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BACKGROUND AND PURPOSE: Kelchlike protein 11 antibodies (KLHL11-IgGs) were first described in 2019 as a marker of paraneoplastic neurological syndromes (PNSs). They have mostly been associated with testicular germ cell tumors (tGCTs). METHODS: Two patients with KLHL11-IgG encephalitis are reported, and the literature is comprehensively reviewed. RESULTS: Patient 1 had been in remission from a tGCT 10 years prior. He developed episodic vertigo and diplopia progressing over a few days. Treatment with corticosteroids (CSs) was started a few days after symptom onset. Patient 2 had transient diplopia, which resolved spontaneously. Visual problems persisted for 7 months, when he additionally developed a progressive cerebellar syndrome. One year after onset, CS treatment was started. Initial magnetic resonance imaging was unremarkable in both patients, but analysis of cerebrospinal fluid (CSF) revealed chronic inflammation. KLHL11-IgG was positive in both patients (Patient 1 only in CSF, Patient 2 in serum). Neoplastic screening has so far not revealed any signs of active underlying malignancy. We found 15 publications of 112 patients in total with KLHL11-IgG encephalitis. Most patients (n = 82) had a cerebellar syndrome with or without signs of rhombencephalitis. The most common symptoms were ataxia (n = 82) and vertigo (n = 47), followed by oculomotor disturbances (n = 35) and hearing disorders (n = 31). Eighty of 84 patients had a GCT as an underlying tumor. CONCLUSIONS: Our cases demonstrate classical symptoms of KLHL11-IgG encephalitis. Early diagnosis and therapy are imperative. As with other PNSs, clinical awareness is needed and further studies are required especially in regard to therapeutic management.
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Enfermedades Cerebelosas , Encefalitis , Masculino , Humanos , Diplopía , Inmunoglobulina G , Vértigo , Autoanticuerpos/análisisRESUMEN
BACKGROUND AND PURPOSE: Neuronal autoantibodies can support the diagnosis of primary autoimmune cerebellar ataxia (PACA). Knowledge of PACA is still sparce. This article aims to highlight the relevance of anti-neurochondrin antibodies and possible therapeutical consequences in people with PACA. METHODS: This is a case presentation and literature review of PACA associated with anti-neurochondrin antibodies. RESULTS: A 33-year-old man noticed reduced control of the right leg in May 2020. During his first clinic appointment at our institution in September 2021, he complained about gait imbalance, fine motor disorders, tremor, intermittent diplopia and slurred speech. He presented a pancerebellar syndrome with stance, gait and limb ataxia, scanning speech and oculomotor dysfunction. Within 3 months the symptoms progressed. An initial cerebral magnetic resonance imaging, June 2020, was normal, but follow-up imaging in October 2021 and July 2022 revealed marked cerebellar atrophy (29% volume loss). Cerebrospinal fluid analysis showed lymphocytic pleocytosis of 11 x 103 /L (normal range 0-4) and oligoclonal bands type II. Anti-neurochondrin antibodies (immunoglobulin G) were detected in serum (1:10,000) and cerebrospinal fluid (1:320, by cell-based indirect immunofluorescence assay and immunoblot, analysed by the EUROIMMUN laboratory). After ruling out alternative causes and neoplasia, diagnosis of PACA was given and immunotherapy (steroids and cyclophosphamide) was started in January 2022. In March 2022 a stabilization of disease was observed. CONCLUSION: Cerebellar ataxia associated with anti-neurochondrin antibodies has only been described in 19 cases; however, the number of unrecognized PACAs may be higher. As anti-neurochondrin antibodies target an intracellular antigen and exhibit a mainly cytotoxic T-cell-mediated pathogenesis, important therapeutic implications may result. Because of the severe and rapid clinical progression, aggressive immunotherapy was warranted. This case highlights the need for rapid diagnosis and therapy in PACA, as stabilization and even improvement of symptoms are attainable.
