Severe Neurological Disability Research Articles

A Review of Antithrombotic Agents for the Treatment of Ischemic Stroke

Ischemic stroke caused by a blockage in blood vessels that supplies blood to the brain, can lead to severe neurological disability or even death if not treated in a timely proper manner. Current treatment for ischemic stroke comprises Intravenous Thrombolytic Therapy (IVT) and Endovascular Therapy (EVT). However, the unmet medical needs lie in the high disability, narrow therapeutic window, low patient eligibility for operations, and recurrent ischemic stroke and bleeding complications. The development of antithrombotic agents is key to reducing complications of current treatment and secondary prevention of ischemic stroke. This review paper covers a wide range of most commonly used antithrombotic medications or advancements in antithrombotic agents, including warfarin, heparins (UFH and LMWH), direct oral anticoagulants (dabigatran, rivaroxaban, apixaban), aspirin, dual-antiplatelet therapies (clopidogrel/aspirin and dipyridamole/aspirin), and Glycoprotein (GP) inhibitors (tirofiban and anfibatide). This paper compares the efficacy and safety of antithrombotic agents and discusses the advancement and potential of GP inhibitors in treating ischemic stroke patients. Based on preclinical and clinical results, it was found that GP inhibitors have higher antithrombotic and neuroprotective efficacy and are relatively safe with a lower rate of bleeding complications among all agents. The novel Anfibatide, a snake venom-derived GPIba inhibitor currently in the early clinical development stage, has shown superior efficacy and safety profile compared to other agents. It has great potential to fulfill the current unmet medical needs in ischemic stroke treatment. It is worth exploring the mechanism of GP inhibitors and their applications in ischemic stroke treatment.

Analysis of cardiopulmonary resuscitation outcomes among critically ill patients at a university hospital, Kafr-El-Sheikh Governorate

Background Cardiopulmonary resuscitation (CPR) is a vital intervention in managing critically ill patients experiencing cardiac arrest (CA). Understanding the factors influencing CPR outcomes is crucial for optimizing resuscitation strategies and improving patients’ survival rates. Aim To analyze the outcome of CPR among critically ill patients. Research questions To fulfill the aim of this study, four research questions were formulated. Design A descriptive exploratory research design was used. Setting Three ICUs affiliated to a university hospital in Kafr-El-Sheikh, Egypt. Sample A purposive sample that included 69 CA patients for 7 months, and a convenience sample of 97 members of the emergency response team working at the above-mentioned setting. Tools Three tools were formulated. Results The highest age category (31.9%) of CA patients was of 61–70 years. Over 7 months, the frequency of CA among critically ill patients was 7.61%. Regarding ICUs’ preparedness, institutional factors affecting emergency readiness had an unsatisfactory practice level (mean±SD=17.04±2.10), and crash cart preparedness was at mean±SD=30.42±4.32. The study showed unsatisfactory practice levels related to International Liaison Committee on Resuscitation 2020 guidelines for total advanced cardiac life support (ACLS) performance with a mean score and SD of 87.81±18.19. Patient outcomes showed a 10.1% overall survival rate at ICU discharge, 82.6% experiencing return of spontaneous circulation, and 89.9% experiencing brain death. Clinical high-risk scores against National Early Warning Score 2 were 98.2 and 88.2% on the first and last days, respectively. Poor cerebral performance category outcome scores were found at 96.5 and 88% on the first and last days, respectively. However, there were insignificant statistical correlations (P>0.05) between different patients’ outcomes and total adult ACLS role during CA based on International Liaison Committee on Resuscitation guidelines 2020. Conclusion CA among critically ill patients creates a significant burden for healthcare facilities and continues to be associated with a high mortality rate. The institutional factors affecting CPR outcomes among CA patients concerning preparedness level have a significant influence on survival. Conversely, the majority of resuscitated patients experienced return of spontaneous circulation, indicating successful initial efforts with severe neurological disability. Recommendations Hospital preparedness for CA situations has to be severely considered through implementing and regularly reviewing institutional policies and ensuring the availability and functionality of necessary resources. Update regular continuous educational programs toward enhancing the performance of emergency response team focusing on ACLS guidelines. Replication of this study on a larger probability sample from different geographical locations in Egypt is recommended.

