Parkinson Disease: Ondo WG

Pahwa R, Factor SA, Lyons KE, Ondo WG, Gronseth G, Bronte-Stewart H, Hallett M, Miyasaki J, Stevens J, Weiner WJ, Anonymous00045. · University of Kansas Medical Center, Kansas City, USA. · Neurology. · Pubmed #16606909 No free full text.

Abstract: OBJECTIVE: To make evidence-based treatment recommendations for the medical and surgical treatment of patients with Parkinson disease (PD) with levodopa-induced motor fluctuations and dyskinesia. To that end, five questions were addressed. 1. Which medications reduce off time? 2. What is the relative efficacy of medications in reducing off time? 3. Which medications reduce dyskinesia? 4. Does deep brain stimulation (DBS) of the subthalamic nucleus (STN), globus pallidus interna (GPi), or ventral intermediate (VIM) nucleus of the thalamus reduce off time, dyskinesia, and antiparkinsonian medication usage and improve motor function? 5. Which factors predict improvement after DBS? METHODS: A 10-member committee including movement disorder specialists and general neurologists evaluated the available evidence based on a structured literature review including MEDLINE, EMBASE, and Ovid databases from 1965 through June 2004. RESULTS, CONCLUSIONS, AND RECOMMENDATIONS: 1. Entacapone and rasagiline should be offered to reduce off time (Level A). Pergolide, pramipexole, ropinirole, and tolcapone should be considered to reduce off time (Level B). Apomorphine, cabergoline, and selegiline may be considered to reduce off time (Level C). 2. The available evidence does not establish superiority of one medicine over another in reducing off time (Level B). Sustained release carbidopa/levodopa and bromocriptine may be disregarded to reduce off time (Level C). 3. Amantadine may be considered to reduce dyskinesia (Level C). 4. Deep brain stimulation of the STN may be considered to improve motor function and reduce off time, dyskinesia, and medication usage (Level C). There is insufficient evidence to support or refute the efficacy of DBS of the GPi or VIM nucleus of the thalamus in reducing off time, dyskinesia, or medication usage, or to improve motor function. 5. Preoperative response to levodopa predicts better outcome after DBS of the STN (Level B).

Ondo WG. · No affiliation provided · Clin Neuropharmacol. · Pubmed #17909309 No free full text.

This publication has no abstract.

Ondo WG, Perkins T, Swick T, Hull KL, Jimenez JE, Garris TS, Pardi D. · Department of Neurology, Baylor College of Medicine, 6550 Fannin, Ste 1801, Houston, TX 77030, USA. · Arch Neurol. · Pubmed #18852348 No free full text.

Abstract: BACKGROUND: Many patients with Parkinson disease (PD) have excessive daytime sleepiness and numerous nocturnal sleep abnormalities. OBJECTIVE: To determine the safety and efficacy of the controlled drug sodium oxybate in a multicenter, open-label, polysomnographic study in subjects with PD and sleep disorders. Design, Setting, and Patients Inclusion required an Epworth Sleepiness Scale (ESS) score greater than 10 and any subjective nocturnal sleep concern, usually insomnia. An acclimation and screening polysomnogram was performed to exclude subjects with sleep-disordered breathing. The following evening, subjects underwent another polysomnogram, followed by an evaluation with the Unified Parkinson Disease Rating Scale (UPDRS) while practically defined off ("off") PD medications, ESS (primary efficacy point), Pittsburgh Sleep Quality Inventory, and Fatigue Severity Scale. Subjects then started sodium oxybate therapy, which was titrated from 3 to 9 g per night in split doses (at bedtime and 4 hours later) across 6 weeks, and returned for subjective sleep assessments. They then returned at 12 weeks after initiating therapy for a third polysomnogram, an off-medication UPDRS evaluation, and subjective sleep assessments. Data are expressed as mean (SD). RESULTS: We enrolled 38 subjects. At screening, 8 had sleep apnea (n = 7) or depression (n = 1). Twenty-seven of 30 subjects completed the study. Three dropped out owing to dizziness (n = 3) and concurrent depression (n = 1). The mean dose of sodium oxybate was 7.8 (1.7) g per night. The ESS score improved from 15.6 (4.2) to 9.0 (5.0) (P < .001); the Pittsburgh Sleep Quality Inventory score, from 10.9 (4.0) to 6.6 (3.9) (P < .001); and the Fatigue Severity Scale score, from 42.9 (13.2) to 36.3 (14.3) (P < .001). Mean slow-wave sleep time increased from 41.3 (33.2) to 78.0 (61.2) minutes (P = .005). Changes in off-medication UPDRS scores were not significant, from 28.4 (10.3) to 26.2 (9.6). CONCLUSION: Nocturnally administered sodium oxybate improved excessive daytime sleepiness and fatigue in PD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00641186.

