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Parkinson’s disease (PD) patients have a number of functional hand impairments. The latency and rate of isometric force generation is impaired in PD. Motor dysfunction is also related to impaired integration of sensory feedback and motor output. Moreover, PD patients exhibit sensory deficits such as decreased spatial and temporal tactile discrimination thresholds of the fingertips. Impairments of reaching and grasping are seen as patients tend to exhibit difficulty in movement initiation to a target. There are deficits in hand preshaping to object geometry. There is a lack of coordination between the timing of the reach and grasp components. Patients have an overall dependence on visual cues to control movement. They exhibit impairments in the planning of where to place their digits, resulting in suboptimal performance of object manipulation. It is hypothesized that predictive force control deficits are a result of central impairments associated with the generation and/or retrieval of sensorimotor memories for movement planning.

Parkinson’s disease is a progressive brain disease produced by degeneration of neurons in the substantia nigra and other brain nuclei. The cause is unknown but environmental and genetic factors are thought to play a role. Clinical symptoms and signs are related to the motor system, cognitive and psychiatric function, and the autonomic nervous system. Rest tremor, bradykinesia, and rigidity are the hallmarks of the disease. As the disease progresses, dementia, hallucinations, paranoia, orthostatic hypotension, and urinary frequency may become major disabling factors in a patient’s life. Parkinson’s disease affects employment, social functioning, and participation in society. Significant numbers of patients lose independence in their activities of daily living and quality of life for patients and caregivers may be impaired. There is no way of slowing the degenerative process or curing the disease.

There is a critical need for new analytics to personalize behavioral data analysis across different fields, including kinesiology, sports science and behavioral neuroscience. Specifically, to better translate and integrate basic research into patient care we need to radically transform the methods by which we describe and interpret movement data. Here we show that hidden in the ‘noise’, smoothed out by averaging movement kinematics data, lies a wealth of information that selectively differentiates neurological and mental disorders such as Parkinson’s disease (PD), deafferentation, Autism Spectrum Disorders (ASD), and Schizophrenia (SZ) from typically developing and typically aging controls. In this report we quantify the continuous forward-and-back pointing movements of participants from a large heterogeneous cohort comprising typical and pathological cases. We empirically estimate the statistical parameters of the probability distributions for each individual in the cohort and report the parameter ranges for each clinical group after characterization of healthy developing and aging groups. We coin this newly proposed platform for individualized behavioral analyses ‘precision phenotyping’ to distinguish it from the type of observational-behavioral phenotyping prevalent in clinical studies or from the ‘one-size-fits-all’ model in basic movement science. We further propose the use of this platform as a unifying statistical framework to characterize brain disorders of known etiology in relation to idiopathic neurological disorders with similar phenotypic manifestations.

Objective: To determine if future studies of coenzyme Q10 and GPI-1485 in Parkinson disease (PD) may be warranted. Methods: We conducted a randomized, double-blind, calibrated futility clinical trial of coenzyme Q10 and GPI-1485 in early untreated PD using placebo data from the DATATOP study to establish the futility threshold. Results: The primary outcome measure (change in total Unified Parkinson's Disease Rating Scale scores over 1 year) did not meet the prespecified criteria for futility for either agent. Secondary analyses using calibration controls and other more recent placebo data question the appropriateness of the predetermined definition of futility, and suggest that a more restrictive threshold may be needed. Conclusions: Coenzyme Q10 and GPI-1485 may warrant further study in Parkinson disease, although the data are inconsistent. Additional factors (cost, availability of other agents, more recent data on placebo outcomes, other ongoing trials) should also be considered in the selection of agents for Phase III studies. NEUROLOGY 2007;68:20-28

Patients with psychogenic parkinsonism (PP), like those with Parkinson's disease (PD), may have tremor, bradykinesia, rigidity, and gait disturbances. Unusual features predominate in PP, but clear psychogenic signs may not be obvious. Because PP may be difficult to diagnose, identifying a wider spectrum of disease manifestations that point toward psychogenic rather than organic parkinsonism could be useful for clinicians.We retrospectively reviewed the charts and clinical data for all patients referred for parkinsonism to a single physician at our movement disorders clinic from 1980 to 2012.Patients with PP represented 1.5% of all patients referred for parkinsonism. Among 36 patients with PP, the most common complaints were tremor (31), gait disturbance (18), fatigue (12), and diminished balance (10). Neurologic examination revealed 12 patients with unusual (functional) postures, 5 with a normal exam, and none with micrographia, hypophonia, or hypomimia. Seven of 36 patients improved, 6 of these with antidepressant therapy.PP is not rare in a movement disorders practice. Leg tremor is more likely in PP than in PD, whereas falls are rare. Unusual (nonphysiologic) postures may be present. The outcome generally is not favorable, although antidepressants are beneficial in some patients with disease duration of2 years. The presence of micrographia, hypophonia, or hypomimia strongly suggests an organic cause of parkinsonism rather than PP.