Outcome and management of decompressive hemicraniectomy in malignant hemispheric stroke following cardiothoracic surgery

Management of malignant hemispheric stroke (MHS) after cardiothoracic surgery (CTS) remains difficult as decision-making needs to consider severe cardiovascular comorbidities and complex coagulation management. The results of previous randomized controlled trials on decompressive surgery for MHS cannot be generally translated to this patient population and the expected outcome might be substantially worse. Here, we analyzed mortality and functional outcome in patients undergoing decompressive hemicraniectomy (DC) for MHS following CTS and assessed the impact of perioperative coagulation management on postoperative hemorrhagic and cardiovascular complications. All patients that underwent DC for MHS resulting as a complication of CTS between June 2012 and November 2021 were included in this observational cohort study. Outcome was determined according to the modified Rankin Scale (mRS) score at 1 and 3–6 months. Clinical and demographic data, anticoagulation management and postoperative hemorrhagic and thromboembolic complications were assessed. In order to evaluate a predictive association between clinical and radiological parameters and the outcome, we used a multivariate logistic regression analysis. Twenty-nine patients undergoing DC for MHS after CTS with a female-to-male ratio of 1:1.9 and a median age of 60 (IQR 49–64) years were identified out of 123 patients undergoing DC for MHS. Twenty-four patients (83%) received pre- or intraoperative substitution. At 30 days, the in-hospital mortality rate and neurological outcome corresponded to 31% and a median mRS of 5 (5–6), which remained stable at 3–6 months [Mortality: 42%, median mRS: 5 (4–6)]. Postoperatively, 15/29 patients (52%) experienced new hemorrhagic lesions and Bayesian logistic regression predicting mortality (mRS = 6) after imputing missing data demonstrated a significantly increased risk for mortality with longer aPPT (OR = 13.94, p = .038) and new or progressive hemorrhagic lesions after DC (OR = 3.03, p = .19). Notably, all but one hemorrhagic lesion occurred before discontinued anticoagulation and/or platelet inhibition was re-initiated. Despite perioperative discontinuation of anticoagulation and/or platelet inhibition, no coagulation-associated cardiovascular complications were noted. In conclusion, Cardiothoracic surgery patients suffering MHS will likely experience severe neurological disability after DC, which should remain a central aspect during counselling and decision-making. The complex coagulation situation after CTS, however, should not per se rule out the option of performing life-saving surgical decompression.

Towards precision medicine for phenylketonuria: The effect of restoring a strict metabolic control in adult patients with early-treated phenylketonuria

Background and objectiveNeonatal screening and early treatment have changed the natural history of PKU, preventing severe neurological and intellectual disability. Nevertheless, the outcome of the disease in early-treated adult patients (ETPKU) is less than optimal, the predictive value of metabolic biomarkers is feeble, and the recommended levels of blood phenylalanine (Phe) for adulthood are controversial. A crucial question whose answer will improve our understanding and treatment of PKU is whether cognitive outcomes can be modulated by levels of Phe even in early-treated adults. To address this question, we carried out an interventional study in seven ETPKU women planning a pregnancy. MethodsThey underwent an extensive neurocognitive assessment at baseline, and 3 and 6 months after having attained the blood Phe concentration recommended to prevent PKU fetopathy, but before pregnancy. ResultsAfter 3 and 6 months with a stable blood Phe level of about 240 μmol/L, all participants experienced significant improvements in almost all neurocognitive domains and tasks. IQ also increased of 11 to 21 points from the last assessment before enrolment. This pattern remained strong and consistent after correction for multiple comparisons. ConclusionOur results indicate that a) strong cognitive improvement is possible even in adulthood and may be demonstrated by lowering Phe near normal levels; b) testing cognition under different metabolic conditions may unveil an individual vulnerability to Phe. These results pave the way for personalised treatment of the disease in adults with ETPKU.

Timing of antenatal corticosteroids and survival without neurologic disabilities at 5½ years in children born before 35 weeks of gestation