Ondo WG, Sethi KD, Kricorian G. · Baylor College of Medicine, Department of Neurology, 6550 Fannin, Houston, TX 77030, USA. · Clin Neuropharmacol. · Pubmed #17909308 No free full text.

Abstract: BACKGROUND: Selegiline orally disintegrating tablet (ODT; Zelapar) is a selective monoamine oxidase B inhibitor developed as an adjunct to levodopa (LD) for Parkinson disease. Most patients on long-term LD therapy eventually experience deterioration at the end of the LD dosing interval, with predictable "wearing off" and "on-off" fluctuations. METHODS: We conducted a 12-week, double-blind, placebo-controlled, parallel-design trial of selegiline ODT. The primary efficacy point was reduction in the percentage of average daily "off" time. Secondary measures included reductions in daily off hours and total daily off time, Clinical Global Impressions-Improvement (CGI-I), and Patient Global Impression-Improvement (PGI-I). Patients on LD received selegiline ODT (1.25 mg/d for 6 weeks, then 2.5 mg/d for 6 weeks) or placebo. Safety and tolerability were measured. RESULTS: The intent-to-treat population included 98 patients receiving selegiline ODT and 50 patients receiving placebo. Combined efficacy results for weeks 10 and 12 revealed an 11.6% reduction in percentage of daily off time for selegiline ODT versus a 9.8% reduction for placebo (NS). PGI-I detected a statistically significant difference between treatment groups in favor of selegiline ODT (P = 0.02), whereas CGI-I detected a strong trend toward improvement (P = 0.06). Selegiline ODT was safe and well tolerated. CONCLUSIONS: This study showed no significant difference in improvement in percentage of off time with selegiline ODT versus placebo. Some clinical impressions (e.g., PGI-I, CGI-I) improved. This result contrasts with an identically designed study that showed a significant improvement in off time with selegiline ODT. A combined analysis of both studies suggested overall efficacy.

Ondo WG, Satija P. · Department of Neurology, Baylor College of Medicine, Houston, Texas 77030-2744, USA. · Mov Disord. · Pubmed #17876853 No free full text.

Abstract: Micrographia is a common, often presenting feature of Parkinson's disease. We assessed a simple writing paradigm in 40 PD patients "off" medications, 40 different PD patients "on" medications, and 64 age- and sex-matched controls. Patients wrote "Today is a nice day" with both eyes open and eyes closed to assess the effects of visual withdrawal (eyes closure). The order (eyes open vs. eyes closed) was alternated. In the "off" medicine group, eye closure increased the writing length by 14.0 +/- 10.1% (P < 0.05) from a mean of 69.1 to 77.7 mm [range -14% to +73%]. The percentage increase was larger in the 20 subjects with the smallest baseline writing size (worse micrographia), compared to the 20 with relatively larger writing (19.5% vs. 7.9%, P < 0.05). Neither the "on" medicine group, nor the control group changed. Simple eye closure significantly increased writing size in "off" PD patients to a similar or greater amount as levodopa. This data suggests that micrographia is not a pure motor hypokinetic feature but is affected by PD similar to other superlearned tasks such as walking. Furthermore, some patients have adapted this simple eye closing strategy when writing, especially signatures.

Moore ST, MacDougall HG, Gracies JM, Ondo WG. · Department of Neurology, Mount Sinai School of Medicine, Box 1135, 1 E 100th St., New York, NY 10029, USA. · Exp Brain Res. · Pubmed #17828529 No free full text.

Abstract: The aim of this study was to quantify the dynamic response of locomotion to the first oral levodopa administration of the day in patients with fluctuating Parkinson's disease (PD). Stride length, walking speed, cadence and gait variability were measured with an ambulatory gait monitor in 13 PD patients (8 males) with a clinical history of motor fluctuations. The Unified Parkinson's Disease Rating Scale (UPDRS) gait score (part 29) was also determined by a movement disorders specialist from video recordings. Subjects arrived in the morning in an 'off' state (no PD medication) and walked for a maximum length of 100 m. They then took their usual morning dose of oral levodopa and repeated the walking task at 13 min intervals (on average) over a 90 min period. Changes in stride length over time were fit with a Hill (Emax) function. Latency (time until stride length increased 15% of the difference between baseline and maximum response) and the Hill coefficient (shape of the 'off-on' transition) were determined from the fitted curve. Latency varied from 4.7 to 53.3 min post-administration [23.31 min (SD 14.9)], and was inversely correlated with age at onset of PD (R = -0.83; P = 0.0004). The Hill coefficient (H) ranged from a smooth hyperbolic curve (0.9) to an abrupt 'off-on' transition (16.9), with a mean of 8.1 (SD 4.9). H correlated with disease duration (R = 0.67; P = 0.01) and latency (R = 0.67; P = 0.01), and increased with Hoehn & Yahr stage in the 'off' state (P = 0.02) from 5.7 (SD 3.5) (H&Y III) to 11.9 (SD 4.7) (H&Y IV). Walking speed correlated with changes in mean stride length, whereas cadence and gait variability did not. UPDRS gait score also reflected improving gait in the majority of subjects (8), providing clinical confirmation of the objective measures of the locomotor response to levodopa. Increasing abruptness (H) of the 'off-on' transition with disease duration is consistent with results from finger-tapping studies, and may reflect reduced buffering capacity of pre-synaptic nigrostriatal dopaminergic neurons. Ambulatory monitoring of gait objectively measures the dynamic locomotor response to levodopa, and this information could be used to improve daily management of motor fluctuations.

