Predictive (subtle or overlooked) initial head CT findings in patients who develop delayed chronic subdural hematoma.

With the aging population, the incidence of chronic subdural hematoma (CSDH) is expected to rise. Once symptomatic the morbidity from CSDH is not insignificant. We studied patients who had a minor head injury and CT brain scan prior to developing CSDH to determine if there were any predictors on these scans for subsequent development of a CSDH. A retrospective review was performed on all patients operated for CSDH over a 3-year period and a review performed on those who had imaging studies at the time of a preceding minor head injury. Seven of 37 patients had CT scans prior to developing CSDH. All had evidence of small increases in CSF intensity on the side or sides of the subsequent CSDH. In conclusion, in those patients with a history of minor head injury prior to developing a CSDH, CT brain demonstrated small increases in cerebral spinal fluid (CSF) intensity on the side or sides of the subsequent CSDH. Recognizing this finding may be helpful in monitoring these patients or initiating medical therapy.

Magnetic Resonance Elastography Demonstrating Low Brain Stiffness in a Patient with Low-Pressure Hydrocephalus: Case Report.

The authors describe the case of a 19-year-old female with shunted aqueductal stenosis who presented with low-pressure hydrocephalus that responded to negative pressure drainage. A magnetic resonance elastography scan performed 3 weeks later demonstrated very low brain tissue stiffness (high brain tissue compliance). An analysis of the importance of this finding in understanding this rare condition is discussed.

The emerging neuroprotective role of mitochondrial uncoupling protein-2 in traumatic brain injury.

Traumatic brain injury (TBI) is a multifaceted disease with intrinsically complex heterogeneity and remains a significant clinical challenge to manage. TBI model systems have demonstrated many mechanisms that contribute to brain parenchymal cell death, including glutamate and calcium toxicity, oxidative stress, inflammation, and mitochondrial dysfunction. Mitochondria are critically regulated by uncoupling proteins (UCP), which allow protons to leak back into the matrix and thus reduce the mitochondrial membrane potential by dissipating the proton motive force. This uncoupling of oxidative phosphorylation from adenosine triphosphate (ATP) synthesis is potentially critical for protection against cellular injury as a result of TBI and stroke. A greater understanding of the underlying mechanism or mechanisms by which uncoupling protein-2 (UCP2) functions to maintain or optimize mitochondrial function, and the conditions which precipitate the failure of these mechanisms, would inform future research and treatment strategies. We posit that UCP2-mediated function underlies the physiological response to neuronal stress associated with traumatic and ischemic injury and that clinical development of UCP2-targeted treatment would significantly impact these patient populations. With a focus on clinical relevance in TBI, we synthesize current knowledge concerning UCP2 and its potential neuroprotective role and apply this body of knowledge to current and potential treatment modalities.

Myeloid sarcoma: a rare case of an orbital mass mimicking orbital pseudotumor requiring neurosurgical intervention.

Objective. A rare case of myeloid sarcoma (MS), previously referred to as granulocytic sarcoma or chloroma, is presented. Representing a unique form of acute myeloid leukemia (AML), MS may rarely occur in adults. Even rarer, MS may occur as the initial presentation of AML. Methods. We report a singular and illustrative case of an orbital pseudotumor mimicking mass in a 65-year-old male as the initial presentation of AML. Results. Neurosurgical intervention was required to establish the definitive diagnosis via right modified orbitofrontozygomatic craniotomy as well as to decompress the optic canal, superior orbital fissure, and orbit. Conclusion. Postoperatively, he reported decreased pain and improvement of his vision. Further examination revealed decreased proptosis and improved extraocular mobility. Pathological findings demonstrated MS. We review the literature and discuss the neurosurgical relevance of MS as the initial presentation of AML.

Increased mortality in patients with severe traumatic brain injury treated without intracranial pressure monitoring.

OBJECT: Evidence-based guidelines recommend intracranial pressure (ICP) monitoring for patients with severe traumatic brain injury (TBI), but there is limited evidence that monitoring and treating intracranial hypertension reduces mortality. This study uses a large, prospectively collected database to examine the effect on 2-week mortality of ICP reduction therapies administered to patients with severe TBI treated either with or without an ICP monitor. METHODS: From a population of 2134 patients with severe TBI (Glasgow Coma Scale [GCS] Score <9), 1446 patients were treated with ICP-lowering therapies. Of those, 1202 had an ICP monitor inserted and 244 were treated without monitoring. Patients were admitted to one of 20 Level I and two Level II trauma centers, part of a New York State quality improvement program administered by the Brain Trauma Foundation between 2000 and 2009. This database also contains information on known independent early prognostic indicators of mortality, including age, admission GCS score, pupillary status, CT scanning findings, and hypotension. RESULTS: Age, initial GCS score, hypotension, and CT scan findings were associated with 2-week mortality. In addition, patients of all ages treated with an ICP monitor in place had lower mortality at 2 weeks (p = 0.02) than those treated without an ICP monitor, after adjusting for parameters that independently affect mortality. CONCLUSIONS: In patients with severe TBI treated for intracranial hypertension, the use of an ICP monitor is associated with significantly lower mortality when compared with patients treated without an ICP monitor. Based on these findings, the authors conclude that ICP-directed therapy in patients with severe TBI should be guided by ICP monitoring.

