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Apart from well-defined factors in neuronal cells1, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia2,3 and blood vessels4. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments, and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in patients with sporadic ALS. Moreover, in plasma of 574 patients with ALS from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently discovered perivascular fibroblast can predict survival of patients with ALS and provide a new conceptual framework to re-evaluate definitions of ALS etiology.

Shoulder pain or paresis should be assessed carefully, as there are many possible causes, which can be osteoarticular, degenerative, inflammatory, or neurological. Weakness or pain can be related to cervicobrachialgia, plexitis, or focal mononeuropathy. The clinical picture should identify any muscular or mechanical origin of paresis responsible for pseudo-paretic functional limitation. Neurogenic scapulalgia with functional deficit implies the compression or entrapment of a nerve trunk including the axillary, long thoracic, accessory, suprascapular, or dorsal scapular nerves. Nerve conduction study and myography together with medical imaging help to identify the relevant etiology. Treatment mostly includes pain relief and physiotherapy, but surgery is rarely necessary.L’épaule douloureuse ou parétique est d’appréhension délicate et de causes variées : ostéoarticulaire, dégénérative, inflammatoire ou neurologique. La faiblesse ou la douleur peuvent être liées à une cervicobrachialgie, une plexite ou une mononeuropathie focale. Le tableau clinique doit distinguer une parésie d’origine musculaire ou mécanique responsable alors d’une limitation fonctionnelle pseudo-parétique. Une scapulalgie déficitaire neurogène implique la recherche d’une mononeuropathie d’enclavement ou compressive d’un tronc nerveux, axillaire, long thoracique, accessoire du XI

chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) has been widely described during the last quarter of the twentieth century. The last 20 years have seen decisive progress in its understanding. The diagnostic criteria have been simplified and the steps of the diagnostic process have been clarified. The phenotypic contours of the disease are now well known, as are the diagnostic pitfalls. From a pathophysiological point of view, the discovery of autoantibodies directed against nodal and paranodal proteins has been a major advance, although it concerns only a minority of patients. These discoveries have a major impact on the therapeutic management of these patients, often suffering from a very active form of the disease. The next 20 years will surely see a further deepening of knowledge about this fascinating disease.La polyradiculoneuropathie inflammatoire démyélinisante chronique est une entité largement décrite au cours du dernier quart du 20

Muscle diseases or myopathies have heterogeneous clinical presentations and etiologies. The principal sign is muscular weakness, whose distribution can help diagnostic orientation. Exercise intolerance, even without weakness at rest, can indicate an underlying myopathy. An isolated CK elevation can have multiple causes, but its persistence after a period of rest can point towards a subclinical myopathy. Isolated myalgia, especially at rest, are usually not associated with muscle disease. If the suspicion of myopathy is high, the patient will be assessed by a neurologist trained in muscle disorders, with correlation of clinical and neurophysiological findings, muscle imaging and, if indicated, muscle biopsy and genetic analysis. Cardiac and respiratory assessments are mandatory if a myopathy is suspected.Les myopathies sont d’étiologie et de présentation hétérogènes. Le signe principal est la faiblesse musculaire, dont la distribution peut orienter le diagnostic. L’intolérance à l’effort, même isolée, peut indiquer une myopathie, en particulier métabolique. Une élévation isolée des créatines kinases (CK) peut avoir des causes multiples mais la persistance d’une valeur anormalement élevée au repos peut être un indice de myopathie subclinique. Les myalgies isolées, notamment au repos, ne sont en général pas associées aux myopathies. Si la suspicion de myopathie est retenue, le patient sera évalué par un neurologue expert en pathologie musculaire, pour complément d’explorations par bilan neurophysiologique (ENMG (électroneuromyographique)), imagerie musculaire et biopsie musculaire ou analyse génétique. Les bilans cardiaque et respiratoire sont indispensables dans tous les cas.

