Neurological Dysfunction In Patients Research Articles

Effect of hyperbaric oxygen on post-stroke depression.

In patients with post-stroke depression (PSD) in diabetes, the situation may be more complex, requiring simultaneous treatment of blood glucose, depressive symptoms, and neurological dysfunction. Hyperbaric oxygen (HBO) therapy can improve tissue oxygen content and improve the situation of ischemia and hypoxia, thus playing a role in protecting brain cells and restoring the function of brain cells. However, there are few studies on HBO therapy for patients with PSD. This study explores the clinical efficacy of such therapy for stroke complicated with depression and diabetes mellitus, and to provide reference and basis for clinical treatment and development through the application of relevant rating scales and laboratory test indicators. To evaluate the clinical effects of HBO therapy on patients with diabetes with PSD. A total of 190 diabetic patients with PSD were randomly divided into observation and control groups (95 patients per group). The control group received escitalopram oxalate 10mg once a day for eight weeks. In addition, the ob-servation group was also given HBO therapy, once a day, five times a week, for eight weeks. The Montgomery Depression Rating Scale (MADRS), National Institutes of Health Stroke Scale (NIHSS), hypersensitive C-reactive protein, tumor necrosis factor (TNF)-α, and fasting glucose levels were compared. There were no significant differences in age, sex, or depression course between the groups (P > 0.05). After HBO treatment, MADRS scores in both groups decreased significantly (14.3 ± 5.2), and were significantly lower in the control group (18.1 ± 3.5). After HBO treatment, NIHSS scores in both groups decreased significantly, and scores in the observation group (12.2 ± 4.0) decreased more than in the control group (16.1 ± 3.4), the difference was statistically significant (P < 0.001). The levels of hypersensitive C-reactive protein and TNF-α in both groups were significantly decreased, and the observation group was significantly lower than the control group (P < 0.001). Fasting blood glucose levels in both groups decreased significantly, and those in the observation group decreased more (8.02 ± 1.10) than in the control group (9.26 ± 1.04), with statistical significance (t = -7.994, P < 0.001). HBO therapy can significantly improve depressive symptoms and neurological dysfunction in patients with PSD, and reduce the levels of hypersensitive C-reactive protein, TNF-α and fasting blood glucose.

Predictive value of neurophysiological monitoring during posterior communicating artery aneurysm clipping for postoperative neurological deficits.

This study aimed to evaluate the diagnostic effect of intraoperative neurophysiological monitoring in identifying intraoperative ischemic events and predicting postoperative neurological dysfunction during PCoA aneurysm clipping, as well as to explore the safe duration of intraoperative temporary clipping of the parent artery. All 71 patients with PCoA aneurysm underwent craniotomy and aneurysm clipping. MEP and SSEP were used for monitoring during operation to evaluate the influence of MEP/SSEP changes on postoperative neurological function. Receiver operating characteristic (ROC) curve analysis was used to calculate optimal duration of intraoperative temporary clipping. Patients with intraoperative MEP/SSEP changes were more likely to develop short-term and long-term neurological deficits than those without MEP/SSEP changes (P < 0.05). From the ROC curve analysis, the safe time from the initiation of temporary clipping during the operation to the early warning of neurophysiological monitoring was 4.5 min (AUC = 0.735, 95%CI 0.5558-0.912). Taking 4.5 min as the dividing line, the incidence of short-term and long-term neurological dysfunction in patients with temporary clipping >4.5 min was significantly higher than that in patients with temporary clipping ≤4.5 min (P = 0.015, P = 0.018). Intraoperative MEP/SSEP changes are significantly associated with postoperative neurological dysfunction in patients with PCoA aneurysms. The optimal duration of temporary clipping of the parent artery during posterior communicating aneurysm clipping was 4.5 min under neurophysiological monitoring.

Enlarged perivascular spaces, neuroinflammation and neurological dysfunction in NMOSD patients.

