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.

Unusual Presentation of Bilateral Carotid Artery Dissection: The Importance of Reasoning Outside the Box.

A bilateral internal carotid artery dissection presenting with atypical symptoms of cerebral hypoperfusion has been rarely reported, especially in the absence of obvious precipitating factors. A middle-aged woman presented to the emergency department with a 2-day-history of progressive left arm numbness and weakness, confusion, disorientation and clumsiness worsened by upright position. A cerebral hypoperfusion condition was hypothesized and confirmed by a CT angiography, which showed bilateral internal carotid dissection with uncertain etiology. Screening for predisposing conditions to spontaneous carotid arteries dissection was basically negative. Regarding potential precipitating factors, the patient had used an electric olive harvester days before symptoms onset, without any painful sensation or sudden sequelae. Portable harvesters in olive growing transmit vibrations to the hand-arm system but it remains to be elucidated if hand-arm vibrations can be implicated in vessels wall injury and dissection. Bilateral carotid artery dissection is an infrequent and life-threatening condition which can rarely present with non-specific symptoms of cerebral hypoperfusion. The absence of typical symptoms and known precipitating factors can made the diagnosis quite hard to achieve.

Contribution of Metabolomics to Multiple Sclerosis Diagnosis, Prognosis and Treatment.

Metabolomics-based technologies map in vivo biochemical changes that may be used as early indicators of pathological abnormalities prior to the development of clinical symptoms in neurological conditions. Metabolomics may also reveal biochemical pathways implicated in tissue dysfunction and damage and thus assist in the development of novel targeted therapeutics for neuroinflammation and neurodegeneration. Metabolomics holds promise as a non-invasive, high-throughput and cost-effective tool for early diagnosis, follow-up and monitoring of treatment response in multiple sclerosis (MS), in combination with clinical and imaging measures. In this review, we offer evidence in support of the potential of metabolomics as a biomarker and drug discovery tool in MS. We also use pathway analysis of metabolites that are described as potential biomarkers in the literature of MS biofluids to identify the most promising molecules and upstream regulators, and show novel, still unexplored metabolic pathways, whose investigation may open novel avenues of research.

Rituximab in AChR subtype of myasthenia gravis: systematic review.

Myasthenia gravis (MG) is a chronic autoimmune disorder of the neuromuscular junction characterised by an autoantibody against acetylcholine receptor (AChR-Ab), autoantibody against muscle-specific kinase (MuSK-Ab), lipoprotein-related protein 4 or agrin in the postsynaptic membrane at the neuromuscular junction. Many patients are resistant to conventional treatment and effective therapies are needed. Rituximab (RTX) is a monoclonal antibody directed against CD20 antigen on B cells which has been successfully employed in anti-MuSK-Ab+MG, but the efficacy in anti-AChR-Ab+MG is still debated. The purpose of this systematic review was to describe the best evidence for RTX in the acetylcholine receptor subtype. The authors undertook a literature search during the period of 1999-2019 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analys methodology, employing (myasthenia)+(gravis)+(RTX) as search terms. The analysis was confined to studies that include at least five patients with confirmed anti-AChR-Ab+MG. Thirteen studies have been selected, showing a good safety. The data obtained were heterogeneous in terms of posology, administration scheme and patients' evaluation, ranging from a minimum of two to a maximum of three cycles. RTX led to a sustained clinical improvement with prolonged time to relapse, in parallel to a reduction or discontinuation of other immunosuppressive therapies. Treatment with RTX appears to work in some but not all patients with anti-AChR-Ab+MG, but randomised controlled trials are needed. Future studies should take into account the subtype of MG and employ reliable measures of outcome and severity focusing on how to identify patients who may benefit from the treatment. Trial registration number: NCT02110706.

Diagnostic and therapeutic aspects of hemiplegic migraine.

Hemiplegic migraine (HM) is a clinically and genetically heterogeneous condition with attacks of headache and motor weakness which may be associated with impaired consciousness, cerebellar ataxia and intellectual disability. Motor symptoms usually last <72 hours and are associated with visual or sensory manifestations, speech impairment or brainstem aura. HM can occur as a sporadic HM or familiar HM with an autosomal dominant mode of inheritance. Mutations in CACNA1A, ATP1A2 and SCN1A encoding proteins involved in ion transport are implicated. The pathophysiology of HM is close to the process of typical migraine with aura, but appearing with a lower threshold and more severity. We reviewed epidemiology, clinical presentation, diagnostic assessment, differential diagnosis and treatment of HM to offer the best evidence of this rare condition. The differential diagnosis of HM is broad, including other types of migraine and any condition that can cause transitory neurological signs and symptoms. Neuroimaging, cerebrospinal fluid analysis and electroencephalography are useful, but the diagnosis is clinical with a genetic confirmation. The management relies on the control of triggering factors and even hospitalisation in case of long-lasting auras. As HM is a rare condition, there are no randomised controlled trials, but the evidence for the treatment comes from small studies.

