Date sent:      	Sun, 9 Dec 2001 

Fibromyalgia (Critical Review)

J of Chronic Fatigue Syndrome, Vol. 9(3/4) 2001, pp. 21-161

Roberto Patarca-Montero, MD, PhD

E. M. Papper Laboratory of Clinical Immunology, Departments
of Medicine, Microbiology and Immunology, University of Miami School of
Medicine, 1600 NW 10th Avenue, Miami, FL 33136.

[....
The the following excerpt is one section of this 140 page article.]


SIMILARITIES AND DIFFERENCES BETWEEN FIBROMYALGIA AND RELATED DISORDERS

There is clinical, and in many cases demographic, overlap between
fibromyalgia, chronic fatigue syndrome, Persian Gulf War syndrome,
silicone implant-associated syndrome, sick building syndrome, multiple
chemical sensitivity, and syndromes including neurally mediated
hypotension, abnormalities of the growth hormone-insulin-like growth
factor-1 axis, chemical intolerance, altered functioning of the
stress-response system, and the presence of autoantibodies (Baschetti,
1999; Bazelmans et al., 1997; Bennett, 1998; Buchwald, 1996; Buskila,
1999,2000; Chambers, 1997; Csef, 1999; Goldenberg, 1997; Granzow, 1999;
Hoffmann et al., 1996; Kelly, 1997; Kenner, 1998; Klimas, 1998; Pocinki,
1997; Robertson, 1999; Sabal, 1997; Slavkin, 1997; Vree, 1997; Wallace,
1997; Wessely and Hotopf, 1999). However, there are differences among the
latter syndromes (Matsumoto, 1999). Fibromyalgia may also be affected by
psychosocial, cultural, psychological and environmental factors (Affleck
et al., 1998; Ben-Zion et al., 1996; Cathebras, 1997; Hadler, 1996;
Hausotter, 1998; Kissel and Mahning, 1998; Kuhn, 2000; Kurtze et al.,
1998; Reid et al., 1997; Schaefer, 1997; Schuck et al., 1997; Turk et
al., 1996). On the other hand, fibromyalgia may complicate other
syndromes (Kelemen and Muller, 1998; Potter, 1997), as is the case in
some patients with hyperlaxity syndromes, such as Benign Joint
Hypermobility Syndrome (Grahame, 2000).

Autoimmune fatigue syndrome: Itoh et al. (1997) found that among children
who chronically complain of nonspecific symptoms such as headache,
fatigue, abdominal pain, and low grade fever, those who were antinuclear
antibody (ANA)-positive (approximately 50% of cases) tended to have
general fatigue and low grade fever, while gastrointestinal problems such
as abdominal pain and diarrhea and orthostatic dysregulation symptoms
were commonly seen in ANA-negative patients. Children who were unable to
go to school more than one day a week were seen significantly more among
ANEW-positive patients than among negative patients. Based on these
observations, the authors concluded that autoimmunity may play a role in
childhood chronic nonspecific symptoms and proposed a new disease entity:
the autoimmune fatigue syndrome in children.

Itoh et al. (1999) described two patients with fibromyalgia who had been
initially diagnosed as having autoimmune fatigue syndrome (AIFS), and
proposed that ANA-positive fibromyalgia or ANA-positive chronic fatigue
syndrome could be forms of AIFS. Itoh et al. (1998) also reported that a
novel autoantibody to a 62 kD protein (anti-Sa) was found in 40% of
ANA-positive children with autoimmune fatigue syndrome. Similarly to
autoimmune diseases, Itoh et al. (2000) found that autoimmune fatigue
syndrome has an immunogenetic background: it is positively associated
with the class I antigen HLA-1361 and with the class II antigen HLA-DR9,
and negatively associated with HLA-DR2.

Behcet's syndrome: Yavuz et al. (1998) found a trend for an increased
frequency of fibromyalgia in female Behcet's syndrome patients. In their
study, 10 (9 of whom were women) of 108 Behcet's syndrome patients (9.2%)
met the American College of Rheumatology criteria for fibromyalgia and,
in contrast to those without fibromyalgia, they had mild to moderate
disease activity in which musculoskeletal complaints were common.

Chronic fatigue syndrome: Despite remarkably different diagnostic
criteria, fibromyalgia and chronic fatigue syndrome have many demographic
and clinical similarities (Bazelmans et al., 1999; Buchwald, 1996a,b;
Clauw and Chrousos, 1997; Demitrack, 1998; Hoffrnann et al., 1996;
Kenner, 1998; Lloyd, 1998; White et al., 2000; Ziem and Donnay, 1995).
More specifically, few differences exist in the domains of symptoms,
examination findings, laboratory tests, functional status, psychosocial
features, and psychiatric disorders. Among the differences between the
two syndromes, Evengard et al. (1998) found that although substance P
levels were normal in the cerebrospinal fluid of 15 patients with chronic
fatigue syndrome, the majority of fibromyalgia patients studied had
increased cerebrospinal fluid levels of substance P. Further
clarification of the similarities and differences between chronic fatigue
syndrome and fibromyalgia may be useful in studies of prognosis and help
define subsets of patients who may benefit from specific therapeutic
interventions.

