Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia.

Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10-4). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.

Biopsy targeting with dynamic contrast-enhanced versus standard neuronavigation MRI in glioma: a prospective double-blinded evaluation of selection benefits.

Current biopsy planning based on contrast-enhanced T1W (CET1W) or FLAIR sequences frequently delivers biopsy samples that are not in concordance with the gross tumor diagnosis. This study investigates whether the quantitative information of transfer constant Ktrans maps derived from T1W dynamic contrast-enhanced MRI (DCE-MRI) can help enhance the quality of biopsy target selection in glioma. 28 patients with suspected glioma received MRI including DCE-MRI and a standard neuronavigation protocol of 3D FLAIR- and CET1W data sets (0.1 mmol/kg gadobutrol) at 3.0 T. After exclusion of five cases with no Ktrans-elevation, 2-6 biopsy targets were independently selected by a neurosurgeon (samples based on standard imaging) and a neuroradiologist (samples based on kinetic parameter Ktrans) per case and tissue samples corresponding to these targets were collected by a separate independent neurosurgeon. Standard technique and Ktrans-based samples were rated for diagnostic concordance with the gross tumor resection reference diagnosis (67 WHO IV; 24 WHO III and II) by a neuropathologist blinded for selection mode. Ktrans-based sample targets differed from standard technique sample targets in 90/91 cases. More Ktrans-based than standard imaging-based samples could be extracted. Diagnoses from Ktrans-based samples were more frequently concordant with the reference gross tumor diagnoses than those from standard imaging-based samples (WHO IV: 30/39 vs. 11/20; p = 0.08; WHO III/II: 12/13 vs. 6/11; p = 0.06). In 4/5 non-contrast-enhancing gliomas, Ktrans-based selection revealed significantly more accurate samples than standard technique sample-selection (10/12 vs. 2/8 samples; p = 0.02). If Ktrans elevation is present, Ktrans-based biopsy targeting provides significantly more diagnostic tissue samples in non-contrast-enhancing glioma than selection based on CET1W and FLAIR-weighted images alone.

Posterior Reversible Encephalopathy Syndrome as an Overlooked Complication of Induced Hypertension for Cerebral Vasospasm: Systematic Review and Illustrative Case.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia associated with cerebral vasospasm is a common cause of secondary neurological decline after aneurysmal subarachnoid hemorrhage (SAH). Triple-H therapy, induced hypertension, hypervolemia, and hemodilution, is often used to treat cerebral vasospasm. However, hypertensive treatment may carry significant medical morbidity, including cardiopulmonary, renal, and intracranial complications. Posterior reversible encephalopathy syndrome (PRES) is a reversible intracranial complication that has rarely been reported in the setting of induced hypertension. METHODS: We present an illustrative case of PRES in a patient with induced hypertension for SAH-related cerebral vasospasm and performed a systematic review. Furthermore, the electronic database MEDLINE was searched for additional data in published studies of PRES after induced hypertension. RESULTS: Overall, 7 case reports presenting 10 patients who developed PRES secondary to induced hypertension were found. Eighty-two percent of the patients were women. In all cases, the clinical symptoms were attributed to cerebral vasospasm before the diagnosis of PRES. The time from onset of induced hypertension to the development of PRES was 7.8±3.8 days. After the diagnosis of PRES and careful taper down of the blood pressure, the neurological symptoms resolved almost completely within a few days in all patients. CONCLUSIONS: PRES in the setting of SAH is an overlooked complication of hypertensive therapy for the treatment of vasospasm. However, the diagnosis of this phenomenon is crucial given the necessity to reverse hypertensive therapy, which is contrary to the usual management of patients with vasospasm.

Non-paraneoplastic limbic encephalitis and central nervous HHV-6B reactivation: Causality or coincidence?

