ABSTRACT
Myasthenia gravis (MG) is a rare, autoimmune, neurological disorder. Most MG patients have autoantibodies against acetylcholine receptors (AChRs). Some have autoantibodies against muscle-specific tyrosine kinase (MuSK) or lipoprotein-receptor-related protein 4 (LRP4), and some are seronegative. Standard of care, which includes anti-cholinesterase drugs, thymectomy, corticosteroids (CS), and off-label use of non-steroidal immunosuppressive drugs (NSISTs), is bounded by potential side effects and limited efficacy in refractory generalized MG (gMG) patients. This highlights the need for new therapeutic approaches for MG. Eculizumab, a monoclonal antibody that inhibits the complement system, has been recently approved in Italy for refractory gMG. A panel of 11 experts met to discuss unmet therapeutic needs in the acute and chronic phases of the disease, as well as the standard of care for refractory patients. Survival was emphasized as an acute phase outcome. In the chronic phase, persistent remission and early recognition of exacerbations to prevent myasthenic crisis and respiratory failure were considered crucial. Refractory patients require treatments with fast onset of action, improved tolerability, and the ability to slow disease progression and increase life expectancy. The Panel agreed that eculizumab would presumably meet the therapeutic needs of many refractory gMG patients. The panel concluded that the unmet needs of current standard of care treatments for gMG are significant. Evaluating new therapeutic options accurately is essential to find the best balance between efficacy and tolerability for each patient. Collecting real-world data on novel molecules in routine clinical practice is necessary to address unmet needs.
ABSTRACT
Multiple sclerosis (MS) is an autoimmune chronic disease characterized by inflammation and demyelination of the central nervous system (CNS). Despite numerous studies conducted, valid biomarkers enabling a definitive diagnosis of MS are not yet available. The aim of our study was to identify a marker from a blood sample to ease the diagnosis of MS. In this study, since there is evidence connecting the serotonin pathway to MS, we used an ELISA (Enzyme-Linked Immunosorbent Assay) to detect serum MS-specific auto-antibodies (auto-Ab) against the extracellular loop 1 (ECL-1) of the 5-hydroxytryptamine (5-HT) receptor subtype 2A (5-HT2A). We utilized an ELISA format employing poly-D-lysine as a pre-coating agent. The binding of 208 serum samples from controls, both healthy and pathological, and of 104 serum samples from relapsing-remitting MS (RRMS) patients was tested. We observed that the serum-binding activity in control cohort sera, including those with autoimmune and neurological diseases, was ten times lower compared to the RRMS patient cohort (p = 1.2 × 10-47), with a sensitivity and a specificity of 98% and 100%, respectively. These results show that in the serum of patients with MS there are auto-Ab against the serotonin receptor type 2A which can be successfully used in the diagnosis of MS due to their high sensitivity and specificity.
Subject(s)
Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Polylysine , Humans , Central Nervous System , Antibodies , Hematologic Tests , BiomarkersABSTRACT
BACKGROUND AND PURPOSE: There are different criteria for the diagnosis of different variants of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guidelines provide specific clinical criteria for each CIDP variant even if their therapeutical impact has not been investigated. METHODS: We applied the clinical criteria for CIDP variants of the 2021 EAN/PNS guidelines to 369 patients included in the Italian CIDP database who fulfilled the 2021 EAN/PNS electrodiagnostic criteria for CIDP. RESULTS: According to the 2021 EAN/PNS clinical criteria, 245 patients achieved a clinical diagnosis of typical CIDP or CIDP variant (66%). We identified 106 patients with typical CIDP (29%), 62 distal CIDP (17%), 28 multifocal or focal CIDP (7%), four sensory CIDP (1%), 27 sensory-predominant CIDP (7%), 10 motor CIDP (3%), and eight motor-predominant CIDP (2%). Patients with multifocal, distal, and sensory CIDP had milder impairment and symptoms. Patients with multifocal CIDP had less frequently reduced conduction velocity and prolonged F-wave latency and had lower levels of cerebrospinal fluid protein. Patients with distal CIDP more frequently had reduced distal compound muscle action potentials. Patients with motor CIDP did not improve after steroid therapy, whereas those with motor-predominant CIDP did. None of the patients with sensory CIDP responded to steroids, whereas most of those with sensory-predominant CIDP did. CONCLUSIONS: The 2021 EAN/PNS criteria for CIDP allow a better characterization of CIDP variants, permitting their distinction from typical CIDP and more appropriate treatment for patients.