Chronic fatigue syndrome (CFS) is a disease entity of so far unknown
etiopathogenesis without specific markers that presents with a complex
array of symptoms in patients with diverse health histories (see
references cited). Fatigue is one of the most prominent features of CFS
and one of the most common medical complaints in general. Patients with
unexplained chronic pain and/or fatigue have been described for centuries
in the medical literature, although the terms used to describe these
symptom complexes have changed frequently. Neurasthenia dominated medical
thinking at the turn of the century; the term "myalgic encephalomyelitis"
was introduced in the United Kingdom in 1957, and in the mid-1980s, the
term "chronic Epstein-Barr virus syndrome" emerged and was then converted
to chronic fatigue syndrome and, by some, to "chronic fatigue immune
dysfunction syndrome." The currently preferred term, albeit a misnomer,
is chronic fatigue syndrome, a name which describes the prominent
clinical features of the illness without any attempt to identify the
cause but has the endorsement of the United States Centers for Disease
Control and Prevention (CDC) and several professional organizations.
Related diseases include fibromyalgia, sick building syndrome, Gulf War
syndrome, and multiple chemical sensitivity syndrome. Opinions on CFS
range from non-disease via psychiatric disorder to a somatic disturbance.
Nevertheless, CFS has emerged as a public health concern over the past
decade in many countries and some court rulings have legitimized the
diagnosis of CFS in some societal settings.

The diagnosis of CFS is based on clinical criteria and it is largely
dependent upon ruling out other organic and psychologic causes of
fatigue. CFS is defined by primary and secondary criteria, which are,
however, largely subjective.   CFS includes cases of long-standing (6
months or longer) fatigue that are not explained by an existing medical
or psychiatric diagnosis, and which cause considerable disabilities in
professional social and/or personal functioning (at least 50% reduction
in baseline level). Other CFS criteria include: fever, painful
adenopathy, muscle weakness, myalgia, headache, migratory arthralgia,
neuropsychologic symptoms, and sleep disorder. Although several studies
have validated these criteria, much controversy persists and an attempt
at formulating new criteria based on laboratory parameters is being
attempted. The working case definition of CFS in 1988 was an attempt to
establish a uniform basis for the previously heterogeneous approaches to
research of this severe and inexplicable state of fatigue. At the same
time, researchers wished to narrow down a pathogenetically founded
disease entity a priori by specifying precise disease criteria. The case
definition has also been used to establish prevalence estimates using
physician-based surveillance and random digit dial telephone surveys.
Although the original 1988 definition was revised in 1994, the empirical
data gathered in accordance with the CFS definition have failed to
confirm the assumption that the disease entity is pathogenetically
uniform.

The onset of CFS may be associated with preceding stressful events and
multiple other precipitants. A study that divided CFS patients into two
groups based on whether onset was sudden or gradual found that the rate
of concurrent psychiatric disease was significantly greater in the
CFS-gradual group relative to the CFS-sudden group. While both CFS groups
showed a significant reduction in information processing ability relative
to controls, impairment in memory was more severe in the CFS-sudden
group. Some authors also make a distinction between an acute phase (up to
one month after the first consultation), a subacute phase (until 6 months
after the onset of the complaints and disabilities) and a chronic phase
(from 6 months after the onset of the complaints and disabilities) of the
disease. CFS evolves towards chronicity in an important number of cases.

Somatic pathogenetic hypotheses for CFS include persisting infections,
intoxications, metabolic or immunologic disturbances, nervous system
diseases, endocrine pathology and psychosomatic influences. An infectious
illness is not uniformly present at the onset and no single infectious
agent has been found. Various components of the central nervous system
appear to be involved in CFS, including the hypothalamic pituitary axes,
pain-processing pathways, sleep-wake cycle, and autonomic nervous system.
Many studies have provided evidence for abnormalities in immunological
markers among individuals diagnosed with CFS. Nonetheless, a clear
picture has not been achieved in any area of research because of the
noticeable variability in the nature and magnitude of the findings
reported by different groups. Moreover, little support has been garnered
for an association between the laboratory abnormalities and the diverse
physical and health status changes in the CFS population. For instance,
some authors think that although a subset of CFS patients with immune
system activation can be identified, serum markers of inflammation and
immune activation are of limited diagnostic usefulness in the evaluation
of patients with CSF and chronic fatigue because changes in their values
may reflect an intercurrent, transient, common condition, such as an
upper respiratory infection, or may be the result of an ongoing
illness-associated process. On the other hand, other authors have found
that CFS patients can be categorized based on immunological findings or
that when patients are classified according to whether the disease
started suddenly or gradually, immunological changes are apparent. It is
also worth noting that although the degree of overlap between
distributions of soluble immune mediators in CFS and controls has fueled
criticism on the validity or clinical significance of immune
abnormalities in CFS, the latter degree of overlap is not unique to CFS
and is also present for instance in sepsis syndrome and HIV-1-associated
disease, clinical entities where studies of immune abnormalities are
providing insight into pathophysiology. The latter statement also applies
to non-immunological parameters in CFS.

Based on the discrepancies described above, some authors argue that the
conceptual model of CFS needs to be changed from one determined by a
single cause/agent to one in which dysfunction is the end stage of a
multifactorial process. A study of author bias in literature citation in
CFS reviews revealed that citation of literature is influenced by the
authors' discipline and nationality, a finding which is compatible with
the lack of consensus and integrated efforts among professionals from
different disciplines who are working on CFS.

Cogan I syndrome: Cogan I syndrome is a rare, inflammatory, systemic
disease that is typically characterized by severe audiovestibular
dysfunction and various inflammatory eye changes (uveitis, scleritis,
keratitis and episcleritis). In a study of ten patients with Cogan I
syndrome, Zierhut et al. (2000) reported other manifestations of this
syndrome, including pericarditis associated with arthritis, and
polyserositis in one patient, and fibromyalgia in two patients.

