Standard osteopathic manipulative treatment acutely improves gait performance in patients with Parkinson's disease.

Patients with Parkinson's disease exhibit a variety of motor deficits which can ultimately result in complete disability. The primary objective of this study was to quantitatively evaluate the effect of osteopathic manipulative treatment (OMT) on the gait of patients with Parkinson's disease. Ten patients with idiopathic Parkinson's disease and a group of eight age-matched normal control subjects were subjected to an analysis of gait before and after a single session of an OMT protocol. A separate group of 10 patients with Parkinson's disease was given a sham-control procedure and tested in the same manner. In the treated group of patients with Parkinson's disease, statistically significant increases were observed in stride length, cadence, and the maximum velocities of upper and lower extremities after treatment. There were no significant differences observed in the control groups. The data demonstrate that a single session of an OMT protocol has an immediate impact on Parkinsonian gait. Osteopathic manipulation may be an effective physical treatment method in the management of movement deficits in patients with Parkinson's disease.

Cognitive functioning after pallidotomy for refractory Parkinson's disease.

BACKGROUND: Earlier approaches to pallidotomy for refractory Parkinson's disease had significant complication rates. More recent approaches show fewer complications, but the effect of pallidotomy on cognition is unclear. The current study was conducted to examine the neuropsychological effects of unilateral pallidotomy. METHODS: Neuropsychological testing was performed on patients with medically refractory, predominantly unilateral Parkinson's disease at baseline and after unilateral ventral pallidotomy (n=28) or after an equivalent period without surgery in control patients (n=10). RESULTS: Pallidotomy patients showed no significant changes from baseline to retesting relative to the control group for any measure. Across all of the tests administered, only five of the surgery patients showed a significant decline, and of these five none declined on more than one test. Depression did not relate to preoperative or postoperative cognition. The pallidotomy group showed a significant improvement in motor functioning and activities of daily living whereas the control group did not. These measures were not associated with the neuropsychological test scores at baseline or retest. CONCLUSIONS: Stereotactic unilateral ventral pallidotomy does not seem to produce dramatic cognitive declines in most patients.

Preoperative indicators of clinical outcome following stereotaxic pallidotomy.

We assessed the utility of preoperative clinical assessment and functional brain imaging with 18F-fluorodeoxyglucose (FDG) and positron emission tomography (PET) in predicting the clinical outcome of stereotaxic pallidotomy for the treatment of advanced Parkinson's disease (PD). Twenty-two PD patients undergoing posteroventral pallidotomy were assessed preoperatively with the Core Assessment Program for Intracerebral Transplantation (CAPIT) ratings measured on and off levodopa; quantitative FDG/PET was also performed before surgery. Preoperative clinical and metabolic measurements were correlated with changes in off-state CAPIT ratings determined 3 months after surgery. Clinical outcome following pallidotomy was also correlated with intraoperative measures of spontaneous pallidal single-unit activity as well as postoperative MRI measurements of lesion volume and location. We found that unilateral pallidotomy resulted in variable clinical improvement in off-state CAPIT scores for the contralateral limbs (mean change 30.9 +/- 15.5%). Postoperative MRI revealed that pallidotomy lesions were comparable in location and volume across the patients. Clinical outcome following surgery correlated significantly with preoperative measures of CAPIT score change with levodopa administration (r = 0.60, p < 0.005) and with preoperative FDG/PET measurements of lentiform glucose metabolism (r = 0.71, p < 0.0005). Operative outcome did not correlate with intraoperative measures of spontaneous pallidal neuronal firing rate. We conclude that preoperative measurements of lentiform glucose metabolism and levodopa responsiveness may be useful indicators of motor improvement following pallidotomy. Both preoperative quantitative measures, either singly or in combination, may be helpful in selecting optimal candidates for surgery.

Metabolic correlates of pallidal neuronal activity in Parkinson's disease.

