Persistent Neurological Impairment Research Articles

Postoperative stroke in acute type A aortic dissection: incidence, outcomes, and perioperative risk factors

BackgroundDespite advances in surgical techniques, the incidence of stroke following acute type A aortic dissection (ATAAD) repair remains markedly high, with substantial immediate and long-term adverse outcomes such as elevated mortality, extended hospital stays, and persistent neurological impairments. The complexity of managing ATAAD extends beyond the operation itself, highlighting a crucial gap in research concerning modifiable preoperative patient conditions and perioperative anesthetic management strategies.ObjectivesThis investigation aimed to elucidate the incidence, consequences, and perioperative determinants of stroke following surgical intervention for acute type A aortic dissection (ATAAD).MethodsIn a multicenter retrospective analysis, 516 ATAAD surgery patients were evaluated. The data included demographic information, clinical profiles, surgical modalities, and outcomes. The primary endpoint was postoperative stroke incidence, with hospital mortality and other complications serving as secondary endpoints.ResultsPostoperative stroke occurred in 13.6% of patients (70 out of 516) and was associated with significant extension of the ICU (median 10 vs. 5 days, P < 0.001) and hospital stay (median 18 vs. 12 days, P < 0.001). The following key independent stroke risk factors were identified: modified Frailty Index (mFI) ≥ 4 (odds ratio [OR]: 4.18, 95% confidence interval [CI]: 1.24–14.1, P = 0.021), common carotid artery malperfusion (OR: 3.76, 95% CI: 1.23–11.44, P = 0.02), pre-cardiopulmonary bypass (CPB) hypotension (mean arterial pressure ≤ 50 mmHg; OR: 2.17, 95% CI: 1.06–4.44, P = 0.035), ≥ 20% intraoperative decrease in cerebral regional oxygen saturation (rSO2) (OR: 1.93, 95% CI: 1.02–3.64, P = 0.042), and post-CPB vasoactive-inotropic score (VIS) ≥ 10 (OR: 2.24, 95% CI: 1.21–4.14, P = 0.01).ConclusionsPostoperative stroke significantly increases ICU and hospital durations in ATAAD surgery patients. These findings highlight the critical need to identify and mitigate major risks, such as high mFI, common carotid artery malperfusion, pre-CPB hypotension, significant cerebral rSO2 reductions, and elevated post-CPB VIS, to improve outcomes and reduce stroke prevalence.Trial RegistrationThai Clinical Trials Registry (TCTR20230615002). Date registered on June 15, 2023. Retrospectively registered.

Impact of age and sex on neuroinflammation following SARS-CoV-2 infection in a murine model.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, is known to infect people of all ages and both sexes. Senior populations have the greatest risk of severe COVID-19, and sexual dimorphism in clinical outcomes has been reported. Neurological symptoms are widely observed in COVID-19 patients, with many survivors exhibiting persistent neurological and cognitive impairment. The present study aims to investigate the impact of age and sex on the neuroinflammatory response to SARS-CoV-2 infection using a mouse model. Wild-type C57BL/6J mice were intranasally inoculated with SARS-CoV-2 lineage B.1.351, a variant known to infect mice. Older male mice exhibited a significantly greater weight loss and higher viral loads in the lung at 3 days post infection. Notably, no viral RNA was detected in the brains of infected mice. Nevertheless, expression of IL-6, TNF-α, and CCL-2 in the lung and brain increased with viral infection. RNA-seq transcriptomic analysis of brains showed that SARS-CoV-2 infection caused significant changes in gene expression profiles, implicating innate immunity, defense response to virus, and cerebrovascular and neuronal functions. These findings demonstrate that SARS-CoV-2 infection triggers a neuroinflammatory response, despite the lack of detectable virus in the brain. Aberrant activation of innate immune response, disruption of blood-brain barrier and endothelial cell integrity, and suppression of neuronal activity and axonogenesis underlie the impact of SARS-CoV-2 infection on the brain. Understanding the role of these affected pathways in SARS-CoV-2 pathogenesis helps identify appropriate points of therapeutic interventions to alleviate neurological dysfunction observed during COVID-19.

Management of lung diseases under ultrasound monitoring: potential to make bronchopulmonary dysplasia in preterm infants as an avoidable disease

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in preterm infants. Despite significant progress in the understanding of its etiology, mechanisms, prevention, and treatment, the prognosis remains poor. BPD not only has a high mortality rate but also causes persistent respiratory, neurological, and cardiovascular impairments in survivors. The author's team has successfully prevented the occurrence of BPD by managing neonatal lung diseases under lung ultrasound monitoring for nearly 7 years, opening up a new approach in BPD prevention. This article provides a brief overview of the approach, aiming to facilitate further research and provide more scientifically sound management strategies to prevent or minimize the occurrence of BPD.

