Quantification of Intracranial Aneurysm Volume Pulsation with 7T MRI.

BACKGROUND AND PURPOSE: Aneurysm volume pulsation is a potential predictor of intracranial aneurysm rupture. We evaluated whether 7T MR imaging can quantify aneurysm volume pulsation. MATERIALS AND METHODS: In Stage I of the study, 10 unruptured aneurysms in 9 patients were studied using a high-resolution (0.6-mm, isotropic) 3D gradient-echo sequence with cardiac gating. Semiautomatic segmentation was used to measure aneurysm volume (in cubic millimeters) per cardiac phase. Aneurysm pulsation was defined as the relative increase in volume between the phase with the smallest volume and the phase with the largest volume. The accuracy and precision of the measured volume pulsations were addressed by digital phantom simulations and a repeat image analysis. In Stage II, the imaging protocol was optimized and 9 patients with 9 aneurysms were studied with and without administration of a contrast agent. RESULTS: The mean aneurysm pulsation in Stage I was 8% ± 7% (range, 2%-27%), with a mean volume change of 15 ± 14 mm3 (range, 3-51 mm3). The mean difference in volume change for the repeat image analysis was 2 ± 6 mm3. The artifactual volume pulsations measured with the digital phantom simulations were of the same magnitude as the volume pulsations observed in the patient data, even after protocol optimization in Stage II. CONCLUSIONS: Volume pulsation quantification with the current imaging protocol on 7T MR imaging is not accurate due to multiple imaging artifacts. Future studies should always include aneurysm-specific accuracy analysis.

Thinner Regions of Intracranial Aneurysm Wall Correlate with Regions of Higher Wall Shear Stress: A 7T MRI Study.

BACKGROUND AND PURPOSE: Both hemodynamics and aneurysm wall thickness are important parameters in aneurysm pathophysiology. Our aim was to develop a method for semi-quantitative wall thickness assessment on in vivo 7T MR images of intracranial aneurysms for studying the relation between apparent aneurysm wall thickness and wall shear stress. MATERIALS AND METHODS: Wall thickness was analyzed in 11 unruptured aneurysms in 9 patients who underwent 7T MR imaging with a TSE-based vessel wall sequence (0.8-mm isotropic resolution). A custom analysis program determined the in vivo aneurysm wall intensities, which were normalized to the signal of nearby brain tissue and were used as measures of apparent wall thickness. Spatial wall thickness variation was determined as the interquartile range in apparent wall thickness (the middle 50% of the apparent wall thickness range). Wall shear stress was determined by using phase-contrast MR imaging (0.5-mm isotropic resolution). We performed visual and statistical comparisons (Pearson correlation) to study the relation between wall thickness and wall shear stress. RESULTS: 3D colored apparent wall thickness maps of the aneurysms showed spatial apparent wall thickness variation, which ranged from 0.07 to 0.53, with a mean variation of 0.22 (a variation of 1.0 roughly means a wall thickness variation of 1 voxel [0.8 mm]). In all aneurysms, apparent wall thickness was inversely related to wall shear stress (mean correlation coefficient, -0.35; P < .05). CONCLUSIONS: A method was developed to measure the wall thickness semi-quantitatively, by using 7T MR imaging. An inverse correlation between wall shear stress and apparent wall thickness was determined. In future studies, this noninvasive method can be used to assess spatial wall thickness variation in relation to pathophysiologic processes such as aneurysm growth and rupture.

Ambivalence among neurologists and neurosurgeons on the treatment of chronic subdural hematoma: a national survey.

No class I evidence exists about the optimal treatment of chronic subdural hematoma (CSDH). The aim of this study was to evaluate current practice of CSDH patients with different neurological grades, and probable ambivalence towards various treatment paradigms, especially primary treatment with high-dose corticosteroids, among vascular neurologists and neurosurgeons. A questionnaire survey containing 4 questions, 1 consisting of cases, was sent to every vascular neurologist (n = 83) and neurosurgical centre (n = 15) in the Netherlands. The various treatment options were related to the treating physician, geographical distribution, both in general and for individual case. Sixty-two percent of surveys were returned. The proportion of patients primarily treated with corticosteroids was 17.5 % in 2009 and 20.5 % in 2010. Surgery by either burr holes or craniotomy was favoured by 61.1 % as primary treatment, and conservative treatment with corticosteroids by 22.4 %. Case studies revealed that surgery was preferred in case of severe neurological symptoms, whereas wait-and-see policy was preferred in case of mild symptoms without midline shift, of which 28 % would administer corticosteroids. Variety in answers was obtained in less pronounced cases. In the Netherlands, neurologists and neurosurgeons appear to favour surgery in CSDH patients as primary treatment, especially in severe cases. An ambivalent approach towards treatment protocols was shown, especially in patients with mild symptoms, regardless of hematoma size. A regimen of high-dose corticosteroids only, is preferred by about a quarter and predominantly in milder cases, and might depend on geographical distribution. These results suggest the need for a well-designed randomized trial.

