Arnd Dörfler

Mutations in the Pericentrin (PCNT) Gene Cause Primordial Dwarfism

Fundamental processes influencing human growth can be revealed by studying extreme short stature. Using genetic linkage analysis, we find that biallelic loss-of-function mutations in the centrosomal pericentrin (PCNT) gene on chromosome 21q22.3 cause microcephalic osteodysplastic primordial dwarfism type II (MOPD II) in 25 patients. Adults with this rare inherited condition have an average height of 100 centimeters and a brain size comparable to that of a 3-month-old baby, but are of near-normal intelligence. Absence of PCNT results in disorganized mitotic spindles and missegregation of chromosomes. Mutations in related genes are known to cause primary microcephaly (MCPH1, CDK5RAP2, ASPM, and CENPJ).

Anticoagulant Reversal, Blood Pressure Levels, and Anticoagulant Resumption in Patients With Anticoagulation-Related Intracerebral Hemorrhage

IMPORTANCE Although use of oral anticoagulants (OACs) is increasing, there is a substantial lack of data on how to treat OAC-associated intracerebral hemorrhage (ICH). OBJECTIVE To assess the association of anticoagulation reversal and blood pressure (BP) with hematoma enlargement and the effects of OAC resumption. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study at 19 German tertiary care centers (2006-2012) including 1176 individuals for analysis of long-term functional outcome, 853 for analysis of hematoma enlargement, and 719 for analysis of OAC resumption. EXPOSURES Reversal of anticoagulation during acute phase, systolic BP at 4 hours, and reinitiation of OAC for long-term treatment. MAIN OUTCOMES AND MEASURES Frequency of hematoma enlargement in relation to international normalized ratio (INR) and BP. Incidence analysis of ischemic and hemorrhagic events with or without OAC resumption. Factors associated with favorable (modified Rankin Scale score, 0-3) vs unfavorable functional outcome. RESULTS Hemorrhage enlargement occurred in 307 of 853 patients (36.0%). Reduced rates of hematoma enlargement were associated with reversal of INR levels <1.3 within 4 hours after admission (43/217 [19.8%]) vs INR of ≥1.3 (264/636 [41.5%]; P < .001) and systolic BP <160 mm Hg at 4 hours (167/504 [33.1%]) vs ≥160 mm Hg (98/187 [52.4%]; P < .001). The combination of INR reversal <1.3 within 4 hours and systolic BP of <160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement (35/193 [18.1%] vs 220/498 [44.2%] not achieving these values; OR, 0.28; 95% CI, 0.19-0.42; P < .001) and lower rates of in-hospital mortality (26/193 [13.5%] vs 103/498 [20.7%]; OR, 0.60; 95% CI, 0.37-0.95; P = .03). OAC was resumed in 172 of 719 survivors (23.9%). OAC resumption showed fewer ischemic complications (OAC: 9/172 [5.2%] vs no OAC: 82/547 [15.0%]; P < .001) and not significantly different hemorrhagic complications (OAC: 14/172 [8.1%] vs no OAC: 36/547 [6.6%]; P = .48). Propensity-matched survival analysis in patients with atrial fibrillation who restarted OAC showed a decreased HR of 0.258 (95% CI, 0.125-0.534; P < .001) for long-term mortality. Functional long-term outcome was unfavorable in 786 of 1083 patients (72.6%). CONCLUSIONS AND RELEVANCE Among patients with OAC-associated ICH, reversal of INR <1.3 within 4 hours and systolic BP <160 mm Hg at 4 hours were associated with lower rates of hematoma enlargement, and resumption of OAC therapy was associated with lower risk of ischemic events. These findings require replication and assessment in prospective studies. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01829581.

Perfusion MRI: The Five Most Frequently Asked Technical Questions

OBJECTIVE This and its companion article address the 10 most frequently asked questions that radiologists face when planning, performing, processing, and interpreting different MR perfusion studies in CNS imaging. CONCLUSION Perfusion MRI is a promising tool in assessing stroke, brain tumors, and patients with neurodegenerative diseases. Most of the impediments that have limited the use of perfusion MRI can be overcome to allow integration of these methods into modern neuroimaging protocols.