Background and objectivesCerebrospinal fluid (CSF) and interstitial fluid exchange along a brain-wide network of perivascular spaces (PVS) termed the ‘glymphatic system’. The aquaporin-4 (AQP4) water channels abundantly expressed on astrocytic endfeet play a key role in the CSF circulation in the glymphatic system. Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating autoimmune disease of the central nervous system (CNS) featured with a specific autoantibody directed against AQP4 in most of patients. Anti-AQP4 antibodies are likely resulting in the impairment of the brain glymphatic system and the enlargement of PVS in NMOSD patients. In the current study, we aimed to demonstrate the features of EPVS detected by MRI and its association with the CSF anti-AQP4 antibody titer, CNS inflammatory markers, and disease severity in NMOSD patients.MethodsWe conducted a retrospective review of a consecutive cohort of 110 patients with NMOSD who had brain MRI. We assessed the correlation of EPVS with markers of neuroinflammation, blood-brain barrier (BBB) function and severity of neurological dysfunction in patients. We used multivariate logistic regression analysis to determine the independent variables associated with disease severity.ResultsThe median number of total-EPVS was 15.5 (IQR, 11-24.2) in NMOSD patients. The number of total-EPVS was significantly related to EDSS score after correcting for the effects of age and hypertension (r=0.353, p<0.001). The number of total-EPVS was also significantly associated with the titer of CSF anti-AQP4 antibody, the albumin rate (CSF/serum ratios of albumin), the CSF albumin, IgG and IgA levels. Logistic regression analysis showed that total-EPVS and serum albumin level were two independent factors to predict disease severity in NMOSD patients (OR=1.053, p=0.028; OR=0.858, p=0.009 respectively). Furthermore, ROC analysis achieved AUC of 0.736 (0.640-0.831, p<0.001) for total-EPVS to determine severe NMOSD (EDSS 4.5-9.5).DiscussionIn our cohort, we found a relationship between EPVS and neuroinflammation and BBB function in NMOSD. Moreover, EPVS might independently predict neurological dysfunction in patients with NMOSD.

Cerebellar syndrome associated with legionellosis: A case report and literature review

IntroductionLegionnaire's disease is a community-acquired pneumonia caused by the Gram-negative bacterium Legionella pneumophila. This disease is often associated with neurological symptoms, the clinical presentation of which can be very varied. Case reportWe report a 47-year-old female patient who developed Legionnaires’ disease with cerebellar symptoms (ataxia, dysarthria and hypermetria). Laboratory tests revealed a biological inflammatory syndrome. The cerebrospinal fluid was sterile. Urinary antigen test and serology were positive for L. pneumophila. An interstitial syndrome of the right upper lobe was detected on chest computed tomography (CT) scan. Brain imaging (magnetic resonance imaging and CT angiography) showed no abnormalities. The outcome was favourable after treatment with spiramycin, levofloxacin and corticosteroids. DiscussionFew cases only (n=110) of Legionnaires’ disease with cerebellar symptoms have been reported in the literature. The pathogenic mechanism behind neurological dysfunction in patients with Legionnaires’ disease is unknown. Neurological symptoms improve with antibiotic therapy and corticosteroids. Extra-pulmonary forms of Legionnaires’ disease are frequent, with neurological symptoms being the most common symptoms. Cerebellar dysfunction may be underestimated and requires appropriate management with antibiotic therapy and corticosteroid therapy. Recommendations for the management of Legionnaire's disease with severe extra-pulmonary symptoms are needed.

Can regional cerebral oxygen saturation monitoring during circulatory arrest time predict postoperative neurological dysfunction in patients undergoing surgical pulmonary thromboendarterectomy? Useful index for short- and long-term outcomes.

A hypothermic circulatory arrest is usually used to correct thoracic aorta pathologies. The emergency treatment of acute type A aortic dissection and elective repair of aortic arch pathologies are the most common indications for using hypothermic circulatory arrest. A hypothermic circulatory arrest can also be used for surgical pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension. Intervals with total circulatory arrest offer a clear surgical field for thrombus and emboli removal from the pulmonary artery branches. The price to pay for intermittent circulatory arrest during pulmonary thromboendarterectomy is postoperative neurological dysfunction due to brain hypothermia and hypoperfusion. A noninvasive method for cerebral monitoring during cardiac surgery is real-time regional cerebral oxygen saturation (rSO2 ). Liu et al. report that continuous monitoring of rSO2 during surgical pulmonary thromboendarterectomy may reduce the long cerebral hypoperfusion time and prevent postoperative neurological dysfunction.

Homocysteine Plasmatic Concentration in Brain-Injured Neurocritical Care Patients: Systematic Review of Clinical Evidence.

