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Stephen G Waxman - One of the best experts on this subject based on the ideXlab platform.
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pediatric Erythromelalgia and scn9a mutations systematic review and single center case series
The Journal of Pediatrics, 2019Co-Authors: Luke Arthur, Kirsty Keen, Madeleine Verriotis, Judy Peters, Alison Kelly, Richard F Howard, Sulayman D Dibhajj, Stephen G Waxman, Suellen M WalkerAbstract:OBJECTIVES: To evaluate the clinical features of Erythromelalgia in childhood associated with gain-of-function SCN9A mutations that increase activity of the Nav1.7 voltage-gated sodium channel, we conducted a systematic review of pediatric presentations of Erythromelalgia related to SCN9A mutations, and compared pediatric clinical presentations of symptomatic Erythromelalgia, with or without SCN9A mutations. STUDY DESIGN: PubMed, Embase, and PsycINFO Databases were searched for reports of inherited Erythromelalgia in childhood. Clinical features, management, and genotype were extracted. Case notes of pediatric patients with Erythromelalgia from the Great Ormond Street Hospital Pain Service were reviewed for clinical features, patient-reported outcomes, and treatments. Children aged over 10 years were recruited for quantitative sensory testing. RESULTS: Twenty-eight publications described Erythromelalgia associated with 15 different SCN9A gene variants in 25 children. Pain was severe and often refractory to multiple treatments, including nonspecific sodium channel blockers. Skin damage or other complications of cold immersion for symptomatic relief were common (60%). SCN9A mutations resulting in greater hyperpolarizing shifts in Nav1.7 sodium channels correlated with symptom onset at younger ages (P = .016). Variability in reporting, and potential publication bias toward severe cases, limit any estimations of overall prevalence. In our case series, symptoms were similar but comorbidities were more common in children with SCN9A mutations. Quantitative sensory testing revealed marked dynamic warm allodynia. CONCLUSIONS: Inherited Erythromelalgia in children is associated with difficult-to-manage pain and significant morbidity. Standardized reporting of outcome and management in larger series will strengthen identification of genotype-phenotype relationships. More effective long-term therapies are a significant unmet clinical need.
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deletion mutation of sodium channel na v 1 7 in inherited Erythromelalgia enhanced slow inactivation modulates dorsal root ganglion neuron hyperexcitability
Brain, 2011Co-Authors: Xiaoyang Cheng, Sulayman D Dibhajj, Lynda Tyrrell, Rene Te H M Morsche, Joost P H Drenth, Stephen G WaxmanAbstract:Gain-of-function missense mutations of voltage-gated sodium channel NaV1.7 have been linked to the painful disorder inherited Erythromelalgia. These mutations hyperpolarize activation, slow deactivation and enhance currents evoked by slow ramp stimuli (ramp currents). A correlation has recently been suggested between the age of onset of inherited Erythromelalgia and the extent of hyperpolarizing shifts in mutant NaV1.7 channel activation; mutations causing large activation shifts have been linked to early age of onset inherited Erythromelalgia, while mutations causing small activation shifts have been linked to age of onset within the second decade of life. Here, we report a family with inherited Erythromelalgia with an in-frame deletion of a single residue—leucine 955 (Del-L955) in DII/S6. The proband did not show symptoms until the age of 15 years, and her affected mother only experienced mild symptoms during adolescence, which disappeared at the age of 38 years. Del-L955 shows no effect on NaV1.7 current density and fast inactivation, but causes an approximately −24 mV shift in activation, together with increases in amplitude of persistent currents and ramp currents. The mutation also produces an approximately −40 mV shift in slow inactivation, which reduces channel availability. Comparison of the effects of the Del-L955 mutation on dorsal root ganglion neuron hyperexcitability with those produced by another inherited Erythromelalgia mutation (L858F) that does not enhance slow inactivation suggests that a delayed age of onset and milder symptoms in association with a large shift of channel activation, enhanced persistent and enhanced ramp currents may be related to the approximately −40 mV shift in slow inactivation for Del-L955, the largest shift thus far demonstrated in mutant NaV1.7 channels. Our results suggest that despite the pivotal role of activation shift in inherited Erythromelalgia development, slow inactivation may regulate clinical phenotype by altering channel availability.
