RESUMO
BACKGROUND: The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis. METHODS: We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disease in two independent case-control series - one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). We also genotyped the repeat in 20 Australian and 31 Indian index patients. We assayed gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)-derived motor-neuron cell lines. RESULTS: In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron of FGF14, which encodes fibroblast growth factor 14. Cosegregation of the repeat expansion with disease in the families supported a pathogenic threshold of at least 250 GAA repeats ([GAA]≥250). There was significant association between FGF14 (GAA)≥250 expansions and LOCA in the French Canadian series (odds ratio, 105.60; 95% confidence interval [CI], 31.09 to 334.20; P<0.001) and in the German series (odds ratio, 8.76; 95% CI, 3.45 to 20.84; P<0.001). The repeat expansion was present in 61%, 18%, 15%, and 10% of French Canadian, German, Australian, and Indian index patients, respectively. In total, we identified 128 patients with LOCA who carried an FGF14 (GAA)≥250 expansion. Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of FGF14 RNA and protein. CONCLUSIONS: A dominantly inherited deep intronic GAA repeat expansion in FGF14 was found to be associated with LOCA. (Funded by Fondation Groupe Monaco and others.).
Assuntos
Ataxia Cerebelar , Expansão das Repetições de DNA , Íntrons , Humanos , Austrália , Canadá , Ataxia Cerebelar/genética , Ataxia Cerebelar/patologia , Ataxia de Friedreich/genética , Ataxia de Friedreich/patologia , Íntrons/genética , Expansão das Repetições de DNA/genéticaRESUMO
BACKGROUND AND OBJECTIVES: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is caused by a mutation in the transthyretin (TTR) gene. Although classically described as rapidly progressive and life-threatening, recent studies on TTR-FAP show significant genetic and phenotypic heterogeneity depending on geographic localization. In light of new therapeutic advances and their implication for patient management, the aim of our study was to determine the prevalence of TTR-FAP within patients with idiopathic neuropathy in a North American population. METHODS: We sequenced the TTR gene in a cohort of patients with idiopathic neuropathy. Genetic screening was performed in 110 patients from two neuromuscular clinics in Montreal, Canada. RESULTS: No variants of unknown significance or pathogenic mutations were detected in the TTR gene. CONCLUSION: Our study confirms that TTR-FAP is a rare entity in our patient population, and that diagnostic yield of screening all patients with idiopathic neuropathy is very low.
Assuntos
Neuropatias Amiloides Familiares , Pré-Albumina , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/epidemiologia , Neuropatias Amiloides Familiares/genética , Canadá/epidemiologia , Estudos de Coortes , Humanos , Mutação/genética , Pré-Albumina/genéticaRESUMO
BACKGROUND: Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS: We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS: A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003). CONCLUSIONS: Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).
Assuntos
Glucocorticoides/administração & dosagem , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/cirurgia , Prednisona/administração & dosagem , Timectomia , Adolescente , Adulto , Idoso , Terapia Combinada , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/classificação , Índice de Gravidade de Doença , Método Simples-Cego , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Botulism is an acute paralytic illness caused by a neurotoxin produced by Clostridium botulinum. Supportive care, including intensive care, is key, but the role of other medical treatments is unclear. This is an update of a review first published in 2011. OBJECTIVES: To assess the effects of medical treatments on mortality, duration of hospitalization, mechanical ventilation, tube or parenteral feeding, and risk of adverse events in botulism. SEARCH METHODS: We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, and Embase on 23 January 2018. We reviewed bibliographies and contacted authors and experts. We searched two clinical trials registers, WHO ICTRP and clinicaltrials.gov, on 21 February 2019. SELECTION CRITERIA: Randomized controlled trials (RCTs) and quasi-RCTs examining the medical treatment of any of the four major types of botulism (infant intestinal botulism, food-borne botulism, wound botulism, and adult intestinal toxemia). Potential medical treatments included equine serum trivalent botulism antitoxin, human-derived botulinum immune globulin intravenous (BIG-IV), plasma exchange, 3,4-diaminopyridine, and guanidine. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology.Our primary outcome was in-hospital death from any cause occurring within four weeks from randomization or the beginning of treatment. Secondary outcomes were death from any cause occurring within 12 weeks, duration of hospitalization, duration of mechanical ventilation, duration of tube or parenteral feeding, and proportion of participants with adverse events or complications of treatment. MAIN RESULTS: A single RCT met the inclusion criteria. Our 2018 search update identified no additional trials. The included trial evaluated BIG-IV for the treatment of infant botulism and included 59 treatment participants and 63 control participants. The control group received a control immune globulin that did not have an effect on botulinum toxin. Participants were followed during the length of their hospitalization to measure the outcomes of interest. There was some violation of intention-to-treat principles, and possibly some between-treatment group imbalances among participants admitted to the intensive care unit and mechanically ventilated, but otherwise the risk of bias was low. There were no deaths in either group, making any treatment effect on mortality inestimable. There was a benefit in the treatment group on mean duration of hospitalization (BIG-IV: 2.60 weeks, 95% confidence interval (CI) 1.95 to 3.25; control: 5.70 weeks, 95% CI 4.40 to 7.00; mean difference (MD) -3.10 weeks, 95% CI -4.52 to -1.68; moderate-certainty evidence); mechanical ventilation (BIG-IV: 1.80 weeks, 95% CI 1.20 to 2.40; control: 4.40 weeks, 95% CI 3.00 to 5.80; MD -2.60 weeks, 95% CI -4.06 to -1.14; low-certainty evidence); and tube or parenteral feeding (BIG-IV: 3.60 weeks, 95% CI 1.70 to 5.50; control: 10.00 weeks, 95% CI 6.85 to 13.15; MD -6.40 weeks, 95% CI -10.00 to -2.80; moderate-certainty evidence), but not on proportion of participants with adverse events or complications (BIG-IV: 63.08%; control: 68.75%; risk ratio 0.92, 95% CI 0.72 to 1.18; absolute risk reduction 0.06, 95% CI 0.22 to -0.11; moderate-certainty evidence). AUTHORS' CONCLUSIONS: We found low- and moderate-certainty evidence supporting the use of BIG-IV in infant intestinal botulism. A single RCT demonstrated that BIG-IV probably decreases the duration of hospitalization; may decrease the duration of mechanical ventilation; and probably decreases the duration of tube or parenteral feeding. Adverse events were probably no more frequent with immune globulin than with placebo. Our search did not reveal any evidence examining the use of other medical treatments including serum trivalent botulism antitoxin.
Assuntos
Botulismo/terapia , Cuidados Críticos/métodos , Imunoglobulinas Intravenosas/uso terapêutico , Toxinas Botulínicas , Hospitalização , Humanos , Imunoglobulinas , Lactente , Nutrição Parenteral , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração ArtificialRESUMO
BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction in which a clinical diagnosis may be confirmed with serological testing. The most common autoantibodies used to support a diagnosis of MG are anti-acetylcholine receptor antibodies and anti-muscle-specific tyrosine kinase antibodies. In cases in which both of these autoantibodies are negative (termed double-seronegative [dSNMG]), other autoantibodies such as low-density lipoprotein receptor-related protein 4 (LRP4) may be used to aid in diagnosis. METHODS: We have undertaken a systematic literature review to identify studies that have assessed the frequency of anti-LRP4 antibodies in dSNMG patients and the characteristics of anti-LRP4+ dSNMG patients (epidemiology, clinical features, electromyographic findings, or management). PubMed, EMBASE, Medline, and Scopus were searched on January 14, 2017, using the medical subject headings "myasthenia gravis" and "low-density lipoprotein receptor-related protein 4" or "LRP4." RESULTS: The initial search identified 367 articles. Fourteen publications met the inclusion criteria. There were ten cross-sectional research studies, three were case series, and one was a case report. The majority of studies were limited by small sample sizes of LRP4+ dSNMG. There has been a wide range of frequencies of anti-LRP4 antibodies detected in different MG patient populations, some involving different laboratory techniques. CONCLUSIONS: LRP4+ dSNMG is more likely than LRP4- dSNMG to have a younger onset of disease and occur in females. LRP4+ dSNMG most often is mild in severity and often involves isolated ocular weakness. It typically responds well to pyridostigmine or prednisone.
