Safety review of current pharmacotherapies for levodopa-treated patients with Parkinson's disease.

INTRODUCTION: Levodopa remains the gold standard for treatment of Parkinson's disease (PD). Patients develop complications with disease progression, necessitating adjunctive therapy to control fluctuations in motor and non-motor symptoms and dyskinesia. Knowledge of medication safety and tolerability is critical to ascertain the benefit-risk ratio and select an adjunctive therapy that provides the highest chance for medication adherence. Posing a challenge are the sheer abundance of options, stemming from the development of several new drugs in recent years, as well as differences in commercial drug availability worldwide. AREAS COVERED: This review evaluates the efficacy, safety, and tolerability of current US FDA-approved pharmacotherapies for levodopa-treated PD patients, including dopamine agonists, monoamine oxidase type-B inhibitors, catechol-O-methyltransferase inhibitors, the N-methyl-D-aspartate receptor antagonist amantadine, and the adenosine receptor antagonist istradefylline. Data were taken from pivotal phase III randomized controlled and post-surveillance studies, when available, that directly led to FDA-approval. EXPERT OPINION: No strong evidence exists to support use of a specific adjunctive treatment for improving Off time. Only one medication has demonstrated improvement in dyskinesia in levodopa-treated PD patients; however, every patient cannot tolerate it and therefore adjunctive therapy should be tailored to an individual's symptoms and risk for specific adverse effects.

Istradefylline for OFF Episodes in Parkinson's Disease: A US Perspective of Common Clinical Scenarios.

The effective management of OFF episodes remains an important unmet need for patients with Parkinson's disease (PD) who develop motor complications with long-term levodopa therapy. Istradefylline is a selective adenosine A2A receptor antagonist for the treatment of patients with PD experiencing OFF episodes while on levodopa/decarboxylase inhibitor. Originally approved in Japan, istradefylline was recently approved in the USA. In this article, we provide a specific review of the four clinical studies that the FDA included in the approval of istradefylline in the USA, and discuss common clinical scenarios, based on our experience, where treatment with istradefylline may benefit patients experiencing motor fluctuations.

Pharmacology and Evidence-Based Strategies for Current and Emerging Treatments for OFF Periods in Parkinson Disease.

​​​​​​​​ Parkinson disease (PD) is a progressive neurodegenerative disease characterized by motor symptoms such as rigidity, resting tremor, and slowed movement in addition to nonmotor symptoms. As the disease advances and a patient's response duration to a levodopa dose is shortened, OFF episodes become more prevalent, negatively impacting their quality of life. Clinicians may employ a variety of therapeutic strategies to reduce OFF time, such as altering the levodopa dose or initiating adjuvant therapy. Medications to treat daily OFF time include dopamine agonists, MAO-B inhibitors, COMT inhibitors, amantadine ER, and adenosine A2A antagonists; as-needed rescue therapies include subcutaneous apomorphine, apomorphine sublingual film, and orally inhaled levodopa; and, when necessary, advanced therapies such as carbidopa/levodopa enteral suspension or DBS may be indicated.

Does post-operative symptomatic lead edema associated with subthalamic DBS implantation impact long-term clinical outcomes?

INTRODUCTION: Post-operative, non-hemorrhagic, non-infectious symptomatic delayed edema around the DBS lead is an uncommon complication of DBS surgery. We investigated whether this complication impacts clinical outcomes or has long-term sequelae. METHODS: All Parkinson's disease (PD) patients with subthalamic nucleus (STN) DBS implantation who developed delayed symptomatic lead edema were identified. UPDRS part III motor, Parkinson's Disease Questionnaire (PDQ-39) total and MoCA scores were analyzed to assess motor outcome, quality of life and cognitive status at 1 year. RESULTS: A total of 260 patients underwent 482 STN lead placements. Of these, 16 patients (20 leads, 4.1% of total 482 leads) developed this delayed complication. None of the patients had edema on immediate post-operative scan. Patients presented with varied symptoms including speech difficulty (n = 8), mild confusion (n = 6), headaches (n = 4), gait difficulty (n = 4) and seizures (n = 3). The mean duration for the diagnosis was 5.8 days after lead implantation and the mean duration for which follow-up CT scans reported complete/near complete resolution or improvement of edema was 4.7 weeks (range 2-10 weeks). At 1-year post-DBS, UPDRS motor scores improved significantly (42.5%, p < .001); quality of life improved, but the change was not statistically significant (21.3%, p = .197). There was no decline in cognitive function at 1 year (26.6 vs 26.4, p = .567). No long-term complication related to lead edema occurred in these patients. CONCLUSION: Symptomatic lead edema after DBS surgery is an uncommon complication which typically resolves over time. In our series, there were no long-term sequelae of this complication and clinical outcomes were comparable to that reported in the literature.

