Trends in Utilization of Magnetic Resonance Imaging for Stroke Patients With Cardiac Rhythm Devices.

Background and Purpose: Magnetic resonance imaging (MRI) is safe for most patients with cardiovascular implantable electronic devices (CIEDs). However, patients presenting with acute ischemic stroke or transient ischemic attack (AIS/TIA) who have CIEDs may undergo MRI less frequently than patients without devices. We assessed contemporary use of MRI for patients with AIS/TIA and the effect of a recent coverage revision by the Center for Medicare and Medicaid Services (CMS) on MRI utilization. Methods: Using Optum® claims data from January 2012 to June 2019, we performed an interrupted time series analysis of MRI utilization during AIS/TIA hospitalizations with the April 2018 CMS coverage revision serving as the intervention. For patients treated after the coverage revision, we used multivariable logistic regression to determine the association between lack of CIED and MRI utilization for AIS/TIA. Results: We identified 417,899 patient hospitalizations for AIS/TIA, of which 30,425 (7%) had a CIED present (CIED vs non-CIED patients: age 77.6 ± 9.8 vs 72.7 ± 12.3 years; 45.5% vs 54.3% female). From 2012 to 2019, annual MRI utilization increased from 3% to 20% for CIED patients and 58% to 66% for non-CIED patients. The CMS coverage revision was associated with a 4.2% absolute additional increase in MRI utilization for CIED patients. Non-CIED patients treated after the CMS coverage revision were substantially more likely than CIED patients to undergo MRI (adjusted OR 6.7, 95% CI: 6.3-7.1, P<.001). Conclusions: MRI utilization has increased for stroke patients with CIEDs but remains far lower than in similar patients without devices.

Increased activation product of complement 4 protein in plasma of individuals with schizophrenia.

Structural variation in the complement 4 gene (C4) confers genetic risk for schizophrenia. The variation includes numbers of the increased C4A copy number, which predicts increased C4A mRNA expression. C4-anaphylatoxin (C4-ana) is a C4 protein fragment released upon C4 protein activation that has the potential to change the blood-brain barrier (BBB). We hypothesized that elevated plasma levels of C4-ana occur in individuals with schizophrenia (iSCZ). Blood was collected from 15 iSCZ with illness duration < 5 years and from 14 healthy controls (HC). Plasma C4-ana was measured by radioimmunoassay. Other complement activation products C3-ana, C5-ana, and terminal complement complex (TCC) were also measured. Digital-droplet PCR was used to determine C4 gene structural variation state. Recombinant C4-ana was added to primary brain endothelial cells (BEC) and permeability was measured in vitro. C4-ana concentration was elevated in plasma from iSCZ compared to HC (mean = 654 ± 16 ng/mL, 557 ± 94 respectively, p = 0.01). The patients also carried more copies of the C4AL gene and demonstrated a positive correlation between plasma C4-ana concentrations and C4A gene copy number. Furthermore, C4-ana increased the permeability of a monolayer of BEC in vitro. Our findings are consistent with a specific role for C4A protein in schizophrenia and raise the possibility that its activation product, C4-ana, increases BBB permeability. Exploratory analyses suggest the novel hypothesis that the relationship between C4-ana levels and C4A gene copy number could also be altered in iSCZ, suggesting an interaction with unknown genetic and/or environmental risk factors.

Cryptogenic new-onset refractory status epilepticus (NORSE) following blood transfusion in a patient with severe anemia.

New-onset refractory status epilepticus (NORSE) is a rare neurological emergency in which a patient without prior seizure disorder develops seemingly unprovoked status epilepticus refractory to treatment. We report the case of a middle-aged woman who developed NORSE after receiving multiple blood transfusions for subacute blood loss anemia secondary to menorrhagia. Although the mechanism is unclear, we propose that sudden changes in blood viscosity and vasogenic tone resulted in cortical edema and irritation. Although seizures have been documented in patients who undergo blood transfusion and develop posterior reversible encephalopathy syndrome (PRES), there was no radiographic evidence of PRES in this case. This is the first reported case of cryptogenic NORSE following blood transfusion.

Hypoperfusion Intensity Ratio Predicts Malignant Edema and Functional Outcome in Large-Vessel Occlusive Stroke with Poor Revascularization.

