Commentary: Differential Diagnosis of Fibromyalgia Syndrome: Proposal of a Model and Algorithm for Patients Presenting with the Primary Symptom of Chronic Widespread Pain

Classic FMS 

The term classic FMS represents the subset of patients whose physical symptoms are suggestive of an underlying mental illness, mediated by overactivity of the limbic system and hypothalamic-pituitary-adrenal axis, causing the multiple symptoms seen in the “classic” cases of FMS in rheumatology clinics. These classic cases probably represent the somatic manifestations of extreme emotional stress and/or psychologic illness, yet are distinct from a true somatization disorder in which there is no real physical illness. It is too simplistic to state that all cases of classic FMS merely represent a somatic manifestation of clinical depression or anxiety, because not all patients with depression or anxiety disorders experience the symptom of widespread allodynia with multiple tender points.

Yet it has been known for almost 20 years that patients with FMS often respond well (at least in the short-term) to low doses of antidepressant medications, suggesting that there is significant overlay between mood disorders and FMS. Recent studies are starting to implicate the role of the limbic structures (hippocampus, amygdyla, and hypothalamus) and neuroendocrine system in the production of FMS symptoms. One study showed differences in circadian cortisol release in FMS vs healthy controls, suggestive of overactivity of the hypothalamic-pituitary-adrenal axis in these patients.11 Various types of thermal, mechanical, and electrical modalities have been applied to FMS and healthy controls, and consistently the FMS group shows signs of central sensitization.12 Positron emission tomography scans and functional MRI studies of the brain activity of subjects with FMS vs healthy controls while they receive innocuous sensory stimulation have shown that the limbic structures of patients with FMS are activated by nonpainful stimuli which only activate the sensory cortex in healthy controls.5

Many studies have attempted to determine how much psychologic overlay exists in classic cases of FMS. One important study reviewed the prevalence of victimization and abuse in FMS, rheumatoid arthritis, multiple sclerosis, and chronic fatigue syndrome (CFS).13 The results showed CFS and FMS patients had a significantly higher prevalence of emotional neglect and abuse, and of physical abuse, with a considerable subgroup experiencing lifelong victimization. Another study of 600 members of a health plan diagnosed with FMS showed an extremely high prevalence of past emotional, physical, and/or sexual trauma associated with the onset of FMS symptoms.14 These findings support etiologic hypotheses suggesting a pivotal role for chronic stress in CFS and FMS and may have important therapeutic implications.

Patients with serious emotional or mental health issues often experience a significant sleep disorder, which probably represents a state of hyper-vigilance due to overactivity of the limbic system. This hyper-vigilance is commonly associated with posttraumatic stress and anxiety disorders, and may explain the well-documented alpha intrusion noted on electroencephalogram sleep studies of patients with FMS.15 Lack of a normal sleep cycle is associated with hippocampal dysfunction, which manifests as short-term memory loss and cognitive deficit, both of which are common symptoms in patients with classic FMS. In lay terms, patients with FMS often use the term fibro-fog to describe this classic symptom of cognitive deficit.

It is not currently known exactly why certain patients with emotional illness or mood disorders will develop the characteristic symptoms of what is termed FMS, and why others with the same level of psychopathology do not experience these symptoms. There could be a combination of factors, including genetic predispositions that may in future research be shown to be associated with the production of FMS symptoms. A recent study of family members and probands of patients with FMS showed that reduced pressure pain thresholds aggregate in families, and FMS coaggregates with major mood disorders in families.16

The relevance for the clinician seeing these patients is the recognition that mental health and mood disorders may be the root cause of the symptoms of widespread pain, allodynia, sleep disorders, and cognitive deficit that could easily be misdiagnosed as FMS. It would seem appropriate for the clinician to refer these patients for cognitive behavioral therapy or other forms of psychologic counseling, rather than for physical therapy. A recent systematic review of the literature has shown that cognitive behavioral therapy is an effective treatment strategy for patients with FMS, along with mild exercise and low-dose antidepressant medication.8

Medical Conditions Misdiagnosed as FMS 

In patients presenting with generalized pain and fatigue, it is imperative that the clinician rule out the presence of any medical condition or disease that is known to cause these symptoms. Hypothyroidism, anemia, rheumatoid arthritis, Lyme disease, rheumatic auto-immune disorders such as ankylosing spondylitis or scleroderma, multiple sclerosis, and occult malignancy are some possible etiologies for symptoms of vague and diffuse musculoskeletal pain associated with pronounced fatigue. Most of this assessment comes in the form of serologic testing through a standard clinical laboratory, to include any or all of the following screening tests: complete red blood count (RBC) with white cell differential, thyroid function tests (T3, T4, TSH), SMA 24 or similar metabolic screening panel, C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR), Lyme test, and rheumatic profile (as indicated).

As simple as these screening tests may be to perform, it is not uncommon for clinicians to fail to have any laboratory tests performed on their patient and still render a diagnosis of FMS. According to ACR guidelines and criteria, a diagnosis of FMS should not be rendered until all lab tests come back negative and fail to detect an organic reason for the symptoms.

