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1.
Artigo em Inglês | MEDLINE | ID: mdl-35172656

RESUMO

Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.

2.
Neuroimage Clin ; 34: 102965, 2022 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-35217500

RESUMO

The objective of this study was to examine if patterns of resting-state brain activity and functional connectivity in cortical and subcortical regions in patients with early symptomatic amyotrophic lateral sclerosis (ALS) resemble those of behavioural variant frontotemporal dementia (bvFTD). In a cross-sectional design, eyes-closed resting-state magnetoencephalography (MEG) data of 34 ALS patients, 18 bvFTD patients and 18 age- and gender-matched healthy controls (HCs) were projected to source-space using an atlas-based beamformer. Group differences in peak frequency, band-specific oscillatory activity and functional connectivity (corrected amplitude envelope correlation) in 78 cortical regions and 12 subcortical regions were determined. False discovery rate was used to correct for multiple comparisons. BvFTD patients, as compared to ALS and HCs, showed lower relative beta power in parietal, occipital, temporal and nearly all subcortical regions. Compared to HCs, patients with ALS and patients with bvFTD had a higher delta (0.5-4 Hz) and gamma (30-48 Hz) band resting-state functional connectivity in a high number of overlapping regions in the frontal lobe and in limbic and subcortical regions. Higher delta band connectivity was widespread in the bvFTD patients compared to HCs. ALS showed a more widespread higher gamma band functional connectivity compared to bvFTD. In conclusion, MEG in early symptomatic ALS patients shows resting-state functional connectivity changes in frontal, limbic and subcortical regions that overlap considerably with bvFTD. The findings show the potential of MEG to detect brain changes in early symptomatic phases of ALS and contribute to our understanding of the disease spectrum, with ALS and bvFTD at the two extreme ends.

3.
NPJ Genom Med ; 7(1): 8, 2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35091648

RESUMO

There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwise unexplained heritability. We therefore investigated association between structural variation in a set of 25 ALS genes, and ALS risk and phenotype. As expected, the repeat expansion in the C9orf72 gene was identified as associated with ALS. Two other ALS-associated structural variants were identified: inversion in the VCP gene and insertion in the ERBB4 gene. All three variants were associated both with increased risk of ALS and specific phenotypic patterns of disease expression. More than 70% of people with respiratory onset ALS harboured ERBB4 insertion compared with 25% of the general population, suggesting respiratory onset ALS may be a distinct genetic subtype.

4.
J Neurol Neurosurg Psychiatry ; 93(1): 82-92, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34663622

RESUMO

OBJECTIVES: To investigate sensitivity of brain MRI and neurological examination for detection of upper motor neuron (UMN) degeneration in patients with amyotrophic lateral sclerosis (ALS). METHODS: We studied 192 patients with ALS and 314 controls longitudinally. All patients visited our centre twice and underwent full neurological examination and brain MRI. At each visit, we assessed UMN degeneration by measuring motor cortex thickness (CT) and pyramidal tract fibre density (FD) corresponding to five body regions (bulbar region and limbs). For each body region, we measured degree of clinical UMN and lower motor neuron (LMN) symptom burden using a validated scoring system. RESULTS: We found deterioration over time of CT of motor regions (p≤0.0081) and progression of UMN signs of bulbar region and left arm (p≤0.04). FD was discriminative between controls and patients with moderate/severe UMN signs (all regions, p≤0.034), but did not change longitudinally. Higher clinical UMN burden correlated with reduced CT, but not lower FD, for the bulbar region (p=2.2×10-10) and legs (p≤0.025). In the arms, we found that severe LMN signs may reduce the detectability of UMN signs (p≤0.043). With MRI, UMN degeneration was detectable before UMN signs became clinically evident (CT: p=1.1×10-10, FD: p=6.3×10-4). Motor CT, but not FD, deteriorated more than UMN signs during the study period. CONCLUSIONS: Motor CT is a more sensitive measure of UMN degeneration than UMN signs. Motor CT and pyramidal tract FD are discriminative between patients and controls. Brain MRI can monitor UMN degeneration before signs become clinically evident. These findings promote MRI as a potential biomarker for UMN progression in clinical trials in ALS.


