Postictal serotonin levels are associated with peri-ictal apnea.

ObjectiveTo determine the relationship between serum serotonin (5-HT) levels, ictal central apnea (ICA), and postconvulsive central apnea (PCCA) in epileptic seizures.MethodsWe prospectively evaluated video EEG, plethysmography, capillary oxygen saturation (SpO2), and ECG for 49 patients (49 seizures) enrolled in a multicenter study of sudden unexpected death in epilepsy (SUDEP). Postictal and interictal venous blood samples were collected after a clinical seizure for measurement of serum 5-HT levels. Seizures were classified according to the International League Against Epilepsy 2017 seizure classification. We analyzed seizures with and without ICA (n = 49) and generalized convulsive seizures (GCS) with and without PCCA (n = 27).ResultsPostictal serum 5-HT levels were increased over interictal levels for seizures without ICA (p = 0.01), compared to seizures with ICA (p = 0.21). In patients with GCS without PCCA, serum 5-HT levels were increased postictally compared to interictal levels (p < 0.001), but not in patients with seizures with PCCA (p = 0.22). Postictal minus interictal 5-HT levels also differed between the 2 groups with and without PCCA (p = 0.03). Increased heart rate was accompanied by increased serum 5-HT levels (postictal minus interictal) after seizures without PCCA (p = 0.03) compared to those with PCCA (p = 0.42).ConclusionsThe data suggest that significant seizure-related increases in serum 5-HT levels are associated with a lower incidence of seizure-related breathing dysfunction, and may reflect physiologic changes that confer a protective effect against deleterious phenomena leading to SUDEP. These results need to be confirmed with a larger sample size study

Functional MRI Correlates of Carbon Dioxide Chemosensing in Persons With Epilepsy

ObjectivesSudden unexpected death in epilepsy (SUDEP) is a catastrophic epilepsy outcome for which there are no reliable premortem imaging biomarkers of risk. Percival respiratory depression is seen in monitored SUDEP and near SUDEP cases, and abnormal chemosensing of raised blood carbon dioxide (CO2) is thought to contribute. Damage to brainstem respiratory control and chemosensing structures has been demonstrated in structural imaging and neuropathological studies of SUDEP. We hypothesized that functional MRI (fMRI) correlates of abnormal chemosensing are detectable in brainstems of persons with epilepsy (PWE) and are different from healthy controls (HC).MethodsWe analyzed fMRI BOLD activation and brain connectivity in 10 PWE and 10 age- and sex-matched HCs during precisely metered iso-oxic, hypercapnic breathing challenges. Segmented brainstem responses were of particular interest, along with characterization of functional connectivity metrics between these structures. Regional BOLD activations during hypercapnic challenges were convolved with hemodynamic responses, and the resulting activation maps were passed on to group-level analyses. For the functional connectivity analysis, significant clusters from BOLD results were used as seeds. Each individual seed time-series activation map was extracted for bivariate correlation coefficient analyses to study changes in brain connectivity between PWE and HCs.Results(1) Greater brainstem BOLD activations in PWE were observed compared to HC during hypercapnic challenges in several structures with respiratory/chemosensing properties. Group comparison between PWE vs. HC showed significantly greater activation in the dorsal raphe among PWE (p < 0.05) compared to HCs. (2) PWE had significantly greater seed-seed connectivity and recruited more structures during hypercapnia compared to HC.SignificanceThe results of this study show that BOLD responses to hypercapnia in human brainstem are detectable and different in PWE compared to HC. Increased dorsal raphe BOLD activation in PWE and increased seed-seed connectivity between brainstem and adjacent subcortical areas may indicate abnormal chemosensing in these individuals. Imaging investigation of brainstem respiratory centers involved in respiratory regulation in PWE is an important step toward identifying suspected dysfunction of brainstem breathing control that culminates in SUDEP and deserve further study as potential imaging SUDEP biomarkers

Excessive Biologic Response to IFNβ Is Associated with Poor Treatment Response in Patients with Multiple Sclerosis

