We tested the hypothesis that dopamine-dependent motor learning mechanism underlies the long-duration response to levodopa in Parkinson disease (PD) based on our studies in a mouse model. By data-mining the motor task performance in dominant and nondominant hands of the subjects in a double-blind randomized trial of levodopa therapy, the effects of activity and dopamine therapy were examined.
We data-mined the Earlier versus Later Levodopa Therapy in Parkinson's Disease (ELLDOPA) study published in 2005 and performed statistical analysis comparing the effects of levodopa and dominance of handedness over 42 weeks.
The mean change in finger-tapping counts from baseline before the initiation of therapy to predose at 9 weeks and 40 weeks increased more in the dominant compared to nondominant hand in levodopa-treated subjects in a dose-dependent fashion. There was no significant difference in dominant vs nondominant hands in the placebo group. The short-duration response assessed by the difference of postdose performance compared to predose performance at the same visit did not show any significant difference between dominant vs nondominant hands.
Active use of the dominant hand and dopamine replacement therapy produces synergistic effect on long-lasting motor task performance during “off” medication state. Such effect was confined to dopamine-responsive symptoms and not seen in dopamine-resistant symptoms such as gait and balance. We propose that long-lasting motor learning facilitated by activity and dopamine is a form of disease modification that is often seen in trials of medications that have symptomatic effects.
Rapid-Onset Dystonia-Parkinsonism (RDP) is caused by mutations in the ATP1A3 gene. This observational study sought to determine if cognitive performance is decreased in patients with RDP compared with mutation-negative controls.
We studied 22 familial RDP patients, 3 non-motor manifesting mutation-positive family members, 29 mutation-negative family member controls in 9 families, and 4 unrelated RDP patients, totaling 58 individuals. We administered a movement disorder assessment, including the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and Unified Parkinson’s Disease Rating Scale (UPDRS), and a cognitive battery of learning, memory, psychomotor speed, attention, and executive function. The cognitive battery was designed to evaluate a wide range of functions; recognition memory instruments were selected to be relatively pure measures of delayed memory, devoid of significant motor or vocal production limitations. Comparisons of standardized cognitive scores were assessed both with and without controlling for psychomotor speed, and similarly for severity of depressive symptoms.
Among RDP patients, a majority had onset of motor symptoms by age 25, and had initial symptom presentation in the upper body (face, mouth, or arm). Among patients, the BFMDRS (mean ± SD, 52.1 ± 29.5) and UPDRS motor subscore (29.8 ± 12.7) confirmed dystonia-parkinsonism. The affected RDP patients performed more poorly, on average, than mutation-negative controls for all learning, memory, psychomotor speed, attention, and executive function scores (all P ≤0.01). These differences persisted after controlling for psychomotor speed and severity of depressive symptoms.
Impaired cognitive function may be a manifestation of ATP1A3 mutation and RDP.
Dystonia; RDP; DYT-12; Rapid-Onset Dystonia-Parkinsonism
Rapid-onset dystonia-parkinsonism (RDP) is a movement disorder associated with mutations in the ATP1A3 gene. Signs and symptoms of RDP commonly occur in adolescence or early adulthood and can be triggered by physical or psychological stress. Mutations in ATP1A3 are also associated with alternating hemiplegia of childhood (AHC). The neuropathologic substrate of these conditions is unknown. The central nervous system of four siblings, three affected by RDP and one asymptomatic, all carrying the I758S mutation in the ATP1A3 gene, was analyzed. This neuropathologic study is the first carried out in ATP1A3 mutation carriers, whether affected by RDP or AHC. Symptoms began in the third decade of life for two subjects and in the fifth for another. The present investigation aimed at identifying, in mutation carriers, anatomical areas potentially affected and contributing to RDP pathogenesis. Comorbid conditions, including cerebrovascular disease and Alzheimer disease, were evident in all subjects. We evaluated areas that may be relevant to RDP separately from those affected by the comorbid conditions. Anatomical areas identified as potential targets of I758S mutation were globus pallidus, subthalamic nucleus, red nucleus, inferior olivary nucleus, cerebellar Purkinje and granule cell layers, and dentate nucleus. Involvement of subcortical white matter tracts was also evident. Furthermore, in the spinal cord, a loss of dorsal column fibers was noted. This study has identified RDP-associated pathology in neuronal populations, which are part of complex motor and sensory loops. Their involvement would cause an interruption of cerebral and cerebellar connections which are essential for maintenance of motor control.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-014-1279-x) contains supplementary material, which is available to authorized users.
