The operational definition of a non-patient with FMS used in our laboratory is: "An individual who meets the American College of Rheumatology (ACR) criteria for FMS who has not consulted a physician, chiropractor, or other health care provider regarding their pain in the last 10 years. This individual does not meet criteria for any other rheumatologic disorder or suffer from chronic fatigue syndrome or other comorbidities that might produce their pain."

We began our studies of patients and non-patients with FMS in order to learn about the pain perception and psychological factors associated with health care seeking for this disorder. However, the study of non-patients has become a crucial component in our efforts to better understand the etiopathogenesis of FMS.

We initially reported that patients with FMS are characterized by a significantly greater number of lifetime psychiatric diagnoses than non-patients and healthy controls. In addition, non-patients do not differ from controls with respect to psychiatric morbidity. A longitudinal follow-up of our non-patients over 2 ½ years has shown that the best predictor of initial health care seeking for FMS is number of lifetime psychiatric diagnoses at baseline. These results strongly suggest that psychiatric illness is more strongly associated with obtaining treatment for FMS, particularly at university-based, rheumatology clinics, than with FMS itself. Moreover, they suggest that any behavioral or biological factors found among both patients and non-patients with FMS are not determined by psychiatric illness.

We have identified 4 variables related to pain perception that distinguish both patients and non-patients with FMS from healthy controls. These are (a) low pain threshold levels at tender points and control points; (b) high scores on an index of sensory discrimination ability; (c) high cerebrospinal fluid (CSF) levels of substance P; and (d) low regional cerebral blood flow (rCBF) in the caudate nucleus. These findings suggest that low pain thresholds and other abnormal pain perceptions in persons with FMS may be related to high levels of nociceptive neurosensory input from the periphery (suggested by high CSF substance P and sensory discrimination index scores) and impaired modulation of this input by basal ganglia structures (suggested by low caudate rCBF).

Over the next 4 years, we wish to examine several related issues concerning abnormal pain perception in persons with FMS

Do patients with FMS show inhibited functional brain activity in basal ganglia structures during painful stimulation?

Do patients with FMS show abnormal functional activity in limbic system brain structures during painful stimulation?

Is abnormal functional brain activity also associated with major depression, chronic fatigue syndrome, or with the undiagnosed illnesses reported by Persian Gulf War veterans?

The study of non-patients has led to important advances in our understanding of abnormal pain perception in FMS. However, it must be noted that these non-patients may not be representative of the entire population of community residents who do not seek care for FMS. In addition, we know little about persons with FMS who cope well with FMS with only primary medical care for their symptoms. Thus, there is a need for additional epidemiologic studies of patients and non-patients with FMS. These studies, however, should distinguish between FMS and chronic or recurrent pain associated with other disorders or comorbidities.

TREATMENT (RX) OF 76 PATIENTS WITH PRIMARY FIBROMYALGIA (1º FM) WITH COMBINED DOPAMINERGIC AND SEROTONERGIC DRUGS.

It has been theorized that FM results from dysfunction of the serotonin (S) neurotransmitter system. We hypothesize that of equal importance is dysfunction of the dopamine (D) system. Thus, we have designed and continue to develop a Rx protocol over the past 12 months using combinations of L-dopa, the immediate S precursor 5-hydroxytryptophan (5-HTP), Fenfluramine (F), Pemoline (Ph) and Phentermine. A total of 122 patients with 1º FM were Rx’d with the method. Dosages and combinations of medications were adjusted on the basis of the patients’ reports of changes in their symptoms (sx) resulting from Rx. Numerical evaluation of efficacy was done using a scale of 0-100 for each of: global lifestyle disruption caused by FM sx, pain, fatigue, AM stiffness/alertness (a measure of sleep hygiene), and depression. Patients were followed for an average of 4.8 months (range 1-12), and were divided into 3 groups according to length of follow-up. 1-4 months, 5-7 months, and 8-12 months. Data were complete on 92 patients. 16 patients dropped out, 5—side effects, 7—inefficacy, 3—misc. reasons (e.g. $$). Of these, 8 restarted the regimen w/o further problems. No lasting adverse side effects were noted. Statistically significant improvement was found in all 3 groups for all 5 parameters (P range e-3 to e-10). In addition, patients enjoyed improvement in many other FM related sx such as sleep hygiene, cognitive function, "asthma", and irritable bowel. Most who took Ph/F lost weight. Advantages of the method are hi efficacy, low cost, and discontinuation of many other meds (e.g. antidepressants, narcotics, GI meds, hypnotics). Disadvantages are the need for frequent phone contacts for med adjustments, a training period for physicians to insure proper administration of the method, and time spent getting 3^rd party payers to cover med costs. These data indicate that a placebo-controlled double blind trial of this Rx is warranted.

