In a large series of adult and pediatric patients with juvenile-onset, unexplained, chronic widespread pain, more than half met rigorous, multi-test diagnostic criteria for small-fiber polyneuropathy (SFPN), according to a report in the April issue of Pediatrics. This finding, said lead author Anne Louise Oaklander, MD, PhD, extends the age range of acquired SFPN into young adulthood, adolescence, and even early childhood.
Dr. Oaklander and coauthor Max M. Klein, PhD, both affiliated with Massachusetts General Hospital and Harvard Medical School in Boston, evaluated 41 consecutive patients with unexplained widespread pain beginning before age 21. Most had extensive medical records that were extracted for the results of objective diagnostic testing for SFPN, which consisted of neurodiagnostic skin biopsy, nerve biopsy, and autonomic function testing. Secondary information came from subjects’ histories, symptoms, examinations, all other tests, and treatments. Healthy, demographically matched volunteers served as controls for SFPN tests.
“We chose for this initial characterization paper to focus on the youngest group with this disease, because they lacked potentially confounding conditions,” Dr. Oaklander told Neurology Reviews. “It can be hard to ascertain the specific cause of peripheral neuropathy in older adults because they have so many potentially neuropathic exposures and conditions. Here, by focusing on children, we were able to study a pure population in whom exposure to alcohol, toxins, nutritional deficiencies, cancer, and diabetes, were absent. The high signal-to-noise ratio enabled us to home in on the likelihood of autoimmune causality in most. Because of the different age-range and causality, we call this juvenile-onset small-fiber polyneuropathy, or JOSeFINE, to distinguish it from classical SFPN of older adults.”
Subjects included children from other countries and various races, demonstrating that JOSeFINE is present outside the US. Seventy-three percent of patients were female. Nearly 70% had been chronically disabled from school or work, and the same number (68%) had hospitalizations. Objective testing diagnosed definite SFPN in 59% and probable SFPN in 17%. Only one of the 41 subjects had entirely normal SFPN test results. Ninety-eight percent of patients also had other complaints thought to represent autonomic symptoms of SFPN (90% had cardiovascular, 82% had gastrointestinal, and 34% had urologic complaints). In addition, 83% reported chronic fatigue and 63% had chronic headache. Neurologic examinations identified reduced sensation in 68% and vasomotor abnormalities in 55%, including 23% with the erythromelalgia variant that produces areas of redness and burning that patients treat by cooling.
In addition, this study investigated the underlying causes of SFPN in this cohort. Several lines of evidence suggested immunologic problems. For example, past histories for 33% of subjects were notable only for history of other autoimmune illness, and extensive blood and urine tests revealed only serologic markers of disordered immunity in 89% of patients. In addition, some patients improved after immunomodulatory treatments. Corticosteroids or IV immune globulin objectively and subjectively benefited 12 of 15 patients (80%).
“This case series provides a new hypothesis about juvenile-onset, unexplained, acquired chronic widespread pain syndromes, implicating acquired SFPN, a biologically plausible diagnosis not previously recognized in children,” Drs. Oaklander and Klein wrote in their published paper. The data, they contend, suggest that SFPN can develop in children as young as preschool age and that juvenile-onset SFPN can persist for decades into adulthood.
“I would like to emphasize that this is not a disease only of children,” said Dr. Oaklander. “In fact, most patients were young adults by the time they reached us for diagnosis. Additionally, we have other patients who were not included in this study whose illness began when they were in their 20s, 30s, and even 40s. We have one older man in his 60s, but clearly the age range of JOSeFINE is different from the type of neuropathy that we associate with diabetes, cancers, and toxic exposures.
“Perhaps the most common label for these patients was pediatric fibromyalgia,” Dr. Oaklander continued. “Others had been called sero-negative Lyme or other vague descriptors. Basically, these are patients who kick around every hospital and pain clinic without a diagnosis. Now, for the first time, we’re offering a framework in which to organize care, with recommended examinations to perform, recommended diagnostic tests, and nonrecommended diagnostic tests—lumbar puncture is not useful, MRI is not useful. We homed in on the tests that are useful—skin biopsy, autonomic function testing—and we identified the blood tests that were most likely to provide supportive evidence—four specific blood tests associated with dysimmunity. Having a specific diagnosis to test for and treat when present may reduce ineffective, costly, and potentially harmful tests and treatments and permit objective testing and definitive treatment of some patients.”