RESUMO
BACKGROUND: Sneddon syndrome is an occlusive vasculopathy that presents clinically with generalized livedo racemosa on the skin and transient ischemic attacks, strokes, and cognitive or motor deficits in the central nervous system. Antiplatelet or anticoagulant therapy is recommended. Due to the limited therapeutic efficacy and the resulting serious complications, we propose combination therapy with additional infusion cycles of alprostadil and captopril and report initial long-term results. PATIENTS AND METHODS: We performed a systematic retrospective analysis of all patients with primary Sneddon syndrome who received combination therapy in our clinic between 1995 and 2020. Therapeutic outcomes were evaluated using descriptive statistics compared to historical controls receiving monotherapy. We also analyzed the event rate of complications when combination therapy was discontinued. RESULTS: During the 99.7 patient-years of follow-up, there were no transient ischemic attacks and the stroke rate dropped to 0.02 per patient-year. In comparison, the rates of transient ischemic attacks and strokes in the historical controls ranged from 0.08 to 0.035 per patient-year. After discontinuation of alprostadil therapy, eight events occurred in three patients. CONCLUSIONS: Combination therapy reduces the long-term incidence of ischemic events in patients with primary Sneddon syndrome.
Assuntos
Alprostadil , Quimioterapia Combinada , Síndrome de Sneddon , Humanos , Feminino , Estudos Retrospectivos , Masculino , Síndrome de Sneddon/epidemiologia , Síndrome de Sneddon/tratamento farmacológico , Pessoa de Meia-Idade , Adulto , Incidência , Alprostadil/uso terapêutico , Alprostadil/administração & dosagem , Ataque Isquêmico Transitório/epidemiologia , Ataque Isquêmico Transitório/prevenção & controle , Ataque Isquêmico Transitório/tratamento farmacológico , Resultado do Tratamento , Transtornos Cerebrovasculares/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Vasodilatadores/uso terapêutico , Vasodilatadores/administração & dosagem , IdosoRESUMO
Elevated cerebrospinal fluid (CSF)/serum quotients of albumin (Q(Alb)) may occur in motor neuron diseases (MND) including amyotrophic lateral sclerosis (ALS), but the pathophysiologic mechanisms underlying these alterations are unclear. Evidence from animal experiments suggests that the arterial carbon dioxide level might affect the Q(Alb), i.e. the function of the blood-CSF barrier (BCB). We therefore compared basic CSF parameters in different forms of MND (ALS, n = 105; lower motor neuron diseases, n = 12; and upper motor neuron diseases, n = 7) and investigated the relationship between elevated Q(Alb) and the arterial partial pressure of carbon dioxide (pCO(2)) in ALS where respiratory insufficiency leads to hypercapnia in the course of the disease. Pathologic elevations of Q(Alb) occurred in 32 of 124 MND patients. In ALS, Q(Alb) significantly correlated with the arterial pCO(2) (r = 0.454; P = 0.001; n = 45). These data indicate that BCB dysfunction is a frequent finding in different forms of MND and may reflect distinct pathophysiological mechanisms. In ALS, an important underlying mechanism might be the influence of the arterial pCO(2) which may alter the CSF flow.
Assuntos
Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Barreira Hematoencefálica , Hipercapnia/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/líquido cefalorraquidiano , Albumina Sérica/metabolismo , Paraplegia Espástica Hereditária/líquido cefalorraquidiano , Adulto JovemRESUMO
Neuroimaging findings in hereditary spastic paraparesis (HSP), especially in complicated HSP (cHSP), are heterogenous. This study aimed to investigate possible in vivo morphological alterations of the whole brain and the amygdala in cHSP as a correlate of cognitive impairment in contrast to pure variants (pHSP). Amygdalar and whole brain volumes of 33 HSP patients (21 pHSP and 12 cHSP) were measured using three-dimensional magnetic resonance imaging (MRI) data sets by region of interest-based volumetry. A neuropsychological test battery was also performed. A significant reduction in whole brain volume compared with the controls, as well as significant correlations with reduced amygdalar volume and a worse neuropsychological test performance was observed only in cHSP patients. Our findings of disproportional amygdalar atrophy only in cHSP substantiate the association of morphologically assessable cerebral degeneration with cognitive impairment in cHSP.