Assuntos
Autoanticorpos/sangue , Proteínas Relacionadas a Receptor de LDL/imunologia , Miastenia Gravis/sangue , Bases de Dados Bibliográficas/estatística & dados numéricos , Humanos , Miastenia Gravis/diagnóstico , Miastenia Gravis/imunologiaRESUMO
BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic progressive or relapsing and remitting disease that usually causes weakness and sensory loss. The symptoms are due to autoimmune inflammation of peripheral nerves. CIPD affects about 2 to 3 per 100,000 of the population. More than half of affected people cannot walk unaided when symptoms are at their worst. CIDP usually responds to treatments that reduce inflammation, but there is disagreement about which treatment is most effective. OBJECTIVES: To summarise the evidence from Cochrane systematic reviews (CSRs) and non-Cochrane systematic reviews of any treatment for CIDP and to compare the effects of treatments. METHODS: We considered all systematic reviews of randomised controlled trials (RCTs) of any treatment for any form of CIDP. We reported their primary outcomes, giving priority to change in disability after 12 months.Two overview authors independently identified published systematic reviews for inclusion and collected data. We reported the quality of evidence using GRADE criteria. Two other review authors independently checked review selection, data extraction and quality assessments.On 31 October 2016, we searched the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects (in theCochrane Library), MEDLINE, Embase, and CINAHL Plus for systematic reviews of CIDP. We supplemented the RCTs in the existing CSRs by searching on the same date for RCTs of any treatment of CIDP (including treatment of fatigue or pain in CIDP), in the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL Plus. MAIN RESULTS: Five CSRs met our inclusion criteria. We identified 23 randomised trials, of which 15 had been included in these CSRs. We were unable to compare treatments as originally planned, because outcomes and outcome intervals differed. CorticosteroidsIt is uncertain whether daily oral prednisone improved impairment compared to no treatment because the quality of the evidence was very low (1 trial, 28 participants). According to moderate-quality evidence (1 trial, 41 participants), six months' treatment with high-dose monthly oral dexamethasone did not improve disability more than daily oral prednisolone. Observational studies tell us that prolonged use of corticosteroids sometimes causes serious side-effects. Plasma exchangeAccording to moderate-quality evidence (2 trials, 59 participants), twice-weekly plasma exchange produced more short-term improvement in disability than sham exchange. In the largest observational study, 3.9% of plasma exchange procedures had complications. Intravenous immunoglobulinAccording to high-quality evidence (5 trials, 269 participants), intravenous immunoglobulin (IVIg) produced more short-term improvement than placebo. Adverse events were more common with IVIg than placebo (high-quality evidence), but serious adverse events were not (moderate-quality evidence, 3 trials, 315 participants). One trial with 19 participants provided moderate-quality evidence of little or no difference in short-term improvement of impairment with plasma exchange in comparison to IVIg. There was little or no difference in short-term improvement of disability with IVIg in comparison to oral prednisolone (moderate-quality evidence; 1 trial, 29 participants) or intravenous methylprednisolone (high-quality evidence; 1 trial, 45 participants). One unpublished randomised open trial with 35 participants found little or no difference in disability after three months of IVIg compared to oral prednisone; this trial has not yet been included in a CSR. We know from observational studies that serious adverse events related to IVIg do occur. Other immunomodulatory treatmentsIt is uncertain whether the addition of azathioprine (2 mg/kg) to prednisone improved impairment in comparison to prednisone alone, as the quality of the evidence is very low (1 trial, 27 participants). Observational studies show that adverse effects truncate treatment in 10% of people.According to low-quality evidence (1 trial, 60 participants), compared to placebo, methotrexate 15 mg/kg did not allow more participants to reduce corticosteroid or IVIg doses by 20%. Serious adverse events were no more common with methotrexate than with placebo, but observational studies show that methotrexate can cause teratogenicity, abnormal liver function, and pulmonary fibrosis.According to moderate-quality evidence (2 trials, 77 participants), interferon beta-1a (IFN beta-1a) in comparison to placebo, did not allow more people to withdraw from IVIg. According to moderate-quality evidence, serious adverse events were no more common with IFN beta-1a than with placebo.We know of no other completed trials of immunosuppressant or immunomodulatory agents for CIDP. Other treatmentsWe identified no trials of treatments for fatigue or pain in CIDP. Adverse effectsNot all trials routinely collected adverse event data; when they did, the quality of evidence was variable. Adverse effects in the short, medium, and long term occur with all interventions. We are not able to make reliable comparisons of adverse events between the interventions included in CSRs. AUTHORS' CONCLUSIONS: We cannot be certain based on available evidence whether daily oral prednisone improves impairment compared to no treatment. However, corticosteroids are commonly used, based on widespread availability, low cost, very low-quality evidence from observational studies, and clinical experience. The weakness of the evidence does not necessarily mean that corticosteroids are ineffective. High-dose monthly oral dexamethasone for six months is probably no more or less effective than daily oral prednisolone. Plasma exchange produces short-term improvement in impairment as determined by neurological examination, and probably produces short-term improvement in disability. IVIg produces more short-term improvement in disability than placebo and more adverse events, although serious side effects are probably no more common than with placebo. There is no clear difference in short-term improvement in impairment with IVIg when compared with intravenous methylprednisolone and probably no improvement when compared with either oral prednisolone or plasma exchange. According to observational studies, adverse events related to difficult venous access, use of citrate, and haemodynamic changes occur in 3% to17% of plasma exchange procedures.It is uncertain whether azathioprine is of benefit as the quality of evidence is very low. Methotrexate may not be of benefit and IFN beta-1a is probably not of benefit.We need further research to identify predictors of response to different treatments and to compare their long-term benefits, safety and cost-effectiveness. There is a need for more randomised trials of immunosuppressive and immunomodulatory agents, routes of administration, and treatments for symptoms of CIDP.
