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Small-Fiber Polyneuropathy May Cause Chronic Widespread Pain in Children

Fitzgerald, Susan

doi: 10.1097/
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More than half among a large series of patients with childhood-onset, unexplained chronic widespread pain met diagnostic criteria for small-fiber polyneuropathy — some of which appeared immune-mediated and improved with immunomodulatory therapies.

Some children and young adults who develop unexplained chronic widespread pain may have small-fiber polyneuropathy, according to researchers at Massachusetts General Hospital (MGH) who reviewed the medical records of 41 patients evaluated at the medical center. This newly reported juvenile-onset polyneuropathy appeared to be immune-mediated in many cases and those patients tended to improve after immunomodulatory therapies, the researchers reported in the April edition of the journal Pediatrics.

“More than half of a large series of patients with childhood-onset, unexplained chronic widespread pain met rigorous, multi-test, diagnostic criteria for small-fiber polyneuropathy [SFPN], which extends the age range of acquired SFPN into early childhood,” the researchers wrote.

Anne Louise Oaklander, MD, PhD, who co-authored the report, told Neurology Today that many of the young patients had bounced from doctor to doctor and diagnosis to diagnosis, all the meanwhile experiencing pain and other debilitating symptoms, hospitalizations, and missed time from school or work.

“The challenge with this condition is that these nerves go everywhere in the body and even though SFPN is a neurological disease it presents with a lot of different symptoms that are not immediately appreciated as neurological,” such as dizziness and fainting, nausea, vomiting, and sometimes intractable constipation, said Dr. Oaklander, an associate professor of neurology and assistant professor of neuropathology at MGH and Harvard Medical School, who coauthored the report with Max M. Klein, PhD, a research fellow in neurology at MGH and a clinical instructor at Harvard. Dr. Oaklander is also a member of the Neurology Today editorial advisory board.

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For the current report, the research pair analyzed medical records for 41 consecutive patients seen at MGH from 2007 to 2011. The records contained results of diagnostic testing for SFPN as well as other tests, and patient histories, symptoms and treatments.

To be diagnosed with SFPN, patients had to have abnormal results for one of three tests used to diagnose SFPN — neurodiagnostic skin biopsy, surgical nerve biopsy, and autonomic function tests. (The researchers used healthy demographically-matched volunteers as “normal controls” so they could compare their testing results to the patients.)

According to the published report, objective testing diagnosed definite SFPN in 59 percent of patients, probable in 17 percent, and possible SFPN in 22 percent. Only one of 41 patients had entirely normal SFPN test results.

Medical records also revealed that about one-third of the patients had a personal history of autoimmune illness and about half had family histories of autoimmunity. Serological markers of disordered immunity — in particular low levels of complement — were identified in 89 percent of patients, the report said. Treatment with corticosteroids and/or immune globulin “objectively and subjectively benefitted 80 percent of patients,” the report said.

Dr. Oaklander said SFPN is certainly not the cause of all unexplained chronic pain in children, but she said that if physicians “don't find evidence of a usual medical cause they should consider the possibility of small-fiber polyneuropathy and refer patients for evaluation rather than wasting time and money with random tests and treatments.”

She cautioned, however, that the findings in the report should be regarded as preliminary and need to be subject to further investigation.

The report in Pediatrics will likely to be met with some questioning by pediatricians and neurologists, in part because the findings are not based on a randomized controlled clinical trial but rather on a retrospective review of patient records. All patients included in the study had been referred to Dr. Oaklander for evaluation, creating “referral bias, which likely elevated the prevalence of SFPN,” reported Dr. Oaklander and coauthor.



“The data suggest that SFPN can develop even in preschool-age children and that juvenile-onset SFPN persist for decades into adulthood,” the researchers concluded. Dr. Oaklander said she has applied for NIH funding to establish a patient registry that would collect prospective data for what she is calling “juvenile-onset small-fiber polyneuropathy, or JOSeFINE.” She said further study of SFPN in children will help “reduce ineffective, costly, and potentially harmful tests and treatments and permit objective testing and definite treatment of some patients.”

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Wolfgang Singer, MD, assistant professor of neurology at the Mayo Clinic in Rochester, MN, told Neurology Today that he was concerned when he read the Pediatrics report because he did not believe that all of the conclusions were necessarily well supported by the evidence presented. “I think we need to be very careful in interpreting these results,” he said.

Dr. Singer noted that normative values for children have not been established for some of the tests used to make the SFPN diagnosis, such as the tests to measure sweat production and autonomic function. Without well-established normative values to use for comparison, it's difficult to say whether the patients in the study tested truly abnormal, he said. He noted that over a third of healthy volunteers used in the study as controls also were reported to have abnormalities on these tests.

“While the frequency of abnormalities was reported to be higher among patients than healthy volunteers, factors other than small-fiber neuropathy could be responsible for this, such as medication effects and deconditioning,” Dr. Singer said. “The evidence to support an immune-mediated process is not well supported at this point and the effects of steroids in the treatment of pain are non-specific.

“My biggest concern about the report is that pediatricians who see a child with chronic pain syndrome may now quickly assume an immune-mediated neuropathy and start the patient on steroids, with all their potential negative effects,” he said.

According to background information in the current report, polyneuropathy has been believed to be rare in children, consisting of occasional cases of acute Guillain-Barré and chronic demyelinating polyneuropathy (CIDP) caused by immune attack on large myelinated motor axons.

John England, MD — Grace Benson professor of neurology and neuroscience and head of the department of neurology at Louisiana State University Health Sciences Center — told Neurology Today, however, that the study is important “because it's the first paper we have that really identifies what could be construed as small-fiber polyneuropathy syndrome in children.”

Dr. England said that both pediatric and adult patients with unexplained chronic pain are sometimes “dismissed as having psychiatric problems.” He said this paper should help raise awareness on the part of clinicians that a small-fiber polyneuropathy may be a possibility. “If there is a question, the patients should be evaluated by a specialty center with neurologists, pediatric neurologists and pain specialists,” he said.

Still, Dr. England said that research is needed and he cautioned against physicians over interpreting the findings of this preliminary research. “It would be a mistake to think this is an explanation for all pain syndromes,” Dr. England said. “I would suspect this is a pretty rare syndrome. Even at this top referral center (MGH), they only had 41 patients referred from all over.”

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•. Oaklander AL, Klein MM. Evidence of small-fiber polyneuropathy in unexplained, juvenile-onset, widespread pain syndrome. Pediatrics 2013;131(4):e1091–1100. E-pub 2013 Mar 11.
    •. Neurology Today archive on polyneuropathy:
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