Clinical Significance of Diffusion Tensor Imaging in Metachromatic Leukodystrophy.

BACKGROUND: Metachromatic leukodystrophy (MLD) is a lysosomal enzyme deficiency disorder leading to progressive demyelination and, consecutively, to cognitive and motor decline. Brain magnetic resonance imaging (MRI) can detect affected white matter as T2 hyperintense areas but cannot quantify the gradual microstructural process of demyelination more accurately. Our study aimed to investigate the value of routine MR diffusion tensor imaging in assessing disease progression. METHODS: MR diffusion parameters (apparent diffusion coefficient [ADC] and fractional anisotropy [FA]) were in the frontal white matter, central region (CR), and posterior limb of the internal capsule in 111 MR datasets from a natural history study of 83 patients (age: 0.5-39.9 years; 35 late-infantile, 45 juvenile, 3 adult, with clinical diffusion sequences of different scanner manufacturers) as well as 120 controls. Results were correlated with clinical parameters reflecting motor and cognitive function. RESULTS: ADC values increase and FA values decrease depending on disease stage/severity. They show region-specific correlations with clinical parameters of motor and cognitive symptoms, respectively. Higher ADC levels in CR at diagnosis predicted a disease course with more rapid motor deterioration in juvenile MLD patients. In highly organized tissues such as the corticospinal tract, in particular, diffusion MR parameters were highly sensitive to MLD-associated changes and did not correlate with the visual quantification of T2 hyperintensities. CONCLUSION: Our results show that diffusion MRI can deliver valuable, robust, clinically meaningful, and easily obtainable/accessible/available parameters in the assessment of prognosis and progression of MLD. Therefore, it provides additional quantifiable information to established methods such as T2 hyperintensity.

The Power of LC-MS Based Multiomics: Exploring Adipogenic Differentiation of Human Mesenchymal Stem/Stromal Cells.

The molecular study of fat cell development in the human body is essential for our understanding of obesity and related diseases. Mesenchymal stem/stromal cells (MSC) are the ideal source to study fat formation as they are the progenitors of adipocytes. In this work, we used human MSCs, received from surgery waste, and differentiated them into fat adipocytes. The combination of several layers of information coming from lipidomics, metabolomics and proteomics enabled network analysis of the biochemical pathways in adipogenesis. Simultaneous analysis of metabolites, lipids, and proteins in cell culture is challenging due to the compound's chemical difference, so most studies involve separate analysis with unimolecular strategies. In this study, we employed a multimolecular approach using a two-phase extraction to monitor the crosstalk between lipid metabolism and protein-based signaling in a single sample (~105 cells). We developed an innovative analytical workflow including standardization with in-house produced 13C isotopically labeled compounds, hyphenated high-end mass spectrometry (high-resolution Orbitrap MS), and chromatography (HILIC, RP) for simultaneous untargeted screening and targeted quantification. Metabolite and lipid concentrations ranged over three to four orders of magnitude and were detected down to the low fmol (absolute on column) level. Biological validation and data interpretation of the multiomics workflow was performed based on proteomics network reconstruction, metabolic modelling (MetaboAnalyst 4.0), and pathway analysis (OmicsNet). Comparing MSCs and adipocytes, we observed significant regulation of different metabolites and lipids such as triglycerides, gangliosides, and carnitine with 113 fully reprogrammed pathways. The observed changes are in accordance with literature findings dealing with adipogenic differentiation of MSC. These results are a proof of principle for the power of multimolecular extraction combined with orthogonal LC-MS assays and network construction. Considering the analytical and biological validation performed in this study, we conclude that the proposed multiomics workflow is ideally suited for comprehensive follow-up studies on adipogenesis and is fit for purpose for different applications with a high potential to understand the complex pathophysiology of diseases.

Subcellular reprogramming of metabolism during cold acclimation in Arabidopsis thaliana.

Metabolite changes in plant leaves during exposure to low temperatures involve re-allocation of a large number of metabolites between sub-cellular compartments. Therefore, metabolite determination at the whole cell level may be insufficient for interpretation of the functional significance of cellular compounds. To investigate the cold-induced metabolite dynamics at the level of individual sub-cellular compartments, an integrative platform was developed that combines quantitative metabolite profiling by gas chromatography coupled to mass spectrometry (GC-MS) with the non-aqueous fractionation technique allowing separation of cytosol, vacuole and the plastidial compartment. Two mutants of Arabidopsis thaliana representing antipodes in the diversion of carbohydrate metabolism between sucrose and starch were compared to Col-0 wildtype before and after cold acclimation to investigate interactions of cold acclimation with subcellular re-programming of metabolism. A multivariate analysis of the data set revealed dominant effects of compartmentation on metabolite concentrations that were modulated by environmental condition and genetic determinants. While for both, the starchless mutant of plastidial phospho-gluco mutase (pgm) and a mutant defective in sucrose-phosphate synthase A1, metabolic constraints, especially at low temperature, could be uncovered based on subcellularly resolved metabolite profiles, only pgm had lowered freezing tolerance. Metabolic profiles of pgm point to redox imbalance as a possible reason for reduced cold acclimation capacity.