Imipramine treatment improves cognitive outcome associated with enhanced hippocampal neurogenesis after traumatic brain injury in mice.

Previous animal and human studies have demonstrated that chronic treatment with several different antidepressants can stimulate neurogenesis, neural remodeling, and synaptic plasticity in the normal hippocampus. Imipramine is a commonly used tricyclic antidepressant (TCA). We employed a controlled cortical impact (CCI) mouse model of traumatic brain injury (TBI) to assess the effect of imipramine on neurogenesis and cognitive and motor function recovery after TBI. Mice were given daily imipramine injections for either 2 or 4 weeks after injury. Bromodeoxyuridine (BrdU) was administered 3-7 days post-brain injury to label the cells that proliferated as a result of the injury. We assessed the effects of imipramine on post-traumatic motor function using a beam-walk test and an assessment of cognitive function: the novel object recognition test (NOR). Histological analyses were performed at 2 and 4 weeks after CCI. Brain-injured mice treated with imipramine showed significantly improved cognitive function compared to a saline-treated group (p<0.001). However, there was no significant difference in motor function recovery between imipramine-treated and saline-treated mice. Histological examination revealed increased preservation of proliferation of Ki-67- and BrdU-positive cells in the hippocampal dentate gyrus (DG) at 2 and 4 weeks after TBI. Immunofluorescence double-labeling with BrdU and neuron-specific markers at 4 weeks after injury showed that most progenitors became neurons in the DG and astrocytes in the hilus. Notably, treatment with imipramine increased preservation of the total number of newly-generated neurons. Our findings provide direct evidence that imipramine treatment contributes to cognitive improvement after TBI, perhaps by enhanced hippocampal neurogenesis.

Elevated serum ubiquitin carboxy-terminal hydrolase L1 is associated with abnormal blood-brain barrier function after traumatic brain injury.

Serum S100B elevations accurately reflect blood-brain barrier (BBB) damage. Because S100B is also present in peripheral tissues, release of this protein may not be specific to central nervous system (CNS) injury. Ubiquitin C-terminal hydrolase 1 (UCHL1), and phosphorylated neurofilament heavy chain (pNF-H) are found exclusively in neurons, but their relationship to BBB dysfunction has not been determined. The objective of this study was to determine the accuracy of serum UCHL1 and pNF-H as measures of BBB integrity after traumatic brain injury (TBI), to and compare them to S100B. We performed a prospective study of 16 patients with moderate to severe TBI (Glasgow Coma Scale [GCS] score ≤12) and 6 patients with non-traumatic headache who had cerebrospinal fluid (CSF) collected by ventriculostomy or lumbar puncture (LP). Serum and CSF were collected at the time of LP for headache patients and at 12, 24, and 48 h after injury for TBI patients. BBB function was determined by calculating albumin quotients (Q(A)), where Q(A)=[albumin(CSF)]/[albumin(serum)]. S100B, UCHL1, and pNF-H were measured by enzyme-linked immunosorbent assay (ELISA). Pearson's correlation coefficient and area under the receiver operator characteristic (ROC) curve were used to determine relationships between serum markers and Q(A). At 12 hours after TBI, a significant relationship was found between Q(A) and serum UCHL1 concentrations (AUC=0.76; 95% CI 0.55,1.00), and between Q(A) and serum S100B concentrations (AUC=0.794; 95% CI 0.57,1.02). There was no significant relationship found between these markers and Q(A) at other time points, or between pNF-H and Q(A) at any time point. We conclude that serum concentrations of UCHL1 are associated with abnormal BBB status 12 h after moderate to severe TBI. This relationship is similar to that observed between serum S100B and Q(A,) despite the fact that S100B may be released from peripheral tissues after multi-trauma. We conclude that peripheral release of S100B after multi-trauma is probably negligible and that UCHL1 may have some utility to monitor BBB disruption following TBI.

Intracranial monitoring in traumatic brain injury.

PURPOSE OF REVIEW: This review focuses on the role of various intracranial monitoring technologies in the diagnosis and therapy of traumatic brain injury injury. RECENT FINDINGS: There exist many controversial points as to the utility of different intracranial monitoring with regard to improvement of outcomes from severe traumatic brain injury. Most recent studies are confirming that the use of multiple modalities in the neurological ICU setting may offer promising results. SUMMARY: Increased adherence to guideline-based and protocol-driven neurointensive care utilizing multimodality in monitoring technology for patients with severe traumatic brain injury is likely to give clinicians increased insight into the elusive mechanisms underlying the complex pathophysiology of this disease process and may further improve outcomes in this patient population.

