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
Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 × 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p.Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 × 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.
Assuntos
Esclerose Lateral Amiotrófica/genética , Saúde da Família , Cinesinas/genética , Mutação/genética , Adulto , Idoso , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
OBJECTIVES: Recent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions. METHODS: Here we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72 mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families. RESULTS: 49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBP or TBK1, whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes. CONCLUSIONS: We here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe.
Assuntos
Esclerose Lateral Amiotrófica/genética , Proteína C9orf72/genética , Proteínas de Ligação a DNA/genética , Mutação , Proteína FUS de Ligação a RNA/genética , Superóxido Dismutase-1/genética , Análise Mutacional de DNA , Predisposição Genética para Doença , Genótipo , Alemanha , Humanos , Linhagem , Proteínas Serina-Treonina Quinases/genéticaRESUMO
Mutations in the senataxin (SETX) gene can cause amyotrophic lateral sclerosis 4 (ALS4), an autosomal dominant form of juvenile onset amyotrophic lateral sclerosis, or result in autosomal recessive ataxia with oculomotor apraxia type 2. Great caution regarding the possible disease causation, especially of missense variations, has to be taken. Here, we evaluated the significance of all previously reported SETX missense mutations as well as six newly identified variations in 54 patients suspected of having ALS4. Yet, epidemiologic and in silico evidence indicates that all newly identified variations and two previously published ALS4-related missense variations (C1554G and I2547T) are most likely non-pathogenic, demonstrating the problems of interpretation of SETX missense alleles in the absence of functional assays.
Assuntos
Esclerose Lateral Amiotrófica/genética , Mutação de Sentido Incorreto , RNA Helicases/genética , Adulto , Estudos de Casos e Controles , Estudos de Coortes , DNA Helicases , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/genética , Enzimas Multifuncionais , Mutação de Sentido Incorreto/fisiologia , Fenótipo , Polimorfismo de Nucleotídeo Único/fisiologiaRESUMO
INTRODUCTION: In myasthenia gravis (MG), depression and anxiety have frequently been reported as comorbidities. However, little is known about personality characteristics in MG patients. We aimed to characterise personality traits in MG and to correlate them with disease severity and disease course. METHODS: The Big Five Inventory data questionnaire was used to investigate personality traits in 44 MG patients and 45 healthy controls similar in age and gender. In 28 MG patients, a caregiver was also available for patient assessments to limit bias associated with social desirability in patients' responses. Patients were assessed with regard to premorbid personality (before manifestation of MG) and to present condition. In addition, anxiety and depression scales (Hospital Anxiety and Depression Scale and Beck Anxiety Inventory) were applied. RESULTS: Compared to controls, MG patients showed significantly higher levels of neuroticism, whereas openness and extraversion were significantly lower. Agreeableness and conscientiousness did not differ between groups. Neuroticism was influenced by disease severity such as generalization of weakness, presence of thymoma, and bulbar involvement as well as disease duration. Neuroticism correlated with premorbid level of neuroticism but also with depression and anxiety scores. CONCLUSION: A personality profile of increased neuroticism and lower openness and extraversion in MG patients may contribute considerably to the perception of disease severity. It may also be related to frequent comorbidities such as anxiety and depression. Although premorbid levels of neuroticism were increased, this characteristic may also increase considerably during the course of the disease. The data indicate that muscle weakness in MG is accompanied or even complicated by psychological aspects. Therefore, a psychological and behavioral intervention in addition to the specific pharmacological therapy might be of particular value.