Electrophysiological and computational studies suggest that nigro-striatal dopamine may play an important role in learning about sequences of environmentally important stimuli, particularly when this learning is based upon step-by-step associations between stimuli, such as in second-order conditioning. If so, one would predict that disruption of the midbrain dopamine system — such as occurs in Parkinson’s disease — may lead to deficits on tasks that rely upon such learning processes. This hypothesis was tested using a “chaining” task, in which each additional link in a sequence of stimuli leading to reward is trained step-by-step, until a full sequence is learned. We further examined how medication (L-dopa) affects this type of learning. As predicted, we found that Parkinson’s patients tested ‘off’ L-dopa performed as well as controls during the first phase of this task, when required to learn a simple stimulus–response association, but were impaired at learning the full sequence of stimuli. In contrast, we found that Parkinson’s patients tested ‘on’ L-dopa performed better than those tested ‘off’, and no worse than controls, on all phases of the task. These findings suggest that the loss of dopamine that occurs in Parkinson’s disease can lead to specific learning impairments that are predicted by electrophysiological and computational studies, and that enhancing dopamine levels with L-dopa alleviates this deficit. This last result raises questions regarding the mechanisms by which midbrain dopamine modulates learning in Parkinson’s disease, and how L-dopa affects these processes. © 2004 Elsevier B.V. All rights reserved.

We report four patients with Parkinson's disease who had an unusual pattern of severe chorea and dystonia in the evenings only. The temporal pattern of abnormal movements and simultaneous monitoring of plasma levodopa and clinical state were consistent with dyskinesias associated with subtherapeutic (low dopa dyskinesias) rather than peak concentrations of levodopa (high dopa dyskinesias). In two patients, addition of a direct-acting dopamine receptor agonist was helpful in ameliorating this complication of antiparkinson therapy.

Pain is reported by nearly 50% of patients with Parkinson's disease. In some patients, it can be more debilitating than the motor deficits. In order to identify the appropriate treatment strategy for each patient, it is useful to categorize pain syndromes as follows: 1) low DOPA (end of dose wearing off, diphasic, or early morning) painful states are associated with inadequate levels of dopamine receptor stimulation; 2) high DOPA (peak dose) painful states occur at times of maximum levodopa efficacy; and 3) many patients report pain that has no obvious relation to dopaminergic medications or may even be caused by other conditions. Low DOPA painful states are best treated by trying to provide more continuous dopaminergic stimulation and thereby reduce or prevent the number and duration of "off" periods. Adding or increasing the dose of direct-acting dopamine receptor agonists or of catechol-o-methyl transferase inhibitors is the best first-line strategy. Other approaches include increasing the frequency of immediate-release levodopa preparations or using controlled-release preparations. More invasive approaches should be considered only when simpler methods fail. These include deep brain stimulation to the pallidum or the subthalamic nucleus, or direct duodenal continuous infusion of levodopa in patients who are unable to undergo surgery. Pain associated with excessive dopaminergic stimulation usually is a result of dystonia or severe chorea. Reduction of levodopa is the first step in attempting to diminish high DOPA states, followed by reduction or cessation of other dopaminergic agents such as selegiline, catechol-o-methyl transferase inhibitors, or direct-acting dopamine receptor agonists. Adding amantadine can reduce chorea significantly and it should be tried if the potential and actual side effects are tolerable to the patient. Deep brain stimulation is a good final option if medication adjustments are ineffective. Nonspecific pains of Parkinson's disease can be difficult to treat. The effective use of central pain suppressant or analgesics is anecdotal and difficult to verify. In untreated early disease, generalized pain or pain related to joint or muscle immobility may be reduced by effective treatment of the underlying Parkinson's disease.

Summary The striatum has been widely implicated in cognition, but a precise understanding of its role remains elusive. Here we present converging evidence for the role of the striatum in feedback-based learning. In a prior functional imaging study, healthy controls showed striatal activity during a feedback-based learning task, which was decreased when the same task was learned without feedback. In the present study, we show that individuals with striatal dysfunction due to Parkinson’s disease are impaired on the feedback-based task, but not on a non-feedback version of the same task. Parkinson’s patients and controls also used different learning strategies depending on feedback structure. This study provides direct behavioural evidence from humans that cortico-striatal systems are necessary for feedbackbased learning on a cognitive task. These findings also link between learning impairments in Parkinson’s disease and the physiological and computational evidence for the role of midbrain dopaminergic systems in feedback processing.

We evaluated kinematics of people with Parkinson's disease (PD) and age-matched controls during cued and uncued reaching movements. Maximum hand velocity, its variability and shoulder-to-shoulder coupling, quantified by phase locking value (PLV), were compared between PD (n=14) and Control (n=4). The PD group achieved significantly lower maximum hand velocities during the reaching movement in comparison to the Control group (p=0.05), whereas the Control group exhibited significantly greater variability (i.e., larger SDs) of maximum hand velocities across the blocks than the PD group (p=0.01). Persons with PD exhibited higher PLVs than the healthy elderly individuals when performing reaching movements with their dominant side (p=0.05), while the PLVs did not differ between groups when the movements were performed with their non-dominant hand. The present study suggests that persons with PD have a reduced ability to: (1) modulate maximum reaching velocity; and (2) alter coordination across the shoulders to different reaching actions. In persons with PD, the velocity-oriented (dominant) limb becomes slowed and less flexible, to the point that its movement dynamics are effectively similar to that of the position-oriented (non-dominant) limb.