Ondo WG, Tintner R, Voung KD, Lai D, Ringholz G. · Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA. · Mov Disord. · Pubmed #15800937 No free full text.

Abstract: We completed a single site, double-blind, placebo-controlled, parallel design study of quetiapine for hallucinations in PD. Thirty-one subjects with PD and prominent visual hallucinations and Mini-Mental State Examination score >21 were randomly assigned in a 2:1 drug to placebo ratio, up to 200 mg daily of quetiapine or matching placebo given in two doses. They were seen at 3 weeks (100 mg/day) and 12 weeks (200 mg/day, with optional dose reduction). Evaluation included the Unified Parkinson's Disease Rating Scale (UPDRS), the Baylor PD Hallucination Questionnaire, and a battery of neuropsychological tests. The demographics between subjects randomized to drug (n = 21) vs. placebo (n = 10) were similar. The final dose of active drug was 200 (n = 11), 150 (n = 2), 100 (n = 3), and 75 (n = 1) mg per day. All placebo subjects were on the equivalent of 200 mg per day. The UPDRS Activities of Daily Living and Motor scores did not significantly change compared to placebo. Compared to placebo, there were no significant changes in our hallucination questionnaire, the Brief Psychiatric Rating Scale (BPRS), or question 12 (hallucination item) of the BPRS. There were no significant changes on any of the neuropsychological measures. Adverse events on drug included sedation (n = 9), but no drug-related adverse events precipitated discontinuation and none were rated as serious. Quetiapine, up to 200 mg daily, was well tolerated and did not worsen UPDRS scores; however, there was no significant improvement in psychosis rating scales compared to placebo. Larger doses of drug and greater sample sizes might be considered in future studies.

Ondo WG, Hunter C, Moore W. · Department of Neurology, Baylor College of Medicine, 6550 Fannin, Suite 1801, Houston, TX 77030, USA. · Neurology. · Pubmed #14718694 No free full text.

Abstract: BACKGROUND: Injections of botulinum toxin A are an effective treatment for sialorrhea in Parkinson's disease (PD). Based on the relatively high rates of dry mouth seen with botulinum toxin B, there is reason to suspect that it may also improve sialorrhea. OBJECTIVE: To determine whether botulinum toxin B (Myobloc; Elan Pharmaceuticals, New York, NY) is a safe and effective treatment for sialorrhea in patients with PD. METHODS: Demographics, PD treatments, head posture, the Unified Parkinson's Disease Rating Scale (UPDRS), two questionnaires regarding drooling, Visual Analogue Scale, global impressions, salivary gland imaging, and a dysphagia questionnaire were assessed in 16 PD subjects with problematic sialorrhea. Patients were then randomized to receive either botulinum toxin B (1,000 units into each parotid gland and 250 units into each submandibular gland) or a pH-matched placebo, using only anatomic landmarks. Patients returned 1 month later to undergo an identical assessment. RESULTS: Compared with placebo, those randomized to drug reported improvement on the Visual Analogue Scale (p < 0.001), global impressions of change (p < 0.005), Drooling Rating Scale (p < 0.05), and Drooling Severity and Frequency Scale (p < 0.001). There was no change in UPDRS, head posture, or Dysphagia Scale. Adverse events were mild and included dry mouth (three patients), worsened gait (two), diarrhea (one), and neck pain (one) in the botulinum toxin B group. CONCLUSION: Anatomically guided injections of botulinum toxin B into the parotid and submandibular glands appear to effectively improve sialorrhea without compromising dysphagia in patients with PD.

Ondo WG, Hunter C. · Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA. · Mov Disord. · Pubmed #12784272 No free full text.

Abstract: Manipulation of gamma-aminobutyrate (GABA) system has been little studied in Parkinson's disease, despite the fact that GABA subserves a large part of the basal ganglia, including the outflow tracts. To test whether antagonism of GABA could improve features of PD, we administered open label intravenous flumazenil to eight practically defined off patients and assessed UPDRS scores, bilateral 1-minute hand-tapping speed, and timed gait tests. Patients demonstrated significantly greater tapping speed, which peaked 40 minutes after injection (P < 0.05). Total motor Unified Parkinson's Disease Rating Scale scores modestly improved (P < 0.05). There were no adverse events. Mechanisms by which flumazenil could improve PD are discussed.