Assuntos
Miastenia Gravis , Personalidade , Humanos , Estudos Prospectivos , Transtornos de Ansiedade/psicologia , Neuroticismo , Inventário de PersonalidadeRESUMO
BACKGROUND AND OBJECTIVES: Nodo-paranodopathies are peripheral neuropathies with dysfunction of the node of Ranvier. Affected patients who are seropositive for antibodies against adhesion molecules like contactin-1 and neurofascin show distinct clinical features and a disruption of the paranodal complex. An axoglial dysjunction is also a characteristic finding of diabetic neuropathy. Here, we aim to investigate a possible association of antibody-mediated nodo-paranodopathy and diabetes mellitus (DM). METHODS: We retrospectively analyzed clinical data of 227 patients with chronic inflammatory demyelinating polyradiculoneuropathy and Guillain-Barré syndrome from multiple centers in Germany who had undergone diagnostic testing for antiparanodal antibodies targeting neurofascin-155, pan-neurofascin, contactin-1-associated protein 1, and contactin-1. To study possible direct pathogenic effects of antiparanodal antibodies, we performed immunofluorescence binding assays on human pancreatic tissue sections. RESULTS: The frequency of DM was 33.3% in seropositive patients and thus higher compared with seronegative patients (14.1%, OR = 3.04, 95% CI = 1.31-6.80). The relative risk of DM in seropositive patients was 3.4-fold higher compared with the general German population. Seropositive patients with DM most frequently harbored anti-contactin-1 antibodies and had higher antibody titers than seropositive patients without DM. The diagnosis of DM preceded the onset of neuropathy in seropositive patients. No immunoreactivity of antiparanodal antibodies against pancreatic tissue was detected. DISCUSSION: We report an association of nodo-paranodopathy and DM. Our results suggest that DM may be a potential risk factor for predisposing to developing nodo-paranodopathy and argue against DM being induced by the autoantibodies. Our findings set the basis for further research investigating underlying immunopathogenetic connections.
Assuntos
Diabetes Mellitus , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Autoanticorpos , Humanos , Nós Neurofibrosos/patologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
Different motor neuron disorders (MNDs) are mainly defined by the clinical presentation based on the predominance of upper or lower motor neuron impairment and the course of the disease. Magnetic resonance imaging (MRI) mostly serves as a tool to exclude other pathologies, but novel approaches such as diffusion tensor imaging (DTI) have begun to add information on the underlying pathophysiological processes of these disorders in vivo. The present study was designed to investigate three different rare MNDs, i.e., primary lateral sclerosis (PLS, N = 25), hereditary spastic paraparesis (HSP, N = 24), and X-linked spinobulbar muscular atrophy (X-SBMA, N = 20), by use of whole-brain-based DTI analysis in comparison with matched controls. This analysis of white matter (WM) impairment revealed widespread and characteristic patterns of alterations within the motor system with a predominant deterioration of the corticospinal tract (CST) in HSP and PLS patients according to the clinical presentation and also in patients with X-SBMA to a lesser degree, but also WM changes in projections to the limbic system and within distinct areas of the corpus callosum (CC), the latter both for HSP and PLS. In summary, DTI was able to define a characteristic WM pathoanatomy in motor and extra-motor brain areas, such as the CC and the limbic projectional system, for different MNDs via whole brain-based FA assessment and quantitative fiber tracking. Future advanced MRI-based investigations might help to provide a fingerprint-identification of MNDs.
Assuntos
Encéfalo/fisiopatologia , Doença dos Neurônios Motores/fisiopatologia , Transtornos Musculares Atróficos/fisiopatologia , Fibras Nervosas Mielinizadas/fisiologia , Paraplegia Espástica Hereditária/fisiopatologia , Adulto , Idoso , Anisotropia , Encéfalo/patologia , Mapeamento Encefálico , Imagem de Tensor de Difusão , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/patologia , Transtornos Musculares Atróficos/patologia , Fibras Nervosas Mielinizadas/patologia , Paraplegia Espástica Hereditária/patologiaRESUMO
BACKGROUND: 153 mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been claimed to be associated with amyotrophic lateral sclerosis (ALS) in familial and sporadic ALS in an autosomal dominant or autosomal recessive pattern with complete or reduced penetrance. The authors now report four ALS pedigrees from Finland, France, Germany and Sweden with either the D90A or E100K SOD1 mutations in some but not all affected members. After re-collecting DNA, the non-segregation of the SOD1 mutations with disease was confirmed by three independent laboratories using different PCR primers: while some of the affected patients carry SOD1 mutations, other affected family members have two wildtype/normal SOD1 genes. In addition, some unaffected members within the same families are carriers of SOD1 gene mutations. To exclude other known genetic causes, the authors ruled out mutations within the genes coding for VAPB, ANG, TDP43, FUS and DCTN1 in affected individuals in the four pedigrees. CONCLUSIONS: The authors find that the D90A and E100K SOD1 gene mutations found in some patients are not the exclusive cause of ALS in these pedigrees. Whether this is also the case for the other 151 SOD1 mutations reported in ALS pedigrees is unknown. The findings have consequences for genetic testing in clinical practice when diagnosing ALS and for genetic counselling in ALS. Some SOD1 mutations may be part of an oligo- or epigentic pattern of inheritance. Such a pattern of inheritance may model other oligo- or polygenetic traits responsible for other forms of ALS.
