Unravelling the etiology of sporadic late-onset cerebellar ataxia in a cohort of 205 patients: a prospective study.

BACKGROUND: Despite recent progress in the field of genetics, sporadic late-onset (> 40 years) cerebellar ataxia (SLOCA) etiology remains frequently elusive, while the optimal diagnostic workup still needs to be determined. We aimed to comprehensively describe the causes of SLOCA and to discuss the relevance of the investigations. METHODS: We included 205 consecutive patients with SLOCA seen in our referral center. Patients were prospectively investigated using exhaustive clinical assessment, biochemical, genetic, electrophysiological, and imaging explorations. RESULTS: We established a diagnosis in 135 (66%) patients and reported 26 different causes for SLOCA, the most frequent being multiple system atrophy cerebellar type (MSA-C) (41%). Fifty-one patients (25%) had various causes of SLOCA including immune-mediated diseases such as multiple sclerosis or anti-GAD antibody-mediated ataxia; and other causes, such as alcoholic cerebellar degeneration, superficial siderosis, or Creutzfeldt-Jakob disease. We also identified 11 genetic causes in 20 patients, including SPG7 (n = 4), RFC1-associated CANVAS (n = 3), SLC20A2 (n = 3), very-late-onset Friedreich's ataxia (n = 2), FXTAS (n = 2), SCA3 (n = 1), SCA17 (n = 1), DRPLA (n = 1), MYORG (n = 1), MELAS (n = 1), and a mitochondriopathy (n = 1) that were less severe than MSA-C (p < 0.001). Remaining patients (34%) had idiopathic late-onset cerebellar ataxia which was less severe than MSA-C (p < 0.01). CONCLUSION: Our prospective study provides an exhaustive picture of the etiology of SLOCA and clues regarding yield of investigations and diagnostic workup. Based on our observations, we established a diagnostic algorithm for SLOCA.

Wrong-site nerve blocks: 10 yr experience in a large multihospital health-care system.

INTRODUCTION: Although wrong-site surgery has garnered extensive scrutiny, the incidence of wrong-site blocks remains unknown. Our study thus sought to quantify the incidence of wrong-site blocks and examine some of their associated risk factors in our multihospital health-care system. METHODS: Using quality-improvement and billing data, we quantified the total number of blocks and wrong-site blocks occurring between July 1, 2002 and June 30, 2012 within the University of Pittsburgh Medical Center Health System. The incidence of wrong-site block was determined by block type, hospital, and type of service involved in performing the block. The incidence of wrong-site block was compared with that of wrong-site surgery. Fisher's exact tests were performed to determine associations between the incidence of wrong-site block and any of the aforementioned variables. A root-cause analysis was performed to determine the source of wrong-site blocks after the implementation of a timeout policy. RESULTS: Of the 85 915 patients receiving blocks, 70 441 received only unilateral blocks, yielding an overall incidence of wrong-site block of 1.28 (95% confidence interval 0.43-2.13) per 10 000 patients receiving unilateral blocks. The incidence of wrong-site block was highest with femoral blocks, and differed from the incidence of wrong-site surgery. All occurrences of wrong-site block after the implementation of the timeout policy involved policy violations. CONCLUSIONS: Our study provides the first incidence data on wrong-site block in a large patient population and can help hospitals to develop policies based on these data. It is yet to be determined whether active intervention can eliminate this adverse event.

The nerve stimulation technique versus the loss of resistance technique for the posterior approach to lumbar plexus block: a randomized, prospective, observer-blinded, pilot study.

