RESUMEN
BACKGROUND: In patients with Parkinson's disease (PD), sleep, mood, cognitive, autonomic, and other non-motor symptoms may fluctuate in a manner similar to motor symptoms. OBJECTIVES: To validate a final version of a patient-rated questionnaire that captures the presence and severity of non-motor fluctuations in levodopa-treated PD patients (NoMoFA). METHODS: We recruited PD subjects from five movement disorders centers across the US and Canada. We assessed the internal consistency, floor and ceiling effects, test-retest reliability, and concurrent validity of NoMoFA. Classical test theory and item response theory methods informed item reduction and Delphi process yielded a final questionnaire. RESULTS: Two hundred subjects and their care-partners participated in the study (age: 66.4 ± 9.6 years; disease duration: 9 ± 5.5 years; median Hoehn and Yahr [H&Y] OFF: 3 [range 1-5]; mean Unified Parkinson's Disease Rating Scale (UPDRS) III ON score: 27.4 ± 14.9). Acceptability of the scale was adequate. There were floor effects in 8/28 items. Cronbach's alpha was 0.894. While eight items had "item-to-total" correlations below the cutoff of 0.4, removing these items did not improve Cronbach's alpha. Test-retest reliability was acceptable (intraclass correlation coefficient [ICC] 0.73; 95% confidence interval, 0.64-0.80). Concurrent validity was adequate with all Spearman's rho values comparing NoMoFA score to other measures of parkinsonian severity showing significance and in the expected direction. A final Delphi panel eliminated one item to avoid redundancy. CONCLUSIONS: The final 27-item self-administered NoMoFA is a valid and reliable questionnaire, capturing both static and fluctuating non-motor symptoms in PD. © 2021 International Parkinson and Movement Disorder Society.
Asunto(s)
Enfermedad de Parkinson , Anciano , Canadá , Humanos , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
OBJECTIVE: Isolated focal dystonia can spread to muscles beyond the initially affected body region, but risk of spread has not been evaluated in a prospective manner. Furthermore, body regions at risk for spread and the clinical factors associated with spread risk are not well characterised. We sought here to prospectively characterise risk of spread in recently diagnosed adult-onset isolated focal dystonia patients. METHODS: Patients enrolled in the Dystonia Coalition with isolated dystonia affecting only the neck, upper face, hand or larynx at onset of symptoms were included. Timing of follow-up visits was based on a sliding scale depending on symptom onset and ranged from 1 to 4 years. Descriptive statistics, Kaplan-Meier survival curves and Cox proportional hazard regression models were used to assess clinical characteristics associated with dystonia spread. RESULTS: 487 enrolled participants (68.3% women; mean age: 55.6±12.2 years) met our inclusion/exclusion criteria. Spread was observed in 50% of blepharospasm, 8% of cervical dystonia, 17% of hand dystonia and 16% of laryngeal dystonia cases. Most common regions for first spread were the oromandibular region (42.2%) and neck (22.4%) for blepharospasm, hand (3.5%) for cervical dystonia and neck for hand (12.8%) and laryngeal (15.8%) dystonia. Increased spread risk was associated with a positive family history (HR=2.18, p=0.012) and self-reported alcohol responsiveness (HR=2.59, p=0.009). CONCLUSIONS: Initial body region affected in isolated focal dystonia has differential risk and patterns of spread. Genetic factors likely influence the risk of spread. These findings can aid clinical prognostication and inform future investigations into potential disease-modifying treatments.
