Karl-Titus Hoffmann

Long-term effects of pallidal deep brain stimulation in tardive dystonia

Objective: High-frequency stimulation of the globus pallidus internus (GPi) is a highly effective therapy in primary dystonia. Recent reports have also demonstrated almost immediate improvement of motor symptoms in patients with tardive dystonia after pallidal deep brain stimulation (DBS). Here, we show the long-term effect of continuous bilateral GPi DBS in tardive dystonia on motor function, quality of life (QoL), and mood. Methods: Nine consecutive patients undergoing DBS for tardive dystonia were assessed during continuous DBS at 3 time points: 1 week, 3 to 6 months, and last follow-up at the mean of 41 (range 18–80) months after surgery using established and validated movement disorder and neuropsychological scales. Clinical assessment was performed by a neurologist not blinded to the stimulation settings. Results: One week and 3 to 6 months after pallidal DBS, Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS) motor scores were ameliorated by 56.4 ± 26.7% and 74.1 ± 15.8%, BFMDRS disability scores by 62.5 ± 21.0% and 88.9 ± 10.3%, and Abnormal Involuntary Movement Scale (AIMS) scores by 52.3 ± 24.1% and 69.5 ± 27.6%, respectively. At last follow-up, this improvement compared with the presurgical assessment was maintained as reflected by a reduction of BFMDRS motor scores by 83.0 ± 12.2%, BFMDRS disability scores by 67.7 ± 28.0%, and AIMS scores by 78.7 ± 19.9%. QoL improved significantly in physical components, and there was a significant improvement in affective state. Furthermore, cognitive functions remained unchanged compared with presurgical status in the long-term follow-up. No permanent adverse effects were observed. Conclusion: Pallidal deep brain stimulation is a safe and effective long-term treatment in patients with medically refractory tardive dystonia.

Pallidal and thalamic deep brain stimulation in myoclonus-dystonia.

Deep brain stimulation (DBS) of the internal globus pallidus (GPi) and ventral intermediate thalamic nucleus (VIM) are established treatment options in primary dystonia and tremor syndromes and have been reported anecdotally to be efficacious in myoclonus‐dystonia (MD). We investigated short‐ and long‐term effects on motor function, cognition, affective state, and quality of life (QoL) of GPi‐ and VIM‐DBS in MD. Ten MD‐patients (nine ε‐sarcoglycan‐mutation‐positive) were evaluated pre‐ and post‐surgically following continuous bilateral GPi‐ and VIM‐DBS at four time points: presurgical, 6, 12, and as a last follow‐up at a mean of 62.3 months postsurgically, and in OFF‐, GPi‐, VIM‐, and GPi‐VIM‐DBS conditions by validated motor [unified myoclonus rating scale (UMRS), TSUI Score, Burke‐Fahn‐Marsden dystonia rating scale (BFMDRS)], cognitive, affective, and QoL‐scores. MD‐symptoms significantly improved at 6 months post‐surgery (UMRS: 61.5%, TSUI Score: 36.5%, BFMDRS: 47.3%). Beneficial effects were sustained at long‐term evaluation post‐surgery (UMRS: 65.5%, TSUI Score: 35.1%, BFMDRS: 48.2%). QoL was significantly ameliorated; affective status and cognition remained unchanged postsurgically irrespective of the stimulation conditions. No serious long‐lasting stimulation‐related adverse events (AEs) were observed. Both GPi‐ and VIM‐DBS offer equally effective and safe treatment options for MD. With respect to fewer adverse, stimulation‐induced events of GPi‐DBS in comparison with VIM‐DBS, GPi‐DBS seems to be preferable. Combined GPi‐VIM‐DBS can be useful in cases of incapaciting myoclonus, refractory to GPi‐DBS alone.

Multisite longitudinal reliability of tract-based spatial statistics in diffusion tensor imaging of healthy elderly subjects

