RESUMO
The "Jumping Frenchmen of Maine" were described by George Beard in 1878. They had an excessive startle response, sometimes with echolalia, echopraxia, or forced obedience. In 1885, Gilles de la Tourette concluded that "jumping" was similar to the syndrome that now bears his name. Direct observations of jumpers have been scarce. We studied eight jumpers from the Because region of Quebec. In our opinion, this phenomenon is not a neurologic disease, but can be explained in psychological terms as operant conditioned behavior. Our cases were related to specific conditions in lumber camps in the 19th and the beginning of the 20th century.
Assuntos
Reflexo de Sobressalto , Síndrome de Tourette/história , Cultura , Diagnóstico Diferencial , Ecolalia/história , França/etnologia , História do Século XIX , História do Século XX , Maine , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/história , Reflexo de Sobressalto/fisiologia , Síndrome de Tourette/diagnósticoRESUMO
The motor score with and without levodopa was estimated in 193 parkinsonian patients with variable length of evolution. The effect of levodopa on akinesia, rigidity, and tremor remained quite stable during the course of the disease. In contrast, the aggravation of gait disorder, postural instability, and dysarthria was more severe, with decreased percentage of improvement on levodopa in patients with longer evolution. It is suggested that aggravation of Parkinson's disease mainly results from increasing severity of cerebral nondopaminergic lesions.
Assuntos
Encéfalo/fisiopatologia , Doença de Parkinson/fisiopatologia , Dopamina/fisiologia , Humanos , Levodopa/uso terapêutico , Pessoa de Meia-Idade , Doença de Parkinson/tratamento farmacológico , Estudos Retrospectivos , Fatores de TempoRESUMO
We studied the new catechol-O-methyltransferase inhibitor tolcapone, 100 and 200 mg, three times daily (tid) in a randomized, double-blind, parallel-group trial involving 202 parkinsonian patients who were experiencing the "wearing-off" phenomenon on levodopa therapy. After 3 months, patients receiving tolcapone had a significant decrease in mean daily levodopa dose requirement compared with placebo-treated patients (p < 0.01). In patients treated with tolcapone 200 mg tid, daily "off" time, measured using patient diaries, was reduced from baseline by 3.25 hours; this reduction was significantly different from that seen in the placebo group (p < 0.01). Moreover, the number of daily levodopa intakes was reduced significantly in each tolcapone group compared with placebo (p < 0.01). We found significant improvements in motor function and overall efficacy in the tolcapone groups (p < 0.01). The most frequent adverse events were associated with levodopa treatment. Dyskinesia developed or worsened in 18% of patients receiving placebo, in 51% receiving tolcapone 100 mg tid, and in 64% receiving 200 mg tid, with most cases occurring within the first 30 days of the study. Diarrhea was the most frequent nondopaminergic event, occurring in 14% on placebo, 13% on tolcapone 100 mg tid, and 19% on 200 mg tid. Overall 18% of patients withdrew because of adverse events: 15% on placebo, 17% on tolcapone 100 mg tid, and 22% on 200 mg tid. We conclude that tolcapone as an adjunct offers promise for the relief of the "wearing-off" phenomenon in levodopa-treated parkinsonian patients.
Assuntos
Antiparkinsonianos/uso terapêutico , Benzofenonas/uso terapêutico , Atividade Motora/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Idoso , Antiparkinsonianos/efeitos adversos , Benzofenonas/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nitrofenóis , Placebos/uso terapêutico , Tolcapona , Resultado do TratamentoRESUMO
We studied the new catechol-O-methyltransferase inhibitor tolcapone, 100 and 200 mg, three times daily (tid) in a randomized, double-blind, parallel-group trial involving 202 parkinsonian patients who were experiencing the "wearing-off" phenomenon on levodopa therapy. After 3 months, patients receiving tolcapone had a significant decrease in mean daily levodopa dose requirement compared with placebo-treated patients (p < 0.01). In patients treated with tolcapone 200 mg tid, daily "off" time, measured using patient diaries, was reduced from baseline by 3.25 hours; this reduction was significantly different from that seen in the placebo group (p < 0.01). Moreover, the number of daily levodopa intakes was reduced significantly in each tolcapone group compared with placebo (p < 0.01). We found significant improvements in motor function and overall efficacy in the tolcapone groups (p < 0.01). The most frequent adverse events were associated with levodopa treatment. Dyskinesia developed or worsened in 18% of patients receiving placebo, in 51% receiving tolcapone 100 mg tid, and in 64% receiving 200 mg tid, with most cases occurring within the first 30 days of the study. Diarrhea was the most frequent nondopaminergic event, occurring in 14% on placebo, 13% on tolcapone 100 mg tid, and 19% on 200 mg tid. Overall 18% of patients withdrew because of adverse events: 15% on placebo, 17% on tolcapone 100 mg tid, and 22% on 200 mg tid. We conclude that tolcapone as an adjunct offers promise for the relief of the "wearing-off " phenomenon in levodopa-treated parkinsonian patients.