Asunto(s)
Trastornos Distónicos/complicaciones , Trastornos Distónicos/diagnóstico , Adulto , Edad de Inicio , Anciano , Estudios de Cohortes , Progresión de la Enfermedad , Trastornos Distónicos/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Análisis de Supervivencia , Evaluación de SíntomasRESUMEN
BACKGROUND: Limited tools are available for the assessment of orthostatic tremor severity and disability. OBJECTIVES: To develop and validate a self-administered orthostatic tremor scale. METHODS: After expert consensus and literature review generating a list of 42 items, the scale was developed and modified for validation after a patient focus group, multiple rounds of Delphi panels, and cognitive interviews. Clinimetric evaluations included assessing content validity, internal consistency, measurement error and reliability, construct validity, and concurrent validity anchored on the examiner's Clinical Global Impression score. RESULTS: Eleven items ranked on a Likert scale from 0 (no disability/severity) to 5 (maximal disability/severity) were evaluated in 54 orthostatic tremor patients (16 men and 38 women; mean age: 69.17 ± 9.64 years; disease duration: 13.83 ± 11.24 years) to probe severity and disability over the preceding 1-week period. The 11-item scale showed good internal consistency (Cronbach's alpha = 0.863) and acceptable (>0.40) item-to-total correlation. However, one item was removed at the final Delphi panel because of significant floor effect, poor item-to-total correlation, and poor factor-loading, leaving the scale with 10 items (10-item Orthostatic Tremor Severity and Disability Scale). Test-retest reliability at 2 weeks was excellent (two-way random intraclass correlation coefficient > 0.90), and the individual item test-retest reliability showed good agreement, with a threshold weighted kappa >0.60 for all items. Exploratory factor analyses revealed a parsimonious two-factor construct accounting for 57.7% of the scale's variance. The 10-item Orthostatic Tremor Severity and Disability Scale scores correlated with the CGI. CONCLUSIONS: The self-administered 10-item Orthostatic Tremor Severity and Disability Scale scale is valid and reliable for capturing orthostatic tremor-related severity and disability. © 2020 International Parkinson and Movement Disorder Society.
Asunto(s)
Evaluación de la Discapacidad , Temblor , Anciano , Análisis Factorial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Psicometría , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , Temblor/diagnósticoRESUMEN
OBJECTIVE: The purpose of this study was to determine whether patients with functional movement disorders (FMDs) differ in their internal versus external locus of control (LOC) and whether LOC in these patients affected disease severity, quality of life, and functional impairment compared with control subjects with degenerative (Parkinson's disease) and nondegenerative (focal dystonia) neurological conditions. METHODS: A total of 156 patients with FMD (N=45), Parkinson's disease (N=64), and focal dystonia (N=47) were recruited between June 2015 and August 2017. The authors administered the general Levenson Multidimensional LOC (LOC-G) and health-specific Multidimensional Health LOC (LOC-H) scales. An internal LOC was represented similarly in both scales: the external LOC included "chance" and "powerful others" in the LOC-G measure and chance, "other people," and "doctors" in the LOC-H measure. Quality of life, functional impairment, and FMD severity were assessed. One-way analysis of variance and adjusted logistic regressions were used, as well as ordinary least-squares between and within groups, respectively. RESULTS: Patients with FMD had lower external chance LOC-G scores compared with patients in the Parkinson's disease group (odds ratio=0.90, p=0.03) and higher internal (odds ratio=1.22, p=0.01) and lower external (odds ratio=0.77, p=0.02) doctors LOC-H scores compared with patients in the focal dystonia group. External powerful others LOC-G score was associated with functional impairment (regression coefficient=-0.04, p=0.02). There were no effects of LOC on quality of life or disease severity. CONCLUSIONS: Patients with FMD exhibited high "within our control" internal general and health-specific frame of reference. LOC had no influence on quality of life or disease severity in this patient population.
Asunto(s)
Trastornos de Conversión/psicología , Trastornos Distónicos/psicología , Control Interno-Externo , Trastornos del Movimiento/psicología , Enfermedad de Parkinson/psicología , Trastornos Psicofisiológicos/psicología , Adulto , Anciano , Trastornos de Conversión/fisiopatología , Estudios Transversales , Trastornos Distónicos/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Movimiento/fisiopatología , Enfermedad de Parkinson/fisiopatología , Trastornos Psicofisiológicos/fisiopatología , Calidad de Vida , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: Review the effect of orthostatic hypotension (OH) and rapid-eye-movement sleep behavioural disorder (RBD) on survival, cognitive impairment and postural stability, and discuss pathogenic mechanisms involved in the association of these two common non-motor features with relevant clinical outcomes in α-synucleinopathies. METHODS: We searched PubMed (January 2007-February 2019) for human studies of OH and RBD evaluating cognitive impairment, postural instability, and survival in Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA) and pure autonomic failure (PAF). Included studies were analysed for design, key results and limitations as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: OH and RBD showed a positive association with cognitive impairment in PD and DLB, conflicting association in PAF, and no association in MSA. OH was correlated with incident falls and postural instability in PD and DLB but not in MSA. The association between RBD and postural instability was inconclusive; positive in five studies, negative in seven. OH, but not RBD, correlated with reduced survival in PD, DLB and MSA. The combination of OH and RBD was associated with cognitive impairment and more rapid progression of postural instability. CONCLUSIONS: OH and RBD yielded individual and combined negative effects on disability in α-synucleinopathies, reflecting a 'malignant' phenotype of PD with early cognitive impairment and postural instability. Underlying mechanisms may include involvement of selected brainstem cholinergic and noradrenergic nuclei.
