Can early clinical parameters predict post-traumatic pituitary dysfunction in severe traumatic brain injury?

BACKGROUND: Post-traumatic hypopituitarism is a major complication after severe head trauma. The aim of our study was to evaluate the possible role of early clinical parameters in the development of endocrine deficits. METHODS: Data on endocrine function, on-admission clinical-, laboratory-, and ICU-monitored parameters were available in 63 patients of the surviving 86 severe head injury patients (post-resuscitation GCS under 8) treated at one neurosurgical center during a 10-year period. RESULTS: Hypopituitarism was diagnosed in 68.3 % of the patients. The most frequently affected pituitary axis was the growth hormone (GH): GH deficiency or insufficiency was present in 50.8 %. Central hypogonadism affected 23.8 % of male patients; hypothyroidism and secondary adrenal failure were found in 22.2 and 9.5 % of the investigated population, respectively. Early onset (within 1 year of brain injury) hypopituitarism was found in 24 patients. No connection was found between the development of hypopituitarism and any of the clinical parameters assessed on-admission or at ICU. Significant correlations were found between early endocrine dysfunctions and surgical intervention (OR: 4.64) and the diagnosis of subdural hematoma (OR: 12). In our population, after road traffic accidents, the development of late-onset hypopituitarism was less prevalent (OR: 0.22). CONCLUSIONS: Since our results do not indicate any reliable predictive parameter for the development of endocrine dysfunction in a cohort of patients with severe traumatic brain injury, regular endocrine screening of this specific patient population seems obligatory.

A statistical model for intervertebral disc degeneration: determination of the optimal T2 cut-off values.

PURPOSE: The aim of this study was to investigate the possibility of quantitative classification in intervertebral disc degeneration using spin-spin relaxation time (T2) cut-off values with regard to morphological classifications. METHODS: Lumbar magnetic resonance (MR) imaging was performed on 21 subjects (a total of 104 lumbar disks). The T2 relaxation time was measured in the nucleus pulposus using a sagittal multi-echo spin-echo sequence. The morphological classification of disc degeneration was assessed independently by three experienced neuroradiologists according to the Pfirrmann and Schneiderman classifications. Receiver operating characteristic analysis was performed among grades to determine T2 cut-off values in each classification. Intra- and interobserver differences were calculated using kappa statistics. RESULTS: Moderate overall interobserver agreement was found between observers in both the Pfirrmann and Schneiderman classification schemes (kappa 0.46 and 0.51), while intraobserver reliability was substantial to almost perfect. The interobserver reliability was only fair in Pfirrmann grades III and IV (kappa 0.33 and 0.36), but the T2 cut-off values still indicated a significant difference between grades (p<0.05). CONCLUSIONS: Interobserver agreement of MR evaluation in patients with intervertebral disc degeneration was only fair to moderate on the classification of more severe disc degeneration in the Pfirrmann and Schneiderman schemes. Based on our results, quantitative T2 cut-off values seem to be a more reliable method to define the degree of disc degeneration, which may help staging intervertebral disc degeneration (IVDD) even if the interobserver reliability is low.

Irony comprehension and context processing in schizophrenia during remission--a functional MRI study.

Schizophrenic patients have Theory of Mind (ToM) deficits even during remission, but it is yet unknown whether this could be influenced. We examined the neural correlates of irony understanding in schizophrenic patients, as an indicator of ToM capacity, and evaluated how linguistic help inserted into the context phase could affect irony comprehension. Schizophrenic patients in remission and healthy controls were subjected to event-related functional MRI scanning while performing irony, 'irony with linguistic help', and control tasks. Patients understood irony significantly worse than healthy controls. The patients showed stronger brain activity in the parietal and frontal areas in the early phase of irony task, however the healthy controls exhibited higher activation in frontal, temporal and parietal regions in the latter phase of the irony task. Interestingly the linguistic help not only improved the patients' ToM performance, but it also evoked similar activation pattern to healthy controls.

Lateralisation of non-metric rhythm.

