KCNA2 IgG autoimmunity in neuropsychiatric diseases.

BACKGROUND: Autoantibodies against the potassium voltage-gated channel subfamily A member 2 (KCNA2) have been described in a few cases of neuropsychiatric disorders, but their diagnostic and pathophysiological role is currently unknown, imposing challenges to medical practice. DESIGN / METHODS: We retrospectively collected comprehensive clinical and paraclinical data of 35 patients with KCNA2 IgG autoantibodies detected in cell-based and tissue-based assays. Patients' sera and cerebrospinal fluid (CSF) were used for characterization of the antigen, clinical-serological correlations, and determination of IgG subclasses. RESULTS: KCNA2 autoantibody-positive patients (n = 35, median age at disease onset of 65 years, range of 16-83 years, 74 % male) mostly presented with cognitive impairment and/or epileptic seizures but also ataxia, gait disorder and personality changes. Serum autoantibodies belonged to IgG3 and IgG1 subclasses and titers ranged from 1:32 to 1:10,000. KCNA2 IgG was found in the CSF of 8/21 (38 %) patients and in the serum of 4/96 (4.2 %) healthy blood donors. KCNA2 autoantibodies bound to characteristic anatomical areas in the cerebellum and hippocampus of mammalian brain and juxtaparanodal regions of peripheral nerves but reacted exclusively with intracellular epitopes. A subset of four KCNA2 autoantibody-positive patients responded markedly to immunotherapy alongside with conversion to seronegativity, in particular those presenting an autoimmune encephalitis phenotype and receiving early immunotherapy. An available brain biopsy showed strong immune cell invasion. KCNA2 autoantibodies occurred in less than 10 % in association with an underlying tumor. CONCLUSION: Our data suggest that KCNA2 autoimmunity is clinically heterogeneous. Future studies should determine whether KCNA2 autoantibodies are directly pathogenic or develop secondarily. Early immunotherapy should be considered, in particular if autoantibodies occur in CSF or if clinical or diagnostic findings suggest ongoing inflammation. Suspicious clinical phenotypes include autoimmune encephalitis, atypical dementia, new-onset epilepsy and unexplained epileptic seizures.

Transcranial sonography in ataxia.

Transcranial sonography (TCS) identifies basal ganglia alterations in extrapyramidal movement disorders such as Parkinson's disease or dystonia. Although only rarely reported, TCS also reveals signal alterations of basal ganglia in several forms of hereditary and nonhereditary ataxia. Here, the examination procedure and its diagnostic value for the classification of ataxia are reviewed. Three TCS studies reported hyperechogenicity of substantia nigra (SN) as a frequent finding in spinocerebellar ataxia type 2, type 3, and type 17, indicating a vulnerability of the nigrostriatal system in SCA patients. A new "cerebellar examination plane" was proposed, allowing better visualization of fourth ventricle enlargement and nucleus dentatus hyperechogenicity as a characteristic finding in SCA3 patients. In sporadic Creutzfeldt-Jakob disease, a blurry inhomogeneous hyperechogenic signal pattern of lentiform nucleus was identified in all of the patients in a small case series. Furthermore, distinct bilateral hyperechogenicity of pallidostriatal regions have been described as a novel diagnostic feature in the sonographic differentiation of extrapyramidal and atactic movement disorders. TCS is a commonly available, noninvasive, and inexpensive diagnostic tool, which provides reliable information about the morphology of the brain in ataxias, even in agitated patients who do not tolerate other imaging techniques. Further neuropathological and multimodal imaging studies are needed to elucidate the precise morphological and pathogenetic background of the detected echosignal pathology, and also to correlate these findings to the various clinical features of this disease entity.

Transcranial sonography in Huntington's disease.

Transcranial sonography (TCS) has become a reliable and sensitive diagnostic tool in the evaluation of extrapyramidal movement disorders, especially in the differentiation of Parkinsonian syndromes. Although only rarely reported, TCS reveals also signal alterations of basal ganglia in Huntington's disease (HD). Distinct findings are related to all of the three symptom domains of the clinical triad of the disease. The TCS finding of substantia nigra hyperechogenicity was related to higher clinical disease severity. A poorer cognitive performance correlated with larger width of third ventricle. Moreover, widths of frontal horns of lateral ventricles measured with TCS corresponded closely to diameters estimated by CT imaging. Depressive symptoms were found to be associated with abnormal echogenicity of mesencephalic raphe structures. Furthermore, a larger number of CAG repeats in the huntingtin gene correlated with presence of SN hyperechogenicity. This review provides information about the examination procedure and its diagnostic value in HD. Possible morphological and pathophysiological mechanisms leading to changes in the reflection of ultrasound waves are discussed in the context of established neuroimaging modalities.

