A novel apparatus for lateral fluid percussion injury in the rat.

Lateral fluid percussion injury (LFPI) is the most commonly used experimental model of human traumatic brain injury (TBI). To date, investigators using this model have produced injury using a pendulum-and-piston-based device (PPBD) to drive fluid against an intact dural surface. Two disadvantages of this method, however, are (1) the necessary reliance on operator skill to position and release the pendulum, and (2) reductions in reproducibility due to variable friction between the piston's o-rings and the cylinder. To counteract these disadvantages, we designed a low-priced, novel, fluid percussion apparatus that delivers a pressure pulse of air to a standing column of fluid, forcing it against the intact dural surface. The pressure waveforms generated by this apparatus are similar to those reported in the LFPI/PPBD literature and had little variation in appearance between trials. In addition, our apparatus produced an acute and chronic TBI syndrome similar to that in the LFPI/PPBD literature, as quantified by histological changes, MRI structural changes and chronic behavioral sequelae.

End-of-dose emergent psychopathology in ambulatory patients with epilepsy on stable-dose lamotrigine monotherapy: a case series of six patients.

OBJECTIVE: Specific psychological withdrawal symptoms following the cessation of treatment with many drugs that affect the central nervous system, including anxiolytics and antidepressants, have been well documented. Studies have investigated withdrawal symptoms associated with some of the older antiepileptic drugs, but the potential for withdrawal symptoms associated with newer antiepileptic drugs, including lamotrigine, has not yet been investigated. METHODS: Using a retrospective chart review, we identified six patients with epilepsy who reported transient emergent psychological symptoms during stable, chronic lamotrigine monotherapy. RESULTS: These symptoms included anxiety, emotional lability, and irritability. In each case, the symptoms resulted in marked subjective distress and reliably occurred in the 1-2h before the patients were due to take their next dose of medication. CONCLUSIONS: Lamotrigine withdrawal symptoms exist and can occur as an end-of-dose phenomenon, even in patients on stable medication doses. End-of-dose withdrawal from lamotrigine is a clinically significant adverse effect that can hamper successful treatment with this medication.

The natural history of cognitive dysfunction in late-onset GM2 gangliosidosis.

BACKGROUND: Late-onset GM2 gangliosidosis (LGG) is a rare disease that is often considered in the differential diagnosis of adolescents and young adults who present with multiple realms of neurologic dysfunction. Cognitive disturbances are common but have not been systematically studied. OBJECTIVE: To determine the natural history of cognitive dysfunction in patients with LGG. DESIGN: Case series and literature review. SETTING: Urban tertiary referral clinic. PATIENTS: Individuals with hexosaminidase A deficiency as the origin of LGG. MAIN OUTCOME MEASURES: Cognitive dysfunction, psychiatric symptoms, and cerebellar, upper motor neuron, lower motor neuron, or extrapyramidal symptoms and signs. RESULTS: Historical and examination data from 62 patients were found. Forty-four percent of LGG patients had some degree of cognitive dysfunction. Cognitive dysfunction was associated with a greater number of other elemental neurologic deficits. In 21 patients with acceptable longitudinal information, 8 (38%) had a static cognitive disorder, whereas progressive dementia was evident in 13 patients (62%), including 2 of our cases with serial neuropsychological testing. Neuroimaging often showed nonspecific cerebellar and/or cerebral atrophy. CONCLUSIONS: Cognitive dysfunction is a frequent manifestation of LGG. Patients who experience cognitive dysfunction are more likely to have a greater number of other neurologic manifestations of the disease. Cognitive dysfunction may take the form of static encephalopathy, but progressive dementia is more often encountered. The pathogenesis of cognitive dysfunction in this disease is unknown, highlighting the need for further study.

JAK/STAT pathway regulation of GABAA receptor expression after differing severities of experimental TBI.

Synaptic inhibition in the adult brain is primarily mediated by the γ-aminobutyric acid (GABA) type A receptor (GABA(A)R). The distribution, properties, and dynamics of these receptors are largely determined by their subunit composition. Alteration of subunit composition after a traumatic brain injury (TBI) may result in abnormal increased synaptic firing and possibly contribute to injury-related pathology. Several studies have shown that the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway can alter GABA(A)R subunit expression. The present study investigated changes in JAK/STAT pathway activation after two different severities of experimental TBI in the mouse using the controlled cortical impact (CCI) model. It also investigated whether modulating the activation of the JAK/STAT pathway after severe controlled cortical impact (CCI-S) with a JAK/STAT inhibitor (WP1066) alters post-traumatic epilepsy development and/or neurological recovery after injury. Our results demonstrated differential changes in both the activation of STAT3 and the expression of the GABA(A)R α1 and γ2 subunit levels that were dependent on the severity of the injury. The change in the GABA(A)R α1 subunit levels appeared to be at least partly transcriptionally mediated. We were able to selectively reverse the decrease in GABA(A)R α1 protein levels with WP1066 treatment after CCI injury. WP1066 treatment also improved the degree of recovery of vestibular motor function after injury. These findings suggest that the magnitude of JAK/STAT pathway activation and GABA(A)R α1 subunit level decrease is dependent on injury severity in this mouse model of TBI. In addition, reducing JAK/STAT pathway activation after severe experimental TBI reverses the decrease in the GABA(A)R α1 protein levels and improves vestibular motor recovery.

