Enhancing European Management of Analgesia, Sedation, and Delirium: A Multinational, Prospective, Interventional Before-After Trial.

BACKGROUND: The objective of this study was to analyze the impact of a structured educational intervention on the implementation of guideline-recommended pain, agitation, and delirium (PAD) assessment. METHODS: This was a prospective, multinational, interventional before-after trial conducted at 12 intensive care units from 10 centers in Germany, Austria, Switzerland, and the UK. Intensive care units underwent a 6-week structured educational program, comprising online lectures, instructional videos, educational handouts, and bedside teaching. Patient-level PAD assessment data were collected in three 1-day point-prevalence assessments before (T1), 6 weeks after (T2), and 1 year after (T3) the educational program. RESULTS: A total of 430 patients were included. The rate of patients who received all three PAD assessments changed from 55% (107/195) at T1 to 53% (68/129) at T2, but increased to 73% (77/106) at T3 (p = 0.003). The delirium screening rate increased from 64% (124/195) at T1 to 65% (84/129) at T2 and 77% (82/106) at T3 (p = 0.041). The pain assessment rate increased from 87% (170/195) at T1 to 92% (119/129) at T2 and 98% (104/106) at T3 (p = 0.005). The rate of sedation assessment showed no signficiant change. The proportion of patients who received nonpharmacological delirium prevention measures increased from 58% (114/195) at T1 to 80% (103/129) at T2 and 91% (96/106) at T3 (p < 0.001). Multivariable regression revealed that at T3, patients were more likely to receive a delirium assessment (odds ratio [OR] 2.138, 95% confidence interval [CI] 1.206-3.790; p = 0.009), sedation assessment (OR 4.131, 95% CI 1.372-12.438; p = 0.012), or all three PAD assessments (OR 2.295, 95% CI 1.349-3.903; p = 0.002) compared with T1. CONCLUSIONS: In routine care, many patients were not assessed for PAD. Assessment rates increased significantly 1 year after the intervention. Clinical trial registration ClinicalTrials.gov: NCT03553719.

Fungal Gut Microbiome in Myasthenia Gravis: A Sub-Analysis of the MYBIOM Study.

An altered gut microbiota is a possible contributing pathogenic factor in myasthenia gravis (MG), an autoimmune neuromuscular disease. However, the significance of the fungal microbiome is an understudied and neglected part of the intestinal microbiome in MG. We performed a sub-analysis of the MYBIOM study including faecal samples from patients with MG (n = 41), non-inflammatory neurological disorder (NIND, n = 18), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 6) and healthy volunteers (n = 12) by sequencing the internal transcribed spacer 2 (ITS2). Fungal reads were obtained in 51 out of 77 samples. No differences were found in alpha-diversity indices computed between the MG, NIND, CIDP and HV groups, indicating an unaltered fungal diversity and structure. Overall, four mould species (Penicillium aurantiogriseum, Mycosphaerella tassiana, Cladosporium ramonetellum and Alternaria betae-kenyensis) and five yeast species (Candida. albicans, Candida. sake, Candida. dubliniensis, Pichia deserticola and Kregervanrija delftensis) were identified. Besides one MG patient with abundant Ca. albicans, no prominent dysbiosis in the MG group of the mycobiome was found. Not all fungal sequences within all groups were successfully assigned, so further sub-analysis was withdrawn, limiting robust conclusions.

Total Plasma Exchange in Neuromuscular Junction Disorders-A Single-Center, Retrospective Analysis of the Efficacy, Safety and Potential Diagnostic Properties in Doubtful Diagnosis.