Leprosy with type 1 reaction in a patient from Ontario, Canada without recent travel misdiagnosed as vasculitic neuropathy: a case report

BackgroundLeprosy is rare within non-endemic countries such as Canada, where cases are almost exclusively imported from endemic regions, often presenting after an incubation period of as many as 20 years. Due to its rarity and prolonged incubation period, diagnosis is often delayed, which may result in neurologic impairment prior to the initiation of treatment. In this report we describe a case that is novel in its incubation period, which is the longest reported to-date and may have contributed to diagnostic delay. The case also uniquely demonstrates the challenges of distinguishing leprosy reactions from new rheumatologic manifestations in a patient with established autoimmune disease.Case presentationWe describe an 84-year-old male patient with rheumatoid arthritis on methotrexate and hydroxychloroquine, with no travel history outside Canada for 56 years, who presented in 2019 with new-onset paresthesias and rash. His paresthesias persisted despite a short course of prednisone, and his rash recurred after initial improvement. He underwent skin biopsy in May 2021, which eventually led to the diagnosis of leprosy. He was diagnosed with type 1 reaction and was started on rifampin, dapsone, clofazimine and prednisone, with which his rash resolved but his neurologic impairment remained.ConclusionThis case report serves to highlight the potential for leprosy to present after markedly prolonged incubation periods. This is especially relevant in non-endemic countries that is home to an aging demographic of individuals who migrated decades ago from endemic countries. The importance of this concept is emphasized by the persistent neurologic impairment suffered by our case due to untreated type 1 reaction. We also demonstrate the necessity of skin biopsy in distinguishing this diagnosis from other autoimmune mimics in a patient with known autoimmune disease.

Repetitive, but Not Single, Mild Blast TBI Causes Persistent Neurological Impairments and Selective Cortical Neuronal Loss in Rats.

Exposure to repeated mild blast traumatic brain injury (mbTBI) is common in combat soldiers and the training of Special Forces. Evidence suggests that repeated exposure to a mild or subthreshold blast can cause serious and long-lasting impairments, but the mechanisms causing these symptoms are unclear. In this study, we characterise the effects of single and tightly coupled repeated mbTBI in Sprague-Dawley rats exposed to shockwaves generated using a shock tube. The primary outcomes are functional neurologic function (unconsciousness, neuroscore, weight loss, and RotaRod performance) and neuronal density in brain regions associated with sensorimotor function. Exposure to a single shockwave does not result in functional impairments or histologic injury, which is consistent with a mild or subthreshold injury. In contrast, exposure to three tightly coupled shockwaves results in unconsciousness, along with persistent neurologic impairments. Significant neuronal loss following repeated blast was observed in the motor cortex, somatosensory cortex, auditory cortex, and amygdala. Neuronal loss was not accompanied by changes in astrocyte reactivity. Our study identifies specific brain regions particularly sensitive to repeated mbTBI. The reasons for this sensitivity may include exposure to less attenuated shockwaves or proximity to tissue density transitions, and this merits further investigation. Our novel model will be useful in elucidating the mechanisms of sensitisation to injury, the temporal window of sensitivity and the evaluation of new treatments.

GABAergic neurons differentiated from BDNF- and Dlx2-modified neural stem cells restore disrupted neural circuits in brainstem stroke

BackgroundBrainstem stroke causes severe and persistent neurological impairment. Due to the limited spontaneous recovery and regeneration of the disrupted neural circuits, transplantation of exogenous neural stem cells (NSCs) was an alternative, while there were limitations for primitive NSCs.MethodsWe established a mouse model of brainstem stroke by injecting endothelin in the right pons. Brain-derived neurotrophic factor (BDNF)- and distal-less homeobox 2 (Dlx2)-modified NSCs were transplanted to treat brainstem stroke. Transsynaptic viral tracking, immunostaining, magnetic resonance imaging, behavioral testing, and whole-cell patch clamp recordings were applied to probe the pathophysiology and therapeutic prospects of BDNF- and Dlx2-modified NSCs.ResultsGABAergic neurons were predominantly lost after the brainstem stroke. No endogenous NSCs were generated in situ or migrated from the neurogenesis niches within the brainstem infarct region. Co-overexpressions of BDNF and Dlx2 not only promoted the survival of NSCs, but also boosted the differentiation of NSCs into GABAergic neurons. Results from transsynaptic virus tracking, immunostaining, and evidence from whole-cell patch clamping revealed the morphological and functional integration of the grafted BDNF- and Dlx2-modified NSCs-derived neurons with the host neural circuits. Neurological function was improved by transplantation of BDNF- and Dlx2-modified NSCs in brainstem stroke.ConclusionsThese findings demonstrated that BDNF- and Dlx2-modified NSCs differentiated into GABAergic neurons, integrated into and reconstituted the host neural networks, and alleviated the ischemic injury. It thus provided a potential therapeutic strategy for brainstem stroke.

