Consensus guidelines for botulinum toxin therapy: general algorithms and dosing tables for dystonia and spasticity.

Botulinum toxin (BT) therapy is a complex and highly individualised therapy defined by treatment algorithms and injection schemes describing its target muscles and their dosing. Various consensus guidelines have tried to standardise and to improve BT therapy. We wanted to update and improve consensus guidelines by: (1) Acknowledging recent advances of treatment algorithms. (2) Basing dosing tables on statistical analyses of real-life treatment data of 1831 BT injections in 36 different target muscles in 420 dystonia patients and 1593 BT injections in 31 different target muscles in 240 spasticity patients. (3) Providing more detailed dosing data including typical doses, dose variabilities, and dosing limits. (4) Including total doses and target muscle selections for typical clinical entities thus adapting dosing to different aetiologies and pathophysiologies. (5) In addition, providing a brief and concise review of the clinical entity treated together with general principles of its BT therapy. For this, we collaborated with IAB-Interdisciplinary Working Group for Movement Disorders which invited an international panel of experts for the support.

Defining spasticity: a new approach considering current movement disorders terminology and botulinum toxin therapy.

Spasticity is a symptom occurring in many neurological conditions including stroke, multiple sclerosis, hypoxic brain damage, traumatic brain injury, tumours and heredodegenerative diseases. It affects large numbers of patients and may cause major disability. So far, spasticity has merely been described as part of the upper motor neurone syndrome or defined in a narrowed neurophysiological sense. This consensus organised by IAB-Interdisciplinary Working Group Movement Disorders wants to provide a brief and practical new definition of spasticity-for the first time-based on its various forms of muscle hyperactivity as described in the current movement disorders terminology. We propose the following new definition system: Spasticity describes involuntary muscle hyperactivity in the presence of central paresis. The involuntary muscle hyperactivity can consist of various forms of muscle hyperactivity: spasticity sensu strictu describes involuntary muscle hyperactivity triggered by rapid passive joint movements, rigidity involuntary muscle hyperactivity triggered by slow passive joint movements, dystonia spontaneous involuntary muscle hyperactivity and spasms complex involuntary movements usually triggered by sensory or acoustic stimuli. Spasticity can be described by a documentation system grouped along clinical picture (axis 1), aetiology (axis 2), localisation (axis 3) and additional central nervous system deficits (axis 4). Our new definition allows distinction of spasticity components accessible to BT therapy and those inaccessible. The documentation sheet presented provides essential information for planning of BT therapy.

Self-Assessment of Disability in Parkinson's Disease: The MDS-UPDRS Part II Versus Clinician-Based Ratings.

BACKGROUND: Parkinson's disease (PD) is characterized by motor and nonmotor symptoms that progress with time, causing disability. The performance of a disease-specific, self-applied tool for assessing disability, the MDS-UPDRS Part II, is tested against generic and rater-based rating scales. METHODS: An international, cross-sectional, observational study was performed. Patients were assessed with the Hoehn and Yahr (HY) and five disability measures: MDS-UPDRS Part II, Schwab and England Scale (S&E), Clinical Impression of Severity Index-PD (CISI-PD) Disability item, Barthel Index (BI), and Rapid Assessment of Disability Scale (RADS). Data analysis included correlation coefficients, Mann-Whitney and Kruskal-Wallis tests, and intraclass-correlation coefficient for concordance. RESULTS: The sample was composed of 451 patients, 55.2% men, with a mean age of 65.06 years (SD = 10.71). Disability rating scales correlated from |0.75| (CISI-PD Disability with BI) to 0.87 (MDS-UPDRS Part II with RADS). In general, MDS-UPDRS Part II showed high correlation coefficients with clinical variables and satisfactory concordance with the rest of disability measures, with ICC ranging from 0.83 (with BI) to 0.93 (with RADS). All disability rating scales showed statistical significant differences in the sample grouped by sex, age, disease duration, and severity level. CONCLUSIONS: The MDS-UPDRS Part II showed an appropriate performance to assess disability in PD, even better than some rater-based, generic or specific, scales applied in this study.

