Expression of the axon-guidance protein receptor Neuropilin 1 is increased in the spinal cord and decreased in muscle of a mouse model of amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a degenerative motor neuron disorder. It is supposed that ALS is at least in part an axonopathy. Neuropilin 1 is an important receptor of the axon repellent Semaphorin 3A and a co-receptor of vascular endothelial growth factor. It is probably involved in neuronal and axonal de-/regeneration and might be of high relevance for ALS pathogenesis and/or disease progression. To elucidate whether the expression of either Neuropilin1 or Semaphorin3A is altered in ALS we investigated these proteins in human brain, spinal cord and muscle tissue of ALS-patients and controls as well as transgenic SOD1G93A and control mice. Neuropilin1 and Semaphorin3A gene and protein expression were assessed by quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry. Groups were compared using either Student t-test or Mann-Whitney U test. We observed a consistent increase of Neuropilin1 expression in the spinal cord and decrease of Neuropilin1 and Semaphorin3A in muscle tissue of transgenic SOD1G93A mice at the mRNA and protein level. Previous studies have shown that damage of neurons physiologically causes Neuropilin1 and Semaphorin3A increase in the central nervous system and decrease in the peripheral nervous system. Our results indicate that this also occurs in ALS. Pharmacological modulation of expression and function of axon repellents could be a promising future therapeutic option in ALS.

Peripheral nerve atrophy together with higher cerebrospinal fluid progranulin indicate axonal damage in amyotrophic lateral sclerosis.

INTRODUCTION: We aimed to investigate whether sonographic peripheral cross-sectional nerve area (CSA) and progranulin (PGRN), a neuritic growth factor, are related to each other and whether they interact to predict clinical and paraclinical measures in amyotrophic lateral sclerosis (ALS). METHODS: We included 55 ALS patients who had forearm median and ulnar nerve CSA, cerebrospinal fluid (CSF) PGRN, and serum PGRN measures available. CSF PGRN was normalized against the CSF / serum albumin ratio (Qalb ). Using age, sex, height, and weight adjusted general linear models, we examined CSA × CSF PGRN interaction effects on various measures. RESULTS: There was a medium-effect size inverse relationship between CSA and CSF PGRN, but not between CSA and serum PGRN. Lower CSA values together with higher CSF PGRN levels were linked to smaller motor amplitudes. DISCUSSION: In ALS, the constellation of peripheral nerve atrophy together with higher CSF PGRN levels indicates pronounced axonal damage. Muscle Nerve 57: 273-278, 2018.

Interaction of physical function, quality of life and depression in Amyotrophic lateral sclerosis: characterization of a large patient cohort.

BACKGROUND: Due to lack of any curative therapy for ALS, symptomatic treatment and maintenance of quality of life (QoL) is very important. We aimed to characterize the affected domains of QoL in ALS patients and to identify factors which are associated with reduced QoL and increased depression. METHODS: 159 ALS patients answered standardized questionnaires (Beck Depression Inventory-II, SF-36 Health Survey questionnaire, revised ALS functional rating scale). Multiple regression analysis was used to identify correlations between clinical features of ALS patients and depression/QoL scores. In addition, QoL data from ALS patients were compared to age-matched reference values representing the German normal population. RESULTS: QoL of ALS patients was reduced in nearly all SF-36-categories. Progression of physical impairment was positively correlated with depression but reduced QoL scores only in items directly related to physical function. However, QoL was considerably influenced by depression, independently from physical impairment. Regarding distinct patient characteristics one of the most interesting findings was that increasing age was correlated with significantly worse QoL results regarding social functioning. CONCLUSIONS: Depressive symptoms had a strong influence on QoL, hence their detection and treatment is of particular importance. Different domains of QoL are differently affected in subgroups of ALS patients. Being aware of these differences can be valuable for both ALS professional and family caregivers and physicians.

Widespread grey matter pathology dominates the longitudinal cerebral MRI and clinical landscape of amyotrophic lateral sclerosis.