Muscle cramps are very common and can reduce quality of life. There are multiple causes, including some physiological conditions, metabolic, endocrine, vascular disorders or neuromuscular diseases. Adequate management first requires differentiating cramps from other muscular phenomena. In most cases, the investigations are limited to a comprehensive history and clinical examination, but a biological, radiological and/or electrophysiological work-up may be useful. Treatment, when needed, is most often symptomatic and is unfortunately based on little evidence.Les crampes musculaires sont fréquentes dans la population générale avec, dans certains cas, une altération importante de la qualité de vie. Leur cause est très variée, pouvant être en lien avec certaines conditions physiologiques ou avec des troubles métaboliques, endocriniens, vasculaires ou neuromusculaires. Une prise en charge adéquate nécessite dans un premier temps de différencier les crampes d’autres phénomènes musculaires. Dans la plupart des cas, les investigations se limitent à une anamnèse et un examen clinique, mais un bilan biologique, radiologique et/ou électrophysiologique peut être parfois indiqué. Le traitement, si nécessaire, est le plus souvent symptomatique et repose malheureusement sur peu d’évidences scientifiques.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease of the adult age. It is an aggressive condition with a mean disease duration of only 3 to 5 years, characterized by progressive weakness and atrophy of limb, bulbar, and respiratory muscles. In general, death is caused by chronic hypoventilation due to respiratory insufficiency. No causal treatment is known today, but the two therapeutic agents authorized in Switzerland for the treatment of ALS can slow disease progression significantly. Other important therapeutic strategies include invasive/non-invasive ventilation, pain therapy, as well as physio-, ergo- and speech therapy on a regular basis.La sclérose latérale amyotrophique (SLA) est la maladie du motoneurone la plus fréquente de l’adulte. C’est une maladie sévère (la survie moyenne est d’environ 3 à 5 ans), caractérisée par une dégénérescence des premier et deuxième motoneurones. Elle se manifeste par un déficit moteur amyotrophiant progressif des membres, de la langue, des muscles bulbaires et respiratoires. En général, le décès est causé par une hypoventilation chronique. Il n’existe actuellement aucun traitement curatif. Les deux médicaments autorisés en Suisse peuvent ralentir significativement la progression de la maladie et plusieurs nouvelles molécules sont à l’essai. Les traitements non médicamenteux/symptomatiques constituent le deuxième pilier de la prise en charge : ventilation non invasive, traitement des symptômes bulbaires, stabilisation du poids, physio et ergothérapie.

Small fiber neuropathies affect small, poorly myelinated sensory Aδ and amyelinated C autonomic fibers. Neuropathic pain is often the main symptom. Positive diagnosis is based on the presence of deficient thermo-algesic sensory signs and/or dysautonomic signs with normal neurography. Several tests help to confirm the involvement of small fibers, ranging from simple tests such as the sympathetic skin response to skin biopsy, which measures the density of intraepidermal nerve fibers. The availability of these different tests varies greatly from one center to another. There are multiple etiologies, from rare genetic causes to the more frequent acquired dysimmune or metabolic causes. However, in more than half of the cases, no etiology is identified.Les neuropathies des petites fibres touchent les petites fibres peu myélinisées sensitives Aδ et amyéliniques C autonomes. La douleur neuropathique est souvent le symptôme principal. Le diagnostic positif repose sur la présence de signes sensitifs thermo-algiques déficitaires et/ou de signes dysautonomiques avec des neurographies normales. Plusieurs examens aident à confirmer l’atteinte des petites fibres, allant de tests simples comme la réponse cutanée sympathique à la biopsie de peau qui mesure la densité des fibres nerveuses intra-épidermiques. L’accessibilité de ces différents examens est très variable d’un centre à l’autre. Les étiologies sont variées, des causes génétiques rares aux causes acquises dysimmunes ou métaboliques plus fréquentes. Toutefois, dans plus de la moitié des cas, aucune étiologie n’est retrouvée.

Imaging studies showed that the structure of the corpus callosum (CC) is affected in amyotrophic lateral sclerosis (ALS). Some clinical studies also suggest that interhemispheric connectivity is altered, since mirror movements seem to occur in ALS. Finally, reduced interhemispheric inhibition (IHI), studied by transcranial magnetic stimulation (TMS), has been reported. It is not known whether there is any association between these findings. Here, we studied the integrity of the CC in ALS on the morphological, the functional, the electrophysiological, and the clinical level. Twenty-seven right-handed ALS patients and 21 healthy right-handed controls were included. Mirror activity (MA) was quantified using surface EMG. Diffusion tensor imaging tractography was used to segment the CC and quantify fractional anisotropy (FA). We studied the diffusivity of the intra-axonal markers N-acetylaspartate+N-acetyl aspartyl glutamate D(tNAA) within the CC. IHI was studied as a marker of CC function using a double-pulse TMS protocol. ALS patients showed significantly decreased FA in the motor segment of the CC (p < 0.01), and IHI was significantly reduced compared to controls (p = 0.01). However, no differences were observed regarding D(tNAA) and MA. The morphological as well as the functional integrity of the CC are altered in ALS. IHI was reduced in ALS, associated with decreased FA in the motor CC. Patients did not exhibit increased MA. Also, no differences within the CC were observed using diffusion-weighted spectroscopy. IHI might serve as a marker of transcallosal pathway disruption in ALS, even before clinical deficits become apparent.

The spectrum of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 infection (SARS-CoV-2), includes different neurologic manifestations of the central and peripheral nervous system. From March through April 2020, in two university hospitals located in western Switzerland, we examined three patients with Guillain-Barré syndrome (GBS) following SARS-CoV-2. These cases were characterized by a primary demyelinating electrophysiological pattern (Acute inflammatory demyelinating polyneuropathy or AIDP) and a less severe disease course compared to recently published case series. Clinical improvement was observed in all patients at week five. One patient was discharged from hospital after full recovery with persistence of minor neurological signs (areflexia). Two of the three patients remained hospitalized: one was able to walk and the other could stand up with assistance. We report three cases of typical GBS (AIDP) occurring after SARS-CoV-2 infection and presenting with a favourable clinical course. Given the interval between COVID-19-related symptoms and neurological manifestations (mean of 15 days) we postulate a secondary immune-mediated mechanism rather than direct viral damage.

