Marc Saake

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.

Perfusion MRI: The Five Most Frequently Asked Technical Questions

OBJECTIVE This and its companion article address the 10 most frequently asked questions that radiologists face when planning, performing, processing, and interpreting different MR perfusion studies in CNS imaging. CONCLUSION Perfusion MRI is a promising tool in assessing stroke, brain tumors, and patients with neurodegenerative diseases. Most of the impediments that have limited the use of perfusion MRI can be overcome to allow integration of these methods into modern neuroimaging protocols.

Safety and Outcome after Thrombolysis in Stroke Patients with Mild Symptoms

Background: Thrombolytic therapy is frequently withheld in patients with minor stroke symptoms. However, recent studies demonstrate that a substantial proportion of these patients dies or remains permanently disabled because of underestimation of symptom severity at baseline or secondary deterioration. We aimed to assess the safety and outcome of thrombolysis therapy in patients with minor but disabling stroke symptoms. Methods: 32 patients presenting with mild symptoms were treated with intravenous recombinant tissue-type plasminogen activator between April 2006 and April 2008. Data were extracted from a prospectively collected database. Baseline demographic data, and clinical, laboratory and imaging findings were analyzed. Outcome was assessed using the modified Rankin Scale (mRS) score at 3 months and was dichotomized into favorable (mRS 0–1) versus unfavorable (mRS 2–6). Results: In the majority of patients, the left hemisphere was affected, with aphasia representing the most common symptom leading to treatment decision. The frequency of perfusion lesion (46%) and vessel occlusion (35%) at baseline was high but had no effect on the outcome at 3 months in our series of treated patients. Outcome was favorable in 94% of patients, and 47% recovered without any persisting symptom. Only one asymptomatic and no symptomatic hemorrhage was observed. Conclusion: Our data support current guidelines and international licenses which give no lower National Institutes of Health Stroke Scale (NIHSS) limit for intravenous thrombolysis (IVT). Considering the accumulating evidence that the natural course in patients with mild symptoms is not as favorable as often assumed and taking the low risk of bleeding in those patients into account, patients with mild but disabling symptoms should be treated with IVT regardless of their baseline NIHSS score.

Optimized intravenous Flat Detector CT for non-invasive visualization of intracranial stents: first results

ObjectiveAs stents for treating intracranial atherosclerotic stenosis may develop in-stent re-stenosis (ISR) in up to 30%, follow-up imaging is mandatory. Residual stenosis (RS) is not rare. We evaluated an optimised Flat Detector CT protocol with intravenous contrast material application (i.v. FD-CTA) for non-invasive follow-up.MethodsIn 12 patients with intracranial stents, follow-up imaging was performed using i.v. FD-CTA. MPR, subtracted MIP and VRT reconstructions were used to correlate to intra-arterial angiography (DSA). Two neuroradiologists evaluated the images in anonymous consensus reading and calculated the ISR or RS. Correlation coefficients and a Wilcoxon test were used for statistical analysis.ResultsIn 4 patients, no stenosis was detected. In 6 patients RS and in two cases ISR by intima hyperplasia perfectly visible on MPR reconstructions of i.v. FD-CTA were detected. Wilcoxon’s test showed no significant differences between the methods (p > 0.05). We found a high correlation with coefficients of the pairs DSA/ FD-CT MIP r = 0.91, DSA/ FD-CT MPR r = 0.82 and FD-CT MIP/ FD-CT MPR r = 0.8.ConclusionIntravenous FD-CTA could clearly visualise the stent and the lumen, allowing ISR or RS to be recognised. FD-CTA provides a non-invasive depiction of intracranial stents and might replace DSA for non-invasive follow-up imaging.

Clinical evaluation of flat-panel detector compared with multislice computed tomography in 65 patients with acute intracranial hemorrhage: initial results. Clinical article.

OBJECT The goal in this study was to compare flat-panel detector (FD) CT with multislice (MS) CT in the visualization of intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), intraventricular hemorrhage, and external ventricular drains (EVDs) to evaluate the diagnostic quality and limitations of the new FD CT imaging modality. METHODS Neuroimages obtained in 65 patients, including 24 with EVDs, were reviewed by 2 independent, experienced clinicians. Lesions in all patients were investigated with FD CT and MS CT. The numbers of slices positive for ICH and SAH were counted, and for ICH the diameter and area of the lesion was measured. The positioning of drains was assessed. The presence of ventricular blood was noted. Statistical analysis was performed by calculating the Pearson correlation coefficient (r) to evaluate the level of inter- and intraobserver agreement, and linear regression analysis was done to visualize the results of the numbers of ICH- and SAH-positive slices. RESULTS The authors found high interobserver agreement regarding the number of slices with evidence of ICH (r = 0.89 for MS CT, r = 0.78 for FD CT) and SAH (r = 0.88 for MS CT, r = 0.9 for FD CT). Thin layers of blood in the ventricles were not detected on FD CT in 36.4% of cases. Six of 7 perimesencephalic SAHs were not seen on FD CT scans. The EVDs could be assessed with both modalities in 83.3% of cases, but the position of the drain could not be determined with FD CT in 16.7% (4 of 24 cases). CONCLUSIONS In some respects, FD CT is of limited use for the visualization of intracranial hemorrhage. However, despite limited contrast resolution, ICH and EVDs can be reliably demonstrated. Perimesencephalic SAH and thin layers of blood in the occipital horns may not be detected using FD CT. Further evaluation and improvement of the image quality is necessary before FD CT will provide identical quality in comparison with MS CT.