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Ataxia Cerebelosa , Masculino , Humanos , Adulto , Autoanticuerpos , Ciclofosfamida , Linfocitos , BiomarcadoresRESUMEN
BACKGROUND: Leptomeningeal inflammation in patients with multiple sclerosis (MS) mainly affects meningeal B-cell follicle-like structures linked to cortical and subpial lesions and can be visualized as leptomeningeal enhancement (LME). OBJECTIVE: To evaluate the evolution of LME under different MS immunotherapies. METHODS: A total of 214 MS patients treated with anti-CD20 therapies or fingolimod at the university hospital Bern were screened for LME. Magnetic resonance imaging (MRI) and medical records were retrospectively evaluated, and comparative statistics were applied. RESULTS: We compared MS patients treated with anti-CD20 therapies (128 patients (59.8%)) or fingolimod (86 patients (40.2%)). Of 128 anti-CD20-treated patients, 108 (84.4%) had no LME, 11 (8.6%) had persistent LME, and 9 (7.0%) showed resolution of LME. Of 86 fingolimod-treated MS patients, 81 (94.2%) had no LME and 5 (5.8%) persistent LME. Patients with LME persistence were older than those without or resolution of LME (p = 0.039). Resolution of LME was more frequent during anti-CD20 compared with fingolimod treatment (p = 0.019). CONCLUSION: We observed LME resolution under treatment with anti-CD20 therapies. As LME might play an important role in cerebral gray matter pathology in MS, further investigations including extensions to higher field strengths, correlation with clinical phenotypes, and comparison with other immunotherapies are needed.
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Clorhidrato de Fingolimod , Esclerosis Múltiple , Humanos , Estudios Retrospectivos , Clorhidrato de Fingolimod/uso terapéutico , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/patología , Meninges/diagnóstico por imagen , Meninges/patología , Imagen por Resonancia Magnética/métodos , InmunoterapiaRESUMEN
INTRODUCTION: Post-COVID-19 syndrome affects approximately 10-25% of people after a COVID-19 infection, irrespective of initial COVID-19 severity. The aim of this project was to assess the clinical characteristics, course, and prognosis of post-COVID-19 syndrome using a systematic multidimensional approach. PATIENTS AND METHODS: An online survey of people with suspected and confirmed COVID-19 and post-COVID-19 syndrome, distributed via Swiss COVID-19 support groups, social media, and our post-COVID-19 consultation, was performed. A total of 8 post-infectious domains were assessed with 120 questions. Data were collected from October 15 to December 12, 2021, and 309 participants were included. Analysis of clinical phenomenology of post-COVID-19 syndrome was performed using comparative statistics. RESULTS: The three most prevalent post-COVID-19 symptoms in our survey cohort were fatigue (288/309, 93.2%), pain including headache (218/309, 70.6%), and sleep-wake disturbances (mainly insomnia and excessive daytime sleepiness, 145/309, 46.9%). Post-COVID-19 syndrome had an impact on work ability, as more than half of the respondents (168/268, 62.7%) reported an inability to work, which lasted on average 26.6 weeks (95% CI 23.5-29.6, range 1-94, n = 168). Quality of life measured by WHO-5 Well-being Index was overall low in respondents with post-COVID-19 syndrome (mean, 95% CI 9.1 [8.5-9.8], range 1-25, n = 239). CONCLUSION: Fatigue, pain, and sleep-wake disturbances were the main symptoms of the post-COVID-19 syndrome in our cohort and had an impact on the quality of life and ability to work in a majority of patients. However, survey respondents reported a significant reduction in symptoms over 12 months. Post-COVID-19 syndrome remains a significant challenge. Further studies to characterize this syndrome and to explore therapeutic options are therefore urgently needed.
