i

Cognitive Impairment Among The Patients With Terminal Illness

By

Abdul Waqas

Department of Applied Psychology

2019
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Cognitive Impairment Among The Patients With Terminal Illness

By

Abdul Waqas

Roll no. 08

Supervisor

Head of department

External of Examination
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Declaration

I declare that “Cognitive impairment among the patients with terminal illness” at The

Islamia University Bahawalpur is my own work, that it has not been submitted before for any

degree or examination in any other university, and that all the sources I have used or quoted

have been indicated and acknowledged as complete references and no part of the thesis has

been plagiarized.

Abdul Waqas
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Certificate

It is certified that this thesis entitled “Cognitive impairment among the patients with

terminal illness” presented by Abdul Waqas has been approved for submission to

department of applied psychology. The Islamia University Bahawalpur.

Dr. Masood Nadeem

(Supervisor)
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Table of Contents
Acknowledgment i
Abstract ii
List of Tables iii
List of Appendices iv
Chapter I: Introduction 1
Introduction 1
Literature review 48
Rationale of the study 55
Objectives 59
Hypothesis 59

Chapter II: Research Methodology 57

Participants 57
Research Design 57
Operational Definitions 57
Data Collection Instrument 59
Data Collection Procedure 60
Statistical Data Analysis 60
Ethical Considerations 61
Chapter III: Results 62
Results 67
Chapter IV: Discussion 67
Discussion 67
Conclusion 73
Limitations 73
References 74
Appendices 92
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Acknowledgement

The whole praises ALLAH ALMIGHTY for the infinite Grave, Immense Mercy, countless

Endowment & all respect and Darood-o- Salam for His beloved Prophet Hazrat Muhammad

(S.A.W.W), creator of the universe, who made us as the Super Creature, blessed us with

bounteous blessing, knowledge and exaltation flourished our thoughts, able to accomplished

the work and thrived our ambition to have cherished fruit of out modest effort in the form of

this write up.

Secondly, I am thankful to my supervisor, Dr. Masood Nadeem, a big thank-you for your

guidance and never ceasing faith in me and my abilities to complete this thesis even when I

had my doubts. Thank-you for your continuous encouragement; and on occasion even going

above and beyond your supervisor duties to help me. I could not have done it without you.

Abdul Waqas
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Abstract

The present study is an attempt to investigate the cognitive impairment among the patients

with terminal illness. The study is to inspect the extent of cognitive impairment among the

patients with respect to gender difference, socioeconomic status and urban/rural areas.

Cognitive impairment includes poor motor coordination, loss of short and long term memory

and identity confusion. Cognitive impairment is started among the patients having terminal

illness. The sample of current study is comprised of N = 80 patients from Victoria, Civil and

BINO Hospital. Purposive random sampling technique was used to collect the data. Patients

completed one questionnaire along with their demographic information. The independent t-

test was used to evaluate the data. There is significant difference detected with respect to

gender differences and socioeconomic status. The conclusion of this study enlightens the

importance of prevention and intervention strategies to reduce the effects of

neuropsychological problems which lead the patients more serious. Counseling also plays a

main role in patient’s neuropsychological and physical wellbeing.

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List of Tables

Table 1 Frequency Distribution of Demographic Questionnaire (N=80) 62

Table 2 Descriptive Statistics of Study Variables (N=80) 63

Table 3 Comparison between Male and Female Patients with Terminal Illness Sample

through Independent Sample t-Test among Cognitive Performance (N=80) 64

Table 4 Comparison between Low and Middle Socioeconomic Status of Patients with

Terminal Illness Sample through Independent Sample t-Test among Cognitive Performance

(N=80 65

Table 5 Comparison between Rural and Urban Patients with Terminal Illness Sample

through Independent Sample t-Test among Cognitive Performance (N=80) 66

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List of Appendices

Appendices A Mini mental state examination (English version) 92

Appendices B Mini mental state examination (Urdu version) 93

Appendices C Informed Consent 95

Appendices D Demographic Sheet 96

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Chapter 1
Introduction

Cognitive Impairment

The loss of intellectual function i.e. of thinking effectively. It may occur briefly after

overdose 0f alcohol use during sepsis, or after severe head injury. Permanent cognitive

impairment may occur in older adults. Approximately half of the population over 85 showed

permanently impaired thinking whenever is tested with standard assessment tools.( Martin, E.

M., Pitrak).

Discipline of Neuroscience

The complicated, multidisciplinary, and quickly developing field of neuroscience looks

at the structure and function of the hum an brain and nervous system. Neuroscience research

draws on cellular and molecular biology, anatomy and physiology, human behavior

and cognition, and other disciplines, to tool out information about how the brain works at

levels previously unrecognized. We have a hundred billion neurons, or brain cells, with close

to a quadrillion connections between them, and we have yet to fully understand a single cell.

(Boykoff, N., Moieni, M., Subramanian, S.K. 2009.)

Neuropsychology

Neuropsychology is a branch of psychology and neurology that aims to understand

how the structure and function of the brain relate to specific psychological processes.

It is scientific in its approach and shares an information processing view of the mind with

cognitive psychology and cognitive science. It is one of the more eclectic of the

psychological disciplines, overlapping at times with areas such as neuroscience, philosophy

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(particularly philosophy of mind), neurology, psychiatry and computer science (particularly

by making use of artificial neural networks).( Angelino, A.F., Treisman ).

Top listed terminal diseases

By Jamie Frater

This is a list of the top incurable terminal diseases. Modern medicine has done much to

eradicate and cure disease, but it has failed in some areas. Of those areas, at least one disease

that cannot be cured is suffered by many people in the world every year – the common cold.

HIV/AIDS

AIDS is the byname of acquired immunodeficiency syndrome – a transmissible disease

of the immune system caused by the human immunodeficiency virus (HIV). HIV slowly

attacks and destroys the immune system, the body’s defense against infection, leaving an

individual vulnerable to a variety of other infections and certain malignancies that eventually

cause death. AIDS is the final stage of HIV infection, during which time fatal infections and

cancers frequently arise.

HIV/AIDS spread to epidemic proportions in the 1980s, particularly in Africa, where the

disease may have originated. Spread was likely facilitated by several factors, including

increasing urbanization and long-distance travel in Africa, international travel, changing

sexual mores, and intravenous drug use. According to the United Nations 2004 report on

AIDS, some 38 million people are living with HIV, approximately 5 million people become

infected annually, and about 3 million people die each year from AIDS. Some 20 million

people have died of the disease since 1981.

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Cardiovascular Disease (CVD)

CVD is a class of diseases that involve the heart or blood vessels. Cardiovascular

disease includes coronary artery diseases (CAD) such as angina and myocardial

infarction (commonly known as a heart attack). Other CVDs include stroke, heart

failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, heart

arrhythmia, congenital heart disease, valvular heart disease, carditis, aortic

aneurysms, peripheral artery disease, thromboembolic disease, and venous thrombosis.

Ebola

Ebola is a virus of the family Filoviridae that is responsible for a severe and often fatal

viral hemorrhagic fever; outbreaks in primates such as gorillas and chimpanzees as well as

humans have been recorded. The disease is characterized by extreme fever, rash, and profuse

hemorrhaging. In humans, fatality rates range from 50 to 90 percent.( ., McCutchan, J. A., et

al. (2004))

The virus takes its name from the Ebola River in the northern Congo basin of central Africa,

where it first emerged in 1976. Outbreaks that year in Zaire (now Congo [Kinshasa]) and The

Sudan resulted in hundreds of deaths, as did another outbreak in Zaire in 1995. Ebola is

closely related to the Marburg virus, which was discovered in 1967, and the two are the only

members of the Filoviridae that cause epidemic human disease. A third related agent, called

Ebola Reston, caused an epidemic in laboratory monkeys in Reston, Virginia, but apparently

is not fatal to humans.

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Diabetes

Diabetes is a disorder of carbohydrate metabolism characterized by impaired ability of

the body to produce or respond to insulin and thereby maintain proper levels of sugar

(glucose) in the blood.

There are two major forms of the disease. Type I diabetes, formerly referred to as insulin-

dependent diabetes mellitus (IDDM) and juvenile-onset diabetes, usually arises in childhood.

Type II diabetes, formerly called non-insulin-dependent diabetes mellitus (NIDDM) and

adult-onset diabetes, usually occurs after 40 years of age and becomes more common with

increasing age. It arises from either sluggish pancreatic secretion of insulin or reduced

responsiveness in target cells of the body to secreted insulin. levels through diet and exercise

and, if necessary, by taking insulin injections or oral medications.

Asthma

Asthma is a chronic disorder of the lungs in which inflamed airways are prone to

constrict, causing episodes of breathlessness, wheezing, coughing, and chest tightness that

range in severity from mild to life-threatening. Inflamed airways become hypersensitive to a

variety of stimuli, including dust mites, animal dander, pollen, air pollution, cigarette smoke,

medications, weather conditions, and exercise. Stress can exacerbate symptoms.

Asthmatic episodes may begin suddenly or may take days to develop. Although an initial

episode can occur at any age, about half of all cases occur in persons younger than 10 years

of age, with boys being affected more often than girls. Among adults, however, the incidence

of asthma is approximately equal in men and women. When asthma develops in childhood, it
 5

is often associated with an inherited susceptibility to allergens, substances such as pollen,

dust mites, or animal dander that may induce an allergic reaction

CANCER

Approximately 70,000 adolescents and young adults (AYAs) between the ages of 15

and 39 years are diagnosed with cancer each year in the United States, which represents 6%

of the cancer population. Diagnoses mostly commonly include leukemia, lymphoma,

sarcoma, melanoma, breast cancer, colorectal cancer, thyroid cancer, testicular cancer, and

brain tumors, among others. Relatively good overall survival (ie, 5-year survival rate of 83%

across disease sites) has resulted in a growing population of AYA cancer survivors. AYA

survivors face unique challenges, many of which stem from the interruption of diagnosis and

treatment during a key phase of psychosocial growth and development. AYA patients must

cope with cancer at a time of identity formation and the establishment of the independence

necessary for adulthood. AYAs report challenges with emotional well-being, body image,

and health management. Social interactions often are strained because families can be

overprotective and friendships difficult to maintain. Romantic relationships can be

challenging because survivors often are uncomfortable about discussing cancer with others.

This state of affairs is surprising in light of data that suggest an important role for cognition

in resuming normal social activities and returning to education and employment after cancer

in non-AYA survivors (ie, children, adults).

Cognition in patients with cancer typically is assessed in three ways. The first is to administer

self-report questionnaires that directly ask patients about changes in their memory,

concentration, word-finding, and other cognitive abilities. Patients’ own perceptions of

cognition arguably are the most clinically meaningful because the goal of the provider is to

improve how the patient feels. The second way is through objective neuropsychological
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testing. Neuropsychological testing typically is administered under optimal conditions (eg, in

a quiet office) rather than in situations in which cognitive lapses might be expected (eg, when

patient is tired, distressed, or distracted). Thus, neuropsychological testing captures patients’

best performance rather than their typical functioning, which may be better reflected by

subjective cognition. The third way is to conduct brain imaging to evaluate structural changes

associated with brain regions known to be important for cognitive functioning or to examine

patterns of activation at the same time cognition is being assessed.

The potentially detrimental effects of cancer and related treatments on cognitive functioning

are emerging as a key focus of cancer survivorship research. Many patients with central

nervous system (CNS) or non-CNS tumors develop cognitive problems during the course of

their disease that can result in diminished functional independence and can continue well into

the survivorship period.

In recent years, growing attention is being paid to the potential adverse effects of

chemotherapy on brain and cognitive function. This central neurotoxicity may manifest as

both acute and delayed complications. Virtually all categories of chemotherapeutic agent

have been associated with adverse neurological effects, including both acute and chronic

encephalopathy. More subtle cognitive dysfunction has also been demonstrated and

frequently manifests as diminished memory, executive function, attention and information

processing speed.

Risk factors among cancer patients

Several factors have been identified that generally increase the risk of developing

neurotoxicity associated with chemotherapy. These include:

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(1) Exposure to higher doses due to planned use of high-dose regimens, or to high

concentrations of the parent drug and/or its metabolite due to impaired systemic clearance

and/or pharmacogenetics modulation of drug pharmacokinetics

(2) Additive or synergistic effects of multi-agent chemotherapy

(3) Additive or synergistic effect of multimodality therapy that includes administration of

chemotherapy either concurrently with or subsequently to cerebral radiation

(4) Intra-arterial administration with blood–brain barrier disruption

(5) Intrathecal administration.

Risk factors – endocrine treatment

A treatment-related risk factor for cognitive decline in breast cancer patients that is of

particular clinical relevance is the combined use of endocrine therapy. Breast cancer patients

undergoing chemotherapy often receive endocrine therapy as well. These therapies

commonly consist of treatment with selective oestrogen receptor modulators (SERMs) such

as tamoxifen and/or aromatase inhibitors (AIs) such as exemestane, anastrozole or letrozole.

Evidence derived from basic as well as clinical research indicates that estradiol, within a time

window of opportunity, can stimulate neuroplasticity in brain areas involved in cognitive

behavior leading to improved performance. Since SERMs and AIs also target brain areas

involved in the regulation of cognitive behavior, it is plausible that these substances may

contribute to cognitive deterioration in breast cancer patients. Blocking estradiol synthesis

with AIs deprives the brain of modulation via estradiol and therefore theoretically results in

decreased neuroplasticity and impaired cognitive functioning. However, surprisingly, studies

in breast cancer patients seem generally to indicate that AIs less consistently adversely

influence cognitive functioning compared with SERMs. Studies specifically addressing the

interaction between chemotherapy and endocrine therapy are sparse and the majority of
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studies have been too small to adequately investigate this interaction. Absence of oestrogen

neuroprotective action in the brain – in the natural, surgical or chemotherapy-induced

postmenopausal brain – makes the brain possibly extra vulnerable to neural damage by

chemotherapy.

Risk factors – information

Information on chemotherapy-associated cognitive problems is more and more

accessible to patients. The reporting of cognitive problems may also be influenced by strictly

cognitive mechanisms that are not rooted in psychological distress or negative affect, but

simply in the extent to which a patient is informed about the possibility of cognitive problems

following chemotherapy. Several studies on cognitive deficits in breast cancer patients

showed that mere information about the association between chemotherapy and cognitive

problems resulted in lower memory performance and higher complaint reporting. These

effects occurred independently of negative affect and pre-existing knowledge. The notion that

mere information can add to the occurrence and maintenance of cognitive problems is

derived from a large body of social psychological research on stereotype threat and priming.