Neuromuscular junction disorders (NJDs) are a heterogeneous group of diseases including myasthenia gravis (MG). In some cases, patients are present with myasthenic symptoms without evidence of autoimmune antibodies, making diagnosis challenging. Total plasma exchange (TPE) has proven efficacy in NJDs. The objective is to describe the safety and efficacy of TPE in NJD patients with questionable disease activity or uncertain diagnosis in order to assess the diagnostic potential of TPE. We report an observational, retrospective cohort study of clinical routine data. All the data were derived from the electronic medical records of the Department of Neurology at University Hospital Essen. We searched for patients with NJDs between 1 July 2018 and 30 June 2021. Of the 303 patients who presented to the department with NJDs, 20 were treated with TPE; 9 patients did not show a measurable benefit from TPE (45%), 6 of whom were diagnosed with seronegative MG. Of these, 3 (50%) had long-standing ocular symptoms. There were decreases in the mean arterial pressure, hemoglobin, hematocrit and fibrinogen during treatment, which were not considered clinically relevant. In (seronegative) myasthenic patients, TPE may help to verify an uncertain diagnosis or to reveal possible muscle damage, allowing unnecessary therapy to be avoided.

Independent risk factors for myasthenic crisis and disease exacerbation in a retrospective cohort of myasthenia gravis patients.

BACKGROUND: Myasthenic crisis (MC) and disease exacerbation in myasthenia gravis (MG) are associated with significant lethality and continue to impose a high disease burden on affected patients. Therefore, we sought to determine potential predictors for MC and exacerbation as well as to identify factors affecting outcome. METHODS: We examined a retrospective, observational cohort study of patients diagnosed with MG between 2000 and 2021 with a mean follow-up of 62.6 months after diagnosis from eight tertiary hospitals in Germany. A multivariate Cox regression model with follow-up duration as the time variable was used to determine independent risk factors for MC and disease exacerbation. RESULTS: 815 patients diagnosed with MG according to national guidelines were included. Disease severity at diagnosis (quantitative MG score or Myasthenia Gravis Foundation of America class), the presence of thymoma and anti-muscle specific tyrosine kinase-antibodies were independent predictors of MC or disease exacerbation. Patients with minimal manifestation status 12 months after diagnosis had a lower risk of MC and disease exacerbation than those without. The timespan between diagnosis and the start of immunosuppressive therapy did not affect risk. Patients with a worse outcome of MC were older, had higher MGFA class before MC and at admission, and had lower vital capacity before and at admission. The number of comorbidities, requirement for intubation, prolonged mechanical ventilation, and MC triggered by infection were associated with worse outcome. No differences between outcomes were observed comparing treatments with IVIG (intravenous immunoglobulin) vs. plasma exchange vs. IVIG together with plasma exchange. CONCLUSIONS: MC and disease exacerbations inflict a substantial burden of disease on MG patients. Disease severity at diagnosis and antibody status predicted the occurrence of MC and disease exacerbation. Intensified monitoring with emphasis on the prevention of infectious complications could be of value to prevent uncontrolled disease in MG patients.

Eculizumab versus rituximab in generalised myasthenia gravis.

OBJECTIVE: Myasthenia gravis (MG) is the most common autoimmune disorder affecting the neuromuscular junction. However, evidence shaping treatment decisions, particularly for treatment-refractory cases, is sparse. Both rituximab and eculizumab may be considered as therapeutic options for refractory MG after insufficient symptom control by standard immunosuppressive therapies. METHODS: In this retrospective observational study, we included 57 rituximab-treated and 20 eculizumab-treated patients with MG to compare the efficacy of treatment agents in generalised, therapy-refractory anti-acetylcholine receptor antibody (anti-AChR-ab)-mediated MG with an observation period of 24 months. Change in the quantitative myasthenia gravis (QMG) score was defined as the primary outcome parameter. Differences between groups were determined in an optimal full propensity score matching model. RESULTS: Both groups were comparable in terms of clinical and demographic characteristics. Eculizumab was associated with a better outcome compared with rituximab, as measured by the change of the QMG score at 12 and 24 months of treatment. Minimal manifestation of disease was more frequently achieved in eculizumab-treated patients than rituximab-treated patients at 12 and 24 months after baseline. However, the risk of myasthenic crisis (MC) was not ameliorated in either group. INTERPRETATION: This retrospective, observational study provides the first real-world evidence supporting the use of eculizumab for the treatment of refractory, anti-AChR-ab positive MG. Nonetheless, the risk of MC remained high and prompts the need for intensified monitoring and further research effort aimed at this vulnerable patient cohort.