Fibromyalgia Is More Than Pain

Fibromyalgia is a condition characterized by a history of diffuse musculoskeletal pain, and the finding of tenderness on examination. Epidemiologic studies suggest that this illness affects approximately 2% of the population, although the prevalence in females is much higher (3.4% of all females, > 7% in those between the ages of 60 – 79).

Although fibromyalgia is defined by its musculoskeletal features, for some time it has been clear that there are a large number of other systemic and localized syndromes that occur commonly in individuals with this illness. There is a significant overlap between fibromyalgia and other systemic illnesses such as chronic fatigue syndrome, somatoform disorders, and other entities such as the Persian Gulf Syndrome. Examples of closely related localized or organ-specific conditions include migraine and tension headaches, irritable bowel syndrome, temporomandibular dysfunction, non-cardiac chest pain, myofascial pain syndrome, and a variety of genitourinary syndromes. These illnesses all occur more commonly in females, and can either be triggered or exacerbated by a variety of stressors, including physical trauma, immune stimulation, and emotional stress.

There are several lines of evidence to suggest that these chronic pain and fatigue conditions may share common pathogenic mechanisms, and that instead of being discrete, separate illnesses, these entities are part of a larger spectrum. In this regard, there are several promising areas of research into these conditions, including the hypothesis that there is a strong familial predisposition to develop these conditions, and that the symptoms are caused by aberrations of various components of the central nervous system. Accordingly, there are several types of treatment that have been shown to be effective for this spectrum of conditions, including low dose of tricyclic compounds, aerobic exercise, and cognitive behavioral therapy.

PATHOPHYSIOLOGY OF NEUROSOMATIC DISORDERS: A SUMMARY

Chronic Fatigue Syndrome is a disorder of the management of sensory input by the brain. Information from inside and outside the body is misperceived, resulting in inappropriate sensations. Touch can be painful, odors can cause illness, climbing a flight of stairs can be like climbing a mountain. If input is dysregulated, output will be also, because the brain will make regulatory decision based on improper "data processing". Actually, processing occurs properly, but "gating", the control of data input and output from processing centers, is dysfunctional. Thus, patients frequently complain, "my body doesn’t work right".

The basic problem is the misperception of the saliency of sensory information by the prefrontal cortex, which regulates sensory gating as well as neurotransmitter secretion by neurons, which secrete the excitatory amino acid glutamate. There appears to be insufficient glutamate secretion resulting in decreased levels of several neurotransmitters, especially norepinephrine. The cause of prefrontal cortex dysfunction is an interaction of genetic, developmental, and environmental factors. Rapid pharmacologic remediation of CFS symptoms can be achieved by multiple approaches to enhance norepinephrine secretion from the locus ceruleus and the superior cervical ganglion.

Norepinephrine (NE) enhances the "signal-to-noise (STN) ratio" in the processing of sensory input by the brain. If there is a high STN ratio, important information will be extracted from a welter of sensory input. If STN ratio is low, much more sensory input will reach the cerebral cortex, some of it irrelevant. STN ratio is low in neurosomatic patients, accounting for misperception of sensory information, as well as distractibility in stimulus situations where cues are increased, environments as disparate as malls and short-term memory testing.

Substance P (SP) lowers STN ratio. There is an "Yin-Yang" relationship between NE and SP – when one is high, the other is low. NE metabolites are low in neurosomatic disorders and SP levels are quite elevated. Reasons for these abnormalities will be discussed.

There are four influences on the development of a neurosomatic illness in an individual.

Genetic susceptibility. This tendency can be strong, weak, or anywhere in between. If it is strong, the patient will develop a neurosomatic illness no matter what, often beginning in childhood. Otherwise, expression of the trait is influenced by other factors.