We previously reported that Parkinson's disease patients could point with their eyes closed as accurately as normal subjects to targets in three-dimensional space that were initially presented with full vision. We have now further restricted visual information in order to more closely examine the individual and combined influences of visual information, proprioceptive feedback, and spatial working memory on the accuracy of Parkinson's disease patients. All trials were performed in the dark. A robot arm presented a target illuminated by a light-emitting diode at one of five randomly selected points composing a pyramidal array. Subjects attempted to "touch" the target location with their right finger in one smooth movement in three conditions: dark, no illumination of arm or target during movement; movement was to the remembered target location after the robot arm retracted; finger, a light-emitting diode on the pointing fingertip was visible during the movement but the target was extinguished; again, movement was to the remembered target location; and target, the target light-emitting diode remained in place and visible throughout the trial but there was no vision of the arm. In the finger condition, there is no need to use visual-proprioceptive integration, since the continuously visualized fingertip position can be compared to the remembered location of the visual target. In the target condition, the subject must integrate the current visible target with arm proprioception, while in the dark condition, the subject must integrate current proprioception from the arm with the remembered visual target. Parkinson's disease patients were significantly less accurate than controls in both the dark and target conditions, but as accurate as controls in the finger condition. Parkinson's disease patients, therefore, were selectively impaired in those conditions (target and dark) which required integration of visual and proprioceptive information in order to achieve accurate movements. In contrast, the patients' normal accuracy in the finger condition indicates that they had no substantial deficits in their relevant spatial working memory. Final arm configurations were significantly different in the two subject groups in all three conditions, even in the finger condition where mean movement endpoints were not significantly different. Variability of the movement endpoints was uniformly increased in Parkinson's disease patients across all three conditions. The current study supports an important role for the basal ganglia in the integration of proprioceptive signals with concurrent or remembered visual information that is needed to guide movements. This role can explain much of the patients' dependence on visual information for accuracy in targeted movements. It also underlines what may be an essential contribution of the basal ganglia to movement, the integration of afferent information that is initially processed through multiple, discrete modality-specific pathways, but which must be combined into a unified and continuously updated spatial model for effective, accurate movement.

Objective : To demonstrate the usefulness of a three dimensional (3D) motion analysis system for the quantitative measurement of tremor in patients with Parkinson's disease (PD). Methods : Six PD patients with hand tremors were studied using a system that employed 3D electromagnetic position sensors to measure the actual, cumulative displacement of the tremoring finger. Patients were studied in different hand positions and activating conditions before and 30, 60, 90 and 120 min after intake of Pramipexole, a dopamine agonist known to reduce tremor. Tremor amplitude and frequency, before and after drug intake, were compared using Mann–Whitney U test and Wilcoxon rank test, respectively. Results : The motion analysis system allowed discrimination of tremor related events from movement artifact and allowed the calculation of real world movement of the finger tremor despite altered hand positions and orientation. Average 3D tremor frequency ranged from 3.71 to 4.34 Hz. Median tremor amplitude (total distance traveled per 5 s interval) decreased with drug from 4.9 to 1.6 cm for resting tremor, 4.5 to 3.7 cm for postural tremor, 3.4 to 3.3 cm for precision tremor, 10.2 to 3.3 cm for tapping activation and 108.6 to 5.7 cm for counting activation. Conclusions : Our method of 3D analysis provides a robust, single quantitative measure of tremor amplitude that is intuitive and likely to reflect the functional impact of tremor. This methodology should be useful in comparing tremor across patients and in measuring the efficacy of therapeutic interventions.

We report three cases of autopsy-proven Binswanger's disease (subcortical arteriosclerotic encephalopathy) with unusual clinical features. Two patients had supranuclear gaze disturbances, early gait dysfunction, and speech disorders suggestive of progressive supranuclear palsy. One of these patients was not demented at the time of death. The third patient had features typical of Parkinson's disease. All three patients were responsive to treatment with levodopa. The clinical spectrum of Binswanger's disease should be expanded to include levodopa-responsive parkinsonism.

Background Often in Parkinson’s disease (PD) motor-related problems overshadow latent non-motor deficits as it is difficult to dissociate one from the other with commonly used observational inventories. Here we ask if the variability patterns of hand speed and acceleration would be revealing of deficits in spatial-orientation related decisions as patients performed a familiar reach-to-grasp task. To this end we use spatial-orientation priming which normally facilitates motor-program selection and asked whether in PD spatial-orientation priming helps or hinders performance. Methods To dissociate spatial-orientation- and motor-related deficits participants performed two versions of the task. The biomechanical version (DEFAULT) required the same postural- and hand-paths as the orientation-priming version (primed-UP). Any differences in the patients here could not be due to motor issues as the tasks were biomechanically identical. The other priming version (primed-DOWN) however required additional spatial and postural processing. We assessed in all three cases both the forward segment deliberately aimed towards the spatial-target and the retracting segment, spontaneously bringing the hand to rest without an instructed goal. Results and Conclusions We found that forward and retracting segments belonged in two different statistical classes according to the fluctuations of speed and acceleration maxima. Further inspection revealed conservation of the forward (voluntary) control of speed but in PD a discontinuity of this control emerged during the uninstructed retractions which was absent in NC. Two PD groups self-emerged: one group in which priming always affected the retractions and the other in which only the more challenging primed-DOWN condition was affected. These PD-groups self-formed according to the speed variability patterns, which systematically changed along a gradient that depended on the priming, thus dissociating motor from spatial-orientation issues. Priming did not facilitate the motor task in PD but it did reveal a breakdown in the spatial-orientation decision that was independent of the motor-postural path.