BACKGROUND: This prospective, randomized, observer-blinded, pilot study compares the effects of the nerve stimulation guidance technique (NS) with the loss of resistance technique (LOR) on readiness for surgery during the posterior approach to lumbar plexus block. METHODS: Thirty ASA status I-III patients who were 18-85 years old and who were undergoing hip fracture repair were enrolled. After parasacral sciatic nerve block, patients were randomly allocated to receive a continuous posterior lumbar plexus block using nerve stimulation (n=15) or a continuous psoas compartment block using the loss of resistance technique (n=15) with 20 ml of 1.5% mepivacaine. A blinded observer monitored for sensory and motor block onsets every 5 minutes. We defined readiness for surgery as complete numbness to the pinprick test and complete motor block on the surgical side. If incomplete, the lumbar plexus block was supplemented with 10 mL of 1.5% mepivacaine through the catheter before surgery. Intraoperative fentanyl or general anesthesia requirements, pain scores, local anesthetic consumption, morphine requirements for breakthrough pain and side effects were monitored. RESULTS: The mean time to readiness for surgery was 12±6 min Group NS and 22±6 min in Group LOR (P=0.03). Three patients in Group NS and 9 patients in Group LOR required additional boluses of local anesthetic through the lumbar plexus catheter before surgery (P=0.113). CONCLUSION: Nerve stimulation allowed faster readiness for surgery than loss of resistance. Nevertheless, the two techniques seem to be comparable in terms of local anesthetic consumption, morphine requirements and pain scores.

Continuous peripheral nerve blocks in acute pain management.

The indications for continuous nerve blocks for the perioperative pain management in hospitalized and ambulatory patients have extended well beyond orthopaedics. These techniques are not only used to control pain in patients undergoing major upper and lower extremity surgery, but also to provide perioperative analgesia in patients undergoing abdominal, plastic, urological, gynaecological, thoracic, and trauma surgeries. Infusion regimens of local anaesthetics and supplements must take into consideration the condition of the patient before and after surgery, the nature and intensity of the surgical stress associated with the surgery, and the possible need for immediate functional recovery. Continuous nerve blocks have proved safe and effective in reducing opioid consumption and related side-effects, accelerating recovery, and in many patients reducing the length of hospital stay. Continuous nerve blocks provide a safer alternative to epidural analgesia in patients receiving thromboprophylaxis, especially with low molecular-weight heparin.

Cell cloning-based transcriptome analysis in Rett patients: relevance to the pathogenesis of Rett syndrome of new human MeCP2 target genes.

More than 90% of Rett syndrome (RTT) patients have heterozygous mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene that encodes the methyl-CpG-binding protein 2, a transcriptional modulator. Because MECP2 is subjected to X chromosome inactivation (XCI), girls with RTT either express the wild-type or mutant allele in each individual cell. To test the consequences of MECP2 mutations resulting from a genome-wide transcriptional dysregulation and to identify its target genes in a system that circumvents the functional mosaicism resulting from XCI, we carried out gene expression profiling of clonal populations derived from fibroblast primary cultures expressing exclusively either the wild-type or the mutant MECP2 allele. Clonal cultures were obtained from skin biopsy of three RTT patients carrying either a non-sense or a frameshift MECP2 mutation. For each patient, gene expression profiles of wild-type and mutant clones were compared by oligonucleotide expression microarray analysis. Firstly, clustering analysis classified the RTT patients according to their genetic background and MECP2 mutation. Secondly, expression profiling by microarray analysis and quantitative RT-PCR indicated four up-regulated genes and five down-regulated genes significantly dysregulated in all our statistical analysis, including excellent potential candidate genes for the understanding of the pathophysiology of this neurodevelopmental disease. Thirdly, chromatin immunoprecipitation analysis confirmed MeCP2 binding to respective CpG islands in three out of four up-regulated candidate genes and sequencing of bisulphite-converted DNA indicated that MeCP2 preferentially binds to methylated-DNA sequences. Most importantly, the finding that at least two of these genes (BMCC1 and RNF182) were shown to be involved in cell survival and/or apoptosis may suggest that impaired MeCP2 function could alter the survival of neurons thus compromising brain function without inducing cell death.

[Epileptogenic brain malformations: radiological and clinical presentation and indications for genetic testing]. / Malformations cérébrales et épilepsie: présentations radiocliniques et implications pour le diagnostic génétique.