Assuntos
Esclerose Amiotrófica Lateral/diagnóstico por imagem , Imageamento por Ressonância Magnética , Córtex Motor/diagnóstico por imagem , Neurônios Motores/patologia , Biomarcadores , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Países Baixos , Neuroimagem , Exame Neurológico , Tratos Piramidais/diagnóstico por imagem
5.
Brain Sci ; 11(12)2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34942899

RESUMO

The ENCALS survival prediction model offers patients with amyotrophic lateral sclerosis (ALS) the opportunity to receive a personalized prognosis of survival at the time of diagnosis. We explored experiences of patients with ALS, caregivers, and physicians with discussing personalized prognosis through interviews with patients and their caregivers, and in a focus group of physicians. Thematic analysis revealed four themes with seven subthemes; these were recognized by the focus group. First, tailored communication: physician's communication style and information provision mediated emotional impact and increased satisfaction with communication. Second, personal factors: coping style, illness experiences, and information needs affected patient and caregiver coping with the prognosis. Third, emotional impact ranged from happy and reassuring to regret. Fourth, regaining control over the future: participants found it helpful in looking towards the future, and emphasized the importance of quality over quantity of life. Personalized prognosis can be discussed with minimal adverse emotional impact. How it is communicated-i.e., tailored to individual needs-is as important as what is communicated-i.e., a good or poor prognosis. Discussing personalized prognosis may help patients with ALS and their caregivers regain control over the future and facilitate planning of the future (care). For many patients, quality of life matters more than quantity of time remaining.

6.
Eur J Paediatr Neurol ; 35: 123-129, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34687976

RESUMO

INTRODUCTION: Traumatic brain injury (TBI) is the main cause of death in children around the world. The last Dutch epidemiological study described the incidence over 10 years ago. Mechanism of injury seems to change with the age of the child, therefore it is important to appreciate different age groups. To be able to lower the impact of childhood TBI, an understanding of current incidence, mechanism of injury and outcome is necessary. METHODS: A nationwide retrospective cohort study was conducted. The Dutch National Trauma Database was used to identify all patients 18 years and younger who were admitted to a Dutch hospital with moderate-severe TBI (Abbreviated Injury Score≥3) in the Netherlands, from January 2015 until December 2017. Subanalyses were done for different age groups. RESULTS: In total, 1413 patients were included, of whom 5% died. The incidence rate of moderate-severe TBI was 14/100,000 person years. Median age was 10.4 years. Largest age group was patients <5 years, incidence rate was highest in patients ≥16 years. Falls were more common than road traffic accidents (RTA), but RTAs occurred far more frequently amongst children over 10. RTAs predominantly consisted of bicycle accidents. Mortality rates increased from youngest to oldest age groups, as did the chances of a Glasgow Outcome Scale score of 3. CONCLUSION: Paediatric moderate-severe TBI represents a significant problem in the Netherlands. Falls are the most common mechanism of injury amongst younger children and RTAs amongst older children. Unique for the Netherlands is the vast amount of bicycle accident related injuries.


Assuntos
Lesões Encefálicas Traumáticas , Adolescente , Lesões Encefálicas Traumáticas/epidemiologia , Criança , Pré-Escolar , Hospitalização , Humanos , Incidência , Países Baixos/epidemiologia , Estudos Retrospectivos
7.
Sci Rep ; 11(1): 19985, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620973

