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

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

Partielle Resistenz Chorea Huntington transgener Mäuse gegen globale cerebrale Ischämie

Excitotoxicity plays a keyrole in acute ischemic neuronal death as well as neurodegenerative diseases such as Huntington's disease (HD). Surprisingly it has been found that HD transgenic mice are resistant to intrastriatal injections of excitotoxic substances. We investigated whether HD transgenic mice are also resistant to global cerebral ischemia, installed by temporary bilateral occlusion of the common carotid arteries. Since the neurons of the hippocampus are known to show the lowest ischemic tolerances we especially investigated these neurons. We found out that HD transgenic mice are partially resistant to a global cerebral ischemia of 15 and 20 minutes duration. After 60 minutes of global cerebral ischemia, no substantial difference between transgenic mice and wildtype littermates could be seen. Neuronal tolerance can be experimentally induced by so-called "preconditioning", where a short-term ischemia triggers the overexpression of neuroprotective proteins, e.g. Heat-shock-proteins, which then induce a tolerance against a second hypoxemia. In our model, ischemic tolerance was not blocked by pre-treatment of mice with cycloheximide, an unspecific protein synthesis inhibitor. We therefore conclude that there must be a different mechanism - independent of the short term expression of endogenous neuroprotective proteins. This mechanism is so far unknown. Our results show that an increased tolerance does not only exist in the striatum of transgenic mice, but also in the hippocampus and that this tolerance also includes ischemic stimuli

Partielle Resistenz Chorea Huntington transgener Mäuse gegen globale cerebrale Ischämie

Excitotoxicity plays a keyrole in acute ischemic neuronal death as well as neurodegenerative diseases such as Huntington's disease (HD). Surprisingly it has been found that HD transgenic mice are resistant to intrastriatal injections of excitotoxic substances. We investigated whether HD transgenic mice are also resistant to global cerebral ischemia, installed by temporary bilateral occlusion of the common carotid arteries. Since the neurons of the hippocampus are known to show the lowest ischemic tolerances we especially investigated these neurons. We found out that HD transgenic mice are partially resistant to a global cerebral ischemia of 15 and 20 minutes duration. After 60 minutes of global cerebral ischemia, no substantial difference between transgenic mice and wildtype littermates could be seen. Neuronal tolerance can be experimentally induced by so-called "preconditioning", where a short-term ischemia triggers the overexpression of neuroprotective proteins, e.g. Heat-shock-proteins, which then induce a tolerance against a second hypoxemia. In our model, ischemic tolerance was not blocked by pre-treatment of mice with cycloheximide, an unspecific protein synthesis inhibitor. We therefore conclude that there must be a different mechanism - independent of the short term expression of endogenous neuroprotective proteins. This mechanism is so far unknown. Our results show that an increased tolerance does not only exist in the striatum of transgenic mice, but also in the hippocampus and that this tolerance also includes ischemic stimuli

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

ObjectiveTo determine demographic characteristics, clinical features, treatment regimens, and outcome of myasthenic crisis (MC) requiring mechanical ventilation (MV).MethodsAnalysis of patients who presented with MC between 2006 and 2015 in a German multicenter retrospective study.ResultsWe 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.ConclusionMortality 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

Early tracheostomy is associated with shorter ventilation time and duration of ICU stay in patients with myasthenic crisis: 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 ¼ 0.01).Patients receiving a tracheostomy, however, were more frequently suffering from multiple comorbidities (20 [18.7%] vs 9 [8.3%]