Ehlers-Danlos syndrome: Fibromyalgia may be concurrent with Ehlers-Danlos
syndrome (Miller et al., 1997), a disease characterized by a genetic
defect in collagen synthesis. In a study of 39 fibromyalgia patients,
Sprott et al. (1998) found evidence for abnormal collagen metabolism by
analyzing urine and serum samples to determine levels of pyridinoline
(Pyd) and deoxypyridinoline (Dpyd), which represent products of lysyl
oxidase-mediated cross-linking in collagen and are indicators of
connective tissue and bone degradation, respectively, and of
hydroxypyroline (Hyp), a collagen turnover marker. Based on the findings
of significantly decreased urine and serum Pyd/Dpyd ratios and urine Hyp
levels in fibromyalgia patients as compared to healthy controls, Sprott
et al. (1998) concluded that decreased levels of collagen cross-linking
may contribute to remodeling of the extracellular matrix and collagen
deposition around the nerve fibers in fibromyalgia, thereby underlying
the lower pain threshold at the tender points (Malleson, 1998; Sprott and
Muller, 1998). The latter results are consistent with the electron
microscopic findings of highly ordered cuffs of collagen around the
terminal nerve fibers in biopsy tissue from all 8 fibromyalgia patients
but none of the control skin samples examined by Sprott et al. (1997) in
a previous study. Moreover, Barkhuizen and Bennett (1999) and Yaron et
al. (1997) reported that serum levels of hyaluronic acid, a breakdown
product of collagen, in fibromyalgia women were significantly elevated
compared to healthy controls and rheumatoid arthritis patients.

Eosinophilia myalgia syndrome: The eosinophilia-myalgia syndrome (EMS)
caused by intake of contaminated L-tryptophan resembles fibromyalgia in
its clinical presentation (Barth et al., 1999; Hudson et al., 1996). In
one study, the similar incidence (81 %) of myalgia and arthralgia and the
presence of antibodies directed against serotonin, gangliosides and
phospholipids in both chronic EMS and fibromyalgia patients, as well as
the predominant production of type 2 cytokines in vitro after stimulation
with different L-tryptophan preparations of peripheral blood mononuclear
cells from fibromyalgia patients, led Barth et al. (1999) to postulate
that EMS may have developed in patients suffering primarily from
fibromyalgia as an allergic reaction towards a more immunogenic
L-tryptophan preparation. Nonetheless, Taylor et al. (1996) point out
that four variables, namely extremity edema, leukocyte count greater than
12.5 X 109/L, dyspnea, and absence of arthralgias, differentiate EMS from
other common myalgia syndromes (sensitivity of 95.6%, a specificity of
96.9%, and positive and negative predictive values of 93.5 and 97.9%,
respectively).

Hepatitis C. Hepatitis C virus (HCV) is both a hepatotropic and a
lymphotropic virus; because of to this latter biological peculiarity, HCV
may trigger a constellation of autoimmune-lymphoproliferative disorders.
Rheumatologic complications of HCV infection are common and include mixed
cryoglobulinemia, vasculitis, sicca symptoms, myalgia, arthritis, carpal
tunnel syndrome, tenosynovitis, and fibromyalgia (Barkhuizen and Bennett,
1997; Buskila, 2000; Ferri and Zigneno, 2000; Jendro et al., 1997;
Killenberg, 2000; Lovy et al., 1996; Rivera et al., 1997). However,
rheumatic complications are not associated with liver disease severity,
subjects' gender, presence of autoantibodies (cryoglobulins, rheumatoid
factor, antinuclear antibodies, antismooth muscle antibodies,
anti-phosphoIipid antibodies and anti-thyroid antibodies) or response to
treatment to interferon-alpha (Buskila et al., 1998; Buskila, 2000;
Jendro et al., 1997; Rivera et al., 1997). The identification of HCV
infection in rheumatic patients is important to minimize the risk of
aggravating hepatitis by prescription of hepatotoxic drugs and because of
the availability of alpha-interferon as a potential virus eradicating
agent. Also, recognizing fibromyalgia in patients with HCV will prevent
misinterpretation of fibromyalgia symptoms as part of the liver disease
and will enable the physician to reassure the patient about these
symptoms and to alleviate them (Buskila et al., 1997).

Hyperkalemic periodic paralysis. Gotze et al. (1998) reported on a 43
year-old woman with hyperkalemic periodic paralysis that was erroneously
diagnosed as having fibromyalgia based on the criteria of the American
College of Rheumatology. Her son and three close relatives also had
histories of muscle pain and fatigue increasing with age.

Hyperparathyroidism: The symptoms of hyperparathyroidism are vague and
often similar to symptoms of depression, irritable bowel syndrome,
fibromyalgia or stress reaction (Allerheiligen et al., 1998).
Hyperparathyroidism is a common cause of hypercalcemia. The hypercalcemia
usually is discovered during a routine serum chemistry profile. Often,
there has been no previous suspicion of this disorder. In most patients
initially believed to be asymptomatic, previously unrecognized symptoms
resolve with surgical correction of the disorder.

Inflammatory bowel disease: Rheumatological complications of inflammatory
bowel disease (Crohn's disease and ulcerative colitis) include peripheral
arthritis and spondylitis, and soft tissue rheumatism, specifically
fibromyalgia. In a study by Buskila et al. (1999), fibromyalgia was
documented in 30 of 113 patients with inflammatory bowel disease (30%),
specifically in 49% of patients with Crohn's disease and 19% with
ulcerative colitis; in controls the rate was 0%. Subjects with Crohn's
disease exhibited more tenderness and reported more frequent and more
severe fibromyalgia associated symptoms than subjects with ulcerative
colitis. Recognizing fibromyalgia in patients with inflammatory bowel
disease will prevent misdiagnosis and ensure correct treatment.