Interferon-beta (IFNβ) is used to inhibit disease activity in multiple sclerosis (MS), but its mechanisms of action are incompletely understood, individual treatment response varies, and biological markers predicting response to treatment have yet to be identified.he relationship between the molecular response to IFNβ and treatment response was determined in 85 patients using a longitudinal design in which treatment effect was categorized by brain magnetic resonance imaging as good (n = 70) or poor response (n = 15). Molecular response was quantified using a customized cDNA macroarray assay for 166 IFN-regulated genes (IRGs).The molecular response to IFNβ differed significantly between patients in the pattern and number of regulated genes. The molecular response was strikingly stable for individuals for as long as 24 months, however, suggesting an individual ‘IFN response fingerprint’. Unexpectedly, patients with poor response showed an exaggerated molecular response. IRG induction ratios demonstrated an exaggerated molecular response at both the first and 6-month IFNβ injections.MS patients exhibit individually unique but temporally stable biological responses to IFNβ. Poor treatment response is not explained by the duration of biological effects or the specific genes induced. Rather, individuals with poor treatment response have a generally exaggerated biological response to type 1 IFN injections. We hypothesize that the molecular response to type I IFN identifies a pathogenetically distinct subset of MS patients whose disease is driven in part by innate immunity. The findings suggest a strategy for biologically based, rational use of IFNβ for individual MS patients

Reply to Moura et al

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2016-03-22T12:26:54Z No. of bitstreams: 1 Silva TM Reply to moura....pdf: 85237 bytes, checksum: 0ec164196a5b68ffd8b3f65c4d46fe04 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2016-03-22T13:11:31Z (GMT) No. of bitstreams: 1 Silva TM Reply to moura....pdf: 85237 bytes, checksum: 0ec164196a5b68ffd8b3f65c4d46fe04 (MD5)Made available in DSpace on 2016-03-22T13:11:31Z (GMT). No. of bitstreams: 1 Silva TM Reply to moura....pdf: 85237 bytes, checksum: 0ec164196a5b68ffd8b3f65c4d46fe04 (MD5) Previous issue date: 2015Federal University of Bahia. Institute for Collective Health. Salvador, BA, BrasilCase Western Reserve University. Center for Global Health. Cleveland, OH, USAFederal University of Bahia. Institute for Collective Health. Salvador, BA, BrasilFederal University of Bahia. Institute for Collective Health. Salvador, BA, Brasil / Federal University of Bahia. Institute for Collective Health. Salvador, BA, BrasilCase Western Reserve University. Center for Global Health. Cleveland, OH, US

Regional cortical thickness changes accompanying generalized tonic-clonic seizures.

ObjectiveGeneralized tonic-clonic seizures are accompanied by cardiovascular and respiratory sequelae that threaten survival. The frequency of these seizures is a major risk factor for sudden unexpected death in epilepsy (SUDEP), a leading cause of untimely death in epilepsy. The circumstances accompanying such fatal events suggest a cardiovascular or respiratory failure induced by unknown neural processes rather than an inherent cardiac or lung deficiency. Certain cortical regions, especially the insular, cingulate, and orbitofrontal cortices, are key structures that integrate sensory input and influence diencephalic and brainstem regions regulating blood pressure, cardiac rhythm, and respiration; output from those cortical regions compromised by epilepsy-associated injury may lead to cardiorespiratory dysregulation. The aim here was to assess changes in cortical integrity, reflected as cortical thickness, relative to healthy controls. Cortical alterations in areas that influence cardiorespiratory action could contribute to SUDEP mechanisms.MethodsHigh-resolution T1-weighted images were collected with a 3.0-Tesla MRI scanner from 53 patients with generalized tonic-clonic seizures (Mean age ± SD: 37.1 ± 12.6 years, 22 male) at Case Western Reserve University, University College London, and the University of California at Los Angeles. Control data included 530 healthy individuals (37.1 ± 12.6 years; 220 male) from UCLA and two open access databases (OASIS and IXI). Cortical thickness group differences were assessed at all non-cerebellar brain surface locations (P < 0.05 corrected).ResultsIncreased cortical thickness appeared in post-central gyri, insula, and subgenual, anterior, posterior, and isthmus cingulate cortices. Post-central gyri increases were greater in females, while males showed more extensive cingulate increases. Frontal and temporal cortex, lateral orbitofrontal, frontal pole, and lateral parietal and occipital cortices showed thinning. The extents of thickness changes were sex- and hemisphere-dependent, with only males exhibiting right-sided and posterior cingulate thickening, while females showed only left lateral orbitofrontal thinning. Regional cortical thickness showed modest correlations with seizure frequency, but not epilepsy duration.SignificanceCortical thickening and thinning occur in patients with generalized tonic-clonic seizures, in cardiovascular and somatosensory areas, with extent of changes sex- and hemisphere-dependent. The data show injury in key autonomic and respiratory cortical areas, which may contribute to dysfunctional cardiorespiratory patterns during seizures, as well as to longer-term SUDEP risk

