The pathophysiology of idiopathic focal hand dystonia (writer's cramp) is characterized by deficient inhibitory basal ganglia function and altered cortical sensorimotor processing. To explore if this is already a primary finding in dystonia for internal movement simulation independent of dystonic motor output or abnormal sensory input, we investigated the neural correlates of movement imagination and observation in patients with writer's cramp. Event-related fMRI was applied during kinesthetic motor imagery of drawing simple geometric figures (imagination task) and passively observing videos of hands drawing identical figures (observation task). Compared with healthy controls, patients with writer's cramp showed deficient activation of the left primary sensorimotor cortex, mesial and left dorsal premotor cortex, bilateral putamen, and bilateral thalamus during motor imagery. No significant signal differences between both groups were found during the observation task. We conclude that internal movement simulation and planning as tested during imagination of hand movements appear to be dysfunctional in patients with writer's cramp, whereas visual signal processing and observation-induced activation are unaffected. Deficient basal ganglia–premotor activation could be a correlate of impaired basal ganglia inhibition and focusing during the selection of motor programs in dystonia. This finding seems to be an intrinsic deficit, as it is found during motor imagery in the absence of dystonic symptoms. © 2012 Movement Disorder Society
One of the most devastating nonmotor manifestations of PD is dementia. There are few established predictors of dementia in PD. In numerous cross-sectional studies, patients with rapid eye movement (REM) sleep behavior disorder (RBD) have increased cognitive impairment on neuropsychological testing, but no prospective studies have assessed whether RBD can predict Parkinson's dementia. PD patients who were free of dementia were enrolled in a prospective follow-up of a previously published cross-sectional study. All patients had a polysomnogram at baseline. Over a mean 4-year follow-up, the incidence of dementia was assessed in those with or without RBD at baseline using regression analysis, adjusting for age, sex, disease duration, and follow-up duration. Of 61 eligible patients, 45 (74%) were assessed and 42 were included in a full analysis. Twenty-seven patients had baseline RBD, and 15 did not. Four years after the initial evaluation, 48% with RBD developed dementia, compared to 0% of those without (P-adjusted = 0.014). All 13 patients who developed dementia had mild cognitive impairment on baseline examination. Baseline REM sleep atonia loss predicted development of dementia (% tonic REM = 73.2 ± 26.7 with dementia, 40.8 ± 34.5 without; P = 0.029). RBD at baseline also predicted the new development of hallucinations and cognitive fluctuations. In this prospective study, RBD was associated with increased risk of dementia. This indicates that RBD may be a marker of a relatively diffuse, complex subtype of PD. © 2012 Movement Disorder Society
Recent studies have demonstrated an association between a Mediterranean-type diet and Alzheimer's risk. We assessed the association between Mediterranean-type diet adherence and Parkinson's disease (PD) status.
Two hundred and fifty-seven PD participants and 198 controls completed the Willett semiquantitative questionnaire that quantifies diet during the past year. Scores were calculated using a 9-point scale; higher scores indicated greater adherence to the Mediterranean-type diet. Logistic regression models were used to assess the association between PD status and Mediterranean-type diet, adjusting for caloric intake, age, sex, education, and ethnicity. Adjusted linear regression models were used to examine the association between Mediterranean-type diet adherence and PD age at onset.
Higher Mediterranean-type diet adherence was associated with reduced odds for PD after adjustment for all covariates (OR, 0.86; 95% CI, 0.77–0.97; P = .010). Lower Mediterranean-type diet score was associated with earlier PD age at onset (β = 1.09; P = .006).
PD patients adhere less than controls to a Mediterranean-type diet. Dietary behavior may be associated with age at onset. © 2012 Movement Disorder Society
Despite the widespread effective use of deep brain stimulation (DBS) for various movement and psychiatric disorders, little is known about its safety and tissue responses.
The University of Florida Deep Brain Stimulation Brain Tissue Network (DBS-BTN) conducted postmortem brain examinations on 26 cases to identify and characterize (using histological techniques) pathologic tissue changes associated with the placement of DBS devices.
We report the unusual finding of prominent collagenous fibrosis around the lead tip in a 74-year-old man with idiopathic Parkinson's disease who had bilateral STN-DBS. Histological study confirmed the diagnosis of idiopathic Parkinson's disease, and there was striking, dense collagenous fibrosis at the distal end of the right DBS lead associated with focal hemosiderin deposition, chronic inflammation, and mild gliosis. We have in our brain bank 25 other DBS cases that on examination showed only mild to moderate gliosis and no dramatic tissue response to DBS lead placement.
We are not aware of any prior reports of such a dramatic reaction to DBS placement to date. © 2012 Movement Disorder Society
Concerns have been raised that persons with serious illnesses participating in high-risk research, such as PD patients in sham surgery trials, have unrealistic expectations and are vulnerable to exploitation. A comparison of enrollees and decliners of such research may provide insights about the adequacy of decision making by potential subjects. We compared 61 enrollees and 10 decliners of two phase II neurosurgical intervention (i.e., cellular and gene transfer) trials for PD regarding their demographic and clinical status, perceptions and attitudes regarding research risks, potential direct benefit, and societal benefit, and perspectives on the various potential reasons for and against participation. In addition to bivariate analyses, a logistic regression model examined variables regarding risks and benefits as predictors of participation status. Enrollees perceived lower risk of harm while tolerating higher risk of harm and were more action oriented, but did not have more advanced disease. Both groups rated hope for benefit as a strong reason to participate, whereas the fact that the study's purpose was not solely to benefit them was rated as “not a reason” against participation. Hope for benefit and altruism were rated higher than expectation of benefit as reasons in favor of participation for both groups. Enrollees and decliners are different in their views and attitudes toward risk. Although both are attracted to research because of hopes of personal benefit, this hope is clearly distinguishable from an expectation of benefit and does not imply a failure to understand the main purpose of research. © 2012 Movement Disorder Society
Mutations in parkin are the most frequent cause of autosomal recessive parkinsonism. Quantitative PCR is used to detect parkin rearrangements. However, the method has an inherent problem—deletion and duplication in the same allelic exon could be determined as normal. To present this misidentification, we report a family with compound heterozygous rearrangements in parkin.
A patient with early-onset parkinsonism and the parents were investigated by quantitative PCR, haplotype analysis, reverse-transcription PCR, and direct sequencing.
A single heterozygous duplication (duplication of exons 6–7) was identified in the patient by quantitative PCR. Detailed analysis of the family revealed the patient carried compound heterozygous of combined deletion (deletion of exons 3–5) and duplication (duplication of exons 3–7).
For correct determination of rearrangement mutation, mutation analysis of the patient as well as other family members and/or break-point analysis of genomic DNA and at the transcript level should be conducted. © 2012 Movement Disorder Society
Impulse control disorders (ICDs) occur frequently in PD patients.
To investigate the possible involvement of the mesostriatal and mesolimbic monoaminergic function in ICDs associated with PD, we examined patients with (n = 10) and without (n = 10) ICDs using the brain [18F]fluorodopa PET.
Patients with ICDs (e.g., pathological gambling, hypersexuality, and compulsive eating) showed up to 35% higher [18F]fluorodopa uptake in the medial orbitofrontal cortex, compared to control patients, but no differences in the striatum. The results remained significant also after excluding subjects with comorbid psychiatric disorders.
Increased monoaminergic activity in the medial orbitofrontal cortex might be associated with increased sensitivity for ICDs under dopamine-replacement therapy in PD. © 2012 Movement Disorder Society
The purpose of this study was to investigate whether heart rate variability parameters can be useful for evaluating cardiac autonomic dysfunction in multiple system atrophy patients.
Both the time and frequency domains of heart rate variability were investigated among 17 multiple system atrophy patients and 27 normal control subjects.
All time- and frequency-domain measures, except the low- to high-frequency ratio, were significantly lower in multiple system atrophy patients than in controls. In multiple system atrophy patients, there were significant inverse correlations between heart rate variability parameters and disease duration, as well as disease severity, but heart rate variability parameters were not affected by other autonomic dysfunctions.
The cardiac autonomic state of multiple system atrophy was characterized by decreases in both sympathetic and parasympathetic tones. Because heart rate variability parameters were not affected by other autonomic dysfunctions, this may be a useful method for evaluating cardiac autonomic dysfunction in multiple system atrophy. © 2012 Movement Disorder Society
We report on a double-blind, crossover pilot trial for the treatment of rapid eye movement behavior disorder (RBD) in 12 patients with Parkinson's disease in whom conventional therapy failed.
We employed a patch of the cholinesterase inhibitor rivastigmine at a dose of 4.6 mg/24 hours for 3 weeks compared with placebo to reduce the frequency of RBD episodes. The number of RBD episodes was monitored by diaries of bed partners.
Rivastigmine was well tolerated in most patients, with minor side effects, mainly related to peripheral cholinergic action, and significantly reduced the mean frequency of RBD episodes during the observation time.