Predictors of Early Neurological Improvement in Patients with Anterior Large Vessel Occlusion and Successful Reperfusion Following Endovascular Thrombectomy-Does CT Perfusion Imaging Matter?

PURPOSE: We aimed to investigate treatment effect of endovascular thrombectomy (EVT) on the change of National Institutes of Health Stroke Scale (NIHSS) scores in acute ischemic stroke (AIS) patients with anterior large vessel occlusion (LVO). Predictors of early neurological improvement (ENI) were assessed in those with successful reperfusion. METHODS: Data on stroke patients from January 2018 to December 2020 were retrospectively analyzed. Anterior LVO was defined as occlusion of internal carotid artery and/or M1/M2 branch of middle cerebral artery. A reduction of at least 8 NIHSS points at 24 h after EVT or NIHSS score ≤ 1 at discharge was defined as ENI. In patients with successful reperfusion (TICI score of 2b/3) and available CT perfusion (CTP) imaging, 20 variables were tested in a smoothed ridge regression for their association with ENI. RESULTS: One hundred seventy two out of 211 patients had successful perfusion with 54 patients achieving ENI. Impact of successful EVT on reducing NIHSS score grew continuously on a daily basis up to the date of discharge. 105 out of 172 patients were included in final regression model. Short time from onset to admission and from groin-puncture to reperfusion, young age, low prestroke disability, high baseline CTP ASPECTS and high follow-up non-contrast CT (NCCT) ASPECTS were significantly associated with ENI. Neither baseline NCCT ASPECTS nor the volume of penumbra or ischemic core measured on CTP were associated with ENI. CONCLUSION: CTP ASPECTS might better predict ENI than non-contrast CT at baseline in patients with successful reperfusion following EVT.

Decline in the number of patients with meningitis in German hospitals during the COVID-19 pandemic.

BACKGROUND AND OBJECTIVES: In 2020, a wide range of hygiene measures was implemented to mitigate infections caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In consequence, pulmonary infections due to other respiratory pathogens also decreased. Here, we evaluated the number of bacterial and viral meningitis and encephalitis cases during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: In a multicentre retrospective analysis of data from January 2016 until December 2020, numbers of patients diagnosed with bacterial meningitis and other types of CNS infections (such as viral meningitis and encephalitis) at 26 German hospitals were studied. Furthermore, the number of common meningitis-preceding ear-nose-throat infections (sinusitis, mastoiditis and otitis media) was evaluated. RESULTS: Compared to the previous years, the total number of patients diagnosed with pneumococcal meningitis was reduced (n = 64 patients/year in 2020 vs. n = 87 to 120 patients/year between 2016 and 2019, all p < 0.05). Additionally, the total number of patients diagnosed with otolaryngological infections was significantly lower (n = 1181 patients/year in 2020 vs. n = 1525 to 1754 patients/year between 2016 and 2019, all p < 0.001). We also observed a decline in viral meningitis and especially enterovirus meningitis (n = 25 patients/year in 2020 vs. n = 97 to 181 patients/year between 2016 and 2019, all p < 0.001). DISCUSSION: This multicentre retrospective analysis demonstrates a decline in the number of patients treated for viral and pneumococcal meningitis as well as otolaryngological infections in 2020 compared to previous years. Since the latter often precedes pneumococcal meningitis, this may point to the significance of the direct spread of pneumococci from an otolaryngological focus such as mastoiditis to the brain as one important pathophysiological route in the development of pneumococcal meningitis.

Cognitive Impairment in Adult Patients with 5q-Associated Spinal Muscular Atrophy.

