RESUMO
Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease (MND) that shares a common clinical, genetic and pathologic spectrum with frontotemporal dementia (FTD). It is highly heterogeneous in its presentation and features. Up to 50% of patients with MND develop cognitive-behavioural symptoms during the course of the disease, meeting criteria for FTD in 10%-15% of cases. In the absence of a precise biomarker, neuropathology is still a valuable tool to understand disease nosology, reach a definite diagnostic confirmation and help define specific subgroups of patients with common phenotypic, genetic and biomarker profiles. However, few neuropathological series have been published, and the frequency of frontotemporal lobar degeneration (FTLD) in MND is difficult to estimate. In this work we describe a large clinicopathological series of MND patients, analysing the frequency of concurrent FTLD changes and trying to define specific subgroups of patients based on their clinical, genetic and pathological characteristics. We performed an observational, retrospective, multicentre case study. We included all cases meeting neuropathological criteria for MND from the Neurological Tissue Bank of the FRCB-IDIBAPS-Hospital Clínic Barcelona Biobank between 1994 and 2022, regardless of their last clinical diagnosis. While brain donation is encouraged in all patients, it is performed in very few, and representativeness of the cohort might not be precise for all patients with MND. We retrospectively reviewed clinical and neuropathological data and describe the main clinical, genetic and pathogenic features, comparing neuropathologic groups between MND with and without FTLD changes and aiming to define specific subgroups. We included brain samples from 124 patients, 44 of whom (35.5%) had FTLD neuropathologic features (i.e. FTLD-MND). Pathologic TDP-43 aggregates were present in 93.6% of the cohort and were more extensive (higher Brettschneider stage) in those with concurrent FTLD (P < 0.001). Motor symptom onset was more frequent in the bulbar region in FTLD-MND cases than in those with isolated MND (P = 0.023), with no differences in survival. We observed a better clinicopathological correlation in the MND group than in the FTLD-MND group (93.8% versus 61.4%; P < 0.001). Pathogenic genetic variants were more common in the FTLD-MND group, especially C9orf72. We describe a frequency of FTLD of 35.5% in our series of neuropathologically confirmed cases of MND. The FTLD-MND spectrum is highly heterogeneous in all aspects, especially in patients with FTLD, in whom it is particularly difficult to define specific subgroups. In the absence of definite biomarkers, neuropathology remains a valuable tool for a definite diagnosis, increasing our knowledge in disease nosology.
Assuntos
Degeneração Lobar Frontotemporal , Doença dos Neurônios Motores , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Degeneração Lobar Frontotemporal/patologia , Degeneração Lobar Frontotemporal/genética , Estudos Retrospectivos , Doença dos Neurônios Motores/patologia , Doença dos Neurônios Motores/genética , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/genética , Demência Frontotemporal/patologia , Demência Frontotemporal/genética , Encéfalo/patologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismoRESUMO
BACKGROUND AND OBJECTIVE: Between 5% and 10% of amyotrophic lateral sclerosis (ALS) cases have a family history of the disease, 30% of which do not have an identifiable underlying genetic cause after a comprehensive study of the known ALS-related genes. Based on a significantly increased incidence of ALS in a small geographical region from Spain, the aim of this work was to identify novel ALS-related genes in ALS cases with negative genetic testing. METHODS: We detected an increased incidence of both sporadic and, especially, familial ALS cases in a small region from Spain compared with available demographic and epidemiological data. We performed whole genome sequencing in a group of 12 patients with ALS (5 of them familial) from this unique area. We expanded the study to include affected family members and additional cases from a wider surrounding region. RESULTS: We identified a shared missense mutation (c.1586C>T; p.Pro529Leu) in the cyclic AMP regulated phosphoprotein 21 (ARPP21) gene that encodes an RNA-binding protein, in a total of 10 patients with ALS from 7 unrelated families. No mutations were found in other ALS-causing genes. CONCLUSIONS: While previous studies have dismissed a causal role of ARPP21 in ALS, our results strongly support ARPP21 as a novel ALS-causing gene.