We studied the clinical characteristics and plasma levodopa (LD) profile of complex, LD-associated dystonia in 33 patients with Parkinson's disease (PD). Generalized, abdominal, respiratory, and myoclonic, but not facial or foot, dystonia could be related to specific phases of the plasma LD cycle. Simultaneous clinical observation and determinations of plasma LD concentrations were often necessary to find the most efficacious dosing schedule for these patients. Maintenance of steady plasma LD concentrations within a dystonia-free window of benefit was the best treatment.

Summary Six patients autopsied by the neuropathology service at UMDNJ—Robert Wood Johnson Medical School between 1985 and 1988 had pathologically typical Lewy-body Parkinson's disease (PD). Review of their clinical records revealed that none had clinically typical PD. Atypical clinical features included juvenile onset, retrocollis, strong family history, and absence of tremor, flexed posture, or levodopa response. One patient had dementia without parkinsonism. We conclude that the clinical spectrum of Lewy-body PD is wider than is generally assumed and that the diagnosis of pathologically typical Parkinson's disease cannot be excluded on clinical grounds alone.

Successful adaptation to novel sensorimotor contexts critically depends on efficient sensory processing and integration mechanisms, particularly those required to combine visual and proprioceptive inputs. If the basal ganglia are a critical part of specialized circuits that adapt motor behavior to new sensorimotor contexts, then patients who are suffering from basal ganglia dysfunction, as in Parkinson's disease should show sensorimotor learning impairments. However, this issue has been under-explored. We tested the ability of 8 patients with Parkinson's disease (PD), off medication, ten healthy elderly subjects and ten healthy young adults to reach to a remembered 3D location presented in an immersive virtual environment. A multi-phase learning paradigm was used having four conditions: baseline, initial learning, reversal learning and aftereffect. In initial learning, the computer altered the position of a simulated arm endpoint used for movement feedback by shifting its apparent location diagonally, requiring thereby both horizontal and vertical compensations. This visual distortion forced subjects to learn new coordinations between what they saw in the virtual environment and the actual position of their limbs, which they had to derive from proprioceptive information (or efference copy). In reversal learning, the sign of the distortion was reversed. Both elderly subjects and PD patients showed learning phase-dependent difficulties. First, elderly controls were slower than young subjects when learning both dimensions of the initial biaxial discordance. However, their performance improved during reversal learning and as a result elderly and young controls showed similar adaptation rates during reversal learning. Second, in striking contrast to healthy elderly subjects, PD patients were more profoundly impaired during the reversal phase of learning. PD patients were able to learn the initial biaxial discordance but were on average slower than age-matched controls in adapting to the horizontal component of the biaxial discordance. More importantly, when the biaxial discordance was reversed, PD patients were unable to make appropriate movement corrections. Therefore, they showed significantly degraded learning indices relative to age-matched controls for both dimensions of the biaxial discordance. Together, these results suggest that the ability to adapt to a sudden biaxial visuomotor discordance applied in three-dimensional space declines in normal aging and Parkinson disease. Furthermore, the presence of learning rate differences in the PD patients relative to age-matched controls supports an important contribution of basal ganglia-related circuits in learning novel visuomotor coordinations, particularly those in which subjects must learn to adapt to sensorimotor contingencies that were reversed from those just learned.

In this study we examined the effect of dopaminergic modulation on learning and memory. Parkinson's patients were tested 'on' versus 'off' dopaminergic medication, using a two-phase learning and transfer task. We found that dopaminergic medication was associated with impaired learning of an incrementally acquired concurrent discrimination task, while patients withdrawn from dopaminergic medication performed as well as controls. In addition, we found a dissociation of the effect of medication within a single two-phase task: patients tested 'on' medication were not impaired at the ability to generalize based on learned information. The deficit among medicated patients appeared to be related specifically to the concurrent, incremental, feedback-based nature of the task: such a deficit was not found in a version of the task in which demands for concurrent error-processing learning were reduced. Taken together with a growing body of evidence emphasizing a role for midbrain dopamine in error-correcting, feedback-based learning processes, the present results suggest a framework for understanding previously conflicting results regarding the effect of medication on learning and memory in Parkinson's disease.

Objective: To investigate risk factors associated with subjective complaints of dizziness in 12 elderly patients with Parkinson disease (PD), in whom no obvious cause for this symptom could be found. Design: A case-controlled study, with patients prospectively recruited in a nonblinded fashion. Setting: Patients were seen by one physician at a neurology outpatient clinic between August 1993 and August 1994 Subjects: Thirty-six patients, all over age 65 years and all with PD; 12 complained of dizziness; 24 did not. Interventions: Patients and controls were screened for blood pressure changes, postural instability, motor severity, multiple sensory deficits, drug use, cardiovascular disease, and diabetes mellitus. Main Outcome Measures: An orthostatic decrease of systolic BP > 15mmHg (odds ratio=6.5; 95% confidence interval=1.22–34.52; χ 2 mh = 6.7; p 5mmHg (odds ratio=11; 95% confidence interval=3.15–38.39; χ 2 mh = 7.14; p Results: The only significant risk factors linked with dizziness were orthostatic decreases in systolic (15mmHg) and diastolic (5mmHg) blood pressure. Conclusions: An orthostatic decrease in blood pressure is associated with unexplained feelings of dizziness in elderly PD patients.