In previous studies, a below-average, average, or above-average intelligence quotient (IQ) in children with SMA was detected but, aside from a severe physical disability, the cognitive performance of adult SMA patients has not yet been evaluated. The intelligence test used in this study, the Wechsler Adult Intelligence Scale, fourth edition (WAIS-IV), was used to measure major intelligence components of adult SMA patients. The WAIS-IV determines four index scores representing verbal comprehension, perceptual reasoning, working memory, and processing speed. Due to time-dependent demands on motor function, the processing speed index score was excluded. IQ index scores of 33 adult SMA patients did not differ from IQ index scores of the normal population. In SMA type-3 patients, the index scores for verbal comprehension, perceptual reasoning, and working memory did not differ from the normal population but showed a trend of IQ scores towards lower points. Patients with SMA type 2 had lower IQ index scores for working memory (90.33 ± 12.95; p = 0.012) and perceptual reasoning (90.73 ± 12.58; p = 0.013) than the normal population. This study provided further evidence that SMA is a multi-systemic disease and may refute the widespread hypothesis that SMA patients might improve their cognitive skills to compensate for their physical impairment.

Assessment of Bulbar Function in Adult Patients with 5q-SMA Type 2 and 3 under Treatment with Nusinersen.

The antisense oligonucleotide nusinersen has been shown to improve trunk and limb motor function in patients with spinal muscular atrophy (SMA). Bulbar dysfunction, which is regularly present in SMA, is not captured by standard motor scores, and validated measurement instruments to assess it have not yet been established. Data on whether and how bulbar function changes under gene-based therapies in adult SMA patients are also unavailable. Here, we present data on the course of bulbar dysfunction assessed prospectively before nusinersen treatment initiation and 6 and 14 months later in 23 adult SMA patients using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). While no improvement in bulbar scores was observed under treatment with nusinersen, the absence of a decline still implies a therapeutic effect of nusinersen on bulbar dysfunction. The results of this study aim to contribute to a standardized assessment of bulbar function in adult SMA patients, which may show therapeutic effects of gene-based therapies that are not evident from standard motor scores.

Gut bacterial microbiota in patients with myasthenia gravis: results from the MYBIOM study.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune neuromuscular disease, with gut microbiota considered to be a pathogenetic factor. Previous pilot studies have found differences in the gut microbiota of patients with MG and healthy individuals. To determine whether gut microbiota has a pathogenetic role in MG, we compared the gut microbiota of patients with MG with that of patients with non-inflammatory and inflammatory neurological disorders of the peripheral nervous system (primary endpoint) and healthy volunteers (secondary endpoint). METHODS: Faecal samples were collected from patients with MG (n = 41), non-inflammatory neurological disorder (NIND, n = 18), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 6) and healthy volunteers (n = 12). DNA was isolated from these samples, and the variable regions of the 16S rRNA gene were sequenced and statistically analysed. RESULTS: No differences were found in alpha- and beta-diversity indices computed between the MG, NIND and CIDP groups, indicating an unaltered bacterial diversity and structure of the microbial community. However, the alpha-diversity indices, namely Shannon, Chao 1 and abundance-based coverage estimators, were significantly reduced between the MG group and healthy volunteers. Deltaproteobacteria and Faecalibacterium were abundant within the faecal microbiota of patients with MG compared with controls with non-inflammatory diseases. CONCLUSION: Although the overall diversity and structure of the gut microbiota did not differ between the MG, NIND and CIDP groups, the significant difference in the abundance of Deltaproteobacteria and Faecalibacterium supports the possible role of gut microbiota as a contributor to pathogenesis of MG. Further studies are needed to confirm these findings and to develop possible treatment strategies.

Nusinersen treatment in adult patients with spinal muscular atrophy: a safety analysis of laboratory parameters.

