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Introduction: Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), is a neurodegenerative autosomal recessive disease caused by TPP1 gene variants, with a spectrum of classic and atypical phenotypes. The aim of treatment is to slow functional decline as early as possible in an attempt to improve quality of life and survival. This study describes the clinical characteristics as well as the response to treatment with cerliponase alfa. Materials and methods: A retrospective study was conducted in five Latin-American countries, using clinical records from patients with CLN2. Clinical follow-up and treatment variables are described. A descriptive and bivariate statistical analysis was performed. Results: A total of 36 patients were observed (range of follow-up of 61-110 weeks post-treatment). At presentation, patients with the classic phenotype (n = 16) exhibited regression in language (90%), while seizures were the predominant symptom (87%) in patients with the atypical phenotype (n = 20). Median age of symptom onset and time to first specialized consultation was 3 (classical) and 7 (atypical) years, while the median time interval between onset of symptoms and treatment initiation was 4 years (classical) and 7.5 (atypical). The most frequent variant was c.827 A > T in 17/72 alleles, followed by c.622C > T in 6/72 alleles. All patients were treated with cerliponase alfa, and either remained functionally stable or had a loss of 1 point on the CLN2 scale, or up to 2 points on the Wells Cornel and Hamburg scales, when compared to pretreatment values. Discussion and conclusion: This study reports the largest number of patients with CLN2 currently on treatment with cerliponase alfa in the world. Data show a higher frequency of patients with atypical phenotypes and a high allelic proportion of intron variants in our region. There was evidence of long intervals until first specialized consultation, diagnosis, and enzyme replacement therapy. Follow-up after the initiation of cerliponase alfa showed slower progression or stabilization of the disease, associated with adequate clinical outcomes and stable functional scores. These improvements were consistent in both clinical phenotypes.
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BACKGROUND: Adherence to treatment in Parkinson's disease (PD) is compromised due to the need for multiple therapies, comorbidities related to aging, and the complexity of therapeutic schemes. In the present study, we aimed to explore adherence to treatment in groups of PD patients from six Latin-American (LA) countries and identify its associated demographic and clinical parameters. METHODS: A multicenter, cross-sectional, exploratory study was conducted from September 2016 to March 2017. Treatment adherence was assessed using the simplified medication adherence questionnaire (SMAQ), applied to patients and caregivers. Sociodemographic and clinical variables (MDS-UPDRS Part III-IV, MMSE, Beck Depression Inventory-II (BDI-II)) were recorded. RESULTS: Eight hundred patients from six LA countries were evaluated. Nonadherence was reported in 58.25% of the population, according to patients. The most frequent issues were forgetfulness and correct timing of doses. A high level of agreement in adherence prevalence and most SMAQ items were observed between patients and their caregivers. The nonadherent population had a significantly higher proportion of unemployment, free access to medication, troublesome dyskinesias and off-periods, lesser years of education, and worse motor, cognitive, and mood scores. In multiple logistic and linear regression analyses, MDS-UPDRS Part III, BDI-II, gender, free access to medication, treatment with dopamine agonists alone, years of education, excessive concerns about adverse effects, and beliefs about being well-treated remained significant contributors to adherence measures. CONCLUSION: Educational strategies, greater involvement of PD patients in decision-making, and consideration of their beliefs and values might be of great need to improve medication adherence in this PD population.