Inflammatory spinal pain: Patients are said to have inflammatory spinal
pain if they fulfill at presentation 4 of the following 5 criteria:
duration of spinal discomfort for at least 3 months, spinal morning
stiffness, age less than 40, insidious onset of symptoms, and no relief
from pain with rest, but improvement with exercise. Inflammatory spinal
pain is typical of the spondylarthropathies. Only in a minority of the
cases it is found in other rheumatic disorders such as rheumatoid
arthritis, fibromyalgia, infectious spondyilitis, or tuberculous
spondylitis (Cantini et al., 1998).

Interstitial cystitis: Interstitial cystitis is a relatively uncommon
disorder characterized by pain in the bladder and pelvic region,
typically accompanied by urinary urgency and frequency (Clauw et al.,
1997). Although genitourinary and musculoskeletal symptoms predominate in
interstitial cystitis and fibromyalgia respectively, both disorders share
a number of features, including similar symptomatology (diffusely
increased peripheral nociception and increased pain sensitivity),
demographics, natural history, aggravating factors, overlapping
conditions (allergies, irritable bowel syndrome) and efficacious therapy
(Clauw et al., 1997). In comparison to the general population,
individuals with interstitial cystitis are 100 times more likely to have
inflammatory bowel disease and 30 times more likely to have systemic
lupus erythematosus (Alagiri et al., 1997).

Irritable bowel syndrome: Irritable bowel syndrome and fibromyalgia are
considered chronic syndromes of altered visceral and somatic perception,
respectively (Chang, 1998; Chang et al., 2000; Chun et al., 1999; Mayer
et al., 1998: Sivri et al., 1996). As many as 70% of patients with
fibromyalgia complain of the symptoms of irritable bowel syndrome, and
approximately 35% of patients with irritable bowel syndrome have also
fibromyalgia (Barton et al., 1999; Chang, 1998). The diagnostic criteria
of the fibromyalgia syndrome include irritable bowel syndrome, and hence
a common etiopathophysiology has been suggested (Azpiroz et al., 2000;
Sperber et al., 1999). Similar to fibromyalgia, a large proportion of
irritable bowel syndrome patients also complain of other functional
disorders, such as headache, noncardiac chest pain, low back pain, sicca
complex, and dysuria (Chang, 1998; Mayer et al., 1998). Sperber et al.
(1999a,b, 2000) and Chang et al. (2000) found that patients with both
irritable bowel syndrome and fibromyalgia have increased severity of
symptoms. However, both hypervigilance and somatic hypoalgesia contribute
to the altered somatic perception in irritable bowel syndrome patients,
while co-morbidity with fibromyalgia results in somatic hyperalgesia in
irritable bowel syndrome patients (Chang, 1998; Chang et al., 2000).
Another distinctive feature was pointed out by the study of Chun et al.
(1999) who found that although patients with fibromyalgia and sphincter
of Oddi dysfunction, type III, share many demographic and psychosocial
characteristics with patients with irritable bowel syndrome (Chun et al.,
1999), the latter have significantly lower rectal pain thresholds and
increased levels of psychologic distress compared to controls.

Leiomyosarcoma: A retroperitoneal leiomyosarcoma was reported in a
patient who had been diagnosed with fibromyalgia (De Tomas Palacios et
al., 1995).

Masticatory myofascial pain: Cimino et al. (1998) reported several
similarities between fibromyalgia and masticatory myofascial pain in 46
patients affected by craniomandibular disorders, the most striking of
which were pain during mandibular function, articular noises, and
headache. Both groups had similar mean scores of muscle pain upon
palpation, mean values of active mouth opening, and mean values of
passive opening. The authors recommend that the physician should be alert
to the need to conduct interdisciplinary evaluations in the diagnosis and
management of fibromyalgia and of masticatory myofascial pain.

Mitochondrial myopathy: Mitochondrial myopathy can also mimic
fibromyalgia and should be included in the differential (Benito-Leon et
al., 1996; Villanova et al., 1999).

Myoadenylate deaminase deficiency: Marin and Connick (1997) described a
patient who was treated unsuccessfully for fibromyalgia for many years
and who ultimately was diagnosed with a rare benign skeletal muscle
metabolic disorder caused by myoadenylate deaminase deficiency.

Myofascial pain syndrome: Myofascial pain syndrome (MPS) is a very common
localized-sometimes also polytopic-painful musculoskeletal condition
associated with trigger points, for which, however, diagnostic criteria
established in well-designed studies are still lacking (Cimino et al.,
1998; Pongratz and Spath, 1998). Fibromyalgia should be included in the
differential diagnosis for myofascial pain of the masticatory or facial
muscles (Aronoff, 1998; Bernstein, 1997; Bohr, 1996; Dao et al., 1997;
Fishbain and Rosomoff, 1996; Galer, 1997; Gantz and Fukuda, 1997;
Goldenberg, 1996; Long, 1997; Nye, 1997; Perle, 1996; Romano, 1997).

Harden et al. (2000) surveyed American Pain Society members and 88.5%
respondents reported that MPS is a legitimate diagnosis, with 81%
describing MPS as distinct from fibromyalgia. The only signs and symptoms
described as essential to the diagnosis of NIPS by greater than 50% of
the sample were regional location, presence of trigger points, and a
normal neurologic examination. Regarding the signs and symptoms
considered to be essential or associated with MPS, more than 80% of
respondents agreed on regional location, trigger points, normal
neurologic examination, reduced pain with local anesthetic or "spray and
stretch," taut bands, tender points, palpable nodules, muscle ropiness,
decreased range of motion, pain exacerbated by stress, and regional pain
described as "dull," "achy," or "deep." Sensory or reflex abnormalities,
scar tissue, and most test results were considered to be irrelevant to
the diagnosis of MPS by a large proportion of the respondents.

