Delayed Neurological Deficits Research Articles

Abstract 1236 Role of Platelets in the Development of Delayed Neurological Deficits after Subarachnoid Hemorrhage in Mice

Abstract 1236 Role of Platelets in the Development of Delayed Neurological Deficits after Subarachnoid Hemorrhage in Mice

Incidence and factors in delayed neurological deficits after subarachnoid hemorrhage in mice

ObjectiveDelayed cerebral ischemia (DCI) is one of the most feared complications in aneurysmal subarachnoid hemorrhage (SAH). Animal models are crucial to studying the disease mechanisms and potential treatments. DCI in rodents was thought to not exist; herein we examine literature and our experience with DCI in rodents. MethodsDaily behavioral performance was assessed every day from day 1 to up to 7 days post-SAH on mice from 5 different studies that used the endovascular perforation model. Performance was graded using an 8-test sensorimotor neuroscore previously described. The daily neuroscore was then used to identify the incidence and timing of delayed neurological deficits (DND), a clinical surrogate for DCI. A total number of 298 mice (134 males, 164 females) were subjected to SAH. Fifty-one mice had histological staining done to identify infarct volume. ResultsThe overall incidence of DND was 33.9%; 27.6% in males and 39.0% in females, but this difference was not statistically significant. The overall incidence of delayed death was 21.1%, and there was no significant difference for delayed mortality in females versus male mice. There is a non-statistically significant trend towards increased infarct volume in mice suffering DND. ConclusionsMice with endovascular puncture induced SAH develop DND at rates comparable to human patients. Future work needs to correlate the DND seen with decreased regional cerebral blood flow, another hallmark of DCI, but in spite of this need, researchers may use the murine models to test therapies for DCI after SAH.

Targeted c-Myc Inhibition and Systemic Temozolomide Therapy Extend Survival in Glioblastoma Xenografts.

Glioblastoma is a highly aggressive disease with poor patient outcomes despite current treatment options, which consist of surgery, radiation, and chemotherapy. However, these strategies present challenges such as resistance development, damage to healthy tissue, and complications due to the blood-brain barrier. There is therefore a critical need for new treatment modalities that can selectively target tumor cells, minimize resistance development, and improve patient survival. Temozolomide is the current standard chemotherapeutic agent for glioblastoma, yet its use is hindered by drug resistance and severe side effects. Combination therapy using multiple drugs acting synergistically to kill cancer cells and with multiple targets can provide increased efficacy at lower drug concentrations and reduce side effects. In our previous work, we designed a therapeutic peptide (Bac-ELP1-H1) targeting the c-myc oncogene and demonstrated its ability to reduce tumor size, delay neurological deficits, and improve survival in a rat glioblastoma model. In this study, we expanded our research to the U87 glioblastoma cell line and investigated the efficacy of Bac-ELP1-H1/hyperthermia treatment, as well as the combination treatment of temozolomide and Bac-ELP1-H1, in suppressing tumor growth and extending survival in athymic mice. Our experiments revealed that the combination treatment of Bac-ELP1-H1 and temozolomide acted synergistically to enhance survival in mice and was more effective in reducing tumor progression than the single components. Additionally, our study demonstrated the effectiveness of hyperthermia in facilitating the accumulation of the Bac-ELP1-H1 protein at the tumor site. Our findings suggest that the combination of targeted c-myc inhibitory biopolymer with systemic temozolomide therapy may represent a promising alternative treatment option for glioblastoma patients.

Delayed Neurological Deficit in Osteoporotic Vertebral Compression Fracture: An Analysis of Surgical Outcome

Delayed Neurological Deficit in Osteoporotic Vertebral Compression Fracture: An Analysis of Surgical Outcome

遅発性神経障害（脊髄～円錐部）を伴う骨粗鬆症性椎体骨折の後方固定術に除圧併用は必要なのか？

遅発性神経障害（脊髄～円錐部）を伴う骨粗鬆症性椎体骨折の後方固定術に除圧併用は必要なのか？

Low-Dose Intravenous Heparin Infusion After Aneurysmal Subarachnoid Hemorrhage is Associated With Decreased Risk of Delayed Neurological Deficit and Cerebral Infarction.

