Fwd: CDC-How biological abnormalities separate CFS from depression

[Guest guest]

How biological abnormalities separate CFS from depression

http://jaapa.com/issues/j20080301/articles/cfs0308.htm

Chronic fatigue syndrome and depression share symptoms and may coexist—but

thanks to new efforts spearheaded by the CDC, skilled clinicians can more

easily tell them apart. M. Erdman, MPAS, PA-C Erdman is

assistant professor and assistant director, Baylor College of Medicine PA

program, and a PA in the Department of Emergency Medicine at Lyndon B.

General Hospital, Houston, Texas. She has indicated no relationships to

disclose relating to the content of this article. Chronic fatigue syndrome

(CFS), also called chronic fatigue immune dysfunction syndrome (CFIDS), is a

multisystem illness characterized by a complex constellation of symptoms. CFS

has long been controversial among health care providers and researchers, in

part because of the difficulty of differentiating it from psychiatric illness.

Much has been written about the underdiagnosis of depression,1,2 but care must

be taken as well to avoid the overdiagnosis of depression

in patients who have unexplained physical symptoms. Although comorbid

depression is a common emotional response to any chronic illness, some patients

with CFS are not clinically depressed. These patients are poorly served when

depression is the only diagnosis they are offered.

Comorbid depression in CFS has been perceived as evidence that CFS is an

atypical manifestation of depression. However, the depression in CFS could be a

result of multiple symptoms, an emotional response to disability, immune system

changes, or alterations in brain physiology.3 Validating patients who have

unexplained symptoms is often difficult. Many clinicians, unaware of the

volumes of evidence pointing to a physiologic etiology to CFS, may be

overdiagnosing depression by default. This article provides an overview of that

evidence and offers clues to differentiating depression from physiologic

illness in a patient who presents with symptoms of CFS.

The 1988 CDC case definition for CFS was revised in 1994 (see Table 1).4 In

2003, Reeves and colleagues pointed out ambiguities in that definition and

offered an approach to guide application of the case definition so that

identification of CFS cases could be more uniform for research studies.5

Patients with CFS defined according to the Reeves’ approach are clinically

distinct from those with unexplained fatigue or depression. The criteria for

CFS specifically recognize that CFS and depression can coexist. The challenge

to the clinician is to decide for each patient whether the fatigue is due to

primary depression, physical illness such as CFS, or a combination.

BACKGROUND Investigators have been studying CFS from an evidence-based

perspective for more than 2 decades. The CDC recently declared, “There is now

abundant scientific evidence that CFS is a real physiological illness. It is not

a form of depression or hypochondriasis. A number of biologic abnormalities have

been identified in people with CFS.”6

The lack of credibility given to CFS has been a key obstacle to understanding

and acceptance of it as a formal disease state. The CDC, in collaboration with

the CFIDS Association of America, initiated a public health campaign to educate

the medical community and the public and to advocate for awareness and

effective management of CFS. The campaign includes increased dissemination of

scientific findings, a CFS Toolkit for clinicians, new continuing medical

education opportunities, detailed information on the CDC Web site, public

service announcements, advertisements, brochures, and a traveling photo

exhibit.7

The campaign was launched during a November 3, 2006, press conference held at

the National Press Club. Identifying CFS as an “urgent reality,” Dr.

Gerberding, director of the CDC, commented that “we are beginning to open the

shroud of mystery that has clouded this illness for a long time.” The Assistant

Secretary of Health and Human Services and the CDC’s Chief of Chronic Viral

Diseases discussed the emerging CFS research and the CDC’s ongoing research

efforts.8

Dr. Komaroff, a pioneer in CFS research from Harvard Medical School,

noted that “there are now more than 4,000 published studies that show

underlying biological abnormalities in patients with this illness. It’s not a

psychological illness. In my mind that debate, which was waged for 20 years,

should now be over.”8

News of the press conference reached the American Medical Association (AMA),

with the report immediately posted to the AMA’s Web site and published in the

November 27, 2006, issue of American Medical News, the online newsletter of

the AMA.9 It was also published in the November 27, 2006, issue of the Journal

of the American Medical Association.10 The prompt attention given by the AMA

highlights the changing attitudes toward the approach to CFS.

