Case Series of Acute Peripheral Neuropathies in Individuals Who Received COVID-19 Vaccination.

Background and Objectives: Vaccination has been critical to managing the COVID-19 pandemic. Autoimmunity of the nervous system, especially among a select set of high-risk groups, can be triggered or enhanced by the contents of vaccines. Here, we report a case series of acute peripheral neuropathies following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report on 11 patients (range: 30-90 years old) who presented at our center between January 2021 and February 2022. Methods: We obtained the patients' history and performed clinical neurological examination and electromyoneurography on all subjects. If necessary, magnetic resonance imaging and laboratory testing, including cerebrospinal fluid analysis and specific antibody testing, were performed. Results: Patients presented with peripheral neuropathies of acute onset between 1 and 40 days after vaccination with different types of COVID-19 vaccines. Most cases (9/11) resolved with a rapid, complete or partial recovery. Conclusions: We found acute peripheral neuropathies in a set of individuals after they received vaccines against SARS-CoV-2. Albeit our observation shows that during extensive vaccination programs, negative side effects on the peripheral nervous system might occur, most of them showed benign clinical evolution. Thus, potential side effects should not hinder the prescription of vaccines. More extensive studies are needed to elucidate populations at risk of developing peripheral neuropathies and mechanisms of autoimmune response in the nervous system.

[Similarities between amyotrophic lateral sclerosis and frontotemporal dementia]. / Similarités entre sclérose latérale amyotrophique et démence frontotemporale.

Frontotemporal dementia (FTD) is characterized by degeneration of the frontal and temporal lobes. Classic symptoms include behavioural alterations and executive dysfunction. Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease of the first and second motoneurones, as well as of cortical neurons, presenting with weakness and wasting of the limb, respiratory and bulbar muscles. Accumulation of a mis-localized protein in the neuronal cytoplasma is the main neuropathological marker of ALS but has also been described in certain FTD-variants. Molecules interfering specifically on this level of mis-localization and toxic aggregation may thus represent a very interesting therapeutic approach in both, ALS and FTD.

La démence frontotemporale (DFT) appartient au spectre des dégénérescences frontotemporales et se présente classiquement par une atteinte comportementale et exécutive. La sclérose latérale amyotrophique (SLA) affecte les motoneurones ainsi que des neurones corticaux, se manifestant classiquement par une amyotrophie, une faiblesse ou des troubles de l'élocution. Le temps de survie n'est que de trois à cinq ans en moyenne. Le marqueur neuropathologique majeur de la SLA est une accumulation toxique de certaines protéines dans les neurones. Ces mêmes agrégations sont également présentes dans certaines formes de la DFT, parlant en faveur des pathomécanismes communs. De ce fait, des molécules intervenant spécifiquement au niveau de ces processus représentent une approche thérapeutique très prometteuse pour les patients atteints d'une SLA ou d'une DFT.

[Muscle cramps]. / Crampes musculaires.

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.

[Cramps and fasciculations: is it amyotrophic lateral sclerosis?] / Crampes et fasciculations : est-ce une sclérose latérale amyotrophique ?

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.

[Muscle disease in the adults: when to suspect it?] / Maladies musculaires de l'adulte : quand évoquer le diagnostic ?

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.

[What have we learned about chronic inflammatory demyelinating polyradiculoneuropathyin the last twenty years ?] / Qu'avons-nous compris en 20 ans sur la polyradiculoneuropathie inflammatoire démyélinisante chronique ?

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 20e siècle. Les 20 dernières années ont vu s'accomplir des progrès décisifs dans sa compréhension. Les critères diagnostiques se sont simplifiés et les étapes de la démarche diagnostique se sont précisées. Les contours phénotypiques de l'affection sont désormais bien connus, de même que les pièges diagnostiques. Sur le plan physiopathologique, la découverte des autoanticorps dirigés contre les protéines nodales et paranodales a été une avancée majeure qui ne concerne toutefois qu'une minorité de patients. Ces découvertes ont un impact majeur sur la prise en charge thérapeutique de ces patients, souffrant souvent d'une forme très active de la maladie. Les 20 prochaines années verront sûrement s'approfondir encore les connaissances sur cette maladie fascinante.

[Treating hereditary neuropathies : a dream come true?] / Traiter les neuropathies héréditaires : un rêve qui devient réalité ?

Hereditary neuropathies have been the subject of recent major therapeutic advances. Treatments based on antisense oligonucleotides (ASO) and small interfering RNA (siRNA) have been developed and are now commercially available to treat hereditary transthyretin amyloidosis (hTTR) and porphyria. More recently, a CRISPR-Cas9 genomic editing treatment targeting the TTR gene has been developed and is being tested in patients with hTTR. Based on their success in hTTR and porphyria, innovative treatments targeting mRNA and DNA are being evaluated in other hereditary neuropathies, including Charcot-Marie-Tooth disease (CMT).