Patients who survive aneurysmal subarachnoid hemorrhage (aSAH) are at risk for delayed neurological deficits (DND) and cerebral infarction. In this exploratory cohort comparison analysis, we compared in-hospital outcomes of aSAH patients administered a low-dose intravenous heparin (LDIVH) infusion (12U/kg/h) vs those administered standard subcutaneous heparin (SQH) prophylaxis for deep vein thrombosis (DVT; 5000U, 3×daily). To assess the safety and efficacy of LDIVH in aSAH patients. We retrospectively analyzed 556 consecutive cases of aSAH patients whose aneurysm was secured by clipping or coiling at a single institution over a 10-yr period, including 233 administered the LDIVH protocol and 323 administered the SQH protocol. Radiological and outcome data were compared between the 2 cohorts using multivariable logistic regression and propensity score-based inverse probability of treatment weighting (IPTW). The unadjusted rate of cerebral infarction in the LDIVH cohort was half that in SQH cohort (9vs 18%; P=.004). Multivariable logistic regression showed that patients in the LDIVH cohort were significantly less likely than those in the SQH cohort to have DND (odds ratio (OR) 0.53 [95% CI: 0.33, 0.85]) or cerebral infarction (OR 0.40 [95% CI: 0.23, 0.71]). Analysis following IPTW showed similar results. Rates of hemorrhagic complications, heparin-induced thrombocytopenia and DVT were not different between cohorts. This cohort comparison analysis suggests that LDIVH infusion may favorably influence the outcome of patients after aSAH. Prospective studies are required to further assess the benefit of LDIVH infusion in patients with aSAH.

Commentary: Low-Dose Intravenous Heparin Infusion After Aneurysmal Subarachnoid Hemorrhage Is Associated With Decreased Risk of Delayed Neurological Deficit and Cerebral Infarction.

Commentary: Low-Dose Intravenous Heparin Infusion After Aneurysmal Subarachnoid Hemorrhage Is Associated With Decreased Risk of Delayed Neurological Deficit and Cerebral Infarction.

Lumbar Drains After Cardiac Surgery: Evidence-Based Solutions for Safe Management.

Lumbar Drains After Cardiac Surgery: Evidence-Based Solutions for Safe Management.

Microthrombi Correlates With Infarction and Delayed Neurological Deficits After Subarachnoid Hemorrhage in Mice.

Delayed neurological deficits are a devastating consequence of subarachnoid hemorrhage (SAH), which affects about 30% of surviving patients. Although a very serious concern, delayed deficits are understudied in experimental SAH models; it is not known whether rodents recapitulate the delayed clinical decline seen in SAH patients. We hypothesized that mice with SAH develop delayed functional deficits and that microthrombi and infarction correlate with delayed decline. Adult C57BL/6J mice of both sexes were subjected to endovascular perforation to induce SAH. Mice were allowed to survive for up to 1 week post-ictus and behavioral performance was assessed daily. Postmortem microthrombi, large artery diameters (to assess vasospasm), and infarct volume were measured. These measures were analyzed for differences between SAH mice that developed delayed deficits and SAH mice that did not get delayed deficits. Correlation analyses were performed to identify which measures correlated with delayed neurological deficits, sex, and infarction. Twenty-three percent of males and 47% of females developed delayed deficits 3 to 6 days post-SAH. Female mice subjected to SAH had a significantly higher incidence of delayed deficits than male mice with SAH. Mice that developed delayed deficits had significantly more microthrombi and larger infarct volumes than SAH mice that did not get delayed deficits. Microthrombi positively correlated with infarct volume, and both microthrombi and infarction correlated with delayed functional deficits. Vasospasm did not correlate with either infarction delayed functional deficits. We discovered that delayed functional deficits occur in mice following SAH. Sex differences were seen in the prevalence of delayed deficits. The mechanism by which microthrombi cause delayed deficits may be via formation of infarcts.

Abstract WP308: Role of Microthrombi and Vasospasm in the Development of Delayed Neurological Deficits After Subarachnoid Hemorrhage in Mice