RESUMO
BACKGROUND AND PURPOSE: Generalized myasthenia gravis (gMG) continues to present significant challenges for clinical management due to an unpredictable disease course, frequent disease fluctuations, and varying response to therapy. The recent availability of new pharmacologic therapies presents a valuable opportunity to reevaluate how this disease is classified, assessed, and managed and identify new ways to improve the clinical care of patients with gMG. METHODS: Narrative review was made of publications identified via searches of PubMed and selected congresses (January 2000-September 2022). RESULTS: New consensus definitions are required to ensure consistency, to better characterize patients, and to identify patients who will benefit from specific drugs and earlier use of these agents. There is a need for more frequent, standardized patient assessment to identify the cause of motor function deficits, provide a clearer picture of the disease burden and its impact on daily living and quality of life (QoL), and better support treatment decision-making. Novel approaches that target different components of the immune system will play a role in more precise treatment of patients with gMG, alongside the development of new algorithms to guide individualized patient management. CONCLUSIONS: gMG has a physical, mental, and social impact, resulting in a considerable burden of disease and substantially decreased QoL, despite standard treatments. The availability of novel, targeted treatments that influence key pathological mediators of gMG, together with new biomarkers, offers the potential to optimize patient management and ultimately enables a greater number of patients to achieve minimal manifestation status and a reduced burden of disease.
Assuntos
Miastenia Gravis , Miastenia Gravis/terapia , Miastenia Gravis/tratamento farmacológico , Humanos , Efeitos Psicossociais da Doença , Qualidade de VidaRESUMO
BACKGROUND: Azathioprine is a widely prescribed drug for patients with chronic inflammatory diseases such as myasthenia gravis or organ transplant recipients. Azathioprine exerts immunosuppressive effects by inhibiting intracellular purine synthesis and reducing the numbers of circulating B and T lymphocytes. Case reports indicate increased risk for serious infections that can occur despite regular measurements of lymphocyte counts during azathioprine therapy. OBJECTIVE: We sought to comprehensively investigate therapy-associated patient risks and the underlying immune dysfunction of azathioprine use. METHODS: Peripheral blood leukocytes were analyzed using single-cell mass and spectral flow cytometry to detect specific effects of azathioprine use on the systemic immune signature. Therapy-associated clinical features were analyzed in 2 independent cohorts of myasthenia gravis patients. RESULTS: Azathioprine therapy selectively induced pronounced CD56dimCD16+ natural killer cell depletion and concomitant IFN-γ deficiency. Cytokine profiling revealed a specific contraction of classical TH1 cells during azathioprine treatment. We further observed an increased occurrence of reactivation of endogenous latent herpesviruses in the azathioprine-treated group versus in patients with myasthenia gravis who were not receiving immunomodulatory treatment; this increased occurrence was validated in an independent cohort. CONCLUSION: Our study highlights the risk of development of adverse events during azathioprine therapy and suggests that natural killer cell monitoring could be valuable in clinical practice.
Assuntos
Herpesviridae , Miastenia Gravis , Humanos , Azatioprina/efeitos adversos , Células Matadoras Naturais , Interferon gama/farmacologia , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/induzido quimicamenteRESUMO
Leptospirosis is a zoonotic infection that can present with neurological manifestations. Although uncommon, it may affect the peripheral nervous system in the form of polyradiculoneuropathy. We report the case of a 30-year-old male who developed flaccid tetraparesis and multiple cranial neuropathies on the fourteenth day of admission to the intensive care unit for fever and multi-organ failure. We also review the existing literature about peripheral nerve damage in leptospirosis and present our hypothesis on the possible pathogenic mechanisms. Electrophysiological findings were consistent with acute demyelinating polyradiculoneuropathy and extensive blood tests were positive for leptospiral IgM and IgG antibodies. Treatment with plasmapheresis was begun, followed by intravenous immunoglobulin (IVIg), and the patient improved slowly. Our work adds to the evidence of leptospirosis infection as a cause of acute demyelinating polyneuropathy. The possibility that leptospirosis-polyradiculoneuropathy may be caused by an immune pathogenesis emphasizes the importance of identifying this entity because immunomodulatory therapy could play a vital role in the recovery process.
Assuntos
Síndrome de Guillain-Barré , Leptospirose , Doenças do Sistema Nervoso Periférico , Polineuropatias , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Masculino , Humanos , Adulto , Imunoglobulinas Intravenosas , Doenças do Sistema Nervoso Periférico/etiologia , Doenças do Sistema Nervoso Periférico/terapia , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/terapia , Síndrome de Guillain-Barré/complicações , Polineuropatias/complicações , Leptospirose/complicações , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/terapiaRESUMO
The SARS-CoV-2 virus that causes the COVID-19 disease, reports hundreds of infections daily, the alterations and sequelae of this new pathogen have been reported globally, due to the seriousness of being an older adult and evolving seriously.