The results of this pilot trial need to be confirmed by further studies on a larger number of patients. © 2012 Movement Disorder Society
It can be difficult to clinically distinguish between classical Parkinson's disease (PD) and progressive supranuclear palsy. Previously, there have been no biomarkers that reliably allow this distinction to be made. We report that an abnormal brain iron accumulation is a marker for ongoing neurodegeneration in both conditions, but the conditions differ with respect to the anatomical distribution of these accumulations. We analyzed quantitative T2′ maps as markers of regional brain iron content from PD and progressive supranuclear palsy patients and compared them to age-matched control subjects. T2-weighted and T2*-weighted images were acquired in 30 PD patients, 12 progressive supranuclear palsy patients, and 24 control subjects at 1.5 Tesla. Mean T2′ values were determined in regions-of-interest in the basal ganglia, thalamus, and white matter within each hemisphere. The main findings were shortened T2′ values in the caudate nucleus, globus pallidus, and putamen in progressive supranuclear palsy compared to PD patients and controls. A stepwise linear discriminant analysis allowed progressive supranuclear palsy patients to be distinguished from PD patients and the healthy controls. All progressive supranuclear palsy patients were correctly classified. No progressive supranuclear palsy patient was classified as a healthy control, no healthy controls were incorrectly classified as having progressive supranuclear palsy, and only 6.7% of the PD patients were incorrectly classified as progressive supranuclear palsy. Regional decreases of T2′ relaxation times in parts of the basal ganglia reflecting increased brain iron load in these areas are characteristic for progressive supranuclear palsy but not PD patients. © 2012 Movement Disorder Society
Sporadic-onset ataxia is common in a tertiary care setting but a significant percentage remains unidentified despite extensive evaluation. Rare genetic ataxias, reported only in specific populations or families, may contribute to a percentage of sporadic ataxia.
Patients with adult-onset sporadic ataxia, who tested negative for common genetic ataxias (SCA1, SCA2, SCA3, SCA6, SCA7, and/or Friedreich ataxia), were evaluated using a stratified screening approach for variants in 7 rare ataxia genes.
We screened patients for published mutations in SYNE1 (n = 80) and TGM6 (n = 118), copy number variations in LMNB1 (n = 40) and SETX (n = 11), sequence variants in SACS (n = 39) and PDYN (n = 119), and the pentanucleotide insertion of spinocerebellar ataxia type 31 (n = 101). Overall, we identified 1 patient with a LMNB1 duplication, 1 patient with a PDYN variant, and 1 compound SACS heterozygote, including a novel variant.
The rare genetic ataxias examined here do not significantly contribute to sporadic cerebellar ataxia in our tertiary care population. © 2012 Movement Disorder Society
Tourette syndrome patients are reported to show automatic imitation (echopraxia), but this has not yet been proven experimentally.
Video clips showing either tics of other Tourette patients or spontaneous movements of healthy subjects were presented to Tourette patients and healthy subjects. Participants' responses were assessed using blinded review of video recordings by 2 independent raters and related to stimuli presented.
Both raters detected more echoes in patients. In a permutation analysis, no healthy subject had echoes above chance level. In contrast, 6 and 5 patients were classified as echoers according to rater 1 and rater 2, respectively, in 1 analysis, and 9 patients were so classified in a second analysis (according to rater 2 only). Concordance between raters was high. Patients echoed both following stimuli showing tics and following stimuli showing spontaneous movements. Most echoes were part of patients' individual tic repertoire.
Echopraxia is a hallmark of Tourette syndrome. © 2012 Movement Disorder Society
Mild cognitive impairment is common in nondemented Parkinson's disease (PD) patients and may be a harbinger of dementia. In view of its importance, the Movement Disorder Society commissioned a task force to delineate diagnostic criteria for mild cognitive impairment in PD. The proposed diagnostic criteria are based on a literature review and expert consensus. This article provides guidelines to characterize the clinical syndrome and methods for its diagnosis. The criteria will require validation, and possibly refinement, as additional research improves our understanding of the epidemiology, presentation, neurobiology, assessment, and long-term course of this clinical syndrome. These diagnostic criteria will support future research efforts to identify at the earliest stage those PD patients at increased risk of progressive cognitive decline and dementia who may benefit from clinical interventions at a predementia stage. © 2012 Movement Disorder Society
Postural deficits in Huntington's disease are linked to functional impairment. We investigated whether assessment of center-of-mass variability using posturography provides objective and quantitative measures that correlate to the severity of motor phenotype, functional measures, and genotype as assessed by a disease burden score (based on repeat length and age). In addition, we investigated whether withdrawing visual feedback facilitates the detection of postural deficits.
Using a force plate, the ability of symptomatic Huntington's disease patients (n = 34) and controls (n = 20) to stand as stably as possible was assessed in eyes-open and eyes-closed conditions.
All posturographic measures (DISTANCE, VELOCITY, and SURFACE of centre-of-mass mobility) were increased in patients and correlated to (1) the UHDRS Total Motor Score, (2) the UHDRS Total Functional Capacity, (3) the UHDRS Functional Assessment Score, and (4) the disease burden score. Correlations to motor and functional measures were stronger when visual feedback was provided.
Posturography may provide useful objective and quantitative measures of postural motor dysfunction in Huntington's disease. © 2012 Movement Disorder Society
Substantia nigra hyperechogenicity assessed by transcranial sonography is a typical finding in up to 90% of patients with idiopathic Parkinson's disease, although its value as a surrogate marker for disease progression in Parkinson's disease is controversial. 123I-FP-CIT–single photon emission computed tomography (SPECT) represents an established paraclinical surrogate marker to quantify the nigrostriatal dopaminergic deficit in Parkinson's disease. Whereas most studies found no correlation between extent of substantia nigra echogenicity and the putaminal FP-CIT binding ratio, a more recent analysis reported opposite results.
In 92 patients with Parkinson's disease the substantia nigra echogenicity was compared with the putaminal FP-CIT binding ratio using an investigator-independent SPECT analysis protocol and with several clinical parameters.
No correlation was found between the substantia nigra hyperechogenicity and the FP-CIT binding ratio or the disease severity.
Substantia nigra hyperechogenicity does not reflect the degree of the nigrostriatal degeneration or the clinical state of the disease progression. © 2012 Movement Disorder Society
To test the association between impaired olfaction and other prodromal features of PD in the Parkinson At-Risk Syndrome Study. The onset of olfactory dysfunction in PD typically precedes motor features, suggesting that olfactory testing could be used as a screening test. A combined strategy that uses other prodromal nonmotor features, along with olfactory testing, may be more efficient than hyposmia alone for detecting the risk of PD. Individuals with no neurological diagnosis completed a mail survey, including the 40-item University of Pennsylvania Smell Identification Test, and questions on prodromal features of PD. The frequency of reported nonmotor features was compared across individuals with and without hyposmia. A total of 4,999 subjects completed and returned the survey and smell test. Of these, 669 were at or below the 15th percentile based on age and gender, indicating hyposmia. Hyposmics were significantly more likely to endorse nonmotor features, including anxiety and depression, constipation, and rapid eye movement sleep behavior disorder symptoms, and to report changes in motor function. Twenty-six percent of subjects with combinations of four or more nonmotor features were hyposmic, compared to 12% for those reporting three or fewer nonmotor features (P < 0.0001). Hyposmia is associated with other nonmotor features of PD in undiagnosed individuals. Further assessment of hyposmic subjects using more specific markers for degeneration, such as dopamine transporter imaging, will evaluate whether combining hyposmia and other nonmotor features is useful in assessing the risk of future neurodegeneration. © 2012 Movement Disorder Society © 2012 Movement Disorder Society
Pain has been studied more intensely as a symptom of Parkinson's disease (PD) in recent years. However, studies on the characteristics and prevalence of pain in PD have yielded conflicting results, prompting us to do a systematic review of the literature. A systematic review of the literature was conducted, using different databases. The last inclusion date was March 15, 2011. The modified Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool was used, which is especially designed for judging prevalence studies on their methodological quality. Only articles that met the predefined criteria were used in this review. We found 18 articles, of which only 8 met the methodological criteria. Prevalence frequency ranges from 40% to 85% with a mean of 67.6%. Pain is most frequently located in the lower limbs, with almost one-half of all PD patients complaining about musculoskeletal pain (46.4%). The pain fluctuates with on-off periods. Surprisingly, only 52.4% of PD patients with pain used analgesics, most often nonopioids. PD patients seem to be predisposed to develop pain and physicians should be aware of pain as a common feature of PD. As many as one-half of PD patients with pain may be missing out on a potentially useful treatment, and proper treatment could increase quality of life in PD patients. © 2012 Movement Disorder Society
Lysosomal protein 2 (LIMP2), the product of the scavenger receptor class B member 2 (SCARB2) gene, is a ubiquitously expressed transmembrane protein that is the mannose-6-phosphate–independent receptor for glucocerebrosidase (β-GCase); a deficiency in this protein causes Gaucher disease. Several studies have shown a link between mutations in the β-GCase gene and diseases characterized clinically by Parkinsonism and by the presence of Lewy body–related pathology. We hypothesized that genetic variants in the SCARB2 gene could be risk factors for Parkinson's disease (PD). A candidate-gene study of 347 Greek patients with sporadic PD and 329 healthy controls was conducted to investigate the association between 5 polymorphisms in the SCARB2 gene (rs6824953, rs6825004, rs4241591, rs9991821, and rs17234715) and the development of PD. The single-locus analysis for the 5 polymorphisms revealed an association only for the rs6825004 polymorphism: the generalized odds ratio (ORG) was 0.68 (95% confidence interval [CI], 0.51–0.90), and the OR for the allelic test was OR = 0.71 (95% CI, 0.56–0.90). Haplotype analysis showed an association for the GCGGT haplotype (P < .01). Our study supports a genetic contribution of the SCARB2 locus to PD; future studies in larger cohorts are necessary to verify this finding. © 2012 Movement Disorder Society
Visual misperception and hallucinations represent a major problem in advanced PD. The pathophysiological mechanisms underlying these symptoms remain poorly understood, with limited tests for their assessment. A recent hypothesis has suggested that visual misperception and hallucinations may arise from disrupted processing in the attentional networks. To assess and quantify visual misperceptions, we developed the novel bistable percept paradigm (BPP), which consists of a battery of “single” and “hidden” monochromatic images that subjects are required to study until they are satisfied that they have recognized everything that the image may represent. In this experiment, 45 patients and 18 age-matched controls performed the BPP. Using an error score value derived from the control group, 23 patients were identified as having significant deficits on the task. Compared to patients who were unimpaired on the task, this group of patients had significantly higher levels of self-reported hallucinations on the SCales for Outcomes in PArkinson's Disease–Psychiatric Complications and also symptoms of rapid eye movement sleep behavior disorder (RBD). Furthermore, impairment on the BPP was associated with significantly reduced performance on an attentional set-shifting task. Patients with impaired performance on the BPP had higher rates of hallucinations, increased symptoms of RBD, and poorer performance on set shifting, suggesting disrupted processing within the attentional control networks. We propose that the BPP may offer a novel approach for exploring the neural correlates underlying visual hallucinations and misperceptions in PD. © 2012 Movement Disorder Society
Friedreich ataxia is a rare disease caused by GAA-trinucleotide-repeat expansions in the frataxin gene, leading to marked reduction of qualitatively normal frataxin protein. Recently, human recombinant erythropoietin was reported to increase frataxin levels in patients with Friedreich ataxia.
