RESUMO
BACKGROUND: Molecular imaging has proven to be a powerful tool to elucidate degenerated paths in a wide variety of neurological diseases and has not been systematically studied in hereditary spastic paraplegias. OBJECTIVES: To investigate dopaminergic degeneration in a cohort of 22 patients with hereditary spastic paraplegia attributed to SPG11 mutations and evaluate treatment response to l-dopa. METHODS: Patients and controls underwent single-photon emission computed tomography imaging utilizing 99m Tc-TRODAT-1 tracer. A single-blind trial with 600 mg of l-dopa was performed comparing UPDRS scores. RESULTS: Reduced dopamine transporter density was universal among patients. Nigral degeneration was symmetrical and correlated with disease duration and motor and cognitive handicap. No statistically significant benefit could be demonstrated with l-dopa intake during the trial. CONCLUSION: Disruption of presynaptic dopaminergic pathways is a widespread phenomenon in patients with SPG11 mutations, even in the absence of parkinsonism. Unresponsiveness to treatment could be related to postsynaptic damage that needs to be further investigated.
Assuntos
Antiparkinsonianos/uso terapêutico , Levodopa/uso terapêutico , Mutação/genética , Transtornos Parkinsonianos , Proteínas/genética , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Estudos de Coortes , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Humanos , Masculino , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Compostos de Organotecnécio/farmacocinética , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/genética , Método Simples-Cego , Estatísticas não Paramétricas , Tomógrafos Computadorizados , Tomografia Computadorizada de Emissão de Fóton Único , Tropanos/farmacocinética , Adulto JovemRESUMO
INTRODUCTION: Dystonia is frequent in Machado-Joseph disease, but several important aspects are not yet defined, such as the detailed clinical profile, response to treatment and anatomical substrate. METHODS: We screened 75 consecutive patients and identified those with dystonia. The Burke-Marsden-Fahn Dystonia Rating Scale was employed to quantify dystonia severity. Patients with dystonia received levodopa 600 mg/day for 2 months and were videotaped before and after treatment. A blinded evaluator rated dystonia in the videos. Patients with disabling dystonia who failed to respond to levodopa treatment received botulinum toxin. Finally, volumetric T1 and diffusion tensor imaging sequences were obtained in the dystonic group using a 3T-MRI scanner to identify areas of gray and white matter that were selectively damaged. RESULTS: There were 21 patients with dystonia (28%): 9 classified as generalized and 12 as focal/segmental. Patients with dystonia had earlier onset and larger (CAG) expansions (28.9 ± 11.7 vs 40.6 ± 11.4; p < 0.001 and 75 vs 70; p < 0.001, respectively). Although group analyses failed to show benefit on levodopa (p = 0.07), some patients had objective improvement. In addition, ten patients received botulinum toxin resulting in a significant change in dystonia scores after 4 weeks (p = 0.03). Patients with dystonia had atrophy at pre- and paracentral cortices; whereas, non-dystonic patients had occipital atrophy. Basal ganglia volume was reduced in both groups, but atrophy at the thalami, cerebellar white matter and ventral diencephali was disproportionately higher in the dystonic group. CONCLUSION: Dystonia in Machado-Joseph disease is frequent and often disabling, but may respond to levodopa. It is associated predominantly with structural abnormalities around the motor cortices and in the thalami.
Assuntos
Encéfalo/patologia , Distúrbios Distônicos/etiologia , Doença de Machado-Joseph/complicações , Adulto , Ataxina-3/genética , Atrofia , Toxinas Botulínicas Tipo A/uso terapêutico , Imagem de Tensor de Difusão , Distúrbios Distônicos/tratamento farmacológico , Distúrbios Distônicos/genética , Distúrbios Distônicos/patologia , Feminino , Substância Cinzenta/patologia , Humanos , Levodopa/uso terapêutico , Doença de Machado-Joseph/genética , Doença de Machado-Joseph/patologia , Doença de Machado-Joseph/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Motor/patologia , Proteínas Repressoras/genética , Índice de Gravidade de Doença , Método Simples-Cego , Tálamo/patologia , Repetições de Trinucleotídeos , Gravação de Videoteipe , Substância Branca/patologiaRESUMO
BACKGROUND: Machado-Joseph disease (MJD) is one of the most common forms of neurodegenerative ataxia characterized by remarkable phenotypic heterogeneity. Although patients frequently report pain, systematic evaluation of this clinical feature is lacking. OBJECTIVES: To compare the frequency of chronic pain among patients with genetically confirmed MJD, an age- and sex-matched healthy control group, and a disease control group of patients with amyotrophic lateral sclerosis (ALS). METHODS: We included 70 patients with MJD, 20 patients with ALS, and 70 control subjects from 2 clinical centers. All individuals underwent assessment with a standardized pain questionnaire. In addition, we used a visual analog scale to quantify pain intensity. RESULTS: Thirty-three patients with MJD (47%), 3 patients with ALS (15%), and 6 controls (9%) reported chronic pain. Lower back pain preceded ataxia in 6 patients with MJD. Twenty-nine patients with MJD had daily pain, which was continuous in 23. The mean visual analog scale score was 6.1 in patients with MJD. Pain was musculoskeletal in 26 patients with MJD, dystonic in 2, neuropathic in 2, and mixed in 3. Typically, pain was lumbar (n = 17) or in the lower limbs (n = 15). We did not find significant differences regarding duration of disease, sex, or severity of ataxia among patients with MJD with and without chronic pain. Expanded (CAG)(n) tandem repeats were longer in patients with MJD who experienced chronic pain (67.3 vs 65.2; P = .04). CONCLUSIONS: In our series, pain was significantly more frequent in patients with MJD than in controls. Chronic pain was a frequent and often disabling complaint among patients with MJD. The lower back was the most frequently reported location of pain in patients with MJD.