaired executive function may have a more profound effect on a patient’s autonomy than memory impairment.

The literature supports the claim by Cooney et al.⁴⁵ that executive function contributes significantly to a patient’s medical decision-making capacity. For patients to give informed consent, they must be able to communicate; understand the risks, benefits, and alternatives for a given procedure; and provide a logical reason for their decision in the context of the treatment situation. Executive function explains the most variance in the ability of patients with Alzheimer’s disease to understand the consequences of their decisions (R²=0.58, p=0.0001), provide rational reasons for their decisions (R²=0.36, p=0.0008), and understand the treatment situation (R²=0.70, p=0.0001).^46,47

These findings have been replicated in patients without Alzheimer’s disease as well. The Executive Interview discriminates between competent and noncompetent medical decision-making abilities in hospitalized medical patients referred for a neuropsychiatric evaluation (p<0.001) and correctly classifies 91% of the ability of elderly retirees to understand medical information relative to the Hopkins Competency Assessment Test.^48,49 Furthermore, Dymek et al.⁵⁰ suggested that executive dysfunction may be the primary neurocognitive mechanism for competency loss in patients with Parkinson’s disease. Their stepwise regression model showed that executive function (assessed with the Executive Interview) explained the most variance in patients’ ability to provide rational reasons for treatment (R²=0.45, p=0.002) and to understand the treatment situation, choices, risks, and benefits (R²=0.56, p<0.0001), whereas tests of memory, attention, and verbal conceptualization and reasoning explained little to none of the variance.

The functional loss associated with executive functional impairment may be behaviorally mediated by apathy. Apathy has been associated with executive functional impairment in patients with dementia, depression, and traumatic brain injury.^42,51,52 Boyle et al.⁴³ demonstrated that executive impairment and apathy scores contributed to 44% of the variance in instrumental activities of daily living in patients with Alzheimer’s disease. Executive function may control the behaviors associated with motivation, and disruption of the neural circuits maintaining executive function may lead to apathy and subsequent functional impairment, resistance to care, and impaired decision-making capacity.

PATHOPHYSIOLOGY OF EXECUTIVE IMPAIRMENT

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Frontal Circuit Anatomy and Physiology
The prefrontal cortex and related subcortical structures comprise striatal-cortical-frontal "control" circuits that are associated with specific executive functions.⁵³ These circuits run from the dorsolateral, orbitofrontal, and mesial prefrontal cortex to the striatum. From there, the path continues to the globus pallidus and the thalamus and then back to the prefrontal cortex. Damage to either gray or white matter in these circuits can be associated with executive deficits. These circuits are partially modulated by several monoaminergic neurotransmitters, particularly dopamine. Dopamine disruption in the prefrontal circuits accounts for a substantial portion of the variance in executive impairment.⁵⁴

Frontal Circuit Perfusion and Oxygenation
The structures within the frontal circuits are particularly sensitive to hypoperfusion and hypoxia.⁵⁵ Tyrosine hydroxylase, the rate-limiting enzyme for dopamine synthesis, is oxygen dependent, and decreased dopamine levels are observed in brain tissue during chronic hypoxic conditions.⁵⁶ Furthermore, as the brain adapts to hypoxia, N-methyl-D-aspartate (NMDA) glutamate receptors become more "excitable," which can lead to calcium-mediated oxidative cell death.⁵⁷ Significant metabolic impairment has been observed in the cerebral cortex in patients with chronic obstructive pulmonary disease and in cerebral white matter in patients with obstructive sleep apnea.^58,59 Oxidative disturbances in the frontal circuit may explain the executive impairments observed in patients with decreased cerebral perfusion, decreased respiratory function, or increased oxygen demand.