The role of corticosteroids in the management of chronic subdural hematoma: a systematic review.

The role of corticosteroids in the management of chronic subdural hematoma (CSDH) remains a matter of debate. Standard surgical treatment has recurrence rates reported between 4 and 26%. We reviewed the safety and effectiveness of corticosteroids both as a monotherapy and as an adjunct to surgery in patients with CSDH. PubMed-MEDLINE, EMBASE and Cochrane databases were searched in July 2011 for randomized controlled trials and for prospective and retrospective cohort studies, reporting on 10 or more adult patients with CSDH. Quality was assessed according to the STROBE checklist. Corticosteroid monotherapy and surgery with corticosteroids as an adjunct were compared with no treatment or surgery only, with regard to lethality, neurological outcome, secondary intervention and complications. Five observational studies were included in this review. There was no randomized allocation of treatment in any study. Secondary intervention rates ranged from 3 to 28%, lethality rates ranged from 0 to 13%, and good outcome was seen in 83-100%. Hyperglycemia occurred more often in patients treated with corticosteroids. In only two studies, one case of gastrointestinal bleeding was observed. Five observational studies suggest that corticosteroids might be beneficial in the treatment of CSDH; however, there is a lack of well-designed trials that support or refute the use of corticosteroids in CSDH. These results encourage further randomized clinical trials to establish the role of corticosteroids in CSDH.

Hypotension in anaesthetized patients during aneurysm clipping: not as bad as expected?

BACKGROUND: Patients with aneurysmal subarachnoid haemorrhage (SAH) often have disturbed autoregulation of cerebral blood flow. A reduction in systemic blood pressure during surgery may therefore lead to delayed cerebral ischaemia (DCI). To assess the incidence and severity of intra-operative hypotension, we performed a retrospective cohort study in 164 patients with recent SAH and surgical clipping of the aneurysm. METHODS: Intra-operative hypotension was defined in three levels of severity, as a decrease in mean arterial pressure (DeltaMAP) of more than 30%, 40% or 50% compared with the pre-operative pressure. For each patient the total amount of time with intra-operative hypotension was retrieved. Logistic regression analysis was performed to study the relation between intra-operative hypotension and the occurrence of DCI and poor outcome. RESULTS: A period with DeltaMAP>30% occurred in 128 patients (78%) with a median duration of this period of 105 min (25-75 per thousand 50-171 min). DeltaMAP>40% occurred in 88 patients (54%) and DeltaMAP>50% occurred in 22 patients (13%). In univariate analysis, DeltaMAP>50% was associated with poor outcome. After adjusting for age and World Federation of Neurological Surgeons grade, the association with poor outcome was no longer statistically significant [odds ratio (OR) 1.018; 95% CI 0.996-1.041]. CONCLUSION: Hypotension during surgical clipping of intracranial aneurysms occurred frequently. In our study population of patients mostly in good clinical condition, hypotension was not confirmed as an independent risk factor for DCI or poor outcome. Anaesthesia may have had a cerebral protective effect.

Current concepts of cerebral oxygen transport and energy metabolism after severe traumatic brain injury.

Before energy metabolism can take place, brain cells must be supplied with oxygen and glucose. Only then, in combination with normal mitochondrial function, sufficient energy (adenosine tri-phosphate (ATP)) can be produced. Glucose is virtually the sole fuel for the human brain. The brain lacks fuel stores and requires a continuous supply of glucose and oxygen. Therefore, continuous cerebral blood flow (CBF), cerebral oxygen tension and delivery, and normal mitochondrial function are of vital importance for the maintenance of brain function and tissue viability. This review focuses on three main issues: (1) Cerebral oxygen transport (CBF, and oxygen partial pressure (PO2) and delivery to the brain); (2) Energy metabolism (glycolysis, mitochondrial function: citric acid cycle and oxidative phosphorylation); and (3) The role of the above in the pathophysiology of severe head injury. Basic understanding of these issues in the normal as well as in the traumatized brain is essential in developing new treatment strategies. These issues also play a key role in interpreting data collected from monitoring techniques such as cerebral tissue PO2, jugular bulb oxygen saturation (SjvO2), near infra red spectroscopy (NIRS), microdialysis, intracranial pressure monitoring (ICP), laser Doppler flowmetry, and transcranial Doppler flowmetry--both in the experimental and in the clinical setting.