Stereotype threat – i.e. fear of confirming a stereotype – has been researched extensively, and

evidence shows that activation of a stereotype or schema unconsciously leads to behaviour

that is in correspondence with that stereotype.

Concepts of stereotype threat and priming are important for explaining the effects of

treatment-related information on complaint reporting and neuropsychological test scores.

Furthermore, it may be that some individuals are particularly vulnerable to these effects. It is

not suggested that these psychological processes should be viewed as alternative explanations

for biological influences. Rather, the possibility is raised that, for certain patients, self-

regulatory and expectancy processes may also play a role – as a contributing, additive or
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meditational influence – in cognitive functioning. The next steps for clinical practice include

the determination of the severity and duration of priming effects and to further understand the

individual variation in these effects. In addition there is a need to explore the possibilities of

diminishing or preventing these effects.

Chemotherapy accelerates aging

The influence of cancer and cancer treatment on the process of cognitive ageing is a

topic that is increasingly receiving attention. There is concern that chemotherapy may induce

accelerated ageing and that it can increase an individual’s susceptibility to late-emerging

cognitive decline or dementia. The underlying development of cognitive impairment in

ageing appears to begin at mid-life. Genetic signatures of brain ageing (i.e. from

transcriptional profiling in post-mortem brains) can be identified in subjects as early as their

40s. Substantial evidence demonstrates that a wide variety of variables in early life are

determinants of cognition in later life. Furthermore, both lifestyle and health-related risk

factors in mid-life are associated with poor cognition decades later. It is plausible that

damage to brain health in young to middle-aged women becomes even more clinically

evident many years later when the brain is extra vulnerable. Therefore it is essential to

investigate how chemotherapy in earlier life may influence cognition in later life.

Different trajectories for chemotherapy-associated cognitive problems have been proposed in

the literature. It could be that long-term cognitive problems result from lack of recovery from

the acute effects of treatment. It could also be that the initial effect of treatment may produce

a cascade of biological events that cause continued cognitive decline with ageing.

Alternatively, chemotherapy may not be sufficient to cause enough redundancy loss to

immediately affect cognitive function, but may produce a delayed effect as ageing continues,

with the slope of change being influenced by a variety of factors.

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Cognitive impairment studies in patients with central nervous system tumors

Evaluating adverse effects of chemotherapy on cognitive function in CNS cancer

patients is often challenging because of the variety of other factors that can impact cognition

in this population, most notably treatment with radiation and tumor progression. Both

radiation and chemotherapy have been reported to share at least one common mechanism for

their adverse effect on brain and cognition: disruption of the neural stem and precursor cell

function. Only recently clinical trials have incorporated cognitive testing into their study

design, providing the opportunity to address these issues in large samples of homogeneously

treated patients. Radiation therapy has been demonstrated to adversely impact brain and

cognition through vascular damage and inflammation, and via damage to neuronal progenitor

cells affecting hippocampal neurogenesis and oligodendroglial formation.

Impairment in processing speed, attention, executive function and memory is commonly seen

in brain tumor survivors previously treated with radiation therapy. Several recent

retrospective studies have examined the effects of radiation dose on different areas of the

brain and cognitive outcomes. These studies provide evidence of a dose–response

relationship between radiation to the bilateral hippocampal region and memory function, in

addition to other brain regions and more heterogeneous cognitive outcomes. Trials are

currently under way in many centers to explore the use of technological advances in radiation

delivery to spare normal tissues from radiation exposure, and to explore different forms of

radiation such as proton therapy that may similarly achieve reduced-dose exposure to the

normal brain and other critical structures. The standard of care for glioblastoma patients has

included concomitant chemo radiation and adjuvant chemotherapy with temozolomide since

2004. A small single-institution study with standard-dose temozolomide reported cognitive

decline in three out of 13 progression-free patients after concurrent chemo radiation and three

cycles of adjuvant chemotherapy. Declines were evident in psychomotor speed, attention and
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executive function, but not in verbal memory or working memory span. The results of a

larger multi-institutional cooperative group trial comparing adjuvant standard-dose

temozolomide and dose-dense temozolomide have also been reported. In patients that were

clinically and radiographically progression-free after concurrent chemoradiation and three

cycles of adjuvant chemotherapy, 30% demonstrated cognitive decline, with no differences

between arms..

Due to the importance of angiogenesis in the growth and spread of cancer, there has been a

great interest in inhibitors of vascular endothelial growth factor (VEGF), such as

bevacizumab. Anti-VEGF agents have been demonstrated to produce rapid radiological

improvement, ostensibly due to their ability to reduce tumor and blood–brain barrier

permeability associated with leaky blood vessels. There is concern that this represents a

‘pseudo response’ which complicates the interpretation of traditional imaging end-points. A

phase II non-comparative study of bevacizumab in a recurrent glioblastoma multiform

(GBM) population included tests of cognition to characterize changes in brain function

associated with bevacizumab therapy. In patients who achieved an objective radiographic

response or who were clinically and radiographically progression-free at 24 weeks, the

majority (75% and 70%, respectively) demonstrated stable or improved cognitive function

relative to their pretreatment baseline. Two placebo-controlled phase III trials with cognitive

end-points in newly diagnosed GBM patients are currently under way and will provide more

information on the impact of bevacizumab on cognitive function.

The long-term outcomes and associated reanalysis from the RTOG 9402 trial recently

reported a doubling of overall survival rates in pure or mixed anaplastic oligodendroglioma

patients with 1p/19q co-deletion who received procarbazine, CCNU and vincristine (PCV)

chemotherapy. This trial did not assess patient-oriented outcomes such as cognitive function

to help determine the net clinical benefit of this survival advantage. However, two single-
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institution studies assessed cognition in anaplastic glioma and GBM patients treated with

regimens that included PCV. Of patients with anaplastic glioma, 35% who were re-evaluated

at a median of 8 months after initiation of treatment demonstrated cognitive decline. In GBM

patients retested at a mean of approximately 8 months after initiating treatment, decreased

cognitive function (in 44–52% of patients) was most commonly observed in the domains of

psychomotor speed, executive function and memory. Unfortunately, these studies were not

designed to distinguish the effects of chemo radiation from adjuvant chemotherapy and did

not control for tumor progression, complicating the interpretation of these results as evidence

of chemotherapy-related neurotoxicity’s.

The effects of cancer chemotherapies on cognitive function have commanded increasing

attention from researchers in the past decade. This is in large part due to early disease

detection and initiation of adjuvant systemic therapies, and consequently, more individuals

who potentially live with long-term consequences of cancer treatments. There is also

increased recognition of the problem among policy makers and survivorship groups.

Empirical evidence now suggests strongly that at least for a subset of individuals, systemic

chemotherapy can give rise to long-standing reduced neuropsychological test performance

and cognitive function. The bulk of this research has compared past chemotherapy recipients

with cancer survivors matched on demographic and disease variables who have undergone

localized cancer treatments such as surgery or non-central nervous system radiation therapy.

However, many questions remain about low neuropsychological performance following

chemotherapy. For example, the degree of cognitive decline some survivors experience after

chemotherapy is unknown, though it appears subtle. Further, underlying mechanisms that

account for reduced neuropsychological performance remain unknown. This article reviews

current understanding of the relationship between adjuvant chemotherapy and its apparent

effects on cognitive function and discusses future directions of research in this area.
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Cognitive declines can have a significant negative impact on cancer patients' quality of life

and on patients' occupational and educational decisions. Patients need to be informed of

potential cognitive effects to help guide informed treatment decision making; past research

with children has led to treatment-regimen modifications that have reduced negative

cognitive impact but maintain treatment efficacy; increasing numbers of individuals with

cancer are concerned about this problem with large numbers (hundreds of thousands) of

individuals undergoing chemotherapy in the United States annually; and cognitive

rehabilitation approaches have been demonstrated to improve functioning among individuals

with other forms of cognitive problems, and these may be effective for cancer patients

experiencing cognitive decline.

What are HIV and AIDS?

HIV, or human immunodeficiency virus, is the virus that causes AIDS. HIV attacks the

immune system by destroying CD4 positive (CD4+) T cells, a type of white blood cell that is

vital to fighting off infection. The destruction of these cells leaves people infected with HIV

vulnerable to other infections, diseases and other complications.

A person infected with HIV is diagnosed with AIDS when he or she has one or

more opportunistic infections (which occur when your immune system is damaged by HIV),

such as pneumonia or tuberculosis, and has a dangerously low number of CD4+ T cells (less

than 200 cells per cubic millimeter of blood).

People with HIV/AIDS are at a higher risk for mental health disorders.

If you are living with HIV, it is important for you to be aware that you have an

increased risk for developing mood, anxiety, and cognitive disorders. For example, people

living with HIV are twice as likely to have depression compared to those who are not infected
 14

with HIV. These conditions may be treatable. Many people with mental health conditions

recover completely.

Some forms of stress can contribute to mental health problems for people living with HIV,

including

 Having trouble getting the services you need

 Experiencing a loss of social support, resulting in isolation

 Experiencing a loss of employment or worries about whether you will be able to

perform your work as you did before

 Having to tell others you are HIV-positive

 Managing your HIV medicines

 Going through changes in your physical appearance or abilities due to HIV/AIDS

 Dealing with loss, including the loss of relationships or even death

 Facing the stigma and discrimination associated with HIV/AIDS

The HIV virus itself also can contribute to mental health problems because it enters and

resides in your brain. Some other opportunistic infections can also affect your nervous system

and lead to changes in your behavior and functioning. Similarly, neuropsychological

disorders, such as mild cognitive changes or more severe cognitive conditions, such

as dementia, are associated with HIV disease.

You can better manage your overall health and well-being if you know how having HIV can

affect your mental health and what resources are available to help you if you need them.
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Individuals who learn they are infected with HIV -- whether chronically or acutely --

commonly experience a range of emotions including:

 anger

 confusion

 anxiety

 shame, guilt, or alienation

 sadness or depression

The psychological impact of such feelings can be profound, and referral to a counselor or

therapist experienced with HIV disease is recommended. In particular, depression is the most

common psychiatric disorder among HIV-infected patients and pharmacological intervention

may be warranted.

Persons diagnosed with primary HIV infection (PHI) are faced with psychological challenges

unique to their early disease stage. A PHI patient presenting with symptoms such as fevers,

rash, or diarrhea may confuse these symptoms with those of AIDS. Patients with PHI should

first be assured that they do not have AIDS and that PHI is an early disease stage after which

many people remain healthy for 10 years or longer, even without treatment. Additionally,

treating factors that may have contributed to infection (for instance, alcohol, drug, or sexual

addiction) can help reduce further transmission, especially during such an episode of high

viremia as found in PHI.

Of equal concern, especially if the clinician decides to initiate antiretroviral therapy during

PHI, is that patients understand why they will be taking potent drugs to fight HIV when most

chronically infected people are advised to wait until mid- or late-stage disease before starting

therapy. An essential issue is whether or not patients should be enrolled into clinical study, if

available. Each patient should be counseled about the pros and cons of such enrollment. Also,
 16

issues regarding potential drug side effects and toxicities, as well as the importance of

adherence, should be explained.

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A Brief History of HAND

Very early in the AIDS epidemic, clinicians noticed prominent “organic” mental and

neurological symptoms in a subset of patients with advanced disease (e.g., Perry and

Jacobsen 1986; Snider et al. 1983), suggesting that the underlying pathogen (not known to be

HIV at the time) likely affected the central nervous system (CNS). Snider and colleagues

(1983) are credited with the first systematic description of the CNS complications of AIDS in

a case series of 50 patients, a proportion of whom exhibited possible AIDS-related dementia.

In these early years, patients with cognitive impairment were often severely demented, which

was viewed as a harbinger of imminent mortality. Although these initial studies of the AIDS

dementia complex (ADC) described the clinical onset of symptoms as insidious in most

cases, many dementia cases had abrupt accelerations sparked by opportunistic infections (or

pulmonary infections with hypoxia), thus obscuring conclusions regarding a possible direct

relationship between HIV and cognitive deficits (e.g., Navia et al. 1986). The existence of

neurocognitive impairment directly attributable to HIV, especially in the medically

asymptomatic phase of disease, was somewhat controversial until 1987, when Grant et al.

published the first comprehensive study of HIV-associated neurocognitive deficits. Findings

from this study provided strong evidence of objective neurocognitive impairment across all

stages of HIV disease (i.e., medically asymptomatic, symptomatic, and AIDS) and in

multiple ability areas, including executive functions, episodic memory, and information

processing speed.

Soon thereafter, the AIDS Task Force of the American Academy of Neurology (AAN) (1991)

convened to outline diagnostic guidelines for classifying the neurologic complications of HIV

infection. At that time, two levels of disturbance were proposed: 1) HIV-associated dementia

(HAD) with motor, behavioral/psychosocial, or combined features; and 2) minor cognitive

motor disorder (MCMD). To meet criteria for a diagnosis of HAD a patient needed to
 18

demonstrate an acquired deficit in at least two neurocognitive domains that caused

impairment in work or activities of daily living (ADLs), as well as evidence of an

abnormality in motor abilities or specified neuropsychiatric or psychosocial functions (e.g.,

motivation, lability, and social behavior). MCMD described a less severe presentation of

HIV-associated neurocognitive impairment that did not meet criteria for HAD, but was

marked by impairment in at least two neurocognitive or behavioral areas that produced a

decline in ADLs. In 1995, Grant and Atkinson expanded the AAN system to include an

additional diagnosis of “subsyndromic neurocognitive impairment” to characterize patients

who demonstrated mild neurocognitive deficits that do not noticeably interfere with ADLs, a

diagnosis which became increasingly more recognized in neuroAIDS research laboratories

and clinics.

While the modified AAN criteria (Grant and Atkinson 1995) were reasonably accurate in

predicting presence of HIV-associated neuropathologies (e.g., Cherner et al. 2002),

researchers and clinicians alike have since recognized the need to update and further structure

the diagnostic criteria for HAND, especially in light of the changing epidemiology of HIV

infection (Antinori et al. 2007). First, the applicability of the old criteria is now limited in the

present age of cART. Prior to the advent of cART, a diagnosis of HAD was associated

strongly with low T-cell counts, high viral loads, and opportunistic infections. With cART

moderating viral severity, persons with HIV typically live longer with milder medical

symptoms. Although cART initiation has been linked to cognitive improvement and

decreased incidence of HAND (e.g., Brodt et al. 1997; Sacktor et al. 1999; 2001), yearly

incidence rates are still 10–25%, suggesting that a variety of factors (e.g., immunological,

genetic, psychosocial) may also play an important role in determining cognitive impairment

(Robertson et al. 2007). Secondly, the modified AAN criteria (Grant and Atkinson 1995) did

not provide specific guidelines for the assessment and determination of neurocognitive
 19

impairment. Considering the increased prevalence of HIV infection since the early diagnostic

criteria and corresponding incident growth of cognitive sequelae, standardization became

increasingly necessary in order to better address risk characteristics and treatment

possibilities. Finally, guidelines regarding possible neurocognitive impairment due to

comorbid conditions with CNS effects (e.g., substance use disorders) were necessarily vague

in the previous diagnostic scheme, which diminished interrater reliability of HAND (Woods

et al. 2004b). This caveat is particularly important in the era of cART as those infected with

HIV began living longer with a host of CNS risk factors, including comorbid infectious

diseases (e.g., hepatitis C virus), substance use disorders (e.g., methamphetamine

dependence), and medical conditions associated with cART treatment (e.g., hyperlipidemia).