BACKGROUND: Nusinersen is an intrathecally administered antisense oligonucleotide (ASO) that improves motor function in patients with spinal muscular atrophy (SMA). In addition to efficacy, the safety of a therapy is the decisive factor for the success of the treatment. For some ASOs, various organ toxicities have been described, such as thrombocytopenia, renal and liver impairment, or coagulation abnormalities. However, systematic data on laboratory parameters under treatment with nusinersen are mainly available from studies in infants and children. Therefore, our aim was to assess the safety of nusinersen therapy in adult SMA patients. METHODS: Laboratory data from 404 nusinersen injections performed in 50 adult patients with SMA type 2 and type 3 were retrospectively analyzed. RESULTS: The total observation period was 76.9 patient-years, and patients received up to 12 injections. Our data provides no new safety concerns. In cerebrospinal fluid (CSF), the mean white blood cell count and lactate remained stable over time. Total CSF protein increased by 2.9 mg/dL. No change in mean platelet count was observed under therapy. Only one patient showed sporadic mild thrombocytopenia. Coagulation parameters and inflammatory markers were stable. The mean creatinine level decreased by 0.09 mg/dL. Analysis of mean liver enzyme levels revealed no relevant changes during treatment. CONCLUSION: Our data demonstrate a favorable safety profile of nusinersen therapy in adult SMA patients under longer-term "real-world" conditions. In particular, we found no evidence of clinically relevant platelet declines, coagulopathies, or renal or hepatic organ toxicities, which are common concerns with the use of ASOs.

Assessment of Health-Related Quality of Life in Adult Spinal Muscular Atrophy Under Nusinersen Treatment-A Pilot Study.

5q-Spinal muscular atrophy (SMA) is a severely disabling inherited neuromuscular disease that progressively reduces the motor abilities of affected individuals. The approval of the antisense oligonucleotide nusinersen, which has been shown to improve motor function in adult SMA patients, changed the treatment landscape. However, little is known about its impact on patients' quality of life (QoL), and there is still a need for adequate patient-reported outcome measures. In this study, we used the short form of the Neuro-QoL (Quality of Life in Neurological Disorders) for upper/lower extremity function to prospectively assess the health-related QoL of 17 adult SMA patients prior to initiation of nusinersen treatment and 2, 6, 10, and 14 months afterwards. At baseline, Neuro-QoL scores strongly correlated with motor function scores (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb Module, RULM), but QoL did not increase significantly during the 14-month treatment period despite significant motor improvement as measured by HFMSE. Our results underline the need for novel, disease-specific assessments of QoL in SMA.

Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.

BACKGROUND: Nusinersen is approved for the treatment of 5q spinal muscular atrophy of all types and stages in patients of all ages. Although clinical trials have shown improvements in motor function in infants and children treated with the drug, data for adults are scarce. We aimed to assess the safety and efficacy of nusinersen in adults with 5q spinal muscular atrophy. METHODS: We did an observational cohort study at ten academic clinical sites in Germany. Patients with genetically confirmed 5q spinal muscular atrophy (age 16-65 years) with a homozygous deletion of exons 7, 8, or both, or with compound heterozygous mutations were eligible for inclusion and received nusinersen treatment in accordance with the label for a minimum treatment time of 6 months to a follow-up of up to 14 months. The primary outcome was the change in the total Hammersmith Functional Motor Scale Expanded (HFMSE) score, assessed at months 6, 10, and 14, and based on pre-post comparisons. This study is registered with the German Clinical Trials Register (number DRKS00015702). FINDINGS: Between July 13, 2017, and May 1, 2019, 173 patients were screened, of whom 139 (80%) were eligible for data analysis. Of these, 124 (89%) were included in the 6-month analysis, 92 (66%) in the 10-month analysis, and 57 (41%) in the 14-month analysis; patients with missing baseline HFMSE scores were excluded from these analyses. Mean HFMSE scores were significantly increased compared with baseline at 6 months (mean difference 1·73 [95% CI 1·05-2·41], p<0·0001), 10 months (2·58 [1·76-3·39], p<0·0001), and 14 months (3·12 [2·06-4·19], p<0·0001). Clinically meaningful improvements (≥3 points increase) in HFMSE scores were seen in 35 (28%) of 124 patients at 6 months, 33 (35%) of 92 at 10 months, and 23 (40%) of 57 at 14 months. To 14-month follow-up, the most frequent adverse effects among 173 patients were headache (61 [35%] patients), back pain (38 [22%]), and nausea (19 [11%]). No serious adverse events were reported. INTERPRETATION: Despite the limitations of the observational study design and a slow functional decline throughout the natural disease course, our data provide evidence for the safety and efficacy of nusinersen in the treatment of adults with 5q spinal muscular atrophy, with clinically meaningful improvements in motor function in a real-world cohort. FUNDING: None.