Subject(s)
Polyradiculoneuropathy, Chronic Inflammatory Demyelinating , Humans , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis , Peripheral Nerves , Neural Conduction/physiology , Databases, FactualABSTRACT
BACKGROUND: Upper eyelid surgery (UES) is a therapeutical strategy used for those patients affected by blepharospasm (BSP) who either do not respond or experience a gradual decrease in responsiveness to botulinum toxin (BoNT) injections. Nevertheless, most of them need to restart with BoNT despite the intervention. AIM: To evaluate the long-term post-surgical response to BoNT in patients with BSP and to identify predictive factors associated to treatment outcome. METHODS: We collected data of 60 BS patients, divided into two groups - blepharoplasty YES (8) and NO (52), collecting demographic - age, sex - and clinical data -disease duration, duration of the treatment with BoNT. Respective responses to injections - evaluated through the differences of both Jancovic Rating Scale and the Blepharospasm Disability Index pre and post BoNT (delta JRS and delta BSDI) just before their periodic three-month injection and after 1 month from it - were compared. Finally, clinical and demographics variables were included in multivariate regression and correlation analyses to assess their impact on the long-term response to injections. RESULTS: Patients who underwent UES had significantly lower delta at both scales, showing a poorer outcome after BoNT treatment. No variable was found to be associated with the response. DISCUSSION: Our data seem to suggest that surgery does not improve response to BoNT injections on the long run. As such, UES could be considered as an efficacious treatment in BSP just if evaluated soon after its performing. Long-term BSP management seems still difficult to be performed adequately and new therapeutical approaches are still needed.
Subject(s)
Blepharospasm , Botulinum Toxins, Type A , Neuromuscular Agents , Humans , Blepharospasm/drug therapy , Blepharospasm/surgery , Eyelids , Treatment Outcome , InjectionsABSTRACT
The purpose of this study was to investigate the epidemiology, management, and economic burden of myasthenia gravis in settings of real clinical practice. The analysis used administrative databases covering around 12 million subjects across Italy and included all adult patients with hospitalization discharge diagnosis or active exemption code for myasthenia gravis or with ≥1 pyridostigmine prescription from 2011 to 2018. The estimated prevalence of myasthenia gravis during 2018 was in the range 13.5-29.3/100,000 people (depending on the criteria applied), corresponding to 8190-17,728 alive patients, when reproportioning data to the entire Italian population. Overall 4397 patients with myasthenia gravis (mean age 61.7 years, 46.6% males) were included. A large pyridostigmine use was observed (84.0%-46.8% from 1st to 3rd year of follow-up), followed by corticosteroids (54.5%-44.6% from 1st to 3rd year of follow-up) and non-steroidal immunosuppressants (16% over follow-up). Total direct healthcare costs for myasthenia gravis were 4-times higher than those of the general population (3771 and 869, respectively), and up to 9-fold increased when considering patients with exacerbation (7827). These findings showed the epidemiologic burden of myasthenia gravis and the complexity of the therapeutic management for the affected patients, with large use of treatments and elevated healthcare expenditures.
ABSTRACT
Following the previously published results of the clinical randomized ZeOxaNMulti trial, we evaluated the potential of the tested product PMA-ZEO (Multizeo Med) in the prevention of chemotherapy-induced side effects (especially peripheral neuropathy) within a 30-month follow-up analysis. The aim was to determine the disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS) in a study-population suffering from colorectal cancer that was previously enrolled in the ZeOxaNMulti trial from April 2015 to October 2018. The participants of the study were randomized to receive either PMA-ZEO or placebo while undergoing oxaliplatin-based chemotherapy. A total of 104 patients (pts) (51% of participants randomized to the PMA-ZEO group and 49% to the placebo group), out of a total of 120 pts included in the ZeOxaNMulti trial in 2015, were followed up until March 2021 and were included in the follow-up analysis. According to the chemotherapy line, 44.2% of patients received chemotherapy in an adjuvant setting, and 55.8% of patients received chemotherapy as first-line treatment. The statistical analysis for DFS, PFS, and OS was performed by comparison of the end results with data from the PMA-ZEO/placebo-intervention start point. The analysis of OS did not show statistically significant differences in the first-line chemotherapy patients randomized to PMA-ZEO than among the placebo group (p = 0.1) over the whole period of follow-up (30 months). However, focusing on the PMA-ZEO supplementation time point (7 months), a positive and statistically significant trend (p = 0.004) was documented in the OS analysis for the first-line chemotherapy patients with increasing months of PMA-ZEO treatment compared to the placebo group. Furthermore, borderline statistical significance was reached for PFS at the PMA-ZEO supplementation time point (7 months) in the first-line chemotherapy patients (p = 0.05) for cancer progression events. After stratification of the first-line chemotherapy patients, statistically relevant trends for OS for age, comorbidities, and oxaliplatin dosage (cycles) were also determined. The overall results for DFS (adjuvant patients), PFS (first-line chemotherapy patients), and OS (adjuvant and first-line chemotherapy patients) were generally slightly better in the PMA-ZEO group than in the placebo group, even though no statistically significant results were obtained between the groups within the follow-up period until 2021 (30 months). Based on this follow-up analysis, protective effects of PMA-zeolite supplementation can be deduced. A positive trend and more importantly, significant results in PFS and OS for specific patient groups during and/or after PMA-ZEO treatment were determined, which supports the use of PMA-ZEO as an oncological supportive therapy.