Previous studies in our laboratory examining pointing and reach-to-grasp movements of Parkinson's disease patients (PDPs) have found that PDPs exhibit specific deficits in movement coordination and in the sensorimotor transformations required to accurately guide movements. We have identified a particular difficulty in matching unseen limb position, sensed by proprioception, with a visible target. In the present work, we further explored aspects of complex sensorimotor transformation and motor coordination using a reach-to-grasp task in which object shape, visual feedback, and dopaminergic medication were varied. Normal performance in this task requires coordinated generation of appropriate reach, to bring the hand to the target, and differentiated grasp, to preshape the hand congruent with object form. In Experiment 1, we tested PDPs in the off-medication state. To examine the dependence of subjects on visual feedback and their ability to implement intermodal sensory integration, we required them to reach and grasp the target objects in three conditions: (1) Full Vision, (2) Object Vision with only the target object visible and, (3) No Vision with neither the moving arm nor the target object visible. PDPs exhibited two types of deficits. First, in all conditions, they demonstrated a generalized slowing of movement or bradykinesia. We consider this an intensive deficit, since it involves largely a modulation of the gain of specific task parameters: in this case, velocity of movement. Second, they were less able than controls to extract critical proprioceptive information and integrate it with vision in order to coordinate the reach and grasp components of movement. These deficits which involve the coordination of different inputs and motor components, we classify as coordinative deficits. As in our previous work, the PDPs' deficits were most marked when they were required to use proprioception to guide their hand to a visible target (Object Vision condition). But even in the full-vision condition, their performance only became fully accurate when both the target and effector (hand) were simultaneously visible. In Experiment 2, PDPs were tested on their dopaminergic replacement therapy. Dopaminergic treatment significantly ameliorated the bradykinesia of the PDPs, but produced no changes in the hand preshaping deficiencies of PDPs. These results suggest that adequate treatment of the PDPs may more readily compensate for intensive, than coordinative deficits, since the latter are likely to depend on specific and time-dependent neural interdependencies that are unlikely to be remediated simply by increasing the gain of a pathway.

We followed 4 patients with Parkinson's disease and severe, intermittent, drenching sweats. One patient was studied with serial plasma levodopa levels and simultaneous clinical examinations. She was observed during a severe sweating episode; this was associated with subtherapeutic plasma levodopa levels (low dopa state). All 4 patients' sweats responded favorably to the institution of agonist therapy. Drenching sweats should be considered part of the spectrum of off-period levodopa-related fluctuations in Parkinson's disease.

Parkinson's disease (PD) results in various types of motor impairments including bradykinesia, tremor and rigidity. Recent research has implicated more fundamental processes at the source of the observed motor deficits. Among these, problems in the sequencing and/or timing of complex movements and in the execution of internally-guided tasks. Furthermore, PD patients exhibit procedural learning deficits which may complicate the interpretation of experimental results of studies involving novel sensorimotor tasks. The reach-to-grasp movement is a complex, overlearned sensorimotor task consisting of two semi-independent components, a relatively simple reach or transport phase and a more complex manipulation or prehension phase. In the present study, we used a novel technique in order to study the evolution of hand preshaping during the reach-to-grasp movement of PD patients and age-matched controls to objects of different shapes in three different spatial locations. Our results indicate that while PD patients are able to specify movement direction as well as controls, their hand preshaping exhibits substantial impairments. Other prehension measures, such as the time to peak aperture (TPA), indicate that PD patients delayed execution of the grasp until visual feedback of their hand was available. Overall, our results suggest that PD patients' internal guidance processes are severely disrupted, having to rely on visual feedback in order to modulate their hand shape to fit the contours of the target objects during a reach-to-grasp movement.

OBJECTIVE: To evaluate the safety of the coadministration of selegiline with cold medications. DATA SOURCES: Clinical literature accessed through MEDLINE(1965–September 2002), IPA database, and Drug-Reax System. The following search terms were used: selegiline, pseudoephedrine, dextromethorphan, MAOI, and drug interactions. Somerset Pharmaceuticals, the marketers of Eldepryl (selegiline HCI), were also contacted. DATA SYNTHESIS: Despite a warning against its concomitant use with pseudoephedrine and dextromethorphan, interactions with selegiline have not been reported. However, there have been reports of patients experiencing adverse events with related agents. CONCLUSIONS: Patients taking selegiline should try to avoid pseudoephedrine and dextromethorphan or use drugs without interaction potential. If selegiline is used with these medications, watch for adverse events or replace selegiline with another drug.

