The usual failure of clinical trials in neurology can be attributed at least in part to their being focused solely on neuroprotection. Neuroprotection, however, is only a part of the complex rejuvenation process of the brain post-injury. The recovery from damage is based on natural, spontaneous processes leading to repair, regeneration and restoration of neurological structures and functions.
In the experimental models of brain and spinal cord injuries, the leukotriene receptor antagonists such as montelukast, an asthma treatment agent reduce neuroinflammation, stimulate neurogenesis and improve functional outcomes in the aged brain as well as in models of spinal cord injury. Clinical data available to date suggest that Cerebrolysin is effective in the treatment of acute and neurodegenerative disorders. The significance of treatment regimen optimisation is well illustrated by a granulocyte colony-stimulating factor trial, which failed to show efficacy due to the poor understanding of the biology of recovery processes with the resulting inadequate treatment protocol employed in the trial.
Clinical management of brain injuries has focused on the prevention of secondary insults and once disabling deficits are established, treatments have proved disappointing. Cell therapies have proved effective in animal models of brain injuries, both in molecular and behavioural terms. In order to achieve meaningful clinical effects, improvements are needed in the quality of the cells and associated molecular factors. The assessment of therapy efficacy includes: behaviour motor rod, water maze, gait analysis ; pathological examination haematoxylin and eosin stain, immuno-histochemistry ; physiological factors spikes, electrocardiogram [ECG] and biochemical factors biomarkers, gene expression.
Several biomarkers are currently in clinical development. Experimental stem cell therapies currently use various cell types: embryonic, foetal, adult bone marrow, adipose tissue and induced pluripotent stem cells iPS cells. Possible routes of administration include: systemic infusion, direct implantation and topical application. Stem cells therapies, however, are in early phase development and safety concerns must be addressed in clinical investigations. An example of cell therapy for brain injury is the use of green fluorescent protein-mesenchymal cells GFP-MSCs in a rat model.
Most importantly, this therapy achieved improvements in functional outcome assessed as performance in the Morris Water Maze experiment. MSC therefore holds considerable potential in the treatment of neurological disorders. There is a place for MSC-based therapies in axonal regeneration.
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However, experimental advances and better understanding have not yet converted into clinical practice. There is a need to develop better stem cell technology and to use this approach in combination with other agents, such as small molecules, which can enhance viability of the transplants as well as work in synergy with MSC for stimulation of endogenous repair mechanisms.
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Recent findings emphasise that patients with severe TBI require analogue sedation and intubation, need to be relaxed and must undergo controlled respiration. In addition, an adequate cerebral perfusion pressure CPP must be maintained. Refractory intracranial hypotension should be treated with forced hyperventilation with a paO 2 below 30 mmHg, high-dosage barbiturates and decompressive craniectomy a life-saving emergency surgical intervention. The therapeutic effect, if any, of hypothermia is currently being investigated in the ongoing Edinburgh Eurotherm Study.
More recently, prospective, RCTs have been initiated with the clear statement of exact target values for intracranial pressure. Therefore, continuous multimodal measurement of cerebral perfusion and oxygenation of the brain is of great importance in the monitoring of therapeutic procedures in patients with severe brain trauma. A complete decompressive craniectomy and venous drainage is important when a haematoma expands.
Recent findings indicate that as soon as oedema subsides following a craniectomy, there is a need for rapid cranioplasty. A compelling need to optimally use time in surgical patients exists. One of the most important challenges of using neurological assessments such as the Glasgow Coma Scale GCS is to reduce the inter-rater variability to an absolute minimum thus maximising the reliability of the measure. A review of the use of the GCS in an injury assessment 46,47 clearly showed that this is a matter that can make results of any trial obsolete.
However, reduction of inter-rater variability is possible through planned training of the raters. The tool is now available as a standalone version but also via Internet in different languages.
Preliminary trends from the study show clear difference between groups with and without training, with a trend towards an increase in the accuracy of GCS assessment after standardised training. As expected, there are notable differences between the different disciplines neurosurgeon, neurologist, intensivist, traumatologist , different hospitals and countries.
Neurosurgeons tend to overestimate bad situations and underestimate good ones. Intensive care personnel seem to achieve the highest benefit. Overall, benefits manifest quickly and appear stable, reliable and, above all, effective. All these symptoms often lead to problems with learning, social adaptation and unfavourable social and psychological consequences.
Patients with brain contusions have significantly poorer cognitive functions than patients with concussions. Consequently, the safety and efficacy of Cerebrolysin, a multimodal and neurotrophic agent with both neuroprotective and neuroregenerative properties, has been evaluated in patients with MTBI related to contusions. Patients were randomised to Cerebrolysin 30 ml once daily [OD] intravenous [iv] infusion for 5 days or placebo normal saline iv infusion OD.