Ondo WG, Levy JK, Vuong KD, Hunter C, Jankovic J. · Department of Neurology, Baylor College of Medicine, Houston, Texas, USA. · Mov Disord. · Pubmed #12360554 No free full text.

Abstract: Atypical antipsychotic medications with lower affinities for D2 receptors are considered useful alternatives to treat drug-induced hallucinations in Parkinson's disease (PD). We conducted a double-blind, placebo-controlled, unforced titration, parallel design study (2:1 drug to placebo randomization ratio) using olanzapine (2.5-10 mg/day to effect) in 30 PD patients with drug-induced hallucinations. We performed an extensive battery of neuropsychological tests, the Unified Parkinson's Disease Rating Scale (UPDRS), assessments of on and off time at baseline and at 9 weeks after starting the medication. Sixteen patients on olanzapine (mean dose, 4.6 mg/night) and 11 on placebo completed the study. Compared with placebo, performance on the UPDRS item 2 (thought disorder), and a structured interview for hallucinations, both tended to improve on drug but neither reached statistical significance. A neuropsychological test battery did not show any significant differences. Total on UPDRS motor scores (P < 0.05) and timed tapping (P < 0.01) worsened while on drug compared to placebo. Bradykinesia (P < 0.01) and gait (P < 0.001) items on the UPDRS largely accounted for this deterioration. After completion of the study, 8 of 16 patients randomly assigned to drug continued olanzapine at a mean dose of 2.4 mg/day. However, at the last recorded visit only 5 of 24 (20.8%) of all patients exposed to drug (including those originally randomly assigned to placebo) remained on olanzapine. In patients with PD, low-dose olanzapine did not significantly improve hallucinations but did worsen motor function.

Jankovic J, Lai EC, Ondo WG, Roberts-Warrior D, Olson SL, Krauss JK, Grossman RG. · Department of Neurology, Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, Texas 77030, USA. · Adv Neurol. · Pubmed #11347232 No free full text.

This publication has no abstract.

Hanna PA, Ratkos L, Ondo WG, Jankovic J. · New Jersey Neuroscience Institute, JFK Medical Center, Edison, USA. · J Neural Transm. · Pubmed #11261747 No free full text.

Abstract: OBJECTIVE/BACKGROUND: To compare the safety and efficacy of pramipexole and pergolide in the treatment of mild to moderate Parkinson's disease (PD). In contrast to pergolide, a D1 and D2 dopamine agonist, pramipexole is a nonergoline dopamine agonist with D2 and preferential D3 dopamine receptor activity. This selective activity may result in clinically different effects. No prospective head-to-head comparison studies of pergolide and pramipexole have been reported. METHODS: Patients with PD who were maintained on an optimal dose of pergolide were converted to pramipexole, typically over a one-month period. Clinical assessments were performed just prior to conversion and after an optimal dose of pramipexole was achieved. RESULTS: Twenty-five patients were converted from pergolide to pramipexole during the period of July, 1997 to January, 1999. Three patients were lost to follow-up, and one patient died. Of the remaining 21 patients there were 11 men and 10 women, mean age was 67.3 years +/- 10.0 (range 51-84). Mean duration of symptoms prior to conversion was 12.5 years +/- 3.4 (range 5-19). All patients (except one) were on concomitant carbidopa/ levodopa and experienced motor fluctuations. After a mean follow-up of 5.9 +/- 2.9 months on pramipexole, the mean levodopa daily dose was reduced from 618.7mg to 581.2mg (16.5% reduction, p = 0.61). The mean daily doses of pergolide and pramipexole (in milligrams per day) were 2.1 +/- 1.5 (0.15-6) and 3.2 +/- 1.1 (0.75-6) respectively. Thirteen patients (62%) reported overall improvement (subjective global response) on pramipexole as compared to pergolide, 5 (24%) were unchanged and 3 (14%) reported worsening. Eighteen of the 21 patients (86%) remained on pramipexole after the study period. Although there was a slight trend toward improved scores on pramipexole, the difference was not statistically significant. CONCLUSION: This open label study failed to provide evidence of superior efficacy of either dopamine agonist. It is possible, however, that while somepatients may benefit more from either pergolide or pramipexole, other patients may obtain additional benefit from other DA agonists or combination therapy. Future randomized, controlled, double-blinded therapeutic trials are needed to determine which, if any, dopamine agonist is superior in the treatment of PD.

LeWitt PA, Ondo WG, Van Lunen B, Bottini PB. · Department of Neurology, Wayne State University School of Medicine and Henry Ford Hospital, Detroit, MI 48034, USA. · Clin Neuropharmacol. · Pubmed #18978491 No free full text.