Assuntos
COVID-19 , Doenças do Sistema Nervoso , Humanos , Idoso , COVID-19/complicações , SARS-CoV-2 , Doenças do Sistema Nervoso/complicações , Progressão da Doença , CogniçãoRESUMO
BACKGROUND: Guillain-Barré syndrome (GBS) is an acute inflammatory neuropathy with a heterogeneous presentation. Although some evidences support the role of autoantibodies in its pathogenesis, the target antigens remain unknown in a substantial proportion of GBS patients. The objective of this study is to screen for autoantibodies targeting peripheral nerve components in Guillain-Barré syndrome. METHODS: Autoantibody screening was performed in serum samples from all GBS patients included in the International GBS Outcome study by 11 different Spanish centres. The screening included testing for anti-ganglioside antibodies, anti-nodo/paranodal antibodies, immunocytochemistry on neuroblastoma-derived human motor neurons and murine dorsal root ganglia (DRG) neurons, and immunohistochemistry on monkey peripheral nerve sections. We analysed the staining patterns of patients and controls. The prognostic value of anti-ganglioside antibodies was also analysed. RESULTS: None of the GBS patients (n = 100) reacted against the nodo/paranodal proteins tested, and 61 (61%) were positive for, at least, one anti-ganglioside antibody. GBS sera reacted strongly against DRG neurons more frequently than controls both with IgG (6% vs 0%; p = 0.03) and IgM (11% vs 2.2%; p = 0.02) immunodetection. No differences were observed in the proportion of patients reacting against neuroblastoma-derived human motor neurons. Reactivity against monkey nerve tissue was frequently detected both in patients and controls, but specific patterns were only detected in GBS patients: IgG from 13 (13%) patients reacted strongly against Schwann cells. Finally, we confirmed that IgG anti-GM1 antibodies are associated with poorer outcomes independently of other known prognostic factors. CONCLUSION: Our study confirms that (1) GBS patients display a heterogeneous repertoire of autoantibodies targeting nerve cells and structures; (2) gangliosides are the most frequent antigens in GBS patients and have a prognostic value; (3) further antigen-discovery experiments may elucidate other potential antigens in GBS.
Assuntos
Autoanticorpos/sangue , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/diagnóstico , Idoso , Animais , Linhagem Celular Tumoral , Estudos de Coortes , Feminino , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Síndrome de Guillain-Barré/epidemiologia , Humanos , Macaca , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Estudos Prospectivos , Ratos , Espanha/epidemiologiaRESUMO
BACKGROUND AND PURPOSE: Distal hereditary motor neuropathies (dHMNs) are a heterogeneous group of disorders characterized by degeneration of the motor component of peripheral nerves. Currently, only 15% to 32.5% of patients with dHMN are characterized genetically. Additionally, the prevalence of these genetic disorders is not well known. Recently, biallelic mutations in the sorbitol dehydrogenase gene (SORD) have been identified as a cause of dHMN, with an estimated frequency in undiagnosed cases of up to 10%. METHODS: In the present study, we included 163 patients belonging to 108 different families who were diagnosed with a dHMN and who underwent a thorough genetic screening that included next-generation sequencing and subsequent Sanger sequencing of SORD. RESULTS: Most probands were sporadic cases (62.3%), and the most frequent age of onset of symptoms was 2 to 10 years (28.8%). A genetic diagnosis was achieved in 37/108 (34.2%) families and 78/163 (47.8%) of all patients. The most frequent cause of distal hereditary motor neuropathies were mutations in HSPB1 (10.4%), GARS1 (9.8%), BICD2 (8.0%), and DNAJB2 (6.7%) genes. In addition, 3.1% of patients were found to be carriers of biallelic mutations in SORD. Mutations in another seven genes were also identified, although they were much less frequent. Eight new pathogenic mutations were detected, and 17 patients without a definite genetic diagnosis carried variants of uncertain significance. The calculated minimum prevalence of dHMN was 2.3 per 100,000 individuals. CONCLUSIONS: This study confirms the genetic heterogeneity of dHMN and that biallelic SORD mutations are a cause of dHMN in different populations.