The efficacy of antenatal corticosteroids for neonatal preterm complications wanes beyond 7 days after treatment. The neurodevelopmental effects of longer treatment-to-birth intervals have not been adequately evaluated. This study aimed to assess the impact of antenatal corticosteroid timing on survival without moderate or severe neurologic disabilities at 5½ years. This was a secondary analysis of the EPIPAGE-2 study, a national population-based cohort (France) that recruited neonates in 2011 and followed them up at 5½ years (results first reported in 2021). Participants were children born alive between 24+0 and 34+6 weeks, with a complete corticosteroid course, delivery >48 hours after the first injection, and neither limitation of care decided before birth nor severe congenital malformation. The study included 2613 children, 2427 of whom were alive at 5½ years; 71.9% (1739/2427) had a neurologic assessment at this age; 1537 had a clinical examination (complete for 1532), and 202 were assessed with a postal questionnaire. Exposure was defined as the interval between the first injection of the last antenatal corticosteroid course and delivery in days, studied in 2 categories (days 3-7 and after day 7), in 4 categories (days 3-7, 8-14, 15-21, and after day 21), and continuously in days. The main outcome was survival at 5½ years without moderate/severe neurologic disabilities, defined as moderate/severe cerebral palsy, or unilateral or bilateral blindness or deafness, or Full-Scale Intelligence Quotient 2 standard deviations below the mean. A multivariate analysis with a generalized estimated equation logistic regression model assessed the statistical association between the main outcomes and the interval from the first corticosteroid injection of the last course to birth. Multivariate analyses were adjusted for potential confounders, defined with a directed acyclic graph: gestational age in days, number of corticosteroid courses, multiple pregnancy, and cause of prematurity in 5 categories. Because neurologic follow-up was complete in only 63.2% of cases (1532/2427), the analyses used imputed data. Among 2613 children, 186 died between birth and 5½ years. Overall survival was 96.6% (95% confidence interval, 95.9-97.0), and survival without moderate or severe neurologic disabilities was 86.0% (95% confidence interval, 84.7-87.0). Survival without moderate or severe neurologic disabilities was lower after day 7 (85.0%) than during the interval from day 3 to day 7 (87.0%) (adjusted odds ratio, 0.70; 95% confidence interval, 0.54-0.89). The association of a >7-day interval between antenatal corticosteroid administration and birth with a lower rate of survival without moderate or severe neurologic disabilities among children aged 5½ years emphasizes the importance of better targeting women at risk of preterm delivery to optimize the timing and thus benefits of treatment.

Pre-aspirin use has no benefit on the neurological disability and mortality after cardiovascular events: A nation-wide population-based cohort study.

To evaluate the effects of aspirin in the primary prevention, we evaluated disability grades and mortality after ischemic/hemorrhagic stroke and myocardial infarction (MI). A retrospective nation-wide propensity score-matched cohort study was performed using the Korean National Health Information Database. From 3,060,639 subjects who were older than 55 and performed national health examinations in 2004 and 2005, we selected the aspirin group (N = 8770) was composed of patients who had received aspirin prior to cardiovascular events. Cox proportional hazards model was used to compare the acquisition times for neurologic disability grades and survival times between the aspirin and control groups. Only in hemorrhagic stroke, the severe neurologic disability risk was higher in the aspirin group (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.02-1.42). The aspirin group was associated with higher 90-day (HR, 1.33; 95% CI, 1.23-1.44) and long-term mortality risk (HR, 1.06; 95% CI, 1.03-1.10) after pooling 3 events. The old age was a strong risk factor for 90-day mortality in hemorrhagic stroke (50s: reference; 60s: HR 2.21, 95% CI 1.50-3.25; 70s: HR 3.63, 95% CI 2.48-5.30; 80s: HR 6.69, 95% CI 4.54-9.65; >90s: HR 11.28, 95% CI 6.46-19.70). Pre-aspirin use in cardiovascular events has detrimental effects on severe neurological disability in hemorrhagic stroke and short-/long-term mortality in 3 cardiovascular events. The use of aspirin for the primary prevention especially in the elderly should be very cautious because the old age is a strong risk factor for 90-day mortality after hemorrhagic stroke.

Long-Term Outcomes of Tracheostomy-Dependent Children.