Developmental issues. If a child feels unsafe for a period of time from birth through puberty, he may become hypervigilant and interpret the saliency of sensory input differently than a child who feels secure. The neurochemical expression of this experience might be elevated levels of SP enabling him to attend to a wide range of stimuli, as well as transiently elevated cortisol with subsequent downregulation of HPA axis. Central NE levels would also be low, contributing to dysautonomia as well as abnormalities in sensory processing in the circuit between the dorsolateral prefrontal cortex, thalamus, and the hippocampus.

Viral encephalopathy. Individuals may be exposed to microbes that produce a persistent infection in neurons and gila without being lytic or initiating an immune response. Susceptibility to such infections would be largely genetically predetermined, but could also be influenced by situational perturbations of the immune response. Persistent CNS viral infections could alter production of transmitters and receptors as well as cellular mechanisms.

Increased susceptibility to environmental stressors due to a reduction in neural plasticity. The summation of causes 1-3 results in an impaired flexibility of the brain to alter the function of its neural networks to deal with changing internal or external circumstances. An example of this deficit may be encountered in the well-known problem that many neurosomatic patients have in making new memories. In order to encode a memory, a fragile neural network must be strengthened. This process may occur by augmenting secretion of glutamate from firing presynaptic neurons by secretion of a retrograde messenger, such as nitric oxide (NO) by the post synaptic neuron. NO diffuses in a paracrine manner into firing neurons in the locality, enhancing glutamate secretion. If insufficient glutamate or NO is secreted, neural networks will not be appropriately reorganized (strengthened) and incoding will be fragile. Neurosomatic patients have an impairment in neural plasticity. Deficiency in the neurobiology of encoding is one example of this pervasive disorder. Thus the individual who is predisposed to develop a neurosomatic disorder may have neural network function dysregulated by overtaxing his capacity for neural plasticity. This concept relates to that of "allostatic load" and explains why most neurosomatic patients develop their illness in a milieu of increased environmental stressors of various types. An example of this propensity may be seen in the predilection of neurosomatic patients to develop their illness after an acute infection, which produces an increase in hypothalamic activity and a decrease in NE (Dunn, 1993) (Watkins, Maier and Goehler, 1995), as do sustained attention, exercise, or orgasm, other activities which may produce or exacerbate symptomatology.

Watkins LR, Maier SF, Goehler LE (1995. Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses, and pathological pain states. Pain 63: 289-302.

Objectives: Digital pressure at 18 anatomically defined tender points [TPs] is one component required for the diagnosis of fibromyalgia syndrome [FMS]. There is a need for highly reliable measures to use as clinical gauges against which new biological measures can be statistically compared. The present analysis assessed the reliability of 2 tenderness severity measures: tender point index [TPI] by digital palpation, average pain threshold [APT] by algometry and their relationships to other clinical measures.

Methods: FMS patients free of analgesic and sedative hypnotic medications for two weeks were enrolled from a University-based rheumatology practice. At 2-week intervals, self-report measures included Visual Analog Scales [PAIN, SLEEP, HEADACHE, STIFFNESS] and validated questionnaires [HAQ-disability, HASSLES-anxiety, CES-Depression]. TP measures were obtained by a single examiner.

Results: Enrolled subjects [N=110] exhibited a quality of life altered by somatic and affective symptoms. Measurement of TP tenderness in 90 "medication-free" FMS patients disclosed a range of TPI and APT values. Analysis of test-retest values showed a reliability for APT [R=0.85] comparable with CESD, HASSLES, HAQ; and better than TPI [R=0.77]. TPI and APT both correlated with PAIN, STIFFNESS, HAQ, while only TPI correlated with CESD. The initial correlation between TPI and APT was high [R=0.63] and increased [R=0.73] with serial assessments. The ratio TPI:APT was dependent on somatic [PAIN, SLEEP, HAQ] but not on affective [HASSLES, CESD] measures.

Conclusions: The wide range of TPI or APT values could be used to stratify patients into clinical subgroups on the basis of tenderness severity. Both TPI and APT are highly reliable measures of tenderness severity to deep pressure at TPs in FMS but they may be most readily applicable to different clinical settings. TPI relates more to psychological measures than does APT. The use of multiple measures to assess FMS enhances understanding of the disorder. 

