Creation and implementation of an electronic health record note for quality improvement in pediatric epilepsy: Practical considerations and lessons learned.

OBJECTIVE: To describe the development of the Pediatric Epilepsy Outcome-Informatics Project (PEOIP) at Alberta Children's Hospital (ACH), which was created to provide standardized, point-of-care data entry; near-time data analysis; and availability of outcome dashboards as a baseline on which to pursue quality improvement. METHODS: Stakeholders involved in the PEOIP met weekly to determine the most important outcomes for patients diagnosed with epilepsy, create a standardized electronic note with defined fields (patient demographics, seizure and syndrome type and frequency and specific outcomes- seizure type and frequency, adverse effects, emergency department visits, hospitalization, and care pathways for clinical decision support. These were embedded in the electronic health record from which the fields were extracted into a data display platform that provided patient- and population-level dashboards updated every 36 hours. Provider satisfaction and family experience surveys were performed to assess the impact of the standardized electronic note. RESULTS: In the last 5 years, 3,245 unique patients involving 13, 831 encounters had prospective, longitudinal, standardized epilepsy data accrued via point-of-care data entry into an electronic note as part of routine clinical care. A provider satisfaction survey of the small number of users involved indicated that the vast majority believed that the note makes documentation more efficient. A family experience survey indicated that being provided with the note was considered "valuable" or "really valuable" by 86% of respondents and facilitated communication with family members, school, and advocacy organizations. SIGNIFICANCE: The PEOIP serves as a proof of principle that information obtained as part of routine clinical care can be collected in a prospective, standardized, efficient manner and be used to construct filterable process/outcome dashboards, updated in near time (36 hours). This information will provide the necessary baseline data on which multiple of QI projects to improve meaningful outcomes for children with epilepsy will be based.

Contribution of rare genetic variants to drug response in absence epilepsy.

OBJECTIVE: We investigated the possible significance of rare genetic variants to response to valproic acid (VPA) and ethosuximide (ETX) in patients with absence epilepsy. Our primary hypothesis was that rare CACNA1H variants are more frequent in ETX-non-responsive patients compared to ETX-responsive. Our secondary hypothesis was that rare variants in GABA-receptor genes are more frequent in VPA-non-responsive patients compared to VPA-responsive. METHODS: We recruited patients with absence epilepsy treated with both VPA and ETX, and performed whole exome sequencing in order to investigate the potential role of rare variants in CACNA1H, other voltage-gated calcium channel (VGCC) genes, or GABA-receptor genes in predicting response to ETX or VPA. RESULTS: Sixty-two patients were included; 12 were ETX-responsive, 14 VPA-responsive, and 36 did not have a clear positive response to either medication. We did not find significant enrichment inCACNA1H rare variants in ETX-responsive patients (odds ratio 3.43; 0.43-27.65; p = 0.20), nor was there enrichment for other VGCC genes. No significant enrichment of GABA-receptor gene rare variants was seen for VPA-non-responsive patients versus VPA-responsive. We found enrichment of rare GABA-receptor variants in our absence cohort compared to controls (odds ratio 3.82; 1.68-8.69). There was no difference in frequency of CACNA1H rs61734410 and CACNA1I rs3747178 polymorphisms between ETX-responsive and ETX-non-responsive groups; these polymorphisms have previously been reported to predict lack of response to ETX in absence epilepsy. SIGNIFICANCE: We conclude that if CACNA1H rare variants predict lack of response to ETX, a larger sample is necessary to test this with sufficient power. Increased GABA-receptor gene rare variant frequency in absence epilepsy patients who fail initial anti-seizure therapy suggests subtle GABA receptor dysfunction may contribute to the underlying pathophysiology.

Most Children With Epilepsy Experience Postictal Phenomena, Often Preventing a Return to Normal Activities of Childhood.