Neurological vertigo in the emergency room in pediatric and adult age: systematic literature review and proposal for a diagnostic algorithm.

Neurological vertigo is a common symptom in children and adults presenting to the emergency department (ED) and its evaluation may be challenging, requiring often the intervention of different medical specialties. When vertigo is associated with other specific symptoms or signs, a differential diagnosis may be easier. Conversely, if the patient exhibits isolated vertigo, the diagnostic approach becomes complex and only through a detailed history, a complete physical examination and specific tests the clinician can reach the correct diagnosis. Approach to vertigo in ED is considerably different in children and adults due to the differences in incidence and prevalence of the various causes. The aim of this systematic review is to describe the etiopathologies of neurological vertigo in childhood and adulthood, highlighting the characteristics and the investigations that may lead clinicians to a proper diagnosis. Finally, this review aims to develop an algorithm that could represent a valid diagnostic support for emergency physicians in approaching patients with isolated vertigo, both in pediatric and adult age.

Cerebrovascular reactivity in multiple sclerosis is restored with reduced inflammation during immunomodulation.

Cerebrovascular reactivity (CVR) reflects the capacity of the brain's vasculature to increase blood flow following a vasodilatory stimulus. Reactivity is an essential property of the brain's blood vessels that maintains nutrient supplies in the face of changing demand. In Multiple Sclerosis (MS), CVR may be diminished with brain inflammation and this may contribute to neurodegeneration. We test the hypothesis that CVR is altered with MS neuroinflammation and that it is restored when inflammation is reduced. Using a breath-hold task during functional Magnetic Resonance Imaging (MRI), we mapped grey matter and white matter CVRs (CVRGM and CVRWM, respectively) in 23 young MS patients, eligible for disease modifying therapy, before and during Interferon beta treatment. Inflammatory activity was inferred from the presence of Gadolinium enhancing lesions at MRI. Eighteen age and gender-matched healthy controls (HC) were also assessed. Enhancing lesions were observed in 12 patients at the start of the study and in 3 patients during treatment. Patients had lower pre-treatment CVRGM (p = 0.04) and CVRWM (p = 0.02) compared to HC. In patients, a lower pre-treatment CVRGM was associated with a lower GM volume (r = 0.60, p = 0.003). On-treatment, there was an increase in CVRGM (p = 0.02) and CVRWM (p = 0.03) that negatively correlated with pre-treatment CVR (GM: r = - 0.58, p = 0.005; WM: r = - 0.60, p = 0.003). CVR increased when enhancing lesions reduced in number (GM: r = - 0.48, p = 0.02, WM: r = - 0.62, p = 0.003). Resolution of inflammation may restore altered cerebrovascular function limiting neurodegeneration in MS. Imaging of cerebrovascular function may thereby inform tissue physiology and improve treatment monitoring.

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.

Tumour-like presentation of atypical posterior reversible encephalopathy syndrome with prominent brainstem involvement.

Typical posterior reversible encephalopathy syndrome (PRES) is a clinical-neuroradiological entity characterised by bilateral white matter oedema, which is usually symmetrical and totally reversible in 2-3 weeks. A 46-year-old man presented with a persistent headache and visual blurring in the right eye. On admission, the clinical examination revealed minimal unsteadiness of gait and elevated blood pressure. A brain MRI showed a hyperintense signal on T2-weighted sequences in the whole brainstem, extended to the spinal cord (C2-C6), the left insula and the right cerebellum. When his blood pressure was controlled, his symptoms gradually improved. The follow-up MRI scan at 3 weeks revealed a dramatic regression of the hyperintense lesions on T2-weighted sequences. The differential diagnosis of PRES is very wide, especially in the case of conspicuous brainstem involvement. Treatable causes of white matter oedema should be always kept in mind to avoid misdiagnosis and prevent complications, such as intracranial haemorrhage.

Novel missense mutation in the ATP1A2 gene associated with atypical sporapedic hemiplegic migraine.

Hemiplegic migraine (HM) is a rare subtype of migraine with aura in which attacks include transient motor weakness or hemiparesis that can last several days. HM is linked to mutations in three different genes, CACNA1A, ATP1A2 and SCN1A, which encode for ion transporters. The clinical spectrum includes atypical symptoms such as impaired consciousness, epileptic seizures, permanent cerebellar ataxia or mental retardation. We describe a novel mutation found in the ATP1A2 gene in a patient with late-onset HM. His attacks were characterised by motor weakness associated with altered mental status, diplopia and ataxia. He also showed up MRI abnormalities and incomplete response to prophylactic therapy with verapamil. Late-onset HM should be considered among the possible causes of focal neurological deficits even in older patients with cerebrovascular risk factors when a stroke appears to be more likely.

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.