Assuntos
Doença de Charcot-Marie-Tooth , Neuropatia Hereditária Motora e Sensorial , Doença de Charcot-Marie-Tooth/genética , Criança , Pré-Escolar , Estudos de Associação Genética , Testes Genéticos , Proteínas de Choque Térmico HSP40 , Heterozigoto , Humanos , Chaperonas Moleculares , MutaçãoRESUMO
BACKGROUND AND PURPOSE: Prognosis of myasthenia gravis (MG) in patients with thymoma is not well established. Moreover, it is not clear whether thymoma recurrence or unresectable lesions entail a worse prognosis of MG. METHODS: This multicenter study was based on dataâ¯fromâ¯aâ¯Spanish neurologist-drivenâ¯MG registry. All patients were aged >18 yearsâ¯atâ¯onsetâ¯and had anti-acetylcholine receptor antibodies.â¯We compared the clinical data of thymomatous and nonthymomatous patients.â¯Prognosis of patients with recurrent or nonresectable thymomas was assessed. RESULTS: We included 964 patients from 15 hospitals; 148 (15.4%) had thymoma-associated MG. Median follow-up time was 4.6 years. At onset, thymoma-associated MG patients were younger (52.0 vs. 60.4 years, p < 0.001), had more generalized symptoms (odds ratio [OR]: 3.02, 95% confidence interval [CI]: 1.95-4.68, p < 0.001) and more severe clinical forms according to the Myasthenia Gravis Foundation of America (MGFA) scale (OR: 1.6, 95% CI: 1.15-2.21, p = 0.005). Disease severity based on MGFA postintervention status (MGFA-PIS) was higher in thymomatous patients at 1 year, 5 years, and the end of follow-up. Treatment refractoriness and mortality were also higher (OR: 2.28, 95% CI: 1.43-3.63, p = 0.001; hazard ratio: 2.46, 95% CI: 1.47-4.14, p = 0.001). Myasthenic symptoms worsened in 13 of 27 patients with recurrences, but differences in long-term severity were not significant. Fifteen thymomatous patients had nonresectable thymomas with worse MGFA-PIS and higher mortality at the end of follow-up. CONCLUSIONS: Thymoma-associated MG patients had more severe myasthenic symptoms and worse prognosis. Thymoma recurrence was frequently associated with transient worsening of MG, but long-term prognosis did not differ from nonrecurrent thymoma. Patients with nonresectable thymoma tended to present severe forms of MG.
Assuntos
Miastenia Gravis , Timoma , Neoplasias do Timo , Humanos , Miastenia Gravis/complicações , Miastenia Gravis/epidemiologia , Recidiva Local de Neoplasia , Estudos Retrospectivos , Timectomia , Timoma/complicações , Timoma/epidemiologia , Neoplasias do Timo/complicações , Neoplasias do Timo/epidemiologiaRESUMO
We report the case of a patient with a clinical phenotype characterized by distal lower limb weakness and pes cavus. The electrophysiological study showed slightly reduced or normal amplitude of motor potentials, a decremental response to repetitive nerve stimulation and post-exercise facilitation. Muscle biopsy showed only mild neurogenic features. Genetic analysis included a clinical exome sequencing, followed by Sanger analysis. Three-dimensional (3D) models were generated with a SwissModel (https://swissmodel.expasy.org/) to explain the clinical observations and reinforce the pathogenic nature of the genetic variant identified. Genetic analysis demonstrated a new de novo heterozygous in frame deletion of the SYT2 gene (NM_177402.4: c.1082_1096del), confirmed by Sanger sequencing, which removes five aminoacids in the C2B domain of synaptotagmin-2 protein, that cause a profound effect on the structure and function of this synaptic vesicle protein. We identified a de novo genetic variant in the SYT2 gene, further supporting its association with a highly stereotyped clinical and electrophysiological phenotype. Our case showed electrophysiological features consistent with a presynaptic dysfunction in the neuromuscular junction with normal post-exercise amplitudes, not supporting the presence of predominant axonal damage. Although the analysis of SYT2 gene should be included in genetic analysis of patients presenting with this clinical phenotype that mimics motor neuropathy, clinicians have to consider the study of neuromuscular transmission to early identify this potentially treatable condition.