Large-scale longitudinal neuroimaging studies with diffusion imaging techniques are necessary to test and validate models of white matter neurophysiological processes that change in time, both in healthy and diseased brains. The predictive power of such longitudinal models will always be limited by the reproducibility of repeated measures acquired during different sessions. At present, there is limited quantitative knowledge about the across-session reproducibility of standard diffusion metrics in 3T multi-centric studies on subjects in stable conditions, in particular when using tract based spatial statistics and with elderly people. In this study we implemented a multi-site brain diffusion protocol in 10 clinical 3T MRI sites distributed across 4 countries in Europe (Italy, Germany, France and Greece) using vendor provided sequences from Siemens (Allegra, Trio Tim, Verio, Skyra, Biograph mMR), Philips (Achieva) and GE (HDxt) scanners. We acquired DTI data (2 × 2 × 2 mm(3), b = 700 s/mm(2), 5 b0 and 30 diffusion weighted volumes) of a group of healthy stable elderly subjects (5 subjects per site) in two separate sessions at least a week apart. For each subject and session four scalar diffusion metrics were considered: fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial (AD) diffusivity. The diffusion metrics from multiple subjects and sessions at each site were aligned to their common white matter skeleton using tract-based spatial statistics. The reproducibility at each MRI site was examined by looking at group averages of absolute changes relative to the mean (%) on various parameters: i) reproducibility of the signal-to-noise ratio (SNR) of the b0 images in centrum semiovale, ii) full brain test-retest differences of the diffusion metric maps on the white matter skeleton, iii) reproducibility of the diffusion metrics on atlas-based white matter ROIs on the white matter skeleton. Despite the differences of MRI scanner configurations across sites (vendors, models, RF coils and acquisition sequences) we found good and consistent test-retest reproducibility. White matter b0 SNR reproducibility was on average 7 ± 1% with no significant MRI site effects. Whole brain analysis resulted in no significant test-retest differences at any of the sites with any of the DTI metrics. The atlas-based ROI analysis showed that the mean reproducibility errors largely remained in the 2-4% range for FA and AD and 2-6% for MD and RD, averaged across ROIs. Our results show reproducibility values comparable to those reported in studies using a smaller number of MRI scanners, slightly different DTI protocols and mostly younger populations. We therefore show that the acquisition and analysis protocols used are appropriate for multi-site experimental scenarios.

PET/MR in dementia and other neurodegenerative diseases

The spectrum of neurodegenerative diseases covers the dementias, parkinsonian syndromes, Huntington disease, amyotrophic lateral sclerosis, and prion diseases. In these entities, brain MRI is often used in clinical routine to exclude other pathologies and to demonstrate specific atrophy patterns. [18F]FDG PET delivers early and sensitive readouts of neural tissue loss, and more specific PET tracers currently in use clinically target β-amyloid plaques or dopaminergic deficiency. The recent integration of PET into MR technology offers a new chance to improve early and differential diagnosis of many neurodegenerative diseases. Initial evidence in the literature is available to support this notion. New emerging PET tracers, such as tracers that bind to tau or α-synuclein aggregates, as well as MR techniques, like diffusion-tensor imaging, resting-state functional MRI, and arterial spin labeling, have the potential to broaden the diagnostic capabilities of combined PET/MRI to image dementias, Parkinson disease, and other neurodegenerative diseases. The ultimate goal is to establish combined PET/MRI as a first-line imaging technique to provide, in a one-stop-shop fashion with improved patient comfort, all biomarker information required to increase diagnostic confidence toward specific diagnoses. The technical challenge of accurate PET data attenuation correction within PET/MRI systems needs yet to be solved. Apart from the projected clinical routine applications, future research would need to answer the questions of whether combined brain PET/MRI is able to improve basic research of neurodegenerative diseases and antineurodegeneration drug testing.

Longitudinal reproducibility of default-mode network connectivity in healthy elderly participants: A multicentric resting-state fMRI study.

To date, limited data are available regarding the inter-site consistency of test-retest reproducibility of functional connectivity measurements, in particular with regard to integrity of the Default Mode Network (DMN) in elderly participants. We implemented a harmonized resting-state fMRI protocol on 13 clinical scanners at 3.0T using vendor-provided sequences. Each site scanned a group of 5 healthy elderly participants twice, at least a week apart. We evaluated inter-site differences and test-retest reproducibility of both temporal signal-to-noise ratio (tSNR) and functional connectivity measurements derived from: i) seed-based analysis (SBA) with seed in the posterior cingulate cortex (PCC), ii) group independent component analysis (ICA) separately for each site (site ICA), and iii) consortium ICA, with group ICA across the whole consortium. Despite protocol harmonization, significant and quantitatively important inter-site differences remained in the tSNR of resting-state fMRI data; these were plausibly driven by hardware and pulse sequence differences across scanners which could not be harmonized. Nevertheless, the tSNR test-retest reproducibility in the consortium was high (ICC=0.81). The DMN was consistently extracted across all sites and analysis methods. While significant inter-site differences in connectivity scores were found, there were no differences in the associated test-retest error. Overall, ICA measurements were more reliable than PCC-SBA, with site ICA showing higher reproducibility than consortium ICA. Across the DMN nodes, the PCC yielded the most reliable measurements (≈4% test-retest error, ICC=0.85), the medial frontal cortex the least reliable (≈12%, ICC=0.82) and the lateral parietal cortices were in between (site ICA). Altogether these findings support usage of harmonized multisite studies of resting-state functional connectivity to characterize longitudinal effects in studies that assess disease progression and treatment response.