Autoantibody-related encephalopathies represent an important differential diagnosis in adult onset epilepsy. Here, we report the case of a 25-year-old patient with new-onset epilepsy and psychotic syndrome, who underwent biopsy resection for etiological classification. MRI analysis and neuropathological examination showed a T-lymphocytic dominated encephalitis with involvement of the limbic system. An indirect immunohistochemistry approach identified autoantibodies against glutamic acid decarboxylase (GAD) in cerebral spinal fluid and serum, which were confirmed by affinity purification / mass spectrometry analysis. Further examinations revealed evidence of chromosomally integrated human herpes virus type 6B (HHV-6B). However, astrocytic expression of HHV-6 lytic protein was detected by double immunofluorescence analysis. The cerebral expression of HHV-6 antigen, a clinical improvement under antiviral therapy as well as an initial finding of HHV-6 IgM antibodies strongly argue for an additional active HHV-6B infection. Review of the literature reveals singular reports of patients with GAD antibody-positive limbic encephalitis and central nervous system infections with HHV-6B. Since herpes simplex virus encephalitis has been recently reported as a trigger of N-methyl-D-aspartate receptor antibody encephalitis, it is tempting to speculate that HHV-6B infections may trigger a non-paraneoplastic form of limbic encephalitis in a parallel cascade.

FLAIR-only progression in bevacizumab-treated relapsing glioblastoma does not predict short survival.

OBJECTIVES: In this study, we analyzed the prognostic value of different MRI progression patterns for survival in patients with recurrent malignant glioma treated with the vascular endothelial growth factor antibody bevacizumab. PATIENTS AND METHODS: Twenty-six adult patients with recurrent malignant glioma treated with bevacizumab or bevacizumab/irinotecan were retrospectively analyzed for the development of contrast-enhanced (T1-weighted MRI) and T2/FLAIR lesions. According to the progression pattern, patients were divided into 3 subgroups: (1) patients with primarily progressive contrast-enhanced lesions in the first MRI after initiation of therapy ('primary PD group'); (2) patients with stable or regressive enhanced lesions but progressive FLAIR lesions ('FLAIR-only PD group'), and (3) patients with stable or regressive contrast-enhanced T1 and FLAIR lesions ('no PD group'). RESULTS: Overall survival (OS) in the 6 patients in the FLAIR-only PD group was not significantly different from the 11 patients in the no PD group (median 311 vs. 254 days, respectively). In contrast, survival in the FLAIR-only PD group was significantly better (p = 0.025) than in the primary PD group. CONCLUSION: FLAIR-only progression is not an independent prognostic factor negatively influencing OS in recurrent glioblastoma treated with bevacizumab and should not lead to discontinuation of bevacizumab therapy.

Impact of Postoperative Changes in Brain Anatomy on Target Volume Delineation for High-Grade Glioma.

High-grade glioma has a poor prognosis, and radiation therapy plays a crucial role in its management. Every step of treatment planning should thus be optimised to maximise survival chances and minimise radiation-induced toxicity. Here, we compare structures needed for target volume delineation between an immediate postoperative magnetic resonance imaging (MRI) and a radiation treatment planning MRI to establish the need for the latter. Twenty-eight patients were included, with a median interval between MRIs (range) of 19.5 (8-50) days. There was a mean change in resection cavity position (range) of 3.04 ± 3.90 (0-22.1) mm, with greater positional changes in skull-distant (>25 mm) resection cavity borders when compared to skull-near (≤25 mm) counterparts (p < 0.001). The mean differences in resection cavity and surrounding oedema and FLAIR hyperintensity volumes were -32.0 ± 29.6% and -38.0 ± 25.0%, respectively, whereas the mean difference in midline shift (range) was -2.64 ± 2.73 (0-11) mm. These data indicate marked short-term volumetric changes and support the role of an MRI to aid in target volume delineation as close to radiation treatment start as possible. Planning adapted to the actual anatomy at the time of radiation limits the risk of geographic miss and might thus improve outcomes in patients undergoing adjuvant radiation for high-grade glioma.

Tidal recruitment assessed by electrical impedance tomography and computed tomography in a porcine model of lung injury*.

