Publications by authors named "Giuseppe Lauria"

217 Publications

Mutations associated with hypokalemic periodic paralysis: from hotspot regions to complete analysis of CACNA1S and SCN4A genes.

Neurogenetics 2021 Oct 5. Epub 2021 Oct 5.

Neurology IV Unit, Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy.

Familial periodic paralyses (PPs) are inherited disorders of skeletal muscle characterized by recurrent episodes of flaccid muscle weakness. PPs are classified as hypokalemic (HypoPP), normokalemic (NormoPP), or hyperkalemic (HyperPP) according to the potassium level during the paralytic attacks. HypoPP is an autosomal dominant disease caused by mutations in the CACNA1S gene, encoding for Cav1.1 channel (HypoPP-1), or SCN4A gene, encoding for Nav1.4 channel (HypoPP-2). In the present study, we included 60 patients with a clinical diagnosis of HypoPP. Fifty-one (85%) patients were tested using the direct sequencing (Sanger method) of all reported HypoPP mutations in CACNA1S and SCN4A genes; the remaining 9 (15%) patients were analyzed through a next-generation sequencing (NGS) panel, including the whole CACNA1S and SCN4A genes, plus other genes rarely associated to PPs. Fifty patients resulted mutated: 38 (76%) cases showed p.R528H and p.R1239G/H CACNA1S mutations and 12 (24%) displayed p.R669H, p.R672C/H, p.R1132G/Q, and p.R1135H SCN4A mutations. Forty-one mutated cases were identified among the 51 patients managed with Sanger sequencing, while all the 9 cases directly analyzed with the NGS panel showed mutations in the hotspot regions of SCN4A and CACNA1S. Ten out of the 51 patients unresolved through the Sanger sequencing were further analyzed with the NGS panel, without the detection of any mutation. Hence, our data suggest that in HypoPP patients, the extension of genetic analysis from the hotspot regions using the Sanger method to the NGS sequencing of the entire CACNA1S and SCN4A genes does not lead to the identification of new pathological mutations.
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http://dx.doi.org/10.1007/s10048-021-00673-2DOI Listing
October 2021

Corneal nerve loss is related to the severity of painful diabetic neuropathy.

Eur J Neurol 2021 Sep 27. Epub 2021 Sep 27.

Division of Cardiovascular Sciences, Cardiac Centre, Faculty of Biology, Medicine and Health, University of Manchester and NIHR/Wellcome Trust Clinical Research Facility, Manchester, UK.

Background And Purpose: Previously it has been shown that patients with painful diabetic neuropathy (PDN) have greater corneal nerve loss compared to patients with painless diabetic neuropathy. This study investigated if the severity of corneal nerve loss was related to the severity of PDN.

Methods: Participants with diabetic neuropathy (n = 118) and healthy controls (n = 38) underwent clinical and neurological evaluation, quantitative sensory testing, nerve conduction testing and corneal confocal microscopy and were categorized into those with no (n = 43), mild (n = 34) and moderate-to-severe (n = 41) neuropathic pain.

Results: Corneal nerve fibre density (p = 0.003), corneal nerve fibre length (p < 0.0001) and cold perception threshold (p < 0.0001) were lower and warm perception threshold was higher (p = 0.002) in patients with more severe pain, but there was no significant difference in the neuropathy disability score (p = 0.5), vibration perception threshold (p = 0.5), sural nerve conduction velocity (p = 0.3) and amplitude (p = 0.7), corneal nerve branch density (p = 0.06) and deep breathing heart rate variability (p = 0.08) between patients with differing severity of PDN. The visual analogue scale correlated significantly with corneal nerve fibre density (r = -0.3, p = 0.0002), corneal nerve branch density (r = -0.3, p = 0.001) and corneal nerve fibre length (r = -0.4, p < 0.0001). Receiver operating curve analysis showed that corneal nerve fibre density had an area under the curve of 0.78 with a sensitivity of 0.73 and specificity of 0.72 for the diagnosis of PDN.

Conclusions: Corneal confocal microscopy reveals increasing corneal nerve fibre loss with increasing severity of neuropathic pain and a good diagnostic outcome for identifying patients with PDN.
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http://dx.doi.org/10.1111/ene.15129DOI Listing
September 2021

Syncope and COVID-19 disease - A systematic review.

Auton Neurosci 2021 11 27;235:102872. Epub 2021 Aug 27.

Department of Medicine, Faculdade de Medicina da Universidade do Porto, Porto, Portugal; Department of Cardiology, Centro Hospitalar Universitário São João, Porto, Portugal. Electronic address:

Background: Syncope is not a common manifestation of COVID-19, but it may occur in this context and it can be the presenting symptom in some cases. Different mechanisms may explain the pathophysiology behind COVID-19 related syncope. In this report, we aimed to examine the current frequency and etiology of syncope in COVID-19.

Methods: A systematic review across PubMed, ISI Web of Knowledge and SCOPUS was performed, according to PRISMA guidelines, in order to identify all relevant articles regarding both COVID-19 and syncope.

Results: We identified 136 publications, of which 99 were excluded. The frequency of syncope and pre-syncope across the selected studies was 4.2% (604/14,437). Unexplained syncope was the most common type (87.9% of the episodes), followed by reflex syncope (7.8% of the cases). Orthostatic hypotension was responsible for 2.2% of the cases and syncope of presumable cardiac cause also accounted for 2.2% of cases. Arterial hypertension was present in 52.0% of syncope patients. The use of angiotensin receptor blockers or angiotensin converting enzyme inhibitors were not associated with an increased incidence of syncope (chi-square test 1.07, p 0.30), unlike the use of beta-blockers (chi-square test 12.48, p < 0.01).

Conclusion: Syncope, although not considered a typical symptom of COVID-19, can be associated with it, particularly in early stages. Different causes of syncope were seen in this context. A reevaluation of blood pressure in patients with COVID-19 is suggested, including reassessment of antihypertensive therapy, especially in the case of beta-blockers.
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http://dx.doi.org/10.1016/j.autneu.2021.102872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393505PMC
November 2021

Fifteen-Year Outcomes Following Valve-Sparing Aortic Root Replacement in Elderly Patients.

Heart Lung Circ 2021 Aug 28. Epub 2021 Aug 28.

