Parkinson Disease: Pahwa R

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).

Simuni T, Lyons KE, Pahwa R, Hauser RA, Comella C, Elmer L, Weintraub D. · Department of Neurology, Northwestern University, Parkinson's Disease and Movement Disorders Center, Chicago, Ill, USA. · Eur Neurol. · Pubmed #19176961 links to  free full text

Abstract: The management of early Parkinson's disease (PD) involves the treatment of motor symptoms, and, increasingly, non-motor symptoms. Given the fast pace of clinical research in PD, clinicians are faced with the challenge of integrating the latest findings into the ongoing care of individual PD patients. Part 1 of this 2-part article reviews efficacy and safety data for the newest PD treatment options, as well as for established therapies. Part 2 of the article, presented here, reviews key data relevant to the assessment of potential neuroprotective therapies and the treatment of non-motor symptoms.

Simuni T, Lyons KE, Pahwa R, Hauser RA, Comella C, Elmer L, Weintraub D. · Department of Neurology, Northwestern University, Parkinson's Disease and Movement Disorders Center, Chicago, Ill 60611, USA. · Eur Neurol. · Pubmed #19176960 links to  free full text

Abstract: The management of early Parkinson's disease (PD) involves the treatment of motor symptoms and, increasingly, non-motor symptoms. Given the fast pace of clinical research in PD, clinicians are faced with the challenge of integrating the latest findings into the ongoing care of individual PD patients. Part 1 of this 2-part article reviews motor symptom efficacy data for the newest PD treatment options, as well as for established therapies. Safety and tolerability data are also reviewed. Part 2 of the article reviews key findings relevant to the assessment of potential neuroprotective therapies and the treatment of non-motor symptoms.

Pahwa R. · No affiliation provided · J Am Med Dir Assoc. · Pubmed #17948613 No free full text.

Abstract: Diagnosis of PD can be difficult in elderly patients because some of the key PD symptoms also may be manifestations of normal aging. Asymmetrical symptom onset, resting tremor,and sustained response to levodopa are key features that suggest a diagnosis of PD. For most patients, PD progresses fairly slowly. The goal of treatment is to control symptoms, thereby allowing quality of life and functional ability to be maintained.Pharmacologic therapies are primarily targeted at stimulating dopaminergic receptors, either by increasing the levels of dopamine or by using dopamine agonists. Levodopa, the main therapy for PD and a precursor of dopamine, has a short half-life and is quickly metabolized.Accordingly, decarboxylase inhibitors, like carbidopa, are almost always administered with levodopa to prevent breakdown in the periphery. Catechol-O-methyltransferase (COMT)inhibitors, which increase dopamine levels by inhibiting the metabolism of levodopa and dopamine, recently have become available, including a tablet containing carbidopa, levodopa,and entacapone. Other pharmaceutical therapies for PD include dopamine agonists, monoamine oxidase-B (MAO-B) inhibitors, anticholinergic agents, and amantadine. Dopamine agonists, anticholinergic agents, and amantadine are associated with an increased risk of hallucinations or other adverse events in elderly patients; therefore, use of these should be avoided in this population.Surgical management, particularly deep brain stimulation(DBS), is an option for patients who are refractory to pharmaceutical therapy. Although patients may not need levodopa as an initial treatment, over time most patients will require this drug to control symptoms. With chronic levodopa therapy, patients ultimately experience a wearing off in levodopa response and other motor complications. Management of wearing off is a significant challenge in the treatment of patients with advanced PD.

Kleiner-Fisman G, Herzog J, Fisman DN, Tamma F, Lyons KE, Pahwa R, Lang AE, Deuschl G. · Parkinson's Disease Research Education and Clinical Center, Philadelphia VA Hospital, Philadelphia, Pennsylvania 19104, USA. · Mov Disord. · Pubmed #16892449 No free full text.