RESUMO

Traumatic brain injury (TBI) is a leading cause of death and disability. Epidemiology seems to be changing. TBIs are increasingly caused by falls amongst elderly, whilst we see less polytrauma due to road traffic accidents (RTA). Data on epidemiology is essential to target prevention strategies. A nationwide retrospective cohort study was conducted. The Dutch National Trauma Database was used to identify all patients over 17 years old who were admitted to a hospital with moderate and severe TBI (AIS ≥ 3) in the Netherlands from January 2015 until December 2017. Subgroup analyses were done for the elderly and polytrauma patients. 12,295 patients were included in this study. The incidence of moderate and severe TBI was 30/100.000 person-years, 13% of whom died. Median age was 65 years and falls were the most common trauma mechanism, followed by RTAs. Amongst elderly, RTAs consisted mostly of bicycle accidents. Mortality rates were higher for elderly (18%) and polytrauma patients (24%). In this national database more elderly patients who most often sustained the injury due to a fall or an RTA were seen. Bicycle accidents were very frequent, suggesting prevention could be an important aspect in order to decrease morbidity and mortality.


Assuntos
Lesões Encefálicas Traumáticas/epidemiologia , Lesões Encefálicas Traumáticas/etiologia , Acidentes por Quedas/estatística & dados numéricos , Acidentes de Trânsito/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Lesões Encefálicas Traumáticas/mortalidade , Estudos de Coortes , Feminino , Hospitalização , Humanos , Incidência , Escala de Gravidade do Ferimento , Masculino , Pessoa de Meia-Idade , Traumatismo Múltiplo/epidemiologia , Traumatismo Múltiplo/etiologia , Traumatismo Múltiplo/mortalidade , Países Baixos/epidemiologia , Estudos Retrospectivos
8.
Artigo em Inglês | MEDLINE | ID: mdl-33829936

RESUMO

The kinesin family member 5A (KIF5A) motor domain variants are typically associated with hereditary spastic paraplegia (HSP) or Charcot-Marie-Tooth 2 (CMT2), while KIF5A tail variants predispose to amyotrophic lateral sclerosis (ALS) and neonatal intractable myoclonus. Variants within the stalk domain of KIF5A are relatively rare. We describe a family of three patients with a complex HSP phenotype and a likely pathogenic KIF5A stalk variant. More family members were reported to have walking difficulties. When reviewing the literature on KIF5A stalk variants, we found 22 other cases. The phenotypes varied with most cases having (complex) HSP/CMT2 or ALS. Symptom onset varied from childhood to adulthood and common additional symptoms for HSP are involvement of the upper limbs, sensorimotor polyneuropathy, and foot deformities. We conclude that KIF5A variants lead to a broad clinical spectrum of disease. Phenotype distribution according to variants in specific domains occurs often in the motor and tail domain but are not definite. However, variants in the stalk domain are not bound to a specific phenotype.


Assuntos
Esclerose Amiotrófica Lateral , Paraplegia Espástica Hereditária , Adolescente , Criança , Estudos de Associação Genética , Humanos , Mutação/genética , Fenótipo , Paraplegia Espástica Hereditária/genética , Adulto Jovem
9.
Neurol Clin Pract ; 11(2): 147-157, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33842068

RESUMO

PURPOSE OF REVIEW: To improve our clinical understanding of facial onset sensory and motor neuronopathy (FOSMN). RECENT FINDINGS: We identified 29 new cases and 71 literature cases, resulting in a cohort of 100 patients with FOSMN. During follow-up, cognitive and behavioral changes became apparent in 8 patients, suggesting that changes within the spectrum of frontotemporal dementia (FTD) are a part of the natural history of FOSMN. Another new finding was chorea, seen in 6 cases. Despite reports of autoantibodies, there is no consistent evidence to suggest an autoimmune pathogenesis. Four of 6 autopsies had TAR DNA-binding protein (TDP) 43 pathology. Seven cases had genetic mutations associated with neurodegenerative diseases. SUMMARY: FOSMN is a rare disease with a highly characteristic onset and pattern of disease progression involving initial sensory disturbances, followed by bulbar weakness with a cranial to caudal spread of pathology. Although not conclusive, the balance of evidence suggests that FOSMN is most likely to be a TDP-43 proteinopathy within the amyotrophic lateral sclerosis-FTD spectrum.

