Xavier J. Caro

The Role and Importance of Small Fiber Neuropathy in Fibromyalgia Pain

Serious investigators of fibromyalgia (FM) realize the profound implications of finding features of small fiber neuropathy (SFN) in this disorder. For the first time, an easily reproducible and generally agreed upon, peripheral tissue lesion has been reported from multiple investigative centers. Understanding how this discovery relates to other features of FM, and how one might utilize it to better comprehend, and care for, afflicted patients’ painful complaints remains a challenge, however. In this article we review how the SFN seen in FM may be placed in context, and suggest how such a tissue abnormality might be used to better understand the pathophysiology of FM, and plan for its effective treatment. We also suggest how finding SFN in FM implies the need for continued focused research within the area of neuropathic disease in FM.

Nerve conduction tests in patients with fibromyalgia syndrome

It is likely that the fibromyalgia syndrome (FMS) is made up of a number of subgroups, each having a unique etiology but all sharing a final common clinical expression. The laboratory identification of one or more of these subgroups would allow better understanding of the syndrome and more specific treatment strategies. We share Dr. Ersoz’s [1] interest in a potential subgroup of FMS patients who complain of peripheral paresthesias. Thus we read with great interest his paper in which he described results of nerve conduction studies (NCS) in FMS. We were disappointed that he was unable to make a meaningful subgroup identification. After careful reading of his paper, however, we were intrigued by certain methodological and statistical issues which, taken together, may have kept Dr. Ersoz from finding a real difference between groups, assuming one exists. Dr. Ersoz’s population of FMS patients was significantly different from those seen by most rheumatologists. His subjects’ average age, 39.2 years, is lower by about 10 years than reported in most other studies [2, 3]. Furthermore, most FMS study populations have about 5–15% men [2, 3]. Therefore, Dr. Ersoz’s cohort, consisting of all younger women, may have helped bias his results and discouraged other researchers from seeking nerve lesions in the larger population of FMS patients. Furthermore, Dr. Ersoz did not provide a description of his normal subject screening procedure in enough detail to assure readers that the control group was not contaminated by other occult systemic or neurologic disorders. In fact, his control population included at least three subjects with abnormal NCS, two who may have been subject to systemic disorders affecting their NCS (one with a median mononeuropathy at the wrist and one with abnormal peroneal nerve conduction) and one with lumbar radiculopathy. According to O’Brien and Dyck [4], clinical researchers seeking to define a ‘‘normal’’ cohort of subjects for the purpose of neuromuscular study should ‘‘exclude persons with neuropathy, [and] also patients with any neurologic disease with unknown effects on nerve conduction and diseases known to predispose to neuropathies.’’ We also noted that Dr. Ersoz did not measure tibial H reflexes in his study. Late NCS responses, such as the H reflex and F wave, are among the most sensitive indicators of peripheral nerve disease [5]. According to Fisher [6], the H reflex may be abnormal in cases of polyneuropathy, even when distal studies are unremarkable. Since Dr. Ersoz did not measure H wave reflexes, he may have lessened the sensitivity of his testing. This is of more than academic interest, since FMS patients included in this kind of study would be expected to have rather subtle nerve abnormalities (i.e., gross abnormalities would exclude the subject as an example of ‘‘secondary’’ FMS). We also felt that the statistical analysis Dr. Ersoz applied to his population data may have hindered his finding a difference between his FMS patients and controls. It is likely, for example, that he was not dealing with normally distributed data points in these groups (the distribution of data points for all FMS subjects’ NCS, including those found to be abnormal, would be skewed and therefore distributed in a nonGaussian fashion). Therefore, nonparametric analysis of these small groups would be more likely to pick up a small but true difference in means. Although we are aware that the use of the t-test on nonparametric data is allowed when the sample size is large enough, Dr. Ersoz might have been better served with the Mann-Whitney test here. We tried to determine if Dr. Ersoz’s study had adequate statistical power to find a small significant X. J. Caro (&) UCLA School of Medicine, Los Angeles, Calif., USA E-mail: xjcaro@earthlink.net

Reply: To PMID 24719395.

tors, resembling that in small-fiber neuropathy (SFN), in the majority of patients with FM (23 of 30). The role of SFN in FM might be better defined considering that there is heterogeneity in this feature; for instance, it could be speculated that small-fiber damage represents an initiating event in some (but not all) patients with FM. Alternatively, it is possible that some patients in whom FM is diagnosed are instead affected by SFN with clinical features mimicking FM. Indeed, widespread pain and sensory symptoms can be a feature of non–length-dependent SFN (7,8). Muscle pain, a main symptom of patients with FM, may also be present in SFN, possibly related to involvement of intramuscular nerve fibers (9). Thus, SFN recently has been implicated in patients whose main symptoms are cramps and myalgia (10). Caro and Winter also evaluated whether degeneration of small nerve fibers occurred in a length-dependent pattern and concluded that although the loss of small nerve fibers was diffuse, distal sites were preferentially affected. Again, this should be reassessed in individual cases. Because the overall mean SD thigh-to-calf ENFD ratio was 1.9 1.0, it is evident that, in at least some patients, proximal fiber loss was greater than, or at least equal to, distal loss, configuring a non–length-dependent pattern more compatible with the widespread pain symptoms of FM. This contrasts with the clinical findings of a “stocking distribution” and diminished pinwheel and vibratory perception in all patients. The relevance of these data is arguable, however, because the data were not precisely quantified, and considerable variability of responses (especially for vibration sense [11]) is usually observed in normal subjects. Although patients with conditions potentially causing polyneuropathy were excluded, 9 patients with FM also had rheumatoid arthritis, which is a condition that is significantly associated with neuropathy (12). In addition, the presence of a relevant number of cases of rheumatoid arthritis in this series could entail a bias with regard to the immunologic findings, e.g., the inverse correlation between serum IL-2R levels and calf ENFD.