Changes of contrast-specific ultrasonic cerebral perfusion patterns in the course of stroke; reliability of region-wise and parametric imaging analysis.

Ultrasound perfusion imaging (UPI) reliably detects size and localization of acute stroke. It remains unclear which time window detects, most sensitively and specifically, early changes of cerebral perfusion patterns and whether region-wise analysis is superior to parametric imaging analysis. Bilateral phase inversion harmonic imaging examinations (bolus kinetic, fitted model function) were performed twice (acutely and 28 h later) in 10 patients with acute ischemic stroke (<12 h). Examinations were evaluated using a region-wise analysis of the time-intensity curve and by parametric images of the time-to-peak intensity maps. Results were correlated in-between the ultrasound examinations and to follow-up cranial computed tomography (CCT) scans. Correlation between the early region-wise UPI examination and follow-up CCT was the strongest (Spearman correlation coefficient 0.76, sensitivity 84%, specificity 96%). Spearman coefficient between the late UPI examination and CCT was 0.51; sensitivity and specificity were 71% and 82%. Values in between UPI examinations were 57% and 88%, with a Spearman coefficient of 0.47 (p for all < 0.001). Values of the analysis of the parametric images were less strong. Concordance between both of the UPI methods was 65% in the early examination and 72% in the late examination. Changes of perfusion patterns are most accurately detected in the early course of stroke, when core of infarction can be differentiated from penumbra and viable tissue. Reperfusion phenomena may impair the diagnostic impact in later examinations. Parametric imaging does not yet seem to be as accurate as region-wise analysis.

Transcranial brain parenchyma sonography in movement disorders: state of the art.

The present paper summarizes recommendations on transcranial sonography (TCS) application in neurodegenerative diseases, resulting from a consensus meeting of the European Society of Neurosonology and Cerebral Hemodynamics. TCS of distinct infra- and supratentorial brain structures detects characteristic changes in several movement disorders, such as abnormal hyperechogenicity of substantia nigra (SN) in Parkinson's disease and of lenticular nucleus in dystonia, Wilson's disease and atypical Parkinsonian disorders. In healthy adults, the TCS finding of marked SN hyperechogenicity indicates a subclinical functional impairment of the nigrostriatal dopaminergic system. The finding of marked SN hyperechogenicity in combination with normal lenticular-nucleus echogenicity discriminates idiopathic Parkinson's disease from multiple-system atrophy and progressive supranuclear palsy with a positive predictive value of more than 90%. As TCS is a quick and noninvasive method, using the same duplex-ultrasound machines as for investigation of intracranial vessels, applicable even in agitated patients, this method has a great potential to be more widely used.

Contrast-enhanced ultrasonic parametric perfusion imaging detects dysfunctional tissue at risk in acute MCA stroke.

Ultrasonic perfusion imaging predicts size and localization of acute stroke. It is unclear whether irreversibly damaged tissue can be differentiated from tissue at risk. Thirty-four patients (ischemic stroke <12 h) were included (Phase Inversion Harmonic Perfusion Imaging; bolus kinetic; fitted model function). Three patterns of perfusion were defined in 14 prespecified regions of interest (ROI): 'normal', 'hypoperfusion', and 'no perfusion'. Clinical status was assessed using the National Institutes of Health Stroke Scale (NIHSS) (at baseline and at days 2 to 4). Cranial Computed Tomography (CCT) (days 2 to 4) displayed final infarction. The pattern 'hypoperfusion' (ROIs presumably representing tissue at risk) was tested twofold: (i) Functional impairment by correlating their number with baseline NIHSS. (ii) Viability by correlating their recruitment rate to infarction with clinical course (DeltaNIHSS days 2 to 4). In addition, various predictive values were assessed. Twenty-seven patients were eligible for analysis. The sum of ROIs with 'no perfusion' and 'hypoperfusion' correlated highest with baseline NIHSS (rho=0.78, P<0.001). Recruitment of hypoperfused ROIs to infarction highly correlated with clinical course (rho=0.79, P<0.001). Clinical course dichotomized the patients into subgroups A ('stable', DeltaNIHSS>or=-3) and B ('improved', DeltaNIHSS

Transcranial ultrasound brain perfusion assessment with a contrast agent-specific imaging mode: results of a two-center trial.