Assuntos
Tonsila do Cerebelo/patologia , Imageamento por Ressonância Magnética , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Paraparesia Espástica/complicações , Adulto , Idoso , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Reprodutibilidade dos Testes , Estatística como AssuntoRESUMO
Amyotrophic lateral sclerosis (ALS) is a devastating disorder of the central nervous system that leads to progressive loss of upper and lower motor neurons. Most cases are sporadic and of unknown aetiology. In this study, we screened 72 patients with sporadic ALS for the presence of DNA copy number variations, in order to identify novel candidate disease genes. We have used sub-megabase resolution BAC array comparative genomic hybridization to detect genomic imbalances in our ALS patient cohort. Aberrations with potential relevance for disease aetiology were verified by oligo array CGH. In 72 patients with sporadic ALS, we identified a total of six duplications and five deletions that scored above our threshold. Nine of these 11 variations were smaller than 1Mb, and five were observed exclusively in ALS patients. In conclusion, non-polymorphic sub-microscopic duplications and deletions observable by array CGH are frequent in patients with sporadic ALS. Analysis of such aberrations serves as a starting point in deciphering the aetiology of this complex disease, given that affected genes can be considered candidates for influencing disease susceptibility.
Assuntos
Esclerose Lateral Amiotrófica/genética , Hibridização Genômica Comparativa , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Esclerose Lateral Amiotrófica/fisiopatologia , Dosagem de Genes , Predisposição Genética para Doença , HumanosRESUMO
OBJECTIVE: X linked spinobulbar muscular atrophy (Kennedy disease (KD)), which is clinically characterised mainly by neuromuscular and endocrine symptoms, has to be considered as a multisystem disorder. Based on clinical evidence of central nervous system involvement, potential KD associated cerebral volume alterations were analysed in vivo. METHODS: Whole brain based analysis of optimised voxel based morphometry (VBM) was applied to three dimensional MRI data from 18 genetically confirmed KD patients and compared with age matched controls. RESULTS: Subtle decreases in grey matter volume, mainly localised in frontal areas, were found, but extensive white matter atrophy was observed, particularly in frontal areas, but also involving multiple additional subcortical areas, the cerebellar white matter and the dorsal brainstem from the midbrain to the medulla oblongata. CONCLUSION: The VBM results demonstrated a morphological correlate of central nervous system involvement in KD, in agreement with aspects of the clinical phenotype (behavioural abnormalities, central-peripheral axonopathy) and with pathohistological findings.
Assuntos
Encéfalo/patologia , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Atrofia Muscular Espinal/diagnóstico , Fibras Nervosas Mielinizadas/patologia , Adulto , Atrofia , Tronco Encefálico/patologia , Cerebelo/patologia , Dominância Cerebral/fisiologia , Lobo Frontal/patologia , Humanos , Masculino , Bulbo/patologia , Mesencéfalo/patologia , Pessoa de Meia-Idade , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patologia , Exame NeurológicoRESUMO
Three-dimensional magnetic resonance imaging of the brain was analyzed using optimized voxel-based morphometry in 21 patients with pure hereditary spastic paraparesis (pHSP) and 12 patients with complicated HSP (cHSP). PHSP patients showed only small regional grey matter volume reduction, whereas significantly decreased grey matter volumes were localized pericentrally in cHSP. In the white matter, several small areas of regional volume reduction were observed in the pHSP patients, whereas the cHSP group exhibited large robust volume reduction involving the entire corpus callosum, a result that was reproduced by an additional region-based MRI analysis. It could be demonstrated that the topography of cerebral volume changes differed markedly in pHSP or cHSP at group level. Corpus callosum thinning seems to be a general feature of cHSP.