Strategies for treatment of dystonia.

Treatment of dystonias is generally symptomatic. To produce sufficient therapy effects, therefore, frequently a multimodal and interdisciplinary therapeutic approach becomes necessary, combining botulinum toxin therapy, deep brain stimulation, oral antidystonic drugs, adjuvant drugs and rehabilitation therapy including physiotherapy, occupational therapy, re-training, speech therapy, psychotherapy and sociotherapy. This review presents the recommendations of the IAB-Interdisciplinary Working Group for Movement Disorders Special Task Force on Interdisciplinary Treatment of Dystonia. It reviews the different therapeutic modalities and outlines a strategy to adapt them to the dystonia localisation and severity of the individual patient. Hints to emerging and future therapies will be given.

Imaging Nigrostriatal Dopaminergic Deficit in Holmes Tremor with 18F-PR04.MZ-PET/CT.

Holmes tremor is an infrequent clinical syndrome characterized by unilateral rest, postural, and action tremor often secondary to a brain lesion. We herein report an interesting case of Holmes tremor studied with PET and F-PR04.MZ, a new high-affinity radioligand for dopamine transporters, currently under investigation at our center. F-PR04.MZ-PET can be useful to study the integrity of the nigrostriatal dopaminergic system to improve diagnosis and therapeutic outcome in patients with Holmes tremor and Parkinson disease.

Parkinson's disease severity levels and MDS-Unified Parkinson's Disease Rating Scale.

BACKGROUND: Severity of PD is usually assessed by means of the motor and disability-based Hoehn and Yahr staging (HY), or clinician and patient global perceptions. Scores of more detailed assessments, as the MDS-UPDRS, have not been translated to a grading that allows assignment of score sections to severity levels. The objective of the present study is to determine cut-off points for PD severity levels based on the MDS-UPDRS. METHODS: International, observational study. Applied assessments were: HY, MDS-UPDRS, Clinical Impression for Severity Index, and Clinical and Patient Global Impression of Severity. The coincidence in severity level (mild, moderate, severe) of at least two clinical classifications plus the patient's gradation was considered "the criterion of severity". Cut-off values for each MDS-UPDRS subscale was determined by triangulation of: 1) percentile 90 of the subscale total score; 2) receiver operating characteristic (ROC) analysis; and 3) ordinal logistic regression (OLR) model. RESULTS: Sample was composed of 452 consecutive PD patients without dementia, 55.3% males, age 65.1 ± 10.7 years and PD duration 8.7 ± 6.3 years. All HY stages were represented. The "criterion", classified 275 patients (60.8% of the sample) as: mild PD, 149 (54.2%); moderate, 82 (29.8%); and severe, 44 (16%). The following MDS-UPDRS cut-off points between mild/moderate and moderate/severe levels were found: Part 1: 10/11 and 21/22; Part 2: 12/13 and 29/30; Part 3: 32/33 and 58/59; and Part 4: 4/5 and 12/13. CONCLUSION: Cut-off points to classify PD patients as mild, moderate, or severe on the basis of their MDS-UPDRS scores are proposed.

Manejo de la sialorrea en personas con enfermedad de Parkinson mediante terapia conductivo conductual y estimulación termo-táctil / Management of sialorrhea in people with Parkinson's disease through behavioral therapy and thermotactile stimulation