Diagnosis, stratification and monitoring of disease progression in amyotrophic lateral sclerosis currently rely on clinical history and examination. The phenotypic heterogeneity of amyotrophic lateral sclerosis, including extramotor cognitive impairments is now well recognized. Candidate biomarkers have shown variable sensitivity and specificity, and studies have been mainly undertaken only cross-sectionally. Sixty patients with sporadic amyotrophic lateral sclerosis (without a family history of amyotrophic lateral sclerosis or dementia) underwent baseline multimodal magnetic resonance imaging at 3 T. Grey matter pathology was identified through analysis of T1-weighted images using voxel-based morphometry. White matter pathology was assessed using tract-based spatial statistics analysis of indices derived from diffusion tensor imaging. Cross-sectional analyses included group comparison with a group of healthy controls (n = 36) and correlations with clinical features, including regional disability, clinical upper motor neuron signs and cognitive impairment. Patients were offered 6-monthly follow-up MRI, and the last available scan was used for a separate longitudinal analysis (n = 27). In cross-sectional study, the core signature of white matter pathology was confirmed within the corticospinal tract and callosal body, and linked strongly to clinical upper motor neuron burden, but also to limb disability subscore and progression rate. Localized grey matter abnormalities were detected in a topographically appropriate region of the left motor cortex in relation to bulbar disability, and in Broca's area and its homologue in relation to verbal fluency. Longitudinal analysis revealed progressive and widespread changes in the grey matter, notably including the basal ganglia. In contrast there was limited white matter pathology progression, in keeping with a previously unrecognized limited change in individual clinical upper motor neuron scores, despite advancing disability. Although a consistent core white matter pathology was found cross-sectionally, grey matter pathology was dominant longitudinally, and included progression in clinically silent areas such as the basal ganglia, believed to reflect their wider cortical connectivity. Such changes were significant across a range of apparently sporadic patients rather than being a genotype-specific effect. It is also suggested that the upper motor neuron lesion in amyotrophic lateral sclerosis may be relatively constant during the established symptomatic period. These findings have implications for the development of effective diagnostic versus therapeutic monitoring magnetic resonance imaging biomarkers. Amyotrophic lateral sclerosis may be characterized initially by a predominantly white matter tract pathological signature, evolving as a widespread cortical network degeneration.

First In Vivo Electromyographic Analysis of Mechanical Load Scenarios of the Cervicothoracic Junction During Daily Activities as a Basis for Future Postoperative Behavioral Instructions.

STUDY DESIGN: Clinical Research. OBJECTIVES: Study participants were twenty- eigth healty volunteers. BACKGROUND: Soft tissue complications after posterior cervicothoracic fusion surgery occur frequently. Postoperative myofascial dehiscence (PMD) can cause disability and pain. So far, it is unknown whether patients can affect PMD development through behavioral adjustment. Consequently, this study aimed to analyze how much mechanical stress daily activities exert on the posterior muscles and fascia at the cervicothoracic junction. MATERIALS AND METHODS: Surface electromyography was applied next to the upper thoracic spine at the trapezius muscle. All volunteers performed 22 different daily activities, such as tooth brushing, dressing, standing up, and different horizontal positions. During the exercises, the electromyographic activity was measured. For each volunteer, root mean square values were determined. All exercises were then repeated with the use of a clavicular bandage to unload the shoulder and cervicothoracic muscles. Afterwards, the rankings were statistically compared interindividually. RESULTS: Among the different tasks, significant differences in regard to the root mean square values were noted. For instance, horizontal positions caused significantly lower muscle activation compared with all other exercises (P≤ 0.001). Notably, no relevant electromyographic differences were detected between the tasks with and without a clavicular bandage. CONCLUSIONS: This in vivo electromyographic analysis of cervicothoracic muscle activity during daily activities demonstrates that myofascial strain differs among various daily activities. Data indicate that potential postoperative mobilization protocols and behavioral instructions may have the potential to reduce the biomechanical load and consequently the risk of PMD and, therefore, may reduce the risk for surgical wound-related complications, disability, and need for revision surgery.

Therapeutic potential of N-acetyl-glucagon-like peptide-1 in primary motor neuron cultures derived from non-transgenic and SOD1-G93A ALS mice.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurons (MN) in the motor cortex, brain stem, and spinal cord. In the present study, we established an ALS in vitro model of purified embryonic MNs, derived from non-transgenic and mutant SOD1-G93A transgenic mice, the most commonly used ALS animal model. MNs were cultured together with either non-transgenic or mutant SOD1-G93A astrocyte feeder layers. Cell viability following exposure to kainate as excitotoxic stimulus was assessed by immunocytochemistry and calcium imaging. We then examined the neuroprotective effects of N-acetyl-GLP-1(7-34) amide (N-ac-GLP-1), a long-acting, N-terminally acetylated, C-terminally truncated analog of glucagon-like peptide-1 (GLP-1). GLP-1 has initially been studied as a treatment for type II diabetes based on its function as insulin secretagogue. We detected neuroprotective effects of N-ac-GLP-1 in our in vitro system, which could be attributed to an attenuation of intracellular calcium transients, not only due to these antiexcitotoxic capacities but also with respect to the increasing knowledge about metabolic deficits in ALS which could be positively influenced by N-ac-GLP-1, this compound represents an interesting novel candidate for further in vivo evaluation in ALS.