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Adesão à Medicação/estatística & dados numéricos , Doença de Parkinson/terapia , Idoso , Cuidadores , Comorbidade , Estudos Transversais , Escolaridade , Emprego , Feminino , Humanos , América Latina , Masculino , Adesão à Medicação/psicologia , Pessoa de Meia-Idade , Doença de Parkinson/psicologia , Análise de Regressão , Índice de Gravidade de Doença , Fatores Sociodemográficos , Inquéritos e QuestionáriosRESUMO
BACKGROUND: The ventral intermediate nucleus (VIM) is the target of choice for Essential Tremor (ET) deep brain stimulation (DBS). Renewed interest in caudal zona incerta (cZI) stimulation for tremor control has recently emerged and some groups believe this approach may address long-term reduction of benefit seen with VIM-DBS. OBJECTIVES: To compare clinical outcomes and DBS programming in the long-term between VIM and cZI neurostimulation in ET-DBS patients. MATERIALS AND METHODS: A retrospective review of 53 DBS leads from 47 patients was performed. Patients were classified into VIM or cZI groups according to the location of the activated DBS contact. Demographics, DBS settings, and Tremor Rating Scale scores were compared between groups at baseline and yearly follow-up to 4 years after DBS. Student t-tests and analysis of variance (ANOVA) were used to compare variables between groups. RESULTS: Relative to baseline, an improvement in ON-DBS tremor scores was observed in both groups from 6 months to 4 years post-DBS (p < 0.05). Although improvement was still significant at 4 years, scores from month 6 to 2 years were comparable between groups but at 3 and 4 years post-DBS the outcome was better in the VIM group (p < 0.01). Stimulation settings were similar across groups, although we found a lower voltage in the VIM group at 3 years post-DBS. CONCLUSIONS: More ventral DBS contacts in the cZI region do improve tremor, however, VIM-DBS provided better long-term outcomes. Randomized controlled trials comparing cZI vs VIM targets should confirm these results.
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OBJECTIVE: To describe the clinical features, etiology, findings from neuroimaging, and treatment results in a series of 29 patients with Holmes tremor (HT). METHODS: A retrospective study was performed based on review of medical records and videos of patients with HT diagnosis. RESULTS: A total of 16 women and 13 men were included. The mean age at the moment of CNS insult was 33.9 ± 20.1 years (range 8-76 years). The most common causes were vascular (48.3%), ischemic, or hemorrhagic. Traumatic brain injury only represented 17.24%; other causes represented 34.5%. The median latency from lesion to tremor onset was 2 months (range 7 days-228 months). The most common symptoms/signs associated with HT were hemiparesis (62%), ataxia (51.7%), hypoesthesia (27.58%), dystonia (24.1%), cranial nerve involvement (24.1%), and dysarthria (24.1%). Other symptoms/signs were vertical gaze disorders (6.8%), bradykinesia/rigidity (6.8%), myoclonus (3.4%), and seizures (3.4%). Most of the patients had lesions involving more than one area. MRI showed lesions in thalamus or midbrain or cerebellum in 82.7% of the patients. Levodopa treatment was effective in 13 out of 24 treated patients (54.16%) and in 3 patients unilateral thalamotomy provided excellent results. CONCLUSIONS: The most common causes of HT in our series were vascular lesions. The most common lesion topography was mesencephalic, thalamic, or both. Treatment with levodopa and thalamic stereotactic lesional surgery seems to be effective.
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Transtornos Cerebrovasculares/diagnóstico , Transtornos Cerebrovasculares/terapia , Mesencéfalo/patologia , Tálamo/patologia , Tremor/diagnóstico , Tremor/terapia , Adolescente , Adulto , Idoso , Transtornos Cerebrovasculares/epidemiologia , Criança , Feminino , Humanos , Levodopa/uso terapêutico , Masculino , Mesencéfalo/cirurgia , Pessoa de Meia-Idade , Psicocirurgia/métodos , Estudos Retrospectivos , Tálamo/cirurgia , Resultado do Tratamento , Tremor/epidemiologia , Adulto JovemRESUMO
Parkinson's disease (PD) patients have an increased risk of falls resulting in important social and economical consequences. Risk factors for falls include the use of psychotropic drugs, which are used for the treatment of PD neuropsychiatric symptoms. We aimed to determine the association between psychotropic drug use and falls in a PD cohort. A cross-sectional study from the NPF QII study UF site was conducted. Subjects reported presence and frequency of falls in the prior year. Frequency was scored from 0 (no falls) to 4 (falling daily). Antidepressants, antipsychotics, cognitive enhancers/stimulants, and benzodiazepines were considered psychotropics. Forty percent of the 647 subjects included had a fall in the previous year. Fallers were found to have clinical signs of a more advanced disease. After adjusting for confounding variables, the regression analysis showed that use of antidepressants alone (adjusted OR 2.2, CI 95 % 1.3-3.8, p = 0.04), benzodiazepines alone (adjusted OR 2.0, CI 95 % 1.1-3.5, p = 0.02), and the combination of antidepressants with benzodiazepines (adjusted OR 4.1, CI 95 % 2.0-8.3, p < 0.0001) were independently associated with the presence of falls. When comparing to those not on psychotropics, subjects on antidepressants alone had a significantly higher mean frequency of falls score (1.07 vs. 0.44, p < 0.0001). The use of antidepressants was independently associated with falls in our PD cohort after considering for confounding variables such as age and measures of disease progression. Other factors related to disease progression should be considered before claiming the use of psychotropic drugs as causative.