High-Resolution Mechanical Imaging of Glioblastoma by Multifrequency Magnetic Resonance Elastography

Objective To generate high-resolution maps of the viscoelastic properties of human brain parenchyma for presurgical quantitative assessment in glioblastoma (GB). Methods Twenty-two GB patients underwent routine presurgical work-up supplemented by additional multifrequency magnetic resonance elastography. Two three-dimensional viscoelastic parameter maps, magnitude |G*|, and phase angle φ of the complex shear modulus were reconstructed by inversion of full wave field data in 2-mm isotropic resolution at seven harmonic drive frequencies ranging from 30 to 60 Hz. Results Mechanical brain maps confirmed that GB are composed of stiff and soft compartments, resulting in high intratumor heterogeneity. GB could be easily differentiated from healthy reference tissue by their reduced viscous behavior quantified by φ (0.37±0.08 vs. 0.58±0.07). |G*|, which in solids more relates to the materials stiffness, was significantly reduced in GB with a mean value of 1.32±0.26 kPa compared to 1.54±0.27 kPa in healthy tissue (P = 0.001). However, some GB (5 of 22) showed increased stiffness. Conclusion GB are generally less viscous and softer than healthy brain parenchyma. Unrelated to the morphology-based contrast of standard magnetic resonance imaging, elastography provides an entirely new neuroradiological marker and contrast related to the biomechanical properties of tumors.

Diffusion tensor imaging in hydrocephalus—findings before and after shunt surgery

BackgroundTo evaluate changes in diffusion tensor imaging (DTI)-derived parameters in patients with hydrocephalus (HC) before and several weeks after shunt surgery.MethodsThirteen HC patients were examined with DTI before and after shunt surgery. In a combined region of interest and whole brain voxel-based analysis, different DTI parameters were compared with an age-matched control group.ResultsAlteration of DTI parameters in HC patients and changes after shunt surgery are regionally different. HC patients show an increase in fractional anisotropy values based on increases in parallel diffusivity in the corticospinal tract. On the other hand, reduced fractional anisotropy values are found in the corpus callosum of HC patients. Following shunt surgery, all DTI parameters showed a trend towards normalization, yet differences to healthy control subjects remained.ConclusionOur results show that DTI parameter changes are regionally dependent and need a careful interpretation of the underlying diffusivities to serve as a diagnostic or follow-up measure in patients with hydrocephalus.

Distance to Thrombus in Acute Middle Cerebral Artery Occlusion A Predictor of Outcome After Intravenous Thrombolysis for Acute Ischemic Stroke

Background and Purpose— In patients with acute middle cerebral artery (MCA) stroke, therapeutic decisions are influenced by the location of the occlusion. This study aimed to analyze clinical outcomes in patients with acute ischemic MCA stroke treated with systemic intravenous thrombolysis (IVT) using recombinant tissue plasminogen activator, according to the location of the occlusion. Methods— Of 621 patients screened, 136 with acute stroke and MCA occlusion confirmed by CT angiography were retrospectively included in this study. The distance from the carotid T to the thrombus (DT) on coronal maximum intensity projection images and the thrombus length were measured. The correlation between DT and the modified Rankin Scale score at 90 days was analyzed. Results— DT was an independent predictor of clinical outcome in stroke patients treated with IVT. A long DT was significantly correlated with a good clinical outcome (modified Rankin Scale score at 90 days ⩽2). A poor clinical outcome was exponentially more likely than a good outcome when the DT was <16 mm (P<0.001). The thrombus length was not correlated with the modified Rankin Scale score at 90 days. A long thrombus (>8 mm) occurred significantly more often in the proximal MCA than the distal MCA (P<0.001). Conclusion— DT is an independent predictor of clinical outcome in patients with acute MCA occlusion treated with IVT. In acute stroke with MCA occlusion confirmed by CT angiography and DT <16 mm, the likelihood of a good clinical outcome after treatment with IVT was exponentially <50%. This might warrant the evaluation of other therapy forms than IVT in patients with proximal MCA occlusion.

Partial-Volume Effect Correction Improves Quantitative Analysis of 18F-Florbetaben β-Amyloid PET Scans