BACKGROUND AND PURPOSE: The purpose of this study was to assess brain perfusion with an ultrasound contrast-specific imaging mode and to prove if the results are comparable between 2 centers using a standardized study protocol. METHODS: A total of 32 individuals without known cerebrovascular disease were included in the study. Perfusion studies were performed ipsilaterally in an axial diencephalic plane after intravenous administration of 0.75 mL of Optison. Offline time intensity curves (TIC) were generated in different anatomic regions. Both centers used identical study protocols, ultrasound machines, and contrast agent. RESULTS: In both centers, the comparison of the parameter time to peak intensity (TPI) revealed significantly shorter TPIs in the main vessel structures compared with any parenchymal region of interest (ROI), whereas no significant differences were seen between the parenchymal ROIs. The parameter peak intensity (PI) varied widely interindividually in both centers, whereas the inter-ROI comparison revealed statistical significance (P < 0.05) in most of the cases according to the following pattern: (1) lentiforme nucleus > thalamus and white matter region, (2) thalamus > white matter region, and (3) main vessel > any parenchymal structure. Similar results were achieved in both centers independently. CONCLUSIONS: The study demonstrates that brain perfusion assessment with an ultrasound contrast-specific imaging mode is comparable between different centers using the same study protocol.

Conservative medical treatment and intravenous thrombolysis in acute stroke from carotid T occlusion.

BACKGROUND: We aimed to analyse the course of early recanalization and corresponding functional outcome in patients with an acute occlusion of the carotid T who were treated conservatively or underwent intravenous thrombolysis. METHODS: Forty-two patients with an acute occlusion of the carotid T within 6 h were recruited from consecutive admissions to a neurological department participating in the Duplex Sonography in Acute Stroke study. All patients underwent a standardized admission and follow-up procedure. Colour-coded duplex sonography was performed on admission, 30 min after thrombolysis, and at 6 and 24 h after onset of symptoms. Recanalization of the carotid T was classified as complete, partial and absent. Functional outcome was rated with the modified Rankin scale (mRS) at 3 months as favourable (mRS 0-2) or poor (mRS 3-6). RESULTS: Within 6 h, complete or partial recanalization occurred in 1 of 27 patients treated conservatively and in 6 of 15 thrombolysed patients. Intravenous thrombolysis predicted early recanalization also after adjustment for age, sex, cardioembolic stroke aetiology and time to treatment (adjusted odds ratio, OR, 39.7; 95% confidence interval, CI, 2.0-801.7; p = 0.016). An early recanalization was the only selected predictor of a favourable outcome (OR, 13.6; 95% CI, 1.0-179.0; p = 0.047) at regression analysis, and was achieved in 3 thrombolysed patients but in none with conservative medical treatment. CONCLUSIONS: In patients treated conservatively, functional outcome is poor and early recanalization rarely occurs. The latter can be achieved by intravenous thrombolysis with a rate comparable to that found at an intra-arterial approach without major intracranial bleeding complications. Early recanalization is associated with a better functional outcome.

Semiquantitative analysis of ultrasonic cerebral perfusion imaging.

The bolus kinetic in ultrasonic cerebral perfusion imaging is the most favored data acquisition and processing technique. However, there has not yet been convincing evidence for the potential to (semi-) quantitatively describe perfusion. Aim of this study was to determine the intraindividual range of relevant perfusion parameters to describe individual physiological cutoff scores. In 20 healthy volunteers, cerebral perfusion was evaluated using the bilateral approach with phase inversion harmonic imaging and the bolus kinetic. Relevant parameters (time-to-peak intensity, TPI; peak width, PW) were derived in 14 regions-of-interest in both hemispheres. The median and quartile deviation (QD) of these values were individually calculated. Within the 20 individuals, the mean QD of TPI was 0.68 s, and there was no case in which any TPI exceeded the mean more than 2 s. With PW, the mean QD was 1.2 s, and the mean was not exceeded by more than 6 s. Intraindividual perfusion parameters, especially TPI, show a considerable small range. Thus, the bolus kinetic derives reliable semiquantitative information once intraindividual comparison can be accomplished. We therefore propose that bilateral examination with the unaffected hemisphere as referential region should be performed in acute stroke. Future studies have to evaluate the potential of this approach of discriminating ischemia and hypoperfusion in the affected hemisphere.