Abstract: Subthalamic nucleus (STN) deep brain stimulation (DBS) is currently the most common therapeutic surgical procedure for patients with Parkinson's disease (PD) who have failed medical management. However, a recent summary of clinical evidence on the effectiveness of STN DBS is lacking. We report the results of such a systematic review and meta-analysis. A comprehensive review of the literature using Medline and Ovid databases from 1993 until 2004 was conducted. Estimates of change in absolute Unified Parkinson's Disease Rating Scale (UPDRS) scores after surgery were generated using random-effects models. Sources of heterogeneity were explored with meta-regression models, and the possibility of publication bias was evaluated. Patient demographics, reduction in medication requirements, change in dyskinesia, daily offs, quality of life, and a ratio of postoperative improvement from stimulation compared to preoperative improvement by medication from each study were tabulated and average scores were calculated. Adverse effects from each study were summarized. Thirty-seven cohorts were included in the review. Twenty-two studies with estimates of standard errors were included in the meta-analysis. The estimated decreases in absolute UPDRS II (activities of daily living) and III (motor) scores after surgery in the stimulation ON/medication off state compared to preoperative medication off state were 13.35 (95% CI: 10.85-15.85; 50%) and 27.55 (95% CI: 24.23-30.87; 52%), respectively. Average reduction in L-dopa equivalents following surgery was 55.9% (95% CI: 50%-61.8%). Average reduction in dyskinesia following surgery was 69.1% (95% CI: 62.0%-76.2%). Average reduction in daily off periods was 68.2% (95% CI: 57.6%-78.9%). Average improvement in quality of life using PDQ-39 was 34.5% +/- 15.3%. Univariable regression showed improvements in UPDRS III scores were significantly greater in studies with higher baseline UPDRS III off scores, increasing disease duration prior to surgery, earlier year of publication, and higher baseline L-dopa responsiveness. Average baseline UPDRS III off scores were significantly lower (i.e., suggesting milder disease) in later than in earlier studies. In multivariable regression, L-dopa responsiveness, higher baseline motor scores, and disease duration were independent predictors of greater change in motor score. No evidence of publication bias in the available literature was found. The most common serious adverse event related to surgery was intracranial hemorrhage in 3.9% of patients. Psychiatric sequelae were common. Synthesis of the available literature indicates that STN DBS improves motor activity and activities of daily living in advanced PD. Differences between available studies likely reflect differences in patient populations and follow-up periods. These data provide an estimate of the magnitude of the treatment effects and emphasize the need for controlled and randomized studies.

Pahwa R, Lyons KE, Hauser RA. · Department of Neurology, University of Kansas Medical Center, 3599 Rainbow Blvd, Kansas City, KS 66160, USA. · Expert Rev Neurother. · Pubmed #15853577 No free full text.

Abstract: Ropinirole (Requip, GlaxoSmithKline) is a novel nonergoline dopamine D2 agonist indicated for the treatment of early and advanced Parkinson's disease. It is mainly metabolized by the liver and its elimination half-life is approximately 5.8 h. When used as monotherapy in early Parkinson's disease, ropinirole improves signs and symptoms of the disorder. When used as an adjunct to levodopa in advanced Parkinson's disease patients with motor fluctuations, ropinirole reduces off time and allows a reduction of levodopa dose. The initial use of ropinirole in early Parkinson's disease to which levodopa is added when necessary, has been demonstrated to lead to a lower incidence of dyskinesias compared with treatment with levodopa alone. An 18F-dihydroxyphenylalanine positron emission tomography study suggested the possibility that ropinirole could slow the progression of loss of dopamine neurons compared with treatment with levodopa but this remains to be proven. Side effects of ropinirole include nausea, somnolence, edema, orthostatic hypotension, hallucinations and dyskinesia. A once-daily formulation of ropinirole is currently in development that has the potential for greater convenience, improved tolerability and greater efficacy.

Lyons KE, Pahwa R. · Department of Neurology, University of Kansas Medical Center, 3599 Rainbow Boulevard, Mailstop 2012, Kansas City, KS 66160, USA. · Curr Neurol Neurosci Rep. · Pubmed #15217543 No free full text.

Abstract: Throughout the past decade, there has been a marked increase in surgical therapies, primarily deep brain stimulation (DBS), for the treatment of advanced Parkinson's disease (PD). DBS of the thalamus has been shown to be effective in reducing parkinsonian tremor; however, it is not the treatment of choice for PD given the progression of other symptoms such as rigidity and bradykinesia. Stimulation of the globus pallidus or the subthalamic nucleus is safe and efficacious in the long-term treatment of all cardinal symptoms of PD, and they are currently the surgeries of choice. Serious adverse events with DBS can occur in 1% to 2% of patients, infection in 5% to 8% of patients, and hardware complications in approximately 25% of patients. Complications associated with DBS are related to the experience of the surgical center. Referring physicians and patients should be aware of the number of surgical procedures and complication rates of any prospective surgical center.

Koller WC, Pahwa R, Lyons KE, Albanese A. · Department of Neurology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7314, USA. · J Neurol Sci. · Pubmed #10500254 No free full text.

Abstract: Stereotaxtic surgery is an effective therapeutic maneuver in the management of advanced Parkinson's disease (PD). Thalamotomy is an effective measure to control tremor but other PD symptoms are not changed. Bilateral operations are associated with a risk of severe speech impairment. Deep brain stimulation (DBS) of the thalamus is as effective as thalamotomy and is associated with fewer side effects. Pallidotomy is effective in reducing contralateral dyskinesias and the cardinal symptoms of PD. Bilateral pallidotomy often results in cognitive dysfunction. Deep brain stimulation of the pallidum replicates the positive effects of pallidotomy and appears to be safer than ablative lesions. Subthalamic DBS is currently under investigation. This procedure may control all PD symptoms, and the dose of levodopa can often be dramatically reduced. Neurotransplantation is a promising surgical approach to PD. However, further investigation is needed to optimize this approach.