A simple, rational approach to laboratory assessment of these patients includes an initial complete blood count as a screen for the common anemias, and the white cell differential to rule out infection or marrow disease. Obvious reasons for excessive fatigue, such as anemia, can be ruled out on the complete blood count by screening for low RBC count, altered hemoglobin, and abnormal RBC indices such as mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration. An ESR or CRP test can help to confirm the presence or absence of systemic inflammation or infection. Although the ESR and CRP tests are nonspecific, extremely high values found on these tests may indicate the need for further serologic testing for underlying auto-immune rheumatic diseases or possible occult malignancy.

Thyroid function tests should be routinely performed in patients who present with the chief complaints of widespread pain and fatigue, to rule out overt hypothyroidism as the cause of these symptoms. Although the classic signs and symptoms of low thyroid function, including fatigue, weakness, cold intolerance, low temperatures, weight changes (usually weight gain), and depression are routinely considered clinically, common musculoskeletal signs and symptoms of hypothyroid include muscle pain, stiffness, muscle cramping, muscle weakness, paresthesia, arthropathy, and sluggish deep tendon reflexes are often not considered.17 The incidence of musculoskeletal symptoms with hypothyroidism has been reported by Khaleeli et al18 to be as high as 30% to 80% depending on the special interests of the diagnosing physician. This is extremely important as it is precisely these vague musculoskeletal symptoms that may drive the patient to the clinician initially. Many of these patients will likely be unaware that they have a thyroid condition, and if missed by the physician, their symptoms may inadvertently be misdiagnosed as FMS.

A standard serologic metabolic chemistry panel such as SMA 24 is useful to evaluate the overall systemic health of the patient presenting with widespread pain and fatigue. This panel includes serum fasting glucose, liver enzymes, cholesterol, blood lipids, and kidney function markers. Of course, these laboratory tests should be correlated with physical examination findings and other diagnostic tests. According to Hench,19 10% to 15% of unselected patients with FMS have isolated abnormal serologic test results without evidence of underlying connective tissue disease, which can often be misleading. If the physical examination findings are suggestive of joint pain and frank soft tissue inflammation, not simply increased pain perception in the soft tissues, additional serologic studies such as a rheumatoid panel and Lyme disease screening tests are warranted.

Again, it is important to note that if laboratory studies are positive for any of the above-noted medical conditions or diseases, a diagnosis of FMS is inappropriate. Stated bluntly, patients who have diseases that go undetected because of shoddy examination and investigation are likely candidates for a misdiagnosis of FMS to explain their constellation of symptoms. As a general rule, no patient should ever be given a diagnosis of FMS without a complete physical examination and basic screening laboratory testing to rule out the underlying medical conditions.

Functional Metabolic Disorders Misdiagnosed as FMS 

More subtle functional disorders may represent various types of subclinical disease states and disorders involving dysfunction of internal organs and metabolism, rather than true pathology. These functional disorders are often not on the busy clinician's radar screen and range the gamut from simple vitamin and mineral deficiencies, to more hidden functional disorders such as intestinal dysbiosis, subtle endocrine imbalances, reactive dysglycemia, post-viral immune suppression, and other conditions that are not readily apparent on standard laboratory screening tests.

Several nutritional deficiencies have been identified in patients with fatigue and widespread tenderness, in whom supplementation with various nutrients including B-vitamins, magnesium, and malic acid has shown positive results.20, 21, 22 In mild to moderate cases of fatigue and widespread achiness, supplementation with the above nutrients may have a significantly positive clinical effect. However, patients with severe fatigue usually do not respond adequately to these supplements alone and require a more comprehensive functional approach. All of these functional disorders have the common denominator of potentially causing symptoms of low energy, fatigue, and widespread achiness, which are difficult to diagnose.

As was stated previously, thyroid function tests should be routinely performed in patients who present with the chief complaints of widespread pain and fatigue, to rule out overt hypothyroidism as the cause of these symptoms. However, more subtle presentations of thyroid dysfunction should also be considered, even when standard laboratory values are within normal range. Although most cases of hypothyroidism will respond well to the use of hormone replacement medication, such as Synthroid (Abbott Laboratories, Abbott Park, Ill), levothyroxine sodium, or Levoxyl (King Pharmaceuticals Research & Development, Bristol, Tenn). However, these medications only contain l-thyroxine (T4). In patients who have T4 to T3 conversion disorders (also known as euthyroid sick syndrome, low T3 syndrome), possibly secondary to a long-term stress disorder, they often do not feel relief of their symptoms when placed on T4 therapy alone. The use of a combination of thyroxine (T4) and triiodothyronine (T3) therapy (eg, Cytomel [Jones Pharma, St. Louis, Mo]) is gaining popularity with many physicians attempting to manage patients refractive to T4 therapy alone. These patients may not have overt abnormalities on standard thyroid laboratory studies and the clinician may need to pay close attention to patient symptomology in the diagnosis of these variants of thyroid dysfunction.

