Introduction
Neurological manifestations can occur during coronavirus disease 19 (COVID-19). Several pathogenic mechanisms have been hypothesized, without conclusive results. In this study, we ...evaluated the most frequent neurological symptoms in a cohort of hospitalized COVID-19 patients, and also investigated the possible relationship between plasmatic inflammatory indices and olfactory disorders (ODs) and between muscle pain and creatine kinase (CK).
Methods
We consecutively enrolled hospitalized COVID-19 patients. A structured questionnaire concerning typical and neurological symptoms, focusing on headache, dizziness, ODs, taste disorders (TDs), and muscle pain, was administrated by telephone interviews.
Results
Common neurological symptoms were reported in the early phase of the disease, with a median onset ranging from 1 to 3 days. Headache showed tension-type features and was more frequently associated with a history of headache. Patients with ODs less frequently needed oxygen therapy. Inflammatory indices did not significantly differ between patients with and without ODs. Muscle pain did not show any association with CK level but was more frequently associated with arthralgia and headache.
Conclusion
In our cohort, ODs were an early symptom of COVID-19, more frequently reported by patients with milder forms of disease. Headache in association with arthralgia and muscle pain seems to reflect the common symptoms of the flu-like syndrome, and not COVID-19 infection-specific.
Background and purpose
Quantification of intraepidermal nerve fibers (IENFs) in skin biopsies is now the tool of choice to diagnose small fiber neuropathies. An adequate normative dataset, necessary ...to assess normality cutoffs, is available for brightfield microscopy but not for immunofluorescence.
Methods
Intraepidermal nerve fiber density data in distal leg skin samples processed with immunofluorescence were collected from 528 healthy individuals from four experienced laboratories worldwide. In all laboratories skin samples were collected, processed and analyzed according to standard procedures. Quantile regression analysis was employed to tailor the fit of the 5° percentile as the normal cutoff value and to test and measure the effect of age, gender, body mass index, race, biopsy site (lateral distal lower leg or medial posterior mid‐calf) and participating laboratory as possible influential variables.
Results
Age, gender and biopsy site showed an independent linear correlation with IENF density. For each decade the 5° quantile IENF cutoff showed a 0.54 fibers/mm decrease, whilst females exhibited a 1.0 fiber/mm cutoff greater than males. Compared to the lateral distal lower leg, biopsies from the calf showed a 3.4 fibers/mm lower 5° percentile cutoff, documenting a variation linked by site.
Conclusions
An age‐ and gender‐adjusted normative dataset for IENF density at the lateral distal lower leg obtained with indirect immunofluorescence is presented for the first time by sharing data from four experienced laboratories worldwide. This dataset can be used as reference for laboratories processing skin biopsies with this technique.
Highlights • Microneurography allows recordings from sympathetic or nociceptive fibers. • Recently it has been widely used to explore autonomic impairments in neurological disorders. • ...Microneurography has also been used to show abnormal nociceptor outflow.
•Inter-rater variation in the use of diagnostic criteria for amyotrophic lateral sclerosis is high.•Revised El Escorial and Awaji criteria are complex and might require training for use.•The Awaji ...criteria have a positive impact on diagnostic sensitivity in subgroups.
This study assesses inter-rater agreement and sensitivity of diagnostic criteria for amyotrophic lateral sclerosis (ALS).
Clinical and electrophysiological data of 399 patients with suspected ALS were collected by eleven experienced physicians from ten different countries. Eight physicians classified patients independently and blinded according to the revised El Escorial Criteria (rEEC) and to the Awaji Criteria (AC). Inter-rater agreement was assessed by Kappa coefficients, sensitivity by majority diagnosis on 350 patients with follow-up data.
Inter-rater agreement was generally low both for rEEC and AC. Agreement was best on the categories “Not-ALS”, “Definite”, and “Probable”, and poorest for “Possible” and “Probable Laboratory-supported”.
Sensitivity was equal for rEEC (64%) and AC (63%), probably due to downgrading of “Probable Laboratory-supported” patients by AC. However, AC was significantly more effective in classifying patients as “ALS” versus “Not-ALS” (p < 0.0001).
Inter-rater variation is high both for rEEC and for AC probably due to a high complexity of the rEEC inherent in the AC.
The gain of AC on diagnostic sensitivity is reduced by the omission of the “Probable Laboratory-supported” category.