Myasthenia gravis (MG) is an autoimmune disease characterised by fluctuating muscle weakness with potentially life-threatening symptoms due to insufficiency of respiratory muscles. Treatment usually includes immunosuppressive drugs and cholinesterase inhibitors. COVID-19 is an infection caused by the newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), defined as a pandemic by the World Health Organisation (WHO). Although guidelines for the management of patients with MG during the COVID-19 pandemic have been published,1 these recommendations are based on theoretical considerations only, as no clinical data are available. We describe four patients with generalised MG affected by COVID-19 (around 10% of patients in our cohort). Clinical data are summarised in table 1. View this table: Table 1 Clinical data of four patients with generalised gravis and SARS-CoV-2 ### Case 1 A 36-year-old female patient, class IIa according to the Myasthenia Gravis Foundation of America (MGFA) score (166 cm, 67 kg), presented to Geneva University Hospital on 15 March 2020 with myalgia, coughing and fever >38°C on the same day. She was taking azathioprine (AZA) 50 mg, reintroduced at the end of January 2020, and pyridostigmine 60 mg five to six times per day. The last deterioration of MG had occurred in January 2020 requiring intravenous immunoglobulin (IVIG) treatment (Myasthenia Muscle Score 65/100). COVID-19 real-time PCR (RT-PCR) revealed a positive result. Chest X-ray showed no pulmonary infiltration and peak flow was at 400 mL (82%). The Myasthenia Muscle …

Systemic amyloidosis is a heterogeneous group of diseases associated with protein misfolding into insoluble beta-sheet rich structures that deposit extracellularly in different organs, eventually compromising their function. There are more than 30 different proteins, known to be amyloidogenic with “light chain” (AL)-amyloidosis being the most common type, followed by transthyretin (ATTR)-, and amyloid protein A (AA)-amyloidosis. Systemic amyloidosis is a rare disease with an incidence of around 10 patients in 1 million inhabitants. Recently several new therapeutic options have been developed for subgroups of amyloidosis patients, and the introduction of novel therapies for plasma cell myeloma has led to an increase in the therapeutic armamentarium for plasma cell disorders, including AL amyloidosis. Among them, proteasome inhibitors, immunomodulatory agents (-imids), and monoclonal antibodies have been successfully introduced into clinical practice. Still, high-quality data from randomised controlled trials regarding the benefit of these cost-intensive drugs in AL amyloidosis are widely lacking, and due to the rarity of the disease many physicians will not gain routine experience in the management of these frail patients. The diagnosis of AL amyloidosis relies on a close collaboration between clinicians, pathologists, imaging experts, and sometimes geneticists. Diagnosis and treatment options in this complex disorder should be discussed in dedicated multidisciplinary boards. In January 2020, the first meeting of the Swiss Amyloidosis Network took place in Zurich, Switzerland. One aim of this meeting was to establish a consensus guideline regarding the diagnostic work-up and the treatment recommendations for systemic amyloidosis tailored to the Swiss health care system. Forty-five participants from different fields in medicine discussed many aspects of amyloidosis. These are the Swiss Amyloidosis Network recommendations which focus on diagnostic work-up and treatment of AL-amyloidosis., Swiss Medical Weekly, 150, ISSN:1424-7860, ISSN:1424-3997

Changes in skin and muscle small blood vessels (SBVs) and microvascular structures of the brain have been reported in patients with amyotrophic lateral sclerosis (ALS). A direct assessment of brain SBVs in vivo is currently not feasible. Retinal vessels are considered a “mirror” of brain SBVs. In this study, we used optic coherence tomography (OCT)-based measurements to detect changes in retinal blood vessels of ALS patients compared to those of healthy controls. We analysed Spectralis-OCT images of 34 ALS patients and 20 HCs. The inner wall thickness (IWT), outer wall thickness (OWT), and lumen diameter (LD) of retinal vessels were assessed using intensity-based measurements. In addition, the different retinal layers were analysed using automated segmentation software. The correlations between the various retinal layers and clinical parameters [e.g., disease duration and revised ALS functional rating scale (ALS-FRS-R)] were examined. The OWT of retinal vessels was higher in ALS patients than in HCs (p = 0.04). There were no differences in the IWT, LD. ALS patients showed a thinning of the outer nuclear layer (ONL) compared to HCs (median 1.63 vs. 1.77, p = 0.002). The whole retinal thickness negatively correlated with the ALS-FRS scale (r = 0.3, p = 0.03). Our study reports retinal vessel pathology in ALS patients. These changes may be related to those observed in SBVs in skin and muscle biopsies. Furthermore, we report a thinning of the ONL in ALS, revealing a possible affection of rods and cones function in ALS.

Primary lateral sclerosis (PLS) is a condition that most neurologists will never personally diagnose. For the estimated several thousand people living with PLS globally, while it may not be life-sh...