Assuntos
Corticosteroides/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Troca Plasmática , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/terapia , Literatura de Revisão como Assunto , Azatioprina/uso terapêutico , Dexametasona/uso terapêutico , Humanos , Interferon beta-1a/uso terapêutico , Metotrexato/uso terapêutico , Metilprednisolona/uso terapêutico , Prednisona/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Osteonecrosis of the femoral head is a debilitating disease that involves impaired blood supply to the femoral head and leads to femoral head collapse. METHODS: We use whole-exome sequencing and Sanger sequencing to analyse a family with inherited osteonecrosis of the femoral head and fluorescent Ca(2+) imaging to functionally characterise the variant protein. RESULTS: We report a family with four siblings affected with inherited osteonecrosis of the femoral head and the identification of a c.2480_2483delCCCG frameshift deletion followed by a c.2486T>A substitution in one allele of the transient receptor potential vanilloid 4 (TRPV4) gene. TRPV4 encodes a Ca(2+)-permeable cation channel known to play a role in vasoregulation and osteoclast differentiation. While pathogenic TRPV4 mutations affect the skeletal or nervous systems, association with osteonecrosis of the femoral head is novel. Functional measurements of Ca(2+) influx through mutant TRPV4 channels in HEK293 cells and patient-derived dermal fibroblasts identified a TRPV4 gain of function. Analysis of channel open times, determined indirectly from measurement of TRPV4 activity within a cluster of TRPV4 channels, revealed that the TRPV4 gain of function was caused by longer channel openings. CONCLUSIONS: These findings identify a novel TRPV4 mutation implicating TRPV4 and altered calcium homeostasis in the pathogenesis of osteonecrosis while reinforcing the importance of TRPV4 in bone diseases and vascular endothelium.
Assuntos
Necrose da Cabeça do Fêmur/metabolismo , Mutação , Canais de Cátion TRPV/genética , Sequência de Aminoácidos , Cálcio/metabolismo , Feminino , Necrose da Cabeça do Fêmur/genética , Humanos , Masculino , Linhagem , Alinhamento de Sequência , Canais de Cátion TRPV/química , Canais de Cátion TRPV/metabolismo , Adulto JovemRESUMO
BACKGROUND: Susac syndrome (SuS) is a rare disorder thought to be caused by autoimmune-mediated occlusions of microvessels in the brain, retina and inner ear leading to central nervous system (CNS) dysfunction, visual disturbances due to branch retinal artery occlusions (BRAO), and hearing deficits. Recently, a role for anti-endothelial cell antibodies (AECA) in SuS has been proposed. OBJECTIVES: To report the clinical and paraclinical findings in the largest single series of patients so far and to investigate the frequency, titers, and clinical relevance of AECA in SuS. PATIENTS AND METHODS: A total of 107 serum samples from 20 patients with definite SuS, 5 with abortive forms of SuS (all with BRAO), and 70 controls were tested for AECA by immunohistochemistry employing primate brain tissue sections. RESULTS: IgG-AECA >1:100 were detected in 25% (5/20) of patients with definite SuS and in 4.3% (3/70) of the controls. Median titers were significantly higher in SuS (1:3200, range 1:100 to 1:17500) than in controls (1:100, range 1:10 to 1:320); IgG-AECA titers >1:320 were exclusively present in patients with SuS; three controls had very low titers (1:10). Follow-up samples (n = 4) from a seropositive SuS patient obtained over a period of 29 months remained positive at high titers. In all seropositive cases, AECA belonged to the complement-activating IgG1 subclass. All but one of the IgG-AECA-positive samples were positive also for IgA-AECA and 45% for IgM-AECA. SuS took a severe and relapsing course in most patients and was associated with bilateral visual and hearing impairment, a broad panel of neurological and neuropsychological symptoms, and brain atrophy in the majority of cases. Seropositive and seronegative patients did not differ with regard to any of the clinical or paraclinical parameters analyzed. CONCLUSIONS: SuS took a severe and protracted course in the present cohort, resulting in significant impairment. Our finding of high-titer IgG1 and IgM AECA in some patients suggest that humoral autoimmunity targeting the microvasculature may play a role in the pathogenesis of SuS, at least in a subset of patients. Further studies are warranted to define the exact target structures of AECA in SuS.