Objectives: Two neurochemical models may be mechanistically relevant to central nervous system [CNS]-mediated pain in fibromyalgia syndrome [FMS]. They are serotonin [5HT] deficiency and excesses of substance P [SP]. New findings in these interdependent models support their validity in FMS.

Methods: FMS patients and controls, medication-free for two weeks, were enrolled and clinically evaluated in a University-based rheumatology practice. Cerebrospinal fluid [CSF] and peripheral platelets [PLT] were collected. CSF was examined by HPLC for metabolites of the tryptophan [TRP]/5HT/kynurenine [KYN] pathways. Platelets were examined for 5HT levels, 5HT uptake, and in vitro aggregation before and after 2-weeks of 5HT uptake inhibitor therapy. SP was measured once in CSF from FMS and controls plus a second time in CSF from 28 FMS an average of 12 months later.

Results: Platelet 5HT levels were low in a subgroup of FMS and correlated with symptoms. Platelet uptake of 5HT was inhibited in vitro by oral use of 5HT uptake inhibitors [SRI]. Platelet aggregation was decreased in untreated FMS but was corrected by SRI. In FMS CSF, low levels of TRP, 5HTRP, and 5HIAA contrasted with high KYN. CSF SP was elevated in most, but not all FMS. It was highest in primary FMS, lower in secondary FMS, and nearly normal in non-FMS disease controls. The presence of diabetes mellitus did not influence CSF SP in FMS. Acute manipulation of lower extremity tender points had little effect on CSF SP. Repeat testing of FMS CSF SP showed an overall increase in CSF SP with time which correlated with pain/tenderness [TPI,TPA] but not with depression.

Conclusions: FMS subgroups exhibit abnormalities in both central and peripheral 5HT which correlate with FMS symptoms and suggest a clinically relevant, widespread defect in 5HT production and/or availability in FMS. FMS subgroups exhibit central abnormalities in SP levels which could be due to low 5HT and appear to change in concert with painful FMS symptoms. Therefore, subgroups of clinically similar FMS may be distinguished biologically by physiologically relevant laboratory abnormalities. 

Spinal stenosis in Fibromyalgia patients

After observing two patients with cervical stenosis whose "chronic fatigue syndrome" improved after surgery, we prospectively evaluated 48 patients diagnosed with chronic fatigue or fibromyalgia syndrome.

We tested the hypotheses that the spinal canal would be stenotic in patients with chronic fatigue and fibromyalgia syndromes, and that decompression of craniovertebral stenosis would lead to improvement in symptomatology and objective neurologic findings.

A detailed neurological history and examination were performed on all patients pre- and post operatively. In addition, those patients undergoing surgery were asked to complete a questionnaire with regard to symptomatology at two time points after surgery. Magnetic resonance scans were obtained on patients with a standardized protocol which allowed quantification of the AP diameter of the spinal canal, and AP and transverse spinal cord diameters at C1 through C7 levels. The AP compression ratio and spinal cord area were calculated for each patient. The foramen magnum was also studied and in selected patients a Cine-MR scan was used to help evaluate a small posterior fossa or Chiari syndrome. The level of the obex above the plane of the foremen magnum was measured.

For those patients with purely congenital cervical stenosis, a laminectomy was carried out based upon those levels which were in the stenotic range. If the cerebellar tonsils or foramen magnum were "tight" or abnormalities of CSF outflow from the posterior fossa were identified, the patient underwent suboccipital craniectomy with laminectomy of C1 and C2, usually with duraplasty. If both conditions were present the patient underwent simultaneous posterior fossa and cervical decompression. If purely anterior spinal cord compression was present then the patient was treated with anterior cervical decompression and fusion.

All patients had positive findings on neurologic history suggestive of myelopathy. Most patients were hyperreflexic and most demonstrated Babinski and other upper motor neuron findings. Seventy to 75% of this group had sensory and/or motor findings in the upper and lower extremities, abnormalities of gait, and other objective changes. The average spinal canal AP diameter in the mid-cervical region was less than 12mm from C3 through C6 and the average spinal cord size was below the lower limits of normal. Decompression of the cervical spinal canal lead to a statistically reliable increase in the AP diameter, AP compression ratio and spinal cord areas. Neurologic symptoms and signs reverted to normal or nearly normal in 60 to 65% of the patients with nearly all the remainder demonstrating improvement of some degree in sensory, motor, reflex, or extrapyramidal abnormalities. Two patients felt that some of their sensory symptoms had worsened. One felt weaker in the upper extremities and one felt their bladder had worsened. Four patients felt they had not changed in their neurologic symptoms.

