Pub Date : 2024-03-13eCollection Date: 2024-01-01DOI: 10.1089/neur.2023.0122
Dmitry Esterov, Ziying Yin, Trevor Persaud, Xiang Shan, Mathew C Murphy, Richard L Ehman, John Huston, Allen W Brown
This study sought to identify whether an anatomical indicator of injury severity as measured by multiparametric magnetic resonance imaging (MRI) including magnetic resonance elastography (MRE), is predictive of a clinical measure of injury severity after moderate-severe traumatic brain injury (TBI). Nine individuals who were admitted to acute inpatient rehabilitation after moderate-to-severe TBI completed a comprehensive MRI protocol prior to discharge from rehabilitation, which included conventional MRI with diffusion tensor imaging (DTI). Of those, five of nine also underwent brain MRE to measure the brain parenchyma stiffness. Clinical severity of injury was measured by the length of post-traumatic amnesia (PTA). MRI-assessed non-hemorrhage contusion score and hemorrhage score, DTI-measured white matter fractional anisotropy, and MRE-measured lesion stiffness were all assessed. A higher hemorrhagic score was significantly associated with a longer length of PTA (p = 0.026). Participants with a longer PTA tended to have a higher non-hemorrhage contusion score and softer contusion lesions than the contralateral control side, although the small sample size did not allow for assessment of a significant association. To our knowledge, this is the first report applying MRI/MRE imaging protocol to quantitate altered brain anatomy after moderate-severe TBI and its association with PTA, a known clinical predictor of post-acute outcome. Future larger studies could lead to the development of prediction models that integrate clinical data with anatomical (MRI), structural (DTI), and mechanical (MRE) changes caused by TBI, to inform prognosis and care planning.
{"title":"Association Between Anatomic and Clinical Indicators of Injury Severity After Moderate-Severe Traumatic Brain Injury: A Pilot Study Using Multiparametric Magnetic Resonance Imaging.","authors":"Dmitry Esterov, Ziying Yin, Trevor Persaud, Xiang Shan, Mathew C Murphy, Richard L Ehman, John Huston, Allen W Brown","doi":"10.1089/neur.2023.0122","DOIUrl":"10.1089/neur.2023.0122","url":null,"abstract":"<p><p>This study sought to identify whether an anatomical indicator of injury severity as measured by multiparametric magnetic resonance imaging (MRI) including magnetic resonance elastography (MRE), is predictive of a clinical measure of injury severity after moderate-severe traumatic brain injury (TBI). Nine individuals who were admitted to acute inpatient rehabilitation after moderate-to-severe TBI completed a comprehensive MRI protocol prior to discharge from rehabilitation, which included conventional MRI with diffusion tensor imaging (DTI). Of those, five of nine also underwent brain MRE to measure the brain parenchyma stiffness. Clinical severity of injury was measured by the length of post-traumatic amnesia (PTA). MRI-assessed non-hemorrhage contusion score and hemorrhage score, DTI-measured white matter fractional anisotropy, and MRE-measured lesion stiffness were all assessed. A higher hemorrhagic score was significantly associated with a longer length of PTA (<i>p</i> = 0.026). Participants with a longer PTA tended to have a higher non-hemorrhage contusion score and softer contusion lesions than the contralateral control side, although the small sample size did not allow for assessment of a significant association. To our knowledge, this is the first report applying MRI/MRE imaging protocol to quantitate altered brain anatomy after moderate-severe TBI and its association with PTA, a known clinical predictor of post-acute outcome. Future larger studies could lead to the development of prediction models that integrate clinical data with anatomical (MRI), structural (DTI), and mechanical (MRE) changes caused by TBI, to inform prognosis and care planning.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":"5 1","pages":"232-242"},"PeriodicalIF":1.8,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10960168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140208463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Traumatic Brain Injury (TBI) is a significant contributor to disability across the world. TBIs vary in severity, and most cases are designated mild TBI (mTBI), involving only brief loss of consciousness and no intracranial findings on imaging. Despite this categorization, many persons continue to report persistent cognitive changes in the months to years after injury, with particular impairment in the cognitive and executive functions of the pre-frontal cortex. For these persons, there are no currently approved medications, and treatment is limited to symptom management and cognitive or behavioral therapy. The current case studies explored the use of the alpha-2A adrenoreceptor agonist, guanfacine, combined with the antioxidant, N-acetylcysteine (NAC), in the treatment of post-TBI cognitive symptoms, based on guanfacine's ability to strengthen pre-frontal cortical function, and the open-label use of NAC in treating TBI. Two persons from our TBI clinic were treated with this combined regimen, with neuropsychological testing performed pre- and post-treatment. Guanfacine + NAC improved attention, processing speed, memory, and executive functioning with minimal side effects in both persons. These results encourage future placebo-controlled trials to more firmly establish the efficacy of guanfacine and NAC for the treatment of cognitive deficits caused by TBI.