Department of Cardiovascular Surgery and Heart Transplantation, University Hospital of Nancy-Brabois, Vandoeuvre-lès-Nancy, France. Electronic address:

Background: Valve-sparing aortic root replacement (VSRR) techniques have several advantages such as preservation of physiological haemodynamics of the native aortic valve and avoidance of prosthetic valve-related complications. However, VSRR procedures are generally performed in young patients and the long-term results in elderly patients (≥65 years) are scarce.

Methods: Fifty-six (56) consecutive patients underwent VSRR surgery by a single surgeon at the current centre between January 2006 and December 2013; a modified "remodelling technique" was typically performed. The mean age was 58.86±12.5 years; Marfan syndrome and bicuspid aortic valve were both present in six patients (10.7%); 38 patients (67.8%) presented with greater than moderate aortic regurgitation; and 17 patients (30.4%) were in New York Heart Association (NYHA) class III before surgery. They were divided into two groups according to their ages receiving VSRR surgery: Group E (elderly patients aged ≥65 years, n=24) and Group Y (young patients aged <65 years, n=32). The primary outcomes were aortic valve-related reoperation, cardiovascular reoperation, all-cause mortality, and functional status.

Results: One (1) patient in Group E was converted to aortic valve replacement as a result of a failed aortic valve repair. No perioperative mortality was observed. The mean follow-up was 11.5±2.9 years. Aortic valve-related reoperation was noted in two patients of each group (one with endocarditis, one with severe aortic regurgitation). Cardiovascular reoperations were observed in three and six patients, and all-cause deaths in seven and two patients in Group E and Group Y, respectively. The 10-year freedom from aortic valve-related reoperation was estimated to be 91.7±5.6% and 92.7±5.0% (p=0.594), the 10-year freedom from cardiovascular reoperation was 86.4±7.3% and 81.1±7.7% (p=0.781), and the cumulative 10-year survival rates were 74.0±9.2% and 93.8±4.3% (p=0.018) in Group E and Group Y, respectively. During follow-up, 6.7% of patients were in NYHA class III and 6.4% of patients developed moderate-to-severe aortic regurgitation. Cox regression analysis failed to identify predictors for primary outcomes.

Conclusion: Valve-sparing aortic root replacement can safely be performed in elderly patients with low early mortality and satisfactory long-term freedom from aortic valve-related and cardiovascular re-intervention.
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http://dx.doi.org/10.1016/j.hlc.2021.07.013DOI Listing
August 2021

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.

JAMA Neurol 2021 Oct;78(10):1236-1248

Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.

Objective: To identify the genetic variants associated with juvenile ALS.

Design, Setting, And Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.

Main Outcomes And Measures: De novo variants present only in the index case and not in unaffected family members.

Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.

Conclusions And Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.
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http://dx.doi.org/10.1001/jamaneurol.2021.2598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406220PMC
October 2021

A novel gain-of-function sodium channel β2 subunit mutation in idiopathic small fiber neuropathy.

J Neurophysiol 2021 Sep 28;126(3):827-839. Epub 2021 Jul 28.

Department of Neurology, Yale University School of Medicine, New Haven, Connecticut.

Small fiber neuropathy (SFN) is a common condition affecting thinly myelinated Aδ and unmyelinated C fibers, often resulting in excruciating pain and dysautonomia. SFN has been associated with several conditions, but a significant number of cases have no discernible cause. Recent genetic studies have identified potentially pathogenic gain-of-function mutations in several pore-forming voltage-gated sodium channel α subunits (Na) in a subset of patients with SFN, but the auxiliary sodium channel β subunits have been less implicated in the development of the disease. β subunits modulate Na trafficking and gating, and several mutations have been linked to epilepsy and cardiac dysfunction. Recently, we provided the first evidence for the contribution of a mutation in the β2 subunit to pain in human painful diabetic neuropathy. Here, we provide the first evidence for the involvement of a sodium channel β subunit mutation in the pathogenesis of SFN with no other known causes. We show, through current-clamp analysis, that the newly identified Y69H variant of the β2 subunit induces neuronal hyperexcitability in dorsal root ganglion neurons, lowering the threshold for action potential firing and allowing for increased repetitive action potential spiking. Underlying the hyperexcitability induced by the β2-Y69H variant, we demonstrate an upregulation in tetrodotoxin-sensitive, but not tetrodotoxin-resistant sodium currents. This provides the first evidence for the involvement of β2 subunits in SFN and strengthens the link between sodium channel β subunits and the development of neuropathic pain in humans. Small fiber neuropathy (SFN) often has no discernible cause, although mutations in the voltage-gated sodium channel α subunits have been implicated in some cases. We identify a patient suffering from SFN with a mutation in the auxiliary β2 subunit and no other discernible causes for SFN. Functional assessment confirms this mutation renders dorsal root ganglion neurons hyperexcitable and upregulates tetrodotoxin-sensitive sodium currents. This study strengthens a newly emerging link between sodium channel β2 subunit mutations and human pain disorders.
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http://dx.doi.org/10.1152/jn.00184.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461825PMC
September 2021

Prolonged distal motor latency of median nerve does not improve diagnostic accuracy for CIDP.

J Neurol 2021 Jun 26. Epub 2021 Jun 26.

Dysimmune Neuropathies Unit, Department of Systems Medicine, Tor Vergata University of Rome, Rome, Italy.

Compression of the median nerve at the carpal tunnel can give demyelinating features and result in distal motor latency (DML) prolongation fulfilling the EFNS/PNS demyelinating criteria for chronic inflammatory demyelinating polyneuropathy (CIDP). Accordingly, being carpal tunnel syndrome (CTS) common in the general population, the EFNS/PNS guidelines recommend excluding the DML of the median nerve when DML prolongation may be consistent with median neuropathy at the wrist from CTS. The main aims of this study were to verify whether the inclusion of DML of the median nerve (when consistent with CTS) could improve electrophysiological diagnostic accuracy for CIDP and if the median nerve at the carpal tunnel was more prone to demyelination. We analyzed electrophysiological data from 499 patients included consecutively into the Italian CIDP Database. According to the EFNS/PNS criteria, 352 patients had a definite, 10 a probable, and 57 a possible diagnosis of CIDP, while 80 were not fulfilling the diagnostic criteria. The inclusion of DML prolongation of median nerve did not improve significantly the diagnostic accuracy for CIDP; overall diagnostic class changed in 6 out of 499 patients (1.2%) and electrodiagnostic class of CIDP changed from not fulfilling to possible in only 2 patients (2.5% of not-fulfilling patients). In conclusion, we can infer that excluding DML prolongation of median nerve does not increase the risk of missing a diagnosis of CIDP thus corroborating the current EFNS/PNS criteria.
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http://dx.doi.org/10.1007/s00415-021-10672-wDOI Listing
June 2021

Dysregulation of Muscle-Specific MicroRNAs as Common Pathogenic Feature Associated with Muscle Atrophy in ALS, SMA and SBMA: Evidence from Animal Models and Human Patients.