Current Diagnostic Nomenclature of HAND

To address the concerns of definitions and causes of neurocognitive impairment in

HIV-infected individuals, the nosology of HAND was recently revisited and subsequently

amended using recommendations from an NIH working group (Antinori et al. 2007). As

displayed in Fig. 1, the redefined criteria allow for three possible research diagnoses: 1)

asymptomatic neurocognitive impairment (ANI); 2) HIV-associated mild neurocognitive

disorder (MND); and 3) HAD. The diagnosis of HAND must be determined by assessing at

least five areas of neurocognitive functioning known to be affected by HIV infection (e.g.,

executive functions, episodic memory, speed of information processing, motor skills,

attention/working memory, language, and sensoriperception). Ideally, these domains would

be evaluated using a performance-based neurocognitive battery and interpreted using

demographically-appropriate normative data, although the criteria allow for use of mental

status exams, such as the HIV Dementia Scale (Morgan et al. 2008; Power et al. 1995) in

resource-limited settings. If observed, neurocognitive impairment cannot be assigned a

 20

HAND diagnosis if it is solely attributed to a comorbid condition (e.g., psychosis or

substance use) or delirium. Due to the high prevalence of CNS comorbidities in HIV

populations, the updated criteria specify guidelines for dealing with incidental (e.g., an

individual with remote history of sporadic methamphetamine use that is unlikely to have

residual cognitive effects), contributing (e.g., an individual with methamphetamine

dependence within one year, but who is exhibiting clear signs of HIV-related cognitive

decline), and confounding (e.g., an individual who is acutely intoxicated on

methamphetamine) conditions.

As a diagnosis of HAND often rests on determining the presence (or absence) of declines in

everyday functioning, it is important to consider the many intricacies and complications

involved in assessing functional impairment. Currently, there are no widely agreed-upon

clinical measures of everyday functioning (see Morgan and Heaton 2009). Performance-

based assessments of everyday functioning are sometimes used in research settings, but the

lack of normative data coupled with lengthy administration protocols make it unlikely that

the currently available measures would be widely used in a clinic setting (Moore et al. 2007).

More commonly, assessments of everyday functioning rely on self-report, using

questionnaires such as Lawton & Brody’s modified Activities of Daily Living scale (Heaton

et al. 2004) and the Patient’s Assessment of Own Functioning (PAOFI; Chelune et al. 1986).

In some cases, proxy (e.g., significant others and caregivers) reports may complement patient

report, particularly in cases of cognitive impairment and poor insight. Similarly, self-reported

functional abilities are oftentimes confounded by psychiatric (e.g., over-reporting due to

depressive symptoms) or socioeconomic (e.g., under-reporting to retain occupational

responsibilities) factors, which must be carefully considered in assessing self-report validity.

 21

HIV-Associated Neurocognitive Disorders (HAND)

HAND represents the range of neurocognitive complications associated with HIV

infection. Although there is currently no cure for HAND, combination antiretroviral therapy

has been shown to be the only option in preventing or delaying the progression of HAND.

There are three major types of HAND:

 Asymptomatic Neurocognitive Impairment (ANI) is diagnosed if testing shows

HIV-associated impairment in cognitive function, but everyday functioning is not

affected.

 Mild Neurocognitive Disorder (MND) is diagnosed if testing shows HIV-associated

impairment in cognitive function, and mild interference in everyday functioning.

 HIV-associated Dementia (HAD) is diagnosed if testing shows marked impairment

in cognitive function, especially in learning of new information, information

processing, and attention or concentration. This impairment significantly limits your

ability to function day-to-day at work, home, and during social activities.

Although a significant proportion of people living with HIV are affected by a mild form of

HAND, there has been significant progress in the treatment of HAND. Since the start of the

epidemic, severe cases of HAND have been on the decline and the most severe form, HAD,

is rare. The majority of people experience more subtle abnormalities in memory and

cognition.

Experienced clinicians can diagnose HAND after carefully ruling out other possible causes of

the symptoms. They may conduct a thorough neurological exam and history,

neuropsychological testing, brain MRI scan, and sometimes lumbar puncture to evaluate the

cerebrospinal fluid to obtain information about the nature and severity of HAND.
 22

1) Asymptomatic Neurocognitive Impairment (ANI)

Considering the growing literature on mild neurocognitive impairment in the absence

of declines in everyday functioning, asymptomatic neurocognitive impairment (ANI) was

added as a diagnosis consistent with earlier references to subsyndromic neurocognitive

impairment (i.e., Grant and Atkinson 1995). This previously unclassified contingent is

estimated to represent the majority of cases of HAND (i.e., over 50% of diagnosed cases) and

21–30% of the asymptomatic HIV-infected individuals (Robertson et al. 2007). The clinical

significance of such “subsyndromic” impairment is less well-established, although it has been

associated with neuropathologic abnormalities (Masliah et al. 1997; Cherner et al. 2007) and

an increased risk of early mortality (Ellis et al. 1997). Detecting patients with mild, yet

demonstrable, neurocognitive impairment (i.e., > 1 SD below the mean of demographically-

adjusted normative scores in at least two cognitive domains) may assist in the effort to pre-

identify those at risk for more significant cognitive as well as functional decline, before

cognitive deficits contribute to a decline in everyday functioning with serious medical

consequences (e.g., medication nonadherence). In principle, as effective treatments for

neurologic complications are developed, intervention at this earliest stage of HAND might

stand the best chance to effect remission, or at least, prevent progression.

2) Mild Neurocognitive Disorder (MND)

Formerly referred to as MCMD, mild neurocognitive disorder (MND) requires mild-

to-moderate neurocognitive impairment (i.e., > 1 SD below the mean of demographically-

adjusted normative scores) in at least two cognitive domains in addition to mild everyday

functioning impairment. Approximately 30–50% of persons with a HAND diagnosis

experience some degree of functional impairment and it is estimated that 20–40% of HAND

diagnoses are of MND, which comprises 5–20% of the HIV population overall. The
 23

prevalence of MND is estimated between 5% to 14% in individuals with early symptoms and

approximately 25% of those with AIDS (Goodkin et al. 2001; Grant and Atkinson 1999).

Mild functional impairment can be classified as meeting at least two of the following criteria:

1) self- or proxy-report of declines in ≥ 2 instrumental activities of daily living (IADLs; e.g.,

financial management); 2) unemployment or a significant reduction in job responsibilities

secondary to reduced cognitive abilities; 3) decline in vocational functioning (e.g., increased

errors, decreased productivity, or greater effort is required to achieve prior levels of

productivity); 4) self- or proxy-report of increased problems in ≥ 2 cognitive ability areas in

day-to-day life (this criterion cannot be used if based only on the self-report of an individual

with current depression, since depression may bias self-report); or 5) scores > 1 SD below the

mean on a performance-based laboratory measure of everyday functioning (e.g., medication

management).

3) HIV-Associated Dementia (HAD)

The most severe form of HAND, HIV-associated dementia (HAD) is marked by at

least moderate-to-severe cognitive impairment (i.e., ≥ 2 SDs below demographically-adjusted

normative means) in at least two cognitive domains along with marked ADL declines that are

not fully attributable to comorbidities or delirium. Additionally, HAD represents the most

severe form of HAND in terms of its functional impact, which requires two or more of the

following: 1) unemployment due to cognitive impairment; 2) self- or proxy-report of

dependence in > 2 IADLs related to cognitive problems; 3) self- or proxy-report of declines

in ≥ 4 cognitive ability areas in day-to-day life (NB. As with a diagnosis of MND, this

criterion is not applicable if based exclusively on the self-report of an individual with current

depression); 4) performance that is > 2 SD below the mean on a performance-based

laboratory measure of everyday functioning (or > 1 SD below the mean on two functional
 24

tests). Reports from the early 1990’s placed an extremely wide range, 6–30%, on the

prevalence of HAD among persons with AIDS (Day et al. 1992; McArthur et al. 1993; Maj et

al. 1994). After the advent of cART in the late 1990’s, estimates appeared to shift downward

with approximately 4% to 7% of persons with AIDS (Grant and Atkinson 1999), with more

recent appraisals suggesting that as few as 1% to 2% of HIV+ persons meet criteria for HAD

(Grant et al. 2005).

Global epidemiology of HIV and HAND

HIV is a truly global disease, affecting roughly 33 million people all over the world. The

number of people infected with HIV in the United States, Western Europe and Oceania

however represent only 4% of worldwide infections (Hemelaar et al. 2006). Most of the

people infected or affected by HIV live in developing countries where cultural values, social

influences, educational opportunities and access to other resources are clearly distinct from

those in the West. Africa and the Middle East account for over 66% of worldwide infections,

Asia for over 20%, Eastern Europe and Central Asia for approximately 4%, and Latin

America and the Caribbean for around 6% (Hemelaar et al. 2006).

In addition to the wide dispersion of HIV around the world, the rapid evolution of the virus

itself has led to considerable genetic variation in a relatively short period of time. In West

Central Africa, where the original cross-species transmissions are believed to have occurred

(Gao et al. 1999), almost all of the nine major subtypes of HIV-1 Group M (A-D, F-H, J, and

K), as well as strains of HIV-1 Groups N and O, and HIV-2 can be found. In other parts of

Africa and other regions of the world however (Fig. (Fig.1),1), certain subtypes and

recombinant forms such as CRF01_AE and CRF02_AG predominate over others (Hemelaar

et al. 2006). The extensive genetic diversity that characterizes HIV along with the geographic

compartmentalization of viral species raises interesting and challenging questions in regards

 25

to associated differences in disease progression (systemic and neurological), effectiveness of

antiretroviral therapy, and the outlook of the constantly evolving pandemic.

The Course of HAND

Unlike other neurodegenerative disorders, such as Alzheimer’s and Huntington’s

diseases, HAND is not invariably progressive and is therefore not an immutable diagnosis.

Indeed, there is tremendous variability in the course of HAND, with evidence now showing

that individuals may display considerable recovery of cognitive functions (e.g., with effective

cART), incident worsening of HAND (e.g., with advancing disease), static neurocognitive

impairment, sustained normality (e.g., Cole et al. 2007), or a fluctuating course. Robertson et

al. (2007) showed that, of HIV-infected persons who were unimpaired at their baseline visit,

21% experienced incident neurocognitive impairment over a relatively brief follow-up

period. However, most persons with incident HAND are initially classified with mild

impairment; that is, it is rare for persons in the current era of cART to transition from

unimpaired to moderately or severely impair in a year (e.g., McArthur 2004). A finding that

is becoming increasingly apparent with regard to the course of HAND is that a significant

proportion of individuals will improve neurocognitively. In the Robertson et al. (2007) study,

of those persons with HAND at baseline, 56% remained impaired whereas 44% no longer

met criteria for impairment. Furthermore, the likelihood of transitioning from milder

neurocognitive impairment to unimpaired (21%) appears to be as likely as transitioning from

unimpaired to mild neurocognitive impairment (23%) (McArthur 2004). Nevertheless, it is

difficult to interpret the data on incident HAND, especially considering the complications of

practice effects (e.g., Woods et al. 2005b) that, if uncorrected, may inflate the rates of

observed improvement (and perhaps also dampen the rates of incident impairment). The

incidence data are also confounded by the necessary use of cutpoints for the classification of
 26

neurocognitive impairment (Carey et al. 2004), which are highly susceptible to mis-

classification errors secondary to normal test-retest variability.

Neuropsychology of HIV infection

HIV-1 enters the CNS early during the course of infection (An et al. 1999; Davis et

al. 1992) and frequently results in neurological disease marked by a set of cognitive, motor,

and behavioral symptoms (Chiodi et al. 1992; Navia et al. 1986b). The significant loss of

neurons and neuronal processes (e.g. dendritic complexity) in people dying of AIDS clearly

correlates with ante-mortem neurocognitive impairment (Masliah et al. 1992, 1997; Mattson

et al. 2005). Cells primarily infected by HIV within the CNS are blood-derived macrophages,

resident microglia, and perhaps astrocytes, but most studies suggest that neurons are not

directly infected (Epstein and Gendelman 1993; Kure et al. 1990; Takahashi et al. 1996;

Trillo-Pazos et al. 2003). The neuronal damage that occurs is likely caused by shed viral

proteins such as gp120 (Dreyer et al. 1990; Lannuzel et al. 1995) and Tat (Behnisch et

al. 2004; Jones et al. 1998; Maragos et al. 2003; Nath et al. 1999) or indirectly through the

elevated production of neurotoxic molecules released by activated astrocytes (Levi et

al. 1993; Merrill et al. 1992; Mollace et al. 1993; Nath et al. 1999; Patton et al. 2000),

macrophages (Gendelman et al. 1994; Levi et al. 1993; Merrill et al. 1992; Nath et al. 1999),

and microglia (Gendelman et al. 1994; Jones et al. 1998; Kramer-Hammerle et al. 2005; Levi

et al. 1993; Mattson et al. 2005; Nath et al. 1999). HIV infection in the brain has widespread

and variable effects but appears to preferentially cause damage to the basal ganglia and deep

white matter (Navia et al. 1986a). However, damage to cortical and subcortical neurons

(hippocampus and putamen) (Archibald et al. 2004; Everall et al. 1999; Moore et al. 2006),

particularly dendritic pathology (Masliah et al. 1997) also are likely to play a role in CNS

disease manifestations.
 27

AIDS Dementia Complex (severe neurocognitive loss and dysfunction)

HIV related neurological diagnoses was recently revised and updated (Antinori et

al. 2007), but there are a number of terms used in the existing literature worth discussing for

purposes of clarity. Navia et al. initially recommended the term AIDS Dementia Complex to

label the severe neurocognitive loss and neurological dysfunction associated with advanced

immunodeficiency (Navia et al. 1986b). Later the American Academy of Neurology

suggested HIV Associated Dementia as a better label (AAN 1991). AIDS Dementia Complex

and HIV Associated Dementia have since been used interchangeably. Patients with some

degree of cognitive impairment but whom did not meet criteria for dementia were classified

as having Minor Cognitive Motor Disorder in the AAN nomenclature although, especially in

the neurological literature, milder forms of neurocognitive disturbance sometimes have been

classified as a lower stage of “dementia” (e.g. Memorial Sloan-Kettering (MSK) scale for

dementia: 1-mild, 2-moderate, 3-severe, 4-end stage, mute) (Price and Sidtis 1990).