{"title":"Combined Use of Guanfacine and <i>N</i>-Acetylcysteine for the Treatment of Cognitive Deficits After Traumatic Brain Injury.","authors":"Siddharth Khasnavis, Timothy Belliveau, Amy Arnsten, Arman Fesharaki-Zadeh","doi":"10.1089/neur.2023.0124","DOIUrl":"10.1089/neur.2023.0124","url":null,"abstract":"<p><p>Traumatic Brain Injury (TBI) is a significant contributor to disability across the world. TBIs vary in severity, and most cases are designated mild TBI (mTBI), involving only brief loss of consciousness and no intracranial findings on imaging. Despite this categorization, many persons continue to report persistent cognitive changes in the months to years after injury, with particular impairment in the cognitive and executive functions of the pre-frontal cortex. For these persons, there are no currently approved medications, and treatment is limited to symptom management and cognitive or behavioral therapy. The current case studies explored the use of the alpha-2A adrenoreceptor agonist, guanfacine, combined with the antioxidant, <i>N</i>-acetylcysteine (NAC), in the treatment of post-TBI cognitive symptoms, based on guanfacine's ability to strengthen pre-frontal cortical function, and the open-label use of NAC in treating TBI. Two persons from our TBI clinic were treated with this combined regimen, with neuropsychological testing performed pre- and post-treatment. Guanfacine + NAC improved attention, processing speed, memory, and executive functioning with minimal side effects in both persons. These results encourage future placebo-controlled trials to more firmly establish the efficacy of guanfacine and NAC for the treatment of cognitive deficits caused by TBI.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":"5 1","pages":"226-231"},"PeriodicalIF":0.0,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10960163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140208464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-05eCollection Date: 2024-01-01DOI: 10.1089/neur.2023.0108
Gabrielle Cataford, Laurie-Anne Monton, Stephanie Karzon, Camille Livernoche-Leduc, Mar Saavedra-Mitjans, Marie-Julie Potvin, Francis Bernard, Lisa Burry, Caroline Arbour, David R Williamson
Traumatic brain injury (TBI) survivors often suffer from agitated behaviors and will most likely receive pharmacological treatments. Choosing an optimal and safe treatment that will not interfere with neurological recovery remains controversial. By interfering with dopaminergic circuits, antipsychotics may impede processes important to cognitive recovery. Despite their frequent use, there have been no large randomized controlled studies of antipsychotics for the management of agitated behaviors during the acute TBI recovery period. We conducted a systematic review and meta-analysis of pre-clinical studies evaluating the effects of antipsychotics post-TBI on both cognitive and motor recovery. MEDLINE and Embase databases were searched up to August 2, 2023. Pre-clinical studies evaluating the effects of antipsychotics on cognitive and motor functions post-TBI were considered. Risk of bias was evaluated with the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. We identified 15 studies including a total of 1188 rodents, mostly conducted in male Sprague-Dawley rats using cortical impact injury. The analysis revealed no consistent effect of haloperidol on motor functions, but risperidone was associated with a significant impairment in motor function on day 5 post-injury (7.05 sec; 95% confidence interval [CI]: 1.47, 12.62; I2 = 92%). Other atypical antipsychotics did not result in impaired motor function. When evaluating cognitive function, haloperidol- (23.00 sec; 95% CI: 17.42-28.59; I2 = 7%) and risperidone-treated rats (24.27 sec; 95% CI: 16.18-32.36; I2 = 0%) were consistently impaired when compared to controls. In studies evaluating atypical antipsychotics, no impairments were observed. Clinicians should avoid the regular use of haloperidol and risperidone, and future human studies should be conducted with atypical antipsychotics.