ABSTRACT
BACKGROUND: Blepharospasm (BS) is a focal dystonia that can be treated successfully with Botulinum toxin (BoNT). During the reclusion due to the Covid 19 pandemic many patients missed the scheduled treatment. OBJECTIVES: Aim of the study is to evaluate Level of Disability (LoD) related to BS during the lockdown period. METHODS: LoD was assessed by an adapted version of Blepharospasm Disability Index (4iBSDI) during reclusion (T1), and three months after the first injection following the lock down phase (T2). 4iBSDI scores were compared between T1 and T2, a correlation between the change of LoD in the two periods (t-delta) and patients' clinical data was analyzed. RESULTS: LoD was not modified between the two periods in most of the patients and it was reduced at T1 in almost one third of the participants. No correlation between t-delta and clinical data was found. CONCLUSIONS: LoD did not increase during the lock down period in most of BS patients although BoNT treatment was suspended. Environmental and psychosocial factors may contribute to determine the LoD due to BS.
Subject(s)
Blepharospasm , Botulinum Toxins, Type A , COVID-19 , Neuromuscular Agents , Blepharospasm/drug therapy , Botulinum Toxins, Type A/adverse effects , Botulinum Toxins, Type A/therapeutic use , Communicable Disease Control , Humans , Neuromuscular Agents/therapeutic use , PandemicsABSTRACT
OBJECTIVES: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired peripheral neuropathy of immunological origin with a clinical presentation and course that are extremely variable. The therapeutic approach generally includes corticosteroid drugs, intravenous immunoglobulins (IVIGs) or plasmapheresis alone or in combination as first line therapy, and immunosuppressants. In 2014 the Italian regulatory agency included subcutaneous immunoglobulins (SCIGs) in the list of off-label drugs reimbursed by the national health service. Our aim is to compare costs and outcomes of IVIG versus SCIG therapy. METHODS: Patients medical records and therapeutic plans were retrospectively analysed to collect data on IVIG treatments 1 year before the switch to SCIG, and after 1 year of treatment with SCIG. A budget impact analysis was conducted through resource identification and quantification, and healthcare and non-health care costs evaluation. RESULTS: 13 of 34 patients affected by CIDP who were referred to our neurophysiopathological unit and treated with IVIG were switched to home-based SCIG. After 1 year of receiving SCIG, 12 patients remained neurologically stable and reported good outcomes. Considering the cost of IVIG (30.97/g) and adding to this the direct and indirect healthcare costs, the total cost of IVIG treatment for the 12 patients in a year was 371 417.06, compared with the cost of SCIG (51.57/g) for a total annual cost of 631 745.16, not including indirect costs. CONCLUSIONS: We observe a higher cost for SCIG treatment versus IVIG, which is not in line with data in the literature. However, SCIGs offer some important safety benefits and improvements in patient quality of life.