DYT12; RDP; Rapid-onset dystonia-parkinsonism; Neuropathology
In an effort to account for deficiencies in axonal transport that limit the effectiveness of neurotrophic factors, this study tested the safety and feasibility, in moderately advanced Parkinson disease (PD), of bilaterally administering the gene therapy vector AAV2-neurturin (CERE-120) to the putamen plus substantia nigra (SN, a relatively small structure deep within the midbrain, in proximity to critical neuronal and vascular structures).
After planning and minimizing risks of stereotactically targeting the SN, an open-label, dose-escalation safety trial was initiated in 6 subjects with PD who received bilateral stereotactic injections of CERE-120 into the SN and putamen.
Two-year safety data for all subjects suggest the procedures were well-tolerated, with no serious adverse events. All adverse events and complications were expected for patients with PD undergoing stereotactic brain surgery.
Bilateral stereotactic administration of CERE-120 to the SN plus putamen in PD is feasible and this evaluation provides initial empirical support that it is safe and well-tolerated.
Classification of evidence:
This study provides Class IV evidence that bilateral neurturin gene delivery (CERE-120) to the SN plus putamen in patients with moderately advanced PD is feasible and safe.
To compare profiles of subjects with and without cervical dystonia (CD)-associated pain, to evaluate the contribution of pain and the motor component of CD on quality of life, and to compare the initial botulinum toxin treatment paradigm between pain groups, baseline data were used from the CD Patient Registry for Observation of OnabotulinumtoxinA Efficacy (CD PROBE), a multicenter, prospective, observational registry designed to capture real-world practices and outcomes for onabotulinumtoxinA CD treatment. Subjects were divided into no/mild pain [Pain Numeric Rating Scale (PNRS) score 0–3] and moderate/severe pain groups (PNRS score 4–10). Descriptive and differential statistics were utilized to compare groups. 1,037 subjects completed the first treatment session, reported baseline botulinum toxin status, and completed baseline PNRS. Those with no/mild pain were significantly older at baseline. Those subjects with moderate/severe pain had higher Toronto Western Spasmodic Torticollis Rating Scale Severity (17.7 ± 5.1 vs. 16.2 ± 5.6, p < 0.0001) and Disability (12.7 ± 6.1 vs. 7.5 ± 5.6, p < 0.0001). CD subjects with moderate/severe pain received a higher mean dose (177.3 ± 82.9 vs. 158.0 ± 67.1 U, p = 0.0001) of onabotulinumtoxinA and were injected in more muscles (4.1 ± 1.4 vs. 3.7 ± 1.2, p < 0.0001) at initial treatment. CD PROBE clearly demonstrates the frequency of pain in CD and substantiates its importance when determining an optimal treatment paradigm. Future analyses of CD PROBE will further our understanding of the treatment patterns and outcomes related to onabotulinumtoxinA therapy for this disabling condition.
Electronic supplementary material
The online version of this article (doi:10.1007/s00415-014-7343-6) contains supplementary material, which is available to authorized users.
Botulinum toxin; Cervical dystonia; Dystonia; Pain
Background and Purpose
To characterize patients with benign essential blepharospasm (BEB) by diagnosis, environmental risk factors and family history.
240 patients with BEB were evaluated through a clinical examination and questionnaire. The questionnaire reviewed personal medical history, demographic factors, risk factors for the development of blepharospasm and family history of dystonia and other neurological conditions.
BEB was more commonly found in females (2.8:1) and 93% of the patients were Caucasian. Fifty percent had pure BEB, 31% had BEB/Meige's syndrome, and 4% had BEB and eyelid opening apraxia (+/- Meige's syndrome). A minority of patients reported preceding photophobia (25%) or other eye conditions (22%). The majority were non-smokers, had no exposure to anti-emetic or antipsychotic agents, had a normal birth history and had no history of head trauma. Seventy-two percent did report a stressful event immediately prior to the development of symptoms. Treatments reported included botulinum toxin (BoNT), oral medications, surgical procedures and acupuncture. Thirty-two percent of patients reported a family history of focal dystonia and BEB was the most commonly reported.
This study confirms previous reports of usual age, sex, caffeine and tobacco use and family history in patients with blepharospasm. New findings include a report on occupation, lower reports of preceding eye conditions and photophobia, and higher reported stressful events. Further, this study shows a change in treatment with an increase in BoNT use and decrease in surgical procedures.
