Abstract Introduction Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Masitinib, a tyrosine kinase inhibitor targeting microglial and mast cell activity in ALS pathogenesis, offers potential neuroprotection. This study presents a post-hoc analysis of long-term survivors treated with masitinib at 4.5 mg/kg/day in study AB10015, comparing observed survival to predicted and historical benchmarks. Methods Study AB10015 was a randomized, double-blind, placebo-controlled trial assessing masitinib with riluzole in ALS patients. Overall survival (OS) was measured from symptom onset to death, encompassing the double-blind period and post-study follow-up, including an optional, open-label program. The ENCALS model predicted survival of long-term survivors (≥5 years). A delay in the need for mechanical assistance, such as permanent ventilation, gastrostomy, tracheostomy, or wheelchair dependence, was used as a surrogate measure for quality of life (QoL). Results Among 130 patients receiving masitinib 4.5 mg/kg/day, the 5-year survival rate from onset was 42.3%, increasing to 50.0% in patients with an ALSFRS-R progression rate from disease onset of <1.1 points/month (AB10015 primary efficacy population) and 52.9% in a subgroup of patients without complete loss of functionality at baseline. Half of the long-term survivors had satisfactory QoL, defined as no mechanical assistance. The median OS for long-term survivors (n=55) was 121 months versus the ENCALS-predicted 42 months, yielding a 79-month residual median survival gain. Long-term survivors were prevalent across ALS baseline prognostic factors, including slow or moderate disease progression rate (ΔFS), severe or moderate functional severity, bulbar or spinal site of onset, respiratory function and age. Long-term survival was less likely in patients with complete loss of function at baseline or fast progressing disease (ΔFS ≥1.1 points/month) at baseline. Conclusions Masitinib treatment in ALS patients showed substantial survival benefit. Long-term survivors were largely independent of ALS prognostic factors, suggesting a subpopulation driven by microglial/mast cell activity. A recently identified biomarker detecting masitinib’s effect on pro-inflammatory microglia may help identify responsive patients.

Monday, April 27April 14, 2020Free AccessAmyotrophic Lateral Sclerosis (ALS) patients experience with Edaravone in Argentina (1693)Cecilia Quarracino, Mariana Bendersky, Natalia Bohorquez Morera, Roberto Rey, and Gabriel RodriguezAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.1693 Letters to the Editor

The term amyotrophic lateral sclerosis mimic syndrome (ALSms) includes pathologies that present signs or symptoms similar to those caused by amyotrophic lateral sclerosis (ALS), which can lead to misdiagnosis. In general, any kind of misdiagnosis can result in negative clinical, psychological and economic consequences as well diagnostic and treatment delay. The objectives were to determine the frequency and to compare the demographic and clinical characteristics of patients with ALS and ALSms in our ALS clinic. We retrospectively studied all patients evaluated from 2007 to 2017 including only patients with a definite final diagnosis. Out of 368 patients with motor neuron disease symptomatology, 43 (11.7%) had an ALSms. The most frequent etiology was compressive myelopathy (32.6%). Multivariate analysis considering positive associations was statistically significant for patients having only upper or lower motor neuron signs in the physical examination, a non-compatible electromyogram (EMG), as well as atypical first symptoms. ALS misdiagnosis is an ongoing and not infrequent problem. From our series of patients, atypical symptoms, absence of EMG pathological findings or isolated upper or lower motor neuron disease should prompt suspicion of a differential diagnosis.