Semi-automatic volumetric assessment of perihemorrhagic edema with computed tomography.

Background and purpose:  Magnetic resonance imaging (MRI) shows perihemorrhagic edema (PHE) after intracerebral hemorrhage (ICH) with high contrast, but the procedure is often difficult or not available for clinical use. The aim of the present study was to establish and validate an observer independent method for quantification of PHE on computed tomography (CT) by comparing with simultaneously performed MRI.

Association of brain functional magnetic resonance activity with response to tumor necrosis factor inhibition in rheumatoid arthritis

OBJECTIVE To test whether brain activity predicts the response to tumor necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA). Since clinical and laboratory parameters have proven unsuccessful in predicting response, we followed a radically different concept, hypothesizing that response to TNFi depends on central nervous system activity rather than the clinical signs of disease. METHODS Sequential testing by functional magnetic resonance imaging (MRI) of the brain, anatomic MRI of the hand, and clinical assessment of arthritis were carried out in 10 patients with active RA before and 3, 7, and 28 days after the start of TNFi treatment. RESULTS Baseline demographic and disease-specific parameters were identical in TNFi responders and nonresponders. The mean ± SEM decrease in the Disease Activity Score in 28 joints after 28 days was -1.8 ± 0.3 in TNFi responders (n = 5) and -0.2 ± 0.1 in nonresponders (n = 5). Responders showed significantly higher baseline activation in thalamic, limbic, and associative areas of the brain than nonresponders. Moreover, brain activity decreased within 3 days after TNFi exposure in the responders, preceding clinical responses (day 7) and responses observed on the anatomic hand MRI (day 28). CONCLUSION These data suggest that response to TNFi depends on brain activity in RA patients, reflecting the subjective perception of disease.

Angiographic CT with intravenous contrast agent application for monitoring of intracranial flow diverting stents

IntroductionIntracranial flow diverting devices are increasingly used to treat cerebral aneurysms. A reliable, non-invasive follow-up modality would be desirable. Our aim was to compare intra-arterial digital subtraction angiography (ia DSA) to angiographic computed tomography with intravenous contrast agent application (iv ACT) in the visualisation of flow diverting devices and aneurysm lumina.MethodsFollow-up monitoring by iv ACT (n = 36) and ia DSA (n = 25) in 14 patients treated with flow diverting devices for intracranial aneurysms was evaluated retrospectively. Images were evaluated by two neuroradiologists in anonymous consensus reading regarding the device deployment, wall apposition, neck coverage of the aneurysm, opacification of the vessel and device lumen, as well as the degree of aneurysm occlusion.ResultsCorresponding ia DSA and iv ACT images were scored identically in all patients regarding the stent deployment, wall apposition and neck coverage, as well as the degree of aneurysm occlusion and patency status of the device and parent artery. Opacification of the parent vessel lumen and perfused parts of the aneurysm was considered slightly inferior for iv ACT in comparison with ia DSA (seven of 36 cases), without impact on diagnosis.ConclusionsWe demonstrated the feasibility and diagnostic value of iv ACT in follow-up imaging of intracranial flow diverting devices. Due to its high spatial resolution and non-invasive character, this novel technique might become a valuable imaging modality in these patients.

Optimized angiographic computed tomography with intravenous contrast injection: an alternative to conventional angiography in the follow-up of clipped aneurysms?

OBJECT The purpose of this study was to evaluate the diagnostic accuracy of an optimized angiographic CT (ACT) program with intravenous contrast agent injection (ivACT) in the assessment of potential aneurysm remnants after neurosurgical clipping compared with conventional digital subtraction angiography (DSA). METHODS The authors report on 14 patients with 19 surgically clipped cerebral aneurysms who were scheduled to undergo angiographic follow-up. For each patient, the authors performed ivACT with dual rotational acquisition and conventional angiography including a 3D rotational run. The ivACT and 3D DSA data were reconstructed with different imaging modes, including a newly implemented subtraction mode with motion correction. Thereafter, the data sets were merged by the dual-volume technique, and freely rotatable 3D images were obtained for further analysis. Observed aneurysm remnants were electronically measured and classified for each modality by 2 experienced neuroradiologists. RESULTS Digital subtraction angiography and ivACT both provided high-quality images without motion artifacts. Artifact disturbances from the aneurysm clips led to a compromised, but still sufficient, image quality in 1 case. The ivACT assessed all aneurysm remnants as true-positive up to a minimal size of 2.6×2.4 mm in accordance with the DSA findings. There was a tendency for ivACT to overestimate the size of the aneurysm remnants. All cases without aneurysm remnants on DSA were scored correctly as true-negative by ivACT. CONCLUSIONS By using an optimized image acquisition protocol as well as enhanced postprocessing algorithms, the noninvasive ivACT seems to achieve results comparable to those of conventional angiography in the follow-up of clipped cerebral aneurysms. The authors have shown that ivACT can provide reliable diagnostic information about potential aneurysm remnants after neurosurgical clipping with high sensitivity and specificity, sufficient for clinical decision making, at least for aneurysms in the anterior circulation located distal to the internal carotid artery. These preliminary results may be a promising step to replace conventional angiography by a noninvasive imaging technique in selected cases after aneurysm clipping.

Brain correlates of short‐term habituation to repetitive electrical noxious stimulation

Habituation to repetitive noxious stimuli is a well‐known phenomenon. We investigated brain correlates of habituation to pain in a transdermal electrical pain model using functional magnetic resonance imaging (fMRI).