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COVID-19 , Encuestas Epidemiológicas , Humanos , COVID-19/complicaciones , COVID-19/diagnóstico , COVID-19/epidemiología , COVID-19/fisiopatología , Fatiga/complicaciones , Fatiga/epidemiología , Dolor/complicaciones , Dolor/epidemiología , Calidad de Vida , SARS-CoV-2/patogenicidad , Suiza/epidemiología , Trastornos Intrínsecos del Sueño/complicaciones , Trastornos Intrínsecos del Sueño/epidemiología , Estudios de Cohortes , Síndrome Post Agudo de COVID-19RESUMEN
Objective: Anti-CD20-treated patients are at risk of a reduced humoral immune response during the SARS-CoV-2 pandemic. Our aim was to compare the antibody response after two vaccinations with the mRNA vaccines BNT162b2 or mRNA-1273 in patients with multiple sclerosis. Methods: Data from the University Hospital of Bern and Cantonal Hospital of Lucerne were retrospectively collected from medical records and then analyzed. Anti-spike IgG serum titers were collected from both centers and were considered to be protective from a value of ≥100 AU/mL. Continuous variables were given as the mean and 95% confidence interval (95% CI); categorical variables were given as frequencies. A Mann-Whitney test and Fisher's exact test as well as a multivariable linear regression analysis with anti-spike IgG (AU/mL) as the dependent variable were run using SPSS Statistic 25 (IBM Corp., Amonk, NY, USA). Results: A total of 74 patients were included; 41/74 (63.51%) were female patients and the mean age was 46.6 years (95% CI 43.4-49.9). Of these patients, 36/74 were vaccinated with BNT162b2 and 38/74 with mRNA-1273, following the national vaccination recommendation. In both vaccine groups, protective anti-spike IgG titers (≥100 AU/mL) were infrequently achieved (5/74: mRNA-1273 3/38; BNT162b2 2/36). Conclusions: In addition to a low rate of protective anti-spike IgG titers in both vaccine groups, we identified a drop in anti-spike IgG serum titers over time. This observation bears therapeutic consequences, as initial positive titers should be checked in case of an infection with the SARS-CoV-2 virus to identify patients who would benefit from an intravenous anti-spike IgG treatment against acute COVID-19.
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Primary CNS Vasculitis - An Overview Abstract. Cerebral vasculitis, especially the primary vasculitis of the central nervous systems (primary CNS vasculitis), are rare inflammatory diseases of the small- and medium-sized vessels of the CNS. The pathogenesis of primary CNS vasculitis is unclear. Infectious triggers are hypothesized to induce an activation of the immune system with resulting inflammation of the blood vessels within the CNS. Clinically, primary CNS vasculitis presents heterogeneously with leading symptoms such as headache, memory impairment and other neurological deficits. A broad diagnostic work-up prior to treatment initiation is crucial. Treatment consists of immunotherapy (pulse and maintenance therapy) and requires long-term neurological treatment and follow-up due to the increased risk of recurrence of the disease.
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Vasculitis del Sistema Nervioso Central , Humanos , Inflamación , Vasculitis del Sistema Nervioso Central/diagnóstico , Vasculitis del Sistema Nervioso Central/patología , Vasculitis del Sistema Nervioso Central/terapiaRESUMEN
Introduction: Post-COVID-19 syndrome affects approximately 10-25% of people suffering from COVID-19 infection, irrespective of initial COVID-19 severity. Fatigue is one of the major symptoms, occurring in 30-90% of people with post-COVID-19 syndrome. This study aims at describing factors associated with fatigue in people with Post-COVID-19 seen in our newly established Post-Covid clinic. Methods: This retrospective single center study included 42 consecutive patients suffering from Post-COVID-19 syndrome treated at the Department of Neurology, University Hospital Bern, between 11/2020 and05/2021. Clinical phenomenology of Post-COVID-19 syndrome with a special focus on fatigue and risk factor identification was performed using Mann-Whitney U Test, Pearson Correlation, and Chi-Quadrat-Test. Results: Fatigue (90.5%) was the most prevalent Post-COVID-19 symptom followed by depressive mood (52.4%) and sleep disturbance (47.6%). Fatigue was in mean severe (Fatigue severity scale (FSS) mean 5.5 points (95% Confidence interval (95CI) 5.1 - 5.9, range .9 - 6.9, n = 40), and it was unrelated to age, COVID-19 severity or sex. The only related factors with fatigue severity were daytime sleepiness and depressed mood. Conclusion: Fatigue is the main symptom of the Post-COVID-19 syndrome in our cohort. Further studies describing this syndrome are needed to prepare the healthcare systems for the challenge of treating patients with Post-COVID-19 syndrome.