The results highlight a need for initiatives to develop simpler and more reproducible diagnostic criteria for ALS in clinical practice and research.
We aimed to characterize in vivo α-synuclein (α-syn) aggregates in skin nerves to ascertain: 1) the optimal marker to identify them; 2) possible differences between synucleinopathies that may justify ...the clinical variability. We studied multiple skin nerve α-syn deposits in 44 patients with synucleinopathy: 15 idiopathic Parkinson's disease (IPD), 12 dementia with Lewy Bodies (DLB), 5 pure autonomic failure (PAF) and 12 multiple system atrophy (MSA). Ten healthy subjects were used as controls. Antibodies against native α-syn, C-terminal α-syn epitopes such as phosphorylation at serine 129 (p-syn) and to conformation-specific for α-syn mature amyloid fibrils (syn-F1) were used. We found that p-syn showed the highest sensitivity and specificity in disclosing skin α-syn deposits. In MSA abnormal deposits were only found in somatic fibers mainly at distal sites differently from PAF, IPD and DLB displaying α-syn deposits in autonomic fibers mainly at proximal sites. PAF and DLB showed the highest p-syn load with a widespread involvement of autonomic skin nerve fibers.
1) p-syn in skin nerves was the optimal marker for the in vivo diagnosis of synucleinopathies; 2) the localization and load differences of aggregates may help to identify specific diagnostic traits and support a different pathogenesis among synucleinopathies.
Background and purpose
We aimed to test the clinical utility of the leg:thigh intraepidermal nerve‐fiber (IENF) density ratio as a parameter to discriminate between length‐dependent small‐fiber ...neuropathy (SFN) and small‐fiber sensory ganglionopathy (SFSG) in subjects with signs and symptoms of small‐fiber pathology.
Methods
We retrospectively evaluated thigh and leg IENF density in 314 subjects with small‐fiber pathology (173 with distal symmetrical length‐dependent SFN and 141 with non‐length‐dependent SFSG). A group of 288 healthy subjects was included as a control group. The leg:thigh IENF density ratio was calculated for all subjects. We used receiver operating characteristic curve analyses to assess the ability of this parameter to discriminate between length‐dependent SFN and SFSG, and the decision curve analysis to estimate its net clinical benefit.
Results
In patients with neuropathy, the mean IENF density was 14.8 ± 6.8/mm at the thigh (14.0 ± 6.9/mm in length‐dependent SFN and 15.9 ± 6.7/mm in patients with SFSG) and 7.5 ± 4.5/mm at the distal leg (5.4 ± 3.2/mm in patients with length‐dependent SFN and 10.1 ± 4.6/mm in patients with SFSG). The leg:thigh IENF density ratio was significantly (P < 0.01) lower in patients with length‐dependent SFN (0.44 ± 0.23) compared with patients with SFSG (0.68 ± 0.28). The area under the curve of the receiver operating characteristic analysis to discriminate between patients with length‐dependent SFN and SFSG was 0.79. The decision curve analysis demonstrated the clinical utility of this parameter.
Conclusions
The leg:thigh IENF ratio represents a valuable tool in the differential diagnosis between SFSG and length‐dependent SFN.
Mutations in OPA1, a dynamin-related GTPase involved in mitochondrial fusion, cristae organization and control of apoptosis, have been linked to non-syndromic optic neuropathy transmitted as an ...autosomal-dominant trait (DOA). We here report on eight patients from six independent families showing that mutations in the OPA1 gene can also be responsible for a syndromic form of DOA associated with sensorineural deafness, ataxia, axonal sensory-motor polyneuropathy, chronic progressive external ophthalmoplegia and mitochondrial myopathy with cytochrome c oxidase negative and Ragged Red Fibres. Most remarkably, we demonstrate that these patients all harboured multiple deletions of mitochondrial DNA (mtDNA) in their skeletal muscle, thus revealing an unrecognized role of the OPA1 protein in mtDNA stability. The five OPA1 mutations associated with these DOA ‘plus’ phenotypes were all mis-sense point mutations affecting highly conserved amino acid positions and the nuclear genes previously known to induce mtDNA multiple deletions such as POLG1, PEO1 (Twinkle) and SLC25A4 (ANT1) were ruled out. Our results show that certain OPA1 mutations exert a dominant negative effect responsible for multi-systemic disease, closely related to classical mitochondrial cytopathies, by a mechanism involving mtDNA instability.