To estimate the 1-, 5-, and 10-year survival and decannulation rates of children with a tracheostomy. Ambidirectional cohort. Tertiary children's hospital. All patients (<18 years) that had a tracheostomy placed between 2009 and 2020 were included and followed until 21 years of age, decannulation, or death. The Kaplan-Meier method estimated cumulative probabilities of death and decannulation. A total of 551 children underwent tracheostomy at a median age of 7.2 months (interquartile range [IQR]: 3.8-49.2). Children were followed for a median of 2.1 years (IQR: 0.7-4.2, range 0-11.5). The cumulative probability of mortality at 1year was 11.9% (95% confidence interval [CI]: 9.4-15.1), at 5years was 26.1% (95% CI: 21.6-31.3), and at 10years was 41.6% (95% CI: 32.7-51.8). Ventilator dependence at index discharge (hazard ratio [HR]: 2.04, 95% CI: 1.10-3.81, p = .03), severe neurologic disability (HR: 2.79, 95% CI: 1.61-4.84, p < .001), and cardiac disease (HR: 1.69, 95% CI: 1.08-2.65, p = .02) were associated with time to death. The cumulative probability of decannulation was 10.4% (95% CI: 8.0-13.5), 44.9% (95% CI: 39.4-50.9), and 54.1% (95% CI: 47.4-61.1) at 1 year, 5 years, and 10 years, respectively. Ventilator dependence (HR: 0.43, 95% CI: 0.31-0.60, p < .001), severe neurologic disability (HR: 0.20, 95% CI: 0.14-0.30, p < .001), and tracheostomy indicated for respiratory failure (HR: 0.68, 95% CI: 0.48-0.96, p = .03) correlated with longer decannulation times. After tracheostomy, estimated mortality approaches 42% by 10 years and decannulation approaches 54%. Children with ventilator support at discharge and severe neurological disability had poorer long-term survival and longer times to decannulation.

GLP-1 receptor agonists as promising disease-modifying agents in WFS1 spectrum disorder.

WFS1 spectrum disorder (WFS1-SD) is a rare monogenic neurodegenerative disorder whose cardinal symptoms are childhood-onset diabetes mellitus, optic atrophy, deafness, diabetes insipidus, and neurological signs ranging from mild to severe. The prognosis is poor as most patients die prematurely with severe neurological disabilities such as bulbar dysfunction and organic brain syndrome. Mutation of the WFS1 gene is recognized as the prime mover of the disease and responsible for a dysregulated ER stress signaling, which leads to neuron and pancreatic β-cell death. There is no currently cure and no treatment that definitively arrests the progression of the disease. GLP-1 receptor agonists appear to be an efficient way to reduce elevated ER stress in vitro and in vivo, and increasing findings suggest they could be effective in delaying the progression of WFS1-SD. Here, we summarize the characteristics of GLP-1 receptor agonists and preclinical and clinical data obtained by testing them in WFS1-SD as a feasible strategy for managing this disease.

ID: 210536 360 Spinal Cord Neural Interface

The spinal cord carries information from the brain to the periphery and vice versa. Interruption in these communication pathways, such as spinal cord injury, causes severe neurological disability and profoundly impacts patients and society. Bioelectronic interfaces have the potential to both record from and stimulate the spinal cord and eventually restore lost neurological functions. However, to date, spinal cord devices have only interfaced with the dorsal aspect of the spinal cord due to both anatomical and technological challenges. Here, we present a new thin-film, flexible electronics to circumferentially interface with the spinal cord, leading to a new paradigm of measuring and stimulating dorsal, lateral, and ventral tracts of the cord simultaneously using one device.

Blood-pressure targets in comatose survivors of cardiac arrest with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention - a BOX sub-study

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Foundation. Background After successful resuscitation from out-of-hospital cardiac arrest (OHCA), patients who remain comatose often need hemodynamic support with vasoactive drugs in order to secure an adequate perfusion pressure to vital organs. However, evidence regarding specific blood-pressure targets is sparse, and patients with concomitant heart disease such as acute ST-elevation myocardial infarction (STEMI) might benefit from a lower afterload and lower doses of vasoactive drugs. Purpose To assess the impact of blood-pressure on biochemical infarct size in comatose survivors of OHCA with STEMI and, further, to investigate whether a high or low mean arterial blood-pressure target is superior in preventing death or severe brain injury. Methods The BOX study (n=789) is a randomized trial with a 2-by-2 factorial design which evaluated a double-blind intervention of a high (77 mmHg) versus a low (63 mmHg) mean arterial blood-pressure target in comatose survivors of OHCA of presumed cardiac cause. In this pre-specified sub-study we included patients who had an initial electrocardiogram with STEMI recorded after return of spontaneous circulation (ROSC). The primary outcome was creatine kinase (CK), creatine kinase MB (CKMB), and troponin T (TnT) levels measured at 48 hours as surrogate markers of infarct size. A secondary outcome was a composite of all-cause death within one year from admission or discharge from the hospital with a Cerebral Performance Category (CPC) of 3 to 4, indicating severe neurological disability or a comatose or vegetative state. Results A total of 350 patients were included. Mean time to ROSC was 21±13 minutes. The mean age was 63±12 years and approximately 4 out of 5 were male. The prevalence of relevant prior medical history was as follows; hypertension 42%, diabetes 12%, chronic ischemic heart disease 20%, percutaneous coronary intervention 11%, coronary artery bypass grafting 4%, and congestive heart failure 10%. Mean CK, CKMB and TnT measured at 48 hours did not differ between the two blood-pressure target groups (p=0.42, p=0.14 and p=0.65, respectively). Within one year, 138 patients (39%) had died or been discharged with a CPC of 3 to 4 with no difference found between high or low blood pressure targets (hazard ratio, 1.02; 95% CI, 0.73-1.43; p=0.9). Conclusion Targeting a high versus a low mean arterial blood-pressure in comatose survivors of OHCA with STEMI did not affect infarct size estimated by coronary biomarkers at 48 hours nor did it result in a significant difference in death or severe neurologic disability. Although not evaluating side effects, this study thus suggests that the use of pharmacologic circulatory support in post-resuscitation care can be limited.