We have used [18F]fluorodeoxyglucose and PET to identify specific metabolic covariance patterns associated with Parkinson's disease and related disorders previously. Nonetheless, the physiological correlates of these abnormal patterns are unknown. In this study we used PET to measure resting state glucose metabolism in 42 awake unmedicated Parkinson's disease patients prior to unilateral stereotaxic pallidotomy for relief of symptoms. Spontaneous single unit activity of the internal segment of the globus pallidus (GPi) was recorded intraoperatively in the same patients under identical conditions. The first 24 patients (Group A) were scanned on an intermediate resolution tomograph (full width at half maximum, 8 mm); the subsequent 18 patients (Group B) were scanned on a higher resolution tomograph (full width half maximum, 4.2 mm). We found significant positive correlations between GPi firing rates and thalamic glucose metabolism in both patient groups (Group A: r = 0.41, P < 0.05; Group B: r = 0.69, P < 0.005). In Group B, pixel-based analysis disclosed a significant focus of physiological-metabolic correlation involving the ventral thalamus and the GPi (statistical parametric map: P < 0.05, corrected). Regional covariance analysis demonstrated that internal pallidal neuronal activity correlated significantly (r = 0.65, P < 0.005) with the expression of a unique network characterized by covarying pallidothalamic and brainstem metabolic activity. Our findings suggest that the variability in pallidal neuronal firing rates in Parkinson's disease patients is associated with individual differences in the metabolic activity of efferent projection systems.

Stereotactic pallidotomy for Parkinson's disease: a long-term follow-up of unilateral pallidotomy.

Eleven patients suffering from Parkinson's disease were followed for up to 4 years after unilateral pallidotomy. We observed persistent contralateral improvement and unexpected ipsilateral improvement of motor symptoms. In addition, there was a protracted relief of contralateral dyskinesias and maintenance of relatively stable levodopa dosage.

Efficacy of bilateral pallidotomy.

Unilateral pallidotomy is a safe and effective treatment for medically refractory bradykinetic Parkinson's disease, especially in those patients with levodopa-induced dyskinesia and severe on-off fluctuations. The efficacy of bilateral pallidotomy is less certain. The authors completed 11 of 12 attempted bilateral pallidotomies among 150 patients undergoing pallidotomy at New York University. In all but one patient, the pallidotomies were separated by at least 9 months. Patients were selected for bilateral pallidotomy if they exhibited bilateral rigidity, bradykinesia, or levodopa-induced dyskinesia prior to treatment or if they exhibited disease progression contralateral to their previously treated side. The Unified Parkinson's Disease Rating Scale (UPDRS) and timed upper-extremity tasks of the Core Assessment Protocol for Intracerebral Transplantation (CAPIT) were administered to all 12 patients in the "off" state (12 hours without receiving medications) preoperatively and again at 6 and 12 months after each procedure. The median UPDRS and contralateral CAPIT scores improved 60% following the initial procedure (p = 0.008, Wilcoxon rank sums test). The second pallidotomy generated only an additional 10% improvement in the UPDRS and CAPIT scores ipsilateral to the original procedure (p = 0.05). Worsened speech was observed in two cases. In the 12th case, total speech arrest was noted during test stimulation. Speech returned within minutes after stimulation was halted. Lesioning was not performed. These results indicate that bilateral pallidotomy has a narrow therapeutic window. Motor improvement ipsilateral to the first lesion leaves little room for further improvement from the second lesion and the risk of speech deficit is greatly enhanced. Chronic pallidal stimulation contralateral to a previously successful pallidotomy may prove to be a safer alternative for the subset of patients who require bilateral procedures.

Selection criteria for unilateral posteroventral pallidotomy.