We performed a 6-month, randomized placebo-controlled, double-blind, dose-response pilot trial to assess the safety and efficacy of erythropoietin in increasing frataxin levels. Sixteen adult patient with Friedreich ataxia were randomly assigned to erythropoietin (n = 11) or matching placebo (n = 5). All patients continued Idebenone treatment (5 mg/kg/day). Treatment consisted of a 6-month scaling-up phase, in which erythropoietin was administered intravenously at the following doses: 20,000 IU every 3 weeks, 40,000 IU every 3 weeks, and 40,000 IU every 2 weeks.
Erythropoietin treatment was safe and well tolerated, but did not result in any significant hematological, clinical, or biochemical effects in Friedreich ataxia patients. © 2012 Movement Disorder Society
Deep brain stimulation of the subthalamic nucleus is an effective treatment for the motor symptoms of Parkinson's disease. Although a range of psychiatric and behavioral problems have been documented following deep brain stimulation, the short-term effects of subthalamic nucleus stimulation on patients' mood have only been investigated in a few studies. Our aim was to compare self-reported mood in Parkinson's patients with deep brain stimulation of the subthalamic nucleus ON versus OFF. Twenty-three Parkinson's patients with bilateral deep brain stimulation of the subthalamic nucleus and 11 unoperated Parkinson's patients completed a mood visual analogue scale twice. Operated patients were tested with deep brain stimulation of the subthalamic nucleus both ON and OFF. All were assessed on medication. The operated Parkinson's group reported feeling significantly better coordinated, stronger, and more contented with deep brain stimulation ON compared to OFF. Fourteen of the 16 mood scales changed in a positive direction when deep brain stimulation of the subthalamic nucleus was ON. When changes in motor scores were taken into account, the operated patients still reported feeling better-coordinated, but also less gregarious with stimulation ON. Unoperated Parkinson's patients showed no differences on any of these measures between their 2 ratings. Short-term changes in deep brain stimulation of the subthalamic nucleus have a small and mostly positive effect on mood, which may be partly related to improvements in motor symptoms. The implications for day-to-day management of patients with deep brain stimulation of the subthalamic nucleus are discussed. © 2012 Movement Disorder Society
The reliability and applicability of published diagnostic criteria for psychogenic movement disorders (PMDs) have never been examined.
Eight movement disorder and six general neurologists rated 14 patients diagnosed with PMD and 14 patients diagnosed with organic movement disorders. Raters provided a dichotomous judgment (i.e., psychogenic or organic) upon review of video-based movement phenomenology and a category of diagnostic certainty based on the Fahn-Williams and Shill-Gerber criteria after accessing standardized clinical information. We measured interobserver agreement on the diagnosis and clinical certainty judgment of PMD.
In both groups of raters, agreements were “fair” on the video-based dichotomous judgment, but improved to “substantial” after access to standardized clinical information. “Slight” to “poor” agreement was reached for the “probable” and “possible” categories of diagnostic certainty corresponding to both diagnostic criteria.
Diagnosis according to clinical available criteria for PMD yields poor diagnostic agreement. © 2012 Movement Disorder Society
The improvement of PD motor symptoms by DBS of the STN depends on exact targeting.
A combination of MRI and multitrajectory microrecordings was used for localization of the STN in a group of 228 consecutive PD patients.
In 1% of our cases, the STN was consistently shifted in the anterior (3.3 ± 0.8mm) and medial (3.0 ± 0.9mm) direction within the target plane, compared to controls. Adjustment of the original target coordinates after intraoperative reevaluation of the MRI and confirmation by typical subthalamic neuronal recordings along the deviant trajectory allowed the implantation of clinically effective electrodes in all cases. The relative improvement of the motor UPDRS at 6-months follow-up in patients with an atypical and typical STN was comparable.
An atypical position of the STN does not need to complicate DBS surgery, if detected by a combination of MRI-based targeting and electrophysiological guidance. © 2012 Movement Disorder Society
It has long been recognized that lesions of the basal ganglia frequently result in dysarthria, in part because many individuals with Parkinson's disease (PD) have impaired speech. Earlier studies of speech production in PD using perceptual, acoustic, and/or kinematic analyses have yielded mixed findings about the characteristics of articulatory movements underlying hypokinetic dysarthria associated with PD: in some cases reporting reduced articulatory output, and in other instances revealing orofacial movement parameters within the normal range. The central aim of this experiment was to address these inconsistencies by providing an integrative description of basic kinematic and acoustic parameters of speech production in individuals with PD. Recordings of lip and jaw movements and acoustic data were collected in 16 individuals with PD and 16 age- and sex-matched neurologically healthy older adults. Our results revealed a downscaling of articulatory dynamics in the individuals with PD, evidenced by decreased amplitude and velocity of lower lip and jaw movements, decreased vocal intensity (dB sound pressure level [SPL]), and reduced second formant (F2) slopes. However, speech rate did not differ between groups. Our finding of an overall downscaling of speech movement and acoustic parameters in some participants with PD provides support for speech therapies directed at increasing speech effort in individuals with PD. © 2012 Movement Disorder Society
Deep brain stimulation of the subthalamic nucleus alleviates motor symptoms in Parkinson's disease patients. However, some patients suffer from cognitive and emotional changes. These side effects are most likely caused by current spread to the cognitive and limbic territories in the subthalamic nucleus. The aim of this study was to identify the motor part of the subthalamic nucleus to reduce stimulation-induced behavioral side effects, by using motor cortex stimulation.
We describe the results of subthalamic nucleus neuronal responses to stimulation of the hand area of the motor cortex and evaluate the safety of this novel technique.
Responses differed between regions within the subthalamic nucleus. In the anterior and lateral electrode at dorsal levels of the subthalamic nucleus, an early excitation (∼5–45 ms) and subsequent inhibition (45–105 ms) were seen. The lateral electrode also showed a late excitation (∼125–160 ms). Focal seizures were observed following motor cortex stimulation.
To prevent seizures the current density should be lowered, so that motor cortex stimulation-evoked responses can be safely used during deep brain stimulation surgery. © 2011 Movement Disorder Society
Apathy, defined as decreased goal-directed activity, has been observed in Parkinson's disease. A number of cognitive/psychiatric features have been documented in essential tremor, yet we are unaware of studies of apathy.
Using the Apathy Evaluation Scale (range = 18–72 [more apathy]), we compared 79 essential tremor cases, 20 dystonia cases, and 39 Parkinson's disease cases with 80 normal controls.
The score of the Apathy Evaluation Scale was higher in essential tremor, dystonia, and Parkinson's disease cases than controls (all P ≤ .04). Parkinson's disease cases had the highest scores. Analyses stratified by presence/absence of depressive symptoms indicated the presence of a group of apathetic but nondepressed cases.