Assuntos
Antiparkinsonianos/farmacologia , Benzofenonas/farmacologia , Inibidores de Catecol O-Metiltransferase , Dopaminérgicos/farmacocinética , Inibidores Enzimáticos/farmacologia , Levodopa/farmacocinética , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Desempenho Psicomotor/efeitos dos fármacos , Idoso , Antiparkinsonianos/efeitos adversos , Benzofenonas/efeitos adversos , Canadá , Método Duplo-Cego , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nitrofenóis , Doença de Parkinson/enzimologia , Tolcapona , Estados UnidosRESUMO
The combination of carbidopa and levodopa (Sinemet) is a highly effective treatment for the symptoms of Parkinson's disease. However, side effects, such as abnormal involuntary movements, fluctuations in motor performance, and "wearing off" phenomena limit its long-term usefulness in some patients. Open-label studies show that controlled-release Sinemet CR is effective in reducing motor fluctuations. This report discusses the results of a 14-week double-blind crossover study comparing the efficacy and tolerability of standard Sinemet with controlled-release Sinemet CR. Overall, there were no statistically significant differences in efficacy between Sinemet CR and standard Sinemet on any of the major efficacy measures, suggesting a clinical equivalence in terms of treating the symptoms of Parkinson's disease. The study also supports the tolerability of Sinemet CR. In summary, Sinemet CR holds the promise of reducing some disturbing side effects of long-term levodopa therapy, thus achieving optimal control of parkinsonian symptoms.
Assuntos
Antiparkinsonianos/administração & dosagem , Carbidopa/administração & dosagem , Levodopa/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Idoso , Ensaios Clínicos como Assunto , Preparações de Ação Retardada , Método Duplo-Cego , Combinação de Medicamentos/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição AleatóriaRESUMO
We report 10 patients with delayed-onset dystonia associated with perinatal asphyxia and 2 associated with asphyxia in childhood. In the perinatal group, the mean age of onset was 12.9 years. Among these patients, dystonia continued to progress for a mean of 7 years, and as long as 28 years. These patients had moderate motor disability; none was wheelchair-bound, and thus their prognosis was better than that of the childhood-onset idiopathic torsion dystonias. The most frequently beneficial drugs were anticholinergics. Since some of these patients closely resembled cases of idiopathic torsion dystonia, the prior occurrence of asphyxia should be used as a criterion of exclusion for that diagnosis.
Assuntos
Envelhecimento/fisiologia , Asfixia Neonatal/complicações , Distonia/etiologia , Asfixia Neonatal/diagnóstico , Asfixia Neonatal/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Desenvolvimento Infantil , Pré-Escolar , Distonia/tratamento farmacológico , Distonia/fisiopatologia , Eletroencefalografia , Feminino , Humanos , Hipóxia/complicações , Lactente , Recém-Nascido , Masculino , Parassimpatolíticos/uso terapêutico , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
Controversy persists about the etiology of Parkinson's disease (PD). Pesticides, herbicides, well-water consumption, head injury, and a family history of PD have been reported as risk factors for PD. The purpose of this study was to (1) investigate the impact of environmental factors on PD risk (2) estimate the chronology, frequency, and duration of those exposures associated with PD; and (3) investigate the effects of family history on PD risk. One-hundred and forty PD cases were recruited from Boston University Medical Center. The control group was composed of 147 friends and in-laws of PD patients. Environmental, medical, and family history data were obtained by structured interview from each participant for events recalled prior to PD onset for cases, or corresponding censoring age for controls (mean age = 56 years of age for each group). A traditional stratified analysis, adjusting for birth cohort and sex, was employed. Four factors were associated with increased risk for PD: (1) head injury (OR=6.23, confidence interval [CI]: 2.58-15.07); (2) family history of PD (OR=6.08, CI: 2.35-15. 58); (3) family history of tremor (OR=3.97, CI: 1.17-13.50); and (4) history of depression (OR=3.01, CI: 1.32-6.88). A mean latency of 36. 5 (SE=2.81) years passed between the age of first reported head injury and PD onset. A mean latency of 22 (SE=2.66) years passed between the onset of the first reported symptoms of depression and onset of PD. Years of education, smoking, and well-water intake were inversely associated with PD risk. PD was not associated with exposure to pesticides or herbicides. These findings support the role of both environmental and genetic factors in the etiology in PD. The results are consistent with a multifactorial model. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:742-749, 1999.