OBJECTIVES: To determine the validity of electrical impedance tomography to detect and quantify the amount of tidal recruitment caused by different positive end-expiratory pressure levels in a porcine acute lung injury model. DESIGN: Randomized, controlled, prospective experimental study. SETTING: Academic research laboratory. SUBJECTS: Twelve anesthetized and mechanically ventilated pigs. INTERVENTIONS: Acute lung injury was induced by central venous oleic acid injection and abdominal hypertension in seven animals. Five healthy pigs served as control group. Animals were ventilated with positive end-expiratory pressure of 0, 5, 10, 15, 20, and 25 cm H2O, respectively, in a randomized order. MEASUREMENTS AND MAIN RESULTS: At any positive end-expiratory pressure level, electrical impedance tomography was obtained during a slow inflation of 12 mL/kg of body weight. Regional-ventilation-delay indices quantifying the time until a lung region reaches a certain amount of impedance change were calculated for lung quadrants and for every single electrical impedance tomography pixel, respectively. Pixel-wise calculated regional-ventilation-delay indices were plotted in a color-coded regional-ventilation-delay map. Regional-ventilation-delay inhomogeneity that quantifies heterogeneity of ventilation time courses was evaluated by calculating the scatter of all pixel-wise calculated regional-ventilation-delay indices. End-expiratory and end-inspiratory computed tomography scans were performed at each positive end-expiratory pressure level to quantify tidal recruitment of the lung. Tidal recruitment showed a moderate inter-individual (r = .54; p < .05) and intra-individual linear correlation (r = .46 up to r = .73 and p < .05, respectively) with regional-ventilation-delay obtained from lung quadrants. Regional-ventilation-delay inhomogeneity was excellently correlated with tidal recruitment intra- (r = .90 up to r = .99 and p < .05, respectively) and inter-individually (r = .90; p < .001). CONCLUSIONS: Regional-ventilation-delay can be noninvasively measured by electrical impedance tomography during a slow inflation of 12 mL/kg of body weight and visualized using ventilation delay maps. Our experimental data suggest that the impedance tomography-based analysis of regional-ventilation-delay inhomogeneity provides a good estimate of the amount of tidal recruitment and may be useful to individualize ventilatory settings.

Visualisation of the temporary cavity by computed tomography using contrast material.

The temporary cavity of a missile produces radial tears in ordnance gelatine, which correlate to the energy transfer. Computed tomography is a useful and non-destructive method to examine gelatine blocks. However, the tears give only few radiocontrast by air filling, which decreases with the time past shooting. Therefore, systematically, a radiocontrast material was searched to enhance the contrast. Different contrast materials were amalgamated to acryl paint, and about 7 g was sealed in a foil bag, which was integrated in the front of a standard 10% gelatine cylinder. Shots with Action-5 expanding bullets were performed from a 5-m distance. Gelatine was scanned by multi-slice computed tomography. The multiplanar reconstructed images were compared to mechanically cut slices of 1 cm thickness. It was shown experimentally that iodine containing water-soluble contrast material did not give sufficient contrast and caused diffusion artefacts. Best results were obtained by barium sulphate emulsion. The amount of acryl paint was sufficient to colour the tears for optical scanning. The radiocontrast of barium leads to satisfying imaging of tears and allowed the creation of a three-dimensional reconstruction of the temporary cavity. Comparison of optical and radiological results showed an excellent correlation, but absolute measures in computed tomographic (CT) images remained lower compared with optically gathered values in the gelatine slices. Combination of paint and contrast material for CT examination will facilitate the evaluation of complex ballistic models and increase accuracy.

Transarterial endovascular treatment in the management of life-threatening intra- and postoperative haemorrhages after otorhinolaryngological surgery.

Management of life-threatening postsurgical bleeding is complex. If conservative or surgical therapy is demanding, an endovascular treatment can be considered. The goal of this study was to evaluate the outcome of endovascular approaches in the diagnosis and therapy of otherwise intractable postoperative haemorrhages with a study design of outcomes research. Charts of all patients with postsurgical bleedings receiving endovascular treatment were reviewed for clinical outcome, complications, and demographic data. 15 patients were identified. They had rhinosurgery (12/15), tonsillectomy (2/15) or transoral tumour debulking (1/15) prior to the endovascular procedure. In more than 70%, the source of bleeding was directly located angiographically and subsequently superselectively embolized. The remaining patients suffered from post-rhinosurgical epistaxis and underwent a bilateral embolization of the sphenopalatine artery. All bleedings were successfully controlled and no procedure-related complication was noted. In conclusion, endovascular treatment of life-threatening postsurgical haemorrhages should be considered if the source of bleeding is unknown or if surgery is difficult and may result in devastating postoperative complications.