Assuntos
Autoanticorpos/sangue , Síndrome de Susac/sangue , Síndrome de Susac/diagnóstico , Adolescente , Adulto , Idoso , Transtornos Cognitivos/etiologia , Doenças do Tecido Conjuntivo/sangue , Transtornos da Audição/etiologia , Humanos , Imunoglobulina G/sangue , Cooperação Internacional , Contagem de Leucócitos , Vasculite Associada ao Lúpus do Sistema Nervoso Central/sangue , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Testes Sorológicos , Síndrome de Susac/complicações , Transtornos da Visão/etiologia , Adulto JovemRESUMO
BACKGROUND: Botulism is an acute paralytic illness caused by a neurotoxin produced by Clostridium botulinum. Supportive care, including intensive care, is key but the role of other medical treatments is unclear. This is an update of a review first published in 2011. OBJECTIVES: To assess the effects of medical treatments on mortality, duration of hospitalization, mechanical ventilation, tube or parenteral feeding and risk of adverse events in botulism. SEARCH METHODS: On 30 March 2013, we searched the Cochrane Neuromuscular Disease Group Specialized Register (30 March 2013), CENTRAL (2013, Issue 3) in The Cochrane Library, MEDLINE (January 1966 to March 2013) and EMBASE (January 1980 to March 2013). We reviewed bibliographies and contacted authors and experts. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials examining the medical treatment of any of the four major types of botulism (infant intestinal botulism, food-borne botulism, wound botulism and adult intestinal toxemia). Potential medical treatments included equine serum trivalent botulism antitoxin, human-derived botulinum immune globulin, plasma exchange, 3,4-diaminopyridine and guanidine. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, assessed risk of bias and extracted data onto data extraction forms.Our primary outcome was in-hospital death from any cause occurring within four weeks. Secondary outcomes were death occurring within 12 weeks, duration of hospitalization, mechanical ventilation, tube or parenteral feeding and risk of adverse events. MAIN RESULTS: A single randomized controlled trial met the inclusion criteria. We found no additional trials when we updated the searches in 2013. This trial evaluated human-derived botulinum immune globulin (BIG) for the treatment of infant botulism and included 59 treatment participants as well as 63 control participants. The control group received a control immune globulin which did not have an effect on botulinum toxin. In this trial there was some violation of intention-to-treat principles, and possibly some between-treatment group imbalances among those participants admitted to the intensive care unit (ICU) and mechanically ventilated, but overall we judged the risk of bias to be low. There were no deaths in either group, making any treatment effect on mortality inestimable. There was a significant benefit in the treatment group on mean duration of hospitalization (BIG: 2.60 weeks, 95% CI 1.95 to 3.25; control: 5.70 weeks, 95% CI 4.40 to 7.00; mean difference (MD) 3.10 weeks, 95% CI 1.68 to 4.52), mechanical ventilation (BIG: 1.80 weeks, 95% CI 1.20 to 2.40; control: 4.40 weeks, 95% CI 3.00 to 5.80; MD 2.60 weeks, 95% CI 1.14 to 4.06), and tube or parenteral feeding (BIG: 3.60 weeks, 95% CI 1.70 to 5.50; control: 10.00 weeks, 95% CI 6.85 to 13.15; MD 6.40 weeks, 95% CI 2.80 to 10.00) but not on risk of adverse events or complications (BIG: 63.08%; control: 68.75%; risk ratio 0.92, 95% CI 0.72 to 1.18; absolute risk reduction 0.06, 95% CI 0.22 to -0.11). AUTHORS' CONCLUSIONS: There is evidence supporting the use of human-derived botulinum immune globulin (BIG) in infant intestinal botulism. A single randomized controlled trial demonstrated significant decreases in the duration of hospitalization, mechanical ventilation and tube or parenteral feeding with BIG treatment. This evidence was of moderate quality for effects on duration of mechanical ventilation but was otherwise of high quality. Our search did not reveal any evidence examining the use of other medical treatments including serum trivalent botulism antitoxin.
Assuntos
Botulismo/terapia , Clostridium botulinum , Imunoglobulinas/uso terapêutico , Hospitalização , Humanos , Lactente , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Peripheral neuropathy is the most common neurologic complication of hepatitis C virus (HCV) infection. The pathophysiology of the neuropathy associated with HCV is not definitively known; however, proposed mechanisms include cryoglobulin deposition in the vasa nervorum and HCV-mediated vasculitis. The optimal treatment for HCV-related peripheral neuropathy has not been established. OBJECTIVES: To assess the effects of interventions (including interferon alfa, interferon alfa plus ribavirin, corticosteroids, cyclophosphamide, plasma exchange, and rituximab) for cryoglobulinemic or non-cryoglobulinemic peripheral neuropathy associated with HCV infection. SEARCH METHODS: On 26 August 2014, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, and EMBASE. We also searched two trials registers, the Networked Digital Library of Theses and Dissertations (NDLTD) (October 2014), and three other databases. We checked references in identified trials and requested information from trial authors to identify any additional published or unpublished data. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) and quasi-RCTs involving participants with cryoglobulinemic or non-cryoglobulinemic peripheral neuropathy associated with HCV infection. We considered any intervention (including interferon alfa, interferon alfa plus ribavirin, corticosteroids, cyclophosphamide, plasma exchange, and rituximab) alone or in combination versus placebo or another intervention ('head-to-head' comparison study design) evaluated after a minimum interval to follow-up of at least six months. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. The planned primary outcome was change in sensory impairment (using any validated sensory neuropathy scale or quantitative sensory testing) at the end of the follow-up period. Other planned outcomes were: change in impairment (any validated combined sensory and motor neuropathy scale), change in disability (any validated disability scale), electrodiagnostic measures, number of participants with improved symptoms of neuropathy (global impression of change), and severe adverse events. MAIN RESULTS: Four trials of HCV-related cryoglobulinemia fulfiled selection criteria and the review authors included three in quantitative synthesis. All studies were at high risk of bias. No trial addressed the primary outcome of change in sensory impairment. No trial addressed secondary outcomes of change in combined sensory and motor impairment, disability, or electrodiagnostic measures. A single trial of HCV-related mixed cryoglobulinemia treated with pegylated interferon alfa (peginterferon alfa), ribavirin, and rituximab versus peginterferon alfa and ribavirin did not show a significant difference in the number of participants with improvement in neuropathy at 36 months post treatment (risk ratio (RR) 4.00, 95% confidence interval (CI) 0.27 to 59.31, n = 9). One study of interferon alfa (n = 22) and two studies of rituximab (n = 61) provided adverse event data. Severe adverse events were no more common with interferon alfa (RR 7.00, 95% CI 0.38 to 128.02) or rituximab (RR 3.00, 95% CI 0.13 to 67.06) compared to the control group. AUTHORS' CONCLUSIONS: There is a lack of RCTs and quasi-RCTs addressing the effects of interventions for peripheral neuropathy associated with HCV infection. At present, there is insufficient evidence from RCTs and quasi-RCTs to make evidence-based decisions about treatment.