{"title":"Cognitive and Motor Function Effects of Antipsychotics in Traumatic Brain Injury: A Systematic Review of Pre-Clinical Studies.","authors":"Gabrielle Cataford, Laurie-Anne Monton, Stephanie Karzon, Camille Livernoche-Leduc, Mar Saavedra-Mitjans, Marie-Julie Potvin, Francis Bernard, Lisa Burry, Caroline Arbour, David R Williamson","doi":"10.1089/neur.2023.0108","DOIUrl":"10.1089/neur.2023.0108","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) survivors often suffer from agitated behaviors and will most likely receive pharmacological treatments. Choosing an optimal and safe treatment that will not interfere with neurological recovery remains controversial. By interfering with dopaminergic circuits, antipsychotics may impede processes important to cognitive recovery. Despite their frequent use, there have been no large randomized controlled studies of antipsychotics for the management of agitated behaviors during the acute TBI recovery period. We conducted a systematic review and meta-analysis of pre-clinical studies evaluating the effects of antipsychotics post-TBI on both cognitive and motor recovery. MEDLINE and Embase databases were searched up to August 2, 2023. Pre-clinical studies evaluating the effects of antipsychotics on cognitive and motor functions post-TBI were considered. Risk of bias was evaluated with the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. We identified 15 studies including a total of 1188 rodents, mostly conducted in male Sprague-Dawley rats using cortical impact injury. The analysis revealed no consistent effect of haloperidol on motor functions, but risperidone was associated with a significant impairment in motor function on day 5 post-injury (7.05 sec; 95% confidence interval [CI]: 1.47, 12.62; I<sup>2</sup> = 92%). Other atypical antipsychotics did not result in impaired motor function. When evaluating cognitive function, haloperidol- (23.00 sec; 95% CI: 17.42-28.59; I<sup>2</sup> = 7%) and risperidone-treated rats (24.27 sec; 95% CI: 16.18-32.36; I<sup>2</sup> = 0%) were consistently impaired when compared to controls. In studies evaluating atypical antipsychotics, no impairments were observed. Clinicians should avoid the regular use of haloperidol and risperidone, and future human studies should be conducted with atypical antipsychotics.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":"5 1","pages":"181-193"},"PeriodicalIF":0.0,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10924062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140095336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-04eCollection Date: 2024-01-01DOI: 10.1089/neur.2023.0133
Tina Tian, Amy M Moore, Paul A Ghareeb, Nicholas M Boulis, Patricia J Ward
Peripheral nerve injuries (PNIs) are common and devastating. The current standard of care relies on the slow and inefficient process of nerve regeneration after surgical intervention. Electrical stimulation (ES) has been shown to both experimentally and clinically result in improved regeneration and functional recovery after PNI for motor and sensory neurons; however, its effects on sympathetic regeneration have never been studied. Sympathetic neurons are responsible for a myriad of homeostatic processes that include, but are not limited to, blood pressure, immune response, sweating, and the structural integrity of the neuromuscular junction. Almost one quarter of the axons in the sciatic nerve are from sympathetic neurons, and their importance in bodily homeostasis and the pathogenesis of neuropathic pain should not be underestimated. Therefore, as ES continues to make its way into patient care, it is not only important to understand its impact on all neuron subtypes, but also to ensure that potential adverse effects are minimized. This piece gives an overview of the effects of ES in animals models and in humans while offering a perspective on the potential effects of ES on sympathetic axon regeneration.
周围神经损伤(PNIs)是一种常见的破坏性损伤。目前的治疗标准依赖于手术干预后缓慢而低效的神经再生过程。实验和临床均表明,电刺激(ES)可改善运动神经元和感觉神经元在周围神经损伤后的再生和功能恢复,但其对交感神经再生的影响却从未被研究过。交感神经元负责无数的平衡过程,包括但不限于血压、免疫反应、出汗和神经肌肉接头结构的完整性。坐骨神经中近四分之一的轴突来自交感神经元,它们在体内平衡和神经病理性疼痛发病机制中的重要性不容低估。因此,随着 ES 不断进入患者护理领域,不仅要了解它对所有神经元亚型的影响,还要确保将潜在的不良影响降至最低。这篇文章概述了 ES 在动物模型和人体中的影响,同时提供了 ES 对交感神经轴突再生的潜在影响的视角。
{"title":"A Perspective on Electrical Stimulation and Sympathetic Regeneration in Peripheral Nerve Injuries.","authors":"Tina Tian, Amy M Moore, Paul A Ghareeb, Nicholas M Boulis, Patricia J Ward","doi":"10.1089/neur.2023.0133","DOIUrl":"10.1089/neur.2023.0133","url":null,"abstract":"<p><p>Peripheral nerve injuries (PNIs) are common and devastating. The current standard of care relies on the slow and inefficient process of nerve regeneration after surgical intervention. Electrical stimulation (ES) has been shown to both experimentally and clinically result in improved regeneration and functional recovery after PNI for motor and sensory neurons; however, its effects on sympathetic regeneration have never been studied. Sympathetic neurons are responsible for a myriad of homeostatic processes that include, but are not limited to, blood pressure, immune response, sweating, and the structural integrity of the neuromuscular junction. Almost one quarter of the axons in the sciatic nerve are from sympathetic neurons, and their importance in bodily homeostasis and the pathogenesis of neuropathic pain should not be underestimated. Therefore, as ES continues to make its way into patient care, it is not only important to understand its impact on all neuron subtypes, but also to ensure that potential adverse effects are minimized. This piece gives an overview of the effects of ES in animals models and in humans while offering a perspective on the potential effects of ES on sympathetic axon regeneration.