Assuntos
Encéfalo/patologia , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Paraparesia Espástica/genética , Paraparesia Espástica/patologia , Adulto , Atrofia/patologia , Encéfalo/fisiologia , Mapeamento Encefálico/métodos , Feminino , Humanos , Imageamento Tridimensional/métodos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão/fisiologiaRESUMO
BACKGROUND: Information on anatomical connectivity in the brain by measurements of the diffusion of water in white matter tracts lead to quantification of local tract directionality and integrity. METHODS: The combination of connectivity mapping (fibre tracking, FT) with quantitative diffusion fractional anisotropy (FA) mapping resulted in the approach of results based on group-averaged data, named tractwise FA statistics (TFAS). The task of this study was to apply these methods to group-averaged data from different subjects to quantify differences between normal subjects and subjects with defined alterations of the corpus callosum (CC). RESULTS: TFAS exhibited a significant FA reduction especially in the CC, in agreement with region of interest (ROI)-based analyses. CONCLUSION: In summary, the applicability of the TFAS approach to diffusion tensor imaging studies of normal and pathologically altered brains was demonstrated.
Assuntos
Anisotropia , Sistema Nervoso Central/patologia , Corpo Caloso/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Adulto , Algoritmos , Engenharia Biomédica/métodos , Encéfalo/patologia , Mapeamento Encefálico/métodos , Difusão , Feminino , Humanos , Masculino , Modelos EstatísticosRESUMO
Thin corpus callosum has been recently observed in two patients with an autosomal dominant trait of hereditary spastic paraplegia (HSP) linked to a novel mutation in the spastin gene (SPG4). In the same two patients cerebellar atrophy has been found. Reportedly, in other members of the same family, there has been a variable presence of mental retardation. We report on the clinical and genetic investigation of an Austrian family with a novel mutation in the spastin gene. Genetic analysis of the SPG4 locus revealed a mutation (C1120A) and a known intronic polymorphism (996-47G>A) of the spastin gene. In one affected family member, previously undescribed dysplasia of the corpus callosum (CC) was found in conjunction with otherwise uncomplicated HSP. Dysplastic CC was not paralleled with cortical atrophy, cognitive impairment or other phenotypic variations. Two further affected family members showed the same mutation and polymorphism, but no evidence of CC abnormalities. We conclude that apparently pure HSP may present with MRI features of dysplastic CC. This finding extended the spastin-related phenotype which is distinct from previous reports of thin CC in HSP.
Assuntos
Adenosina Trifosfatases/genética , Corpo Caloso/patologia , Paraplegia Espástica Hereditária/genética , Adulto , Análise Mutacional de DNA/métodos , Saúde da Família , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo Genético , Paraplegia Espástica Hereditária/patologia , EspastinaRESUMO
The clinical phenotype of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) varies. This variability is seen not only between kindreds with different mutations but also in families sharing the same mutation. Inheritance of tau haplotype (H1) and genotype (H1/H1) has been established as a risk factor for some neurodegenerative disorders with parkinsonism. We assessed the effect of tau polymorphism on the clinical features of FTDP-17 in 61 cases from 30 separately ascertained families with four different tau mutations, including P301L, +16, N279K, and P301S. There were no significant differences of age at symptomatic onset and disease duration between H1/H1 and H1/H2 genotypes. The comparison between tau genotype and type of initial clinical sign showed an association between the H1/H1 genotype and parkinsonian phenotype and between the H1/H2 genotype and frontotemporal dementia phenotype (OR=11.7; 95% confidence interval, 1.4-98.7; P=0.008). Our results suggest that tau genotype does not influence the disease course. However, it may predispose to a specific clinical sign in the early stage of FTDP-17.
Assuntos
Demência/genética , Proteínas Associadas aos Microtúbulos/genética , Transtornos Parkinsonianos/genética , Proteínas tau/genética , Adulto , Idade de Início , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
OBJECTIVE: To characterize the earliest symptoms of X-linked bulbospinal neuronopathy (Kennedy disease [KD]) during the course of the disease, including a definition of the age of onset. METHODS: We describe the earliest symptoms, signs on clinical investigation, electrophysiological and muscle biopsy specimen findings, and creatine kinase levels in 34 patients with KD. Correlations were made among the CAG-repeat length and clinical symptoms, age at onset, and the presence of electrophysiological and laboratory findings. RESULTS: Our findings indicate that the age at onset of KD is in adolescence which is earlier than previously thought. Most frequently early symptoms are gynecomastia, muscle pain, and premature muscular exhaustion. Weakness is not a typical initial symptom and is frequently found in distal limbs if present early. We found a correlation between the of number of CAG repeats and the age at onset of weakness but not to the age at onset of KD. Furthermore, no correlations were found between the occurrence of gynecomastia, tremor, increased creatine kinase levels, and additional myopathic changes in muscle biopsy specimens. CONCLUSIONS: Our data show that KD is a multisystem disorder with onset in adolescence. Because of the heterogeneity of clinical presentation and no correlation between the number of CAG repeats and most of the clinical hallmarks of KD, we suggest that other environmental or genetic factors contribute to the manifestation of specific organ systems in KD.