Patients with Parkinson's disease, essential tremor, and dystonia had elevated apathy scores. Features of apathy seemed to occur in these conditions independent of depressive symptoms. The mechanistic basis for the apparent increased features of apathy in essential tremor and dystonia deserves further study. © 2011 Movement Disorder Society
Mutations in the glucocerebrosidase gene are associated with Parkinson's disease and Lewy body dementia. However, whether these alterations have any effect on the clinical course of Parkinson's disease is not clear. The glucocerebrosidase coding region was fully sequenced in 225 Parkinson's disease patients, 17 pathologically confirmed Lewy body dementia patients, and 186 controls from Spain. Twenty-two Parkinson's disease patients (9.8%) and 2 Lewy body dementia patients (11.8%) carried mutations in the glucocerebrosidase gene, compared with only 1 control (0.5%); P = .016 and P = .021 for Parkinson's disease and Lewy body dementia, respectively. The N370S and the L444P mutations represented 50% of the alterations. Two novel variants, L144V and S488T, and 7 previously described alterations were also found. Alterations in glucocerebrosidase were associated with a significant risk of dementia during the clinical course of Parkinson's disease (age at onset, years of evolution, and sex-adjusted odds ratio, 5.8; P = .001). Mutation carriers did not show worse motor symptoms, had good response to L-dopa, and tended to present the intermediate parkinsonian phenotype. Our findings suggest that mutations in the glucocerebrosidase gene not only increase the risk of both Parkinson's disease and Lewy body dementia but also strongly influence the course of Parkinson's disease with respect to the appearance of dementia. © 2011 Movement Disorder Society
The purpose of this study was to determine if there was a common pattern in movements during REM sleep behavior disorder (RBD).
We blindly compared video-monitored movements during RBD (n = 136 clips) and wakefulness/arousal (n = 53 clips) in patients with Parkinson's disease (n = 29) and without parkinsonism (idiopathic RBD, n = 31; narcolepsy, n = 5).
The scorers accurately guessed the sleep/wake stage of 94% of video clips. Compared with wake movements, RBD movements were faster and more often repeated, jerky, and pseudohallucinatory, not self-centered, never associated with tremor, and rarely involved the environment in an appropriate manner. A specific posture of the hand (limp wrist with flexed digits) during grasping movements was evidenced during RBD in 48% of patients, reminiscent of hand-babbling in babies.
These characteristics of movements were found in the 3 conditions (Parkinson's disease, idiopathic RBD, and primary narcolepsy), delineating a common motor signature of RBD. © 2011 Movement Disorder Society
Although Parkinson's disease (PD) is traditionally considered a motor output disorder, recent evidence suggests that people with PD may have sensory and perceptual impairments that may underlie movement impairments. Yet there has not been any direct testing of perceptual judgments, especially when manipulating the sensory feedback on which these judgments are made. The present study investigated how perception might be influenced by sensory feedback to contribute to height estimations and obstacle stepping in PD relative to healthy age-matched control participants. Perceptual judgment accuracy was evaluated by judging 3 typically encountered obstacle heights in 2 sensory feedback conditions: (1) vision of foot available and (2) without vision of foot (reliance on proprioceptive feedback to estimate height). Then participants proceeded to walk and step over the obstacle. Fifteen individuals with PD and 15 healthy control participants completed the task. As seen with toe elevation, toe elevation variability, and toe error measures, individuals with PD overestimated the obstacle height and were significantly more variable when relying solely on proprioception (in contrast to when vision was available) compared with healthy controls, although no differences between groups in obstacle crossing were found. These results support the notion that sensory deficits may contribute to inaccuracy of perceptual judgment and has the potential to contribute to gait behaviors such as tripping and falling, especially when vision is not available. Future studies should carefully consider the impact of sensory and perceptual deficits that might contribute to movement planning problems and consequentially movement impairments. © 2011 Movement Disorder Society
Parkinson's disease is heterogeneous, both in terms of motor symptoms and mood. Identifying associations between phenotypic variants of motor and mood subtypes may provide clues to understand mechanisms underlying mood disorder and symptoms in Parkinson's disease. A total of 513 patients were assessed using the Hospital Anxiety and Depression Scale, and separately classified into anxious, depressed, and anxious-depressed mood classes based on latent class analysis of a semistructured interview. Motor subtypes assessed related to age-of-onset, rate of progression, presence of motor fluctuations, lateralization of motor symptoms, tremor dominance, and the presence of postural instability and gait symptoms and falls. The directions of observed associations tended to support previous findings with the exception of lateralization of symptoms, for which there were no consistent or significant results. Regression models examining a range of motor subtypes together indicated increased risk of anxiety in patients with younger age-of-onset and motor fluctuations. In contrast, depression was most strongly related to axial motor symptoms. Different risk factors were observed for depressed patients with and without anxiety, suggesting heterogeneity within Parkinson's disease depression. Such association data may suggest possible underlying common risk factors for motor subtype and mood. Combined with convergent evidence from other sources, possible mechanisms may include cholinergic system damage and white matter changes contributing to non-anxious depression in Parkinson's disease, while situational factors related to threat and unpredictability may contribute to the exacerbation and maintenance of anxiety in susceptible individuals. © 2011 Movement Disorder Society
Restless leg syndrome (RLS) is a major healthcare burden with increasing prevalence. It has been demonstrated that periodic limb movements (PLM) can occur as an isolated phenomenon, but they are often associated with this syndrome and are the only symptom of this disorder that can be measured electrophysiologically. The aim of this study was to examine the sleep-wake behavior and the presence of limb movement in a rat model of RLS induced by lesioning the A11 dopaminergic nuclei with the neurotoxin 6-hydroxydopamine (6-OHDA). Rats were implanted with electrodes for electrocorticography and electromyography. Sleep recordings were monitored during light/dark periods lasting 12 hours each and were evaluated on days 7, 15, and 28 after injection of the drug or phosphate-buffered saline (PBS). A control group that did not receive any injection was also included. Wakefulness percentages were generated for 4-hour segments of the dark period, yielding the following 3 bins: 7 PM to 11 PM, 11 PM to 3 AM, and 3 PM to 7 PM. Additionally, slow wave sleep, paradoxical sleep, wakefulness, and limb movements were evaluated over the entire 12 hours of the light/dark cycle. All A11-lesioned rats exhibited an increased percentage of wakefulness during the last block of the dark period, as would be expected for an animal model of this syndrome. In addition, at all time points after lesioning, these animals presented increased frequencies of limb movement during both the light and the dark periods. These alterations were reversed by the acute administration of the dopaminergic agonist pramipexole. This animal model strengthens the notion that 6-OHDA–induced A11 lesions can be a valid animal model for RLS and PLM. © 2011 Movement Disorder Society
Freezing of gait is a common and disabling symptom of parkinsonism. However, the corresponding anatomic structures have yet to be clearly elucidated.
We performed diffusion tensor imaging on 40 subjects with white matter changes. We compared apparent diffusion coefficient values and fraction anisotropy values of 7 candidate anatomic structures between 14 patients with freezing of gait (freezing of gait group) and 26 without freezing of gait (control group).
Fraction anisotropy values of the bilateral pedunculopontine nucleus, bilateral superior premotor cortex, right orbitofrontal area, and left supplement motor area were significantly lower in the freezing of gait group than in the control group. In contrast, there were no significant differences in apparent diffusion coefficient values between freezing of gait and control groups.
Our findings suggest that the bilateral pedunculopontine nucleus, bilateral superior premotor cortex, right orbitofrontal area, and left supplement motor area are closely related to freezing of gait. © 2011 Movement Disorder Society
Classically, clinical trials are based on the placebo-control design. Our aim was to analyze the placebo effect in Huntington's disease.
Placebo data were obtained from an international, longitudinal, placebo-controlled trial for Huntington's disease (European Huntington's Disease Initiative Study Group). One-hundred and eighty patients were evaluated using the Unified Huntington Disease Rating Scale over 36 months. A placebo effect was defined as an improvement of at least 50% over baseline scores in the Unified Huntington Disease Rating Scale, and clinically relevant when at least 10% of the population met it.
Only behavior showed a significant placebo effect, and the proportion of the patients with placebo effect ranged from 16% (first visit) to 41% (last visit). Nondepressed patients with better functional status were most likely to be placebo-responders over time.
In Huntington's disease, behavior seems to be more vulnerable to placebo than overall motor function, cognition, and function © 2011 Movement Disorder Society
Levodopa-induced dyskinesia represents disabling complication of long-term therapy with dopaminergic drugs in treating Parkinson's disease (PD). Recently, our group demonstrated that PD patients with levodopa-induced dyskinesia were characterized by abnormal volumetric changes in the inferior prefrontal gyrus. In this study, the functional relevance of this structural abnormality was explored using functional magnetic resonance imaging. Ten dyskinetic PD patients and 10 nondyskinetic PD patients were studied in the OFF phase with functional magnetic resonance imaging while performing externally and internally triggered visuomotor tasks. Although neither group demonstrated behavioral differences during execution of motor tasks, magnetic resonance imaging analysis detected significant changes in target cortical regions. In particular, PD patients with levodopa-induced dyskinesia showed significant overactivity in the supplementary motor area and underactivity in the right inferior prefrontal gyrus during execution of both tasks when compared with PD patients without levodopa-induced dyskinesia. Moreover, these prefrontal functional alterations were significantly correlated with Abnormal Involuntary Movement Scale scores. This functional magnetic resonance imaging study together with our previous volumetric findings highlights the role of the prefrontal cortex in the neuronal mechanisms of dyskinesia. © 2011 Movement Disorder Society
Neuroacanthocytoses are neurodegenerative disorders marked by phenotypic and genetic heterogeneity. There are several associated genetic loci, and many defects, including gene deletions and insertions, and missense, nonsense, and splicing mutations, have been found spread over hundreds of kilobases of genomic DNA. In some cases, specific diagnosis is unclear, particularly in the early stages of disease or when there is an atypical presentation. Determination of the precise genetic defect allows assignment of the diagnosis and permits carrier detection and genetic counseling. The objective of this report was to utilize exome sequencing for genetic diagnosis in the neuroacanthocytosis syndromes.
