Clinical criteria and diagnostic assessment of fibromyalgia: position statement of the Italian Society of Neurology-Neuropathic Pain Study Group

Background The role of central and/or peripheral nervous system dysfunction is basically fundamental in fibromyalgia. Aim The aim of this position statement on behalf of the Neuropathic Pain Study Group of the Italian Society of Neurology is to give practical guidelines for the clinical and instrumental assessment of fibromyalgia (FM) in the neurological clinical practice, taking into consideration recent studies. Methods Criteria for study selection and consideration were original studies, case-controls design, use of standardized methodologies for clinical practice, and FM diagnosis with ACR criteria (2010, 2011, 2016). Results ACR criteria were revised. For diagnostic procedure of small-fiber pathology, 47 studies were totally considered. Recent diagnostic criteria should be applied (ACR, 2016). A rheumatologic visit seems mandatory. The involvement of small fibers should request at least 2 among HRV + SSR and/or laser-evoked responses and/or skin biopsy and/or corneal confocal microscopy, eventually followed by monitoring of metabolic and/or immunological/ and or/paraneoplastic basis, to be repeated at 1-year follow-up. Conclusions The correct diagnostic approach to FM could promote the exclusion of the known causes of small-fiber impairment. The research toward common genetic factors would be useful to promote a more specific therapeutic approach. Supplementary Information The online version contains supplementary material available at 10.1007/s10072-023-06836-3.


Introduction
Fibromyalgia (FM) is a complex and common syndrome, whose main clinical element is represented by chronic non-specific pain associated with numerous and various other symptoms, linked to the involvement of the nervous system such as fatigue, insomnia, and emotional distress. Pain in FM is most typically classified as nociplastic; the terminological definition of nociplastic pain was formulated by the IASP in 2017 and defined as "pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain" [1]. The need to classify pain in a new third category originates from the observation of a more elusive subtype of pain with mechanisms that are not yet fully understood, compared to the two classic typologies of pain, nociceptive and neuropathic pain, caused respectively by non-neural tissue damage, producing an activation of nociceptors with a normal functioning of the somatosensory nervous system, and by damage to the somatosensory system [2]. Nonetheless, it is evident that FM patients may experience overlap between the three different types of pain, nociceptive and neuropathic in addition to nociplastic pain [2], even in the presence of normal functioning of the somatosensory nervous system [3]. A more complete understanding of the pathophysiological mechanisms of pain may in the future lead to an overcoming of the current pain classification. Impaired pain processing, consisting of central pain amplification or decreased pain modulation along the descending pathway, or a combination of these two types of dysfunctions, is the most distinctive element in FM [2]. However, it is currently not clear whether the detectable alterations have a primary or secondary origin at the level of the central or the peripheral nervous system, indeed such alterations being identifiable at both levels. At the same time, a predominantly non-length-dependent neuropathy, of a non-developmental type, frequently accompanies patients with FM [4].
Considering that FM is frequently comorbid with autoimmune pathologies and since in patients with FM there are measurable altered cytokine levels, it has been hypothesized that this syndrome may be due to autoimmune processes, as demonstrated in mice by transfer of purified IgG from individuals with FM [5].
The complex and only partially known pathophysiological basis in addition to diagnostic criteria based only on subjective symptoms in the absence of specific clinical signs and recognized biomarkers means that FM is underdiagnosed and undertreated. For these reasons, an aura of stigma and the burden of inadequate medical and social support still weigh on the affected patients.
The clinical features included in the diagnostic criteria are largely attributable to central and/or peripheral nervous system dysfunction; so far, the role of the neurologist is of evident utility in the diagnosis and clinical management of FM.
The aim of this position statement on behalf of the Neuropathic Pain Study Group of the Italian Society of Neurology (SIN) is to give practical guidelines for the clinical and instrumental assessment of FM in the neurological clinical practice, taking into consideration recent studies.

Methods
This is a position statement on diagnostic assessment of fibromyalgia, based on a not structured review.

Eligibility criteria and search strategy
For clinical criteria, we took into consideration the American College of Rheumatology criteria for adult and childhood fibromyalgia.
For instrumental assessment, studies on neurophysiological, psychophysical, autonomic, and other instrumental techniques applied to clinical assessment of FM, with special regard to sensory and autonomic neuropathy, were searched on PubMed. The search strings are reported in Table 1. The search was not filtered for study type. Two authors independently assessed studies and any disagreement was planned to be solved by consensus with a third author. Main original data were thus revised. Criteria for study selection and consideration were: original studies, case-controls design, use of standardized methodologies for clinical practice, FM diagnosis with ACR criteria (2010,2011,2016). Reviews and case reports were not considered. Figure 1 reports the flow chart showing the total number of identified, screened, included, and excluded records. We thus took into consideration studies in the last 10 years, and summarized publications within 5 years (2018-2022) in tables.
Search strings and retrieved records are reported separately for each considered instrumental technique in Table 1.