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AIMS: Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) have been proposed to define "MOG encephalomyelitis" (MOG-EM), with published diagnostic and "red flag" criteria. We aimed to evaluate these criteria in a routine clinical setting. METHODS: We retrospectively analyzed patients with borderline/positive MOG-IgG and applied the diagnostic and red flag criteria to determine likelihood of MOG-EM diagnosis. Para-/clinical parameters were described and analyzed with chi-square test. RESULTS: In total, 37 patients fulfilled MOG-EM diagnostic criteria (female-to-male ratio: 1.6:1, median onset age: 28.0 years [IQR 18.5-40.5], n = 8 with pediatric onset). In 24/37, red flags were present, predominantly MOG-IgG at assay cutoff and/or MRI lesions suggestive of multiple sclerosis (MS). As proposed in the consensus criteria, these patients should rather be described as "possible" MOG-EM. Of these, we classified 13 patients as "unlikely" MOG-EM in the presence of the red flag "borderline MOG-IgG" with negative MOG-IgG retest or coincidence of ≥1 additional red flag. This group mainly consisted of patients diagnosed with MS (n = 11). Frequency of cerebrospinal fluid (CSF-)-specific oligoclonal bands (OCB) is significantly lower in definite vs possible and unlikely MOG-EM (P = .0005). CONCLUSION: Evaluation of diagnostic and red flag criteria, MOG-IgG retesting (incl. change of assay), and CSF-specific OCB are relevant in clinical routine cohorts to differentiate MOG-EM from MS.
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Autoanticuerpos/sangre , Encefalomielitis/sangre , Encefalomielitis/diagnóstico por imagen , Inmunoglobulina G/sangre , Glicoproteína Mielina-Oligodendrócito/sangre , Adolescente , Adulto , Estudios de Cohortes , Femenino , Células HEK293 , Humanos , Imagen por Resonancia Magnética/tendencias , Masculino , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Postural tachycardia syndrome (POTS) is a form of autonomic dysfunction characterized by symptoms of orthostatic intolerance, often accompanied by sudomotor dysfunction and gastrointestinal dysmotility. Recently, evidence has accumulated that in a subset of patients, the pathogenesis of dysautonomia may be immune-mediated. The aim of the current report was to evaluate the use of intravenous immunoglobulin (IVIG) treatment in patients with progressive and/or refractory immune-mediated POTS. METHODS: We retroactively assessed the effect and tolerance of monthly administered IVIG in six patients using autonomic function testing, standardized symptom questionnaires, and patients' symptom diaries both before and 6 months into IVIG treatment. Objective outcome measures included heart rate increase after 10 min of head-up tilt as well as duration and anhidrotic area in a thermoregulatory sweat test. Subjective outcome measures were patient reports and symptom ratings from the symptom questionnaire. RESULTS: All patients responded to immunomodulatory treatment, regardless of disease duration. After 6 months of IVIG, symptom severity was reduced by nearly 40%. Autonomic function testing showed improved cardiovascular functioning by 50% and a reduction of anhidrotic areas by one third. Overall, tolerance of IVIG treatment was poor, but could be improved by a reduction in infusion rate, premedication with steroids, and additional intravenous hydration. CONCLUSIONS: Using subjective but also standardized objective measures, the case series describes promising effects of IVIG treatment in POTS patients with immune-mediated dysautonomia. By reducing the infusion rate, pretreatment with steroids, and intravenous hydration, tolerance could be improved, and no patient had to discontinue the treatment.
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Síndrome de Taquicardia Postural Ortostática , Disautonomías Primarias , Frecuencia Cardíaca , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Síndrome de Taquicardia Postural Ortostática/tratamiento farmacológico , Disautonomías Primarias/tratamiento farmacológicoRESUMEN
Neuroanatomy and Pathophysiology of Pain Perception Abstract. Nociception, the possibility of our sensory nervous system to detect painful and therefore potentially harmful stimuli, is crucial for survival. In essence it serves as a "detect and protect" mechanism. For this reason, many features of this complex network, for example the nociceptors, are evolutionary highly preserved. To guarantee an adequate and fast response to prevent tissue damage, the information has to be processed in a fast and stable manner. To this account, the network is designed to be able to potentiate the information at any level. However, sometimes triggered by pathophysiological factors like inflammation, this functional and structural plasticity can become maladaptive, leading to chronification of pain and in this way become a disease itself. Nociception starts in the periphery by activation of a nociceptor which is a highly specialized neuron of the somatosensory nervous system. Some of them are thinly myelinated Aδ fibers, others unmyelinated C fibers. The free nerve endings in the skin or other tissues are equipped with different receptors and ion channels to translate noxious stimuli (like temperature or pressure) into electrochemical signals. These are transmitted to the dorsal horn of the spinal cord, where the second neuron is activated via excitatory amino acids (like glutamate) and other substances, a process which is modulated by inhibitory interneurons. This second neuron projects to cerebral locations, mostly to the thalamus but also to hypothalamus and amygdala, where the usually fast emotional and vegetative reaction is generated. The third order neuron then terminates in the somatosensory cortex and is embedded in a complex network, the so called "pain matrix". Areas involved are for example the prefrontal cortex, where decision making happens, and the limbic structures, where pain memory and learning processes take place. Descending projections from the locus coeruleus, raphe nuclei and the rostroventral medulla oblongata to the spinal cord can either facilitate or inhibit the nociceptive information. Sensitization leading to enhanced activation of the nociceptive pathways can take place at any level, which can become a "circulus vitiosus", finally underlying a chronic pain disorder.