Long Term Response to Levodopa in Parkinson's Disease.

BACKGROUND: Levodopa is the most efficacious medication in controlling the motor symptoms of Parkinson's disease (PD). There continues to be a controversy as to whether levodopa remains effective after years of therapy. OBJECTIVE: To assess the long-term effectiveness of levodopa in PD patients. METHODS: The response to levodopa in PD patients undergoing a levodopa challenge for deep brain stimulation (DBS) surgery evaluation from June 1997 through March 2017 were evaluated. The patients were broken into four groups based on disease duration (Group I: 0- 5 years, Group II: 6- 10 years, Group III: 11- 15 years, and Group IV:≥16 years). Levodopa response was calculated based on the changes in Unified Parkinson's Disease Rating Scale (UPDRS) motor and activities of daily living (ADL) scores in the medication ON and OFF states. RESULTS: A total of 361 PD patients were included. The mean age in Group I was 59.4 years with a mean disease duration of 3.9 years (n = 29), Group II was 61 years with a mean disease duration of 8.1 years (n = 131), Group III was 64 years with a mean disease duration of 12.8 years (n = 143), and IV was 66.5 years with a mean disease duration of 18.5 years (n = 58). There was a significant improvement in UPDRS motor and ADL scores after the levodopa challenge for all groups. CONCLUSIONS: In a subgroup of PD patients who were evaluated for DBS surgery, there was a marked improvement in UPDRS motor and ADL scores which did not decrease with disease progression.

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease patients over 75 years of age.

INTRODUCTION: Deep brain stimulation (DBS) is an effective therapy for Parkinson's disease (PD). However, its effect in older patients is not extensively studied, as they are often excluded from DBS surgery due to concerns of complications or reduced benefit. We assessed clinical outcomes after subthalamic nucleus (STN) DBS in older patients (age > 75 years) with PD. METHODS: All PD patients above 75 years who underwent STN-DBS between 1999 and 2015 were included. Unified Parkinson's Disease Rating Scale (UPDRS) scores and Parkinson's Disease Questionnaire (PDQ-39) scores were assessed up to 4 years after surgery. Other measures included were complications/adverse events, levodopa equivalent dose, and cognitive function. RESULTS: A total of 30 patients underwent 52 lead placements. Mean age at surgery was 77.5 years (range 75.0-84.5 years). Post-DBS, motor scores improved by 30.8% after 1-year and 27.3% after a mean of 2.5 years (p < .001). All motor sub-scores improved, however axial signs did not change over time. OFF time and dyskinesia duration reduced significantly (p < .001), whereas quality of life, activities of daily living and cognitive function did not significantly change. The following adverse events were noted: transient post-operative confusion (36% of patients), gait difficulty (13.3% of patients), hemorrhage (3.8% of leads), personality changes (3.3% of patients), lead revision (1.9% of leads), seizure (1.9% of leads), and infection (1.9% of leads). CONCLUSIONS: STN-DBS improves motor outcomes in patients over 75 years of age; however, there was no change in quality of life. Although post-surgical transient confusion was common, there were no serious adverse events and the incidence of other complications was typical for DBS surgery.

Benefits and risks of unilateral and bilateral ventral intermediate nucleus deep brain stimulation for axial essential tremor symptoms.