Int J Mol Sci 2021 May 26;22(11). Epub 2021 May 26.

Neurology IV-Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133 Milan, Italy.

Motor neuron diseases (MNDs) are neurodegenerative disorders characterized by upper and/or lower MN loss. MNDs include amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). Despite variability in onset, progression, and genetics, they share a common skeletal muscle involvement, suggesting that it could be a primary site for MND pathogenesis. Due to the key role of muscle-specific microRNAs (myomiRs) in skeletal muscle development, by real-time PCR we investigated the expression of miR-206, miR-133a, miR-133b, and miR-1, and their target genes, in G93A-SOD1 ALS, Δ7SMA, and KI-SBMA mouse muscle during disease progression. Further, we analyzed their expression in serum of -mutated ALS, SMA, and SBMA patients, to demonstrate myomiR role as noninvasive biomarkers. Our data showed a dysregulation of myomiRs and their targets, in ALS, SMA, and SBMA mice, revealing a common pathogenic feature associated with muscle impairment. A similar myomiR signature was observed in patients' sera. In particular, an up-regulation of miR-206 was identified in both mouse muscle and serum of human patients. Our overall findings highlight the role of myomiRs as promising biomarkers in ALS, SMA, and SBMA. Further investigations are needed to explore the potential of myomiRs as therapeutic targets for MND treatment.
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http://dx.doi.org/10.3390/ijms22115673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198536PMC
May 2021

The neurophysiological lesson from the Italian CIDP database.

Neurol Sci 2021 May 21. Epub 2021 May 21.

Dysimmune Neuropathies Unit, Department of Systems Medicine, Tor Vergata University of Rome, Rome, Italy.

Introduction: Electrophysiological diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) may be challenging. Thus, with the aim ofproviding some practical advice in electrophysiological approach to a patient with suspected CIDP, we analyzed electrophysiological data from 499 patients enrolled inthe Italian CIDP Database.

Methods: We calculated the rate of each demyelinating feature, the rate of demyelinating features per nerve, the diagnostic rate for upper andlower limb nerves, and, using a ROC curve analysis, the diagnostic accuracy of each couple of nerves and each demyelinating feature, for every CIDP subtype.Moreover, we compared the electrophysiological data of definite and probable CIDP patients with those of possible and not-fulfilling CIDP patients, and by a logisticregression analysis, we estimated the odds ratio (OR) to make an electrophysiological diagnosis of definite or probable CIDP.

Results: The ulnar nerve had the highestrate of demyelinating features and, when tested bilaterally, had the highest diagnostic accuracy except for DADS in which peroneal nerves were the most informative.In possible and not-fulfilling CIDP patients, a lower number of nerves and proximal temporal dispersion (TD) measurements had been performed compared to definiteand probable CIDP patients. Importantly, OR for each tested motor nerve and each TD measurement was 1.59 and 1.33, respectively.

Conclusion: Our findingsdemonstrated that the diagnosis of CIDP may be missed due to inadequate or incomplete electrophysiological examination or interpretation. At the same time, thesedata taken together could be useful to draw a thoughtful electrophysiological approach to patients suspected of CIDP.
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http://dx.doi.org/10.1007/s10072-021-05321-zDOI Listing
May 2021

Persistence of Elevated Procalcitonin in a Patient with Coronavirus Disease 2019 Uncovered a Diagnosis of Medullary Thyroid Carcinoma.

AACE Clin Case Rep 2021 Sep-Oct;7(5):288-292. Epub 2021 May 12.

Division of Endocrinology and Metabolism, Department of Medicine, Hospital Santa Croce e Carle, Cuneo, Italy.

Objective: During the ongoing coronavirus disease 2019 pandemic, procalcitonin (PCT) levels have proven useful in assisting clinicians to diagnose bacterial superinfection. However, in the absence of signs of infection or at the resolution thereof, inappropriately and persistently high PCT levels may suggest and reveal the presence of other pathologies. We report a patient with severe acute respiratory syndrome coronavirus 2 pneumonia with initially elevated PCT levels that persisted during recovery, prompting the diagnosis of medullary thyroid carcinoma (MTC).

Methods: A 43-year-old man presented with a 2-day history of fever, sneezing, sore throat, and dry cough. His PCT was 94 ng/mL (normal value, 0.00-0.10 ng/mL), and he was positive for severe acute respiratory syndrome coronavirus 2 RNA.

Results: Empirical antibiotic therapy was administered for 7 days, but despite a clinical improvement, serum PCT remained high (84 ng/mL). Serum calcitonin (CTN) was 2120 pg/mL (normal, ≤12 pg/mL). Cytologic examination of thyroid nodules and CTN measurement of the aspiration needle washout confirmed MTC. The patient underwent total thyroidectomy with bilateral cervical lymph node dissection. Lowered CTN (986 pg/mL) and PCT (16 ng/mL) levels were observed 48 hours after surgery. A close follow-up was planned following the results of gene analysis.

Conclusion: PCT can be a useful biochemical marker of MTC suspicion in patients with inflammatory conditions and persistently elevated PCT, even after resolution. In our case, high levels of PCT in a patient with coronavirus disease 2019 pneumonia without signs of bacterial infection led to MTC diagnosis.
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http://dx.doi.org/10.1016/j.aace.2021.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113110PMC
May 2021

Prevalence, determinants and practical implications of inappropriate hospitalizations in older subjects: A prospective observational study.