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Acidentes por Quedas/estatística & dados numéricos , Antidepressivos/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Psicotrópicos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antipsicóticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicotrópicos/efeitos adversosRESUMO
BACKGROUND: DBS has proven to be an effective therapy for Parkinson's disease, essential tremor, and primary dystonia. Mixed results have been reported in case series for other hyperkinetic disorders, and sparse data are available regarding secondary movement disorders. We report on the clinical effects of bilateral globus pallidus internus (GPi) DBS, a progressive mitochondrial cytopathy. METHODS: A single patient with myoclonus and dystonia syndrome secondary to a mitochondrial cytopathy with history of perinatal hypoxia was identified from our University of Florida DBS database. Demographics, clinical, surgical, and DBS data were documented. RESULTS: At 6 months post-DBS, we observed a 32% (361 to 527) improvement on quality of life (36-item Medical Outcome Study Short-Form Health Survey; SF-36). Objective clinical scales revealed a 33% (143 to 96) improvement in the Unified Myoclonus Rating Scale (UMRS) total score. The UMRS action myoclonus subsection revealed a 29% (69 to 46) improvement. No significant changes were observed in the Burke-Fahn-Mardsen Dystonia Rating Scale (BFMDRS). After 1-year follow-up, a worsening of 59% (527 to 215) was observed in the SF-36 scale, of 19% (28.5 to 35) in the BFMDRS, and of 23% (96 to 124) in the UMRS. However, the frequency and intensity of action myoclonus scores remained lower when compared to baseline scores. CONCLUSIONS: Although we observed a loss of benefit in the long term for most quality-of-life and clinical outcomes, the DBS effects on action myoclonus seemed to remain stable. Longer follow-up studies are necessary to confirm our short-term and unblinded findings.
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BACKGROUND: Aspiration pneumonia is an important cause of morbidity and mortality in Parkinson's disease (PD). Clinical characteristics of PD patients in addition to specific alterations in swallowing mechanisms contribute to higher swallowing times and impairment in the effective clearance of the airway. These issues may render patients more prone to dysphagia and aspiration events. We aimed to determine the frequency of aspiration events in a hospitalized PD cohort, and to report the number of in-hospital swallow evaluations. METHODS: A retrospective single center chart review of 212 PD patients who had 339 hospital encounters was performed from January 2011 to March 2013. Demographics, clinical characteristics, and reasons for encounters were documented. The number of in-hospital aspiration events and the number of swallowing evaluations and also the implementation of aspiration precautions were recorded. RESULTS: The cohort had a mean age of 74.1 (SD = 10.1) years with mean disease duration of 6 (SD = 6.3) years. Fifty-two hospital encounters (15.3%) were related to a pulmonary cause. In-hospital aspiration pneumonia events were reported in 8 (2.4%) of the total encounters. Swallow evaluations were performed in 25% of all cases, and aspiration precautions were initiated in 32% of the encounters. The data revealed that 1/8 patient had swallowing evaluations performed prior to an aspiration event. CONCLUSIONS: In-hospital aspiration pneumonia events were reported in 2.4% of the hospitalized PD cohort. Preventive measures and precautions were not routinely performed, however rates of aspiration were relatively low. The results highlight the need for more research into screening and monitoring of swallowing problems in PD patients during hospital encounters.