INTRODUCTION: Many experts assume bilateral deep brain stimulation (DBS) is necessary to improve axial tremor in essential tremor (ET). In the largest clinical trial of DBS for ET to date evaluating a non-directional, constant current device, we studied the effects of unilateral and staged bilateral DBS on axial tremor. METHODS: We included all participants from the original trial with unilateral ventral intermediate nucleus (VIM) DBS and 90-day follow up at minimum. Primary outcomes were changes in pooled axial subscores in the Clinical Rating Scale for Tremor (CRST) at 90 and 180 days after activation of unilateral VIM DBS compared to pre-operative baseline (n=119). Additionally, we performed within-subject analyses for unilateral versus bilateral DBS at 180 days in the cohort who underwent staged surgery to bilateral DBS (n=39). RESULTS: Unilateral VIM DBS improved midline tremor by 58% at 90 days (median[IQR]) (3[3] to 1[2], p<0.001) and 65% at 180 days (3[3] to 1[2], p<0.001) versus pre-op baseline. In the staged to bilateral DBS cohort, midline tremor scores further improved after bilateral DBS at 180 days by 63% versus unilateral DBS (3[3] to 1[3], p=0.007). There were, however, 35 additional DBS and surgery-related adverse events, 14 related to incoordination, gait impairment, or speech impairment, versus 6 after unilateral DBS. CONCLUSION: Unilateral VIM DBS for ET significantly improved associated axial tremor. Staged bilateral DBS was associated with additional axial tremor improvement but also additional adverse events. Unilateral VIM DBS may be sufficient to achieve a goal of contralateral limb and axial tremor attenuation.

Symptomatic, non-infectious, non-hemorrhagic edema after subthalamic nucleus deep brain stimulation surgery for Parkinson's disease.

OBJECT: We review our experience with Parkinson's disease (PD) patients who underwent subthalamic nucleus (STN) deep brain stimulation (DBS) and then developed noninfectious, non-hemorrhagic, delayed, symptomatic brain edema associated with a DBS lead. METHODS: All PD patients who underwent STN DBS lead implantation from 2007 to 2015 were included. The same neurosurgeon performed all surgeries, typically in staged fashion, utilizing single pass microelectrode recordings (MER) within a stereotactic frame. A brain CT was obtained in recovery and subsequently if indicated. RESULTS: There were 189 patients who underwent 363 STN lead implantations among which 35 (9.6%) represent re-implantations of removed leads in 28 (14.8%) patients. Among the 363 STN leads implanted, there were 12 (3.3%) cases of delayed symptomatic edema associated with a DBS lead involving 10 (5.3%) of the patients studied. Of the 328 leads representing first-time operations, there were 9 (2.1%) cases of delayed symptomatic edema in 7 (3.7%) patients, one of whom (14.3%) presented with seizures. For lead re-implantations, there were 3 (8.6%) cases of the brain edema in 3 (10.7%) patients; all presenting with seizures. For the 35 re-implantations, the trajectory to target was the same or very similar via the same burr hole as prior surgery in 17 (48.6%); 3 (17.6%) of whom developed edema. There was no case of brain edema in the 18 re-operated cases using a different burr opening. Edema patients were treated with a course of anticonvulsant medication and dexamethasone. Lead-associated edema resolved over generally a 4 to 6-week course. CONCLUSIONS: Noninfectious, non-hemorrhagic, delayed, symptomatic brain edema occurs in approximately 3% of implanted leads and is more common in re-implantations (9%) compared to new implantations (2%). In re-implantations, the edema is more common when the same trajectory is used (18%) compared to a new trajectory (0%). The edema generally occurs 3 to 8 days after implantation, although immediate post-op CT is normal and seizures are a common presenting feature.

Thalamic DBS with a constant-current device in essential tremor: A controlled clinical trial.

INTRODUCTION: This study of thalamic deep brain stimulation (DBS) investigated whether a novel constant-current device improves tremor and activities of daily living (ADL) in patients with essential tremor (ET). METHODS: A prospective, controlled, multicenter study was conducted at 12 academic centers. We investigated the safety and efficacy of unilateral and bilateral constant-current DBS of the ventralis intermedius (VIM) nucleus of the thalamus in patients with essential tremor whose tremor was inadequately controlled by medications. The primary outcome measure was a rater-blinded assessment of the change in the target limb tremor score in the stimulation-on versus stimulation-off state six months following surgery. Multiple secondary outcomes were assessed at one-year follow-up, including motor, mood, and quality-of-life measures. RESULTS: 127 patients were implanted with VIM DBS. The blinded, primary outcome variable (n = 76) revealed a mean improvement of 1.25 ± 1.26 points in the target limb tremor rating scale (TRS) score in the arm contralateral to DBS (p < 0.001). Secondary outcome variables at one year revealed significant improvements (p ≤ 0.001) in quality of life, depression symptoms, and ADL scores. Forty-seven patients had a second contralateral VIM-DBS, and this group demonstrated reduction in second-sided tremor at 180 days (p < 0.001). Serious adverse events related to the surgery included infection (n = 3), intracranial hemorrhage (n = 3), and device explantation (n = 3). CONCLUSION: Unilateral and bilateral constant-current VIM DBS significantly improves upper extremity tremor, ADL, quality of life, and depression in patients with severe ET.