There are contradictory results on lateralisation and localisation of rhythm processing. Our aim was to test whether there is a hemispheric dissociation of metric and non-metric rhythm processing. We created a non-metric rhythm stimulus without a sense of metre and we measured brain activities during passive rhythm perception. A total of 11 healthy, right-handed, native female Hungarian speakers aged 21.3 ± 1.1 were investigated by functional magnetic resonance imaging (fMRI) using a 3T MR scanner. The experimental acoustic stimulus consisted of comprehensive sentences transformed to Morse code, which represent a non-metric rhythm with irregular perceptual accent structure. Activations were found in the right hemisphere, in the posterior parts of the right-sided superior and middle temporal gyri and temporal pole as well as in the orbital part of the right inferior frontal gyrus. Additional activation appeared in the left-sided superior temporal region. Our study suggests that non-metric rhythm with irregular perceptual accents structure is confined to the right hemisphere. Furthermore, a right-lateralised fronto-temporal network extracts the continuously altering temporal structure of the non-metric rhythm.

Layer-specific activity of tissue non-specific alkaline phosphatase in the human neocortex.

The ectoenzyme tissue non-specific alkaline phosphatase (TNAP) is mostly known for its role in bone mineralization. However, in the severe form of hypophosphatasia, TNAP deficiency also results in epileptic seizures, suggesting a role of this enzyme in brain functions. Accordingly, TNAP activity was shown in the neuropil of the cerebral cortex in diverse mammalian species. However in spite of its clinical significance, the neuronal localization of TNAP has not been investigated in the human brain. By using enzyme histochemistry, we found an unprecedented pattern of TNAP activity appearing as an uninterrupted layer across diverse occipital-, frontal- and temporal lobe areas of the human cerebral cortex. This marked TNAP-active band was localized infragranulary in layer 5 as defined by quantitative comparisons on parallel sections stained by various techniques to reveal the laminar pattern. On the contrary, TNAP activity was localized in layer 4 of the primary visual and somatosensory cortices, which is consistent with earlier observations on other species. This result suggests that the expression of TNAP in the thalamo-recipient granular layer is an evolutionary conserved feature of the sensory cortex. The observations of the present study also suggest that diverse neurocognitive functions share a common cerebral cortical mechanism depending on TNAP activity in layer 5. In summary, the present data point on the distinctive role of layer 5 in cortical computation and neurological disorders caused by TNAP dysfunctions in the human brain.

Quantitative proton MRI and MRS of the rat brain with a 3T clinical MR scanner.

OBJECTIVE: To demonstrate the capability of a clinical 3T human scanner in performing quantitative MR experiments in the rat brain. MATERIAL AND METHODS: In vivo, measurements on eight Wistar rats were performed. Longitudinal relaxation time (T1) and transverse relaxation time (T2) measurements were set up at a spatial resolution of 0.3×0.3×1mm(3). Diffusion-weighted imaging was also applied and the evaluation included both mono- and biexponential approaches (b-value up to 6000s/mm(2)). Besides quantitative imaging, the rat brain was also scanned at a microscopic resolution of 130×130×130µm(3). Quantitative proton spectroscopy was also carried out on the rat brain with water as internal reference. RESULTS: T1 and T2 for the rat brain cortex were 1272±85ms and 75±2ms, respectively. Diffusion-weighted imaging yielded accurate diffusion coefficient measurements at both low and high b-value ranges. The concentrations of MR visible metabolites were determined for the major resonances (i.e., N-acetyl-aspartate, choline and creatine) with acceptable accuracy. CONCLUSION: The results suggest that quantitative imaging and spectroscopy can be carried out on small animals on high-field clinical scanners.

The effect of carotid stenting on rheological parameters, free radical production and platelet aggregation.