Coronary Artery Aneurysm Rupture in a Patient With Polyarteritis Nodosa.

We present the case of a 42-year-old male patient with ST-segment elevation myocardial infarction and pericardial effusion due to rupture of the left anterior descending artery most likely secondary to polyarteritis nodosa. Successful surgery was performed under cardiopulmonary bypass using antegrade and retrograde cardioplegia combined. (Level of Difficulty: Intermediate.).

Volumetric computed tomography (VCT): a new technology for noninvasive, high-resolution monitoring of tumor angiogenesis.

Volumetric computed tomography (VCT) is a technology in which area detectors are used for imaging large volumes of a subject with isotropic imaging resolution. We are experimenting with a prototype VCT scanner that uses flat-panel X-ray detectors and is designed for high-resolution three-dimensional (3D) imaging. Using this technique, we have demonstrated microangiography of xeno-transplanted skin squamous cell carcinomas in nude mice. VCT shows the vessel architecture of tumors and animals with greater detail and plasticity than has previously been achieved, and is superior to contrast-enhanced magnetic resonance (MR) angiography. VCT and MR images correlate well for larger tumor vessels, which are tracked from their origin on 3D reconstructions of VCT images. When compared with histology, small tumor vessels with a diameter as small as 50 microm were clearly visualized. Furthermore, imaging small vessel networks inside the tumor tissue improved discrimination of vital and necrotic regions. Thus, VCT substantially improves imaging of vascularization in tumors and offers a promising tool for preclinical studies of tumor angiogenesis and antiangiogenic therapies.

Thalamus lesions in chronic and acute seizure disorders.

INTRODUCTION: Transient signal changes in the pulvinar have been described following status epilepticus. However, we observed persistent thalamus changes after seizures. The purpose of this study was to characterize thalamus changes in patients with seizure disorders and to correlate imaging findings with clinical features. METHODS: We searched among 5,500 magnetic resonance imaging (MRI) exams performed in patients with seizures and identified 43 patients. The MRI scans of these patients were reviewed and correlated with clinical data. RESULTS: We identified four patterns of thalamus lesions: (a) fluid attenuated inversion recovery-hyperintense pulvinar lesions (20 patients), as known from status epilepticus. Ten patients in this group had a status epilepticus. Among the remaining patients, three had frequent seizures and seven had sporadic seizures. Twelve patients had follow-up exams for a median of 11 months. The lesions had persisted in 11/12 cases in the last available exam and were reversible in one case only. In seven cases, cone-shaped thalamus atrophy resulted, (b) linear defects in the medial and anterior thalamus (five patients), accompanied by atrophy of the mamillary body and the fornix in patients with chronic epilepsy, (c) extensive bilateral thalamus lesions in two patients with a syndrome caused by mutation in the mitochondrial polymerase gamma, and (d) other thalamus lesions not associated with the seizure disorder (16 patients). CONCLUSION: The spectrum of thalamus lesions in patients with seizure disorders is wider than previously reported. Postictal pulvinar lesions can persist and may result in thalamic atrophy. Linear defects in the anterior thalamus are associated with limbic system atrophy.

Noninvasive imaging after stent-assisted coiling of intracranial aneurysms: comparison of 3-T magnetic resonance imaging and 64-row multidetector computed tomography--a pilot study.