Parkinson's disease (PD) is primarily an α-synucle- inopathy, rather than a tauopathy, but there is evidence for an indirect association of tau with the pathogenetic process in PD. We therefore assessed the frequency in PD of the tau A0 allele, a dinucleotide repeat marker that has been associated with a sporadic tauopathy, progressive supranuclear palsy (PSP). We found the A0 allele to comprise 79.2% of 758 alleles from PD patients and 71.2% of 264 control alleles (P = 0.008). We also performed a meta-analysis of three previous reports, two of which failed to produce statistically significant results. Taken together, they also support a PD/A0 allelic association, even after correction for misdiagnosis of PSP as PD (P< 0.001). The A0/A0 genotype frequency in our patients (62.3%) did not differ significantly from that in controls (53.0%, P = 0.062), but the meta-analysis, even after correction for misdiagnosis, showed a significant result, with P = 0.002. The frequency of A0 allele and the A0/A0 genotype were compatible with Hardy-Weinberg equilibrium. The frequency of the A0 allele and the A0/A0 genotype in our patients with familial PD was not significantly greater than in those with sporadic PD. We conclude that the tau protein may play a small role in the pathogenesis of PD and that biochemical characterization of this role may suggest opportunities for PD prophylaxis. © 2001 Movement Disorder Society.

We report a 45-year-old woman with a 3-year history of continuous dystonic movements of tongue and palate with intermittent episodes of noticeable worsening lasting 6 to 8 h. The movements began immediately after a viral illness. The only contributory history is that the patient received high doses of prochlorperazine 22 years earlier for hyperemesis gravidarum. The patient appears to have an unusual focal lower cranial dystonia. Proposed etiologies may be idiopathic or related to prior use of a phenothiazine with a viral trigger.

Recently, a functional polymorphism in the promoter region of the serotonin transporter gene has been linked to anxiety. In cell culture, the short allele of this polymorphism synthesizes less serotonin transporter, resulting in a reduction of the removal of serotonin from the synaptic cleft. This pilot study examines depression and anxiety in Parkinson's disease patients as a function of the variation in this polymorphism. Thirty-two patients were geno typed and then blindly administered the Hamilton Depression and Anxiety Scales. Clinical data on the neurologic features of the disease were also gathered. Patients with the short allele of the serotonin transporter promotor scored significantly higher on both the depression and anxiety measures. There were no differences between groups for any neurologic variable. Patients with the short allele were more likely to have scores for anxiety and depres sion that indicated "caseness." This study suggests that the short allele of the serotonin transporter gene may represent a significant risk factor for the development of anxiety and depression in Parkinson's disease patients. (J Geriatr Psychiatry Neurol 1999; 12:49-52).

OBJECTIVE:To compare the costs of pharmacotherapy in patients with Parkinson's disease before and after converting from standard Sinemet to extended-release Sinemet CR.DESIGN:Investigators retrospectively reviewed records of patients converting from Sinemet to Sinemet CR for efficacy and total drug costs. Cost-effectiveness was evaluated retrospectively from data collected in prospective Sinemet CR efficacy trials.SETTING:Parkinson's disease clinic at a tertiary care university teaching hospital.PATIENTS:100 patients with motor fluctuations who had undergone an initial 6-month course of Sinemet therapy, followed by a 6-month course of Sinemet CR.MAIN OUTCOME MEASURES:Total cost was measured as the cost of Sinemet formulations plus the costs of other antiparkinson medications. Differences in pre- and postconversion costs were compared by using the paired, two-tailed Student's t-test. A substudy of 39 patients on the cost-effectiveness of conversion measured the ratio of daily medication costs to the daily hours “on” without chorea.RESULTS:While total daily medication costs after conversion increased by 21%, patients experienced either a comparable or an improved degree of disease control with Sinemet CR. Patients who were also taking selegiline were able to decrease selegiline expense by 20%. The costs of other adjunctive medications did not differ significantly after conversion. The cost-effectiveness analysis revealed an increase in postconversion on time by 2.2 hours (p = 0.0001), accompanied by a $2.85 decrease in total cost per hour on without chorea (p = 0.11).CONCLUSIONS:Although Sinemet CR is more costly, it may be more cost-effective in patients with motor fluctuations. Some patients may be able to reduce adjunctive medications.

The dopamine D4 receptor (D4DR) has a highly polymorphic region in the third exon which has been associated with novelty seeking (NS) behavior. Due to the central position of dopamine and the documented low NS in Parkinson's disease (PD), the frequency of the exon 3 variants of D4DR in 95 PD patients and 47 controls was investigated. A significantly higher frequency of exon 3 alleles with six or more repeat units was found in the PD group (p = 0.039). This provides evidence that some forms of the highly polymorphic D4DR may represent a genetic susceptibility factor for PD.

A polymorphic 44-nucleotide insertion/deletion in the promoter region of the serotonin transporter gene (5-HTTLPR) has been shown to affect the level of expression of the serotonin transporter protein. An association between anxiety-related behavioural traits and the short form of the 5-HTTLPR has been reported. We determined the 5-HTTLPR genotype in genomic DNA samples from 84 subjects (47 Parkinson's disease patients and 37 controls) with a mean age of 67.4 years. The TPQ of Cloninger was used to obtain values for harm avoidance (HA), reward dependence and novelty seeking for all subjects. Analysis of variance showed a significant influence of the s-allele of the 5-HTTLPR on HA in both subject groups, with no significant interaction between diagnosis and genotype. Subjects with the l/l-genotype had significantly lower mean HA scores than the l/s subjects (P < 0.04) and s/s subjects (P < 0.003). A linear change in HA with genotype was observed, indicating a gene dose effect of the 5-HTTLPR s-allele on this personality dimension. Based on these findings it is suggested that there may be increased influence of the 5-HTTLPR short allele on anxiety-related traits during aging. Psychiatr Genet 8:41–44 c 1998 Lippincott-Raven Publishers.