Guillain-Barré Syndrome Mimicking Brainstem Death Following Traumatic Intracerebral Hemorrhage (P12-7.006)

<h3>Objective:</h3> NA <h3>Background:</h3> NA <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 73-year-old man attended the ED following an assault where he sustained multiple traumatic blows to the head. He was alert, complained of headache but provided a detailed account. There were facial injuries but no clinical signs of cranial or skull base fractures. There was injury to the right eye, in which he had pre-existing visual impairment from previous injury. Vision was normal in the left. Right pupillary light reflex was absent but left was normal. The remainder of the neurological examination was unremarkable. CT-Head identified a small traumatic subarachnoid hemorrhage over the left cerebral convexity and a small contusion in the left temporo-parietal region. Vitreous hemorrhage was evident in the right eye. Clinically stable, follow-up CT on day 3 showed small intra-cerebral haemorrhage within the contusion, with minimal mass effect. However, on day 8, his GCS dropped and he was admitted to the ITU for airway management. Both pupils were non-responsive to light. Expansion of haemorrhage was suspected, however repeat CT was stable. EEG showed slowing over the left hemisphere without epileptiform activity. MRI excluded alternative causes for his neurological status such as brainstem ischaemia. With no clinical improvement, formal brainstem death testing was initiated. No potential confounders were recognised. The pupillary, corneal, oculocephalic, cough and gag reflexes were absent. Unexpectedly, deep tendon reflexes were absent in all limbs. A peripheral nerve stimulator using a train-of-four test protocol found no response. Post-traumatic Guillain-Barré syndrome (GBS) was suspected. Intravenous immunoglobulin was commenced. Nerve conduction studies found absent motor and sensory responses in all limbs. EMG showed fibrillation potentials and sharp waves. These findings were consistent with acute motor-sensory axonal neuropathy (AMSAN) variant of GBS. Serum Anti-GM1 antibodies were identified. After multiple rounds of plasmapheresis the patient was weaned from the ventilator. Nevertheless, severe neurological disability remained. <h3>Conclusions:</h3> NA <b>Disclosure:</b> Dr. Finegan has nothing to disclose. Dr. Ryan has nothing to disclose. Michael J. Hennessy has nothing to disclose. Kevin Murphy has nothing to disclose. Dr. Crowley has nothing to disclose. Dr. Elamin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche .

Paraneoplastic encephalitis: clinically based approach on diagnosis and management.

Paraneoplastic neurological syndromes (PNSs) comprise a subset of immune-mediated nervous system diseases triggered by an underlying malignancy. Each syndrome usually shows a distinct clinical presentation and outcome according to the associated neural antibodies. PNSs generally have a subacute onset with rapid progression and severe neurological disability. However, some patients may have hyperacute onset or even show chronic progression mimicking neurodegenerative diseases. Updated diagnostic criteria for PNS have been recently established in order to increase diagnostic specificity and to encourage standardisation of research initiatives related to PNS. Treatment for PNS includes oncological therapy and immunomodulation to halt neurological deterioration although current treatment options are seldom effective in reversing disability. Nevertheless, growing knowledge and better understanding of PNS pathogenesis promise better recognition, earlier diagnosis and novel treatment strategies. Considering that PNSs provide a model of effective anticancer immunity, the impact of these studies will extend far beyond the field of neurology.

DIA-based technology explores hub pathways and biomarkers of neurological recovery in ischemic stroke after rehabilitation.