Genomic DNA from 2 patients with clinical features of chorea-acanthocytosis was subjected to targeted exon capture. Captured DNA was subjected to ultrahigh throughput next-generation sequencing. Sequencing data were assembled, filtered against known human variant genetic databases, and results were analyzed.
Both patients were compound heterozygotes for mutations in the VPS13A gene, the gene associated with chorea-acanthocytosis. Patient 1 had a 4-bp deletion that removes the 5′ donor splice site of exon 58 and a nucleotide substitution that disrupts the 5′ donor splice site of exon 70. Patient 2 had a dinucleotide deletion in exon 16 and a dinucleotide insertion in exon 33. No mutations were identified in the XK, PANK2, or JPH3 gene loci.
Exome sequencing is a valuable diagnostic tool in the neuroacanthocytosis syndromes. These studies may provide a better understanding of the function of the associated proteins and provide insight into the pathogenesis of these disorders. © 2011 Movement Disorder Society
Deep brain stimulation has been used as a means of reducing dyskinesias in various conditions, including Parkinson's disease and dystonia for many years. Recently, owing to the clinical similarities between L-dopa induced dyskinesia and chorea, deep brain stimulation has now been implemented as a novel treatment method in both Huntington's disease and neuroacanthocytosis, and a paucity of case studies exist reporting its efficacy. This review will summarize the case studies of deep brain stimulation in both Huntington's disease and neuroacanthocytosis, and discuss the possible implications and limitations associated with these reports. As both these disorders are often refractory to medication and difficult to treat, deep brain stimulation may be a useful treatment option in the future. © 2011 Movement Disorder Society
Freezing of gait in Parkinson's disease can be difficult to study in the laboratory. Here we investigate the use of a variable-width doorway to provoke freeze behavior together with new objective methods to measure it. With this approach we compare the effects of anti-parkinsonian treatments (medications and deep-brain stimulation of the subthalamic nucleus) on freezing and other gait impairments. Ten “freezers” and 10 control participants were studied. Whole-body kinematics were measured while participants walked at preferred speed in each of 4 doorway conditions (no door present, door width at 100%, 125%, and 150% of shoulder width) and in 4 treatment states (offmeds/offstim, offmeds/onstim, onmeds/offstim, onmeds/onstim). With no doorway, the Parkinson's group showed characteristic gait disturbances including slow speed, short steps, and variable step timing. Treatments improved these disturbances. The Parkinson's group slowed further at doorways by an amount inversely proportional to door width, suggesting a visuomotor dysfunction. This was not improved by either treatment alone. Finally, freeze-like events were successfully provoked near the doorway and their prevalence significantly increased in narrower doorways. These were defined clinically and by 2 objective criteria that correlated well with clinical ratings. The risk of freeze-like events was reduced by medication but not by deep-brain stimulation. Freeze behavior can be provoked in a replicable experimental setting using the variable-width doorway paradigm, and measured objectively using 2 definitions introduced here. The differential effects of medication and deep-brain stimulation on the gait disturbances highlight the complexity of Parkinsonian gait disorders and their management. © 2011 Movement Disorder Society
Pain and other nonmotor symptoms in PD are increasingly recognized as a major cause of reduced health-related quality of life. Pain in PD may be categorized into a number of different subtypes, including musculoskeletal, dystonic, radicular neuropathic, and central pain. The onset of pain can vary in relation to motor symptoms, and may precede the appearance of motor symptoms by several years, or occur after the diagnosis of PD has been made. Pain in PD is frequently under-recognized and is often inadequately treated. Levodopa-related dystonia may respond to manipulation of dopaminergic medication. Dopaminergic therapy may also improve musculoskeletal pain related to rigidity and akinesia, as well as akathisia in PD. Botulinum toxin injections can be effective for treatment of painful focal dystonia. Pain and dysesthesia have been reported to improve with DBS, in some cases. Increased understanding of basal ganglia pathways has provided further insights into the pathogenesis of pain in PD, but the exact mechanism of pain processing and modulation remains unclear. © 2011 Movement Disorder Society
The diagnosis of Parkinson's disease rests on motor signs of advanced central dopamine deficiency. There is an urgent need for disease biomarkers. Clinicopathological evidence suggests that α-synuclein aggregation, the pathological signature of Parkinson's disease, can be detected in gastrointestinal tract neurons in Parkinson's disease. We studied whether we could demonstrate α-synuclein pathology in specimens from unprepped flexible sigmoidoscopy of the distal sigmoid colon in early subjects with Parkinson's disease. We also looked for 3-nitrotyrosine, a marker of oxidative stress. Ten subjects with early Parkinson's disease not treated with dopaminergic agents (7 men; median age, 58.5 years; median disease duration, 1.5 years) underwent unprepped flexible sigmoidoscopy with biopsy of the distal sigmoid colon. Immunohistochemistry studies for α-synuclein and 3-nitrotyrosine were performed on biopsy specimens and control specimens from a tissue repository (23 healthy subjects and 23 subjects with inflammatory bowel disease). Nine of 10 Parkinson's disease samples were adequate for study. All showed staining for α-synuclein in nerve fibers in colonic submucosa. No control sample showed this pattern. A few showed light α-synuclein staining in round cells. 3-Nitrotyrosine staining was seen in 87% of Parkinson's disease cases but was not specific for Parkinson's disease. This study suggests a pattern of α-synuclein staining in Parkinson's disease that was distinct from healthy subjects and those with inflammatory bowel disease. The absence of this pattern in subjects with inflammatory bowel disease suggests it is not a sequel of inflammation or oxidative stress. 3-Nitrotyrosine immunostaining was common in all groups studied, suggesting oxidative stress in the colonic submucosa. © 2011 Movement Disorder Society.
Contraversive eye deviation (CED) is most often observed intraoperatively during subthalamic nucleus implantation for Parkinson's disease and considered to result from wrong electrode positioning. We report on a woman, bilaterally implanted in the subthalamic nucleus for severe Parkinson's disease disclosing long-lasting CED only when the stimulators were activated separately. Clinical examination and eye movements recording in this patient showed that CED occurred when stimulation was applied at the site and at similar intensity used for the best antiparkinsonian effect. These results suggest that the subthalamic area may be involved in orienting movements, either through the subthalamic nucleus itself or the fibers from the Frontal Eye Fields. Interestingly, this report shows that CED may be corrected by bilateral stimulation and that CED may not necessarily implicate electrode repositioning. © 2007 Movement Disorder Society
Approximately 10% of Parkinson's disease (PD) patients have young-onset PD (YOPD). From a public health perspective, YOPD is an important subgroup of PD patients, because they are expected to remain active users of the health care system for many decades. Health care utilization and medical comorbidity during hospitalization have not been assessed in these patients. The objectives of this study were to compare YOPD patients to control patients in terms of (1) hospital utilization and outcomes, and (2) medical comorbidities during hospitalization. The Nationwide Inpatient Sample (NIS) provides yearly data on hospital admissions and discharges from approximately 1,000 hospitals. NIS data sets (1998–2003) were used to identify persons 18 to 40 years of age, including 714 PD patients and 2,007 randomly selected control patients (1:3 ratio). Hospital length of stay (P < 0.001) and number of discharge diagnoses (P < 0.001) were higher in PD than control patients. PD patients were more likely than controls to be discharged to a short-term hospital (odds ratio [OR], 2.23; 95% confidence interval [CI], 1.30–3.84; P = 0.004) or a skilled nursing facility (OR, 4.14; 95% CI, 3.06–5.61; P < 0.001); 20.4% required transfer to a short-term hospital or another facility. The most common discharge diagnosis-related group code in PD patients was psychosis (23% of patients), whereas pneumonia and hip or pelvic fractures were not associated with PD. YOPD patients had greater health care utilization and hospital morbidity than controls. Upon discharge, 1 in 5 required transfer to a short-term hospital or another facility. Psychosis was the most common comorbidity, whereas several comorbidities associated with older PD patients (e.g., fractures) were not common. © 2006 Movement Disorder Society
About one-third of patients with Parkinson's disease (PD) are diagnosed with apathy in cross-sectional studies. However, once patients with concomitant depression and dementia are excluded, the frequency of apathy drops to 5% to 10%. Several scales have been recommended to rate apathy in PD, but specific psychiatric interviews have not been developed, and recently proposed standardized diagnostic criteria are still in the validation process. Most studies assessing the association between subthalamic deep brain stimulation (STN-DBS) and apathy have reported a relative increase in the frequency and severity of apathy, although discrepant findings have also been reported. Several mechanisms to explain apathy in PD have been proposed, from dopaminergic imbalances in frontal-basal ganglia circuits to dysfunction of nondopaminergic circuits and the cingulate gyrus. Future studies should provide reliable and valid instruments to diagnose apathy in PD, and should examine the mechanism of apathy accounting for relevant confounders, such as depression and cognitive deficits, and important contextual factors. Finally, treatment for apathy in PD should not be restricted to psychoactive drugs, but should also include nonpharmacological techniques such as psychotherapy and occupational therapy. © 2012 Movement Disorder Society