It is often important to evaluate adrenal status in the chronically fatigued patient because increases in catecholamines and upregulation of the sympathetic nervous system have been implicated in FMS, as previously discussed. Morning serum cortisol and urinary catecholamine metabolites can be beneficial in assessing adrenal dysfunction, including the low cortisol and elevated catecholamine pattern of posttraumatic stress disorder. In patients with this pattern, psychologic counseling and stress-reducing lifestyle modifications are imperative.

In summary, there appear to be a certain subset of patients who may receive an inappropriate diagnosis of FMS and do not display the entire spectrum of clinical elements indicative of classic FMS, do not show any positive laboratory findings indicative of overt organic pathology or disease, yet have significant functional deficits in certain organ systems. The functional approach to the treatment of these patients is not centered around any one agent or modality as the curative, or even palliative, solution. Treatment is centered on the principle that restoration of proper cellular metabolism, through balancing the endocrine system, the repletion of nutritional deficiencies, and the reduction of cumulative toxic load and oxidative stress will allow normalization of mitochondrial respiration, cellular energy production, and ultimately to a reduction in the signs and symptoms of low energy, fatigue, and widespread achiness. Many of these factors can be addressed by simple lifestyle changes by the patient, including eating a fresh-food varied and balanced diet, consuming reasonable vitamin and mineral supplementation, and engaging in stress management techniques such as regular light exercise, proper sleep, adequate recreation and relaxation, deep-breathing exercises, yoga, meditation, prayer, etc.

Musculoskeletal Disorders Misdiagnosed as FMS 

Patients with FMS present with widespread pain in multiple body regions. In addition, the character and distribution of this widespread pain are typically poorly described by the patient as vague and diffuse. This presents a diagnostic conundrum because of generally poor knowledge about musculoskeletal disorders within primary care medicine23 and the fact that standard internal medicine textbooks (eg, Cecil's or Harrison's) present a limited subset of potential etiologies and, thus, diagnoses for these kinds of pains. Symptoms that do not follow dermatome or radicular pain distributions, or commonly known visceral referred pain patterns, could easily be misdiagnosed as “widespread pain,” leading to a misdiagnosis of FMS. However, there are well-documented pain generators in the musculoskeletal tissues that are not typically recognized by clinicians whose training is more focused on visceral referred pain patterns.

As early as the 1930s, Kellgren24 showed that deep somatic tissues (ligaments, muscles, and periosteum) exposed to hypertonic saline injection produce unusual referred pain distributions often at a sizeable distance from the injection site. Bogduk et al25, 26 have provided compelling evidence that it is common for patients to present with pains of unusual, but predictable and reproducible, distribution that clearly emanate from spinal facet and sacroiliac joints, which are distinct from radicular pain. Their elegant studies used anesthetic joint blocks to confirm that the facet and sacroiliac joints were in fact the source of many patients' pain.25, 26

Unfortunately, the diagnosis of facet and sacroiliac joint pain is not a simple matter. Radiologic studies, MRI and computerized tomography scans, and bone scan have little diagnostic yield because there is not necessarily any pathoanatomic changes in these joints associated with the referred pain patterns. Unusual patterns of back or neck pain coupled with negative diagnostic imaging studies might lead the unwary clinician to declare FMS as the diagnosis, when in fact the pain is emanating from the facet or sacroiliac joints.

Even the well-known classic presentation of spinal disk herniation with neck/back pain and radicular pain into the upper/lower extremities is not as simple to diagnose as once thought. This “classic presentation” of disk herniation is actually rather uncommon. Studies have shown that internal disk derangements and/or annular tears without frank herniation are common and do not cause dermatome pain. These cases of discogenic pain can manifest as symptoms of buttock or thigh pain, even pain in the lower leg, without any true irritation of the existing nerve roots.27 Using the presence of pain distal to the knee to rule-in radicular pain rather than discogenic referred pain is untenable given the fact that internal disk derangement alone can result in distal leg pain. It is also possible that false-negative MRI results can occur, in which the patient truly has a serious disk derangement but the MRI fails to image the protrusion adequately.28 Therefore, the unexplained presence of odd or unusual pain in the distal extremities could cause a physician to erroneously believe that the pain might not be emanating from a disk and instead choose FMS as the diagnosis.

Lastly, one of the most common causes of unusual referred pain in the torso and extremities is the phenomenon of myofascial referred pain. Myofascial trigger points (TrP) have been documented as a common clinically important cause of referred pain, also of atypical character and distribution.29 Trigger points are often found in the muscles of the upper extremity, shoulder, and posterior neck, and cause unusual referred pain patterns into the head, face, and upper extremity.30 These TrPs palpate as tender nodules in an area of taut bands of skeletal muscle and represent some unknown type of focal muscle dysfunction. Trigger points may easily be mistaken for the tender points (TeP) found in FMS. Clearly, the TePs found in FMS are not areas of muscle dysfunction but rather areas of cutaneous tenderness that are thought to be peripheral hyperalgesia zones because of central sensitization. Tender points do not have any palpable tissue texture change and are not associated with taut bands of skeletal muscle. The inability of physicians to differentiate between the TrPs of myofascial pain and the TePs found in FMS may lead to an overdiagnosis of FMS.31