Hypothermia Reduces Perihemorrhagic Edema After Intracerebral Hemorrhage

Background and Purpose— The prognosis of spontaneous intracerebral hemorrhage (sICH) is poor because of the mass effect arising from the hematoma and the associated peri-hemorrhagic edema, leading to increased intracranial pressure. Because the efficacy of surgical and anti-edematous treatment strategies is limited, we investigated the effects of mild induced hypothermia in patients with large sICH. Methods— Twelve patients with supratentorial sICH >25 mL were treated by hypothermia of 35°C for 10 days. Evolution of hematoma volume and perifocal edema was measured by cranial CT. Functional outcome was assessed after 90 days. These patients were compared to patients (n=25; inclusion criteria: sICH volume >25 mL, no acute restriction of medical therapy on admission) from the local hemorrhage data bank (n=312). Side effects of hypothermia were analyzed. Results— All patients from both groups needed mechanical ventilation and were treated in a neurocritical care unit. All hypothermic patients (mean age, 60±10 years) survived until day 90, whereas 7 patients died in the control group (mean age, 67±7 years). Absolute hematoma size on admission was 58±29 mL (hypothermia) compared to 57±31 mL (control). In the hypothermia group, edema volume remained stable during 14 days (day 1, 53±43 mL; day 14, 57±45 mL), whereas edema significantly increased in the control group from 40±28 mL (day 1) to 88±47 mL (day 14). ICH continuously dissolved in both groups. Pneumonia rate was 100% in the hypothermia group and 76% in controls (P=0.08). No significant side effects of hypothermia were observed. Conclusions— Hypothermia prevented the increase of peri-hemorrhagic edema in patients with large sICH.

The POST trial: initial post-market experience of the Penumbra system: revascularization of large vessel occlusion in acute ischemic stroke in the United States and Europe

Background and purpose The purpose of this study was to assess the initial post-market experience of the device and how it is compared with the Penumbra Pivotal trial used to support the 510k application. Methods A retrospective case review of 157 consecutive patients treated with the Penumbra system at seven international centers was performed. Primary endpoints were revascularization of the target vessel (TIMI score of 2 or 3), good functional outcome as defined by a modified Rankin scale (mRS) score of ≤2 and incidence of procedural serious adverse events. Results were compared with those of the Penumbra pivotal trial. Results A total of 157 vessels were treated. Mean baseline values at enrollment were: age 65 years, NIHSS score 16. After use of the Penumbra system, 87% of the treated vessels were revascularized to TIMI 2 (54%) or 3 (33%) as compared with 82% reported in the Pivotal trial. Nine procedural serious adverse events were reported in 157 patients (5.7%). All-cause mortality was 20% (32/157), and 41% had a mRS of ≤2 at 90-day follow-up as compared with only 25% in the Pivotal trial. Patients who were successfully revascularized by the Penumbra system had significantly better outcomes than those who were not. Conclusion Initial post-market experience of the Penumbra system revealed that the revascularization rate and safety profile of the device are comparable to those reported in the Pivotal trial. However, the proportion of patients who had good functional outcome was higher than expected.

Efficient drug-delivery using magnetic nanoparticles — biodistribution and therapeutic effects in tumour bearing rabbits

UNLABELLED To treat tumours efficiently and spare normal tissues, targeted drug delivery is a promising alternative to conventional, systemic administered chemotherapy. Drug-carrying magnetic nanoparticles can be concentrated in tumours by external magnetic fields, preventing the nanomaterial from being cleared by metabolic burden before reaching the tumour. Therefore in Magnetic Drug Targeting (MDT) the favoured mode of application is believed to be intra-arterial. Here, we show that a simple yet versatile magnetic carrier-system (hydrodynamic particles diameter <200nm) accumulates the chemotherapeutic drug mitoxantrone efficiently in tumours. With MDT we observed the following drug accumulations relative to the recovery from all investigated tissues: tumour region: 57.2%, liver: 14.4%, kidneys: 15.2%. Systemic intra-venous application revealed different results: tumour region: 0.7%, liver: 14.4 % and kidneys: 77.8%. The therapeutic outcome was demonstrated by complete tumour remissions and a survival probability of 26.7% (P=0.0075). These results are confirming former pilot experiments and implying a milestone towards clinical studies. FROM THE CLINICAL EDITOR This team of investigators studied drug carrying nanoparticles for magnetic drug targeting (MDT), demonstrating the importance of intra-arterial administration resulting in improved clinical outcomes in the studied animal model compared with intra-venous.