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early and late onset inherited Erythromelalgia genotype phenotype correlation
Brain, 2009Co-Authors: Sulayman D Dibhajj, Yong Yang, Lynda Tyrrell, Yan Li, Emmanuella M Eastman, Stephen G WaxmanAbstract:Inherited Erythromelalgia (IEM), an autosomal dominant disorder characterized by severe burning pain in response to mild warmth, has been shown to be caused by gain-of-function mutations of sodium channel Nav1.7 which is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons. Almost all physiologically characterized cases of IEM have been associated with onset in early childhood. Here, we report the voltage-clamp and current-clamp analysis of a new Nav1.7 mutation, Q10R, in a patient with clinical onset of Erythromelalgia in the second decade. We show that the mutation in this patient hyperpolarizes activation by only −5.3 mV, a smaller shift than seen with early-onset Erythromelalgia mutations, but similar to that of I136V, another mutation that is linked to delayed-onset IEM. Using current-clamp, we show that the expression of Q10R induces hyperexcitability in DRG neurons, but produces an increase in excitability that is smaller than the change produced by I848T, an early-onset Erythromelalgia mutation. Our analysis suggests a genotype–phenotype relationship at three levels (clinical, cellular and molecular/ion channel), with mutations that produce smaller effects on sodium channel activation being associated with a smaller degree of DRG neuron excitability and later onset of clinical signs.
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Mutation I136V alters electrophysiological properties of the Na_V1.7 channel in a family with onset of Erythromelalgia in the second decade
Molecular Pain, 2008Co-Authors: Xiaoyang Cheng, Lynda Tyrrell, Sulayman D Dib-hajj, Stephen G WaxmanAbstract:Background Primary Erythromelalgia is an autosomal dominant pain disorder characterized by burning pain and skin redness in the extremities, with onset of symptoms during the first decade in the families whose mutations have been physiologically studied to date. Several mutations of voltage-gated Na^+ channel Na_V1.7 have been linked with primary Erythromelalgia. Recently, a new substitution Na_V1.7/I136V has been reported in a Taiwanese family, in which pain appeared at later ages (9–22 years, with onset at 17 years of age or later in 5 of 7 family members), with relatively slow progression (8–10 years) to involvement of the hands. The proband reported onset of symptoms first in his feet at the age of 11, which then progressed to his hands at the age of 19. The new mutation is located in transmembrane segment 1 (S1) of domain I (DI) in contrast to all Na_V1.7 mutations reported to date, which have been localized in the voltage sensor S4, the linker joining segments S4 and S5 or pore-lining segments S5 and S6 in DI, II and III. Results In this study, we characterized the gating and kinetic properties of I136V mutant channels in HEK293 cells using whole-cell patch clamp. I136V shifts the voltage-dependence of activation by -5.7 mV, a smaller shift in activation than the other Erythromelalgia mutations that have been characterized. I136V also decreases the deactivation rate, and generates larger ramp currents. Conclusion The I136V substitution in Na_V1.7 alters channel gating and kinetic properties. Each of these changes may contribute to increased excitability of nociceptive dorsal root ganglion neurons, which underlies pain in Erythromelalgia. The smaller shift in voltage-dependence of activation of Na_V1.7, compared to the other reported cases of inherited Erythromelalgia, may contribute to the later age of onset and slower progression of the symptoms reported in association with this mutation.
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a nav1 7 channel mutation associated with hereditary Erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity
The Journal of Physiology, 2007Co-Authors: Patrick L Sheets, Sulayman D Dibhajj, Stephen G Waxman, James O Jackson, Theodore R CumminsAbstract:Mutations in the TTX-sensitive voltage-gated sodium channel subtype Nav1.7 have been implicated in the painful inherited neuropathy, hereditary Erythromelalgia. Hereditary Erythromelalgia can be difficult to treat and, although sodium channels are targeted by local anaesthetics such as lidocaine (lignocaine), some patients do not respond to treatment with local anaesthetics. This study examined electrophysiological differences in Nav1.7 caused by a hereditary Erythromelalgia mutation (N395K) that lies within the local anaesthetic binding site of the channel. The N395K mutation produced a hyperpolarized voltage dependence of activation, slower kinetics of deactivation, and impaired steady-state slow inactivation. Computer simulations indicate that the shift in activation is the major determinant of the hyperexcitability induced by Erythromelalgia mutations in sensory neurons, but that changes in slow inactivation can modulate the overall impact on excitability. This study also investigated lidocaine inhibition of the Nav1.7-N395K channel. We show that the N395K mutation attenuates the inhibitory effects of lidocaine on both resting and inactivated Nav1.7. The IC50 for lidocaine was estimated at 500 μm for inactivated wild-type Nav1.7 and 2.8 mm for inactivated Nav1.7-N395K. The N395K mutation also significantly reduced use-dependent inhibition of lidocaine on Nav1.7 current. In contrast, a different hereditary Erythromelalgia mutation (F216S), not located in the local anaesthetic binding site, had no effect on lidocaine inhibition of Nav1.7 current. Our observation of reduced lidocaine inhibition on Nav1.7-N395K shows that the residue N395 is critical for lidocaine binding to Nav1.7 and suggests that the response of individuals with hereditary Erythromelalgia to lidocaine treatment may be determined, at least in part, by their specific genotype.
