Comorbidity in myasthenia gravis: multicentric, hospital-based, and controlled study of 178 Italian patients.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder with fluctuating weakness that causes significant disability and morbidity. Comorbidities may influence the course of MG, particularly in specific subgroups. The aim of this study is to investigate the frequency of comorbidities in MG patients compared to healthy controls (HC) and to evaluate their distribution according to age at disease onset, sex, and disease severity. METHODS: MG patients attending the University Hospital "Paolo Giaccone" in Palermo and "SS Annunziata" Hospital in Chieti were enrolled; HC were enrolled from the general population. Non-parametric statistics and logistic regression were used to assess the association of specific comorbidities according to age at disease onset, sex, disease subtypes, and severity of the disease. RESULTS: A total of 356 subjects were included in the study: 178 MG patients (46% F; median age 60 years [51-71]) and 178 sex- and age-matched HC (46% F, median age 59 years [50-66]). Overall, 86% of MG patients and 76% of HC suffered from comorbidities, and MG patients had a higher number of comorbidities compared to HC. Patients with late-onset suffered from more comorbidities than those with early-onset MG. Hypertension was more common in male patients with MG, while thymic hyperplasia, osteoporosis, and autoimmune diseases were more common in females. Respiratory disorders and thymoma were more common in patients with more severe disease (p < 0.05 for all comparisons). CONCLUSION: MG patients, particularly those with late onset, showed a higher prevalence of comorbidities than HC. Assessment of comorbidities in MG is an essential issue to identify the appropriate treatment and achieve the best management.

Predictors for progression in amyotrophic lateral sclerosis associated to SOD1 mutation: insight from two population-based registries.

BACKGROUND: Uncovering distinct features and trajectories of amyotrophic lateral sclerosis (ALS) associated with SOD1 mutations (SOD1-ALS) can provide valuable insights for patient' counseling and stratification for trials, and interventions timing. Our study aims to pinpoint distinct clinical characteristics of SOD1-ALS by delving into genotype-phenotype correlations and factors that potentially impact disease progression. METHODS: This is a retrospective observational study of a SOD1-ALS cohort from two Italian registers situated in the regions of Emilia-Romagna, Piedmont and Valle d'Aosta. RESULTS: Out of 2204 genotyped ALS patients, 2.5% carried SOD1 mutations, with a M:F ratio of 0.83. SOD1-ALS patients were younger, and more frequently reported a family history of ALS and/or FTD. SOD1-ALS had a longer survival compared to patients without ALS-associated gene mutations. However, here was considerable variability in survival across distinct SOD1 mutations, with an average survival of less than a year for the L39V, G42S, G73S, D91N mutations. Among SOD1-ALS, multivariate analysis showed that, alongside established clinical prognostic factors such as advanced age at onset and high progression rate at diagnosis, mutations located in exon 2 or within highly conserved gene positions predicted worse survival. Conversely, among comorbidities, cancer history was independently associated with longer survival. INTERPRETATION: Within the context of an overall slower disease, SOD1-ALS exhibits some degree of heterogeneity linked to the considerable genetic diversity arising from the multitude of potential mutations sites and specific clinical prognostic factors, including cancer history. Revealing the factors that modulate the phenotypic heterogeneity of SOD1-ALS could prove advantageous in improving the efficacy of upcoming therapeutic approaches.

Quantitative dopamine transporter imaging assessment in Parkinson's disease patients carrying GBA gene mutations compared with idiopathic PD patients: A case-control study.

BACKGROUND: Genetic risk factors impact around 15% of Parkinson's disease (PD) patients and at least 23 variants have been identified including Glucocerebrosidase (GBA) gene variants. Using different clinical and instrumental qualitative-based data, various studies have been published on GBA-PD cohorts which suggested possible differences in dopaminergic nigrostriatal denervation pattern, particularly in caudate and putamen nuclei. METHODS: This retrospective study included two consecutive homogenous cohorts of GBA-PD and idiopathic (I-PD) patients. Each consecutive GBA-PD patient has been matched with a 1:1 pairing method with a consecutive I-PD subject according to age, age at disease onset, sex, Hoehn & Yahr (H&Y) staging scale and comorbidity level (CCI). Semiquantitative volumetric data by the DaTQUANTTM software integrated in the DaTSCAN exam performed at time of the diagnosis (SPECT imaging performed according to current guidelines of I-123 FPCIT SPECT imaging) were extrapolated. Bilateral specific binding ratios (SBR) at putamen and caudate levels were calculated, using the occipital lobes uptake. The Mann-Whitney test was performed to compare the two cohorts while the Spearman's test was used to find correlations between motor and volumetric data in each group. Bonferroni correction was used to account for multiple comparisons. RESULTS: Two cohorts of 25 patients each (GBA-PD and I-PD), were included. By comparing GBA-PD and I-PD patients, lower SBR values were found in the most affected anterior putamen and left caudate of the GBA-PD cohort. Furthermore, in the GBA-PD cohort the SBR of the most affected posterior putamen negatively correlated with the H&Y scale. However, none of these differences or correlations remained significant after Bonferroni correction for multiple comparisons. CONCLUSIONS: We observed differences in SBR values in GBA-PD patients compared with I-PD. However, these differences were no longer significant after Bonferroni multiple comparisons correction highlighting the need for larger, longitudinal studies.