Clinical Implication of Dosimetry of Computed Tomography- and Fluoroscopy-Guided Intrathecal Therapy With Nusinersen in Adult Patients With Spinal Muscular Atrophy.

Background: Spinal muscular atrophy (SMA) is a genetic disorder that leads to progressive tetraparesis. Nusinersen is the first approved drug for the treatment of SMA and is administered via intrathecal injections. Neuromyopathic scoliosis and spondylodesis can impede lumbar punctures, thus necessitating the use of radiological imaging. Furthermore, dosimetry of this potentially lifelong therapy should be supervised. Methods: Fluoroscopy-assisted or computed tomography (CT)-guided intrathecal injections of nusinersen were performed in adult patients with SMA type 2 and 3. The mean effective dose was compared in patients with and without spondylodesis as well as in those with SMA type 2 and 3. The dosimetry was analyzed in relation to the motor function evaluated with the Revised Upper Limb module (RULM) score and the Hammersmith Functional Motor Scale-Expanded (HFMSE) score. Results: Fifteen patients with SMA type 2 and 3 underwent radiological imaging-assisted intrathecal injections. The mean effective dose per CT-guided injection per patient was 2.59 (±1.67) mSv (n = 12). The mean dose area product (DAP) per fluoroscopy-guided injection per patient was 200.48 (±323.67) µGym2 (n = 3). With increase in the number of injections, the effective dose (r = -0.23) (p < 0.05) and the DAP (r = -0.09) (p > 0.05) decreased. The mean effective dose in 4 patients without spinal fusion (SMA type 2) was 1.39 (±0.51) mSv, whereas that in 8 patients with spondylodesis (SMA type 2 and 3) was 3.21 (±1.73) mSv. The mean effective dose in 5 SMA type 2 patients with spondylodesis was 2.68 (±1.47) mSv (n = 5) and in 3 SMA type 3 patients was 4.00 (±1.82) mSv. Dosimetry did not show significant correlation with the clinical severity of the disease (RULM score: r = -0.045, p > 0.05 and HFMSE score: r = -0.001, p > 0.05). Conclusions: In SMA type 2 and 3 patients undergoing radiological imaging-assisted injections, the effective dose and DAP decreased during therapy with nusinersen. The mean effective dose in patients with spondylodesis was higher than that in patients without spondylodesis. Dosimetry should be monitored carefully in order to detect and prevent unnecessary radiation exposure.

Neurofilament Heavy Chain and Tau Protein Are Not Elevated in Cerebrospinal Fluid of Adult Patients with Spinal Muscular Atrophy during Loading with Nusinersen.

Nusinersen is the first approved drug for the treatment of spinal muscular atrophy (SMA). Treatment of SMA with nusinersen is based on a fixed dosing regimen. For other motoneuron diseases, such as amyotrophic lateral sclerosis (ALS), biomarkers are available for clinical diagnostics; however, no such biomarkers have yet been found for SMA. Serum and cerebrospinal fluid (CSF) samples of 11 patients with adult SMA type 3 were prospectively collected and analyzed during loading with nusinersen. Neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase were investigated as potential biomarkers of motor neuron destruction. No significant pathological alterations in levels of neurofilament heavy chain, tau protein, or S100B protein were detected in the CSF or blood samples under baseline conditions or during loading with nusinersen. Neuron-specific enolase was marginally elevated in CSF and blood samples without significant alteration during treatment. In a mixed cohort of adult patients with SMA type 3, neurofilament heavy chain, tau protein, S100B protein, and neuron-specific enolase do not serve as potential biomarkers during the loading phase of nusinersen. The slow progression rate of SMA type 3 may not lead to detectable elevation of levels of these common markers of axonal degradation.

