Serum neurofilament light chain in distinct phenotypes of amyotrophic lateral sclerosis: A longitudinal, multicenter study.

OBJECTIVE: To assess the performance of serum neurofilament light chain (sNfL) in clinical phenotypes of amyotrophic lateral sclerosis (ALS). METHODS: In 2949 ALS patients at 16 ALS centers in Germany and Austria, clinical characteristics and sNfL were assessed. Phenotypes were differentiated for two anatomical determinants: (1) upper and/or lower motor involvement (typical, typMN; upper/lower motor neuron predominant, UMNp/LMNp; primary lateral sclerosis, PLS) and (2) region of onset and propagation of motor neuron dysfunction (bulbar, limb, flail-arm, flail-leg, thoracic onset). Phenotypes were correlated to sNfL, progression, and survival. RESULTS: Mean sNfL was - compared to typMN (75.7 pg/mL, n = 1791) - significantly lower in LMNp (45.1 pg/mL, n = 413), UMNp (58.7 pg/mL n = 206), and PLS (37.6 pg/mL, n = 84). Also, sNfL significantly differed in the bulbar (92.7 pg/mL, n = 669), limb (64.1 pg/mL, n = 1305), flail-arm (46.4 pg/mL, n = 283), flail-leg (53.6 pg/mL, n = 141), and thoracic (74.5 pg/mL, n = 96) phenotypes. Binary logistic regression analysis showed highest contribution to sNfL elevation for faster progression (odds ratio [OR] 3.24) and for the bulbar onset phenotype (OR 1.94). In contrast, PLS (OR 0.20), LMNp (OR 0.45), and thoracic onset (OR 0.43) showed reduced contributions to sNfL. Longitudinal sNfL (median 12 months, n = 2862) showed minor monthly changes (<0.2%) across all phenotypes. Correlation of sNfL with survival was confirmed (p < 0.001). CONCLUSIONS: This study underscored the correlation of ALS phenotypes - differentiated for motor neuron involvement and region of onset/propagation - with sNfL, progression, and survival. These phenotypes demonstrated a significant effect on sNfL and should be recognized as independent confounders of sNfL analyses in ALS trials and clinical practice.

Performance of serum neurofilament light chain in a wide spectrum of clinical courses of amyotrophic lateral sclerosis-a cross-sectional multicenter study.

BACKGROUND AND PURPOSE: The objective was to assess the performance of serum neurofilament light chain (sNfL) in amyotrophic lateral sclerosis (ALS) in a wide range of disease courses, in terms of progression, duration and tracheostomy invasive ventilation (TIV). METHODS: A prospective cross-sectional study at 12 ALS centers in Germany was performed. sNfL concentrations were age adjusted using sNfL Z scores expressing the number of standard deviations from the mean of a control reference database and correlated to ALS duration and ALS progression rate (ALS-PR), defined by the decline of the ALS Functional Rating Scale. RESULTS: In the total ALS cohort (n = 1378) the sNfL Z score was elevated (3.04; 2.46-3.43; 99.88th percentile). There was a strong correlation of sNfL Z score with ALS-PR (p < 0.001). In patients with long (5-10 years, n = 167) or very long ALS duration (>10 years, n = 94) the sNfL Z score was significantly lower compared to the typical ALS duration of <5 years (n = 1059) (p < 0.001). Furthermore, in patients with TIV, decreasing sNfL Z scores were found in correlation with TIV duration and ALS-PR (p = 0.002; p < 0.001). CONCLUSIONS: The finding of moderate sNfL elevation in patients with long ALS duration underlined the favorable prognosis of low sNfL. The strong correlation of sNfL Z score with ALS-PR strengthened its value as progression marker in clinical management and research. The lowering of sNfL in correlation with long TIV duration could reflect a reduction either in disease activity or in the neuroaxonal substrate of biomarker formation during the protracted course of ALS.

Association of Lesion Location and Depressive Symptoms Poststroke.

