Weaning and extubation failure in myasthenic crisis: a multicenter analysis.

Myasthenic crisis (MC) requiring mechanical ventilation is a serious complication of myasthenia gravis (MG). Here we analyze the frequency and risk factors of weaning- and extubation failure as well as its impact on the clinical course in a large cohort. We performed a retrospective chart review on patients treated for MC in 12 German neurological departments between 2006 and 2015. Weaning failure (WF) was defined as negative spontaneous breathing trial, primary tracheostomy, or extubation failure (EF) (reintubation or death). WF occurred in 138 episodes (64.2%). Older Age (p = 0.039), multiple comorbidities (≥ 3) (p = 0.007, OR = 4.04), late-onset MG (p = 0.004, OR = 2.84), complications like atelectasis (p = 0.008, OR = 3.40), pneumonia (p < 0.0001, OR = 3.45), cardio-pulmonary resuscitation (p = 0.005, OR = 5.00) and sepsis (p = 0.02, OR = 2.57) were associated with WF. WF occurred often in patients treated with intravenous immungloblins (IVIG) (p = 0.002, OR = 2.53), whereas WF was less often under first-line therapy with plasma exchange or immunoadsorption (p = 0.07, OR = 0.57). EF was observed in 58 of 135 episodes (43.0%) after first extubation attempt and was related with prolonged mechanical ventilation, intensive care unit stay and hospital stay (p ≤ 0.0001 for all). Extubation success was most likely in a time window for extubation between day 7 and 12 after intubation (p = 0.06, OR = 2.12). We conclude that WF and EF occur very often in MC and are associated with poor outcome. Older age, multiple comorbidities and development of cardiac and pulmonary complications are associated with a higher risk of WF and EF. Our data suggest that WF occurs less frequently under first-line plasma exchange/immunoadsorption compared with first-line use of IVIG.

Seronegative myasthenic crisis: a multicenter analysis.

Myasthenic crisis (MC) is a life-threatening condition for patients with myasthenia gravis (MG). Seronegative patients represent around 10-15% of MG, but data on outcome of seronegative MCs are lacking. We performed a subgroup analysis of patients who presented with MC with either acetylcholine-receptor-antibody-positive MG (AChR-MG) or seronegative MG between 2006 and 2015 in a retrospective German multicenter study. We identified 15 seronegative MG patients with 17 MCs and 142 AChR-MG with 159 MCs. Seronegative MCs were younger (54.3 ± 14.5 vs 66.5 ± 16.3 years; p = 0.0037), had a higher rate of thymus hyperplasia (29.4% vs 3.1%; p = 0.0009), and were more likely to be female (58.8% vs 37.7%; p = 0.12) compared to AChR-MCs. Time between diagnosis of MG and MC was significantly longer in seronegative patients (8.2 ± 7.6 vs 3.1 ± 4.4 years; p < 0.0001). We found no differences in duration of mechanical ventilation (16.2 ± 15.8 vs 16.5 ± 15.9 days; p = 0.94) and length of stay at intensive care unit (17.6 ± 15.2 vs 17.8 ± 15.4 days; p = 0.96), or in-hospital mortality (11.8% vs. 10.1%; p = 0.69). We conclude that MC in seronegative MG affects younger patients after a longer period of disease, but that crisis treatment efficacy and outcome do not differ compared to AChR-MCs.

Early Tracheostomy Is Associated With Shorter Ventilation Time and Duration of ICU Stay in Patients With Myasthenic Crisis-A Multicenter Analysis.