Malformations of cortical development (MCD) represent a major cause of developmental disabilities and severe epilepsy. Advances in imaging and genetics have improved the diagnosis and classification of these conditions. Up to now, eight genes have been involved in different types of MCD. Lissencephaly-pachygyria and subcortical band heterotopia (SBH) represent a malformative spectrum resulting from mutations of either LIS1 or DCX genes. LIS1 mutations cause a more severe malformation in the posterior brain regions. DCX mutations usually cause anteriorly predominant lissencephaly in males and SBH in female patients. Additional forms are X-linked lissencephaly with corpus callosum agenesis and ambiguous genitalia associated with mutations of the ARX gene. Lissencephaly with cerebellar hypoplasia (LCH) encompass heterogeneous disorders named LCH type a to d. LCHa are related with mutation in LIS1 or DCX, LCHb with mutation of RELN gene, and LCHd could be related with TUBA1A gene. Polymicrogyria encompass a wide range of clinical, aetiological and histological findings. Among several syndromes, recessive bilateral fronto-parietal polymicrogyria has been associated with mutations of the GPR56 gene. Bilateral perisylvian polymicrogyria showed a linkage to chromosome Xq28 in some pedigrees, and mutations in SRPX2 gene in others conditions. X-linked bilateral periventricular nodular heterotopia (BPNH) consists of BPNH with focal epilepsy in females and prenatal lethality in males. Filamin A (FLNA) mutations have been reported in some families and in sporadic patients. It is possible to infer the most likely causative gene by brain imaging studies and other clinical findings. Based on this experience, a detailed phenotype analysis is needed to develop the most efficient research on MCD in the future.

International normalized ratio and prothrombin time values before the removal of a lumbar plexus catheter in patients receiving warfarin after total hip replacement.

BACKGROUND: There is a paucity of data regarding the coagulation status when discontinuing perineural catheters in patients receiving anticoagulant after operation. This retrospective study was designed to establish international normalized ratio (INR) and prothrombin time (PT) at the time of removal of lumbar plexus perineural catheters in patients receiving warfarin after total hip replacement. METHODS: Patients who received a continuous lumbar plexus nerve block for postoperative analgesia and received warfarin after total hip surgery between August 2002 and June 2007 were included in this retrospective study. PT and INRs were recorded before surgery and every day after operation along with any post-surgical nerve injury and bleeding related to the removal of the perineural catheter. RESULTS: Six hundred and seventy patients met the inclusion criteria. Almost all lumbar plexus catheters (89%) were removed on postoperative day 2. At the time of the perineural catheter removal, 36.2% of patients had an INR >1.4 (range: 1.5-3.9). One case of local bleeding was recorded at the time of the catheter removal with an INR of 3.0. This was managed with a direct pressure at the site. CONCLUSIONS: Although in this retrospective analysis, we demonstrated that lumbar plexus catheters were removed with an INR > or =1.5, additional data are required to confirm the safety of such an approach.

Mutations in the AP1S2 gene encoding the sigma 2 subunit of the adaptor protein 1 complex are associated with syndromic X-linked mental retardation with hydrocephalus and calcifications in basal ganglia.

Fried syndrome, first described in 1972, is a rare X-linked mental retardation that has been mapped by linkage to Xp22. Clinical characteristics include mental retardation, mild facial dysmorphism, calcifications of basal ganglia and hydrocephalus. A large four-generation family in which the affected males have striking clinical features of Fried syndrome were investigated for linkage to X-chromosome markers; the results showed that the gene for this condition lies within the interval DXS7109-DXS7593 in Xp22.2. In total, 60 candidate genes located in this region, including AP1S2, which was recently shown to be involved in mental retardation, were screened for mutations. A mutation in the third intron of AP1S2 was found in all affected male subjects in this large French family. The mutation resulted in skipping of exon 3, predicting a protein with three novel amino-acids and with termination at codon 64. In addition, the first known large Scottish family affected by Fried syndrome was reinvestigated, and a new nonsense mutation, p.Gln66X, was found in exon 3. Using CT, both affected patients from the French family who were analysed had marked calcifications of the basal ganglia, as previously observed in the first Scottish family, suggesting that the presence of distinctive basal ganglia calcification is an essential parameter to recognise this syndromic disorder. It may be possible to use this feature to identify families with X-linked mental retardation that should be screened for mutations in AP1S2.

Single-dose aprepitant vs ondansetron for the prevention of postoperative nausea and vomiting: a randomized, double-blind phase III trial in patients undergoing open abdominal surgery.