INTRODUCTION: Carotid artery stenting has become a possible treatment of significant carotid stenosis. The risk of stent occlusion and restenosis might be increased by abnormal rheological conditions amplified platelet aggregation and free radical production during the operation. AIMS: The aim of our study was to assess the changes in hemorheological parameters, platelet aggregation, and catalase activity after endovascular treatment of carotid stenosis. METHODS: 18 patients (11 men, ages 68 +/- 9 years and 7 women, ages 62 +/- 8 years) suffering from significant carotid stenosis and treated with carotid endovascular intervention were examined. Alteration in hemorheological parameters as well as epinephrine-, ADP-, and collagen-induced platelet aggregation were evaluated. Antioxidant reserve was characterized by the determination of catalase activity. The measurements were carried out directly before and after the procedure and 1, 2, 5 days and 1 month following the intervention. Preceding the operation the patients were administered a maximum dose (300 mg) of clopidogrel. RESULTS: Hematocrit, plasma fibrinogen concentration (PFC) and whole blood-, and plasma viscosity values (WBV and PV) significantly decreased immediately after stenting (p<0.001). By the fifth day following the intervention the PFC, WBV, PV, red blood cell (RBC) aggregation and ADP-induced platelet aggregation significantly increased (p<0.0001) compared to values measured postprocedurally. At 1 month follow-up these parameters, except whole blood viscosity, decreased significantly compared to measurements made on the 5th day. On the other hand, catalase activity showed significant elevation by the end of the first month. CONCLUSION: Hemorheological parameters and platelet aggregation showed specific changes following carotid stenting. Abnormal changes of the rheological conditions and increasing platelet activation are the most pronounced in the first week following stenting, which may lead to early stent occlusion. Oxidative stress production returned to baseline levels only by the end of the first month.

1H-MRS experiences after bilateral DBS of the STN in Parkinson's disease.

UNLABELLED: The objective of this study was to evaluate the changes in the concentrations of certain brain metabolites in 13 patients with Parkinson's disease before and after bilateral subthalamic nucleus (STN DBS). The N-acetylaspartate (NAA)/choline (Chol), NAA/creatine (Cr), Chol/Cr ratios were determined by single voxel Proton magnetic resonance spectroscopy ((1)H-MRS) studies on 1.0T unit using short TE stimulated echo acquisition mode (STEAM) sequence. Spectra were obtained from the right and left globus pallidus, and left fronto-basal cortex. The patients were also assessed according to the UPDRS part III, in the "medication-on and off" conditions. CONCLUSIONS: after STN DBS cortical NAA/Cho, NAA/Cr ratios increased significantly, which were highly correlated with the significant improvements of the UPDRS scores.

Rescuing neurons and glia: is inhibition of apoptosis useful?

Traumatic brain injury (TBI) represents a leading cause of death in western countries. Despite all research efforts we still lack any pharmacological agent that could effectively be utilized in the clinical treatment of TBI. Detailed unraveling of the pathobiological processes initiated by/operant in TBI is a prerequisite to the development of rational therapeutic interventions. In this review we provide a summary of those therapeutic interventions purported to inhibit the cell death (CD) cascades ignited in TBI. On noxious stimuli three major forms of CD, apoptosis, autophagia and necrosis may occur. Apoptosis can be induced either via the mitochondrial (intrinsic) or the receptor mediated (extrinsic) pathway; endoplasmic reticular stress is the third trigger of caspase-mediated apoptotic processes. Although, theoretically pan-caspase inhibition could be an efficient tool to limit apoptosis and thereby the extent of TBI, potential cross-talk between various avenues of CD suggests that more upstream events, particularly the preservation of the cellular energy homeostasis (cyclosporine-A, poly ADP ribose polymerase (PARP) inhibition, hypothermia treatment) may represent more efficient therapeutic targets hopefully also translated to the clinical care of the severely head injured.

[Microeletrode guided stereotactic pallidotomy and pallido-thalamotomy for treatment of Parkinson's disease]. / Tratamiento de la enfermedad de Parkinson con palidotomía y palido-talamotomíaestereotáctica guiada por microelectrodos.