BACKGROUND: Myasthenic crisis (MC) requiring mechanical ventilation (MV) is a rare and serious complication of myasthenia gravis. Here we analyzed the frequency of performed tracheostomies, risk factors correlating with a tracheostomy, as well as the impact of an early tracheostomy on ventilation time and ICU length of stay (LOS) in MC. METHODS: Retrospective chart review on patients treated for MC in 12 German neurological departments between 2006 and 2015 to assess demographic/diagnostic data, rates and timing of tracheostomy and outcome. RESULTS: In 107 out of 215 MC (49.8%), a tracheostomy was performed. Patients without tracheostomy were more likely to have an early-onset myasthenia gravis (27 [25.2%] vs 12 [11.5%], p = 0.01). Patients receiving a tracheostomy, however, were more frequently suffering from multiple comorbidities (20 [18.7%] vs 9 [8.3%], p = 0.03) and also the ventilation time (34.4 days ± 27.7 versus 7.9 ± 7.8, p < 0.0001) and ICU-LOS (34.8 days ± 25.5 versus 12.1 ± 8.0, p < 0.0001) was significantly longer than in non-tracheostomized patients. Demographics and characteristics of the course of the disease up to the crisis were not significantly different between patients with an early (within 10 days) compared to a late tracheostomy. However, an early tracheostomy correlated with a shorter duration of MV at ICU (26.2 days ± 18.1 versus 42.0 ± 33.1, p = 0.006), and ICU-LOS (26.2 days ± 14.6 versus 42.3 ± 33.0, p = 0.003). CONCLUSION: Half of the ventilated patients with MC required a tracheostomy. Poorer health condition before the crisis and late-onset MG were associated with a tracheostomy. An early tracheostomy (≤ day 10), however, was associated with a shorter duration of MV and ICU-LOS by 2 weeks.

MuSK-antibodies are associated with worse outcome in myasthenic crisis requiring mechanical ventilation.

Myasthenic crisis (MC) is a life-threatening condition for patients with myasthenia gravis (MG). Muscle-specific kinase-antibodies (MuSK-ABs) are detected in ~ 6% of MG, but data on outcome of MuSK-MCs are still lacking. We made a subgroup analysis of patients who presented with MC with either acetylcholine-receptor-antibody positive MG (AchR-MG) or MuSK-MG between 2006 and 2015 in a retrospective German multicenter study. We identified 19 MuSK-AB associated MCs in 15 patients and 161 MCs in 144 patients with AchR-ABs only. In contrast to patients with AchR-AB, MuSK-AB patients were more often female (p = 0.05, OR = 2.74) and classified as Myasthenia Gravis Foundation of America-class IV before crisis (p = 0.04, OR = 3.25). MuSK-AB patients suffer more often from multiple chronic disease (p = 0.016, OR = 4.87) and were treated more invasively in terms of plasma exchanging therapies (not significant). The number of days of mechanical ventilation (MV) (43.0 ± 53.1 vs. 17.4 ± 18; p < 0.0001), days on an intensive care unit (ICU) (45.3 ± 49.5 vs. 21.2 ± 19.7; p < 0.0001), and hospital-length of stay (LOS) (55.9 ± 47.6 vs. 28.8 ± 20.9 days; p < 0.0001) were significantly increased in MuSK-MC. Remarkable is that these changes were mainly due to patients with MusK-ABs only, whereas patients' outcome with both antibodies was similar to AchR-MCs. Furthermore, our data showed a shortened duration of MV after treatment with plasma exchanging therapies compared to treatment with intravenous immunoglobulin in MuSK-MCs. We conclude that MuSK-AB-status is associated with a longer need of MV, ICU-LOS, and hospital-LOS in MC, and therefore recommend early initiation of a disease-specific therapy.

Myasthenic crisis demanding mechanical ventilation: A multicenter analysis of 250 cases.