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Transtornos de Deglutição/etiologia , Doença de Parkinson/complicações , Pneumonia Aspirativa/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Deglutição , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Aspirativa/etiologia , Estudos RetrospectivosRESUMO
BACKGROUND: Parkinson's disease patients are more likely to be hospitalized, have higher rates of hospital complications, and have an increased risk of deterioration during hospitalization. Length of stay is an important underlying factor for these increased risks. We aimed to investigate potential medication errors that may occur during hospitalization and its impact on length of hospital stay. METHODS: A cross-sectional chart review of 339 consecutive hospital encounters from 212 PD subjects was performed. Medication errors were defined as wrong timing or omission of administration for dopaminergic drugs and administration of contraindicated dopamine blockers. An analysis of covariance was applied to examine whether these medication errors were related to increased length of hospital stays. RESULTS: A significant effect for dopaminergic administration (p<0.01) on length of hospital stay was observed. Subjects who had delayed administration or missed at least one dose stayed longer (M=8.2 days, SD=8.9 vs. M=3.6 days SD=3.4). Contraindicated dopamine blocking agents were administered in 23% (71/339) of cases, and this was also significantly related to an increased length of stay (M=8.2 days, SD=8.9 vs. M=3.6 days SD=3.4), p<0.05. Participants who received a contraindicated dopamine blocker stayed in the hospital longer (M=7.5 days, SD=9.1) compared to those who did not (M=5.9 days, SD=6.8). Neurologists were consulted in 24.5% of encounters. Specialty consultation had no effect on the medication related errors. CONCLUSIONS: Missing dopaminergic dosages and administration of dopamine blockers occur frequently in hospitalized Parkinson's disease patients and this may impact length of stay. These potentially modifiable factors may reduce the risk of a longer stay related to hospitalization.
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Antiparkinsonianos/administração & dosagem , Antipsicóticos/uso terapêutico , Dopaminérgicos/administração & dosagem , Antagonistas de Dopamina/efeitos adversos , Hospitalização , Erros de Medicação , Doença de Parkinson/tratamento farmacológico , Acidentes por Quedas/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Antipsicóticos/efeitos adversos , Contraindicações , Estudos Transversais , Antagonistas de Dopamina/administração & dosagem , Esquema de Medicação , Registros Eletrônicos de Saúde , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Encaminhamento e Consulta/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
UNLABELLED: Impulse control disorders (ICD) in Parkinson's disease (PD) have attracted increasing interest. They are characterized by the inability to control the impulse to perform an act that can be detrimental to them or to others. Although dopamine agonists (DA), as a group, have been associated with impulse control disorders (ICD), piribedil has rarely been reported to cause them. METHOD: Case reports of six parkinsonian patients on piribedil presenting pathological gambling (PG). RESULTS: All of the patients presented ICD associated with piribedil use. Two of them received this medication as first treatment and four of them who had developed ICDs secondary to other DA that reappeared with piribedil. CONCLUSION: Despite piribedil is commercially available in only a few countries, it should be considered in the differential diagnosis of PG in patients with PD.
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Antiparkinsonianos/efeitos adversos , Agonistas de Dopamina/efeitos adversos , Jogo de Azar/induzido quimicamente , Doença de Parkinson/tratamento farmacológico , Piribedil/efeitos adversos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/psicologia , Fatores de Risco , Resultado do TratamentoRESUMO
Impulse control disorders (ICD) in Parkinson's disease (PD) have attracted increasing interest. They are characterized by the inability to control the impulse to perform an act that can be detrimental to them or to others. Although dopamine agonists (DA), as a group, have been associated with impulse control disorders (ICD), piribedil has rarely been reported to cause them. Method Case reports of six parkinsonian patients on piribedil presenting pathological gambling (PG). Results All of the patients presented ICD associated with piribedil use. Two of them received this medication as first treatment and four of them who had developed ICDs secondary to other DA that reappeared with piribedil. Conclusion Despite piribedil is commercially available in only a few countries, it should be considered in the differential diagnosis of PG in patients with PD. .