Pahwa R, Stacy MA, Factor SA, Lyons KE, Stocchi F, Hersh BP, Elmer LW, Truong DD, Earl NL, Anonymous00439. · University of Kansas Medical Center, Kansas City, KS 66160, USA. · Neurology. · Pubmed #17404192 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy of ropinirole 24-hour prolonged release (ropinirole 24-hour) as an adjunct to levodopa in patients with Parkinson disease (PD) and motor fluctuations. METHODS: In a double-blind, placebo-controlled, 24-week study, 393 subjects with PD were randomized to ropinirole 24-hour (n = 202) or placebo (n = 191). The primary outcome measure was reduction in hours of daily "off" time. RESULTS: At week 24, the mean dose of ropinirole 24-hour was 18.8 mg/day with a mean reduction in daily levodopa of 278 mg. There was a mean reduction in daily "off" time of 2.1 hours in the ropinirole 24-hour group and 0.3 hours with placebo. Secondary outcome measures including change in hours and percent of daily "on" time and "on" time without troublesome dyskinesia, Unified PD Rating Scale motor and activities of daily living subscales, Beck Depression Inventory-II, PDQ-39 subscales of mobility, activities of daily living, emotional well-being, stigma and communication, and PD Sleep Scale were significantly improved at week 24 with ropinirole 24-hour. The most common adverse events (AE) with ropinirole 24-hour were dyskinesia, nausea, dizziness, somnolence, hallucinations, and orthostatic hypotension and AEs led to study withdrawal in 5% of both the active and placebo groups. CONCLUSION: Ropinirole 24-hour was effective and well tolerated as adjunct therapy in patients with Parkinson disease (PD) not optimally controlled with levodopa. Ropinirole 24-hour demonstrated an improvement in both motor and non-motor PD symptoms, while permitting a reduction in adjunctive levodopa dose.

Lyons KE, Davis JT, Pahwa R. · University of Kansas Medical Center, Department of Neurology, Kansas City, KS 66160, USA. · Stereotact Funct Neurosurg. · Pubmed #17259749 No free full text.

Abstract: Levodopa responsiveness has been shown to be the best predictor of improvement after subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson's disease (PD). The objective of this study was to assess the effect of STN DBS on PD patients intolerant to levodopa due to severe acute side effects such as intolerable nausea. There were 10 patients in the study who received STN DBS for PD. Five patients who were intolerant to levodopa were matched based on age, disease duration, sex and presurgical disease severity to 5 patients taking levodopa and demonstrating a good levodopa response. Both groups had a significant improvement in Unified Parkinson's Disease Rating Scale activities of daily living and motor subscales as well as tremor, rigidity and bradykinesia scores at 3, 6 and 12 months after surgery compared to baseline, and these improvements were equivalent between the two groups. Patient global ratings also indicated significant improvements at all follow-up visits. There were no differences in stimulator settings between the two groups at the 3-, 6- or 12-month follow-up visits. In conclusion, although levodopa responsiveness is the best predictor for outcome after STN DBS, carefully selected PD patients intolerant to levodopa can have significant improvement.

Eng ML, Lyons KE, Greene MS, Pahwa R. · University of Kansas Medical Center, University of Kansas, School of Pharmacy, Department of Pharmacy Practice, Kansas City, KS 66160-7231, USA. · J Altern Complement Med. · Pubmed #16722790 No free full text.

Abstract: OBJECTIVES: This study evaluates the effects of sequential tui na massage, acupuncture, and instrument-delivered qigong for patients with Parkinson disease (PD) over a 6-month period. DESIGN: Patients received weekly treatments, which included tui na massage prior to acupuncture followed by instrument-delivered qigong. Each patient was assessed at baseline and at 6 months. SETTING: The setting was an outpatient research/academic clinic for patients with PD and nonacademic acupuncture clinic. SUBJECTS: Twenty-five (25) patients with idiopathic PD were the subjects. OUTCOME MEASURES: Before and after treatment patients were evaluated with the Unified Parkinson Disease Rating Scale (UPDRS), Hoehn and Yahr Staging (H&Y), Schwab and England Activities of Daily Living (S & E), Beck Depression Inventory (BDI), Parkinson's Disease Questionnaire (PDQ-39) quality of life assessment, and patient global assessments. RESULTS: There were no significant improvements in treatment measures; however, there was a 2.4-point worsening in UPDRS motor scores (24.0 versus 26.4, p = 0.018). There was a 16% improvement in the PDQ- 39 total score (23.2 versus 19.6, p = 0.044) and a 29% improvement in the BDI (9.6 versus 6.8, p = 0.006). Sixteen (16) patients reported moderate to marked improvement. There were no adverse effects. CONCLUSIONS: Acupuncture is safe and well tolerated in patients with PD. Most patients reported subjective improvement. The BDI and PDQ-39 total score, measuring depression and quality of life, demonstrated some improvement, but UPDRS motor scores worsened.