OBJECTIVE: To determine demographic characteristics, clinical features, treatment regimens, and outcome of myasthenic crisis (MC) requiring mechanical ventilation (MV). METHODS: Analysis of patients who presented with MC between 2006 and 2015 in a German multicenter retrospective study. RESULTS: We identified 250 cases in 12 participating centers. Median age at crisis was 72 years. Median duration of MV was 12 days. Prolonged ventilation (>15 days) depended on age (p = 0.0001), late-onset myasthenia gravis (MG), a high Myasthenia Gravis Foundation of America Class before crisis (p = 0.0001 for IVb, odds ratio [OR] = infinite), number of comorbidities (>3 comorbidities: p = 0.002, OR 2.99), pneumonia (p = 0.0001, OR 3.13), and resuscitation (p = 0.0008, OR 9.15). MV at discharge from hospital was necessary in 20.5% of survivors. Patients with early-onset MG (p = 0.0001, OR 0.21), thymus hyperplasia (p = 0.002, OR 0), and successful noninvasive ventilation trial were more likely to be ventilated for less than 15 days. Noninvasive ventilation in 92 cases was sufficient in 38%, which was accompanied by a significantly shorter duration of ventilation (p = 0.001) and intensive care unit (ICU) stay (p = 0.01). IV immunoglobulins, plasma exchange, and immunoadsorption were more likely to be combined sequentially if the duration of MV and the stay in an ICU extended (p = 0.0503, OR 2.05). Patients who received plasma exchange or immunoadsorption as first-line therapy needed invasive ventilation significantly less often (p = 0.003). In-hospital mortality was 12%, which was significantly associated with the number of comorbidities (>3) and complications such as acute respiratory distress syndrome and resuscitation. Main cause of death was multiorgan failure, mostly due to sepsis. CONCLUSION: Mortality and duration of MC remained comparable to previous reports despite higher age and a high disease burden in our study. Prevention and treatment of complications and specialized neurointensive care are the cornerstones in order to improve outcome.

Value of the eazyplex® CSF direct assay in rapid diagnosis of invasive meningococcal disease - Case report.

There is a need for easy-to-use molecular assays for diagnosis of invasive meningococcal disease. Here, we report the rapid identification of Neisseria meningitidis in a cerebrospinal fluid sample from a patient with purulent meningitis using a commercially available loop-mediated isothermal amplification assay, resulting in a prompt de-escalation of the initial empiric antibiotic therapy.

Optimizing Cardiac Out-Put to Increase Cerebral Penumbral Perfusion in Large Middle Cerebral Artery Ischemic Lesion-OPTIMAL Study.

INTRODUCTION: In unsuccessful vessel recanalization, clinical outcome of acute stroke patients depends on early improvement of penumbral perfusion. So far, mean arterial blood pressure (MAP) is the target hemodynamic parameter. However, the correlations of MAP to cardiac output (CO) and cerebral perfusion are volume state dependent. In severe subarachnoid hemorrhage, optimizing CO leads to a reduction of delayed ischemic neurological deficits and improvement of clinical outcome. This study aims to investigate the effect of standard versus advanced cardiac monitoring with optimization of CO on the clinical outcome in patients with large ischemic stroke. METHODS AND ANALYSIS: The OPTIMAL study is a prospective, multicenter, open, into two arms (1:1) randomized, controlled trial. Sample size estimate: sample sizes of 150 for each treatment group (300 in total) ensure an 80% power to detect a difference of 16% of a dichotomized level of functional clinical outcome at 3 months at a significance level of 0.05. Study outcomes: the primary endpoint is the functional outcome at 3 months. The secondary endpoints include functional outcome at 6 months follow-up, and complications related to hemodynamic monitoring and therapies. DISCUSSION: The results of this trial will provide data on the safety and efficacy of advanced hemodynamic monitoring on clinical outcome. ETHICS AND DISSEMINATION: The trial was approved by the leading ethics committee of Freiburg University, Germany (438/14, 2015) and the local ethics committees of the participating centers. The study is performed in accordance with the Declaration of Helsinki and the guidelines of Good Clinical Practice. It is registered in the German Clinical Trial register (DRKS; DRKS00007805). Dissemination will include submission to peer-reviewed professional journals and presentation at congresses. Hemodynamic monitoring may be altered in a specific stroke patient cohort if the study shows that advanced monitoring is safe and improves the functional outcome.

The impairment of small nerve fibers in severe sepsis and septic shock.