By 24 + 2.7 weeks after surgery, 80% of the patients felt improved in most of a list of 18 symptoms. Fifteen to 20% felt that they were unchanged with fewer than 10% feeling that they had worsened in some symptoms. By 78 + 26 weeks after surgery, the questionnaire was repeated with more detail. Approximately 10 to 15% reported they were worse in some types of symptomatology; 10 to 20% felt they were unchanged in some of their symptoms with the remainder reporting some degree of improvement. More than half felt 50% or more improved after surgery. Nearly all patients improved in some spheres.

Conclusion: There is a subset of patients with the diagnosis of chronic fatigue-immunodeficiency syndrome or fibromyalgia syndrome who suffer from some element of craniovertebral compression. This is primarily congenital in nature and appears relatively normal unless more highly quantified analysis of the spinal canal and posterior fossa are carried out. Detailed neurological history and physical findings in this group of patients are consistent with a chronic myelopathy. The majority of the signs and symptoms can be reversed in these patients with craniocervical decompression.

This study does not provide insight into how many patients with ID-CFS or FMS may actually suffer from craniovertebral radiological compression. The problem is potentiated by the relative lack of quantification of craniovertebral radiological evaluation.

Diagnosis and Classification of Fibromyalgia: Where do we draw the line?

According to the 1990 American College of Rheumatology criteria the diagnosis of fibromyalgia is based on the history of widespread pain and the finding of 11 or more out of 18 designated tender pint areas. Rheumatologists often encounter other scenarios:

1. Patients with widespread pain who only have 6 or 7 tender points.
2. Patients with regional pain associated with sleep disturbance and multiple tender points.
3. FM patients with widespread pain and a few criteria tender points but multiple tender points in other locations.
4. FM patients who have pain allover and have the physical finding of allodynia.
5. FM patients with associated major depression
6. FM patients who are fully functional and patients who are very dysfunctional.
7. FM patients with the findings of neurally mediated hypotension.
8. FM patients with an associated growth hormone deficiency.

Epidemiological studies suggest that fibromyalgia is at one end of a spectrum of chronic pain. This often starts with regional pain syndromes and ends in severe, widespread intractable pain with allodynia. Diagnosing fibromyalgia is analogous to diagnosing hypertension; a critical question is: where do we draw the line? The salient feature of fibromyalgia appears to be an abnormality of central pain processing. A discussion of how this notion could be incorporated into diagnostic criteria seems relevant. Consideration also needs to be given to providing guidelines for the diagnosis of fibromyalgia subsets. For instance most practitioners can readily differentiate between their patients with simple fibromyalgia and those with complex fibromyalgia. The latter group usually have significant psychosocial problems and are more likely to be dysfunctional. Examples of possible subsets include: Major depression, widespread allodynia, primary sleep disorders (e.g. sleep apnea), neurally mediated hypotension, growth hormone deficiency, and a primary pain diagnosis (e.g. RA, SLE, RSD, etc.). Fibromyalgia is more than a pain syndrome. The possibility of developing a Multi-Axial classification, similar to that used in psychiatry should be explored. Before any recommendations could be implemented a multi-center study would have to be initiated to validate the proposed changes. 

Neurally Mediated Hypotension in Fibromyalgia Patients

Recent studies have identified a strong association between chronic fatigue syndrome and several related syndromes of orthostatic intolerance, the most notable of which is neurally mediated hypotension. Because chronic fatigue is an extremely common symptom in those with fibromyalgia, we sought to determine whether abnormalities in response to upright tilt table testing would be evident in those satisfying the ACR criteria for diagnosis of fibromyalgia.

In this study (Clin Exp Rheumatol 1997;15:239-46), 12 of 20 fibromyalgia patients (60%), but no controls had an abnormal drop in blood pressure during the first 45 minutes (stage 1) of upright 70 degree tilt (P<0.001), and another seven with fibromyalgia developed hypotension after the infusion of isoproterenol. All 18 who tolerated upright tilt for more than 10 minutes reported worsening or provocation of their typical widespread fibromyalgia pain during stage 1, whereas controls were asymptomatic.