Assuntos
Debilidade Muscular/fisiopatologia , Doenças Neuromusculares/diagnóstico , Junção Neuromuscular/fisiopatologia , Doenças do Sistema Nervoso Periférico/diagnóstico , Sinaptotagmina II/genética , Adulto , Eletrodiagnóstico , Mutação da Fase de Leitura , Humanos , Extremidade Inferior/fisiopatologia , Masculino , Doenças Neuromusculares/genética , Doenças Neuromusculares/fisiopatologia , Linhagem , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/fisiopatologiaRESUMO
OBJECTIVE: To study baseline serum neurofilament light chain (sNfL) levels as a prognostic biomarker in Guillain-Barré syndrome (GBS). METHODS: We measured NfL in serum (98 samples) and cerebrospinal fluid (CSF) (24 samples) of patients with GBS prospectively included in the International GBS Outcome Study (IGOS) in Spain using single-molecule array (SiMoA) and compared them with 53 healthy controls (HCs). We performed multivariable regression to analyse the association between sNfL levels and functional outcome at 1 year. RESULTS: Patients with GBS had higher NfL levels than HC in serum (55.49 pg/mL vs 9.83 pg/mL, p<0.0001) and CSF (1308.5 pg/mL vs 440.24 pg/mL, p=0.034). Patients with preceding diarrhoea had higher sNfL than patients with respiratory symptoms or no preceding infection (134.90 pg/mL vs 47.86 pg/mL vs 38.02 pg/mL, p=0.016). sNfL levels correlated with Guillain-Barré Syndrome Disability Score and Inflammatory Rasch-built Overall Disability Scale (I-RODS) at every timepoint. Patients with pure motor variant and Miller Fisher syndrome showed higher sNfL levels than patients with sensorimotor GBS (162.18 pg/mL vs 95.50 pg/mL vs 38.02 pg/mL, p=0.025). Patients with acute motor axonal neuropathy cute motor axonal neuropathy had higher sNfL levels than other variants (190.55 pg/mL vs 46.79 pg/mL, p=0.013). sNfL returned to normal levels at 1 year. High baseline sNfL levels were associated with inability to run (OR=1.65, 95% CI 1.14 to 2.40, p=0.009) and lower I-RODS (ß -2.60, 95% CI -4.66 to -0.54, p=0.014) at 1 year. Cut-off points predicting clinically relevant outcomes at 1 year with high specificity were calculated: inability to walk independently (>319 pg/mL), inability to run (>248 pg/mL) and ability to run (<34 pg/mL). CONCLUSION: Baseline sNfL levels are increased in patients with GBS, are associated with disease severity and axonal variants and have an independent prognostic value in patients with GBS.
RESUMO
BACKGROUND AND OBJECTIVE: Oculopharyngeal muscular dystrophy (OPMD) is a genetic disorder caused by an abnormal expansion of GCN triplets within the PABPN1 gene. Previous descriptions have focused on lower limb muscles in small cohorts of patients with OPMD, but larger imaging studies have not been performed. Previous imaging studies have been too small to be able to correlate imaging findings to genetic and clinical data. METHODS: We present cross-sectional, T1-weighted muscle MRI and CT-scan data from 168 patients with genetically confirmed OPMD. We have analysed the pattern of muscle involvement in the disease using hierarchical analysis and presented it as heatmaps. Results of the scans were correlated with genetic and clinical data. RESULTS: Fatty replacement was identified in 96.7% of all symptomatic patients. The tongue, the adductor magnus and the soleus were the most commonly affected muscles. Muscle pathology on MRI correlated positively with disease duration and functional impairment. CONCLUSIONS: We have described a pattern that can be considered characteristic of OPMD. An early combination of fat replacement in the tongue, adductor magnus and soleus can be helpful for differential diagnosis. The findings suggest the natural history of the disease from a radiological point of view. The information generated by this study is of high diagnostic value and important for clinical trial development.