Early false-negative diffusion-weighted imaging in brainstem infarction.

It has been well established that acute ischemic lesions can be identified with diffusion-weighted imaging before they are detected on computed axial tomography or conventional magnetic resonance imaging sequences. Previous studies examining the sensitivity and specificity of diffusion-weighted imaging for acute stroke have dealt primarily with cortical stroke. Only limited information is available on the accuracy and temporal evolution of findings on diffusion-weighted imaging in patients with brainstem infarction. We present a case of lateral medullary infarction with false-negative diffusion-weighted imaging 16 hours after symptom onset and a brief review of the literature on the utility of diffusion-weighted imaging in early detection of brainstem stroke. Cases with false-negative initial imaging are increasingly more commonly reported in the literature, with initial images being obtained from 0.5 to over 24 hours after symptom onset. This delay in radiographic confirmation of brainstem stroke emphasizes the continuing need for accurate clinical diagnoses, especially in the early hours after symptom onset, when thrombolysis remains a treatment option. Delays in diagnosis and initiation of treatment of brainstem stroke may increase the associated morbidity and mortality.

Effects of JAK2-STAT3 signaling after cerebral insults.

The JAK2-STAT3 signaling pathway has been shown to regulate the expression of genes involved in cell survival, cell proliferation, cell-cycle progression, and angiogenesis in development and after cerebral insults. Until recently, little has been known about the effects of this pathway activation after cerebral insults and if blocking this pathway leads to better recovery. This review exams the role of this pathway after 3 cerebral insults (traumatic brain injury, stroke, and status epilepticus).

Blocking leukotriene synthesis attenuates the pathophysiology of traumatic brain injury and associated cognitive deficits.

Neuroinflammation is a component of secondary injury following traumatic brain injury (TBI) that can persist beyond the acute phase. Leukotrienes are potent, pro-inflammatory lipid mediators generated from membrane phospholipids. In the absence of injury, leukotrienes are undetectable in the brain, but after trauma they are rapidly synthesized by a transcellular event involving infiltrating neutrophils and endogenous brain cells. Here, we investigate the efficacy of MK-886, an inhibitor of 5-lipoxygenase activating protein (FLAP), in blocking leukotriene synthesis, secondary brain damage, synaptic dysfunction, and cognitive impairments after TBI. Male Sprague Dawley rats (9-11weeks) received either MK-886 or vehicle after they were subjected to unilateral moderate fluid percussion injury (FPI) to assess the potential clinical use of FLAP inhibitors for TBI. MK-886 was also administered before FPI to determine the preventative potential of FLAP inhibitors. MK-886 given before or after injury significantly blocked the production of leukotrienes, measured by reverse-phase liquid chromatography coupled to tandem mass spectrometry (RP LC-MS/MS), and brain edema, measured by T2-weighted magnetic resonance imaging (MRI). MK-886 significantly attenuated blood-brain barrier disruption in the CA1 hippocampal region and deficits in long-term potentiation (LTP) at CA1 hippocampal synapses. The prevention of FPI-induced synaptic dysfunction by MK-886 was accompanied by fewer deficits in post-injury spatial learning and memory performance in the radial arm water maze (RAWM). These results indicate that leukotrienes contribute significantly to secondary brain injury and subsequent cognitive deficits. FLAP inhibitors represent a novel anti-inflammatory approach for treating human TBI that is feasible for both intervention and prevention of brain injury and neurologic deficits.

GABA(A) receptor regulation after experimental traumatic brain injury.

The gamma-aminobutyric acid (GABA) type A receptor (GABA(A)R) is responsible for most fast synaptic inhibition in the adult brain. The GABA(A)R protein is composed of multiple subunits that determine the distribution, properties, and dynamics of the receptor. Several studies have shown that the Janus kinase/signal transducer and activator of transcription (JaK/STAT) and early growth response 3 (Egr3) signaling pathways can alter GABA(A)R subunit expression after status epilepticus (SE). In this study we investigated changes in these pathways after experimental TBI in the rat using a lateral fluid percussion injury (FPI) model. Our results demonstrated changes in the expression of several GABA(A)R subunit levels after injury, including GABA(A)R α1 and α4 subunits. This change appears to be transcriptional, and there is an associated increase in the phosphorylation of STAT3, and an increase in the expression of Egr3 and inducible cAMP element repressor (ICER) after FPI. These findings suggest that the activation of the JaK/STAT and Egr3 pathways after TBI may regulate injury-related changes in GABA(A)R subunit expression.