The foundations of the clinical classification of movement disorders rest on the precise definition of the words used to describe the disorders. Here we argue that the current use of the term stereotypy falls well short of the precision needed for either clinical or academic use, and fails both to provide a clinically useful diagnostic category and to define a set of conditions that are linked pathophysiologically. The difficulty in defining this concept is not a new one as our review of the history of the term demonstrates. We synthesise this historical background, explore why clinicians have felt it necessary to use the category of stereotypy for certain movements rather than the related category of tics, discuss the multiple uses of the term in current research and clinical practice and on this basis suggest a new definition and classification. © 2011 Movement Disorder Society
Parkinson's disease provides a useful model for studying the neural substrates of emotional processing. The striato-thalamo-cortical circuits, like the mesolimbic dopamine system that modulates their function, are thought to be involved in emotional processing. As Parkinson's disease is histopathologically characterized by the selective, progressive, and chronic degeneration of the nigrostriatal and mesocorticolimbic dopamine systems, it can therefore serve as a model for assessing the functional role of these circuits in humans. In the present review, we begin by providing a synopsis of the emotional disturbances observed in Parkinson's disease. We then discuss the functional roles of the striato-thalamo-cortical and mesolimbic circuits, ending with the conclusion that both these pathways are indeed involved in emotional processing. © 2012 Movement Disorder Society
Parkinson's disease (PD) characteristically presents with asymmetrical symptoms, contralateral to the side of the most extensive cerebral affection. This intriguing asymmetry, even included in the definition for diagnosing PD, however, is still part of a mystery. The relation with handedness as a common indicator of cerebral asymmetry might provide a clue in the search for causal factors of asymmetrical symptom onset in PD. This possible relationship, however, is still under debate. The objective of this study was to establish whether a relation between handedness and dominant PD side exists. We searched for cross-sectional or cohort studies that registered handedness and onset side in PD patients in PubMed, EMBASE, and Web of Science from their first record until 14 February 2011. Data about handedness and dominant PD side was extracted. Authors who registered both but not described their relation were contacted for further information. Odds ratios (ORs) were analyzed with a fixed effect Mantel-Haenszel model. Heterogeneity and indications of publication bias were limited. Our electronic search identified 10 studies involving 4405 asymmetric PD patients. Of the right-handed patients, 2413 (59.5%) had right-dominant and 1644 (40.5%) had left-dominant PD symptoms. For the left-handed patients this relation was reversed, with 142 (40.8%) right-dominant and 206 (59.2%) left-dominant PD symptoms. Overall OR was 2.13 (95% confidence interval [CI], 1.71–2.66). Handedness and symptom dominance in PD are firmly related with each other in such a way that the PD symptoms emerge more often on the dominant hand-side. Possible causal factors are discussed. © 2011 Movement Disorder Society
The impact of apathy on health-related quality of life (HRQOL) in recently diagnosed Parkinson's disease (PD) has not been systematically investigated. The objective of this cross-sectional survey (ANIMO study) was to examine the contribution of apathy to HRQOL in a Spanish sample of recently diagnosed PD patients. PD patients, diagnosed within 2 years of inclusion, were recruited at 102 outpatient clinics in 82 communities throughout Spain. Apathy was quantified using the Lille Apathy Rating Scale and HRQOL with the EuroQol-5D questionnaire. A mean EuroQol-5D index score of 0.89 obtained from population references in Spain was used as the cutoff for this study. The relationship between apathy and the dichotomized EuroQol-5D index score (<0.89 [lower HRQOL] vs ≥0.89 [reference]) was examined using multiple logistic regression analysis, adjusting for sociodemographic and clinical variables. We consecutively recruited 557 patients (60.3% men) with a mean age of 68.8 ± 9.7 years. Apathy was diagnosed in 291 (52.2%) and was related to problems in each of the EuroQoL dimensions. Apathetic PD patients showed EuroQol-5D index scores significantly lower than those without apathy (0.64 vs 0.83). In an adjusted model, apathetic PD patients were 2.49 times more likely to have lower HRQOL than nonapathetic patients (odds ratio, 2.49; 95% confidence interval, 1.49–4.15, P < 0.01). Apathy is very common in those with recently diagnosed PD and is one of the major clinical determinants of HRQOL in this disease. It should be one of the primary concerns among clinicians who provide treatment to individuals affected by PD. © 2011 Movement Disorder Society
Sialorrhea (drooling) is a common symptom of Parkinson's disease (PD) that can significantly impair a patient's health and quality of life. Fifty-four PD subjects with troublesome sialorrhea were enrolled using a multicenter, randomized, double-blind, sequential-dose escalation design in which subjects received a single intraglandular treatment with botulinum toxin type B (doses of 1,500 Units [0.3 mL]; 2,500 Units [0.5 ml]; or 3,500 Units [0.7 ml]) or placebo. Postinjection, subjects were followed acutely for 4 weeks and long-term for up to 20 weeks. Safety/tolerability, as assessed by adverse events, was the primary outcome measure. Efficacy, as assessed by the Drooling Frequency and Severity Scale and unstimulated salivary flow rate, was secondary. Gastrointestinal-related adverse events occurred more frequently in the active groups versus placebo group (31% vs 7%), with dry mouth being most common (15%). There were no serious adverse events attributed to botulinum toxin type B or discontinuations due to adverse events from treatment. At 4 weeks postinjection, Drooling Frequency and Severity Scale scores significantly improved versus placebo (−1.3 ± 1.3) in a dose-related manner (−2.1 ± 1.2, P = 0.0191; −3.3 ± 1.4, P < 0.0001; −3.5 ± 1.1, P < 0.0001, respectively) and unstimulated salivary flow rates significantly decreased in all active groups versus placebo (P ≤ 0.0009). Furthermore, treated subjects appeared to have more sustained improvement in sialorrhea than placebo subjects. We conclude that intraglandular injection of botulinum toxin type B was safe, tolerable, and efficacious in treating sialorrhea in PD patients. Additional studies are warranted to further confirm the drug's robust efficacy, as well as evaluate its effect with repeated dosing. © 2011 Movement Disorder Society
Abnormal postures of the trunk are a typical feature of Parkinson's disease (PD). These include Pisa syndrome (PS), a tonic lateral flexion of the trunk associated with slight rotation along the sagittal plane. In this study we describe clinical, electromyographic (EMG), and radiological features of PS in a group of 20 PD patients. All patients with trunk deviation underwent EMG and radiological (RX and CT scan) investigation. Clinical characteristics of patients with PS were compared with a control group of PD patients without trunk deviation. PD patients with PS showed a significantly higher score of disease asymmetry compared with the control group. In the majority of patients with PS, trunk bending was contralateral to the side of symptom onset. EMG showed abnormal tonic hyperactivity on the side of the deviation in the paravertebral thoracic muscles and in the abdominal oblique muscles. CT of the lumbar paraspinal muscles showed muscular atrophy more marked on the side of the deviation, with a craniocaudal gradient. PS may represent a complication of advanced PD in a subgroup of patients who show more marked asymmetry of disease and who have detectable hyperactivity of the dorsal paravertebral muscles on the less affected side. This postural abnormality deserves attention and proper early treatment to prevent comorbidities and pain. © 2011 Movement Disorder Society
Evidence suggests that both motor and nonmotor symptoms contribute to health status in Parkinson's disease. Less clear is how much change in health status can be expected if these clinical variables change. In addition, anxiety, separate from depression, has rarely been examined as a predictor of health status. We used hierarchical multiple regression analysis and standardized beta coefficients in a prevalent cohort of 462 patients with Parkinson's disease to explore the relative impact on health status (measured using the Parkinson's Disease Questionnaire) of 5 well-recognized symptom domains in Parkinson's disease: motor signs, depression, anxiety, cognition, and other nonmotor symptoms. In the health status scores, 19.6% of variance was explained by age, number of comorbidities, disease duration, and levodopa equivalent dose. Younger age predicted worse health status. A full regression model containing baseline variables and all 5 symptom domains explained 56% of the variance in health status. The standardized beta coefficient for depression was 2.1, 1.6, and 1.3 times that of motor signs, anxiety, and other nonmotor symptoms, respectively. Our findings provide a ranking order of clinical variables for their relative impact on health status in Parkinson's disease and show that depression has more than twice the impact of motor signs on health status. Anxiety and other nonmotor symptoms are also important separate determinants of poor health status in Parkinson's disease. Our results will help to guide the development of individual care and service planning for patients with Parkinson's disease. © 2011 Movement Disorder Society
