Small Fiber Neuropathy Rising in the US, But Why Is a Mystery

Megan Brooks

November 03, 2021

Over the past two decades, there has been a significant increase in the number of adults in the United States with small fiber neuropathy (SFN), but in many cases, no cause can be determined.

The exact reason for the increase in isolated SFN "remains unclear," Christopher J. Klein, MD, of the Mayo Clinic in Rochester, Minnesota, told Medscape Medical News.

However, "we noted during the study period the population has had increased BMI, which appears to be a risk factor for this disorder, with many (50%) developing either glucose impairment or frank diabetes during the study period even if not present at first small fiber neuropathy presentation, also with associated higher triglyceride levels," he explained.

The study was published online October 27 in Neurology.

Significant Upward Trend

Investigators reviewed the records of all 94 adults diagnosed with pure SFN (no large fiber involvement) between 1998 and 2017 in Olmsted and adjacent counties in Minnesota — and compared them with 282 adults of similar age and gender who did not have neuropathy.

The incidence of SFN over the entire study period was 1.3 per 100,000 per year and the prevalence was 13.3 per 100,000.

There was a "significant upward trend" in SFN incidence over the study period that could not be attributed to the availability of intraepidermal nerve fiber density testing, the authors report.

The median age of onset of SFN was 54 years and two thirds were women (67%).

Diabetes, obesity, and hypertriglyceridemia were significantly more common in patients with SFN compared with matched controls. These metabolic risk factors are also associated with peripheral neuropathy regardless of fiber type.

Autonomic symptoms were common and generally mild, affecting 85% of patients with SFN, and included male erectile dysfunction, constipation, light-headedness and palpitations, urinary symptoms, diarrhea, dry eyes and mouth, sweat abnormalities, and gastroparesis.

Insomnia and use of opioid pain medication were more common in those with SFN than matched controls.

More than one third (36%) of patients with SFN developed large fiber neuropathy an average of 5.3 years after developing SFN.

During an average follow-up of 6.1 years, adults with SFN were significantly more likely to suffer myocardial infarction (46% vs 27%; odds ratio [OR] 2.0; 95% CI, 1.8 - 4.9), congestive heart failure (27% vs 12%; OR, 2.6; 95% CI, 1.4 - 4.8), peripheral vascular disease (22% vs 6%; OR, 4.0; 95% CI, 1.9 - 8.1), stroke (24% vs 10%; OR, 2.8; 95% CI, 1.5 - 5.3), diabetes (51% vs 22%; OR, 4.6; 95% CI, 2.8 - 7.6) and rheumatologic disease (30% vs 7%; OR, 5.3; 95% CI, 2.8 - 10.4).

For 70% of patients, no cause for SFN could be determined. Diabetes (15%) was the most common cause identified. Other less common causes included Sjögren syndrome, lupus, amyloidosis, and Fabry disease.

"It is important to quantitatively diagnose patients with SFN as many non-neurological musculoskeletal causes can mimic the disorder," said Klein.

"If rates of progression are rapid, sinister causes such as out-of-control diabetes, hereditary [transthyretin] TTR amyloidosis, and Fabry disease can be responsible. For other patients, rates of progression are slow and generally do not lead to significant neurologic impairments," he added.

"However," he said, "internal medicine follow-up is important for all as this disorder associates with development with higher risk of cardiovascular disease, including commonly heart attacks."

Of note, although mean age at death was not significantly different in patients with SFN than controls (70 vs 73 years), there was a significantly higher number of deaths in patients with SFN (n = 18; 19%) than in matched controls (n = 35; 12%) from the time of symptom onset, the researchers report.

Important Research

This "important" study sheds light on the comorbidities and longitudinal consequences of SFN, write Brian Callaghan, MD, with the University of Michigan, Ann Arbor, and J. Robinson Singleton, MD, with the University of Utah, Salt Lake City, in an accompanying editorial in Neurology.

The study demonstrates clearly that SFN has "metabolic risk factors similar to those seen for sensory predominant peripheral neuropathies affecting a broader range of fiber types. As a result, therapies that address metabolic risk factors are likely to help prevent or treat both conditions," they write.

Callaghan and Singleton add that a key strength of the study is the detailed follow-up that examines SFN progression over time.

"The authors found that patients with SFN do not report high disability and that progression tends to be slow. Therefore, patients with SFN can be counseled that progression and disability are likely to be modest in most cases. However, when patients do progress quickly, uncommon etiologies should be sought," the editorialists write.

The study was supported by the Mayo Clinic Foundation, Mayo Clinic Center for Individualized Medicine, and Mayo Clinic Center of MS and Autoimmune Neurology. Klein has received teaching honorarium from Ackea pharmaceuticals for lectures on hereditary transthyretin amyloidosis and Fabry disease, consulted for Pfizer regarding tafamidis (all compensation for consulting activities is paid directly to Mayo Clinic), and participated in the clinical trials for inotersen and patisiran but received no personal compensation for his participation. Callaghan consults for DynaMed, performs medical legal consultations including consultations for the Vaccine Injury Compensation Program, and receives research support from the American Academy of Neurology. Singleton has consulted for Regenacy.

Neurology. Published online October 27, 2021. Abstract, Editorial

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