Translating new findings in the laboratory into therapies for patients is a slow and expensive process. The development of therapies for neurodegenerative diseases is further complicated by the difficulty in determining whether the drug truly retards the slow degenerative process or provides only symptomatic benefit. In this issue, Aviles-Olmos et al. describe a first in Parkinson’s disease (PD) patient study using a drug previously approved for diabetes treatment. In addition to suggesting that the drug may indeed be disease modifying in PD, their innovative approach suggests there may be more rapid and inexpensive avenues for testing novel therapies in PD.
Collecting and managing data for clinical and translational research presents significant challenges for clinical and translational researchers, many of whom lack needed access to data management expertise, methods, and tools. At many institutions, funding constraints result in differential levels of research informatics support among investigators. In addition, the lack of widely shared models and ontologies for clinical research informatics and health information technology hampers the accurate assessment of investigators’ needs and complicates the efficient allocation of crucial resources for research projects, ultimately affecting the quality and reliability of research. In this article, we present a model for providing flexible, cost-efficient institutional support for clinical and translational research data management and informatics, the Research Management Team (RMT), and describe our initial experiences with deploying this model at our institution.
We report new clinical features of delayed motor development, hypotonia, and ataxia in two young children with mutations (R756H and D923N) in the ATP1A3 gene. In adults, mutations in ATP1A3 cause rapid-onset dystonia-Parkinsonism (RDP, DYT12) with abrupt onset of fixed dystonia. The parents and children were examined and videotaped, and samples were collected for mutation analysis. Case 1 presented with fluctuating spells of hypotonia, dysphagia, mutism, dystonia, and ataxia at 9 months. After three episodes of hypotonia, she developed ataxia, inability to speak or swallow, and eventual seizures. Case 2 presented with hypotonia at 14 months and pre-existing motor delay. At age 4 years, he had episodic slurred speech, followed by ataxia, drooling, and dysarthria. He remains mute. Both children had ATP1A3 gene mutations. To our knowledge, these are the earliest presentations of RDP, both with fluctuating features. Both children were initially misdiagnosed. RDP should be considered in children with discoordinated gait, and speech and swallowing difficulties.
Rapid-onset dystonia-parkinsonism (RDP) is caused by a variety of missense mutations in the ATP1A3 gene. Psychiatric comorbidity has been reported, although systematic examination of psychiatric disease in individuals with RDP is lacking. This study examines psychiatric morbidity for 23 patients with RDP in 10 families with family member control subjects and in 3 unrelated patients with RDP, totaling 56 individuals.
Twenty-nine ATP1A3 mutation–positive individuals were examined; 26 exhibited motor symptoms (motor manifesting carrier [MMC]) and 3 did not (nonmotor manifesting carriers [NMC]). Twenty-seven ATP1A3 mutation-negative participants (noncarriers [NC]) were included. Rates of psychiatric illness for patients with RDP and related asymptomatic gene mutation carriers were compared with those for related nonmutation carriers. Outcome measures included the Unified Parkinson's Disease Rating Scale, Burke-Fahn-Marsden Dystonia Rating Scale, Instrumental Activities of Daily Living, Composite International Diagnostic Interview, Structured Clinical Interview for DSM-IV, Hamilton Depression Scale, Hamilton Anxiety Scale, and Yale-Brown Obsessive-Compulsive Scale.
NMC participants did not report any history of psychiatric disorder. Findings in MMC and NC groups included anxiety (MMC 48, NC 41%), mood (MMC 50%, NC 22%), psychotic (MMC 19%, NC 0%), and substance abuse/dependence (MMC 38%, NC 27%).
ATP1A3 mutations cause a wide spectrum of motor and nonmotor features. Psychotic symptoms tended to emerge before or concurrent with motor symptom onset, suggesting that this could be another expression of the ATP1A3 gene mutation.
A woman from Italy presented with dystonic leg symptoms at the age of 59. Rapid-onset dystonia-parkinsonism (RDP) was not suspected until 3 affected children (2 male, 1 female) with presentations consistent with the disorder were recognized.
The mother and four of her children (3 with and 1 without dystonia) were evaluated with an extensive battery including standardized history questionnaire and rating scales. In addition, all four children had cognitive testing and three of the four children had psychiatric interviews.
In this family, a T613M mutation in the ATP1A3 gene was confirmed, the most common mutation present in patients with RDP. The proband's limb dystonia was atypical of RDP, symptoms of the others affected included dysarthria, asymmetric limb dystonia, and dysphagia more consistent with RDP. The two sons developed dystonia-parkinsonism in adolescence after consuming large amounts of alcohol. All 3 of those with psychiatric interviews reached diagnosable thresholds for mood disorder (bipolar or dysthymia) and some form of anxiety disorder.