10.
J Neurol ; 268(7): 2533-2540, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33547953

RESUMO

Cognitive and behavioural impairment in amyotrophic lateral sclerosis (ALS) negatively influences the quality of life and survival, and, therefore, screening for these impairments is recommended. We developed a cognitive screening tool, the amyotrophic lateral sclerosis-frontotemporal dementia-cognitive screen (ALS-FTD-Cog) and aimed to validate it in patients with ALS. During the current study, the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was published and we, therefore, decided to compare these two cognitive screening methods. The ALS-FTD-Cog was administered to 72 patients with ALS, 21 patients with behavioural variant FTD (bvFTD) and 34 healthy controls. Twenty-nine patients with ALS underwent the ECAS. ROC curve analyses were performed and sensitivity and specificity of the ALS-FTD-Cog and ECAS were calculated, with a neuropsychological examination (NPE) as the gold standard. Cognitive impairment was present in 28% of patients with ALS. ROC curve analyses of the ALS-FTD-Cog and ECAS showed an area under the curve (AUC) of 0.72 (95% CI 0.58-0.86) and 0.95 (95% CI 0.86-1.03), respectively. Compared to a full NPE, sensitivity and specificity of the ALS-FTD-Cog were 65.0% and 63.5% and of the ECAS 83.3% and 91.3%, respectively. The sensitivity and specificity of the ALS-FTD-Cog in patients with bvFTD were 94.4% and 100%, respectively. Test characteristics of the ALS-FTD-Cog were moderate, suggesting restricted practical value, as compared to a comprehensive NPE. The ECAS had an excellent AUC and high sensitivity and specificity, indicating that it is a valid screening instrument for cognitive impairment in ALS.


Assuntos
Esclerose Amiotrófica Lateral , Transtornos Cognitivos , Demência Frontotemporal , Esclerose Amiotrófica Lateral/complicações , Esclerose Amiotrófica Lateral/diagnóstico , Cognição , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Demência Frontotemporal/complicações , Demência Frontotemporal/diagnóstico , Humanos , Testes Neuropsicológicos , Qualidade de Vida
11.
Neurology ; 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33472922

RESUMO

OBJECTIVE: To assess time trends in MND incidence, prevalence and mortality and investigate geographical clustering of MND cases in the Netherlands from 1998 to 2017, we analyzed data from the Netherlands Personal Records database, the Netherlands MND Center and the Netherlands Patient Association of Neuromuscular Diseases. METHODS: In this prospective cohort study, Poisson regression was used to assess time trends in MND risk. We calculated age- and sex-standardized, observed and expected cases for 1,694 areas. Bayesian smoothed risk mapping was used to investigate geographical MND risk. RESULTS: We identified 7,992 MND cases, reflecting an incidence of 2.64 (95% CI 2.62-2.67) per 100,000 person-years and a prevalence of 9.5 (95% CI 9.1-10.0) per 100,000 persons. Highest age-standardized prevalence and mortality rates occurred at a later age in men than in women (p<0.001). Unadjusted mortality rates increased by 53.2% from 2.57 in 1998 to 3.86 per 100,000 person-years in 2017. After adjustment for age and sex, an increase in MND mortality rate of 14.1% (95% CI 5.7%-23.2%, p<0.001) remained. MND relative risk ranged from 0.78 to 1.43 between geographical areas; multiple urban and rural high-risk areas were identified. CONCLUSIONS: We found a significant national increase in MND mortality from 1998 through 2017, only partly explained by an ageing Dutch population, and also a geographic variability in MND risk, suggesting a role for environmental or demographic risk factors.

