Arnd Doerfler

Blockade of TNF-α rapidly inhibits pain responses in the central nervous system

There has been a consistent gap in understanding how TNF-α neutralization affects the disease state of arthritis patients so rapidly, considering that joint inflammation in rheumatoid arthritis is a chronic condition with structural changes. We thus hypothesized that neutralization of TNF-α acts through the CNS before directly affecting joint inflammation. Through use of functional MRI (fMRI), we demonstrate that within 24 h after neutralization of TNF-α, nociceptive CNS activity in the thalamus and somatosensoric cortex, but also the activation of the limbic system, is blocked. Brain areas showing blood-oxygen level-dependent signals, a validated method to assess neuronal activity elicited by pain, were significantly reduced as early as 24 h after an infusion of a monoclonal antibody to TNF-α. In contrast, clinical and laboratory markers of inflammation, such as joint swelling and acute phase reactants, were not affected by anti-TNF-α at these early time points. Moreover, arthritic mice overexpressing human TNF-α showed an altered pain behavior and a more intensive, widespread, and prolonged brain activity upon nociceptive stimuli compared with wild-type mice. Similar to humans, these changes, as well as the rewiring of CNS activity resulting in tight clustering in the thalamus, were rapidly reversed after neutralization of TNF-α. These results suggest that neutralization of TNF-α affects nociceptive brain activity in the context of arthritis, long before it achieves anti-inflammatory effects in the joints.

Small interfering RNA-mediated xCT silencing in gliomas inhibits neurodegeneration and alleviates brain edema

Neurodegeneration and brain edema are hallmarks of human malignant brain tumors. Here we show that genetic or pharmacological inhibition of the glutamate transporter xCT (Xc− system, encoded by SLC7a11) in vivo leads to abrogated neurodegeneration, attenuated perifocal edema and prolonged survival. These results show a crucial role for xCT in glioma-induced neurodegeneration and brain edema, corroborating the concept that edema formation may be in part a consequence of peritumoral cell death.

Imaging of sellar and parasellar lesions

The sellar and parasellar region is an anatomically complex area where a number of neoplastic, infectious, inflammatory, developmental and vascular pathologies can occur. Differentiation among various etiologies may not always be easy, since many of these lesions may mimic the clinical, endocrinologic and radiologic presentations of pituitary adenomas. The diagnosis of sellar lesions involves a multidisciplinary effort, and detailed endocrinologic, ophthalmologic and neurologic testing are essential. CT and, mainly, MRI are the imaging modalities to study and characterise normal anatomy and the majority of pathologic processes in this region. We here provide an overview of the most relevant MRI and CT characteristics together with clinical findings of pituitary tumors, vascular, inflammatory and infectious lesions found in the sellar/parasellar region in order to propose an appropriate differential diagnosis.

Brain Tissue Water Uptake after Middle Cerebral Artery Occlusion Assessed with CT

Background and Purpose. To study whether computed tomography (CT) can measure the water content of early ischemic edema. Methods. The authors obtained cranial CT in 5 groups of rats subjected to 1 hour (n = 8),2 hours (n = 11),3 hours (n = 13),4 hours (n = 13), or 6 hours (n = 14) of right middle cerebral artery (MCA) occlusion. Immediately after CT, the authors removed the rats’ brains and determined tissue water content by the dry‐wet weight method. They correlated brain x‐ray attenuation with brain tissue water content. Results. Mean brain tissue water content remained constant in the nonischemic left hemispheres at 77.9%± 0.6% and increased up to 79.3%± 1.0% in the right hemispheres after 6 hours of permanent right MCA occlusion. X‐ray attenuation remained constant in the left hemispheres at 75.6 ± 2.2 Hounsfield units (HU) and decreased to 71.7 ± 3.4 HU in the right hemispheres after 6 hours of right MCA occlusion. The decrease in x‐ray attenuation correlated significantly with the increase in ischemic brain tissue water content (y= 217.3 – 1.8 ×x; r= .55, P < .0001). That means that a 1% increase in hemispheric tissue water content causes a decrease in x‐ray attenuation of 1.8 HU. Conclusions. After MCA occlusion, immediate brain tissue net water uptake is associated with a decrease in x‐ray attenuation. CT can monitor ischemic edema in an acute stroke.

The angiotensin II type 1-receptor blocker candesartan increases cerebral blood flow, reduces infarct size, and improves neurologic outcome after transient cerebral ischemia in rats