Os distúrbios do controle do impulso (DCI) na doença de Parkinson (DP) têm atraído crescente interesse. Eles são caracterizados pela incapacidade da pessoa em controlar o impulso para realizar um ato que pode ser prejudicial a ela própria ou aos outros. Embora os agonistas dopaminérgicos (AD), como um grupo, têm sido associados com distúrbios do controle do impulso, o piribedil tem sido relatado raramente como causa dos mesmos. Método Relatos de seis casos de pacientes parkinsonianos em uso de piribedil apresentando jogo patológico (JP). Resultados Todos os pacientes apresentaram DCI com o uso do piribedil. Dois deles receberam piribedil como primeiro tratamento e quatro deles que haviam desenvolvido DCI devido a outro AD, reapresentaram o quadro com piribedil. Conclusão Apesar de o piribedil estar disponível comercialmente apenas em alguns países, deveria ser considerado no diagnóstico diferencial de JP em pacientes com DP. .
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Animais , Circulação Cerebrovascular/fisiologia , Homeostase/fisiologia , Lobo Parietal/embriologia , Pressão Sanguínea/fisiologia , Desenvolvimento Embrionário e Fetal , Feto/fisiologia , Fluxometria por Laser-Doppler , Ovinos/embriologiaRESUMO
PURPOSE OF REVIEW: Later stage Parkinson's disease, sometimes referred to as advanced disease, has been characterized by motor complication, as well as by the potential emergence of nonlevodopa responsive motor and nonmotor symptoms. The management of advanced stage Parkinson's disease can be complex. This review summarizes the currently available treatment strategies for addressing advanced Parkinson's disease. RECENT FINDINGS: We will discuss the latest pharmacological strategies (e.g., inhibitors of dopamine-metabolizing enzymes, dopamine agonists, and extended release dopamine formulations) for addressing motor dysfunction. We will summarize the risks and benefits of current invasive treatments. Finally, we will address the current evidence supporting the treatment of nonmotor symptoms in the advanced Parkinson's disease patient. We will conclude by detailing the potential nonpharmacological and multidisciplinary approaches for advanced stage Parkinson's disease. SUMMARY: The optimization of levodopa is, in most cases, the most powerful therapeutic option available; however, medication optimization requires an advanced understanding of Parkinson's disease. Failure of conventional pharmacotherapy should precipitate a discussion of the potential risks and benefits of more invasive treatments. Currently, there are no comparative studies of invasive treatment. Among the invasive treatments, deep brain stimulation has the largest amount of existing evidence, but also has the highest individual per patient risk. Nonmotor symptoms will affect quality of life more than the motor Parkinson's disease symptoms, and these nonmotor symptoms should be aggressively treated. Many advanced Parkinson's disease patients will likely benefit from multi and interdisciplinary Parkinson's disease teams with multiple professionals collaborating to develop a collective and tailored strategy for an individual patient.
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Antiparkinsonianos/uso terapêutico , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , HumanosRESUMO
OBJECTIVE: Formulate a definition and describe the clinical characteristics of PD patients with a "brittle response" (BR) to medications versus a "non-brittle response" (NBR), and characterize the use of DBS for this population. METHODS: An UF IRB approved protocol used a retrospective chart review of 400 consecutive PD patients presenting to the UF Center for Movement Disorders and Neurorestoration. Patient records were anonymized and de-identified prior to analysis. SPSS statistics were used to analyze data. RESULTS: Of 345 included patients, 19 (5.5%) met criteria for BR PD. The BR group was comprised of 58% females, compared to 29% in the NBR group (Pâ=â.008). The former had a mean age of 63.4 compared to 68.1 in the latter. BR patients had lower mean weight (63.5 vs. 79.6, Pâ=â<.001), longer mean disease duration (12.6 vs. 8.9 years, Pâ=â.003), and had been on LD for more years compared to NBR patients (9.8 vs. 5.9, Pâ=â.001). UPDRS motor scores were higher (40.4 vs. 30.0, Pâ=â.001) in BR patients. No differences were observed regarding the Schwab and England scale, PDQ-39, and BDI-II. Sixty-three percent of the BR group had undergone DBS surgery compared to 18% (Pâ=â.001). Dyskinesias were more common, severe, and more often painful (Pâ=â<.001) in the BR group. There was an overall positive benefit from DBS. CONCLUSION: BR PD occurred more commonly in female patients with a low body weight. Patients with longer disease duration and longer duration of LD therapy were also at risk. The BR group responded well to DBS.