In an attempt to refine the indications for posteroventral pallidotomy (PVP) the authors instituted strict selection criteria which are based on the experience gained from the first 60 pallidotomy patients treated at their institution. In addition to clinical evaluation, all pallidotomy candidates undergo neuropsychological testing and 18F-fluoro-deoxyglucose utilization positron emission tomography (FDG/PET). The data from which these criteria were developed are presented as are early clinical results. The authors demonstrate that these criteria enhance the efficacy of the procedure by assuring therapeutic response and reducing the incidence of post-operative dementia. Their indications and contraindications for pallidotomy are discussed.

Central motor loop oscillations in parkinsonian resting tremor revealed by magnetoencephalography.

A variety of clinical and experimental findings suggest that parkinsonian resting tremor results from the involuntary activation of a central mechanism normally used for the production of rapid voluntary alternating movements. However, such central motor loop oscillations have never been directly demonstrated in parkinsonian patients. Using magnetoencephalography, we recorded synchronized and tremor-related neuromagnetic activity over wide areas of the frontal and parietal cortex. The spatial and temporal organization of this activity was studied in seven patients suffering from early-stage idiopathic Parkinson's disease (PD). Single equivalent current dipole (ECD) analysis and fully three-dimensional distributed source solutions (magnetic field tomography, MFT) were used in this analysis. ECD and MFT solutions were superimposed on high-resolution MRI. The findings indicate that 3 to 6 Hz tremor in PD is accompanied by rhythmic subsequent electrical activation at the diencephalic level and in lateral premotor, somatomotor, and somatosensory cortex. Tremor-evoked magnetic activity can be attributed to source generators that were previously described for voluntary movements. The interference of such slow central motor loop oscillations with voluntary motor activity may therefore constitute a pathophysiologic link between tremor and bradykinesia in PD.

Regional metabolic correlates of surgical outcome following unilateral pallidotomy for Parkinson's disease.

Stereotaxic ventral pallidotomy has been employed in the symptomatic treatment of patients with advanced Parkinson's disease (PD). To understand the pathophysiology of clinical outcome following this procedure, we studied 10 PD patients (5 men and 5 women; mean age 60.0 +/- 6.1 years; mean Hoehn and Yahr stage 3.8 +/- 1.0) with quantitative 18F-fluorodeoxyglucose (FDG) and positron emission tomography (PET). All patients were scanned preoperatively; 8 of 10 patients were rescanned 6 to 8 months following surgery. Clinical performance was assessed off medications before and after surgery using standardized timed motor tasks. We found that preoperative lentiform metabolism correlated significantly with improvement in contralateral motor tasks at 1 week, 3 months, and 6 months following unilateral pallidotomy (p<0.03). Postoperatively, significant metabolic increases were noted in the primary motor cortex, lateral premotor cortex, and dorsolateral prefrontal cortex (p<0.01) of the hemisphere that underwent surgery. Improvement in contralateral limb motor performance correlated significantly with surgical declines in thalamic metabolism (p<0.01) and increases in lateral frontal metabolism (p<0.05). Principal components analysis disclosed a significant covariance pattern characterized by postoperative declines in ipsilateral lentiform and thalamic metabolism associated with bilateral increase in supplementary motor control metabolism. Subject scores for this pattern correlated significantly with improvements in both contralateral and ipsilateral limb performance (p<0.005). These results suggest that pallidotomy reduced the preoperative overaction of the inhibitory pallidothalamic projection. Clinical improvement may be associated with modulations in regional brain metabolism occurring remote from the lesion site.

Current trends in the pharmacologic and surgical treatment of Parkinson's disease.

Recently, there has been a surge in the research regarding the pharmacologic and surgical treatment of Parkinson's disease. This article reviews the latest modes of medical and surgical therapy for Parkinson's disease. The latest drug therapy has consisted of levodopa, a combination of levodopa and carbidopa (Sinemet/Sinemet CR), and monoamine oxidase type B (MAO-B) inhibitors (selegiline hydrochloride). The surgical treatment modalities have been stereotaxic implantations of dopamine-producing tissues (such as adrenal medulla and fetal mesencephalon) into the caudate nucleus and ventral pallidotomy of patients with Parkinson's disease. The most recent work has been in the field of gene therapy. The implantation of cells genetically modified to express trophic factors and tyrosine hydroxylase for the synthesis of L-dopa from tyrosine has been proposed as a possible route for the treatment of Parkinson's disease. Although the etiology of the disease is still unknown, two recent theories are discussed.