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":"5 1","pages":"172-180"},"PeriodicalIF":0.0,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10924057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140095335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-29eCollection Date: 2024-01-01DOI: 10.1089/neur.2023.0058
Andreia Morais, Joon Yong Chung, Limin Wu, Cenk Ayata, Bruce Simon, Michael J Whalen
Non-invasive vagus nerve stimulation (nVNS) has recently been suggested as a potential therapy for traumatic brain injury (TBI). We previously demonstrated that nVNS inhibits cortical spreading depolarization, the electrophysiological event underlying migraine aura, and is relevant to TBI. Our past work also suggests a role for interleukin-1 beta (IL-1β) in cognitive deficits after closed head injury (CHI) in mice. We show that nVNS pre-treatment suppresses CHI-associated spatial learning and memory impairment and prevents IL-1β activation in injured neurons, but not endothelial cells. In contrast, nVNS administered 10 min after CHI was ineffective. These data suggest that nVNS prophylaxis might ameliorate neuronal dysfunction associated with CHI in populations at high risk for concussive TBI.
{"title":"Non-Invasive Vagal Nerve Stimulation Pre-Treatment Reduces Neurological Dysfunction After Closed Head Injury in Mice.","authors":"Andreia Morais, Joon Yong Chung, Limin Wu, Cenk Ayata, Bruce Simon, Michael J Whalen","doi":"10.1089/neur.2023.0058","DOIUrl":"10.1089/neur.2023.0058","url":null,"abstract":"<p><p>Non-invasive vagus nerve stimulation (nVNS) has recently been suggested as a potential therapy for traumatic brain injury (TBI). We previously demonstrated that nVNS inhibits cortical spreading depolarization, the electrophysiological event underlying migraine aura, and is relevant to TBI. Our past work also suggests a role for interleukin-1 beta (IL-1β) in cognitive deficits after closed head injury (CHI) in mice. We show that nVNS pre-treatment suppresses CHI-associated spatial learning and memory impairment and prevents IL-1β activation in injured neurons, but not endothelial cells. In contrast, nVNS administered 10 min after CHI was ineffective. These data suggest that nVNS prophylaxis might ameliorate neuronal dysfunction associated with CHI in populations at high risk for concussive TBI.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":"5 1","pages":"150-158"},"PeriodicalIF":0.0,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10908330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140023617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-29eCollection Date: 2024-01-01DOI: 10.1089/neur.2023.0109
Rabea Iris Pantelatos, Jonas Stenberg, Turid Follestad, Oddrun Sandrød, Cathrine Elisabeth Einarsen, Anne Vik, Toril Skandsen
The aims of this study were (1) to report outcome and change in outcome in patients with moderate and severe traumatic brain injury (mo/sTBI) between 6 and 12 months post-injury as measured by the Glasgow Outcome Scale Extended (GOSE), (2) to explore if demographic/injury-related variables can predict improvement in GOSE score, and (3) to investigate rate of improvement in Disability Rating Scale (DRS) score, in patients with a stable GOSE. All surviving patients ≥16 years of age who were admitted with mo/sTBI (Glasgow Coma Scale [GCS] score ≤13) to the regional trauma center in Central Norway between 2004 and 2019 were prospectively included (n = 439 out of 503 eligible). GOSE and DRS were used to assess outcome. Twelve-months post-injury, 13% with moTBI had severe disability (GOSE 2-4) versus 27% in sTBI, 26% had moderate disability (GOSE 5-6) versus 41% in sTBI and 62% had good recovery (GOSE 7-8) versus 31% in sTBI. From 6 to 12 months post-injury, 27% with moTBI and 32% with sTBI had an improvement, whereas 6% with moTBI and 6% with sTBI had a deterioration in GOSE score. Younger age and higher GCS score were associated with improved GOSE score. Improvement was least frequent for patients with a GOSE score of 3 at 6 months. In patients with a stable GOSE score of 3, an improvement in DRS score was observed in 22 (46%) patients. In conclusion, two thirds and one third of patients with mo/sTBI, respectively, had a good recovery. Importantly, change, mostly improvement, in GOSE score between 6 and 12 months was frequent and argues against the use of 6 months outcome as a time end-point in research. The GOSE does, however, not seem to be sensitive to actual change in function in the lower categories and a combination of outcome measures may be needed to describe the consequences after TBI.
