A new study of childhood-onset chronic pain could change the way that clinicians evaluate and treat unexplained pain in kids. Anne Louise Oaklander and Max Klein of the Massachusetts General Hospital in Boston, US, found that 59 percent of 41 young patients they studied with unexplained, widespread chronic pain could be diagnosed with small-fiber peripheral neuropathy, and another 17 percent were classified as “probable” cases.
Adult-onset small-fiber peripheral neuropathy is a well-known cause of chronic pain in middle age and beyond, but “the idea that previously healthy children, teens, and young adults could develop this is somewhat of a new concept,” Oaklander said. She hopes that the characterization of this syndrome, which the authors call juvenile-onset small-fiber neuropathy, or JOSeFiNE, will influence the way that pediatricians think about pain, and offer them a roadmap for diagnosis and possible treatment of SFPN.
Christopher Klein, a neurologist at the Mayo Clinic in Rochester, Minnesota, US, who was not involved in the study (and is no relation to study author Max Klein), said the authors should be commended for searching for the roots of unexplained, debilitating pain in children. “It’s a serious attempt to ascertain the potential organic cause of the kids’ pain,” he said.
The report was published March 11 in Pediatrics.
In older adults, SFPN is most often caused by diabetes, vitamin deficiency, cancer, or chemotherapy, and involves the loss of the small, mostly unmyelinated sensory and autonomic nerve axons in the peripheral nervous system, which notably include the pain-sensing cells. Patients often suffer from widespread chronic pain, and may have autonomic disturbances as well. An objective diagnosis of SFPN is made by skin biopsy showing loss of nociceptive epidermal nerve fibers and by tests of autonomic function (heart rate regulation and other tests). But this sort of diagnosis is not usually considered in patients whose chronic widespread pain began in childhood or adolescence.
In 2007, Oaklander described a formerly healthy 20-year-old man who developed erythromelalgia—burning pain with redness and swelling of his hands and feet. She diagnosed SFPN (Paticoff et al., 2007). After that, she said, “[physicians] started sending me more and more cases” of what looked like SFPN in juveniles from around the US and the world. “I thought, ‘I’d better start keeping track of these cases,’” she said. “Through that process, it became clear to me that this was a distinct syndrome.”
In the new study, Oaklander and Max Klein systematically analyzed all the clinical data from 41 patients, who had all been under age 21 when their pain began. Based on results of objective measures including skin and nerve biopsies and physiological measures of autonomic function, more than half of the patients met diagnostic criteria for SFPN (frankly abnormal measure on at least one definitive test), and most of the rest were categorized as probable or possible cases (mildly abnormal results on one or more tests). In only one patient were the tests entirely normal.
Christopher Klein raised the point that they might have made a diagnosis in even more subjects had they included quantitative sensory testing (QST). “Some patients might have normal test results in [biopsy and autonomic tests] because those tests measure loss of function, but they don’t measure exaggerated function, like [sensory] nerve hyperexcitability,” which can also be a feature of SFPN, Klein said. Oaklander agreed that QST might indeed have expanded the SFPN diagnosis to more patients, but she wanted this initial characterization to be as rigorous as possible by including only objective tests. Although informative, QST relies on patients’ subjective report of sensation.
Although the authors themselves conducted many of the skin biopsies, all of the autonomic function testing and most of the wealth of additional tests came from the extensive medical records accrued by these children over the years at other academic medical centers. “These were very sick kids, and their parents were diligent about seeking medical help for them,” said Oaklander. In the quest for diagnosis and treatment, the children underwent countless tests. In some cases, she said, “they had pretty much been subjected to all possible tests and treatments.” Finding out which tests had or had not been informative was a goal for the researchers, considering that some of the tests pose significant risks to children, and are expensive. “MRI was not helpful, spinal tap was not helpful,” said Oaklander. Strikingly, most other tests for neuropathy—including nerve-conduction tests and electromyography—did not even hint at the condition in the kids.
Some patterns did emerge from the medical histories. A third of the patients had a history of autoimmune disease, and many more displayed immune-related abnormalities on blood tests. “This paper shows again that autoimmunity may be important” in neuropathic pain, said Christopher Klein, an idea that has recently emerged in adults but is new for children. In some of the children, tests detected autoantibodies to voltage-gated potassium channels (VGKC) or N-type calcium channels—molecules that have recently been implicated in chronic pain (see PRF related news story).
And for some of the patients, their pain and other symptoms were improved or even cured by corticosteroids or immune globulin—therapies that modulate the immune system. But Oaklander cautioned physicians not to assume that such treatment would be appropriate for all cases of childhood pain, or even SFPN. “These are serious medications with serious side effects,” said Oaklander. “We’d like to encourage consideration and appropriate evaluation of the patients. We certainly don’t want the pendulum to swing the other way,” she said, and lead to random use of immunotherapy.
Oaklander says this report is by no means the final word on JOSeFiNE, but rather it offers a starting point to consider neuropathy in young people. “Once you’ve seen these cases are possible, it opens your eyes. And when you see [patients] improve with treatment, it makes a believer out of you, especially considering there are no competing theories or effective treatments,” she said. “Already, some physicians have become aware [of the work] and modified their practice accordingly” by considering the diagnosis of small-fiber polyneuropathy in their young patients, she said.
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