Fibromyalgia: Making a Firm Diagnosis, Understanding Its Pathophysiology

Fibromyalgia syndrome (FMS) is characterized by chronic musculoskeletal aches and pains as well as multiple tender points on palpation by an examiner. It is more common in women than men; about 90% of patients are women. The most common age of presentation is between 30 and 60 years.^1-3 However, FMS has been well described among juveniles.^4,5

FMS is a common condition. It is encountered among 2.1%, 5%, and 10% to 20% of patients seen in a family practice, internal medicine clinic, and rheumatic disease clinic, respectively.⁶ The prevalence of FMS in a community was found to be between 2% in Wichita, Kan,⁷ and 3.3% in London, Ontario.⁸ The prevalence increases with age until 65 to 79 years.^7,8 More than 7% of women had FMS in the 55 to 64 age group in a Canadian study⁸ and in the 60 to 79 age group in a US study.⁷

The term "primary fibromyalgia" is used when a significant underlying or concomitant condition that may contribute to pain is absent. FMS may be classified as "concomitant" when another condition, such as rheumatoid arthritis (RA), osteoarthritis, or hypothyroidism is present and may contribute to pain or fatigue of FMS. However, currently the term FMS, or fibromyalgia, is collectively applied to both primary and concomitant types.

We describe clinical features, diagnosis, and pathophysiology in this article. Management is discussed in a future article.

CLINICAL FEATURES

Symptoms. Besides widespread pain, patients complain of many other symptoms, such as fatigue, poor sleep, a subjective swelling of soft tissues (and sometimes of the joints), paresthesia, cognitive dysfunction, and symptoms of other associated conditions, such as irritable bowel syndrome (IBS), headaches, restless legs syndrome, and temporomandibular dysfunction (Table 1).^2,3,9 There is no significant correlation between subjective swelling or subjective numbness and psychological status.⁹ Common sites of pain or stiffness are low back, neck, shoulder region, arms, hands, knees, hips, thighs, legs, and feet. Chest pain is not uncommon and is accompanied by tender points in the chest wall (also see differential diagnosis). Fatigue is common in FMS and may be the presenting feature in some cases because of its severity. Several factors may contribute to, or aggravate, fatigue and pain in FMS, such as nonrestorative sleep, deconditioning, overwork, psychological factors, and poor coping skills.¹⁰ Patients are also sensitive to environmental stimuli, such as noise.⁹

Signs. Patients with FMS look healthy, but often they seem fatigued and in pain. Examination of the joints shows no objective swelling (unless there is concomitant arthritis), but some patients have marked joint tenderness on palpation. Despite neurologic symptoms, such as weakness and numbness, neurologic examination in FMS perseis normal. The most significant physical finding in FMS is the presence of multiple tender points in a widespread distribution. For the purpose of diagnosis (see below), one needs to examine 18 specified sites (Box, Figure 1), by application of a force of approximately 4 kg (roughly the pressure one needs to whiten the nail bed when pressing against a firm surface), using the index finger or the thumb. Note that the proper way of examining a tender point needs to be learned, as in the case of examining other physical signs in medicine, such as hepatomegaly or splenomegaly. An underestimation of the number of tender points in a patient with FMS is the most important reason for missing a diagnosis of this disorder.
 

LABORATORY INVESTIGATIONS

It may surprise many physicians to learn that a diagnosis of FMS does not require any specific laboratory testing, since "ruling out" does not apply to FMS. Laboratory tests, including radiology, should be requested only if another concomitant condition is suspected by careful history taking and physical examination.There is no reason to order tests of antinuclear antibodies or rheumatoid factor unless clinically indicated. However, a complete blood count and a chemistry panel with blood urea( nitrogen, creatinine, and hepatic enzymes are useful to monitor side effects of drugs either for FMS or a concomitant condition. Although the prevalence of hypothyroidism does not seem increased in FMS compared with the normal population, we obtain T₄ and thyroid-stimulating hormone levels in patients with significant fatigue, even in the absence of other features of hypothyroidism.