BACKGROUND: A decrease of small nerve fibers in skin biopsies during the course of critical illness has been demonstrated recently. However, the diagnostic use of skin biopsies in sepsis and its time course is not known. METHODS: Patients (n=32) with severe sepsis or septic shock were examined using skin biopsies, neurological examination, nerve conduction studies, and sympathetic skin response in the first week after onset of sepsis, 2 weeks and 4 months later and compared to gender- and age-matched healthy controls. RESULTS: Skin biopsies at the ankle and thigh revealed a significant decrease of intraepidermal nerve fiber density (IENFD) during the first week of sepsis and 2 weeks later. All patients developed critical illness polyneuropathy (CIP) according to electrophysiological criteria and 11 showed IENFD values lower than the 0.05 quantile. Four patients were biopsied after 4 months and still showed decreased IENFD. Results of nerve conduction studies and IENFD did considerably change over time. No differences for survival time between patients with IEFND lower and larger than 3.5 fibers/mm were found. CONCLUSIONS: Skin biopsy is able to detect an impairment of small sensory nerve fibers early in the course of sepsis. However, it may not be suited as a prognostic parameter for survival. TRIAL REGISTRATION: German Clinical Trials Register, DRKS-ID: DRKS00000642, 12/17/2010.

Does the clinical phenotype of fatal familial insomnia depend on PRNP codon 129 methionine-valine polymorphism?

Fatal familial insomnia (FFI) is a rare, hereditary prion-protein disease. Methionine-valine polymorphism at codon 129 of the prion-protein gene (PRNP) determines the phenotype in other hereditary prion-protein diseases, but association with the clinical phenotype in FFI remains uncertain. Early clinical findings in FFI comprise disturbances of the sleep-wake cycle and mild neuropsychiatric changes which typically emerge during middle to late adulthood. Here we describe an unusually early onset and rapid progression of FFI associated with dorsal midbrain involvement in a female patient with PRNP mutation at codon 178 and homozygote methionine polymorphism at codon 129. Early dorsal midbrain involvement became apparent by total loss of REM sleep and isolated bilateral trochlear nerve palsy. Early onset and rapid progression disease type associated with dorsal midbrain involvement may indicate a different spatiotemporal distribution of the neurodegenerative process in FFI patients with PRNP mutation and codon 129 methionine homozygosity compared to methioninevaline heterozygosity.

Nocturnal groaning (catathrenia) and epilepsy.

We report the case of a patient with idiopathic generalized epilepsy who ten years after the onset of his epilepsy also developed recurring nocturnal paroxysmal episodes reminiscent of his seizure semiology. Video monitoring and polysomnography revealed episodes of nocturnal groaning. Escalation of antiepileptic treatment was avoided.

Defective cellular localization of mutant ATP7B in Wilson's disease patients and hepatoma cell lines.

BACKGROUND & AIMS: Wilson's disease, a hereditary disorder caused by mutations in the Wilson's disease gene (ATP7B), leads to hepatic and/or neurological pathology resulting from cellular copper overload. In vitro studies showed that ATP7B, located in the trans-Golgi network, traffics to a cytoplasmic vesicular compartment in response to increased copper concentration. Mislocalization and failed intracellular trafficking of ATP7B mutants are suggested to be among disease-causing mechanisms; however, the effect of mutations on ATP7B localization in human tissues has not been directly shown. Therefore, we characterized the subcellular localization of normal and mutant ATP7B in human livers and in hepatoma cell lines. METHODS: Subcellular distribution of ATP7B in liver tissue from 3 control individuals and 3 Wilson's disease patients harboring a homozygous H1069Q-ATP7B mutation was analyzed by using immunogold electron microscopy. In addition, 14 ATP7B mutants tagged to green fluorescent protein were generated and expressed in HuH-7 and HepG2 cells; intracellular localization of these mutants was characterized by confocal microscopy. RESULTS: In hepatocytes, ATP7B was localized in trans-Golgi vesicles, whereas H1069Q-ATP7B was trapped in the endoplasmic reticulum. Similar results were observed for wild-type ATP7B and H1069Q-ATP7B expressed in hepatoma cells. Most ATP7B proteins harboring missense mutations were distributed similarly to wild-type ATP7B. In contrast, truncated ATP7B mutants showed a diffuse, clustered, cytoplasmic pattern, distinct from the trans-Golgi network or endoplasmic reticulum. CONCLUSIONS: These results provide a detailed demonstration of the ATP7B distribution in control and diseased human livers and indicate that several Wilson's disease mutations lead to incorrect localization of ATP7B to distinct cell compartments.