Neurovascular Manifestations of Iron-Deficient Anemia: Narrative Review and Practical Reflections through a Teaching Case.

Anemia is one of the most frequent diseases worldwide, affecting one-third of the general population. Anemia in general and in particular, iron-deficient anemia (IDA), has been associated to a higher risk of thrombotic manifestations, including ischemic stroke and cerebral venous thrombosis (CVT), as well as systemic extra-cerebral arterial and venous thrombosis. Despite these data, anemia is seldom considered as an etiological factor of stroke. An individual case encompassing all known neurovascular and systemic arterial and venous thrombotic manifestations related to IDA is presented with the focus on clinical reasoning issues in the diagnostic pathways, starting from the neuroradiological signs. The main questions have been identified and addressed in a narrative review of the most relevant data in the literature from a pragmatic and clinical viewpoint. The presented case concerns a 46-year-old man admitted to the Stroke Unit because of acute ischemic stroke with multiple thrombi in large intracranial and extracranial vessels, multifocal ischemic lesions in several arterial territories and the concurrent finding of asymptomatic CVT, pulmonary embolism with lung infarction and aortic thrombosis. An extended diagnostic work-up excluded the main etiologies (arterial dissection, cardiac embolism, genetic and acquired prothrombotic disorders, such as cancer and antiphospholipid syndrome), except for a severe IDA, such as to require blood transfusions followed by anticoagulant therapy for the several thrombotic manifestations. Neuroimaging and systemic vascular findings have been analyzed, and the main issues proposed by the case in the diagnostic pathway have been identified and discussed in a pragmatic clinical road map reviewing the data provided by the literature. Conclusions: IDA is a common but treatable condition that, independently or synergically, may increase the risk of thrombotic events. The diagnostic and therapeutic approach has not yet been defined, and each case should be individually addressed in a pragmatic clinical road map.

EEG Abnormalities During Delirium as a Prodromal Feature of Dementia with Lewy Bodies: A Case Report.

Background: A 79-year-old woman was admitted to the Neurology Clinic of the University of Chieti-Pescara for a syncope. At admission, the occurrence of an acute stroke was ruled out. Her cognitive status was unimpaired. After three days from the hospitalization, the patient experienced an episode of mixed delirium. Objective: The present case report shows a case of delirium-onset dementia with Lewy bodies (DLB) with a specific electroencephalographic (EEG) pattern from its prodromal stage. Methods: Delirium was assessed by 4AT test. During the hospitalization, the patient underwent a quantitative EEG (QEEG) with spectral analysis. At six months from the episode of delirium, she was tested by neuropsychological evaluation, QEEG, and 18F-fluorodeoxyglucose PET/CT to assess the onset of a possible cognitive decline. Results: At baseline, the QEEG exam showed a dominant frequency (DF) in the pre-alpha band (7.5 Hz) with a dominant frequency variability (DFV) of 2 Hz. This pattern is typical of DLB at early stage. After six months, she reported attention deficits in association with cognitive fluctuation and REM sleep behavior disorder. The neurological examination revealed signs of parkinsonism. Cognitive status resulted to be impaired (MoCA = 15/30). QEEG recording confirmed the presence of a DLB-typical pattern (DF = 7.5 Hz, DFV = 2.5 Hz). The 18F-FDG-PET/CT showed a moderate bilateral posterior hypometabolism (occipital and temporal cortex), with relative sparing of the posterior cingulate cortex compared to cuneus/precuneus (Cingulate Island sign), and mild bilateral hypometabolism in frontal regions (suggestive of a DLB diagnosis). Conclusion: EEGs may represent supportive and validated biomarkers for delirium-onset prodromal DLB.

Muscarinic Receptors Expression in the Peripheral Blood Cells Differentiate Dementia with Lewy Bodies from Alzheimer's Disease.