Copyright © 2016 World Federation of Neurology on behalf of the Research Group on Motor Neuron Diseases, A large GGGGCC-repeat expansion mutation (HREM) in C9orf72 is the most common known cause of ALS and FTD in European populations. Sequence variations immediately downstream of the HREM region have previously been observed and have been suggested to be one reason for difficulties in interpreting RP-PCR data. Our objective was to determine the properties of these sequence variations with regard to prevalence, the range of variation, and effect on disease prognosis. We screened a multi-national cohort (n = 6981) for the HREM and samples with deviant RP-PCR curves were identified. The deviant samples were subsequently sequenced to determine sequence alteration. Our results show that in the USA and European cohorts (n = 6508) 10.7% carried the HREM and 3% had a sequence variant, while no HREM or sequence variants were observed in the Japanese cohort (n = 473). Sequence variations were more common on HREM alleles; however, certain population specific variants were associated with a non-expanded allele.In conclusion, we identified 38 different sequence variants, most located within the first 50 bp downstream of the HREM region. Furthermore, the presence of an HREM was found to be coupled to a lower age of onset and a shorter disease survival, while sequence variation did not have any correlation with these parameters.

Neuromuscular junction (NMJ) disruption is an early pathogenic event in amyotrophic lateral sclerosis (ALS). Yet, direct links between NMJ pathways and ALS-associated genes such as FUS, whose heterozygous mutations cause aggressive forms of ALS, remain elusive. In a knock-in Fus-ALS mouse model, we identified postsynaptic NMJ defects in newborn homozygous mutants that were attributable to mutant FUS toxicity in skeletal muscle. Adult heterozygous knock-in mice displayed smaller neuromuscular endplates that denervated before motor neuron loss, which is consistent with 'dying-back' neuronopathy. FUS was enriched in subsynaptic myonuclei, and this innervation-dependent enrichment was distorted in FUS-ALS. Mechanistically, FUS collaborates with the ETS transcription factor ERM to stimulate transcription of acetylcholine receptor genes. Co-cultures of induced pluripotent stem cell-derived motor neurons and myotubes from patients with FUS-ALS revealed endplate maturation defects due to intrinsic FUS toxicity in both motor neurons and myotubes. Thus, FUS regulates acetylcholine receptor gene expression in subsynaptic myonuclei, and muscle-intrinsic toxicity of ALS mutant FUS may contribute to dying-back motor neuronopathy.

Reply : Adult-onset distal spinal muscular atrophy: a new phenotype associated with KIF5A mutations

Annals of Clinical and Translational Neurology 6(12), 2384-2394 (2019). doi:10.1002/acn3.50930, Published by Wiley, Chichester [u.a.]

Several independent prognostic factors, such as age of onset, type of onset, body mass index (BMI), and progression rate have been identified for amyotrophic lateral sclerosis (ALS) in Caucasians. The aim of this study was to identify such factors in Chinese patients and to compare their impact with German patients.Comparison of prognostic factors was based on two hospital-based registries. The registry of the German Network for Motor Neuron Diseases contains 3100 patients with ALS. The Chinese registry comprises 2101 patients who were collected between 2003 and 2015 in the metropolitan area of Beijing.Disease progression was slower in China [median loss of 0.50 points (IQR 0.26-0.87 points) versus 0.55 points (IQR 0.28-1.00 points) of ALS functional rating scale revised (ALS-FRS-R) score per month; p 0.0001]. Survival of patients with ALS was similar in Germany and China (p 0.05). We found that younger age of onset (p 0.0001), spinal onset (p 0.0001), high BMI (p 0.0001) and low progression rate (p 0.0001) were positive prognostic factors in China as well as in Germany.Prognostic factors, which are known to modify the course of disease in Caucasians, apply to Chinese patients as well. The results indicate that despite the apparent differences regarding genotype and clinical phenotype, findings from interventional studies in Caucasians aiming at disease-modifying prognostic factors (such as body weight) may be transferred to Chinese patients.

The syndrome of pathological laughing and crying (PLC) is characterized by episodes of involuntary outbursts of emotional expression. Although this phenomenon has been referred to for over a century, a clear-cut clinical definition is still lacking, and underlying pathophysiological mechanisms are not well understood. In particular, it remains ill-defined which kind of stimuli-contextually appropriate or inappropriate-elicit episodes of PLC, and if the phenomenon is a result of a lack of inhibition from the frontal cortex ("top-down-theory") or due to an altered processing of sensory inputs at the brainstem level ("bottom-up-theory"). To address these questions, we studied ten amyotrophic lateral sclerosis (ALS) patients with PLC and ten controls matched for age, sex and education. Subjects were simultaneously exposed to either emotionally congruent or incongruent visual and auditory stimuli and were asked to rate pictures according to their emotional quality. Changes in physiological parameters (heart rate, galvanic skin response, activity of facial muscles) were recorded, and a standardized self-assessment lability score (CNS-LS) was determined. Patients were influenced in their rating behaviour in a negative direction by mood-incongruent music. Compared to controls, they were influenced by negative stimuli, i.e. they rated neutral pictures more negatively when listening to sad music. Patients rated significantly higher on the CNS-LS. In patients, changes of electromyographic activity of mimic muscles during different emotion-eliciting conditions were explained by frontal cortex dysfunction. We conclude that PLC is associated with altered emotional suggestibility and that it is preferentially elicited by mood-incongruent stimuli. In addition, physiological reactions as well as behavioural changes suggest that this phenomenon is primarily an expression of reduced inhibitory activity of the frontal cortex, since frontal dysfunction could explain changes in physiological parameters in the patient group. We consider these findings being important for the clinical interpretation of emotional reactions of ALS patients.