Some patients may exhibit both MPS and fibromyalgia (Dao et al., 1998).
For instance, of the 162 female participants with a history of myofascial
face pain, Raphael et al. (2000) found that 38 (23.5 percent) reported a
history of fibromyalgia. Patients who have myofascial face pain and a
history of widespread pain suggestive of fibromyalgia are likely to have
more persistent and debilitating myofascial face pain and to have higher
rates of depression and somatization symptoms than those who have no
history of widespread pain. Raphael and Marbach (2000) also found reduced
fertility among women with myofascial face pain, but restricted to those
who self-report a history of fibromyalgia.

The most important criteria for differential diagnosis are the presence
of tender points (TePs) and widespread, nonspecific, soft tissue pain in
fibromyalgia, compared with regional and characteristic referred pain
patterns with discrete muscular trigger points (TrPs) and taut bands of
skeletal muscle in MPS. Myofascial TrPs are found within a taut band of
skeletal muscle and have a characteristic "nodular" texture upon
palpation. TrPs are thought to develop after trauma, overuse or prolonged
spasm of muscles. Local treatment applied to TePs is ineffective, yet
specific treatment of TrPs is often dramatically effective.

Fibromyalgia is a systemic disease process, apparently caused by
dysfunction of the limbic system and/or neuroendocrine axis, and often
requiring a multidisciplinary treatment approach, while MPS is a
condition that arises from the referred pain and muscle dysfunction
caused by TrPs, which often respond to manual treatment methods such as
ischemic compression and various specific stretching techniques
(Schneider, 1995).

Orofacial pain: Heir (1997) and Bailey (1997) stress that pain problems
associated with the orofacial region need to be evaluated thoroughly
because the differential diagnosis is broad-ranging including diseases
such as Lyme disease and fibromyalgia.

Osteomalacia: Reginato et al. (1999) point out that osteomalacia is
usually neglected when compared with other metabolic bone diseases and
may present with a variety of clinical and radiographic manifestations
mimicking other musculoskeletal disorders, including fibromyalgia.

Osteoporosis: Fibromyalgia is considered a risk factor and has been
associated with osteoporosis. Early detection and implementation of
appropriate nutritional supplementation (calcium/vitamin D), resistive
and weight bearing exercise, and specific bone mineral enhancing
pharmacological therapy may be indicated in pre-, peri-, and
postmenopausal subjects (Dessein and Stanwix, 2000; Swezey and Adams,
1999).

Pain syndromes: Pain syndromes can be divided anatomically into those
which cause generalized pain, such as fibromyalgia syndrome and
myofascial pain syndromes, and those which are confined to one regional
anatomical area (Carette, 1996). The latter group comprise those of the
neck, shoulder, elbow, wrist/hand, hip, knee and ankle/foot (Linaker et
al., 1999). Diffuse pain syndromes, such as fibromyalgia, are more common
in women and in some, like fibromyalgia and polymyalgia rheumatics, in
older persons (Gowin, 2000). Fibromyalgia also may be a secondary
phenomenon associated with some of the other diffuse pain syndromes, such
as those of neoplastic or endocrinological etiology.

Several chronic pain syndromes may mimic fibromyalgia by (1) the
occurrence of wide spread pain, (2) the chronicity of complaints, (3) the
preponderance of females in some of these, and (4) the lack of objective
data to be derived from imaging techniques and laboratory tests
(Menninger, 1998). Differential diagnosis requires examination of the
locomotor system under biomechanical auspices both at rest and during
movement in order to diagnose hyper- and hypomobility syndromes;
treatment of these conditions is guided by principles to improve
biomechanical function. In addition, the skin needs to be examined to
detect panniculosis (also called "celluiitis"), which may be mixed up
with fibromyalgia due to its preferential occurrence in peri- or
postmenopausal women (Menninger, 1998). Vertebral fractures and
fibromyalgia, while very different and unrelated clinical conditions, are
common pain conditions that can, at times, be difficult to diagnose and
manage (Hall, 1999). Distinction between fibromyalgia and other chronic
pain syndromes is also relevant in terms of prognosis, as illustrated by
a study by MacFarlane et al. (1996) who found that although chronic
widespread pain in the community has a generally good prognosis, those
with additional symptoms associated with fibromyalgia were more likely
still to have chronic widespread pain 2 years later.

Pentazocine-induced fibrous myopathy: A case report by Sinsawaiwong et
al. (1998) on a 47-year-old woman who had a 4-year history of
intramuscular pentazocine injections in the lower extremities, and who
developed gradual stiffness and weakness of the lower extremities
illustrates that caution in long term usage and early recognition of
pentazocine toxicity as a neuromuscular complication are important in
order to prevent irreversible drug-induced fibrous myopathy and localized
neuropathy. The latter condition should also be differentiated from
fibromyalgia.

Persian Gulf War syndrome: Since the Persian Gulf War ended in 1991,
veterans have reported an increased prevalence, as compared to
contemporary military personnel that was not deployed, of diverse,
unexplained symptoms, including some consistent with the chronic fatigue
syndrome, fibromyalgia, and multiple chemical sensitivity (Alloway et
al., 1998; Hodgson and Kipen, 1999; Nicolson and Nicolson, 1998;
Self-reported illness and health status among Gulf War veterans. A
population-based study. The Iowa Persian Gulf Study Group, 1997).
Although some veterans have wondered if their development of systemic
lupus erythematosus, amyotrophic lateral sclerosis, or fibromyalgia might
be related to Gulf War service, an examination by Smith et al. (2000) of
hospitalizations of regular, active-duty service personnel deployed to
the Persian Gulf War (n = 551,841) compared with nondeployed Gulf War era
service personnel (n = 1,478,704) did not support Gulf War service and
disease associations. Other controlled epidemiological studies in Gulf
War veterans and controls describe significant excesses of symptoms that
were not clearly associated with pathologic disease (Hodgson and Kipen,
1999).