Cytokine and Hormonal-Mediated Executive Impairment
Wilson et al.⁶⁰ reviewed the link between inflammatory mediators and cognitive impairment. Their article discussed how cytokines may alter neurotransmission and how they may be directly neurotoxic to structures in the frontal circuits. Executive impairment has been observed in patients receiving interferon- treatment for melanoma, leukemia, and amyotrophic lateral sclerosis.^61–63 These cognitive deficits resolve after interferon- treatment ceases.⁶³

Hormonal disturbances also likely contribute to executive impairment. Persistent cortisol elevation is associated with cerebral atrophy in patients with Cushing’s disease and depression.^64,65 Chronically elevated levels of cortisol are found in primates and humans with executive impairment.^66,67

MEASURES OF EXECUTIVE FUNCTION

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Several neuropsychiatric tests are sensitive to executive function. The Wisconsin Card Sorting Test⁹ is an often-used formal executive measure. In the Wisconsin Card Sorting Test, the patient is asked to sort differently marked cards into categories based on feedback from the examiner.⁶⁸ The patient must adapt to changing categories, depending on the examiner’s positive or negative feedback. During the Stroop Task,⁶⁹ another executive measure, subjects are graded on their ability to name the ink color of words, including colors, printed on cards. The Tower of Hanoi⁷⁰ tests patients’ ability to determine the least number of moves required to stack three different rings in predetermined positions. Unfortunately, these tests are difficult to administer and are seldom used as screening measures.

However, other measures of executive function, such as the Executive Interview and the CLOX (mentioned previously), are more easily administered by clinicians.^6,7 It is important to note that not all clock-drawing tasks are the same and some, particularly the CLOX, are more sensitive to executive function than others. The wording of the instructions, continued prompting throughout the task, and the presence of a previously drawn outer circle can all affect the "executiveness" of the task. If one does not administer the task in an "executive" manner, the "executiveness" of the task may be lost, leaving it sensitive only to constructional praxis. For example, during the executive task CLOX1, the patient is presented with a blank page and asked to "Draw me a clock that says 1:45. Set the numbers and hands on the face so that a child could read them." Once the patient begins the task, no further assistance is permitted from the examiner. Potential intrusions, such as hands, face, and child, are introduced as part of the instructions. Similarly, asking the patient to set the time to 1:45 creates another level of ambiguity, allowing for the potential perseveration of "4" and "5." Figure 1 shows examples of impaired clocks (CLOX1) drawn by patients with medical illnesses.

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FIGURE 1.  Examples of Impairment on the CLOX1, an Executive Clock-Drawing Task, in Hospitalized Medically Ill Patientsa aEach patient was presented with a blank page and asked to "Draw me a clock that says 1:45. Set the numbers and hands on the face so that a child could read them." Once the patient began the task, no further assistance was permitted from the examiner.

Other examples of convenient executive measures include the Trail Making test part B and verbal fluency tasks. The Trail Making test part B⁷¹ requires patients to connect letters and numbers in an alternating sequence within a specified period; thus, it evaluates sustained attention and the ability to transition between two cognitive sets. Verbal fluency tasks have patients name as many different words as possible that meet a specified criterion (e.g., words that start with the letter "A") in a given amount of time.⁷⁰ Most of these instruments take less than 5 minutes to administer, and the information learned from their use can have a direct impact on patient care.

TREATMENT OF EXECUTIVE IMPAIRMENT

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Pharmacological Strategies
Effective treatments for executive impairment in patients with psychiatric or neurological illness generally increase monoamine neurotransmitter activity, particularly dopaminergic activity, in the prefrontal cortex. The effects of dopamine agonists on frontal function are complex and may be both nonlinear and dependent on baseline levels.⁷² Adults with attention-deficit hyperactivity disorder who were treated with methylphenidate had significant executive improvement.⁷³ Patients with brain tumors who were treated with methylphenidate had significant executive improvement that was independent of improved mood.⁷⁴ Sertraline, a selective serotonin reuptake inhibitor that may also have dopaminergic activity, has been found to improve executive function in depressed patients with mild traumatic brain injury.⁷⁵