Rationale: Microthrombosis has been suggested as a major factor contributing to delayed neurological deterioration in patients after subarachnoid hemorrhage (SAH). However, experimental studies on the role of microthrombi in delayed deficits after SAH has not been investigated. Our hypothesis is that, following SAH, mice which develop delayed neurological deficits have a greater number of microthrombi than mice which do not develop delayed neurological deficits. Methods: SAH was induced in adult male and female C57BL/6 mice via endovascular perforation. Mice were randomly assigned into sham (n=6/sex) or SAH groups (n=22-24/sex). Neurobehavior was performed on days 1-3, 5, and 7 post-SAH using a composite neuroscore. Animals were sacrificed on the day of delayed deficits or 7 days post-SAH. Microthrombi count and vessel diameters (for vasospasm) were measured using H&E stained brain slices. All outcomes were performed and all data were analyzed by a blinded investigator. Results: Seventeen percent (4/24) of male mice and thirty-six percent (8/22) of female mice developed delayed deficits on days 3-5 post-SAH (Figures 1A and 1B). Those mice which developed delayed deficits had significantly more microthrombi in their brains than mice which did not develop delayed deficits; vasospasm did not correlate with delayed deficits. Additionally, female SAH mice develop delayed deficits at a higher frequency than males (Figure 1C). Conclusions: This work shows for the first time delayed deficits in a SAH mouse model. Further, microthrombi correlated with delayed deficits, whereas no correlation was between delayed deficits and vasospasm. The data within this study suggests that preventing microthrombi may improve functional recovery and reduce the risk of delayed deficits.

Risk Factors for Proximal Junctional Fracture Following Fusion Surgery for Osteoporotic Vertebral Collapse with Delayed Neurological Deficits: A Retrospective Cohort Study of 403 Patients.

Introduction Approximately 3% of osteoporotic vertebral fractures develop osteoporotic vertebral collapse (OVC) with neurological deficits, and such patients are recommended to be treated surgically. However, a proximal junctional fracture (PJFr) following surgery for OVC can be a serious concern. Therefore, the aim of this study is to identify the incidence and risk factors of PJFr following fusion surgery for OVC. Methods This study retrospectively analyzed registry data collected from facilities belonging to the Japan Association of Spine Surgeons with Ambition (JASA) in 2016. We retrospectively analyzed 403 patients who suffered neurological deficits due to OVC below T10 and underwent corrective surgery; only those followed up for ≥2 years were included. Potential risk factors related to the PJFr and their cut-off values were calculated using multivariate logistic regression analysis and receiver operating characteristic (ROC) analysis. Results Sixty-three patients (15.6%) suffered PJFr during the follow-up (mean 45.7 months). In multivariate analysis, the grade of osteoporosis (grade 2, 3: adjusted odds ratio (aOR) 2.92; p=0.001) and lower instrumented vertebra (LIV) level (sacrum: aOR 6.75; p=0.003) were independent factors. ROC analysis demonstrated that lumbar bone mineral density (BMD) was a predictive factor (area under curve: 0.72, p=0.035) with optimal cut-off value of 0.61 g/cm2 (sensitivity, 76.5%; specificity, 58.3%), but that of the hip was not (p=0.228). Conclusions PJFr was found in 16% cases within 4 years after surgery; independent risk factors were severe osteoporosis and extended fusion to the sacrum. The lumbar BMD with cut-off value 0.61 g/cm2 may potentially predict PJFr. Our findings can help surgeons select perioperative adjuvant therapy, as well as a surgical strategy to prevent PJFr following surgery.

Delayed Neurological Deficit after Traumatic Odontoid Fracture

Fractures of the odontoid process can lead to gross instability of the atlantoaxial complex and present a significant risk for a potentially catastrophic spinal cord injury. Type II odontoid fractures are the most common odontoid fractures and are unstable that may displace anteriorly or posteriorly. If left untreated, the patient may develop atlantoaxial dislocation that causes neurological deficit also progressive myelopathy.We described the surgical management of four patients with a delayed neurological deficit after odontoid fracture with a history of trauma and after triggered by traditional massage. Traction several days before operation applied to achieve reduction of atlantoaxial dislocation.Posterior instrumentation and correction of atlantoaxial dislocation were performed with interarticular screw fixation (Harm technique) in all of the patients.All of the four patients showed a reduction of the atlantoaxial dislocation and also a neurological improvement. Cervical traction followed by posterior instrumented correction may be an effective alternative to treating delayed neurological deficits after traumatic odontoid fracture.

Delayed Neurological Deficit after Traumatic Odontoid Fracture

Fractures of the odontoid process can lead to gross instability of the atlantoaxial complex and present a significant risk for a potentially catastrophic spinal cord injury. Type II odontoid fractures are the most common odontoid fractures and are unstable that may displace anteriorly or posteriorly. If left untreated, the patient may develop atlantoaxial dislocation that causes neurological deficit also progressive myelopathy.We described the surgical management of four patients with a delayed neurological deficit after odontoid fracture with a history of trauma and after triggered by traditional massage. Traction several days before operation applied to achieve reduction of atlantoaxial dislocation.Posterior instrumentation and correction of atlantoaxial dislocation were performed with interarticular screw fixation (Harm technique) in all of the patients.All of the four patients showed a reduction of the atlantoaxial dislocation and also a neurological improvement. Cervical traction followed by posterior instrumented correction may be an effective alternative to treating delayed neurological deficits after traumatic odontoid fracture.

