Showing papers by "Raffaele Dubbioso published in 2020"

The Italian multicenter experience with edaravone in amyotrophic lateral sclerosis

Abstract: The aim of the study is to analyze the ALS disease progression and respiratory function of Italian patients treated with edaravone (EVN), as well as the adherence to, and the effects of, the therapy We performed an observational study of patients treated with EVN from May 2017 to May 2019, in 39 Italian ALS Centers Taking into account ALS patients with at least 12 months of EVN treatment, we compared the decline of ALSFRS-R and FVC with a group of matched historical controls from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, using both descriptive and survival analysis approaches A total of 331 ALS Italian patients treated with EVN and 290 matched historical controls were recruited in this study No significant differences on disease progression or respiratory function were found comparing the two cohorts in both descriptive and survival analyses The EVN treatment was overall well tolerated The study showed that EVN treatment was well tolerated No significant differences were reported in ALS patients treated and not treated with EVN, in terms of both disease progression and respiratory function These findings prove that further studies are required to better clarify whether EVN could be considered an effective treatment for ALS disease

The emotional impact of COVID-19 outbreak in amyotrophic lateral sclerosis patients: evaluation of depression, anxiety and interoceptive awareness.

Abstract: Dear Editor, Infectious disease outbreaks such as COVID-19, as well as other public health events, can cause emotional distress and anxiety even in people not at high risk of getting sick [1–3]. People with neurodegenerative diseases, particularly those associated with impaired respiratory function, are at risk of severe complications and more likely to report negative mental health outcomes. In this context, amyotrophic lateral sclerosis (ALS) patients are particularly vulnerable to either medical complications of infection or emotional distress in terms of anxiety and depression. Importantly, anxiety and depression have been already reported in 30% [4] and 44% [4] of these patients, respectively. The percentages of these psychiatric symptoms are above the rates of general population and are more severe in patients who present concomitant cognitive and behavioural dysfunctions or express a wish to die [5]. Additionally, studies have shown that emotional distress, such as anxiety and depression, seems to be strongly linked to inner bodily sensations, the so-called interoceptive awareness or self-awareness [6]. Lastly, ALS patients may also exhibit maladaptive coping strategies [7], which make them even more susceptible to detrimental neuropsychiatric effects of the outbreak. On these bases, we aimed to investigate the emotional impact of COVID-19 outbreak in a sample of ALS by assessing anxiety, depression symptoms and self-awareness and comparing such results with those obtained by their caregivers. This study was conducted on a group of patients with definite or probable diagnosis of ALS (n = 23; age (years) = 61.91 ± 2.08; sex (M/F) = 13/10; education level (years) = 11.30 ± 0.79; disease duration (years) = 2.99 ± 0.32), whose cognitive and psychopathological baseline data were collected before the outbreak (January and February 2020). During the outbreak, these patients completed a follow-up assessment between the 20th of March and 5th of April, by means of an online interview and with the same trained interviewers (F.P.A. and M.S.) of baseline data. Scales were sent to the patients in advance via mail to prepare them for the interviews and consisted of Hamilton Depression Scale (HDS) [8] and Beck Anxiety Inventory (BAI) [9] to identify clinically relevant depression and anxiety by measuring the severity of symptoms and the Self-Awareness Questionnaire (SAQ) to assess the experience and frequency of internal bodily feelings, evaluating both somatosensory and visceral sensations [10]. During the outbreak, these psychological scales were also applied to ALS patients’ caregivers as control group (n = 21, age (years) = 57.9 ± 3.42, sex (M/F) = 10/11, education (years) = 12.10 ± 0.76). Demographic data (age, sex and education) did not significantly differ between patients and caregivers (all p > 0.45). Neither patients nor caregivers got infected with the virus. At baseline, cognitive assessment of patients showed mild cognitive impairment involving executive (ALS-eci) or nonexecutive (i.e. memory) functions (ALS-neci) in 73.91% (17/ 23) as assessed by the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) [11]. Motor dysfunction evaluated with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) did not significantly worsen during the follow-up (before outbreak, average ± standard deviation: 32.35 ± 7.38, range 21–45; during outbreak, average ± standard deviation: 31.83 ± 8.53, range 16–45, p = 0.47). Moreover, a paired t test showed that in patients’ sample scores on depression, anxiety and self-awareness tests were Natascia De Lucia and Francesco Pio Ausiello equally contributing as first authors

Dealing with immune-mediated neuropathies during COVID-19 outbreak: practical recommendations from the task force of the Italian Society of Neurology (SIN), the Italian Society of Clinical Neurophysiology (SINC) and the Italian Peripheral Nervous System Association (ASNP).

