MRI roadmap-guided transendocardial delivery of exon-skipping recombinant adeno-associated virus restores dystrophin expression in a canine model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) cardiomyopathy patients currently have no therapeutic options. We evaluated catheter-based transendocardial delivery of a recombinant adeno-associated virus (rAAV) expressing a small nuclear U7 RNA (U7smOPT) complementary to specific cis-acting splicing signals. Eliminating specific exons restores the open reading frame resulting in translation of truncated dystrophin protein. To test this approach in a clinically relevant DMD model, golden retriever muscular dystrophy (GRMD) dogs received serotype 6 rAAV-U7smOPT via the intracoronary or transendocardial route. Transendocardial injections were administered with an injection-tipped catheter and fluoroscopic guidance using X-ray fused with magnetic resonance imaging (XFM) roadmaps. Three months after treatment, tissues were analyzed for DNA, RNA, dystrophin protein, and histology. Whereas intracoronary delivery did not result in effective transduction, transendocardial injections, XFM guidance, enabled 30±10 non-overlapping injections per animal. Vector DNA was detectable in all samples tested and ranged from <1 to >3000 vector genome copies per cell. RNA analysis, western blot analysis, and immunohistology demonstrated extensive expression of skipped RNA and dystrophin protein in the treated myocardium. Left ventricular function remained unchanged over a 3-month follow-up. These results demonstrated that effective transendocardial delivery of rAAV-U7smOPT was achieved using XFM. This approach restores an open reading frame for dystrophin in affected dogs and has potential clinical utility.

Parallel transmit excitation at 1.5 T based on the minimization of a driving function for device heating.

PURPOSE: To provide a rapid method to reduce the radiofrequency (RF) E-field coupling and consequent heating in long conductors in an interventional MRI (iMRI) setup. METHODS: A driving function for device heating (W) was defined as the integration of the E-field along the direction of the wire and calculated through a quasistatic approximation. Based on this function, the phases of four independently controlled transmit channels were dynamically changed in a 1.5 T MRI scanner. During the different excitation configurations, the RF induced heating in a nitinol wire immersed in a saline phantom was measured by fiber-optic temperature sensing. Additionally, a minimization of W as a function of phase and amplitude values of the different channels and constrained by the homogeneity of the RF excitation field (B1) over a region of interest was proposed and its results tested on the benchtop. To analyze the validity of the proposed method, using a model of the array and phantom setup tested in the scanner, RF fields and SAR maps were calculated through finite-difference time-domain (FDTD) simulations. In addition to phantom experiments, RF induced heating of an active guidewire inserted in a swine was also evaluated. RESULTS: In the phantom experiment, heating at the tip of the device was reduced by 92% when replacing the body coil by an optimized parallel transmit excitation with same nominal flip angle. In the benchtop, up to 90% heating reduction was measured when implementing the constrained minimization algorithm with the additional degree of freedom given by independent amplitude control. The computation of the optimum phase and amplitude values was executed in just 12 s using a standard CPU. The results of the FDTD simulations showed similar trend of the local SAR at the tip of the wire and measured temperature as well as to a quadratic function of W, confirming the validity of the quasistatic approach for the presented problem at 64 MHz. Imaging and heating reduction of the guidewire were successfully performed in vivo with the proposed hardware and phase control. CONCLUSIONS: Phantom and in vivo data demonstrated that additional degrees of freedom in a parallel transmission system can be used to control RF induced heating in long conductors. A novel constrained optimization approach to reduce device heating was also presented that can be run in just few seconds and therefore could be added to an iMRI protocol to improve RF safety.

Hearing loss in multiple sclerosis.

Hearing loss in an uncommon symptom in multiple sclerosis (MS). In nine patients with MS, seven with unilateral hearing loss and two with bilateral impairment, accompanying symptoms and signs included facial numbness, hemifacial paresis or spasms, ipsilateral limb ataxia, nystagmus, vertigo, tinnitus, and spastic-ataxic gait. Central auditory dysfunction was suggested by audiometric findings and/or by brainstem auditory evoked potentials in all nine patients. Clinical improvement in two was accompanied by return toward normal in the results of audiometric or electrophysiologic studies. Hearing impairment should be sought in patients with MS and appropriate studies pursued.