BACKGROUND AND PURPOSE: Follow-up imaging after stent-assisted coiling of intracranial aneurysms is limited by signal loss in the stented vessel segment using magnetic resonance imaging or by streak artifacts caused by aneurysm coils using multidetector computed tomography. In the search for a noninvasive surveillance in this condition, we propose a technique to minimize streak artifacts in multidetector computed tomography by gated data reconstruction and shifting the reconstruction window. METHODS: The effect of the gated data acquisition in 64-row computed tomographic angiography (gCTA) on artifact reduction was evaluated in a preliminary phantom study and compared with nongated CTA, time-of-flight magnetic resonance angiography (TOF-MRA), and digital subtraction angiography (DSA). Scans were also obtained from 5 patients treated with stent-assisted coiling as part of their follow-up protocol. The length of impaired vessel segments (LIVS) in TOF-MRA and gCTA was compared and correlated with the stent's length, the number of coils, and the packing density. The assessment of treatment outcome in TOF-MRA and gCTA was compared with DSA as the standard of reference. RESULTS: The phantom study revealed 2 aspects: first, a distinct reduction of streak artifacts caused by coils using gated data acquisition; and second, because artifact orientation could be rotated systematically by shifting the reconstruction window, visualization of treated vessel segments was significantly superior in gCTA. In magnetic resonance imaging, all stented vessel segments were characterized by signal loss in both phantom and patients. The LIVS was 78% shorter in gCTA (4.86 ± 6.93 mm) compared with that in TOF-MRA (21.82 ± 7.47 mm, P < 0.01). In TOF-MRA, the LIVS correlated with the stent's length, in gCTA with the number of coils. With regard to assessment of treatment outcome, gCTA and TOF-MRA correlated with DSA in 3 and in none of 5 patients, respectively. CONCLUSIONS: Gated CTA is a promising technique to reduce the amount of artifacts induced by stent-assisted intracranial coils. Image quality and assessment of treatment outcome in patients with stent-assisted coiling is superior compared with TOF-MRA.

Inhibition of urokinase activity reduces primary tumor growth and metastasis formation in a murine lung carcinoma model.

RATIONALE: Lung cancer is the most common malignancy in humans. Urokinase (uPA) plays a crucial role in carcinogenesis by facilitating tumor cell invasion and metastasis. OBJECTIVES: We investigated the effect of the highly specific urokinase inhibitor CJ-463 (benzylsulfonyl-D-Ser-Ser-4-amidinobenzylamide) on tumor growth, metastasis formation, and tumor vascularization in the murine Lewis lung carcinoma (LLC) and a human small lung cancer model. METHODS: A quantity of 3 x 10(6) LLC cells were subcutaneously injected into the right flank of C57Bl6/N mice, uPA knock out, and uPA receptor knockout mice. Seven days later mice were randomized to receive intraperitoneally either saline (control group), CJ-463 (10 and 100 mg/kg, twice a day), or its ineffective stereoisomer (10 mg/kg, twice a day). Tumor volume was measured every second day and metastasis formation was monitored by volumetric-computed tomography. Twelve days after onset of treatment mice were killed and tumors were prepared for histologic examination. MEASUREMENTS AND MAIN RESULTS: Treatment with CJ-463 resulted in a significant inhibition of primary tumor growth, with the highest efficacy seen in the 100 mg/kg group. In addition, histological analysis of the lung revealed a significant reduction in lung micrometastasis in the 100 mg/kg group. Similarly, a reduced seeding of tumor cells into the lung after intravenous injection of LLC cells was observed in inhibitor-treated mice. In these mice, treatment with CJ-463 appeared not to significantly alter the relative extent of tumor vascularization. In vitro, proliferation of LLC cells remained unchanged upon inhibitor treatment. CJ-463 was found to similarly reduce tumor growth in uPA receptor knockout mice, but was ineffective in uPA knockout mice. CONCLUSIONS: Our results suggest that synthetic low-molecular-weight uPA-inhibitors offer as novel agents for treatment of lung cancer.

Health Economic Aspects of Aneurysmal Subarachnoid Hemorrhage: Factors Determining First Year In-Hospital Treatment Expenses.