Subject(s)
Immunoglobulins, Intravenous , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating , Cost-Benefit Analysis , Humans , Immunoglobulins, Intravenous/therapeutic use , Infusions, Subcutaneous , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/diagnosis , Polyradiculoneuropathy, Chronic Inflammatory Demyelinating/drug therapy , Quality of Life , Retrospective Studies , State MedicineABSTRACT
Chemotherapy-induced peripheral neuropathy (CIPN) is the most frequently reported adverse effect of oxaliplatin. In this study, we set out to evaluate the role of the panaceo-micro-activation (PMA) zeolite in the reduction of the incidence of CIPN and hematological and liver toxicity. The possible impact of the PMA-zeolite as an adjuvant therapeutic agent is based on its detoxification properties toward agents promoting the development of neuropathy (e.g., ammonium - recognized as a neurotoxic agent produced by tumors), as well as its positive impact on immunity and oxidative stress through its effects in the gastrointestinal tract. From April 2015 to October 2018, a total of 120 patients (pts) diagnosed with predominantly colorectal cancer requiring oxaliplatin-based chemotherapy were randomized to receive either the PMA-zeolite (Multizeo Med) or placebo while undergoing oxaliplatin-based chemotherapy. A nerve-conduction study (NCS) was planned at the baseline, after three and six months of chemotherapy, to evaluate CIPN. Furthermore, the evaluation of hematological and liver toxicity was performed during every cycle of chemotherapy. 70.6% and 64.3% of patients developed CIPN in the placebo and the PMA-zeolite group, respectively. Patients treated with the PMA-zeolite were able to undergo more cycles of chemotherapy (p = 0.03), which also indicates a significant improvement in tolerance to the therapy. The group treated with the PMA-zeolite showed a lower CIPN (although not statistically significant within the whole group of subjects) compared to patients receiving placebo. This advantage was, however, statistically significant in men (p = 0.047). In addition, supplementation with the PMA-zeolite resulted in a lower incidence of severe-grade hematological toxicity (trend toward statistical significance of p = 0.09 was observed). Cancer patients may benefit from the therapy with the appropriate certified zeolite-products (e.g., the PMA-zeolite) for human use in CIPN. The lower CIPN (statistically significant results in the male subgroup) was accompanied by a trend of lower incidence of severe-grade hematological toxicity. Furthermore, these benefits led to a better tolerance toward chemotherapy (increase in cycles) and allow an improved compliance with the oncological treatment protocol.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Colorectal Neoplasms/drug therapy , Neuroprotective Agents/administration & dosage , Peripheral Nervous System Diseases , Zeolites/administration & dosage , Administration, Oral , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Double-Blind Method , Female , Humans , Male , Middle Aged , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/prevention & controlABSTRACT
Myasthenia gravis is a well-treatable disease, in which a prompt diagnosis and an adequate management can achieve satisfactory control of symptoms in the great majority of patients. Improved knowledge of the disease pathogenesis has led to recognition of patient subgroups, according to associated antibodies, age at onset and thymus pathology, and to a more personalized treatment. When myasthenia gravis is suspected on clinical grounds, diagnostic confirmation relies mainly on the detection of specific antibodies. Neurophysiological studies and, to a lesser extent, clinical response to cholinesterase inhibitors support the diagnosis in seronegative patients. In these cases, the differentiation from congenital myasthenia can be challenging. Treatment planning must consider weakness extension and severity, disease subtype, thymus pathology, together with patient characteristics and comorbidities. Since most subjects with myasthenia gravis require long-term immunosuppressive therapy, surveillance of expected and potential adverse events is critical. For patients refractory to conventional immunosuppression, the use of biologic agents is highly promising. These recommendations are addressed to non-experts on neuromuscular transmission disorders. The diagnostic procedures and therapeutic approaches hereafter described are largely accessible in Italy.
Subject(s)
Myasthenia Gravis/diagnosis , Myasthenia Gravis/therapy , Female , Humans , Italy/epidemiology , Male , Myasthenia Gravis/epidemiology , Practice Guidelines as TopicABSTRACT
Adiponectin (Acrp30) is an adipokine widely studied for its beneficial metabolic properties. It circulates as low molecular weight (LMW), medium molecular weight (MMW), and high molecular weight (HMW) oligomers. The latter exerts the most potent biological effects. Acrp30 attracted renewed interest with the finding that it was associated with the development and progression of immune disorders. The mechanisms underlying this association and the role of Acrp30 in the pathophysiology of immune-mediated conditions remain unknown. Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by chronic activation of the immune system, impaired antibody production, and imbalanced cytokine production. In the attempt to shed light on the expression of Acrp30 in CVID, we: (a) investigated total Acrp30 and its oligomerization state in CVID patients undergoing maintenance Ig replacement therapy; (b) assessed the effects of Ig replacement therapy on Acrp30 expression in treatment-naïve CVID patients, namely, patients not treated before diagnosis, before and after the first Ig administration; and (c) evaluated the correlation between Acrp30 levels and clinical phenotypes of the disease. As controls, we analyzed healthy subjects and patients affected by a non-immunodeficiency chronic inflammatory demyelinating polyneuropathy (CIDP), before and after Ig infusion. We found that total Acrp30 and HMW oligomers were decreased in CVID but not in CIDP patients versus controls. Moreover, Acrp30 levels were correlated with IgA levels and were associated with two CVID phenotypes, namely, autoimmune cytopenia and enteropathy. Receiver operating characteristic curve analysis indicated that Acrp30 modulation is specific for CVID patients. Acrp30 and HMW levels quickly and dramatically increased after Ig infusion only in eight treatment-naïve CVID patients but not in five CIDP patients. This finding indicates that Ig administration per se is not able to induce an increase of Acrp30, but the specific cellular and/or molecular background proper of CVID seems to be essential. In conclusion, our data indicate that Acrp30 is specifically related to CVID activity. Further studies are required to understand the biological role of Acrp30 and its possible use as disease biomarker in CVID.