Assuntos
Predisposição Genética para Doença/genética , Doença de Parkinson/etiologia , Doença de Parkinson/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Traumatismos Craniocerebrais/complicações , Demografia , Depressão/complicações , Depressão/genética , Exposição Ambiental , Saúde da Família , Feminino , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , New England/epidemiologia , Doença de Parkinson/epidemiologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/epidemiologia , Doença de Parkinson Secundária/etiologia , Doença de Parkinson Secundária/genética , Fatores de Risco , Fumar , Tremor/complicações , Tremor/genéticaRESUMO
The role of genetics in Parkinson disease (PD) continues to be an area of considerable interest and controversy. We collected information involving the nuclear families of 948 consecutively ascertained PD index cases from the University of Virginia (UVA) Health System, the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson (RWJ) School of Medicine, and Boston University (BU) School of Medicine. We performed a segregation analysis to assess evidence for the presence of a Mendelian pattern of familial transmission. The proportion of male (60.4%) and female (39.6%) cases, the mean age of onset (57.7 years), and the proportion of affected fathers (4.7%), mothers (6.6%), brothers (2.9%), and sisters (3.2%) were similar across the three sites. While most of the index cases were male, modestly more of the reported affected relatives were female. These analyses support the presence of a rare major Mendelian gene for PD in both the age-of-onset and susceptibility model. The age-of-onset model provides evidence for a gene that influences age-dependent penetrance of PD, influencing age of onset rather than susceptibility. We also found evidence for a Mendelian gene influencing susceptibility to the disease. It is not evident whether these two analyses are modeling the same gene or different genes with different effects on PD. The finding of significant genes influencing penetrance for PD raises the question of whether these may interact with environmental factors or other genes to increase the risk for PD. Such gene environment interactions, involving reduced penetrance in PD, may explain the low concordance rates among monozygotic twins for this disease.
Assuntos
Predisposição Genética para Doença/genética , Doença de Parkinson/genética , Idade de Início , Idoso , Saúde da Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Núcleo FamiliarRESUMO
The effect and clinical significance of tolcapone withdrawal on erythrocyte catechol-O-methyltransferase (COMT) activity, levodopa pharmacokinetics, and levodopa requirements were investigated in 59 patients with fluctuating parkinsonism who were randomized to receive placebo or tolcapone 100 or 200 mg three times daily for 6 weeks. Tolcapone withdrawal caused a transient elevation in COMT activity by 64% in patients receiving 100 mg three times daily and by 128% in those receiving 200 mg three times daily at approximately 1-2 weeks after discontinuation of drug. Thereafter, COMT activity was declining but did not reach baseline values by the 12-week study endpoint. However, this had no effect on plasma levodopa and 3-O-methyldopa (3-OMD) concentrations or on levodopa requirements. During treatment, tolcapone increased "on" time and decreased "off" time; after discontinuation of study medication and levodopa dose adjustment, on and off times were similar to baseline. Withdrawal was generally well tolerated; no patients withdrew from the trial during the posttreatment period, and no serious adverse events were observed. In conclusion, the transient increase in erythrocyte COMT activity observed after discontinuation oftolcapone is not associated with changes in peripheral levodopa metabolism and therefore has no significant clinical consequences in terms of levodopa requirements, clinical symptoms, or adverse events.