BACKGROUND: Spontaneous aneurysmal subarachnoid hemorrhage (SAH) is a common neurosurgical emergency with a high case fatality rate. The clinical course of SAH generates high health economic expenses. Here we highlight possible cost-driving factors for in-hospital care expenses for the first year. Furthermore, results are compared with ischemic stroke treatment. METHODS: One hundred and one patients with aneurysmal SAH treated in our hospital from 2007 through 2009 were included. The Hunt and Hess (HH) scale, World Federation of Neurosurgical Societies (WFNS) scale, Fisher Scale, and further outcome-relevant data were recorded. Expenses were calculated using the German fixed case rate classification system consisting of Diagnosis-Related Groups (DRG) and the Operation and Procedure catalogue (OPS). Overall acute length of stay (LOS) and LOS on the intensive care unit (ICU) were separately evaluated. Expenses were compared with formerly published first-year costs of ischemic stroke. RESULTS: Fifty-four percent of the patients (median age 52 years, 69% females) received coiling and 46% clipping. Acute in-hospital treatment accounted for 82% of total in-hospital expenses, while consequential in-hospital treatment accounted only for 18%. Altogether, the total first-year in-hospital expenses for all patients were as high as €2,650,002, resulting in average SAH in-hospital treatment expenses of €26,238 per patient for the first year. Poor clinical condition on admission and longer stay in ICU are the main cost-driving factors. The impact of the aneurysm treatment method is debatable. Only a poor HH grade and longer ICU stay are independent cost-driving factors. SAH treatment expenses are far higher than treatment costs for ischemic stroke in the literature (€6,731 for first-year inpatient and €3,287 for outpatient treatment). CONCLUSIONS: Clinical condition and LOS determine in-hospital expenses after SAH. Aneurysmal SAH prevalently results in a relevant economic impact on the health system exceeding formerly published treatment expenses for ischemic stroke.

Spinocerebellar ataxia type 14: refining clinicogenetic diagnosis in a rare adult-onset disorder.

OBJECTIVES: Genetic variant classification is a challenge in rare adult-onset disorders as in SCA-PRKCG (prior spinocerebellar ataxia type 14) with mostly private conventional mutations and nonspecific phenotype. We here propose a refined approach for clinicogenetic diagnosis by including protein modeling and provide for confirmed SCA-PRKCG a comprehensive phenotype description from a German multi-center cohort, including standardized 3D MR imaging. METHODS: This cross-sectional study prospectively obtained neurological, neuropsychological, and brain imaging data in 33 PRKCG variant carriers. Protein modeling was added as a classification criterion in variants of uncertain significance (VUS). RESULTS: Our sample included 25 cases confirmed as SCA-PRKCG (14 variants, thereof seven novel variants) and eight carriers of variants assigned as VUS (four variants) or benign/likely benign (two variants). Phenotype in SCA-PRKCG included slowly progressive ataxia (onset at 4-50 years), preceded in some by early-onset nonprogressive symptoms. Ataxia was often combined with action myoclonus, dystonia, or mild cognitive-affective disturbance. Inspection of brain MRI revealed nonprogressive cerebellar atrophy. As a novel finding, a previously not described T2 hyperintense dentate nucleus was seen in all SCA-PRKCG cases but in none of the controls. INTERPRETATION: In this largest cohort to date, SCA-PRKCG was characterized as a slowly progressive cerebellar syndrome with some clinical and imaging features suggestive of a developmental disorder. The observed non-ataxia movement disorders and cognitive-affective disturbance may well be attributed to cerebellar pathology. Protein modeling emerged as a valuable diagnostic tool for variant classification and the newly described T2 hyperintense dentate sign could serve as a supportive diagnostic marker of SCA-PRKCG.

The enterprise stent for the treatment of intracranial aneurysms: stenting strategies.

BACKGROUND: Self-expanding microstents are typically placed before a wide-necked aneurysm is filled with coils. Alternatively, the stent may be placed at the end of the procedure, when the coil mass blocks or slows down the flow in the parent artery or a branching vessel. PATIENTS AND METHODS: Between March 2007 and 2009, 20 aneurysms in 20 patients were treated with a total of 21 Enterprise stents. Nine aneurysms had reopened after coiling, eleven aneurysms were primarily treated, seven after acute subarachnoid hemorrhage. Eight aneurysms were primarily filled with coils and the stent was placed when the flow in the parent or a branching artery was blocked or slowed down. In four of these cases in which secondary stenting was considered an option in advance, the "artery at risk" was initially catheterized with a microcatheter. RESULTS: Stent placement was successful in 19 aneurysms. In a reopened basilar tip aneurysm, Y-like stent placement through a Neuroform stent failed. With secondary stent placement (n = 8), all affected vessels could be safely reopened. None of these patients suffered from transient or permanent neurologic deficits. Using the jailing technique, it was possible to place two parallel stents in the internal carotid artery and posterior cerebral artery (PCA) in a reopened wide-necked PCA aneurysm. CONCLUSION: Apart from the primary use of the Enterprise stent in wide-necked aneurysm secondary stenting after coiling is a feasible technique to reopen occluded parent or branching arteries. Initial microcatheter placement in the artery which is at risk to get occluded when filling the aneurysm is a valuable option.