BACKGROUND AND OBJECTIVE: Malignant cerebral edema (MCE) is a well-known complication in patients with acute ischemic stroke with core infarcts ≥ 80 mL caused by large-vessel occlusions. MCE can also develop in patients with smaller infarcts with moderate -to-large volume of tissue at risk who do not achieve successful revascularization with endovascular thrombectomy (ET). Features that predict the development of MCE in this population are not well-described. We aim to identify predictors of MCE and 90-day functional outcome in stroke patients with an anterior circulation large vessel occlusion (LVO) and a < 80 mL ischemic core who do not achieve complete reperfusion. METHODS: We reviewed our institutional stroke registry and included patients who achieved unsuccessful revascularization, mTICI 0-2a, after ET and whose baseline imaging was notable for a core infarct < 80 mL, a Tmax > 6 s volume ≥ 80 mL, and a mismatch ratio ≥ 1.8. MCE was defined as ≥ 5 mm of midline shift on follow-up imaging, obtained 6-48 h after the pre-ET perfusion scan. RESULTS: Thirty-six patients met inclusion criteria. Unadjusted analysis demonstrated that younger age, higher systolic blood pressure, larger core volume, and higher hypoperfusion intensity ratio (HIR) were associated with MCE (all p < 0.02). In multivariate logistic regression analysis, age, HIR, and core infarct volume were independent predictors of MCE. The optimal HIR threshold to predict MCE was ≥ 0.54 (OR 14.7, 95% CI 2.4-78.0, p = 0.003). HIR was also associated with 3-month mRS (HIR ≥ 0.54 for mRS of 3-6: OR 10.8, 95% CI 1.9-44.0, p = 0.02). CONCLUSIONS: Younger age, larger core infarct volume, and higher HIR are predictive of MCE in patients with anterior circulation LVO, moderate-to-large tissue at risk, and suboptimal revascularization. HIR is correlated with three-month functional outcomes.

Tilt-Corrected Region Boundaries May Enhance the Alberta Stroke Program Early Computed Tomography Score for Less Experienced Raters.

BACKGROUND: The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is widely used to quantify early ischemic changes in the anterior circulation but has limited inter-rater reliability. AIMS: We investigated whether application of 3-dimensional boundaries outlining the ASPECTS regions improves inter-rater reliability and accuracy. METHODS: We included all patients from our DEFUSE 2 database who had a pretreatment noncontrast computed tomography scan (NCCT) of acceptable quality. Six raters (2 neuroradiologists, 2 vascular neurologists, and 2 neurology residents) scored ASPECTS of each NCCT without ("CT-native") and with the superimposed boundary template ("CT-template"). Gold-standard ASPECTS were generated by the 2 neuroradiologists through joint adjudication. Inter-rater reliability and accuracy were assessed using the intraclass correlation coefficient (ICC) for full-scale agreements and Gwet's AC1 for dichotomized (ASPECTS 0-6 vs 7-10) agreements. RESULTS: Eighty-two patients were included. Inter-rater reliability improved with higher training level for both CT-native (ICC = .15, .31, .54 for residents, neurologists, and radiologists, respectively) and CT-template (ICC = .18, .33, .56). Use of the boundary template improved correlation with the gold-standard for one resident on full-scale agreement (ICC increased from .01 to .31, P = .01) and another resident on dichotomized agreement (AC1 increased from .36 to .64, P = .01), but resulted in no difference for other raters. The template did not improve ICC between raters of the same training level. CONCLUSIONS: Inter-rater reliability of ASPECTS improves with physician training level. Standardized display of ASPECTS region boundaries on NCCT does not improve inter-rater reliability but may improve accuracy for some less experienced raters.

Dermatological Manifestations of Postural Tachycardia Syndrome Are Common and Diverse.

BACKGROUND AND PURPOSE: Postural tachycardia syndrome (POTS) is a syndrome of orthostatic intolerance in the setting of excessive tachycardia with orthostatic challenge, and these symptoms are relieved when recumbent. Apart from symptoms of orthostatic intolerance, there are many other comorbid conditions such as chronic headache, fibromyalgia, gastrointestinal disorders, and sleep disturbances. Dermatological manifestations of POTS are also common and range widely from livedo reticularis to Raynaud's phenomenon. METHODS: Questionnaires were distributed to 26 patients with POTS who presented to the neurology clinic. They were asked to report on various characteristics of dermatological symptoms, with their answers recorded on a Likert rating scale. Symptoms were considered positive if patients answered with "strongly agree" or "agree", and negative if they answered with "neutral", "strongly disagree", or "disagree". RESULTS: The most commonly reported symptom was rash (77%). Raynaud's phenomenon was reported by over half of the patients, and about a quarter of patients reported livedo reticularis. The rash was most commonly found on the arms, legs, and trunk. Some patients reported that the rash could spread, and was likely to be pruritic or painful. Very few reported worsening of symptoms on standing. CONCLUSIONS: The results suggest that dermatological manifestations in POTS vary but are highly prevalent, and are therefore of important diagnostic and therapeutic significance for physicians and patients alike to gain a better understanding thereof. Further research exploring the underlying pathophysiology, incidence, and treatment strategies is necessary.