Research into CFS is ongoing at the National Institutes of Health (NIH). This

includes the trans-NIH working group for CFS research, an effort to have all of

the institutes in the NIH contribute. Thirteen currently participate, and seven

new research grants have been awarded with the goal of better understanding how

the brain functions in relation to CFS.11

REVIEW OF THE LITERATURE What does this important news and educational push by

the CDC mean to physician assistants? First and foremost, care must be taken

to stay informed and to consider new evidence. Because depression with

somatization can initially manifest similarly to CFS, PAs must take care to

keep up with ever-increasing evidence that CFS has identifiable biological

underpinnings.

CFS and depression share certain symptoms, but many others, such as sore

throat, lymphadenopathy, arthralgias, myalgias, and postexertional fatigue, are

not typical of psychiatric illness. In addition, patients with CFS generally do

not have the usual depressive symptoms of anhedonia, guilt, and lack of

motivation.12-14 The fatigue of depression seems to be motivation-related and

milder than in CFS. When tested, depressed persons score highest on feelings of

low self-esteem manifested as self-criticism and feelings of worthlessness and

guilt, but CFS patients score highest on physical symptom-related points such

as pain, sleep disruption, and lack of energy.15 People with depression tend

to be withdrawn and without a sense of hope, whereas people with CFS are

typically more proactive about seeking treatment, are hopeful for recovery, and

often join support groups and lobby for research funding.16 Striving for

improved quality of life is uncommon in depressed

persons.

The CDC’s CFS Research Group has contributed approximately 80 publications to

peer-reviewed journals since 2000. Much of this information has come from the

Wichita CFS Surveillance Study, launched by CDC researchers in 1997, which

collected data from 90,000 subjects and performed extensive clinical

assessments of approximately 7,000.17,18 Observing the data, Reyes and

colleagues posited that CFS may be associated with genetic and environmental

determinants.17 Fourteen papers resulting from the Wichita study speaking to

these very issues appeared in a special April 2006 issue of Pharmacogenomics.

In the Witchita study, data were collected over 2 days on hospitalized

patients from the general population, including 227 patients with CFS, patients

who had other unexplained illnesses causing fatigue, and nonfatigued controls.

The CFS patients’ psychiatric status, sleep physiology, and cognitive function

were evaluated, and neuroendocrine status, autonomic nervous system function,

systemic cytokines, and peripheral blood gene expression were measured.18

Then, in a unique public health effort, a multidisciplinary and international

group of 20 investigators was formed to offer new insight and algorithms for

interpretation and integration of the Wichita data. It was also hoped that the

group might be able to identify molecular markers and discover the

pathophysiology of CFS. The group was divided into teams with representation

from the disciplines of medicine, mathematics, biology, engineering, and

computer science.

One of the most significant observations was that CFS patients have certain

markers that are related to brain activity that mediates the stress response.

They also have different gene activity levels, which affect the body’s ability

to adapt to significant stressors, such as infection, injury, and trauma. The

Wichita investigators noted that CFS has at least four distinct clinical

profiles that implicate different sets of subtle alterations in the

hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system.18

Other research findings revolve around abnormalities of the brain, immune

system, endocrine function, and energy metabolism. Studies of abnormalities in

HPA axis function and hormonal stress responses have given rise to the most

reproducible findings, showing that the hormone system in the hypothalamus and

pituitary functions differently in CFS patients than in healthy controls,

depressed persons, and persons with other illnesses.