Background: Hyperhomocysteinemia (HHcy) is considered as an independent risk factor for several diseases, such as cardiovascular, neurological and autoimmune conditions. Atherothrombotic events, as a result of endothelial dysfunction and increased inflammation, are the main mechanisms involved in vascular damage. This review article reports clinical evidence on the relationship between the concentration of plasmatic homocysteine (Hcy) and acute brain injury (ABI) in neurocritical care patients. Materials and methods: a systematic search of articles in the PubMed and EMBASE databases was conducted, of which only complete studies, published in English in peer-reviewed journals, were included. Results: A total of 33 articles, which can be divided into the following 3 subchapters, are present: homocysteine and acute ischemic stroke (AIS); homocysteine and traumatic brain injury (TBI); homocysteine and intracranial hemorrhage (ICH)/subarachnoid hemorrhage (SAH). This confirms that HHcy is an independent risk factor for ABI and a marker of poor prognosis in the case of stroke, ICH, SAH and TBI. Conclusions: Several studies elucidate that Hcy levels influence the patient’s prognosis in ABI and, in some cases, the risk of recurrence. Hcy appears as biochemical marker that can be used by neuro-intensivists as an indicator for risk stratification. Moreover, a nutraceutical approach, including folic acid, the vitamins B6 and B12, reduces the risk of thrombosis, cardiovascular and neurological dysfunction in patients with severe HHcy that were admitted for neurocritical care.

Individualized management objectives for hypoxic-ischemic brain injury after cardiac arrest

Hypoxic-ischemic brain injury after cardiac arrest is the main cause of death and neurologic dysfunction in patients after the return of spontaneous circulation. The mechanisms of ischemic and hypoxic brain injury include hypoxia of brain tissue caused by the cessation of cerebral blood flow during the initial cardiac arrest and cerebrovascular dysfunction and reperfusion injury after the recovery of circulation. Cerebral circulatory perfusion, cerebral autoregulation, and cerebral edema can be monitored and controlled as therapeutic targets. In this study, from the aspects of body temperature, mean arterial pressure, oxygen concentration, partial pressure of carbon dioxide in the artery, and cerebral edema, monitoring methods such as measurement of cerebral oxygen saturation, assessment of cerebral blood flow, imaging of the brain, and measurement of intracranial pressure were introduced to explore individual management objectives for hypoxic-ischemic brain injury.

Altered Spontaneous Brain Activity Related to Neurologic Dysfunction in Patients With Cerebral Small Vessel Disease.

Cerebral small vessel disease (CSVD) encompasses several diseases affecting the small arteries, arterioles, venules, and capillaries of the brain and refers to several pathological processes and etiologies. Neuroimaging is considered the gold standard for detecting CSVD, which can present diverse features on MRI. Cerebral microbleeds (CMBs) in CSVD have been demonstrated to play a synergistic role in both cerebrovascular and neurodegenerative pathology. Considering previous studies on brain structural abnormalities in CSVD, in the present study, we aimed to explore altered spontaneous brain activity among CSVD patients using amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF) and regional homogeneity (ReHo) methods based on resting-state functional MRI. In this study, we recruited 24 CSVD patients with CMBs (CSVD-c), 42 CSVD patients without CMBs (CSVD-n) and 36 healthy controls from outpatient clinics in Shandong Provincial Hospital affiliated to Shandong First Medical University between September 2018 and June 2019. All subjects underwent 3-T MRI, including blood oxygen level-dependent (BOLD) and susceptibility-weighted imaging (SWI). Anatomic structures were segmented, ALFF/fALFF values were calculated, and ReHo maps were generated. Further statistical analysis was applied to study the difference in ALFF/fALFF/ReHo among the three groups and the association between ALFF/fALFF/ReHo changes in different brain regions and clinical characteristics. Twenty-four CSVD-c patients (age: 67.54 ± 6.00 years, 10 females), 42 CSVD-n patients (age: 66.33 ± 5.25 years, 22 females) and 36 healthy subjects (age: 64.14 ± 8.57 years, 19 females) were evaluated. Compared with controls, the CSVD-c group showed significantly increased ALFF values in the right insula, putamen and left precuneus; decreased fALFF values in the right precentral gyrus and postcentral gyrus; and increased ReHo values in the left precuneus, fusiform gyrus, right supplementary motor area (SMA), and superior frontal gyrus. Notably, the mean ALFF values of the right insula and putamen were not only significantly related to all clinical parameters but also demonstrated the best performance in Receiver Operating Characteristic (ROC) curve analysis. These findings reveal CSVD-c patients have dysfunctions in the default mode network, sensorimotor network and frontoparietal network, which may implicate the underlying neurophysiological mechanisms of intrinsic brain activity. The correlation between altered spontaneous neuronal activity and clinical parameters provides early useful diagnostic biomarkers for CSVD.