Ischemic stroke (IS) is a common disease that causes severe and long-term neurological disability in people worldwide. Although rehabilitation is indispensable to promote neurological recovery in ischemic stroke, it is limited to providing a timely and efficient reference for developing and adjusting treatment strategies because neurological assessment after stroke treatment is mostly performed using scales and imaging. Therefore, there is an urgent need to find biomarkers that can help us evaluate and optimize the treatment plan. We used data-independent acquisition (DIA) technology to screen differentially expressed proteins (DEPs) before and after ischemic stroke rehabilitation treatment, and then performed Gene Ontology (GO) and pathway enrichment analysis of DEPs using bioinformatics tools such as KEGG pathway and Reactome. In addition, the protein-protein interaction (PPI) network and modularity analysis of DEPs were integrated to identify the hub proteins (genes) and hub signaling pathways for neurological recovery in ischemic stroke. PRM-targeted proteomics was also used to validate some of the screened proteins of interest. Analyzing the serum protein expression profiles before and after rehabilitation, we identified 22 DEPs that were upregulated and downregulated each. Through GO and pathway enrichment analysis and subsequent PPI network analysis constructed using STRING data and subsequent Cytoscape MCODE analysis, we identified that complement-related pathways, lipoprotein-related functions and effects, thrombosis and hemostasis, coronavirus disease (COVID-19), and inflammatory and immune pathways are the major pathways involved in the improvement of neurological function after stroke rehabilitation. Complement-related pathways, lipoprotein-related functions and effects, thrombosis and hemostasis, coronavirus disease (COVID-19), and inflammation and immunity pathways are not only key pathways in the pathogenesis of ischemic stroke but also the main pathways of action of rehabilitation therapy. In addition, IGHA1, LRG1, IGHV3-64D, and CP are upregulated in patients with ischemic stroke and downregulated after rehabilitation, which may be used as biomarkers to monitor neurological impairment and recovery after stroke.

Expanding the DARS phenotype: Late-adult onset myelopathy and leukoencephalopathy

A significant proportion of adult-onset neurological disorders remain diagnostic odysseys despite extensive evaluation. Hypomyelination with Brainstem and Spinal Cord Involvement and Leg Spasticity (HBSL) is an autosomal recessive disorder caused by mutations in the cytoplasmic aspartyl-tRNA synthetase (DARS) gene involved in mRNA translation. Clinical features of patients with DARS mutations include developmental delay, leg spasticity, cerebellar dysfunction, cognitive impairment and epilepsy. Most reported cases have been infantile-onset with severe neurological disability and neuroimaging abnormalities. To our knowledge, late- or adult-onset cases have never been reported in the literature. Here, we report for the first time, with video documentation and six-year clinical follow-up, an ethnic Malay patient with onset of spasticity and ataxia in late-adulthood, carrying a pathogenic DARS mutation discovered via whole-genome sequencing. His clinical and radiological findings were consistent with HBSL, but this diagnosis was not considered as, up until now, HBSL has only been reported with childhood/adolescent-onset. This case highlights that HBSL/DARS mutations should now be considered in the differential diagnosis of adult-onset spastic paraplegia and/or leukoencephalopathy.

Exploring the hub mechanisms of ischemic stroke based on protein-protein interaction networks related to ischemic stroke and inflammatory bowel disease

Ischemic stroke is highly concerning because it often leads to severe long-term neurological disability. Among clinical trials, ischemic stroke and inflammatory bowel disease interactions have been increasingly reported in recent years. Therefore, using bioinformatics approaches to explore novel protein interactions between them is of interest. We performed this exploratory analysis by using bioinformatics tools such as string to analyze gene data downloaded from NHGRI-GWAS data related to ischemic stroke and inflammatory bowel disease. We constructed a prospective protein interaction network for ischemic stroke and inflammatory bowel disease, identifying cytokine and interleukin-related signaling pathways, Spliceosome, Ubiquitin–Proteasome System (UPS), Thrombus, and Anticoagulation pathways as the crucial biological mechanisms of the network. Furthermore, we also used data-independent acquisition mass spectrometry (DIA-MS) to detect differential protein expression in eight samples, which also suggested that immune system, signal transduction, and hemostasis-related pathways are key signaling pathways. These findings may provide a basis for understanding the interaction between these two states and exploring possible molecular and therapeutic studies in the future.