Abstract: Since December 2019 when the novel coronavirus, currently named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), outbreak has been described in Wuhan, Hubei region, China, the situation has dramatically evolved [1–4]. The World Health Organization (WHO) has recently declared coronavirus disease 2019 (COVID-19) a public health emergency of international concern [5]. The pandemic, as declared by the WHO, has led to > 2.000.000 cases and > 130.000 COVID-19-related deaths worldwide reported as of April 2020, in all continents spreading on a logarithmic scale in Europe and the USA. Italy is currently one of the most affected countries together with the USA, Spain, France and Germany. There are no known proven therapies for treating this virus and no vaccine to prevent the infection at this time. As the rate of hospitalization is very high among symptomatic cases, with an increased need to have access to intensive care units (ICUs) and mortality in the order of 3% globally [3], European hospitals have been forced to intensively reduce elective activities, including outpatient activity, in order to face the high numbers of admissions. In addition, action by governments to contain the outbreak and slowdown the spread of COVID-19 has restricted regions and nations by reducing their mobility within countries and across borders. Symptoms of COVID-19 are variable but typically include fever, cough, respiratory symptoms and diarrhoea. Severity ranges frommild to severe and the virus may lead to pneumonia, acute respiratory distress syndrome and death. It has been reported that more than one-third of patients experienced various neurological symptoms including the involvement of central nervous system (i.e. dizziness, headache, impaired consciousness, ataxia and epilepsy), peripheral nervous

Neurophysiological Signatures of Motor Impairment in Patients with Rett Syndrome.

Abstract: Objective Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder due to pathogenic mutations in the MECP2 gene. Motor impairment constitutes the core diagnostic feature of RTT. Preclinical studies have consistently demonstrated alteration of excitation/inhibition (E/I) balance and aberrant synaptic plasticity at the cortical level. We aimed to understand neurobiological mechanisms underlying motor deficit by assessing in vivo synaptic plasticity and E/I balance in the primary motor cortex (M1). Methods In 14 patients with typical RTT, 9 epilepsy control patients, and 11 healthy controls, we applied paired-pulse transcranial magnetic stimulation (TMS) protocols to evaluate the excitation index, a biomarker reflecting the contribution of inhibitory and facilitatory circuits in M1. Intermittent TMS-theta burst stimulation was used to probe long-term potentiation (LTP)-like plasticity in M1. Motor impairment, assessed by ad hoc clinical scales, was correlated with neurophysiological metrics. Results RTT patients displayed a significant increase of the excitation index (p = 0.003), as demonstrated by the reduction of short-interval intracortical inhibition and increase of intracortical facilitation, suggesting a shift toward cortical excitation likely due to GABAergic dysfunction. Impairment of inhibitory circuits was also confirmed by the reduction of long-interval intracortical inhibition (p = 0.002). LTP-like plasticity in M1 was abolished (p = 0.008) and scaled with motor disability (all p = 0.003). Interpretation TMS is a method that can be used to assess cortical motor function in RTT patients. Our findings support the introduction of TMS measures in clinical and research settings to monitor the progression of motor deficit and response to treatment. ANN NEUROL 2020;87:763-773.

Brain Plasticity in Charcot-Marie-Tooth Type 1A Patients? A Combined Structural and Diffusion MRI Study.

Abstract: Central nervous system involvement has been described in peripheral neuropathies, including different forms of Charcot-Marie-Tooth (CMT) disease. The aim of our study was to systematically investigate possible brain structural modifications in CMT1A patients, using volumetric MRI, and diffusion tensor imaging (DTI). In this prospective cross-sectional study, from May 2017 to May 2019, we acquired 3T MRI brain scans of genetically confirmed CMT1A patients and age- and sex-comparable healthy controls. Patients also underwent clinical and electrophysiological examinations assessing motor and sensory domains. Voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) analyses were performed using a non-parametric approach based on permutations, including age and sex (and total intracranial volume for VBM) as nuisance covariates. When between-group differences emerged at VBM or TBSS analyses, the first eigenvariate was extracted from the cluster and its age- and sex-adjusted standardized residuals tested for correlation with clinical and electrophysiological variables. Twenty CMT1A patients (34.5 ± 11.1 years; M/F:11/9) were enrolled, along with 20 healthy controls (30.1 ± 10.2 years; M/F:11/9). The VBM analysis revealed clusters of significantly increased GM volume in CMT1A patients compared to healthy controls, encompassing the bilateral cerebellar lobules III-VI and the left hippocampus (all ps = 0.04), with no differences in terms of DTI metrics at the TBSS analysis. A negative correlation (r = -0.502, p = 0.03) emerged between ulnar compound motor action potential and the z-scores corresponding to the right cerebellar cluster of augmented GM volume. Our data show evidence of structural reorganization in the brain of CMT1A patients, possibly reflecting neural plasticity mechanisms in response to peripheral nerve pathology and modulating the effect of axonal degeneration on functional impairment.