Cone-Beam Computed Tomography (CBCT) dacryocystography for imaging of the nasolacrimal duct system.

PURPOSE: To evaluate the usefulness and safety of cone-beam computed tomography (CBCT) dacryocystography in detecting lesions, identifying coexisting soft-tissue changes and determining treatment options in patients with epiphora. PATIENTS AND METHODS: Unilateral digital subtraction dacryocystography and CBCT dacryocystography were carried out on 45 patients. Stenoses and occlusions were identified and coexisting changes such as septal deviation and dacryoliths were noted. The diameter of the bony lacrimal duct of affected and unaffected side was measured and related to the clinically evident epiphora. An attempt was made to base the subsequent therapeutic planning on the CBCT dacryocystographic findings. Additionally, the radiation dose levels for CBCT dacryocystography in comparison to those of multislice computed tomography (MSCT) were evaluated in a standardized head-neck Rando-Alderson phantom. RESULTS: Nasolacrimal duct obstructions were present in 37/45 patients, 18 with a stenosis and 19 with an occlusion in parts of the lacrimal outflow system. The minimal bony diameter of the side with epiphora was significantly decreased compared to the unaffected side. Coexisting soft-tissue changes did not correlate significantly with the clinical sign of epiphora. Eight patients showed no underlying reason for the epiphora and were treated conservatively. A total of eleven patients received interventional therapy for their stenosis and 23 patients had to be treated surgically. A further three patients received medical treatment for infection, before surgery and interventional therapy, respectively, were carried out. Dose levels for CBCT imaging remained far below those of MSCT. CONCLUSION: CBCT dacryocystography is a safe and time-efficient modality for assessing the nasolacrimal duct system in patients with epiphora. CBCT dacryocystography provides detailed images of the nasolacrimal drainage system, surrounding soft tissue, and bony structures in one diagnostic tour. It allows clear measurement of the bony nasolacrimal duct and displays information beyond that of the drainage lumen, improving the planning of therapeutic interventional and surgical procedures.

A combination hybrid-based vaccination/adoptive cellular therapy to prevent tumor growth by involvement of T cells.

Cancer immunotherapy with dendritic cell-tumor cell fusion hybrids induces polyclonal stimulation against a variety of tumor antigens, including unknown antigens. Hybrid cells can prime CTLs, which subsequently develop antitumor responses. The aim of this study was to enhance the known antitumor effect of hybrid vaccination (HC-Vacc) and hybrid-primed adoptive T-cell therapy (HC-ACT) using the poorly immunogenic Lewis lung carcinoma (LLC1) model. The strategy used was a combination of a double HC-Vacc alternating with HC-ACT (HC-Vacc/ACT). Using flat-panel volumetric computer tomography and immunohistochemistry, we showed a significant retardation of tumor growth (85%). In addition, a significant delay in tumor development, a reduction in the number of pulmonary metastases, and increased survival times were observed. Furthermore, the tumors displayed significant morphologic changes and increased apoptosis, as shown by up-regulation of gene expression of the proapoptotic markers Fas, caspase-8, and caspase-3. The residual tumor masses seen in the HC-Vacc/ACT-treated mice were infiltrated with CD4+ and CD8+ lymphocytes and showed elevated IFNgamma expression. Moreover, splenic enlargement observed in HC-Vacc/ACT-treated mice reflected the increased functionality of T cells, as also indicated by increased expression of markers for CTL activation, differentiation, and proliferation (Cd28, Icosl, Tnfrsf13, and Tnfsf14). Our findings indicate that the combination therapy of dendritic cell-tumor cell HC-Vacc/ACT is a very effective and a promising immunotherapeutic regimen against poorly immunogenic carcinomas.