Assuntos
Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/uso terapêutico , Benzofenonas/efeitos adversos , Levodopa/uso terapêutico , Doença de Parkinson/fisiopatologia , Síndrome de Abstinência a Substâncias/fisiopatologia , Idoso , Antiparkinsonianos/sangue , Benzofenonas/farmacocinética , Catecol O-Metiltransferase/sangue , Método Duplo-Cego , Eritrócitos/efeitos dos fármacos , Eritrócitos/enzimologia , Feminino , Humanos , Levodopa/sangue , Levodopa/farmacocinética , Masculino , Nitrofenóis , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/enzimologia , Síndrome de Abstinência a Substâncias/enzimologia , Tolcapona , Tirosina/análogos & derivados , Tirosina/sangue , Regulação para Cima/efeitos dos fármacosRESUMO
Adductor laryngeal breathing dystonia (ALBD) is a rare disorder in which patients have persistent inspiratory stridor, usually normal voice, and cough. Physical exam is characterized by paradoxical movement of the vocal cords on inspiration. These patients have involuntary action-induced spasms of the adductor laryngeal muscles on inspiration. There has been no uniformly satisfactory treatment for the disease. Speech therapy, psychotherapy, and pharmacotherapy have all had limited success. We report the successful use of botulinum toxin type A in seven patients with adductor laryngeal breathing dystonia. All patients received bilateral thyroarytenoid injections. All patients had toxin effect within 72 hours, reaching maximal effect within 2 weeks with sustained improvement for an average of 13.8 weeks. Adverse effects included breathy voice and mild choking on liquids. Both resolved, on average, within 2 weeks. This retrospective study supports the safe and effective use of botulinum toxin type A in the treatment of adductor laryngeal breathing dystonia.
Assuntos
Toxinas Botulínicas/uso terapêutico , Músculos Laríngeos/fisiopatologia , Laringismo/terapia , Respiração/fisiologia , Prega Vocal/fisiopatologia , Distúrbios da Voz/terapia , Feminino , Humanos , Laringismo/epidemiologia , Laringismo/fisiopatologia , Masculino , Pessoa de Meia-Idade , Sons Respiratórios/efeitos dos fármacos , Estudos Retrospectivos , Fatores de Tempo , Distúrbios da Voz/epidemiologia , Distúrbios da Voz/fisiopatologiaRESUMO
OBJECTIVE: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. METHODS: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. RESULTS: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. CONCLUSIONS: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors.
Assuntos
Doença de Huntington/genética , Expansão das Repetições de Trinucleotídeos , Adulto , Idade de Início , Alelos , Feminino , Genótipo , Humanos , Doença de Huntington/diagnóstico , MasculinoAssuntos
Distonia Muscular Deformante/tratamento farmacológico , Genes Dominantes , Levodopa/uso terapêutico , Dopamina beta-Hidroxilase/sangue , Distonia Muscular Deformante/sangue , Distonia Muscular Deformante/genética , Distonia Muscular Deformante/fisiopatologia , Humanos , Linhagem , Fatores de TempoRESUMO
BACKGROUND: Microtubule-associated protein tau (MAPT) has been associated with several neurodegenerative disorders including forms of parkinsonism and Parkinson disease (PD). We evaluated the association of the MAPT region with PD in a large cohort of familial PD cases recruited by the GenePD Study. In addition, postmortem brain samples from patients with PD and neurologically normal controls were used to evaluate whether the expression of the 3-repeat and 4-repeat isoforms of MAPT, and neighboring genes Saitohin (STH) and KIAA1267, are altered in PD cerebellum. METHODS: Twenty-one single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 were genotyped in the GenePD Study. Single SNPs and haplotypes, including the H1 haplotype, were evaluated for association to PD. Relative quantification of gene expression was performed using real-time RT-PCR. RESULTS: After adjusting for multiple comparisons, SNP rs1800547 was significantly associated with PD affection. While the H1 haplotype was associated with a significantly increased risk for PD, a novel H1 subhaplotype was identified that predicted a greater increased risk for PD. The expression of 4-repeat MAPT, STH, and KIAA1267 was significantly increased in PD brains relative to controls. No difference in expression was observed for 3-repeat MAPT. CONCLUSIONS: This study supports a role for MAPT in the pathogenesis of familial and idiopathic Parkinson disease (PD). Interestingly, the results of the gene expression studies suggest that other genes in the vicinity of MAPT, specifically STH and KIAA1267, may also have a role in PD and suggest complex effects for the genes in this region on PD risk.