Weight loss, dysphagia and supplement intake in patients with amyotrophic lateral sclerosis (ALS): impact on quality of life and therapeutic options.

BACKGROUND: Weight loss is a frequent feature in the motor neuron disease Amyotrophic lateral sclerosis (ALS). In this study we investigated possible causes of weight loss in ALS, its impact on mood/quality of life (QOL) and the benefit of high calorie nutritional/other dietary supplements and percutaneous endoscopic gastrostomy (PEG). METHODS: 121 ALS patients were interviewed and answered standardized questionnaires (Beck depression inventory - II, SF36 Health Survey questionnaire, revised ALS functional rating scale). Two years after the initial survey we performed a follow-up interview. RESULTS: In our ALS-cohort, 56.3% of the patients suffered from weight loss. Weight loss had a negative impact on QOL and was associated with a shorter survival. Patients who took high calorie nutritional supplements respectively had a PEG stated a great benefit regarding weight stabilization and/or QOL.38.2% of our patients had significant weight loss without suffering from dysphagia. To clarify the reasons for weight loss in these patients, we compared them with patients without weight loss. The two groups did not differ regarding severity of disease, depression, frontotemporal dementia or fasciculations, but patients with weight loss declared more often increased respiratory work. CONCLUSIONS: Weight loss is a serious issue in ALS and cannot always be attributed to dysphagia. Symptomatic treatment of weight loss (high calorie nutritional supplements and/ or PEG) should be offered more frequently.

Differential sirtuin expression patterns in amyotrophic lateral sclerosis (ALS) postmortem tissue: neuroprotective or neurotoxic properties of sirtuins in ALS?

BACKGROUND/AIMS: Sirtuins (SIRT1-7; class III histone deactylases) modulate fundamental mechanisms in age-related neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We assessed the expression levels of sirtuins in human postmortem ALS and control brain and spinal cord. METHODS AND RESULTS: By quantitative real-time PCR, a significant reduction of SIRT1 and SIRT2 was detected in homogenates of the primary motor cortex (white and gray matter), while there were no differences in spinal cord homogenates. When specifically analyzing mRNA and protein expression in the gray matter (cortical layers I-VI of the precentral gyrus, ventral/dorsal horn of the spinal cord) by in situ hybridization histochemistry and immunohistochemistry, we found increased levels of SIRT1, SIRT2 and SIRT5 in ALS which were significant for SIRT1 and SIRT5 mRNA in the spinal cord. CONCLUSION: Our results indicate a general reduction of SIRT1 and SIRT2 in ALS primary motor cortex, while in situ hybridization histochemistry and immunohistochemistry showed neuron-specific upregulation of SIRT1, SIRT2 and SIRT5, particularly in the spinal cord. Opposed effects have been described for SIRT1 and SIRT2: while SIRT1 activation is mainly associated with neuroprotection, SIRT2 upregulation is toxic to neuronal cells. Novel therapeutic approaches in ALS could therefore target SIRT1 activation or SIRT2 inhibition.

Cranial nerve involvement in patients with immune-mediated neuropathy: An observational blink reflex study.

OBJECTIVE: This study aimed to assess cranial nerve involvement in a large adult cohort of patients with immune-mediated neuropathy undergoing immunoglobulin treatment by measuring blink reflex R1 latency prolongation in correlation with clinical findings and nerve conduction studies. METHODS: 104 patients underwent blink reflex examination and ulnar nerve conduction studies and were assessed by the Inflammatory Neuropathy Cause and Treatment disability score, the revised Amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) and focused clinical examination. RESULTS: Prolonged R1 latencies were identified in 23 of 104 patients (22.1 %). These patients had more severe functional impairments according to the ALSFRS-R, yet only five clinically presented with bulbar dysfunction, facial- or trigeminal nerve impairment. Overall R1 latency was inversely correlated to ulnar motor conduction velocity. In preliminary follow-up assessments under continuous immunoglobulin treatment, prolonged R1 latencies partially improved. CONCLUSIONS: Cranial nerve involvement is a common feature in immune-mediated neuropathies and is associated with a more severe disease stage. Here, R1 prolongation was detected less frequently compared to previously reported untreated cohorts. SIGNIFICANCE: Blink reflex studies can detect subclinical cranial nerve involvement in immune-mediated neuropathies. Further studies are needed to evaluate the clinical utility of measuring R1 latency.