Assuntos
Antivirais/uso terapêutico , Crioglobulinemia/complicações , Hepatite C/complicações , Fatores Imunológicos/uso terapêutico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Corticosteroides/uso terapêutico , Anticorpos Monoclonais Murinos/uso terapêutico , Antivirais/efeitos adversos , Crioglobulinemia/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Hepacivirus , Hepatite C/tratamento farmacológico , Humanos , Interferon-alfa/efeitos adversos , Interferon-alfa/uso terapêutico , Doenças do Sistema Nervoso Periférico/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Ribavirina/efeitos adversos , Ribavirina/uso terapêutico , RituximabRESUMO
Radial neuropathy is the third most common upper limb mononeuropathy after median and ulnar neuropathies. Muscle weakness, particularly wrist drop, is the main clinical feature of most cases of radial neuropathy, and an understanding of the radial nerve's anatomy generally makes localizing the lesion straightforward. Electrodiagnosis can help confirm a diagnosis of radial neuropathy and may help with more precise localization of the lesion. Nerve imaging with ultrasound or magnetic resonance neurography is increasingly used in diagnosis and is important in patients lacking a history of major arm or shoulder trauma. Radial neuropathy most often occurs in the setting of trauma, although many other uncommon causes have been described. With traumatic lesions, the prognosis for recovery is generally good, and for patients with persistent deficits, rehabilitation and surgical techniques may allow substantial functional improvement.
Assuntos
Neuropatia Radial , Humanos , Neuropatia Radial/diagnóstico , Neuropatia Radial/etiologia , Nervo Radial/lesõesRESUMO
The femoral and obturator nerves both arise from the L2, L3, and L4 spinal nerve roots and descend into the pelvis before emerging in the lower limbs. The femoral nerve's primary function is knee extension and hip flexion, along with some sensory innervation to the leg. The obturator nerve's primary function is thigh adduction and sensory innervation to a small area of the medial thigh. Each may be injured by a variety of potential causes, many of them iatrogenic. Here, we review the anatomy of the femoral and obturator nerves and the clinical features and potential etiologies of femoral and obturator neuropathies. Their necessary investigations, including electrodiagnostic studies and imaging, their prognosis, and potential treatments, are discussed in this chapter.
Assuntos
Nervo Obturador , Doenças do Sistema Nervoso Periférico , Humanos , Nervo Obturador/anatomia & histologia , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Nervo Femoral/lesões , Nervo Femoral/fisiologia , Neuropatia FemoralRESUMO
Meralgia paresthetica is a common but probably underrecognized syndrome caused by dysfunction of the lateral femoral cutaneous nerve. The diagnosis is based on the patient's description of sensory disturbance, often painful, on the anterolateral aspect of the thigh, with normal strength and reflexes. Sensory nerve conduction studies and somatosensory evoked potentials may be used to support the diagnosis, but both have technical limitations, with low specificity and sensitivity. Risk factors for meralgia paresthetica include obesity, tight clothing, and diabetes mellitus. Some cases are complications of hip or lumbar spine surgery. Most cases are self-limited, but a small proportion of patients remain with refractory and disabling symptoms. Treatment options include medications for neuropathic pain, neurolysis, neurectomy, and radioablation, but controlled trials to compare efficacy are lacking.
