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Appendix B
Possible Factors Underlying
Chronic Multisymptom Illness
Chronic multisymptom illness (CMI)—like several other syndromes,
including fibromyalgia, chronic fatigue syndrome (CFS), and irritable bowel
syndrome (IBS)—lacks characteristic biomarkers. In the absence of other
diseases that would explain the symptoms, its diagnosis is based on symp-
tom criteria. CMI can consist of diverse symptoms that vary among people
or even within the same person over time. The symptoms may be related
to central nervous system upregulation (amplification) of neural signals
that have a somatic or visceral origin rather than originating exclusively in
bodily conditions. That mechanism is similar to the current understanding
of IBS in deployed Gulf War veterans, which appears to develop by the
combination of gastroenteritis, leading to gut mucosal immune dysfunction
and inflammation, and impairment of the brain’s ability to reduce or down-
regulate neural signals from the gastrointestinal tract related to the deploy-
ment experience (Drossman, 1999; IOM, 2010; Spiller and Garsed, 2009).
The dysregulation of the “brain–gut axis,” malfunctioning of the visceral
signaling regulatory system, leads to the characteristic symptoms of IBS.
Although the degree to which the brain enhances neurologic signals
from the body in CMI has yet to be determined, it is recognized that the
brain’s ability to filter incoming signals is highly modifiable by environ-
mental and psychologic factors. For example, the number of symptoms
that people report correlates with psychologic and environmental factors,
including levels of anxiety and depression and the degree of stress after
exposure to abuse or war trauma (Bair, 2003; IOM, 2008; Vaccarino et
al., 2009; Zaubler and Katon, 1996). Such correlations do not imply that
the symptoms reported are indicative of a psychiatric disorder. In those
203
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204 GULF WAR AND HEALTH
who have pain, these correlations are explained in part by the effects of
stressors on limbic areas of the brain (in particular, the cingulate cortex)
that are associated with pain regulation. For example, a history of physi-
cal and sexual abuse is associated with increased reports of pain in people
who have IBS, and increased pain correlates with enhanced activation of
the midcingulate cortex, an area at the interface of pain regulation and
emotional input (Ringel et al., 2008). In addition, peripheral inflammatory
states associated with increased cytokine activation may in turn alter brain
functioning, producing “sickness behavior.” These phenomena may help to
explain the emotional distress and increased symptom awareness associated
with CMI (Dantzer et al., 2008). That putative mechanism is illustrated in
Figure B-1, which demonstrates that somatic and visceral sensations (for
example, muscle pain, fatigue, and abdominal pain) are experienced as
symptoms only when the signal amplitude is above the brain’s perception
threshold. Thus, peripheral neural signals arising from an injury might be
above the perception threshold and be experienced as a symptom, and other
regulatory signals (for example, increased gut signals after eating) might be
received in the brain but not experienced as a symptom unless one overeats
or has a gastrointestinal disorder, such as functional dyspepsia. In addition,
the brain’s ability to downregulate incoming signals (that is, to raise the
threshold level) will depend on regulatory processes and the person’s cogni-
tive and emotional state. Thus, injuring oneself might not be experienced as
a symptom when one is distracted during a sports event until the event is
FIGURE B-1 Putative mechanism by which the body perceives symptoms.
Figure B-1
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APPENDIX B 205
over. Conversely, anxiety about an injury and hypervigilance to the affected
part can lead to increased pain. In CMI, central factors may lead to a lower
sensation threshold and, if this is the case, centrally targeted treatments
would probably have therapeutic value by increasing sensation thresholds,
as occurs in treatment for other conditions, such as fibromyalgia, CFS,
and IBS. There is some evidence that patients who have similar somatic
symptoms have higher concentrations of substance P (which transmits pain)
in their blood and cerebrospinal fluid than people who do not have such
symptoms (Clauw, 2009). In those patients, direct pressure on the skin or
inflation of a balloon in the esophagus causes pain at a much lower level of
pressure than in people who do not have these somatic symptoms.
In addition, central measures of hormonal stress, such as an altered
response of the hypothalamic-pituitary-adrenal axis, reveal an inappropri-
ate flattened response to additional stress that may reflect a more sustained
central overactivity in patients who have visceral hypersensitivity (such as
IBS) or somatic hypersensitivity (such as fibromyalgia) (Clauw, 2009).
Nonrestorative sleep can be reproduced in normal volunteers who are
subjected to disruption of deep stage four sleep and is a typical sleep pattern
in patients who have IBS. When deep stage four sleep is repeatedly disrupted,
affected people can develop myalgia, heightened pain, presence of tender
points on examination, and disrupted sleep patterns afterward. Further
research is needed to assess whether use of programs and agents that restore
a better sleep pattern may also lead to improvement in other symptoms.
In summary, the multiple symptoms of CMI, like the symptoms associ-
ated with other functional somatic syndromes, may arise from at least two
factors: an impairment of the brain in its downregulating of incoming nerve
signals originating in the body and an increase in or amplification of bodily
nerve signals for any of a variety of reasons (such as injury or infection).
The degree to which those factors interact in CMI is an important topic
for future research.
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