With true HIV Associated Dementia, patient profiles were marked by severe behavioral

changes, attention and executive dysfunction, psychomotor slowing, and memory impairment

(Bornstein et al. 1993; Stern et al. 2001). Minor Cognitive Motor Disorder patient profiles

were characterized by impaired cognitive and motor speed, working memory, and new

learning, but most aspects of language (except fluency) and long term memory (semantic)

were relatively unimpaired. As the scope of cognitive dysfunction in HIV infection has

become more evident, it has been suggested that for research and epidemiological purposes

HIV-Associated Neurocognitive Disorders (HAND) be used as a more comprehensive title,

with three broad subdivisions depending on the degree of cognitive impairment and

associated changes in everyday functioning: Asymptomatic Neurocognitive Impairment,

HIV-associated Mild Neurocognitive Disorder, and HIV-Associated Dementia.

Asymptomatic Neurocognitive Impairment is defined by performance at least 1 standard

 28

deviation (SD) below the mean of demographically adjusted normative scores in at least two

cognitive areas (attention-working memory, speed of information processing, language,

abstraction-executive, complex perceptual motor skills, memory, including learning and

recall, simple motor skills or sensory perceptual abilities), but without any apparent changes

in activities of daily living. Mild Neurocognitive Disorder, previously referred to as Minor

Cognitive and Motor Disorder, features the same test performance criteria as above, but with

notable changes (at least mild) in activities of daily living. HIV-Associated Dementia

requires performance of at least 2 SD below demographically corrected normative means in

at least two different cognitive areas, as well as marked difficulty in activities of daily living

due to cognitive impairment (Antinori et al. 2007). Diagnosis of all three forms of HAND

also requires a determination that the observed neurocognitive impairment and/or functional

disturbance cannot be explained by co-morbid (non-HIV related) conditions.

Patterns of Neurocognitive Dysfunction with HIV

HIV infection characteristically generates a “sub-cortical” pattern of neurocognitive

dysfunction with deficits predominantly affecting executive functions, speed of information

processing, attention/working memory, motor speed, new learning and retrieval of new

information, while long term (semantic) memory, many language skills, and visuo-spatial

abilities may remain intact (Dawes et al. 2008; Grant et al. 1987; Heaton et al. 1995). This

average pattern of neuropsychological impairment, reported by numerous studies before and

after the advent of highly active antiretroviral therapy, has shaped the development of current

and future test batteries used across the US and internationally.

The pattern of neurocognitive dysfunction, however, is not consistent across individuals

(Dawes et al. 2008) and may be even less consistent across individuals from markedly

different backgrounds. Individuals exhibit considerable variation in strength and weakness of

 29

ability domains such as verbal memory, visual memory, processing speed, attention/working

memory, executive function, and motor skills. Some may exhibit strong motor skills with

weak executive functions and verbal memory, some may retain processing speed but show

decreased visual memory and executive functions, and still others may feature strong

memory but weak motor skills (Dawes et al. 2008). Test batteries used in international

settings tend to be limited to fewer of the ability domains above, and to have a fixed focus on

effects of fronto-striatal and white matter involvement. As such, a battery focused on motor

skills and verbal learning may miss significant impairment in processing speed and attention,

or vice versa. Differences in patterns of dysfunction may be due to differences in HIV

neuropathology and co-morbid conditions. Distinct patterns of co-morbidities, such as higher

rates of intravenous drug use in the US compared to high prevalence of Hepatitis C in rural

China (Heaton et al. 2008) may have varying effects on the CNS and performance on

neuropsychological testing. In some cases the impact of CNS opportunistic infections or prior

injury or illness may entirely preclude the detection of any direct effects of HIV on the

nervous system. Determining the biological and environmental sources of these different

patterns of impairment, and how they affect activities of daily living, remain important goals

of HIV research in both the US and internationally. In addition, any evolving changes in

neurological outcomes may be missed by prior and even ongoing studies that use focused test

batteries tailored to fronto-striatal and white matter involvement. For example, if older people

are more represented in a study population, more “cortical” patterns may occur, but may be

missed by assessment focused on sub-cortical dysfunction. Extensive batteries frequently

used for neuropsychological assessments in the US may cover a wide range of abilities, but

may not be an option for studies in resource-limited settings due to limitations in time, local

expertise, and availability of valid test instruments and norms. It should be kept in mind

however that, especially in this evolving epidemic, we cannot assume that neurocognitive
 30

abilities not assessed by the test battery being used are unaffected. Unfortunately, even if we

change (expand) our batteries now, at the expense of considerable time, money and resistance

from other colleagues in the field, there will be little previous data to compare with the new

findings.

Negative consequences of HIV and co-occurring mental illness

Below we review some of the particular difficulties that can arise as a result of having

both HIV infection and SMI. It is important to note that not all HIV-infected individuals will

face these challenges, but for those who have these co-occurring problems, thoughtful and

targeted treatment is paramount.

Health outcomes and medication adherence

SMI is associated with a more rapid and harder-to-treat progression of HIV disease.

These worsened disease outcomes can be caused by non-adherence to HIV medication, which

can lead to worsened immune response, increased HIV replication, and development of drug-

resistant viral mutations. Other, less obvious, connections may also exist. Specifically, there

is likely a relationship between stress, depression and immune response such that HIV

infection may progress more rapidly in individuals with these symptoms (Leserman, 2003).

Given the risk for worse HIV disease outcomes, treatment advocates have used the presence

of a coexisting psychiatric illness as a reason to suggest more aggressive and comprehensive

clinical management of HIV infection (Angelino & Treisman, 2001).

As indicated above, HIV infection and SMI comorbidity appear to be detrimental for

medication adherence. In addition to the problems caused by non-adherence to HIV

medications, there may be equally significant difficulties caused by non-adherence to

psychotropic medications. Depressive symptoms have long been linked to poor medication

adherence among HIV+ persons, and treatment with antidepressant medication appears to

improve antiretroviral adherence among those with a current mental health problem,
 31

especially those with more complex medication regimens (Kumar & Encinosa, 2009). One

can easily imagine a scenario where non-adherence to psychiatric medications leads to

disrupted mood or other significant psychiatric symptoms that may then lead to non-

adherence to anti-HIV medications. In addition, poorly controlled HIV leads to a higher

likelihood of HIV transmission when individuals engage in risk behaviors. In a current study

by our group, we have found that HIV+ individuals with comorbid bipolar disorder have

significantly worse adherence to their antiretroviral medication than a comparable group of

HIV+ individuals without bipolar disorder. The proportion of persons with an ART

adherence level above 90 percent was nearly twofold higher in the HIV+ persons without

bipolar disorder (Moore et al., in press).

Risk behavior engagement

Most adults who have been diagnosed with HIV are sexually active (Lansky et al.,

2000), and a substantial proportion report engaging in unsafe sexual or drug injection

practices (Heckman et al., 1998). Research findings show that SMI clients are highly

vulnerable to contracting HIV partly because of the relationship between SMI and low SES,

which places this population in contact with high-risk populations (Parry, Blank, & Pithey,

2007). For those who have both HIV and SMI, the risk of transmitting HIV to others may be

particularly great, given that individuals with prolonged psychiatric illnesses can exhibit poor

judgment, affective instability and impulsivity. These symptoms may increase engagement in

higher risk for HIV transmission behaviors.

Suicide risk

One very concerning problem among persons with HIV and SMI is suicidality.

Comorbid psychiatric illnesses, especially major depressive disorder and substance use

disorders, have been found to be highly predictive of suicidal ideation in HIV+ individuals. A

recent study of HIV+ persons in a large multi-site cohort found that individuals with a history
 32

of suicidal ideation and suicide attempt reported significantly higher levels of current

depressive symptoms and had a significantly higher prevalence of current major depressive

disorder, as well as higher levels of plasma HIV RNA (Badiee et al., 2011). Given that prior

suicidal ideation and behavior were associated with current depression in this population, it is

possible that these individuals may still be at risk for future suicidal ideation and behavior.

HIV treating clinicians should be cognizant of past suicidal ideation or behavior, and monitor

these patients carefully for current mood disturbances, as these individuals may still be at risk

for suicide.

Neurocognitive ability

Neuropsychological impairment is another possible negative consequence of the

comorbidity between HIV and SMI, and this impairment may exacerbate other possible

outcomes such as increased engagement in risk behaviors and worse medication adherence. It

is well known that HIV infection can result in neuropsychological impairment in

approximately 50 percent of patients (Heaton, et al., 2010). It is widely recognized that

specific mental illnesses can lead to varying levels of neuropsychological impairments too. In

one of the few studies of neuropsychological functioning among HIV+ individuals with SMI

(specifically bipolar disorder), the authors found that these individuals have worse sustained

attention and worse overall daily functioning than HIV-infected individuals without bipolar

disorder (Posada et al, 2011).

Cardiovascular disease

Heart disease

Heart and blood vessel disease (also called heart disease) includes numerous problems,

many of which are related to a process called atherosclerosis.

 33

Atherosclerosis is a condition that develops when a substance called plaque builds up in the

walls of the arteries. This buildup narrows the arteries, making it harder for blood to flow

through. If a blood clot forms, it can block the blood flow. This can cause a heart attack or

stroke.

Heart attack

A heart attack occurs when the blood flow to a part of the heart is blocked by a blood

clot. If this clot cuts off the blood flow completely, the part of the heart muscle supplied by

that artery begins to die.

Most people survive their first heart attack and return to their normal lives, enjoying many

more years of productive activity. But experiencing a heart attack does mean that you need to

make some changes.

The medications and lifestyle changes that your doctor recommends may vary according to

how badly your heart was damaged, and to what degree of heart disease caused the heart

attack.

Stroke

An ischemic stroke (the most common type of stroke) occurs when a blood vessel that

feeds the brain gets blocked, usually from a blood clot.

When the blood supply to a part of the brain is cut off, some brain cells will begin to die. This

can result in the loss of functions controlled by that part of the brain, such as walking or

talking.

A hemorrhagic stroke occurs when a blood vessel within the brain bursts. This is most often

caused by uncontrolled hypertension (high blood pressure).

 34

Some effects of stroke are permanent if too many brain cells die after being starved of

oxygen. These cells are never replaced.

The good news is that sometimes brain cells don’t die during stroke — instead, the damage is

temporary. Over time, as injured cells repair themselves, previously impaired function

improves. (In other cases, undamaged brain cells nearby may take over for the areas of the

brain that were injured.)

Either way, strength may return, speech may get better and memory may improve. This

recovery process is what stroke rehabilitation is all about.

Heart failure

Heart failure, sometimes called congestive heart failure, means the heart isn’t pumping

blood as well as it should. Heart failure does not mean that the heart stops beating — that’s a

common misperception. Instead, the heart keeps working, but the body’s need for blood and

oxygen isn’t being met.

Heart failure can get worse if left untreated. If your loved one has heart failure, it’s very

important to follow the doctor’s orders.

Arrhythmia

Arrhythmia refers to an abnormal heart rhythm. There are various types of arrhythmias.

The heart can beat too slow, too fast or irregularly.

Bradycardia, or a heart rate that’s too slow, is when the heart rate is less than 60 beats per

minute. Tachycardia, or a heart rate that’s too fast, refers to a heart rate of more than 100

beats per minute.

 35

An arrhythmia can affect how well your heart works. With an irregular heartbeat, your heart

may not be able to pump enough blood to meet your body’s needs.

Heart valve problems

When heart valves don’t open enough to allow the blood to flow through as it should, a

condition called stenosis results. When the heart valves don’t close properly and thus allow

blood to leak through, it’s called regurgitation. If the valve leaflets bulge or prolapse back

into the upper chamber, it’s a condition called prolapse. Discover more about the roles your

heart valves play in healthy circulation.

Heart failure (HF) is a major health problem in developed countries that affects

approximately 1%–2% of the adult population with a rising prevalence to 6%–10% in people

over 65 years and to ≥ 10% among persons 70 years of age or older.[1] Heart failure HF is

associated to increased mortality and morbidity, frequent hospital admissions and reduced

quality of life and functional status.

As Heart failure HF incidence increases according with aging, also geriatric conditions must

be taken in account in the evaluation of cognitive impairment in Heart failure HF population.

Cognitive impairment is one of the most common co-occurring chronic conditions among

elderly people with Heart failure HF. Its incidence varies widely from 25% to about 70%–

80% depending on the characteristics of the sample and of the disease, instruments used to

assess cognition and study design.

Several cerebral areas and different cognitive domains can be involved in patients with Heart

failure HF developing deficits in cognition. Furthermore, different pathophysiological

processes like cerebral hypoperfusion due to alteration of cardiac output or cerebrovascular

reactivity, arterial hypotension, production of proinflammatory cytokines or depressed mood

are called into question in the determination of cognitive impairment.

 36

Presence of cognitive impairment may interfere with self-care that is the active decision-

making process aimed to maintain health, deal with incident disease and operate changes in

personal behaviors or specific treatment if necessitated by worsening symptoms. Deficits in

cognition may be related also to increased mortality, higher rates of hospital admission and

functional impairment. Some studies focused on the role of pharmacological and non-

pharmacological interventions in reversing cognitive impairment even if no absolute

consensus was reached.

The present review gathers available evidence on epidemiology of cognitive impairment in

patients with Heart failure HF, on brain and cognitive areas affected, on the tools to be used

to assess cognition. Moreover, pathophysiological processes of cognitive impairment and

finally the impact of such deficit in Heart failure HF population were discussed.

Cognitive impairment in HF patients: epidemiology

Incidence of cognitive damage in HF patients varies widely depending on the studied

population (outpatients or inpatients, age, sample sizes), features of disease (subtypes or

severity of disease, diagnostic criteria), the neuropsychological tests used to define cognitive

impairment and the different study designs.

