Matthew B. Jensen

The promise and potential pitfalls of serum biomarkers for ischemic stroke and transient ischemic attack.

Background:Ischemic stroke and transient ischemic attack can be difficult to diagnose clinically, and both acute and preventive therapies carry some risk. Serum biomarkers could increase diagnostic certainty by helping to distinguish cerebral ischemia from common mimics such as focal seizure, complicated migraine, and psychogenic spells. Biomarkers could also identify patients at high risk for future vascular events, which would aid in management decisions. Review Summary:There are many potential obstacles to finding these biomarkers, which are reviewed here, including the blood brain barrier, confounding by other conditions, and imperfect gold standards for use in validation. Diagnostic biomarkers are likely to be molecules found predominantly in brain tissue with rapid entry into the blood, whereas risk-stratification biomarkers may be related to the concept of an active atherosclerotic plaque. Many promising serum molecules have been examined in small series of patients with cerebrovascular disease. Conclusion:Large series examining many candidate molecules will be needed to find valid biomarkers, and this should be followed by use in future intervention trials to prove their utility.

Functional connectivity changes in the language network during stroke recovery

Several neuroimaging studies have examined language reorganization in stroke patients with aphasia. However, few studies have examined language reorganization in stroke patients without aphasia. Here, we investigated functional connectivity (FC) changes after stroke in the language network using resting‐state fMRI and performance on a verbal fluency (VF) task in patients without clinically documented language deficits.

Potential biomarkers for the diagnosis of stroke.

Stroke is common, with a high rate of disability and death, and current therapies are both highly time sensitive and carry some risk, making rapid diagnosis important. Many cases of stroke are difficult to diagnose clinically during the acute phase, and there are limitations to the ability of diagnostic imaging to help with the necessary speed. A reliable and valid biomarker would be invaluable for this common clinical situation, as it has been with myocardial infarction. A large number of molecules have been evaluated for this role, both in the laboratory and in patients, but the results to date have been disappointing. In this article, we review the operative concepts in the search for a diagnostic biomarker of stroke, a few of the promising candidates and the current challenges to validation.

The prophylactic use of an antiepileptic drug in intracerebral hemorrhage.

OBJECTIVE Patients with intracerebral hemorrhage (ICH) are at increased risk for both early seizures and later epilepsy. There is a common, but unproven, practice of prescribing a prophylactic antiepileptic drug (PAED) to prevent seizures, but the safety and efficacy of this practice is unclear, as is the optimal drug for this purpose. The objective of the study is to evaluate whether patients presenting with acute, spontaneous intracerebral hemorrhage (ICH) benefit from prescription of prophylactic antiepileptic drug (PAED). METHOD All patients with a discharge diagnosis of acute, spontaneous ICH admitted to our institution in the calendar years 2004 and 2007 were included. We retrospectively reviewed the records for baseline characteristics, hospital course, PAED use, early seizures, length of stay, discharge disposition, and death. RESULTS 157 patients met our criteria for review. 46 (29%) patients were placed on a PAED. 12 (7.6%) had early seizures. 11% of patients placed on a PAED had an early seizure versus 6.3% who not placed on a PAED. Death or hospice discharge was less common in patients prescribed a PAED, while length of stay was longer, however neither of these differences were significant after adjustment for multiple comparisons. INTERPRETATIONS Our study confirms previous reports that patients with acute, spontaneous ICH are at an increased risk for early seizures. PAED use in our series was not significantly associated with the risk of early seizures, long-term epilepsy, disability, or death.

Injected Versus Oral Cyclosporine for Human Neural Progenitor Grafting in Rats.

BACKGROUND Neural cell transplantation is a promising therapy for stroke, but rejection of human cells in animal models is an obstacle to furthering this research. Many antirejection strategies have been reported, but few comparison data are available. We asked if human neural cell grafts would have different survival or differentiation with injected or oral cyclosporine regimens. METHODS Rats received intracerebral grafts of human embryonic stem cell-derived neural progenitors, and 6 rats each were randomized to 4 cyclosporine regimens: 1) daily injections, 2) initial injections followed by oral drug in the drinking water, 3) oral drug only, or 4) no cyclosporine. Histology was performed 14 days after grafting for quantification of markers of human cells, neural cell types, and immune cells. RESULTS More rats in the injection (6/6) and injection+oral (5/6) groups had surviving graft cells than in the oral (1/6) and control (3/6) groups (p<0.05), with a trend toward a greater number of surviving graft cells as well. All rats with surviving graft cells also had these cells co-label for a neural progenitor marker, and a minority of graft cells co-labeled for a cell division marker and a neuronal marker. Rats with areas of dead graft cell debris were seen in all of the groups. In these areas, cells that labeled for microglial markers also contained the human nuclear marker in their cytoplasm, suggesting phagocytosis of the graft cells. CONCLUSIONS Human neural cell survival in rat brain tissue differed between cyclosporine regimens, but microglial phagocytosis of graft cells occurred in all the groups. Frequent injection of laboratory animals is undesirable, and a compromise strategy of peritransplant injections followed by drug in the drinking water showed good results in preventing graft cell rejection. Further research is needed to optimize the antirejection approach for this application.