This study proposes a Speech Therapy treatment for individuals with sialorrhea (saliva production perceived by patient as excessive) as a consequence of Parkinson Disease (PD). Method: A prospective study in 18 individuals with PD diagnosis was taken and divided into two groups: A) received only Cognitive Behavioral Therapy (CBT) (swallowing process awareness), while B) received CBT plus Thermal Tactile Stimulation (TTS) (cold sensory stimulation to the pharyngeal anterior pillars and oral cavity). The intervention lasted 5 weeks. The purpose of this research was to prove the effectiveness of Speech Therapy in dealing with sialorrhea and to assess a significant difference between CBT and CBT plus TTS. A t-student parameter test and the Mann-Withney test were used. Resulted: The assessment by the Clinical Scale for Parkinson Sialorrhea (SCS-PD) prior to therapy was CBT group was 2.6 and 11.5 ± 9.4 ± 4.2 group difference was not statistically significant. After therapy was 3.5 ± 2.8 and 4.6 ± 3.5 both showed a statistically significant difference compared to baseline (p < 0.001), not having statistically significant difference between them. Conclusion: These tests showed that both treatments are effective to decrease sialorrhea perception in individuals with PD. Nevertheless, no statistical significant differences were noted between both treatments.

Introducción: Este estudio propone un tratamiento Fonoaudiológico para trabajar con personas que presentan sialorrea (producción de saliva que el paciente percibe como excesiva) producto de la Enfermedad de Parkinson (EP). Método: Dieciocho personas con diagnóstico de EP y sialorrea, las cuales se dividieron en dos grupos; A: recibió sólo Terapia Cognitivo Conductual (TCC) (concientización del proceso deglutorio), mientras el B: recibió TCC más Estimulación Termo Táctil (ETT) (se realiza estimulación sensorial con frío a los pilares faríngeos anteriores y cavidad oral), la intervención se realizó por 5 semanas. El objetivo de la presente investigación es evidenciar la efectividad de la terapia Fonoaudiológica en el abordaje de la sialorrea y evaluar si existe una diferencia significativa entre la TCC y la TCC más ETT. Se utilizó la prueba paramétrica t-student, y Test de Mann-Withney, se consideró significativo un p < 0,05. Resultados: La valoración mediante la Escala Clínica de la Sialorrea para Parkinson (SCS-PD) previo a la terapia en grupo con TCC 11,5 ± 2,6 y el grupo 9,4 ± 4,2 diferencia que no es estadísticamente significativa. Posterior a la terapia fue 3,5 ± 2,8 y 4,6 ± 3,5 ambos presentaron una diferencia estadísticamente significativa respecto a la basal (p < 0,001), no habiendo diferencia estadísticamente significativa entre ellas. Conclusión: Estas pruebas demostraron que ambos tratamientos son efectivos para disminuir la percepción de sialorrea en las personas con EP. Sin embargo, no se evidencian diferencias estadísticamente significativas entre ambos tratamientos.

A randomized study of rotigotine dose response on 'off' time in advanced Parkinson's disease.

BACKGROUND: Previous phase III studies in patients with advanced Parkinson's disease (PD) not adequately controlled on levodopa demonstrated significant reduction of 'off' time with rotigotine transdermal system up to 16 mg/24 h. However, the minimal effective dose has not been established. OBJECTIVE: This international, randomized, double-blind, placebo-controlled study (SP921; NCT00522379) investigated rotigotine dose response up to 8 mg/24 h. METHODS: Patients with advanced idiopathic PD (≥2.5 h of daily 'off' time on stable doses of levodopa) were randomized 1:1:1:1:1 to receive rotigotine 2, 4, 6, or 8 mg/24 h or placebo, titrated over 4 weeks and maintained for 12 weeks. The primary efficacy variable was change from baseline to end of maintenance in absolute time spent 'off'. RESULTS: 409/514 (80%) randomized patients completed maintenance. Mean (±SD) baseline daily 'off' times (h/day) were placebo: 6.4 (±2.5), rotigotine 2-8 mg/24 h: 6.4 (±2.6). Rotigotine 8 mg/24 h was the minimal dose to significantly reduce 'off' time versus placebo. LS mean (±SE) absolute change in daily 'off' time (h/day) from baseline was -2.4 (±0.28) with rotigotine 8 mg/24 h, and -1.5 (±0.26) with placebo; absolute change in 'off' time in the 8 mg/24 h group compared with placebo was -0.85 h/day (95% CI -1.59, -0.11; p = 0.024). There was an apparent dose-dependent trend. Adverse events (AEs) reported at a higher incidence in the rotigotine 8 mg/24 h group versus placebo included application site reactions, nausea, dry mouth, and dyskinesia; there was no worsening of insomnia, somnolence, orthostatic hypotension, confusional state or hallucinations, even in patients ≥75 years of age. CONCLUSIONS: The minimal statistically significant effective dose of rotigotine to reduce absolute 'off' time was 8 mg/24 h. The AE profile was similar to previous studies.

