Idiopathic small-fiber neuropathy (I-SFN), clinically characterized by burning pain in distal extremities and autonomic dysfunction, is a disorder of small-caliber nerve fibers of unknown etiology with limited treatment options. Functional variants of voltage-gated sodium channel Na v 1.7, encoded by SCN9A, have been identified in approximately one-third of I-SFN patients. These variants render dorsal root ganglion (DRG) neurons hyperexcitable. Sodium channel Na v 1.8, encoded by SCN10A, is preferentially expressed in small-diameter DRG neurons, and produces most of the current underlying the upstroke of action potentials in these neurons. We previously demonstrated two functional variants of Na v 1.8 that either enhance ramp current or shift activation in a hyperpolarizing direction, and render DRG neurons hyperexcitable, in I-SFN patients with no mutations of SCN9A. We have now evaluated additional I-SFN patients with no mutations in SCN9A, and report a novel I-SFN-related Na v 1.8 mutation I1706V in a patient with painful I-SFN. Whole-cell voltage-clamp recordings in small DRG neurons demonstrate that the mutation hyperpolarizes activation and the response to slow ramp depolarizations. However, it decreases fractional channels resistant to fast inactivation and reduces persistent currents. Current-clamp studies reveal that mutant channels decrease current threshold and increase the firing frequency of evoked action potentials within small DRG neurons. These observations suggest that the effects of this mutation on activation and ramp current are dominant over the reduced persistent current, and show that these pro-excitatory gating changes confer hyperexcitability on peripheral sensory neurons, which may contribute to pain in this individual with I-SFN.
We report for the first time a mutation of NaV1.8 which impairs inactivation, in patients with painful I-SFN. Together with our earlier results, our observations indicate that an array of NaV1.8 mutations, which affect channel function in multiple ways, can contribute to the pathophysiology of painful peripheral neuropathy.
Frontal lobe and behavioral symptoms are more prevalent and severe in MCI and AD patients with significant depressive symptoms as compared with patients without depressive symptoms.
Seizures after intracerebral hemorrhage are repeatedly seen. Whether the development of seizures after intracerebral hemorrhage affects survival in the long term is unknown. This study aims to determine the relation between seizures (i.e., with and without anti-epileptic therapy) and long-term mortality risk in a large patient population with intracerebral hemorrhage. We retrospectively included patients with a non-traumatic ICH in all three hospitals in the South Limburg region in the Netherlands between January 1st 2004 and December 31st 2009, and we assessed all-cause mortality until March 14th 2016. Patient who did not survive the first seven days after intracerebral hemorrhage were excluded from analyses. We used Cox multivariate analyses to determine independent predictors of mortality. Of 1214 patients, 783 hemorrhagic stroke patients fulfilled the inclusion criteria, amongst whom 37 (4.7%) patients developed early seizures (within 7 days after hemorrhage) and 77 (9.8%) developed late seizures (more than 7 days after hemorrhage). Seizure development was not significantly related to mortality risk after correction for conventional vascular risk factors and hemorrhage severity. However, we found a small but independent relation between the use of anti-epileptic drugs and a lower long-term mortality (HR = 0.32, 95% CI 0.11–0.91). In our large population, seizures and epilepsy did not relate independently to an increased mortality risk after hemorrhage.
BackgroundThe intracerebral hemorrhage (ICH) score is a commonly used prognostic model for 30-day mortality in ICH, based on five independent predictors (ICH volume, location, Glasgow Coma Scale, age, and intraventricular extension). Use of oral anticoagulants (OAC) is also associated with mortality but was not considered in the ICH score. We investigated (a) whether the predictive performance of ICH score is similar in OAC-ICH and non-OAC-ICH and (b) whether addition of OAC use to the ICH score increases the prognostic performance of the score.MethodsWe retrospectively selected all consecutive adult non-traumatic ICH cases (three hospitals, region South-Limburg, the Netherlands 2004–2009). Mortality at 30 days was recorded. Using univariable and multivariable logistic regression, association between OAC use and 30-day mortality was tested. Then (a) we computed receiver operating characteristic (ROC) curves for ICH score and determined the area under the curve (AUC) in OAC-ICH and non-OAC-ICH. Then (b) we created a New ICH score by adding OAC use to the ICH score. We calculated correlation between 30-day mortality and ICH score, respectively, New ICH score using Spearman correlation test. We computed ROC curves and calculated the AUC.ResultsWe analyzed 1,232 cases, 282 (22.9%) were OAC related ICH. Overall, 30-day mortality was 39.3%. OAC use was independently associated with 30-day mortality (OR 2.09, 95% CI, 1.48–2.95; p < 0.001), corrected for the five predictors of the ICH score. The ICH score performed slightly better in non-OAC-ICH (AUC 0.840) than in OAC-ICH (AUC 0.816), but this difference was not significant (p = 0.39). The ICH score and the New ICH score were both significantly correlated with 30-day mortality (rho 0.58, p < 0.001 and 0.59, p < 0.001, respectively). The AUC for the ICH score was 0.837, for New ICH score 0.840. This difference was not significant.ConclusionThe ICH score is a useful tool for predicting 30-day mortality both in patient who use and patients who do not use OAC. Although OAC use is an independent predictor of 30-day mortality, addition of OAC use to the existing ICH score does not increase the prognostic performance of this score.
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