The relationship between neurological function trajectory, assessed by repeated NIHSS measurement, and long-term cardiovascular events, recurrent stroke, and mortality after ischemic stroke.

Clinically significant changes in neurological deficits frequently occur after stroke onset, reflecting further neurological injury or neurological improvement. However, the National Institutes of Health Stroke Scale (NIHSS) score is only evaluated once in most studies, usually at stroke onset. Utilizing repeated measures of NIHSS scores to identify different trajectories of neurological function may be more informative and provide more useful predictive information. We determined the association of neurological function trajectories with long-term clinical outcomes after ischemic stroke. A total of 4025 participants with ischemic stroke from the China Antihypertensive Trial in Acute Ischemic Stroke were included. Patients were recruited from 26 hospitals across China between August 2009 and May 2013. A group-based trajectory model was used to identify distinct neurological function trajectories, as measured by NIHSS at admission, 14 days or hospital discharge, and 3 months. Study outcomes were cardiovascular events, recurrent stroke, and all-cause mortality during 3-24 months after ischemic stroke onset. Cox proportional hazards models were used to examine the associations of neurological function trajectories with outcomes. We identified three distinct subgroups of NIHSS trajectories: persistent severe (persistent high NIHSS scores during the 3-month follow-up), moderate (NIHSS scores started at around 5 and gradually reduced), and mild (NIHSS scores always below 2). The three trajectory groups had different clinical profiles and different risk of stroke outcomes at 24-month follow-up. Compared to the mild trajectory group, patients in the persistent severe trajectory group had a higher risk of cardiovascular events (multivariable-adjusted hazard ratios (95% confidence intervals) = 1.77 (1.10-2.86)), recurrent stroke (1.82 (1.10-3.00)), and all-cause mortality (5.64 (3.37-9.43)). Those with moderate trajectory had an intermediate risk: 1.45 (1.03-2.04) for cardiovascular events and 1.52 (1.06-2.19) for recurrent stroke. Longitudinal neurological function trajectories derived from repeated NIHSS measurements during the first 3 months after stroke provide additional predictive information and are associated with long-term clinical outcomes. The trajectories characterized by persistent severe and moderate neurological impairment were associated with increased risk of subsequent cardiovascular events.

Neurological outcomes after surgery and postoperative rehabilitation for cervical radiculopathy due to disc disease: a 2-year-follow-up of a randomized clinical trial

Reports on neurological outcomes in patients with cervical radiculopathy (CR) undergoing surgery and postoperative rehabilitation are important to inform prognosis. This 2-year-follow-up of a randomized clinical trial aimed to compare secondary neurological outcomes between structured postoperative rehabilitation and a standard approach after surgery for CR. A secondary aim was to increase knowledge about recovery of neurological impairments in relation to patient-reported neck disability. Neurological outcomes included assessment of sensibility, motor function, arm reflexes and the Spurling test. A total of 153 and 135 participants (> 70% response rate) completed the clinical examination. Between-group differences, changes over time, and associations between persistent neurological impairments and the Neck Disability Index were investigated. No between-group differences were reported (p > 0.07), and neurological impairments in sensibility, motor function, and a positive Spurling test decreased over time in both groups (p < 0.04). Persistent impairments in sensibility and reflex arm were most frequent at follow-up, whereas, a persistent positive Spurling test, and impairments in motor function were associated with higher NDI score. Neurological outcomes improved over time in patients undergoing surgery for CR with no between-group differences., However, persistent neurological impairments were common, and associated with poorer outcome for patient-reported neck disability.Clinical registration: clinicaltrial.gov NCT01547611, 08/03/2012, Title: Outcome of physiotherapy after surgery for cervical disc disease: a prospective multi-centre trial.

The impact of pregnancy and childbirth on pelvic sensation: a prospective cohort study

Pelvic organ prolapse, urinary, bowel and sexual dysfunction, collectively called pelvic floor dysfunction (PFD) affects 1 in 3 women and has a significant public health impact. The causes of PFD are not fully understood but involve injury to connective tissue and motor nerve during childbirth. Women with PFD also have sensory nerve impairment, and it is likely this occurs during childbirth, but this has never been investigated. In the current study 150 women underwent quantitative sensory testing for vibration sensation at the vagina and clitoris, and stretch sensation at the vagina and introitus, in the third trimester, 3 and 6 months postnatal. Antenatally vibration sensation was reduced but stretch sensation was normal. Postnatally vibration sensation deteriorated whilst stretch sensation initially deteriorated but recovered by 6 months postnatal to antenatal levels (all p < 0.001). Mode of birth had a significant impact on sensation, with caesarean section appearing neuroprotective, normal vaginal birth resulted in a transient deterioration in sensation that recovered by 6 months, whilst assisted vaginal delivery was prolonged suggesting persistent neurological impairment (all p < 0.015). Further research is required to study the clinical effect of these changes on pelvic floor dysfunction in the medium and long-term.