Clinical characterisation of women with persistent genital arousal disorder: the iPGAD-study.

Persistent Genital Arousal Disorder (PGAD) is a rare condition-mostly in women-where patients perceive prolonged genital arousal without any sexual desire or stimulation. Etiopathological considerations reach from peripheral to central issues over local disturbance of the pudendal nerve to neuropathy, psychosocial, and pharmacological theories. Since well controlled clinical studies about PGAD in conjunction with a mental and somatic health status are missing, this study is a detailed clinical investigation of PGAD patients compared to healthy controls. 26 women who fulfilled diagnostic criteria for PGAD were compared to 26 age matched healthy controls. Investigations included comparison of vegetative, gynaecological and sexual history, psychiatric features as well as a (neuro-)radiological, neurophysiological and gynaecological examination. Moreover, a detailed clinical characterisation of PGAD symptoms was performed. PGAD symptoms were mostly characterised as tingling or prickling and were permanently present. In over 80%, PGAD symptoms were located in the clitoris. Almost 70% reported radiations to other regions of the body. Most frequent trigger factors were tight clothes, mental stress, driving a car/bus/bicycle and sexual intercourse. Relieving factors were mainly distraction, relaxation, physical exercise, masturbation and swimming. In group comparisons, PGAD presented with significant higher rates of sexual dysfunctions, spontaneous orgasms, swelling of the genitals, extraordinary lubrication as well as higher rates in depression, agoraphobia, generalized anxiety disorder and lifetime panic disorder. Significantly more PGAD patients were diagnosed with restless legs symptoms. In contrast childhood traumatization, somatization disorder, suicidality, gynaecological as well as neurophysiological examination of the pudendal nerve were not different between the groups. MRI of the brain, pelvis and spinal cord was unsuspicious and incidental findings - including Tarlov cysts or pelvic venous congestion - were equally distributed among the groups. In summary, our study provides a careful characterization of women with PGAD highlighting a serious mental burden, most probably as a consequence of PGAD. With the current set of clinical investigations there was no evidence of a clear causal relationship to a specific clinical finding as it has been previously discussed. Future studies and additional techniques will have to further explore where and how in the peripheral or central nervous systems PGAD develops.

Analysis of routine blood parameters in patients with amyotrophic lateral sclerosis and evaluation of a possible correlation with disease progression-a multicenter study.

Objective: Amyotrophic lateral sclerosis (ALS) pathogenesis is still unclear, its course is considerably variable, and prognosis is hard to determine. Despite much research, there is still a lack of easily accessible markers predicting prognosis. We investigated routine blood parameters in ALS patients regarding correlations with disease severity, progression rate, and survival. Additionally, we analyzed disease and patients' characteristics relating to baseline blood parameter levels. Methods: We analyzed creatine kinase (CK), albumin (ALB), creatinine (CREA), total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG) levels around time of diagnosis in 1,084 ALS patients. We carried out linear regression analyses including disease and patients' characteristics with each blood parameter to detect correlations with them. Linear regression models were performed for ALSFRS-R at study entry, its retrospectively defined rate of decay and prospectively collected progression rate. Different survival analysis methods were used to examine associations between blood parameters and survival. Results: We found higher CK (p-value 0.001), ALB (p-value <0.001), CREA (p-value <0.001), and HDL levels (p-value 0.044) at time of diagnosis being associated with better functional status according to ALSFRS-R scores at study entry. Additionally, higher CREA levels were associated with lower risk of death (p-value 0.003). Conclusions: Our results indicate potential of CK, ALB, CREA, and HDL as disease severity or progression markers, and may also provide clues to ALS pathogenesis. However, these values are highly dependent on other variables, and further careful, longitudinal analyses will be necessary to prove the relevance of our findings.

Neurological management and work-up of neurotoxicity associated with CAR T cell therapy.