MDS-UPDRS to assess non-motor symptoms after STN DBS for Parkinson's disease.

OBJECTIVE: To determine if the non-motor sections of the Movement Disorder Society's (MDS) version of the Unified Parkinson's Disease Rating Scale (UPDRS) could supplement the original UPDRS as a patient completed assessment of changes in non-motor symptoms in Parkinson's disease (PD) patients after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS). METHODS: Thirty PD patients who underwent bilateral STN DBS were assessed using the total UPDRS and the non-motor sections of the MDS-UPDRS prior to surgery and one year following surgery. This study focuses on non-motor symptoms as assessed by Part I of the UPDRS and Part 1A and 1B of the MDS-UPDRS. RESULTS: One year following surgery, no individual non-motor symptoms or the total mentation score of the UPDRS were significantly changed. In comparison, the MDS-UPDRS showed significant improvements in sleep and urinary problems and a trend towards improvement in anxiety, constipation, daytime sleepiness, fatigue and pain. CONCLUSIONS: This study provides evidence that the MDS-UPDRS non-motor sections, when completed by the patients, can supplement the original version of the UPDRS as an effective method of measuring changes in non-motor symptoms after DBS. It also reinforces the benefits of bilateral STN DBS on non-motor symptoms of PD.

Deep brain stimulation for essential tremor.

Essential tremor is the most common tremor disorder and is characterized by a postural and kinetic tremor. Most commonly, the disease involves the upper extremities, although other body parts may be affected. Essential tremor is seen most often in adults and may markedly limit abilities to perform daily activities. Medications often fail to control the tremor adequately. In the past, ventral intermediate nucleus of the thalamus (VIM) thalamotomy was the surgery of choice for medication-resistant patients with disabling tremor. With technological advances, deep brain stimulation (DBS) to the VIM has replaced thalamotomy as the operation of choice for patients with essential tremor, given the heightened risk of permanent neurological deficits associated with ablative surgery. Multiple studies have demonstrated that unilateral VIM DBS has significant short- and long-term benefits for targeted tremor. Unilateral VIM DBS may also improve head and voice tremor, although most commonly bilateral stimulation is required for adequate control. However, bilateral thalamic stimulation is associated with a higher incidence of neurological deficits, particularly speech and gait problems. Investigations of DBS of other brain target areas for essential tremor, such as the posterior subthalamic area and the subthalamic nucleus, are ongoing.

Long-term benefits in quality of life after unilateral thalamic deep brain stimulation for essential tremor.

OBJECT: The goal of this study was to evaluate short- and long-term benefits in quality of life (QOL) after unilateral deep brain stimulation (DBS) for essential tremor (ET). METHODS: Patients who received unilateral DBS of the ventral intermediate nucleus of the thalamus between 1997 and 2010 and who had at least 1 follow-up evaluation at least 1 year after surgery were included. Their QOL was assessed with the Parkinson Disease Questionnaire-39 (PDQ-39), and ET was measured with the Fahn-Tolosa-Marin tremor rating scale (TRS) prior to surgery and then postoperatively with the stimulation in the on mode. RESULTS: Ninety-one patients (78 at 1 year; 42 at 2-7 years [mean 4 years]; and 22 at >7-12 years [mean 9 years]) were included in the analysis. The TRS total, targeted tremor, and activities of daily living (ADL) scores were significantly improved compared with presurgical scores up to 12 years. The PDQ-39 ADL, emotional well-being, stigma, and total scores were significantly improved up to 7 years after surgery compared with presurgical scores. At the longest follow-up, only the PDQ-39 stigma score was significantly improved, and the PDQ-39 mobility score was significantly worsened. CONCLUSIONS: Unilateral thalamic stimulation significantly reduces ET and improves ADL scores for up to 12 years after surgery, as measured by the TRS. The PDQ-39 total score and the domains of ADL, emotional well-being, and stigma were significantly improved up to 7 years. Although scores were improved compared with presurgery, other than stigma, these benefits did not remain significant at the longest (up to 12 years) follow-up, probably related in part to changes due to aging and comorbidities.