Sulayman D Dibhajj - One of the best experts on this subject based on the ideXlab platform.
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pediatric Erythromelalgia and scn9a mutations systematic review and single center case series
The Journal of Pediatrics, 2019Co-Authors: Luke Arthur, Kirsty Keen, Madeleine Verriotis, Judy Peters, Alison Kelly, Richard F Howard, Sulayman D Dibhajj, Stephen G Waxman, Suellen M WalkerAbstract:OBJECTIVES: To evaluate the clinical features of Erythromelalgia in childhood associated with gain-of-function SCN9A mutations that increase activity of the Nav1.7 voltage-gated sodium channel, we conducted a systematic review of pediatric presentations of Erythromelalgia related to SCN9A mutations, and compared pediatric clinical presentations of symptomatic Erythromelalgia, with or without SCN9A mutations. STUDY DESIGN: PubMed, Embase, and PsycINFO Databases were searched for reports of inherited Erythromelalgia in childhood. Clinical features, management, and genotype were extracted. Case notes of pediatric patients with Erythromelalgia from the Great Ormond Street Hospital Pain Service were reviewed for clinical features, patient-reported outcomes, and treatments. Children aged over 10 years were recruited for quantitative sensory testing. RESULTS: Twenty-eight publications described Erythromelalgia associated with 15 different SCN9A gene variants in 25 children. Pain was severe and often refractory to multiple treatments, including nonspecific sodium channel blockers. Skin damage or other complications of cold immersion for symptomatic relief were common (60%). SCN9A mutations resulting in greater hyperpolarizing shifts in Nav1.7 sodium channels correlated with symptom onset at younger ages (P = .016). Variability in reporting, and potential publication bias toward severe cases, limit any estimations of overall prevalence. In our case series, symptoms were similar but comorbidities were more common in children with SCN9A mutations. Quantitative sensory testing revealed marked dynamic warm allodynia. CONCLUSIONS: Inherited Erythromelalgia in children is associated with difficult-to-manage pain and significant morbidity. Standardized reporting of outcome and management in larger series will strengthen identification of genotype-phenotype relationships. More effective long-term therapies are a significant unmet clinical need.
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deletion mutation of sodium channel na v 1 7 in inherited Erythromelalgia enhanced slow inactivation modulates dorsal root ganglion neuron hyperexcitability
Brain, 2011Co-Authors: Xiaoyang Cheng, Sulayman D Dibhajj, Lynda Tyrrell, Rene Te H M Morsche, Joost P H Drenth, Stephen G WaxmanAbstract:Gain-of-function missense mutations of voltage-gated sodium channel NaV1.7 have been linked to the painful disorder inherited Erythromelalgia. These mutations hyperpolarize activation, slow deactivation and enhance currents evoked by slow ramp stimuli (ramp currents). A correlation has recently been suggested between the age of onset of inherited Erythromelalgia and the extent of hyperpolarizing shifts in mutant NaV1.7 channel activation; mutations causing large activation shifts have been linked to early age of onset inherited Erythromelalgia, while mutations causing small activation shifts have been linked to age of onset within the second decade of life. Here, we report a family with inherited Erythromelalgia with an in-frame deletion of a single residue—leucine 955 (Del-L955) in DII/S6. The proband did not show symptoms until the age of 15 years, and her affected mother only experienced mild symptoms during adolescence, which disappeared at the age of 38 years. Del-L955 shows no effect on NaV1.7 current density and fast inactivation, but causes an approximately −24 mV shift in activation, together with increases in amplitude of persistent currents and ramp currents. The mutation also produces an approximately −40 mV shift in slow inactivation, which reduces channel availability. Comparison of the effects of the Del-L955 mutation on dorsal root ganglion neuron hyperexcitability with those produced by another inherited Erythromelalgia mutation (L858F) that does not enhance slow inactivation suggests that a delayed age of onset and milder symptoms in association with a large shift of channel activation, enhanced persistent and enhanced ramp currents may be related to the approximately −40 mV shift in slow inactivation for Del-L955, the largest shift thus far demonstrated in mutant NaV1.7 channels. Our results suggest that despite the pivotal role of activation shift in inherited Erythromelalgia development, slow inactivation may regulate clinical phenotype by altering channel availability.