Evaluation of oxidative damage to biomolecules and inflammation in patients with urea cycle disorders

Urea cycle disorders (UCD) are inborn errors of metabolism that occur due to a loss of function in enzymes and transporters involved in the urea cycle, causing an intoxication by hyperammonemia and accumulation of metabolites. Patients can develop hepatic encephalopathy (HE), severe neurological and motor disabilities, and often death. The mechanisms involved in the pathophysiology of UCD are many and complex, but there are strong indications that oxidative stress and inflammation are present, being responsible for at least part of the cellular damage that occurs in these diseases. The aim of this study was to evaluate oxidative and nitrosative damage and inflammation in UCD, to better understand the pathophysiology mechanisms of these diseases. We evaluated the nitrite and nitrate content, thiobarbituric acid-reactive substances (TBARS), carbonyl protein content and a panel of cytokines in plasma sample of 14 patients. The UCD patients group consisted of individuals affected with ornithine transcarbamylase deficiency (n = 8), carbamoyl phosphate synthetase deficiency (n = 2), argininosuccinate synthetase deficiency (n = 2); arginase 1 deficiency (n = 1) and argininosuccinate lyase deficiency (n = 1). Patients mean age at diagnosis was 5.25 ± 9.86 years-old and mean concentrations were compared with healthy individuals of matched age and gender. We found a significant reduction in nitrogen reactive species in patients when compared to controls. TBARS was increased in patients, indicating lipid peroxidation. To evaluate protein oxidative damage in UCD, the carbonyl content was measured, and the results also demonstrated an increase in this biomarker. Finally, we found that UCD patients have enhanced concentrations of cytokines, with pro-inflammatory interleukins IL-6, IL-8, interferon-γ and TNF-α, and anti-inflammatory IL-10 being increased when compared to the control group. In conclusion, our results demonstrate that oxidative stress and inflammation occurs in UCD and probably contribute to the severe brain damage present in patients.

Longitudinal perturbations of plasma nuclear magnetic resonance profiles in neonatal encephalopathy.

Neonatal encephalopathy (NE) is a major cause of mortality and severe neurological disability in the neonatal period and beyond. We hypothesized that the degree of brain injury is reflected in the molecular composition of peripheral blood samples. A sub-cohort of 28 newborns included in the HYPOTOP trial was studied. Brain injury was assessed by magnetic resonance imaging (MRI) once per patient and neurodevelopment at 24 months of age was evaluated using the Bayley III Scales of Infant and Toddler Development. The nuclear magnetic resonance (NMR) profile of 60 plasma samples collected before, during, and after cooling was recorded. In total, 249 molecular features were quantitated in plasma samples from newborns and postnatal age showed to affect detected NMR profiles. Lactate, beta-hydroxybutyrate, pyruvate, and three triglyceride biomarkers showed the ability to discern between different degrees of brain injury according to MRI scores. The prediction performance of lactate was superior as compared to other clinical and biochemical parameters. This is the first longitudinal study of an ample compound panel recorded by NMR spectroscopy in plasma from NE infants. The serial determination of lactate confirms its solid position as reliable candidate biomarker for predicting the severity of brain injury. The use of nuclear magnetic resonance (NMR) spectroscopy enables the simultaneous quantitation of 249 compounds in a small volume (i.e., 100 μL) of plasma. Longitudinal perturbations of plasma NMR profiles were linked to magnetic resonance imaging (MRI) outcomes of infants with neonatal encephalopathy (NE). Lactate, beta-hydroxybutyrate, pyruvate, and three triglyceride biomarkers showed the ability to discern between different degrees of brain injury according to MRI scores. Lactate is a minimally invasive candidate biomarker for early staging of MRI brain injury in NE infants that might be readily implemented in clinical guidelines for NE outcome prediction.

Cost effectiveness of a telerehabilitation intervention vs home based care for adults with severe neurologic disability: A randomized clinical trial.

Several options are available for the care of neurological conditions including care delivered in rehabilitation centres, at home or remotely. While economic studies are available comparing centres and homes, very little economic data relates to mobile teams comparing face-to-face and remote care. To conduct an economic study comparing face-to-face care at home and care delivered remotely (tele-rehabilitation). A randomised clinical study with two groups; a control group receiving home care and an experimental group receiving tele-rehabilitation. The primary outcome measure was the ICER (Incremental Cost Effectiveness Ratio). Patients with severe neurological disabilities. 80 patients were enrolled in the study; 77 were analysed to calculate the ICER, which was positive and located in the SW quadrant. A bootstrap with 1000 replications was positioned at 72.8% in the SW quadrant. Tele-rehabilitation is an acceptable alternative to the management of neurological patients at home. In the mildest cases, remote-rehabilitation may even be dominant. More extensive studies are needed to specify the indications.