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Neuroanatomía , Nociceptores , Humanos , Dolor , Percepción del Dolor , Médula EspinalRESUMEN
BACKGROUND: In multiple sclerosis (MS), the frequency of hypogammaglobulinemia is unknown. We aimed to evaluate the frequency of reduced immunoglobulin (Ig) concentrations and its association with immunotherapy and disease course in two independent MS cohorts. METHODS: In our retrospective cross-sectional study, MS patients and control patients with head or neck pain from Bern University Hospital (Bern, Switzerland) and Eginition University Hospital (Athens, Greece) were included. The lower limits of normal (LLN) for serum Ig concentration were IgG < 700 mg/dl, IgM < 40 mg/dl, and IgA < 70 mg/dl. Mann-Whitney U test, analysis of variance test, and multiple linear regression analysis were employed. RESULTS: In total, 327 MS patients were retrospectively identified (Bern/Athens: n = 226/101). Serum IgG concentrations were frequently under LLN in both MS cohorts (Bern/Athens: 15.5%/14.9%), even when considering only untreated patients (Bern/Athens: 7.9%/8.6%). MS patients (n = 327) were significantly more likely to have IgG concentrations below LLN and below 600 mg/dl in comparison with controls (n = 58) (p = 0.015 and 0.047, respectively). Between both patient groups, no significant differences were found in frequencies of IgA and IgM concentrations under LLN [n (MS patients/controls): IgA 203/30, IgM 224/24]. Independently of age, secondary progressive MS patients had lower IgG concentrations than relapsing-remitting and primary progressive patients (both: p ⩽ 0.01). After adjusting for sex, age, and disease course, IgG concentrations were lower in patients treated with rituximab (p = 0.001; n = 42/327), intravenous corticosteroids (p < 0.001; n = 16/327), natalizumab (p < 0.001; n = 48/327), and fingolimod (p = 0.003; n = 6/327). CONCLUSION: Our study demonstrated high prevalence rates of reduced serum IgG concentrations in MS patients with and without disease-modifying treatments. The significance of lower IgG concentrations at the levels noted is unclear considering that infections or interference with antibody production generally occur when IgG levels are much lower, at or below 400 mg/dl. However, the information is useful to monitor IgG levels especially with anti-B-cell therapies and consider IgG substitution when levels drop below 400 mg/dl.
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INTRODUCTION: In acute inflammatory optic neuritis (ON) as a typical onset of multiple sclerosis (MS), only few studies have investigated plasma exchange (PLEX) as a sequential treatment after insufficient response to high-dose intravenous glucocorticosteroids. Therefore, we aimed to investigate treatment outcome on visual acuity (VA) with PLEX in patients with steroid-refractory ON. METHODS: In our retrospective monocentric study, medical records were screened for patients with acute ON as their first relapse with sequential MS diagnosis or with an established MS diagnosis from the Bern University Hospital (Switzerland) that were treated with PLEX between 2016 and 2018 due to lacking steroid response. VA prior to steroid administration, and before and after PLEX were assessed and compared using the Friedman multiple comparison test. RESULTS: In total, 18 patients were included in the analysis. Interval from symptom onset to PLEX was 20.3 days (mean, 95% CI 14.8-25.9). Relevant functional improvement (VA of ≥0.5, after a mean of 15.9 (13.3-18.5) days after start of PLEX) was detected in 16/18 (88.9%) with a significant amelioration as compared to VA before glucocorticosteroids and before PLEX (p < 0.0001). VA improvement at a later time point (38.1 weeks, 25.2-51.0) was present in 15/16 (93.8%) patients. No serious adverse events were detected. PLEX could be performed via peripheral access in 13/18 patients (72.2%). CONCLUSION: Our study demonstrates significant improvements of VA with PLEX in a cohort of MS patients with steroid-refractory ON. High response rates may be due to the timely treatment initiation. Despite the small sample size, our data support the early use of PLEX in steroid-refractory ON with a favorable safety profile.
