Manfred Kaps

Consensus on Microembolus Detection by TCD

Transcranial Doppler ultrasound is capable of detecting microembolic material, both gaseous and solid, within the intracranial cerebral arteries. To avoid discrediting this promising and exciting new technique, experts in this field met in January 1997 in Frankfurt, Germany, to discuss the limitations and problems of embolus detection and to determine guidelines for its proper use in clinical practice, as well as in scientific investigations. In particular, the authors suggest that studies report the following parameters: (1) ultrasound device, (2) transducer type and size, (3) insonated artery, (4) insonation depth, (5) algorithms for signal intensity measurement, (6) scale settings, (7) detection threshold, (8) axial extension of sample volume, (9) fast Fourier transform (FFT) size (number of points used), (10) FFT length (time), (11) FFT overlap, (12) transmitted ultrasound frequency, (13) high-pass filter settings, and (14) recording time. There was agreement that no current system of automatic embolus detection has the required sensitivity and specificity for clinical use.

Dual Antiplatelet Therapy With Clopidogrel and Aspirin in Symptomatic Carotid Stenosis Evaluated Using Doppler Embolic Signal Detection The Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) Trial

Background—Evidence for efficacy of dual antiplatelet therapy in stroke is limited. Symptomatic carotid stenosis patients are at high risk of early recurrent stroke. In this group, asymptomatic microembolic signals (MES), detected by transcranial Doppler ultrasound (TCD), are markers of future stroke and transient ischemic attack (TIA) risk. They offer a surrogate marker to evaluate antiplatelet therapy, but no multicenter study has evaluated the feasibility of this approach. Methods and Results—Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) is a randomized, double-blind study in subjects with recently symptomatic ≥50% carotid stenosis. Patients were screened with TCD, and if MES were detected, they were randomized to clopidogrel and aspirin or aspirin monotherapy. Repeated TCD recordings were made on days 2 and 7. MES were detected in 110 of 230 patients by online analysis at baseline, of whom 107 were randomized. Intention-to-treat analysis revealed a significant reduction in the primary end point: 43.8% of dual-therapy patients were MES positive on day 7, as compared with 72.7% of monotherapy patients (relative risk reduction 39.8%; 95% CI, 13.8 to 58.0; P=0.0046). The secondary end point of MES frequency per hour was reduced (compared with baseline) by 61.4% (95% CI, 31.6 to 78.2; P=0.0013) in the dual-therapy group at day 7 and by 61.6% (95% CI, 34.9 to 77.4; P=0.0005) on day 2. There were 4 recurrent strokes and 7 TIAs in the monotherapy group versus no stroke and 4 TIAs in the dual-therapy group that were treatment emergent and ipsilateral to the qualifying carotid stenosis; 2 additional ipsilateral TIAs occurred before treatment started. MES frequency was greater in the 17 patients with recurrent ipsilateral events compared with the 90 without (mean±SD: 24.4±27.7 versus 8.9±11.5 per hour; P=0.0003). Conclusions—In patients with recently symptomatic carotid stenosis, combination therapy with clopidogrel and aspirin is more effective than aspirin alone in reducing asymptomatic embolization. Doppler MES detection is a feasible method to evaluate the efficacy of antiplatelet therapy in multicenter studies.

Evidence for a direct association between cortical atrophy and cognitive impairment in relapsing–remitting MS

Cognitive deficits affecting memory, attention and speed of information processing are common in multiple sclerosis (MS). The mechanisms of cognitive impairment remain unclear. Here, we examined the association between neuropsychological test performance and brain atrophy in a group of mildly disabled patients with relapsing-remitting MS. We applied voxel-based morphometry (SPM2) to investigate the distribution of brain atrophy in relation to cognitive performance. Patients had lower scores than control subjects on tests of memory and executive function, including the PASAT, Digit Span Backward and a test of short-term verbal memory (Memo). Among patients, but not healthy controls, performance on the PASAT, a comprehensive measure of cognitive function and reference task for the cognitive evaluation of MS-patients, correlated with global grey matter volume as well as with grey matter volume in regions associated with working memory and executive function, including bilateral prefrontal cortex, precentral gyrus and superior parietal cortex as well as right cerebellum. Compared to healthy subjects, patients showed a volume reduction in left temporal and prefrontal cortex, recently identified as areas predominantly affected by diffuse brain atrophy in MS. A comparison of low performers in the patient group with their matched control subjects showed more extensive and bilateral temporal and frontal volume reductions as well as bilateral parietal volume loss, compatible with the progression of atrophy found in more advanced MS-patients. These findings indicate that MS-related deficits in cognition are closely associated with cortical atrophy.