Response to intracranial hypertension treatment as a predictor of death in patients with severe traumatic brain injury.

OBJECT: The normalization of increased intracranial pressure (ICP) in patients with severe traumatic brain injury (TBI) is assumed to limit secondary brain injury and improve outcome. Despite evidence-based recommendations for monitoring and treatment of elevated ICP, there are few studies that show an association between response to ICP-directed therapeutic regimens and adjusted mortality rate. This study utilizes a large prospective database to examine the effect of response to ICP-lowering therapy on risk of death within the first 2 weeks of injury in patients who sustained TBI and are older than 16 years. METHODS: The current study is based on 1426 patients with severe TBI (Glasgow Coma Scale [GCS] score < 9) of whom 388 were treated for elevated ICP (> 25 mm Hg) between 2000 and 2008 at 22 trauma centers enrolled in a New York State quality improvement program. This prospectively collected database also contains information including age, admission GCS score, pupillary status, CT scanning parameters, and hypotension, which are all known early prognostic indicators of death. Treatment of elevated ICP consisted of administration of mannitol, hypertonic saline, barbiturates, and/or drainage of CSF or decompressive craniectomy. The factors predicting ICP response to treatment and predicting death at 2 weeks were evaluated using logistic regression analyses. RESULTS: Increasing age and fewer hours of elevated ICP on Day 1 were found to be significant predictors (p = 0.001 and 0.0003, respectively) of a positive response to treatment. Response to ICP-lowering therapy (p = 0.03), younger age (p < 0.0001), fewer hours of elevated ICP (p < 0.0001), and absence of arterial hypotension on Day 1 (p = 0.001) significantly predicted reduced risk of death. CONCLUSIONS: Patients who responded to ICP-lowering treatment had a 64% lower risk of death at 2 weeks than those who did not respond after adjusting for factors that independently predict risk of death.

Perforation of the right cardiac ventricular wall by polymethylmethacrylate after lumbar kyphoplasty.

The authors report the case of a 74-year-old woman who underwent an L-2 vertebral kyphoplasty. The patient experienced delayed postoperative hemodynamic deterioration that may have been caused by embolization of polymethylmethacrylate (PMMA) cement through the right cardiac ventricular wall. Cardiac and pulmonary embolization of bone cement can develop as a complication of vertebral kyphoplasty. Surgeons should be alert to this potentially life-threatening condition when performing this increasingly popular form of spine procedure.

Marked recovery of functional metabolic activity and laminar volumes in the rat hippocampus and dentate gyrus following postnatal hypothyroid growth retardation: a quantitative cytochrome oxidase study.

Similar to cretinism in human children, absence or deficiency of thyroid hormones in rats and mice during early postnatal development results in marked retardation of brain development along with behavioral and cognitive deficits. Less is known about brain recovery from postnatal hypothyroidism. [Farahvar, A., Meisami, E., 2007. Novel two-dimensional morphometric maps and quantitative analysis reveal marked growth and structural recovery of the rat hippocampal regions from early hypothyroid retardation. Experimental Neurology.] found, by means of morphometric maps, that surface areas of hippocampal cortex and its CA1-CA4 regions which were significantly reduced in developing hypothyroid rats, show nearly complete growth recovery upon restoration of thyroid function. Here we explore the ability of hippocampal synapse-rich neuronal fiber layers to show recovery from early hypothyroid growth retardation. Rat pups were made hypothyroid from birth to day 25 (weaning) or up to young adulthood (day 90) by a treatment with the reversible goitrogen, PTU (n-propylthiouracil), in the drinking water. Recovery was induced by withdrawal of PTU at weaning and analysis of cytochrome oxidase (CytOx)-stained serial sections of the hippocampus and dentate gyrus at the ages of 25 and 90 days. CytOx stains the synapse-rich fiber layers of the hippocampal formation (HCF). Volumetric growth of molecular layer, stratum oriens and radiatum and dentate hilar region showed complete or nearly complete recovery from marked and significant growth retardation induced by early postnatal hypothyroidism. Also the reduced CytOx staining intensity in the hypothyroid rat HCF layers showed marked recovery following hormonal restoration. Results indicate remarkable growth plasticity of the HCF and ability of the synapse-rich fiber layers to show complete recovery of metabolic and functional neural activity from deleterious effects of early hypothyroidism. Mitochondrial CytOx is highly localized to the synapse-rich fiber layers of the HCF and its activity and histochemical staining intensity correlates positively with functional metabolic activity of neural tissue. Thus hippocampus and dentate gyrus neuronal fiber layers and their oxidative activity show remarkable ability to recover from the postnatal hypothyroid growth retardation. The results indicate that some brain regions are less vulnerable to early developmental insults and can recover.