BACKGROUND: Depressive symptoms are a common stroke sequela, yet their neurobiological substrates are still unclear. We sought to determine if they are associated with specific lesion locations. METHODS: In a prospective observational study, 270 patients with stroke were tested twice with the Hospital Anxiety and Depression Scale around day 6 and again 6 months poststroke and voxel-based lesion behavior mapping was performed. RESULTS: Frequency of depressive symptoms (depression subscale of the Hospital Anxiety and Depression Scale >7) after 6 months was 19.6 %. Higher Hospital Anxiety and Depression Scale scores for depression around day 6 were the only variable associated with depressive symptoms after 6 months in a multiple logistic regression. Lesions in the right putamen were significantly associated with depressive symptoms after 6 months in the voxel-based lesion behavior mapping. CONCLUSIONS: Lesions in the right basal ganglia might increase the risk of depressive symptoms 6 months poststroke.

Association of Lesion Location and Depressive Symptoms Poststroke.

BACKGROUND AND PURPOSE: Poststroke depression is a common stroke sequel, yet its neurobiological substrates are still unclear. We sought to determine whether specific lesion locations are associated with depressive symptoms after stroke. METHODS: In a prospective study, 270 patients with first ever stroke were repeatedly tested with the depression subscale of the Hospital Anxiety and Depression Scale within the first 4 weeks and 6 months after stroke. Voxel-based lesion behavior mapping based on clinical imaging was performed to test for associations between symptoms of depression and lesion locations. RESULTS: Frequency of poststroke depression (Hospital Anxiety and Depression Scale-D score >7) after 6 months was 19.6%. Higher Hospital Anxiety and Depression Scale-D scores for depression within the first 4 weeks were the only independent predictor for poststroke depression after 6 months in a multiple logistic regression also including age, sex, lesion volume, stroke severity, Barthel-Index, and the anxiety subscale of the Hospital Anxiety and Depression Scale. Nonparametric permutation-test based voxel-based lesion behavior mapping identified a cluster of voxels mostly within the left ventrolateral prefrontal cortex where lesions were significantly associated with more depressive symptoms after 6 months. No such association was observed within the right hemisphere despite better lesion coverage. CONCLUSIONS: Lesions in the left ventrolateral prefrontal cortex increase the risk of depressive symptoms 6 months poststroke. Lesions within the right hemisphere are unrelated to depressive symptoms. Recognition of left frontal lesions as a risk factor should help in the early diagnosis of poststroke depression through better risk stratification. The results are in line with evidence from functional imaging and noninvasive brain stimulation in patients without focal brain damage indicating that dysfunction in the left lateral prefrontal cortex contributes to depressive disorders.

Inflammatory Mechanisms in the Pathophysiology of Diabetic Peripheral Neuropathy (DN)-New Aspects.

The pathogenesis of diabetic neuropathy is complex, and various pathogenic pathways have been proposed. A better understanding of the pathophysiology is warranted for developing novel therapeutic strategies. Here, we summarize recent evidence from experiments using animal models of type 1 and type 2 diabetes showing that low-grade intraneural inflammation is a facet of diabetic neuropathy. Our experimental data suggest that these mild inflammatory processes are a likely common terminal pathway in diabetic neuropathy associated with the degeneration of intraepidermal nerve fibers. In contrast to earlier reports claiming toxic effects of high-iron content, we found the opposite, i.e., nutritional iron deficiency caused low-grade inflammation and fiber degeneration while in normal or high non-heme iron nutrition no or only extremely mild inflammatory signs were identified in nerve tissue. Obesity and dyslipidemia also appear to trigger mild inflammation of peripheral nerves, associated with neuropathy even in the absence of overt diabetes mellitus. Our finding may be the experimental analog of recent observations identifying systemic proinflammatory activity in human sensorimotor diabetic neuropathy. In a rat model of type 1 diabetes, a mild neuropathy with inflammatory components could be induced by insulin treatment causing an abrupt reduction in HbA1c. This is in line with observations in patients with severe diabetes developing a small fiber neuropathy upon treatment-induced rapid HbA1c reduction. If the inflammatory pathogenesis could be further substantiated by data from human tissues and intervention studies, anti-inflammatory compounds with different modes of action may become candidates for the treatment or prevention of diabetic neuropathy.