Asunto(s)
Hipotensión Ortostática/complicaciones , Trastorno de la Conducta del Sueño REM/complicaciones , Sinucleinopatías/complicaciones , Sinucleinopatías/fisiopatología , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/fisiopatología , Progresión de la Enfermedad , Humanos , Hipotensión Ortostática/fisiopatología , Equilibrio Postural , Trastorno de la Conducta del Sueño REM/fisiopatología , Sinucleinopatías/mortalidadRESUMEN
Obtaining reliable longitudinal information about everyday functioning from individuals with Parkinson's disease (PD) in natural environments is critical for clinical care and research. Despite advances in mobile health technologies, the implementation of digital outcome measures is hindered by a lack of consensus on the type and scope of measures, the most appropriate approach for data capture (eg, in clinic or at home), and the extraction of timely information that meets the needs of patients, clinicians, caregivers, and health care regulators. The Movement Disorder Society Task Force on Technology proposes the following objectives to facilitate the adoption of mobile health technologies: (1) identification of patient-centered and clinically relevant digital outcomes; (2) selection criteria for device combinations that offer an acceptable benefit-to-burden ratio to patients and that deliver reliable, clinically relevant insights; (3) development of an accessible, scalable, and secure platform for data integration and data analytics; and (4) agreement on a pathway for approval by regulators, adoption into e-health systems and implementation by health care organizations. We have developed a tentative roadmap that addresses these needs by providing the following deliverables: (1) results and interpretation of an online survey to define patient-relevant endpoints, (2) agreement on the selection criteria for use of device combinations, (3) an example of an open-source platform for integrating mobile health technology output, and (4) recommendations for assessing readiness for deployment of promising devices and algorithms suitable for regulatory approval. This concrete implementation guidance, harmonizing the collaborative endeavor among stakeholders, can improve assessments of individuals with PD, tailor symptomatic therapy, and enhance health care outcomes. © 2019 International Parkinson and Movement Disorder Society.
Asunto(s)
Enfermedad de Parkinson/fisiopatología , Evaluación del Resultado de la Atención al Paciente , Teléfono Inteligente , Telemedicina , Dispositivos Electrónicos Vestibles , Seguridad Computacional , Análisis de Datos , Visualización de Datos , Aprobación de Recursos , Necesidades y Demandas de Servicios de Salud , Humanos , Ciencia de la Implementación , Aplicaciones Móviles , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: PD psychosis is often associated with cognitive impairment, including dementia, and involves dopaminergic, serotonergic, and cholinergic mechanisms. OBJECTIVE: To evaluate the differential effect of the antipsychotic pimavanserin, a selective serotonin 2A receptor inverse agonist, in PD psychosis patients with versus without cognitive impairment and in those receiving versus not receiving cognitive-enhancing medications. METHODS: Data from the pivotal randomized clinical trial of pimavanserin for PD psychosis were stratified by (1) screening MMSE score as cognitively impaired (21-24) versus unimpaired (≥25) and (2) concomitant use versus nonuse of cognitive-enhancing medications. The primary outcome measure was change in the PD-adapted Scale for the Assessment of Positive Symptoms. RESULTS: Mean (pimavanserin vs. placebo) change from baseline was larger in the cognitively impaired (n = 50; -6.62 vs. -0.91; P = 0.002) versus the cognitively unimpaired (n = 135; -5.50 vs. -3.23; p = 0.046) group. The comparable change was -6.04 versus -2.18 (P = 0.012) and -5.66 versus -3.15 (P = 0.041) in patients treated (n = 69) and not treated (n = 116) with concomitant cognitive-enhancing medication. Pimavanserin was similarly tolerated across all cognitive groups with no additional safety concerns identified. Overall adverse event rates were comparable across the concomitant cognitive-enhancing medication groups; however, rates of serious adverse events and discontinuations attributed to adverse events were increased in patients taking cholinesterase inhibitors. CONCLUSIONS: The antipsychotic effect of pimavanserin is robust in PD patients with cognitive impairment and may be enhanced by concomitant cognitive-enhancing medication use. Future prospective studies are needed to confirm these preliminary findings. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Antipsicóticos/uso terapéutico , Trastornos del Conocimiento/tratamiento farmacológico , Nootrópicos/uso terapéutico , Enfermedad de Parkinson/complicaciones , Piperidinas/uso terapéutico , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/etiología , Urea/análogos & derivados , Anciano , Anciano de 80 o más Años , Trastornos del Conocimiento/etiología , Método Doble Ciego , Femenino , Humanos , Masculino , Escala del Estado Mental , Persona de Mediana Edad , Resultado del Tratamiento , Urea/uso terapéuticoRESUMEN
Progressive ambulatory impairment and abnormal white matter (WM) signal on neuroimaging come together under the diagnostic umbrella of vascular parkinsonism (VaP). A critical appraisal of the literature, however, suggests that (1) no abnormal structural imaging pattern is specific to VaP; (2) there is poor correlation between brain MRI hyperintensities and microangiopathic brain disease and parkinsonism from available clinicopathologic data; (3) pure parkinsonism from vascular injury ("definite" vascular parkinsonism) consistently results from ischemic or hemorrhagic strokes involving the SN and/or nigrostriatal pathway, but sparing the striatum itself, the cortex, and the intervening WM; and (4) many cases reported as VaP may represent pseudovascular parkinsonism (e.g., Parkinson's disease or another neurodegenerative parkinsonism, such as PSP with nonspecific neuroimaging signal abnormalities), vascular pseudoparkinsonism (e.g., akinetic mutism resulting from bilateral mesial frontal strokes or apathetic depression from bilateral striatal lacunar strokes), or pseudovascular pseudoparkinsonism (e.g., higher-level gait disorders, including normal-pressure hydrocephalus with transependimal exudate). These syndromic designations are preferable over VaP until pathology or validated biomarkers confirm the underlying nature and relevance of the leukoaraiosis. © 2015 International Parkinson and Movement Disorder Society.
Asunto(s)
Trastornos Cerebrovasculares/clasificación , Trastornos Parkinsonianos/clasificación , Trastornos Cerebrovasculares/patología , Trastornos Cerebrovasculares/fisiopatología , Humanos , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/fisiopatología , SíndromeRESUMEN
Animal models have been used to gain pathophysiologic insights into Parkinson's disease (PD) and aid in the translational efforts of interventions with therapeutic potential in human clinical trials. However, no disease-modifying therapy for PD has successfully emerged from model predictions. These translational disappointments warrant a reappraisal of the types of preclinical questions asked of animal models. Besides the limitations of experimental designs, the one-size convergence and oversimplification yielded by a model cannot recapitulate the molecular diversity within and between PD patients. Here, we compare the strengths and pitfalls of different models, review the discrepancies between animal and human data on similar pathologic and molecular mechanisms, assess the potential of organoids as novel modeling tools, and evaluate the types of questions for which models can guide and misguide. We propose that animal models may be of greatest utility in the evaluation of molecular mechanisms, neural pathways, drug toxicity, and safety but can be unreliable or misleading when used to generate pathophysiologic hypotheses or predict therapeutic efficacy for compounds with potential neuroprotective effects in humans. To enhance the translational disease-modification potential, the modeling must reflect the biology not of a diseased population but of subtypes of diseased humans to distinguish What data are relevant and to Whom.