ABSTRACT
This is the first multicenter Italian experience with rufinamide as an adjunctive drug in children, adolescents and adults with Lennox-Gastaut syndrome. The patients were enrolled in a prospective, add-on, open-label treatment study from 11 Italian centers for children and adolescent epilepsy care. Forty-three patients (26 males, 17 females), aged between 4 and 34 years (mean 15.9 ± 7.3, median 15.0), were treated with rufinamide for a mean period of 12.3 months (range 3-21 months). Twenty patients were diagnosed as cryptogenic and 23 as symptomatic. Rufinamide was added to the baseline therapy at the starting dose of 10mg/kg body weight, evenly divided in two daily doses and then increased by 10mg/kg approximately every 3 days up to a maximum of 1000 mg/day in children aged ≥4 years with a body weight less than 30 kg. In patients more than 30 kg body weight, rufinamide could be titrated up to 3200 mg/day. After a mean follow-up period of 12.3 months (range 3-21 months), the final mean dose of rufinamide was 33.5mg/kg/24h (range 11.5-60) if combined to valproic acid, and of 54.5mg/kg/24h (range 21.8-85.6) without valproic acid. The response rate (≥50% decrease in countable seizures) was 60.5% (26 of 45 patients) in total; 51.1% experienced a 50-99% reduction in seizure frequency and complete seizure control was achieved in the last 4 weeks follow-up by 9.3% of patients. Two patients (4.7%) had a 25-50% seizure reduction, while seizure frequency remained unchanged in 13 (30.2%) and increased in 2 (4.7%). Reliable data for atypical absence seizures and myoclonic seizures were not available, as these are usually impossible to count. Ten patients (23.2%) reported adverse side effects, while taking rufinamide. They were generally mild and transient and most frequently included vomiting, drowsiness, irritability and loss of appetite. In conclusion, rufinamide as an adjunctive therapy reduced the number of drop attacks and major motor seizures in about 60% of patients with Lennox-Gastaut syndrome and produced only mild or moderate adverse side effects.
Subject(s)
Anticonvulsants/therapeutic use , Triazoles/therapeutic use , Adolescent , Adult , Anticonvulsants/administration & dosage , Anticonvulsants/adverse effects , Child , Child, Preschool , Drug Therapy, Combination , Female , Humans , Intellectual Disability/drug therapy , Italy , Lennox Gastaut Syndrome , Male , Spasms, Infantile/drug therapy , Treatment Outcome , Triazoles/administration & dosage , Triazoles/adverse effects , Valproic Acid/administration & dosage , Valproic Acid/therapeutic use , Young AdultABSTRACT
PURPOSE: To evaluate the efficacy and safety of levetiracetam (LEV) in refractory crypto/symptomatic, partial or generalised epilepsy in children, adolescents and young adults. METHODS: We performed a prospective open label add-on study in 99 patients (age 12 months to 32 years, mean 14 years) with partial or generalised, crypto/symptomatic seizures. Levetiracetam was added to no more than two baseline AEDs and the efficacy was rated according to seizure type and frequency. RESULTS: LEV was initiated at the starting dose of 10mg/kg/day with 5-day increments up to 50 mg/kg/day, unless it was not tolerated. Concomitant therapy was generally not modified throughout the study. After a mean follow-up period of 6.7 months (range 3 weeks to 29 months), 11 patients (11.1%) were free of seizures (cryptogenic partial epilepsy, 5; symptomatic partial epilepsy, 6). A more than 75% seizure decrease was found in 14 patients (14.1%) and >50% in 8 (8.1%). Seizures were unchanged in 38 (38.4%), and worsened in 23 (23.2%). Mild and transient adverse side effects were found in 17 patients (17.2%), mostly represented by irritability and drowsiness. CONCLUSION: LEV appears to be well tolerated in children and adolescents with severe epilepsy and seems to be a broad spectrum AED, though in our experience, it was more effective against partial seizures with or without secondarily generalisation. LEV efficacy in other epilepsy syndrome should be evaluated further in homogeneous, more selected patients.