INTRODUCTION: Treatment with CD19 chimeric antigen receptor (CAR) T cells is an innovative therapeutic approach for patients with relapsed/refractory diffuse large B cell lymphoma (r/rDLBCL) and B-lineage acute lymphoblastic leukemia (r/rALL). However, convincing therapeutic response rates can be accompanied by cytokine release syndrome (CRS) and severe neurotoxicity termed immune effector cell-associated neurotoxicity syndrome (ICANS). METHODS: Single center, prospective observational study of fifteen consecutive r/r DLBCL patients treated with Tisagenlecleucel within 1 year at Hannover Medical School. Extensive neurological work-up prior to CAR T cell infusion included clinical examination, cognitive testing (Montreal-Cognitive-Assessment), brain MRI, electroencephalogram, electroneurography, and analysis of cerebrospinal fluid. After CAR T cell infusion, patients were neurologically examined for 10 consecutive days. Afterwards, all patients were assessed at least once a week. RESULTS: ICANS occurred in 4/15 patients (27%) within 6 days (4-6 days) after CAR T cell infusion. Patients with ICANS grade 2 (n = 3) exhibited similar neurological symptoms including apraxia, expressive aphasia, disorientation, and hallucinations, while brain MRI was inconspicuous in either case. Treatment with dexamethasone rapidly resolved the clinical symptoms in all three patients. Regarding baseline parameters prior to CAR T cell treatment, patients with and without ICANS did not differ. CONCLUSIONS: In our cohort, ICANS occurred in only every fourth patient and rather low grade neurotoxicity was found during daily examination. Our results demonstrate that a structured neurological baseline examination and close monitoring are helpful to detect CAR T cell related neurotoxicity already at an early stage and to potentially prevent higher grade neurotoxicity.

Onset and spreading patterns of upper and lower motor neuron symptoms in amyotrophic lateral sclerosis.

INTRODUCTION: The potential linkage between upper (UMN) and lower motor neuron (LMN) involvement in amyotrophic lateral sclerosis (ALS) has not yet been fully elucidated. There is ongoing discussion as to whether ALS is primarily a disease of UMNs or LMNs. METHODS: We performed a retrospective analysis of 189 ALS patients from our ALS outpatient database to investigate the different spreading patterns of UMN and LMN affection in disease progression in relation to the onset region. RESULTS: The body region with the highest UMN involvement at onset in general also had the highest frequency of LMN signs and vice versa. This is in line with the hypothesis of a focal onset of disease, which then spreads to adjacent areas. However, there was a great variation between ALS phenotypes. DISCUSSION: These observations support the hypothesis of focal damage of a localized group of motor neurons, which then spreads to adjacent motor neurons.

Value of quantitative analysis of routine clinical MRI sequences in ALS.

Simple morphological assessment of conventional MRI used in routine neurological diagnostic work-up lacks sensitivity and specificity for amyotrophic lateral sclerosis (ALS). Quantitative analysis of routine MRI sequences might, however, be more suitable to reveal ALS-related pathological cerebral alterations. We investigated 10 ALS patients and 10 age- and sex-matched healthy controls by MRI. Brain maps of T2 relaxation time (T2), relative proton density (PD), and apparent diffusion coefficient (ADC) were obtained. Values of these parameters were measured in 22 selected brain regions, and compared among the patients and the controls by using paired t-test with Bonferroni corrected alpha level (= 0.002). In ALS patients, increased PD was found in the pyramidal tract, corpus callosum, and white and grey matter. T2 elongation was found at the genu of corpus callosum, and at the posterior limb of the internal capsule (ICP). ADC values showed a tendency towards an increase in patients, which was only significant at the ICP. PD therefore appeared to be the most sensitive parameter for the detection of degenerative changes not only in the motor system but also in extramotor brain regions.

Nerve ultrasound findings in Sjögren's syndrome-associated neuropathy.