Grady et al. (1998) reported that of 250 Gulf War veterans evaluated, 139
(56%) were referred for rheumatology consultation, which was the most
common elective subspecialty referral. Of the patients evaluated, 82
(59%) had soft tissue syndromes, 19 (14%) had rheumatic disease, and 38
(27%) had no rheumatic disease. The most common soft tissue syndromes
were patello-femoral syndrome (33 patients [25%]), mechanical low back
pain (23 patients [18%]), and fibromyalgia (22 patients [17%1). Grady et
al. (1998) concluded that the rheumatic manifestations in Gulf War
veterans are similar to symptoms and diagnoses described in previous wars
and are not unique to active duty soldiers. After analyzing the rheumatic
manifestations of 145 Persian Gulf War veterans, Escalante and Fischbach
(1998) found that although the most common diagnosis was fibromyalgia
(33.8%), followed by various soft tissue problems (17.2%), nonspecific
arthralgias (9.6%), and clinical or radiographic osteoarthritis (11.0%),
no specific rheumatic diagnosis is characteristic of Gulf War veterans
with unexplained illness. However, pain is common and widespread in these
patients, and their health related quality of life is poor. Further
research is necessary to determine the cause of the symptoms of veterans
of the Gulf War.

Phenobarbital-induced fibromyalgia: A case report by Goldman and Krings
(1995) illustrates fibromyalgia induced by the anticonvulsant
phenobarbital in a female swimming instructor who was seen with chronic
bilateral shoulder pain and loss of range of motion. The patient, who was
taking medication for tonic/clonic seizures, recalled that her symptoms
began after her anticonvulsant medication was switched from hydantoin
sodium to phenobarbital.

Phosphate diabetes: Based on measurements of phosphate reabsorption by
the proximal renal tubule, phosphate clearance and renal threshold
phosphate concentration, nine out of 87 CFS patients in one study also
fulfilled the diagnostic criteria for phosphate diabetes (phosphate
depletion due to abnormal renal reabsorption of phosphate by the proximal
tubule) (De Lorenzo et al., 1998). The authors concluded that phosphate
diabetes should be considered in the differential diagnosis of CFS.
Laroche and Tack (1999) also pointed out that hypophosphoremia secondary
to moderate idiopathic phosphate diabetes should be included in the
differential diagnosis of primary fibromyalgia.

Polymyalgia rheumatica: Polymyalgia rheumatica (PMR) is a disease of
unknown etiology characterized by severe myalgia and stiffness at
shoulder girdle and pelvic girdle muscles and by normal serum creatine
kinase levels. Marked elevation of erythrocyte sedimentation rate, acute
onset within two weeks, and appearance in the aged are also additional
characteristics of PMR. Ten to 50% of PMR patients have a concomitant
temporal arteritis (giant cell arteritis). For the differential diagnoses
of PMR, rheumatoid arthritis, polymyositis, fibromyalgia, malignancies,
infections and depression should be considered (Nishikai, 1999).

Post-cardiac injury rheumatism: Another disorder listed in the
differential diagnosis for fibromyalgia is post-cardiac injury rheumatism
(PIR) (Mukhopadhyay et al., 1995). In a study by Mukhopadhyay et al.
(1995), out of the 249 patients who survived cardiac surgery, 20 (8%) and
22 (9%) patients had early and late PIR, respectively. Earlier onset
(within two weeks of surgery), milder articular involvement, absence of
constitutional features and laboratory abnormalities and good response to
analgesics were characteristics of early PIR. In contrast, late PIR which
occurred between the third and fourteenth week after surgery was
associated with more marked articular involvement along with systemic and
laboratory abnormalities and required longer analgesic therapy, steroid
support or prolonged physiotherapy in different combinations.

Post-Lyme disease syndrome: Despite antibiotic treatment, a sequel of
Lyme disease (or Lyme borreliosis) may be a post-Lyme disease syndrome
characterized by persistent arthralgia, fatigue, and neurocognitive
impairment that is probably induced by Lyme disease. Bujak et al. (1996)
found that of 23 patients with post-Lyme disease syndrome, 7 (30%) had
fibromyalgia (FM), 3 (13%) had chronic fatigue syndrome, and 10 (43%) had
similar but milder symptoms but did not meet the criteria for either.
Late Lyme disease or post-Lynne disease syndrome must be distinguished by
clinical characteristics from fibromyalgia (the commonest source of
misdiagnosis in several studies) (Berman and Wenglin, 1995; Ellenbogen,
1997; Rahn and Felz, 1998). A case can be defined as borreliosis only if
either the typical erythema migrans is reliably identified by a physician
or if a characteristic late manifestation of Lyme disease is accompanied
by unequivocal serological and/or bacteriological evidence of Borrelia
burgdorferi infection (Frey et al., 1995, 1998; Graninger, 1996; Nadelman
et al., 1999; Sigal, 1995). Within the musculoskeletal system, the only
reliably characteristic symptom is true synovitis, as defined by the
palpable swelling of a joint. Mere jointpain or the subjective pain
syndrome of fibromyalgia do not constitute a defining symptom for
borreliosis (Graninger, 1996). Fallon et al. (1999) reported increased
Fibromyalgia Impact Questionnaire total score, muscle pain, and joint
pain in fibromyalgia patients as compared to post-Lyme disease syndrome
patients.