Assuntos
Músculo Esquelético/diagnóstico por imagem , Distrofia Muscular Oculofaríngea/diagnóstico por imagem , Adulto , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Distrofia Muscular Oculofaríngea/complicações , Distrofia Muscular Oculofaríngea/patologia , Tomografia Computadorizada por Raios XRESUMO
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a clinical, pathological and genetic continuum. OBJECTIVES: The purpose of the present study was to assess the mutation burden that is present in patients with concurrent ALS and FTD (ALS/FTD) not carrying the chromosome 9 open reading frame 72 (C9orf72) hexanucleotide repeat expansion, the most important genetic cause in both diseases. METHODS: From an initial group of 973 patients with ALS, we retrospectively selected those patients fulfilling diagnostic criteria of concomitant ALS and FTD lacking the repeat expansion mutation in C9orf72. Our final study group consisted of 54 patients clinically diagnosed with ALS/FTD (16 with available postmortem neuropathological diagnosis). Data from whole exome sequencing were used to screen for mutations in known ALS and/or FTD genes. RESULTS: We identified 11 patients carrying a probable pathogenic mutation, representing an overall mutation frequency of 20.4%. TBK1 was the most important genetic cause of ALS/FTD (n=5; 9.3%). The second most common mutated gene was SQSTM1, with three mutation carriers (one of them also harboured a TBK1 mutation). We also detected probable pathogenic genetic alterations in TAF15, VCP and TARDBP and possible pathogenic mutations in FIG4 and ERBB4. CONCLUSION: Our results indicate a high genetic burden underlying the co-occurrence of ALS and FTD and expand the phenotype associated with TAF15, FIG4 and ERBB4 to FTD. A systematic screening of ALS and FTD genes could be indicated in patients manifesting both diseases without the C9orf72 expansion mutation, regardless of family history of disease.
Assuntos
Esclerose Lateral Amiotrófica/genética , Demência Frontotemporal/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/complicações , Proteínas de Ligação a DNA/genética , Feminino , Flavoproteínas/genética , Demência Frontotemporal/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Monoéster Fosfórico Hidrolases/genética , Proteínas Serina-Treonina Quinases/genética , Receptor ErbB-4/genética , Estudos Retrospectivos , Proteína Sequestossoma-1/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Proteína com Valosina/genéticaRESUMO
AIM: To determine the motor phenotype and outcome in a clinically ascertained group of patients with motor neuron disease (MND) and frontotemporal dementia (FTD). METHODS: This is an observational retrospective clinical study of patients fulfilling the clinical criteria for MND-FTD. A contemporary series of patients with amyotrophic lateral sclerosis (ALS) without dementia were included for comparison. Demographic, clinical, genetic, and neuropathological data were collected. A descriptive and comparative data analysis was performed. RESULTS: We identified 22 patients with MND-FTD. Selective distal upper limb muscle weakness and atrophy with non-significant lower limb weakness during follow-up was the most frequent motor pattern, present in 18 patients - in 15 of them associated with severe dysphagia. Aspiration pneumonia was the most common cause of death (12/19; 63%) despite gastrostomy. One-third of the patients did not develop upper motor neuron dysfunction. When compared to classic ALS without dementia (n = 162), these features were significantly different. A neuro-pathological examination was performed on 7 patients, and it confirmed the presence of MND with TDP43 protein aggregates in all patients. CONCLUSIONS: The MND-FTD patients frequently displayed a distinctive motor pattern characterized by weakness and atrophy in distal upper limb muscles and dysphagia, with no or little spreading to other regions. These features may help to define specific subgroups of patients, which is important with regard to clinical management, outcome, and research.
Assuntos
Proteínas de Ligação a DNA/genética , Demência Frontotemporal , Doença dos Neurônios Motores , Debilidade Muscular/diagnóstico , Extremidade Superior , Idoso , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/fisiopatologia , Esclerose Lateral Amiotrófica/psicologia , Sintomas Comportamentais/diagnóstico , Feminino , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/genética , Demência Frontotemporal/fisiopatologia , Demência Frontotemporal/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/diagnóstico , Doença dos Neurônios Motores/genética , Doença dos Neurônios Motores/fisiopatologia , Doença dos Neurônios Motores/psicologia , Avaliação de Resultados em Cuidados de Saúde , Administração dos Cuidados ao Paciente/métodos , Estudos Retrospectivos , Extremidade Superior/patologia , Extremidade Superior/fisiopatologiaRESUMO
BACKGROUND AND PURPOSE: The incidence, underlying physiopathology, features and association with lesion topography of visual hallucinations in acute stroke have scarcely been investigated. METHODS: Patients with a diagnosis of acute stroke (ischaemic or haemorrhagic) in any vascular territory, admitted within 24 h after the onset of symptoms, were consecutively included in the study. Patients with a previous history of psychosis or cognitive impairment were excluded. They and/or their caregivers answered a structured hallucination and sleep questionnaire at admission, within the first 15 days and at the clinical follow-up 3-6 months after discharge. Lesion location (IMAIOS online atlas) and leukoaraiosis (Wahlund scale) were determined by magnetic resonance imaging or computed tomography scan. Subsets of patients also underwent a neuropsychological evaluation (N = 50) and an electroencephalogram (N = 33) before discharge. RESULTS: In all, 77 patients with a mean age of 71 ± 12 years were included of whom 57.1% were men. The incidence of visual hallucinations was 16.7%. These hallucinations were mostly complex, in black and white and self-limited. The appearance of hallucinations was not influenced by age, sex, neuropsychological performance during admission or modified Rankin scale score at discharge. Visual hallucinations were associated with occipital cortex lesions (P = 0.04), and with sleep disturbances during and before admission (P = 0.041 and P = 0.03 respectively). CONCLUSIONS: Visual hallucinations are relatively frequent in patients with acute stroke and they are self-limited. Patients with occipital lesions and sleep disturbances are more likely to suffer them.