BACKGROUND: Central nervous system disruption of cholinergic (ACh) signaling, which plays a major role in cognitive processes, is well documented in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). The expression of muscarinic ACh receptors type 1 and 4 (CHRM1 and CHRM4) has been reported to be altered in the brain of DLB patients. OBJECTIVE: We aim to assess the peripheral gene expression of CHRM1 and 4 in DLB as a possible marker as compared to AD and healthy control (HC) subjects. METHODS: Peripheral blood mononuclear cells were collected from 21 DLB, 13 AD, and 8 HC matched subjects. RT-PCR was performed to estimate gene expression of CHRM1 and CHRM4. RESULTS: Peripheral CHRM1 expression was higher and CHRM4 was lower in DLB and AD compared to HC, whereas both CHRM1 and CHRM4 levels were higher in AD compared to DLB patients. Receiver operating characteristics curves, with logistic regression analysis, showed that combining peripheral CHRM1 and CHRM4 levels, DLB and AD subjects were classified with an accuracy of 76.0%. CONCLUSION: Alterations of peripheral CHRM1 and CHRM4 was found in both AD and DLB patients as compared to HC. CHRM1 and CHRM4 gene expression resulted to be lower in DLB patients compared to AD. In the future, peripheral CHRM expression could be studied as a possible marker of neurodegenerative conditions associated with cholinergic deficit and a possible marker of response to acetylcholinesterase inhibitors.

Cortical network modularity changes along the course of frontotemporal and Alzheimer's dementing diseases.

Cortical network modularity underpins cognitive functions, so we hypothesized its progressive derangement along the course of frontotemporal (FTD) and Alzheimer's (AD) dementing diseases. EEG was recorded in 18 FTD, 18 AD, and 20 healthy controls (HC). In the FTD and AD patients, the EEG recordings were performed at the prodromal stage of dementia, at the onset of dementia, and three years after the onset of dementia. HC underwent three EEG recordings at 2-3-year time interval. Information flows underlying EEG activity recorded at electrode pairs were estimated by means of Mutual Information (MI) analysis. The functional organization of the cortical network was modelled by means of the Graph theory analysis on MI adjacency matrices. Graph theory analysis showed that the main hub of HC (Parietal area) was lost in FTD patients at onset of dementia, substituted by provincial hubs in frontal leads. No changes in global network organization were found in AD. Despite a progressive cognitive impairment during the FTD and AD progression, only the FTD patients showed a derangement in the cortical network modularity, possibly due to dysfunctions in frontal functional connectivity.

Real-Time Monitoring of Levetiracetam Effect on the Electrophysiology of an Heterogenous Human iPSC-Derived Neuronal Cell Culture Using Microelectrode Array Technology.

Levetiracetam (LEV) is a broad-spectrum and widely used antiepileptic drug that also has neuroprotective effects in different neurological conditions. Given its complex interaction with neuronal physiology, a better comprehension of LEV effects on neurons activity is needed. Microelectrode arrays (MEAs) represent an advanced technology for the non-invasive study of electrophysiological activity of neuronal cell cultures. In this study, we exploited the Maestro Edge MEA system, a platform that allows a deep analysis of the electrical network behavior, to study the electrophysiological effect of LEV on a mixed population of human neurons (glutamatergic, GABAergic and dopaminergic neurons, and astrocytes). We found that LEV significantly affected different variables such as spiking, single-electrode bursting, and network bursting activity, with a pronounced effect after 15 min. Moreover, neuronal cell culture completely rescued its baseline activity after 24 h without LEV. In summary, MEA technology confirmed its high sensitivity in detecting drug-induced electrophysiological modifications. Moreover, our results allow one to extend the knowledge on the electrophysiological effects of LEV on the complex neuronal population that resembles the human cortex.

Diabetes Mellitus and Amyotrophic Lateral Sclerosis: A Systematic Review.

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a degenerative disorder which affects the motor neurons. Growing evidence suggests that ALS may impact the metabolic system, including the glucose metabolism. Several studies investigated the role of Diabetes Mellitus (DM) as risk and/or prognostic factor. However, a clear correlation between DM and ALS has not been defined. In this review, we focus on the role of DM in ALS, examining the different hypotheses on how perturbations of glucose metabolism may interact with the pathophysiology and the course of ALS. METHODS: We undertook an independent PubMed literature search, using the following search terms: ((ALS) OR (Amyotrophic Lateral Sclerosis) OR (Motor Neuron Disease)) AND ((Diabetes) OR (Glucose Intolerance) OR (Hyperglycemia)). Review and original articles were considered. RESULTS: DM appears not to affect ALS severity, progression, and survival. Contrasting data suggested a protective role of DM on the occurrence of ALS in elderly and an opposite effect in younger subjects. CONCLUSIONS: The actual clinical and pathophysiological correlation between DM and ALS is unclear. Large longitudinal prospective studies are needed. Achieving large sample sizes comparable to those of common complex diseases like DM is a challenge for a rare disease like ALS. Collaborative efforts could overcome this specific issue.