We report our long-term experience using enteral levodopa infusions in 22 patients with Parkinson's disease and severe motor fluctuations. Amelioration of intractable dyskinesias was the most important factor that determined whether patients chose to continue using the infusion pump system. Mechanical and physical problems associated with enteral access were the most common reasons for which patients discontinued pump use. Nearly all patients continued to have dramatically increased on time for the duration of follow up, suggesting that technically less-cumbersome systems that provide continuous dopaminergic stimulation are worthwhile and should be developed.

We studied the nature and frequency of nonmotor "off" phenomena in 130 consecutive patients with Parkinson's disease (PD) with motor fluctuations.Twenty-two patients (17%) experienced nonmotor fluctuations as an end-of-dose phenomenon. Previously unreported, or little appreciated, nonmotor "off" states include sensory dyspnea, nausea, facial flushing, cough, hunger, unilateral limb edema, proximal limb pain, and trigeminal neuralgia-like pain. We attempted treatment modification in 12 of 22 patients; nonmotor "off" symptoms improved in nine of these 12 patients (75%). Recognizing these phenomena will prevent unnecessary tests and treatments.NEUROLOGY 1996;47: 1180-1183

The cause of progressive supranuclear palsy (PSP) is not known and has been little studied.The one previous controlled epidemiologic survey, performed at our center in 1986, found small-town experience and greater educational attainment as PSP risks, but, in retrospect, these results may have been produced by ascertainment bias. Since that time, several anecdotal reports have implicated heredity and various environmental exposures in the cause of some cases of PSP. To clarify the results of the previous study and to evaluate the more recently implicated candidate factors in a controlled fashion, we mailed a validated 69-item questionnaire to 91 personally examined patients with PSP and 104 unmatched controls with other neurologic conditions for which they had been referred to our tertiary neurologic center. We were able to match 75 subjects from each group by year of birth, sex, and race and subjected them to a separate matched-pair analysis. We allowed surrogates to supply any or all of the responses. Questions concerned hydrocarbon, pesticide, and herbicide exposure; urban/rural living; auto repair and other occupations; head trauma; educational attainment; maternal age; and family history of PSP, parkinsonism, dementia, and other neurologic conditions. A statistically significant finding was that patients with PSP were less likely to have completed at least 12 years of school (matched odds ratio = 0.35, 95% CI = 0.12-0.95, p = 0.022; unmatched odds ratio = 0.44, 95% CI = 0.21-0.89, p = 0.020). We hypothesize that this result may be a proxy for poor early-life nutrition or for occupational or residential exposure to an as-yet unsuspected toxin. Future studies should examine these potential risk factors in PSP.NEUROLOGY 1996;47: 148-154

We report a patient with Meige syndrome (segmental cranial dystonia) who had neuropathology changes of Parkinson's disease on postmortem examination. Neuropathologic examination showed typical and atypical Lewy bodies in the pigmented nuclei of the brainstem (substantia nigra, locus ceruleus), the nucleus basalis of Meynert, and the nucleus ambiguus. Neurochemical analysis of postmortem brain tissue showed evidence for decreased dopamine turnover in the substantia nigra, striatum, and nucleus accumbens. We propose that some cases of Meige syndrome may be included in the spectrum of Lewy body disease.

We used a family history questionnaire, semi-structured interview, and personal examination of secondary cases to collect data on the prevalence of Parkinson's disease (PD) in relatives of patients seen consecutively for 1 year and assessed the proportion of secondary cases of PD as a function of pedigree completeness. Survival analysis methods were applied to estimate the lifetime risk and age-at-onset distribution of PD among first-degree relatives of probands. When we considered siblings of probands with affected parents, the cumulative risk increased significantly over siblings of probands without affected parents, suggesting significant familial aggregation in a subset of randomly ascertained families. We further analyzed 80 multicase families with two or more affected individuals. Age-adjusted segregation ratios approaching 0.5 and similar proportions of affected parents and siblings, as well as the distribution of ancestral secondary cases, were compatible with an autosomal dominant mode of inheritance with reduced penetrance in a subset of PD

We report the clinical response of a parkinsonian patient with severe motor fluctuations who was begun on continuous, nighttime-only levodopa infusions accompanied by oral carbidopa/levodopa use during the day. Sleep disturbances improved immediately. There was a gradual reduction in "off" time and severity of dyskinesias during the waking day. Nighttime-only levodopa infusions have a carryover benefit to the waking hours and may be suitable for long-term therapy to reduce daily motor fluctuations in some patients with Parkinson's disease.