Prevalence of hereditary transthyretin amyloid polyneuropathy in idiopathic progressive neuropathy in conurban areas.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTR amyloidosis) is a rare, genetically heterogenous, and clinically variable autosomal dominant disease that severely reduces life expectancy. As treatment options grow, a proper diagnostic approach is mandatory especially in non-endemic regions with diverse genetic backgrounds. METHODS: We examined 102 neuropathy patients at a German neuromuscular centre. Common causes of polyneuropathy were ruled out by medical history and extensive laboratory testing to define a cohort of patients with progressive polyneuropathy classified as idiopathic. Molecular genetic testing of the entire TTR gene was performed, and the detected amyloidogenic and non-amyloidogenic variants were associated with the observed clinical phenotypes and results of prior diagnostic testing. RESULTS: Two of 102 patients tested positive for amyloidogenic mutations (p.Ile127Val and p.Glu81Lys), while a variant of unknown significance, p.Glu26Ser, was found in 10 cases. In both positive cases, previous negative biopsy results were proved by gene sequencing to be false negative. In case of the p.Glu81Lys mutation we detected clinical presentation (combination of severe polyneuropathy and cardiomyopathy), ethnic background (patient of polish origin, mutation only reported in Japanese families before), and disease course clearly differed from well-known cases of the same mutation in the literature. CONCLUSIONS: In conclusion, transthyretin hereditary amyloid polyneuropathy (ATTR-PN) should be considered in cases of otherwise idiopathic polyneuropathy. Sequencing of the four exons of the TTR gene should be considered the key step in diagnosis, while tissue biopsy possibly leads to false negative results.

Feasibility and safety of intrathecal treatment with nusinersen in adult patients with spinal muscular atrophy.

BACKGROUND: Nusinersen is an intrathecally administered antisense oligonucleotide (ASO) and the first approved drug for the treatment of spinal muscular atrophy (SMA). However, progressive neuromyopathic scoliosis and the presence of spondylodesis can impede lumbar punctures in SMA patients. Our aim was to assess the feasibility and safety of the treatment in adults with SMA. METHODS: For the intrathecal administration of nusinersen, we performed conventional, fluoroscopy-assisted and computer tomography (CT)-guided lumbar punctures in adult patients with type 2 and type 3 SMA. We documented any reported adverse events and performed blood tests. RESULTS: We treated a total of 28 adult SMA patients (9 patients with SMA type 2 and 19 patients with SMA type 3) aged between 18-61 years with nusinersen. The mean Revised Upper Limb Module (RULM) score at baseline in SMA type 2 and SMA type 3 patients was 9.9 ± 4.6 and 29.5 ± 8.5, respectively. The mean Hammersmith Functional Motor Scale Expanded (HFMSE) score at baseline was 3.1 ± 2.5 and 31.2 ± 18.1, respectively. Half of the SMA type 3 patients were ambulatory at treatment onset. In total, we performed 122 lumbar punctures with 120 successful intrathecal administrations of nusinersen. Lumbar punctures were well tolerated, and no serious adverse events occurred. CONCLUSIONS: Our data demonstrate the feasibility and tolerability of intrathecal treatment with nusinersen in adults with SMA type 2 and type 3. However, treatment can be medically and logistically challenging, particularly in patients with SMA type 2 and in patients with spondylodesis.

CIDP, myasthenia gravis, and membranous glomerulonephritis - three autoimmune disorders in one patient: a case report.