Fibromyalgia in adult age
The first studies on FM date back to sixteenth century observations, which saw slow progress toward the formulation of recognized diagnostic criteria. The term FM was coined only in 1976, from the union of the words "fibro" and "mio," to highlight the involvement of the fibrous and muscular tissue and the word "algia," indicating pain as an essential element for the diagnosis. The first diagnostic criteria were formulated by a scientific society only in 1990, thanks to the lack of prejudices and the farsightedness of the College of Rheumatology (ACR), which, despite the absence of clinical tests to objectify the pathology, believed it could not ignore this condition. The 1990 diagnostic criteria emphasized the role of tender points, tenderness of at least 11 of 18 specific body sites, and the role of diffuse pain defined as pain persisting for at least 3 months in both supra-pelvic and subpelvic regions in addition to axial pain [51].
A strong limitation of these criteria was represented by the fact that at least 25% of patients affected by FM do not fully satisfy the ACR criteria proposed, since in addition to the subjectivity of the response to the pressure exerted, as well as the difficulty for clinicians to apply 4 kg of strength, it has been widely experienced that acupressure tenderness in male subjects appears less evident than in female subjects,  Hence, in 2010, the ACR also published the first revision of the criteria, in which the search for the positivity of tender points has seen its diagnostic role disappear, replaced by a greater weight given to subjective symptoms [52]. Subsequently, in 2011, the same authors proposed a modified version of the ACR criteria to allow diagnosis through a self-assessment based on six somatic symptoms considered predominant (non-refreshing sleep, fatigue, cognitive deficits, headache, depression, and abdominal pain) among a list of 41 symptoms proposed in the Symptom Severity Score (SS) of the 2010 ACR criteria to be reserved for research purposes only and to introduce a quantitative measure of disease severity, the Fibromyalgia Severity Scale (FS score, range from 0 to 31) resulting from the sum of the widespread pain index (WPI) score and the modified SS score [53]. The last revision of the ACR criteria dates back to 2016 and changes the definition of widespread pain, defined as present in at least four of five regions (excluding the jaw, chest, and abdomen); specifies somatic symptoms such as headache, pain, or cramps abdominal pain and depression; adds the FS scale, and introduces the criterion according to which the diagnosis of FM should be done regardless of other diagnoses and that the diagnosis of FM must not lead to the exclusion of the presence of other relevant concomitant pathologies [54].

Fibromyalgia in children
Although fibromyalgia is highly prevalent in adulthood, it can be present also in the developmental age. In children and adolescents, its prevalence is poorly studied and varies between 7 and 15% of new visits to pediatric rheumatology clinics [55]. Girls/boys ratio is 4:1 and age at diagnosis ranges from 13 to 15 years, although diagnoses at younger ages are reported [56].
Diagnostic criteria for juvenile fibromyalgia (JFM) were first described in 1985 by Yunus and Masi [57] and subsequently revised in 2010 [58], with peculiarities as compared to the criteria for adulthood. Laboratory and diagnostic tests are often negative [56]. Clinically, JFM is characterized by chronic and widespread pain, which can be spontaneous or evoked by painful or non-painful stimuli. It is associated with fatigue and highly disabling symptoms [59]: headache in two-thirds of cases, abdominal pain [60], sleep disorders, such as periodic limb movement [61], and psychiatric disorders, such as depression and anxiety [62,63].
Growing pains can be considered precursors of JFM [64].

Diagnostic procedures
In the following paragraph, we summarize the main studies on technical procedures of small-fiber function and autonomic system assessment that fulfilled our inclusion criteria ( Fig. 1). Nerve conduction studies-NCS-and electromyography-EMG-Apart from few studies in favor of electroneurography signs compatible with sensory neuropathy [6,7], nerve conduction study and electromyography are generally within normal limits in FM patients [8][9][10][11]. Lawson et al. found a mild sural and medial plantar (MP) response amplitude reduction in those subjects reporting symptoms of neuropathic pain, distal small-fiber neuropathy, and markers of metabolic syndrome [7]. The lack of a previous neurological assessment [6] or the presence of signs of neuropathic pain [7] could suggest cautiousness in interpreting abnormal NCV findings, but their routine execution in the presence of clinical signs of polyneuropathies or pain of neuropathic origin seems strongly recommended.