The phenotype and age of onset is broader than previously reported in RDP, suggesting that it could be under-reported. Prior to this study, neuropsychologic symptoms associated with RDP were under-appreciated. Those patients who are at risk or suspected of having RDP should be cautioned to avoid excessive alcohol intake. Further study is needed to assess if the cognitive and psychiatric features are part of a broader RDP phenotype and this may have implications for future research into genetic susceptibility for psychiatric disease.
Dystonia; RDP; DYT-12; Rapid-onset dystonia-parkinsonism
Despite evidence suggesting that patient attitudes towards therapy may influence treatment outcomes, the impact of these factors on treatment for Parkinson’s disease is poorly understood. These two surveys, based in Japan and the US, investigated the attitudes of patients towards antiparkinsonian medications, the complications of these therapies, and how these differ across geographies.
The US PRELUDE survey collected data from May 13 to May 20, 2003, from 300 interviews with patients with Parkinson’s disease from the National Parkinson Foundation. The Japanese survey was carried out from June to December 2008 in a stepwise manner using questionnaires (n = 3548) followed by interviews with those who had consented to participate in the questionnaire (n = 407). Both surveys assessed the attitudes of patients towards therapies for Parkinson’s disease and associated complications.
Dyskinesia was not a major challenge of therapy for Parkinson’s disease, and wearing-off caused greater concern in the US, while hallucinations had a greater emphasis in Japan. Patients who had previously experienced dyskinesia were less concerned about this side effect than those who had not. Although pill burden was thought to be a concern in the US, Japanese patients did not indicate that pill burden would limit their drug intake. There were also discrepancies between the perspectives and concerns of patients and those of their treating physicians.
Recognizing patient perspectives regarding therapies for Parkinson’s disease and associated complications, as well as certain cultural influences, is important in the management of parkinsonian symptoms. Acknowledging these concerns may improve the standard of care in patients with Parkinson’s disease. In addition, improved patient education and effective patient–physician communication in both countries may improve compliance and treatment outcomes in patients with the disease.
Parkinson’s disease; patient concerns; dyskinesia; wearing-off; hallucinations
A registry of patients with cervical dystonia (Cervical Dystonia Patient Registry for Observation of onaBotulinumtoxinA Efficacy [CD PROBE]) was initiated to capture data regarding physician practices and patient outcomes with onabotulinumtoxinA (BOTOX®, Allergan, Inc., Irvine, CA, USA). Methods and baseline demographics from an interim analysis are provided.
This is a prospective, multicenter, clinical registry in the United States enrolling subjects with cervical dystonia (CD) who are toxin naïve and/or new to the physicians' practices, or who had been in a clinical trial but received their last injection ≥ 16 weeks prior to enrollment. Subjects are followed over 3 injection cycles of onabotulinumtoxinA, with assessments at time of injection and 4-6 weeks later. Information on physician's practice, patient demographics, CD disease history, duration of treatment intervals and neurotoxin dose, dilution, use of electromyography, and muscles injected are collected. Outcomes are assessed by physicians and subjects using various questionnaires.
This ongoing registry includes 609 subjects with the following baseline data: 75.9% female, 93.6% Caucasian, mean age 57.6 ± 14.3, age at symptom onset 48.3 ± 16.2, and time to diagnosis 5.4 ± 8.6 years, with an additional 1.0 ± 3.5 years before treatment. Of those employed at the time of diagnosis, 36.6% stopped working as a result of CD. CD PROBE, the largest clinical registry of CD treatment, will provide useful data on current treatment practices with onabotulinumtoxinA, potentially leading to refinements for optimization of outcomes.
We present a 74-year old woman with inherited myoclonus-dystonia, with predominant myoclonus and a novel mutation in the ε-sarcoglycan gene. The patient reports a life-long history of rapid, jerking movements, most severe in the upper extremities as well as a postural and action tremor. Bilateral deep brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus was performed, and the patient demonstrated moderate clinical improvement in myoclonus. We studied the effects on myoclonus and tremor of varying DBS frequency and amplitude. The frequency tuning curve for myoclonus was similar to that of tremor, suggesting similar mechanisms by which DBS alleviates both disorders.
stimulation frequency; stimulation amplitude; epsilon-sarcoglycan gene; thalamus; movement disorders
Parkinson’s disease is a commonly encountered neurodegenerative disorder primarily found in aged populations. A number of medications are available to control symptoms, although these are less effective in advanced disease. Deep brain stimulation provides a practicable alternative at this stage, although a minority of patients meet the strict criteria for surgery. Novel medications that provide enhanced symptomatic control remain in developmental demand. Both gene and cell-based therapies have shown promise in early clinical studies. A major unmet need is a treatment that slows or stops disease progression.