Chapter 11 - Paraneoplastic motor disorders

Paraneoplastic neurological disorders (PNDs) are heterogeneous clinicopathologic syndromes that occur throughout the neuraxis resulting from damage to organs or tissues remote from the site of a malignant neoplasm or its metastases. The discordance between severe neurological disability and even an indolent malignancy suggests an underlying neuroimmunologic host immune response that inflicts nervous tissue damage while inhibiting malignant tumor growth. Motor system involvement, like other symptoms and signs, is associated with focal or diffuse involvement of the brain, spinal cord, peripheral nerve, neuromuscular junction or muscle, alone or in combination due to an underlying neuroimmune and neuroinflammatory process targeting neural-specific antigens. Unrecognized and therefore untreated, PNDs are often lethal making early detection and aggressive treatment of paramount importance. While the combination of clinical symptoms and signs, and analysis of detailed body and neuroimaging, clinical neurophysiology and electrodiagnostic studies, and tumor and nervous system tissue biopsies are all vitally important, the certain diagnosis of a PND rests with the discovery of a corresponding neural-specific paraneoplastic autoantibody in the blood and/or spinal cerebrospinal fluid.

550 FINGOLIMOD IN MULTIPLE SCLEROSIS: BRADYCARDIA, ATRIOVENTRICULAR BLOCKS AND EFFECT ON THE QT-INTERVAL. A PROSPECTIVE STUDY.

Abstract Multiple Sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) that is mainly characterized by inflammatory demyelination, leading to severe neurological disability. MS typically affects young adults and usually arise with acute relapses, followed by partial or complete remission period. Currently, there is no definite treatment for MS. However Sphingosine-1-phosphate receptor modulators (S1PRMs), a class of disease-modifying treatments (DMTs), have shown a positive effect of the S1P pathway and S1PRMs on immune cell trafficking and neuroprotection, leading to the approval of 3 drugs (Fingolimod (Gilenya®), Siponimod (Mayzent®), and Ozanimod (Zeposia®)) for MS treatment [1]. Since S1PR have extensive expression on cardiomyocytes and vascular endothelial cells, cardiovascular effect, such as atrioventricular block (AVB), sinus bradycardia, orthostatic hypotension or hypertension, are expected [2]. At present, the approved S1PRMs require 6-h continuous cardiac monitoring after first dose and after every up titration. Nevertheless, so far no study has investigated the risk of cardiovascular adverse events in MS patients treated with S1PRMs. The aim of the present study was to define the incidence of cardiovascular adverse events (AEs) in relapsing-MS patients, without cardiac pre-existing conditions, treated with Fingolimod 0.5 mg/die. We enrolled 9 consecutive patients (mean age 34 years) admitted to the Neurology Department at University of Bari, between February and May 2022. All patients underwent 12 lead ECG, trans-thoracic Echocardiogram and BP evaluation. A six hours continuous monitoring of heart rate and blood pressure by telemetry started immediately after Fingolimod administration. A 12 lead ECG was obtained at the 5th and 6th hour of monitoring. During six hours monitoring blood pressure did not change significantly. As regards the entity of the HR changes, we found a decrease of 12 ± 8 bpm especially between the 2nd and the 3rd hour of monitoring; at the 3rd hour of monitoring, two of our youngest patients experienced a second degree type 1 AVB but normal atrio-ventricular conduction restored during the 5th hour of monitoring. All patients remained asymptomatic and were discharged in good clinical conditions after the end of six hour monitoring. Given the higher incidence of cardiovascular AEs in patients with MS receiving S1PRMs, a comprehensive assessment of patient conditions is recommended. During Fingolimod treatment, heart rate, brady-arrhythmias, and blood pressure should be monitored via active electrocardiography recording for at least 6 h after the first dose; monitoring could be potentially prolonged according to patient situation, although in our cohort the maximal conduction delay occurred within 3 hours. Our perspective is to obtain a long-term follow-up (1–3 years) focusing on heart rate and blood pressure variations, in order to elaborate a prediction model of cardiovascular risk in patients receiving S1PRMs. [1] Zhao Z, et al. Front Immunol. 2021 Dec 7;12:795574. [2] Paolicelli D et al. J Clin Pharmacol. 2015 Oct;55(10):1131-6.