Spin-lattice distribution MRI maps nigral pathology in progressive supranuclear palsy (PSP) during life: a pilot study.

An MRI biomarker for Parkinsonism has long been sought, but almost all attempts at conventional field strengths have proved unsatisfactory, since patients and controls are not separated. The exception is Spin-Lattice Distribution MRI (SLD-MRI), a technique which detects changes in the substantia nigra (SN) due to changes in the spin-lattice relaxation time, T1. This easily separates patients with Parkinson's disease (PD) from control subjects at 1.5 Tesla, suggesting that it may be sensitive to presymptomatic disease. SLD-MRI demonstrates a topography of signal change within the SN which is the same as the known topography of pathological change, where the lateral portions of the nucleus are more affected than the medial. In a further step towards its validation, we apply SLD-MRI to a disease control, Progressive Supranuclear Palsy (PSP), the most common of the atypical forms of Parkinsonism. In PSP the topography of pathological change in the SN is reversed. We therefore hypothesized that PSP would show a topography of SLD-MRI signal change in the SN that is the reverse of PD (i.e. the medial portion is more affected than the lateral). All 7 patients showed such a topography of MR signal, and all patients were separated from control subjects. Although this is a step toward validation of SLD-MRI with respect to sensitivity and disease specificity, nevertheless we stress that this is a pilot project only. Validation will only be possible when comparing larger cohorts of PSP, PD and control subjects.

Olfactory deficits and cognitive dysfunction in Parkinson's disease.

BACKGROUND: Olfactory deficits and executive dysfunction have been reported in Parkinson's disease (PD). However, the association between these deficits has not been thoroughly examined. METHODS: We studied 44 PD subjects and 17 age-matched controls. In PD subjects, symptoms were assessed with the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr scale. Cognition in both groups was assessed by a neuropsychological battery. Olfactory identification and sensitivity was evaluated with the Sniffin' Sticks® test and olfactory detection threshold, respectively. RESULTS: PD subjects showed significant deficits in olfactory function and working memory, executive function, speed of information processing, visuospatial skills and phonological verbal fluency tests when compared with the control group. Moreover, there was a significant correlation between olfactory sensory deficits and executive dysfunction. In PD patients with up to 12 months of motor symptoms, results were equivalent. CONCLUSION: Our preliminary results suggest a significant association between olfactory deficits and impairments of executive functions in PD.

Clinical spectrum of Kufor-Rakeb syndrome in the Chilean kindred with ATP13A2 mutations.

We report the clinical features of the original Chilean family with Kufor-Rakeb syndrome (KRS) that led to the discovery of the ATP13A2 gene at the PARK9 locus. KRS is a rare juvenile-onset autosomal recessive disease characterized by progressive Parkinsonism, pyramidal signs, and cognitive decline in addition to vertical gaze palsy and facial-faucial-finger minimyoclonus. Neurological and neuropsychological examination during a 10-year period, videotaping, neuroimaging, and measurement of DNA methylation of the ATP13A2 promoter region were performed. The youngest 5 of 17 children of nonconsanguineous parents, carrying compound-heterozygous ATP13A2 mutations, had normal development until ages ∼10 to 12 years, when school performance deteriorated and slowness, rigidity, and frequent falls developed. Examination revealed bradykinesia, subtle postural/action tremor, cogwheel rigidity, spasticity, upward gaze palsy, smooth pursuit with saccadic intrusions, and dementia. Additional signs included facial-faucial-finger minimyoclonus, absent postural reflexes, visual/auditory hallucinations, and insomnia. Levodopa response could not be fully judged in this family. T2* magnetic resonance imaging sequences revealed marked diffuse hypointensity of the caudate (head and body) and lenticular nucleus bilaterally. Disease progression was slow including epilepsy, cachexia, and anarthria. Four affected members died after 28.5 ± 5.5 (mean ± SD) years of disease. Two heterozygous carriers, the mother and eldest sibling, showed jerky perioral muscle contractions and clumsiness of hand movements. There was no significant correlation between DNA methylation of the ATP13A2 promoter region and disease progression. The marked caudate and lenticular nucleus T2*-hypointensity suggests that KRS might belong to the family of neurodegenerative diseases associated with brain iron accumulation.