Validation of the depletion kinetic in semiquantitative ultrasonographic cerebral perfusion imaging using 2 different techniques of data acquisition.

OBJECTIVE: To validate the potential of ultrasonographic depletion imaging for semiquantitatively visualizing cerebral parenchymal perfusion with contrast burst depletion imaging (CODIM) in comparison with phase inversion harmonic depletion imaging (PIDIM) in healthy volunteers. METHODS: Thirteen healthy adults were examined with both CODIM and PIDIM in accordance with previously described criteria. In addition to the perfusion coefficient, the time to decrease image intensity to 10% above equilibrium intensity from the initial value and the relative error (deviation of measured data from the fitted model) were evaluated to compare the reliability of both techniques in 3 different regions of interest. RESULTS: Perfusion coefficient values did not show significantly differing values in both groups (1.57-1.64 * 10(-2) s(-1) for CODIM and 1.42-1.58 * 10(-2) s(-1) for PIDIM). The relative error was significantly smaller in the PIDIM group (0.38-0.53 for CODIM and 0.18-0.25 for PIDIM; P < .002). CONCLUSIONS: Phase inversion harmonic depletion imaging proved to be more reliable than CODIM because values of the relative error were significantly lower in PIDIM even in this relatively small cohort. This is of interest because the underlying technique, phase inversion harmonic imaging, is more widely available than contrast burst imaging.

Reliability of semiquantitative ultrasonic perfusion imaging of the brain.

BACKGROUND AND PURPOSE: Contrast burst depletion imaging (CODIM) visualizes cerebral perfusion by destruction of microbubbles and observation of image intensity course. Because of its complexity, artifacts occur. Criteria of reliability to improve diagnostic significance were created and validated. METHODS AND RESULTS: Eighteen healthy volunteers were examined with 2 echo contrast agents (ECAs) and 3 frame rates in 3 regions of interest (ROIs). Perfusion coefficient (PC), Tmin (time to decrease intensity to 10% of its max), and relative error (RE) (deviation of measured data from fitted model) were determined. PC differed significantly neither between CA nor between frame rates (overall mean = 1.60 +/- 0.21 x 10(-2) s-1). Tmin differed significantly between frame rate groups (P < .001, 33.4 +/- 11.2 s/0.5 Hz; 3.6 +/- 2.5 s/5 Hz) since it is related to destruction of microbubbles that occurs with each frame and to the perfusion rate. RE was higher in the Optison group and tended to decrease in ROIs closer to the probe. CONCLUSIONS: PC was independent of frame rate and ECA. Tmin was shorter with higher frame rates. Due to a very rapid decay at 5 Hz, the ideal frame rate should be about 1 Hz, that is, because the number of frames acquired within Tmin and therefore signal-to-noise ratio is higher at 1 Hz. Since the algorithm is complex (high RE) and more artifacts should occur in patients (insufficient bone window, etc), a triggering of the insonations by, for example, heart rate could decrease artifacts and increase diagnostic power of CODIM.

Parameters of cerebral perfusion in phase-inversion harmonic imaging (PIHI) ultrasound examinations.