BACKGROUND: After a seizure, individuals with epilepsy have reported diverse symptoms in the postictal period, especially motor and cognitive dysfunction. However, these phenomena have not been well characterized in children, and their impact on patient well-being is not understood. We hypothesized that in a subset of epilepsy patients, postictal symptoms would affect their ability to return to normal childhood activities. METHODS: To test our hypothesis, a survey-based approach was used to characterize the type, frequency, and duration, as well as the impact of these symptoms on the ability of these children to return to their normal activities. RESULTS: In this prospective study, data were analyzed from 208 patients seen in the pediatric neurology outpatient clinic at the Alberta Children's Hospital. We found that 86% (179 out of 208) of respondents reported postictal symptoms, with the most common symptom category being fatigue, sleepiness, and/or tiredness (90%; 161 of 179). The greatest impact resulted from weakness or being unable to move normally, which prevented 78% of those affected (71 of 91) from returning to normal activities after a seizure. Children who had focal seizures were more likely to experience postictal fatigue, sleepiness, or tiredness (P = 0.01; Bonferroni corrected), but no other postictal symptoms were significantly associated with a specific seizure type or epilepsy syndrome. CONCLUSIONS: The results of this study further our understanding of the frequency, type, and duration of symptoms experienced in the postictal period and how these symptoms impact children with epilepsy. It is clear that postictal phenomena often occur after epileptic seizures and have a significant impact on the lives of children with epilepsy.

The relationship between d-beta-hydroxybutyrate blood concentrations and seizure control in children treated with the ketogenic diet for medically intractable epilepsy.

Objective: The ketogenic diet (KD) is a proven treatment for drug-resistant (DR) seizures in children and adolescents. However, the relationship between seizure control and the most commonly measured metabolite of the diet, the ketone body d-beta-hydroxybutyrate (D-BHB), is controversial. This study was performed to clarify the relationship because specific ketone bodies may be useful as biomarkers of diet efficacy. Methods: Families of children with DR seizures were approached for participation in this open-label, prospective study when they were referred for the KD at two western Canadian children's hospitals. Inclusion criteria included documentation of DR seizures without exclusion based on age, sex, seizure, or syndrome type. Patients were excluded if they were referred for treatment of a metabolic disorder independent of seizures. Seizures were quantified via parental report and standardized as seizure frequency per 28 days. Epilepsy syndromes were identified on the basis of the medical record. Blood D-BHB was determined by tandem mass spectrometry. Results: A total of 23 patients were recruited from both sites. Data from five individuals were excluded because these seizures occurred in clusters, leaving 18 patients for the primary analysis. In the latter group, a clear positive correlation was present between measures of seizure frequency and D-BHB concentrations. However, this failed to reach statistical significance, likely because of the relatively small numbers. Significance: A trend clearly exists between seizure frequency and D-BHB levels, so we should not be dissuaded by the lack of statistical significance because it possibly results from methodological techniques, especially sample size. These results call for a larger prospective study in which seizure frequency is assessed at the point of care in a standardized fashion so as to determine whether D-BHB can be used as a reliable biomarker of KD efficacy.

Sevoflurane in acute myocardial infarction: a pilot randomized study.

BACKGROUND: Experimental evidence suggests that the inhalational anesthetic sevoflurane has a cardioprotective effect. Our objective was to determine if sedation with sevoflurane will reduce infarct size in patients with acute myocardial infarction (MI) who are treated with primary percutaneous coronary intervention (PCI). METHODS: We randomized 50 patients presenting with a first acute ST-elevation MI treated by primary PCI within 6 hours from symptom onset to sedation with sevoflurane inhalation or standard sedation (control). Coronary flow at the end of PCI was assessed by corrected Thrombolysis In Myocardial Infarction frame count. Myocardial reperfusion was assessed by ST-segment resolution 60 minutes post-PCI. Infarct size was assessed by release of creatinine kinase (CK) and troponin T. RESULTS: There was no difference in the primary end point: troponin T or CK release adjusted to the area at risk, between groups. However, among patients with anterior MI, there was a trend toward lower CK (P = .05) and nonsignificant decrease in troponin (P = .11) levels in the sevoflurane group. Corrected Thrombolysis In Myocardial Infarction frame count was 12.3 ± 1.5 in the sevoflurane group and 15.6 ± 9.1 in the control group (P = .16). There was more ST resolution in patients treated by sevoflurane 80.7% ± 25.8% versus 56.6% ± 35.7% (P = .01). Sevoflurane had no significant adverse effect during administration. CONCLUSIONS: Sevoflurane administration during primary PCI did not reduce infarct size. There was a trend toward a reduction in infarct size among patients with anterior MI. Sevoflurane administration was associated with improvement in ST-segment resolution.

Remote ischemic postconditioning during percutaneous coronary interventions: remote ischemic postconditioning-percutaneous coronary intervention randomized trial.