OBJECTIVE:Chronic neurological disorders generate disabilities affecting multiple aspects of life, including sexuality.OBJECTIVE:To describe the presence of sexual dysfunction and comorbidities in a population with chronic neurological disorders. To analyze the relationship between disability and sexual dysfunction.METHODS:A cross-sectional case-control study was carried out. Patients with amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson's disease (PD), and stroke of at least one year since the onset of symptoms were included, and compared with controls with no neurological disease, matched by age and sex.RESULTS:We included 71 participants: 29 controls, with a mean age of 49.4 years, and 42 patients with a mean age of 53.8 years. Sexual dysfunction was present in 22.5% of the controls and 77.5% of the patients. A statistically significant relationship between sexual dysfunction and disability was found in the logistic regression analysis (OR = 20.38, 95%CI: 2.5 -165.86).CONCLUSIONS:Disability proved to be the main variable related to the presence of sexual dysfunction. Patients with ALS had the worst rates of sexual dysfunction. Patients with MS were similar to the control group. As for the PD group, no patient had normal sexuality. Finally, in stroke patients, the presence of comorbidities and their treatment may have negatively influenced sexuality. These findings showed that patients with chronic neurological diseases have sexual dysfunction and underscore the need for neurologists to know and address this problem.

La esclerosis lateral amiotrófica (ELA) es una enfermedad neurodegenerativa de causa desconocida, caracterizada por el compromiso simultáneo de las neuronas motoras superior e inferior. Los estudios epidemiológicos han estimado su incidencia anual entre 0,31 y 3,2, y su prevalencia entre 0,8 y 8,5 casos por 100.000 habitantes. La información epidemiológica existente en nuestro país es limitada a centros especializados. El presente trabajo presenta los resultados de un estudio epidemiológico en ELA realizado en la Ciudad Autónoma de Buenos Aires (CABA). Se llevó a cabo un estudio multicéntrico retrospectivo. Se incluyeron pacientes con ELA definida y probable de acuerdo con criterios de El Escorial, evaluados entre el 1 de enero de 2012 y el 31 de diciembre de 2013, que vivían en la CABA al inicio de los síntomas. El cálculo de incidencia se basó en el censo de 2010. Se incluyeron 103 pacientes (55 hombres), con una edad media de 64 años. El 58% cumplieron criterios para la ELA definida. El inicio de los síntomas fue en miembros inferiores en el 39%, extremidades superiores en el 25% y bulbar en el 26%. El tiempo medio hasta el diagnóstico fue de 14,5 meses. Treinta nuevos casos/pacientes fueron diagnosticados entre el 01/06/2012 y el 01/06/2013, con una tasa de incidencia de 1,04 por 100.000 habitantes. Las características epidemiológicas de la ELA en la CABA son similares a las reportadas en la literatura. Son necesarios estudios más amplios para determinar si estos hallazgos son aplicables al resto de la población argentina. Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease of unknown cause, characterized by the simultaneous involvement of the upper and lower motor neurons. Epidemiological studies have estimated its annual incidence between 0.31 and 3.2 and its prevalence between 0.8 and 8.5 cases per 100,000 inhabitants. The epidemiological information in our country is limited to specialized centers. The present study presents the results of an epidemiological study in ELA performed in the Autonomous City of Buenos Aires (CABA). A multicentric retrospective study was conducted. Patients with defined and probable ALS according to the El Escorial Criteria, evaluated between January 1, 2012 and December 31, 2013, who lived in the CABA at the onset of symptoms, were included. The calculation of the incidence was based on the 2010 census. We included 103 patients (55 men), with a mean age of 64 years. The onset of symptoms was in the lower limbs at 39%, upper extremities at 25% and bulbar at 26%. The initial symptom was weakness in 58% and dysarthria in 20%; 9% had dementia associated with ALS. The mean time to diagnosis was 14.5 months. Thirty new cases/patients were diagnosed between 01/06/2012 and 01/06/2013, with an incidence rate of 1.04 per 100,000 inhabitants. The epidemiological characteristics of ALS in CABA are similar to those reported in the universal literature. Further studies are needed to determine if these findings are applicable to the rest of the Argentine population.

