Perispinal etanercept for post-stroke neurological and cognitive dysfunction: scientific rationale and current evidence.

There is increasing recognition of the involvement of the immune signaling molecule, tumor necrosis factor (TNF), in the pathophysiology of stroke and chronic brain dysfunction. TNF plays an important role both in modulating synaptic function and in the pathogenesis of neuropathic pain. Etanercept is a recombinant therapeutic that neutralizes pathologic levels of TNF. Brain imaging has demonstrated chronic intracerebral microglial activation and neuroinflammation following stroke and other forms of acute brain injury. Activated microglia release TNF, which mediates neurotoxicity in the stroke penumbra. Recent observational studies have reported rapid and sustained improvement in chronic post-stroke neurological and cognitive dysfunction following perispinal administration of etanercept. The biological plausibility of these results is supported by independent evidence demonstrating reduction in cognitive dysfunction, neuropathic pain, and microglial activation following the use of etanercept, as well as multiple studies reporting improvement in stroke outcome and cognitive impairment following therapeutic strategies designed to inhibit TNF. The causal association between etanercept treatment and reduction in post-stroke disability satisfy all of the Bradford Hill Criteria: strength of the association; consistency; specificity; temporality; biological gradient; biological plausibility; coherence; experimental evidence; and analogy. Recognition that chronic microglial activation and pathologic TNF concentration are targets that may be therapeutically addressed for years following stroke and other forms of acute brain injury provides an exciting new direction for research and treatment.

[Growing skull fracture]. / De 'groeiende schedelfractuur'.

BACKGROUND: Growing skull fracture (GSF) is a rare complication of cranial trauma in children younger than 3 years. It is characterised by the presence of a dural defect due to which herniation of the brain tissue can develop, with cystic transformation and resulting cerebral damage. CASE DESCRIPTION: A 5-month-old baby girl presented at the emergency department following a fall from the staircase. Upon examination she showed a left parietal subgaleal haematoma and right-sided hemiparesis. MRI examination of the brain showed a skull fracture and dural defect with progressive herniation of the brain tissue. Neurosurgical reconstruction was carried out. CONCLUSION: GSF is a rare complication of cranial trauma in young children as a result of rupture of the dura and separating fracture edges. This can lead to cerebral damage and early recognition is important. GSF needs to be considered in children younger than 3 years with a (pulsating) subgaleal haematoma. The diagnosis is made by MRI scan of the brain and neurosurgical treatment consists of watertight closure of the dura combined with skull reconstruction.

Widespread and prolonged increase in (R)-(11)C-PK11195 binding after traumatic brain injury.

UNLABELLED: Our objective was to measure (R)-(11)C-PK11195 binding as an indirect marker of neuronal damage after traumatic brain injury (TBI). METHODS: Dynamic (R)-(11)C-PK11195 PET scans were acquired for 8 patients 6 mo after TBI and for 7 age-matched healthy controls. (R)-(11)C-PK11195 binding was assessed using the simplified reference tissue model. Because of widespread traumatic changes in TBI, an anatomic reference region could not be defined. Therefore, supervised cluster analysis was used to generate an appropriate reference tissue input. RESULTS: Increased whole-brain binding of (R)-(11)C-PK11195 was observed in TBI patients. Regional analysis indicated that increased (R)-(11)C-PK11195 binding was widespread over the brain. CONCLUSION: Six months after TBI, there was a prolonged and widespread increase in (R)-(11)C-PK11195 binding, which is indicative of diffuse neuronal damage.

Increased cerebral (R)-[(11)C]PK11195 uptake and glutamate release in a rat model of traumatic brain injury: a longitudinal pilot study.

BACKGROUND: The aim of the present study was to investigate microglia activation over time following traumatic brain injury (TBI) and to relate these findings to glutamate release. PROCEDURES: Sequential dynamic (R)-[(11)C]PK11195 PET scans were performed in rats 24 hours before (baseline), and one and ten days after TBI using controlled cortical impact, or a sham procedure. Extracellular fluid (ECF) glutamate concentrations were measured using cerebral microdialysis. Brains were processed for histopathology and (immuno)-histochemistry. RESULTS: Ten days after TBI, (R)-[(11)C]PK11195 binding was significantly increased in TBI rats compared with both baseline values and sham controls (p < 0.05). ECF glutamate values were increased immediately after TBI (27.6 ± 14.0 µmol·L(-1)) as compared with the sham procedure (6.4 ± 3.6 µmol·L(-1)). Significant differences were found between TBI and sham for ED-1, OX-6, GFAP, Perl's, and Fluoro-Jade B. CONCLUSIONS: Increased cerebral uptake of (R)-[(11)C]PK11195 ten days after TBI points to prolonged and ongoing activation of microglia. This activation followed a significant acute posttraumatic increase in ECF glutamate levels.