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Objective: Differential diagnosis of neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) or mimics can be challenging, especially in patients with atypical presentations and negative serostatus for aquaporin-4 antibodies (AQP4-Ab). This brief research report describes magnetic resonance imaging (MRI) findings focusing on quantitative apparent diffusion coefficient (ADC) histogram analysis as a potential tool to differentiate NMOSD from MS. Methods: Longitudinal MRI data obtained during routine clinical examinations were retrospectively analyzed in a patient with histologically determined cerebral NMOSD, a patient with an acute tumefactive MS lesion, and a patient with ischemic stroke. Histogram analyses of ADC maps were evaluated. Results: A patient diagnosed with MS experienced a severe rebound after fingolimod withdrawal and a single daclizumab injection. Cerebral NMOSD manifestation was confirmed by brain biopsy. However, the patient did not fulfill consensus criteria for NMOSD and was AQP4-Ab negative. Comparison of ADC histogram analyses of this patient with those from a patient with MS and one with ischemic stroke revealed differential ADC characteristics: namely a more pronounced and prolonged ADC leftward shift in inflammatory than in ischemic pathology, even more accentuated in NMOSD versus MS. Conclusion: ADC map histograms and ADC threshold values for different conditions may be useful for differentiation of large inflammatory brain lesions and further studies are merited.
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OBJECTIVE: To estimate non-invasively the amount, recruitment pattern and discharge frequency of spinal motor neurons (MN) at contraction strength >20% of maximal voluntary contraction (MVC) of small hand muscles. METHODS: A peripheral collision technique was used and consisted of supramaximal electrical stimuli at Erb's point and at the wrist, synchronizing descending volleys of action potential during voluntary isometric contractions of the abductor digiti minimi muscle at 20-80% of MVC strength and 1-8â¯s of contraction duration. Responses of 13 healthy volunteers were quantified and analysed using a recently described model of MN behaviour. RESULTS: A linear relationship between MN discharge and force generation was noticed with R2â¯=â¯0.996, and was confirmed using the simulation results (R2â¯=â¯0.997) for contraction durations up to 8â¯s. For each investigated force level, discharge frequency and recruitment pattern were calculated for individual MN. CONCLUSIONS: Using this method, MN discharge properties during voluntary activity can be estimated non-invasively. SIGNIFICANCE: This method provides new opportunities for the non-invasive study of MN behaviour, and could be expanded to patients with conduction failure and during fatigue.
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Electromiografía/métodos , Potenciales Evocados Motores/fisiología , Neuronas Motoras/fisiología , Contracción Muscular/fisiología , Nervios Periféricos/fisiología , Potenciales de Acción/fisiología , Adulto , Estimulación Eléctrica/métodos , Femenino , Mano/inervación , Mano/fisiología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Progress in the treatment of multiple sclerosis Abstract. Especially the immunotherapy of multiple sclerosis demonstrates that neurology has developed into a specialty with multiple therapeutic options. Progress in basic science, translational research but also innovative clinical study designs were pivotal for this advancement. Whereas the disease is still not curable, especially in early stages stabilization is often feasible. The multitude of available immunotherapies often facilitate individualized treatment approaches. However, due to rare but potentially severe side effects patients and MS-therapists alike are confronted with new dimensions of critical benefit-risk considerations. Wheras also for chronic progressive disease immunotherapeutic options are increasing, neuroprotective or -regenerative approaches are still in developmental stages. Thus, further effort is also needed for the optimization of symptomatic therapy.