BACKGROUND AND PURPOSE: The phenotype of Sjögren's syndrome-associated neuropathy has been better characterized in recent years. However, Sjögren's syndrome-associated neuropathy remains an underdiagnosed entity with only few insights considering the pathomechanisms of nerve damage. Nerve ultrasound has proven to be a useful and efficient tool in detecting nerve damage of autoimmune origin. We, therefore, aimed to evaluate this method for Sjögren's syndrome-associated neuropathy. METHODS: Patients with Sjögren's syndrome and clinical signs of neuropathy underwent sonographic examination of both median and ulnar nerves. Nerve thickening was classified for cross-sectional areas of >12 mm² at the median nerve and for >10 mm² at the ulnar nerve. Fascicle thickening was documented for cross-sectional areas ≥5 mm² at the median and ≥3 mm² at the ulnar nerve. RESULTS: Forty-three patients were included in the analysis (median age 60 years [interquartile range 53-73 years], female rate 60%). 31/43 patients (72%) showed abnormalities on nerve ultrasound, while nerve thickening was found more frequently than fascicle thickening (90% vs. 52% of patients with sonographic abnormalities, respectively). Abnormal findings were observed more frequently at the median nerve and in proximal localization. Abnormal findings on nerve conduction studies were evident in 36/43 patients (84%). Nerve conduction studies revealed a tendency of demyelinating nerve damage patterns being associated with abnormal findings on nerve ultrasound. CONCLUSIONS: In addition to nerve conduction studies, nerve ultrasound may have a supporting role in the diagnosis of Sjögren's syndrome-associated neuropathy. Also, our data support an immune-mediated inflammatory demyelinating pathogenesis of Sjögren's syndrome-associated neuropathy.

CIDP associated with Sjögren's syndrome.

BACKGROUND: This study addresses the challenging characterisation and differentiation of CIDP versus CIDP in association with Sjögren's syndrome to facilitate the process in clinical routine. METHODS: Patients with both CIDP and Sjögren's syndrome and CIDP without Sjögren's syndrome were compared concerning relevant differences in clinical, laboratory and electrophysiological findings. 154 patients who fulfilled the diagnostic EFNS/PNS criteria for CIDP were included in the analysis. 54 of these patients additionally fulfilled the ACR/EULAR classification criteria for Sjögren's syndrome. RESULTS: The frequency of female patients was higher in patients with CIDP and Sjögren's syndrome (52%) versus CIDP patients without Sjögren's syndrome (28%). Furthermore, the occurrence of cranial nerve impairment was significantly higher in patients with Sjögren's syndrome (39% versus 14%). There were no significant group differences in the evaluation of initial symptoms, severity of disability judged by INCAT disability scale score, presence or distribution of sensory deficits, limb weakness and the presence of ataxia, pain or dysautonomia, CSF laboratory or electrophysiological findings. CONCLUSIONS: In conclusion, our data indicate that cranial nerve impairment and female gender might represent red flags for an additional Sjögren's syndrome in patients with CIDP. The patterns of clinical disabilities and electrophysiological findings due to peripheral nerve damage are similar in both CIDP entities.

Treatment expectations and patient-reported outcomes of nusinersen therapy in adult spinal muscular atrophy.

BACKGROUND: The antisense-oligonucleotide (ASO) nusinersen has recently been approved as the first genetically modifying therapy for 5q-associated spinal muscular atrophy (SMA) based on randomized sham-controlled trials in infants and children. The efficacy in adults with long disease history and advanced disease status is still widely unknown; the same applies to specific expectations of adult SMA patients and to what extent they are met and may impact outcome measures. METHODS: In a longitudinal monocentric study in adult patients with SMA types 2-4, the Stanford Expectations of Treatment Scale (SETS) was assessed prior to and during nusinersen treatment. Treatment outcome was evaluated using patient-reported outcomes (PROs) as well as objectively quantifiable motor outcome measures. RESULTS: Adult SMA patients had high expectations of nusinersen treatment effectiveness regarding increase in muscle strength and disease stabilization. Via PROs, 75% stated improvements in muscle strength, endurance and independence under therapy which was in line with slight improvements in quantifiable motor scores during a  ten month observation period. In contrast, patients only expressed few negative expectations which further decreased during therapy. CONCLUSIONS: This study showed mainly positive treatment expectations and PROs in patients undergoing nusinersen treatment along with measurable functional improvement in adult SMA patients. Moreover, treatment expectations did not significantly influence outcome measures.