{"title":"Improvement in Functional Outcome from 6 to 12 Months After Moderate and Severe Traumatic Brain Injury Is Frequent, But May Not Be Detected With the Glasgow Outcome Scale Extended.","authors":"Rabea Iris Pantelatos, Jonas Stenberg, Turid Follestad, Oddrun Sandrød, Cathrine Elisabeth Einarsen, Anne Vik, Toril Skandsen","doi":"10.1089/neur.2023.0109","DOIUrl":"10.1089/neur.2023.0109","url":null,"abstract":"<p><p>The aims of this study were (1) to report outcome and change in outcome in patients with moderate and severe traumatic brain injury (mo/sTBI) between 6 and 12 months post-injury as measured by the Glasgow Outcome Scale Extended (GOSE), (2) to explore if demographic/injury-related variables can predict improvement in GOSE score, and (3) to investigate rate of improvement in Disability Rating Scale (DRS) score, in patients with a stable GOSE. All surviving patients ≥16 years of age who were admitted with mo/sTBI (Glasgow Coma Scale [GCS] score ≤13) to the regional trauma center in Central Norway between 2004 and 2019 were prospectively included (<i>n</i> = 439 out of 503 eligible). GOSE and DRS were used to assess outcome. Twelve-months post-injury, 13% with moTBI had severe disability (GOSE 2-4) versus 27% in sTBI, 26% had moderate disability (GOSE 5-6) versus 41% in sTBI and 62% had good recovery (GOSE 7-8) versus 31% in sTBI. From 6 to 12 months post-injury, 27% with moTBI and 32% with sTBI had an improvement, whereas 6% with moTBI and 6% with sTBI had a deterioration in GOSE score. Younger age and higher GCS score were associated with improved GOSE score. Improvement was least frequent for patients with a GOSE score of 3 at 6 months. In patients with a stable GOSE score of 3, an improvement in DRS score was observed in 22 (46%) patients. In conclusion, two thirds and one third of patients with mo/sTBI, respectively, had a good recovery. Importantly, change, mostly improvement, in GOSE score between 6 and 12 months was frequent and argues against the use of 6 months outcome as a time end-point in research. The GOSE does, however, not seem to be sensitive to actual change in function in the lower categories and a combination of outcome measures may be needed to describe the consequences after TBI.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":"5 1","pages":"139-149"},"PeriodicalIF":1.8,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10908320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140023608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-20eCollection Date: 2024-01-01DOI: 10.1089/neur.2023.0129
Nick D Jeffery, John H Rossmeisl, Tom R Harcourt-Brown, Nicolas Granger, Daisuke Ito, Kari Foss, Damian Chase
Although many interventions for acute spinal cord injury (SCI) appear promising in experimental models, translation directly from experimental animals to human patients is a large step that can be problematic. Acute SCI occurs frequently in companion dogs and may provide a model to ease translation. Recently, incision of the dura has been highlighted in both research animals and human patients as a means of reducing intraspinal pressure, with a view to improving perfusion of the injured tissue and enhancing functional recovery. Observational clinical data in humans and dogs support the notion that it may also improve functional outcome. Here, we report the results of a multi-center randomized controlled trial of durotomy as an adjunct to traditional decompressive surgery for treatment of severe thoracolumbar SCI caused by acute intervertebral disc herniation in dogs. Sample-size calculation was based on the proportion of dogs recovering ambulation improving from an expected 55% in the traditional surgery group to 70% in the durotomy group. Over a 3.5-year period, we enrolled 140 dogs, of which 128 had appropriate duration of follow-up. Overall, 65 (51%) dogs recovered ambulation. Recovery in the traditional decompression group was 35 of 62 (56%) dogs, and in the durotomy group 30 of 66 (45%) dogs, associated with an odds ratio of 0.643 (95% confidence interval: 0.320-1.292) and z-score of -1.24. This z-score indicates trial futility to reach the target 15% improvement over traditional surgery, and the trial was terminated at this stage. We conclude that durotomy is ineffective in improving functional outcome for severe acute thoracolumbar SCI in dogs. In the future, these data can be compared with similar data from clinical trials on duraplasty in human patients and will aid in determining the predictive validity of the "companion dog model" of acute SCI.