BACKGROUND: The neurokinin(1) antagonist aprepitant is effective for prevention of chemotherapy-induced nausea and vomiting. We compared aprepitant with ondansetron for prevention of postoperative nausea and vomiting. METHODS: Nine hundred and twenty-two patients receiving general anaesthesia for major abdominal surgery were assigned to receive a single preoperative dose of oral aprepitant 40 mg, oral aprepitant 125 mg, or i.v. ondansetron 4 mg in a randomized, double-blind trial. Vomiting episodes, use of rescue therapy, and nausea severity (verbal rating scale) were documented for 48 h after surgery. Primary efficacy endpoints were complete response (no vomiting and no use of rescue therapy) 0-24 h after surgery and no vomiting 0-24 h after surgery. The secondary endpoint was no vomiting 0-48 h after surgery. RESULTS: Aprepitant at both doses was non-inferior to ondansetron for complete response 0-24 h after surgery (64% for aprepitant 40 mg, 63% for aprepitant 125 mg, and 55% for ondansetron, lower bound of 1-sided 95% CI > 0.65), superior to ondansetron for no vomiting 0-24 h after surgery (84% for aprepitant 40 mg, 86% for aprepitant 125 mg, and 71% for ondansetron; P < 0.001), and superior for no vomiting 0-48 h after surgery (82% for aprepitant, 40 mg, 85% for aprepitant, 125 mg, and 66% for ondansetron; P < 0.001). The distribution of peak nausea scores was lower in both aprepitant groups vs ondansetron (P < 0.05). CONCLUSIONS: Aprepitant was non-inferior to ondansetron in achieving complete response for 24 h after surgery. Aprepitant was significantly more effective than ondansetron for preventing vomiting at 24 and 48 h after surgery, and in reducing nausea severity in the first 48 h after surgery. Aprepitant was generally well tolerated.

Lidocaine versus ropivacaine for continuous interscalene brachial plexus block after open shoulder surgery.

BACKGROUND: This study compared the postoperative infusion of 1% lidocaine and 0.2% ropivacaine for continuous interscalene analgesia in patients undergoing open shoulder surgery. METHODS: Forty patients undergoing open shoulder surgery received an interscalene brachial plexus block with 30 ml of either 1.5% lidocaine (n = 20) or 0.5% ropivacaine (n = 20), followed by a continuous patient-controlled interscalene analgesia with 1% lidocaine or 0.2% ropivacaine, respectively. A blinded observer recorded the quality of analgesia and recovery of motor function during the first 24 h of infusion. RESULTS: Onset of the block occurred after 7.5 (5-40) min with lidocaine and 30 (10-60) min with ropivacaine (P = 0.0005). Postoperative pain intensity was higher with lidocaine than ropivacaine for the first 8 h of infusion. The ratio between boluses given and demanded from the pump was 0.5 (0.13-0.7) with lidocaine and 0.7 (0.4-1.0) with ropivacaine (P = 0.005). Rescue IV tramadol was required during the first 24 h of infusion by 16 patients of the lidocaine group (84%) and eight patients of the ropivacaine group (46%) (P = 0.05). At the 16 h and 24 h observation times a larger proportion of patients receiving ropivacaine had complete regression of motor block (70% and 95%) than patients receiving lidocaine (50% and 55%) (P = 0.05 and P = 0.013, respectively). CONCLUSIONS: Although 1% lidocaine can be effectively used for postoperative patient-controlled interscalene analgesia, 0.2% ropivacaine provides better pain relief and motor function.

Reduction of operating and recovery room times and overnight hospital stays with interscalene blocks as sole anesthetic technique for rotator cuff surgery.