Impact of comorbidities and co-medication on disease onset and progression in a large German ALS patient group.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with loss of muscle function. The pathogenesis is still unclear and the heterogeneity of ALS phenotypes is huge. We investigated a large population of ALS patients and controls concerning comorbidities and medications to detect specific risk or protective factors regarding onset and progression of ALS. METHODS: We investigated a cohort of 200 ALS patients pro- and retrospectively compared to a control group. For comparison of frequencies of comorbidities and medication intake, uni- and multivariate binary logistic regressions were performed. To analyze the influence of comorbidities and medication on the progression of ALS, we used linear regression analysis. RESULTS: ALS patients showed a relevantly higher prevalence of strokes and depression compared to controls. Moreover, ALS patients reported relevantly more often regular physical activity and their BMI was lower. The coexistence of coronary heart disease was associated with a relevantly faster disease progression. Intake of contraceptives was relevantly higher in controls compared with ALS patients. CONCLUSIONS: Our results suggest stroke, lower BMI, and regular physical activity as risk factors for ALS. Strokes could be a possible trigger of the pathogenetic pathway of ALS and the lower BMI with consecutively lower rate of hyperlipidemia supports the hypothesis of premorbid hypermetabolism in ALS patients. Coexistence of coronary heart disease possibly has a negative influence on respiratory involvement. Contraceptives could be beneficial due to a protective effect of estrogen. Information on influencing factors can help to elucidate the pathogenesis of ALS or provide approaches for possible therapeutic options.

Neuro-Sjögren: Peripheral Neuropathy With Limb Weakness in Sjögren's Syndrome.

Objective: Sjögren's syndrome is a heterogeneous inflammatory disorder frequently involving peripheral nerves with a wide spectrum of sensory modalities and distribution patterns. The objective of this cross-sectional study was to determine characteristics of Sjögren's syndrome as a cause for severe neuropathy with limb weakness. Methods: One hundred and eighty four patients with polyneuropathy associated with limb weakness underwent routine diagnostics including investigations for Sjögren's syndrome. Forty-four patients with Sjögren's syndrome (ACR-EULAR classification criteria) and severe neuropathy were identified. Results: Sjögren's syndrome was found at a median age of 63 years and the gender distribution showed a balanced female-male ratio of 1:1. Anti-SSA(Ro) antibodies were detected in 48% while seronegative patients were diagnosed with Sjögren's syndrome based on sialadenitis on minor salivary gland biopsy with a focus score ≥1. The majority of patients (93%) were diagnosed with Sjögren's syndrome after neurological symptoms appeared. Limbs were symmetrically involved in 84% of patients (57% tetraparesis, 27% paraparesis). Sensory function was not affected in 11% of patients indicating that Sjögren's syndrome associated neuropathy can present as a pure motor syndrome. Electrophysiological measurements did not reveal pathognomonic findings (23% demyelinating pattern, 36% axonal pattern, 41% both demyelinating and axonal damage signs). More than half of our patients fulfilled the European Federation of Neurological Societies (EFNS) diagnostic criteria for CIDP indicating that distinction between Neuro-Sjögren and other causes of neuropathy such as CIDP is challenging. Interpretation: Our findings show that severe neuropathy with limb weakness is often associated with Sjögren's syndrome. This is of great importance in identifying and understanding the causes of immune mediated polyneuropathy.

Influence of Environment and Lifestyle on Incidence and Progress of Amyotrophic Lateral Sclerosis in A German ALS Population.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease mainly affecting upper and lower motor neurons in the brain and spinal cord. Pathogenesis of ALS is still unclear, and a multifactorial etiology is presumed. The remarkable clinical heterogeneity between different phenotypes of ALS patients suggests that environmental and lifestyle factors could play a role in onset and progression of ALS. We analyzed a cohort of 117 ALS patients and 93 controls. ALS patients and controls were compared regarding physical activity, dietary habits, smoking, residential environment, potentially toxic environmental factors and profession before symptom onset and throughout the disease course. Data were collected by a personal interview. For statistical analysis descriptive statistics, statistical tests and analysis of variance were used. ALS patients and controls did not differ regarding smoking, diet and extent of physical training. No higher frequency of toxic influences could be detected in the ALS group. ALS patients lived in rural environment considerably more often than the control persons, but this was not associated with a higher percentage of occupation in agriculture. There was also a higher percentage of university graduates in the ALS group. Patients with bulbar onset were considerably more often born in an urban environment as compared to spinal onset. Apart from education and environment, ALS phenotypes did not differ in any investigated environmental or life-style factor. The rate of disease progression was not influenced by any of the investigated environmental and life-style factors. The present study could not identify any dietary habit, smoking, physical activity, occupational factor as well as toxic influences as risk factor or protective factor for onset or progression of ALS. Living in rural environment and higher education might be associated with higher incidence of ALS.