The goal of the present study was to test the impact of administration time of the angiotensin II type 1–receptor blocker candesartan on cerebral blood flow (CBF), infarct size, and neuroscore in transient cerebral ischemia. Therefore, 1-hour middle cerebral artery occlusion (MCAO) was followed by reperfusion. Rats received 0.5-mg/kg candesartan intravenously 2 hours before MCAO (pretreatment), 24 hours after MCAO, every 24 hours after MCAO, or 2 hours before and every 24 hours after MCAO. Infarct size (mm3) and a neuroscore at day 7 were compared with controls. CBF was quantified by radiolabeled microspheres and laser-Doppler flowmetry. Compared with controls (95 ± 8), infarct size in candesartan-treated groups was smaller (59 ± 5, 68 ± 10, 28 ± 3, and 15 ± 3, respectively; P < 0.05). Although there was no difference in neuroscore between pretreatment and controls (1.55 ± 0.18, 1.80 ± 0.13), other treatment regimens resulted in improved neuroscores (1.33 ± 0.16, 1.11 ± 0.11, 0.73 ± 0.15; P < 0.05). CBF in pretreated animals at 0.5 hours after MCAO was significantly higher than in controls (0.58 ± 0.09 mL · g−1 ·· min−1 and 44% ± 7% of baseline compared with 0.49 ± 0.06 mL · g−1 ·· min−1 and 37% ± 6%, microspheres and laser-Doppler flowmetry; P < 0.05). Thus, candesartan reduces infarct size even if administered only during reperfusion. Apart from pretreatment, other treatment regimens result in significantly improved neuroscores. In the acute phase of cerebral ischemia, candesartan increases CBF.

Clinical outcome and neuropsychological deficits after right decompressive hemicraniectomy in MCA infarction

Abstract.Background and Purpose: The purpose of this study was to analyse in detail the functional outcome and the neuropsychological deficits in patients with space-occupying infarction of the non-dominant hemisphere one year after surgery. Methods: Postoperative complications and retrospective consent to surgery were assessed in a semi-structured interview in 26 patients. Functional outcome was measured with the Barthel-Index (BI) and Rankin-Scale. Neuropsychological tests in 14 patients focused on visuo-spatial and visuo-constructive abilities, attention, spatial span and self-rated mood. Results: The one-year survival rate was 69 % (18 of 26). The functional outcome was good (BI ≥ 90) in 3 patients, fairly good (BI 75–85) in 6, moderate (BI 30–70) in 6, and poor (BI 0–25) in 3 patients. Age was an independent predictor of outcome, patients above 52 years had a BI of 50 or below. Neuropsychological tests (14 of 18) showed profound attention deficits in all patients, and visuo-spatial and visuo-constructive deficits in patients with lower formal education. Retrospectively, 4 of 18 patients would not give consent to surgery again, mostly because of the bad quality of life postoperatively. Conclusion: Older patients do not seem to benefit from decompressive hemicraniectomy; more than half of the surviving younger patients have a good outcome and live independently. Attention deficits are prominent in all patients; visuo-spatial and constructive deficits are less pronounced in patients with higher formal education. Retrospective agreement to decompressive hemicraniectomy is high in patients with good functional outcome.

Flat Detector CT in the Evaluation of Brain Parenchyma, Intracranial Vasculature, and Cerebral Blood Volume: A Pilot Study in Patients with Acute Symptoms of Cerebral Ischemia

BACKGROUND AND PURPOSE: The viability of both brain parenchyma and vascular anatomy is important in estimating the risk and potential benefit of revascularization in patients with acute cerebral ischemia. We tested the hypothesis that when used in conjunction with IV contrast, FD-CT imaging would provide both anatomic and physiologic information that would correlate well with that obtained by using standard multisection CT techniques. MATERIALS AND METHODS: Imaging of brain parenchyma (FD-CT), cerebral vasculature (FD-CTA), and cerebral blood volume (FD-CBV) was performed in 10 patients. All patients also underwent conventional multisection CT, CTA, CTP (including CBV, CTP-CBV), and conventional catheter angiography. Correlation of the corresponding images was performed by 2 experienced neuroradiologists. RESULTS: There was good correlation of the CBV color maps and absolute values between FD-CBV and CTP-CBV (correlation coefficient, 0.72; P < .001). The Bland-Altman test showed a mean difference of CBV values between FD-CT and CTP-CBV of 0.04 ± 0.55 mL/100 mL. All vascular lesions identified with standard CTA were also visualized with FD-CTA. Visualization of brain parenchyma by using FD-CT was poor compared with that obtained by using standard CT. CONCLUSIONS: Both imaging of the cerebral vasculature and measurements of CBV by using FD-CT are feasible. The resulting vascular images and CBV measurements compared well with ones made by using standard CT techniques. The ability to measure CBV and also visualize cerebral vasculature in the angiography suite may offer significant advantages in the management of patients. FD-CT is not yet equivalent to CT for imaging of brain parenchyma.