P14. Outcome and predictive factors in rapid progressive cervical spondylotic myelopathy: A retrospective case control study

<h3>BACKGROUND CONTEXT</h3> Cervical spondylotic myelopathy (CSM) is a major cause of cervical spinal cord dysfunction in people over 55 years of age. Most patients with CSM usually present with chronic and phased compression, however, some patients with CSM develop rapid severe neurological dysfunction without any trauma. To our knowledge, markers that can be used for early identi cation of patients with potential to develop rapid neurological deterioration have not been totally identified. <h3>PURPOSE</h3> Here, we evaluate epidemiological, clinical and radiographic features associated with the development and prognosis of rapid progressive cervical spondylotic myelopathy (rp-CSM). <h3>STUDY DESIGN/SETTING</h3> Retrospective study <h3>PATIENT SAMPLE</h3> A total of 175 patients. <h3>OUTCOME MEASURES</h3> Modified Japanese Orthopaedic Association (mJOA) score, Torg-Pavlov Ratio (TPR), intervertebral disc level compression ratio and increased signal intensity (ISI) on T2W1. <h3>METHODS</h3> A retrospective study was carried out for 175 patients diagnosed with CSM between March 2011 and January 2017 at West China Hospital. Patients were divided into rp-CSM group and chronic CSM (c-CSM) group based on the time taken for neurological deterioration to occur and the severity of preoperative neurological dysfunction. The clinical outcomes were assessed using the Modified Japanese Orthopaedic Association (mJOA) score, and imaging parameters such as Torg-Pavlov Ratio (TPR), intervertebral disc level compression ratio and increased signal intensity (ISI) on T2W1. Multivariate analysis was used to compare the outcomes between the two groups and identify potential predictors for rapid neurological dysfunction in CSM patients. <h3>RESULTS</h3> Out of the 175 patients enrolled in the study, 25 developed rp-CSM (18 males; median age 59.04 ± 12.81 years) and the remaining 75 (54 males; median age 56.88 ± 12.31 years) were used as controls for the study (c- CSM group). The average time taken to develop severe neurological deterioration was 0.8 month in rp-CSM group and 24-month in c-CSM group (p = 0.001), while the preoperative mJOA scores were 6 in rp-CSM patients and 12 in c-CSM patients (p = 0.014). In addition, rp-CSM patients demonstrated worse outcomes than the controls in one year after surgery (mJOA improvement rate 54.5% and 80%, respectively, p = 0.021). There were no differences in the clinical parameters evaluated between the two groups except for the history of diabetes and smoking. Analysis of radiographic parameters indicated that TPR MRI, intervertebral disc level compression ratio and increased signal intensity (ISI) on T2W1 were poor in rp-CSM patients compared to c-CSM patients. Regression analysis also showed that the history of diabetes, TPR MRI < 0.4, compression ratio ≥50%, and the sagittal diameter of ISI ≥ 50% of spinal canal diameter on T2W1 were strongly associated with the rapid progressive neurological dysfunction in patients with CSM. <h3>CONCLUSIONS</h3> The prognosis of rapid progressive CSM is worse than that of common chronic CSM. The rapid neurological deterioration can be identified by TPR MRI (<0.4), compression ratio (≥50%), sagittal diameter of ISI (≥50% of spinal canal diameter). Besides, a history of diabetes is a risk factor for the development of rp-CSM. <h3>FDA DEVICE/DRUG STATUS</h3> This abstract does not discuss or include any applicable devices or drugs.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Perioperative Neurological Evaluation and Management to Lower the Risk of Acute Stroke in Patients Undergoing Noncardiac, Nonneurological Surgery: A Scientific Statement From the American Heart Association/American Stroke Association.

Perioperative stroke is a potentially devastating complication in patients undergoing noncardiac, nonneurological surgery. This scientific statement summarizes established risk factors for perioperative stroke, preoperative and intraoperative strategies to mitigate the risk of stroke, suggestions for postoperative assessments, and treatment approaches for minimizing permanent neurological dysfunction in patients who experience a perioperative stroke. The first section focuses on preoperative optimization, including the role of preoperative carotid revascularization in patients with high-grade carotid stenosis and delaying surgery in patients with recent strokes. The second section reviews intraoperative strategies to reduce the risk of stroke, focusing on blood pressure control, perioperative goal-directed therapy, blood transfusion, and anesthetic technique. Finally, this statement presents strategies for the evaluation and treatment of patients with suspected postoperative strokes and, in particular, highlights the value of rapid recognition of strokes and the early use of intravenous thrombolysis and mechanical embolectomy in appropriate patients.