In a cross-sectional descriptive study on forty-four HF outpatients ≥ 65 years, 52% of whom

in New York Heart Association (NYHA) class III or IV, mean age 76 years and mean left

ventricular ejection fraction (LVEF) 37%, cognitive impairment, defined as a score on

montreal cognitive assessment (MOCA) test < 26, was detected in > 70% of the

sample.[2] Similar results were obtained in a randomized controlled trial aimed to assess the

effects of a tailored intervention on self-care in 176 patients hospitalized for acute heart

failure: 74% of them screened positive for mild cognitive impairment (MCI) defined as score

on MOCA test of 17–25, 9% scored < 17 points and 17% proved to have normal
 37

cognition.[3] In a group of twenty patients with previous myocardial infarction, symptoms of

HF in NYHA III-IV and a LVEF < 40%, a moderate or severe episodic long-term memory

impairment, evaluated with the Riverhead Behavioral memory test, in 25% of patients

emerged.[4] The mini mental state examination (MMSE) revealed cognitive impairment in

54% in a group of fifty patients (mean age: 67.3 years) who were admitted for acute

decompensation and without a history of myocardial infarction/stroke during the previous 6

months and with LVEF lower than 45%.[5] In a longitudinal study on 140 outpatients, 35.7%

females, mean age 68.9 years with no previous history of neurological or psychiatric disease,

62% of the sample demonstrated some degree of cognitive impairment assessed through

different tools.[6] Finally, the systematic review of Vogel’s compared the risk of cognitive

impairment in a pooled sample of 2937 HF patients to 14,848 controls (healthy subjects or

with other cardiovascular disease) and underlined as cognitive impairment was 1.62 times

greater in HF group.

Cognitive impairment in HF patients: cognitive areas and cerebral regions involved

Cognitive damage in HF involves different domains,[8],[9] in particular HF adversely

affects learning memory and delay recall, attention, executive function, psychomotor speed

and working memory. Language and visuospatial ability are less affected in patients with HF

even if very few studies assessed them in these patients.

In a cross-sectional study involving 249 patients with chronic systolic HF compared to age

and education-matched 63 healthy people and 102 participants with major chronic disease

other than HF, HF patients showed worse score in memory (P < 0.0001), psychomotor speed

(P < 0.0001) and executive functions (P< 0.0002) assessed through validated tools (Hopkins

verbal learning test for memory, digit symbol and trail making test A (TMT-A) for

psychomotor speed and TMT-B and controlled oral word association (COWA) for executive
 38

function). In the systematic review by Vogel’s pooled analysis showed diminished

performance in memory, psychomotor speed/attention (assessed with TMT-A) and global

cognition (tested with MMSE) when comparing HF patients to healthy subjects. Also in 577

hospitalized patients with acute HF, mean age 71 years, females about 50% of the sample,

33% showed memory problems, 40% slower processing speed and 56% impairment in

executive tasks.

A global deterioration test as MOCA was frequently used to assess cognition as in the cross-

sectional study by Harkness, et al. that analyzed forty-four outpatients ≥ 65 years with HF:

cognitive domains showing significant differences (P < 0.01) in sub scores were short-term

memory, visuospatial ability, executive function and language. Athilingham, et al. performed

MOCA test in a group of 90 community-dwelling adults, 76.6% of whom with systolic HF:

mean MOCA score was lower in the systolic group than in diastolic patients with statistically

significant difference (22.9 ± 2.31 vs. 24.8 ± 2.76, P = 0.03); visuospatial/executive function

and attention subtests score were significantly lower in patients with systolic dysfunction

(P = 0.026 and P = 0.049, respectively) while abstraction and delayed recall were more

compromised in patients with diastolic HF (P = 0.014 and P = 0.048, respectively).

 39

Did cognitive function decline over time in HF populations tested regularly?

In a cohort of 702 community-dwelling people, 80 years of age and older (mean age at

baseline 83.5 years) who were tested five times in a period of eleven years through selected

tools assessing processing speed (symbol digit test, perceptual speed), visuospatial abilities

(block design test), short-term (digit span), episodic (prose recall, picture memory) and

semantic memory (verbal meaning): 13% of the sample presented HF, spatial abilities and

episodic memory were the most compromised tasks in patients with HF compared to other

people and measures of episodic memory declined more over time compared to other

cognitive domains.

Trying to summarize the interesting data regarding the cognitive areas affected in HF

patients, most of the studies on the relation between memory tasks and HF reveal deficits

both on immediate and delayed recall, while semantic memory is less compromised.

Attention and psychomotor speed seemed to be impaired in most studies, but not in all

ones. Data on working memory are instead more conflicting. Measurements of the executive

function were impaired in most of the available studies.

Neuroanatomical damages may concern both grey and white matter and they can be studied

through magnetic resonance imaging (MRI) with several methods such as T1 or T2-weighted

images, voxel-based morphometry, diffusion technique, functional MRI.

In 1991, Schmidt, et al. found a higher rate of cerebral infarcts (20% vs. 0%, P < 0.05) and

cortical (50% vs. 5%, P < 0.01) and ventricular (55% vs. 15%, P < 0.02) atrophy at brain

MRI in twenty patients with idiopathic dilated cardiomyopathy and no neurological

symptoms compared to twenty age-matched controls determining a worse cognitive

performance. Woo, et al, analyzed changes in regional grey matter volumes of areas deputed

to specific role in cognition (e.g., parahippocampal gyrus, frontal cortex), CO2 regulation
 40

(e.g., cerebellar nuclei) and sympathetic and parasympathetic control (e.g., insula) in nine

patients with HF NYHA class III-IV patients and 27 healthy controls obtaining a significant

grey matter loss in both left and right insular cortex (larger in the right side) in HF patients.

Both cerebellar cortex and deep cerebellar nuclei involved in the autonomic and respiratory

control, were affected thus compromising response to CO2 and increasing the risk to develop

a Cheyne-Stokes breathing pattern. The authors stated that ischemia processes with

consequent reduction in perfusion, impaired effectiveness of neural autoregulation and

diminished cerebral blood flow may play a role in the origin of grey matter loss and such

damage can cause cognitive impairment, autonomic disturbances and sleep-disordered

breathing.

Kumar, et al., studied the mammillary body volumes and cross-sectional fornix areas, which

are involved in spatial and working memory processes, using high-resolution T1-weighted

MRI in chronic HF patents, revealing reduced dimensions with hypoxic/ischemic processes

and thiamine deficiency. High-resolution T1-weighted MRI scans detected significantly

lower left (P = 0.014) and right (P = 0.014) global putamen volumes, particularly in bilateral

rostral, mid-dorsal and medial caudal regions in 16 HF patients (mean age: 54.1 years, 75%

male) compared to 32 controls (mean age: 52.4 years, 75% male); however, no

neuropsychological evaluation was taken into account.[17] Putamen is a basal ganglia structure

playing a significant role in motor function, motivation, emotional regulation, language

processing and memory function, which are often impaired in HF patients; hypoxic or

ischemic processes are called into question in determining such damages.

Cerebral metabolic changes can be detected in patients with HF. In fifty adult patients with

advanced clinically stable HF (LVEF ≤ 35%, mean age 41.8 years), and in twenty healthy

controls proton magnetic resonance spectroscopy was obtained by specific regions of

occipital grey matter and parietal white matter calculating absolute levels of four metabolites
 41

(N-acetylaspartate, creatine, choline, and myo-inositol): in parietal region creatine levels

decreased more in HF patients than in controls, while in occipital region all metabolites

reached lower levels engendering the hypothesis that distinct brain areas show a different

susceptibility to chronic hypoperfusion; creatine levels significantly correlated with peak

oxygen consumption (P < 0.01), half-recovery time, NYHA functional class (P < 0.05) both

in occipital and parietal regions, with duration of symptoms and LVEF (P = 0.05) in parietal

and with serum sodium concentration (P < 0.01) in occipital area and significantly improved

in both brain regions after successful heart transplantation occurred in ten patients.[18] Finally,

in a murine model of congestive HF, the expression of molecules involved in β-amyloid

metabolism, apoptosis and inflammation was impaired and cognitive behaviour was altered

three months after induction of cardiac failure thus providing the hypothesis that congestive

HF increases the risk of cognitive impairment and changes in Alzheimer disease related

protein markers.

Cognitive impairment in heart failure: pathophysiology

Reduction in cerebral blood flow (CBF) is often referred as a determinant in brain

changes affecting people with HF. In 17 HF patients, NYHA class II or III compared with 18

elderly healthy volunteers, a reduction of CBF, evaluated with 99mTC-HMPAO single photon

emission computed tomography (SPECT) was detected involving in particular the left and

right precuneus and cuneus and the right lateral temporoparietal cortex and posterior

cingulated gyrus; furthermore, reduction in posterior cortical areas was directly correlated

with cognitive deficits measured with the cambridge mental disorders of the elderly

examination (CAMDEX).

CBF depends on several variables such as cardiac output, blood pressure and cerebrovascular

reactivity; low cardiac output, low systolic blood pressure and impaired autoregulatory
 42

mechanisms might impair CBF determining neuro-anatomic and neuropsychological

changes.[8]

Cerebrovascular reactivity was measured with transcranial Doppler using a hypercapnic gas

mixture as a vasodilating agent, demonstrating a significant reduction of blood flow velocity

at middle cerebral arteries after carbon dioxide in HF patients compared to all the controls,

correlated to the severity of NYHA class and to left ventricular ejection fraction.

Cardiac output is another important determinant of CBF. First studies about systemic

hypoperfusion and cognition focused on pre- and post-heart transplantation patients; in small

samples of subjects with end-stage HF, candidate to transplantation, a certain degree of

impairment in cognitive function, especially memory tasks, was documented and,

furthermore, the transplanted patients demonstrated significantly improved cognition. These

data, though limited by the confounding role of psychological conditions such as anxiety or

depression, seemed to confirm the hypothesis that decreased cardiac function can cause

chronic hypoperfusion and consequent cerebral damage. To avoid confounding factors,

subsequent studies considered patients with a less severe stage of HF disease measuring the

cardiac pump function as LVEF or cardiac output (CO).

In 1504 community-dwelling subjects from the Framingham Heart Study (mean age: 61

years), free of clinical dementia or stroke and only 7% of whom suffering from prevalent

cardiovascular disease, cardiac index, measured with cardiac MRI, was independently related

to neuroimaging markers of preclinical dementia and accelerated brain aging such as total

brain volume (positive relation, P = 0.03) and lateral ventricular volume (inverse relation, P =

0.048) and, in post-hoc analysis, low cardiac index (< 2.5 L/min per m2) was seen to be

significantly correlated with poorer performance at TMT-A evaluating psychomotor

speed.[24] The authors speculated that decreased cardiac output can lower systemic blood flow
 43

thus reducing cerebral perfusion and impairing autoregolatory mechanisms so that affected

brain blood flow homeostasis may lead to clinical or subclinical damages by exacerbating

microvessel changes or Alzheimer disease neuropathology.

Cognitive evaluation was performed in seventy-two geriatric subjects, mean age 69.1 years

(range 56–85 years), with stable cardiovascular disease further divided into two groups

according to CO non-invasively measured through transthoracic echocardiogram: in tests of

executive function, including sequencing and planning, but not in other cognitive domains

such as memory or visuospatial task, patients with lower CO (< 4.0 L/min) seemed to

performed worse than the normal CO group (≥ 4.0 L/min). Moreover, arterial hypotension

can be coupled with cognitive impairment in older patients with HF. In a large Italian study

involving 13,635 patients without clinical cerebrovascular disease or dementia (1583 of

whom affected by HF), cognitive impairment was detected in 26% of HF subjects and in 19%

of remaining population; systolic blood pressure below 130 mmHg predicted cognitive

impairment only in patients with HF and, in multiple logistic regression, any increase of 10

mmHg had a protective effect against cognitive impairment with a OR = 0.78 (95%CI: 0.71–

0.86).

Recently, obesity and depression of mood were added as additional risk factors for poor

cognitive performance in older adults with HF. An interaction between hypoperfusion and

obesity was especially recorded for its adverse effect on attention/executive

function. Depression of mood might play an interactive role in determining changes of

cognitive function in patients with HF. Both depression and cognitive impairment proved to

be associated with neuroanatomical changes as WMH or brain grey matter reduction in

subcortical and cortical regions so that it can be assumed that they are the result of structural

change due to HF; furthermore, relevant data to explain the relationship between HF,

depression of mood and cognitive impairment seem to derive from studies about
 44

neurohormones as cortisol or about proinflammatory cytokines (i.e., IL-6, TNF-α, C-reactive

protein).[30] The relation between depression (assessed by the Beck Depression Inventory II),

cognitive impairment (measured with neuropsychological tests) and cerebral perfusion

(through transcranial Doppler) was investigated in a group of 89 patients with HF: depression

was associated with impairment in attention/executive function, language and motor function

(P < 0.05) while global CBF was related with memory performance (P = 0.04).

Several experiences focused their attention on cardiac variables, laboratory parameters and

demographic and clinical elements that can be related with HF. The results are often

conflicting due to different methodologies, variety in the choice of the sample, variable aims

of single studies. The role of left ventricular ejection fraction (LVEF) has been explored by

Zuccalà, et al. in a small sample of older adults (mean age 76.6 years) with chronic heart

failure (NYHA class III, LVEF 44%) obtaining a non-linear positive correlation between

LVEF and MMSE global score, being cognitive performance significantly lower in subjects

with LVEF ≤ 30%. Other experiences, involving outpatients with known chronic HF (age:

55–77 years), stated a relationship between neuropsychological functioning (measured

through different tools such as global tests like MMSE, Repeatable battery for the assessment

of neuropsychological status or the cambridge cognition test or specific scales for individual

domains) and LVEF. In fifty-five patients with HF NYHA class I-III, mean age 55.3 years,

predominantly men, LVEF, measured with equilibrium radionuclide ventriculography

performed with a multicrystal gamma camera in the left anterior oblique view, was related to

subjective cognitive impairment, assessed through Cerebral Insufficiency Self Report

Inventory while peak oxygen uptake, obtained by cardiopulmonary exercise testing, was

correlated with objective cognitive impairment. In the study by Festa, et al. that analyzed 207

patients with HF (range of age 17–72 years), the effect of ejection fraction on memory varied

with age: in fact subjects younger than 63 years showed no variation in memory function
 45

across LVEF levels, while people older than 63 years presented a significant decrease in

memory performance (especially verbal delayed recall and recognition) when LVEF was

lower than 30% (P < 0.02). In a larger study on 1114 persons of the Framingham Heart Study

offspring Cohort, with not known diagnosis of HF and no history of clinical stroke or

dementia (mean age 67 years, more than half female), LVEF as a continuous variable was not

related to any brain aging features, such as pre-clinical brain MRI changes or deficits in

neuropsychological tests linked to vascular or degenerative cognitive impairment. However,

when LVEF levels were divided into quintiles, the lowest quintile (Q1), with an ejection

fraction < 62%, showed a poorer performance of delayed memory. Finally, also in the

absence of neuropsychological evaluation, a modest dose response relationship between

cerebral grey matter volume and LVEF (r = 0.51, P = 0.06), such that the lesser the LVEF,

the greater the grey matter volume loss, but not between white matter volume and ejection

fraction, is recorded in a small sample of patients with transient ischemic attack undergoing

an MRI and a transthoracic echocardiogram.