Lyons KE, Pahwa R. · Department of Neurology, University of Kansas Medical Center, Kansas City, 66160, USA. · Clin Neuropharmacol. · Pubmed #16614538 No free full text.

Abstract: OBJECTIVES: This study was performed to determine if conversion from sustained release carbidopa/levodopa (SR-CL) with or without entacapone to carbidopa/levodopa/entacapone (CLE; Stalevo) improves motor functioning and quality of life in Parkinson disease (PD) patients and to assess patient tolerance and drug preference. METHODS: PD patients reporting suboptimal symptom control with SR-CL were converted to CLE. The basic conversion was 1 SR-CL 25/100 to 1 25/100/200 CLE and 1 SR-CL 50/200 to 1 37.5/150/200 CLE with additional changes as necessary. RESULTS: There were 62 patients with an average age of 68 years and an average disease duration of 11 years. CLE was preferred by 42 patients and SR-CL was preferred by 20 patients. In those that preferred CLE, Unified Parkinson Disease Rating Scale (UPDRS) mentation and motor subscores, Parkinson Disease Questionnaire-39 (PDQ-39) quality-of-life activities of daily living (ADL) and bodily discomfort subscores, and Epworth Sleepiness Scale (ESS) scores were significantly improved. There were no significant changes in any measures in the group that preferred SR-CL. Common adverse effects in the group that preferred CLE included nausea, vomiting, increased dyskinesia or off time, dizziness, and somnolence. The most common adverse events in the group preferring SR-CL were increased off time or dyskinesia, nausea, and vomiting. CONCLUSIONS: A majority of patients suboptimally controlled on SR-CL can be successfully converted to CLE with improvements in motor function, quality of life, and sleepiness. Older patients, with longer disease duration not previously exposed to entacapone, may better tolerate CLE after the addition of entacapone.

Liu W, McIntire K, Kim SH, Zhang J, Dascalos S, Lyons KE, Pahwa R. · Department of Physical Therapy and Rehabilitation Sciences, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160-7601, USA. · Parkinsonism Relat Disord. · Pubmed #16157502 No free full text.

Abstract: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective for the treatment of advanced Parkinson's disease. Most studies have evaluated the effectiveness of DBS of the STN using clinical motor scores or simple timed tests of motor function. There have been few studies that quantitatively assessed the outcome of STN DBS using multiple testing paradigms. In the current study, 11 patients who had bilateral STN DBS were quantitatively evaluated under four conditions using gait, postural control, and gait initiation. The four conditions included the medication on/stimulation on (M_on/S_on), medication on/stimulation off (M_on/S_off), medication off/stimulation on (M_off/S_on), and medication off/stimulation off (M_off/S_off) conditions. DBS of the STN significantly increased walking speed with and without levodopa, but had no influence on the cadence. The addition of levodopa had a minimal additional effect on walking speed. The effect of STN DBS on gait initiation approached the significant level. The mean values of lateral body sway during quiet standing increased moderately with medication and/or DBS, but the changes were not statistically significant. Future studies need to determine whether or not there is a potential negative effect of STN DBS on the postural control.

Holloway RG, Shoulson I, Fahn S, Kieburtz K, Lang A, Marek K, McDermott M, Seibyl J, Weiner W, Musch B, Kamp C, Welsh M, Shinaman A, Pahwa R, Barclay L, Hubble J, LeWitt P, Miyasaki J, Suchowersky O, Stacy M, Russell DS, Ford B, Hammerstad J, Riley D, Standaert D, Wooten F, Factor S, Jankovic J, Atassi F, Kurlan R, Panisset M, Rajput A, Rodnitzky R, Shults C, Petsinger G, Waters C, Pfeiffer R, Biglan K, Borchert L, Montgomery A, Sutherland L, Weeks C, DeAngelis M, Sime E, Wood S, Pantella C, Harrigan M, Fussell B, Dillon S, Alexander-Brown B, Rainey P, Tennis M, Rost-Ruffner E, Brown D, Evans S, Berry D, Hall J, Shirley T, Dobson J, Fontaine D, Pfeiffer B, Brocht A, Bennett S, Daigneault S, Hodgeman K, O'Connell C, Ross T, Richard K, Watts A, Anonymous00163. · Department of Neurology, University of Rochester, 1351 Mt. Hope Avenue, Suite 220, Rochester, NY 14620, USA. · Arch Neurol. · Pubmed #15262734 links to  free full text