The importance of testing deep brain stimulation lead impedances before final lead implantation.

BACKGROUND: In the setting of a deep brain stimulation (DBS) lead with defective electrical circuitry, potential patient morbidity and additional surgery may be avoided if impedance testing of the brain lead is performed prior to final lead implantation. In the present report, detection of a short circuit upon lead placement and prior to lead anchoring was detected utilizing recently released DBS hardware and software (Medtronic, Minneapolis, MN). This report suggests that neurosurgeons need to be aware and consider the use of the newly available DBS testing equipment. METHODS: During the first DBS lead placement in a 69-year-old man with advanced idiopathic Parkinson's disease undergoing bilateral subthalamic nucleus DBS over staged procedures, test stimulation and lead impedance testing were accomplished prior to lead anchoring. An external neurostimulator (ENS) was affixed to an updated clinician programmer and connected to the DBS lead with a screening cable specific for the ENS and DBS. RESULTS: Impedance testing demonstrated a short circuit involving the 1 and 3 lead-electrode bipolar combination in a visually intact lead. The lead was replaced, repeat impedance testing and test stimulation were completed and the intact lead was secured. Subsequent DBS surgeries were completed uneventfully. The lead abnormality was verified by the manufacturer. CONCLUSIONS: This case highlights a new method to test DBS lead circuitry at the time of placement. The method may also be employed to directly test lead integrity when localizing a DBS system short or open circuit of unclear etiology. Our case suggests that the method is valuable and should be utilized.

The impact of bilateral subthalamic stimulation on non-motor symptoms of Parkinson's disease.

OBJECTIVE: To evaluate the impact of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) on the prevalence of non-motor symptoms reported by Parkinson's disease (PD) patients one year following surgery and to examine whether there was an association between number of non-motor symptoms reported and quality of life (QoL). METHODS: Twenty-four patients who received bilateral STN DBS and had follow-up evaluations one year after surgery were included in this study. Patients' motor function was evaluated with the Unified Parkinson's Disease Rating Scale, non-motor symptoms were assessed with the Non-Motor Symptom questionnaire (NMSQuest) and quality of life was assessed with the PDQ-39. RESULTS: There was a mean of 12 non-motor symptoms reported prior to surgery which was significantly reduced to a mean of 7 symptoms one year after surgery. Autonomic symptoms were the most frequently reported and demonstrated the greatest reductions following surgery. Twenty-seven of the 30 items represented in the NMSQuest were reported less frequently one year after surgery compared to before surgery. The reduction in non-motor symptoms was significantly correlated with total QoL scores and the subscales of mobility, activities of daily living, cognition and bodily discomfort. CONCLUSIONS: Non-motor symptoms are common in patients with advanced PD. The number of non-motor symptoms was significantly decreased one year following bilateral STN DBS which was associated with a significant improvement in QoL. Further studies focused on specific non-motor symptoms are warranted in order to fully understand the impact and mechanisms of STN DBS on these symptoms.

Hospitalization in Parkinson disease: a survey of National Parkinson Foundation Centers.

OBJECTIVES: To explore current practices and opinions regarding hospital management of Parkinson disease (PD) patients in specialized PD Centers. METHODS: Fifty-one out of 54 National Parkinson Foundation (NPF) Centers worldwide completed an online survey regarding hospitalization of PD patients. RESULTS: Many Centers were concerned about the quality of PD-specific care provided to their patients when hospitalized. Primary concerns were adherence to the outpatient medication schedule and poor understanding by hospital staff of medications that worsen PD. Few Centers had a policy with their primary hospital that notified them when their patients were admitted. Rather, notification of hospitalization came often from the patient or a family member. Several Centers (29%) reported not finding out about a hospitalization until a routine clinic visit after discharge. Quick access to outpatient PD care following discharge was a problem in many Centers. Elective surgery, fall/fracture, infection, and mental status changes, were identified as common reasons for hospitalization. CONCLUSIONS: There is a perceived need for PD specialists to be involved during hospitalization of their patients. Improvement in communication between hospitals and PD Centers is necessary so that hospital clinicians can take advantage of PD specialists' expertise. Education of hospital staff and clinicians regarding management of PD, complications of PD, and medications to avoid in PD is critical. Most importantly, outpatient access to PD specialists needs to be improved, which may prevent unnecessary hospitalizations in these patients.