Blood pressure variations might play an important role in HF both for prognosis and for the

risk of cognitive impairment: in fact, according to available data, lower systolic pressure

seemed to be related with increased mortality but also with an elevated risk of cognitive

deficits due to cerebral hypoperfusion, chronic hypotension and excessive use of

antihypertensive drugs, although not all data are in agreement on this aspect. In a sample of

1075 Italian older adults, 8.2% with congestive heart failure and 23% with a score < 24 at

MMSE, systolic blood pressure was negatively related with NYHA classes only in subjects

with cognitive impairment (r = −0.981, P < 0.02). Regarding diastolic blood pressure, the

proof on its influence in the relationship between HF and cognitive impairment are poorer. In

a community-based cohort of 1301 individuals ages 75 years or older followed for a period of

nine years to examine the presence of dementia or Alzheimer disease, 205 subjects claimed
 46

HF at enrollement while 440 developed dementia. Heart failure was linked with an increased

risk of dementia (HR: 1.84, 95%CI: 1.35–2.51); antihypertensive drug use lowered the risk of

developing cognitive impairment in patients with HF (HR: 0.97, 95%CI: 0.78–1.20) with the

tendency to gain a protective role even if non-significant; patients with high systolic blood

pressure and HF showed a reduced risk of dementia compared with subjects with HF only but

normal blood pressure values (HR: 1.84, 95%CI: 1.19–2.84 vs. 2.53, 95%CI: 1.48–4.31).

Low diastolic blood pressure seemed to play an additive role in term of developing dementia

in individuals with HF and diastolic blood pressure values < 70 mmHg (HR: 3.07, 95%CI:

1.67–5.61 vs. 1.55, 95%CI: 1.13–2.13). Among laboratory tests, B-type natriuretic peptide

(BNP) has the most consistent data regarding the relationship with cognitive impairment in a

general elderly population, in individuals with cardiovascular disease and in patients with

HF. In a cohort of 464 individuals, mean age 79 years, MMSE was administered at baseline

and after a follow-up period of five years: BNP was the only variable connected with decline

of MMSE over time and it was associated with new diagnosis of dementia, defined according

to diagnostic and statistical manual of mental disorders (DSM)-IV criteria and to guidelines

with an OR: 1.53 (95%CI: 1.09–2.16, P = 0.013) together with length of education and

diagnosis of hypertension that showed a protective influence. In the Rancho Bernardo Study,

a population-based study, elevated NT-proBNP values were independently associated with

poor cognitive function on MMSE (OR: 2.0, 95%CI: 1.1–3.6, P = 0.02) and on measures of

psychomotor speed (TMT-B, OR: 1.7, 95%CI: 1.2–2.7, P = 0.01), but not with test of

semantic memory (category fluency, P = 0.19).[46]Also in a group of 56 adults with

cardiovascular disease (27% suffering from HF, 34% from myocardial infarction), with a

mean age of 70 years, a LVEF 58% and an average BNP of 122 pg/mL, BNP levels predicted

Dementia Rating Scale score after adjusting for several demographic and medical

confounders. Regarding individuals with HF, in sixty patients hospitalized for exacerbation
 47

of HF (mean age 65.5 years, mean LVEF 32.9 and average BNP plasma level 683.3 pg/mL),

BNP was related with MMSE (r = 0.12, P = 0.02) but not with other memory and learning

test.

More consistent data linked cognition and functional status assessed by NYHA class or 6 min

walking test. More severe degree of HF status, expressed by a NYHA class III-IV was an

independent correlate of an impaired performance on at least baseline examination (P <

0.001). In fact, in 83 patients hospitalized for HF, exacerbation revealed that NYHA class IV

was associated with a MMSE < 24 with an OR = 4.1 (95%CI: 1.0–16.4) in a multivariate

model. In eighty elderly outpatients with stable HF, the distance walked at 6 min test and

MMSE score were positively associated even after adjustment for demographic features,

indexes of disease severity, comorbidities, level of disability and quality of life.

 48

Literature review

Those prospective studies with a pre-treatment assessment also indicated the

importance of a baseline measure, as several studies observed lower than expected cognitive

performance in breast cancer patients who are about to undergo chemotherapy in comparison

to reference data of non-cancer subjects or cancer patients with lower disease stages who will

not need chemotherapy. Up till now, no explanation has been found for these decreased

cognitive scores at baseline. Surgery (under general anaesthesia), distress, fatigue or disease-

associated immune responses cannot yet clarify this observation.

The literature has shown that cognitive changes can arise during treatment and can persist up

to several years after completion of treatment. Studies have largely followed patients up to 1–

2 years post-treatment. Only a few studies have investigated the very late (i.e. ⩾5 years post-

treatment) effects of chemotherapy, but those that have shown long-term cognitive problems

in chemotherapy-exposed breast cancer survivors. A recent large study showed that breast

cancer survivors who received CMF chemotherapy (cyclophosphamide, methotrexate, 5-

fluorouracil) on average 20 years previously were more likely to have lower performance on

memory, information processing speed and psychomotor speed compared with women

without a history of cancer. The magnitude of the effects was comparable to approximately

6 years of age-related decline in cognitive function.

A few retrospective studies have been published examining the risk of dementia in breast

cancer survivors up to 15 years after completion of cytotoxic treatment; these studies used

data from the linked Surveillance, Epidemiology and End Results (SEER)–Medicare

database. None of these studies showed any clear evidence for the existence of such a

relationship, although several methodological issues limit the validity and interpretation of

the studies.
 49

From the literature it is clear that not all patients are affected equally by chemotherapy. The

finding that a subgroup of patients experience persistent post-treatment cognitive decline has

led to the examination of patient- and disease-related risk factors for cognitive change.

Most studies failed to identify a relationship between treatment-related cognitive decline and

age, IQ, education, baseline cognitive function and a host of other factors such as depression,

anxiety, stress, fatigue, disease stage, hemoglobin levels and treatment-induced menopause.

When an association between a sociodemographic or clinical predictor and cognitive

dysfunction has been found the relationship is generally weak. However, given the small

sample sizes in nearly all studies, exploration of any sociodemographic or clinical predictors

is likely to be underpowered. This is also the case for genetic factors (e.g. vulnerable alleles

of genes such as APOE and COMT) that have been examined as potential risk factors for

cognitive decline.

Neuroimaging studies in breast cancer patients indicate structural changes in the brain

associated with certain chemotherapeutic agents, and have started to shed light on the brain

alterations that may be part of the mechanisms underlying the observed cognitive dysfunction

in patients following administration of chemotherapeutic compounds without targeted CNS

delivery.

To our knowledge, no studies have examined objective neuropsychological performance or

conducted brain imaging in samples that comprise exclusively cancer survivors diagnosed as

AYAs; only two studies have focused on self-reported subjective cognitive impairment.

Prasad et al9 found that cancer survivors diagnosed between the ages of 15 and 24 years often

experienced cognitive impairment, with 22% reporting problems with memory, 14% with

task efficiency, and 13% with organization. Self-reported impairments in task efficiency were

associated with unemployment and depression. Rey et al found that 58% of AYAs with
 50

breast cancer report problems with concentration or memory in the first 28 months after

diagnosis. These findings are consistent with studies of cognition in cancer survivors

diagnosed as children who demonstrated impairment on neuropsychological tests of attention,

memory, processing speed, and cognitive fluency despite IQ scores in the normal

range. Moreover, neurocognitive deficits in childhood cancer survivors are associated with

structural abnormalities observed through brain imaging. Thus, available data suggest that

cognitive impairment is likely a significant problem in cancer survivors diagnosed as AYAs.

Over the last 10–15 years, increasing evidence has revealed the occurrence of acute and long-

term cognitive problems for a subset of patients following chemotherapy applied in the

treatment of non-CNS malignancies. In breast cancer patients alone, over 60

neuropsychological studies have been published that have investigated whether adjuvant

chemotherapy is associated with cognitive impairment. In the early years most of these

studies had a cross-sectional design and provided us with a snapshot of the prevalence of

cognitive impairment and the characteristics associated with this impairment at specific

moments post-chemotherapy. In recent years, prospective neuropsychological studies on the

incidence of cognitive problems arising from pre- to post-chemotherapy supported the

previous observed relationship between chemotherapy exposure and cognitive problems by

demonstrating cognitive decline post-treatment relative to pre-treatment cognitive

performance.

Prior to the era of highly active antiretroviral therapy, the cumulative risk of developing HIV

associated dementia was estimated to be between 15–20% (McArthur et al. 1993). Incidence

of HIV dementia in the MACS cohort was estimated to decrease by 53% from 21.1 per 1,000

person-years between 1990 to 1992, to 10.5 per 1,000 person-years between 1996 to 1998

(Sacktor et al. 2001). Although definitions used vary from the current HAND rubric, these

estimates illustrate the decrease in the incidence of dementia with the introduction of highly
 51

active antiretroviral therapy, and the seemingly paradoxical finding of increased prevalence

of dementia with patients surviving longer. The clinical spectrum of the disease has shifted

from the severe and devastating form of dementia commonly encountered in association with

advanced AIDS (typically end-stage disease) before the introduction of protease inhibitors

and highly active antiretroviral therapy, to the milder and more manageable forms of HAND.

More recent studies conducted in patients on highly active antiretroviral therapy, estimate

that the prevalence of neurocognitive dysfunction (based on neuropsychological assessments)

in HIV populations ranges from 20–37%, even with treatment (Robertson et al. 2007b;

Sacktor et al. 2001; Sacktor et al. 2002). The CHARTER study group recently presented

findings from comprehensive neuropsychological evaluations (lasting 2 to 2.5 h) on a large

unselected population of 1,555 HIV-positive patients and reported that, overall, 45% of the

cohort had neurocognitive impairment based on a global neuropsychological rating, although

prevalence of impairment also varied considerably based upon levels of co-morbidity

(Heaton et al. 2009).

Reports of the prevalence and presentation of HIV-associated neurocognitive disorders have

demonstrated remarkable variability across international studies and at present a very limited

amount of data is available on HAND in resource-limited settings. For example, the

prevalence of HIV-Associated Dementia in sub-Saharan Africa has been reported to be from

as low as 3% (Belec et al. 1989) to as high as 54% (Howlett et al. 1989), at least in part to

due differences in definition and ascertainment methods. In one of the earliest international

studies of HIV-associated cognitive impairment, the World Health Organization found fairly

consistent rates of impairment on a relatively small test battery, of 19.1% (Zaire), 15.3%

(Kenya), 18.4% (Thailand), and 13.0% (Brazil), and more substantial neurological

impairment rates of approximately 41% (Zaire), 40% (Kenya), 66% (Thailand), and 54%

(Brazil) in symptomatic individuals (Maj et al. 1994). Clifford et al. (2007) report that the
 52

International HIV Dementia Scale, a brief screening tool, did not detect any significant

differences in cognitive status between HIV positive and negative subjects in Ethiopia

consistent with clinical impression (Clifford et al. 2007). Contrastingly, studies in India,

China, and Uganda reported prevalence rates of 56%, 34%, and 31% respectively (Heaton et

al. 2008; Robertson et al. 2007a; Yepthomi et al. 2006). HIV-1 subtype C predominates in

India, subtype B and CRF01_AE in China, and subtypes A and D in Uganda. These

discrepancies could be the result of varying neurovirulence of viral subtypes, different

environmental factors, or a consequence of underappreciated cultural nuances and differences

in the neuropsychological methods used in the different studies.

In terms of the patterns of neuropsychological effects observed across different countries, a

pilot study investigating the neurobehavioral effects of HIV-1 infection in China reported a

pattern of deficits in abstraction/executive function, information processing speed, and

learning consistent with Western studies (Cysique et al. 2007b). This study found no

significant country effects on the global neuropsychological score or measures of executive

function, attention, learning, memory, or motor functions, although significant country effects

on tasks of verbal fluency and speed of processing were reported. In addition, this study

found that moderately high levels of depression did not account for neuropsychological

performance in either the US or Chinese HIV positive groups, and that neuropsychological

performance did correlate with complaints of cognitive difficulties in everyday life as well as

with unemployment status.

In a larger study of former plasma donors in rural China, Heaton et al. (2008) administered

the same international test battery to 203 HIV+ and 198 HIV− adults who were mostly

farmers (mean education = 5.6 years) (Heaton et al. 2008). Results of uninfected controls

were used to create demographically corrected neuropsychological norms, which classified

37% of the HIV+ group as impaired. The normed test results were sensitive to both HIV and).
 53

Finally, participants classified as impaired reported more cognitive difficulties in their

everyday lives and decreased independence in performing instrumental activities of daily

living (such as financial management, shopping, housekeeping, and cooking).

Another study evaluating the pattern of neuropsychological performance in a sample of HIV

positive patients and HIV negative control subjects in Uganda revealed significant group

differences on measures of verbal learning and memory, speed of processing, attention and

executive functioning (Robertson et al. 2007a). Gupta et al. (2007) compared a sample of 119

adults in India infected with HIV-1 subtype C who were not on antiretroviral therapy, with

normative data derived from an Indian sample of 540 healthy volunteers (with comparable

gender distribution, age, and education) and with a matched cohort of 126 healthy, HIV-1-

seronegative individuals (Gupta et al. 2007). They found a high rate (60.5%) of mild to

moderate cognitive deficits in the HIV patients but no evidence of true dementia. The

neuropsychological profile was characterized by deficits in fluency, working memory, and

learning and memory, once again similar to patterns that have been observed in the West.

A study reporting HIV-1 subtype-associated differences in neurological disease was recently

reported by Sacktor et al. (2007), in a small Ugandan cohort. These investigators found that

subtype D was associated with higher dementia prevalence than those with subtype A at

similar disease stage (Sacktor et al. 2007). Subtype D has also been reported to be associated

with faster progression of systemic HIV disease (Kaleebu et al. 2002; Laeyendecker et

al. 2006). Robertson et al. (2008) reported substantial differences in baseline neurocognitive

test means across seven resource limited countries (Malawi, South Africa, Zimbabwe,

Thailand, India, Peru and Brazil) between unmatched groups of patients with low levels of

co-morbid conditions (Robertson et al. 2008). In the first randomized clinical trial observing

neurocognitive effects of antiretroviral treatment in treatment naïve patients from multiple

resource limited settings, Robertson et al. (2009) found substantial improvement across
 54

multiple time points of follow up from week 24 out to week 96 across seven RLS countries

(Robertson et al. 2009). The analysis was limited to 293 participants who were randomized to

treatment with didanosine enteric-coated (ddI) + emtricitabine (FTC) + atazanavir (ATV) in

the AIDS Clinical Trials Group (ACTG) Study A5175 (PEARLS), and did not include groups

on alternate treatment regimens or untreated control groups for comparison. Significant

improvements in neuropsychological functioning after initiating antiretroviral therapy were

determined after controlling for baseline function, age, sex, country, CD4, plasma HIV-1

RNA stratum, and years of education. Notably, the magnitude of improvement in

neurocognitive functioning varied across the countries and could not be explained by

systemic disease factors. Improved neurocognitive functioning may be due to control of HIV

viral load through antiretroviral effects, uncontrolled practice effects on repeated test

administrations, or both and demonstrate the need for further normative comparison data

collection (including norms for change that consider practice effects and normal test-retest

variability) in resource limited settings.