The correlation between ancestry and color in two cities of Northeast Brazil with contrasting ethnic compositions

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2016-09-26T13:18:26Z No. of bitstreams: 1 Silva TM The correlation between....pdf: 687942 bytes, checksum: 8f0043ba4a58b61816551a4d3611a093 (MD5)Approved for entry into archive by Ana Maria Fiscina Sampaio ([email protected]) on 2016-09-26T13:40:21Z (GMT) No. of bitstreams: 1 Silva TM The correlation between....pdf: 687942 bytes, checksum: 8f0043ba4a58b61816551a4d3611a093 (MD5)Made available in DSpace on 2016-09-26T13:40:21Z (GMT). No. of bitstreams: 1 Silva TM The correlation between....pdf: 687942 bytes, checksum: 8f0043ba4a58b61816551a4d3611a093 (MD5) Previous issue date: 2015CNPqFederal University of Bahia. Institute for Collective Health. Salvador, BA, Brasil.Case Western Reserve University. Center for Global Health. Cleveland, OH, USA.Federal University of Bahia. Institute for Collective Health. Salvador, BA, Brasil.Federal University of Bahia. Institute for Collective Health. Salvador, BA, Brasil.State University Santa Cruz. Ilhéus, BA, Brasil.State University Santa Cruz. Ilhéus, BA, Brasil.Case Western Reserve University. Department of Genetics. Cleveland, OH, USA.Federal University of Bahia. Institute for Collective Health. Salvador, BA, Brasil.Case Western Reserve University. Department of Genetics. Cleveland, OH, USA / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil.Federal University of Bahia. Institute for Collective Health. Salvador, BA, Brasil.Case Western Reserve University. Center for Global Health. Cleveland, OH, USA.The degree of admixture in Brazil between historically isolated populations is complex and geographically variable. Studies differ as to what the genetic and phenotypic consequences of this mixing have been. In Northeastern Brazil, we enrolled 522 residents of Salvador and 620 of Fortaleza whose distributions of self-declared color were comparable to those in the national census. Using the program Structure and principal components analysis there was a clear correlation between biogeographic ancestry and categories of skin color. This correlation with African ancestry was stronger in Salvador (r=0.585; Po0.001) than in Fortaleza (r=0.236; Po0.001). In Fortaleza, although self-declared blacks had a greater proportion of European ancestry, they had more African ancestry than the other categories. When the populations were analyzed without pseudoancestors, as in some studies, the relationship of ‘race’ to genetic ancestry tended to diffuse or disappear. The inclusion of different African populations also influenced ancestry estimates. The percentage of unlinked ancestry informative markers in linkage disequilibrium, a measure of population structure, was 3–5 times higher in both Brazilian populations than expected by chance. We propose that certain methods, ascertainment bias and population history of the specific populations surveyed can result in failure to demonstrate a correlation between skin color and genetic ancestry. Population structure in Brazil has important implications for genetic studies, but genetic ancestry is irrelevant for how individuals are treated in society, their health, their income or their inclusion. These track more closely with perceived skin color than genetic ancestry

Serum serotonin levels in patients with epileptic seizures.

Profound cardiovascular and/or respiratory dysfunction is part of the terminal cascade in sudden unexpected death in epilepsy (SUDEP). Central control of ventilation is mediated by brainstem rhythm generators, which are influenced by a variety of inputs, many of which use the modulatory neurotransmitter serotonin to mediate important inputs for breathing. The aim of this study was to investigate epileptic seizure-induced changes in serum serotonin levels and whether there are potential implications for SUDEP. Forty-one epileptic patients were pooled into 2 groups based on seizure type as (1) generalized tonic-clonic seizures (GTCS) of genetic generalized epilepsy and focal to bilateral tonic-clonic seizures (FBTCS; n = 19) and (2) focal seizures (n = 26) based on clinical signs using surface video-electroencephalography. Postictal serotonin levels were statistically significantly higher after GTCS and FBTCS compared to interictal levels (P = .002) but not focal seizures (P = .941). The change in serotonin (postictal-interictal) was inversely associated with a shorter duration of tonic phase of generalized seizures. The interictal serotonin level was inversely associated with a shorter period of postictal generalized electroencephalographic suppression. These data suggest that peripheral serum serotonin levels may play a role in seizure features and earlier postseizure recovery; these findings merit further study

Postictal serotonin levels are associated with peri-ictal apnea.