Histological quantification of brain tissue inflammatory cell infiltration after focal cerebral infarction: a systematic review

Ischemic stroke is a leading cause of death and disability, and current treatments to limit tissue injury and improve recovery are limited. Cerebral infarction is accompanied by intense brain tissue inflammation involving many inflammatory cell types that may cause both negative and positive effects on outcomes. Many potential neuroprotective and neurorestorative treatments may affect, and be affected by, this inflammatory cell infiltration, so that accurate quantification of this tissue response is needed. We performed a systematic review of histological methods to quantify brain tissue inflammatory cell infiltration after cerebral infarction. We found reports of multiple techniques to quantify different inflammatory cell types. We found no direct comparison studies and conclude that more research is needed to optimize the assessment of this important stroke outcome.

Histological quantification of astrocytosis after cerebral infarction: a systematic review

Accurate histological quantification of astrocytosis after cerebral infarction is needed as this process may affect, and be affected by, many potential restorative treatments under investigation. We performed a systematic review to determine the most reliable histological method reported for measurement of postinfarction astrocytosis. We found reports of multiple techniques to quantify various parameters of immunohistochemical staining for the astrocyte marker glial fibrillary acidic protein on photomicrographs with several software packages. We found no studies directly comparing techniques. We conclude that the reported methods seem reasonable, but the descriptions were often insufficiently detailed to allow for replication, and the lack of comparison data makes the best method unclear. Further research is needed to optimize the analysis of this important tissue outcome after cerebral infarction.

Histological methods for ex vivo axon tracing: A systematic review.

Objectives: Axon tracers provide crucial insight into the development, connectivity, and function of neural pathways. A tracer can be characterized as a substance that allows for the visualization of a neuronal pathway. Axon tracers have previously been used exclusively with in vivo studies; however, newer methods of axon tracing can be applied to ex vivo studies. Ex vivo studies involve the examination of cells or tissues retrieved from an organism. These post mortem methods of axon tracing offer several advantages, such as reaching inaccessible tissues and avoiding survival surgeries. Methods: In order to evaluate the quality of the ex vivo tracing methods, we performed a systematic review of various experimental and comparison studies to discern the optimal method of axon tracing. Results: The most prominent methods for ex vivo tracing involve enzymatic techniques or various dyes. It appears that there are a variety of techniques and conditions that tend to give better fluorescent character, clarity, and distance traveled in the neuronal pathway. We found direct comparison studies that looked at variables such as the type of tracer, time required, effect of temperature, and presence of calcium, however, there are other variables that have not been compared directly. Discussion: We conclude there are a variety of promising tracing methods available depending on the experimental goals of the researcher, however, more direct comparison studies are needed to affirm the optimal method.

Effects of neural differentiation maturity status of human induced pluripotent stem cells prior to grafting in a subcortical ischemic stroke model

Neural cell grafting is a promising therapy for stroke, but the optimal differentiation status of the cells prior to grafting is unclear. We grafted cells at different maturity stages (days 28, 42, or 56 of in vitro neural differentiation) into the brains of eight-week-old rats one week after subcortical ischemic stroke, and assessed motor and sensory behavioral recovery over one month. We did not find a difference between the grafted or control groups on behavioral recovery, or on brain tissue outcomes including infarct size, microgliosis, or astrocytosis. Further research is needed into mechanisms of benefit of neural cell grafting for stroke.

Survey of prophylactic antiseizure drug use for non-traumatic intracerebral hemorrhage

Abstract Objective: Prophylactic antiseizure drugs (PAD) are commonly prescribed for non-traumatic intracerebral hemorrhage (ICH) despite limited evidence for this indication. We sought to determine the current prescribing patterns of the use of a PAD for ICH. Methods: A 36-item survey was distributed to physicians who manage ICH patients soliciting details of PAD prescription in their practice. Results: A total of 199 physicians responded to the survey, all of who manage 50 or more ICH patients per year. The respondents were neurologists (32%), neurosurgeons (11%), and intensivists (57%) in academia (69%) and private practice (31%). Prophylactic antiseizure drugs prescriptions used: never (33%), 1–33% (35%), 34–66% (14%), 67–99% (9%) of the time, or always (9%). Most respondents performed electroencephalographic and serum level monitoring in at least some patients. Levetiracetam was used most often (60%), followed by fosphenytoin (37%), for a usual duration of days (36%), weeks (47%), or months (17%). Prophylactic antiseizure drugs prescription varied by patient characteristics and physician specialty. Perception of physician community consensus regarding PAD use for ICH among respondents ranged from strongly (7%) or weakly (23%) against the practice, to a fairly equal division of opinion (41%), to weakly (27%) or strongly (4%) in favor of the practice. Conclusions: We found variability of multiple aspects of the current prescribing patterns and opinions regarding the use of a PAD for ICH. This variability is likely secondary to insufficient data. Clinical equipoise exists for this issue, and controlled trials would be both justified and useful.