Natural Course of Perihemorrhagic Edema After Intracerebral Hemorrhage

Background and Purpose— There is only limited knowledge on the time course of perihemorrhagic edema (PHE) after intracerebral hemorrhage (ICH). We aimed to investigate the chronological PHE course and its relation to in-hospital mortality in a large retrospective ICH cohort. Methods— Patients with supratentorial ICH treated at our institution between 2006 and 2009, who had received at least 3 CT scans in the course of conservative treatment, were included in the present analysis. PHE at Days 1, 2, 3, 4 to 6, 7 to 11, 12 to 16, 17 to 21, and >22 was assessed using a threshold based semiautomatic volumetric algorithm. A chart review was performed to achieve data on duration of stay, ventilation, treatment with external ventricular drains, and in-hospital mortality. Results— Two hundred nineteen patients aged 69.9±10.5 years with deep (n=103) or lobar (n=116) ICH were included in the study. Mean ICH volume was 35.7±31.5 mL. Mean absolute PHE volume significantly increased from initially 32.6±29.9 mL to 63.7±46.7 mL at Days 7 to 11. No significant changes were observed at later time points. ICH volume was strongly correlated with absolute PHE volume (&rgr;=0.8, P<0.001) and inversely correlated with relative PHE (&rgr;=−0.4 to −0.5, P<0.001). Increase in absolute PHE between Days 1 and 3 was significantly predictive for in-hospital mortality (P=0.014, ExpB=1.04). Conclusions— PHE develops early after ICH and doubles within the first 7 to 11 days after the initial bleeding event. This additional mass effect may contribute to secondary clinical deterioration and mortality, especially in larger ICH. Because of its inverse correlation with ICH volume, relative PHE may not be suitable for analyses considering the clinical impact of PHE.

Flat Panel Detector Angiographic CT for Stent-Assisted Coil Embolization of Broad-Based Cerebral Aneurysms

BACKGROUND AND PURPOSE: The purpose of this work was to evaluate angiographic CT (ACT) in the combined application of a self-expanding neurovascular stent and detachable platinum coils in the management of broad-based and fusiform intracranial aneurysms. MATERIALS AND METHODS: Eleven patients harboring wide-necked intracranial aneurysms were treated with a flexible self-expanding neurovascular stent and subsequent aneurysm embolization with platinum microcoils. ACT was performed after the interventional procedure to analyze stent position and the relationship of coils to the stent. Postprocessing included multiplanar reconstructions (MPRs) and maximum intensity projections (MIPs). ACT volume datasets were postprocessed for soft tissue visualization. RESULTS: Accurate stent placement with subsequent coil occlusion of the aneurysms was feasible in all of the patients. Similar to nonsubtracted digital subtraction angiography (DSA) images, radiopaque platinum stent markers showed excellent visibility in ACT as well. The stent struts themselves, hardly visible in nonsubtracted DSA, were visible in MPRs and MIPs of ACT in all of the patients. In aneurysms larger than 10 mm in diameter, accurate stent assessment at the level of the coils was limited due to beam hardening artifacts. Postprocedural ACT in all of the patients did not reveal any evidence of procedure-related intracranial hemorrhage. CONCLUSION: ACT provides cross-sectional, 3D visualization of endovascular stents otherwise hardly visible with plain fluoroscopy. ACT enables us to accurately determine stent position, which may be helpful in complex stent-assisted aneurysm coiling procedures. However, in aneurysms larger than 10 mm in diameter, beam hardening artifacts caused by the endoaneurysmal coil package impair visibility of the stent. Further data are necessary to evaluate the usefulness of ACT in stent-assisted aneurysm coiling.

Intraventricular Fibrinolysis and Lumbar Drainage for Ventricular Hemorrhage

Background and Purpose— Both intraventricular fibrinolysis (IVF) and lumbar drainage (LD) may reduce the need for exchange of external ventricular drainage (EVD) and shunt surgery in patients with intracerebral hemorrhage and severe intraventricular hemorrhage. We investigated the feasibility and safety of IVF followed by early LD for the treatment of posthemorrhagic hydrocephalus. Methods— This prospective study included patients with spontaneous ganglionic intracerebral hemorrhage and severe intraventricular hemorrhage with acute obstructive posthemorrhagic hydrocephalus who received an EVD (n=32). The treatment algorithm started with IVF (4 mg recombinant tissue plasminogen activator every 12 hours) until clearance of the third and fourth ventricles from blood. Thereupon, EVD was clamped and if clamping was unsuccessful, communicating posthemorrhagic hydrocephalus was assumed and LD placed. EVD was removed if there was neither an increase of intracranial pressure nor ventricle enlargement on CT. A ventriculoperitoneal shunt was indicated if “LD weaning” was unsuccessful for >10 days. Outcome was assessed at 90 and 180 days using the modified Rankin Scale. Results— IVF resulted in fast clearance of the third and fourth ventricles (73±50 hours). However, early EVD removal was only possible in 4 patients. The remaining 28 patients developed communicating posthemorrhagic hydrocephalus. In all of these patients, early LD was capable to replace EVD. EVD exchange was not necessary and EVD duration was 105±59 hours. Only one patient required a ventriculoperitoneal shunt. At 180 days, 20 (62.5%) patients had a good (modified Rankin Scale 0 to 3) outcome and 5 (15.6%) patients had died. One patient had asymptomatic ventricular rebleeding. Conclusions— In patients with secondary intraventricular hemorrhage and posthemorrhagic hydrocephalus, the combined treatment approach of IVF and early LD is safe and feasible, avoids EVD exchange, and may markedly reduce the need for shunt surgery.