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Estimulação Encefálica Profunda , Doença de Parkinson/tratamento farmacológico , Idoso , Discinesias/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Hereditary spastic paraplegia (HSP) type 2 is a proteolipid protein (PLP1)-related genetic disorder that is characterized by dysmyelination of the central nervous system resulting primarily in limb spasticity, cognitive impairment, nystagmus, and spastic urinary bladder of varying severity. Previously reported PLP1 mutations include duplications, point mutations, or whole gene deletions with a continuum of phenotypes ranging from severe Pelizaeus-Merzbacher disease (PMD) to uncomplicated HSP type 2. In this manuscript we report a novel PLP1 missense mutation (c.88G>C) in a family from Argentina. This mutation is in a highly conserved transmembrane domain of PLP1 and the mutant protein was found to be retained in the endoplasmic reticulum when expressed in vitro. Due to the variable expressivity that characterizes these disorders our report contributes to the knowledge of genotype-phenotype correlations of PLP1-related disorders.
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Mutação , Proteína Proteolipídica de Mielina/genética , Paraplegia Espástica Hereditária/genética , Feminino , Humanos , Masculino , LinhagemRESUMO
BACKGROUND: Blepharospasm is a focal cranial dystonia, which could be idiopathic in origin or secondary to an underlying disorder that commonly impairs quality of life. Botulinum toxin (BoNT) injections have become the treatment of choice; however, a less favorable response to BoNT is expected in secondary blepharospasm. No studies have been conducted comparing outcomes between blepharospasm cohorts. We therefore aim to compare BoNT outcomes in primary and secondary blepharospasm subjects. METHODS: A retrospective review of 64 blepharospasm subjects receiving BoNT therapy was conducted. Demographics, BoNT treatment schedules, duration of BoNT therapy, and side effects were recorded. Outcome measures were duration of benefit, peak-dose benefit recorded with the Clinical Global Impressions Scale (CGIS), and related side effects. RESULTS: No difference was found between the two cohorts regarding duration of benefit from treatment (primary 9.47 weeks vs. secondary 9.63 weeks, pâ=â0.88). Perceived peak-dose benefit was more commonly reported as "very much improved" in secondary patients, but this was not significant (pâ=â0.13). Higher BoNT dosages were required in both groups over time, with a mean increase of 20.5% in primary and 26.5% in secondary blepharospasm. Ptosis (8%) and diplopia (6%) were the most common reported side effects. Mean follow-up in years was similar between groups, 3.6 years for primary vs. 2.4 years for secondary blepharospasm (pâ=â0.17). DISCUSSION: BoNT injections were effective with comparable benefits seen in both primary and secondary blepharospasm populations. Clinicians should be aware of the similar benefit from BoNT reported in secondary blepharospasm patients. The average duration of benefit in this cohort was comparable with previous reports.
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We describe a 73-year-old female patient with Parkinson disease who developed impulse control disorders (ICDs) and dopamine dysregulation syndrome (DDS) owing to piribedil overdose. She was initially put on piribedil 150 mg; and owing to disease progression, levodopa was added 4 years later. Three years later, piribedil was raised to 200 mg; but presumably owing to a misunderstanding, she took 400 mg/d, which was well tolerated and produced an improvement in her parkinsonian symptoms.However, over the next few weeks, she started shopping compulsively, buying unnecessary clothes and food. In addition, she visited her dog's veterinarian several times a day with nonsense queries. She began to have financial problems and family disruption. During an examination, mild dyskinesia was evident.We diagnosed ICDs and most likely dopamine dysregulation syndrome DDS. Piribedil doses were decreased to 200 mg/d and levodopa increased up to 750 mg/d, with a clear improvement in compulsive behavior without worsening of the dyskinesia.Our case shows that even in cases in which regular doses of dopamine agonists are harmless, dose increments can induce these unwanted effects.