13.
BMC Neurol ; 20(1): 446, 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33308184

RESUMO

BACKGROUND: Personalized ENCALS survival prediction model reliably estimates the personalized prognosis of patients with amyotrophic lateral sclerosis. Concerns were raised on discussing personalized prognosis without causing anxiety and destroying hope. Tailoring communication to patient readiness and patient needs mediates the impact of prognostic disclosure. We developed a communication guide to support physicians in discussing personalized prognosis tailored to individual needs and preferences of people with ALS and their families. METHODS: A multidisciplinary working group of neurologists, rehabilitation physicians, and healthcare researchers A) identified relevant topics for guidance, B) conducted a systematic review on needs of patients regarding prognostic discussion in life-limiting disease, C) drafted recommendations based on evidence and expert opinion, and refined and finalized these recommendations in consensus rounds, based on feedback of an expert advisory panel (patients, family member, ethicist, and spiritual counsellor). RESULTS: A) Topics identified for guidance were 1) filling in the ENCALS survival model, and interpreting outcomes and uncertainty, and 2) tailoring discussion to individual needs and preferences of patients (information needs, role and needs of family, severe cognitive impairment or frontotemporal dementia, and non-western patients). B) 17 studies were included in the systematic review. C) Consensus procedures on drafted recommendations focused on selection of outcomes, uncertainty about estimated survival, culturally sensitive communication, and lack of decisional capacity. Recommendations for discussing the prognosis include the following: discuss prognosis based on the prognostic groups and their median survival, or, if more precise information is desired, on the interquartile range of the survival probability. Investigate needs and preferences of the patients and their families for prognostic disclosure, regardless of cultural background. If the patient does not want to know their prognosis, with patient permission discuss the prognosis with their family. If the patient is judged to lack decisional capacity, ask the family if they want to discuss the prognosis. Tailor prognostic disclosure step by step, discuss it in terms of time range, and emphasize uncertainty of individual survival time. CONCLUSION: This communication guide supports physicians in tailoring discussion of personalized prognosis to the individual needs and preferences of people with ALS and their families.


Assuntos
Esclerose Amiotrófica Lateral , Comunicação , Educação de Pacientes como Assunto/métodos , Relações Médico-Paciente , Revelação da Verdade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
14.
Artigo em Inglês | MEDLINE | ID: mdl-33177049

RESUMO

Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases. For instance, the majority of patients with sporadic amyotrophic lateral sclerosis (up to 97%) and a substantial proportion of patients with frontotemporal lobar degeneration (~45%) exhibit TDP-43 positive neuronal inclusions, suggesting a role for this protein in disease pathogenesis. In addition, TDP-43 inclusions are evident in familial ALS phenotypes linked to multiple gene mutations including the TDP-43 gene coding (TARDBP) and unrelated genes (eg, C9orf72). While TDP-43 is an essential RNA/DNA binding protein critical for RNA-related metabolism, determining the pathophysiological mechanisms through which TDP-43 mediates neurodegeneration appears complex, and unravelling these molecular processes seems critical for the development of effective therapies. This review highlights the key physiological functions of the TDP-43 protein, while considering an expanding spectrum of neurodegenerative diseases associated with pathogenic TDP-43 deposition, and dissecting key molecular pathways through which TDP-43 may mediate neurodegeneration.

15.
Brain Commun ; 2(2): fcaa064, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32954321

RESUMO

Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in C9orf72, polyglutamine expansions in ATXN2 and polyalanine expansions in NIPA1. Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by polyglutamine expansions in ATXN1, suggested a similar disease association for the repeat expansion in ATXN1. We, therefore, performed a large-scale international study in 11 700 individuals, in which we showed a significant association between intermediate ATXN1 repeat expansions and amyotrophic lateral sclerosis (P = 3.33 × 10-7). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in Drosophila, further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis.