Eur J Intern Med 2021 08 1;90:89-95. Epub 2021 May 1.

Section of Geriatrics, Department of Medical Sciences, AOU Città della Salute e della Scienza - Molinette, Turin, Italy.

In a context of high demand for hospital services among older people, we aimed to assess the rate and determinants of inappropriate hospitalizations of older patients, and to what extent they were associated with inappropriate hospital stay. This prospective observational multicentre study evaluated a random sample of consecutive patients aged ≥ 70 years accessing the Emergency Department (ED) of two Italian tertiary hospitals. A standardized comprehensive geriatric assessment was carried out in each patient, including the Blaylock Risk Assessment Screen Scale (BRASS) for identification of patients at risk of difficult discharge. Inappropriate hospitalization was defined by the ED physician when patients did not necessitate hospital-provided procedures but was due to social reasons or lack of an alternative care-setting. Among 1877 patients (median age 80.7 years, 50.1% male), with a high prevalence of functional dependence and social isolation (around 30% and 25%, respectively), 767 (40.9%) were hospitalized. Incidence of inappropriate hospitalization was 14.6% (95% CI 12.1%-17.1%) and was associated with moderate-high risk of difficult discharge at BRASS (OR = 1.98, 95% CI 1.16-3.39, p = 0.013) and the presence of dementia with behavioural disorders (OR = 1.79, 95% CI 1.10-2.91, p = 0.020). Compared with patients appropriately admitted, inappropriate hospitalizations had shorter length of hospital stay but accounted for 1059/9154 days of stay (11.6%). Inappropriate hospitalizations occurred in less than 15% of cases, mainly accounted for by patients no longer manageable at home, but contributed to the greatest proportion of inappropriate hospital stay. These findings highlight the need of implementing appropriate home-care services and ensuring rapid access to suitable care-facilities for community-dwelling frail older patients.
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http://dx.doi.org/10.1016/j.ejim.2021.04.006DOI Listing
August 2021

The unfolded protein response in amyotrophic later sclerosis: results of a phase 2 trial.

Brain 2021 Oct;144(9):2635-2647

3rd Neurology Unit and Motor Neuron Disease Centre, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan 20133, Italy.

Strong evidence suggests that endoplasmic reticulum stress plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through altered regulation of proteostasis. Robust preclinical findings demonstrated that guanabenz selectively inhibits endoplasmic reticulum stress-induced eIF2α-phosphatase, allowing misfolded protein clearance, reduces neuronal death and prolongs survival in in vitro and in vivo models. However, its safety and efficacy in patients with ALS are unknown. To address these issues, we conducted a multicentre, randomized, double-blind trial with a futility design. Patients with ALS who had displayed an onset of symptoms within the previous 18 months were randomly assigned in a 1:1:1:1 ratio to receive 64 mg, 32 mg or 16 mg of guanabenz or placebo daily for 6 months as an add-on therapy to riluzole. The purpose of the placebo group blinding was to determine safety but not efficacy. The primary outcome was the proportion of patients progressing to higher stages of disease within 6 months as measured using the ALS Milano-Torino staging system, compared with a historical cohort of 200 patients with ALS. The secondary outcomes were the rate of decline in the total revised ALS functional rating scale score, slow vital capacity change, time to death, tracheotomy or permanent ventilation and serum light neurofilament level at 6 months. The primary assessment of efficacy was performed using intention-to-treat analysis. The treatment arms using 64 mg and 32 mg guanabenz, both alone and combined, reached the primary hypothesis of non-futility, with the proportions of patients who progressed to higher stages of disease at 6 months being significantly lower than that expected under the hypothesis of non-futility and a significantly lower difference in the median rate of change in the total revised ALS functional rating scale score. This effect was driven by patients with bulbar onset, none of whom (0/18) progressed to a higher stage of disease at 6 months compared with those on 16 mg guanabenz (4/8; 50%), the historical cohort alone (21/49; 43%; P = 0.001) or plus placebo (25/60; 42%; P = 0.001). The proportion of patients who experienced at least one adverse event was higher in any guanabenz arm than in the placebo arm, with higher dosing arms having a significantly higher proportion of drug-related side effects and the 64 mg arm a significantly higher drop-out rate. The number of serious adverse events did not significantly differ between the guanabenz arms and the placebo. Our findings indicate that a larger trial with a molecule targeting the unfolded protein response pathway without the alpha-2 adrenergic related side-effect profile of guanabenz is warranted.
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http://dx.doi.org/10.1093/brain/awab167DOI Listing
October 2021

Hydropathicity-based prediction of pain-causing NaV1.7 variants.

BMC Bioinformatics 2021 Apr 23;22(1):212. Epub 2021 Apr 23.

Department of Toxicogenomics, Section Clinical Genomics, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands.

Background: Mutation-induced variations in the functional architecture of the NaV1.7 channel protein are causally related to a broad spectrum of human pain disorders. Predicting in silico the phenotype of NaV1.7 variant is of major clinical importance; it can aid in reducing costs of in vitro pathophysiological characterization of NaV1.7 variants, as well as, in the design of drug agents for counteracting pain-disease symptoms.

Results: In this work, we utilize spatial complexity of hydropathic effects toward predicting which NaV1.7 variants cause pain (and which are neutral) based on the location of corresponding mutation sites within the NaV1.7 structure. For that, we analyze topological and scaling hydropathic characteristics of the atomic environment around NaV1.7's pore and probe their spatial correlation with mutation sites. We show that pain-related mutation sites occupy structural locations in proximity to a hydrophobic patch lining the pore while clustering at a critical hydropathic-interactions distance from the selectivity filter (SF). Taken together, these observations can differentiate pain-related NaV1.7 variants from neutral ones, i.e., NaV1.7 variants not causing pain disease, with 80.5[Formula: see text] sensitivity and 93.7[Formula: see text] specificity [area under the receiver operating characteristics curve = 0.872].

Conclusions: Our findings suggest that maintaining hydrophobic NaV1.7 interior intact, as well as, a finely-tuned (dictated by hydropathic interactions) distance from the SF might be necessary molecular conditions for physiological NaV1.7 functioning. The main advantage for using the presented predictive scheme is its negligible computational cost, as well as, hydropathicity-based biophysical rationalization.
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http://dx.doi.org/10.1186/s12859-021-04119-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063372PMC
April 2021

Cognitive and behavioural impairment in amyotrophic lateral sclerosis: A landmark of the disease? A mini review of longitudinal studies.