Assuntos
Neuropatia Femoral , Humanos , Neuropatia Femoral/terapia , Neuropatia Femoral/diagnóstico , Síndromes de Compressão Nervosa/diagnóstico , Síndromes de Compressão Nervosa/terapiaAssuntos
Antibióticos Antineoplásicos/efeitos adversos , Ácido Micofenólico/efeitos adversos , Estado Epiléptico/induzido quimicamente , Acil Coenzima A/imunologia , Anticorpos/sangue , Eletroencefalografia , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Pessoa de Meia-Idade , Doenças Musculares/induzido quimicamente , Doenças Musculares/tratamento farmacológico , Estado Epiléptico/diagnósticoRESUMO
OBJECTIVES: Traditional student feedback questionnaires are imperfect course evaluation tools, largely because they generate low response rates and are susceptible to response bias. Preliminary research suggests that prediction-based methods of course evaluation - in which students estimate their peers' opinions rather than provide their own personal opinions - require significantly fewer respondents to achieve comparable results and are less subject to biasing influences. This international study seeks further support for the validity of these findings by investigating: (i) the performance of the prediction-based method, and (ii) its potential for bias. METHODS: Participants (210 Year 1 undergraduate medical students at McGill University, Montreal, Quebec, Canada, and 371 Year 1 and 385 Year 3 undergraduate medical students at the University Medical Center Groningen [UMCG], University of Groningen, Groningen, the Netherlands) were randomly assigned to complete course evaluations using either the prediction-based or the traditional opinion-based method. The numbers of respondents required to achieve stable outcomes were determined using an iterative process. Differences between the methods regarding the number of respondents required were analysed using t-tests. Differences in evaluation outcomes between the methods and between groups of students stratified by four potentially biasing variables (gender, estimated general level of achievement, expected test result, satisfaction after examination completion) were analysed using multivariate analysis of variance (manova). RESULTS: Overall response rates in the three student cohorts ranged from 70% to 94%. The prediction-based method required significantly fewer respondents than the opinion-based method (averages of 26-28 and 67-79 respondents, respectively) across all samples (p < 0.001), whereas the outcomes achieved were fairly similar. Bias was found in four of 12 opinion-based condition comparisons (three sites, four variables), and in only one comparison in the prediction-based condition. CONCLUSIONS: Our study supports previous findings that prediction-based methods require significantly fewer respondents to achieve results comparable with those obtained through traditional course evaluation methods. Moreover, our findings support the hypothesis that prediction-based responses are less subject to bias than traditional opinion-based responses. These findings lend credence to prediction-based as an accurate and efficient method of course evaluation.
Assuntos
Educação de Graduação em Medicina/normas , Estudantes de Medicina/psicologia , Análise de Variância , Atitude do Pessoal de Saúde , Currículo/normas , Humanos , Países Baixos , Variações Dependentes do Observador , Grupo Associado , Quebeque , Inquéritos e Questionários/normasRESUMO
BACKGROUND: Most university faculty members are expected to teach. Many would benefit from instruction designed to improve lecturing. AIMS: To explore the impact of a program in which video-recorded lectures were critiqued by peers. METHOD: Sixteen lecturers participated in this qualitative study. Four agreed to have an undergraduate lecture video-recorded for peer review. Twelve participated in review sessions wherein the lecturer and three peers viewed and critiqued the recorded lecture. All discussions were recorded and transcribed for thematic analysis. Subsequently, semi-structured interviews were conducted with each lecturer and all 12 peer reviewers. Three pairs of research team members independently conducted thematic analyses of the discussion transcripts and the interviews; then all members met to develop consensus on major emergent themes. RESULTS: Six themes were identified: (1) the benefits of peer review; (2) the components of successful peer review; (3) the value of reflection on teaching experiences; (4) the inherent stress in peer evaluations; (5) the elements of successful lecturing; (6) lecturing as performance. CONCLUSIONS: The benefits of peer assessment of lecturing (PAL) were enthusiastically endorsed by all 16 participants. The PAL program is now supported by the McGill Faculty Development Committee and plans to implement regular PAL sessions in place.
Assuntos
Educação de Graduação em Medicina/normas , Revisão por Pares , Ensino/normas , Humanos , Entrevistas como Assunto , Gravação em VídeoRESUMO
OBJECTIVE: This article examines the benefit and feasibility of introducing a new, simulation-based learning intervention for junior psychiatry residents. METHOD: Junior psychiatry residents were invited to participate in a new simulation-based learning intervention focusing on agitated patients. Questionnaires were used to explore the success of the intervention. RESULTS: Participants (N=12) reported increases in self-assessed knowledge. Pre/post comparison of ratings indicated increases in comfort and perceived competence both in evaluating and managing agitated patients after the intervention. Participants reported improvements in knowledge and skills and appreciated feedback. Some indicated the need for continued practice and suggested that their anxiety was still prominent. Overall, the intervention was well received and seen as useful. CONCLUSIONS: Simulation may be well suited to teaching residents to work with agitated patients. More research is needed to determine whether this kind of educational intervention leads to changes in patient care.