BACKGROUND: The effort to decrease hospital stays and to increase operating room efficacy has become an important consideration in the practice of anesthesia. METHODS: Fifty-three patients who underwent shoulder rotator cuff repair in the sitting position were divided into four groups according to the anesthesia technique used: Group 1 (general anesthesia), Group 2 (interscalene block), Group 3 (interscalene combined with general anesthesia) and Group 4 (general anesthesia combined with local injection of local anesthetics). Interscalene blocks were performed preoperatively, using a nerve stimulator. After appropriately locating the brachial plexus, a mixture of 40 ml of 2% lidocaine and 0.5% bupivacaine (v/v) was injected. RESULTS: As compared to general anesthesia, the use of an interscalene block alone reduced the following operating room times: 1) from the patient's arrival in the operating room to the beginning of surgery and 2) from the end of surgery to the patient's departure from the operating room. Use of the interscalene block also resulted in a reduction of recovery time when compared to Groups 1, 3 and 4 by 40, 56 and 66%, respectively. Compared to Group 1, this anesthesia technique was furthermore associated with a 64% decrease in the number of patients hospitalized overnight. CONCLUSIONS: This study confirms that the interscalene block as sole anesthesia technique is safe and effective and can contribute to shorten the hospital length of stay of patients undergoing shoulder rotator cuff surgery.

Measurement of cardiac function in conscious rats.

The goal of this study was to establish that 1. blood velocity profile in the rat aorta is parabolic, and 2. measure of left ventricular thickening fraction can be used in rats. Spontaneously hypertensive and normotensive Wistar Kyoto rats were instrumented with a 20-MHz pulsed Doppler flow probe around the thoracic aorta and a 20-MHz pulsed Doppler thickening probe on the left ventricle. Doppler frequency shifts were measured throughout the entire aorta diameter, and individual blood velocity profiles were constructed. It was demonstrated that blood velocity in the ascending aorta of rats is laminar; therefore, cardiac output can be measured using the pulsed Doppler method. In Wistar Kyoto rats, left ventricular thickening fraction was 24 +/- 1% and 25 +/- 1%, 2 and 3 weeks following surgery. In spontaneously hypertensive rats, left ventricular thickening fraction was 22 +/- 2%. Halothane depressed left ventricular thickening fraction, whereas isoproterenol increased left ventricular thickening fraction in conscious rats. Thus, pulsed Doppler technique is a valuable tool for evaluating cardiovascular function in conscious rats.

[Peripheral blocks for the lower limb: lumbar plexus]. / Blocchi periferici per l'arto inferiore: il plesso lombare.

BACKGROUND: The techniques of continuous peripheral blockades have shown to be efficient in postoperative pain control, in the various orthopaedic procedures of the limbs. The aim of this study is to evaluate the existing data about the use of a continuous blockade of the lumbar plexus or femoral nerve, together with the indications for technique and therapy. METHODS: We considered the principal results of prospective, randomised studies described in literature about the assessment of a continuous peripheral blockade of the lumbar plexus or the femoral nerve in limb surgery. Furthermore we described the principal techniques for positioning the perinerval catheters in the considered sites, and the advised dosage regimen. RESULTS: The various studies report an adequate costs/benefits relation concerning the used techniques. The analysed studies not only report an adequate efficacy of the postoperative pain control, but often show an important benefit in terms of functional recovery of the operated limbs and on final outcome of the patient. CONCLUSIONS: The use of continuous blockades of the lumbar plexus or femoral nerve shows to be an important and effective instrument not only in terms of positive effects on postoperative pain control, but also in terms of relevant advantages concerning final outcome after surgery. Nevertheless these techniques should not be considered as the only approach to postoperative pain in the orthopaedic patient, but have to be included in a global, multidisciplinary and multimodal approach.

Regional anesthesia for outpatient orthopedic surgery.

The constant search for increased efficiency and reduction of hospital length of stay has led to an increase number of major orthopedic procedures performed as outpatients and the increase in the associated intensity and duration of acute postoperative pain. Although, it is well established that single peripheral blocks provide adequate anesthesia and excellent immediate postoperative analgesia in patients undergoing minor ambulatory orthopedic surgery, the postoperative acute pain benefit is limited to less than 24 hours. However, many patients required over 24 hours of intensive postoperative analgesia. Furthermore the need for immediate postoperative physical therapy in orthopedics dictates that local anesthetics be chosen on the basis of their safety and ability to produce preferential sensory blocks. As early as 1946, Ansbro proposed the use of continuous nerve blocks to prolong the duration of analgesia of nerve block technique during anesthesia. Continuous nerve blocks have also been used for the acute postoperative pain control of patients undergoing major orthopedic surgery as in-patients. This technique has been proven to be safe and effective in controlling acute postoperative pain and improve functional outcome. The recent introduction of safer local anesthetics producing preferential sensory blocks along with the development of ambulatory pumps has allow to extend the use of these continuous block techniques to ambulatory patients. Recent development also included the use of cox2 inhibitors along with cold maximize postoperative analgesia. This multimodal approach has been proven to be safe and efficacious as much for resting pain than pain associated with exercise.