The aim was to evaluate phase-inversion harmonic imaging (PIHI) with respect to brain perfusion imaging using a novel "bilateral approach" (depth of examination: 150 mm) and established unilateral approach (100 mm). After bolus injection of two contrast agents (CA, Optison and SonoVue), perfusion-related parameters (time-to-peak intensity, Itpk, peak intensity, Ipk, and peak width, Wpk) were extracted by fitting a model function to time-intensity curves for different regions-of-interest (ROI) in 14 volunteers. In 207 (92%) of 224 ipsilateral ROIs and in 165 (98%) of 168 contralateral ROIs (372 or 95% of 392 altogether), parameters could be derived. Itpk and Wpk of gray matter ROIs did not vary in or between both CA groups (18.1-21.9 s and 7.9-14.2 s). ROIs within arteries showed significantly shorter Itpk (16.1-16.7 s) and longer Wpk (12.8-28.3 s). Level of significance was 0.05 (two-sided). Newer CAs are usable for nonlinear imaging over a wider range of acoustic intensities, so that sensitivity of PIHI is sufficient to image the brain bilaterally. This approach proves to be reliable in patients with adequate bone windows. For acute stroke patients, this implies that both hemispheres can be compared in one instead of two examinations, reducing time of examination by 50%. Furthermore, evaluation of regions close to the probe becomes possible. Thus, the "bilateral approach" should be considered as a new standard approach of acute ultrasonic perfusion imaging.

Brain perfusion imaging of a craniopharyngioma by transcranial duplex sonography.

BACKGROUND AND PURPOSE: The aim of this study was to test a new ultrasound software tool to assess pathological perfusion in a brain tumor patient. METHODS: Tissue harmonic imaging (THI) enables an improved depiction of brain morphology, employing nonlinear parenchyma and ultrasound contrast agent (UCA) backscatter information. With specialized software, morphological information can be separated from perfusion information. Both can be superimposed at a preferred mixing ratio in a single image. RESULTS: Using THI and a perfluoropropane-based UCA, a pathologic perfusion pattern described by abnormal perfused areas in the tumor region could be demonstrated. After superimposing morphologic and perfusion information, subtle structural tumor inhomogeneities were depicted. Craniopharyngioma structure and perfusion defect were confirmed by T2-weighted and perfusion-weighted magnetic resonance imaging. CONCLUSION: Transcranial duplex sonography in combination with contrast specific imaging methods might be helpful to visualize perfusion defects without loss of morphological information.

Contrast burst depletion imaging (CODIM): a new imaging procedure and analysis method for semiquantitative ultrasonic perfusion imaging.

BACKGROUND AND PURPOSE: Established methods of ultrasonic perfusion imaging using a bolus application of echo contrast agent provide only qualitative data because of various physical phenomena. This study was intended to investigate whether a new ultrasound perfusion imaging method termed contrast burst depletion imaging (CODIM) may provide semiquantitative measures of parenchymal perfusion independent of examination depth and acoustic energy distribution. METHODS: In a system with a constant concentration of contrast agent, analyzing the decrease in image intensity that occurs with microbubble-destructive imaging modes yields parameters that are considered to correlate with tissue perfusion. This method was first evaluated with a perfusion model that showed that the main resulting parameter "perfusion coefficient" (PC) is a monotonic nonlinear function of flow velocity. Seventeen human volunteers were then scanned according to this method with the use of 2 different contrast agents. Results were correlated with those from perfusion-weighted MRI examinations. RESULTS: The PC did not show significant differences in gray matter areas (ranging from 1.466x10(-2) x s(-1) to 1.641x10(-2) x s(-1)) of the brain despite different insonation depths (eg, ipsilateral and contralateral thalamus). In contrast, white matter exhibited significantly lower perfusion values in both imaging modes (PC: 0.604x10(-2) x s(-1) to 0.745x10(-2) x s(-1); P<0.05). CONCLUSIONS: CODIM is a promising new tool of imaging parenchymal (brain) perfusion in healthy persons. The method provides semiquantitative and depth-independent perfusion parameters and in this way overcomes the limitations of the perfusion methods using a bolus kinetic. Further investigations must be done to evaluate the potential of the method in patients with perfusion deficits.

Brain perfusion and ultrasonic imaging techniques.