Neocortical atrophy reduces PET signal intensity, potentially affecting the diagnostic efficacy of β-amyloid (Aβ) brain PET imaging. This study investigated whether partial-volume effect correction (PVEC), adjusting for this atrophy bias, improves the accuracy of 18F-florbetaben Aβ PET. Methods: We analyzed 18F-florbetaben PET and MRI data obtained from 3 cohorts. The first was 10 patients with probable Alzheimer disease (AD) and 10 age-matched healthy controls (HCs), the second was 31 subjects who underwent in vivo imaging and postmortem histopathology for Aβ plaques, and the third was 5 subjects who underwent PET and MRI at baseline and 1 y later. The imaging data were coregistered and segmented. PVEC was performed using the voxel-based modified Müller-Gärtner method (PVELab, SPM8). From the PET data, regional and composite SUV ratios (SUVRs) with and without PVEC were obtained. In the MRI data, mesial temporal lobe atrophy was determined by the Scheltens mesial temporal atrophy scale and gray matter volumes by voxel-based morphometry. Results: In cohort 1, PVEC increased the effect on AD-versus-HC discrimination from a Cohen d value of 1.68 to 2.0 for composite SUVRs and from 0.04 to 1.04 for mesial temporal cortex SUVRs. The PVEC-related increase in mesial temporal cortex SUVR correlated with the Scheltens score (r = 0.84, P < 0.001), and that of composite SUVR correlated with the composite gray matter volume (r = −0.75, P < 0.001). In cohort 2, PVEC increased the correlation coefficient between mesial temporal cortex SUVR and histopathology score for Aβ plaque load from 0.28 (P = 0.09) to 0.37 (P = 0.03). In cohort 3, PVEC did not affect the composite SUVR dynamics over time for the Aβ-negative subject. This finding was in contrast to the 4 Aβ-positive subjects, in 2 of whom PVEC changed the composite SUVR dynamics. Conclusion: The influence of PVEC on 18F-florbetaben PET data is associated with the degree of brain atrophy. Thus, PVEC increases the ability of 18F-florbetaben PET to discriminate between AD patients and HCs, to detect Aβ plaques in the atrophic mesial temporal cortex, and potentially to evaluate changes in brain Aβ load over time. As such, the use of PVEC should be considered for quantitative 18F-florbetaben PET scans, especially in assessing patients with brain atrophy.

Cerebellar manifestation of PML under fumarate and after efalizumab treatment of psoriasis

Fumaric acid, first applied topically in psoriasis, has also been used orally since the mid-1980s. A preparation of dimethyl fumarate, BG-12, reduces disease activity in multiple sclerosis (MS) [2] and has been licensed, with recent market introduction in Europe. Despite common lymphopenia, no serious opportunistic infections had been attributed to it before two recent cases of progressive multifocal leukoencephalopathy (PML) [1, 9], with two more cases on file with the manufacturer [8]. We report details of one of these additional cases. A Caucasian man, diagnosed with psoriasis in 1995, received local corticosteroids and occasionally steroid tablets, vitamin D3-analogues, UVB therapy, and acitretin. Treatment with efalizumab (2006–2007) was satisfactory, but discontinued for superficial spreading malignant melanoma on the cheek (Clark-level II, excision in sano). Oral fumarate (Fumaderm , Biogen-Idec) was initiated in 2007 (Fig. 1, top panel). He was referred in July 2010 with a two-month history of slurred speech, unstable walking, and progressive decline in left-sided coordination that eventually left him unable to climb stairs. Examination showed left-sided hemiataxia and dysarthria without motor, sensory, or cognitive impairment. On brain magnetic resonance imaging (MRI, Fig. 1 bottom panel), lesions in the left cerebellar peduncle and pons enhanced with gadolinium. Polymerase chain reaction (qPCR) detected [2,000 copies of JCV-DNA/ml (Universities Leipzig, Düsseldorf) in the cerebrospinal fluid (CSF), which was otherwise normal. Peripheral blood analysis revealed lymphopenia, CD4? T cell deficiency (131/ll), and reduced IgG concentration (Fig. 1, middle panel). After exclusion of malignoma, HIV, and tuberculosis, lymphopenia was regarded as fumarate-induced. We discontinued fumarate, substituted immunoglobulin, and initiated mirtazapine [5] in August 2010. Clinical course stabilized and improved to walking for 20 min with bilateral assistance. In October 2010, an acute lower respiratory tract infection led to clinical worsening, but resolved with antibiotic treatment. In March 2011, JCVPCR of CSF was reported negative (University Leipzig). In September 2011, walking distance decreased to 410 m with walking frame; brain MRI showed a new, non-enhancing lesion in the right cerebellar peduncle; CSF JCV-PCR detected 19 copies/ml (NIH), identifying only the virulent ‘‘prototype’’, with undetectable non-virulent ‘‘archetype’’. Since deterioration was gradual rather than acute, and in the absence of Gd-enhancing lesions, the relapse was not considered PML-associated ‘‘immune reconstitution induced syndrome’’ (PML-IRIS). Treatment with M. Stoppe E. Thomä J. Claßen F. Then Bergh (&) Department of Neurology, University of Leipzig, Liebigstraße 20, 04103 Leipzig, Germany e-mail: ThenBerF@medizin.uni-leipzig.de