Destructive subependymal cysts following ventriculitis-pathomechanisms and treatment.

Ventriculitis may complicate neurosurgical procedures, for example, due to shunt or external ventricular drainage infection. Clearance of the infection with subsequent intravenous antibiotic therapy and shunt reinsertion, if necessary, are the standard treatment procedures with a high rate of success. Here, we report on a protracted complication, the development of destructive subependymal cysts, illustrate its treatment and discuss the pathomechanisms. The 2-year-and-9-month-old girl was admitted 5 weeks after a shunt revision with symptoms of shunt infection. Ventriculitis caused by Streptococcus salivarius (S. salivarius) was diagnosed and intravenous antibiotic treatment was performed. A new shunt system was implanted after clearance of infection and the girl did not show clinical signs of infection thereafter. A routine follow-up magnetic resonance imaging (MRI) revealed progressive and space-occupying multifocal subependymal cysts with partial destruction of the corpus callosum including compression of the ventricular system. Endoscopic broad-based laser fenestration of all cysts resulted in sustained regression of cavity formation. The cognitive development of the girl assessed 2 years afterward was completely normal. We conclude that routine follow-up MRI investigations are recommended 6 months after successful treatment of ventriculitis to detect protracted postinflammatory destructive subependymal cyst formations. Endoscopic broad-based laser-assisted cyst fenestration can stop progression and lead to regression of postinfectious subependymal cysts.

Contemporary microsurgical concept for the treatment of Cushing's disease: endocrine outcome in 83 consecutive patients.

BACKGROUND: Evidence suggests that occult adenoma remnants are responsible for persistent Cushing's disease (CD) following transsphenoidal surgery (TSS). To optimize the outcome, we have adapted our microsurgical concept. The influence of our surgical strategy on remission rate and pituitary function is presented. DESIGN AND PATIENTS: 83 patients undergoing TSS for newly diagnosed CD. An enlarged resection was performed in 36 patients. A modified exploration technique with radial incisions was performed in 19 patients in whom an adenoma was not readily detectable. RESULTS: The overall remission rate of primary surgery was 84·3% (70/83). A remission rate of 87·5% (63/72) was achieved in microadenomas. Six patients with microadenomas were re-operated for persistence, and hypercortisolism was corrected in five of them. With re-operation included, the overall remission rate for microadenomas was 94·4%. No procedure-related complications occurred in primary surgery. Of the patients in remission, 72·5% had early postoperative random cortisol levels below 2 µg/dl, 17·4% had cortisol levels between 2 and 5 µg/dl, and 10·1% had cortisol levels >5 µg/dl. 15·2% of the patients with microadenomas developed postoperative partial hypopituitarism and 3% diabetes insipidus. No increased rate of hypopituitarism was found with enlarged adenomectomy compared to selective adenomectomy. Only a slightly higher rate of partial hypopituitarism (23·1%) was found if extensive exploration was required. CONCLUSION: With our microsurgical concept, a high initial cure rate is achievable with minimal surgical morbidity. Enlarged adenomectomy has no adverse effect on the rate of postoperative hypopituitarism. Early repeat surgery is a successful option if CD persists.

Clinical and molecular characterisation of a Parkinson family with a novel PINK1 mutation.

Homozygous mutations in the PINK1 gene have been shown to cause early-onset parkinsonism. Here, we describe a novel homozygous mutation (Q126P), identified in two affected German sisters with a clinical phenotype typical for PINK1-associated parkinsonism. We analysed lactate, pyruvate, carnitine and acylcarnitine blood levels, lactate levels under exercise and in the cerebrospinal fluid, activity of respiratory chain complexes I-IV in muscle biopsies and proteasomal activity in immortalized lymphoblasts, but found no evidence for mitochondrial or proteasomal dysfunction. MR spectroscopy revealed raised myoinositol levels in the basal ganglia of both patients, reflecting possible astroglial proliferation.

Three-dimensional constructive interference in steady-state magnetic resonance imaging in syringomyelia: advantages over conventional imaging.

OBJECT: Neuroradiology has become indispensable in detecting the pathophysiology in syringomyelia. Constructive interference in steady-state (CISS) magnetic resonance (MR) imaging can provide superior contrast at the sub-arachnoid tissue borders. As this region is critical in preoperative evaluation, the authors hypothesized that CISS imaging would provide superior assessment of syrinx pathology and surgical planning. METHODS: Based on records collected from a database of 130 patients with syringomyelia treated at the authors' institution, 59 patients were prospectively evaluated with complete neuroradiological examinations. In addition to routine acquisitions with FLAIR, T1- and T2-weighted, and contrast-enhanced MR imaging series, the authors obtained sagittal cardiac-gated sequences to visualize cerebrospinal fluid (CSF) pulsations and axial 3D CISS MR sequences to detect focal arachnoid webs. Statistical qualitative and quantitative evaluations of spinal cord/CSF contrast, spinal cord/CSF delineation, motion artifacts, and artifacts induced by pulsatile CSF flow were performed. RESULTS: The 3D CISS MR sequences demonstrated a contrast-to-noise ratio significantly better than any other routine imaging sequence (p < 0.001). Moreover, 3D CISS imaging can detect more subarachnoid webs and cavitations in the syrinx than T2-weighted MR imaging with less flow-void artifact. The limitation of 3D CISS imaging is a susceptibility to motion artifacts that can cause reduced spatial resolution. Lengthy acquisition times for axial segments can be reduced with multiplanar reconstruction of 3D CISS-generated sagittal images. CONCLUSIONS: Constructive interference in steady-state imaging is the MR sequence of choice in the preoperative evaluation of syringomyelia, allowing significantly higher detection rates of focal subarachnoid webs, whereas standard T2-weighted MR imaging shows turbulent CSF flow voids. Constructive interference in steady-state MR imaging enables the neurosurgeon to accurately identify cases requiring decompression for obstructed CSF. Motion artifacts can be eliminated with technical variations.