Abstract: BACKGROUND: The best way to initiate dopaminergic therapy for early Parkinson disease remains unclear. OBJECTIVE: To compare initial treatment with pramipexole vs levodopa in early Parkinson disease, followed by levodopa supplementation, with respect to the development of dopaminergic motor complications, other adverse events, and functional and quality-of-life outcomes. DESIGN: Multicenter, parallel-group, double-blind, randomized controlled trial. SETTING: Academic movement disorders clinics at 22 sites in the United States and Canada. PATIENTS: Patients with early Parkinson disease (N = 301) who required dopaminergic therapy to treat emerging disability, enrolled between October 1996 and August 1997 and observed until August 2001. INTERVENTION: Subjects were randomly assigned to receive 0.5 mg of pramipexole 3 times per day with levodopa placebo (n = 151) or 25/100 mg of carbidopa/levodopa 3 times per day with pramipexole placebo (n = 150). Dosage was escalated during the first 10 weeks for patients with ongoing disability. Thereafter, investigators were permitted to add open-label levodopa or other antiparkinsonian medications to treat ongoing or emerging disability. MAIN OUTCOME MEASURES: Time to the first occurrence of dopaminergic complications: wearing off, dyskinesias, on-off fluctuations, and freezing; changes in the Unified Parkinson's Disease Rating Scale and quality-of-life scales; and adverse events. RESULTS: Initial pramipexole treatment resulted in a significant reduction in the risk of developing dyskinesias (24.5% vs 54%; hazard ratio, 0.37; 95% confidence interval [CI], 0.25-0.56; P<.001) and wearing off (47% vs 62.7%; hazard ratio, 0.68; 95% CI, 0.49-0.63; P =.02). Initial levodopa treatment resulted in a significant reduction in the risk of freezing (25.3% vs 37.1%; hazard ratio, 1.7; 95% CI, 1.11-2.59; P =.01). By 48 months, the occurrence of disabling dyskinesias was uncommon and did not significantly differ between the 2 groups. The mean improvement in the total Unified Parkinson's Disease Rating Scale score from baseline to 48 months was greater in the levodopa group than in the pramipexole group (2 +/- 15.4 points vs -3.2 +/- 17.3 points, P =.003). Somnolence (36% vs 21%, P =.005) and edema (42% vs 15%, P<.001) were more common in pramipexole-treated subjects than in levodopa-treated subjects. Mean changes in quality-of-life scores did not differ between the groups. CONCLUSIONS: Initial treatment with pramipexole resulted in lower incidences of dyskinesias and wearing off compared with initial treatment with levodopa. Initial treatment with levodopa resulted in lower incidences of freezing, somnolence, and edema and provided for better symptomatic control, as measured by the Unified Parkinson's Disease Rating Scale, compared with initial treatment with pramipexole. Both options resulted in similar quality of life. Levodopa and pramipexole both appear to be reasonable options as initial dopaminergic therapy for Parkinson disease, but they are associated with different efficacy and adverse-effect profiles.

Pahwa R, Wilkinson SB, Overman J, Lyons KE. · Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA. · J Neurosurg. · Pubmed #12854747 No free full text.

Abstract: OBJECT: Bilateral subthalamic nucleus (STN) stimulation is increasingly used in patients with advanced Parkinson disease (PD). This study was performed to evaluate the long-term efficacy and safety of bilateral STN stimulation in cases of PD. METHODS: The authors performed a prospective, open-label study in patients with PD who underwent bilateral STN stimulation. The authors compared motor scores and activities of daily living (ADL) scores based on the Unified PD Rating Scale (UPDRS) obtained before surgery while patients were in the medication-off state with scores obtained at follow-up evaluations of these patients while in the medication-off/stimulator-on state. Data contained in patient diaries were also compared. Thirty-three patients with PD were evaluated 12 months postoperatively and 19 were evaluated at a mean follow-up time of 28 months. A comparison between UPDRS scores obtained in patients in the medication-off/stimulator-on state and those obtained when patients were in the baseline medication-off state showed a 27% improvement in ADL scores and a 28% improvement in motor scores after surgery. There was a 57% reduction in the use of levodopa-equivalent medication doses. The percentage of the waking day that patients were in the medication-on state increased from 38 to 72%. Surgical complications included seizures (three patients), confusion (five patients), hemiballismus (one patient), and visual disturbance (one patient). Stimulation-related adverse effects were mild. Device-related events included nine lead replacements, seven lead revisions, six extension replacements, and 12 implantable pulse generator (IPG) replacements; one IPG was cleaned and one IPG was placed in a pocket because of the presence of a shunt. CONCLUSIONS: Bilateral STN simulation is associated with a significant improvement in the motor features of PD. Device-related events were common in the first 20 patients who underwent surgery, often requiring repeated surgeries.

Woods SP, Fields JA, Lyons KE, Koller WC, Wilkinson SB, Pahwa R, Tröster AI. · Department of Psychiatry & Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA. · Acta Neurochir (Wien). · Pubmed #11810392 No free full text.