Different cortical excitability profiles in hereditary brain iron and copper accumulation

Abstract: Neurodegeneration with brain iron accumulation (NBIA) and Wilson’s disease (WD) is considered the prototype of neurodegenerative disorders characterised by the overloading of iron and copper in the central nervous system. Growing evidence has unveiled the involvement of these metals in brain cortical neurotransmission. Aim of this study was to assess cortical excitability profile due to copper and iron overload. Three patients affected by NBIA, namely two patients with a recessive hereditary parkinsonism (PARK9) and one patient with aceruloplasminemia and 7 patients with neurological WD underwent transcranial magnetic stimulation (TMS) protocols to assess cortical excitability. Specifically, we evaluated the motor thresholds that reflect membrane excitability related to the voltage-gated sodium channels in the neurons of the motor system and the ease of activation of motor cortex via glutamatergic networks, and ad hoc TMS protocols to probe inhibitory-GABAergic (short interval intracortical inhibition, SICI; short-latency afferent inhibition, SAI; cortical silent period, CSP) and excitatory intracortical circuitry (intracortical facilitation, ICF). Patients with NBIA exhibited an abnormal prolongation of CSP respect to HC and WD patients. On the contrary, neurological WD displayed higher motor thresholds and reduced CSP and SICI. Hereditary conditions due to overload of copper and iron exhibited peculiar cortical excitability profiles that can help during differential diagnosis between these conditions. Moreover, such results can give us more clues about the role of metals in acquired neurodegenerative disorders, such as Parkinson disease, Alzheimer disease, and multiple sclerosis.

Probing Context-Dependent Modulations of Ipsilateral Premotor-Motor Connectivity in Relapsing-Remitting Multiple Sclerosis

Abstract: Objective: We employed dual-site TMS to test whether ipsilateral functional premotor-motor connectivity is altered in relapsing-remitting Multiple Sclerosis (RR-MS) and is related to central fatigue. Methods: Twelve patients with RR-MS and 12 healthy controls performed a visually cued Pinch-NoPinch task with their right hand. During the reaction time (RT) period of Pinch and No-Pinch trials, single-site TMS was applied to the left primary motor cortex (M1) or dual-site TMS was applied to the ipsilateral dorsal premotor cortex (PMd) and to M1. We traced context-dependent changes of corticospinal excitability and premotor-motor connectivity by measuring Motor-Evoked Potentials (MEPs) in the right first dorsal interosseus muscle. Central fatigue was evaluated with the Fatigue Scale for Motor and Cognitive Functions (FSMS). Results: In both groups, single-pulse TMS revealed a consistent increase in mean MEP amplitude during the Reaction Time (RT) period relative to a resting condition. Task-related corticospinal facilitation increased toward the end of the RT period in Pinch trials, while it decreased in No-Pinch trials. Again, this modulation of MEP facilitation by trial type was comparable in patients and controls. Dual-site TMS showed no significant effect of a conditioning PMd pulse on ipsilateral corticospinal excitability during the RT period in either group. However, patients showed a trend toward a relative attenuation in functional PMd-M1 connectivity at the end of the RT period in No-Pinch trials, which correlated positively with the severity of motor fatigue (r = 0.69; p = 0.007). Conclusions: Dynamic regulation of corticospinal excitability and ipsilateral PMd-M1 connectivity is preserved in patients with RR-MS. MS-related fatigue scales positively with an attenuation of premotor-to-motor functional connectivity during cued motor inhibition. Significance: The temporal, context-dependent modulation of ipsilateral premotor-motor connectivity, as revealed by dual-site TMS of ipsilateral PMd and M1, constitutes a promising neurophysiological marker of fatigue in MS.

Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients.