Hyperacute measurement of intracranial pressure, cerebral perfusion pressure, jugular venous oxygen saturation, and laser Doppler flowmetry, before and during removal of traumatic acute subdural hematoma.

OBJECT: The poor prognosis for traumatic acute subdural hematoma (ASDH) might be due to underlying primary brain damage, ischemia, or both. Ischemia in ASDH is likely caused by increased intracranial pressure (ICP) leading to decreased cerebral perfusion pressure (CPP), but the degree to which these phenomena occur is unknown. The authors report data obtained before and during removal of ASDH in five cases. METHODS: Five patients who underwent emergency evacuation of ASDH were monitored. In all patients, without delaying treatment, a separate surgical team (including the senior author) placed an ICP monitor and a jugular bulb catheter, and in two patients a laser Doppler probe was placed. The ICP prior to removing the bone flap in the five patients was 85, 85, 50, 59, and greater than 40 mm Hg, resulting in CPPs of 25, 3, 25, 56, and less than 50 mm Hg, respectively. Removing the bone flap as well as opening the dura and removing the blood clot produced a significant decrease in ICP and an increase in CPP. Jugular venous oxygen saturation (SjvO2) increased in four patients and decreased in the other during removal of the hematoma. Laser Doppler flow also increased, to 217% and 211% compared with preevacuation flow. CONCLUSIONS: Intracranial pressure is higher than previously suspected and CPP is very low in patients with ASDH. Removal of the bone flap yielded a significant reduction in ICP, which was further decreased by opening the dura and evacuating the hematoma. The SjvO2 as well as laser Doppler flow increased in all patients but one immediately after removal of the hematoma.

Impaired cerebral mitochondrial function after traumatic brain injury in humans.

OBJECT: Oxygen supply to the brain is often insufficient after traumatic brain injury (TBI), and this results in decreased energy production (adenosine triphosphate [ATP]) with consequent neuronal cell death. It is obviously important to restore oxygen delivery after TBI; however, increasing oxygen delivery alone may not improve ATP production if the patient's mitochondria (the source of ATP) are impaired. Traumatic brain injury has been shown to impair mitochondrial function in animals; however, no human studies have been previously reported. METHODS: Using tissue fractionation procedures, living mitochondria derived from therapeutically removed brain tissue were analyzed in 16 patients with head injury (Glasgow Coma Scale Scores 3-14) and two patients without head injury. Results revealed that in head-injured patients mitochondrial function was impaired, with subsequent decreased ATP production. CONCLUSIONS: Decreased oxygen metabolism due to mitochondrial dysfunction must be taken into account when clinically defining ischemia and interpreting oxygen measurements such as jugular venous oxygen saturation, arteriovenous difference in oxygen content, direct tissue oxygen tension, and cerebral blood oxygen content determined using near-infrared spectroscopy. Restoring mitochondrial function might be as important as maintaining oxygen delivery.

Neurobehavioral protection by the neuronal calcium channel blocker ziconotide in a model of traumatic diffuse brain injury in rats.

OBJECT: Abnormal accumulation of intracellular calcium following traumatic brain injury (TBI) is thought to contribute to a cascade of cellular events that lead to neuropathological conditions. Therefore, the possibility that specific calcium channel antagonists might exert neuroprotective effects in TBI has been of interest. The focus of this study was to examine whether Ziconotide produces such neuroprotective effects. METHODS: The authors report that the acceleration-deceleration model of TBI developed by Marmarou, et al., induces a long-lasting deficit of neuromotor and behavioral function. The voltage-sensitive calcium channel blocker Ziconotide (also known as SNX-111 and CI-1009) exerts neuroprotective effects in this model of diffuse brain injury (DBI) in rats. The dose and time of injection of Ziconotide chosen for the present study was based on the authors' previous biochemical studies of mitochondria. Rats were trained in a series of motor and memory tasks, following which they were subjected to DBI using the Marmarou, et al., model. At 3, 5, and 24 hours, all rats were injected with 2 mg/kg Ziconotide for a total cumulative dose of 6 mg/kg Ziconotide. Control brain-injured animals were injected with an equal volume of saline vehicle at each of these time points. The rats were tested for motor and cognitive performance at 1, 3, 7,14, 21, 28, 35, and 42 days postinjury. Saline-treated rats displayed severe motor and cognitive deficits after DBI. Compared with saline-treated control animals, rats treated with Ziconotide displayed better motor performance during inclined plane, beam balance, and beam walk tests; improved memory while in the radial arm maze; and improved learning while in the Morris water maze. CONCLUSIONS: These results demonstrated that the acceleration-deceleration model, which had been developed by Marmarou, et al., induces severe motor and cognitive deficits. We also demonstrated that Ziconotide exhibits substantial neuroprotective activity in this model of TBI. Improvement was observed in both motor and cognitive tasks, even though treatment was not initiated until 3 hours after injury. These findings support the development of neuronal N-type calcium channel antagonists as useful therapeutic agents in the treatment of TBI.