Animal experimentation requires a solid and rational moral foundation. Objective and emphatic decision-making and protocol evaluation by researchers and ethics committees remain a difficult and ...sensitive matter. This article presents three perspectives that facilitate a consideration of the minimally acceptable standard for animal experiments, in particular, in tissue engineering (TE) and regenerative medicine. First, we review the boundaries provided by law and public opinion in America and Europe. Second, we review contemporary moral theory to introduce the Neo-Rawlsian contractarian theory to objectively evaluate the ethics of animal experiments. Third, we introduce the importance of available reduction, replacement, and refinement strategies, which should be accounted for in moral decision-making and protocol evaluation of animal experiments. The three perspectives are integrated into an algorithmic and graphic harm-benefit analysis tool based on the most relevant aspects of animal models in TE. We conclude with a consideration of future avenues to improve animal experiments.
Sleep-related disorders have been reported to have a higher prevalence in multiple sclerosis (MS) than in the general population. They are often undervalued for the presence of more severe physical ...problems and the occurrence at night, without a direct observation in common clinical practice, but if not recognized and treated they can negatively affect the quality of life causing daytime drowsiness and worsening fatigue. Sleep related disorders most commonly reported in MS are as follows: insomnia, sleep-related breathing disorders (SRBD), restless legs syndrome (RLS) and periodic limb movement disorders (PLMD). Secondary narcolepsy, REM sleep behavior disorder (RBD) and propriospinal myoclonus have been also described in some case reports or series. The purpose of this review is to correlate the more common sleep disturbances in MS patients to the involvement of specific brain regions, analyzing their relationship with MRI findings. While insomnia is usually secondary to other disabling symptoms such as nocturia or pain, SRBD, RLS, narcolepsy, RBD and propriospinal myoclonus in MS patients can be the consequence of an injury of specific central nervous system (CNS) areas. Lesions in the pontine tegmentum and the dorsal medulla have been associated with SRBD, spinal cord lesions or atrophy with RLS, bilateral lesions in the lateral hypothalamus with narcolepsy-like symptoms, lesions in the dorsal pontine tegmentum with RBD and intramedullary demyelinating plaques in spinal cord with propriospinal myoclonus. MS specialists and general neurologists should be aware of these comorbidities since neuroimaging, which is routinely performed in MS, could provide helpful clinical indications on patients with secondary sleep-related disorders and to categorize symptomatic patients who need to underdo more in-depth sleep studies.
•Insomnia, SRBD, RLS and PLMD have a higher prevalence in MS patients.•Narcolepsy, RBD and propriospinal myoclonus have been reported in some case reports.•Sleep disorders in MS can arise from damage to specific CNS areas.•MRI could provide helpful indications on MS patients with sleep disorders.
Background and purpose
Visualization of phosphorylated α‐synuclein at serine 129 (p‐syn) in skin nerves is a promising test for the in vivo diagnosis of synucleinopathies. Here the aim was to ...establish the intra‐ and inter‐laboratory reproducibility of measurement of intraneural p‐syn immunoreactivity in two laboratories with major expertise (Würzburg and Bologna).
Methods
In total, 43 patients affected by Parkinson's disease (PD 21 patients), dementia with Lewy bodies (DLB 1), rapid eye movement sleep behaviour disorder (RBD 11), multiple system atrophy (MSA‐P 4) and small fibre neuropathy (SFN 6) were enrolled. Skin biopsy was performed at the C7 paravertebral spine region and distal skin sites (thigh or leg). The analysis was standardized in both laboratories and carried out blinded on a single skin section double stained with antibodies to p‐syn and the pan‐axonal marker protein gene product 9.5. Fifty skin sections were randomly selected for the analysis: 25 from C7 and 25 from distal sites. Differently classified sections were re‐evaluated to understand the reasons for the discrepancy.
Results
The intra‐laboratory analysis showed an excellent reproducibility both in Würzburg (concordance of classification 100% of sections; K = 1; P < 0.001) and Bologna (96% of sections; K = 0.92; P < 0.001). Inter‐laboratory analysis showed reproducibility in 45 sections (90%; K = 0.8; P < 0.001) and a different classification in five sections, which was mainly due to fragmented skin samples or weak fluorescent signals.
Conclusions
Analysis of p‐syn showed excellent inter‐ and intra‐laboratory reproducibility supporting the reliability of this technique. The few ascertained discordances were important to further improve the standardization of this technique.
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