Impulse control disorders and related disorders (hobbyism-punding and dopamine dysregulation syndrome) occur in 15% to 20% of Parkinson's disease (PD) patients. We assessed the validity and reliability of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease–Rating Scale (QUIP-RS), a rating scale designed to measure severity of symptoms and support a diagnosis of impulse control disorders and related disorders in PD. A convenience sample of PD patients at a movement disorders clinic self-completed the QUIP-RS and were administered a semistructured diagnostic interview by a blinded trained rater to assess discriminant validity for impulse control disorders (n = 104) and related disorders (n = 77). Subsets of patients were assessed to determine interrater reliability (n = 104), retest reliability (n = 63), and responsiveness to change (n = 29). Adequate cutoff points (both sensitivity and specificity values >80% plus acceptable likelihood ratios) were established for each impulse control disorder and hobbyism-punding. Interrater and retest reliability (intraclass correlation coefficient r) were >0.60 for all disorders. Participants in an impulse control disorder treatment study who experienced full (t = 3.65, P = .004) or partial (t = 2.98, P = .01) response demonstrated significant improvement on the rating scale over time, while nonresponders did not (t = 0.12, P = .91). The QUIP-RS appears to be valid and reliable as a rating scale for impulse control disorders and related disorders in PD. Preliminary results suggest that it can be used to support a diagnosis of these disorders, as well as to monitor changes in symptom severity over time. © 2011 Movement Disorder Society
The objective of this work was to evaluate the Movement Disorders Society (MDS) Task Force–proposed screening checklist for detecting Parkinson's disease dementia (PD-D) in relation to full neuropsychological testing. An MDS Task Force has proposed diagnostic procedures for PD-D, which have not been fully validated against more extensive neuropsychological testing. PD subjects were recruited from 2 specialty centers. A neuropsychologist evaluated them for dementia as part of routine clinical care. Independent clinical neurologists administered the MDS PD-D screening checklist. Diagnosis of PD-D by the 2 methods was compared. Ninety-one PD subjects had a mean age of 66.3 (SD = 9.7) years and a mean PD duration of 8.8 (SD = 6.1) years. Seven subjects (7.7%) met all 8 screening checklist criteria from the MDS PD-D screening tool and were classified as probable PD-D. Fifteen (16.5%) subjects were classified as PD-D by full neuropsychological assessment. The screening checklist showed 100% specificity, but only 46.7% sensitivity, for diagnosing PD-D compared to the full neuropsychological assessment. PD-D cases missed by the PD-D screening tool were largely due to 2 checklist items that were not endorsed (absence of depression and Mini-Mental State Examination [MMSE] scores <26). There was moderate agreement between these 2 methods for determination of PD-D (kappa = 0.59, P < .001). The MDS-PD-D screening checklist is highly accurate for detecting PD-D if all items are endorsed. However, for cases that do not meet these criteria, full neuropsychological testing is needed to differentiate PD-D from milder cognitive impairment. Revision of the checklist by altering or eliminating the 2 problematic checklist items may improve sensitivity. © 2011 Movement Disorder Society
Freezing of gait (FOG) is an incapacitating problem in Parkinson's disease that is difficult to manage therapeutically. We tested the hypothesis that impaired rhythm and amplitude control is a common mechanism of freezing which is also present during other rhythmic tasks. Therefore, we compared the occurrence and spatiotemporal profiles of freezing episodes during upper limb motion, lower limb motion, and FOG. Eleven freezers, 12 non-freezers, and 11 controls performed a rhythmic bilateral finger movement task. The triggering effect of movement speed, amplitude, and coordination pattern was evaluated. Regression slopes and spectral analysis addressed the spatial and temporal kinematic changes inherent to freezing episodes. The FOG Questionnaire score significantly predicted severity of upper limb freezing, present in 9 freezers, and of foot freezing, present in 8 freezers. Similar to gait, small-amplitude movements tended to trigger upper limb freezing, which was preceded by hastened movement and a strong amplitude breakdown. Upper limb freezing power spectra were broadband, including increased energy in the “freeze band” (3–8 Hz). Contrary to FOG, unilateral upper limb freezing was common and occurred mainly on the disease-dominant side. The findings emphasize that a core motor problem underlies freezing which can affect various movement effectors. This deficit may originate on the disease-dominant body side and interfere with amplitude and timing regulation during repetitive limb movements. These results may shift current thinking on the origins of freezing as being not exclusively a gait failure. © 2011 Movement Disorder Society
We aimed to examine associations among serum 25-hydroxyvitamin D levels, 1,25-dihyroxyvitamin D levels, vitamin D receptor polymorphisms, vitamin D binding protein gene polymorphisms, and the severity of Parkinson's disease. In 137 patients, the severity of Parkinson's disease was evaluated using Hoehn & Yahr stage and Unified Parkinson's Disease Rating Stage by neurologists and compared with 25-hydroxyvitamin D, 1,25-hydroxyvitamin D, vitamin D receptor polymorphisms, ie, FokI (rs10735810), BsmI (rs1544410), Cdx2 (rs11568820), ApaI (rs7976091), and TaqI (rs731236), and vitamin D binding protein gene polymorphisms GC1 (rs7041)/GC2 (rs4588) in a cross-sectional study. Mean ± standard deviation levels of 25-hydroxyvitamin D were 21.1 ± 9.0 ng/mL. Levels were deficient (<20 ng/mL) in 49% of patients. In contrast, 1,25-hydroxyvitamin D levels were considered normal in all patients. Higher circulating 25-hydroxyvitamin D levels were significantly associated with milder Parkinson's disease evaluated by Hoehn & Yahr stage (P = .002) and total Unified Parkinson's Disease Rating Stage (P = .004) even after multivariate adjustment for 8 covariates, including disease duration. However, significant associations were not observed in 1,25-hydroxyvitamin D levels. Under multivariate analysis with 25-hydroxyvitamin D as well as other 8 covariates including disease duration, carriers of vitamin D receptor FokICC genotype had a milder form of Parkinson's disease: odds ratio, 0.32; 95% confidence interval, 0.16 to 0.66, P = 0.002. These results suggest that higher 25-hydroxyvitamin D levels and the vitamin D receptor FokICC genotype may be independently associated with milder forms of Parkinson's disease. However, significant associations were not observed in 1,25-hydroxyvitamin D levels. © 2011 Movement Disorder Society
The objective of this study was to further explore the effect of CAG repeat length on the rate of clinical progression in patients with Huntington's disease. The dataset included records for 569 subjects followed prospectively at the Baltimore Huntington's Disease Center. Participants were seen for a mean of 7.1 visits, with a mean follow-up of 8.2 years. Subjects were evaluated using the Quantified Neurologic Examination and its Motor Impairment subscale, the Mini-Mental State Examination, and the Huntington's disease Activities of Daily Living Scale. By itself, CAG repeat length showed a statistically significant but small effect on the progression of all clinical measures. Contrary to our previous expectations, controlling for age of onset increased the correlation between CAG repeat length and progression of all variables by 69% to 159%. Graphical models further supported the idea that individuals with smaller triplet expansions experience a more gradual decline. CAG repeat length becomes an important determinant of clinical prognosis when accounting for age of onset. This suggests that the aging process itself influences clinical outcomes in Huntington's disease. Inconsistent results in prior studies examining CAG repeat length and progression may indeed reflect a lack of age adjustment. © 2011 Movement Disorder Society
The purpose of this study was to evaluate the incidence of augmentation over 66 weeks of treatment with ropinirole in patients with primary restless legs syndrome (RLS). Augmentation is the main complication of long-term dopaminergic treatment of RLS. Despite widespread use of ropinirole in RLS, no studies have prospectively and systematically assessed the incidence of augmentation with its use. The study consisted of 26 weeks of double-blind flexible-dose treatment with ropinirole or placebo, followed by 40 weeks of open-label ropinirole treatment.. Patients had no previous history of augmentation. Potential cases of augmentation were identified with the Structured Interview for the Diagnosis of Augmentation and the Augmentation Severity Rating Scale and through reporting of adverse events. Cases were blindly evaluated by an expert panel using the NIH diagnostic criteria for augmentation. Four hundred and four patients participated in the double-blind study and 269 in the open-label phase, with a discontinuation rate of 42%. IRLS baseline scores improved at the end of the double-blind (DB) phase (mean ± SE) by −15.9 ± 0.76 for ropinirole, by −13.4 ± 0.77 for placebo (P < .05) and by −20.4 ± 0.55 during the open-label phase. The incidence rates of augmentation were 3.5% for ropinirole and <1% for placebo during the DB phase and 3% during the open-label phase. Clinically significant augmentation occurred in 3%, <1%, and 2%, respectively. Discontinuation of treatment occurred in 50% of all patients (7 of 14) with augmentation. The incidence of augmentation was 3.1% higher with ropinirole than with placebo. New patients with first episodes of augmentation continued to cumulate at a stable rate over the duration of this study. © 2012 Movement Disorder Society
Perampanel is a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor antagonist. Two multicenter randomized, double-blind, placebo-controlled, parallel-group phase III studies assessed the efficacy and safety of adjunctive perampanel in patients with Parkinson's disease and motor fluctuations.
In both phase III studies (301 and 302), levodopa-treated patients were randomized and treated with once-daily oral placebo (n = 504), perampanel 2 mg (n = 509), or perampanel 4 mg (n = 501). The primary end point was change in daily “off” time from baseline. The treatment period was 30 weeks in study 301 and 20 weeks in study 302.
For any efficacy end point, perampanel 2 or 4 mg was not superior to placebo. Perampanel was well tolerated up to 4 mg/day.