DIAGNOSIS

Despite a common notion, diagnosis of FMS is disarmingly simple. It can, and should, be diagnosed by its own characteristics of widespread pain and multiple tender points; another concomitant condition, such as arthritis or hypothyroidism, does not exclude the diagnosis of FMS, as stated by the American College of Rheumatology (ACR) criteria.² Putting it another way, if a patient has FMS as well as RA, this patient has both FMS and RA. Although the ACR criteria (see Box, Figure 1) were developed for classification of FMS (so that researchers can use a uniform set of criteria for patient selection), these criteria have been found to be very useful for the diagnosis of FMS in clinical practice. A patient with FMS may have many symptoms, but he or she needs only present with widespread pain (as defined in the Box) and 11 or more tender points among the 18 sites specified in ACR criteria. Note that a patient with FMS may be tender in many more sites (including bones) besides these 18. Some patients have diffuse tenderness "everywhere" on palpation. Such a phenomenon does not necessarily imply high psychological distress. Such diffuse tenderness on palpation or a significant psychiatric disease does not influence a diagnosis of FMS (as long as a patient satisfies the ACR criteria).

Now, a frequent question we hear from practicing physicians is: "Should one diagnose FMS if a patient has widespread pain but not 11 tender points?" For a clinical purpose, we suggest that a patient who has otherwise characteristic symptoms of FMS (eg, fatigue, poor sleep, morning fatigue, and 1 or more associated conditions; see Table 1), but only 6 to 10 tender points, should be treated for FMS.
 

DIFFERENTIAL DIAGNOSIS

Several conditions may mimic FMS, as shown in Table 2. As emphasized before, a patient may have FMS as well as any of the conditions listed in this table. For example, chest pain with localized tenderness in the chest wall in a patient with FMS would suggest that the chest pain is part of FMS. However, this patient may also have a concurrent intrathoracic pathology that can be diagnosed by appropriate history, physical examination, and laboratory tests. In another example of a concomitant disease, a 69-year-old female patient in our practice had complained of pain and numbness in the legs when she first presented with FMS with a normal neurologic examination. Three years later the pain as well as numbness in the legs became more intense. The pain was worse upon walking. This patient could no longer do her dishes standing because of bothering backache. Neurologic examination showed signs of L5-S1 root compression. A clinical diagnosis of spinal stenosis was made and an MRI scan of the lumbar spine was ordered. MRI confirmed spinal stenosis that was treated surgically. The numbness and pain were substantially relieved following the surgery.

PATHOPHYSIOLOGIC MECHANISMS OF FMS

Pathogenesis of FMS is incompletely understood. Despite muscle pain, no histologic or biochemical abnormalities in the muscles have been demonstrated.¹¹ It is now known that pain and fatigue, as well as several other symptoms, are central in origin, the most important mechanism being central sensitization.

Central sensitization. Neurons in the CNS undergo structural, chemical, and functional changes following a peripheral noxious stimulus (such as mechanical, chemical, or thermal injuries), leading to heightened sensitivity of the neurons both at spinal and supraspinal levels. The process is called central sensitization with the following characteristics: an exaggerated response to a peripheral stimulus that is normally painful (hyperalgesia); an experience of pain following a normally nonpainful stimulus, such as touch (allodynia); persistence of pain; greater intensity of pain (which is also unpleasant); and wider distribution of pain than the area of original stimulation.¹² A phenomenon related to central sensitization is called "wind-up" in animal models and temporal summation in humans. This phenomenon is mediated by N-methyl-D-aspartate (NMDA) receptors. It is characterized by a progressive increase in pain secondary with each brief but repeated peripheral stimulus of the C fibers at a certain interval, for example, 2 seconds.^9,12

In FMS, however, there is no obvious peripheral tissue injury except trauma-induced inflammation (for example, from automobile accidents) in some patients. So the cause of nociceptor activation in a majority of these patients remains unclear. We have postulated that the CNS of some patients with FMS and similar disorders (such as headaches and IBS) are inherently hyperresponsive because of genetic susceptibility or childhood trauma, or both. An otherwise inapparent ("silent") source of peripheral nociception, such as mechanical stress in the cervical or lumbar spine, or such spinal stress generated by poor posture or degenerative disease, may now trigger central sensitization in these susceptible individuals. Other sources of peripheral nociception, such as arthritis or a painful peripheral neurologic disease, may also initiate and perpetuate central sensitization.⁹

Central sensitization is mediated by presynaptic release of neurokinins, for example, substance P (SP) and by excitatory amino acids, such as glutamate and aspartate, that activate postsynaptic NMDA receptors. As a result, remarkable intramembranous and intracellular changes take place in the postsynaptic neurons, such as alteration of cell membrane permeability, influx of calcium, and activation of second messengers, all of which contribute to orchestrate marked neuronal changes leading to central sensitization.⁹ Normally, there is also an inhibitory system that dampens hypersensitization. The inhibitory activities are mediated by serotonin, norepinephrine(, endorphins, and other neurochemicals. However, the inhibitory system may be dysfunctional in central sensitization.