Functional connectivity of the human insular cortex during noxious and innocuous thermal stimulation

The insula plays a key role in brain processing of noxious and innocuous thermal stimuli. The anterior and the posterior portions of the insular cortex are involved in different ways in nociceptive and thermoceptive processing. Therefore, their stimulus-specific functional connectivity may also differ. Here we used functional magnetic resonance imaging (fMRI) to investigate the activity and functional connectivity of insular cortex subregions during noxious and innocuous thermal stimulation. In 11 healthy subjects, psychophysically controlled noxious and innocuous warm and cold stimuli were applied to the left forearm. To differentiate between the subregions of the insular cortex involved in pain processing and those involved in temperature processing, a 2×2 factorial fMRI analysis was performed. Pain processing insular areas (main effect of pain) were detected in bilateral aINS and contralateral pINS. Temperature processing insular areas (main effect of temperature) were also found in bilateral aINS and contralateral pINS. The individual signal time courses from the pain- and temperature processing insular activation clusters were used for calculation and comparison of stimulus-specific functional connectivity of aINS and pINS by means of a correlation analysis. As expected, both aINS and pINS were functionally connected to a large brain network - which predominantly includes areas involved in nociception and thermoception: primary (S1) and secondary (S2) somatosensory cortices, cingulate gyrus, prefrontal cortex (PFC) and parietal association cortices (PA). When statistically compared, during both noxious and innocuous stimulation, aINS was more strongly connected to PFC and to ACC than was pINS; pINS meanwhile was more strongly connected to S1 and to the primary motor cortex (M1). Interestingly, S2 was more strongly connected to aINS than to pINS during painful stimulation but not during innocuous thermal stimulation. We conclude that aINS is more strongly functionally connected to areas known for affective and cognitive processing, whereas pINS is more strongly connected with areas known for sensory-discriminative processing of noxious and somatosensory stimuli.

Integrated whole-body PET/MR hybrid imaging: clinical experience.

ObjectivesIntegrated whole-body positron emission tomography (PET)/magnetic resonance (MR) scanners have recently been introduced and potentially offer new possibilities in hybrid imaging of oncologic patients. Integration of PET in a whole-body MR system requires new PET detector technology and new approaches to attenuation correction of PET data based on MR imaging. The aim of this study was to evaluate the clinical performance and image quality parameters of integrated whole-body PET/MR hybrid imaging in intraindividual comparison with PET/CT in oncologic patients. Materials and MethodsEighty patients underwent a single-injection, dual-imaging protocol including whole-body PET/computed tomography (CT) and subsequent whole-body PET/MR hybrid imaging. Positron emission tomography/computed tomography was performed after adequate resting time (73 ± 13 minutes post injectionem of 227 ± 52.7 MBq Fluor-18-Fluordesoxyglucose, 3 minutes of acquisition time for each of 7 bed positions), followed by PET/MR (172 ± 33 minutes post injectionem, 10 minutes acquisition time for each of 4 bed positions). Positron emission tomographic data for both modalities were reconstructed iteratively. Two observers evaluated the following parameters: qualitative correlation of tracer-avid lesions in PET/CT versus PET/MR and PET image quality of PET/CT versus PET/MR. Magnetic resonance image quality of standard sequences (T1-weighted, T2-weighted), performance of the Dixon sequence for MR-based attenuation correction in comparison with corresponding T1-weighted images, artifacts in PET/MR data, and spatial coregistration of PET and MR data were evaluated by another observer. ResultsIn 70 of the 80 patients, both image data sets were complete. In these patients, 192 tracer-avid lesions were identified on PET/CT; 195, on PET/MR. A total of 187 lesions were identified concordantly by both modalities, and this corresponds to an agreement rate of 97.4%. The overall PET image quality was rated good to excellent for PET from PET/CT (12/28, excellent, 42.9%; 16/28, good, 57.1%; 0/28, poor, 0.0%) and slightly superior compared with PET from PET/MR, which was rated good (3/28, excellent, 10.7%; 20/28, good, 71.4%; 5/28, poor, 17.9%) in a subset of 28 patients. The overall image quality of the MR image data sets in all 70 of the 80 patients was rated excellent (260/280, excellent, 92.8%; 15/280, good, 5.4%; 5/280, poor, 1.8%). The Dixon sequence and conversion to &mgr;-maps for MR-based attenuation correction provided robust tissue segmentation in all 280 bed positions of the acquired PET/MR data. No artifacts such as elevated noise and radiofrequency disturbances related to hardware cross talk between the PET and MR components in the hybrid system could be detected in the MR images. Nomajor spatial mismatches between PET and MR data were detected. ConclusionsIntegrated PET/MR hybrid imaging is feasible in a clinical setting with similar detection rates as those of PET/CT. Attenuation correction can be performed sufficiently with Dixon sequences, although bone is disregarded. The administration of specific radiotracers and dedicated imaging sequences will foster this hybrid imaging modality in various indications.