OBJECTIVE: To perform an epidemiological study of ALS in the Autonomous City of Buenos Aires (CABA). BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by involvement of the upper and lower motor neurons. Epidemiological studies have estimated an annual incidence between 0.31 and 3.2 x 100.000 inhabitants, and its prevalence between 0.8 and 8.5 cases per 100.000 inhabitants. There are no reliable data from Latin America in general and Argentina in particular. This information would be most helpful for developing health policies. DESIGN/METHODS:We performed a retrospective multicenter study. We included patients with ALS according to the El Escorial criteria evaluated between January 1, 2012 and December 31, 2013 and living in CABA at the onset of symptoms. The mean and interquartile range (IQR) were used as measures of dispersion. The calculation of incidence was based on the 2010 census. RESULTS:We identified 103 patients (41 men), mean age 66.7 years (IQR 20). 30 patients were diagnosed between 01/01/2012 and 31/12/2012, with an incidence rate of 1.04 x 100,000 inhabitants. Familial ALS was identified in 1.9[percnt] of our patients, and 14,6[percnt] had lived in rural areas. Among this group 58,3[percnt] met criteria for definite ALS, and 31,1[percnt] for probable ALS. The region initially affected was lower limbs in 38,8[percnt], upper limbs in 25,2[percnt] and bulbar in 26.2[percnt]. The first symptom was weakness in 58.3[percnt] and dysarthria in 20.4[percnt]. 9[percnt] had ALS-FTD. Mean time to diagnosis was 14.28 months. CONCLUSIONS:The estimated incidence was within the range of other epidemiological studies, but lower than what was found in other Latin America regions. It is possible that the heterogeneous healthcare system in CABA (different health insurances, private and public practice) may have limited the identification of some patients. Study Supported by: not supported. Disclosure: Dr. Perez Akly has nothing to disclose. Dr. Albanese has nothing to disclose. Dr. Barroso has nothing to disclose. Dr. Bendersky has nothing to disclose. Dr. Bettini has nothing to disclose. Dr. Di Egidio has nothing to disclose. Dr. Fulgenzi has nothing to disclose. Dr. Fiorotto has nothing to disclose. Dr. Gargiulo Monachelli has nothing to disclose. Dr. Jauregui has nothing to disclose. Dr. Landriscina has nothing to disclose. Dr. Mazia has nothing to disclose. Dr. Melcom has nothing to disclose. Dr. Reisin has received personal compensation for activities with Shire Pharmaceuticals Group as a consultant. Dr. Rey has received personal compensation for activities with Novartis, Pfizer Inc., Valeant Pharmaceuticals, Merck Serono, Biogen Idec, Avanir Pharmaceuticals, Janssen Pharmaceutica, Eil Lilly & Company, and Organon Pharmaceuticals. Dr. Rodriguez has nothing to disclose. Dr. Rugiero has nothing to disclose. Dr. Salutto has nothing to disclose. Dr. Tillard has nothing to disclose.

Objectives: Mitochondrial dysfunction has been reported in the central nervous system, hepatocytes and peripheral blood lymphocytes from patients with sporadic amyotrophic lateral sclerosis (SALS). However, the status of skin mitochondria has not been reported, in spite of the fact that SALS patients present skin abnormalities. The objective of the present study was to compare mitochondrial ultrastructural parameters in keratinocytes from patients with SALS and healthy controls. Methods: Our study was based on the analysis of 112 skin mitochondria from 5 SALS patients and 99 organelles from 4 control subjects by electron microscopy. Results: Computerized image analysis showed that mitochondrial major axis length, area and perimeter of the organelle were significantly smaller in SALS respect of healthy control subjects. Morphologically, SALS mitochondria presented cristolysis and breakage of the outer membrane. Conclusions: Mitochondrial dysfunction in the skin may possibly reflect changes occurring in mitochondria of the central nervous system. The analysis of mitochondrial morphology in this tissue may be of value to follow disease progression and, eventually, the effectiveness of current therapies for SALS.