Persistent olfactory learning deficits during and post-COVID-19 infection.

Quantifying olfactory impairments can facilitate early detection of Coronavirus disease 2019 (COVID-19). Despite being a debated topic, many reports provide evidence for the neurotropism of SARS-CoV-2. However, a sensitive, specific, and accurate non-invasive method for quantifying persistent neurological impairments is missing to date. To quantify olfactory detectabilities and neurocognitive impairments in symptomatic COVID-19 patients during and post-infection periods, we used a custom-built olfactory-action meter (OAM) providing accurate behavioral readouts. Ten monomolecular odors were used for quantifying olfactory detectabilities and two pairs of odors were employed for olfactory matching tests. We followed cohorts of healthy subjects, symptomatic patients, and recovered subjects for probing olfactory learning deficits, before the Coronavirus Omicron variant was reported in India. Our method identifies severe and persistent olfactory dysfunctions in symptomatic patients during COVID-19 infection. Symptomatic patients and recovered subjects showed significant olfactory learning deficits during and post-infection periods, 4-18 months, in comparison to healthy subjects. On comparing olfactory fitness, we found differential odor detectabilities and olfactory function scores in symptomatic patients and asymptomatic carriers. Our results indicate probable long-term neurocognitive deficits in COVID-19 patients imploring the necessity of long-term tracking during post-infection period. Differential olfactory fitness observed in symptomatic patients and asymptomatic carriers demand probing mechanisms of potentially distinct infection routes.

Neurological complications in adult allogeneic hematopoietic stem cell transplant patients: Incidence, characteristics and long-term follow-up in a multicenter series.

Neurological complications (NCs) represent a diagnostic and clinical challenge in allogeneic hematopoietic stem cell transplant (alloHSCT) patients. We retrospectively analyzed NC incidence, etiology, timing, characteristics, outcome, and long-term effects in 2384 adult patients transplanted in seven Italian institutions between January 2007 and December 2019. Ninety-three (3.9%) patients were affected by 96 NCs that were infectious (29.2%), immune/inflammatory (26%), drug-related (12.5%), cerebrovascular (5.2%), metabolic (3.1%), related to central nervous system disease relapse (11.5%) and malignancy (3.1%), or undefined (9.4%). Six patients (6.4%) had neurological manifestations of chronic graft-versus-host disease (GVHD). NCs occurred on average at day +128 (from -5 to +4063). Early (< day +120) and late NCs had similar frequencies (46.9% vs 53.1%, p = 0.39). Thirty-one patients (33.3%) were affected by acute or chronic GVHD at the NC onset. With a median follow-up of 25.4 (0.4-163) months, the overall mortality due to NCs was 22.6%. The median time between NC onset and death was 36 (1-269) days. Infectious NCs were the main cause (61.9%) of NC-related mortality. A persistent neurological impairment occurred in 20.4% patients, 57.9% of whom being affected by immune/inflammatory NCs. This study highlights the rare, yet severe impact of alloHSCT-associated NCs on patient survival and long-term functional ability.

Olfactory dysfunction and potential mechanisms caused by volatile organophosphate dichlorvos in the silkworm as a model animal

Volatile pesticides impair olfactory function in workers/farmers and insects, but data on molecular responses and mechanisms are poorly understood. This study aims to reveal the mechanisms of olfactory dysfunction in the silkworm after exposure to volatile dichlorvos. Our results demonstrated that acute exposure for 12 h significantly reduced electroantennogram responses, and over 62.50% of the treated male moths cannot locate the pheromone source. Transcriptional and proteomic responses of the antennae and heads were investigated. A total of 101 differentially expressed genes (DEGs) in the antennae, 138 DEGs in the heads, and 43 differentially expressed proteins (DEPs) in the heads including antennae were revealed. We discovered that upregulations of Arrestin1 and nitric oxide synthase1 (NOS1) may inhibit cyclic nucleotide-gated channels and hinder calcium influx in the antennae. In the central nervous systems (CNS), downregulations of tyrosine hydroxylase (TH) and tyrosine decarboxylase (TDC) may inhibit olfactory signal transduction by reducing the second messenger biosynthesis. Meanwhile, an abnormal increase of brain cell apoptosis was revealed by Annexin V-mCherry staining, often leading to persistent neurologic impairment. Taken together, this study highlighted olfactory dysfunction caused by dichlorvos, which may provide a novel perspective for understanding the toxicity mechanism of volatile pesticides in other organisms.