Post-Polio syndrome: Fibromyalgia may mimic some of the symptoms of
post-poliomyelitis syndrome, a disorder characterized by new weakness,
fatigue, and pain decades after paralytic poliomyelitis (Trojan and
Cashman, 1995). Trojan and Cashman (1995) found that 10 (10.5%) of 95
post-polio patients met the criteria for fibromyalgia, and another 10
patients had borderline fibromyalgia. Post-polio syndrome patients with
fibromyalgia were more likely than patients without fibromyalgia to be
female (80% vs. 40%) and to complain of generalized fatigue (100% vs. 71
%), but were not distinguishable in terms of age at presentation to
clinic, age at polio, length of time since polio, physical activity,
weakness at polio, motor strength scores on examination, and the presence
of new weakness, muscle fatigue, or joint pain. Approximately 50% of
post-polio syndrome patients in both the fibromyalgia and borderline
fibromyalgia groups responded to low-dose, nighttime amitriptyline
therapy.

Posttraumatic stress disorder: Traumatic events can result in a set of
symptoms including nightmares, recurrent and intrusive recollections,
avoidance of thoughts or activities associated with the traumatic event,
and symptoms of increased arousal such as insomnia and hypervigilance.
These posttraumatic stress disorder (PTSD)-like symptoms are frequently
observed in persons with chronic pain syndromes. Approximately 56% of a
sample of 93 fibromyalgia patients studied by Sherman et al. (2000)
reported clinically significant levels of PTSD-like symptoms (PTSD+). The
PTSD+patients reported significantly greater levels of pain, emotional
distress, life interference, and disability than did the patients without
clinically significant levels of PTSD-like symptoms (PTSD-). Over 85% of
the PTSD+ patients compared with 50% of the PTSD- patients demonstrated
significant disability. Based on response to the Multidimensional Pain
Inventory, a significantly smaller percentage of PTSD+ patients were
classified as adaptive copers (15%) compared with the PTSDgroup (48.2%)
(Sherman et al., 2000). Amir et al. (1997) also documented that PTSD
subjects suffering from fibromyalgia were more tender, reported more
pain, lower quality of life, higher functional impairment and suffered
more psychological distress than the PTSD patients not having
fibromyalgia. Therefore, clinicians should assess the presence of these
symptoms, as the failure to attend to them in treatment may impede
successful outcomes.

Sarcoid arthritis: Gran and Bohmer (1996) reported the development of
secondary fibromyalgia in two patients with Sarcoid arthritis. Although
acute Sarcoid arthritis is usually a self-limiting joint disease,
recurrences may occasionally occur and some cases develop chronic
sarcoidosis of the lungs.

Scleritis: Fan and Florakis (1996) presented a case report of a patient
with Scleritis and fibromyalgia, and proposed that additional cases might
suggest that the fibromyalgia be added to the list of etiologies of
scleritis.

Silicone breast implant-associated disease: Although some authors in
older studies have suggested a link with fibromyalgia or soft tissue
rheumatism (Bridges et al., 1996; Cuellar et al., 1995; Fuchs et al.,
1995; Levenson et al., 1996; Vasey, 1997; Vasey and Aziz, 1995; Young et
al., 1995), immunologic and other sequels of silicone breast implantation
such as collagen vascular diseases or fibromyalgia have not been
confirmed in large studies and reviews (Blackburn et al., 1997; Brown et
al., 1998; Friis et al., 1997; Lai et al., 2000; Levine et al., 2000;
Nyren et al., 1998; Peters et al., 1997; Thomas et al., 1997; Wolfe,
1999; Wolfe and Anderson, 1999). Several reports have discussed the
possible silicone breast implant-associated induction of autoimmunity, in
particular antipolymer antibodies whose presence has also been reported
in fibromyalgia (Angell, 1997; Edlavitch, 1997; Ellis et al., 1997;
Everson and Blackburn, 1997; Korn, 1997; Lamm, 1997). However, many
studies have failed to find evidence for autoimmunity or other
immunological abnormalities. For instance, Blackburn et al. (1997) found
that the levels of interleukin-6, interleukin-8, tumor necrosis
factor-alpha, soluble intercellular adhesion molecule-1, and soluble
interleukin-2 receptor were not different in silicone breast implant
disease patients from those seen in normal subjects and were
significantly less than those seen when examining chronic inflammatory
disorders such as rheumatoid arthritis or systemic lupus erythematosus.
Although Young et al. (1995) found a higher frequency of HLA-DR53 among
symptomatic breast implant patients and Bridges et al. (1996) reported 5%
positivity for antinuclear antibodies among silicone breast implant
patients, these findings have not pan out in larger analyses.
Nonetheless, some studies have found that breast implants appear to be
more common in patients with than in those without fibromyalgia, an
observation that has led some authors to postulate that there may be a
common, predisposing set of psychosocial characteristics that are shared
between those who have fibromyalgia and those who undergo silicone breast
implantation (Wolfe and Anderson, 1999).