Abstract: BACKGROUND: The long-term neuropsychological and quality of life (QOL) outcomes of unilateral thalamic deep brain stimulation (DBS) in patients with intractable Parkinson's disease (PD) have not heretofore been described. METHOD: Six patients diagnosed with PD underwent unilateral DBS implantation into a verified thalamic VIM nucleus target. Participants completed presurgical neuropsychological evaluation and follow-up assessment at approximately one year postsurgery. FINDINGS: Compared to their presurgical scores, PD patients exhibited significant improvement on measures of conceptualization, verbal memory, emotional adjustment, and QOL at one-year follow-up. A few nominal declines were observed across the battery of tests. INTERPRETATION: These data provide preliminary support for the long-term neurocognitive safety and QOL improvements following thalamic stimulation in patients with PD.

Hutton JT, Metman LV, Chase TN, Juncos JL, Koller WC, Pahwa R, LeWitt PA, Samii A, Tsui JK, Calne DB, Waters CH, Calabrese VP, Bennett JP, Barrett R, Morris JL. · Neurology Research & Education Center, Covenant Medical Center-Lakeside, 4102 24th St., Lubbock, TX 79410, USA. · Mov Disord. · Pubmed #11391739 No free full text.

Abstract: N-0923 is a non-ergot, dopaminergic D(2) agonist designed to be transdermally available. It has anti-parkinsonian effects when infused intravenously. An adhesive matrix patch was developed to deliver N-0923 transdermally (N-0923 TDS). In this phase II trial, we evaluated the effectiveness of various doses of N-0923 TDS at replacing levodopa. Eighty-five Parkinson's disease (PD) patients were randomized to placebo or one of four doses of N-0923 TDS for 21 days. Change in daily levodopa dose was the primary efficacy measure. Significantly greater reductions in levodopa dose were achieved as compared to placebo for the two highest doses of N-0923 TDS. Patients treated with 33.5 mg and 67 mg N-0923 TDS decreased levodopa use by 26% and 28%, vs. 7% for placebo. N-0923 TDS was safe and well tolerated.

Shoulson I, Penney J, McDermott M, Schwid S, Kayson E, Chase T, Fahn S, Greenamyre JT, Lang A, Siderowf A, Pearson N, Harrison M, Rost E, Colcher A, Lloyd M, Matthews M, Pahwa R, McGuire D, Lew MF, Schuman S, Marek K, Broshjeit S, Factor S, Brown D, Feigin A, Mazurkiewicz J, Ford B, Jennings D, Dilllon S, Comella C, Blasucci L, Janko K, Shulman L, Wiener W, Bateman-Rodriguez D, Carrion A, Suchowersky O, Lafontaine AL, Pantella C, Siemers E, Belden J, Davies R, Lannon M, Grimes D, Gray P, Martin W, Kennedy L, Adler C, Newman S, Hammerstad J, Stone C, Lewitt P, Bardram K, Mistura K, Miyasaki J, Johnston L, Cha JH, Tennis M, Panniset M, Hall J, Tetrud J, Friedlander J, Hauser R, Gauger L, Rodnitzky R, Deleo A, Dobson J, Seeberger L, Dingmann C, Tarsy D, Ryan P, Elmer L, Ruzicka D, Stacy M, Brewer M, Locke B, Baker D, Casaceli C, Day D, Florack M, Hodgeman K, Laroia N, Nobel R, Orme C, Rexo L, Rothenburgh K, Sulimowicz K, Watts A, Wratni E, Tariot P, Cox C, Leventhal C, Alderfer V, Craun AM, Frey J, McCree L, McDermott J, Cooper J, Holdich T, Read B, Anonymous00161. · No affiliation provided · Neurology. · Pubmed #11222787 No free full text.

Abstract: BACKGROUND: Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy. RESULTS: Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant. CONCLUSION: Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD.

Hristova A, Lyons K, Tröster AI, Pahwa R, Wilkinson SB, Koller WC. · Department of Neurology, University of Kansas Medical Center, Kansas City, USA. · Clin Neuropharmacol. · Pubmed #11020125 No free full text.

Abstract: We studied the effect and temporal profile of deep brain stimulation (DBS) of the globus pallidus and subthalamic nucleus on the motor signs of Parkinson's disease (PD). Four patients with bilateral deep brain stimulators of the globus pallidus and four patients with bilateral deep brain stimulators of the subthalamus were studied while taking no medication and at 15 and 30 minutes and 1, 2, 4, and 6 hours after turning stimulation on. An immediate (15 minutes) and sustained (6 hours) benefit was observed for all the motor manifestations of PD for both stimulation sites. Deep brain stimulation of the globus pallidus and subthalamus is highly effective in reducing all the cardinal motor features of PD.

Fields JA, Tröster AI, Wilkinson SB, Pahwa R, Koller WC. · Department of Neurology, University of Kansas Medical Center, Kansas City 66160-7314, USA. · Clin Neurol Neurosurg. · Pubmed #10536904 No free full text.