Treatment-Induced Neuropathy in Diabetes (TIND)-Developing a Disease Model in Type 1 Diabetic Rats.

Treatment-induced neuropathy in diabetes (TIND) is defined by the occurrence of an acute neuropathy within 8 weeks of an abrupt decrease in glycated hemoglobin-A1c (HbA1c). The underlying pathogenic mechanisms are still incompletely understood with only one mouse model being explored to date. The aim of this study was to further explore the hypothesis that an abrupt insulin-induced fall in HbA1c may be the prime causal factor of developing TIND. BB/OKL (bio breeding/OKL, Ottawa Karlsburg Leipzig) diabetic rats were randomized in three groups, receiving insulin treatment by implanted subcutaneous osmotic insulin pumps for 3 months, as follows: Group one received 2 units per day; group two 1 unit per day: and group three 1 unit per day in the first month, followed by 2 units per day in the last two months. We serially examined blood glucose and HbA1c levels, motor- and sensory/mixed afferent conduction velocities (mNCV and csNCV) and peripheral nerve morphology, including intraepidermal nerve fiber density and numbers of Iba-1 (ionized calcium binding adaptor molecule 1) positive macrophages in the sciatic nerve. Only in BB/OKL rats of group three, with a rapid decrease in HbA1c of more than 2%, did we find a significant decrease in mNCV in sciatic nerves (81% of initial values) after three months of treatment as compared to those group three rats with a less marked decrease in HbA1c <2% (mNCV 106% of initial values, p ≤ 0.01). A similar trend was observed for sensory/mixed afferent nerve conduction velocities: csNCV were reduced in BB/OKL rats with a rapid decrease in HbA1c >2% (csNCV 90% of initial values), compared to those rats with a mild decrease <2% (csNCV 112% of initial values, p ≤ 0.01). Moreover, BB/OKL rats of group three with a decrease in HbA1c >2% showed significantly greater infiltration of macrophages by about 50% (p ≤ 0.01) and a decreased amount of calcitonin gene related peptide (CGRP) positive nerve fibers as compared to the animals with a milder decrease in HbA1c. We conclude that a mild acute neuropathy with inflammatory components was induced in BB/OKL rats as a consequence of an abrupt decrease in HbA1c caused by high-dose insulin treatment. This experimentally induced neuropathy shares some features with TIND in humans and may be further explored in studies into the pathogenesis and treatment of TIND.

COMP-Ang-1 Improves Glucose Uptake in db/db Mice with Type 2 Diabetes.

Cartilage oligomeric matrix protein (COMP)-Angiopoietin-1 is a potent angiopoietin-1 (Ang-1) variant that possesses therapeutic potential in angiogenesis and vascular endothelial dysfunction. Noteworthy, we have shown that COMP-Ang-1 improves hyperglycemia and neuroregeneration in ob/ob mice. However, the mechanism of the antidiabetic effect of COMP-Ang-1 is completely unknown. Therefore, we elucidated the diabetes protective molecular mechanisms of COMP-Ang-1 in diabetic db/db mouse model. COMP-Ang-1 (0.5 ng/g body weight) or aqueous NaCl solution was injected intraperitoneally per day in 21 consecutive days into 3-month old, male db/db mice (n=10 per group). Blood glucose and HbA1c levels were determined at baseline and 21 days after COMP-Ang-1 or NaCl treatment. The effect of COMP-Ang-1 on glucose uptake was investigated by euglycemic-hyperinsulinemic clamp studies and key genes of glucose metabolism were studied by Western blot analysis. Our findings indicate that COMP-Ang-1 improves glucose metabolism in a tissue specific manner by regulating HIF-1α transcriptional genes of GLUT-1 expression.

Late onset dHMN II caused by c.404C>G mutation in HSPB1 gene.