Neurosci Lett 2021 05 15;754:135898. Epub 2021 Apr 15.

3rd Neurology Unit and Motor Neuron Diseases Centre, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy; Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Via Festa del Perdono 7, 20122, Milan, Italy.

Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease marked by progressive loss of motor abilities. Approximately half of patents with ALS experience cognitive (ALSci) or behavioural impairment (ALSbi) during the course of the disease, with a small percentage developing overt frontotemporal dementia (FTD). ALSci and/or ALSbi can occur simultaneously with motor neuron degeneration or develop in advanced stages of the disease, but it can even precede motor involvement in some cases, namely in ALS patients meeting criteria for FTD. Despite clear evidence that cognitive/behavioural impairment may appear early in the course of ALS, no prominent deterioration seems to occur with disease progression. Longitudinal studies have failed to reach conclusive results on the progression of cognitive and behavioural involvement in ALS. This may be due to some structural limitations of the studies, such as attrition rate, practice effect, short-time interval between neuropsychological assessments, but it can also be due to the heterogeneity of ALS phenotypes. The objective of this review is to provide a comprehensive and critical analysis of results of longitudinal studies highlighting cognitive and behavioural domains mainly affected by neurodegeneration pointing out the determinants that might be associate with the development and worsening of frontotemporal symptoms in ALS. At this regard, older age, rapidly progressing ALS, bulbar-onset, advanced disease stages are among factors mainly associated with cognitive and behavioural involvement. Moreover, the progression of cognitive and behavioural deficits seems to be not directly related to the slope of motor disability, thus suggesting the independence of neuropsychological and motor functional decline in ALS. Cognitive and motor involvement may indeed present with distinct trajectories suggesting a differential vulnerability of motor and non-motor cortical networks. In this scenario, determining the progression of extra-motor involvement in ALS may help refine understanding of the clinical implications of cognitive and behavioural abnormalities, and provide clues to the aetiology of the disease.
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http://dx.doi.org/10.1016/j.neulet.2021.135898DOI Listing
May 2021

Facial Onset Sensory and Motor Neuronopathy: New Cases, Cognitive Changes, and Pathophysiology.

Neurol Clin Pract 2021 Apr;11(2):147-157

Universitair Medisch Centrum Utrecht (EMJB, HSG, JI, MP, LHB, JHV, MAE), Department of Neurology, Utrecht, The Netherlands; Brighton and Sussex Medical School (AWB, ME, RB, PNL), Clinical Imaging Sciences Centre, Brighton, United Kingdom; Hurstwood Park Neurological Centre (AWB, ME, SJA, RB, AN), Haywards Heath, United Kingdom; Hospital Universitari i Politècnic La Fe (JFVC), ALS Unit, Department of Neurology, Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (JFVC), Madrid, Spain; Department of Neurology (JP), Rostock University Medical Center and German Center for Neurodegenerative Diseases (DZNE), Germany; Department of Neurology (CAV), Haukeland University Hospital and Department of Clinical Medicine, Bergen, Norway; Department of Neurology (JPF), Hospital Clínico Universitario de Santiago, Santiago, Spain; Department of Neurology (MPP, MAAA), Hospital Universitari de Bellvitge, Barcelona, Spain; ALS/MND Centre (EDB, GL), 3rd Neurology Unit, Fondazione IRCCS Institute Neurologico Carlo Besta, Milan, Italy; Department of Biomedical and Clinical Sciences "Luigi Sacco" (GL), University of Milan, Milan, Italy; Department of Neurology and Neurosurgery (WBVRP, PVSS, ASBO), Federal University of São Paulo (UNIFESP), São Paulo, Brazil; National Institutes of Health (CT), National Human Genome Research Institute, Bethesda, United States of America; Memorial Sloan Kettering Cancer Center (OH), NY; King's College Hospital NHS Foundation Trust (AA-C), London, United Kingdom; and Department of Neuroscience (PNL), Brighton and Sussex Medical School, Brighton, United Kingdom.

Purpose Of Review: To improve our clinical understanding of facial onset sensory and motor neuronopathy (FOSMN).

Recent Findings: We identified 29 new cases and 71 literature cases, resulting in a cohort of 100 patients with FOSMN. During follow-up, cognitive and behavioral changes became apparent in 8 patients, suggesting that changes within the spectrum of frontotemporal dementia (FTD) are a part of the natural history of FOSMN. Another new finding was chorea, seen in 6 cases. Despite reports of autoantibodies, there is no consistent evidence to suggest an autoimmune pathogenesis. Four of 6 autopsies had TAR DNA-binding protein (TDP) 43 pathology. Seven cases had genetic mutations associated with neurodegenerative diseases.

Summary: FOSMN is a rare disease with a highly characteristic onset and pattern of disease progression involving initial sensory disturbances, followed by bulbar weakness with a cranial to caudal spread of pathology. Although not conclusive, the balance of evidence suggests that FOSMN is most likely to be a TDP-43 proteinopathy within the amyotrophic lateral sclerosis-FTD spectrum.
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http://dx.doi.org/10.1212/CPJ.0000000000000834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032419PMC
April 2021

SARS-COV-2 comorbidity network and outcome in hospitalized patients in Crema, Italy.

PLoS One 2021 25;16(3):e0248498. Epub 2021 Mar 25.

Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy.