OBJECTIVE: Authors evaluated the therapeutic effect of the MRI and microelectrodeguided stereotactic pallido- and pallido-thalamotomy in 33 patients with Parkinson's disease (PD), whose symptoms were refractory to pharmacological therapy. MATERIAL AND METHODS: The patients were evaluated according to the internationally standardized rating scales (UPDRS part II, III, Schawb & England, Hoehn & Yahr, and Fahn) at six timepoints: before the operation, and 2 days, 3, 6, 9 and 12 months postoperatively. The patients were divided into 2 groups. Those in group A had relief of all main parkinsonian symptoms after pallidotomy including tremor. The patients in group B had no relief of tremor after pallidotomy. For them the pallidotomy was completed by thalamotomy in the same sitting, which had resulted in cessation of tremor. RESULTS: The following results were obtained by using the UPDRS part III: after pallidotomy "On state" mean: preoperative 51.2, postoperative at 2nd day 29.5 at 3, 6 and 9th month 26, and at 12th month 28.7. "Off state" mean: preoperative 64.3, postoperative at 2nd day 31.6, at 3, 6 and 9th month 26, and at 12th months 30.5. After pallidothalamotomy "On state" mean: preoperative 43.5, postoperative at 2nd day 27.9, at 3rd month 22.9, at 6th month 22.8, and at 9 and 12th month 24.5. "Off state" mean: preoperative 62.6, postoperative at 2nd day 38, at 3rd month 30, at 6th month 31,8 and at 9 and 12th month 33.8. CONCLUSIONS: For those patients, whose tremor was not successfully controlled by pallidotomy, the combined pallido-thalamotomy was effective. The clinical symptomps, according to the rating scales, improved significantly in both groups (student t: P<0.0001), but bilateral lesioning carried higher surgical morbidity.

Ablative stereotactic surgery improves manual performance time in Parkinson's disease.

The objective of this study was to determine the influence of stereotactic ablative surgical interventions on the time required for the performance of manual tasks (i.e. performance time) in patients with Parkinson's disease (PD). We studied 28 patients after pallidotomy and pallido-thalamotomy who were evaluated at four time: before the operation, and 2 days, 3 and 6 months postoperatively. The speed of performance of handwriting and drawing were assessed by means of a chronometer using certain parts of an international standard scale (modified by Fahn). The patients were also assessed according to the Unified Parkinson's Disease Rating Scale (UPDRS) part III. The patients were divided into two groups. Those in group A had relief of all main Parkinsonian symptoms after pallidotomy including tremor. The patients in group B had no relief of tremor straight after pallidotomy. For them the pallidotomy was completed with thalamotomy in the same sitting, which had resulted in cessation of tremor. The time of performance of the manual tasks diminished significantly in all cases in both groups (Student's t-test: p<0.0001). No complications developed following pallidotomy. Pallido-thalamotomy caused transient adverse effects in two patients, and one patient developed permanent adverse effects such as dysarthria and dysequilibrium. Significant improvements were observed in the speed of handwriting and drawing in both groups, but pallido-thalamotomy was accompanied with complications.

Spectrin breakdown products in the cerebrospinal fluid in severe head injury--preliminary observations.

BACKGROUND: Calcium-induced proteolytic processes are considered key players in the progressive pathobiology of traumatic brain injury (TBI). Activation of calpain and caspases after TBI leads to the cleavage of cytoskeletal proteins such as non-erythroid alpha II-spectrin. Recent reports demonstrate that the levels of spectrin and spectrin breakdown products (SBDPs) are elevated in vitro after mechanical injury, in the cerebrospinal fluid (CSF) and brain tissue following experimental TBI, and in human brain tissue after TBI. METHODS: This study was initiated to detect spectrin and SBDP accumulation in the ventricular CSF of 12 severe TBI-patients with raised intracranial pressure (ICP). Nine patients with non-traumatically elevated ICP and 5 undergoing diagnostic lumbar puncture (LP) served as controls. Intact spectrin and calpain and caspase specific SBDPs in CSF collected once a day over a several day period were assessed via Western blot analysis. Parameters of severity and outcome such as ICP, Glasgow Coma Scale and Glasgow Outcome Scale were also monitored in order to reveal a potential correlation between these CSF markers and clinical parameters. RESULTS: In control patients undergone LP no immunoreactivity was detected. Non-erythroid alpha-II-spectrin and SBDP occurred more frequently and their level was significantly higher in the CSF of TBI patients than in other pathological conditions associated with raised ICP. Those TBI patients followed for several days post-injury revealed a consistent temporal pattern for protein accumulation with the highest level achieved on the 2(nd) -3(rd) days after TBI. CONCLUSION: Elevation of calpain and caspase specific SBDPs is a significant finding in TBI patients indicating that intact brain spectrin- and SBDP-levels are closely associated with the specific neurochemical processes evoked by TBI. The results strongly support the potential utility of these surrogate markers in the clinical monitoring of patients with severe TBI and provide further evidence of the role of calcium-induced, calpain- and caspase-mediated structural proteolysis in TBI.

Studies of mdx mice.