Objective: Motor Unit Number Index (MUNIX) is a quantitative neurophysiological method that reflects loss of motor neurons in Amyotrophic Lateral Sclerosis (ALS) in longitudinal studies. It has been utilized in one natural history ALS study and one drug trial (Biogen USA) after training and qualification of raters. Methods: Prior to testing patients, evaluators had to submit test-retest data of 4 healthy volunteers. Twenty-seven centres with 36 raters measured MUNIX in 4 sets of 6 different muscles twice. Coefficient of variation of all measurements had to be

Default in-phase coupling of hand movements needs to be suppressed when temporal coordination is required for out-of-phase bimanual movements. There is lack of knowledge on how the brain overrides these default in-phase movements to enable a required interval of activity between hands. We used a visually cued bimanual temporal coordination (vc-BTC) paradigm with a constant rhythmical time base of 1 s, to test the accuracy of in-phase and out-of-phase (0.1, 0.2,…,0.9) finger tapping. We hypothesized that (1) stronger anatomical and effective interhemispheric connectivity between the hand areas of the primary motor cortex (M1HAND) predict higher temporal offsets between hands in the out-of-phase conditions of the vc-BTC; (2) patients with relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) have reduced interhemispheric connectivity and altered between-hand coupling. Anatomical connectivity was determined by fractional anisotropy of callosal hand motor fibers (FA-hCMF). Effective connectivity was probed by short interval interhemispheric inhibition (S-IHI) using paired-coil transcranial magnetic stimulation (TMS). In healthy subjects, higher FA-hCMF and S-IHI correlated with higher temporal offsets between hands in the out-of-phase conditions of the tapping test. FA-hCMF was reduced in patients with RRMS but not in CIS, while S-IHI was reduced in both patient groups. These abnormalities were associated with smaller temporal offsets between hands leading to less deviation from the required phasing in the out-of-phase tapping conditions. Findings provide multiple levels of evidence that callosal anatomical and effective connectivity between the hand areas of the motor cortices play important roles in visually cued bimanual temporal coordination performance.

Criteria for assessing upper motor neuron pathology in lower motor neuron disease (LMND) still remain major issues in clinical diagnosis. This study was designed to investigate patients with the clinical diagnosis of adult pure LMND by use of whole brain based diffusion tensor imaging (DTI) to delineate alterations of corticoefferent pathways in vivo. Comparison of fractional anisotropy (FA) maps was performed by whole brain-based spatial statistics for 37 LMND patients vs. 53 matched controls to detect white matter structural alterations. LMND patients were clinically differentiated in fast and slow progressors. Furthermore, tract specific alterations were investigated by fiber tracking techniques according to the staging hypothesis for amyotrophic lateral sclerosis (ALS). The analysis of white matter structural connectivity demonstrated widespread and characteristic patterns of alterations in patients with LMND, predominantly along the corticospinal tract (CST), with multiple clusters of regional FA reductions in the motor system at p

Flail arm syndrome (FAS) is a variant of motor neuron disease which is characterized by progressive, predominantly proximal weakness and atrophy of the upper limbs (UL). Because of its heterogeneous presentation and its relatively slow progression, differential diagnosis may be difficult particularly in the early stages of the disease. The aim of this study was to investigate typical clinical features of FAS with special regard to initial symptoms and differences to classical Charcot type amyotrophic lateral sclerosis (ALS). We retrospectively evaluated the clinical features of 42 FAS patients who were seen in the outpatient clinics of 4 German centers between 2000 and 2010 and compared them to 146 sex-matched control patients with classical spinal-onset ALS. FAS patients were younger (54.7 ± 9.3 versus 59.4 ± 12.2 years), male patients were predominantly affected (3.8:1 versus 1.9:1), and FAS patients showed a prolonged survival (53 versus 33 months) compared to classical ALS patients. The share of patients with initial misdiagnoses was 54.8% and led to ineffective therapy with immunoglobulins in 26%. Initial symptoms were most frequently present either in distal muscles only or in both proximal and distal muscle groups combined (76%) and showed an asymmetric distribution pattern in the majority of cases (76%). Although all patients developed symmetric and predominantly proximal UL weakness and atrophy during the course of their disease, we found that most patients initially showed asymmetric and predominantly distal distribution of symptoms. This may contribute to difficulties in differential diagnosis and to ineffective treatment regimes.