Perampanel failed to significantly improve motor symptoms versus placebo. There was also no effect on the duration or disability of levodopa-induced dyskinesia. © 2011 Movement Disorder Society
Heterozygous mutations in the glucocerebrosidase gene lead to an increased risk for and to more severe alpha-synuclein-associated pathology in Parkinson's disease. As both glucocerebrosidase and alpha-synuclein interact with fatty acids, we hypothesized that cerebrospinal fluid fatty acid levels are altered in these Parkinson's disease patients.
Cerebrospinal fluid levels of 13 fatty acids in 8 Parkinson's disease patients with a heterozygous glucocerebrosidase mutation were compared with those of 41 idiopathic Parkinson's disease patients and 30 controls using gas chromatography.
Parkinson's disease patients with a heterozygous glucocerebrosidase mutation had lower levels of palmitoleic (P ≤ .007), oleic (P ≤ .016), linoleic (P ≤ .005), arachidonic (P ≤ .003), eicosapentaenoic (P ≤ .003) and decosahexaenoic (P ≤ .03) acids and lower levels of total fatty acids (P < .005) compared with both idiopathic Parkinson's disease patients and control subjects.
These results suggest that abnormalities of fatty acid metabolism are specifically involved in the pathogenesis of Parkinson's disease associated with a heterozygous glucocerebrosidase mutation. © 2011 Movement Disorder Society
Parkinson's disease is inversely associated with cigarette smoking, but its relation with passive smoking or environmental tobacco smoke exposure is rarely examined.
Within a case–control study, we assessed the association between Parkinson's disease and living or working with active smokers. Cases were newly diagnosed with idiopathic Parkinson's disease (n = 154) from western Washington State in 2002–2008. Age- and sex-matched controls (n = 173) were neurologically normal and unrelated to cases.
Compared with never active or passive tobacco smokers, we observed reduced Parkinson's disease risks for ever passive only smokers (OR, 0.34; 95% CI, 0.16–0.73), similar to those for ever active smokers (OR, 0.35; 95% CI, 0.17–0.73). Among persons whose only tobacco smoke exposure was passive smoking at home, risk was inversely associated with years exposed.
These observations parallel those well established for active smoking. However, it remains unresolved whether a true protective effect of tobacco smoke, generally detrimental to health, underlies these associations. © 2011 Movement Disorder Society
Carriers of fragile X mental retardation 1 (FMR1) repeat expansions in the premutation range (55–200 CGG repeats) often develop a syndrome of kinetic tremor, cerebellar ataxia, and parkinsonism; designated the fragile X–associated tremor ataxia syndrome (FXTAS). Neurological signs have not been reported in carriers of gray zone (45–54 CGG repeats) expansions.
We describe 3 patients with FMR1 gray zone alleles who meet diagnostic criteria for FXTAS.
Our cases suggest that the definition of the FXTAS may need to be broadened to include individuals with FMR1 repeat expansions in the gray zone. These neurological signs may be due to elevated levels of expanded CGG repeat FMR1 mRNA in the gray zone carriers, similar to the changes seen in premutation carriers with FXTAS. © 2011 Movement Disorder Society
There are no data available concerning whether patients with cervical dystonia who have recurrent or new symptoms after peripheral denervation surgery benefit similarly from pallidal deep brain stimulation compared with patients who receive primarily pallidal stimulation.
Data on 7 cervical dystonia patients with recurrent or progressive dystonia after peripheral denervation who underwent pallidal stimulation were prospectively collected. Deep brain stimulation was performed in Mannheim/Hannover, Germany, or in Umea, Sweden. To the subgroup from Mannheim/Hannover, a second group of patients without previous peripheral surgery was matched. Assessments included the Toronto Western Spasmodic Torticollis Rating Scale and the Burke-Fahn-Marsden dystonia rating scale, as well as the Tsui scale in the Swedish patients.
The 4 patients from Mannheim/Hannover experienced sustained improvement from pallidal stimulation by a mean of 57.5% according to the Toronto Western Spasmodic Torticollis Rating Scale (P < .05) and by a mean of 69.5% according to the Burke-Fahn-Marsden dystonia rating scale (P < .05) at long-term follow-up of 40.5 months. The patients from Umea had a mean Tsui score of 7 prior to surgery and a mean score of 3 at the mean follow-up of 8 months (62.5%). In the matched group the Toronto Western Spasmodic Torticollis Rating Scale improved by 58.8% and the Burke-Fahn-Marsden dystonia rating scale by 67% (P < .05) at long-term follow-up (mean, 41.5 months).
Patients who had prior peripheral surgery for cervical dystonia experience improvement from subsequent pallidal stimulation that is comparable to that of de novo patients. © 2011 Movement Disorder Society
Using a validated questionnaire, we screened eye symptoms (burning sensation, grittiness, dry eye) in 333 first-degree relatives of 140 probands with different forms of primary adult-onset dystonia, 208 healthy subjects, and 293 patients with primary blepharospasm.
The rate of eye symptoms was similar in the relatives of focal dystonia patients and in healthy subjects (adjusted HR, 1.1; 95% CI, 0.7–1.7; P = .69), thus suggesting a common origin of eye symptoms in both groups. A higher rate was observed in blepharospasm patients (adjusted HR, 2; 95% CI, 1.4–2.9; P < .0001). Relatives of focal dystonia patients who developed blepharospasm were more likely to have preceding eye symptoms than were relatives who developed focal dystonia other than blepharospasm (BSP) or relatives who did not develop dystonia.
Eye symptoms reported by relatives of patients with focal dystonia probably result from eye diseases and are not part of the clinical spectrum of blepharospasm. © 2011 Movement Disorder Society
The feasibility and validity of Web-based assessments in Parkinson's disease is unknown. The objectives of this study were to develop and to compare home Web-based assessments with office-based assessments.
Methods: We tested feasibility and validity using a longitudinal, randomized crossover design. Patients were assessed at baseline and after 6 and 12 weeks using both assessments including the Unified Parkinson's Disease Rating Scale, the Unified Dyskinesia Rating scale, timed tests, and quality-of life and Non-Motor Symptoms questionnaires.
Forty-two patients were included (22 men, 20 women; mean age, 64.7 ± 9.0 years). Only 2 patients (5%) dropped out. The mean intraclass correlation coefficient between Web- and office-based assessments ranged from 0.67 (first visit) to 0.75 (last visit) and 0.81 and 0.82 for doctor- and patient-administered scales, respectively. No differences in responsiveness (P = 0.63), and data precision (P = 0.11) were found, but Web-based assessments had fewer missing values (P = 0.01).
Web-based assessments offer a feasible format for assessing PD-related impairment from home. © 2011 Movement Disorder Society
Parkinson's disease (PD) is a common neurodegenerative disorder of unknown etiology. The characteristic α-synuclein aggregation of PD is also a feature of Sanfilippo syndrome, a storage disorder caused by α-N-acetylglucosaminidase (NAGLU) gene mutations. We explored genetic links between these disorders and studied the pathology of Sanfilippo syndrome to investigate a common pathway toward α-synuclein aggregation.
We typed the 2 single-nucleotide polymorphisms that tag the common haplotypes of NAGLU in 926 PD patients and 2308 controls and also stained cortical tissue from 2 cases of Sanfilippo A syndrome using the anti-α-synuclein antibody, Per7.
Allelic analysis showed an association between rs2071046 and risk for PD (P 1.3 × 10−3). Intracellular α-synuclein accumulation was observed in the cortical tissue of both Sanfilippo A syndrome cases.
This study suggests a possible role of NAGLU in susceptibility to PD while extending evidence for α-synuclein aggregation in the brain in lysosomal storage disorders. Our findings support a mechanism involving lysosomal dysfunction more generally in the pathogenesis of PD. © 2011 Movement Disorder Society
The aim of the current study was to test the hypothesis of a fundamental impairment of vocal pacing in patients with spinocerebellar ataxia and Parkinson's disease.
Thirty-one patients with spinocerebellar ataxia, 42 patients with Parkinson's disease, and 43 healthy controls had to repeat a single syllable at a self-chosen isochronous pace. The coefficient of variance for interval length and the change in interval length with successive utterances were used to describe pace stability.
Ataxic and parkinsonian patients both showed a significant instability of vocal pace performance. Ataxic speakers featured difficulties in keeping the pace immediately from the beginning of the task, whereas parkinsonian patients accelerated the pace in the course of the performance. The results support differential roles of cerebellar and basal ganglia pathways in motor speech performance.
Cerebellar function may be required for the general precision of interval timing, whereas basal ganglia rather serve to maintain rhythm stability over time. © 2011 Movement Disorder Society
Although leucine-rich repeat kinase 2 (LRRK2) is the gene most commonly linked to autosomal dominant inherited Parkinson's disease (PD), there have been few reports in Asia, probably because of population-specific differences in allele frequencies.
We identified a large Korean PD family with the p.Tyr1699Cys mutation in LRRK2 and analyzed genealogical, clinical, and genetic data from the family.
Although the clinical findings of these patients were indistinguishable from those of patients with sporadic PD, the patients with the p.Tyr1699Cys mutation demonstrated clinical heterogeneity including differences in age at onset, rate of disease progression, clinical phenotype, and prognosis.
This is the first report describing an Asian PD family with the p.Tyr1699Cys mutation in LRRK2. The affected members of this family showed clinical heterogeneity. © 2011 Movement Disorder Society