Abstract: As neurosurgical treatment of parkinsonian symptoms has become increasingly popular, concern about the cognitive morbidity which may result from such interventions has risen proportionately. Previous reports of cognitive difficulties associated with pallidotomy and thalamotomy, especially in bilateral cases, have provided the impetus for research into chronic electrical deep brain stimulation procedures which are believed to be safer than ablation. Given the lack of neurobehavioral research following bilateral deep brain stimulation procedures, this preliminary study of six Parkinson's disease patients undergoing staged bilateral pallidal stimulation was undertaken. A battery of tests assessing attention, executive function, visuomotor coordination, language, visuoperceptual function, learning memory and mood revealed no significant change in overall level of cognitive functioning after either unilateral or bilateral pallidal deep brain stimulation. No significant declines were observed about three months following bilateral stimulation, and in fact, significant gains in delayed recall and relief of anxiety symptoms were noted. It was concluded from this preliminary data that bilateral pallidal stimulation for the treatment of Parkinson's disease, at least in the absence of operative complications, offers a cognitively safe alternative to ablation.

Muniz AS, Nobre FF, Liu H, Lyons KE, Pahwa R, Liu W, Nadal J. · Biomedical Engineering Program, COPPE, Federal University of Rio de Janeiro, Brazil P.O. Box 68.510, 21941-972 - BRAZIL. · Conf Proc IEEE Eng Med Biol Soc. · Pubmed #19163765 No free full text.

Abstract: This study aims at applying an artificial neural network for the evaluation of the effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) on Parkinson disease (PD) patients with and without medication. A sample of 15 PD patients who have undergone STN DBS were evaluated under four test conditions: medication off and stimulation off (mof-sof), medication off and stimulation on (mof-son), medication on and stimulation off (mon-sof) and medication on and stimulation on (mon-son). A control group with 30 subjects was also evaluated. Principal component analysis (PCA) was applied on vertical ground reaction force (vGRF) and the first six principal component scores (PC score) were obtained in both groups. Those PCs scores were used as input in a probabilistic neural network (PNN). PNN presented satisfactory classification performance in the separation of controls and PD with 90.1% accuracy, 69.2% sensitivity and 100% specificity. The stimulation mof-son and mon-son conditions presented better results compared to mon-sof. In the mof-son condition, 41.7% were classified as normal, while further enhancement (63.3%) was given by the mon-son condition. These results indicated the potentiality of PNN to quantitatively evaluate treatment effects. Furthermore, STN DBS shows improvement on vGRF pattern in PD patients, most substantially when used with medication.

Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ, Rothlind J, Sagher O, Reda D, Moy CS, Pahwa R, Burchiel K, Hogarth P, Lai EC, Duda JE, Holloway K, Samii A, Horn S, Bronstein J, Stoner G, Heemskerk J, Huang GD, Anonymous00097. · Hines VA Hospital, Center for Management of Complex Chronic Care, Hines, Illinois 60141, USA. · JAMA. · Pubmed #19126811 links to  free full text

Abstract: CONTEXT: Deep brain stimulation is an accepted treatment for advanced Parkinson disease (PD), although there are few randomized trials comparing treatments, and most studies exclude older patients. OBJECTIVE: To compare 6-month outcomes for patients with PD who received deep brain stimulation or best medical therapy. DESIGN, SETTING, AND PATIENTS: Randomized controlled trial of patients who received either deep brain stimulation or best medical therapy, stratified by study site and patient age (< 70 years vs > or = 70 years) at 7 Veterans Affairs and 6 university hospitals between May 2002 and October 2005. A total of 255 patients with PD (Hoehn and Yahr stage > or = 2 while not taking medications) were enrolled; 25% were aged 70 years or older. The final 6-month follow-up visit occurred in May 2006. INTERVENTION: Bilateral deep brain stimulation of the subthalamic nucleus (n = 60) or globus pallidus (n = 61). Patients receiving best medical therapy (n = 134) were actively managed by movement disorder neurologists. MAIN OUTCOME MEASURES: The primary outcome was time spent in the "on" state (good motor control with unimpeded motor function) without troubling dyskinesia, using motor diaries. Other outcomes included motor function, quality of life, neurocognitive function, and adverse events. RESULTS: Patients who received deep brain stimulation gained a mean of 4.6 h/d of on time without troubling dyskinesia compared with 0 h/d for patients who received best medical therapy (between group mean difference, 4.5 h/d [95% CI, 3.7-5.4 h/d]; P < .001). Motor function improved significantly (P < .001) with deep brain stimulation vs best medical therapy, such that 71% of deep brain stimulation patients and 32% of best medical therapy patients experienced clinically meaningful motor function improvements (> or = 5 points). Compared with the best medical therapy group, the deep brain stimulation group experienced significant improvements in the summary measure of quality of life and on 7 of 8 PD quality-of-life scores (P < .001). Neurocognitive testing revealed small decrements in some areas of information processing for patients receiving deep brain stimulation vs best medical therapy. At least 1 serious adverse event occurred in 49 deep brain stimulation patients and 15 best medical therapy patients (P < .001), including 39 adverse events related to the surgical procedure and 1 death secondary to cerebral hemorrhage. CONCLUSION: In this randomized controlled trial of patients with advanced PD, deep brain stimulation was more effective than best medical therapy in improving on time without troubling dyskinesias, motor function, and quality of life at 6 months, but was associated with an increased risk of serious adverse events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00056563.