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early and late onset inherited Erythromelalgia genotype phenotype correlation
Brain, 2009Co-Authors: Sulayman D Dibhajj, Yong Yang, Lynda Tyrrell, Yan Li, Emmanuella M Eastman, Stephen G WaxmanAbstract:Inherited Erythromelalgia (IEM), an autosomal dominant disorder characterized by severe burning pain in response to mild warmth, has been shown to be caused by gain-of-function mutations of sodium channel Nav1.7 which is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons. Almost all physiologically characterized cases of IEM have been associated with onset in early childhood. Here, we report the voltage-clamp and current-clamp analysis of a new Nav1.7 mutation, Q10R, in a patient with clinical onset of Erythromelalgia in the second decade. We show that the mutation in this patient hyperpolarizes activation by only −5.3 mV, a smaller shift than seen with early-onset Erythromelalgia mutations, but similar to that of I136V, another mutation that is linked to delayed-onset IEM. Using current-clamp, we show that the expression of Q10R induces hyperexcitability in DRG neurons, but produces an increase in excitability that is smaller than the change produced by I848T, an early-onset Erythromelalgia mutation. Our analysis suggests a genotype–phenotype relationship at three levels (clinical, cellular and molecular/ion channel), with mutations that produce smaller effects on sodium channel activation being associated with a smaller degree of DRG neuron excitability and later onset of clinical signs.
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a nav1 7 channel mutation associated with hereditary Erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity
The Journal of Physiology, 2007Co-Authors: Patrick L Sheets, Sulayman D Dibhajj, Stephen G Waxman, James O Jackson, Theodore R CumminsAbstract:Mutations in the TTX-sensitive voltage-gated sodium channel subtype Nav1.7 have been implicated in the painful inherited neuropathy, hereditary Erythromelalgia. Hereditary Erythromelalgia can be difficult to treat and, although sodium channels are targeted by local anaesthetics such as lidocaine (lignocaine), some patients do not respond to treatment with local anaesthetics. This study examined electrophysiological differences in Nav1.7 caused by a hereditary Erythromelalgia mutation (N395K) that lies within the local anaesthetic binding site of the channel. The N395K mutation produced a hyperpolarized voltage dependence of activation, slower kinetics of deactivation, and impaired steady-state slow inactivation. Computer simulations indicate that the shift in activation is the major determinant of the hyperexcitability induced by Erythromelalgia mutations in sensory neurons, but that changes in slow inactivation can modulate the overall impact on excitability. This study also investigated lidocaine inhibition of the Nav1.7-N395K channel. We show that the N395K mutation attenuates the inhibitory effects of lidocaine on both resting and inactivated Nav1.7. The IC50 for lidocaine was estimated at 500 μm for inactivated wild-type Nav1.7 and 2.8 mm for inactivated Nav1.7-N395K. The N395K mutation also significantly reduced use-dependent inhibition of lidocaine on Nav1.7 current. In contrast, a different hereditary Erythromelalgia mutation (F216S), not located in the local anaesthetic binding site, had no effect on lidocaine inhibition of Nav1.7 current. Our observation of reduced lidocaine inhibition on Nav1.7-N395K shows that the residue N395 is critical for lidocaine binding to Nav1.7 and suggests that the response of individuals with hereditary Erythromelalgia to lidocaine treatment may be determined, at least in part, by their specific genotype.
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temperature dependence of Erythromelalgia mutation l858f in sodium channel nav1 7
Molecular Pain, 2007Co-Authors: Angelika Lampert, Sulayman D Dibhajj, Anthony M Rush, Xiaoliang Wang, Yong Yang, Stephen G WaxmanAbstract:Background The disabling chronic pain syndrome Erythromelalgia (also termed erythermalgia) is characterized by attacks of burning pain in the extremities induced by warmth. Pharmacological treatment is often ineffective, but the pain can be alleviated by cooling of the limbs. Inherited Erythromelalgia has recently been linked to mutations in the gene SCN9A, which encodes the voltage-gated sodium channel Nav1.7. Nav1.7 is preferentially expressed in most nociceptive DRG neurons and in sympathetic ganglion neurons. It has recently been shown that several disease-causing Erythromelalgia mutations alter channel-gating behavior in a manner that increases DRG neuron excitability.
K Kvernebo - One of the best experts on this subject based on the ideXlab platform.