Coronary artery disease (CAD) has emerged as the leading cause of death and disability in

the United States. According to an estimate by the World Health Organization (WHO), by the

year 2020, both CAD and depression will be the two major causes of disability-adjusted life

years. CAD continues to be a major focus of clinical and epidemiological research.

Cross-sectional and longitudinal data suggest a bidirectional link between depression and

CAD. In cross-sectional studies done in the past, between 19 and 66 percent of patients with

myocardial infarction (MI) have some mental disorder, primarily depressive and anxiety

states.9,10,11–14 In several studies, 17 to 44 percent of patients with CAD also have a diagnosis

of major depression. Another study found that 27 percent of patients undergoing coronary

artery bypass graft surgery (CABG) had depression after the surgery.
 55

Several studies suggest that patients who experience depression after an MI are at higher risk

for SCD. In a Washington state health maintenance organization (HMO) study from 1980 to

1994, Empana et al compared 2,228 patients with depression to a control group of 4,164

patients. Patients in both groups were ages 40 to 79. He found that presence and severity of

clinical depression in patients is associated with higher risk of cardiac arrest resulting in

death. In this case-controlled study, they found that clinically depressed patients had a higher

odds ratio (OR) of a cardiac arrest (OR, 1.88; 95% CI, 1.59–2.23). This finding persisted

even after adjustment for confounding factors, such as cigarette smoking, heavy alcohol

consumption, diabetes, hypertension, prior MI, and prior CHF (OR, 1.43; 95% CI, 1.18–

1.73). Compared with non-depressed patients, the risk of cardiac arrest increased in less

severely depressed patients with an OR of 1.30 (95% CI, 1.04–1.63) and further increased in

severely depressed patients with an OR of 1.77(95% CI, 1.28-2.45).

Rationale of the Study

Neurological complications are secondary to the treatment of terminal illness and may

be an important contributor to these patient’s ailment. The current study aimed to express the

occurrence of neurological complications of terminal illness from the first stage of disease.

Persons living with terminal illness have many challenges including successfully adhering to

treatment recommendations in order to maintain optimal health, negotiating disclosure of

ailment level and coping with possible strategies. These are significant challenges; yet, for

terminally ill persons who also have mental health difficulties, these and other, challenges

can be amplified. As such, the co-occurrence of terminal illness and mental illness poses a

significant public health problem and represents a difficult challenge for those who treat and

care for these persons.

 56

Objectives

 To measure the significant gender differences in neuropsychological problems among

the patients with terminal illness.

 To check the differences between low and middle socioeconomic status of patients

with terminal illness in neuropsychological problems.

 To investigate the differences between rural and urban residence of patients with

terminal illness in neuropsychological problems.

Hypotheses

 There would be a significant gender differences in neuropsychological problems

among the patients with terminal illness.

 There would be a differences between low and middle socioeconomic status of

patients with terminal illness in neuropsychological problems.

 There would be a differences between rural and urban residence of patients with

terminal illness in neuropsychological problems.

 57

Chapter 2
Research Methodology
Participants

Total sample comprised of (N=80) patients in which 28 cancer patients, 50 heart

patients and 02 AIDS patients are included. Informed consent of the participants were taken

before collecting the responses.

Research design

Cross-sectional quantitative research design was used.

Inclusion criteria

This study is only confined to the cancer, AIDS and cardiovascular patients. There is no

age discrimination.

Exclusion criteria

This study is not applicable to the patients suffering from some other disease except

cancer, AIDS and cardiovascular failure.

Measures and covariates

Operational definitions: operational definitions are as follows.

Neuropsychology

Neuropsychology is the study of the structure and function of the brain as they relate to

specific psychological processes and behaviors.

 58

Cognitive Impairment

A disturbance of mental function due to brain trauma, associated with one or more of the

following: neurocognitive,psychotic, neurotic, behavioral, or psychophysiologic manifestatio

ns, or mental impairment.

Terminal illness

Terminal illness or end-stage disease is an incurable disease that cannot be adequately

treated and is reasonably expected to result in the death of the patient. This term is more

commonly used for progressive diseases such as cancer or advanced heart disease than

for trauma.

Cancer

Cancer is a group of diseases involving abnormal cell growth with the potential to

invade or spread to other parts of the body.

AIDS

Human immunodeficiency virus infection and acquired immune deficiency

syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human

immunodeficiency virus (HIV).

Cardiovascular failure

Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood

vessels. Cardiovascular disease includes coronary artery diseases (CAD) such

as angina and myocardial infarction (commonly known as a heart attack). Other CVDs

include stroke, heart failure, hypertensive heart disease, rheumatic heart

disease, cardiomyopathy, heart arrhythmia, congenital heart disease, valvular heart

 59

disease, carditis, aortic aneurysms, peripheral artery disease, thromboembolic disease,

and venous thrombosis.

Data collection Instrument

The study was used the mini mental state examination scale developed by Folstein and

colleagues.

Mini-Mental State

Folstein and colleagues published the Mini Mental State examination (MMSE) for

brief quantitative assessment of cognitive function 30 years ago (Folstein et al. 1975). Since

then it has been translated into many languages and has become the most widely used brief

test of cognition in clinical and research settings, with adequate validation. The aim of the

examination is to:screen for cognitive impairmentassess the severity of any

impairmentmonitor change by serial testingIt relies heavily on verbal cognitive function at

the expense of nondominant hemisphere skills and is vulnerable to the vagaries of scoring by

different observers. Nevertheless, it has stood the test of time and provides a common and

widely understood tool to measure global cognitive function. STRUCTURE: The MMSE is a

collection of questions that test various cognitive domains including orientation to time and

place, repetition, verbal recall, attention and calculation, language and visual construction.

EXAMINATION: of the mental state is essential in evaluating psychiatric patients. Many

investigators have added quantitative assessment of cognitive performance to the standard

examination, and have documented reliability and validity of the several “clinical tests of the

sensorium”. The available batteries are lengthy. For example, WITHERS and HINTON’S test

includes 33 questions and requires about 30 min to administer and score. The standard WAIS

requires even more time. However, elderly patients, particularly those with delirium or

dementia syndromes, cooperate well only for short periods. Therefore, we devised a
 60

simplified, scored form of the cognitive mental status examination, the “Mini-Mental State”

(MMS) which includes eleven questions, requires only 5-10 min to administer, and is

therefore practical to use serially and routinely. It is “mini” because it concentrates only on

the cognitive aspects of mental functions, and excludes questions concerning mood, abnormal

mental experiences and the form of thinking. But within the cognitive realm it is thorough.

The MMS is shown in the appendix. Questions are asked in the order listed and scored

immediately. The tester (psychiatric resident, nurse, or volunteer) is instructed first to make

the patient comfortable, to establish rapport, to praise successes.

Demographic information

A demographic information questionnaire was constructed by the researcher. It

includes necessary demographical information about the respondents. The demographic data

about patients includes: name, age, gender, father name, father profession (not compulsory),

residence, contact number, email address.

Data Collection Procedure

Mini mental state examination Scale was used. MMSE was translated three times to

check the validity of scale (urdu version). The sample was comprised of N=80 patients and

taken from Victoria hospital, Civil hospital and BINO hospital Bahawalpur. Purposive

random sampling technique was used to collect the data. Permission was taken by the MS of

hospitals to conduct the research. Participants were asked to fill up the questionnaire after

telling them that their identity will not be disclosed and the information given by them only

would be used for the research purposes. The questionnaire distributed to the patients is

consisted of two sections. First section consist of demographic information. The demographic

variables including name, age, gender, father name, father occupation, contact number and

email address were asked. Second section consist of MMSE items.

 61

Patients were asked to respond honestly as possible. The researcher delivered the necessary

instruction and guidelines before distributing the questionnaire and made sure that the

participants had completed the questionnaires completely and correctly. It takes almost 20-25

minutes.

When the questionnaires were filled, the session was terminated after checking that whole

items were responded by the individuals. Questionnaires was then checked and rated

according to the scoring manual. It was a time consuming task to collect the data.

Statistical Data Analysis

The data of quantitative study was analyzed through SPSS. The mean and standard

deviation of all variables was calculated for quantitative data. The independent t-test was

used to compare the quantitative data. The value P = 0.05 was taken as significant.

Ethical Considerations

First of all permission was taken from the higher research committee of the Department

to conduct research on this hidden problem of the patients having some terminal illness like

AIDS, Cardiovascular Failure and cancer. Then permission letter was issued from the Head

of Department Applied Psychology to the MS of Victoria hospital, Civil hospital, BINO

hospital, doctor hospital to get permission for the collection of research data. The informed

consent was given to the patients before distributing the questionnaire to inform that the

information collected from them would be confidential and would be used for the research

purposes. After collecting the responses from the respondents, again it was reassured that

their responses would not be disclosed and only used for the purpose of study.
 62

Chapter 3
Results

Table 1
Frequency Distribution of Demographic Questionnaire (N=80)

Respondent’s Characteristics f (%)

Male 42 (42.5)
Gender
Female 38 (47.5)
Uneducated 34 (42.5)
Primary 27 (33.8)
Education
Middle 14 (17.5)
Matric 5 (6.3)
Married 66 (82.5)
Marital Status
Unmarried 14 (17.5)
Low 29 (36.3)
Socioeconomic Status
Middle 51 (63.7)
Urban 49 (61.2)
Residence
Rural 31 (38.8)

The results of the table confirmed the Impact of cognitive impairment among the patients

with terminal illness according to the gender difference ,Qualification base, Marital standard ,

Family system and among the Socioeconomic status.

 63

Table 2
Descriptive Statistics of Study Variables (N=80)

Variables Range
M SD Minimum Maximum

Age 50.26 8.75 21 65

Cognitive Performance 3
13.56 4.99 21
Orientation 2
6.35 2.51 10
Registration 0
.58 .65 2
Attention and
.88 .79 0 4
Calculation

Recall 0
1.03 .90 3
Language and Praxis 0
4.74 1.93 9

The results of this table confirmed that prevalence of cognitive impairment

among patients with terminal illness and results indicated that moderate

level of cognitive impairment was found among respondents, although

cognitive impairment was found all type of neurological problems such

as orientation, registration, attention and calculation, recall and language

and praxis.
 64

Table 3

Comparison between Male and Female Patients with Terminal Illness Sample through

Independent Sample t-Test among Cognitive Performance (N=80)

Variable Male (n =42) Female (n =38) 95%CI

M SD M SD T p LL UL

Cognitive Performance 11.5 4.37 15.79 4.73 -4.17 .00 -6.27 -2.21

Orientation 5.67 2.41 7.11 2.44 -2.66 .01 -2.52 -.36

Registration .43 .55 .74 .32 -2.16 .03 -.59 -.02

Attention & Calculation .62 .66 1.16 .82 -3.24 .00 -.87 -.21

Recall .74 .73 1.34 .97 -3.17 .00 -.98 -.22

Language and Praxis 4.10 1.91 5.45 1.70 -3.33 .00 -2.16 -.54

This table showed that significant gender differences in cognitive performance (orientation,

registration, attention and calculation, recall, language and praxis). While, the mean score of

cognitive performance (orientation, registration, attention and calculation, recall, language

and praxis) was significantly higher among female patients with terminal illness than male

patients with terminal illness.

 65

Table 4

Comparison between Low and Middle Socioeconomic Status of Patients with Terminal Illness
Sample through Independent Sample t-Test among Cognitive Performance (N=80)

Variable Low (n =29) Female (n =51) 95%CI

M SD M SD T p LL UL
Cognitive Performance 10.31 3.87 15.41 4.63 -5.02 .00 -7.12 -3.08
Orientation 5.10 2.24 7.06 2.40 -3.59 .00 -3.04 -.87
Registration .41 .50 .67 .71 -1.69 .10 -.55 .05
Attention and
.59 .57 1.04 .85 -2.57 .01 -.81 -.10
Calculation
Recall .66 .86 1.24 .86 -2.90 .01 -.98 -.18
Language and Praxis 3.55 1.53 5.41 1.81 -4.66 .00 -2.65 -1.07

This table showed that significant socioeconomic (low & middle) status differences in
cognitive performance (orientation, attention and calculation, recall, language and praxis).
While, the mean score of cognitive performance (orientation, registration, attention and
calculation, recall, language and praxis) was higher among middle socioeconomic status of
patients with terminal illness than low socioeconomic status of patients with terminal illness.
 66

Table 5

Comparison between Rural and Urban Patients with Terminal Illness Sample through
Independent Sample t-Test among Cognitive Performance (N=80)

Variable Rural (n =31) Urban (n =49) 95%CI

M SD M SD T p LL UL
Cognitive Performance 10.94 4.43 15.22 4.63 -4.10 .00 -6.37 -2.21
Orientation 5.19 2.33 7.08 2.36 -3.50 .00 -2.96 -.82
Registration .39 .56 .69 .68 -2.10 .04 -.60 -.02
Attention and
.58 .85 1.06 .69 -2.78 .01 -.83 -.14
Calculation
Recall .81 .83 1.16 .92 -2.98 .08 -.76 -.05
Language and Praxis 3.97 1.89 5.22 1.81 -2.98 .00 -2.10 -.42

This table showed that significant rural and urban residence differences in cognitive
performance (orientation, registration, attention and calculation, language and praxis). While,
the mean score of cognitive performance (orientation, registration, attention and calculation,
recall, language and praxis) was higher among urban residence patients with terminal illness
than rural residence patients with terminal illness.
 67

Chapter 4
Discussion
The current study revolves around the neuropsychological conditions of three main

terminal illnesses including cardiovascular disease, Cancer and AIDS. This modern study

confirmed that prevalence of cognitive impairment among patients with terminal illness and

results indicated that moderate level of cognitive impairment was found among respondents,

although cognitive impairment was found all type of neurological problems such as

orientation, registration, attention and calculation, recall and language and praxis.