16.
Expert Rev Neurother ; 20(9): 895-906, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32749157

RESUMO

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by the progressive loss of upper and lower motor neurons. ALS has traditionally been classified within the domain of neuromuscular diseases, which are a unique spectrum of disorders that predominantly affect the peripheral nervous system. However, over the past decades compounding evidence has emerged that there is extensive involvement of the central nervous system. Therefore, one can question whether it remains accurate to classify ALS as a neuromuscular disorder. AREAS COVERED: In this review, the authors sought to discuss current approaches toward disease classification and how we should classify ALS based on novel insights from clinical, imaging, pathophysiological, neuropathological and genetic studies. EXPERT OPINION: ALS exhibits the cardinal features of a neurodegenerative disease. Therefore, classifying ALS as a neuromuscular disease in the strict sense has become untenable. Diagnosing ALS however does require significant neuromuscular expertise and therefore neuromuscular specialists remain best equipped to evaluate this category of patients. Designating motor neuron diseases as a separate category in the ICD-11 is justified and adequately deals with this issue. However, to drive effective therapy development the fields of motor neuron disease and neurodegenerative disorders must come together.


Assuntos
Esclerose Amiotrófica Lateral/classificação , Doenças Neurodegenerativas/classificação , Doenças Neuromusculares/classificação , Humanos
17.
Ann Neurol ; 88(4): 796-806, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32627229

RESUMO

OBJECTIVE: The rs12608932 single nucleotide polymorphism in UNC13A is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) susceptibility, and may underlie differences in treatment response. We aimed to characterize the clinical, cognitive, behavioral, and neuroimaging phenotype of UNC13A in patients with ALS. METHODS: We included 2,216 patients with ALS without a C9orf72 mutation to identify clinical characteristics associated with the UNC13A polymorphism. A subcohort of 428 patients with ALS was used to study cognitive and behavioral profiles, and 375 patients to study neuroimaging characteristics. Associations were analyzed under an additive genetic model. RESULTS: Genotyping rs12608932 resulted in 854 A/A, 988 A/C, and 374 C/C genotypes. The C allele was associated with a higher age at symptom onset (median years A/A 63.5, A/C 65.6, and C/C 65.5; p < 0.001), more frequent bulbar onset (A/A 29.6%, A/C 31.8%, and C/C 43.1%; p < 0.001), higher incidences of ALS-FTD (A/A 4.3%, A/C 5.2%, and C/C 9.5%; p = 0.003), lower forced vital capacity at diagnosis (median percentage A/A 92.0, A/C 90.0, and C/C 86.5; p < 0.001), and a shorter survival (median in months A/A 33.3, A.C 30.7, and C/C 26.6; p < 0.001). UNC13A was associated with lower scores on ALS-specific cognition tests (means A/A 79.5, A/C 78.1, and C/C 76.6; p = 0.037), and more frequent behavioral disturbances (A/A 16.7%, A/C 24.4%, and C/C 27.7%; p = 0.045). Thinner left inferior temporal and right fusiform cortex were associated with the UNC13A single nucleotide polymorphism (SNP; p = 0.045 and p = 0.036). INTERPRETATION: Phenotypical distinctions associated with UNC13A make it an important factor to take into account in clinical trial design, studies on cognition and behavior, and prognostic counseling. ANN NEUROL 2020;88:796-806.


Assuntos
Esclerose Amiotrófica Lateral/genética , Proteínas do Tecido Nervoso/genética , Idoso , Esclerose Amiotrófica Lateral/complicações , Esclerose Amiotrófica Lateral/patologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único
18.
Artigo em Inglês | MEDLINE | ID: mdl-32627599

RESUMO

OBJECTIVE: A recent case-series described patients with ALS to improve and/or stabilize after treatment with intravenous high-dose Penicillin G/Hydrocortisone (PenGH). In this study, we determine the safety and efficacy of intravenous PenGH versus placebo in combination with riluzole in patients with ALS. METHODS: Patients diagnosed with ALS according to the El Escorial criteria were randomized double-blind to four quarterly cycles of 21 d of intravenous PenGH or placebo in a 5:3 ratio. The primary outcome was change from baseline to week 48 in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). Secondary outcomes were lung function, muscle strength, plasma creatinine, clinical stage, gastrostomy placement, quality of life and occurrence of adverse of events. RESULTS: In total, 16 patients were randomized (10 PenGH and 6 placebo), of which 6 (40%) completed the study. Patients treated with PenGH progressed with 2.2 (95% CI 1.1-3.3) ALSFRS-R points per month and PenGH treatment did not halt disease progression (p = 0.002). No significant differences were found between PenGH or placebo (mean difference 0.5, 95% CI -1.01 to ∞, p = 0.28). Although PenGH was well-tolerated, 6 patients (38%, 3 in each arm) had thrombotic complications due to the intravenous administration method. CONCLUSIONS: Treatment with PenGH does not halt disease or reverse progression in patients with ALS and showed no statistical difference with those who received placebo. Prolonged intravenous administration therapies may inflate thrombosis risk.


