Faignart N, Nguyen K, Soroken C, Poloni C, Downs HM , et al.
European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society •
The small-fiber polyneuropathies (SFN) are a class of diseases in which the small thin myelinated (Aδ) and/or unmyelinated (C) fibers within peripheral nerves malfunction and can degenerate. SFN usually begins in the farthest, most-vulnerable axons, so distal neuropathic pain and symptoms from microvascular dysregulation are common. It is well known in adults, e.g. from diabetes, human immunodeficiency virus, or neurotoxins, but considered extremely rare in children, linked mostly with pathogenic genetic variants in voltage-gated sodium channels. However, increasing evidence suggests that pediatric SFN is not rare, and that dysimmunity is the most common cause. Because most pediatric neurologists are unfamiliar with SFN, we report the diagnosis and management of 5 Swiss children, aged 6-11y, who presented with severe paroxysmal burning pain in the hands and feet temporarily relieved by cooling-the erythromelalgia presentation. Medical evaluations revealed autoimmune diseases in 3 families and 3/5 had preceding or concomitant infections. The standard diagnostic test (PGP9.5-immunolabeled lower-leg skin biopsy) confirmed SFN diagnoses in 3/4, and autonomic function testing (AFT) was abnormal in 2/3. Blood testing for etiology was unrevealing, including genetic testing in 3. Paracetamol and ibuprofen were ineffective. Two children responded to gabapentin plus mexiletine, one to carbamazepine, two to mexiletine plus immunotherapy (methylprednisolone/IVIg). All recovered within 6 months, remaining well for years. These monophasic tempos and therapeutic responses are most consistent with acute post-infectious immune-mediated causality akin to Guillain-Barré large-fiber polyneuropathy. Skin biopsy and AFT for SFN, neuropathic-pain medications and immunotherapy should be considered for acute sporadic pediatric erythromelalgia.
We tested the hypothesis that acquired small-fiber polyneuropathy (SFPN), previously uncharacterized in children, contributes to unexplained pediatric widespread pain syndromes. Forty-one consecutive patients evaluated for unexplained widespread pain beginning before age 21 had medical records comprehensively analyzed regarding objective diagnostic testing for SFPN (neurodiagnostic skin biopsy, nerve biopsy, and autonomic function testing), plus histories, symptoms, signs, other tests, and treatments. Healthy, demographically matched volunteers provided normal controls for SFPN tests. Age at illness onset averaged 12.3 ± 5.7 years; 73% among this poly-ethnic sample were female (P = .001). Sixty-eight percent were chronically disabled, and 68% had hospitalizations. Objective testing diagnosed definite SFPN in 59%, probable SFPN in 17%, and possible SFPN in 22%. Only 1 of 41 had entirely normal SFPN test results. Ninety-eight percent of patients had other somatic complaints consistent with SFPN dysautonomia (90% cardiovascular, 82% gastrointestinal, and 34% urologic), 83% reported chronic fatigue, and 63% had chronic headache. Neurologic examinations identified reduced sensation in 68% and vasomotor abnormalities in 55%, including 23% with erythromelalgia. Exhaustive investigations for SFPN causality identified only history of autoimmune illnesses in 33% and serologic markers of disordered immunity in 89%. Treatment with corticosteroids and/or intravenous immune globulin objectively and subjectively benefited 80% of patients (12/15). More than half among a large series of patients with childhood-onset, unexplained chronic widespread pain met rigorous, multitest, diagnostic criteria for SFPN, which extends the age range of acquired SFPN into early childhood. Some cases appeared immune-mediated and improved with immunomodulatory therapies.