Cerebral water accumulation-clinically denoted as brain edema-is a potentially life threatening complication of almost every intracranial neuropathological state. The molecular membrane water channel aquaporin-4 (AQP4) has been shown to be present at the blood-brain barrier (BBB) where it plays pivotal role in the transport of water between the tissue water compartments of the brain. Accumulating evidence indicates that the blockade of AQP4 function at the BBB would be a new therapeutic approach to the treatment and prevention of brain swelling. The cytoskeletal protein dystrophin has been shown to be involved in the maintenance of the polarized expression of AQP4 at the BBB. In order to further elucidate the mechanisms responsible for the highly polarized AQP4 expression, we studied brain tissue water accumulation during induction of brain edema in dystrophin-null transgenic mice (mdx-bgeo) and control mice. Immunofluorescence and immunoelectron microscopic analyses of dystrophin-null brains revealed a dramatic reduction of AQP4 in astroglial end-feet surrounding capillaries (BBB) and at the glia limitans (cerebrospinal fluid-brain interface). The AQP4 protein is mislocalized, because immunoblotting showed that the total AQP4 protein abundance was unaltered. Brain edema was induced by i.p. injection of distilled water and 8-deamino-arginine vasopressin. Changes in cerebral water compartments were assessed by diffusion-weighted MRI (DWI) with determination of the apparent diffusion coefficient (ADC). In dystrophin-null mice and control mice, ADC gradually decreased by 5-6% from baseline levels during the first 35 min, indicating the initial phase of intracellular water accumulation is similar in the two groups. At this point, the control mice sustained an abrupt, rapid decline in ADC to 58%+/-2.2% of the baseline at 52.5 min, and all of the animals were dead by 56 min. After a consistent delay, the dystrophin-null mice sustained a similar decline in ADC to 55%+/-3.4% at 66.5 min, when all of the mice were dead. These results demonstrate that dystrophin is necessary for polarized distribution of AQP4 protein in brain where facilitated movements of water occur across the BBB and cerebrospinal fluid-brain interface. Moreover, these results predict that interference with the subcellular localization of AQP4 may have therapeutic potential for delaying the onset of impending brain edema.

Comparison of regional vasomotor responses to acetazolamide and CO2 in rabbit cerebrum and cerebellum, measured by a hydrogen clearance method.

AIM: Many investigators have proved the usefulness of acetazolamide provocation and the carbon dioxide test for assessment of the local cerebrovascular reactivity by measurement of the regional cerebral blood flow in patients with occlusive cerebrovascular disease. Data originating from a comparison of these two different vasomotor stimuli as concerns the differences in sensitivity to them in various parts of the central nervous system are scarce. Our aim was to compare the cerebral blood flow responses to hypercapnic and acetazolamide stimuli in different brain regions. METHODS: The cerebral blood flow was measured in the cerebrum (cortex and caudate nucleus) and cerebellum (cortex), as measured by a hydrogen clearance method in anaesthetized, artificially ventilated rabbits. RESULTS: In normocapnia, the cerebral blood flow values in the cerebrum and the cerebellum differed significantly. The cerebral blood flow responses to both vasodilatory stimuli were to be significantly higher in the cerebrum than in the cerebellum, but the relative increases, i.e. the mean relative reactivities, were similar in the different regions measured. CONCLUSION: The regional dissimilarity might explain to some extent the different sensitivities of the various brain areas to sudden blood pressure changes (infarction or haemorrhage). The results further suggest that heterogeneity in cerebrovascular reactivity should be considered in the assessment of vasoreactivity in patients with occlusive cerebrovascular disease. Since the comparison of the carbon dioxide and acetazolamide-induced cerebrovascular reactivities revealed a strong linear relationship, it was concluded that acetazolamide provocation is equivalent to the carbon dioxide test in the evaluation of cerebrovascular reactivity.

Fast method for longitudinal relaxation time and water content mapping of the human brain on a clinical MR scanner.