[Advances in the medical treatment of Parkinson's disease]. / Avances en tratamiento medico de la enfermedad de Parkinson.

Parkinson's disease (PD) is a common progressive neurodegenerative disorder. Dopamine replacement therapy considerably reduces motor handicap. Although levodopa continues as the gold standard for efficacy, its chronic use is associated with potentially disabling motor complications. Strategies to treat levodopa-related motor complications are only partially effective. Best results are currently achieved with invasive strategies via subcutaneous (s.c.) or intraduodenal delivery of apomorphine or levodopa, or deep brain stimulation of the subthalamic nucleus. This presentation will develop the current treatment principles for PD: (1) L-dopa does not accelerate disease progression, (2) no treatment modality exerts neuroprotective effects, (3) L-dopa is more effective than dopamine agonists in alleviating motor symptoms and improving the activities of daily living (ADL) score, in parkinsonian patients, (4) Treatment with dopamine agonist is associated with fewer motor complications than L-dopa. (5) Dopamine agonist therapy is associated with more frequent adverse events than L-dopa therapy, such as hallucinations and somnolence. There is no evidence of a long-term benefit with initial dopamine agonist therapy.

Features associated with the development of non-motor manifestations in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder, predominantly characterized by the presence of motor symptoms. However, the non motor manifestations (NMM) are a frequent complaint in the PD patients. There is a lack of information about the risk factors associated with the NMM in these patients. The aim of this study is to evaluate the prevalence of the more common NMM in a population of PD patients and to determine the features associated with its development. We studied 124 ambulatory PD patients. NMM were defined by the presence of neuropsychiatric manifestations, cognitive disorder, autonomic dysfunction or sleep related problems. In a multivariate analysis we found that the years of evolution of the PD and the presence of cognitive dysfunction are the risk factors for the neuropsychiatric and autonomic manifestations, whereas axial impairment is a risk factor for cognitive disorders and dyskinesias is for sleep related problems. In conclusion, this study shows that the features related to the PD progression appear as the main risk factors associated with NMM.

Features associated with the development of non-motor manifestations in Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder, predominantly characterized by the presence of motor symptoms. However, the non motor manifestations (NMM) are a frequent complaint in the PD patients. There is a lack of information about the risk factors associated with the NMM in these patients. The aim of this study is to evaluate the prevalence of the more common NMM in a population of PD patients and to determine the features associated with its development. We studied 124 ambulatory PD patients. NMM were defined by the presence of neuropsychiatric manifestations, cognitive disorder, autonomic dysfunction or sleep related problems. In a multivariate analysis we found that the years of evolution of the PD and the presence of cognitive dysfunction are the risk factors for the neuropsychiatric and autonomic manifestations, whereas axial impairment is a risk factor for cognitive disorders and dyskinesias is for sleep related problems. In conclusion, this study shows that the features related to the PD progression appear as the main risk factors associated with NMM.