(1)H MRSI has evolved as an important tool to study the onset and progression of brain damage in multiple sclerosis. Abnormal increases in total creatine, total choline and myoinositol have been noted in multiple sclerosis. However, the pathobiochemical mechanisms related to these changes are still largely unclear. The combination of (1)H MRSI and (1)H-decoupled (31)P MRSI can specify to what extent phosphorylated components of total creatine and total choline contribute to this increase. Combined (1)H and (31)P MRSI data were obtained at 3 T in 22 patients with multiple sclerosis and in 23 healthy controls, and aligned with structural MRI to allow for correction for partial volume effects caused by cerebrospinal fluid and lesion load. A significant increase in total creatine was found in multiple sclerosis, and this was attributed to equal changes in the phosphorylated and unphosphorylated components. The concentrations of the putative glial markers total creatine and myoinositol in lesion-free (1)H MRSI voxels correlated with the global lesion load. We conclude that changes in total creatine are not related to altered energy metabolism, but rather indicate gliosis. Together with the increase in myoinositol, total creatine can be considered as a biomarker for disease severity. A significant total choline increase was mainly a result of choline components not visible by (31)P MRS. The origin of this residual choline fraction remains to be investigated.

In relapsing-remitting multiple sclerosis (RRMS) the corpus callosum (CC) is often and early affected by macroscopic lesions when investigated by conventional MRI. We sought to determine to which extent microstructural and effective disconnection of the CC are already present in RRMS patients at the earliest stages of the disease prior to evidence of macroscopic CC lesion. We compared 16 very early RRMS patients (median expanded disability status scale (EDSS), 1.5; range, 0–2.0) to an age-matched group of healthy controls and focused analysis to the motor CC, i.e. that part of the CC relaying interhemispheric motor information. A combined functional magnetic resonance imaging/diffusion tensor imaging fiber-tracking procedure was applied to identify the callosal motor fibers (CMFs) connecting the hand areas of the primary motor cortices of the two hemispheres. Fractional anisotropy (FA) within the motor CC (FA-CC) assessed the CMF microstructural integrity. Bifocal paired transcranial magnetic stimulation (TMS) tested short-interval interhemispheric inhibition (S-IHI), an established measure of CMF effective connectivity. FA-CC and S-IHI were significantly reduced in early RRMS compared to healthy controls. Furthermore, a significant linear correlation between microstructure (FA-CC) and function (S-IHI) in the controls was broken down in the patients. These abnormalities were obtained in the absence of macroscopic CMF lesion in conventional MRI, and whilst motor hand/arm function in the nine-hole-peg test and corticospinal conduction time were normal. Findings suggest that reductions in FA and S-IHI may serve as surrogate markers of motor callosal disconnection at the earliest stages of RRMS prior to development of macroscopic lesion.

Although motor neuron degeneration is the predominant feature in ALS, recent data point to a more widespread pathology also comprising non-motor symptoms. Retinal thinning has been reported in a variety of neurodegenerative conditions. Yet, studies of retinal involvement in ALS are sparse and results are heterogeneous. We studied retinal alterations in ALS using a systematic approach combining Optical Coherence Tomography (OCT), Diffusion Tensor Imaging (DTI) and clinical phenotyping. We hypothesized that selective changes of specific retinal layers may be a reflection of overall neurodegeneration as measured by DTI. Spectral domain OCT images were analyzed to calculate the average thickness of retinal layers in 71 ALS patients and 20 controls. In 30 patients, the region of interest (ROI) based fractional anisotrophy (FA) was measured in the corticospinal tract (CST), as this region is preferentially affected by motor neuron degeneration. Clinical data were collected for correlation analysis. Patients showed a significant thinning of the inner nuclear layer (INL; p = 0.04) and the retinal nerve fibre layer (RNFL; p = 0.004) compared to controls. We saw significant correlations between retinal thickness and FA values of the CST in patients (p = 0.005). No significant correlation between clinical parameters and retinal involvement was observed. Our study provides evidence for a retinal involvement in ALS. Interestingly, ALS patients show a reduction in FA of the CST, which is correlated to retinal thinning. We conclude that retinal involvement is in fact associated to overall neurodegeneration and may be regarded as a potential technical biomarker in ALS.

