title: Burning pain: axonal dysfunction in erythromelalgia.
abstract: Erythromelalgia (EM) is a rare neurovascular disorder characterized by intermittent severe burning pain, erythema, and warmth in the extremities on heat stimuli. To investigate the underlying pathophysiology, peripheral axonal excitability studies were performed and changes with heating and therapy explored. Multiple excitability indices (stimulus-response curve, strength-duration time constant (SDTC), threshold electrotonus, and recovery cycle) were investigated in 23 (9 EMSCN9A+ and 14 EMSCN9A-) genetically characterized patients with EM stimulating median motor and sensory axons at the wrist. At rest, patients with EM showed a higher threshold and rheobase (P < 0.001) compared with controls. Threshold electrotonus and current-voltage relationships demonstrated greater changes of thresholds in both depolarizing and hyperpolarizing preconditioning electrotonus in both EM cohorts compared with controls in sensory axons (P < 0.005). When average temperature was raised from 31.5°C to 36.3°C in EMSCN9A+ patients, excitability changes showed depolarization, specifically SDTC significantly increased, in contrast to the effects of temperature previously established in healthy subjects (P < 0.05). With treatment, 4 EMSCN9A+ patients (4/9) reported improvement with mexiletine, associated with reduction in SDTC in motor and sensory axons. This is the first study of primary EM using threshold tracking techniques to demonstrate alterations in peripheral axonal membrane function. Taken together, these changes may be attributed to systemic neurovascular abnormalities in EM, with chronic postischaemic resting membrane potential hyperpolarization due to Na/K pump overactivity. With heating, a trigger of acute symptoms, axonal depolarization developed, corresponding to acute axonal ischaemia. This study has provided novel insights into EM pathophysiology.
authors.affiliation: Department of Neurology, Sydney Children's Hospital and School of Women's and Children's Health, University of New South Wales, Sydney, Australia.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Farrar
authors.affiliation: Department of Neurology and Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Brain and Mind Centre, The University of Sydney, Sydney, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Howells
authors.affiliation: Department of Neurology, Sydney Children's Hospital and School of Women's and Children's Health, University of New South Wales, Sydney, Australia.
authors.forename: Peter I
authors.initials: PI
authors.lastname: Andrews
authors.affiliation: Translational Neuroscience Facilities (TNF), Department of Physiology, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Randwick, Sydney, Australia.
authors.forename: Cindy S-Y
authors.initials: CS
authors.lastname: Lin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001369:Axons / Q000473:pathology* / Q000502:physiology*; D016022:Case-Control Studies; D002648:Child; D003198:Computer Simulation; D004916:Erythromelalgia / Q000150:complications* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics; D009431:Neural Conduction / Q000235:genetics; D010146:Pain / Q000209:etiology* / Q000473:pathology*; D012720:Severity of Illness Index; D013696:Temperature; D055815:Young Adult
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human