Acute neuroimmune modulation attenuates the development of anxiety-like freezing behavior in an animal model of traumatic brain injury.

Chronic anxiety is a common and debilitating result of traumatic brain injury (TBI) in humans. While little is known about the neural mechanisms of this disorder, inflammation resulting from activation of the brain's immune response to insult has been implicated in both human post-traumatic anxiety and in recently developed animal models. In this study, we used a lateral fluid percussion injury (LFPI) model of TBI in the rat and examined freezing behavior as a measure of post-traumatic anxiety. We found that LFPI produced anxiety-like freezing behavior accompanied by increased reactive gliosis (reflecting neuroimmune inflammatory responses) in key brain structures associated with anxiety: the amygdala, insula, and hippocampus. Acute peri-injury administration of ibudilast (MN166), a glial cell activation inhibitor, suppressed both reactive gliosis and freezing behavior, and continued neuroprotective effects were apparent several months post-injury. These results support the conclusion that inflammation produced by neuroimmune responses to TBI play a role in post-traumatic anxiety, and that acute suppression of injury-induced glial cell activation may have promise for the prevention of post-traumatic anxiety in humans.

MALDI mass spectrometric imaging of lipids in rat brain injury models.

Matrix-assisted laser desorption ionization/ionization imaging mass spectrometry (MALDI IMS) with a time-of-flight analyzer was used to characterize the distribution of lipid molecular species in the brain of rats in two injury models. Ischemia/reperfusion injury of the rat brain after bilateral occlusion of the carotid artery altered appearance of the phospholipids present in the hippocampal region, specifically the CA1 region. These brain regions also had a large increase in the ion abundance at m/z 548.5 and collisional activation supported identification of this ion as arising from ceramide (d18:1/18:0), a lipid known to be associated with cellular apoptosis. Traumatic brain injury model in the rat was examined by MALDI IMS and the area of damage also showed an increase in ceramide (d18:1/18:0) and a remarkable loss of signal for the potassium adduct of the most abundant phosphocholine molecular species 16:0/18:1 (PC) with a corresponding increase in the sodium adduct ion. This change in PC alkali attachment ion was suggested to be a result of edema and influx of extracellular fluid likely through a loss of Na/K-ATPase caused by the injury. These studies reveal the value of MALDI IMS to examine tissues for changes in lipid biochemistry and will provide data needed to eventually understand the biochemical mechanisms relevant to tissue injury.

Injury-related production of cysteinyl leukotrienes contributes to brain damage following experimental traumatic brain injury.

The leukotrienes belong to a family of biologically active lipids derived from arachidonate that are often involved in inflammatory responses. In the central nervous system, a group of leukotrienes, known as the cysteinyl leukotrienes, is generated in brain tissue in response to a variety of acute brain injuries. Although the exact clinical significance of this excess production remains unclear, the cysteinyl leukotrienes may contribute to injury-related disruption of the brain-blood barrier and exacerbate secondary injury processes. In the present study, the formation and role of cysteinyl leukotrienes was explored in the fluid percussion injury model of traumatic brain injury in rats. The results showed that levels of the cysteinyl leukotrienes were elevated after fluid percussion injury with a maximal formation 1 hour after the injury. Neutrophils contributed to cysteinyl leukotriene formation in the injured brain hemisphere, potentially through a transcellular biosynthetic mechanism. Furthermore, pharmacological reduction of cysteinyl leukotriene formation after the injury, using MK-886, resulted in reduction of brain lesion volumes, suggesting that the cysteinyl leukotrienes play an important role in traumatic brain injury.

Epidemiology of posttraumatic epilepsy: a critical review.

PROBLEM: Traumatic brain injury (TBI) is a major cause of epilepsy. We need to understand its frequency and its contribution to the total spectrum of the convulsive disorders. METHODS: A review of selected articles dealing with epilepsy after brain trauma was undertaken. RESULTS: The number of epidemiologic studies of posttraumatic seizures has increased substantially over the past 40-50 years, offering steadily increasing knowledge of the frequency, natural history, and risk factors of this well-recognized complication of TBI. In general, the incidence of posttraumatic seizures varies with the time period after injury and population age range under study, as well as the spectrum of severity of the inciting injuries, and has been reported to be anywhere from 4 to 53%. As high as 86% of patients with one seizure after TBI will have a second in the next 2 years. Longer-term remission rates of 25-40% have been reported. Significant risk factors for the development of seizures in the first week after injury include acute intracerebral hematoma (especially subdural hematoma), younger age, increased injury severity, and chronic alcoholism. Significant risk factors for the development of seizures >1 week after TBI include seizures within the first week, acute intra-cerebral hematoma (especially subdural hematoma), brain contusion, increased injury severity, and age >65 years at the time of injury. CONCLUSIONS: Epilepsy is a frequent consequence of brain injury in both civilian and military populations. We understand some factors associated with its development, but there remain many unanswered questions.