RESUMEN
Background: Hemidystonia is defined as dystonia restricted to one side of the body. It is traditionally believed to result from a lesion in the contralateral hemisphere. Objectives: To describe a series of hemidystonia patients without lesions on brain imaging. Methods: We searched for individuals with potential hemidystonia who were included in the Dystonia Coalition or Movement Disorder Society Genetic mutation database (MDSgene), and conducted a systematic review. Results: We found 10 individuals classified as hemidystonia or with homolateral limb dystonia among 3696 cases enrolled by the Dystonia Coalition, 9 cases in MDSgene, and one idiopathic case in the literature. None had evidence of a brain lesion. Body distributions used to define hemidystonia varied considerably and were not always restricted to one side of the body. Conclusions: Hemidystonia may be idiopathic or genetic, without any obvious brain lesion. The varied use of the term suggests the need for more specific clinical criteria to define "half the body."
RESUMEN
Clinical trials of putative disease-modifying therapies in neurodegeneration have obeyed the century-old principle of convergence, or lumping, whereby any feature of a clinicopathologic disease entity is considered relevant to most of those affected. While this convergent approach has resulted in important successes in trials of symptomatic therapies, largely aimed at correcting common neurotransmitter deficiencies (e.g., cholinergic deficiency in Alzheimer's disease or dopaminergic deficiency in Parkinson's disease), it has been consistently futile in trials of neuroprotective or disease-modifying interventions. As individuals affected by the same neurodegenerative disorder do not share the same biological drivers, splitting such disease into small molecular/biological subtypes, to match people to therapies most likely to benefit them, is vital in the pursuit of disease modification. We here discuss three paths toward the splitting needed for future successes in precision medicine: (1) encourage the development of aging cohorts agnostic to phenotype in order to enact a biology-to-phenotype direction of biomarker development and validate divergence biomarkers (present in some, absent in most); (2) demand bioassay-based recruitment of subjects into disease-modifying trials of putative neuroprotective interventions in order to match the right therapies to the right recipients; and (3) evaluate promising epidemiologic leads of presumed pathogenetic potential using Mendelian randomization studies before designing the corresponding clinical trials. The reconfiguration of disease-modifying efforts for patients with neurodegenerative disorders will require a paradigm shift from lumping to splitting and from proteinopathy to proteinopenia.
Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/genética , Enfermedad de Alzheimer/terapia , Biomarcadores , EnvejecimientoRESUMEN
A 48-year-old man was referred to the movement disorders clinic for 10 years of progressive slurred speech, spasticity, limb incoordination, and wide-based gait. Extensive neurologic workup was inconclusive, including serum and CSF testing, neuroimaging, EMG/NCS, exome sequencing, and mitochondrial testing. An ataxia repeat expansion panel ultimately revealed the final diagnosis. In this report, we review the clinical characteristics of a rare, late-onset, autosomal recessive cerebellar ataxia and discuss the importance of pursuing targeted gene testing to avoid diagnostic delays, especially as new treatments for this and other genetic diseases become available.
Asunto(s)
Ataxia Cerebelosa , Degeneraciones Espinocerebelosas , Masculino , Humanos , Persona de Mediana Edad , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/genética , Ataxia , Espasticidad Muscular/diagnóstico , Espasticidad Muscular/genética , Razonamiento ClínicoRESUMEN
STUDY OBJECTIVES: To evaluate the health-related quality of life (HRQoL) in patients with upper airway respiratory syndrome (UARS) and obstructive sleep apnea (OSA) compared to the general population (GP) in Lima, Peru, and to explore the variables associated with differences in HRQoL in patients with UARS. METHODS: This was a retrospective study of medical and polysomnography records from 2009-2014 in a referral sleep medicine center for patients aged 18-64 years. UARS was defined by polysomnography as follows: apnea-hypopnea index < 5 events/h, oxygen saturation ≥ 92%, respiratory effort-related arousal index ≥ 5. HRQoL was assessed using the 36-Item Short Form Survey (version 1) questionnaire validated in Peru. The GP HRQoL was obtained from a population-based survey. Linear and logistic regression analyses were conducted. RESULTS: We reviewed 1,329 polysomnograms and selected 888. UARS and OSA were diagnosed in 93 and 795 participants, respectively. The GP cohort consisted of 641 participants. Total HRQoL mean scores (95% confidence interval) in patients with UARS, patients with OSA, and the GP were 67.4 (63.7-71.1), 66.9 (65.4-68.4), and 82.9 (81.6-84.3), respectively. Patients with UARS and patients with OSA had a 5.5 times (95% confidence interval, 3.3-9.2) and 6.2 times (95% confidence interval, 4.6-8.4) greater probability of having a low total HRQoL score compared to patients in the GP, respectively. In patients with UARS, muscle pain, use of psychotropic medication, obesity, and depression were negatively correlated with the total HRQoL score. CONCLUSIONS: The impact of OSA and UARS on HRQoL is similar between disease groups and markedly worse when compared to the impact in the GP. In patients with UARS, the presence of muscle pain, obesity, female sex, depression, and use of psychotropic medication negatively impacted HRQoL. CITATION: Vizcarra-Escobar D, Duque KR, Barbagelata-Agüero F, Vizcarra JA. Quality of life in upper airway resistance syndrome. J Clin Sleep Med. 2022;18(5):1263-1270.