Improvement in mitochondrial dysfunction as a new surrogate efficiency measure for preclinical trials: dose-response and time-window profiles for administration of the calcium channel blocker Ziconotide in experimental brain injury.

OBJECT: Determining the efficacy of a drug used in experimental traumatic brain injury (TBI) requires the use of one or more outcome measures such as decreased mortality or fewer neurological and neuropsychological deficits. Unfortunately, outcomes in these test batteries have a fairly large variability, requiring relatively large sample sizes, and administration of the tests themselves is also very time consuming. The authors previously demonstrated that experimental TBI and human TBI induce mitochondrial dysfunction. Because mitochondrial dysfunction is easy to assess compared with neurobehavioral endpoints, it might prove useful as an outcome measure to establish therapeutic time windows and dose-response curves in preclinical drug testing. This idea was tested in a model of TBI in rats. METHODS: Animals treated with the selective N-type voltage-sensitive calcium channel blocker Ziconotide (also known as SNX-111 and CI-1009) after cortical impact displayed significant improvement in brain mitochondrial function. When a single intravenous bolus injection of 4 mg/kg Ziconotide was given at different time intervals, ranging from 15 minutes before injury to 10 hours after injury, mitochondrial function was improved at all time points, but more so between 2 and 6 hours postinjury. The authors evaluated the effects on mitochondrial function of Ziconotide at different doses by administering 0.5 to 6 mg/kg as a single bolus injection 4 hours after injury, and found 4 mg/kg to be the optimum dose. CONCLUSIONS: The authors established these time-window profiles and dose-response curves on the basis of mitochondrial outcome measures in a total of 42 rats because there were such low standard deviations in these tests. Establishing similar time-window profiles and dose-response curves by using neurobehavioral endpoints would have required using 114 rats in much more elaborate experiments.

Mitochondrial dysfunction after experimental traumatic brain injury: combined efficacy of SNX-111 and U-101033E.

We recently demonstrated that posttraumatic administration of the N-type calcium channel blocker SNX-111 (S) and a novel blood-brain barrier penetrating antioxidant U-101033E (U), significantly alleviated mitochondrial dysfunction induced by traumatic brain injury (TBI) in rats. The present study was designed to determine whether a combination of S and U, which act on different biochemical mechanisms of secondary brain injury, would be more efficacious than either drug alone. Brain mitochondria from injured and uninjured hemispheres were isolated and examined at 12 h post TBI induced by a severe controlled cortical impact injury. S at 1.0 mg/kg significantly increased both State 3 and 4 rates and produced a slight increase in P/O ratio, and there was virtually no change in RCI. U at 1.0 mg/kg did not show any protection. However, the combined treatment of S at 1.0 mg/kg and U at 1.0 mg/kg eliminated the uncoupling effect of S, and restored not only State 3 rates and P/O ratios but also RCI to near sham values. These results provide further evidence that both reactive oxygen species and perturbation of cellular calcium homeostasis participate in the pathogenesis of TBI-induced mitochondrial dysfunction, and support the idea of using combined therapy with lower drug doses.

The timing of congenital brachial plexus injury: a study of electromyography findings in the newborn piglet.