Assuntos
Alucinações , Lobo Occipital/diagnóstico por imagem , Transtornos do Sono-Vigília , Acidente Vascular Cerebral , Idoso , Idoso de 80 Anos ou mais , Feminino , Alucinações/diagnóstico por imagem , Alucinações/etiologia , Alucinações/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/fisiopatologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/fisiopatologiaRESUMO
BACKGROUND: We report a case of stroke due to stenosis caused by a myxoma in the common carotid artery with no evidence of a cardiac origin. Only 1 such case has been reported previously in the literature. METHODS: A previously healthy 37-year-old woman presented with repeated episodes of acute focal deficits together with motor, sensory, and language symptoms typical of left internal carotid territory involvement. Brain magnetic resonance imaging showed acute and subacute ischemic lesions in the territory of the left middle cerebral artery and border zone infarcts (middle cerebral artery with anterior and posterior cerebral arteries). Magnetic resonance angiography showed a filling defect in the distal portion of the left common carotid artery causing stenosis over 70%. Transesophageal echocardiography showed no embolic sources. Blood tests ruled out a prothrombotic state. RESULTS: The image was initially interpreted as a possible subacute thrombus and anticoagulation was started. No changes were observed in the follow-up carotid ultrasound examination after 12 days of treatment. A gelatinous mass was removed during carotid surgery. No subjacent lesion was observed in the vessel wall. Pathology examination showed a spindle cell fibromyxoid tissue with fibrinoid material typical of myxoma. CONCLUSIONS: We hypothesize that the myxoma originated in the vessel, or alternatively, that a cardiac myxoma embolized without leaving a residual cardiac tumor. Although exceptional, myxoma should be added to the list of unusual causes of carotid artery stenosis causing stroke.
Assuntos
Artérias Carótidas/patologia , Constrição Patológica/complicações , Mixoma/complicações , Acidente Vascular Cerebral/etiologia , Adulto , Constrição Patológica/etiologia , Feminino , Humanos , Angiografia por Ressonância Magnética , Imageamento por Ressonância Magnética , Acidente Vascular Cerebral/diagnósticoRESUMO
Serological tests are important to detect autoantibodies (autoAbs) in patients with autoimmune neuropathies (AN) and myasthenia gravis (MG) as they are biomarkers for diagnosis, stratification, treatment selection, and monitoring. However, tests to detect autoAbs frequently lack proper standardization and results differ across diagnostic laboratories. We compared results for tests routinely performed in Spanish diagnostic laboratories to detect AN and MG autoAbs. In the Spanish Society of Immunology Autoimmunity Group national workshop, serum samples from 13 patients with AN or MG were tested for anti-ganglioside, anti-myelin-associated glycoprotein (MAG), anti-nicotinic acetylcholine receptor (AChR), and anti-muscle-specific kinase (MuSK) autoAbs using reference methods and were distributed for analysis to 27 participating laboratories using their routine methods. Overserved were inter-laboratory variability and worryingly low sensitivity, especially for anti-ganglioside immunoglobulin G and anti-MAG autoAb detection. This pilot study reflects autoAbs detection state of the art in AN and MG testing in leading diagnostic laboratories in Spain, highlighting the need for standardization prior to clinical use.