La enfermedad de Parkinson (EP) es un trastorno neurodegenerativo, caracterizado predominan-temente por la presencia de síntomas motores. No obstante, la presencia de manifestaciones no motoras (MNN) son frecuentes en los pacientes con EP. Existe escasa información sobre los factores de riesgo asociados con la aparición de MNN en dichos pacientes. El objetivo de este estudio fue evaluar la prevalencia de las MNN más comunes en una población de pacientes portadores de EP y determinar los factores de riesgo asociados con su aparición. Estudiamos 124 pacientes portadores de EP atendidos en forma ambulatoria. La presencia de MNN fue definida por la aparición de manifestaciones neuropsiquiátricas, trastorno cognitivo, disfunción autonómica o alteraciones del sueño. En el análisis multivariado encontramos que los años de evolución de la EP y la presencia de disfunción cognitiva son los principales factores de riesgo para las manifestaciones neuropsiquiátricas y autonómicas, mientras que el compromiso axial es el mayor factor de riesgo para la aparición de manifestaciones cognitivas y la presencia de discinesias es el principal factor asociado con la aparición de trastornos del sueño. En conclusión, este estudio muestra que los factores asociados a la progresión de la EP son los principales factores de riesgo para la aparición de las MNN en nuestra población.

Déficit de la olfacción en la enfermedad de Parkinson: un síntoma a considerar en la práctica clínica: [revisión] / Olfaction deficit in parkinson disease: a symptom to considerate in clinical practice: [review]

Se estima que entre el 0,8 y 1,42% de la población general presenta algún grado de disfunción olfativa. En estudios epidemiológicos de población general han demostrado que esto aumenta con la edad, llegando a afectar al 29% de las personas entre 70 y 79 años. Las causas más comunes del déficit de olfacción en el adulto mayor son trauma de cráneo, inflamación del tracto respiratorio alto de etiología tanto infecciosa como alérgica y las enfermedades degenerativas del sistema nervioso central como la enfermedad de Alzheimer y de Parkinson. El 60 al 90% de los pacientes con Enfermedad de Párkinson tiene déficit olfativo, siendo uno de los síntomas más frecuentes de la enfermedad. Se presenta en forma precoz y bilateral, el déficit en general no es a todos los olores, permaneciendo la habilidad de reconocer algunos. En esta revisión, se caracteriza la forma de presentación de este trastorno y su impacto como un marcador biológico en la enfermedad de Parkinson...

Between 0,8 to 1,42% of the population presents some grade of smell dysfunction. Several epidemiological studies have demonstrated that this increases with the age, affecting to 29% of subjects between 70 and 79 years. The more common causes of this dysfunction are skull trauma, inflammation of upper respiratory tract of infectious or allergic etiologies and the degenerative diseases of the central nervous system, mainly Alzheimer and Parkinson disease. Between 60 to 90% of the patients with Parkinson Disease have smell deficit, being one of the more common symptoms in this disease. Usually this smell dysfunction is presented bilaterally and it appears early in the course of the disease. In this review is characterized the clinical presentation of this dysfunction and its impact as a biological marker in the PD...

Quetiapine for insomnia in Parkinson disease: results from an open-label trial.

Quetiapine is an atypical antipsychotic with sedative properties frequently used to treat hallucinations and psychosis in Parkinson disease (PD). The objective of this trial is to evaluate quetiapine for insomnia in nonpsychotic PD patients. Fourteen consecutive PD patients with frequent insomnia and without psychotic symptoms were treated openly for 12 weeks with a single evening dose of quetiapine. The dose was adjusted according to clinical improvement and tolerance. The severity of insomnia was assessed using the Pittsburgh Sleep Quality Index (PSQI), daytime sleepiness was evaluated with the Epworth Sleep Scale (ESS), and motor performance was evaluated using the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS). All evaluations were done before and 1, 2, and 3 months after initiation of treatment. Total PSQI basal scores were 13.6 +/- 3.7 points. The PSQI score improved in 11 patients and was reduced by 3.8 +/- 3.9 points by the end of the study (P < 0.01). The ESS score was reduced by 4.3 +/- 3.7 points (P < 0.01). The mean quetiapine dose was 31.9 mg/day. No significant change was observed in the motor scale. Two patients were discontinued due to nonserious adverse effects. These results suggest that quetiapine may be a safe and effective treatment of insomnia in PD patients. Double-blind studies will probably confirm these findings.