Introduction

Fibromyalgia syndrome and small fiber neuropathy are two distinct pain conditions, but they may be difficult to distinguish. Electrophysiological examinations have revealed distinct characteristics in nerve conduction, although the two conditions show commonalities in clinical presentation. Fibromyalgia syndrome is often described as a deeply located chronic widespread pain condition that often goes along with depression and fatigue. On the other hand, small fiber neuropathy leads to more superficial burning pain in the distal extremities (and nails, nose, and ears) often accompanied by sensory disturbances and autonomic dysfunction. Based on these descriptions, it seems that the two are easily distinguishable. Yet, differential diagnosis can be challenging due to the shared commonalities and overlapping symptoms. Both conditions involve chronic pain, which can make it difficult to differentiate between them based solely on subjective reports from patients. Additionally, there is a lack of specific diagnostic tests, further complicating the differentiation process. The current study we review here wanted to investigate whether there are clinical examination findings for distinguishing fibromyalgia from small fiber neuropathy.

Methods

In this retrospective study, two distinct clinical cohorts were analyzed. These included 158 women with fibromyalgia syndrome and 53 with small fiber neuropathy. The participants did not have polyneuropathy, based on normal neurological and nerve conduction exams.

Diagnosing fibromyalgia syndrome was based on the diagnostic criteria by the American College of Rheumatology, and the diagnostic criteria for small fiber neuropathy were based on Devigili et al. (2008).

The characteristics of pain were described in terms of character, intensity, location, radiation, onset, relieving, and aggravating factors. Pain intensity was rated on a 0-10 numeric rating scale. Pain questionnaires were filled and included:

• Neuropathic Pain Symptom Inventory (NPSI)
• Graded Chronic Pain Scale (GCPS)
• Pain Catastrophizing Scale (PCS)
• Pain chronicity was rated on the Mainz Pain Staging System (MPSS)
• For depressive symptoms, the “Allgemeine Depressionsskala” (ADS) was administered

A general medical assessment was held that registered comorbidities, family history, and laboratory data. Further, the participants’ small nerve fiber functions were examined by a wide array of specialized tests:

• Intraepidermal nerve fiber density (IENFD) quantified on 6-mm skin punch biopsies taken from the lower leg and upper thigh
• Corneal nerve fiber length (NFL), density (NFD), and branching (NFB) determined by corneal confocal microscopy (CCM)
• Individual sensory profiles established by quantitative sensory testing (QST) at the dorsal foot
• Latencies and peak-to-peak amplitudes (PPA), when recording pain-related evoked potential (PREP) at the feet

Results

The characteristics of the included participants can be seen in the table below. What emerges here is that the onset of symptoms occurs at a younger age and the diagnosis of fibromyalgia syndrome is established at a younger age compared to the diagnosis of small fiber neuropathy.

The results indicate that distinguishing fibromyalgia from small fiber neuropathy may be possible based on the following findings:

• People with fibromyalgia syndrome reported less frequent burning (41.8% vs 84.9%) and stabbing pain (24.7% vs 66%) compared to those with small fiber neuropathy.
• Fibromyalgia patients described their pain as widespread muscle soreness, while pain in those with small fiber neuropathy had more distal pain.
• Warmth, rest and physical activity alleviated pain in fibromyalgia syndrome whereas cold and stress evoked pain. Contrastingly, people with small fiber neuropathy indicated that cold, warmth and touch could be both painful and pain relieving. Those with fibromyalgia syndrome reported more aggravating factors compared to those with small fiber neuropathy.

Using the questionnaires, it emerged that the NPSI pressure score, the evoked pain score and the GCPS pain intensity score were best at distinguishing fibromyalgia from small fiber neuropathy. However significant differences were found between the two patient groups, the ranges of scores widely overlap.

When we take a look at the reported comorbidities, people with fibromyalgia syndrome more often report additional symptoms (median of 8) compared to those with small fiber neuropathy (median of 4). The symptoms that people with fibromyalgia syndrome report more compared to people with small fiber neuropathy include:

• Gastrointestinal symptoms
• Urogenital symptoms
• Sleep problems
• Fatigue
• Apathy
• Cognitive impairment or problems of attention
• Depressed mood

Contrastingly, people with small fiber neuropathy more often than people with fibromyalgia syndrome report paresthesias such as tingling, numbness, and hypersensitivity to touch.

The family history of people with fibromyalgia syndrome revealed that mental disorders and chronic pain were mostly present in family members. On the other hand, they had fewer family members suffering from neurological diseases than patients who had small fiber neuropathy.

Another finding was that people with small fiber neuropathy often had an impaired glucose metabolism, resulting in higher HbA1c levels and higher blood glucose levels.

People with small fiber neuropathy had less frequently attempted to reduce symptoms through the use of pharmacological and nonpharmacological means compared to people suffering from fibromyalgia syndrome.

In people with small fiber neuropathy, the neurological examination revealed more sensory abnormalities in thermal hypoesthesia. Quantitative sensory testing showed a small fiber impairment in 35% of people with small fiber neuropathy while this was only 15% in those with fibromyalgia syndrome. Those with small fiber neuropathy were different in cold detection and pain thresholds, mechanical detection and pain thresholds and pain pressure threshold.

• People with fibromyalgia detected cold temperatures when these were -2.2 degrees Celsius while people with small fiber neuropathy detected cold only at -3.9 degrees Celsius.
• The threshold when cold became pain was 16° Celsius in fibromyalgia patients while this was 11° in people with small fiber neuropathy.
• More pressure was required before people with small fiber neuropathy detected it (4.9 mN) compared to people with fibromyalgia (2.1 mN)
• This pressure became painful at 27.9 mN in people with small fiber neuropathy while it only became painful at 59.7 mN in those with fibromyalgia syndrome.
• A lower pain pressure threshold was seen in people with fibromyalgia syndrome (368 kPa) versus people with small fiber neuropathy (441 kPa).