Potential and Limitations of Transcranial Color-Coded Sonography in Stroke Patients

BACKGROUND AND PURPOSE Transcranial color-coded duplex sonography (TCCS) enables visualization of the intracranial parenchymal structures and measurement of blood flow velocity in the basal cerebral arteries. The present study aims to evaluate prospectively the clinical usefulness of TCCS in patients with acute stroke. METHODS Eighty-four consecutive patients with central nervous symptoms suggesting acute stroke were investigated within the first 48 hours after clinical onset. TCCS was performed with a 2.5-MHz sector transducer through the temporal bone window. CT was available in all patients. RESULTS Forty-eight patients suffered from an infarction or a transient ischemic attack (TIA) in the territory of the middle cerebral artery (MCA). Fifteen of them showed an MCA occlusion, and 12 of the 15 developed recanalization during follow-up. Twelve revealed an increased, decreased, or oscillating flow pattern in the MCA main stem, and 21 patients had no ultrasonic abnormalities. The positive and negative predictive values of a pathological flow pattern in patients with MCA infarctions or TIA were .92 and .48, respectively. Fifteen patients suffered from an intracerebral hematoma, which could be diagnosed by TCCS in 14 cases. The positive and negative predictive values of a pathological parenchymal echo pattern were .88 and .96, respectively. Three patients suffered from an infarction and one from a TIA in the posterior cerebral artery territory. One female patient with an acute deterioration of a hemiparesis showed a glioma. The dropout rate due to an insufficient acoustic temporal bone window was 20% (17/84). CONCLUSIONS TCCS is a noninvasive bedside method that provides rapid and reliable data regarding stroke subtype and mechanism immediately after onset. Window failure is a serious limitation of this method.

A comparison of transesophageal echocardiography and transcranial Doppler sonography with contrast medium for detection of patent foramen ovale.

Background Patent foramen ovale as a possible stroke risk factor can be diagnosed with transcranial Doppler sonography (TCD) by detecting intravenous contrast medium crossing from the right to the left atrium. The present study evaluates the reliability of this method. Summary of Report We performed TCD and transesophageal echocardiography simultaneously in 50 patients using galactose microbubbles. We observed bubble signals passing the middle cerebral artery in 7 patients less than 20 seconds after injection; we found positive TCD tests in 14 patients using the Valsalva maneuver. With transesophageal echocardiography patent foramen ovale could be detected in 15 patients (sensitivity, 0.93; specificity, 1; P<.01). Conclusions TCD with echo contrast is a reliable screening tool for patent foramen ovale. A standardized procedure including the Valsalva maneuver is essential to prevent false-negative results.

Practice Standards for Transcranial Doppler Ultrasound: Part I—Test Performance

Indications for the clinical use of transcranial Doppler (TCD) continue to expand while scanning protocols and quality of reporting vary between institutions. Based on literature analysis and extensive personal experience, an international expert panel started the development of guidelines for TCD performance, interpretation, and competence. The first part describes complete diagnostic spectral TCD examination for patients with cerebrovascular diseases. Cranial temporal bone windows are used for the detection of the middle cerebral arteries (MCA), anterior cerebral arteries (ACA), posterior cerebral arteries (PCA), C1 segment of the internal carotid arteries (ICA), and collateralization of flow via the anterior (AComA) and posterior (PComA) communicating arteries; orbital windows—for the ophthalmic artery (OA) and ICA siphon; the foraminal window—for the terminal vertebral (VA) and basilar (BA) arteries. Although there is a significant individual variability of the circle of Willis with and without disease, the complete diagnostic TCD examination should include bilateral assessment of the M2 (arbitrarily located at 30‐40 mm depth), M1 (40‐65 mm) MCA [with M1 MCA mid‐point at 50 mm (range 45‐55 mm), average length 16 mm (range 5‐24 mm), A1 ACA (60‐75 mm), C1 ICA (60‐70 mm), P1‐P2 PCA (average depth 63 mm (range 55‐75 mm), AComA (70‐80 mm), PComA (58‐65 mm), OA (40‐50 mm), ICA siphons (55‐65 mm), terminal VA (40‐75 mm), proximal (75‐80), mid (80‐90 mm), and distal (90‐110 mm) BA]. The distal ICA on the neck (40‐60 mm) can be located via submandibular windows to calculate the VMCA/VICA index, or the Lindegaard ratio for vasospasm grading after subarachnoid hemorrhage. Performance goals of diagnostic TCD are to detect and optimize arterial segment‐specific spectral waveforms, determine flow direction, measure cerebral blood flow velocities and flow pulsatility in the above‐mentioned arteries. These practice standards will assist laboratory accreditation processes by providing a standard scanning protocol with transducer positioning and orientation, depth selection and vessel identification for ultrasound devices equipped with spectral Doppler and power motion Doppler.