Asunto(s)
Calidad de Vida , Apnea Obstructiva del Sueño , Resistencia de las Vías Respiratorias , Femenino , Humanos , Mialgia , Obesidad , Estudios Retrospectivos , Apnea Obstructiva del Sueño/diagnóstico , SíndromeRESUMEN
BACKGROUND: Hereditary spastic paraplegia (HSP) encompasses several rare genetic disorders characterized by progressive lower extremity spasticity and weakness caused by corticospinal tract degeneration. Published literature on genetically confirmed pediatric HSP cases is limited. METHODS: We conducted a retrospective review of childhood-onset HSP cases followed in the neuromuscular clinics at Children's and Emory Healthcare in Atlanta. Clinical presentation, family history, examination, electrodiagnostic data, neuroimaging, genetic test results, comorbidities, and treatment were recorded. RESULTS: Sixteen patients with HSP (eight males, eight females) with a mean age 19 years ± 15.7 years were included. Ten patients (66%) presented with gait difficulty. Seven (44%) were ambulatory at the last clinic follow-up visit with an average disease duration of 7.4 years. Genetically confirmed etiologies included SPAST (3 patients), MARS (2), KIF1A (2), KIF5A (1), SACS (1), SPG7 (1), REEP1 (1), PNPT1 (1), MT-ATP6 (1), and ATL1 (1). Symptom onset to genetic confirmation on an average was 8.2 years. Sensory motor axonal polyneuropathy was found in seven patients, and two exhibited cerebellar atrophy on magnetic resonance imaging (MRI) of the brain. Neurological comorbidities included developmental delay (n = 9), autism (n = 5), epilepsy (n = 3), and attention-deficit/hyperactivity disorder (n = 2). CONCLUSIONS: In our study, a significant proportion (70%) of subjects with childhood-onset HSP had comorbid neurocognitive deficits, polyneuropathy with or without neuroimaging abnormalities, and rare genetic etiology. Genetic diagnosis was established either through inherited genetic neuropathy panel or whole-exome sequencing, which supports the utility of whole-exome sequencing in aiding in HSP diagnosis.