The application of scales and characteristics of disability in the common genotypes of Charcot-Marie-Tooth disease

Objective: To analyze the correlations among different common scales for evaluating the severity of the first-visit Charcot-Marie-Tooth disease (CMT), and explore the cross-sectional characteristics of neurological dysfunction in patients with four common genotypes (CMT1A, CMT1X, CMT2A and MPZ-related CMT) at their first visits. Methods: A total of 117 genetically confirmed CMT patients (aged ≥10 years) from the Department of Neurology of the Third Xiangya Hospital from 2009 to 2019 were included in the study, which consisted of 45 CMT1A, 41 CMT1X, 19 CMT2A, and 12 MPZ-related CMT patients. Clinical data of these patients at first visits were collected and neurological deficits were evaluated by Charcot-Marie-Tooth Neuropathy Score (CMTNS), Charcot-Marie-Tooth Examination Score (CMTES), Overall Neuropathy Limitation Scale (ONLS) and Functional Disability Scale (FDS). Spearman's correlation was performed to analyze the relationship between CMTNS, CMTES, ONLS and FDS. The age of onset, duration of disease, scores of CMTNS, CMTES, ONLS and FDS were compared among four genotypes. Results: In the 117 CMT patients, the male to female ratio was 1.79/1, and the age of onset was (19±13) years. The duration of disease was 10(3, 15) years, and the scores of CMTNS, CMTES, ONLS and FDS were 11.4±6.2, 8.8±5.7, 2.7±1.4 and 2.6±1.3, respectively. There was a significant correlation between CMTES, ONLS, FDS and CMTNS in the overall CMT patients and four subtypes respectively (r≥0.40, P<0.05). CMTNS, CMTES and ONLS scores of four subtypes showed positive correlations with duration of disease (P<0.05), but FDS scores of CMT1A, CMT1X and MPZ-related CMT patients exhibited no correlation with duration of disease (P>0.05) at their first visits. The age of onset in CMT2A patients was younger than that of the patients with the other three genotypes (P<0.05), furthermore, the scores of four scales in early-onset CMT2A patients were higher than those of adult-onset type CMT2A patients (CMTNS: P=0.031, CMTES: P=0.048, ONLS: P=0.042, FDS: P=0.047). In CMT1X patients, the males had higher scores than those of females for all four scales (CMTNS: P=0.028, CMTES: P=0.014, ONLS: P=0.023, FDS: P=0.002). Conclusions: CMTNS, CMTES and ONLS could be used in natural history studies and clinical trials according to the different clinical situations. In the four genotypes, CMT2A patients have younger age of onset, and the earlier the age of onset, the severer the dysfunction. Moreover, male CMT1X patients relatively have severer neurological dysfunction than female patients.

Outcome and predictive factors in rapid progressive cervical spondylotic myelopathy: A retrospective case-control study

BackgroundCervical spondylotic myelopathy (CSM) is a major cause of cervical spinal cord dysfunction in people over 55 years of age. Most patients with CSM usually present with chronic and phased compression, however, some patients with CSM develop rapid severe neurological dysfunction without any trauma. To our knowledge, markers that can be used for early identification of patients with potential to develop rapid neurological deterioration have not been totally identified. Here, we evaluate epidemiological, clinical and radiographic features associated with the development and prognosis of rapid progressive cervical spondylotic myelopathy (rp-CSM). MethodsA retrospective study was carried out for 175 patients diagnosed with CSM between March 2011 and January 2017 at West China Hospital. Patients were divided into rp-CSM group and chronic CSM (c-CSM) group based on the time taken for neurological deterioration to occur and the severity of preoperative neurological dysfunction. The clinical outcomes were assessed using the Modified Japanese Orthopaedic Association (mJOA) score, and imaging parameters such as Torg-Pavlov Ratio (TPR), intervertebral disc level compression ratio and increased signal intensity (ISI) on T2W1. Multivariate analysis was used to compare the outcomes between the two groups and identify potential predictors for rapid neurological dysfunction in CSM patients. ResultsOut of the 175 patients enrolled in the study, 25 developed rp-CSM (18 males; median age 59.04 ± 12.81 years) and the remaining 75 (54 males; median age 56.88 ± 12.31 years) were used as controls for the study (c-CSM group). The average time taken to develop severe neurological deterioration was 0.8 month in rp-CSM group and 24 month in c-CSM group (p = 0.001), while the preoperative mJOA scores were 6 in rp-CSM patients and 12 in c-CSM patients (p = 0.014). In addition, rp-CSM patients demonstrated worse outcomes than the controls in one year after surgery (mJOA improvement rate 54.5 % and 80 %, respectively, p = 0.021). There were no differences in the clinical parameters evaluated between the two groups except for the history of diabetes and smoking. Analysis of radiographic parameters indicated that TPR MRI, intervertebral disc level compression ratio and increased signal intensity (ISI) on T2W1 were poor in rp-CSM patients compared to c-CSM patients. Regression analysis also showed that the history of diabetes, TPR MRI < 0.4, compression ratio ≥50 %, and the sagittal diameter of ISI ≥ 50 % of spinal canal diameter on T2W1 were strongly associated with the rapid progressive neurological dysfunction in patients with CSM. ConclusionThe prognosis of rapid progressive CSM is worse than that of common chronic CSM. The rapid neurological deterioration can be identified by TPR MRI (<0.4), compression ratio (≥50 %), sagittal diameter of ISI (≥50 % of spinal canal diameter). Besides, a history of diabetes is a risk factor for the development of rp-CSM.