Distal hereditary motor neuropathy (dHMN) type II is genetically heterogeneous. We report three siblings of a German family with late onset distal motor neuropathy due to the c.404C>G mutation in heat-shock 27-kDa protein 1 gene (HSPB1/HSP27). A 36-year-old mutation carrier, daughter of one sibling, did not present any clinical or electrophysiological abnormalities. The index patient (oldest brother) developed weakness of the distal lower limbs and nocturnal muscle cramps at the age of 54. After 5 years this patient developed an l-DOPA-responsive hypokinetic rigid syndrome, establishing a diagnosis of Parkinson's disease. Although none of the three other mutation carriers displayed Parkinsonian signs, a pathogenic relationship with Parkinson's disease remains a possibility, based on the known molecular pathology of HSPB1. The rare pathogenic HSPB1 c.404C>G mutation may predispose for late-onset of dHMN type II.

Phenotype of matrin-3-related distal myopathy in 16 German patients.

OBJECTIVE: To characterize the phenotype of patients with distal myopathy with vocal cord and pharyngeal weakness due to the p.S85C mutation in the matrin-3 gene (MATR3, Mendelian Inheritance in Man 164015). Recently, it has been suggested that patients with this mutation may suffer from familial amyotrophic lateral sclerosis. METHODS: Sixteen patients from 6 families with late onset distal myopathy associated with the p.S85C MATR3 mutation were characterized. RESULTS: Patients had a predominantly distal muscle weakness, most severely affecting ankle and wrist dorsiflexion. Relevant proximal and axial weakness was found in 6 and respiratory impairment in 5 patients. Dysphagia was diagnosed in 6 and mild voice abnormalities were found in 7 patients. However, laryngoscopy revealed normal vocal cord function. Creatine kinase was normal or mildly elevated. Electromyographically, spontaneous activity was found in 10 of 14 patients and complex repetitive discharges in 9 of 14 patients. Magnetic resonance imaging revealed severe fatty degeneration of distal and upper posterior leg and of paraspinal muscles. Histopathology ranged from mild myopathic to severe dystrophic changes including vacuoles. Absence of sarcomeres in the perinuclear region and abnormal invaginations of nuclei were found ultrastructurally. Haplotype analysis showed a common disease-specific haplotype of the 6 families and suggested that these families form a separate cluster. INTERPRETATION: In contrast to the 2 previously reported families, MATR3-related distal myopathy might be associated with relevant axial, proximal, and respiratory muscle weakness but without vocal cord palsy. There were no clinical, electrophysiological, or histopathological signs of lower motor neuron involvement.

A randomized, double-blind comparison of antiepileptic drug treatment in the elderly with new-onset focal epilepsy.

OBJECTIVE: To compare the effectiveness of controlled-released carbamazepine (CR-CBZ) to levetiracetam (LEV) and to lamotrigine (LTG) in elderly patients with newly diagnosed focal epilepsy. METHODS: Randomized, double-blind, parallel-group trial conducted between January 2007 and August 2011, in 47 ambulatory or hospital sites in Germany, Austria, or Switzerland. Eligible participants were aged ≥ 60, had new-onset epilepsy, had no acute illness as the cause of their seizures, and had no contraindication to the drugs in the trial. Patients were randomized 1:1:1 to CR-CBZ, LTG, or LEV. Doses were up-titrated for 6 weeks and could be maintained or adjusted depending on seizure relapse or tolerability over an additional period of 52 weeks. Primary outcome was the retention to treatment at week 58; secondary measures related to seizure and adverse event frequency. RESULTS: Of 361 randomized patients, 359 were included (CR-CBZ n = 121, LTG n = 117, LEV n = 122) in the modified intent-to-treat population (mean age [range] 71.4 [60-95] years). At week 58, the retention rate for LEV was significantly higher than for CR-CBZ (61.5% vs. 45.8%, p = 0.02), and similar to LTG (55.6%). Seizure freedom rates at weeks 30 and 58 were not different across the groups. Twice as many patients receiving CR-CBZ discontinued due to adverse events or death compared to those in the LEV group (32.2% vs. 17.2%; odds ratio 2.28, 95% confidence interval [CI] 1.25-4.19, p = 0.007), whereas discontinuation was intermediate for LTG (26.3%). Median daily doses of completers (n = 195) were CR-CBZ 380.0 mg/day (333.0-384.0), LTG 95 mg/day (94.0-97.0), and LEV 950 mg/day (940.0-985.0). SIGNIFICANCE: In the initial monotherapy of focal epilepsy in the elderly, 1-year retention to LEV was higher compared to CR-CBZ due to better tolerability. Retention of LTG was intermediate and close to LEV, but did not differ significantly from either comparators. NCT00438451, www.clinicaltrials.gov.