Reference tissue models and blood-brain barrier disruption: lessons from (R)-[11C]PK11195 in traumatic brain injury.

UNLABELLED: (R)-[(11)C]PK11195 is a tracer for activated microglia. The purpose of this study was to assess the validity of the simplified reference tissue model for analyzing (R)-[(11)C]PK11195 studies in traumatic brain injury (TBI), where blood-brain barrier disruptions are likely. METHODS: Dynamic (R)-[(11)C]PK11195 scans were acquired at 3 time points after TBI. Plasma input-derived binding potential (BP(ND)(PI)), volume of distribution (V(T)) and K(1)/k(2), and simplified reference tissue model-derived binding potential (BP(ND)(SRTM)) were obtained. Simulations were performed to assess the effect of varying K(1)/k(2). RESULTS: Early after TBI, an increase in V(T), but not in BP(ND)(PI), was found. Early K(1)/k(2) correlated with V(T) and BP(ND)(SRTM) but not with BP(ND)(PI). One and 6 mo after TBI, BP(ND)(SRTM) correlated with BP(ND)(PI). CONCLUSION: Early after TBI, (R)-[(11)C]PK11195 studies should be analyzed using plasma input models.

Cerebral microdialysis of interleukin (IL)-1beta and IL-6: extraction efficiency and production in the acute phase after severe traumatic brain injury in rats.

BACKGROUND: As a research tool, cerebral microdialysis might be a useful technique in monitoring the release of cytokines into the extracellular fluid (ECF) following traumatic brain injury (TBI). We established extraction efficiency of Interleukin(IL)-1ss and Interleukin(IL)-6 by an in vitro microdialysis-perfusion system, followed by in vivo determination of the temporal profile of extracellular fluid cytokines after severe TBI in rats. MATERIALS AND METHODS: In vitro experiments using a polyether sulfon (PES) microdialysis probe especially developed for recovery of macromolecules such as cytokines, were carried out to establish the extraction efficiency of IL-1ss and IL-6 from artificial cerebrospinal fluid (CSF) with defined IL-1ss and IL-6 concentrations. In vivo experiments in which rats were subjected to TBI or sham and microdialysis samples were collected from the parietal lobe for measurement of cytokines. FINDINGS: The extraction efficiency was maximal 6.05% (range, 5.97-6.13%) at 0.5 microl/min(-1) and decreased at higher flow rates. Both cytokines were detectable in the dialysates. Highest IL-1ss levels were found within 200 min, highest IL-6 concentrations were detected at later intervals (200-400 min). No differences were found between the TBI and control groups. CONCLUSIONS: Cerebral microdialysis allows measurement of cytokine secretion in the ECF of brain tissue in rats.

Evaluation of reference tissue models for the analysis of [11C](R)-PK11195 studies.

[(11)C](R)-PK11195 is a marker of activated microglia, which can be used to measure inflammation in neurologic disorders. The purpose of the present study was to define the optimal reference tissue model based on a comparison with a validated plasma input model and using clinical studies and Monte Carlo simulations. Accuracy and reproducibility of reference tissue models were evaluated using Monte Carlo simulations. The effects of noise and variation in specific binding, nonspecific binding and blood volume were evaluated. Dynamic positron emission tomography scans were performed on 13 subjects, and radioactivity in arterial blood was monitored online. In addition, blood samples were taken to generate a metabolite corrected plasma input function. Both a (validated) two-tissue reversible compartment model with K(1)/k(2) fixed to whole cortex and various reference tissue models were fitted to the data. Finally, a simplified reference tissue model (SRTM) corrected for nonspecific binding using plasma input data (SRTM(pl_corr)) was investigated. Correlations between reference tissue models (including SRTM(pl_corr)) and the plasma input model were calculated. Monte Carlo simulations indicated that low-specific binding results in decreased accuracy and reproducibility. In this respect, the SRTM and SRTM(pl_corr) performed relatively well. Varying blood volume had no effect on performance. In the clinical evaluation, SRTM(pl_corr) and SRTM had the highest correlations with the plasma input model (R(2)=0.82 and 0.78, respectively). SRTM(pl_corr) is optimal when an arterial plasma input curve is available. Simplified reference tissue model is the best alternative when no plasma input is available.