Embolic Cerebral Insults After Transapical Aortic Valve Implantation Detected by Magnetic Resonance Imaging

OBJECTIVES This study assessed the rate of periprocedural embolic ischemic brain injury during transapical aortic valve replacement in 25 consecutive patients. BACKGROUND Transcatheter aortic valve implantation is rapidly being established as a new therapeutic approach for aortic valve stenosis. Although initial clinical results are promising, it is unknown whether mobilization and embolization of calcified particles may lead to cerebral ischemia. METHODS Twenty-five consecutive patients (10 men, 15 women, mean age: 81 ± 5 years, mean log EuroSCORE [European System for Cardiac Operative Risk Evaluation]: 32 ± 10%) scheduled for transapical aortic valve implantation were included. All patients received a baseline cerebral magnetic resonance imaging scan. The scan was repeated approximately 6 days after valve implantation. The magnetic resonance imaging studies included axial diffusion-weighted, T(2)-weighted, fluid attenuated inversion recovery-weighted, and T(2) gradient echo sequences. Standardized assessment of the neurologic status was performed before aortic valve replacement and post-operatively. RESULTS Transapical aortic valve implantation was successfully performed in all patients. In 17 patients (68%), new cerebral lesions could be detected, whereas 8 patients showed no new cerebral insults. The pattern of distribution and morphology were typical of embolic origin. Despite the high incidence of morphologically detectable lesions, only 5 patients showed clinical neurologic alterations. Out of these patients, only 1 suffered from a permanent stroke. CONCLUSIONS New embolic ischemic cerebral insults are detected in 68% of patients after transapical valve implantation. Clinical symptoms are rare and usually transitory. Larger trials will need to establish the clinical significance of asymptomatic ischemic lesions as well as the rate of ischemic events in patients undergoing transfemoral valve replacement.

Metal Artifact Reduction for Clipping and Coiling in Interventional C-Arm CT

BACKGROUND AND PURPOSE: Metallic implants induce massive artifacts in CT images which deteriorate image quality and often superimpose structures of interest. The purpose of this study was to apply and evaluate a dedicated MAR method for neuroradiologic intracranial clips and detachable platinum coiling events. We here report the first clinical results for MAR in FDCT. MATERIALS AND METHODS: FDCT volume scans of several patients treated with endovascular coiling or intracranial clipping were corrected by using a dedicated FDCT MAR correction algorithm combined with an edge-preserving attenuation-normalization method in the projection space. Corrected and uncorrected images were compared by 2 experienced radiologists and evaluated for several image-quality features. RESULTS: After application of our algorithm, implant delineation and visibility were highly improved. CT values compared with values in metal artifact−unaffected areas showed good agreement (average correction of 1300 HU). Image noise was reduced overall by 27%. Intracranial hemorrhage in the direct surroundings of the implanted coil or clip material was displayed without worrisome metal artifacts, and our algorithm even allowed diagnosis in areas where extensive information losses were seen. The high spatial resolution provided by FDCT imaging was well preserved. CONCLUSIONS: Our MAR method provided metal artifact−reduced images in every studied case. It reduced image noise and corrected CT values to levels comparable with images measured without metallic implants. An overall improvement of brain tissue modeling and implant visibility was achieved. MAR in neuroradiologic FDCT imaging is a promising step forward for better image quality and diagnosis in the presence of metallic implants.