Abstract: OBJECTIVE: To assess the safety and adverse effect profile of continued use of intermittent subcutaneous apomorphine to treat "off" episodes in subjects with advanced Parkinson disease. METHODS: The study enrolled subjects with Hoehn and Yahr stage II-V Parkinson disease who were experiencing "off" events despite an optimized oral medication regimen. After baseline assessment and subcutaneous apomorphine dose titration (2-10mg/dose), subjects received > or =12 months of open-label treatment, as needed, for "off" episodes. RESULTS: Of the 546 subjects in the study population, the majority used apomorphine on a daily basis; the average dose was 4.0 mg. A total of 187 subjects discontinued treatment because of adverse events (AEs). Most AEs were mild to moderate and expected with apomorphine. The AEs most commonly classified as definitely, probably, or possibly treatment related were nausea and vomiting, dyskinesia, dizziness, somnolence, hallucination, yawning, and injection site bruising. Serious AEs occurred in 199 subjects, but only 27 were considered to be probably or possibly treatment related. None of the 45 deaths recorded in the study were attributed to apomorphine. CONCLUSIONS: Long-term use of intermittent apomorphine dosing for treatment of "off" episodes was generally associated with mild-to-moderate AEs.

Sitburana O, Rountree S, Ondo WG. · Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, USA. · J Neurol Sci. · Pubmed #18556024 No free full text.

Abstract: Atypical antipsychotics (AA) are generally associated with weight gain. We determined body mass index (BMI) change in Parkinson's disease (PD) before and after taking AA and compared against PD controls and Alzheimer's disease (AD) patients on AA. In 66 consecutive PD subjects started on AA who had accurate weights for more than 6 months before and after initiation of AA, we compared weight change before and after AA use, against a control group of sixty-one sex-matched PD subjects, and against twenty-eight AD subjects taking AA. A linear regression model was created to compare weight changes. Fifty-nine PD subjects had complete data, quetiapine (n=53) and clozapine (n=6). The mean BMI change in the period before starting AA was 0.00 kg/m(2)/month over 1.95+/-1.41 years. After starting AA, subjects lost 0.03 kg/m(2)/month (95% CI 0.62-1.21, P<0.0001), comparing PD before AA to the same PD patients after AA. In 61 PD controls, the mean BMI loss was 0.01 kg/m(2)/month (95% CI 0.15-0.94, P=0.007) comparing PD on AA vs. PD controls. The BMI for 28 AD subjects on AA increased 0.01 kg/m(2)/month (95% CI 0.26-0.83, P<0.0001), comparing PD on AA vs. AD on AA. The weight loss seen in the PD/AA group, compared to AD, suggest uniquely altered weight homeostasis in PD.

Moore ST, MacDougall HG, Ondo WG. · Department of Neurology, Mount Sinai School of Medicine, Box 1135, 1 E 100th Street, New York, NY 10029, USA. · J Neurosci Methods. · Pubmed #17928063 No free full text.

Abstract: Freezing of gait (FOG) is common in advanced Parkinson's disease (PD), is resistant to treatment and negatively impacts quality of life. In this study an ambulatory FOG monitor was validated in 11 PD patients. The vertical linear acceleration of the left shank was acquired using an ankle-mounted sensor array that transmitted data wirelessly to a pocket PC at a rate of 100 Hz. Power analysis showed high-frequency components of leg movement during FOG in the 3-8 Hz band that were not apparent during volitional standing, and power in this 'freeze' band was higher (p=0.00003) during FOG preceded by walking (turning or obstacles) than FOG preceded by rest (gait initiation). A freeze index (FI) was defined as the power in the 'freeze' band divided by the power in the 'locomotor' band (0.5-3 Hz) and a threshold chosen such that FI values above this limit were designated as FOG. A global threshold detected 78% of FOG events and 20% of stand events were incorrectly labeled as FOG. Individual calibration of the freeze threshold improved accuracy and sensitivity of the device to 89% for detection of FOG with 10% false positives. Ambulatory monitoring may significantly improve clinical management of FOG.

Ondo WG, Lai D. · Baylor College of Medicine, 6550 Fannin, Ste 1801, Houston, TX 77030, USA. · Parkinsonism Relat Disord. · Pubmed #17702628 No free full text.

Abstract: Three hundred consecutive patients taking DA either for Parkinson's disease (PD, 207), restless legs syndrome (RLS, 89), or both (4) were interviewed about changes in gambling, spending, sexual activity, or other impulsive activities subsequent to DA. Regression models identified risk factors for impulsivity. Overall, 19.7% reported any increased impulsivity: 30 gambling, 26 spending, 11 sexual activity, and 1 wanton traveling. Only 11/59 felt the change was deleterious. Increased impulsivity correlated with a younger age (p=0.01), larger doses of DA (p<0.001), and PD, as opposed to RLS (p<0.01), but this lost significance after correcting for dose (p=0.09). Increased impulsivity is common but usually not deleterious.