Incidence and localization of cortical and thalamic peri-ictal diffusion-weighted imaging (DWI) abnormalities were investigated in patients with status epilepticus (SE). Clinical characteristics and EEG features were compared between patients with and without peri-ictal regional DWI restriction. Such correlations are important to improve the understanding of causes and significance of peri-ictal DWI restriction.We retrospectively investigated 69 SE-patients treated in our emergency department in whom SE was confirmed by EEG and MRI including DWI was performed.19/69 patients presented with peri-ictal DWI restriction: 18/19 with cortical restriction, 13 of them with additional thalamic restriction, and 1/19 with thalamic restriction only. 17/69 patients had DWI restrictions related to other pathologies, so that a possible overlap with peri-ictal DWI restriction could not be determined. In 33/69 patients no peri-ictal DWI restriction was detected. In contrast to SE-patients without DWI restriction, those with peri-ictal DWI restriction always presented with regional/unilateral epileptiform discharges (p0.001). The EEG of SE-patients with peri-ictal DWI restriction was predominated by circumscribed periodic lateralized epileptiform discharges (PLEDs) (p0.001) and by repetitive seizure patterns (p=0.009), while PLEDs occurred infrequently and EEG patterns were more variable in extent in patients without DWI restriction. Patients with peri-ictal diffusion had more often a quantitative disorder of consciousness (p=0.05) compared to patients without peri-ictal DWI restriction. No significant differences were found concerning age of patients, preceding generalized tonic-clonic seizures, and mortality.Patients with peri-ictal DWI restriction presented with a rather uniform EEG pattern characterized by circumscribed PLEDs possibly resulting from local cortical metabolic disturbances and with intermittent seizure patterns. The frequently observed quantitative disorder of consciousness despite circumscribed EEG patterns could be related to epileptic activity in the temporal lobe and cortico-thalamic synchronization. The higher percentage of bilateral status patterns and subcortical lesions in patients without peri-ictal DWI restrictions suggest a different pathomechanism.

Amyotrophic lateral sclerosis (ALS) is an aggressive degeneration of upper and lower motor neurons and thus affects both the central and the peripheral nervous system. Clinically, the disease is characterized by rapidly progressing atrophy and paresis of all muscle groups with a letal outcome after three to six years due to paresis of the respiratory muscles. So far, no causal treatment is known.

Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved., Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.

Objective Lithium has been widely used to treat bipolar affective disorder for over 60 years. Still, its acute effects in human cerebral cortex are poorly understood. This study aimed at investigating the acute effects of lithium on motor cortex excitability as measured by transcranial magnetic stimulation (TMS). Methods Ten healthy young adults participated in a double-blind placebo-controlled randomized crossover study with four sessions, where a single oral dose of lithium carbonate (450 mg, 900 mg, or 1350 mg) or placebo was tested. Focal TMS of the hand area of left motor cortex was used to test resting and active motor thresholds, motor evoked potential input–output curve (MEP IO-curve), slope of the MEP IO-curve and paired-pulse measures of intracortical inhibition and facilitation before, and two and four hours after drug administration. Results Two hours post drug administration, 450 mg of lithium carbonate increased the slope of the MEP IO-curve while 1350 mg tended to decrease it. Lithium had no effect on motor thresholds, or intracortical inhibition or facilitation. Conclusions The acute effects of lithium on MEP IO-curve, a marker of corticospinal excitability, are consistent with an inverted U-shaped dose–response relationship. Significance Findings are important for our understanding of the therapeutic and toxic effects of lithium on the human central nervous system.

The GGGGCC-hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. This study determined the frequency of C9orf72 repeat expansions in different motor neuron diseases (amyotrophic lateral sclerosis (ALS), motor neuron diseases affecting primarily the first or the second motor neuron and hereditary spastic paraplegia). Whereas most studies on C9orf72 repeat expansions published so far rely on a polymerase chain reaction-based screening, we applied both polymerase chain reaction-based techniques and Southern blotting. Furthermore, we determined the sensitivity and specificity of Southern blotting of the C9orf72 hexanucleotide repeat in DNA derived from lymphoblastoid cell lines. C9orf72 repeat expansions were found in 27.1% out of 166 familial ALS patients, only once in 68 sporadic ALS patients, and not in 61 hereditary spastic paraplegia patients or 52 patients with motor neuron diseases affecting clinically primarily either the first or the second motor neuron. We found hints for a correlation between C9orf72 repeat length and the age of onset. Somatic instability of the C9orf72 repeat was observed in lymphoblastoid cell lines compared with DNA derived from whole blood from the same patient and therefore caution is warranted for repeat length determination in immortalized cell lines.

Profilin 1 is a central regulator of actin dynamics. Mutations in the gene profilin 1 (PFN1) have very recently been shown to be the cause of a subgroup of amyotrophic lateral sclerosis (ALS). Here, we performed a large screen of US, Nordic, and German familial and sporadic ALS and frontotemporal dementia (FTLD) patients for PFN1 mutations to get further insight into the spectrum and pathogenic relevance of this gene for the complete ALS/FTLD continuum. Four hundred twelve familial and 260 sporadic ALS cases and 16 ALS/FTLD cases from Germany, the Nordic countries, and the United States were screened for PFN1 mutations. Phenotypes of patients carrying PFN1 mutations were studied. In a German ALS family we identified the novel heterozygous PFN1 mutation p.Thr109Met, which was absent in controls. This novel mutation abrogates a phosphorylation site in profilin 1. The recently described p.Gln117Gly sequence variant was found in another familial ALS patient from the United States. The ALS patients with mutations in PFN1 displayed spinal onset motor neuron disease without overt cognitive involvement. PFN1 mutations were absent in patients with motor neuron disease and dementia, and in patients with only FTLD. We provide further evidence that PFN1 mutations can cause ALS as a Mendelian dominant trait. Patients carrying PFN1 mutations reported so far represent the "classic" ALS end of the ALS-FTLD spectrum. The novel p.Thr109Met mutation provides additional proof-of-principle that mutant proteins involved in the regulation of cytoskeletal dynamics can cause motor neuron degeneration. Moreover, this new mutation suggests that fine-tuning of actin polymerization by phosphorylation of profilin 1 might be necessary for motor neuron survival.