Assuntos
Esclerose Lateral Amiotrófica/genética , Mutação/genética , Superóxido Dismutase/genética , Adulto , Idade de Início , Idoso , Alelos , Esclerose Lateral Amiotrófica/patologia , DNA/genética , Progressão da Doença , Feminino , Finlândia , Genes Dominantes/genética , Genes Recessivos/genética , Alemanha , Haplótipos , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/fisiologia , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Superóxido Dismutase-1 , SuéciaRESUMO
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
Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders with heterogeneous clinical presentation but common neuropathological characteristics and pathophysiological substrates, which led to the view of ALS and FTLD representing two manifestations of a clinicopathological spectrum. For both diseases, changes in metabolism of beta-amyloid precursor protein (APP) are reported. In a pilot study, we analyzed cerebrospinal fluid from patients of the ALS-FTLD spectrum for APP processing products. ALS patients show elevated absolute levels of soluble APP and a shift towards the nonamyloidogenic APP processing pathway in contrast to patients with FTLD or ALS + FTLD. Changes in Abeta pattern could be described, allowing separation of patients with pure FTLD from ALS + FTLD. Combination of sAPP and Abeta values improves group differentiation. These findings may provide information on pathophysiological processes in the ALS-FTLD disease spectrum and could have impact in neurochemical diagnosis. We propose to expand this study to larger patient groups comprising followed up cases with known neuropathology.
Assuntos
Precursor de Proteína beta-Amiloide/líquido cefalorraquidiano , Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Demência/líquido cefalorraquidiano , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Área Sob a Curva , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Curva ROCRESUMO
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
BACKGROUND: Idiopathic Parkinson's syndrome (IPS) and motor neuron disorders (MND) are generally considered as distinct clinicopathological entities. However, cooccurrence of different neurodegenerative disorders is more frequent than would be expected. Therefore, there is an ongoing discussion whether some entities represent parts of a common spectrum. OBJECTIVE AND METHODS: We describe clinical hallmarks and treatment options in a group of 8 patients who had combined features of both a dopa-responsive parkinsonian syndrome and MND. RESULTS: All patients exhibited a typical clinical picture of IPS, and all were treated with levodopa or other dopaminergic drugs with good clinical response. The patients also showed clinical and electrophysiological signs of upper and/or lower motor neuron degeneration. Noticeably, in contrast to well-known distinct entities like the amyotrophic lateral sclerosis-parkinsonism/ dementia complex in southwest New Guinea, we did not observe any cognitive decline during the observation period except in 1 patient. CONCLUSION: This comorbidity of two neurodegenerative diseases supports the ongoing discussion of a pathophysiological and clinical overlap of disease processes. Due to the potent pharmacological options for the IPS symptoms in these overlap syndromes, these patients should be offered optimal symptomatic dopaminergic therapy.
Assuntos
Doença dos Neurônios Motores/complicações , Doença dos Neurônios Motores/fisiopatologia , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/fisiopatologia , Adulto , Idoso , Antiparkinsonianos/uso terapêutico , Dopaminérgicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/patologia , Transtornos Parkinsonianos/patologia , SíndromeRESUMO
OBJECTIVE: Several independent prognostic factors, such as age of onset, type of onset, body mass index (BMI), and progression rate have been identified for amyotrophic lateral sclerosis (ALS) in Caucasians. The aim of this study was to identify such factors in Chinese patients and to compare their impact with German patients. METHODS: Comparison of prognostic factors was based on two hospital-based registries. The registry of the German Network for Motor Neuron Diseases contains 3100 patients with ALS. The Chinese registry comprises 2101 patients who were collected between 2003 and 2015 in the metropolitan area of Beijing. RESULTS: Disease progression was slower in China [median loss of 0.50 points (IQR 0.26-0.87 points) versus 0.55 points (IQR 0.28-1.00 points) of ALS functional rating scale revised (ALS-FRS-R) score per month; p < 0.0001]. Survival of patients with ALS was similar in Germany and China (p > 0.05). We found that younger age of onset (p < 0.0001), spinal onset (p < 0.0001), high BMI (p < 0.0001) and low progression rate (p < 0.0001) were positive prognostic factors in China as well as in Germany. INTERPRETATION: Prognostic factors, which are known to modify the course of disease in Caucasians, apply to Chinese patients as well. The results indicate that despite the apparent differences regarding genotype and clinical phenotype, findings from interventional studies in Caucasians aiming at disease-modifying prognostic factors (such as body weight) may be transferred to Chinese patients.