Отлучение от искусственной вентиляции легких у пациента с постгипоксической энцефалопатией и центральной гипертермией

Актуальность. Постгипоксическое повреждение центральной нервной системы часто сопровождается полиорганной дисфункцией, персистирующим неврологическим дефицитом и может осложниться центральной гипертермией. Целью данного исследования было проанализировать литературные данные о методах лечения гипертермии центрального генеза и предложить стратегию отлучения от респираторной терапии у такого пациента. Материалы и методы. Поиск литературных источников проводился в базах данных PubMed и MedLine за последние 13 лет. Поисковыми словами были «гипертермия центрального генеза» и «отлучение от искусственной вентиляции легких у детей с постгипоксической энцефалопатией». Наблюдение и лечение пациента осуществлялись на клинической базе кафедры анестезиологии и интенсивной терапии Львовского национального медицинского университета имени Данила Галицкого в отделении анестезиологии с койками интенсивной терапии КНП «Львовская областная клиническая больница «ОХМАТДЕТ» в сентябре — октябре 2018 года. Результаты. У ребенка в возрасте 7 мес. после перенесенной клинической смерти и успешного восстановления спонтанного кровообращения развились постгипоксическая энцефалопатия, синдром полиорганной дисфункции и гипертермия центрального генеза. Это привело к росту минутной вентиляции легких, тахикардии и, соответственно, проблеме с отлучением от респираторной поддержки. Кроме того, у пациента был клинически значимый гипертонус мышц нижних конечностей с постоянным спонтанным разведением в тазобедренных суставах более 180°. В лечение был добавлен баклофен в дозе 0,3 мг/кг/сут per os, которая через 7 дней была увеличена до 0,6 мг/кг/сут. На 3-и сутки с момента назначения баклофена температура тела стала стабильно ниже 38 °C, на 5-е сутки не превышала 37,5 °C. Отлучение от искусственной вентиляции легких проводилось поэтапно — от принудительно-вспомогательного режима искусственной вентиляции легких с постепенным снижением параметров поддержки до вспомогательного режима с ежедневным увеличением интервала спонтанного дыхания пациента без респираторной поддержки, начиная от 2–4 ч в дневной период времени в течение 2–3 дней и перехода к плановой вспомогательной вентиляции только в ночное время и полному отлучению от вспомогательной вентиляции. Полное отлучение от искусственной вентиляции легких произошло на 7-е сутки с момента назначения баклофена. Выводы. Контроль над лихорадкой у пациентов, перенесших повреждения центральной нервной системы, может улучшить результаты лечения, особенно если будут разработаны более эффективные стратегии мониторинга и лечения гипертермии.

BDNF blood serum linkage with BDNF gene polymorphism (rs6265) in thyroid pathology patients in the West-Ukrainian population.

Objective. Brain-derived neurotrophic factor (BDNF) is identified as an important growth factor involved in learning and memory. Patients with Hashimoto's thyroiditis can suffer from cognitive dysfunction, whereas BDNF is directly regulated by thyroid hormones. It seems reasonable to propose that changes in BDNF expression underlie some of the persistent neurological impairments associated with hypothyroidism. Methods. The study involved a total of 153 patients with various forms of thyroid pathology. BDNF levels in the sera of the patients and healthy individuals were quantified using enzyme-linked immunosorbent assay with highly sensitive Human BDNF ELISA Kit. Genotyping of the BDNF (rs6265) gene polymorphism using TaqMan probes and TaqMan Genotyping Master Mix (4371355) on CFX96™Real-Time PCR Detection System. Polymerase chain reaction (PCR) for TaqMan genotyping was carried out according to the kit instructions. Results. Distribution rs6265 variants in the patients depending on the different types of thyroid pathology showed no significant difference in the relative frequency of BDNF polymorphic variants. Presence of hypothyroidism, regardless of its cause (autoimmune or postoperative), there was a decrease in the serum BDNF levels in all genotypes carriers compared with the control group. The analysis of the correlation between BDNF levels and the levels of thyroid-stimulating hormone (TSH), thyroxine (T4), anti-thyroglobulin (anti-Tg), and anti-thyroid peroxidase (anti-TPO) antibodies showed a significant inverse relationship between BDNF and TSH levels (p<0.001), a direct correlation between BDNF and T4 levels in the blood (p<0.001), and a weak direct relationship between anti-Tg and BDNF levels (p=0.0157). Conclusion. The C allele presence is protective and associates with the lowest chances for reduced serum BDNF levels in thyroid pathology patients in the West-Ukrainian population. However, the T-allele increases the risk of low BDNF levels almost 10 times in observed subjects.