{"title":"Randomized Controlled Trial of Durotomy as an Adjunct to Routine Decompressive Surgery for Dogs With Severe Acute Spinal Cord Injury.","authors":"Nick D Jeffery, John H Rossmeisl, Tom R Harcourt-Brown, Nicolas Granger, Daisuke Ito, Kari Foss, Damian Chase","doi":"10.1089/neur.2023.0129","DOIUrl":"10.1089/neur.2023.0129","url":null,"abstract":"<p><p>Although many interventions for acute spinal cord injury (SCI) appear promising in experimental models, translation directly from experimental animals to human patients is a large step that can be problematic. Acute SCI occurs frequently in companion dogs and may provide a model to ease translation. Recently, incision of the dura has been highlighted in both research animals and human patients as a means of reducing intraspinal pressure, with a view to improving perfusion of the injured tissue and enhancing functional recovery. Observational clinical data in humans and dogs support the notion that it may also improve functional outcome. Here, we report the results of a multi-center randomized controlled trial of durotomy as an adjunct to traditional decompressive surgery for treatment of severe thoracolumbar SCI caused by acute intervertebral disc herniation in dogs. Sample-size calculation was based on the proportion of dogs recovering ambulation improving from an expected 55% in the traditional surgery group to 70% in the durotomy group. Over a 3.5-year period, we enrolled 140 dogs, of which 128 had appropriate duration of follow-up. Overall, 65 (51%) dogs recovered ambulation. Recovery in the traditional decompression group was 35 of 62 (56%) dogs, and in the durotomy group 30 of 66 (45%) dogs, associated with an odds ratio of 0.643 (95% confidence interval: 0.320-1.292) and z-score of -1.24. This z-score indicates trial futility to reach the target 15% improvement over traditional surgery, and the trial was terminated at this stage. We conclude that durotomy is ineffective in improving functional outcome for severe acute thoracolumbar SCI in dogs. In the future, these data can be compared with similar data from clinical trials on duraplasty in human patients and will aid in determining the predictive validity of the \"companion dog model\" of acute SCI.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":"5 1","pages":"128-138"},"PeriodicalIF":1.8,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10898236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139984768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-19eCollection Date: 2024-01-01DOI: 10.1089/neur.2023.0114
Luke J Weisbrod, Thomas T Nilles-Melchert, Judith R Bergjord, Daniel L Surdell
Traumatic spinal cord injury (SCI) is a cause of significant morbidity, often resulting in long-term disability. We aimed to compare outcomes after riluzole versus patients who received placebo or standard of care with no specific intervention. MEDLINE, Embase, Scopus, and Cochrane Library database searches yielded 92 records, and five met the study inclusion criteria. Fixed-effect and random-effects models were used to establish odds ratios (ORs) and mean difference (MD) with 95% confidence intervals (CIs) for each outcome. The results of the pooled analysis showed that in patients with acute traumatic SCI, riluzole resulted in increased American Spinal Injury Association (ASIA) motor scores at 3 months (MD 0.26, 95% CI [-0.10,0.61], I2 = 0%; p = 0.157) and 6 months (MD 0.21, 95% CI [-0.17,0.60], I2 = 0%; p = 0.280) and change in ASIA Impairment Scale (AIS) at 3 months (OR 0.59, 95% CI [-0.12,1.30], I2 = 0%, p = 0.101) and 6 months (OR 0.28, 95% CI [-0.50,1.06], I2 = 0%, p = 0.479) in comparison to the control groups, though not to a level of statistical significance. Riluzole resulted in fewer adverse events than the control groups (OR -0.12, 95% CI [-1.59,1.35], I2 = 0%, p = 0.874) and lower mortality (OR -0.20, 95% CI [-1.03,0.63], I2 = 0%, p = 0.640), though also not to a level of statistical significance. These meta-analyses suggest that riluzole for the treatment of traumatic SCI is safe and results in improved neurological outcomes when compared to controls, though not to a level of statistical significance. More robust prospective, randomized studies are necessary to help inform the safety and efficacy of riluzole for traumatic SCI.