Assuntos
Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/fisiopatologia , Progressão da Doença , Sistema de Registros , Idade de Início , Idoso , Esclerose Lateral Amiotrófica/mortalidade , Pequim/epidemiologia , Feminino , Alemanha/epidemiologia , Humanos , Masculino , PrognósticoRESUMO
We illustrate a white caucasian patient with a severe sensorimotor neuropathy due to vitamin B6 hypervitaminosis. The patient used the pendulum to calculate his daily metabolic demands and ingested 9.6g pyridoxine/day. To our knowledge, this is the highest dosage of vitamin B6 administered to humans over prolonged periods of time ever reported in the medical literature. The unique aspect of this case is the muscle weakness and motor findings on electrophysiological testing in what is suggested by the literature to be a pure sensory neuronopathy.
Assuntos
Transtornos Neurológicos da Marcha/induzido quimicamente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Vitamina B 6/intoxicação , Complexo Vitamínico B/intoxicação , Idoso , Humanos , Masculino , Automedicação , Índice de Gravidade de Doença , Vitamina B 6/efeitos adversos , Complexo Vitamínico B/efeitos adversosRESUMO
Non-invasive ventilation (NIV) is known to improve quality of life and to prolong survival in amyotrophic lateral sclerosis (ALS) patients. However, little is known about the circumstances of dying in ventilated ALS patients. In the light of the debate on legalizing euthanasia it is important to provide empirical data about the process of dying in these patients. In a structured interview, 29 family caregivers of deceased ALS patients were asked about their own and the patient's attitude toward physician-assisted suicide (PAS) and euthanasia, circumstances of dying, and the use of palliative medication. Quantitative and qualitative content analysis was performed on the data. Non-recurring suicidal thoughts were reported by five patients. Three patients and seven relatives had thought about PAS. Seventeen caregivers described the patients' death as "peaceful", while choking was reported in six bulbar patients. In final stages of dying, the general practitioner (GP) was involved in the treatment of 10 patients, with palliative medication including sedatives and opiates being administered in eight cases. In conclusion, in contrast to the Netherlands, where 20% of terminal ALS patients die from PAS or euthanasia, only a small minority of our patients seems to have thought about PAS. The legal situation in Germany (where euthanasia is illegal), a bias due to the selection of NIV patients as well as a high percentage of religious patients and those with good levels of social support from family and friends, might account for this. Most of our patients died peacefully at home from carbon dioxide narcosis, but choking was described in some bulbar patients. Thus, palliative care, especially the use of opiates, anxiolytics and sedatives should be optimized, and the involvement of GP should be strongly encouraged, especially in bulbar patients.
Assuntos
Esclerose Lateral Amiotrófica/enfermagem , Esclerose Lateral Amiotrófica/psicologia , Atitude Frente a Morte , Cuidadores/psicologia , Eutanásia/psicologia , Cuidados Paliativos/psicologia , Respiração com Pressão Positiva/psicologia , Suicídio Assistido/psicologia , Adulto , Idoso , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Mutations in NIPA1 cause hereditary spastic paraplegia type 6 (SPG6 HSP). Sequencing of the whole gene has revealed alterations of either of two nucleotides in eight of nine SPG6 HSP families reported to date. By analysing CpG methylation, we provide a mechanistic explanation for a mutational hotspot to underlie frequent alteration of one of these nucleotides. We also developed PCR RFLP assays to detect recurrent NIPA1 changes and screened 101 independent HSP patients, including 45 index patients of autosomal dominant HSP families. Our negative finding in this cohort for which several other causes of HSP had been excluded suggests NIPA1 alterations at mutational hotspots to be less frequent than previously thought. Nevertheless, the assays introduced represent a valid pre-screen easily implementable in the molecular diagnosis of HSP.