Novel two-dimensional morphometric maps and quantitative analysis reveal marked growth and structural recovery of the rat hippocampal regions from early hypothyroid retardation.

Effects of postnatal hypothyroidism and recovery from this condition on regional growth of the rat hippocampus (HC) were studied using two-dimensional (2D) foldout, morphometric maps of HC and its constituent CA1-CA4 regions. The maps were derived from unfolding serial coronal sections of the rat forebrain, consisting of the entire rostrocaudal extent of HC pyramidal cell layer in the normal control and hypothyroid weanling (P25, postnatal day 25) and young adult (P90) male rats, as well as animals allowed to recover from hypothyroid-induced growth retardation at weaning. The maps revealed novel views of HC regions for assessment of topological relationships and measurement of surface areas of the HC cortical sheet (pyramidal cell layer). In normal control P90 rats, the unfolded HC on each side extended 4 times more laterally than rostrocaudally; total HC surface area was about 40 mm(2), compared to 30 mm(2) in the weanling, indicating 35% growth from P25 to P90; CA1 took up 52% of the total HC surface area, followed by CA3 (31%) and CA2 and CA4, 8% each. Hypothyroidism resulted in significant (p<0.01) 11% and 20% reductions in the HC surface area in P25 and P90 rats, respectively; CA1 and CA4 regions suffered the most reductions while CA3 and CA2 regions the least. Recovering rats examined at P90 exhibited remarkable growth plasticity and recovery in HC regions, as evident by their near normal HC cortical surface area values, compared to age-matched controls. The 2D maps also revealed growth deficits in all HC regions of the hypothyroid rats; recovery in these parameters occurred across all dimensions, although the anterior-posterior growth was more severely affected than the mediolateral one. These results are confirmed and extended by volumetric analysis of laminar volumes of HC regions presented in a companion paper [Farahvar, A., Darwish, N., Sladek, S., Meisami, E., in press. Marked recovery of functional metabolic activity and laminar volumes in the rat hippocampus and dentate gyrus following postnatal hypothyroid growth retardation: a quantitative cytochrome oxidase study. Exp. Neurol.]. These results imply that HC regions, in contrast to whole brain, possess exceptional growth plasticity, as shown by ability to dramatically recover from early hypothyroid retardation; also 2D morphometric maps are useful tools to visualize complex and convoluted regional sheet of HC cortex and depict quantitative aspects of growth in normal and experimental conditions.

Lentiviral vector-mediated transduction of neural progenitor cells before implantation into injured spinal cord and brain to detect their migration, deliver neurotrophic factors and repair tissue.

PURPOSE: Stem cells represent an attractive source for cell replacement therapy in neurological disorders due to their self-renewal and multi-potency. Genetic manipulation of these cells may allow controlled release of therapeutic proteins, suppress immune rejection, or produce essential neurotransmitters. Furthermore, when the expression cassette is incorporated into the host genome ex vivo, this technique also may be used as a method to trace cells following implantation into tissues of interest. METHODS: We explored the possibility of transducing pluripotent fetal rat cortical neural progenitor cells (NPCs) using lentiviral vectors encoding the green fluorescent protein (GFP) or neurotrophic factors (BDNF, CNTF, D15A, GDNF, MNT and NT-3) prior to implanting these cells into the contused spinal cord or injured brain. RESULTS: In vitro staining of these cells for neural markers (such as nestin, GFAP, Tuj-1 and RIP) after transduction did not reveal any significant difference from non-transduced cells. When they were transduced with a vector encoding CNTF or MNT, however, cells started expressing GFAP in vitro. Following delayed (1 week) implantation into the lesion site of the moderately contused rat spinal cord or the injured brain, transduced cells survived up to 12 weeks post-implantation (the longest time point examined) and most of the NPCs turned into an astrocytic phenotype in the spinal cord, but not in the brain. Nestin and GFP positive cells were detected in the brain, but not in the spinal cord lesion. GFP positive cells in the spinal cord migrated rostrally and caudally from the lesion/implantation site towards uninjured tissue. CONCLUSIONS: Novel findings in this study are the longterm expression of a foreign gene in NPCs using lentiviral vectors; this enabled tracking of the cells following implantation. This expression also allowed the observation that NPCs developed differently in the injured spinal cord and brain. Moreover, NPCs could be transduced to overexpress neurotrophic factors. In sum, NPC survival and the long-term transgene expression that allows easy tracking of migrating cells make NPCs promising candidates for implantation into the injured spinal cord or brain and a potentially powerful tool to enhance regeneration when transduced ex vivo to produce therapeutic molecules.