Asunto(s)
Paraplejía Espástica Hereditaria , Adolescente , Adulto , Niño , Preescolar , Exorribonucleasas/genética , Femenino , Humanos , Cinesinas , Masculino , Proteínas de Transporte de Membrana/genética , Mutación , Neuroimagen , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/genética , Espastina/genética , Secuenciación del Exoma , Adulto JovenRESUMEN
BACKGROUND: Movement disorders can be associated with anti-neuronal antibodies. METHODS: We conducted a systematic review of cases with documented anti-neuronal antibodies in serum and/or cerebrospinal fluid published in PubMed before April 1, 2020. Only patients with at least one movement disorder were included. We used random forests for variable selection and recursive partitioning and regression trees for the creation of a data-driven decision algorithm, integrated with expert's clinical feedback. RESULTS: Three hundred and seventy-seven studies met eligibility criteria, totaling 844 patients and 13 antibodies: amphiphysin, GAD, GlyR, mGluR1, ANNA-2/Ri, Yo/PCA-1, Caspr2, NMDAR, LGI-1, CRMP5/CV2, ANNA-1/Hu, IgLON5, and DPPX. Stiffness/rigidity/spasm spectrum symptoms were more frequently associated with amphiphysin, GAD, and GlyR; ataxia with mGluR1, ANNA-2/Ri, Yo/PCA-1, Caspr2, and ANNA-1/Hu; dyskinesia with NMDAR and paroxysmal movement with LGI1; chorea/choreoathetosis with CRMP5/CV2, IgLON5, and NMDAR; myoclonus with GlyR and DPPX; tremors with ANNA2/Ri and anti-DPPX; and parkinsonism with IgLON5 and NMDAR. Data-driven classification analysis determined the following diagnostic predictions (with probability selection): psychiatric symptoms and dyskinesia predicted NMDAR (71% and 87%, respectively); stiffness/rigidity/spasm and ataxia, GAD (67% and 47%, respectively); ataxia and opsoclonus, ANNA-2/Ri (68%); chorea/choreoathetosis, CRMP5/CV2 (41%). These symptoms remained the top predictors in random forests analysis. The integration with an expert opinion analysis refined the precision of the approach. Breast and lung tumors were the most common tumors. On neuroimaging, cerebellar involvement was associated with GAD and Yo/PCA-1; temporal involvement with Caspr2, LGI-1, ANNA-1/Hu. CONCLUSION: Selected movement disorders are associated with specific anti-neuronal antibodies. The combination of data-driven and expert opinion approach to the diagnosis may assist early management efforts.
Asunto(s)
Ataxia Cerebelosa , Corea , Trastornos del Movimiento , Autoanticuerpos , Moléculas de Adhesión Celular Neuronal , Humanos , EspasmoRESUMEN
Dopamine agonists are one of the main stay of treatment option for Parkinson disease (PD). Side effects that develop from their use are generally categorized into behavioral and non-behavioral. Behavioral side effects include: impulse control behavior disorder (ICD), psychosis and cognitive impairment. Non-behavioral side effects include: nausea/vomiting, "sleep attacks", leg swelling, weight gain and orthostasis. The aim of this study is to evaluate the clinicians' response to PD patients who developed behavioral side effects from dopamine agonists, in comparison to those patients who developed only non-behavioral side effects. We performed a retrospective chart review of all patients diagnosed with PD over a two year period. Among 313 patients who were on a dopamine agonist, 156 reported side effects. Sixty-five patients reported behavioral (with or without non-behavioral) side effects, while 91 experienced only non-behavioral side effects. Forty-nine out of the 65 patients (75.3%) who experienced behavioral side effects had their dopamine agonist dose decreased compared to 53 out of 91patients (58.2%) who experienced only non-behavioral side effects (Chi square = 4.92, p < 0.05). Patients with behavioral side effects were 3 times more likely have their dose decreased (OR = 3.3; 95%CI = 1.442-7.551; P = 0.005). However, neither taper speed nor the occurrence of dopamine agonist withdrawal syndrome (DAWS) differed between the two groups. Amongst PD patients treated with dopamine agonists, the presence of behavioral side effects independently increased the chance of dopamine agonist dose reduction. Prospective studies are needed to confirm these findings.
RESUMEN
BACKGROUND: Postural instability is a disease milestone signaling advanced disease. OBJECTIVES: To estimate the onset of postural instability in monogenic parkinsonisms. METHODS: We systematically reviewed studies (PubMed 1996-2017) in SNCA, PRKN, PINK1, DJ-1, LRRK2, ATP13A2, FBXO7, VPS35, DNAJC6, or SYNJ1-related monogenic parkinsonisms, with documented postural instability. Genes with ≥ 15 patients were included in an individual-patient meta-analysis and compared with a retrospectively collected sporadic Parkinson's disease cohort from our center. The primary outcome measure was the progression-free survival from postural instability using Kaplan-Meier survival curves. Cox proportional hazards analyses were summarized using hazards ratio (HR). RESULTS: Of 2085 eligible studies, 124 met full criteria (636 patients) for the systematic review, whereas a total of 871 subjects (270 from sporadic cohort, 601 monogenic parkinsonisms) were included in the individual-patient meta-analysis. Postural instability was reported in 80% of DJ-1, 40% of PRKN, 39% of PINK1, 34% of ATP13A2, 31% of LRRK2, and 29% of SNCA patients. Progression-free survival from postural instability at 10 years after disease onset was longest in ATP13A2 (97%) and shortest in SNCA (50%). Halfway between these two extremes were PRKN (88%), PINK1 (87%), and LRRK2 (81%), similar to sporadic Parkinson's disease (72%). Higher risk of postural instability was observed in SNCA (HR = 3.2, p = 0.007) and DJ-1 (HR = 3.96, p = 0.001) compared to sporadic Parkinson's disease. Young age at onset in PINK1 and female sex in LRRK2 were associated with a decreased risk of postural instability. CONCLUSIONS: Monogenic parkinsonisms exhibit differential timelines to postural instability, informing prognostic counseling and interpretation of future genotype-specific treatment trials.