{"title":"Safety and Efficacy of Riluzole in Traumatic Spinal Cord Injury: A Systematic Review With Meta-Analyses.","authors":"Luke J Weisbrod, Thomas T Nilles-Melchert, Judith R Bergjord, Daniel L Surdell","doi":"10.1089/neur.2023.0114","DOIUrl":"10.1089/neur.2023.0114","url":null,"abstract":"<p><p>Traumatic spinal cord injury (SCI) is a cause of significant morbidity, often resulting in long-term disability. We aimed to compare outcomes after riluzole versus patients who received placebo or standard of care with no specific intervention. MEDLINE, Embase, Scopus, and Cochrane Library database searches yielded 92 records, and five met the study inclusion criteria. Fixed-effect and random-effects models were used to establish odds ratios (ORs) and mean difference (MD) with 95% confidence intervals (CIs) for each outcome. The results of the pooled analysis showed that in patients with acute traumatic SCI, riluzole resulted in increased American Spinal Injury Association (ASIA) motor scores at 3 months (MD 0.26, 95% CI [-0.10,0.61], <i>I<sup>2</sup></i> = 0%; <i>p</i> = 0.157) and 6 months (MD 0.21, 95% CI [-0.17,0.60], <i>I</i><sup>2</sup> = 0%; <i>p</i> = 0.280) and change in ASIA Impairment Scale (AIS) at 3 months (OR 0.59, 95% CI [-0.12,1.30], <i>I</i><sup>2</sup> = 0%, <i>p</i> = 0.101) and 6 months (OR 0.28, 95% CI [-0.50,1.06], <i>I</i><sup>2</sup> = 0%, <i>p</i> = 0.479) in comparison to the control groups, though not to a level of statistical significance. Riluzole resulted in fewer adverse events than the control groups (OR -0.12, 95% CI [-1.59,1.35], <i>I</i><sup>2</sup> = 0%, <i>p</i> = 0.874) and lower mortality (OR -0.20, 95% CI [-1.03,0.63], <i>I</i><sup>2</sup> = 0%, <i>p</i> = 0.640), though also not to a level of statistical significance. These meta-analyses suggest that riluzole for the treatment of traumatic SCI is safe and results in improved neurological outcomes when compared to controls, though not to a level of statistical significance. More robust prospective, randomized studies are necessary to help inform the safety and efficacy of riluzole for traumatic SCI.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":"5 1","pages":"117-127"},"PeriodicalIF":0.0,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10898229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139984769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-30eCollection Date: 2024-01-01DOI: 10.1089/neur.2023.0086
Lauren P Giesler, William T O'Brien, Georgia F Symons, Sabrina Salberg, Gershon Spitz, Robb Wesselingh, Terence J O'Brien, Richelle Mychasiuk, Sandy R Shultz, Stuart J McDonald
Traumatic brain injuries (TBIs) and concussions are prevalent in collision sports, and there is evidence that levels of exposure to such sports may increase the risk of neurological abnormalities. Elevated levels of fluid-based biomarkers have been observed after concussions or among athletes with a history of participating in collision sports, and certain biomarkers exhibit sensitivity toward neurodegeneration. This study investigated a cohort of 28 male amateur athletes competing in "Masters" competitions for persons >35 years of age. The primary objective of this study was to compare the levels of blood and saliva biomarkers associated with brain injury, inflammation, aging, and neurodegeneration between athletes with an extensive history of collision sport participation (i.e., median = 27 years; interquartile range = 18-44, minimum = 8) and those with no history. Plasma proteins associated with neural damage and neurodegeneration were measured using Simoa® assays, and saliva was analyzed for markers associated with inflammation and telomere length using quantitative real-time polymerase chain reaction. There were no significant differences between collision and non-collision sport athletes for plasma levels of glial fibrillary acidic protein, neurofilament light, ubiquitin C-terminal hydrolase L1, tau, tau phosphorylated at threonine 181, and brain-derived neurotrophic factor. Moreover, salivary levels of genes associated with inflammation and telomere length were similar between groups. There were no significant differences between groups in symptom frequency or severity on the Sport Concussion Assessment Tool-5th Edition. Overall, these findings provide preliminary evidence that biomarkers associated with neural tissue damage, neurodegeneration, and inflammation may not exhibit significant alterations in asymptomatic amateur athletes with an extensive history of amateur collision sport participation.