Intracranial Hemorrhage in Patients with Haematological Malignancy, a Nested Case-Control Study

BackgroundIntracranial hemorrhage (ICH) is one of the most serious side-effects of severe thrombocytopenia in hematology patients. ICH is rare, but can have devastating consequences (death/major morbidity). It is unknown why some patients bleed and others do not. This study's aims were to identify risk factors for ICH in patients with hematologic disorders, and identify the short-term outcomes for these patients at 30 days (major morbidity/mortality).MethodsThe InCiTe study is a UK-wide case-control study of ICH nested within a 4 year prospective surveillance study (ISRCTN05026912). Each ICH case was matched to one control. Cases were adult hematology patients (≥ 16 yrs) who had any type or severity of ICH and were receiving, about to receive or had just received myeloablative chemotherapy or hematopoietic stem cell transplant (HSCT). Only patients treated with curative intent were included. Control patients fulfilled the same inclusion criteria as cases (apart from ICH) and were treated at the same hospital immediately before the index case. Cases and controls were matched to type of treatment (chemotherapy or HSCT) so that potential transplant-related risk factors could be assessed. Hospitals across the UK participated in monthly e-mail reporting of any cases of ICH occurring during the preceding calendar month. Case and control forms were sent to any participating hospital reporting an eligible case.ResultsMonthly reporting occurred between June 2011 & June 2015. Over 90% of hospitals reported every month whether or not a case of ICH had occurred. 148 ICH cases were reported during the study from 84 recruiting hospitals. Median age of cases was 60 years (range 17 to 80), 50% were male, 61% (90/148) had acute myeloid leukemia, of whom 13 had acute promyelocytic leukemia. 91% (134/148) were being treated/about to be treated with chemotherapy, 8% (12/148) were undergoing an allogeneic HSCT, and 1% (2/148) an autologous HSCT. Only 18% (26/148) were in complete remission (CR) from their hematologic malignancy at time of ICH. Median platelet count at time of ICH was 17 x 109/L (IQR 8 to 37). In the 4 days preceding ICH, cases had median 3 days with platelet count < 50 x 109/L (IQR 1.75 to 4), 1.5 days with platelet count < 20 x 109/L (IQR 0 to 3), and 0 days with platelet count < 10 x 109/L (IQR 0 to 2).140 cases and matched controls were used to assess ICH risk factors. Variables considered for inclusion within the model were: Hb, WCC, creatinine, CRP, albumin, platelet count, platelet refractoriness, sex, age, hematologic diagnosis, CR status, use of anticoagulants, height, weight, abnormal coagulation, liver impairment, hypertension, previous CNS abnormality, renal impairment, recent history of bleeding, smoking, diabetes, ischaemic heart disease, use of therapeutic antibiotics, and antifungals.Independent risk factors for ICH identified from a multivariable conditional logistic regression analysis were: WCC (OR 1.2 per 1 x 109/L rise in WCC; 95% CI 1.05 to 1.36; P < 0.0001); CRP (OR 1.01 per 1mg/L increase in CRP; 95% CI 1 to 1.01; P = 0.006), platelet refractoriness (OR 5.3; 95% CI 1.29 to 21.76; P = 0.01); female gender (OR 2.78; 95% CI 1.28 to 6.03; P = 0.006); and use of therapeutic antibiotics (OR 0.34; 95% CI 0.12 to 0.92; P = 0.03). Creatinine (OR 1.01 per 1µmol/L rise in creatinine; 95% CI 1 to 1.02; P = 0.06) was borderline significant.Less than a third of patients who had an ICH survived the event with no long term sequelae. 75 cases (51%) died within 30 days, of these 87% (65/75) died due to their ICH. 28% (42/148) had a Glasgow Coma Scale < 9 at time of ICH, of these 81% (34/42) died. 73 cases survived, however, 40% (29/73) had a persistent neurological impairment at 30 days, and of these only 17% (5/29) were independent in all activities of daily living. 30 day survival was 49.3 % (95% CI 40.8 to 57.2) for cases and 93.5% (95% CI 84.7 to 97.3) for controls.DiscussionRisk factors for ICH that were identified in this large case-control study relate to infection or sepsis: these include a high WCC (possibly also due to presence of leukemic cells in circulation), high CRP (inflammation increases the risk of bleeding), and platelet refractoriness; use of antibiotics decreases the risk. By comparison, platelet count and haemoglobin were not identified as important factors. Outcomes after ICH were poor. The role of further risk-adjusted strategies as a preventative strategy requires more research.FundingNHSBT DisclosuresNo relevant conflicts of interest to declare.

Thrombotic Events with Neisseria Meningitidis Vaccination in Patients with Paroxysmal Nocturnal Hemoglobinuria, UK Experience