Effects of isoflurane anesthesia on F-waves in the sciatic nerve of the adult rat.

INTRODUCTION: Nerve conduction studies provide insights into the functional consequences of axonal and myelin pathology in peripheral neuropathies. We investigated whether isoflurane inhalation anesthesia alters F-wave latencies and F-persistence in the sciatic nerve of adult rats. METHODS: Ten rats were investigated at 3 different isoflurane concentrations followed by ketamine-xylazine injection anesthesia. To assess F-wave latencies, a stimulation paradigm was chosen to minimize H-reflex masking of F-waves. RESULTS: F-wave persistence rates were reduced with 3.5% isoflurane concentration at 4 and 10 Hz supramaximal stimulation and marginally reduced with 2.5% isoflurane when compared with ketamine-xylazine. F-wave amplitudes decreased progressively with rising stimulus frequency in all types of anesthesia and most at 3.5% isoflurane concentration. CONCLUSIONS: The type of anesthesia and the stimulus repetition rate have an impact on some F-wave parameters. Higher isoflurane concentrations and repetition rates are not recommended in experimental studies using rat neuropathy models where F-waves are of interest.

Prevalence of nonconvulsive seizures and nonconvulsive status epilepticus in dogs and cats with a history of cluster seizures: A retrospective study.

BACKGROUND: Nonconvulsive seizures (NCS) and nonconvulsive status epilepticus (NCSE) are frequently observed in human patients. Diagnosis of NCS and NCSE only can be achieved by the use of electroencephalography (EEG). Electroencephalographic monitoring is rare in veterinary medicine and consequently there is limited data on frequency of NCS and NCSE. OBJECTIVES: Determine the prevalence of NCS and NCSE in dogs and cats with a history of cluster seizures. ANIMALS: Twenty-six dogs and 12 cats. METHODS: Retrospective study. Medical records of dogs and cats with cluster seizures were reviewed. Electroencephalography was performed in order to identify electrographic seizure activity after the apparent cessation of convulsive seizure activity. RESULTS: Nonconvulsive seizures were detected in 9 dogs and 2 cats out of the 38 patients (29%). Nonconvulsive status epilepticus was detected in 4 dogs and 2 cats (16%). Five patients had both NCS and NCSE. A decreased level of consciousness was evident in 6/11 patients with NCS, 3/6 also had NCSE. Mortality rate for patients with NCS (73%) and NCSE (67%) was much higher than that for patients with no seizure activity on EEG (27%). CONCLUSION AND CLINICAL IMPORTANCE: Prevalence of NCS and NCSE is high in dogs and cats with a history of cluster seizures. Nonconvulsive seizures and NCSE are difficult to detect clinically and are associated with higher in hospital mortality rates. Results indicate that prompt EEG monitoring should be performed in dogs and cats with cluster seizures.

User expectations and experiences of an assistive robotic arm in amyotrophic lateral sclerosis: a multicenter observational study.