Assuntos
Testes Genéticos/métodos , Proteínas de Membrana/genética , Polimorfismo de Fragmento de Restrição/genética , Paraplegia Espástica Hereditária/genética , Estudos de Coortes , Metilação de DNA , Análise Mutacional de DNA , Humanos , Dados de Sequência MolecularRESUMO
BACKGROUND: Becker-Kiener muscular dystrophy (BMD) represents an X-linked genetic disease associated with myocardial involvement potentially resulting in dilated cardiomyopathy (DCM). Early diagnosis of cardiac involvement may permit earlier institution of heart failure treatment and extend life span in these patients. Both echocardiography and nuclear imaging methods are capable of detecting later stages of cardiac involvement characterised by wall motion abnormalities. Cardiovascular magnetic resonance (CMR) has the potential to detect cardiac involvement by depicting early scar formation that may appear before onset of wall motion abnormalities. METHODS: In a prospective two-center-study, 15 male patients with BMD (median age 37 years; range 11 years to 56 years) underwent comprehensive neurological and cardiac evaluations including physical examination, echocardiography and CMR. A 16-segment model was applied for evaluation of regional wall motion abnormalities (rWMA). The CMR study included late gadolinium enhancement (LGE) imaging with quantification of myocardial damage. RESULTS: Abnormal echocardiographic results were found in eight of 15 (53.3%) patients with all of them demonstrating reduced left ventricular ejection fraction (LVEF) and rWMA. CMR revealed abnormal findings in 12 of 15 (80.0%) patients (p = 0.04) with 10 (66.6%) having reduced LVEF (p = 0.16) and 9 (64.3%) demonstrating rWMA (p = 0.38). Myocardial damage as assessed by LGE-imaging was detected in 11 of 15 (73.3%) patients with a median myocardial damage extent of 13.0% (range 0 to 38.0%), an age-related increase and a typical subepicardial distribution pattern in the inferolateral wall. Ten patients (66.7%) were in need of medical heart failure therapy based on CMR results. However, only 4 patients (26.7%) were already taking medication based on clinical criteria (p = 0.009). CONCLUSION: Cardiac involvement in patients with BMD is underdiagnosed by echocardiographic methods resulting in undertreatment of heart failure. The degree and severity of cardiac involvement in this population is best characterised when state-of-the-art CMR methods are applied. Further studies need to demonstrate whether earlier diagnosis and institution of heart failure therapy will extend the life span of these patients.
Assuntos
Cardiomiopatia Dilatada/patologia , Imagem Cinética por Ressonância Magnética , Distrofia Muscular de Duchenne/complicações , Miocárdio/patologia , Função Ventricular Esquerda , Adolescente , Adulto , Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Dilatada/terapia , Criança , Meios de Contraste , Ecocardiografia , Eletrocardiografia , Gadolínio DTPA , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Muscular de Duchenne/patologia , Distrofia Muscular de Duchenne/fisiopatologia , Distrofia Muscular de Duchenne/terapia , Valor Preditivo dos Testes , Estudos Prospectivos , Índice de Gravidade de Doença , Volume Sistólico , Adulto JovemRESUMO
Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of the motor system. Bulbar symptoms such as dysphagia and dysarthria are frequent features of ALS and can result in reductions in life expectancy and quality of life. These dysfunctions are assessed by clinical examination and by use of instrumented methods such as fiberendoscopic evaluation of swallowing and videofluoroscopy. Laryngospasm, another well-known complication of ALS, commonly comes to light during intubation and extubation procedures in patients undergoing surgery. Laryngeal and pharyngeal complications are treated by use of an array of measures, including body positioning, compensatory techniques, voice and breathing exercises, communication devices, dietary modifications, various safety strategies, and neuropsychological assistance. Meticulous monitoring of clinical symptoms and close cooperation within a multidisciplinary team (physicians, speech and language therapists, occupational therapists, dietitians, caregivers, the patients and their relatives) are vital.