Abstract: Background: Four main clinical phenotypes have been traditionally described in patients mutated in SCN4A, including sodium-channel myotonia (SCM), paramyotonia congenita (PMC), Hypokaliemic type II (HypoPP2), and Hyperkaliemic/Normokaliemic periodic paralysis (HyperPP/NormoPP); in addition, rare phenotypes associated with mutations in SCN4A are congenital myasthenic syndrome and congenital myopathy. However, only scarce data have been reported in literature on large patient cohorts including phenotypes characterized by myotonia and episodes of paralysis. Methods: We retrospectively investigated clinical and molecular features of 80 patients fulfilling the following criteria: (1) clinical and neurophysiological diagnosis of myotonia, or clinical diagnosis of PP, and (2) presence of a pathogenic SCN4A gene variant. Patients presenting at birth with episodic laryngospasm or congenital myopathy-like phenotype with later onset of myotonia were considered as neonatal SCN4A. Results: PMC was observed in 36 (45%) patients, SCM in 30 (37.5%), Hyper/NormoPP in 7 (8.7%), HypoPP2 in 3 (3.7%), and neonatal SCN4A in 4 (5%). The median age at onset was significantly earlier in PMC than in SCM (p < 0.01) and in Hyper/NormoPP than in HypoPP2 (p = 0.02). Cold-induced myotonia was more frequently observed in PMC (n = 34) than in SCM (n = 23) (p = 0.04). No significant difference was found in age at onset of episodes of paralysis among PMC and PP or in frequency of permanent weakness between PP (n = 4), SCM (n = 5), and PMC (n = 10). PP was more frequently associated with mutations in the S4 region of the NaV1.4 channel protein compared to SCM and PMC (p < 0.01); mutations causing PMC were concentrated in the C-terminal region of the protein, while SCM-associated mutations were detected in all the protein domains. Conclusions: Our data suggest that skeletal muscle channelopathies associated with mutations in SCN4A represent a continuum in the clinical spectrum.

Multimodal finger-printing of the human precentral cortex forming the motor hand knob

Abstract: Transcranial magnetic stimulation (TMS) of the precentral hand knob can evoke motor evoked potentials (MEP) in contralateral hand muscles. Biophysical modelling points to the dorsal premotor cortex (PMd) in the superficial crown-lip region as primary site of TMS-induced neuronal excitation. Here, we used a sulcus-aligned MRI-informed TMS mapping approach to determine the optimal site (hotspot) for evoking MEPs in the precentral hand knob. Individual precentral hotspot location varied along the rostro-caudal axis. Individuals with a more rostral location had longer MEP latencies. Spatiotemporal hotspot rostrality was associated with higher precentral myelin-related signals, stronger movement-related activation of PMd in the precentral crown, and higher temporal precision during paced finger tapping. Together, our multimodal mapping approach provides first-time evidence for behaviourally relevant, structural and functional phenotypic variation in the crown of human precentral motor hand knob. The results have important implications for physiological and interventional TMS studies targeting the precentral hand knob.

Multimodal evaluation of an Italian family with a hereditary spastic paraplegia and POLR3A mutations.

Abstract: We describe an Italian family with adult-onset pure hereditary spastic paraplegia due to biallelic variants in POLR3A gene [c.1909 + 22G > A and c.3839dupT (p.M1280fs*20]. MRI showed a mild hyperintensity of superior cerebellar peduncles and cervical spinal cord atrophy. The neurophysiological metrics about intracortical excitability showed higher values of motor thresholds and a significant reduction of short interval intracortical inhibition (SICI) in the patient with a more severe phenotype. Our multimodal evaluation further expands the wide phenotypic spectrum associated with mutations in the POLR3A gene. An extensive genotype-phenotype correlation study is necessary to explain the role of the many new mutations on the function of protein.

Primary Progressive Multiple Sclerosis Under Anti-TNFα Treatment: A Case Report.

Abstract: Antagonists of tumour necrosis factor α (TNFα) are a common therapeutic choice for autoimmune diseases. Although they are effective and relatively safe, an increasing number of immune-mediated adverse events have been reported. Among these, neurological adverse effectsm such as consisting of demyelinating events in the central and peripheral nervous system were described. Demyelination of the central nervous system is a rare complication after treatment with TNFα antagonists. Here, we report a case of multiple sclerosis under treatment with TNFα antagonists and discuss its etiopathogenesis. This 45-year-old female patient developed signs and symptoms suggestive of primary progressive multiple sclerosis during treatment with adalinumab for nodular cystic acne, and magnetic resonance imaging of the patient showed typical lesions of demyelinating disease.