OBJECTIVE: Permanent congenital brachial plexus palsy is a recognized serious complication associated with shoulder dystocia. The timing and etiology of this injury remains controversial. Previous authorities have used adult-derived, non-brachial plexus data to extrapolate the anticipated timing for electromyographic denervation changes to date such injuries in the newborn. With use of a domestic swine model, this investigation tests the hypothesis that electromyographic evidence of brachial plexus denervation in the newborn is temporally different than that in the adult. STUDY DESIGN: Five healthy 2-day-old and two adult pigs underwent unilateral sharp transection of the brachial plexus. Daily electromyographic studies were performed in brachial plexus innervated muscle groups on the involved and contralateral (control) front limbs. Postmortem measurements of the transected nerve segments were obtained in one piglet and one adult animal. Representative hard copy recordings of individual electromyographic studies were collected. RESULTS: Immediately after surgical transection of the brachial plexus, no electromyographic evidence of denervation was observed. Uniformly in the newborn piglets, at 24 hours after transection, denervation in the form of fibrillation potentials, positive sharp waves, and complex repetitive discharges was seen. Serial testing demonstrated proximal to distal gradients of denervation over the next 24 to 48 hours. A delay in electromyographic evidence of denervation was observed in the two adult pigs until days 5 and 8, respectively. Control limb studies remained normal throughout the study period. Nerve length measurements for individual muscle groups were as follows for the adult and newborn pigs, respectively: deltoid 11.4 cm, 2.5 cm; cleidobrachialis 16.0 cm, 4.0 cm; triceps 15.5 cm, 4.5 cm; forelimb flexors 26.0 cm, 6.5 cm; and extensor carpi radialis 31.0 cm, 9.0 cm. CONCLUSION: Electromyographic evidence of brachial plexus denervation after surgical transection differs between the newborn and the adult pig. Consistent with wallerian degeneration, a correlation exists between length of the distal nerve segment and timing for electromyographic signs of denervation. These findings suggest it would be inappropriate to extrapolate the anticipated timing for electromyographic changes in the newborn on the basis of previously established adult non-brachial plexus data.

Mitochondrial dysfunction after experimental and human brain injury and its possible reversal with a selective N-type calcium channel antagonist (SNX-111).

We have recently demonstrated in a rat model that traumatic brain injury induces perturbation of cellular calcium homeostasis with an overload of cytosolic calcium and excessive calcium adsorbed on the mitochondrial membrane, consequently the mitochondrial respiratory chain-linked oxidative phosphorylation was impaired. We report the effect of a selective N-type calcium channel blocker, SNX-111 on mitochondrial dysfunction induced by a controlled cortical impact. Intravenous administration of SNX-111 at varying times post injury was made. The concentration titration profile revealed SNX-111 at 4 mg kg-1 to be optimal, and the time window to be administration at 4 h post-injury, in line with that reported on the effect of SNX-111 in experimental stroke. Under optimal conditions, SNX-111 significantly improved the mitochondrial respiratory chain-linked functions, such as the electron transfer activities with both succinate and NAD-linked substrates, and the accompanied energy coupling capacities measured as respiratory control indices (RCI) and ATP synthesis (P/O ratio), and the energy linked Ca2+ transport. In order to assess the applicability of these data to the clinical setting, we have initiated studies with brain tissue which has to be resected during surgical treatment. Five patients suffered from brain trauma, one from intracranial hypertension due to stroke (noninfarcted tissue was taken), and one from epilepsy. Our data revealed that brain mitochondria derived from the patient with intracranial hypertension and the patient with epilepsy were tightly coupled with good respiratory rates with glutamate and malate as substrates, and high P/O ratios. The rates of respiration and ATP synthesis were severely impaired in the brain mitochondria isolated from traumatized patients. These results indicate that investigation of brain mitochondrial functions can be used as a measure for trauma-induced impairment of brain energy metabolism. The time window for the effect of SNX-111 in mitochondrial function and the (preliminary) similarity between mitochondrial dysfunction in experimental animals and humans make the drug appear to be well suited for clinical trials in severe head injury.

Avoiding secondary brain injury after severe head trauma: monitoring and management.

Research has demonstrated that much of the mortality and morbidity in severely head-injured patients is due to secondary injury. The development of techniques to monitor cerebral blood flow, arteriovenous difference of oxygen or saturation of jugular venous blood flow with oxygen, and cerebral metabolic rate of oxygen has led to recognition, treatment, and prevention of secondary insults. This article examines the theoretical basis for the utilization of these techniques to guide the treatment of severely injured patients. Special emphasis is given to the factors governing both cerebral blood flow and cerebral blood volume, and how these factors can be monitored and manipulated to strike an optimal balance between the two. This information can aid in determining when it is safe to operate on patients with non-life-threatening conditions.