OBJECTIVE: Robotic arms are innovative assistive devices for ALS patients with progressive motor deficits of arms and hands. The objective was to explore the patients´ expectations towards a robotic arm system and to assess the actual experiences after the provision of the device. METHODS: A prospective observational study was conducted at 9 ALS centers in Germany. ALS-related functional deficits were assessed using the ALS-Functional Rating Scale-revised (ALSFRS-R). Motor deficit of the upper limbs was determined using a subscore of three arm-related items of the ALSFRS-R (items 4-6; range 0-12 points). User expectations before provision (expectation group, n = 85) and user experiences after provision (experience group, n = 14) with the device (JACO Assistive Robotic Device, Kinova, Boisbriand, QC, Canada) were assessed. RESULTS: In the total cohort, mean ALSFRS-R subscore for arm function was 1.7 (SD: 2.0, 0-9) demonstrating a severe functional deficit of the upper limbs. In the expectation group (n = 85), the following use cases of the robotic arm have been prioritized: handling objects (89%), close-body movements (88%), pressing buttons (87%), serving drinks (86%), and opening cabinets and doors (85%). In the experience group (n = 14), handling objects (79%), serving drinks (79%), near-body movements (71%), pushing buttons (71%), serving food (64%), and opening doors (64%) were the most frequent used cases. Most patients used the device daily (71.4%, n = 10), and 28.6% (n = 4) several times a week. All patients of the experience group found the device helpful, felt safe while using the device, and were satisfied with its reliability. NPS of the assistive robotic arm revealed 64% "promoters" (strong recommendation), 29% "indifferents" (uncertain recommendation) and 7% "detractors" (no recommendation). Total NPS was + 57 demonstrating strong patient satisfaction. CONCLUSIONS: Initiation of procurement with a robotic assistive arm was confined to patients with severe functional deficit of the upper limbs. User experience underlined the wide spectrum of use cases of assistive robotic arms in ALS. The positive user experience together with high satisfaction underscore that robotic arm systems serve as a valuable treatment option in ALS patients with severe motor deficits of the arms.

Temporary and highly variable recovery of neuromuscular dysfunction by electrical stimulation in the follow-up of acute critical illness neuromyopathy: a pilot study.

BACKGROUND: In sepsis-associated critical illness neuromyopathy (CIPNM) serial electrical stimulation of motor nerves induces a short-lived temporary recovery of compound muscle action potentials (CMAPs) termed facilitation phenomenon (FP). This technique is different from other stimulation techniques published. The identification of FP suggests a major functional component in acute CIPNM. METHODS: From our previous study cohort of 18 intensive care unit patients with sepsis associated CIPNM showing profound muscle weakness and low or missing CMAPs on nerve conduction studies, six patients with different severity could be followed. In a pilot sub-study we analyzed the variability of FP during follow up. Over up to 6 weeks we performed 2-6 nerve conduction studies with our novel stimulation paradigm. Motor nerves were stimulated at 0.2-0.5 Hz with 60-100 mA at 0.2-0.5 ms duration, and CMAP responses were recorded. Standard motor nerve conduction velocities (NCV) could be done when utilizing facilitated CMAPs. Needle electromyography was checked once for spontaneous activity to discover potential denervation and muscle fiber degeneration. Serum electrolytes were checked before any examination and corrected if abnormal. RESULTS: In all six patients a striking variability in the magnitude and pattern of FP could be observed at each examination in the same and in different motor nerves over time. With the first stimulus most CMAPs were below 0.1 mV or absent. With slow serial pulses CMAPs could gradually recover with normal shape and near normal amplitudes. With facilitated CMAPs NCV measurements revealed low normal values. With improvement of muscle weakness subsequent tests revealed larger first CMAP amplitudes and smaller magnitudes of FP. Needle EMG showed occasional spontaneous activity in the tibialis anterior muscle. CONCLUSION: In this pilot study striking variability and magnitude of FP during follow-up was a reproducible feature indicating major fluctuations of neuromuscular excitability that may improve during follow-up. FP can be assessed by generally available electrophysiological techniques, even before patients could be tested for muscle strength. Large scale prospective studies of the facilitation phenomenon in CIPNM with or without sepsis are needed to define diagnostic specificity and to better understand the still enigmatic pathophysiology. TRIAL REGISTRATION: This trial was registered at the Leipzig University Medical Center in 2021 after approval by the Ethics Committee.