Parkinson’s disease; levodopa; motor fluctuations; adenosine A2A antagonists; deep brain stimulation; gene therapy
Nonmotor symptoms of Parkinson's disease (PD) may emerge secondary to the underlying pathogenesis of the disease, while others are recognized side effects of treatment. Inevitably, there is an overlap as the disease advances and patients require higher dosages and more complex medical regimens. The non-motor symptoms that emerge secondary to dopaminergic therapy encompass several domains, including neuropsychiatric, autonomic, and sleep. These are detailed in the paper. Neuropsychiatric complications include hallucinations and psychosis. In addition, compulsive behaviors, such as pathological gambling, hypersexuality, shopping, binge eating, and punding, have been shown to have a clear association with dopaminergic medications. Dopamine dysregulation syndrome (DDS) is a compulsive behavior that is typically viewed through the lens of addiction, with patients needing escalating dosages of dopamine replacement therapy. Treatment side effects on the autonomic system include nausea, orthostatic hypotension, and constipation. Sleep disturbances include fragmented sleep, nighttime sleep problems, daytime sleepiness, and sleep attacks. Recognizing the non-motor symptoms that can arise specifically from dopamine therapy is useful to help optimize treatment regimens for this complex disease.
This review updates understanding and research on blepharospasm, a subtype of focal dystonia. Topics covered include clinical aspects, pathology, pathophysiology, animal models, dry eye, photophobia, epidemiology, genetics, and treatment. Blepharospasm should be differentiated from apraxia of eyelid opening. New insights into pathology and pathophysiology are derived from different types of imaging, including magnetic resonance studies. Physiologic studies indicate increased plasticity and trigeminal sensitization. While botulinum neurotoxin injections are the mainstay of therapy, other therapies are on the horizon.
= Burke-Fahn-Marsden dystonia rating scale;
= botulinum neurotoxin;
= deep brain stimulation;
= diffusion tensor imaging;
= voxel-based morphometry.
Since the original descriptions of hedonistic homeostatic dysregulation syndrome and pathological gambling in Parkinson's disease, impulse control disorders, such as compulsive spending, punding, or binge eating, are increasingly recognized. Although the term hedonistic homeostatic dysregulation syndrome has been supplanted by the concept of the dopamine dysregulation syndrome, the features of severe dyskinesias, cyclical mood disorder with hypomania or manic psychosis, and impairment of social and occupational functioning in the setting of increased intake of antiparkinson therapy remain. At this time, impulse control disorder is defined as maladaptive behaviors that emerge with disease progression and increasing antiparkinson medications. These behaviors may be disruptive, such as punding, or destructive, such as compulsive spending, gambling, binge eating, or hypersexuality.
Ropinirole is a dopamine agonist, approved for use to treat symptoms of early and advanced Parkinson’s disease, is now available in a 24-hour formulation in addition to the immediate release version. This review discusses the mode of action of ropinirole and compares the pharmacokinetics of both formulations. Pivotal studies leading to the approval of both preparations are reviewed in terms of efficacy, dose range and side effects. Patient factors such as compliance are discussed in terms of the place for ropinirole in the armamentarium of Parkinson’s disease therapies.
ropinirole extended release; ropinirole immediate release Parkinson’s disease
Pesticides and correlated lifestyle factors (e.g., exposure to well-water and farming) are repeatedly reported risk factors for Parkinson's disease (PD), but few family-based studies have examined these relationships.
Using 319 cases and 296 relative and other controls, associations of direct pesticide application, well-water consumption, and farming residences/occupations with PD were examined using generalized estimating equations while controlling for age-at-examination, sex, cigarette smoking, and caffeine consumption.
Overall, individuals with PD were significantly more likely to report direct pesticide application than their unaffected relatives (odds ratio = 1.61; 95% confidence interval, 1.13–2.29). Frequency, duration, and cumulative exposure were also significantly associated with PD in a dose-response pattern (p ≤ 0.013). Associations of direct pesticide application did not vary by sex but were modified by family history of PD, as significant associations were restricted to individuals with no family history. When classifying pesticides by functional type, both insecticides and herbicides were found to significantly increase risk of PD. Two specific insecticide classes, organochlorines and organophosphorus compounds, were significantly associated with PD. Consuming well-water and living/working on a farm were not associated with PD.
These data corroborate positive associations of broadly defined pesticide exposure with PD in families, particularly for sporadic PD. These data also implicate a few specific classes of pesticides in PD and thus emphasize the need to consider a more narrow definition of pesticides in future studies.