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nonspecific capillary proliferation and vasculopathy indicate skin hypoxia in Erythromelalgia
Archives of Dermatology, 2011Co-Authors: Ole Magne Kalgaard, O P F Clausen, O J Mellbye, Torstein Hovig, K KverneboAbstract:Objective: To report on the histopathologic findings of affected skin in consecutively collected biopsy specimens from 49 patients with Erythromelalgia (EM). Design: Skin biopsy specimens were obtained from the foot arch and analyzed by light microscopy, immunofluorescence microscopy, and electron microscopy. Setting: Oslo University Hospital―Gaustad, University of Oslo, Oslo, Norway. Participants: Thirty-one patients had primary EM, 17 patients had secondary EM, and 1 patient had erythromelalgic syndrome. Main Outcome Measure: Evidence of microvascular abnormalities in skin biopsy specimens. Results: Light microscopy showed evidence of capillary proliferation in 10 of 31 patients with primary EM and in 1 of 17 patients with secondary EM. The biopsy specimen from the patient with erythromelalgic syndrome showed numerous capillary nests with endothelial cell defects and a slight perivascular inflammatory reaction. Among the 17 secondary EM cases, sparse perivascular lymphocyte infiltrations were observed in the biopsy specimens from 2 patients with chronic myelogenous leukemia and 1 patient with diabetes mellitus. Eleven patients also had signs of vasculopathy based on findings of immunodeposits of C3 and fibrin. Six of 30 patients with primary EM showed endothelial abnormalities on electron microscopy. All 3 investigations showed unremarkable biopsy results in 16 cases. Conclusions: Histopathologic analysis is not useful as a routine diagnostic tool in EM because no morphological changes are specific to EM. The capillary proliferation and vasculopathy are assumed to be a consequence of intermittent skin hypoxia (vascular hypothesis of pathogenesis). Whether the proliferation is a consequence of EM or a pathogenic factor in the development of the disease is uncertain.
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pain in primary Erythromelalgia a neuropathic component
Pain, 2004Co-Authors: Kristin Orstavik, K Kvernebo, Cato Mork, Ellen JorumAbstract:Abstract Erythromelalgia is a condition characterized by attacks of red, hot, painful extremities with relief of symptoms by cooling and aggravation by warmth. Although the main emphasis has been on pathophysiological mechanisms related to circulatory changes, recent reports have focused on an involvement of efferent small nerve fibers indicating a neuropathic component. Since the symptoms resemble those described in neuropathic pain, we wanted to investigate the possible affection of afferent nerve fibers. Twenty-five patients with primary Erythromelalgia were examined by neurological testing, neurography and quantitative sensory testing. Thresholds for heat, cold, heat-pain and cold-pain detection were compared with those of a group of 29 healthy controls. The patients had significantly higher median heat (39.5 (36.1–40.8) and cold (29.3 (27.1–30.8)-detection thresholds at the dorsal aspects of their feet compared to the controls (37.0 (35.4–37.7) and 31.2 (30.3–31.5) respectively). These findings show an impaired small fiber function inside or close to the symptomatic area in this group of Erythromelalgia patients. Seven patients had brush-evoked allodynia and fourteen had punctate hyperalgesia inside or close to the symptomatic areas in their feet. When comparing the individual results, there is a tendency to clustering of patients in two separate groups; reduced small fiber input/no hyperalgesia and normal thermal thresholds/hyperalgesia. Our results showing an affection of afferent small nerve fibers together with the nature of the symptoms, suggest that the pain experienced by Erythromelalgia patients could have a neuropathic component.
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reduced skin capillary density during attacks of Erythromelalgia implies arteriovenous shunting as pathogenetic mechanism
Journal of Investigative Dermatology, 2002Co-Authors: Cato Mork, K Kvernebo, Claes Asker, Goran E SalerudAbstract:Erythromelalgia is characterized by burning pain, erythema, and increased temperature in acral skin. The pain is aggravated by warming and relieved by cooling. Increased microvascular arteriovenous shunting in deep dermal plexa has been hypothesized as the pathogenetic mechanism of pain in affected skin, inducing hypoxia during pain attacks. The aim of this study was to quantify skin capillary density in erythromelalgic patients before and after heat provocation, as increased skin temperature should increase the need for nutritive blood supply by the capillaries. Fourteen patients and 10 healthy control subjects were studied using an enhanced technique of computer-assisted analysis of capillary bed morphology and temperature measurements before and after central body heating. The increase in acral skin temperature was significantly higher (p
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impaired neurogenic control of skin perfusion in Erythromelalgia
Journal of Investigative Dermatology, 2002Co-Authors: Cato Mork, Ole Magne Kalgaard, K KverneboAbstract:Erythromelalgia is a clinical diagnosis characterized by erythema, increased temperature and burning pain in acral skin. The pain is relieved by cooling and aggravated by warming. The symptoms have been hypothesized to be caused by skin hypoxia due to increased arteriovenous shunting. We examined skin microvascular perfusion in response to vasoconstrictory and vasodilatory stimuli, to characterize local and central neurogenic reflexes as well as vascular smooth muscle and vascular endothelial function, using laser Doppler perfusion measurements in 14 patients with primary Erythromelalgia and healthy control persons. Skin perfusion preceding provocative stimuli was significantly reduced in patients with Erythromelalgia (p
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microvascular arteriovenous shunting is a probable pathogenetic mechanism in Erythromelalgia
Journal of Investigative Dermatology, 2000Co-Authors: Cato Mork, Claes Asker, Goran E Salerud, K KverneboAbstract:Erythromelalgia is a condition consisting of red, warm, and burning painful extremities. Symptoms are relieved by cold and aggravated by heat. A wide variety of etiologic conditions can cause Erythromelalgia, but one common pathogenetic mechanism, microvascular arteriovenous shunting, has been hypothesized. The aim of this study was to test this hypothesis. Quantification of skin microvascular perfusion using laser Doppler perfusion imaging and skin temperature at rest and after central body heating was performed in 14 patients with Erythromelalgia and 11 controls. Attacks of Erythromelalgia were induced in eight patients after heat provocation. In the plantar region of the foot, the location of numerous anatomical arteriovenous shunts, these patients significantly increased the skin perfusion as compared with asymptomatic patients with Erythromelalgia and controls. In the dorsal region with few arteriovenous shunts no significant differences between the groups were demonstrated. The results show a relation between clinical symptoms and increased perfusion in the region of numerous anatomical arteriovenous shunts, and support the hypothesis of increased thermoregulatory arteriovenous shunt flow during attacks in primary Erythromelalgia.