We report onset, course, correlations with comorbidities, and diagnostic accuracy of nasopharyngeal swab in 539 individuals suspected to carry SARS-COV-2 admitted to the hospital of Crema, Italy. All individuals underwent clinical and laboratory exams, SARS-COV-2 reverse transcriptase-polymerase chain reaction on nasopharyngeal swab, and chest X-ray and/or computed tomography (CT). Data on onset, course, comorbidities, number of drugs including angiotensin converting enzyme (ACE) inhibitors and angiotensin-II-receptor antagonists (sartans), follow-up swab, pharmacological treatments, non-invasive respiratory support, ICU admission, and deaths were recorded. Among 411 SARS-COV-2 patients (67.7% males) median age was 70.8 years (range 5-99). Chest CT was performed in 317 (77.2%) and showed interstitial pneumonia in 304 (96%). Fatality rate was 17.5% (74% males), with 6.6% in 60-69 years old, 21.1% in 70-79 years old, 38.8% in 80-89 years old, and 83.3% above 90 years. No death occurred below 60 years. Non-invasive respiratory support rate was 27.2% and ICU admission 6.8%. Charlson comorbidity index and high C-reactive protein at admission were significantly associated with death. Use of ACE inhibitors or sartans was not associated with outcomes. Among 128 swab negative patients at admission (63.3% males) median age was 67.7 years (range 1-98). Chest CT was performed in 87 (68%) and showed interstitial pneumonia in 76 (87.3%). Follow-up swab turned positive in 13 of 32 patients. Using chest CT at admission as gold standard on the entire study population of 539 patients, nasopharyngeal swab had 80% accuracy. Comorbidity network analysis revealed a more homogenous distribution 60-40 aged SARS-COV-2 patients across diseases and a crucial different interplay of diseases in the networks of deceased and survived patients. SARS-CoV-2 caused high mortality among patients older than 60 years and correlated with pre-existing multiorgan impairment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248498PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993836PMC
April 2021

Non-extensitivity and criticality of atomic hydropathicity around a voltage-gated sodium channel's pore: a modeling study.

J Biol Phys 2021 03 18;47(1):61-77. Epub 2021 Mar 18.

Department of Data Science and Knowledge Engineering, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands.

Voltage-gated sodium channels (NavChs) are pore-forming membrane proteins that regulate the transport of sodium ions through the cell membrane. Understanding the structure and function of NavChs is of major biophysical, as well as clinical, importance given their key role in cellular pathophysiology. In this work, we provide a computational framework for modeling system-size-dependent, i.e., cumulative, atomic properties around a NavCh's pore. We illustrate our methodologies on the bacterial NavAb channel captured in a closed-pore state where we demonstrate that the atomic environment around its pore exhibits a bi-phasic spatial organization dictated by the structural separation of the pore domains (PDs) from the voltage-sensing domains (VSDs). Accordingly, a mathematical model describing packing of atoms around NavAb's pore is constructed that allows-under certain conservation conditions-for a power-law approximation of the cumulative hydropathic dipole field effect acting along NavAb's pore. This verified the non-extensitivity hypothesis for the closed-pore NavAb channel and revealed a long-range hydropathic interactions law regulating atom-packing around the NavAb's selectivity filter. Our model predicts a PDs-VSDs coupling energy of [Formula: see text] kcal/mol corresponding to a global maximum of the atom-packing energy profile. Crucially, we demonstrate for the first time how critical phenomena can emerge in a single-channel structure as a consequence of the non-extensive character of its atomic porous environment.
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http://dx.doi.org/10.1007/s10867-021-09565-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981368PMC
March 2021

Reply to "Takotsubo Syndrome in Patients with COVID-19: a Systematic Review of Published Cases".

SN Compr Clin Med 2021 Jan 3:1-2. Epub 2021 Jan 3.

Division of Emergency Medicine, A.O. Santa Croce e Carle, University of Turin, via Michele Coppino 26, 12100 Cuneo, Italy.

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http://dx.doi.org/10.1007/s42399-020-00716-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778717PMC
January 2021

Corneal confocal microscopy compared with quantitative sensory testing and nerve conduction for diagnosing and stratifying the severity of diabetic peripheral neuropathy.

BMJ Open Diabetes Res Care 2020 12;8(2)

Division of Cardiovascular Sciences, Cardiac Centre, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK

Introduction: Diabetic neuropathy can be diagnosed and assessed using a number of techniques including corneal confocal microscopy (CCM).

Research Design And Methods: We have undertaken quantitative sensory testing, nerve conduction studies and CCM in 143 patients with type 1 and type 2 diabetes without neuropathy (n=51), mild neuropathy (n=47) and moderate to severe neuropathy (n=45) and age-matched controls (n=30).

Results: Vibration perception threshold (p<0.0001), warm perception threshold (WPT) (p<0.001), sural nerve conduction velocity (SNCV) (p<0.001), corneal nerve fiber density (CNFD) (p<0.0001), corneal nerve branch density (CNBD) (p<0.0001), corneal nerve fiber length (CNFL) (p=0.002), inferior whorl length (IWL) (p=0.0001) and average nerve fiber length (ANFL) (p=0.0001) showed a progressive abnormality with increasing severity of diabetic neuropathy. Receiver operating characteristic curve analysis for the diagnosis of diabetic neuropathy showed comparable performance in relation to the area under the curve (AUC) but differing sensitivities and specificities for vibration perception threshold (AUC 0.79, sensitivity 55%, specificity 90%), WPT (AUC 0.67, sensitivity 50%, specificity 76%), cold perception threshold (AUC 0.64, sensitivity 80%, specificity 47%), SNCV (AUC 0.70, sensitivity 76%, specificity 54%), CNFD (AUC 0.71, sensitivity 58%, specificity 83%), CNBD (AUC 0.70, sensitivity 69%, specificity 65%), CNFL (AUC 0.68, sensitivity 64%, specificity 67%), IWL (AUC 0.72, sensitivity 70%, specificity 65%) and ANFL (AUC 0.72, sensitivity 71%, specificity 66%).

Conclusion: This study shows that CCM identifies early and progressive corneal nerve loss at the inferior whorl and central cornea and has comparable utility with quantitative sensory testing and nerve conduction in the diagnosis of diabetic neuropathy.
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http://dx.doi.org/10.1136/bmjdrc-2020-001801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754626PMC
December 2020

Two independent mouse lines carrying the Nav1.7 I228M gain-of-function variant display dorsal root ganglion neuron hyperexcitability but a minimal pain phenotype.

Pain 2021 06;162(6):1758-1770

Department of Neurology, Yale University School of Medicine, New Haven, CT, United States.