Laser and nociceptive evoked potentials
Ten studies tested pain-related evoked potentials in patients with FM. Four studies showed increased amplitude of laser-evoked potentials (LEPs) and reduced habituation in patients with FM, supporting an abnormal central elaboration of pain and pain matrix hyper excitability [12][13][14][15]. Accordingly, Aδ LEP amplitude, conditioned by a preceding C-fiber LEP, was significantly higher in patients with FM than in healthy controls, supporting the hypothesis of pain matrix hyper excitability [16]. Three studies used pain-related evoked potentials (PREPs) to detect small-fiber pathology in FM with contrasting findings [3,17,18]. In a case-control study involving 25 patients with FM, Üçeyler and colleagues reported reduced amplitudes of pain-related evoked potentials elicited by surface concentric electrodes in patients with FM compared to control subjects, supporting abnormalities of small fibers [17]. Two studies, using LEPs, did not confirm Aδ fiber function abnormalities, suggesting that small-fiber pathology negligibly affects somatosensory system function in FM and is not a significant contributor to the pathophysiology of this condition [3,18]. In the study of Fasolino and colleagues in 57 patients with FM, LEP parameters fell within normative ranges and did not differ in patients with or without small-fiber pathology, detected through skin biopsy [3]. In the study of Van Assche and colleagues, none of the 1 3 92 patients enrolled showed signs of loss of function of the nociceptive responses evoked by Aδ fiber activations [18].
Two recent studies assessing multichannel LEPs in patients with FM and small-fiber impairment showed abnormal N2P2 habituation index, more marked in patients with reduced IENFD, and reduced amplitude of the P2 component, not coherent with the site of denervation [11,19] ( Table 2). In summary, laser-evoked potentials reflect abnormal pain processing at both peripheral and central levels in FM, with amplitude amplification occurring in the presence of peripheral denervation. Nevertheless, clear amplitude loss or even the absence of cortical components should be considered as a sign of severe Aδ fiber impairment ( Table 2).
Patients with FM, beside pain, often present a constellation of complaints, like persistent fatigue, gastrointestinal dysmotility, dizziness, and syncope that can be expression of a dysfunction of the autonomic nervous system (ANS). Also, in patients with a history of vasovagal syncope, a higher prevalence of FM compared to the general population has been reported [20]. Different hypotheses have been formulated to explain autonomic disturbances in fibromyalgia, including abnormal hypothalamic-pituitary axis functioning and autonomic small-fiber impairment. Many studies, most of them based on the analysis of heart rate variability (HRV) at rest or following physical challenges, have found ANS dysfunctions in FM [21][22][23][24][25][26][27][28]. The idea has prevailed that FM is characterized by an altered sympatho-vagal balance with an increase in sympathetic and decrease in parasympathetic activity. Few studies assessed sudomotor function in FM.
Sympathetic skin response amplitude in patients is not generally different from controls [15,29]. However, it correlates with disease severity as assessed by clinical questionnaires [29]. Conversely, SSR latency has been found to be significantly longer in FM compared to controls and the response totally absent in a percent varying from 15 to 18% of patients [15]. Moreover, using electrochemical skin conductance analysis, sudomotor function has been found to be significantly impaired in patients with FM [29]. Autonomic symptoms are more severe in women affected by FM who also complain of more intense pain [27]. Moreover, a significant correlation has been found between the prevalence of autonomic symptoms and the impact of FM on general health status [25].
In conclusion, the data present in literature are strongly oriented toward an association between FM and dysautonomia that further deteriorates patients' quality of life, so the evaluation of autonomic involvement could offer information on the severity of the disease (Table 3).

Skin biopsy
In the last decade, several studies showed evidence of smallfiber pathology in a variable proportion of patients with A similar finding has also been reported in JFM [33]. Heterogeneity between studies and, often, small population size prevented conclusive findings. Skin denervation was mostly reported as not length-dependent pattern [3,17,34]; however, in a subset of patients, a length-dependent distribution has been described [10,11], leading to a challenging distinction from the small-fiber neuropathy. The presence of a more severe pain phenotype and anxiety associated with generalized denervation has been also reported [4,10]. Myelinated dermal fibers have been found to be usually spared [14,17], although a loss of Meissner corpuscles at fingertips has been observed [14]. In addition to nerve loss, morphological changes such as lower density of regenerating nerve fiber positive to growth-associated protein (GAP) 43 [17] and a reduction of diameter in dermal nerve fibers have also been reported [8]. The observation of increased peptidergic innervation of cutaneous arteriole-venues shunts in the glabrous skin of patients with fibromyalgia [34] suggested a neurogenic microvascular dysfunction that may imply the coexistence of peripheral mechanisms underlying pain [17,[35][36][37][38]. Along with cutaneous denervation at proximal leg, an aberrant cutaneous and systemic miRNA expression pattern was found in patients with fibromyalgia [34]. Finally, the finding of reduced mitochondrial chain activities and bioenergetics levels and increased levels of oxidative stress in the skin biopsies of 20 women with FM compared to controls [39] suggests a role of oxidative stress, mitochondrial dysfunction, and inflammation in the pathophysiology of pain in fibromyalgia. (Table 4). Skin biopsy is the elective test for small-fiber pathology. Its evaluation in patients with FM is suggested to ensure small-fiber involvement.