Mark D. P. Davis - One of the best experts on this subject based on the ideXlab platform.
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Erythromelalgia.
Current treatment options in cardiovascular medicine, 2020Co-Authors: Mark D. P. Davis, Thom RookeAbstract:No treatment is consistently effective in the management of patients with Erythromelalgia. There is a dearth of adequate studies examining the response of Erythromelalgia to therapy. Most recommendations are suggested based on case reports, small case series, and anecdotal reports. The management of Erythromelalgia is difficult and frequently involves a multidisciplinary approach. An approach to management of individuals with Erythromelalgia includes patient education, learning to avoid episodes relieving discomfort of the episodes, controlling secondary and underlying factors, and use of drugs used to control Erythromelalgia.
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Erythromelalgia.
Current treatment options in cardiovascular medicine, 2020Co-Authors: Mark D. P. Davis, Thom RookeAbstract:No treatment is consistently effective in the management of patients with Erythromelalgia. There is a dearth of adequate studies examining the response of Erythromelalgia to treatment. Most recommendations are suggested based on case reports, small case series, and anecdotal reports. The management of Erythromelalgia is difficult and frequently involves a multidisciplinary approach. An approach to management of individuals with Erythromelalgia includes patient education, learning to avoid episodes, relieving discomfort of the episodes, controlling secondary and underlying factors, and use of drugs used to control Erythromelalgia.
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Erythromelalgia identification of a corticosteroid responsive subset
Journal of The American Academy of Dermatology, 2017Co-Authors: Gabriel L Paganiestevez, Mark D. P. Davis, Paola Sandroni, James C WatsonAbstract:Background Corticosteroids (CS) may benefit certain patients with Erythromelalgia. Objectives Our objective was to determine clinical predictors of corticosteroid-responsive Erythromelalgia. Methods Patients with Erythromelalgia who received CS were identified and stratified into corticosteroid nonresponders (NRs), partial corticosteroid responders (PSRs), complete corticosteroid responders (CSRs), and steroid responders (SRs = PSRs + CSRs). In the study variable analysis, P Results The median (interquartile range) age of the 31-patient cohort was 47 years (26-57 years), and 22 (71%) were female. Fourteen (45%) were NRs, 17 (55%) SRs, 8 (26%) PSRs, and 9 (29%) CSRs. A subacute temporal profile to disease zenith ( P = .003; odds ratio [OR] = 0.069 [95% confidence interval {CI}, 0.011-0.431]). Six (67%) CSRs reported a disease precipitant (eg, surgery, trauma, or infection; P = .007; OR = 12.667 [95% CI, 2-80.142]). SR patients received CS sooner than NR at 3 (3-12) versus 24 (17-45) months ( P = .003). A high-dose CS trial (≥200 mg prednisone cumulatively) was administered to 17 (55%) patients, of whom 13 (76%) were SRs ( P = .012; OR = 8.125 [95% CI, 1.612-40.752]). Limitations This was a retrospective case series. Conclusion An infectious, traumatic, or surgical precipitant and subacute presentation may portend CR Erythromelalgia. A transient "golden window" where CS intervention is useful may exist before irreversible nociceptive remodeling and central sensitization occurs.