Delayed Neurological Deficit after Traumatic Odontoid Fracture

Delayed Neurological Deficit after Traumatic Odontoid Fracture

Delayed Neurological Deficits after Osteoporotic Vertebral Fractures: Clinical Outcomes after Surgery.

Study DesignRetrospective cohort.PurposeTo review the clinical presentation of operated patients with delayed neurological deficits after osteoporotic vertebral fractures (OVFs).Overview of LiteratureDelayed neurological deficits can occur from 1 week to 5.7 months after OVFs. Baba has reported 78% good-to-excellent improvement (i.e., ≥50%) after 20 posterior (Cotrel-Dubousset) and 7 anterior (Kaneda in 4, Zielke ventral derotational spondylodesis in 2, and un-instrumented anterior fusion in 1) fusions. Predictive factors for neurological deficits include burst type, vacuum sign, kyphosis, angular instability, and retropulsion.MethodsPatients with neurological deficits after OVF who received spinal operations between 2000 and 2016 were included.ResultsTotally, 28 patients with a mean age of 77 years underwent surgery. Neurological deficits occurred at an average of 5.4 weeks after the onset of back pain. The most common site was L1. Burst fracture was present in 14 patients and vacuum sign in seven. Surgery was performed within an average of 3.9 days of the onset of neurological deficit. Baba's score improved significantly from 5.96 to 9.81, with good-to-excellent improvement in 18 (64%) patients. Better outcomes based on Baba's scores (improvement>60% [median]) were associated with compression fractures, preoperative retropulsion of <41%, and correction of >16%. Poor improvement in Baba's scores (<25%) was associated with surgical complications and burst fracture type. Twenty-two patients (79%) regained walking ability, and seven of 15 (47%) patients demonstrated improved sphincter control at the latest follow-up. Six Frankel grade B patients did not achieve neurological recovery, four of whom exhibited postoperative surgical complications and died at 2 years because of medical problems. Implant migration occurred in six patients, albeit this was of no clinical significance.ConclusionsAlthough OVFs are commonly considered benign, delayed neurological deficits can occur. The significant improvement in clinical function after surgery for neurological deficits is associated with compression (and not burst) fractures, lack of surgical complications, and optimal restoration of retropulsion.

Calpastatin inhibits motor neuron death and increases survival of hSOD1(G93A) mice.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with a poorly understood cause and no effective treatment. Given that calpains mediate neurodegeneration in other pathological states and are abnormally activated in ALS, we investigated the possible ameliorative effects of inhibiting calpain over-activation in hSOD1(G93A) transgenic (Tg) mice in vivo by neuron-specific over-expression of calpastatin (CAST), the highly selective endogenous inhibitor of calpains. Our data indicate that over-expression of CAST in hSOD1(G93A) mice, which lowered calpain activation to levels comparable to wild-type mice, inhibited the abnormal breakdown of cytoskeletal proteins (spectrin, MAP2 and neurofilaments), and ameliorated motor axon loss. Disease onset in hSOD1(G93A) /CAST mice compared to littermate hSOD1(G93A) mice is delayed, which accounts for their longer time of survival. We also find that neuronal over-expression of CAST in hSOD1(G93A) transgenic mice inhibited production of putative neurotoxic caspase-cleaved tau and activation of Cdk5, which have been implicated in neurodegeneration in ALS models, and also reduced the formation of SOD1 oligomers. Our data indicate that inhibition of calpain with CAST is neuroprotective in an ALS mouse model. CAST (encoding calpastatin) inhibits hyperactivated calpain to prevent motor neuron disease operating through a cascade of events as indicated in the schematic, with relevance to amyotrophic lateral sclerosis (ALS). We propose that over-expression of CAST in motor neurons of hSOD1(G93A) mice inhibits activation of CDK5, breakdown of cytoskeletal proteins (NFs, MAP2 and Tau) and regulatory molecules (Cam Kinase IV, Calcineurin A), and disease-causing proteins (TDP-43, α-Synuclein and Huntingtin) to prevent neuronal loss and delay neurological deficits. In our experiments, CAST could also inhibit cleavage of Bid, Bax, AIF to prevent mitochondrial, ER and lysosome-mediated cell death mechanisms. Similarly, CAST over-expression in neurons attenuated pathological effects of TDP-43, α-synuclein and Huntingtin. These results suggest a potential value of specific small molecule inhibitors of calpains in delaying the development of ALS. Read the Editorial Highlight for this article on page 140.