Moore ST, MacDougall HG, Gracies JM, Cohen HS, Ondo WG. · Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA. · Gait Posture. · Pubmed #17046261 No free full text.

Abstract: A new system for long-term monitoring of gait in Parkinson's disease (PD) has been developed and validated. The characteristics of every stride taken over 10-h epochs were acquired using a lightweight ankle-mounted sensor array that transmitted data wirelessly to a small pocket PC at a rate of 100 Hz. Stride was calculated from the vertical linear acceleration and pitch angular velocity of the leg with an accuracy of 5 cm. Results from PD patients (5) demonstrate the effectiveness of long-term monitoring of gait in a natural environment. The small, variable stride length characteristic of Parkinsonian gait, and fluctuations of efficacy associated with levodopa therapy, such as delayed onset, wearing off, and the 'off/on' effect, could reliably be detected from long-term changes in stride length.

Friedman JH, Berman RM, Goetz CG, Factor SA, Ondo WG, Wojcieszek J, Carson WH, Marcus RN. · Parkinson Disease and Movement Disorders Center, NeuroHealth, Warwick, Rhode Island 02886, USA. · Mov Disord. · Pubmed #17013906 No free full text.

Abstract: Psychosis affects at least 5% to 8% of medication-treated patients with idiopathic Parkinson's disease (PD). Treatment options include reducing medications used for the treatment of PD-related motor symptoms or introducing an atypical antipsychotic drug. Only clozapine has been demonstrated to be efficacious and tolerated in double-blind controlled trials. This study evaluated the effect of aripiprazole, an atypical antipsychotic, on psychosis in PD in an open-label pilot study. Fourteen patients meeting entry criteria were started on aripiprazole 1 mg/day and titrated up to a maximum dose of 5 mg as needed. Subjects were evaluated on the Unified Parkinson's Disease Rating Scale (UPDRS) part III for motor function, the Neuropsychiatric Inventory (NPI), and the Brief Psychiatric Rating Scale (BPRS) for psychiatric response. Statistically significant improvement in mean BPRS and positive BPRS subscales occurred with open-label aripiprazole, but eight subjects discontinued the study due to worsened Parkinsonism (three), worsened psychosis (two), worsening of both (two), and lack of efficacy (one). While some patients had a favorable response, aripiprazole was associated with an exacerbation of motor symptoms. In this small study on psychosis in PD, aripiprazole did not appear promising.

Ondo WG, Silay YS. · Department of Neurology, Baylor College of Medicine, Houston, Texas, USA. · Mov Disord. · Pubmed #16830315 No free full text.

Abstract: Flumazenil is a short-acting intravenously administered gamma-aminobutyric acid (GABA) antagonist used to reverse the effects of benzodiazepines. Based upon current basal ganglion models in Parkinson's disease (PD), flumazenil could normalize neuronal signaling at several different locations. We conducted a double-blind, placebo controlled, single dose, cross-over trial of flumazenil and placebo in 16 subjects with PD. Subjects were primarily assessed with serial tapping tests (1 minute for each hand) at 15-minute intervals for 90 minutes after infusion. Secondary assessments included the Unified Parkinson's Disease Rating Scale (UPDRS) Motor part at baseline and 45 minutes after infusion, and global impressions. Subjects then underwent a 90-minute washout and entered the opposite arm of the cross-over. Change in tapping speed compared to baseline improved throughout the 90-minute period (P < 0.0001) and at each individual time (P < 0.01), except for 15 minutes status after infusion, with flumazenil compared to placebo. UPDRS scores tended to improve more on drug, but this finding was not significant. The medication was well tolerated. The most common adverse event on drug was a sense of "light-headedness" or "dizziness." GABA antagonists represent a novel potential treatment class for PD.

Ondo WG, Silay Y, Almaguer M, Jankovic J. · Department of Neurology, Baylor College of Medicine, Houston, Texas, USA. · Mov Disord. · Pubmed #16673406 No free full text.

Abstract: The safety and efficacy of subthalamic nucleus (STN) deep brain stimulation (DBS) in patients who have had a previous unilateral pallidotomy is not clear. We identified 10 patients (9 male) at the Baylor College of Medicine Parkinson's Disease Center who underwent STN DBS after prior unilateral pallidotomy. Demographics, efficacy as determined by off Unified Parkinson's Disease Rating Scale (UPDRS) part III scores, and levodopa equivalent dosing were analyzed. We then compared these to an age- and sex-matched group of 25 DBS patients who had no prior pallidotomy. After their initial pallidotomy (mean age, 51.8 +/- 10.8 years), the mean UPDRS motor off medicine scores improved from 51.3 +/- 14.3 to 34.9 +/- 12.8, and the UPDRS dyskinesia score improved from 1.8 +/- 1.0 to 0.8 +/- 0.7. Their STN DBS off UPDRS motor scores (mean age, 56.0 +/- 10.2 years) improved by 16.0% from 53.1 +/- 9.7 (range, 42-68) to 44.6 +/- 11.1 (range, 25-67). In contrast, the UPDRS off motor scores in a control group of 25 DBS patients improved by 49.9%, from 49.7 +/- 11.1 to 25.7 +/- 18.9, (16.0% vs. 49.9%; P < 0.001). Changes in UPDRS dyskinesia scores were similar in both groups. AE thought to be related to the STN DBS following pallidotomy included worse dysarthria (three) and worse balance (two). STN DBS patients with prior pallidotomy had less improvement in UPDRS off motor score compared to other STN DBS patients, despite relatively good outcomes immediately after their pallidotomy. This may be partially due to a selection bias, but it may also indicate that prior pallidotomy is a negative predictor of outcome of STN DBS and should be considered in patient selection.