Assuntos
Esclerose Amiotrófica Lateral , Esclerose Amiotrófica Lateral/tratamento farmacológico , Método Duplo-Cego , Humanos , Hidrocortisona , Penicilina G , Qualidade de Vida
19.
Artigo em Inglês | MEDLINE | ID: mdl-32643415

RESUMO

A change in our current approach toward drug development is required to improve the likelihood of finding effective treatment for patients with amyotrophic lateral sclerosis (ALS). The aim of the Treatment Research Initiative to Cure ALS (TRICALS) is to extend the collective effort with industry and consolidate drug development paths. TRICALS has begun a series of meetings on how to best move the field forward collaboratively, thereby addressing five major topics in ALS clinical trials: (1) preclinical research, (2) biomarker development, (3) eligibility criteria, (4) efficacy endpoints and (5) innovative trial design. There is an appetite for ongoing discussions of these major topics in clinical trials between representatives from academia, patient advocacy groups, industry partners and funding bodies. Industry is open to fundamentally change drug development for ALS and shorten the time to effective therapy for patients by implementing promising innovations in biomarker development, trial design, and patient selection. There is however, a pressing need from all stakeholders for regulatory discussions and amendments of current guidelines to successfully adopt innovation in future clinical development lines.


Assuntos
Esclerose Amiotrófica Lateral , Esclerose Amiotrófica Lateral/tratamento farmacológico , Biomarcadores , Humanos , Seleção de Pacientes , Resultado do Tratamento
20.
J Neurol Neurosurg Psychiatry ; 91(8): 867-875, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32576612

RESUMO

OBJECTIVE: To determine the prevalence and prognostic value of weight loss (WL) prior to diagnosis in patients with amyotrophic lateral sclerosis (ALS). METHODS: We enrolled patients diagnosed with ALS between 2010 and 2018 in a population-based setting. At diagnosis, detailed information was obtained regarding the patient's disease characteristics, anthropological changes, ALS-related genotypes and cognitive functioning. Complete survival data were obtained. Cox proportional hazard models were used to assess the association between WL and the risk of death during follow-up. RESULTS: The data set comprised 2420 patients of whom 67.5% reported WL at diagnosis. WL occurred in 71.8% of the bulbar-onset and in 64.2% of the spinal-onset patients; the mean loss of body weight was 6.9% (95% CI 6.8 to 6.9) and 5.5% (95% CI 5.5 to 5.6), respectively (p<0.001). WL occurred in 35.1% of the patients without any symptom of dysphagia. WL is a strong independent predictor of survival, with a dose response relationship between the amount of WL and the risk of death: the risk of death during follow-up increased by 23% for every 10% increase in WL relative to body weight (HR 1.23, 95% CI 1.13 to 1.51, p<0.001). CONCLUSIONS: This population-based study shows that two-thirds of the patients with ALS have WL at diagnosis, which also occurs independent of dysphagia, and is related to survival. Our results suggest that WL is a multifactorial process that may differ from patient to patient. Gaining further insight in its underlying factors could prove essential for future therapeutic measures.


Assuntos
Esclerose Amiotrófica Lateral/diagnóstico , Perda de Peso , Idoso , Esclerose Amiotrófica Lateral/mortalidade , Esclerose Amiotrófica Lateral/patologia , Peso Corporal , Progressão da Doença , Feminino , Humanos , Masculino , Prevalência , Prognóstico , Estudos Prospectivos
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