BACKGROUND: Remote ischemic preconditioning may result in reduction in infarct size during percutaneous coronary intervention (PCI). It is unclear whether remote ischemic postconditioning (RIPost) will reduce the incidence of myocardial injury after PCI, and whether ischemic conditioning of a larger remote organ (thigh versus arm) would provide further myocardial protection. METHODS AND RESULTS: We randomized 360 patients presenting with stable or unstable angina (28% of patients) and negative Troponin T at baseline to 3 groups: 2 groups received RIPost (induced by ischemia to upper or lower limb), and a third was the control group. RIPost was applied during PCI immediately after stent deployment, by three 5-minute cycles of blood pressure cuff inflation to >200 mm Hg in the arm or thigh (20 mm Hg in the control) with 5-minute breaks between each cycle. The primary end-point was the proportion of patients with Troponin T levels >3×ULN postprocedure (at 6 or 18-24 hours), where ULN stands for upper limit of normal. A total of 120 patients were randomized to each group. There were no differences in baseline characteristics between the 3 groups. The primary outcome occurred in 30%, 35%, and 35% of the arm, thigh, and control groups, respectively (P=0.64). There were no differences in creatine kinase or high sensitivity C-reactive protein levels after PCI or in the incidence of acute kidney injury between the groups. CONCLUSIONS: RIPost during PCI did not reduce the incidence of periprocedural myocardial injury. Similar effect was obtained when remote ischemia was induced to the upper or lower limb. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00970827.

The impact of industry representative's visits on utilization of coronary stents.

BACKGROUND: The interaction between physicians and industry is complex and essential for improvement of medical care. However, conflict of interests may affect decision process. Our aim was to test if promotional visits by industry representatives affect treatment patterns and the use of various stents during percutaneous coronary interventions. METHODS: Medical records of 1,145 consecutive patients who underwent percutaneous coronary intervention in an academic institution over 1-year period were retrospectively reviewed and linked to presence or absence of industry representative. We compared use of bare-metal stents, drug-eluting stents (DES), and balloon catheters according to company presence. RESULTS: A total of 1,785 stents were implanted in 1,145 patients; 60.8% were DES. More DES per case were implanted when a representative was present (1.71 ± 0.9 vs 1.60 ± 0.93, P = .023). There was no difference in the utilization of balloons and bare-metal stents between groups. Stent cost per case was higher when a representative was present (Can $1,703.5 ± 1,314.4 vs 1,468.9 ± 1,273.3, P < .001). For all companies marketing DES, there was increase in the use of the company's DES when their sale representative was present with less use of the competitors' stents. CONCLUSIONS: Sale representative presence was associated with increased use of the representative company's stents during percutaneous coronary interventions. The effect was more pronounced on use of the company's DES and resulted in higher procedural cost.

Contrast volume use in manual vs automated contrast injection systems for diagnostic coronary angiography and percutaneous coronary interventions.

BACKGROUND: Contrast-induced nephropathy (CIN) is an important cause of iatrogenic morbidity and mortality. The amount of contrast delivered has a major effect on CIN and is operator-dependent. A few studies suggested that the use of automated contrast injection systems is associated with reduced contrast volume. It is unknown whether this is true when smaller amounts of contrast are used and how this is affected by training. METHODS: Volume of contrast media was measured in 1358 consecutive patients undergoing diagnostic catheterization and percutaneous coronary intervention (PCI) from January 31 to May 31, 2011. Patients were allocated to manual stopcock-manifold contrast injection (1052 patients) or automated contrast injection (306 patients). RESULTS: No significant difference in contrast volume use was found between manual and automated contrast injection systems, respectively: diagnostic catheterization, 72 ± 40 mL vs 96 ± 63 mL (P = 0.08); diagnostic catheterization with left ventricular angiography, 98 ± 40 mL vs 95 ± 35 mL (P = 0.51); PCI, 206 ± 82 mL vs 205 ± 90 mL (P = 0.84); diagnostic catheterization and PCI, 264 ± 83 mL vs 253 ± 93 mL (P = 0.51). No significant difference in CIN incidence, according to contrast injection systems, was found among patients receiving PCI (manual 9.8% vs automated 7.4%, P = 0.43). Using smaller sized catheters during diagnostic procedures was associated with injection of smaller amounts of contrast (P < 0.0001). CONCLUSIONS: The use of automated contrast injection for diagnostic catheterization and PCI is not associated with reduced contrast volume as compared with manual injection. The use of smaller calibre catheters might reduce contrast volume.

GPI-1046 increases presenilin-1 expression and restores NMDA channel activity.