Pahwa R, Lyons KE, Wilkinson SB, Simpson RK, Ondo WG, Tarsy D, Norregaard T, Hubble JP, Smith DA, Hauser RA, Jankovic J. · Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA. · J Neurosurg. · Pubmed #16619653 No free full text.

Abstract: OBJECT: The effects of thalamic deep brain stimulation (DBS) on essential tremor (ET) and Parkinson disease (PD) have been well documented, but there is a paucity of long-term data. The aim of this study was to evaluate the long-term safety and efficacy of DBS of the ventralis intermedius nucleus (VIM) of the thalamus for PD and ET. METHODS: Thirty-eight of 45 patients enrolled at five sites completed a 5-year follow-up study. There were 26 patients with ET and 19 with PD undergoing 29 unilateral (18 ET/11 PD) and 16 bilateral (eight ET/eight PD) procedures. Patients with ET were evaluated using the Tremor Rating Scale, and patients with PD were evaluated using the Unified Parkinson's Disease Rating Scale. The mean age of patients with ET was 70.2 years and 66.3 years in patients with PD. Unilaterally implanted patients with ET had a 75% improvement of the targeted hand tremor; those with bilateral implants had a 65% improvement in the left hand and 86% in the right compared with baseline. Parkinsonian patients with unilateral implants had an 85% improvement in the targeted hand tremor and those with bilateral implants had a 100% improvement in the left hand and 90% improvement in the right. Common DBS-related adverse events in patients receiving unilateral implants were paresthesia (45%) and pain (41%), and in patients receiving implants bilaterally dysarthria (75%) and balance difficulties (56%) occurred. Device-related surgical revisions other than IPG replacements occurred in 12 (27%) of the 45 patients. CONCLUSIONS: Thalamic stimulation is safe and effective for the long-term management of essential and Parkinsonian tremors. Bilateral stimulation can cause dysarthria and incoordination and should be used cautiously.

Deng H, Le WD, Hunter CB, Ondo WG, Guo Y, Xie WJ, Jankovic J. · Department of Neurology, Baylor College of Medicine, Houston, Tex 77030, USA. · Arch Neurol. · Pubmed #16476817 links to  free full text

Abstract: BACKGROUND: Mutations in the parkin gene (PRKN) cause autosomal recessive early-onset Parkinson disease (EOPD). OBJECTIVE: To investigate the presence of mutations in the PRKN gene in a white family with EOPD and the genotype-phenotype correlations. DESIGN: Twenty members belonging to 3 generations of the EOPD family with 4 affected subjects underwent genetic analysis. Direct genomic DNA sequencing, semiquantitative polymerase chain reaction, real-time quantitative polymerase chain reaction, and reverse-transcriptase polymerase chain reaction analyses were performed to identify the PRKN mutation. RESULTS: Compound heterozygous mutations (T240M and EX 5_6 del) in the PRKN gene were identified in 4 patients with early onset (at ages 30-38 years). Although heterozygous T240M and homozygous EX 5_6 del mutations in the PRKN gene have been previously described, this is, to our knowledge, the first report of these mutations in compound heterozygotes. The phenotype of patients was that of classic autosomal recessive EOPD characterized by beneficial response to levodopa, relatively slow progression, and motor complications. All heterozygous mutation carriers (T240M or EX 5_6 del) and a 56-year-old woman who was a compound heterozygous mutation carrier (T240M and EX 5_6 del) were free of any neurological symptoms. CONCLUSIONS: Compound heterozygous mutations (T240M and EX 5_6 del) in the PRKN gene were found to cause autosomal recessive EOPD in 4 members of a large white family. One additional member with the same mutation, who is more than 10 years older than the mean age at onset of the 4 affected individuals, had no clinical manifestation of the disease. This incomplete penetrance has implications for genetic counseling, and it suggests that complex gene-environment interactions may play a role in the pathogenesis of PRKN EOPD.