Assuntos
Expressão Gênica/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Doença de Parkinson/genética , Proteínas tau/genética , Idoso , Encéfalo/metabolismo , Encéfalo/patologia , Cromossomos Humanos Par 17/genética , Estudos de Coortes , Análise Mutacional de DNA , Expansão das Repetições de DNA/genética , Feminino , Testes Genéticos , Genótipo , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
BACKGROUND: Polymorphisms in the glutathione S-transferase pi gene (GSTP1), encoding GSTP1-1, a detoxification enzyme, may increase the risk of Parkinson disease (PD) with exposure to pesticides. Using the GenePD Study sample of familial PD cases, we explored whether GSTP1 polymorphisms were associated with the age at onset of PD symptoms and whether that relation was modified by exposure to herbicides. METHODS: Seven single-nucleotide polymorphisms (SNPs) were genotyped and tested for association with PD onset age in men in three strata: no exposure to herbicides, residential exposure to herbicides, and occupational exposure to herbicides. Haplotypes were similarly evaluated in stratified analyses. RESULTS: Three SNPs were associated with PD onset age in the group of men occupationally exposed to herbicides. Three additional SNPs had significant trends for the association of PD onset age across the herbicide exposure groups. Haplotype results also provided evidence that the relation between GSTP1 and onset age is modified by herbicide exposure. One haplotype was associated with an approximately 8-years-earlier onset in the occupationally exposed group and a 2.8-years-later onset in the nonexposed group. CONCLUSIONS: Herbicide exposure may be an effect modifier of the relation between glutathione S-transferase pi gene polymorphisms and onset age in familial PD.
Assuntos
Glutationa S-Transferase pi/genética , Herbicidas/efeitos adversos , Doenças Profissionais/induzido quimicamente , Doenças Profissionais/genética , Exposição Ocupacional/efeitos adversos , Doença de Parkinson Secundária/genética , Medição de Risco/métodos , Suscetibilidade a Doenças/induzido quimicamente , Feminino , Predisposição Genética para Doença/genética , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson Secundária/induzido quimicamente , Fatores de RiscoRESUMO
Free and total gamma-aminobutyric acid (GABA) and homocarnosine concentrations were measured in the lumbar cerebrospinal fluid (CSF) of patients with Friedreich's ataxia, Huntington's chorea, and Parkinson's disease (with and without levodopa treatment), and compared with those determined in control subjects. Values found in Friedreich's ataxia or Parkinson's disease were not significantly different from those in controls. Unexpectedly, in Huntington patients, known to have a characteristic decrease in GABA concentrations in specific brain areas, CSF concentrations of total GABA and homocarnosine were significantly higher, whereas free GABA was not different from controls. These findings indicate that the measurement of CSF GABA and homocarnosine in patients with CNS degenerative diseases should be interpreted cautiously.
Assuntos
Carnosina/líquido cefalorraquidiano , Dipeptídeos/líquido cefalorraquidiano , Ataxia de Friedreich/líquido cefalorraquidiano , Doença de Huntington/líquido cefalorraquidiano , Doença de Parkinson/líquido cefalorraquidiano , Ácido gama-Aminobutírico/líquido cefalorraquidiano , Adulto , Idoso , Carnosina/análogos & derivados , Feminino , Humanos , Levodopa/farmacologia , Masculino , Pessoa de Meia-IdadeRESUMO
The reduction or loss of cytochrome P450 enzyme activity as a result of mutations in the CYP2D6 gene has been suggested as a risk factor for Parkinson's disease (PD). Conflicting results among reported studies of the prevalence of mutations among patients with PD suggested a more comprehensive genotyping and an analysis of the interactions with other suspected risk factors and family history. We determined the frequency of seven CYP2D6 mutations among 109 patients with PD and 110 control subjects. Family history of PD, age of onset, exposure to pesticides or herbicides, and well-water consumption were obtained for all cases. There was no significant difference in frequency between patients with PD and control subjects for any mutant allele and no significant association with family history, onset age, or environmental exposures. We sought to increase the power of our study by combining reports from the literature, choosing allele frequencies as the most informative measure. Although we found variability in reported allele frequencies for control subjects that made a meta-analysis problematic, summing all reports demonstrated no difference in CYP2D6 mutation frequency between patients with PD and control subjects. This comprehensive study of CYP2D6 mutations demonstrates that other genes or shared environmental exposures account for the familial risk of PD.