Assuntos
Internato e Residência/métodos , Simulação de Paciente , Psiquiatria/educação , Agitação Psicomotora/terapia , Adulto , Estudos de Viabilidade , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Projetos Piloto , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Determine if distributed practice of of neurological exam (NE) skills in first year medical school produces sustained improvements in the skills of second year students. METHODS: A prospective, controlled, non-blinded study conducted at McGill University (class size = 180 students). Expanded teaching of muscle stretch reflexes was provided to first year medical students. A structured examination of muscle stretch reflexes (max score = 100) was administered in second year medical school after a required two week rotation in Neurology. Results for class A (received the intervention in first year) were compared to the results for the preceding class B (had not received the intervention). RESULTS: 77 of 177 (44%) eligible in class A and 69 of 166 (42%) eligible students in class B participated. Results were analyzed separately for each of the two examiners. Mean (SD) scores were 95.2 (5.6) for class A (intervention) and 81.7 (11.1) for class B (control) for the first examiner and 90.4 (8.2) for class A and 83.8 (11.7) for class B for the second examiner. Results were statistically significant (Mann-Whitney test z = 5.27, p<0.0001 first examiner and z = 2.67, p<0.0038 second examiner). CONCLUSIONS: Distributed practice of muscle stretch reflexes during first year medical school results in improved performance by second year medical students after their mandatory clinical rotation in neurology, even when examined up to 14 months after the intervention. This finding has implications for the teaching of the NE.
Assuntos
Exame Neurológico , Neurologia/educação , Reflexo de Estiramento/fisiologia , Estudantes de Medicina , Ensino/métodos , Estudos de Casos e Controles , Educação de Graduação em Medicina/métodos , Avaliação Educacional , Feminino , Humanos , Masculino , Estudos ProspectivosRESUMO
Despite the growing accessibility of clinical sequencing, functional interpretation of variants remains a major hurdle to molecular diagnostics of Mendelian diseases. We aimed to describe a new adult-onset myopathy with muscle weakness and hyperCKemia caused by a nonsense variant in muscular LMNA-interacting protein (MLIP). Following RNA-sequencing, differential expression analysis uncovered a significant downregulation of this gene, which had a surprisingly mild effect on MLIP protein expression. RT-PCR and long-read sequencing (LRS) both support an important transcriptome shift in the patient, where decreased MLIP levels are seemingly due to nonsense-mediated decay of transcripts containing the exon 5 mutation. Moreover, a compensatory mechanism upregulates the functionally lacking isoforms and generates novel transcripts. These results support the recently discovered clinical implications of MLIP variants in myopathies, highlighting for the first time its relevance in adult-onset cases. These results also underline the power of LRS as a tool for the functional assessment of variants of unknown significance (VUS), as well as the definition of accurate isoform profile annotations in a tissue-specific manner.
RESUMO
BACKGROUND: Botulism is an acute paralytic illness caused by a neurotoxin produced by Clostridium botulinum. Supportive care, including intensive care, is key but the role of other medical treatments is unclear. OBJECTIVES: To assess the effects of medical treatments on mortality, duration of hospitalization, mechanical ventilation, tube or parenteral feeding and risk of adverse events in botulism. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Specialized Register (10 January 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (10 January 2010 in The Cochrane Library, Issue 4 2010), MEDLINE (January 1966 to January 2011) and EMBASE (January 1980 to January 2011). We reviewed bibliographies, and contacted authors and experts. SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials examining the medical treatment of any of the four major types of botulism (infant intestinal botulism, food-borne botulism, wound botulism and adult intestinal toxemia). Medical treatments included equine serum trivalent botulism antitoxin, human-derived botulinum immune globulin, plasma exchange, 3,4-diaminopyridine and guanidine. DATA COLLECTION AND ANALYSIS: Two authors selected studies, assessed risk of bias and extracted data independently onto data extraction forms.Our primary outcome was in-hospital death from any cause occurring within four weeks. Secondary outcomes were death occurring within 12 weeks, duration of hospitalization, mechanical ventilation, tube or parenteral feeding and risk of adverse events. MAIN RESULTS: A single randomized controlled trial met the inclusion criteria. This trial evaluated human-derived botulinum immune globulin for the treatment of infant botulism. This study included 59 treatment patients and 63 control patients. There were no deaths in either group making any treatment effect on mortality inestimable. There was a significant benefit in the treatment group on duration of hospitalization (mean difference (MD) 3.10 weeks, 95% confidence interval (CI) 1.68 to 4.52), mechanical ventilation (MD 2.60 weeks, 95% CI 1.14 to 4.06), and tube or parenteral feeding (MD 6.40 weeks, 95% CI 2.80 to 10.00) but not on risk of adverse events or complications (relative risk reduction 0.92, 95% CI 0.72 to 1.18; absolute risk reduction 0.06, 95% CI 0.22 to -0.11). AUTHORS' CONCLUSIONS: There is good evidence supporting the use of human-derived botulinum immune globulin in infant intestinal botulism. A single randomized controlled trial demonstrated significant decreases in the duration of hospitalization, mechanical ventilation and tube or parenteral feeding among treated patients. Our search did not reveal any evidence examining the use of other medical treatments including serum trivalent botulism antitoxin.