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epidermal nerve fiber quantification in patients with Erythromelalgia
JAMA Dermatology, 2017Co-Authors: William G Mantyh, Paola Sandroni, James P B Dyck, Peter J Dyck, Janean K Engelstad, William J Litchy, Mark D. P. DavisAbstract:Importance Erythromelalgia is a clinical diagnosis based on intermittent warmth, erythema, and pain in the distal extremities. One problem facing physicians is how to objectively test for this disease. Given that other painful conditions of the distal extremities (ie, neuropathy related to human immunodeficiency virus, diabetes, or Fabry disease) can be evaluated with a skin biopsy to visualize pathologically decreased densities of the small nerve fibers that innervate the epidermis, one hypothesis is that Erythromelalgia could similarly be associated with a loss of epidermal nerve fiber density (ENFD). Objectives To examine whether Erythromelalgia is associated with a structural loss of small fibers using the ENFD technique and to compare this with functional studies of small nerve fibers. Design, Setting, and Participants In a retrospective study of 52 consecutive patients with Erythromelalgia who were seen between September 1, 2010, and September 22, 2015, patients were interviewed and examined and their conditions clinically diagnosed by a board-certified dermatologist at a large tertiary referral center, where ENFD testing became a routine part of evaluating Erythromelalgia in 2010. Thus, all 52 consecutive patients were included solely based on their clinical diagnosis of Erythromelalgia. For quantification of ENFD, observers were masked to all patient information except for name and clinic number. Main Outcomes and Measures The hypothesis that patients with Erythromelalgia would have decreased ENFD was formulated before data collection. Epidermal nerve fiber density, the primary outcome, is a measurement of the density of small nerve fibers within the epidermis. Secondary measures included functional small fiber evaluation, such as autonomic (heart rate, blood pressure, and sweat testing) and subjective testing of pain. Results In this cohort study, 52 consecutively seen patients were identified (female, 42 [80%]; median age, 44 years; age range, 13-82 years). Whereas only 5 of 52 patients (10%) had ENFD at or below the fifth percentile of healthy control individuals, most patients had functional abnormalities of these small fibers; 29 patients (60%) had abnormal sweat test results, 21 (42%) had abnormal pain thresholds, and 20 (38%) had abnormal blood pressure or heart rate control. Conclusions and Relevance Unlike other diseases of the small nerve fibers that cause acral pain syndromes, Erythromelalgia is not characterized by loss of ENFD. However, most patients have impaired function of these small fibers. Physicians would benefit from performing functional rather than structural small fiber studies when evaluating Erythromelalgia.
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infrequent scn9a mutations in congenital insensitivity to pain and Erythromelalgia
Journal of Neurology Neurosurgery and Psychiatry, 2013Co-Authors: Christopher J Klein, Mark D. P. Davis, Paola Sandroni, Yanhong Wu, Dean H Kilfoyle, Ralitza H Gavrilova, Peter J DyckAbstract:Objective Mutations in SCN9A have been reported in (1) congenital insensitivity to pain (CIP); (2) primary Erythromelalgia; (3) paroxysmal extreme pain disorder; (4) febrile seizures and recently (5) small fibre sensory neuropathy. We sought to investigate for SCN9A mutations in a clinically well-characterised cohort of patients with CIP and Erythromelalgia. Methods We sequenced all exons of SCN9A in 19 clinically well-studied cases including 6 CIP and 13 Erythromelalgia (9 with family history, 10 with small-fibre neuropathy). The identified variants were assessed in dbSNP135, 1K genome, NHLBI-Exome Sequencing Project (5400-exomes) databases, and 768 normal chromosomes. Results In Erythromelalgia case 7, we identified a novel Q10>K mutation. In CIP case 6, we identified a novel, de novo splicing mutation (IVS8-2A>G); this splicing mutation compounded with a nonsense mutation (R523>X) and abolished SCN9A mRNA expression almost completely compared with his unaffected father. In CIP case 5, we found a variant (P610>T) previously considered causal for Erythromelalgia, supporting recently raised doubt on its causal nature. We also found a splicing junction variant (IVS24-7delGTTT) in all 19 patients, this splicing variant was previously considered casual for CIP, but IVS24-7delGTTT was in fact the major allele in Caucasian populations. Conclusions Two novel SCN9A mutations were identified, but frequently polymorphism variants are found which may provide susceptibility factors in pain modulation. CIP and Erythromelalgia are defined as genetically heterogeneous, and some SCN9A variants previously considered causal may only be modifying factors.
Cato Mork - One of the best experts on this subject based on the ideXlab platform.
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pain in primary Erythromelalgia a neuropathic component
Pain, 2004Co-Authors: Kristin Orstavik, K Kvernebo, Cato Mork, Ellen JorumAbstract:Abstract Erythromelalgia is a condition characterized by attacks of red, hot, painful extremities with relief of symptoms by cooling and aggravation by warmth. Although the main emphasis has been on pathophysiological mechanisms related to circulatory changes, recent reports have focused on an involvement of efferent small nerve fibers indicating a neuropathic component. Since the symptoms resemble those described in neuropathic pain, we wanted to investigate the possible affection of afferent nerve fibers. Twenty-five patients with primary Erythromelalgia were examined by neurological testing, neurography and quantitative sensory testing. Thresholds for heat, cold, heat-pain and cold-pain detection were compared with those of a group of 29 healthy controls. The patients had significantly higher median heat (39.5 (36.1–40.8) and cold (29.3 (27.1–30.8)-detection thresholds at the dorsal aspects of their feet compared to the controls (37.0 (35.4–37.7) and 31.2 (30.3–31.5) respectively). These findings show an impaired small fiber function inside or close to the symptomatic area in this group of Erythromelalgia patients. Seven patients had brush-evoked allodynia and fourteen had punctate hyperalgesia inside or close to the symptomatic areas in their feet. When comparing the individual results, there is a tendency to clustering of patients in two separate groups; reduced small fiber input/no hyperalgesia and normal thermal thresholds/hyperalgesia. Our results showing an affection of afferent small nerve fibers together with the nature of the symptoms, suggest that the pain experienced by Erythromelalgia patients could have a neuropathic component.