Dopaminergic medications may also improve frontal circuit function in patients with nonneurological medical illness. Cancer patients are often cognitively impaired from narcotic medications used for pain control. Although executive measures were not employed, general cognition improved in cancer patients treated with methylphenidate, suggesting that further study may show similar improvements of executive function.⁷⁶ Fatigue is a predictor of poor executive function in survivors of bone marrow transplant, and methylphenidate has been used to successfully treat cancer-induced fatigue and perhaps similarly improve executive function.^77,78

Maintaining or restoring oxidative or perfusion deficits in the frontal circuits may have a positive effect on executive function. Patients with obstructive sleep apnea or congestive heart failure have executive improvements with oxygen therapy.^25,79 With regard to perfusion, the Prospective Study of Pravastatin in the Elderly at Risk (the PROSPER Study)⁸⁰ is a randomized, placebo-controlled trial that is in process to study the effects of pravastatin on cognition as well as other morbidities that may yield information regarding the use of cholesterol-lowering medications in preserving executive function. The results of a retrospective cohort study⁸¹ suggested that geriatric patients taking cholesterol-lowering medications may be less likely to have dementia and may be more likely to have improved MMSE and CLOX scores compared to patients not taking these medications.

Unfortunately, several studies have found no improvement in executive function in patients treated with antihypertensives, and some antihypertensives may worsen executive function, perhaps by decreasing frontal circuit perfusion.^82–85 Antithrombotic medication in patients at risk for cardiovascular disease is more promising. In a double-blind, placebo-controlled trial of patients receiving low doses of aspirin (75 mg/day) or low doses of warfarin (an international normalized ratio of 1.5),⁸⁶ patients taking either aspirin or warfarin performed better on an executive task than those taking placebo.

Nonpharmacological Strategies
Physical activity in old age seems to be specifically associated with measures of cognition.⁸⁷ However, not all cognitive functions may be as relevant to physical activity as executive function. A recently published meta-analysis of the exercise literature⁸⁸ concluded that the effect of exercise on cognition is limited to measures of executive function. As previously discussed, executive function is thought to be mediated by specific "frontal systems." Aerobic fitness appears to protect individuals from age-related frontal atrophy and to improve frontal metabolism, as seen by functional magnetic resonance imaging.^89,90 Thus, exercise may offer a means of either preventing or reversing age-related declines in executive function and therefore instrumental activities of daily living. This may be due to improved cerebral oxygenation/perfusion, decreased inflammatory mediators, and/or decreased stress hormones in people who exercise.

SUMMARY

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Recent studies have suggested that executive impairment is common in patients with medical illness across a wide spectrum of diagnoses. Some studies have shown that this impairment is associated with functional outcomes independent of psychiatric comorbidities. Executive impairment has been associated with functional deficits that include incapacity to consent, increased resistance to care, decreased ability to comply with medication taking, and poorer performance of activities of daily living. Because executive impairment may undermine attempts to obtain informed consent for treatment, undermine treatment adherence, and complicate efforts to safely discharge patients into the community, medical patients should be screened for executive deficits when the clinician has such concerns. Several convenient measures, such as the CLOX, can help clinicians detect executive impairment.

Many conditions associated with executive impairment may be preventable or reversible. Some executive impairments may be iatrogenic. Dopaminergic medications have a positive effect on executive function in patients with psychiatric illness and may have similar benefits in patients with medical illness. It may also be appropriate to discuss an exercise program.

Much more research, however, is needed. We do not know if the executive deficits observed in hospitalized patients resolve after discharge into the community or if they improve or worsen with medical treatments. There is a dearth of information regarding iatrogenic causes and treatments for executive deficits in medically ill patients. We do not know the effects of psychiatric medications, such as atypical antipsychotics, antidepressants, and cognitive enhancers (acetylcholinesterase inhibitors or NMDA antagonists), on executive function in this population. Nor do we know how executive function affects aftercare and medication compliance. Might routine screening improve functional outcome in these patients? The literature is beginning to shed light on these matters, but more systematic research needs to be done to optimize patient care and improve functional outcome.

REFERENCES

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