Stereotactic ventral pallidotomy for Parkinson's disease.

Eighteen patients with medically intractable Parkinson's disease that was characterized by bradykinesia, rigidity, and marked "on-off" fluctuations underwent stereotactic ventral pallidotomy under local anesthesia. Targeting was aided by anatomic coordinates derived from the MRI, intraoperative cell recordings, and electrical stimulation prior to lesioning. A nonsurgically treated group of seven similarly affected individuals was also followed. Assessment of motor function was made at baseline and at 3-month intervals for 1 year. Following the lesioning, patients improved in bradykinesia, rigidity, resting tremor, and balance with resolution of medication-induced contralateral dyskinesia. When compared with preoperative baseline, all quantifiable test scores after surgery improved significantly with the patients off medications for 12 hours: UPDRS by 65%, and CAPIT subtest scores on the contralateral limb by 38.2% and the ipsilateral limb by 24.2%. Walk scores improved by 45%. Medication requirements were unchanged, but the patients who had had surgery were able to tolerate larger doses because of reduced dyskinesia. Ventral pallidotomy produces statistically significant reduction in parkinsonism and contralateral "on" dyskinesia without morbidity or mortality and with a short hospitalization in Parkinson's disease patients for whom medical therapy has failed.

Anatomic and physiological considerations in pallidotomy for Parkinson's disease.

Our ongoing study of ventral pallidotomy for the control of Parkinson's disease in selected patients has provided the opportunity to explore the topographical and somatotopic organization of the human globus pallidus. Utilizing microelectrode techniques we have obtained recordings which were correlated with data from MPTP-parkinsonian primates. In addition, we performed pre- and post-operative FDG/PET scans in these patients. Our studies reveal similarities between the MPTP-parkinsonian primate model and human Parkinson's disease in terms of physiologic recordings and responses. However, we have encountered significant differences between dominant and non-dominant hemisphere representations, particularly for the hand, in the human. In addition, our PET studies confirmed, as in previous parkinsonian primate models, glucose hypermetabolism in the lenticular area of Parkinson's disease patients. This hypermetabolism is dramatically altered by creation of a lesion in the globus pallidus medialis. This is demonstrated by follow-up PET scans which reveal not only a decrease in metabolism of the operated lenticular region, but also in the frontal cortical projections. These combined observations of the cellular activity in the globus pallidus and the observed changes in PET metabolism support the selection of the pallidum for lesioning and control of Parkinson's disease, and offer insight into the underlying physiology of this disorder. The above physiological and PET data will be clinically correlated with our ongoing series of 35+ patients.

Pharmacokinetics and in vivo specificity of [11C]dl-threo-methylphenidate for the presynaptic dopaminergic neuron.