Advances in neurosonology have generated several techniques of ultrasonic perfusion imaging employing ultrasound echo contrast agents (ECAs). Doppler imaging techniques cannot measure the low flow velocities that are associated with parenchymal perfusion. Ultrasonic perfusion imaging, therefore, is a combination of a contrast agent-specific ultrasound imaging technique (CAI) mode and a data acquisition and processing (DAP) technique that is suited to observe and evaluate the perfusion kinetics. The intensity in CAI images is a measure of ECA concentration but also depends on various other parameters, e.g. depth of examination. Moreover, ECAs can be destroyed by ultrasound, which is an artifact but can also be a feature. Thus, many different DAPs have been developed for certain CAI techniques, ECAs and target organs. Although substantial progress in ECA and CAI technology can be foreseen, ultrasound contrast imaging has yet to reliably differentiate between normal and pathological perfusion conditions. Destructive imaging techniques, such as contrast burst imaging (CBI) or time variance imaging (TVI), in combination with new DAP techniques provide sufficient signal-to-noise ratio (SNR) for transcranial applications, and consider contrast agent kinetics and destruction to eliminate depth dependency and to calculate semi-quantitative parameters. Since ultrasound machines are widely accessible and cost-effective, ultrasonic perfusion imaging techniques should become supplementary standard perfusion imaging techniques in acute stroke diagnosis and monitoring. This paper gives an overview on different CAI and DAP techniques with special focus on recent innovations and their clinical potential.

Comparison between echo contrast agent-specific imaging modes and perfusion-weighted magnetic resonance imaging for the assessment of brain perfusion.

BACKGROUND AND PURPOSE: Contrast burst imaging (CBI) and time variance imaging (TVI) are new ultrasonic imaging modes enabling the visualization of intravenously injected echo contrast agents in brain parenchyma. The aim of this study was to compare the quantitative ultrasonic data with corresponding perfusion-weighted MRI data (p-MRI) with respect to the assessment of brain perfusion. METHODS: Twelve individuals with no vascular abnormalities were examined by CBI and TVI after an intravenous bolus injection of 4 g galactose-based microbubble suspension (Levovist) in a concentration of 400 mg/mL. Complementary, a dynamic susceptibility contrast MRI, ie, p-MRI, of each individual was obtained. In both ultrasound (US) methods and p-MRI, time-intensity curves were calculated offline, and absolute time to peak intensities (TPI), peak intensities (PI), and peak width (PW) of US investigations and TPI, relative cerebral blood flow (CBF) and relative cerebral blood volume (CBV) of p-MRI examinations were determined in the following regions of interest (ROIs): lentiform nucleus (LN), white matter (WM), posterior (PT), and anterior thalamus (AT). In addition, the M(2) segment of the middle cerebral artery (MCA) was evaluated in the US, and the precentral gyrus (PG) was examined in the p-MRI examinations. In relation to a reference parenchymal ROI (AT), relative TPIs were compared between the US and p-MRI methods and relative PI of US investigations with the ratio of CBF (rCBF) of p-MRI examinations in identical ROIs. RESULTS: Mean TPIs varied from 18.3+/-5.0 (AT) to 20.1+/- 5.8 (WM) to 17.2+/-4.9 (MCA) seconds in CBI examinations and from 19.4+/-5.3 (AT) to 20.4+/-4.3 (WM) to 17.3+/-4.0 (MCA) seconds in TVI examinations. Mean PIs were found to vary from 581.9+/-342.4 (WM) to 1522.9+/-574.2 (LN) to 3400.9+/- 621.7 arbitrary units (MCA) in CBI mode and from 7.5+/-4.6 (WM) to 17.5+/-4.9 (LN) to 46.3+/-7.1 (MCA) arbitrary units in TVI mode. PW ranged from 7.3+/-4.5 (AT) to 9.1+/-4.0 (LN) to 24.3+/-12.8 (MCA) seconds in CBI examinations and from 7.1+/-3.9 (AT) to 8.7+/-3.5 (LN) to 26.7+/-18.2 (MCA) seconds in TVI examinations. Mean TPI was significantly shorter and mean PI and mean PW were significantly higher in the MCA compared with all other ROIs (P<0.05). Mean TPI of the p-MRI examinations ranged from 22.0+/-6.9 (LN) to 23.0+/-6.8 (WM) seconds; mean CBF ranged from 0.0093+/- 0.0041 (LN) to 0.0043+/-0.0021 (WM). There was no significant difference in rTPI in any ROI between US and p-MRI measurements (P>0.2), whereas relative PIs were significantly higher in areas with lower insonation depth such as the LN compared with rCBF. CONCLUSIONS: In contrast to PI, TPI and rTPI in US techniques are robust parameters for the evaluation of cerebral perfusion and may help to differentiate physiological and pathological perfusion in different parenchymal regions of the brain.