Pooled analysis of three large clinical trials to determine the optimal dose of dolasetron mesylate needed to prevent postoperative nausea and vomiting. The Dolasetron Prophylaxis Study Group.

STUDY OBJECTIVE: To identify the maximally effective dolasetron dose (i.e., maximum efficacy with minimum adverse events) for prevention of postoperative nausea and vomiting (PONV) using the statistical power generated in a pooled patient sample from three large, nearly identical clinical trials. DESIGN: Three randomized, multicenter, placebo-controlled, double-blinded trials. SETTING: Trials 1, 2, and 3 enrolled patients at 10, 25, and 17 hospitals and/or surgical centers, respectively. PATIENTS: A total of 1,946 ASA physical status, I, II, and III patients. Trials 1 and 2 enrolled only female patients (n = 916) undergoing gynecologic surgery. Trial three enrolled 722 females (approximately 70% gynecologic surgeries) and 308 males (approximately 46% orthopedic surgeries) undergoing a variety of surgical procedures. INTERVENTIONS: All surgical procedures used balanced general anesthesia. Patients received 12.5, 25, 50, or 100 mg of the antiemetic, dolasetron, near the end of anesthesia. MEASUREMENTS AND MAIN RESULTS: Efficacy endpoints were identical and measured for 24 hours: complete response (no vomiting or rescue medication) and maximum nausea, reported using a 100-mm visual analog scale (VAS). Safety was assessed using adverse event reports, laboratory and electrocardiographic data, and vital signs. All four dolasetron doses produced significant increases in complete response and decreases in maximum VAS nausea compared with placebo (p < 0.01). No increased efficacy was observed with dolasetron doses higher than 12.5 mg. Safety was similar between each dolasetron dose and placebo. CONCLUSION: Dolasetron 12.5 mg, given near the end of anesthesia, is the maximally effective dose studied for preventing postoperative nausea and vomiting.

Characterization of a highly complex region in Xq13 and mapping of three isodicentric breakpoints associated with preleukemia.

The chromosomal abnormality represented by an isodicentric X chromosome [idic(X)(q13)] is associated with a subset of acute myeloid leukemia (AML) and preleukemia observed in elderly females. A previous study localized the breakpoints of two acquired isodicentric X chromosomes associated with myelodysplasia to a 450-kb region proximal to the XIST gene. Here we report the construction and extensive characterization of a reliable 1-Mb P1 artificial chromosome and bacterial artificial chromosome contig covering a highly problematic region in Xq13 that includes the previously described isodicentric breakpoint region. In addition to mapping of the brain-specific gene (NAP1L2) and the phosphoglyceryl kinase alpha subunit 1 gene (PHKA1) and generation and mapping of a large number of STSs throughout the contig, we have mapped a putative transcriptional regulatory protein (HDACL1), and 35 ESTs. Sequencing data, Southern blot analysis, and fiber-FISH analysis have permitted characterization of extensive region-specific duplications and triplications in addition to an unusually high concentration of long interspersed repeat elements, both of which could be implicated in isodicentric chromosome formation and other Xq13 chromosome aberrations. FISH analysis of metaphase chromosomes from two previously unpublished AML patients and one preleukemic patient using cosmid clones and selected subclones allowed mapping of the idic(X)(q13) breakpoints to a 100-kb interval, consistent with the involvement of an X-linked gene in the genesis of this form of preleukemia, disruption of which may represent a preliminary step in progression to AML. Assembly and physical mapping of this complex 1-Mb contig establish a foundation for ongoing sequencing and gene identification projects in the region.