Postpartum neuralgic amyotrophy.

We report 11 women with at least one episode of neuralgic amyotrophy occurring postpartum. One woman had three episodes-two postpartum and a third occurring after minor foot surgery. Two others had a second episode, one following a first trimester spontaneous abortion and one after a viral syndrome. Pain followed delivery from as little as 1 to 2 hours to up to 2 weeks and usually lasted from a few weeks to several months. Weakness, if delayed, followed onset of pain by 2 or 3 days up to 5 weeks. Four of the episodes were bilateral. Clinical weakness and electrodiagnostic findings varied widely, from involvement of a single peripheral nerve (e.g., long thoracic, anterior interosseous) to multiple bilateral proximal and distal nerves. Functional recovery was excellent (90 to 100%) in 8 of the 10 with adequate follow-up, requiring as little as 2 weeks or up to 3 years. Two women have moderate persisting weakness (both bilateral) at 3 years and 2 years. Five patients went on to subsequent deliveries without recurrence of neuralgic amyotrophy. Only one of the 11 women had a history suggesting familial neuralgic amyotrophy, a disorder generally thought to be associated particularly with postpartum episodes. Although the etiology of postpartum neuralgic amyotrophy remains unknown, an immunologic mechanism is suspected. Focal demyelination may play a role in some, but clearly axonal degeneration is predominant in the majority.

Brachial plexopathy: recurrent cancer or radiation?

We reviewed clinical and electrodiagnostic features of 16 patients with neoplastic brachial plexopathy (NBP) and 17 patients with radiation-induced plexopathy (RBP). The groups were similar in symptom-free interval after cancer diagnosis and location of the plexus lesions. NBP patients had pain and Horner's syndrome; RBP patients had paresthesias, but rarely Horner's. NBP patients presented earlier after symptom onset and had a shorter course. RBP patients more frequently had abnormal sensory and normal motor nerve conduction studies and characteristically had fasciculations or myokymia on EMG.

Ischemic optic neuropathy: a complication of cardiopulmonary bypass surgery.

Ischemic optic neuropathy followed cardiopulmonary bypass surgery in the postoperative period in 7 of 7685 consecutive procedures. Th visual loss was unilateral in four patients and bilateral in three and there was little improvement. This ischemic infarction of the optic nerve disk was attributed to hypotension, hypothermia, and activation of certain complement factors by the bypass procedure.

Neurologic complications of liver transplantation.

Nineteen adult patients underwent 21 orthotopic liver transplants at the Cleveland Clinic between November 1984, and August 1986. Eight of 19 (42%) patients developed seizures. One patient suffered a single seizure, and seven patients had multiple, generalized seizures. Two of these seven patients became comatose after several days of seizure activity. Over several weeks, both of these patients regained consciousness--however, they exhibited a cerebellar-type syndrome, manifested as severe ataxia, weakness, and dysarthria. Both patients have improved, but remain neurologically impaired. Laboratory evaluation included serum electrolytes, magnesium, osmolality, and cyclosporine levels. Neurologic testing consisted of cerebrospinal fluid (CSF) analysis, computed tomographic (CT) scanning, and electroencephalography (EEG). Although the CSF protein was mildly elevated in two patients, all cultures remained sterile. None of the CT scans demonstrated any abnormalities. In five patients, the EEG showed generalized slowing consistent with diffuse encephalopathy. Other factors associated with seizures in transplant patients were analyzed, including fluid retention, hypertension, high-dose steroids, hypomagnesemia, graft dysfunction, and demyelinization. Many of our patients had the first three of these factors, since all but one developed their seizures within the first ten postoperative days. Only one patient had mild hypomagnesemia. Trough cyclosporine levels (whole blood, HPLC) were not in the toxic range (greater than 500 ng/mL). The serum osmolality was elevated in all four patients in whom it was measured, ranging from 309 to 341 mOsm/kg. Only three patients exhibited graft dysfunction--two moderate and one severe. The cause of neurologic toxicity following transplantation is unclear. Although many factors have been implicated, no common denominator has emerged. Several reports have linked cyclosporine with seizures and other neurologic problems, such as the cerebellar-type syndrome exhibited in two of our patients. Future studies should include magnetic resonance (MR) imaging of the head and measuring osmolality and cyclosporine levels in the blood and CSF.