Assuntos
Cromossomos Humanos X/genética , Ligação Genética , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/fisiopatologia , Adulto , Idade de Início , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia Muscular Espinal/diagnósticoRESUMO
BACKGROUND: Recently, TAR DNA-binding protein 43 (TDP-43) was identified as the major component of ubiquitin-positive tau-negative neuronal and glial inclusions in the most common form of frontotemporal lobar degeneration (FTLD) and in amyotrophic lateral sclerosis (ALS). It was demonstrated that different TDP-43 profiles correspond to clinical phenotypes of FTLD or ALS subgroups, and the differential diagnostic potential of TDP-43 was suggested. OBJECTIVES: To examine TDP-43 in cerebrospinal fluid (CSF) and to analyze whether it could serve as a diagnostic marker. DESIGN: We characterized CSF TDP-43 by immunoblot using different TDP-43 antibodies and determined the relative TDP-43 levels in CSF samples from patients. SETTING: Academic research. PATIENTS: Twelve patients with FTLD, 15 patients with ALS, 9 patients with ALS plus FTLD, 3 patients with ALS plus additional signs of frontal disinhibition, and 13 control subjects. MAIN OUTCOME MEASURES: Results of TDP-43 immunoblot. RESULTS: Polyclonal TDP-43 antibodies recognized a 45-kDa band in all analyzed samples. Two monoclonal and N-terminus-specific antibodies did not detect any specific bands, but C-terminus-specific antibodies detected a 45-kDa band and additional bands at approximately 20 kDa in all CSF samples. Relative quantification of 45-kDa bands revealed significant differences among the diagnostic groups (P =.046). Specifically, patients with ALS (P =.03) and FTLD (P =.02) had higher TDP-43 levels than controls but with a prominent overlap of values. CONCLUSION: Although there is no evidence of pathologically altered TDP-43 proteins in CSF, TDP-43 levels in CSF might aid in characterizing subgroups of patients across the ALS and FTLD disease spectrum.
Assuntos
Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Esclerose Lateral Amiotrófica/diagnóstico , Proteínas de Ligação a DNA/líquido cefalorraquidiano , Demência/líquido cefalorraquidiano , Demência/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/psicologia , Biomarcadores/líquido cefalorraquidiano , Demência/complicações , Feminino , Humanos , Immunoblotting , Masculino , Pessoa de Meia-IdadeRESUMO
Tangier disease is a rare autosomal recessive disorder caused by mutations in the recently identified ATP-binding cassette transporter 1 gene (ABC1). A typical clinical manifestation of Tangier disease is peripheral neuropathy. Former studies differentiated between two manifestations: the more frequent mono- or polyneuropathic form and a syringomyelia-like type. It is unknown whether specific mutations in the ABC1 gene or a particular genetic background are responsible for either of these forms. A family is presented comprising a case with a severe syringomyelia-like phenotype of Tangier disease and absence of cardiovascular disease. Sequencing analysis of the ABC1 gene was performed. A new homozygous C-->T transition in exon 18 was found in the index patient. This mutation results in a stop codon at position 909 (R909X) leading to premature termination of translation. Her clinically asymptomatic daughters, her sister and one of her nieces were heterozygous. Sural nerve biopsies were studied in the index patient at the age of 45 and 54 years; both revealed a severe neuropathy, characterized by a subtotal and finally complete loss of nerve fibres. The entire loss of Schwann cells resulted in an extraordinary form of endoneurial sclerosis. Only rare capillaries, lipid-laden macrophages and fibroblasts had survived in the endoneurium. This case appears to be unique in respect to the underlying novel mutation in the ABC1 gene and its association with complete endoneurial sclerosis of all fascicles in the sural nerve and absence of cardiovascular disease.