BACKGROUND: Longitudinal relaxation time (T(1)) map generation from human brain slices renders possible the in vivo follow-up of the changes in T(1) values during the course of several pathologies such as stroke, multiple sclerosis, traumatic brain injury etc. T(1) values can be converted to water contents, thus brain oedema reducing therapy can be non-invasively evaluated. The purpose of the study was to work out a fast and simple MRI method to obtain T(1) and water maps of the human brain. METHOD: The T(1) values of Gadolinium solutions with different concentrations were determined by means of MRI methods at a clinical MR scanner operating at 1 Tesla. In order to validate these measurements, T(1) values of the same Gadolinium solutions were also quantified with a relaxometer operating at the same field strength. T(1) and water maps from the brains of healthy volunteers were obtained with an inversion prepared spoiled gradient echo sequence (turbo-FLASH). FINDINGS: The T(1) values of Gadolinium solutions measured with the relaxometer showed a strong correlation (r > 0.999) with those determined with MRI sequences on the whole body scanner. The fastest MRI method to produce T(1) and consequent water maps from human brain was the inversion prepared turbo-FLASH sequence. CONCLUSIONS: The implemented turbo-FLASH method can produce T(1) and water map of a single virtual brain slice within 2 minutes. However, brain tissue containing haemorrhage should be excluded from the measurement due to the large influence of excessive haemoglobin concentration on longitudinal relaxation. The proposed method is available on most of the MR scanners, thus T(1) and water mapping of human brain can be routinely performed.

Cocaine- and amphetamine-regulated transcript peptide (CART) is a selective marker of rat granule cells and of human mossy cells in the hippocampal dentate gyrus.

Cocaine- and amphetamine-regulated transcript (CART) peptide immunocytochemistry was used to reveal cellular localization in the dentate gyrus and in Ammon's horn of the rat and human hippocampal formations. In the rat dentate gyrus, only granule cells were labeled, whereas in humans, only mossy cells of the hilar region expressed CART peptide immunoreactivity. In the rat, CART-positive granule cells were located at the molecular layer border of the granule cell layer and had no features that would distinguish them from other granule cells. The mossy fiber bundle was labeled in the hilus as well as along the entire CA3 area of Ammon's horn. In the human, CART-immunoreactive mossy cells displayed the characteristic thorny excrescences both on their somata and their main dendrites. Axon collaterals of mossy cells could be seen in the hilus and the main axons formed a dense band in the inner molecular layer of the dentate gyrus, suggesting that mossy cells are the principal source of the associational pathway. Granule cells of the dentate gyrus and pyramidal neurons of the human hippocampal formation were devoid of CART peptide immunoreactivity. A few labeled non-pyramidal cells and a large group of strongly immunostained axons of unknown origin were present in all layers of CA1-3. Granule cells are the main excitatory cell population of the dentate gyrus while mossy cells are in a key position in controlling activity of granule cells. The specific location of CART peptide in the dentate granule cells of rodents and in the mossy cells of the human hippocampus may indicate involvement of neuronal circuitry of the dentate gyrus in the memory-related effects of cocaine and amphetamine. Independently of its functional role, CART peptide can be used as a specific marker of human mossy cells and of the dentate associational pathway. The sensitivity of CART peptide to postmortem autolysis may restrict the use of this marker in surgically removed hippocampi or in human brains removed and fixed shortly after death.

Axosomatic synapses on granule cells are preserved in human non-infiltrating tumour or lesion-related and mesial temporal sclerotic epilepsy, but markedly reduced in tumour-infiltrated dentate gyrus with or without epilepsy.

Granule cells of the human hippocampal dentate gyrus were examined. In controls, granule cells displayed somatic spines and cell nuclei with small infoldings. In addition, the cytoplasm of human granule cells always displayed lipofuscin. Subsurface cisterns of endoplasmic reticulum were frequently observed in the human granule cells. Two types of axosomatic synapses were found; most frequently symmetric and less frequently asymmetric. Many of the axosomatic synapses were isolated by glial processes in tumour or lesion-related epileptic patients, but the ultrastructural characteristics of granule cells were not different from those of the control patients. Large bundles of reactive astroglial fibres appeared regularly in all layers of the dentate gyrus. In tumour infiltrated hippocampi, glial processes dominated the neuropil and the number of perisomatic synapses was markedly reduced. Reduction in the number of perisomatic synapses did not correlate with severity and duration of seizures but did correlate with the malignancy of the tumour. It is suggested that reduction of perisomatic inhibition may not be a characteristic of granule cells in the epileptic human dentate gyrus.