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hemolytic and thrombotic condition. Patients can experience severe anemia due to intravascular hemolysis, thrombotic events, renal impairment and pulmonary hypertension. Symptomatic patients are treated with complement inhibitors either in clinical trials or with eculizumab the only licensed treatment in the UK. Due to the mechanism of action of eculizumab, it increases susceptibility to Neisseria infection, including Neisseria meningitidis. To reduce this risk of infection, worldwide practice is for patients to be vaccinated at least 2 weeks prior to receiving eculizumab (serogroups A, C, Y, W 135 and B). It was noted within the PNH National Service at Leeds (UK) that a small number of patients deteriorated with enhanced intravascular hemolysis and thrombosis during the period between vaccination and eculizumab, leading to a review of practice. We report five of 121 patients with events in the intervening 2 weeks between vaccination and commencement of eculizumab from 2002-2012:A 44 year female presented with hemolysis and hemoglobinuria, with a granulocyte PNH clone of 99.4%. She was transfusion dependent and on anticoagulation. She consented to the PNH pilot eculizumab study, undergoing meningococcal vaccination as per protocol. Twenty two days later, she suffered an ischemic stroke with left hemiplegia and permanent weakness, resulting in exclusion from the study. Two years later she received eculizumab in the TRIUMPH study.A 37 year male presented with hemoglobinuria and fatigue with a granulocyte PNH clone of 99.58%. He had significant hemolysis, managed initially with warfarin and blood transfusions. He consented to start eculizumab and received meningococcal vaccination. 4 days later he presented with a symptomatic right hepatic vein thrombosis, promptly commenced eculizumab.A 29 year male, with abdominal pain and hemoglobinuria for 3 years developed a stroke and portal vein thrombosis leading to a diagnosis of PNH, with a granulocyte PNH clone of 84.99%. He commenced anticoagulation. Four months after the stroke he received meningococcal vaccination in preparation for scheduled commencement with eculizumab. He experienced a left central retinal vein thrombosis 15 days after its administration prior to starting eculizumab.A 47 year old male, was diagnosed with haemolytic PNH but only had mild symptoms and anaemia. Twenty four years later, he developed increasing hemolysis and symptoms; granulocyte PNH clone of 96.45%. Eculizumab was planned and he received meningococcal vaccination, but presented ten days later with acute renal failure secondary to massive intravascular haemolysis, necessitating emergency eculizumab therapy.A 35 year female, with a granulocyte PNH clone of 99.87%. Although she had active intravascular hemolysis, eculizumab was declined, and anticoagulation commenced. Four years later she consented to start eculizumab, receiving meningococcal vaccination. She was admitted 24 hours later with a stroke and commenced eculizumab the same day, but has persistent neurological impairment to date. See Table 1 Discussion: The close time proximity of these serious events to the patients' vaccinations raised concern that the complement system was being activated by administration of the vaccine, precipitating complications of PNH. It is also concerning that 4 of the 5 patients experienced thrombotic events despite therapeutic anticoagulation, confirming that anticoagulation only partially mitigates the risk of thrombosis in patients with PNH. The decision was taken to administer the vaccination immediately after the first dose of eculizumab, with therapeutic doses of antibiotic (ciprofloxacin 500mg bd) for the first 14 days post vaccination, followed by long term meningococcal prophylaxis (penicillin V or erythromycin 500mg bd) whilst receiving a complement inhibitor. Since this change in practice in 2012 we have commenced eculizumab therapy in 211 patients with no similar complications as described. Thus the change in practice appears to reduce the occurrence of these severe complications associated with vaccinations prior to initiating anti-complement therapy. Whilst it is possible these events could have been caused by the underlying condition of PNH, we would advise colleagues to also adopt a change in practice to reduce potentially significant complications. Disclosures Arnold: Alexion Pharmaceuticals: Honoraria. Kelly:Alexion: Honoraria. Munir:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria. Pike:Apellis: Research Funding. Riley:Alexion: Honoraria. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference Support; Biocryst: Membership on an entity's Board of Directors or advisory committees. Hillmen:Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding.

Effect of mirror therapy on hand functions in Egyptian chronic stroke patients

BackgroundMost stroke survivors (more than 60%) suffer from persistent neurological impairments that significantly affect activities of daily living. Hand functions are essential for doing daily living and working activities. Mirror therapy is shown to be effective in improving hand functional recovery in stroke patients.ObjectiveThis study aimed to determine the effect of mirror therapy on improving hand functions in Egyptian chronic stroke patients.Subjects and methodsThirty chronic ischemic stroke patients from both sexes participated in the study. Their ages ranged from 45 to 65 years. They were randomly assigned into two equal groups: the study group that received a selected physical therapy program in addition to the mirror therapy and the control group that received the same selected physical therapy program but without a mirror therapy. Treatment sessions were conducted three times per week for 8 weeks. Range of motion (ROM) of the wrist extension and forearm supination, hand grip strength, and the time of Jebson Hand Function Test (JHFT) were measured before and after the treatment program.ResultsThere were statistically significant increases in the range of motion of the wrist extension and forearm supination and hand grip strength with a decrease in the time of Jebson Hand Function Test in both groups post-treatment. Post-treatment improvement was more significant in the study group compared to the control group.ConclusionMirror therapy had a positive effect on improving hand motor functional skills in a sample of Egyptian chronic stroke patients.

Long-Term Cardiovascular Diseases of Heatstroke: A Delayed Pathophysiology Outcome.