These results identify a strong association between fibromyalgia and neurally mediated hypotension. Further studies will be needed to determine the contribution of autonomic responses to upright stress in the pathophysiology of pain and other symptoms in fibromyalgia, and randomized trials are needed to determine whether the medications available to treat neurally mediated hypotension will afford relief to those with fibromyalgia. 

Multi-disciplinary Treatment Approach is Successful in Reducing FMS Symptoms

The successful treatment of fibromyalgia is the focus of the presentation. Clinical data will be presented from approximately 260 patients which illustrates the complex neurological basis of this dysfunction and how a multi-disciplinary treatment approach is needed to reduce the symptoms. The presentation will utilize materials from the motorneuron pool models (Basmajian – Muscles Alive 1985) and the Neural Plasticity Model. The data to be presented will include surface electromyography data, physiotherapy findings and trigger point data, psychological test results and quantitative EEG measures. The presentation will conclude with a single case study which clearly demonstrates the expected changes as predicted by the model. 

Noradrenergic Transmitter Activity and Sensitivity in the Sympathetic System and Locus Coeruleus in Fibromyalgia patients

Psychiatric illness has traditionally been introduced as a possible etiologic factor for the development and maintenance of the Fibromyalgia Syndrome, though no casual link is ever established. This is mainly based on the high degree of psychiatric comorbitity in this patient population. Epidemiological studies have indicated that up to 11/3 of the fibromyalgia patients have a history of panic disorder and an equal part had a history of affective disorder. In two previous trials we have shown that a portion of adult females with primary fibromyalgia and no psychiatric history do share some common features and suffer from a psychobiological dysfunction similar to what is reported among patients with panic disorder. We will discuss a hypothesis that there could be an increased noradrenergic transmitter activity and sensitivity in the sympathetic system and in Locus Coeruleus even though this cannot be determined by the level of catecolamines in blood or urine.

A majority of fibromyalgia patients do respond to drug treatment with antidepressants of the SSRI type (paroxetine). They display however a delayed response to treatment compared to other patient groups. This may be of importance when reviewing a number of negative drug trials previously performed. Further details will be discussed including implications for the diagnostic concept of fibromyalgia. 

How to Effectively Treat Fibromyalgia – A Clinical Perspective

Our research and experience with well over 1000 patients with fibromyalgia and CFIDS have shown that effective treatment is currently available. Patients are most likely to improve if all the underlying processes are treated in an integrated manner. Our model proposed that hypothalamic, immune and neurotransmitter dysfunction, (possibly secondary to mitochondrial dysfunction), combined with inadequate nutritional status, cause persistence of the disease process.

The hypothalamus is involved in:

1.Sleep –these results often with inadequate deep restorative sleep. Treatment with the medications Ambien, Desyrel, Soma, Elavil, Flexeril, Klonopin and/or Xanax, the herbal remedies (Melissa, Valerian and Passiflora) and Melatonin (3/10mg) are very helpful.

2. Hormonal Regulation – Subclinical and/or overt hypothyroidism, adrenal insufficiency (including low DHEA), and ovarian/testicular hypofunction are common and treatment of these is also very beneficial.

3. Autonomic Function – Treatment of NMH (especially in younger patients) may be helpful.

Immune dysfunction results in frequent (often opportunistic) infections including poorly defined mycoplasma, rickettsial and viral infections. Inadequate levels of nutrients can occur from:malabsorption caused by bowel infections and poor membrane transport, increased nutrient utilization caused by the illness, and inadequate intake. Nutritional deficiencies can cause mitochondrial and immune dysfunction as well as persistent muscle shortening and multiple other problems. Although our understanding of fibromyalgia is still in an early state, research and clinical experience show that fibromyalgia is now a disease for which effective treatment is available. A placebo-controlled study of this approach is nearing completion. 