Abstract: Small-fiber neuropathy (SFN), characterized by distal unmyelinated or thinly myelinated fiber loss, produces a combination of sensory dysfunction and neuropathic pain. Gain-of-function variants in the sodium channel Nav1.7 that produce dorsal root ganglion (DRG) neuron hyperexcitability are present in 5% to 10% of patients with idiopathic painful SFN. We created 2 independent knock-in mouse lines carrying the Nav1.7 I228M gain-of-function variant, found in idiopathic SFN. Whole-cell patch-clamp and multielectrode array recordings show that Nav1.7 I228M knock-in DRG neurons are hyperexcitable compared with wild-type littermate-control neurons, but despite this, Nav1.7 I228M mice do not display mechanical or thermal hyperalgesia or intraepidermal nerve fiber loss in vivo. Therefore, although these 2 Nav1.7 I228M knock-in mouse lines recapitulate the DRG neuron hyperexcitability associated with gain-of-function mutations in Nav1.7, they do not recapitulate the pain or neuropathy phenotypes seen in patients. We suggest that the relationship between hyperexcitability in sensory neurons and the pain experienced by these patients may be more complex than previously appreciated and highlights the challenges in modelling channelopathy pain disorders in mice.
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http://dx.doi.org/10.1097/j.pain.0000000000002171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119301PMC
June 2021

Cognitive reserve is associated with altered clinical expression in amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2021 05 2;22(3-4):237-247. Epub 2020 Dec 2.

3rd Neurology Unit and Motor Neuron Diseases Centre, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy and.

: Long-term life experiences, such as education, occupational attainment, leisure activities, and bilingualism, have been considered proxies of cognitive reserve (CR). In neurodegenerative disease, CR is considered as a modulator of a more favorable cognitive trajectory and motor functions. Our study investigated the role of CR on cognitive and motor involvement in a large cohort of incident patients with amyotrophic lateral sclerosis (ALS). : Cognition assessment and clinical and demographic information were obtained in 101 incident ALS patients. CR was measured based on years of education, occupational attainment, amount of leisure activities, and bilingualism. Correlation and regression analyses were performed to test the association between CR and the clinical expression of ALS. : We found that all proxies of CR were positively associated with executive functions, verbal fluency, and memory domains. Motor impairment was inversely related to educational level and occupational attainment. Regression analysis documented the association between CR and cognitive performances in all patients and the predictive role of CR in modulating motor functional disability in patients with bulbar-onset. : Our findings showed that CR mediates the extent of cognitive decline and that of functional bulbar impairment, suggesting that the concept of reserve applied to ALS should encompass cognitive and motor domains.
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http://dx.doi.org/10.1080/21678421.2020.1849306DOI Listing
May 2021

Life with chronic pain during COVID-19 lockdown: the case of patients with small fibre neuropathy and chronic migraine.

Neurol Sci 2021 Feb 17;42(2):389-397. Epub 2020 Nov 17.

Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy.

Objective: We aimed at investigating the impact of COVID-19-related distress on patients with chronic pain, highlighting the effects of changes in individual habits and public health care reconfiguration on physical and psychological health.

Methods: During the pandemic, 80 participants (25 patients with small fibre neuropathy (SFN), 42 patients with chronic migraine (CM) and 13 patients' healthy family members (HFM)) were asked to evaluate their COVID-19 complains, changes in habits and clinical management, behaviour, mood, loneliness, quality of life (QoL), physical and mental health and coping strategies. Data were analysed by Spearman rho correlations and Mann-Whitney U tests.

Results: Patients had lower QoL, lower physical health and higher catastrophizing attitude towards pain than HFM. During the pandemic, SFN patients referred greater decline in clinical symptoms, worries about contagion and discomfort for disease management changes than CM patients. In the SFN group, the higher levels of disability were associated with suffering from changes in neurologist-patient relationship. CM patients complained of agitation/anxiety that was related to feelings of loneliness, depressive mood and catastrophism.

Discussion: Despite similar complains of change in habits and worries about COVID-19 pandemic, SFN and CM patients had distinct reactions. In SFN patients, pandemic distress impacted on physical health with worsening of clinical conditions, especially suffering from changes in their care. In CM patients, pandemic distress affected behaviour, mainly with psychological frailty. This suggests the need to customize public health care for patients with distinct chronic pain conditions.
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http://dx.doi.org/10.1007/s10072-020-04890-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670980PMC
February 2021

Diagnosis of Neuropathy and Risk Factors for Corneal Nerve Loss in Type 1 and Type 2 Diabetes: A Corneal Confocal Microscopy Study.

Diabetes Care 2021 01 3;44(1):150-156. Epub 2020 Nov 3.

Institute of Cardiovascular Sciences, Cardiac Centre, Faculty of Medical and Human Sciences, The University of Manchester and NIHR/Wellcome Trust Clinical Research Facility, Manchester, U.K.

Objective: To assess the diagnostic utility of corneal confocal microscopy (CCM) for diabetic peripheral neuropathy (DPN) and the risk factors for corneal nerve loss.

Research Design And Methods: A total of 490 participants, including 72 healthy control subjects, 149 with type 1 diabetes, and 269 with type 2 diabetes, underwent detailed assessment of peripheral neuropathy and CCM in relation to risk factors.

Results: Corneal nerve fiber density (CNFD) ( < 0.0001 and < 0.0001), corneal nerve fiber branch density (CNBD) ( < 0.0001 and < 0.0001), and corneal nerve fiber length (CNFL) ( < 0.0001 and = 0.02) were significantly lower in patients with type 1 and type 2 diabetes compared with control subjects. CNFD ( < 0.0001), CNBD ( < 0.0001), and CNFL ( < 0.0001) were lower in type 1 diabetes compared with type 2 diabetes. Receiver operating characteristic curve analysis for the diagnosis of DPN demonstrated a good area under the curve for CNFD of 0.81, CNBD of 0.74, and CNFL of 0.73. Multivariable regression analysis showed a significant association among reduced CNFL with age (β = -0.27, = 0.007), HbA (β = -1.1; = 0.01), and weight (β = -0.14; = 0.03) in patients with type 2 diabetes and with duration of diabetes (β = -0.13; = 0.02), LDL cholesterol (β = 1.8, = 0.04), and triglycerides (β = -2.87; = 0.009) in patients with type 1 diabetes.