dl-threo-Methylphenidate (Ritalin) was labeled with carbon-11 (t1/2:20.4 minutes) in order to measure its pharmacokinetics, to evaluate it as a radiotracer for the presynaptic dopaminergic neuron, and to examine its sensitivity to the loss of dopaminergic neurons. Positron emission tomographic (PET) studies were carried out in the baboon to determine specificity for the presynaptic dopaminergic neuron and in humans to assess sensitivity to neuronal loss. Studies with [11C]dl-threo-methylphenidate ([11C]MP) in baboon demonstrated high regional uptake in the striatum. Peak uptake (0.04%/cc) occurred at 5-15 minutes post-injection. The half-time for clearance from peak uptake for [11C]MP was 60 minutes and the ratio between the radioactivity in the striatum and that in the cerebellum (ST/CB) ranged from 2.2 to 2.6 at 40 minutes. Repeated measures in the same baboon showed < or = 8% variability in the ST/CB ratio. Pretreatment with unlabeled methylphenidate (0.5 mg/kg) or GBR12909 (1.5 mg/kg) 30 minutes prior to [11C]MP injection markedly reduced the striatal but not the cerebellar uptake of [11C]MP, demonstrating the saturable and specific binding of [11C]MP to a site on the dopamine transporter in the brain. In both cases, the ratio of striatum to cerebellum (ST/CB) after pretreatment was reduced by about 43%. The ratios of distribution volumes at the steady-state for the striatum to cerebellum (ST/CB) for these two separate studies in the same baboon were reduced by 37 and 38%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurophysiological properties of pallidal neurons in Parkinson's disease.

Neuronal properties of the human globus pallidus (GP) are not known. Since GP is the major output of the basal ganglia, it may be involved in the pathophysiology of Parkinson's disease. We studied 12 patients with medically resistant Parkinson's disease by using single cell recording of the GP during stereotaxic pallidotomy to define neuronal firing rate and its modulation during active and passive movements. Different frequency and pattern of single cell activity was found in globus pallidus externus compared with globus pallidus internus. Discharge rates of 19% of GP cells were modulated by passive contralateral movements. Pallidal units were most often related solely to single joint movement. Different patterns of activity in relation to the two different movements of the same joint were often observed. We identified somatotopically arranged cell clusters that alter discharge rate with related movements. These findings suggest at least a partial somatotopic organization of the human GP and similarity with experimental results in both healthy and MPTP monkeys, providing a rationale for surgical or pharmacological targeting of GP for treating Parkinson's disease.

Anatomic and physiological considerations in pallidotomy for Parkinson's disease.

Our ongoing study of central pallidotomy for the control of Parkison's disease in selected patients has provided the opportunity to explore the topographical and somatotopic organization of the human globus pallidus. Utilizing microelectrode techniques we have obtained recordings which were correlated with data from MPTP-parkinsonian primates. In addition, we performed pre- and postoperative FDG/PET scans in these patients. Our studies reveal similarities between the MPTP-parkisonian primate model and human Parkinson's disease in terms of physiological recordings and responses. However, we have encountered significant differences between dominant and nondominant hemisphere representations, particularly for the hand, in the human. In addition, our PET studies confirmed, as in previous parkinsonian primate models, glucose hypermetabolism in the lenticular area of Parkinson's disease patients. This hypermetabolism is dramatically altered by creation of a lesion in the globus pallidus medialis. This is demonstrated by follow-up PET scans which reveal not only a decrease in metabolism of the operated lenticular region, but also in the frontal cortical projections. These combined observations of the cellular activity in globus pallidus and the observed changes in PET metabolism support the selection of the pallidum for lesioning and control of Parkinson's disease, and offer insight into the underlying physiology of this disorder. The above physiological and PET data will be clinically correlated with our ongoing series of 35+ patients.

Neuropsychiatric and neuropsychological findings in conduct disorder and attention-deficit hyperactivity disorder.

Neuropsychiatric and neuropsychological evaluations were performed in a pilot study of adolescents with DSM-III-R disruptive behavior disorders, including conduct disorder (CD) and attention-deficit hyperactivity disorder (ADHD). The following comparisons were made: 1) CD comorbid with ADHD vs. CD only; 2) all subjects with ADHD vs. all non-ADHD; and 3) all subjects with CD vs. all non-CD. The CD + ADHD group had increased left-sided soft signs compared with the CD group. CD + ADHD subjects significantly underperformed CD subjects on several executive functioning measures, with no differences on Verbal IQ subtests. Results are discrepant with previous findings of deficient verbal functioning in delinquent populations. However, findings may not be generalizable because of sampling limitations.