BACKGROUND: We present a patient fulfilling the electrophysiological criteria for definite chronic inflammatory demyelinating polyneuropathy (CIDP), antibody-positive myasthenia gravis (MG), and membranous glomerulonephritis (MGN) confirmed by biopsy. To our knowledge, this is the first case of the concomitant appearance of these three autoimmune diseases in a single patient. CASE REPRESENTATION: A 42-year-old Caucasian male presented with rapidly progressive gait disturbance, distal weakness of the lower extremities, ascending hypoesthesia, impaired fine motor skills, and beginning cranial nerve palsy showing dysarthrophonia, facial paralysis, and eye movement abnormalities and was diagnosed as rapid onset (atypical) CIDP. After 3 months, the patient complained of increasing physical exhaustion, reduction of his walking distance, worsening of the residual dysphagia, and dysarthria with an inability to swallow. AChR antibodies (17.0 nmol/L, RF < 0.4) and titin antibodies were positive and repetitive nerve stimulation showed an abnormal decrement matching the criteria of myasthenia gravis. Over time the patient developed severe acute-on-chronic renal failure with high-grade proteinuria resulting in generalized edema followed by secondary hyperparathyroidism and dialysis-dependent renal failure. Renal biopsy confirmed beginning anti-phospholipase A2 receptor antibody membranous nephropathy. CONCLUSION: All three diseases are of autoimmune origin with distinctive immunopathogenetic mechanisms. The present case of CIDP, MG, and MGN occurring in one patient indicates a common underlying immune mechanism in these distinct conditions, including the involvement of autoantibodies and T cells.

Efficacy and safety of a single occipital nerve blockade in episodic and chronic cluster headache: A prospective observational study.

Background Treatment options for cluster headache (CH) include acute, transitional and prophylactic strategies. We assessed the efficacy and safety of a single occipital nerve block (ONB) in patients with episodic (eCH) and chronic CH (cCH). Methods In this prospective, observational study 101 CH were treated with a single ONB using triamcinolone 10 mg and bupivacaine. Attack frequency, pain intensity and side effects were assessed at days 1 and 7 after ONB and thereafter weekly for 60 days until recurrence of attacks. Results Baseline mean daily attack frequency was 2.9 ± 2.5 (eCH) and 3.3 ± 2.9 (cCH), which was reduced to 0.7 ± 1.2 (eCH) and 1.1 ± 1.4 (cCH) after one day ( p = 0.08 for group difference) and to 1.1 ± 1.6 (eCH) and 1.9 ± 2.3 (cCH) after seven days ( p = 0.01 for group difference). In patients with eCH the pain-free period lasted longer compared to cCH ( p = 0.004). There was no association between the presence of local anesthesia and treatment response ( p = 0.88). No serious adverse events occurred. Conclusion ONB is an easy, safe and effective transitional treatment option in case of insufficient response of CH to treatment both in patients with eCH and cCH. Patients with eCH have a better and more sustainable treatment response.

Clinical Features of Neuromuscular Disorders in Patients with N-Type Voltage-Gated Calcium Channel Antibodies.

Neuromuscular junction disorders affect the pre- or postsynaptic nerve to muscle transmission due to autoimmune antibodies. Members of the group like myasthenia gravis and Lambert-Eaton syndrome have pathophysiologically distinct characteristics. However, in practice, distinction may be difficult. We present a series of three patients with a myasthenic syndrome, dropped-head syndrome, bulbar and respiratory muscle weakness and positive testing for anti-N-type voltage-gated calcium channel antibodies. In two cases anti-acetylcholin receptor antibodies were elevated, anti-P/Q-type voltage-gated calcium channel antibodies were negative. All patients initially responded to pyridostigmine with a non-response in the course of the disease. While one patient recovered well after treatment with intravenous immunoglobulins, 3,4-diaminopyridine, steroids and later on immunosuppression with mycophenolate mofetil, a second died after restriction of treatment due to unfavorable cancer diagnosis, the third patient declined treatment. Although new antibodies causing neuromuscular disorders were discovered, clinical distinction has not yet been made. Our patients showed features of pre- and postsynaptic myasthenic syndrome as well as severe dropped-head syndrome and bulbar and axial muscle weakness, but only anti-N-type voltage-gated calcium channel antibodies were positive. When administered, one patient benefited from 3,4-diaminopyridine. We suggest that this overlap-syndrome should be considered especially in patients with assumed seronegative myasthenia gravis and lack of improvement under standard therapy.