Median-to-Ulnar Nerve Communication in Carpal Tunnel Syndrome: An Electrophysiological Study.

The median-to-ulnar communicating branch (MUC) is an asymptomatic variant of the upper limb innervation that can lead to interpretation errors in routine nerve conduction studies. The diagnosis of carpal tunnel syndrome (CTS) or ulnar nerve lesions can be complicated by the presence of MUC. In this study, we describe electrophysiological features of MUC in CTS patients presenting to our clinic. We enrolled MUB cases from consecutive CTS patients referred to our laboratory between the years 2014 and 2019. MUC was present in 53 limbs (36 patients) from the studied population. MUC was bilateral in 53% of patients. MUC type II was the most common subtype (74%), followed by types III and I; more coexisting MUC types were found in the majority of tested limbs. A positive correlation was demonstrated between the severity of CTS and the presence of positive onset, faster CV, or a double component of the compound muscle action potentials. We emphasize the importance of suspecting the presence of MUC in CTS in the presence of a positive onset or a double component in routine motor conduction studies.

Agitation and Dementia: Prevention and Treatment Strategies in Acute and Chronic Conditions.

Agitation is a behavioral syndrome characterized by increased, often undirected, motor activity, restlessness, aggressiveness, and emotional distress. According to several observations, agitation prevalence ranges from 30 to 50% in Alzheimer's disease, 30% in dementia with Lewy bodies, 40% in frontotemporal dementia, and 40% in vascular dementia (VaD). With an overall prevalence of about 30%, agitation is the third most common neuropsychiatric symptoms (NPS) in dementia, after apathy and depression, and it is even more frequent (80%) in residents of nursing homes. The pathophysiological mechanism underlying agitation is represented by a frontal lobe dysfunction, mostly involving the anterior cingulate cortex (ACC) and the orbitofrontal cortex (OFC), respectively, meaningful in selecting the salient stimuli and subsequent decision-making and behavioral reactions. Furthermore, increased sensitivity to noradrenergic signaling has been observed, possibly due to a frontal lobe up-regulation of adrenergic receptors, as a reaction to the depletion of noradrenergic neurons within the locus coeruleus (LC). Indeed, LC neurons mainly project toward the OFC and ACC. These observations may explain the abnormal reactivity to weak stimuli and the global arousal found in many patients who have dementia. Furthermore, agitation can be precipitated by several factors, e.g., the sunset or low lighted environments as in the sundown syndrome, hospitalization, the admission to nursing residencies, or changes in pharmacological regimens. In recent days, the global pandemic has increased agitation incidence among dementia patients and generated higher distress levels in patients and caregivers. Hence, given the increasing presence of this condition and its related burden on society and the health system, the present point of view aims at providing an extensive guide to facilitate the identification, prevention, and management of acute and chronic agitation in dementia patients.

Hyperconnectivity in Dementia Is Early and Focal and Wanes with Progression.

We investigated in a longitudinal multicenter cohort study functional cortical connectivity changes along the course of frontotemporal dementia (FTD) and Alzheimer's disease (AD) from the prodromal stage of the diseases. Electroencephalography (EEG) was recorded in 18 FTD and 18 AD patients at the prodromal stage of dementia, at dementia onset, and 3 years after dementia onset. Twenty healthy controls (HC) underwent EEG recordings at the same time interval as the patients. Mutual information (MI) analysis measured the strength of functional network connectivity. FTD and AD patients showed greater MI at the prodromal stage of dementia (FTD vs. HC P = 2 × 10-8; AD vs. HC P = 4 × 10-3). Local connectivity was higher in left and right frontal areas of FTD (P = 7 × 10-5 and 0.03) and in left and right posterior areas in AD (P = 3 × 10-5 and 5 × 10-5) versus HC. We showed cortical hyperconnectivity at the prodromal stage of dementia in areas involved in the specific pathological process of FTD (frontal regions) and AD (posterior regions). Hyperconnectivity disappeared during follow-up, thus suggesting that it is an early electrophysiological feature of dementia, potentially useful to identify prodromal FTD and AD.