Gastrointestinal dysfunction in postural tachycardia syndrome.

BACKGROUND: Postural tachycardia syndrome (POTS) is a dysautonomia defined by an exaggerated increase in heart rate upon changing posture. It is associated with disturbances involving multiple organ systems, including neurologic, dermatologic, and gastrointestinal (GI) symptoms. Previous studies identified GI complaints in these patients and showed gastric emptying and electrical activity abnormalities. However, the full spectrum of GI symptoms and their impact on quality of life remains unclear. METHODS: A 30-question survey of GI symptoms was collected from 28 patients with POTS seen in the Boston Medical Center Autonomic Clinic. Answers were recorded on a Likert rating scale. Symptoms were positive if patients answered "strongly agree" or "agree" and negative if they answered "strongly disagree" or "disagree." Responses were collected and analyzed. RESULTS: The most commonly reported GI symptoms were nausea (86%), irregular bowel movements (71%), abdominal pain (70%), and constipation (70%). Additionally, 82% of patients reported having GI symptoms more than once per week, and 71% reported having seen a GI specialist, and symptoms did not improve with changes in position. Twelve patients had undergone a gastric emptying study, and six of these patients reported receiving a diagnosis of gastroparesis or delayed gastric emptying. CONCLUSIONS: GI disturbances are common, frequent, and prolonged in patients with POTS, likely impacting quality of life. Given the importance of the enteric nervous system to normal GI functioning, the same autonomic impairment leading to POTS may result in abnormal gut motility and ultimately subjective GI discomfort.

A survey-based analysis of symptoms in patients with postural orthostatic tachycardia syndrome.

Postural orthostatic tachycardia syndrome (POTS) is a type of dysautonomia seen most commonly in young women and children. It is defined as an increase in heart rate of 30 beats per minute (bpm) or more within 10 minutes of standing in adults, or by 40 bpm or more in children in the absence of orthostatic hypotension. In addition to typical autonomic symptoms, POTS patients report a wide range of subjective complaints in multiple organ systems, though the exact frequencies are unclear. To address the symptom frequency, we had 39 patients with POTS at our institution complete an intake form consisting of a list of 37 symptoms. The most frequently reported symptoms included palpitations, lightheadedness, and headache, although sleep disturbances, gastrointestinal complaints, sensitivity to temperature, and rash were also common.

Prokineticin 2 is an endangering mediator of cerebral ischemic injury.

Stroke causes brain dysfunction and neuron death, and the lack of effective therapies heightens the need for new therapeutic targets. Here we identify prokineticin 2 (PK2) as a mediator for cerebral ischemic injury. PK2 is a bioactive peptide initially discovered as a regulator of gastrointestinal motility. Multiple biological roles for PK2 have been discovered, including circadian rhythms, angiogenesis, and neurogenesis. However, the role of PK2 in neuropathology is unknown. Using primary cortical cultures, we found that PK2 mRNA is up-regulated by several pathological stressors, including hypoxia, reactive oxygen species, and excitotoxic glutamate. Glutamate-induced PK2 expression is dependent on NMDA receptor activation and extracellular calcium. Enriched neuronal culture studies revealed that neurons are the principal source of glutamate-induced PK2. Using in vivo models of stroke, we found that PK2 mRNA is induced in the ischemic cortex and striatum. Central delivery of PK2 worsens infarct volume, whereas PK2 receptor antagonist decreases infarct volume and central inflammation while improving functional outcome. Direct central inhibition of PK2 using RNAi also reduces infarct volume. These findings indicate that PK2 can be activated by pathological stimuli such as hypoxia-ischemia and excitotoxic glutamate and identify PK2 as a deleterious mediator for cerebral ischemia.