Heatstroke, defined as an elevated core body temperature above 40°C accompanied by altered mental status (e.g., confusion, disorientation, seizure and coma), is the most severe and life-threatening condition in the spectrum of heat-related illnesses. Heatstroke patients may present with multi-organ dysfunction, but with rapid cooling and organ failure management, a full recovery often occurs within weeks. Long-term impairment is rare, with neurological impairment occurring most frequently. Despite an abundance of research on the persistent neurological and hepatic impairments, our knowledge of the long-term cardiovascular events in patients with heatstroke history is poor. We wondered whether heatstroke leads to cardiovascular diseases long after full recovery. Using Pubmed, Web of Science and Scopus, we gathered cohort studies looking at cardiovascular disease incidence or mortality as an outcome, including heatstroke animal studies. Based on the available literature, we found that a history of heatstroke is associated with an increased risk of cardiovascular diseases, including ischemic heart disease, heart failure and atrial fibrillation. Delayed metabolic disturbances occurring in exertional heatstroke mice are linked to the formation of atherosclerosis and the development of heart failure. These processes provide potential pathophysiological pathways leading to ischemic heart disease and heart failure in heatstroke patients. Our findings may massively impact our understanding of heatstroke recovery and the follow up of heatstroke patients. Therefore larger, more adequately powered cohort studies with cardiovascular disease as an outcome, in tandem with animal studies examining the underlying pathophysiology, are required to confirm or reject these findings and answer the proposed questions.

Zinc Concentration Dynamics Indicate Neurological Impairment Odds after Traumatic Spinal Cord Injury.

Traumatic Spinal Cord Injury (TSCI) is debilitating and often results in a loss of motor and sensory function caused by an interwoven set of pathological processes. Oxidative stress and inflammatory processes are amongst the critical factors in the secondary injury phase after TSCI. The essential trace element Zinc (Zn) plays a crucial role during this phase as part of the antioxidant defense system. The study aims to determine dynamic patterns in serum Zn concentration in patients with TSCI and test for a correlation with neurological impairment. A total of 42 patients with TSCI were enrolled in this clinical observational study. Serum samples were collected at five different points in time after injury (at admission, and after 4 h, 9 h, 12 h, 24 h, and 3 days). The analysis of the serum Zn concentrations was conducted by total reflection X-ray fluorescence (TXRF). The patients were divided into two groups—a study group S (n = 33) with neurological impairment, including patients with remission (G1, n = 18) and no remission (G0, n = 15) according to a positive AIS (American Spinal Injury Association (ASIA) Impairment Scale) conversion within 3 months after the trauma; and a control group C (n = 9), consisting of subjects with vertebral fractures without neurological impairment. The patient data and serum concentrations were examined and compared by non-parametric test methods to the neurological outcome. The median Zn concentrations in group S dropped within the first 9 h after injury (964 µg/L at admission versus 570 µg/L at 9 h, p < 0.001). This decline was stronger than in control subjects (median of 751 µg/L versus 729 µg/L, p = 0.023). A binary logistic regression analysis including the difference in serum Zn concentration from admission to 9 h after injury yielded an area under the curve (AUC) of 82.2% (CI: 64.0–100.0%) with respect to persistent neurological impairment. Early Zn concentration dynamics differed in relation to the outcome and may constitute a helpful diagnostic indicator for patients with spinal cord trauma. The fast changes in serum Zn concentrations allow an assessment of neurological impairment risk on the first day after trauma. This finding supports strategies for improving patient care by avoiding strong deficits via adjuvant nutritive measures, e.g., in unresponsive patients after trauma.

Dynamic Balance of Microglia and Astrocytes Involved in the Remyelinating Effect of Ginkgolide B.

Multiple sclerosis (MS) is an inflammatory demyelinating disorder in the central nervous system (CNS), in which remyelination failure results in persistent neurologic impairment. Ginkgolide B (GB), a major terpene lactone and active component of Ginkgo biloba, has neuroprotective effects in several models of neurological diseases. Here, our results show, by using an in vivo cuprizone (CPZ)-induced demyelinating model, administration of GB improved behavior abnormalities, promoted myelin generation, and significantly regulated the dynamic balance of microglia and astrocytes by inhibiting the expression of TLR4, NF-κB and iNOS as well as IL-1β and TNF-α, and up-regulating the expression of Arg-1 and neurotrophic factors. GB treatment also induced the generation of oligodendrocyte precursor cells (OPCs). In vitro cell experiments yielded the results similar to those of the in vivo model. The dynamic balance by decreasing microglia-mediated neuroinflammation and promoting astrocyte-derived neurotrophic factors should contribute to endogenous remyelination. Despite GB treatment may represent a novel strategy for promoting myelin recovery, the precise mechanism of GB targeting microglia and astrocytes remains to be further explored.