Pahwa R, Koller WC, Trosch RM, Sherry JH, Anonymous00059. · University of Kansas Medical Center, 3599 Rainbow Blvd, Kansas City, KS 66160, USA. · J Neurol Sci. · Pubmed #17466338 No free full text.

Abstract: OBJECTIVE: To further explore the efficacy and safety of subcutaneous apomorphine (APO) in treating off episodes in APO-naïve patients with advanced Parkinson's disease (PD). METHODS: 56 patients receiving optimized oral anti-PD medication were evaluated on separate days for response to single increasing doses of APO. Acute response to oral anti-PD medication and APO dose escalation (2-10 mg) was evaluated under unblinded conditions. At the 4 mg APO dose, placebo was randomly introduced under double-blind crossover conditions. RESULTS: Mean changes from pre-dose in Unified Parkinson's Disease Rating Scale motor scores indicated significant improvement following APO 4 mg versus placebo at 20 min (p=0.0002), 40 min (p<0.0001; maximum improvement) and 90 min (p=0.0229). Improvements showed significant dose-response at 20 min, 40 min (both p<0.0001) and 90 min (p=0.0049). Adverse events were more common with APO than placebo, and also showed significant dose-response (p<0.0001). Common adverse events associated with APO included yawning, dizziness, nausea, somnolence and dyskinesias, and were generally mild to moderate. There were no significant differences between APO and placebo in the incidence of hypotension associated with a postural change from a sitting to standing position. CONCLUSIONS: Subcutaneous APO provided rapid, effective relief of off episodes associated with advanced PD.

LeWitt PA, Lyons KE, Pahwa R, Anonymous00261. · Clinical Neuroscience Center, Southfield, MI 48034, USA. · Neurology. · Pubmed #17438216 No free full text.

Abstract: BACKGROUND: In patients experiencing motor fluctuations, a major treatment challenge is the reduction of "off" time, particularly upon awakening. Rotigotine (Neupro) is a novel dopaminergic agonist with 24-hour transdermal delivery. METHODS: A randomized, double-blind, placebo-controlled trial (PREFER Study) was performed to assess efficacy and safety with two targeted transdermal doses of rotigotine in subjects with advanced Parkinson disease with > or =2.5 hours of daily "off" time. Subjects were randomized to receive placebo patches (n = 120) or rotigotine up to either 8 mg/24 hours (n = 120) or 12 mg/24 hours (n = 111). The primary efficacy measures compared changes from baseline to the end of week 24 in the number of daily hours "off" and responder rates for subjects achieving > or =30% reduction in "off" time. RESULTS: Compared to placebo, there were significant decreases in mean "off" time of 1.8 hours/day for the rotigotine 8 mg/24 hours group and 1.2 hours/day for the 12 mg/24 hours group. For rotigotine 8 and 12 mg/24 hours groups, > or =30% responder rates were 56.6% and 55.1% compared to the 34.5% placebo response. "On" time without dyskinesia after awakening was more than doubled in both rotigotine treatment groups vs placebo. Drug-related adverse effects included typical dopaminergic side effects, which were generally mild/moderate in intensity. Patch application site reactions including erythema and pruritus were mild to moderate and transient in the majority of instances. CONCLUSIONS: Transdermal rotigotine significantly improved "off" time in subjects with Parkinson disease not optimally controlled with levodopa and was safe and well tolerated, with typical dopaminergic side effects and occasional application site reactions.

Warren L, Gibson R, Ishihara L, Elango R, Xue Z, Akkari A, Ragone L, Pahwa R, Jankovic J, Nance M, Freeman A, Watts RL, Hentati F. · Research and Development, GlaxoSmithKline Pharmaceuticals, Research Triangle Park, NC 27709, USA. · Parkinsonism Relat Disord. · Pubmed #17433753 No free full text.

Abstract: The Leucine-rich repeat kinase 2 (LRRK2) gene has been identified as a disease susceptibility gene for Parkinson's disease (PD), with G2019 (6055G>A) being the most frequent mutation. This mutation was present in 42% (38/91) of Tunisian families and 2% (1/39) of US families we have studied. A founding haplotype was identified in our data and it is shared by families from Tunisia, US, European and Middle Eastern countries. The most recent common founder of the mutation was dated to 2600 (95% CI: 1950-3850) years ago although additional studies are warranted to ensure an accurate age estimate for this mutation.