Design of the therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (TRAFFIC) trial.

The Therapeutic Angiogenesis With Recombinant Fibroblast Growth Factor-2 for Intermittent Claudication (TRAFFIC) is a large, randomized, placebo-controlled, regimen-finding trial of intra-arterial recombinant fibroblast growth factor-2 in patients with intermittent claudication. This report describes the major design considerations and end points in TRAFFIC.

Acute hemodynamic changes during carotid artery stenting.

To determine the clinical significance of acute hemodynamic disturbances during stenting in the carotid sinus region, we assessed the relation between intraprocedural changes in heart rate (HR) and blood pressure (BP) and adverse neurologic and cardiac outcomes. Eighteen patients underwent carotid stenting with the Wallstent (Schneider Inc). Suitable candidates had at least 60% diameter stenosis of the carotid artery by angiography. Initial and nadir HR and BP were recorded during the predilatation, stent delivery, and postdilatation periods. Bradycardia was defined as HR < or =60 beats/min and hypotension as systolic BP < or =100 mm Hg. Nineteen Wallstents were successfully deployed in all 19 carotid arteries. Some degree of bradycardia or hypotension occurred in 68% of carotid stent procedures, but administration of vasoactive medications was necessary in only 7 patients (37%) with more persistent hemodynamic disturbances. Hypotension or the need for continuous vasopressor therapy was significantly more common during postdilatation (32%) than in the predilatation period (5%) (p = 0.02). Bradycardia was not reduced by prophylactic atropine. In 1 patient the hemodynamic response to stenting may have contributed to an adverse neurologic and cardiac outcome. Thus, despite frequent fluctuations in HR and BP, most carotid stenting procedures were performed with excellent overall results, even in patients at high risk.

Mechanism and frequency of brachial plexus injury in open-heart surgery: a prospective analysis.

A computer-assisted prospective analysis of 531 patients undergoing open-heart operations revealed that 26 patients (5%) sustained brachial plexus injury. In 22 of the 26 patients (85%), the lesion involved the lower trunk or C8-T1 nerve roots. Electromyograms confirmed the clinical impression in 13 patients. In 19 of the 26 patients (73%), the side on which the plexus lesion was found correlated with the side of internal jugular vein cannulation. Because of the anatomical proximity of the lower trunk to the internal jugular vein and the preponderance of lower trunk lesions, we postulate that traumatic cannulation may be a major mechanism of plexus injury. Thus, the resulting syndrome of pain, dysesthesias, and hand weakness may sometimes be preventable.

Solitary primary lymphoma of the sciatic nerve: case report.

An unusual case of a solitary extranodal primary lymphoma of the sciatic nerve in a patient presenting with sciatica and a left footdrop is described. Magnetic resonance imaging was successful in identifying a fusiform lesion in the sciatic nerve in the left infragluteal region. Surgical exploration and biopsy confirmed this as a B cell lymphoma. An extensive metastatic work-up has not identified other sites of lymphomatous involvement.

Detection of atherosclerosis using a novel positron-sensitive probe and 18-fluorodeoxyglucose (FDG).