Although uncontrolled case series have reported neurologic problems
believed to be associated with silicone breast implants, one review
report (Rosenberg, 1996) failed to find any evidence that silicone breast
implants are causally related to the development of any neurologic
diseases. The latter study found that although neurologic symptoms were
frequently endorsed, including fatigue (82%), memory loss and other
cognitive impairment (76%), and generalized myalgias (66%), most patients
(66%) had normal neurological examinations. Findings reported as abnormal
were mild and usually subjective, including sensory abnormalities in 23%,
mental status abnormalities in 13%, and reflex changes in 8%. No pattern
of laboratory abnormalities was seen, either in combination or in
attempts to correlate them with the clinical situation. Laboratory
studies appeared to be random without an attempt to confirm or correlate
with a particular diagnosis. Diagnoses by physicians endorsing the
concept that SBIs cause illness included "human adjuvant disease" in all
cases, memory loss and other cognitive impairment ("silicone
encephalopathy") and/or "atypical neurologic disease syndrome" in 73%,
"atypical neurologic multiple sclerosis-like syndrome" in 8%, chronic
inflammatory demyelinating polyneuropathy in 23%, and some other type of
peripheral neuropathy in 18%. There was no coherence in making these
diagnoses; the presence of any symptoms in these women was sufficient to
make these diagnoses. Alternatively, after review of the data, no
neurologic diagnosis could be made in 82%. Neurologic symptoms could be
explained in some cases by depression (n = 16), fibromyalgia (n = 9),
radiculopathy (n = 7), anxiety disorders (n = 4), multiple sclerosis (n =
4), multifocal motor neuropathy (n = 1), carpal tunnel syndrome (n =1),
dermatomyositis (n =1), and other psychiatric disorders (n = 3).

Sjoegren's syndrome: Sjoegren's syndrome, the second most common
autoimmune rheumatic disease, refers to keratoconjunctivitis sicca and
xerostomia resulting from immune lymphocytes that infiltrate the lacrimal
and salivary glands (Fox et at., 2000). Sjoegren's syndrome is included
in the differential for the diagnosis for fibromyalgia, and the
distinction between fibromyalgia patients with low titer antinuclear
antibodies and primary Sjoegren's syndrome remains difficult (Fox, 1997;
Fox et al., 1998). Giles and Isenberg (2000) reported that fibromyalgia
was present in 9 out of 74 (12%) patients with primary Sjoegren's
syndrome compared with 11/216 (5%) lupus patients and none of secondary
Sjoegren's syndrome patients. Giles and Isenberg (2000) also reported
that fatigue in patients with primary or secondary Sjoegren's syndrome is
not due to the coexistence of fibromyatgia in most cases. Dohrenbusch et
al. (1996) found a higher prevalence of fibromyalgia in Sjoegren's
syndrome (44% among primary and 5% among secondary Sjoegren's syndrome
patients).

Skinache syndrome: Chronic pain of unknown etiology, and characterized by
cutaneous trigger points, has been coined the skinache syndrome (Bassoe,
1995). In contrast to fibromyalgia, the skinache syndrome has a simple
and effective cure: subcutaneous injection of lidocaine.

Systemic lupus erythematosus: Fibromyalgia and systemic lupus
erythematosus may be co-morbid conditions (Bennett, 1997; Godfrey et al.,
1998; Handa et al., 1998; Lopez-Osa et al., 1999; Romano, 1995, 1997;
Romano, 1995), and patients with SLE maybe at increased risk to develop
secondary fibromyalgia (Grate et al., 1999). SLE is in the differential
in the diagnosis of fibromyalgia (Calvo-Alen et al., 1995). Health
related quality of life is impaired both among women with fibromyalgia or
SLE, with fibromyalgia patients reporting greater impairment along
several dimensions (Da Costa et al., 2000). Bruce et al. (1999)
documented that in an outpatient population of SLE patients (81 studied),
fatigue severity correlates with poor health status and a higher tender
point count. Wang et al. (1998) also reported that fatigue in SLE
patients is highly correlated with the presence of fibromyalgia and not
with lupus disease activity. In patients with SLE, factors associated
with quality of life and fibromyalgia seem to have a greater influence on
the severity of reported fatigue than does the level of current disease
activity (Abu-Shakra et al., 1999; Bruce et al., 1999; Gladman et al.,
1997; Petri, 1995). Akkasilpa et al. (2000) found that SLE patients with
fibromyalgic tender points are less likely to be good "copers."

Although fibromyalgia and SLE may co-exist, Gladman et al. (2000) found
that patients with inactive SLE demonstrate neurocognitive dysfunction
that is not associated with co-morbid fibromyalgia or with specific organ
involvement or organ damage. Moreover, Taylor et al. (2000) reported that
only a minority (10% of 216 assessed) of lupus patients with fatigue
fulfil the American College of Rheumatology criteria for fibromyalgia. In
one study, fibromyalgia symptomatology did not correlate with lupus
severity (Grate et al., 1999).

Temporomandihular disorder: Patients with chronic fatigue syndrome,
fibromyalgia, myofascial pain syndrome, and temporomandibular disorder
(TMD) share many clinical illness features such as myalgia, fatigue,
sleep disturbances, impairment in ability to perform activities of daily
living as a consequence of these symptoms, and other co-morbid conditions
(such as irritable bowel syndrome, interstitial cystitis, and others)
(Aaron et al., 2000). Fibromyalgia and myofascial pain syndrome are
causes of TMD, and fibromyalgia patients often suffer from symptoms of
TMD with the intensity of local pain correlating with that of general
body pain (De Laat, 1997; HedenbergMagnusson et al., 1997, 1999;
Pennachio et al., 1998; Stohler, 1999). Conversely, patients with TMD and
chronic facial pain may also manifest pain or increased pain sensitivity
at remote sites outside of the head and neck region that may be secondary
to impaired endogenous opioid systems (Kashima et al., 1999; Korszun et
al., 1998; Wright et al., 1997) or to dysregulations in the
hypothalamic-pituitary axis (Auvenshine, 1997). Miller et al. (1997)
documented an unusual case of temporomandibular disorder in the presence
of both fibromyalgia and Ehlers-Danlos syndrome. Plesh et al. (1996)
points out that despite the overlap between fibromyalgia, myofascial pain
syndrome and temporomandibular disorder, they are distinct clinical
entities, and TMD patients show less evidence of distress than
fibromyalgia patients.

( . . . )

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