The Potential Value of Targeting Ferroptosis in Early Brain Injury After Acute CNS Disease.

Acute central nervous system (CNS) disease is very common and with high mortality. Many basic studies have confirmed the molecular mechanism of early brain injury (EBI) after acute CNS disease. Neuron death and dysfunction are important reasons for the neurological dysfunction in patients with acute CNS disease. Ferroptosis is a nonapoptotic form of cell death, the classical characteristic of which is based on the iron-dependent accumulation of toxic lipid reactive oxygen species. Previous studies have indicated that this mechanism is critical in the cell death events observed in many diseases, including cancer, tumor resistance, Alzheimer’s disease, Parkinson’s disease, stroke, and intracerebral hemorrhage (ICH). Ferroptosis may also play a very important role in EBI after acute CNS disease. Unresolved issues include the relationship between ferroptosis and other forms of cell death after acute CNS disease, the specific molecular mechanisms of EBI, the strategies to activate or inhibit ferroptosis to achieve desirable attenuation of EBI, and the need to find new molecular markers of ferroptosis that can be used to detect and study this process in vivo after acute CNS disease.

Loss‐ and Gain‐of‐Function Mutations in the Type 1 IP3 Receptor (IP3R1) Affect Myogenic Constriction of Cerebral Resistance Arteries in Response to Intraluminal Pressure

The constriction and relaxation of resistance arteries/arterioles in response to changes in intraluminal pressure, referred to as the myogenic response, is a key physiological mechanism for the regulation of blood pressure and flow. Despite the recognized contribution of phospholipase C activity and IP3‐mediated intracellular Ca2+ release to the myogenic response, a lack of selective pharmacological agents to target the predominant IP3R1 Ca2+ release channel has prevented interrogation of this key mechanism. Mutations in the IP3R1 are known to produce either loss‐of‐function (LOF) or gain‐of‐function (GOF) phenotypes in humans that impact cerebellar activity (e.g. ataxia), yet the effect of these mutations on the cardiovascular system is not established. Here, we employed a novel genetic knock‐in mouse model with a single point mutation in the transmembrane S6 helix of IP3R1 that confers either a LOF (D2594A) or GOF (D2594K) phenotype. In preliminary experiments, the LOF and GOF mutations shifted IP3‐mediated ER Ca2+ release ~2‐fold to the right and left, respectively, compared to wild‐type (WT) IP3R1 in permeabilized HEK293 cells. In endothelium‐denuded posterior cerebral arteries of 3–4 month old WT mice, myogenic vasoconstriction was evident at ≥40 mmHg, maximal at ~120 mmHg, and declined at &gt;120 mmHg (n=7). In contrast, myogenic constriction was initiated at a higher pressure (≥50 mmHg) and was smaller in amplitude in arteries of heterozygous IP3R1 LOF mice (n=8). In IP3R1 GOF vessels (n=7), myogenic tone developed at a lower pressure (≥20 mmHg), was maximal at ~80 mmHg, and declined at &gt;90 mmHg. Relative levels of phosphorylation of myosin regulatory light chain (LC20) and myosin phosphatase targeting subunit (MYPT1) at 10, 40, 80 and 120 mmHg, and of globular (G‐) actin content at 10, 60 and 120 mmHg, in arteries from WT, LOF and GOF mice were assessed by ultra‐high sensitivity immunoblotting. An identical pressure‐dependent increase in phospho‐LC20 content was detected in WT, LOF and GOF vessels (n=5 each). Although phospho‐MYPT1‐T855 content increased with intraluminal pressure in arteries of WT and LOF mice, it did not change in vessels of GOF mice. Elevation of intraluminal pressure decreased in G‐actin content in arteries of WT mice, did not affect G‐actin content in LOF vessels, and caused a significantly greater decrease in GOF arteries. Taken together, these data demonstrate that genetic modification of IP3R1‐mediated Ca2+ mobilization affects the myogenic response of cerebral arteries to intraluminal pressure, a vascular impairment that may contribute to neurological dysfunction in patients with LOF and GOF IP3R1 mutations.Support or Funding InformationThis work was funded by the following research grants from the Canadian Institutes of Health Research: MOP‐97988 (WCC) MOP‐142467 (APB) and PJT‐155963 (APB, WC and WCC).