Videotapes of patients with Huntington's chorea, tardive dyskinesia (TD), and L-DOPA-induced chorea in Parkinson's disease were taken while the patients were seated with their legs dangling. The videotapes were scored in a blinded fashion for suppressibility of dyskinesias. Most patients with TD or L-DOPA-induced chorea substantially suppressed their involuntary movements, whereas most patients with Huntington's chorea did not. There was a small overlap between the TD and Huntington's chorea groups and suppressibility therefore could not absolutely distinguish between them. Suppressibility testing may nonetheless be a valuable clinical tool since a good, excellent, or complete suppressibility rating was highly suggestive of TD but not Huntington's chorea. TD and L-DOPA-induced chorea may be more pathophysiologically similar to each other than either is to Huntington's chorea.

Summary A patient with Parkinson's disease had severe levodopa-associated leg pain in a beginning-of-dose and peak-dose pattern. Local anesthetic block of the lumbar sympathetic chain or differential epidural block did not alter the pain. Spinal anesthesia abolished the pain. We postulate that levodopa-associated pain in Parkinson's disease either originates in or is mediated by spinal cord dopaminergic systems.

Neurology 1996;46:276-277 The role of specialist care in the emerging managed health delivery system is changing. Most health maintenance organizations (HMOs) are limiting access to specialists because of concerns about cost. Despite the need to control spending, there is optimism that specialists can "prove their worth," presumably by providing a much better outcome even if it means a higher price. To convince payers not to skimp on specialty care, however, we need more data on qualitative improvements in care provided by specialist consultants. [1] Specialists will need to prove their usefulness to generalists acting as gatekeepers of the health delivery system. Can this be done? To evaluate the impact of specialist contributions to inpatient management, we assessed the usefulness of neurologic consultations in a university setting for 5 months in 1994. We arbitrarily defined a consultation as useful if it met one of the following criteria: (1) The neurologist's differential diagnosis contained a diagnosis (whether ultimately correct or not) that had not been included by the referring physician. (2) The neurologist suggested even a single procedure not previously ordered by the primary physician that was ultimately useful in making the correct diagnosis or eliminating other alternative diagnoses. The procedure must have been done. (3) The neurologist suggested a treatment regimen that was carried out by the referring physician and was different from the regimen proposed by the primary physician prior to the consultation. If no treatment regimen had been proposed by the referring physician, the consultation was considered useful. (4) We elected to consider a consultation as not useful if it only confirmed the primary physician's differential diagnosis or management. We …

Reply from the Authors: We thank Dr. Whelan for her interest in our efforts. As a university consultation service, we are inclined to think that no ridiculous diagnoses or misguided treatment regimens were proposed, although this is by no means certain. …

We report two patients with a primarily akinetic form of parkinsonism who were nonresponsive to treatment with levodopa. At autopsy, both patients had many Lewy bodies in brainstem and diencephalic nuclei, with sparse Lewy bodies in association cortices and more numerous Lewy bodies in the limbic cortices, consistent with the transitional form of Lewy body disease. These cases emphasize that (1) Lewy body Parkinson's disease cannot be excluded on the basis of atypical presentation or levodopa nonresponsiveness, and (2) the clinicopathologic spectrum of Lewy body disease is varied.

In eight dogs, a 20 cm section of isolated jejunum with intact blood supply was externalized to the abdominal wall and used as a device for levodopa (LD) administration. Overall, Sinemet tablets and LD suspension produced similar plasma levodopa concentrations with oral and pouch administration. The most ideal plasma concentration curves were obtained for CR-3, a sustained release Sinemet preparation, given through the jejunal pouches. Plasma LD concentrations rose within the first hour after administration of CR-3 and remained constant for the next 3 h, before falling slowly. Isolated jejunal pouches may therefore be an effective, simple means of maintaining constant plasma LD concentrations in parkinsonian patients with motor fluctuations and may diminish the deleterious effects of erratic gastric emptying and competition with food-derived amino acids at the gut/blood transport system.

We report clinical and computed tomography (CT) findings in 17 patients with progressive supranuclear palsy (PSP). Patients were divided into four clinical groups according to the severity of the disease and functional disability. In Grade 1, patients demonstrated minor disability and decreased anteroposterior (AP) diameter of the midbrain tegmentum was present. As the disease progressed clinically to Grade 2, more severe atrophy of the pons and midbrain and dilatation of the quadrigeminal plate cistern were noted. The most severe stages of clinical disability (Grades 3 and 4) were characterized radiologically by dilatation of the aqueduct, progressive dilatation of the third and fourth ventricles and atrophy of the temporal lobes. Cortical atrophy was variable and not a prominent radiological feature. Midbrain and pontine AP diameters were significantly smaller in PSP patients than normal patients. Serial studies showed progressive involution of the pons and midbrain and enlargement of the third ventricle. While the most obvious CT changes in PSP occur late in the disease, CT may in fact suggest the correct diagnosis long before the classic clinical picture is evident.

We report the clinical course of 35 patients with Parkinson's disease who experienced an initially favorable response to pergolide and who were taking the drug for at least 6 months. The duration of pergolide treatment was 6-50 (25 +/- 16 SD) months. Of the 14 patients who remained on pergolide for over 2 years, 12 remained less disabled for 26 +/- 17 SD months, seven enjoyed increased "on" time for 39 +/- 8 SD months, and nine had a lower Hoehn-Yahr stage for 25 +/- 17 SD months. Pergolide was discontinued after 5-39 months in eight patients; six patients then deteriorated. Pergolide can remain efficacious in the treatment of Parkinson's disease for up to 50 months.