Background Recently, a link between resting motor threshold (RMT) and local tissue microstructure, as indexed by fractional anisotropy (FA), was demonstrated in large parts of white matter. However, regions showing such correlations were generally found outside of the corticospinal tract (CST). Therefore, the question arises whether other electrophysiologic measurements could be more locally related to microstructural properties of the CST. In this study, we explored the relationship between such measurements and regional FA in a group of healthy volunteers. Objective/Hypothesis We hypothesized that RMT might be more related to an overall susceptibility of white matter to TMS, whereas other electrophysiologic markers might be more specifically related to properties of the CST only. Methods Thirty-seven subjects were included. We studied RMT, active motor threshold (AMT), intensity to evoke a motor-evoked potential (MEP) of 1 mV (S1mV), MEP input-output curve (IO-curve), and central motor conduction time (CMCT) using transcranial magnetic stimulation, and FA of the corticospinal tract using diffusion tensor magnetic resonance imaging. We performed voxel-wise and TBSS correlation analysis between these electrophysiologic measurements and FA. In addition, we tested for significant correlation between these parameters and mean diffusivity (MD). Results On voxel-wise analysis, we did not detect significant correlations between any electrophysiologic parameter (RMT, AMT, S1mV, IO curve slope, CMCT) and FA. With TBSS, we detected correlations between FA and bilateral AMT, as well as left-hemispheric S1mV, but these correlations were found in locations unlikely to contribute to motor pathways. Conclusions Although a relationship between structure and function has been shown in many other regions of the brain, it seems to be much more challenging to demonstrate such a relationship in the CST of healthy subjects.

Electromyographic mirror activity (MA) refers to involuntary activation of the non-active limb during intended strictly unilateral movements of the other limb. MA occurs in the majority of healthy adults but little is known about its neurophysiological foundation. Here we examined in healthy adults the hypothesis that transcallosal interhemispheric inhibition (IHI) between the primary motor cortices determines the extent to which MA occurs. IHI was tested by an established paired transcranial magnetic stimulation protocol [A. Ferbert et al. (1992) J. Physiol. (Lond.), 453, 525-546]. In a first experiment we found that the magnitudes of IHI and MA were inversely correlated. In a second experiment we sought to establish a more causative relation by exploring the changes induced by low-frequency repetitive transcranial magnetic stimulation of primary motor cortex on IHI and MA. These changes were also significantly inversely correlated, i.e. a repetitive transcranial magnetic stimulation-induced increase in IHI was associated with a decrease in MA, and a decrease in IHI was associated with an increase in MA. These results provide strong and consistent evidence that transcallosal inhibitory interhemispheric interaction provides a significant route by which unwanted MA during intended unimanual motor tasks can be controlled.

In amyotrophic lateral sclerosis (ALS) patients with known genetic cause, mutations in chromosome 9 open reading frame 72 (C9orf72) and superoxide dismutase 1 (SOD1) account for most familial and late-onset sporadic cases, whereas mutations in fused in sarcoma (FUS) can be identified in just around 5% of familial and 1% of overall sporadic cases. There are only few reports on de novo FUS mutations in juvenile ALS patients. To date, no systematic evaluation on the frequency of de novo FUS mutations in early-onset ALS patients has been conducted. Here, we screened a cohort of 14 early-onset sporadic ALS patients (onset age

MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression and specific mircoRNA "fingerprints" are thought to contribute to and/or reflect certain disease conditions. Recently, we identified surprisingly homogeneous signatures of circulating miRNAs in the serum of familial amyotrophic lateral sclerosis (ALS) patients, which were already present in presymptomatic carriers of ALS gene mutations. Here, we characterize circulating miRNAs in the serum of sporadic ALS patients. We show that, in contrast to familial ALS, miRNA signatures of sporadic ALS are highly heterogeneous suggesting a number of different etiologies. Nevertheless, 2 miRNAs, miR-1234-3p and miR-1825, could be identified to be consistently downregulated in sporadic ALS. Bioinformatic analysis revealed miRNA fingerprints resembling those of familial ALS patients and mutation carriers in 61% of sporadic ALS patients, while the remaining subgroup had clearly different miRNA signatures. These data support a higher than expected contribution of genetic factors also to sporadic ALS. Moreover, our results indicate a more heterogeneous molecular etiology of sporadic ALS compared with (mono)genic cases, which should be considered for the development of disease modifying treatments.