Asunto(s)
Enfermedad de Parkinson , Trastornos Parkinsonianos , Estudios de Cohortes , Femenino , Genotipo , Humanos , Enfermedad de Parkinson/genética , Estudios RetrospectivosRESUMEN
Genes associated with parkinsonism may also be implicated in carcinogenesis, but their interplay remains unclear. We systematically reviewed studies (PubMed 1967-2019) reporting gene variants associated with both parkinsonism and cancer. Somatic variants were examined in cancer samples, whereas germline variants were examined in cancer patients with both symptomatic and asymptomatic (carriers) genetic parkinsonisms. Pooled proportions were calculated with random-effects meta-analyses. Out of 9,967 eligible articles, 60 were included. Of the 28 genetic variants associated with parkinsonism, six were also associated with cancer. In cancer samples, SNCA was predominantly associated with gastrointestinal cancers, UCHL1 with breast cancer, and PRKN with head-and-neck cancers. In asymptomatic carriers, LRRK2 was predominantly associated with gastrointestinal and prostate cancers, PRKN with prostate and genitourinary tract cancers, GBA with sarcoma, and 22q11.2 deletion with leukemia. In symptomatic genetic parkinsonism, LRRK2 was associated with nonmelanoma skin cancers and breast cancers, and PRKN with head-and-neck cancers. Cancer was more often manifested in genetic parkinsonisms compared to asymptomatic carriers. These results suggest that intraindividual genetic contributions may modify the co-occurrence of cancer and neurodegeneration.
Asunto(s)
Neoplasias , Enfermedad de Parkinson , Trastornos Parkinsonianos , Humanos , Masculino , Neoplasias/genética , Enfermedad de Parkinson/genéticaRESUMEN
OBJECTIVE: To evaluate whether orthostatic hypotension (OH) or supine hypertension (SH) is associated with brain atrophy and white matter hyperintensities (WMH), we analyzed clinical and radiologic data from a large multicenter consortium of patients with Parkinson disease (PD) and dementia with Lewy bodies (DLB). METHODS: Supine and orthostatic blood pressure (BP) and structural MRI data were extracted from patients with PD and DLB evaluated at 8 tertiary-referral centers in the United States, Canada, Italy, and Japan. OH was defined as a systolic/diastolic BP fall ≥20/10 mm Hg within 3 minutes of standing from the supine position (severe ≥30/15 mm Hg) and SH as a BP ≥140/90 mm Hg with normal sitting BP. Diagnosis-, age-, sex-, and disease duration-adjusted differences in global and regional cerebral atrophy and WMH were appraised with validated semiquantitative rating scales. RESULTS: A total of 384 patients (310 with PD, 74 with DLB) met eligibility criteria, of whom 44.3% (n = 170) had OH, including 24.7% (n = 42) with severe OH and 41.7% (n = 71) with SH. OH was associated with global brain atrophy (p = 0.004) and regional atrophy involving the anterior-temporal (p = 0.001) and mediotemporal (p = 0.001) regions, greater in severe vs nonsevere OH (p = 0.001). The WMH burden was similar in those with and without OH (p = 0.49). SH was not associated with brain atrophy (p = 0.59) or WMH (p = 0.72). CONCLUSIONS: OH, but not SH, was associated with cerebral atrophy in Lewy body disorders, with prominent temporal region involvement. Neither OH nor SH was associated with WMH.