Results showed a strong trend towards improvement of cognitive functions in the Cerebrolysin-treated group in comparison with the placebo group. Cerebrolysin therapy, therefore, can improve CASI scores and enhance cognitive recovery. Long-term cognitive impairment after critical illness CIACI is an increasingly recognised problem that affects patients 1 year after ICU discharge and is probably lifelong.
Deficits occurred in both older and younger patients, and a longer duration of delirium was independently associated with worse global cognition at 3 and 12 months.
Dementia prevention in ICU patients has enormous scope. Cerebrolysin is currently the only neurotrophic agent in clinical use and acts by mimicking neurotrophic factors NTFs and by stimulating the endogenous production of NTF in brain tissue. Experimental studies revealed neuroprotection and neuroregeneration properties.
Results of clinical trials in stroke, TBI and dementia suggest the clinical efficacy of Cerebrolysin in these indications. The efficacy of Cerebrolysin persists for up to several months after treatment, suggesting not only symptomatic benefits, but also a diseasedelaying potential.
These data suggest that Cerebrolysin can support early mobilisation of patients, an important outcome for the majority of injured patients. Initial unpublished results show that compared with untreated TBI patients, Cerebrolysin significantly improved hemodynamic parameters at 3 months and 1 year following treatment and showed a favourable safety profile in this group of patients. Treating patients in the ICU with a Cerebrolysin regimen appears to be justified based on the experience of the author and on published clinical data see Figure 3.
The findings need verification in appropriately designed RCTs but, if positive, will support a major therapeutic breakthrough in the management of ICU patients. Endogenous neuromodulation is a better therapeutic target since it more accurately reflects biological reality of neurological disorders. Pathophysiological mechanisms represent imbalances in normal neurobiological processes, and endogenous molecules e.
NTFs are vital components of brain protection and recovery that alter DNA expression, generate post-lesional patterns of molecular synergism and rebalance major neurobiological processes.
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This concept can be illustrated by the example of nerve growth factor as potential natural enhancer or potential natural inhibitor of cellular death see Figure 4. Cerebrolysin has similar actions to NTFs and therefore can stimulate natural defence activities within the injured nervous tissue. Moreover, a significant dose-dependent effect was seen for Cerebrolysin on GOS score at 10 and 30 days. The results of this large retrospective study show significant beneficial effects of early Cerebrolysin treatment in TBI patients and justify a large prospective study to further support the use of Cerebrolysin in this indication.
The most frequent TBI-related conditions with psychiatric relevance are affective alterations e. The exact nature of the behavioural alterations and psychiatric symptoms is largely dependent on the type and localisation of the injury and also on premorbid patient characteristics e.
Thus, the inter-individual variability as well as the prognosis of each patient varies widely, so an individualised treatment approach is mandatory. In recent years, diagnostic and therapeutic options for TBI have considerably improved and understanding of the pathophysiological mechanisms leading to the psychiatric symptoms is increasing. Nevertheless, psychiatric symptoms in TBI are often chronic; 73 patients and their families require long-term support by an expert team.
Possible psychiatric consequences of TBI can be diverse, including combinations of: post-traumatic personality change, mood changes, anxiety, attentional deficits, thought and executive function disturbances, behavioural changes e.
Traumatic Brain Injury in older adults: does age matter? — Monash University
This timely book reports recent progress in research on traumatic brain injury TBI by leading investigators encompassing translational and clinical studies. The text covers epidemiology, pathophysiology, brain imaging, cognition, behavioral sequelae, and clinical trials of innovativetreatments, including new approaches to rehabilitation. The range of TBI mechanisms represented in this cutting-edge book includes closed head trauma and blast-related injury, and the spectrum of TBI severity.
Chapters offer a developmental perspective, including the effects of TBI on cognitive development in children and outcome studies in adults.
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Contributors from various countries provide a global perspective on this worldwide health problem. The editors have synthesized the contents in a concludingchapter. Researchers and clinicians will find this volume to be an informative, authoritative reference for current TBI research. About The Author. Harvey S. Levin was previously a mem Select Parent Grandparent Teacher Kid at heart. Age of the child I gave this to:. Hours of Play:.
Tell Us Where You Are:. Preview Your Review. Thank you. Your review has been submitted and will appear here shortly. Extra Content. From the Author This timely book reports recent progress in research on traumatic brain injury TBI by leading investigators encompassing translational and clinical studies. Levin, David H. Shum and Raymond C. Chan: PrefacePart 1: Introduction1. David L. Brent E.
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Masel and Douglas S. Jia Huang, David H. Shum, Raymon C. Chan and Allana L. Allana L. Canty, David H. Shum, Harvey S.