HPA axis abnormalities, including hypercortisolemia, elevated urinary free

cortisol, and exaggerated cortical response to corticotrophin, appear in

persons with depression.19 In patients with CFS, however, the opposite appears

to be true. CFS patients have lower plasma cortisol than do controls and have a

reduced response to corticotrophin. In a direct comparison study, depressed

patients had the highest levels of circulating cortisol, normal controls had

lower levels, and CFS patients had the lowest levels.20 Urinary free cortisol

(UFC) excretion was significantly higher in patients with depression than in

healthy comparison subjects, and UFC excretion was significantly lower in

patients with CFS than in the comparison group in a 1998 study. The CFS

patients who had comorbid depressive illness retained the profile of UFC

excretion of those with CFS alone, which suggests a different pathophysiologic

basis for depressive symptoms in CFS.21

A comprehensive review of neuroendocrine studies in 2001 also confirmed HPA

abnormalities in CFS patients.22 Another study showed low cortisol levels in

CFS patients compared to controls and determined that depression in CFS may be

different from classic depression.23 More recently, in 2006, reduced basal HPA

axis function in CFS patients was confirmed, showing lower free cortisol and

cortisone levels.24 Others have found that dehydroepiandrosterone was lower in

patients with CFS than in depressed persons or controls.25

Imaging studies, including MRI, CT, and various nuclear scans, have shown

inflammation, reduced blood flow, and impaired cellular function in the brains

of patients with CFS.26,27 There is objective evidence that CFS patients who

underwent blood oxygen level dependent functional MRI studies had significant

auditory information processing difficulties.28 In many with CFS, cognitive

function is impaired.29-31 Positron emission tomography and single-photon

emission tomography of the brain have shown frontal hypoperfusion in both

depressive disorders and CFS,32 but the patterns are different, with additional

differences in perfusion of various parts of the brain and brain stem.33,34

Many immune system studies have demonstrated abnormal immune system cells in

patients with CFS and shown that the system is in a state of chronic

activation, as if responding to a foreign invader.35-37 Nijs and De Meirleir

provided an overview of studies showing impairments of the 2-5A

synthetase/RNase L pathway in CFS, with associated decreased natural killer

cell function and deregulation of apoptotic pathways.38 A panel of experts

determined that changes in immune responses found in CFS patients fall outside

normal ranges, but they were not able to determine whether these abnormalities

were a cause or a result of the illness.39 Gene expression studies show genes

that control the activation of the immune system are abnormally expressed in

patients with CFS.40-42

Biological distinctions between CFS and depression have been found by

measuring electrodermal activity and skin temperature in nondepressed subjects

with CFS, subjects with depression, and healthy controls. Skin temperature

differed significantly among all three groups, with the CFS group averaging 3

to 4°C higher than the depressed and healthy controls, respectively. The levels

of skin conductance were significantly lower in the CFS group than in the other

two groups.43

Depressed patients typically have reduced rapid eye movement (REM) latency and

increased REM density on sleep studies, but this is not usually present in CFS;

instead, patients with CFS often have a lack of slow-wave deep sleep, sleep

cycle disturbance, and frequent awakenings.44 As primary sleep disorders cause

fatigue, sleep studies may be indicated to rule out sleep apnea, periodic leg

movement disorder, and other sleep-related illnesses.

RESOURCES AND DIAGNOSIS With the new focus from the CDC and research that

points to biological markers for CFS, clinicians can be more objective in their

approach to patients with symptoms of this disease. Many conditions need to be

ruled out, and the CDC’s Toolkit offers guidelines for the workup of a patient

with CFS symptoms. The toolkit can be accessed at www.cdc.gov/cfs/toolkit.htm.

Elements of the initiative that are available via the CDC Web site are a quick

reference brochure, free continuing medical education courses, and a 65-page

manual on CFS science and research. CDC researchers and collaborators present

programs about CFS at conferences, academic institutions, and health care

centers. Details can be found at

www.cfids.org/sparkcfs/health-professionals.asp.

The differences between CFS and depression suggest that someday people with

CFS might be identified by various physiologic measures. In an outpatient

setting, differentiating CFS from depression should be focused on the history

and on physical signs and symptoms. Focusing on diagnostic criteria should help

to reach an accurate diagnosis. The Toolkit instructs on the appropriate

laboratory tests. In addition, if appropriate, sleep studies and cortisol

testing may be helpful. The Hospital Anxiety and Depression Scale can be used

to assess level of depression and may be a good starting point for discussing

the patient’s experience and determining if anhedonia is the result of a

generalized sense of hopelessness or caused by pain and exhaustion.

CONCLUSION Having knowledge and experience with CFS, remaining objective, and

assuring that the patient meets the accepted diagnostic criteria will aid the

astute clinician in making an accurate diagnosis. Using the Toolkit and having

the CDC’s other resources easily accessible in the clinical setting can make for

more productive encounters with patients presenting with unexplained symptoms of

fatigue. Ongoing research into specific brain, hormonal, and immunologic

abnormalities consistent with CFS will undoubtedly continue to shed new light

onto the etiology of this frustrating illness, with possibilities for finding

diagnostic markers that can be used to more easily identify CFS. Although the

debate about CFS as a medical or psychiatric condition will likely continue, it

is not likely that depression will be proven to be the primary cause. JAAPA

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