Frequency and satisfaction of conventional and complementary or alternative therapies for neuromuscular disorders.

BACKGROUND: Causal therapies are not yet available for most neuromuscular diseases. Additionally, data on the use of complementary or alternative therapies (CAM) in patients groups with a variety of different neuromuscular diseases are rare. This retrospective cross-sectional study aims to record the frequency of use and satisfaction of conventional therapies and complementary or alternative medicine (CAM) in patients with neuromuscular disorders in order to compare them afterwards. METHODS: Patients from the University of Leipzig (Department and Outpatient Department of Neurology), the Friedrich-Baur-Institute (Department of Neurology), the Hoher Meißner Clinic (Department of Neurology) and the German Society for Muscular Diseases (DGM e.V.) were included. The focus of this study has been on patients with chronic neuromuscular diseases. Our data are based on standardised questionnaires in analogue form from three German neuromuscular centres and in digital form from the official website of the German Society for Muscular Diseases. Therapy satisfaction was assessed with the Patient Evaluation of Global Response (PEGR) ranking scale (very satisfactory + 2 to very unsatisfactory - 2). RESULTS: Of 192 questionnaires analysed, the most common diagnoses were spinal muscular atrophy (n = 42; 21.9%), muscular dystrophies (n = 41; 21.4%) and myotonic dystrophies (n = 38; 19.8%). More than half (n = 112; 58.3%) used both conventional and CAM treatments. Physiotherapy (n = 165) was used most frequently within all treatments with conventional manual (PEGR 1.25, p = 0.013; CI 95%) and aquatic therapy (PEGR 1.3, p = 0.038) showing significantly higher satisfaction compared to therapy on training equipment. Less-used therapies such as psychotherapy (n = 53; PEGR 1.2) were also satisfactory. Within CAM, massages (n = 96) were the most reported and meditation (PEGR 1.5) was best rated. Massage therapy was significantly more satisfactory than progressive muscle relaxation (p = 0.003) and chiropractic treatment (p = 0.036). Chiropractic treatment (PEGR - 0.1) was rated most negatively. No significant differences were found between the group of conventional therapies and CAM users regarding social and disease-dependent factors. CONCLUSIONS: Treatment with conventional therapy (manual, aquatic therapy) and some CAM therapies can be recommended if adequately indicated.

Associations of lesion location, structural disconnection, and functional diaschisis with depressive symptoms post stroke.

Introduction: Post-stroke depressive symptoms (PSDS) are common and relevant for patient outcome, but their complex pathophysiology is ill understood. It likely involves social, psychological and biological factors. Lesion location is a readily available information in stroke patients, but it is unclear if the neurobiological substrates of PSDS are spatially localized. Building on previous analyses, we sought to determine if PSDS are associated with specific lesion locations, structural disconnection and/or localized functional diaschisis. Methods: In a prospective observational study, we examined 270 patients with first-ever stroke with the Hospital Anxiety and Depression Scale (HADS) around 6 months post-stroke. Based on individual lesion locations and the depression subscale of the HADS we performed support vector regression lesion-symptom mapping, structural-disconnection-symptom mapping and functional lesion network-symptom-mapping, in a reanalysis of this previously published cohort to infer structure-function relationships. Results: We found that depressive symptoms were associated with (i) lesions in the right insula, right putamen, inferior frontal gyrus and right amygdala and (ii) structural disconnection in the right temporal lobe. In contrast, we found no association with localized functional diaschisis. In addition, we were unable to confirm a previously described association between depressive symptom load and a network damage score derived from functional disconnection maps. Discussion: Based on our results, and other recent lesion studies, we see growing evidence for a prominent role of right frontostriatal brain circuits in PSDS.

Remote digital assessment of amyotrophic lateral sclerosis functional rating scale - a multicenter observational study.