"Pusher syndrome" following cortical lesions that spare the thalamus.

Stroke patients with "pusher syndrome" show severe misperception of their own upright body orientation although visual-vestibular processing is almost intact. This dissociation argues for a second graviceptive system in humans for the perception of body orientation. Recent studies revealed that the posterior thalamus is an important part of this system. The present investigation aimed to study the cortical representation of this system beyond the thalamus. We evaluated 45 acute patients with and without contraversive pushing following left-or right-sided cortical lesions sparing the thalamus. In both hemispheres, the simple lesion overlap associated with contraversive pushing typically centered on the insular cortex and parts of the postcentral gyrus. The comparison between pusher patients and controls who were matched with respect to age, lesion size, and the frequency of spatial neglect, aphasia and visual field defects revealed only very small regions that were specific for the pusher patients with cortical damage sparing the thalamus. Obviously, the cortical structures representing our control of upright body orientation are in close anatomical proximity to those areas that induce aphasia in the left hemisphere and spatial neglect in the right hemisphere when lesioned. We conclude that in addition to the subcortical area previously identified in the posterior thalamus, parts of the insula and postcentral gyrus appear to contribute at cortical level to the processing of the afferent signals mediating the graviceptive information about upright body orientation.

Management and outcome after internal carotid artery laceration during surgery of the paranasal sinuses.

CONCLUSIONS: The injury to the cavernous portion of the internal carotid artery (ICA) during endonasal sinus surgery is a potentially fatal complication, which can be prevented by systematic analysis of preoperative CT imaging in order to exclude vascular malformations. Immediate management is critical and requires interdisciplinary cooperation between the otolaryngologist and interventional neuroradiologist. OBJECTIVE: The purpose of this article is to present two cases of injury to the cavernous portion of the ICA during routine endonasal sinus surgery for chronic sinusitis and to review the management and outcome of this vascular emergency. PATIENTS AND METHODS: A database of all patients surgically treated for chronic sinusitis between 1994 and 2004 was reviewed retrospectively. Additionally a review of the literature for all published case reports of ICA injury was performed. RESULTS: We report two cases of ICA lacerations that occurred during routine endoscopic sinus surgery. Both patients were successfully treated by employing neuroradiological procedures including balloon and/or coil occlusion of various portions of the cavernous ICA. According to the literature the outcome depends on the presence or absence of vascular anomalies or aneurysm of the ICA with a very poor prognosis in cases of laceration of a pre-existing and unrecognized aneurysm.

Intraoperative visualization of residual tumor: the role of perfusion-weighted imaging in a high-field intraoperative magnetic resonance scanner.

BACKGROUND: High-field, intraoperative magnetic resonance imaging (iMRI) achieves free tumor margins in glioma surgery by involving anatomic neuronavigation and sophisticated functional imaging. OBJECTIVE: To evaluate the role of perfusion-weighted iMRI as an aid to detect residual tumor and to guide its resection. METHODS: Twenty-two patients undergoing intraoperative scanning (in a dual-room 1.5-T magnet setting) during the resection of high-grade gliomas were examined with perfusion-weighted iMRI. The generated relative cerebral blood volume (rCBV) maps were scrutinized for any hot spots indicative of tumor remnants, and region-of-interest analysis was performed. Differences among the rCBV region-of-interest estimates in residual tumor, free tumor margins, and normal white matter were analyzed. Histopathology of the tissue specimens and the neurosurgeon's intraoperative macroscopic estimations were considered the reference standards. RESULTS: In all cases, diagnostic rCBV perfusion maps were generated. Interpretation of perfusion maps demonstrated that gross total resection of gliomas was achieved in 4 of 22 cases (18%), which was macroscopically and histopathologically verified, whereas in 18 of 22 cases (82%), the perfusion-weighted iMRI revealed hot spots indicating subtotal tumor removal. The latter proved to be true in all but 1 case. The receiver-operating characteristic curves of the qualitative visual and quantitative analyses showed excellent sensitivity and specificity rates. Statistical analysis demonstrated statistically significant differences for the mean rCBV and maximum rCBV between residual disease and tumor-free margins (P = .002 for both). CONCLUSION: Perfusion-weighted iMRI may be implemented easily into imaging protocols and may assist the surgeon in detecting residual tumor volume.