A Stage-Based Approach to Therapy in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder that features progressive, disabling motor symptoms, such as bradykinesia, rigidity, and resting tremor. Nevertheless, some non-motor symptoms, including depression, REM sleep behavior disorder, and olfactive impairment, are even earlier features of PD. At later stages, apathy, impulse control disorder, neuropsychiatric disturbances, and cognitive impairment can present, and they often become a heavy burden for both patients and caregivers. Indeed, PD increasingly compromises activities of daily life, even though a high variability in clinical presentation can be observed among people affected. Nowadays, symptomatic drugs and non-pharmaceutical treatments represent the best therapeutic options to improve quality of life in PD patients. The aim of the present review is to provide a practical, stage-based guide to pharmacological management of both motor and non-motor symptoms of PD. Furthermore, warning about drug side effects, contraindications, as well as dosage and methods of administration, are highlighted here, to help the physician in yielding the best therapeutic strategies for each symptom and condition in patients with PD.

The Pharmacology of Visual Hallucinations in Synucleinopathies.

Visual hallucinations (VH) are commonly found in the course of synucleinopathies like Parkinson's disease and dementia with Lewy bodies. The incidence of VH in these conditions is so high that the absence of VH in the course of the disease should raise questions about the diagnosis. VH may take the form of early and simple phenomena or appear with late and complex presentations that include hallucinatory production and delusions. VH are an unmet treatment need. The review analyzes the past and recent hypotheses that are related to the underlying mechanisms of VH and then discusses their pharmacological modulation. Recent models for VH have been centered on the role played by the decoupling of the default mode network (DMN) when is released from the control of the fronto-parietal and salience networks. According to the proposed model, the process results in the perception of priors that are stored in the unconscious memory and the uncontrolled emergence of intrinsic narrative produced by the DMN. This DMN activity is triggered by the altered functioning of the thalamus and involves the dysregulated activity of the brain neurotransmitters. Historically, dopamine has been indicated as a major driver for the production of VH in synucleinopathies. In that context, nigrostriatal dysfunctions have been associated with the VH onset. The efficacy of antipsychotic compounds in VH treatment has further supported the notion of major involvement of dopamine in the production of the hallucinatory phenomena. However, more recent studies and growing evidence are also pointing toward an important role played by serotonergic and cholinergic dysfunctions. In that respect, in vivo and post-mortem studies have now proved that serotonergic impairment is often an early event in synucleinopathies. The prominent cholinergic impairment in DLB is also well established. Finally, glutamatergic and gamma aminobutyric acid (GABA)ergic modulations and changes in the overall balance between excitatory and inhibitory signaling are also contributing factors. The review provides an extensive overview of the pharmacology of VH and offers an up to date analysis of treatment options.

Percutaneous endoscopic gastrostomy, body weight loss and survival in amyotrophic lateral sclerosis: a population-based registry study.

OBJECTIVE: To assess the role of percutaneous endoscopic gastrostomy (PEG) insertion, and its timing, on ALS survival, and to study prognostic factors of survival before and after PEG placement in a population-based setting. METHODS: In this observational population-based, registry study, we enrolled patients with newly- diagnosed ALS, according to the El Escorial revised criteria, who were resident in the Emilia Romagna Region, and who developed severe dysphagia needing enteral nutritional support. The primary outcome measure was tracheostomy-free survival after PEG recommendation. RESULTS: There were 210 patients needing PEG, out of an incident cohort of 545 patients from the Emilia Romagna Registry for ALS, who were diagnosed between 2009 and 2013. One hundred and ninety-three patients were included in the study, and 17 were excluded because they were already tracheostomized at the time of PEG placement. Of the 193 patients included in the study, 152 underwent PEG, whereas 41 did not undergo the procedure. Patients who did not undergo PEG, among the eligible ones, had the same tracheostomy-free survival from onset as patients who did (25 vs. 32 months, p = 0.21). Tracheostomy-free survival from PEG recommendation was greater in patients who underwent PEG placement than in patients who did not (6 vs. 2 months, p = 0.008). Median tracheostomy-free survival from PEG insertion was eight months (95% CI5-12); 30 days after PEG placement, survival was 89.60%. At Cox multivariable analysis, the hazard of death or tracheostomy after PEG insertion was significantly influenced by the difference between BMI at the time of the PEG procedure and BMI at diagnosis (HR 1.05, 95% CI 1.02-1.08; p = 0.002). The hazard of death or tracheostomy was not affected by the timing of PEG insertion. CONCLUSIONS: The present study, although it has some limitations, suggests a gain of tracheostomy-free survival from the time of PEG recommendation for patients who undergo PEG placement, and, among patients who undergo PEG, a greater survival if PEG is inserted before a significant weight loss occurs, and if nutritional support avoids further weight loss. Should this association between prevention of weight loss and better clinical outcome be confirmed by further studies, it would have important implications for disease management.