BACKGROUND: Previously we showed that 6-hydroxydopamine lesions of the substantia nigra eliminate corticostriatal LTP and that the neuroimmunolophilin ligand (NIL), GPI-1046, restores LTP. METHODS: We used cDNA microarrays to determine what mRNAs may be over- or under-expressed in response to lesioning and/or GPI-1046 treatment. Patch clamp recordings were performed to investigate changes in NMDA channel function before and after treatments. RESULTS: We found that 51 gene products were differentially expressed. Among these we found that GPI-1046 treatment up-regulated presenilin-1 (PS-1) mRNA abundance. This finding was confirmed using QPCR. PS-1 protein was also shown to be over-expressed in the striatum of lesioned/GPI-1046-treated rats. As PS-1 has been implicated in controlling NMDA-receptor function and LTP is reduced by lesioning we assayed NMDA mediated synaptic activity in striatal brain slices. The lesion-induced reduction of dopaminergic innervation was accompanied by the near complete loss of NDMA receptor-mediated synaptic transmission between the cortex and striatum. GPI-1046 treatment of the lesioned rats restored NMDA-mediated synaptic transmission but not the dopaminergic innervation. Restoration of NDMA channel function was apparently specific as the sodium channel current density was also reduced due to lesioning but GPI-1046 did not reverse this effect. We also found that restoration of NMDA receptor function was also not associated with either an increase in NMDA receptor mRNA or protein expression. CONCLUSION: As it has been previously shown that PS-1 is critical for normal NMDA receptor function, our data suggest that the improvement of excitatory neurotransmission occurs through the GPI-1046-induced up-regulation of PS-1.

Diverse interneuron populations have highly specific interconnectivity in the rat piriform cortex.

Previous studies have suggested that the patterns of innervation and high interconnectivity of the piriform cortex (PC) provide for strong olfactory hippocampal memory; however, these same attributes may create high seizurogenic tendencies. Thus, understanding this wiring is important from a physiological and pathophysiological perspective. Distinct interneurons expressing differing calcium binding proteins (CBPs), parvalbumin (PV), calbindin (CB), and calretinin (CR), have been shown to exist in PC. However, a comprehensive examination of the distribution and innervation patterns of these neurons has not been done. Thus the purpose of this study was to combine the analysis of the CBP cell localization with analysis of their innervation patterns. Each type was differentially localized in the three layers of the PC. Only CR-positive neurons were found in layer 1. PV and CB are coexpressed in layers 2-3, most expressing both PV and CB. A morphological estimate of the dendritic extent for each subtype showed that PV and PV/CB cells demonstrated equally wide, horizontal and vertical arborizations, whereas CB cells had wide horizontal and restricted vertical arborizations. CR cells had restricted horizontal and very long vertical arborizations. Postsynaptic morphological targeting was also found to be specific, namely, PV(+) and PV/CB(+) nerve terminals (NTs) innervate perisomatic regions of principal cells. CR(+) NTs innervate only dendrites of principal cells, and CB(+) NTs innervate both somata and dendrites of principal cells. These data show highly complex innervation patterns for all of the CBP interneurons of the PC and form a basis for further studies in the plasticity of this region.

Kindling-induced alterations in GABAA receptor-mediated inhibition and neurosteroid activity in the rat piriform cortex.

The piriform cortex makes strong interconnections with limbic structures (amygdala, entorhinal cortex and hippocampus) that are involved in memory processing. These connections have also been implicated in the development of temporal lobe epilepsy. However, little is known about how neurones in this region may change during seizure genesis. Here we tested the hypothesis that in the kindling model of temporal lobe epilepsy GABAA receptor-mediated inhibition is altered in the piriform cortex. To do this we performed whole-cell patch-clamp recordings in piriform cortex brain slices obtained from non-kindled and amygdala-kindled adult rats. We found that kindling coincided with an increase in the amplitude and duration of miniature inhibitory post-synaptic currents (mIPSCs) recorded from non-pyramidal neurones, whereas the mIPSCs occurring on pyramidal (excitatory) cells did not change. Non-stationary noise analysis of mIPSCs occurring on the non-pyramidal neurones showed that inferred unitary conductance of synaptic channels were the same before and after kindling, implying that the channel number increased significantly. Immunocytochemical analysis of the inhibitory innervation showed that it was also unaltered by seizure induction. We also found that the effect of the positive modulator tetrahydrodeoxycorticosterone was reduced on the pyramidal neurones after kindling. In contrast, the potentiating effects of tetrahydrodeoxycorticosterone on non-pyramidal cells were about the same after kindling as in control (sham) rats. These data indicate that amygdala kindling causes a shift in the inhibition 'balance' between the pyramidal and non-pyramidal cells, perhaps leading to the disinhibition of pyramidal cells.