Assuntos
Autoanticorpos , Miastenia Gravis , Humanos , Miastenia Gravis/diagnóstico , Miastenia Gravis/sangue , Miastenia Gravis/imunologia , Autoanticorpos/sangue , Projetos Piloto , Espanha , Masculino , Feminino , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/sangue , Pessoa de Meia-Idade , Receptores Colinérgicos/imunologia , Adulto , IdosoRESUMO
OBJECTIVE: The objective was to determine the mean duration of diagnosis delay for patients with myasthenia gravis from five European countries and explore the impact of >1 year diagnosis delay. METHODS: Patients with myasthenia gravis (N = 387) from Europe (France/Germany/Italy/Spain/United Kingdom) and their physicians participated in the Adelphi Real World Myasthenia Gravis Disease Specific Programme™. Diagnosis delay (time from symptom onset to diagnosis) was calculated and characteristics described for patients experiencing >1 year and ≤1 year diagnosis delay. Denominators varied according to outcome as missing data were not imputed. RESULTS: Mean (standard deviation) diagnosis delay was 363.1 (520.9) days, and 27.1% (105 out of 387) of patients experienced diagnosis delay >1 year. Among patients with >1 year and ≤1 year diagnosis delay, respectively, 69.2% (72 out of 104) and 17.4% [45 out of 259] had initially received a different diagnosis (physician-reported); 40.0% (42 out of 105) and 24.1% (68 out of 282) were Myasthenia Gravis Foundation of America class III at the time of the survey (physician-reported); 72.4% (76 out of 105) and 61.3% (173 out of 282) had fatigue (subjective physician reporting from a pre-selected list of symptoms); 30.5% (32 out of 105) and 17.4% (49 out of 282) had anxiety and 21.9% (23 out of 105) and 13.1% (37 out of 282) had depression (both subjective physician reporting from a pre-selected list, Likert-style); and mean (standard deviation) MG-QoL-15r score was 14.4 (5.50) and 12.6 (7.84) (self-reported by N = 43 and N = 74 patients, respectively). INTERPRETATION: More than a quarter of patients with myasthenia gravis experienced diagnosis delay of >1 year. These patients had a different clinical profile with regards to severity, symptoms, comorbidities and MG-QoL-15r score, compared with patients experiencing ≤1 year diagnosis delay.
RESUMO
BACKGROUND AND OBJECTIVES: Autoantibody discovery in complex autoimmune diseases is challenging. Diverse successful antigen identification strategies are available, but, so far, have often been unsuccessful, especially in the discovery of protein antigens in which conformational and post-translational modification are critical. Our study assesses the utility of a human membrane and secreted protein microarray technology to detect autoantibodies in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: A cell microarray consisting of human embryonic kidney-293 cells expressing >5,000 human proteins was used. First, a validation step was performed with 4 serum samples from patients with autoimmune nodopathy (AN) to assess the ability of this technology to detect circulating known autoantibodies. The ability of the cell microarray technology to discover novel IgG autoantibodies was assessed incubating the array with 8 CIDP serum samples. Identified autoantibodies were subsequently validated using cell-based assays (CBAs), ELISA, and/or tissue immunohistochemistry and analyzed in a cohort of CIDP and AN (n = 96) and control (n = 100) samples. RESULTS: Serum anti-contactin-1 and anti-neurofascin-155 were detected by the human cell microarray technology. Nine potentially relevant antigens were found in patients with CIDP without other detectable antibodies; confirmation was possible in six of them: ephrin type-A receptor 7 (EPHA7); potassium-transporting ATPase alpha chain 1 and subunit beta (ATP4A/4B); leukemia-inhibitory factor (LIF); and interferon lambda 1, 2, and 3 (IFNL1, IFNL2, IFNL3). Anti-ATP4A/4B and anti-EPHA7 antibodies were detected in patients and controls and considered unrelated to CIDP. Both anti-LIF and anti-IFNL antibodies were found in the same 2 patients and were not detected in any control. Both patients showed the same staining pattern against myelinating fibers of peripheral nerve tissue and of myelinating neuron-Schwann cell cocultures. Clinically relevant correlations could not be established for anti-LIF and anti-IFNL3 antibodies. DISCUSSION: Our work demonstrates the utility of human cell microarray technology to detect known and discover unknown autoantibodies in human serum samples. Despite potential CIDP-associated autoantibodies (anti-LIF and anti-IFNL3) being identified, their clinical and pathogenic relevance needs to be elucidated in bigger cohorts.