Inflow Cannula Position as Predictor for Neurological Dysfunction in Patients with HeartMate 3 Left Ventricular Assist Device

The relation between left ventricular assist device (LVAD) inflow cannula malposition and pump thrombus has been reported. This study aimed to investigate pump position, derived from chest X-rays of HM3 patients, in correlation to any neurological dysfunction (ND) and specifically to ischemic stroke (IS) and intracranial hemorrhage (ICH). This retrospective analysis was performed on routinely acquired X-rays of 33 patients (Age: 62.4±9.3 yrs, male: 89.5%, BMI: 28.3±4.9kg/m2) implanted with a HM3 between 2014 and 2017. Device position was quantified in patients with and without any neurological dysfunction (noND) from frontal and lateral X-ray parameters characterizing the inflow cannula (IC), pump depth in relation to spine, diaphragm or horizontal line. The analysis of X-rays (38.6±24.3 days postoperative) revealed a significant smaller IC angle of HM3 patients with any ND vs. noND (2.52±11.59° vs. 13.92±9.74°, p=0.029). Additionally, the IC angle in the frontal view (IS: 0.23±11.34° vs. noIS: 13.92±9.45°, p=0.012) as well as the pump depth (IS: 19.7±16.8mm vs. noIS: 38.3±19.6mm, p=0.044) were significantly smaller for HM3 patients with IS. Using receiver operating characteristic (ROC) curve-derived cut-points, IC angle <10.06° provided 100% sensitivity and 72% specificity (C-statistic=0.867) for predicting IS. Stratified by IC angle, freedom from any IS at 12 months was 100% (>10.06°) and 50.4% (<10.06°) respectively (p=0.004). Further, no significant differences were found in any parameter between patients with and without ICH. In HM3 patients, inflow cannula malposition identified from X-rays serves as a risk factor for neurological dysfunction and especially ischemic stroke.

Omega-3 fatty acid supplementation can prevent changes in mitochondrial energy metabolism and oxidative stress caused by chronic administration of L-tyrosine in the brain of rats.

Deficiency of hepatic enzyme tyrosine aminotransferase characterizes the innate error of autosomal recessive disease Tyrosinemia Type II. Patients may develop neurological and developmental difficulties due to high levels of the amino acid tyrosine in the body. Mechanisms underlying the neurological dysfunction in patients are poorly known. Importantly, Tyrosinemia patients have deficient Omega-3 fatty acids (n-3 PUFA). Here, we investigated the possible neuroprotective effect of the treatment with n-3 PUFA in the alterations caused by chronic administration of L-tyrosine on important parameters of energetic metabolism and oxidative stress in the hippocampus, striatum and cerebral cortex of developing rats. Chronic administration of L-tyrosine causes a decrease in the citrate synthase (CS) activity in the hippocampus and cerebral cortex, as well as in the succinate dehydrogenase (SDH) and isocitrate dehydrogenase (IDH) activities, and an increase in the α-ketoglutarate dehydrogenase activity in the hippocampus. Moreover, in the striatum, L-tyrosine administration caused a decrease in the activities of CS, SDH, creatine kinase, and complexes I, II-III and IV of the mitochondrial respiratory chain. We also observed that the high levels of L-tyrosine are related to oxidative stress in the brain. Notably, supplementation of n-3 PUFA prevented the majority of the modifications caused by the chronic administration of L-tyrosine in the cerebral enzyme activities, as well as ameliorated the oxidative stress in the brain regions of rats. These results indicate a possible neuroprotective and antioxidant role for n-3 PUFA and may represent a new therapeutic approach and potential adjuvant therapy to Tyrosinemia Type II individuals.

Morphologic variations of the second cervical vertebra in Down syndrome compared with age-matched peers.