Conclusions: CCM identifies more severe corneal nerve loss in patients with type 1 diabetes compared with type 2 diabetes and shows good diagnostic accuracy for DPN. Furthermore, the risk factors for a reduction in corneal nerve fiber length differ between type 1 and type 2 diabetes.
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http://dx.doi.org/10.2337/dc20-1482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783929PMC
January 2021

Computational pipeline to probe NaV1.7 gain-of-function variants in neuropathic painful syndromes.

Sci Rep 2020 10 21;10(1):17930. Epub 2020 Oct 21.

Dipartimento di Scienze Ambientali, Informatica e Statistica, Universitá Ca' Foscari Venezia, Venezia-Mestre, Italy.

Applications of machine learning and graph theory techniques to neuroscience have witnessed an increased interest in the last decade due to the large data availability and unprecedented technology developments. Their employment to investigate the effect of mutational changes in genes encoding for proteins modulating the membrane of excitable cells, whose biological correlates are assessed at electrophysiological level, could provide useful predictive clues. We apply this concept to the analysis of variants in sodium channel NaV1.7 subunit found in patients with chronic painful syndromes, by the implementation of a dedicated computational pipeline empowering different and complementary techniques including homology modeling, network theory, and machine learning. By testing three templates of different origin and sequence identities, we provide an optimal condition for its use. Our findings reveal the usefulness of our computational pipeline in supporting the selection of candidates for cell electrophysiology assay and with potential clinical applications.
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http://dx.doi.org/10.1038/s41598-020-74591-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578092PMC
October 2020

Idiopathic distal sensory polyneuropathy: ACTTION diagnostic criteria.

Neurology 2020 12 14;95(22):1005-1014. Epub 2020 Oct 14.

From the Beth Israel Deaconess Medical Center (R.F., C.G.), Harvard Medical School, MA; University of Rochester Medical Center (J.S.G., R.H.D., D.N.H.), Rochester, NY; Department of Neurology (C.G.F.), School of Mental Health and Neuroscience, Maastricht University Medical Center+, Maastricht, the Netherlands; Department of Anesthesiology (S.H.), Washington University in St. Louis School of Medicine, St. Louis, MO; Neuroalgology Unit (G.L.), Fondazione IRCCS Istituto Neurologico "Carlo Besta," Milan, Italy; Department of Biomedical and Clinical Sciences "Luigi Sacco" (G.L.), University of Milan,Milan, Italy; Phoenix Neurological Associates (T.L.), Phoenix, AZ; Weill Cornell Medicine-Qatar (R.A.M.), Qatar Foundation, Education City, Doha, Qatar; University of Utah (J.R.S.), Salt Lake City, UT; Virginia Commonwealth University (A.G.S.), Richmond, VA; Biogen (J.B.), Cambridge, MA; University of Michigan (E.F.), Ann Arbor, MI; Johns Hopkins School of Medicine (A.H., M.P.), Baltimore, MD; University of Vermont (N.K.), Burlington, VT; Chromocell Corp (H.M.), North Brunswick, NJ; Harvard Medical School (A.L.O.), Boston, MA; Departments of Neurology and Medicine (A.P.), and Vanderbilt Heart and Vascular Institute, Nashville, TN; NuFactor Specialty Pharmacy (E.R.), Temecula, CA; University of Maryland (J.W.R.), Baltimore, MD; Aptinyx (S.S.), INC., Evanston. IL; Amgen (D.S.), Cambridge, MA; University of Haifa (R.T.), Haifa, Israel; and University of Würzburg (N.Ü.), Würzburg, Germany.

Objective: To present standardized diagnostic criteria for idiopathic distal sensory polyneuropathy (iDSP) and its subtypes: idiopathic mixed fiber sensory neuropathy (iMFN), idiopathic small fiber sensory neuropathy (iSFN), and idiopathic large fiber sensory neuropathy (iLFN) for use in research.

Methods: The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION) public-private partnership with the Food and Drug Administration convened a meeting to develop consensus diagnostic criteria for iMFN, iSFN, and iLFN. After background presentations, a collaborative, iterative approach was used to develop expert consensus for new criteria.

Results: An iDSP diagnosis requires at least 1 small fiber (SF) or large fiber (LF) symptom, at least 1 SF or LF sign, abnormalities in sensory nerve conduction studies (NCS) or distal intraepidermal nerve fiber density (IENFD), and exclusion of known etiologies. An iMFN diagnosis requires that at least 1 of the above clinical features is SF and 1 clinical feature is LF with abnormalities in sensory NCS or IENFD. Diagnostic criteria for iSFN require at least 1 SF symptom and at least 1 SF sign with abnormal IENFD, normal sensory NCS, and the absence of LF symptoms and signs. Diagnostic criteria for iLFN require at least 1 LF symptom and at least 1 LF sign with normal IENFD, abnormal sensory NCS, and absence of SF symptoms and signs.

Conclusion: Adoption of these standardized diagnostic criteria will advance research and clinical trials and spur development of novel therapies for iDSPs.
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http://dx.doi.org/10.1212/WNL.0000000000010988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734920PMC
December 2020

Syncope at SARS-CoV-2 onset.

Auton Neurosci 2020 12 21;229:102734. Epub 2020 Sep 21.

Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy; Department of Clinical Neurosciences, Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy. Electronic address:

We describe clinical and laboratory findings in 35 patients tested positive for SARS-CoV-2 by reverse transcriptase-polymerase chain reaction on nasopharyngeal swab experiencing one or multiple syncope at disease onset. Clinical neurologic and cardiologic examination, and electrocardiographic findings were normal. Chest computed tomography showed findings consistent with interstitial pneumonia. Arterial blood gas analysis showed low pO, pCO, and ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO/FiO) indicating hypocapnic hypoxemia. Patients who presented with syncope showed significantly lower heart rate as compared to 68 SARS-CoV-2 positive that did not. Such poorer than expected compensatory heart rate increase may have led to syncope based on individual susceptibility. We speculate that SARS-CoV-2 could have caused angiotensin-converting enzyme-2 (ACE2) receptor internalization in the nucleus of the solitary tract and other midbrain nuclei, impairing baroreflex and chemoreceptor response, and inhibiting the compensatory tachycardia during acute hypocapnic hypoxemia.
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http://dx.doi.org/10.1016/j.autneu.2020.102734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505046PMC
December 2020
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