Evidence for central sensitization in FMS. Strong neurophysiologic evidence supports a state of central sensitization in FMS.^9,13,14 One study demonstrated significant reduction of the pain threshold in FMS patients compared with normal controls following an innocuous electrocutaneous stimulation that was associated with unpleasant pain, dysesthesia, and anatomical spread of pain.¹⁵ Other examples of central sensitization have been summarized,⁹ and include temporal summation,¹⁴ decreased cerebral blood flow in the caudate nucleus and thalamus by single-photon emission computed tomography¹⁶ and augmented pain processing.¹⁷

There is also central sensitivity- related neurochemical disturbance in FMS, eg, increased SP and decreased 5-hydroxyindole acetic acid (5-HIAA, a metabolite of serotonin) in the cerebrospinal fluid, and decreased serum serotonin.¹⁸ Both increased SP and decreased serotonin help to explain increased pain sensitivity in FMS.

Endocrine aberrations. Neuroendocrine abnormalities may play an important role in FMS.¹⁹ These include hypothalamic-pituitary-adrenal (HPA) axis disturbance with an exaggerated adrenocorticotropin (ACTH) response to corticotropin-releasing hormone with normal cortisol response. Relative hypocortisolemia in FMS is not due to a primary failure of the adrenal cortex and seems to be of hypothalamic origin. Note that these findings are different from those found in depression where hyperreactivity of the HPA axis has been demonstrated at all levels, including hypercortisolemia that escapes dexamethasone( suppression.

Growth hormone (GH) deficiency in FMS²⁰ may partly explain a lack of energy among patients with FMS. GH is secreted mostly during non-rapid eye movement (REM) sleep, which is disturbed in FMS (see below).

Nonrestorative sleep. Most patients with FMS sleep poorly and wake up tired in the morning. Alpha intrusion of non-REM sleep in FMS indicates arousals during the restorative phase of sleep architecture. Phasic alpha sleep, in particular, is associated with increased pain and tender points the next morning.²¹ However, routine sleep electroencephalographic testing has no practical utility unless other sleep problems, eg, REM sleep behavior disorder and sleep apnea, are clinically suspected. Poor sleep the previous night predicts pain the next day.²²

Psychological factors. Psychological distress aggravates pain and fatigue in FMS. Most studies have shown an increased frequency of both present and lifetime anxiety, stress, and depression in patients with FMS compared with normal as well as RA control groups.²³ Poor coping skills may also perpetuate pain. However, it is clear that psychological factors are not necessary in causing FMS. Only about 30% to 40% of patients have psychological disturbance, and in many of these cases distress may be secondary to chronic pain itself.²³

Genetic factors. Genetics is quite likely to play a role in FMS.⁹ There is familial aggregation in FMS.²⁴ Genetic markers include T102C polymorphism of the 5-HT2-A receptor gene²⁵ and a probable linkage with the HLA.²⁶ Genome mapping of multicase families with FMS is currently in progress.

Summary of pathophysiologic mechanisms. FMS is a multifactorial condition with many triggering or interacting factors, such as genetics, neuroendocrine aberrations, psychological distress, trauma, peripheral sources of nociception (for example, inflammation), poor sleep, deconditioning, or overactivities (Figure 2), which may initiate and sustain central sensitization leading to chronic pain and exaggerated response to various stimuli. It is now clear that the symptoms of FMS may be explained by both biological and psychosocial- behavioral factors, with much variability in the relative contributions of these elements in an individual patient.

CENTRAL SENSITIVITY SYNDROMES (CSS)

Yunus^9,27 was the first to postulate and demonstrate that several common chronic illnesses, such as fibromyalgia, IBS, headaches, and primary dysmenorrhea, are related conditions with many similar features with a common pathophysiology. These are currently called "functional somatic syndromes," an intriguing name for a group of disorders that manifest as dysfunction in the neuroendocrine systems. It now seems that the common binding pathophysiologic glue of these conditions is central sensitization; hence the term "central sensitivity" or "CSS" has been suggested.⁹ CSSs include FMS, IBS, chronic fatigue syndrome, myofascial pain syndrome, restless legs syndrome, temporomandibular dysfunction syndromes, multiple chemi-cal sensitivity, post-traumatic stress disorder, depression, and other similar conditions.⁹