Objective: To describe the survival in patients with ALS and the subgroup of patients who survive more than 5 years. Background The survival in Amyotrophic Lateral Sclerosis (ALS) is usually 2 to 5 years. Those who live more than 5 years are considered patients with prolonged survival(ALSps).There are few data of life expectancy in ALS in South America and Argentina. Design/Methods: We reviewed medical records of patients with diagnosis of ALS according with the Escorial criteria between 2001 and 2010 in two centres of Buenos Aires, Argentina. We divided them into two groups according the months of survival (more or less than 60 months). The age, gender, time onset to diagnosis, site of onset and first symptom were analyzed. Qualitative categories were analyzed with x² and Quantitative with T-test. Results: Of 193 ALS patients, survival data were available in 133. The mean survival was 35 months. 15.8% (n=21) lived over 60 months (ALSps). ALSps patients with spinal onset were younger than patients with a survival below 60 months ( 50 vs. 58 years)(p=0.01), while there was no difference in patients with bulbar onset (63vs.61 years)(p=NS). There were no differences in gender, site of onset and first symptom between the two groups, although all bulbar patients with prolonged survival started with dysarthria. Time onset to diagnosis was significantly longer in ALSps (28 vs 14 months)(p Conclusions: The mean survival in ALS in our series was 35 months and 15.8% outlived over 5 years, similar to other reports in literature. ALSps patients had a longer time to diagnosis and the patients with spinal onset were younger than those who lived less than 5 years. Dysarthria was the first symptom in all bulbar ALSps patients, this finding has not been reported previously. Disclosure: Dr. Bettini has nothing to disclose. Dr. Rugiero has nothing to disclose. Dr. Gonorazky has nothing to disclose. Dr. Rey has nothing to disclose. Dr. Cristiano has nothing to disclose. Dr. Rodriguez has nothing to disclose. Dr. Sica has nothing to disclose.

This article briefly describes the already known clinical features and pathogenic mechanisms underlying sporadic amyotrophic lateral sclerosis, namely excitoxicity, oxidative stress, protein damage, inflammation, genetic abnormalities and neuronal death. Thereafter, it puts forward the hypothesis that astrocytes may be the cells which serve as targets for the harmful action of a still unknown environmental agent, while neuronal death may be a secondary event following the initial insult to glial cells. The article also suggests that an emergent virus or a misfolded infectious protein might be potential candidates to accomplish this task.

Studies on amyotrophic lateral sclerosis (ALS) suggest cognitive impairment associated with fronto-temporal dysfunction (FTD); particularly implicate executive dysfunction and behavioral disorders like irritability and disinhibition. Since fronto-temporal pathophysiology can alter social cognition we studied whether social cognition dysfunction can occur in ALS. Nine consecutive non dement patients (MMSE > 23) with ALS, 3 bulbar and 6 limb-onset (The Scorial critera), matched by age and education with 11 controls underwent neurologic, neuropsychologic, neuropsychiatric (NPI) and functional (ALSFRS-R) examinations. An exploratory analysis of social cognition was performed with “reading the mind in the eyes test (RMEt)”. ALS patients performed significantly worse than controls on RMEt (ALS = 19,88+/-3.21 vs controls = 25.09+/-1,51; p < .001). No association was observed between social perception, general cognition (including WCST), behavioral disorders and functional impairment. Patients with bulbar vs limb-onset ALS were not different in social perception. these preliminary data suggest the presence of social cognition impairment in patients with ALS and these findings expands the scope of cognitive dysfunction detected in ALS, and bolsters the view of ALS as a multisystem disorder involving cognitive as well as motor deficits.

Sporadic amyotrophic lateral sclerosis (sALS) is considered a multifactorial disease with genetic and environmental factors causing motor neuron degeneration. OBJECTIVE: To describe the epidemiological and occupational characteristics of patients with sALS who attended the Ramos Mejía Hospital at Buenos Aires, Argentina. METHOD: We analyzed the medical records of sALS patients diagnosed between 2001 and 2008. All occupations were coded according to the International Standard Classification of Occupation (ISCO). RESULTS: 187 patients were assessed, 38.5% were women and 61.5% men. Mean age at diagnosis was 55 years. 16% of them came from rural areas; 68% of the studied population had no health insurance. 40% were employed in elementary occupations, 19 were technicians and 8 handicraftsmen. CONCLUSION: The most represented profession was elementary occupation. A large proportion of patients came from rural areas, which might suggest an increased risk of environmental exposure to an unknown agent in those regions.

Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder. Worse prognostic factors in ALS are: (a) advanced age, (b) bulbar onset, and (c) short time between onset and diagnosis. Progesterone (PROG) has been associated with neuroprotective and promyelinating activities in injury, ischemia and degeneration of the central and peripheral nervous system. Cortisol is connected to the response to stress situations and could contribute to neuronal damage. The goals of this study were: (i) to investigate whether PROG levels are modified by ALS prognostic factors and (ii) to determine whether cortisol follows the same pattern. We determined serum steroid levels in 27 patients with sporadic ALS (sALS) and 21 controls. Both steroid hormones showed significantly increased levels in ALS patients versus controls (mean±SEM: PROG ALS vs. control: 0.54±0.05 vs. 0.39±0.04 ng/mL, p<0.05; cortisol ALS vs. control: 17.02±1.60 vs. 11.83±1.38 μg/dL, p<0.05).1 A trend towards higher levels of PROG were demonstrated in spinal onset patients compared with bulbar onset (p=0.07), positive correlation with survival time (RRho=0.43, p=0.04) and a trend towards significance with time to diagnosis (RRho=0.36, p=0.06). These correlations have not been demonstrated for cortisol. Elevated serum steroid levels in sALS were probably due to hyperfunction of the hypothalamic-pituitary-adrenal axis. However, only PROG correlated with better prognostic factors. Future studies will determine if the different behavior of PROG and cortisol relate to any particular role they might play during the course of this motor neuron degenerative disease. 1Conversion factors from conventional units to SI units: Progesterone ng/mL to nmol/L=3.18 Cortisol μg/dL to nmol/L=27.59

el stroke es una de las principales causas de discapacidad y muerte. Las Unidades de Stroke (US) mejoraron el tratamiento de la enfermedad cerebrovascular. comparar la atención del stroke agudo en una sala de Neurología general (SNe) y en una US. retrospectivamente se revisó la atención de pacientes con stroke agudo en la SNe en el periodo comprendido entre agosto de 1997 a agosto de 1998 (previo a la apertura de US) y la atención en la US en el lapso de tiempo desde agosto de 2004 a agosto de 2005. Se evaluaron los tiempos en llegar al hospital, en pasar a la sala apropiada y el tiempo de internamiento en el hospital. hubo 164 pacientes; 69 (42,09%) en la SNe y 95 (57,93%) en US. El 86,32% de los casos en US fueron stroke isquémico, en SNe fueron el 72,46%. El tiempo en llegar al hospital fue similar para ambas salas. El lapso en ingresar en la sala especializada fue de 4 horas 19 minutos en US y de 3 días 43 minutos en Neurología (p= 0,003). El tiempo medio de estancia hospitalaria fue 7 días 16 horas en US y 23 días 13 horas en la sala de Neurología general (p= 0,001). en la US con un equipo multidisciplinario hubo un menor tiempo de internamiento que en la SNe. La presencia de un médico neurólogo entrenado en patología cerebrovascular, junto con una US, aceleró el ingreso en una sala especializada. No hubo diferencias en las complicaciones ni en la mortalidad. Stroke is a major cause of disability and death. Stroke Units (SU) have improved the treatment of cerebrovascular disease. To compare the care of patients with acute stroke in a general ward (GW) and in a SU. We retrospectively reviewed the records of patients with acute stroke admitted in the GW (August 1997 to August 1998, before the existence of SU at hospital) and in the SU (August 2004 to August 2005). There were 164 patients, 69 (42.09%) in the GW and 95 (57.93%) in SU. Time to arrival at the hospital was similar for both groups. Time to be admitted was 4 hours 19 minutes in SU and 3 days 43 minutes in GW (p = 0.003). The average length of hospital stay was 7 days 16 hours for SU and 23 days 13 hours for GW (p = 0.001). In a SU, with a multidisciplinary team, there was a shorter hospital stay than in GW. The presence of a specialist in cerebrovascular disease with the SU sped up the entrance to an appropriate room. There were no differences in complications or mortality.