OBJECTIVEAtlantoaxial instability is an important cause of pain and neurological dysfunction in patients with Down syndrome (DS), frequently requiring instrumented fusion of the upper cervical spine. This study provides a quantitative analysis of C2 morphology in DS patients compared with their peers without DS to identify differences that must be considered for the safe placement of instrumentation.METHODSA retrospective chart review identified age-matched patients with and without DS with a CT scan of the cervical spine. Three-dimensional reconstructions of these scans were made with images along the axis of, and perpendicular to, the pars, lamina, facet, and transverse foramen of C2 bilaterally. Two of the authors performed independent measurements of anatomical structures using these images, and the average of the 2 raters' measurements was recorded. Pedicle height and width; pars axis length (the distance from the facet to the anterior vertebral body through the pars); pars rostrocaudal angle (angle of the pars axis length to the endplate of C2); pars axial angle (angle of the pars axis length to the median coronal plane); lamina height, length, and width; lamina angle (angle of the lamina length to the median coronal plane); and transverse foramen posterior distance (the distance from the posterior wall of the transverse foramen to the tangent of the posterior vertebral body) were measured bilaterally. Patients with and without DS were compared using a mixed-effects model accounting for patient height.RESULTSA total of 18 patients with and 20 patients without DS were included in the analysis. The groups were matched based on age and sex. The median height was 147 cm (IQR 142-160 cm) in the DS group and 165 cm (IQR 161-172 cm) in the non-DS group (p < 0.001). After accounting for variations in height, the mean pars rostrocaudal angle was greater (50.86° vs 45.54°, p = 0.004), the mean transverse foramen posterior distance was less (-1.5 mm vs +1.3 mm, p = 0.001), and the mean lamina width was less (6.2 mm vs 7.7 mm, p = 0.038) in patients with DS.CONCLUSIONSPatients with DS had a steeper rostrocaudal trajectory of the pars, a more posteriorly positioned transverse foramen posterior wall, and a narrower lamina compared with age- and sex-matched peers. These variations should be considered during surgical planning, as they may have implications to safe placement of instrumentation.

Newly validated biomarkers of brain damage may shed light into the role of oxidative stress in the pathophysiology of neurocognitive impairment in dietary restricted phenylketonuria patients.

Despite a strict dietary control, patient with hyperphenylalaninemia or phenylketonuria may show cognitive and/or behavioral disorders. These comorbid deficits are of great concern to patients, families, and health organizations. However, biomarkers capable of detecting initial stages of neurological damage are not commonly employed. The pathogenesis of phenylketonuria is complex in nature. Increasingly, the role of oxidative stress has gained acceptance and biomarkers reflecting oxidative damage to the brain and easily accessible in peripheral biofluids have been validated using mass spectrometry techniques. In the present review, the role of oxidative stress in the pathogenesis of phenylketonuria and hyperphenylalaninemia has been updated. Moreover, we report on newly validated brain-specific lipid peroxidation biomarkers and inform on their relevance in the detection and monitoring of neurological damage in phenylketonuric patients. In preliminary studies, a correlation between lipid peroxidation biomarkers and neurological dysfunction in patients with PKU was reported. However, there is a need of adequately powered trials to confirm the validity of these biomarkers for early detection of brain damage, initiation of treatment, and reliably monitor evolving disease both in phenylketonuria and hyperphenylalaninemia.

Deep chronic microvascular white matter ischemic change as an independent predictor of acute brain infarction after thoracic aortic replacement.

Postoperative brain injury is a cause of mortality and morbidity in patients who undergo thoracic aortic replacement. Chronic microvascular white matter ischemic change (WMIC) has been shown to be associated with acute brain infarction in the general population. WMIC has also been shown to be an independent predictor of non-focal neurocognitive changes, generalized seizures, and temporary neurologic dysfunction in patients who undergo thoracic aortic replacement. The aim of this study is to determine if WMIC is a risk factor for acute brain infarction in patients who undergo thoracic aortic replacement. A case-control study of patients who underwent thoracic aortic replacement between 2001 and 2014 were reviewed for neurological changes after surgery and acute brain infarction on postoperative diffusion-weighted imaging (DWI) magnetic resonance imaging (MRI). Patients with neurological changes were matched with control patients who underwent thoracic aortic replacement and had postoperative neurological symptoms without acute brain infarctions. Acute infarction was re-assessed by reviewing DWI sequences on postoperative MRI. WMIC was assessed on FLAIR and T2WI sequences on both preoperative and postoperative MRI. Logistic regression was performed assessing the relationship of WMIC and acute ischemic infarction. 5171 patients underwent thoracic aortic replacement; 179 had postoperative neurological changes, and of those 53 patients had acute brain infarction on postoperative DWI. Patients with deep WMIC were more likely to have acute DWI infarctions after thoracic aortic replacement (P = 0.023). Our matched retrospective case-controlled study shows deep WMIC to be a predictor of acute brain infarction on DWI after thoracic aortic replacement.