ObjectiveTo determine the relationship between serum serotonin (5-HT) levels, ictal central apnea (ICA), and postconvulsive central apnea (PCCA) in epileptic seizures.MethodsWe prospectively evaluated video EEG, plethysmography, capillary oxygen saturation (SpO2), and ECG for 49 patients (49 seizures) enrolled in a multicenter study of sudden unexpected death in epilepsy (SUDEP). Postictal and interictal venous blood samples were collected after a clinical seizure for measurement of serum 5-HT levels. Seizures were classified according to the International League Against Epilepsy 2017 seizure classification. We analyzed seizures with and without ICA (n = 49) and generalized convulsive seizures (GCS) with and without PCCA (n = 27).ResultsPostictal serum 5-HT levels were increased over interictal levels for seizures without ICA (p = 0.01), compared to seizures with ICA (p = 0.21). In patients with GCS without PCCA, serum 5-HT levels were increased postictally compared to interictal levels (p < 0.001), but not in patients with seizures with PCCA (p = 0.22). Postictal minus interictal 5-HT levels also differed between the 2 groups with and without PCCA (p = 0.03). Increased heart rate was accompanied by increased serum 5-HT levels (postictal minus interictal) after seizures without PCCA (p = 0.03) compared to those with PCCA (p = 0.42).ConclusionsThe data suggest that significant seizure-related increases in serum 5-HT levels are associated with a lower incidence of seizure-related breathing dysfunction, and may reflect physiologic changes that confer a protective effect against deleterious phenomena leading to SUDEP. These results need to be confirmed with a larger sample size study

The incidence and significance of periictal apnea in epileptic seizures.

OBJECTIVE:The aim of this study was to investigate periictal central apnea as a seizure semiological feature, its localizing value, and possible relationship with sudden unexpected death in epilepsy (SUDEP) pathomechanisms. METHODS:We prospectively studied polygraphic physiological responses, including inductance plethysmography, peripheral capillary oxygen saturation (SpO2 ), electrocardiography, and video electroencephalography (VEEG) in 473 patients in a multicenter study of SUDEP. Seizures were classified according to the International League Against Epilepsy (ILAE) 2017 seizure classification based on the most prominent clinical signs during VEEG. The putative epileptogenic zone was defined based on clinical history, seizure semiology, neuroimaging, and EEG. RESULTS:Complete datasets were available in 126 patients in 312 seizures. Ictal central apnea (ICA) occurred exclusively in focal epilepsy (51/109 patients [47%] and 103/312 seizures [36.5%]) (P < .001). ICA was the only clinical manifestation in 16/103 (16.5%) seizures, and preceded EEG seizure onset by 8 ± 4.9 s, in 56/103 (54.3%) seizures. ICA ≥60 s was associated with severe hypoxemia (SpO2 <75%). Focal onset impaired awareness (FOIA) motor onset with automatisms and FOA nonmotor onset semiologies were associated with ICA presence (P < .001), ICA duration (P = .002), and moderate/severe hypoxemia (P = .04). Temporal lobe epilepsy was highly associated with ICA in comparison to extratemporal epilepsy (P = .001) and frontal lobe epilepsy (P = .001). Isolated postictal central apnea was not seen; in 3/103 seizures (3%), ICA persisted into the postictal period. SIGNIFICANCE:ICA is a frequent, self-limiting semiological feature of focal epilepsy, often starting before surface EEG onset, and may be the only clinical manifestation of focal seizures. However, prolonged ICA (≥60 s) is associated with severe hypoxemia and may be a potential SUDEP biomarker. ICA is more frequently seen in temporal than extratemporal seizures, and in typical temporal seizure semiologies. ICA rarely persists after seizure end. ICA agnosia is typical, and thus it may remain unrecognized without polygraphic measurements that include breathing parameters