OBJECTIVE: Remote self-assessment of the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) using digital data capture was investigated for its feasibility as an add-on to ALSFRS-R assessments during multidisciplinary clinic visits. METHODS: From August 2017 to December 2021, at 12 ALS centers in Germany, an observational study on remote assessment of the ALSFRS-R was performed. In addition to the assessment of ALSFRS-R during clinic visits, patients were offered a digital self-assessment of the ALSFRS-R - either on a computer or on a mobile application ("ALS-App"). RESULTS: An estimated multicenter cohort of 4,670 ALS patients received care at participating ALS centers. Of these patients, 971 remotely submitted the ALSFRS-R, representing 21% of the multicenter cohort. Of those who opted for remote assessment, 53.7% (n = 521) completed a minimum of 4 ALSFRS-R per year with a mean number of 10.9 assessments per year. Different assessment frequencies were found for patients using a computer (7.9 per year, n = 857) and mobile app (14.6 per year, n = 234). Patients doing remote assessments were more likely to be male and less functionally impaired but many patients with severe disability managed to complete it themselves or with a caregiver (35% of remote ALSFRS-R cohort in King's Stage 4). CONCLUSIONS: In a dedicated ALS center setting remote digital self-assessment of ALSFRS-R can provide substantial data which is complementary and potentially an alternative to clinic assessments and could be used for research purposes and person-level patient management. Addressing barriers relating to patient uptake and adherence are key to its success.

Temporary reversal of nerve and muscle dysfunction by serial electrical stimulation in critical illness neuromyopathy.

OBJECTIVE: Critical Illness Neuromyopathy (CIPNM) is a complication in sepsis patients with still enigmatic disease mechanisms. We investigated a novel electrical stimulation method to better define neuromuscular dysfunction in patients with CIPNM. METHODS: We studied 18 sepsis CIPNM patients on intensive care units, 13 at an early and 5 at a later disease stage, 7 sepsis control, and 8 neuropathy control patients. We applied slow conditioning electrical pulses at motor nerves and directly at the muscle to investigate a facilitation phenomenon (FP) of small or absent compound motor action potentials (CMAPs). RESULTS: Serial pulses induced a 2 to 490-fold increase in CMAP amplitudes in 17/18 Intensive Care Unit (ICU)-CIPNM patients (p < 0.001). These effects were short lived and reproducible. Direct muscle stimulation in the tibialis anterior muscle resulted in up to 130-fold FP in 7/9 patients tested (p < 0.01). In 4/5 post-ICU CIPNM patients FP was up to 10-fold. None of the 7 ICU sepsis control patients without CIPNM with similar disease severity and none of 8 neuropathy patients showed FP (p < 0.001). On needle EMG only 5/16 ICU patients tested revealed spontaneous activity. CONCLUSIONS: Conditioning electrical stimulation detected a functional component of the disease process showing temporary improvement in sepsis-associated CIPNM. SIGNIFICANCE: New test differentiates functional from degenerative pathology.

Functional predictors of treatment induced diabetic neuropathy (TIND): a prospective pilot study using clinical and neurophysiological functional tests.

BACKGROUND: A treatment-induced drop in HbA1c has been suggested to be a risk factor for TIND. METHODS: From 60 included patients with severe diabetes mellitus (HbA1c over 8.5) only 21 patients adhered to the study protocol over 1 year with a battery of autonomic nervous system tests scheduled before and after starting antidiabetic treatment. RESULTS: In patients with a drop of HbA1c greater than 2 per cent points only some neurophysiologic tests and lab values tended to deteriorate with a trend to improve at later time points along the study. None of these changes were statistically significant, most likely because the study failed to reach the planned number of patients. CONCLUSION: Poor adherence to diabetes treatment and to following the study protocol were the assumed obstacles in our patient cohort selected for very high HbA1c levels. In future studies a multi-center trial and case numbers of up to 500 patients may be needed to account for drop outs in the range observed here. Moreover, the number of tests in each patient at each visit may have to be reduced and special educational group sessions are warranted to cope with the limited adherence. Trial registration Ethic Committee University of Leipzig 439/15-ek. Registered 22 April 2016.