CCM
Considering the elective innervation of the cornea by C fibers, corneal confocal bio-microscopy is a reliable method to assess small nerve fiber pathology. While the study by Oudejans clearly reported diagnostic cut-off values and relied on widely agreed parameters including nerve fiber length, nerve fiber density, and branching, the study by Ramirez investigated different parameters (stromal nerve thickness and corneal sub-basal plexus nerve density) and did not provide diagnostic cut-off values [40,41]. More recent studies confirmed utility of corneal confocal microscopy in FM with abnormalities in most of the patients, frequently in association with severity of clinical expression [10,42]. Changes in corneal innervation and Langerhans cells were detected in FM patients and those with small-fiber neuropathy [43].
To summarize, corneal confocal microscopy confirmed the presence of small-fiber impairment in FM, although the clinical picture did not resemble neuropathic pain, especially in patients with severe anxiety and depression [44]. Its evaluation in FM patients could reliably confirm impairment of small afferents (Table 5).

Microneurography
Microneurography represents an ideal technique to explore the peripheral nociceptor system and to record intraneural single C-fiber action potentials from nociceptors. Multiple C-fibers can be recorded simultaneously for hours [65], thereby allowing the assessment of individual firing behavior to various external stimuli. The application of microneurography in FM is unfortunately limited. Using this technique, C-nociceptors were recorded in female FM patients [45]. The results were compared with those collected in female patients with smallfiber neuropathy and controls. The majority of FM patients showed abnormal firing of C-nociceptors. Many silent nociceptors exhibit hyper excitability resembling that in smallfiber neuropathy, but high activity-dependent slowing of conduction velocity is more common in FM patients, and may constitute a hallmark. The main conclusion of this study was that abnormal peripheral C-nociceptor ongoing activity and increased mechanical sensitivity could contribute to the pain and tenderness referred by FM patients [45]. Essentially, the same results were found in a second paper from the same group [10] showing that FM patients showed hyper excitability and sensitization of mechanoresponsive (1A fibers) and mechano-insensitive (1B) nociceptors. If confirmed this is an important contribution as it may suggest that peripheral nociceptors are functionally abnormal in FM in agreement with the morphological abnormalities disclosed by skin biopsy. An important limitation of these papers is the lack of correlation with morphological analysis of peripheral nociceptors that prevent to correlate the functional abnormalities highlighted by microneurography with the morphological abnormalities disclosed by skin biopsy. Presently, microneurography seems a promising tool to evaluate nociceptors abnormalities, but the procedure is of limited diffusion in clinical practice with few application in patients with FM.

QST
Quantitative sensory testing (QST), a standardized method used to assess somatosensory system function, if a comprehensive protocol is applied, allows to detect sensory and pain profiles, and to hypothesize the underlying mechanisms (i.e., peripheral versus central nervous involvement, focal versus generalized sensory dysfunction) [46].
In fibromyalgia, QST findings showed a certain heterogeneity in the sensory threshold abnormalities. However, a common result between different studies is the presence of hypersensitivity or gain of function to a broad of standardized sensory stimuli [8,10,17,33,47,48]. In particular, increased mechanical pain sensitivity (MPS) and reduced pressure pain thresholds (PPT) are commonly reported [3,17], that suggest prevalent mechanism of central sensitization [46]. Moreover, a high rate of aftersensation after mechanical stimuli is also described [47] while, less commonly, mechanical dynamic allodynia is reported [3,40,47]. Additionally, in a subset of patients, also, mechanical detection thresholds (MDT) can be increased, that, unrelated to other evidence of large nerve fiber impairment, probably is supposed to be due to impaired C-tactile afferents in the context of a small-fiber pathology [10].
Compared with small-fiber neuropathy, patients with FM with or without epidermal denervation have different sensory phenotypes [48], suggesting that despite the coexistence of skin denervation and small-fiber pathology, SFN and FM have different mechanisms underlying pain [3,48,49] Finally, the application of dynamic protocols of temporal summation and conditioned pain modulation (CPM) showed significant dysfunction of the diffuse noxious inhibitory control (DNIC) [29,50], rising the hypothesis of altered endogenous pain mechanisms, compared with healthy controls. (Table 6) In conclusion, considering the consistent methodological heterogeneity between studies, future research needs to investigate with a multimodal approach, the potential role of QST-based algorithm in stratification of FM patients for clinical and research purposes.