The Role of Microorganisms in Chronic Fatigue and Fibromyalgia

Chronic Fatigue immune Dysfunction Syndrome (CFIDS) and Fibromyalgia (FMS) are illnesses with increased reported frequency in the U.S. and other industrialized countries. Despite multidisciplinary investigations into the causes of CFIDS and FMS, their etiology remains unknown. Similarly, no specific diagnostic tests or therapies exist. There is no published data implicating a specific virus or other microbe as the cause of CFIDS and FMS. However, it appears that infectious agents, among other environmental factors, can precipitate the syndrome. A variety of common viruses can be reactivated in some CFIDS patients, including the HTLV-II, EBV, cytomegalovirus, herpes simplex viruses 1 and 2, human herpes viruses 6,7 and coxsackievirus. Most investigators believe that virus reactivation could be occurring secondarily to some immunologic disturbance.

Since mycoplasma and chlamydia have been implicated in reactive arthritis with some overlapping symptomatology with CFIDS and FMS, this study was undertaken to determine the prevalence of the mycoplasma and chlamydia genomes in two different groups of patients who were classified as having either typical or idiopathic chronic fatigue syndrome, using polymerase chain reaction (PCR) methodology. The role of these organisms in causing dysregulation of interferon induced genes and cytokine production was also examined.

Qualitative PCR showed that targeted DNA sequence from the gneus mycoplasma and the species M. fermentans were amplified in 52% and 24% of typical CFIDS patients and in 36% and 16% of idiopathic CFIDS patients respectively. In contrast, these genomes were found in only 14% and 4% of healthy control subjects respectively – (P<0.0001). While Chlamydia trachomatis genome was detected in about 17% of typical or idiopathic CFIDS, none of the control subjects were positive for this bacterium. To examine the possible involvement of mycoplasma and chlamydia in cytokine dysregulation in CFIDS and FMS, lymphocytes from mycoplasma-positive and mycoplasma-negative patients were cultured with mitogen and mycoplasma antigens. Both groups of patients showed enhancement of IL-6 and TNF-a, which may indicate infectious agents, other than mycoplasma, re involved in the pathogenesis of CFIDS. Importantly, the mycoplasma-positive CFIDS group also showed suppression of IL-2 production and an increase in the lymphoproliferative response to lipopolysaccharide and mycoplasma antigens.

In addition, we evaluated the apoptotic cell population, interferon alpha and interferon induced 2-5A synthetase and PKR gene transcript in CFIDS, FMS and healthy controls. Increased apoptotic cell population was observed in CFIDS individuals, as compared to healthy controls (26% + 12.9 +and 9.9% to 4.2%, respectively). The increased apoptotic subpopulation in CFIDS individuals was accompanied by an abnormal cell arrest in the S phase and the G2/M boundary of the cell cycle as compared to the control group (from 8.6 + 1.2 to 22.8 + 2.4 and from 3.6 + 0.82 to 24.3 + 3.4, respectively). Also, CFIDS individuals exhibited enhanced 2-5A synthetase, PKR mRNA and protein levels. In 60% of the CFIDS samples (n=29) treated with 2-aminopurine (2-Ap) (a potent inhibitor of PKR) or with pyrrolidine dithiocarbamate (PDTC) (an inhibitor of NF-kB). The programmed cell death was reversed by more than 50%. Moreover, these molecular markers (2-5A synthetase, PKR, NF-kB, apoptosis and cell cycle) were found abnormal in patients with CFIDS and FMS who were exposed to methyl tertiary-butyl ether and benzene contaminating water, indicating factors other than infectious agents play role in CFIDS and FMS.

CONCLUSION: These results suggest the role of copathogens or cofactors for mycoplasma, chlamydia and toxic chemicals in CFIDS or FMS. PKR and NF-kB mediated apoptosis and dysregulated cytokine production in CFIDS or FMS may contribute to the pathogenesis and fatigue symptomatology associated with these diseases. 

Genetic Factors in Fibromyalgia Syndrome

Although familial occurrence of fibromyalgia syndrome (FMS) has been commonly observed, data on genetic role in this condition are limited. A few studies have reported familial aggregation and association with HLA, and we have studied genetic linkage of FMS with HLA in multicase families.