Ondo WG, Fayle R, Atassi F, Jankovic J. · Baylor College of Medicine, Houston, TX 77030, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #16291885 links to  free full text

Abstract: BACKGROUND: Excessive daytime somnolence (EDS) commonly complicates Parkinson's disease (PD). The aetiology of EDS is probably multifactorial but is probably exacerbated by dopaminergic medications. Modafinil is a wake-promoting agent approved for use in narcolepsy, but it is often used to treat a variety of somnolent conditions. METHOD: A double blind, placebo controlled parallel design trial was conducted to assess the efficacy of modafinil (200-400 mg/day) for the treatment of EDS in PD. The primary efficacy measure was the Epworth Sleepiness (ES) scale score. Secondary efficacy points included the Unified Parkinson's Disease Rating Scale (UPDRS), the Fatigue Severity Scale, the Hamilton Depression Scale, and the multiple sleep latency test (MSLT). RESULTS: Of a total of 40 subjects (29 men, mean (SD) age 64.8 (11.3) years), randomised to modafinil or placebo, 37 completed the study. Modafinil failed to significantly improve ES scores compared with placebo (2.7 v 1.5 points improvement, respectively, p = 0.28). MSLT failed to improve with modafinil relative to placebo (-0.16 v -0.70, respectively, p = 0.14). UPDRS, global impressions, Fatigue Severity Scale, and Hamilton Depression Scale scores were unchanged. Adverse events were minimal. CONCLUSION: Modafinil failed to significantly improve EDS in PD compared with placebo. The drug did not alter motor symptoms in PD and was well tolerated.

Ondo WG, Bronte-Stewart H, Anonymous00126. · Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA. · Stereotact Funct Neurosurg. · Pubmed #16205106 No free full text.

Abstract: BACKGROUND: Deep brain stimulation (DBS) is gaining wide acceptance as treatment for Parkinson's disease (PD), essential tremor, and dystonia. METHODS: A 40-item questionnaire commissioned by the DBS Study Group was sent to 46 centers that had performed at least 25 DBS implantations. These centers were identified through the DBS Study Group, other professional societies, and with the assistance of the Medtronic Corporation. The results were then tabulated and descriptive analyses were performed. RESULTS: Thirty-six of 47 centers (77%) responded, they had implanted 4,553 patients. The timing for bilaterally implanted patients varied, as 13 sites almost always implanted simultaneously whereas 14 sites almost never implanted simultaneously. Stereotactic frames included Leksell (n = 19), CRW (n = 15) and Compass (n = 2). Post-placement imaging was routinely performed by almost all centers and included MRI (n = 23), CT (n = 4), CT/MRI variably (n = 5), and ventriculography (n = 1). Two centers used more than one electrode per side. The 34 centers that used a single electrode averaged 2.3 +/- 1.4 passes per electrode (range: 1-18 passes). Most centers used macro-stimulation to confirm placement by assessing the intra-operative clinical response (n = 34), and to assess for adverse events (n = 26) at high voltages, averaging 6.7 +/- 2.3 V (range: 4-10). The initial activation averaged 18 +/- 12 days after electrode placement (average range: 11 +/- 10 to 28 +/- 18 days, absolute range: 1-90 days). Most sites had several programmers; however, the primary programmers were neurology staff (n = 15), the neurologist (n = 13), neurosurgery staff (n = 6), the neurosurgeon (n = 2), or a physiatrist (n = 1). Twelve centers automatically reduced PD medications on the day of initial activation, 9 centers reduced them variably, and 16 centers initially did not reduce them. Eventually, 80.4% of patients were reported to have some dose reduction, and 47.1% had a greater than 50% reduction of PD medications. CONCLUSIONS: Strategies regarding DBS placement and adjustment vary in North America.

Ondo WG, Lai D. · Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA. · Mov Disord. · Pubmed #15597336 No free full text.

Abstract: There is considerable controversy regarding the relationship between essential tremor (ET) and Parkinson's disease (PD), especially when tremor is the dominant feature of PD or there is a family history of tremor. Reduced olfaction function is one of the initial signs of PD. In contrast, ET has relatively preserved olfaction. To infer whether the tremor-dominant subgroup of PD is intrinsically different from mainstream PD, we tested olfaction using the University of Pennsylvania Smell Identification Test-40 (UPSIT) in this group and compared the findings with those of patients with non-tremor-dominant "regular" PD. We then evaluated predictors of reduced UPSIT scores within the tremor-dominant group. Overall, olfaction did not differ between tremor-dominant PD and regular PD; however, the subgroup of tremor-dominant PD with a family history of tremor had less olfaction loss than those without a family history (P = 0.0007) or those with regular PD (P = 0.0350). Other clinical features of this tremor-dominant PD with a family history of tremor group mostly resembled those without a family history. This finding suggests that patients with a family history of tremor may represent a different disease process even though, aside from differences in olfaction, they are clinically similar to other patients with tremor-dominant parkinsonism. It additionally suggests phenotypic overlap between PD and ET.