Inflammation contributes to atherosclerotic plaque remodeling, enlargement and rupture. Non-invasive imaging of coronary artery inflammation could help target therapy to 'vulnerable' atheromata, but is limited because of small tissue mass and arterial motion. Local radiopharmaceutical imaging may overcome some of these limitations. We used a positron-sensitive fiberoptic probe, which can distinguish positron emissions from annihilation photons, to identify diseased from healthy endothelium in an atherosclerotic model. New Zealand White rabbits underwent Fogarty-catheter injury of an iliac artery and then were fed a high-fat diet for 3 weeks. Fasted animals received 90-180 MBq of 18-fluorodeoxyglucose (FDG) 2-4 h before sacrifice and harvest of injured and uninjured iliacs. Arteries were incised longitudinally and the probe was placed in contact with the arterial intima. Multiple measurements were obtained along 1 cm artery segments in 60 s intervals, and corrected for 18F decay and background. Measurements were recorded over 93 injured and normal artery segments in 11 animals. Mean probe Z-scores were 4.8-fold higher (CI 3.4-6.3) over injury atherosclerosis compared with uninjured normal iliac artery segments (P<0.001). Gamma counting confirmed that injured artery segments accumulated more FDG per gram than did normal segments (0.203% x kg injected dose per gram of tissue versus 0.042, P<0.001). Non-arterial tissue also accumulated FDG avidly, particularly reticuloendothelial tissues and blood. Delayed sacrifice, 4 h compared with 2 h after animal FDG injection, further reduced blood background counts and improved the signal-to-noise ratio. Histopathology confirmed that injured iliac artery had significantly higher intimal and medial cross-sectional area compared with uninjured artery. Injured artery also had significantly higher macrophage and smooth muscle cell density. Positron-sensitive probe counts correlated with the intima to media ratio (r =0.63, P = 0.03). Our positron-sensitive probe distinguishes atherosclerotic from healthy artery in a blood-free field. Intravascular study of plaque biology may be feasible using FDG and a positron-sensitive probe.

Blood speed imaging with an intraluminal array.

In applications in which Doppler processing is not possible, such as side-looking intravascular imaging systems, decorrelation methods can be used to estimate blood speed. Here, a method is presented measuring relative blood speed using an FIR filter bank to estimate temporal decorrelation rates. It can be implemented in a modern commercially available ultrasound imaging system with no additional hardware. Both simulations and experiments using an intraluminal scanner appropriate for coronary artery applications have tested the system. In this study, the FIR filter bank is contrasted with previous methods, and its utility is further demonstrated with real-time color flow images from a pig model.

Variability in diagnosing Creutzfeldt-Jakob disease using standard and proposed diagnostic criteria.

INTRODUCTION: Creutzfeldt-Jakob disease (CJD) is a rapidly progressive dementia with a median survival of 2-14 months. The diagnosis can only be made accurately by biopsy/autopsy. However, this is not always feasible or desirable. Thus, diagnostic criteria have been proposed by UCSF, European MRI-CJD Consortium, and WHO. We will compare these criteria. PATIENTS AND METHODS: Retrospective study of 31 patients (average age of 69.2 years) between 2003 to 2010 by ICD9 codes 046.1, 046.11, and 046.19. RESULTS: All patients presented with rapidly progressive dementia (mean duration of 4.25 months). Pyramidal and extrapyramidal findings, myoclonus, cerebellar changes, akinetic mutism, and visual disturbances were observed in 6.5-48.4%. Five had periodic pattern on EEG. CSF biomarker 14-3-3 was positive in 11. Tau was positive in 6. Neuron specific enolase was positive in 9. By consensus (kappa = 0.62), MRI was "typical" of CJD in 23 with cortical ribboning (n = 16), basal ganglia hyperintensity (n = 15), or combination (n = 8). By WHO criteria, which does not include neuroimaging, CJD was diagnosed in 10, but 14 if any CSF biomarker was used (p = NS). The UCSF criteria, which does not include CSF biomarkers, diagnosed 18 cases, and the European MRI-CJD Consortium, which includes neuroimaging and CSF biomarkers but with less neurological signs, diagnosed 23 cases (p < 0.05 and p < 0.001, respectively). CJD-mimics included urosepsis, neurosarcoidosis, idiopathic left temporal lobe epilepsy, alcohol intoxication, central nervous system vasculitis, viral encephalitis, and non-Hodgkin's lymphoma. CONCLUSION: This study illustrates the variability in diagnosing CJD and emphasizes the diagnostic utility of neuroimaging. It also highlights false-positives that occur with neuroimaging.