Position statement
Neurological management of FM patient-clinical criteria are as follows: 1) Patients with generalized pain should be taken into consideration for FM diagnosis. 2) Recent diagnostic criteria should be applied (ACR, 2016). Diagnosis of FM is based on the sum of WPI (WPI) > 7 and symptom severity scale (SSS) score > 5 OR WPI of 4-6 and SSS score > 9. Severity of FM is also based on the sum between WPI and SSS scores. For fatigue, waking unrefreshed, and cognitive symptoms, the questionnaire should be followed. For headache comorbidity, International Headache Society criteria [66] should be applied. For depression, neurologist should consider the presence of depressive symptoms, using clinical impression, sustained by clinical criteria Severe anxiety or depression distorts fibromyalgia symptoms The study supports the present of a complex mechanisms underlying pain Small-fiber pathology does not significantly affect somatosensory system (DSM V). For abdominal pain, the description of such symptom since at least 3 months should be considered. For juvenile age, the same criteria should be applied, with the recommendation to be administered by a clinician or health care professional. In addition, the WPI would consider the last 3 months, instead of the last week [58]. 3) A careful investigation of personal and familiar history of neurological conditions, as well as a detailed objective examination of neurological deficit, with particular regard to multimodal sensations, including tactile, vibration, nociceptive, and thermal ones, seems mandatory in the clinical approach of patients with suspected FM. The huge expression of central sensitization phenomena could contribute to hide myopathies and central and peripheral neurogenic pathologies. In the new classification, other conditions leading to pain do not exclude FM, so the definition of associated syndromes outside those included in the classification should complete the diagnosis. The clinical neurological examination would contribute to define deficit in central and peripheral nervous system, and to proceed with the adequate diagnostic measures. In the supplementary section, the neurological diseases with diffuse pain with possible association with FM are described (Supplementary section). 4) A rheumatologic visit should also be requested, if lacking, to clarify frequent comorbid conditions 5) In the case of FM diagnosis, the involvement of small somatic and autonomic fibers, frequently not associated to objective signs of sensitive and autonomic dysfunctions, would request the diagnostic procedures detailed in the above reported paragraph. At least two among HRV + SSR and/or laser-evoked responses and/or skin biopsy and/or corneal confocal microscopy should be suggested. Microneurography is rarely available. The QST could also be suggested, although this is a psychophysical technique, based on subjective responses, that may not reflect small nerve fibers dysfunctions. The presence of objective signs of small-fiber impairment should be followed by monitoring of possible metabolic and/or immunological and/or paraneoplastic basis, with basal assessment of blood tests [67]. Such tests could be repeated at 1-year follow-up (Fig. 2).

Limitations
This position statement was based on an expert opinion taking into consideration recent literature. However, we did not perform a systematic review, and considered main studies exploring only the last 10 years in PubMed.

Conclusions
This shared document has the function of helping clinical neurologists and neurophysiologists in the diagnosis of FM disease although we are still far from understanding Fig. 2 Flow chart reporting the proposal simplified diagnostic assessment for patients with FM. *Glucose dysmetabolism assessment: renal, thyroid, and liver function tests; B12 vitamin and folate blood levels; erythrocyte sedimentation rate; blood cell count. **For associated neurological conditions, consider the supplementary section. ***For tests useful to consider causes of small-fiber neuropathy, consider Gemignani et al. [66] mechanisms that could sustain FM clinical picture in single cases. To clarify these mechanisms will definitively improve FM treatment with a precision medicine approach. The altered pain processing at central level and the frequent involvement of somatic and autonomic small fibers justify the interest and the competence of the neurologists, who may give an important aid to the diagnosis of associated central and peripheral nervous system conditions, as well as novel input to the research about the fundamental causes of the disease. Recent studies on voltage-gated ionic channels [3,68] showed genetic abnormalities in several patients with FM, similar to those found in patients with neuropathic pain.
The correct diagnostic approach to FM could promote the exclusion of the known causes of small-fiber impairment, and the research toward common genetic factors, useful to promote a more specific therapeutic approach.