Autoimmunity against the β2 adrenergic receptor and muscarinic-2 receptor in complex regional pain syndrome

Summary Complex regional pain syndrome patient sera contain functional active autoantibodies against the β2 adrenergic receptor and muscarinic‐2 receptor, supporting the concept of an autoimmune etiology in CRPS. ABSTRACT Complex regional pain syndrome (CRPS) is a painful condition affecting one or more extremities of the body, marked by a wide variety of symptoms and signs that are often difficult to manage because the pathophysiology is incompletely understood. Thus, diverse treatments might be ineffective. A recent report revealed the presence of autoantibodies against differentiated autonomic neurons in CRPS patients. However, it remained unclear how the antibodies act in the development of CRPS. We therefore aimed to characterize these antibodies and identify target antigens. Functional properties of affinity‐purified immunoglobulin G of control subjects or CRPS patients were assessed using a cardiomyocyte bioassay. Putative corresponding receptors were identified using antagonistic drugs, and synthesized peptide sequences corresponding to segments of these receptors were used to identify the target epitopes. Chinese hamster ovary cells were transfected with putative receptors to ensure observed binding. Further, changes in the intracellular Ca2+ concentration induced by agonistic immunoglobulin G were measured using the Ca2+‐sensitive fluorescent dye fura‐2 assay. Herein, we demonstrate the presence of autoantibodies in a subset of CRPS patients with agonistic‐like properties on the β2 adrenergic receptor and/or the muscarinic‐2 receptor. We identified these autoantibodies as immunoglobulin G directed against peptide sequences from the second extracellular loop of these receptors. The identification of functionally active autoantibodies in serum samples from CRPS patients supports an autoimmune pathogenesis of CRPS. Thus, our findings contribute to the further understanding of this disease, could help in the diagnosis in future, and encourage new treatment strategies focusing on the immune system.

Noninvasive Quantification of Brain Edema and the Space-Occupying Effect in Rat Stroke Models Using Magnetic Resonance Imaging

Background and Purpose— Brain edema is a life-threatening consequence of stroke and leads to an extension of the affected tissue. The space-occupying effect due to brain edema can be quantified in rat stroke models with the use of MRI. The present study was performed to test 2 hypotheses: (1) Can quantification of the space-occupying effect due to brain edema serve as a noninvasive measure for brain water content? (2) Does morphometric assessment of brain swelling allow determination of true infarct size on MRI after correction for the space-occupying effect of edema? Methods— Thirty rats were subjected to permanent suture middle cerebral artery occlusion. MRI was performed after 6 or 24 hours, and hemispheric swelling was assessed morphometrically. Interobserver and intraobserver agreements were determined for MRI measurements. In study I, the space-occupying effect due to brain edema was correlated with the absolute brain water content by the wet/dry method. In study II, lesion volumes corrected and uncorrected for edema were calculated on MRI and on TTC staining and compared. Results— Interobserver and intraobserver agreements for MRI measurements were excellent (r ≥0.97). Brain water content and hemispheric swelling correlated well after 6 and 24 hours (r ≥0.95). Corrected lesion volumes correlated with r =0.78 between TTC staining and MRI. Without edema correction, lesion volumes were overestimated by 20.3% after 6 hours and by 29.6% after 24 hours of ischemia. Conclusions— Morphometric assessment of hemispheric swelling on MRI can determine the increase in absolute brain water content noninvasively and can also provide ischemic lesion volumes corrected for brain edema.

Training of executive functions in Parkinson's disease

Cognitive disturbances are common in Parkinsons disease (PD). Examination of cognitive function often reveals deficits in executive functions, including maintenance and inhibition of attention, flexibility in thinking, and planning. The involvement of the dopaminergic system in cognitive executive functions has been suggested by numerous studies. The aim of the present study was to analyze the effect of cognitive training on cognitive performance of PD-patients (N=26). Half of the patients participated in a cognitive training regimen, while the other patients only received standard treatment. The outcome showed improved performance of the group with cognitive treatment in two executive tasks after the training period, while no improvement was seen in the standard-treatment group. The results indicate that specific training is required for improvement of executive functions, while general rehabilitation is not sufficient. Thus, PD-patients might benefit from a short-term cognitive executive function training program that is tailored to the individual patients needs.

Transcranial Doppler ultrasound findings in middle cerebral artery occlusion.

We evaluated the efficacy of transcranial Doppler ultrasonography in 23 patients suffering from acute middle cerebral artery occlusion. The diagnosis of occlusion was most suggestive when all basal arteries except the affected middle cerebral artery were detectable. Enhanced blood flow velocity in the anterior cerebral artery due to leptomeningeal collateralization was used as a corroborating criterion. With frequent follow-up examinations, we monitored reperfusion of the M1 segment resulting from recanalization or embolus migration in 16 patients. Those patients undergoing recanalization within days after onset of the first symptoms revealed variable clinical courses and lesion patterns on computed tomography, indicating the crucial importance of early and efficient leptomeningeal collateral blood supply. Transcranial Doppler ultrasonography was able to exclude middle cerebral artery occlusion with accuracy, which provides important clinical information. However, distal branch occlusions could not be detected with sufficient exactness.