This contemporary study showed that there is significant gender differences in cognitive

performance (orientation, registration, attention and calculation, recall, language and praxis).

While, the mean score of cognitive performance (orientation, registration, attention and

calculation, recall, language and praxis) was significantly higher among female patients with

terminal illness than male patients with terminal illness including AIDS, Cancer and

cardiovascular disease. Female patients listen more attentively to their doctors and follow

their advice properly to reduce the bad impact of neuropsychological problems and perform

better cognitive performance (orientation, registration, attention and calculation, recall,

language and praxis) as compare to male terminal ill patients.

In the similar study, female cancer and AIDS patients develop a more accurate understanding

of their illness than do men to reduce their anxiety and stress. At the prescan visit interview

and, before patients discussed re-staging scan results with their doctors, there were no

significant gender differences in illness under-standing. At the postscan visit interview, after

patients had discussed scan results with their doctors, women were significantly more likely

than men to understand that their cancer/AIDS was incurable and that they had an advanced

stage cancer/AIDS. Female patients accept the reality of approachable death and try to

perform better cognitive performance as compare to male patients (Brodt et al. 1997).
 68

Additionally, in another similar study it is revealed that female advanced cancer patients were

significantly more likely than their male counterparts to report having had discussions of life

expectancy with their oncologists at some point during the course of their disease. Results of

this study also suggest that this gender difference in having had discussions of life expectancy

with oncologists may explain the observed gender difference in patients’ understanding that

their disease is incurable (Dietrich, et al2008).

In parallel studies, it is found that between 17 and 44 percent of female patients with

coronary artery disease also have major depression. According to the American Heart

Association, female patients hospitalized for a heart attack are roughly three times as likely as

the male patients to experience depression. As many as 40 percent of female patients

undergoing coronary artery bypass surgery suffer from depression (Zuccalà, G., Pedone ,C.,

Cesari, M., et al. 2003).

In a comparable Research, it indicate that there could be physiological connections with heart

disease. The biological and chemical factors that trigger mental health issues also could

influence heart disease (Hjelm, C., Dahl, A., Brostrom, A., et al).

In contrast, some researches does not firmly link stress and heart disease in female patients,

but there’s a growing belief that it’s an additional risk factor in them, and maybe even more

dangerous than some others (Hawkins, L.A., Kilian, S., Firek, A., et al. 2012).

In some similar studies researchers have found that a high prevalence of HIV infection in

male patients with serious chronic mental illnesses. Prevalence rates in mentally ill male

inpatients and outpatients have been reported to be between 5% and 23%, compared with a

range of 0.3% to 0.4% in female patients in the United States of America over comparable

time periods. Some studies have reported behavioural risk factors for transmission of HIV in

male patients between 30% and 60% with severe mental illnesses. These risks include high
 69

rates of sexual contact with multiple partners, injecting drug use, sexual contact with

injecting drug users, sexual abuse (in which women are particularly vulnerable to HIV

infection), unprotected sex between men and low use of condoms. Besides these behavioural

risks, mental disorders may also interfere with the ability to acquire and/or use information

about HIV/AIDS and thus to practise safer behaviours or increase the likelihood of situations

occurring in which risk behaviours are more common Kalechstein, A. D., Hinkin, C. H., van

Gorp, W. G., Castellon, S. A., & Satz, P. (1998).

Another similar study on HIV/AIDS found that the prevalence of mental illnesses in HIV-

infected male individuals is substantially higher than in the female individuals. Furthermore,

HIV tends to be concentrated in highly vulnerable, marginalized and stigmatized populations;

in particular, sex workers, men who have sex with men, drug users and prisoners have higher

levels of mental health disorders than the general population. Increased psychological distress

among people with HIV infection is common (Levine, A. J., Hardy, D. J., Miller, E.,

Castellon, S. A., Longshore, D., & Hinkin, C. H. (2006).

The present study found a significant socioeconomic (low & middle) status differences in

cognitive performance (orientation, attention and calculation, recall, language and praxis).

While, the mean score of cognitive performance (orientation, registration, attention and

calculation, recall, language and praxis) was higher among middle socioeconomic status of

patients with terminal illness than low socioeconomic status of patients with terminal illness.

In contrast, it is found that some terminally ill patients with low socioeconomic status,

although aware of their approaching death, prefer to limit their confrontation with the

threatening truth that they are dying by avoiding asking their physician certain questions or

by refraining from all further prognostic discussions. It seems important to acknowledge both

such patient-chosen dosing of bad news and patients’ needs for mental exile. Rest from
 70

repetitive exposure to the “truth” may be a normal and important part of patients’ coping with

their awareness of forthcoming death, not merely a symptom of pathological denial.

(Chelune, G. J., Heaton, R. K., & Lehman, R. A. 1986).

In some similar studies in both low- and high socioeconomic status have reported higher rates

of depression in low socioeconomic HIV-positive people compared with high socioeconomic

HIV-positive people. The level of distress often seems to be related to the severity of

symptoms of HIV infection. Family relationships and the support of a partner can influence

mental health consequences (AAN, 1991).

In contrast, in another study researchers found that HIV infection can be associated with high

risk of suicide or attempted suicide in high socioeconomic people. The psychological

predictors of suicidal ideation in HIV-infected individuals include concurrent substance-use

disorders, past history of depression and presence of hopelessness (Bassel, C., Rourke, S. B.,

Halman, M. H., & Smith, M. L, 2002).

In contrast, some studies have consistently indicated that adjustment disorders and major

depression are common psychiatric disorders among cancer patients who belongs to high and

middle socioeconomic class and are more common in patients with advanced cancer and/or in

cancer patients who are terminally ill as compare to patients who belongs to low

socioeconomic class (Ferrell, B.R., Hassey, R., Dow, K. 1997).

Similarly, Ferrel et al found that almost half of cancer patients with low socioeconomic status

had been diagnosed with a psychiatric disorder, and that most of them had an adjustment

disorder and/or major depression.

In a divergent study, several researchers found that the prevalence of these psychiatric

disorders in terminally ill cancer patients of high and middle class by rigorous diagnostic

methods (eg, structured clinical interview) have revealed rates of adjustment disorders of 9%
 71

to 35% and rates of major depression of 8% to 26%. Because a diagnosis of life-threatening

illness now meets the traumatic stressor exposure criteria of the Diagnostic and Statistical

Manual of Mental Disorders (DSM-IV) for post-traumatic stress disorder (PTSD), several

studies have focused on PTSD or post-traumatic stress symptoms in cancer

patients. Although the results have demonstrated that 3% to 35% of cancer patients from

high socioeconomic class experience full-syndrome PTSD or post-traumatic stress symptoms

(Nokia, M.S., Anderson, M.L., Shors, T.J. 2012).

Some handful similar studies have focused specifically on anxiety in advanced or terminally

ill cancer patients. Estimates of prevalence of anxiety disorders range from 2% to 14% of

patients with advanced cancer. Generalized anxiety disorder (4.8%–5.8%) and panic disorder

(5.5%), the most common diagnoses, were found at rates that exceeded those found in the

general adult population (3.1% and 2.7% respectively. Significant anxiety symptoms are

estimated in 25% to 48% of advanced cancer patients. Elevated rates of anxiety disorders and

symptoms are also more common in females, unmarried patients, high socioeconomic class

and those with poor physical functioning (Prasad, P.K., Hardy, K.K., Zhang, N., et al. 2015).

Similar past studies, it is found that Heart Failure patients with low socioeconomic status had

poorer performance compared to healthy and high socioeconomic people in memory,

psychomotor speed, and executive functioning (Riegel, B., Lee, C.S., Dickson, V.V., et al).

In some studies, Some investigators have found that Heart Failure and Heart Failure severity

were associated with cognitive deficits in low socioeconomic individuals, but others have not

found significant associations between HF and cognitive deficits (Roman, D.D., Kubo, S.H.,

Ormaza, S., et al).

 72

In contrast, studies have shown that Cognitive deficits in Heart Failure have been

investigated, but the studies have yielded mixed results about the association between

HeartFailure and cognitive deficits (Liang, S.Y., Li XP).

In another similar study, it is found that depression is common in Heart disease in low SES,

occurring in 21.5% of patients in a meta-analysis. Depressive symptoms overlap with signs of

cognitive deficits (e.g., decreased attention) in them. In a low SES population-based study,

comorbidity (i.e., depression and anemia) attenuated cognitive impairment in heart. However,

cognitive impairment was measured during a telephone interview using a brief questionnaire

rather than a neuropsychological test battery (Miller, L.A., Spitznagel, M.B., Alosco M, et

al).

Conclusion

Nowadays, terminal illness like cardiovascular disease, Cancer and AIDS are becoming

more common in Pakistan like other developed and under developed countries. This ailment

sometimes accompanied with other neuropsychological problems such cognitive deficits

stress, depression and hypertension. The goal of the present study was to elucidate the

probable synergistic effect of neuropsychological problems like stress, anxiety and

depression in terminally ill patients. This study provides prevalence of neuropsychological

distress that is comparable with findings of other studies in the world.

The impact terminal illnesses and their related clinical factors on mental health of individual

draws attention for researchers to further investigate the interrelationship between

neuropsychological, mental, and physical aspects of terminally ill patients. Based on our

results, we can recommend that, the individuals with terminal illness should be considered for

the appropriate screening, treatment and comprehensive care for the disease and its

neuropsychological bad effects. Second, establishment of a social support group mechanism

 73

is needed to reduce stress and the negative life events associated with neuropsychological

distress. The findings are important in terms of their relevance to identifying high-risk groups

for generalized neuropsychological distress and, thus, preventing distress through integrating

mental health services with support program.

Limitations
 It will be difficult to find significant relationship from the data because sample size is

(80) is too small.

 Data can be collected from three hospitals from Bahawalpur .

 Much of data selected for research is self- report data which is problematic because

respondent can provide only socially desirable responses rather than truthful one.
 74

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Appendices
Appendices A
Mini mental state examination (English version)
 93

Appendices B

Mini mental state examination (Urdu version)

‫ سینری اور ریل گاڑی ۔ (جواب ملنے پر یہ چیریں یاد‬،‫۔ آپ یہ چیزیں دہرائیں بلب‬۱
)۳( ‫کردائیں)۔۔۔۔۔۔۔۔۔ ۔۔۔۔۔۔‬
‫۔ آپ کے آخری بیٹے یا بیٹی کی شادی کو کتنا عرصہ ہوا ہے۔ یا پاکستان کو بنے‬۲
)۱(‫کتنا عرصہ ہو گیاہے۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔‬
3. Ask the family for memory disturbance on the individual’s
functioning (eg. ability to, work, shop, cook , pay bills return
home without getting lost) record family comments.
Over here‫۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔‬
)۳(‫۔ جو چیزیں میں نے آپ کو یاد کرادئیں تھیں وہ دھرائیں۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔‬۴

5. Ask the individual to name object in the room ( e.g, chair,

desk, lamp……………………(1)
‫ ۔ آپ اپنے ہال کنگھا کر کے دکھائیں۔ دکھائیں کے دانت کیسے صاف کرتے‬۶
)۱(‫ہیں۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔‬
7. Ask the patient to identify family members is
…………………….(1) Ask the patient to close his eyes. Put a
key in his hand and ask him what is it.........................................
8. Ask the patient to count to
10…………………………………………..………….. (1)
Write the no of animals he gave over
here…………………………………………………………….
Ask the patient and his family members (both) if he has
disturbances in executing functioning in his daily life, (e.g.,
ability to work, plan activities, Budget)
Write comments over here
…………………………………………………………………………
.
 ‫‪94‬‬

‫‪۲‬۔ یہ کون سا موسم ہے؟۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔(‪)۱‬‬ ‫‪۱‬۔ یہ کون سا سال ہے؟۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔(‪)۱‬‬

‫‪۴‬۔ یہ کون سا دن ہے؟۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔(‪)۱‬‬ ‫‪۳‬۔ یہ کون سی تاریخ ہے۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔(‪)۱‬‬
‫‪۶‬۔ یہ کون سا ملک ہے؟۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔(‪)۱‬‬ ‫‪۵‬۔ یہ کون سا مہینہ ہے؟۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔(‪)۱‬‬

‫‪۷‬۔ یہ کون ساصوبہ ہے؟۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔(‪۸ )۱‬۔ یہ کون سا شہر ہے؟۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔(‪)۱‬‬

‫‪۹‬۔ یہ کون سا محلہ ہے؟ ۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔(‪۱۰ )۱‬۔ یہ کون سی گلی ہے۔؟۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔(‪)۱‬‬

‫‪۱۱‬۔ آپ یہ چیزیں دہرائیں ۔ سکہ ‪ ،‬سیب‪ ،‬میز‪( ،‬جواب ملنے پر یہ چیزیں یاد‬
‫کروائیں)۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔‬
‫‪ ۱۲‬۔ آپ کو اگر سو روپے دین اور اس میں سے سات روپے نکال لیں تو آپ کے پاس‬
‫کتنے بچے۔ (جواب ملنے پر مزید سات روپے نکلوائیں۔ ہی عمل مزید چار مرتبہ‬
‫دہرائیں۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔(‪ )۵‬یا کہیں لفظ اتور کے ھروف کوالٹی ترتیب میں‬
‫دہرائیں۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔‬
‫‪۱۳‬۔ جو تین چیزیں میں نے آپ کو یاد کروائیں تھیں وہ‬
‫دھرائیں۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔(‪)۳‬‬
‫‪۱۴‬۔ایک ایک کر کے گھٹری اور پنسل دکھائیں اور پوچھیں یہ کیا‬
‫ہیں۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔(‪)۲‬‬
‫‪۱۵‬۔ یہ دھرائیں ابھی نہیں تو کبھی نہیں۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔‬
‫‪ ۱۶‬۔ایک کاغذ اپنے ہاتھ میں لیں اس کو آدھا تہہ کریں اور اس کو فرش پر‬
‫رکھیں۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔(‪)۳‬‬
‫‪ ۱۷‬۔ایک خالی کاغذ پر لکھیں۔ اپنی آنکھیں بند کرلیں۔ مریض سے کہیں کہ کاغذ پر‬
‫لکھا پڑھیں اور اس پر عمل کریں (‪)۱‬‬
‫‪ ۱۸‬۔مریض سے کہیں کہ کہ کوئی جملہ لکھیں۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔(‪)۱‬‬
‫‪ ۱۹‬۔مریض سے کہیں کہ درج ذیل خاکہ بنائیں۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔۔(‪)۱‬‬
 95

Appendices C
 ‫‪96‬‬

‫‪Appendices D‬‬

‫ذاتی کوائف‬
‫نامہ‬