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reduced skin capillary density during attacks of Erythromelalgia implies arteriovenous shunting as pathogenetic mechanism
Journal of Investigative Dermatology, 2002Co-Authors: Cato Mork, K Kvernebo, Claes Asker, Goran E SalerudAbstract:Erythromelalgia is characterized by burning pain, erythema, and increased temperature in acral skin. The pain is aggravated by warming and relieved by cooling. Increased microvascular arteriovenous shunting in deep dermal plexa has been hypothesized as the pathogenetic mechanism of pain in affected skin, inducing hypoxia during pain attacks. The aim of this study was to quantify skin capillary density in erythromelalgic patients before and after heat provocation, as increased skin temperature should increase the need for nutritive blood supply by the capillaries. Fourteen patients and 10 healthy control subjects were studied using an enhanced technique of computer-assisted analysis of capillary bed morphology and temperature measurements before and after central body heating. The increase in acral skin temperature was significantly higher (p
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impaired neurogenic control of skin perfusion in Erythromelalgia
Journal of Investigative Dermatology, 2002Co-Authors: Cato Mork, Ole Magne Kalgaard, K KverneboAbstract:Erythromelalgia is a clinical diagnosis characterized by erythema, increased temperature and burning pain in acral skin. The pain is relieved by cooling and aggravated by warming. The symptoms have been hypothesized to be caused by skin hypoxia due to increased arteriovenous shunting. We examined skin microvascular perfusion in response to vasoconstrictory and vasodilatory stimuli, to characterize local and central neurogenic reflexes as well as vascular smooth muscle and vascular endothelial function, using laser Doppler perfusion measurements in 14 patients with primary Erythromelalgia and healthy control persons. Skin perfusion preceding provocative stimuli was significantly reduced in patients with Erythromelalgia (p
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Erythromelalgia in a patient with AIDS.
Journal of The European Academy of Dermatology and Venereology, 2000Co-Authors: Cato Mork, Ole Magne Kalgaard, Bjørn Myrvang, Knut KverneboAbstract:Erythromelalgia is a clinical syndrome characterized by burning pain in the extremities together with erythema and increased skin temperature. Typically, the patients experience relief from cold, and aggravation from warmth. Symptoms are hypothesized to be caused by arteriovenous shunting and reduced nutritive skin capillary perfusion with corresponding tissue hypoxia. Erythromelalgia is most often primary, but may be secondary to a wide variety of diseases. We report Erythromelalgia in a patient with acquired immune deficiency syndrome (AIDS). At peak pain intensity he actively cooled hands and feet for more than 12 h/day. Many doctors handling human immunodeficiency virus/AIDS patients are unfamiliar with Erythromelalgia, and the condition can easily be overlooked, especially the more common milder cases.
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microvascular arteriovenous shunting is a probable pathogenetic mechanism in Erythromelalgia
Journal of Investigative Dermatology, 2000Co-Authors: Cato Mork, Claes Asker, Goran E Salerud, K KverneboAbstract:Erythromelalgia is a condition consisting of red, warm, and burning painful extremities. Symptoms are relieved by cold and aggravated by heat. A wide variety of etiologic conditions can cause Erythromelalgia, but one common pathogenetic mechanism, microvascular arteriovenous shunting, has been hypothesized. The aim of this study was to test this hypothesis. Quantification of skin microvascular perfusion using laser Doppler perfusion imaging and skin temperature at rest and after central body heating was performed in 14 patients with Erythromelalgia and 11 controls. Attacks of Erythromelalgia were induced in eight patients after heat provocation. In the plantar region of the foot, the location of numerous anatomical arteriovenous shunts, these patients significantly increased the skin perfusion as compared with asymptomatic patients with Erythromelalgia and controls. In the dorsal region with few arteriovenous shunts no significant differences between the groups were demonstrated. The results show a relation between clinical symptoms and increased perfusion in the region of numerous anatomical arteriovenous shunts, and support the hypothesis of increased thermoregulatory arteriovenous shunt flow during attacks in primary Erythromelalgia.