Blood Metabolomic Predictors of 1-Year Outcome in Subarachnoid Hemorrhage.

Delayed neurological deficit (DND) is the most important cause of morbidity and mortality in patients with subarachnoid hemorrhage (SAH) whose aneurysms have been secured. However, the methods currently used to predict the development of DND, such as trans-cranial Doppler or levels biochemical markers in blood and cerebrospinal fluid are not very accurate. Venous blood was drawn from 50 patients with SAH, admitted to the neurosurgical department Umeå University Hospital, at day 1-3 and day 7 after the bleed. The clinical status of the patients was followed up approximately 1 year after this episode and classified according to the Glasgow Outcome Score (GOS). Results showed considerable differences in blood metabolomic patterns between day 1-3 and 7 after the hemorrhage. Fifty-six out of 98 metabolites could be identified from our in-house library and 17 of these metabolites changed significantly from day 1-3 to 7 after the bleed. One of these, myo-inositol, was predictive of clinical outcome even after correction for multiple testing. An estimation of the diagnostic accuracy of high levels of this substance in predicting good outcome (GOS 4-5) yielded a sensitivity of .763 and a specificity of .5 at the optimal cut off point. SAH is an event with a profound effect on blood metabolomics profiles. Myo-inositol might be an interesting compound for future study to focus on in the search for metabolic markers in venous blood of delayed neurological deterioration in SAH patients.

Does Intraoperative Angiographic Vasospasm during Aneurysm Clipping influence the Incidence of Delayed Cerebral Vasospasm and Delayed Neurological Deficit?

Aims: Delayed cerebral vasospasm (dCVS) occurs in more than half of the patients with SAH and is associated with delayed neurological deficits (DND) mostly between days 4 and 15 after ictus. The incidence of acute CVS within 72 hours after SAH is controversial. Acute surgically-induced CVS might influence the incidence of dCVS and outcome of patients undergoing clipping or coiling of ruptured and unruptured aneurysms. The aim of this study was to elucidate the incidence of intraoperative angiographic CVS (iCVS) during aneurysm surgery and analyze its possible role on the risk for dCVS and DND.

A Case of Surgically Treated by Transperitoneal Approach in Delayed Neurological Deficit after Sacral Fracture - A Case Report -

A Case of Surgically Treated by Transperitoneal Approach in Delayed Neurological Deficit after Sacral Fracture - A Case Report -

Correlation Among Systemic Inflammatory Parameter, Occurrence of Delayed Neurological Deficits, and Outcome After Aneurysmal Subarachnoid Hemorrhage

The role and impact of systemic inflammatory response after aneurysmal subarachnoid hemorrhage remain to be elucidated. To assess the time course and correlation of systemic inflammatory parameters with outcome and the occurrence of delayed ischemic neurological deficits (DINDs) after subarachnoid hemorrhage. Besides the baseline characteristics, daily interleukin-6 (IL-6), procalcitonin, C-reactive protein levels, and leukocyte counts were prospectively measured until day 14 after subarachnoid hemorrhage. Occurrence of infectious complications and application of therapeutic hypothermia were assessed as confounding factors. The primary end point was outcome after 3 months, assessed by Glasgow outcome scale; the secondary end point was the occurrence of DINDs. During a 3-year period, a total of 138 patients were included. All inflammatory parameters measured were higher in patients with unfavorable outcome (Glasgow outcome scale score, 1-3). After adjustment for confounding factors, elevated IL-6 and leukocyte counts remained significant risk factors for unfavorable outcome. The odds ratio for log IL-6 was 4.07 (95% confidence interval, 1.18 to 14.03; P = .03) and for leukocyte counts was 1.24 (95% confidence interval, 1.06-1.46, P = .008). The analysis of the time course established that IL-6 was the only significantly elevated parameter in the early phase in patients with unfavorable outcome. Higher IL-6 levels in the early phase (days 3-7) were associated with the occurrence of DINDs. The adjusted odds ratio for log IL-6 was 4.03 (95% confidence interval, 1.21-13.40; P = .02). Higher IL-6 levels are associated with worse clinical outcome and the occurrence of DINDs. Because IL-6 levels were significantly elevated in the early phase, they might be a useful parameter to monitor.