Les neuropathies héréditaires ont fait l'objet d'avancées thérapeu­tiques majeures. Ainsi, des traitements à base d'oligonucléotides antisens (ASO) et d'ARN interférentiels (ARNi) ont récemment été développés et sont maintenant disponibles pour traiter efficacement la neuropathie amyloïde familiale à transthyrétine (NAF-TTR) et la porphyrie. Encore plus récemment, des traitements d'édition génomique de type CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats-Cas9) ciblant le gène TTR ont été mis au point et sont testés chez des patients avec une NAF-TTR. Forts de leur succès dans la NAF-TTR et la porphyrie, ces traitements innovants ciblant l'ARNm et l'ADN sont en cours d'évaluation dans d'autres neuropathies héréditaires, dont la maladie de Charcot-Marie-Tooth (CMT).

[Neurological shoulder pain and weakness : practical attitudes]. / Douleurs et faiblesse de l'épaule neurologique : attitudes pratiques.

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 XIe nerf crânien, suprascapulaire ou dorsal de la scapula. Au besoin l'ENMG (électroneuromyogramme)et l'imagerie débrouilleront les multiples étiologies. Le traitement requiert le plus souvent une antalgie et une rééducation, rarement une chirurgie.

[Small fiber neuropathy diagnosis]. / Diagnostiquer une neuropathie des petites fibres.

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.

Hot-spot KIF5A mutations cause familial ALS.

Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 × 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p.Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 × 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.

Comprehensive analysis of the mutation spectrum in 301 German ALS families.

OBJECTIVES: Recent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions. METHODS: Here we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72 mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families. RESULTS: 49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBP or TBK1, whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes. CONCLUSIONS: We here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe.

Retinal involvement in amyotrophic lateral sclerosis: a study with optical coherence tomography and diffusion tensor imaging.

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.

[Amyotrophic lateral sclerosis]. / Amyotrophe Lateralsklerose. Diagnostik und Therapieoptionen.

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.

Are nerve conduction studies altered in functional neurological disorders?

Background: Functional neurological disorders represent conditions without a readily identifiable origin or laboratory-supported diagnostic. We report a case of functional neurological disorder, presenting with muscle weakness with alterations in F-waves on the affected side. Case report: A retrospective case review of a patient seen in clinic. Electrophysiological evaluation included nerve conduction studies, including recording of F-waves in lower limbs, and needle EMG. A patchy sensory loss and unilateral muscle weakness of the left lower limb persisted nine days after a 40-year-old female patient developed bilateral lower limb weakness following a laparoscopic surgery. MRI was negative for radicular compression, myelopathy, or lumbosacral plexopathy. F-waves of the peroneal and tibial nerves on the left were absent or of reduced persistence and amplitude compared to the asymptomatic right side. Significance: The observation of unilateral alterations of F-wave parameters could be interpreted as an asymmetrical decrease of alpha motor neuron excitability on L4 - S2 segments. In the absence of peripheral nervous system dysfunction or a structural lesion, the results here suggest a central control dysfunction or point to a more complex peripheral role. Further research is necessary to determine the frequency of these findings in a larger group of patients while incorporating other late responses, such as H (Hoffman) reflex, and measures of cortical excitability.

Relaxation-weighted 23Na magnetic resonance imaging maps regional patterns of abnormal sodium concentrations in amyotrophic lateral sclerosis.

Objectives: Multiparametric magnetic resonance imaging (MRI) is established as a technical instrument for the characterisation of patients with amyotrophic lateral sclerosis (ALS). The contribution of relaxation-weighted sodium (23NaR) MRI remains to be defined. The aim of this study is to apply 23NaR MRI to investigate brain sodium homeostasis and map potential alterations in patients with ALS as compared with healthy controls. Materials and Methods: Seventeen patients with ALS (mean age 61.1 ± 11.4 years, m/f = 9/8) and 10 healthy control subjects (mean age 60.3 ± 15.3 years, m/f = 6/4) were examined by 23NaR MRI at 3 T. Regional sodium maps were obtained by the calculation of the weighted difference from two image data sets with different echo times (TE1 = 0.3 ms, TE2 = 25 ms). Voxel-based analysis of the relaxation-weighted maps, together with 23Na concentration maps for comparison, was performed. Results: ROI-based analyses of relaxation-weighted brain sodium concentration maps demonstrated increased sodium concentrations in the upper corticospinal tracts and in the frontal lobes in patients with ALS; no differences between ALS patients and controls were found in reference ROIs, where no involvement in ALS-associated neurodegeneration could be anticipated. Conclusion: 23NaR MRI mapped regional alterations within disease-relevant areas in ALS which correspond to the stages of the central nervous system (CNS) pathology, providing evidence that the technique is a potential biological marker of the cerebral neurodegenerative process in ALS.