Familial Aggregation, Pellegrino, et al (Arch Phys Med Rehabil 1989; 70: 61-63) studied 17 patients with FMS from a support group and their 50 close relatives (parents and siblings), and found that 52% of the relatives studied had fibromyalgia. Based on their analysis, they suggested an autosomal dominant inheritance. Buskila, et al (J Rheumatolo 1997; 24:941-944) randomly selected 30 patients with FMS from their rheumatology clinic and studies 91 of their first degree relatives (FDRs) (parents, siblings and children) and found that 26% of the FDRs had FMS (14% among males and 41% in the female). Since the prevalence of FMS in the community is around 2-3%, these data suggest familial aggregation. However, such aggregation may result from a common family environment and/or from genetic influence.

HLA Association, Burda, et al (Clin Exp Rheumatol 1986; 4: 355-357) HLA typed class I and II antigens among 18 patients with FMS and 23 normal controls and found a significant association with DR4. The numbers studied are obviously small. Branco, et al (J Musculoske Pain 1996; 4: 21-27) studied 52 patients with FMS and 869 normal controls with HLA typing and found a statistically significant association with HLA B58, DR8 and DR5. However, Horven, et al in an earlier report (J Rheumatol 1992; 19: 1269-1270) found no HLA association among 60 patients with FMS, as compared with 159 controls. These inconsistencies of results from different centers may reflect a weak or no true association of FMS with HLA, or perhaps the confounding effects of heterogeneity among the fibromyalgia patients.

HLA Linkage Study. While HLA association of a disease may be due to genetic factors, it may also result from several biases, including selection or referral bias. HLA linkage analysis of multicase families, on the other hand, is very helpful in determination of genetic linkage. We studied 40 multicase families with fibromyalgia where at least one FDR besides the proband also had FMS. Forty probands of 107 of there available FDRs were studied by a clinical protocol and HLA typed for class I and II antigens. Depression was assessed by Zung depression scale. FMS was diagnosed by ACR criteria. Haplotypes were determined without any knowledge of the diagnosis. For linkage analysis, we used two powerful sibship tests, ie, criterion N (which tests for significant haplotype sharing among affected sibs) and criterion T (which tests for significant non-sharing of haplotypes between affected and non-affected sibs) (Green and Shah, Ann Hum Gen 1992; 56: 331-338). The criteria and there means and variances of each sibship was added and normalized criterion, S, was compared with standard normal results. Clinical evaluation showed that 74% of the siblings, 53% of children and 42% of the parents had FMS. Linkage analysis showed an S value of 1.897 (P=0.029), without significant differences between depressed and non-depressed groups (Yunus, et al, Arthritis Rheum 1996; 39: 8275). The results thus showed a significant linkage of a disease susceptibility gene to HLA in fibromyalgia.

Conclusion. Familial aggregation in FMS has been documented, but only limited studies are available at this time on the role of genetics in FMS. Results of HLA association are currently inconclusive. Our study of 40 multicase families showed a rather weak linkage with an HLA haplotype. Independent confirmation of our finding is warranted. Further genetic studies should explore both HLA and non-HLA markers. 

Epidemiological Considerations in Identifying Cases of Fibromyalgia Syndrome

Fibromyalgia is one of a constellation of painful musculoskeletal disorders that have been delineated since rheumatism was mentioned in the Hippocratic writings. With the publication of the American College of Rheumatology 1990 classification criteria for fibromyalgia, a simple, uniform case definition became available for clinical investigation of the disorder. Case definition is pivotal in epidemiologic studies and the ACR 1990 criteria have the advantage of simplicity. Prior to this, various criteria were used by a number of investigators and included other features such as morning stiffness, non-restorative sleep and aggravating features (e.g. cold weather), in addition to pain and tenderness. Criteria that may be sensible in clinical practice may not be as useful for evaluation of a large population. The ACR criteria require the examination of 18 tender points and this may discourage incorporating fibromyalgia into large surveys with a physical examination component. However, modification of the ACR criteria by increasing the number of criteria to incorporate associated features, such as irritable bowel or bladder, sleep disorder, cognitive difficulties, psychological distress, or chronic fatigue, into the definition of fibromyalgia will tend to increased the heterogeneity of the populations studied. Changing the ACR by requiring more extensive physical examination or laboratory testing or diagnostic imaging would tend to hamper the conduct or feasibility of epidemiologic and clinical projects.

In conclusion, despite some disadvantages, the ACR 1990 classification criteria for FMS have provided researches at different centers with a simple, uniform means of classifying fibromyalgia cases in various populations.