{"title":"Investigating the Association Between Extended Participation in Collision Sports and Fluid Biomarkers Among Masters Athletes.","authors":"Lauren P Giesler, William T O'Brien, Georgia F Symons, Sabrina Salberg, Gershon Spitz, Robb Wesselingh, Terence J O'Brien, Richelle Mychasiuk, Sandy R Shultz, Stuart J McDonald","doi":"10.1089/neur.2023.0086","DOIUrl":"10.1089/neur.2023.0086","url":null,"abstract":"<p><p>Traumatic brain injuries (TBIs) and concussions are prevalent in collision sports, and there is evidence that levels of exposure to such sports may increase the risk of neurological abnormalities. Elevated levels of fluid-based biomarkers have been observed after concussions or among athletes with a history of participating in collision sports, and certain biomarkers exhibit sensitivity toward neurodegeneration. This study investigated a cohort of 28 male amateur athletes competing in \"Masters\" competitions for persons >35 years of age. The primary objective of this study was to compare the levels of blood and saliva biomarkers associated with brain injury, inflammation, aging, and neurodegeneration between athletes with an extensive history of collision sport participation (i.e., median = 27 years; interquartile range = 18-44, minimum = 8) and those with no history. Plasma proteins associated with neural damage and neurodegeneration were measured using Simoa<sup>®</sup> assays, and saliva was analyzed for markers associated with inflammation and telomere length using quantitative real-time polymerase chain reaction. There were no significant differences between collision and non-collision sport athletes for plasma levels of glial fibrillary acidic protein, neurofilament light, ubiquitin C-terminal hydrolase L1, tau, tau phosphorylated at threonine 181, and brain-derived neurotrophic factor. Moreover, salivary levels of genes associated with inflammation and telomere length were similar between groups. There were no significant differences between groups in symptom frequency or severity on the Sport Concussion Assessment Tool-5th Edition. Overall, these findings provide preliminary evidence that biomarkers associated with neural tissue damage, neurodegeneration, and inflammation may not exhibit significant alterations in asymptomatic amateur athletes with an extensive history of amateur collision sport participation.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":"5 1","pages":"74-80"},"PeriodicalIF":0.0,"publicationDate":"2024-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10923547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140095337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-30eCollection Date: 2024-01-01DOI: 10.1089/neur.2023.0067
Denes V Agoston
Major determinants of the biological background or reserve, such as age, biological sex, comorbidities (diabetes, hypertension, obesity, etc.), and medications (e.g., anticoagulants), are known to affect outcome after traumatic brain injury (TBI). With the unparalleled data richness of coronavirus disease 2019 (COVID-19; ∼375,000 and counting!) as well as the chronic form, long-COVID, also called post-acute sequelae SARS-CoV-2 infection (PASC), publications (∼30,000 and counting) covering virtually every aspect of the diseases, pathomechanisms, biomarkers, disease phases, symptomatology, etc., have provided a unique opportunity to better understand and appreciate the holistic nature of diseases, interconnectivity between organ systems, and importance of biological background in modifying disease trajectories and affecting outcomes. Such a holistic approach is badly needed to better understand TBI-induced conditions in their totality. Here, I briefly review what is known about long-COVID/PASC, its underlying-suspected-pathologies, the pathobiological changes induced by TBI, in other words, the TBI endophenotypes, discuss the intersection of long-COVID/PASC and TBI-induced pathobiologies, and how by considering some of the known factors affecting the person's biological background and the inclusion of mechanistic molecular biomarkers can help to improve the clinical management of TBI patients.
{"title":"Traumatic Brain Injury in the Long-COVID Era.","authors":"Denes V Agoston","doi":"10.1089/neur.2023.0067","DOIUrl":"10.1089/neur.2023.0067","url":null,"abstract":"<p><p>Major determinants of the biological background or reserve, such as age, biological sex, comorbidities (diabetes, hypertension, obesity, etc.), and medications (e.g., anticoagulants), are known to affect outcome after traumatic brain injury (TBI). With the unparalleled data richness of coronavirus disease 2019 (COVID-19; ∼375,000 and counting!) as well as the chronic form, long-COVID, also called post-acute sequelae SARS-CoV-2 infection (PASC), publications (∼30,000 and counting) covering virtually every aspect of the diseases, pathomechanisms, biomarkers, disease phases, symptomatology, etc., have provided a unique opportunity to better understand and appreciate the holistic nature of diseases, interconnectivity between organ systems, and importance of biological background in modifying disease trajectories and affecting outcomes. Such a holistic approach is badly needed to better understand TBI-induced conditions in their totality. Here, I briefly review what is known about long-COVID/PASC, its underlying-suspected-pathologies, the pathobiological changes induced by TBI, in other words, the TBI endophenotypes, discuss the intersection of long-COVID/PASC and TBI-induced pathobiologies, and how by considering some of the known factors affecting the person's biological background and the inclusion of mechanistic molecular biomarkers can help to improve the clinical management of TBI patients.</p>","PeriodicalId":74300,"journal":{"name":"Neurotrauma reports","volume":"5 1","pages":"81-94"},"PeriodicalIF":0.0,"publicationDate":"2024-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10923549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140095338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}