On the other hand, proximal intraepidermal nerve fiber density (IENFD) was reduced more in fibromyalgia syndrome, but the distal fiber density did not differ between both conditions.

Questions and thoughts

Distinguishing fibromyalgia from small fiber neuropathy can be possible when we consider the following rules of thumb.

• At symptom onset, people with fibromyalgia syndrome tend to be on average 10 years younger than those with small fiber neuropathy
• Pain characteristics reveal more burning/stabbing pain with small fiber neuropathy while pain in fibromyalgia is more described as muscle soreness-like pain
• Pain localization is widespread in fibromyalgia syndrome and more distal or acral in the extremities in small fiber neuropathy
• Cold and stress can trigger pain in fibromyalgia syndrome and physical activity, rest and warmth can give pain relief. In contrast, small fiber neuropathy patients report cold, warmth and touch as both pain-relieving and pain-triggering factors.
• Paresthesias such as tingling, numbness and hypersensitivity to touch are frequently reported symptoms in small fiber neuropathy, while this is infrequent in fibromyalgia syndrome
• Patients with fibromyalgia more frequently reported comorbidities such as gastrointestinal and urogenital symptoms, sleep problems and fatigue, apathy, cognitive impairments or problems of attention and depressed mood.
• Quantitative sensory testing may reveal differences when you compare people with small fiber neuropathy and fibromyalgia syndrome. These are more often pathological in small fiber neuropathy patients and reflect problems with peripheral afferent nerve fibers. When compared with normal values, the sensory testing was normal in almost all patients. Nonetheless, differences between both conditions existed. The authors indicated that this may be caused by the differences in included people in both patient groups.

This study was important because accurately distinguishing fibromyalgia from small fiber neuropathy is crucial for appropriate treatment and management. While fibromyalgia is primarily a central sensitization disorder characterized by widespread pain and tenderness, small fiber neuropathy is a peripheral neuropathy that affects the small nerve fibers responsible for transmitting pain signals. The underlying mechanisms and treatment approaches for these conditions differ, making an accurate diagnosis essential for providing targeted and effective interventions.

Mean disease duration differed largely between those with fibromyalgia syndrome and small fiber neuropathy, as can be seen in the baseline characteristics. This is logical since fibromyalgia symptoms occur nearly 10 years before the onset of symptoms arising from small fiber neuropathy. What is astonishing is the large delay in diagnosis of fibromyalgia. It took nearly 8 years before these women got diagnosed with fibromyalgia. Although the time to diagnosis was faster in small fiber neuropathy, it also took nearly 3 years before it was diagnosed. Physiotherapy can probably speed up this process by referring people who present with these characteristics to specialized care. Therefore, when you recognize these symptoms, you should be referring these people.

Talk nerdy to me

The study conducted a subgroup analysis based on symptom duration. It can be speculated that someone with a longer disease history can report more symptoms than someone who only just developed symptoms. Also because the participants were older when they got diagnosed with small fiber neuropathy you could speculate about this. On the other hand, those with fibromyalgia in this cohort lived with the disease for more than 15 years, while those with small fiber neuropathy with only 4 years. These differences could probably echo in the results. Therefore, it was important to do this subgroup analysis. This analysis revealed that after taking pain medication, people with fibromyalgia still had more pain than those diagnosed with small fiber neuropathy. They also had more additional symptoms, and pain-aggravating factors but also pain-relieving factors. Those with fibromyalgia had more often attempted nonpharmacological therapies and psychotherapies in the past. People with small fiber neuropathy had less intraepidermal nerve fiber density (IENFD) in the lower leg.

Having diabetes mellitus was an exclusion criterion, but this can also lead to the development of small fiber neuropathy. People with small fiber neuropathy had more often an impaired glucose metabolism. However, the authors noticed that their data on the prevalence of impaired glucose metabolism may be biased because previously diagnosed diabetes mellitus was an exclusion criterion.

The people with fibromyalgia and small fiber neuropathy in these cohorts received analgesic medications that were in accordance with the national and international guidelines, however, those with fibromyalgia often found no relief, resulting in numerous insufficient analgesic treatment attempts. People with small fiber neuropathy on the other hand, mostly could effectively relieve pain when prescribed anti-neuropathic pain treatment.

The results of this study are not generalizable to men, since only women were included.

Take home messages

Clinical examination findings for distinguishing fibromyalgia from small fiber neuropathy include more muscle soreness-like pain and widespread pain in fibromyalgia that is often accompanied by sleep problems, fatigue, concentration problems, and depressed mood.  Small fiber neuropathy leads to a more neuropathic pain phenotype and distal pain accompanied by additional paresthesias.

Reference

Jänsch S, Evdokimov D, Egenolf N, Meyer Zu Altenschildesche C, Kreß L, Üçeyler N. Distinguishing fibromyalgia syndrome from small fiber neuropathy: a clinical guide. Pain Rep. 2024 Jan 24;9(1):e1136. doi: 10.1097/PR9.0000000000001136. PMID: 38283649; PMCID: PMC10811691.  

Devigili G, Tugnoli V, Penza P, Camozzi F, Lombardi R, Melli G, Broglio L, Granieri E, Lauria G. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain. 2008 Jul;131(Pt 7):1912-25. doi: 10.1093/brain/awn093. Epub 2008 Jun 4. PMID: 18524793; PMCID: PMC2442424.