Deep brain stimulation for Parkinson disease: an expert consensus and review of key issues.

OBJECTIVE: To provide recommendations to patients, physicians, and other health care providers on several issues involving deep brain stimulation (DBS) for Parkinson disease (PD). DATA SOURCES AND STUDY SELECTION: An international consortium of experts organized, reviewed the literature, and attended the workshop. Topics were introduced at the workshop, followed by group discussion. DATA EXTRACTION AND SYNTHESIS: A draft of a consensus statement was presented and further edited after plenary debate. The final statements were agreed on by all members. CONCLUSIONS: (1) Patients with PD without significant active cognitive or psychiatric problems who have medically intractable motor fluctuations, intractable tremor, or intolerance of medication adverse effects are good candidates for DBS. (2) Deep brain stimulation surgery is best performed by an experienced neurosurgeon with expertise in stereotactic neurosurgery who is working as part of a interprofessional team. (3) Surgical complication rates are extremely variable, with infection being the most commonly reported complication of DBS. (4) Deep brain stimulation programming is best accomplished by a highly trained clinician and can take 3 to 6 months to obtain optimal results. (5) Deep brain stimulation improves levodopa-responsive symptoms, dyskinesia, and tremor; benefits seem to be long-lasting in many motor domains. (6) Subthalamic nuclei DBS may be complicated by increased depression, apathy, impulsivity, worsened verbal fluency, and executive dysfunction in a subset of patients. (7) Both globus pallidus pars interna and subthalamic nuclei DBS have been shown to be effective in addressing the motor symptoms of PD. (8) Ablative therapy is still an effective alternative and should be considered in a select group of appropriate patients.

Head positioning and risk of pneumocephalus, air embolism, and hemorrhage during subthalamic deep brain stimulation surgery.

PURPOSE: The objective of the present study was to evaluate the risk of pneumocephalus, venous air embolism (VAE), and intracranial hemorrhage in subthalamic nucleus (STN) deep brain stimulation (DBS) patients operated in the strict supine (head and body flat) position. METHODS: This was a retrospective review of clinical records and brain imaging of patients who underwent STN DBS between January 2007 and June 2009 at the University of Kansas Medical Center. RESULTS: A total of 61 patients underwent 114 lead implantations (53 staged bilateral and 8 unilateral). No case involved a transventricular route. Intracranial air volumes ranged from 0 to 7.02 cm³ (mean 0.98 ± 1.42 cm³). Pneumocephalus volumes were highly skewed with no air present after 44 (38.6%) lead implantations, >0 to 1 cm³ in 35 (30.7%), >2 to 3 cm³ in 17 (14.9%), and >3 cm³ (average 4.97 cm³) in 9 (7.9%). There was no incidence of clinically apparent VAE or symptomatic intracranial hemorrhage. There was no association between age, degree of atrophy, sagittal angle of surgical approach, number of microelectrode runs (MERs), distance of gyrus from inner skull bone at the entry point, or surgical side and pneumocephalus. However, the majority of lead implantations (100 leads; 88%) required only one MER and there were minimal measurable distances between entered gyrus and adjacent bone. CONCLUSIONS: Our data suggest that strict supine positioning during STN DBS surgery results in minimal intracranial air and is not associated with VAE or symptomatic intracranial hemorrhage when the operative method described is used.

Safety and efficacy of newly formulated selegiline orally disintegrating tablets as an adjunct to levodopa in the management of 'off' episodes in patients with Parkinson's disease.

OBJECTIVE: Patients receiving levodopa for Parkinson's disease experience motor fluctuations and immobility ('off' episodes) between doses. This study assessed adjunctive Zelapar (selegiline orally disintegrating tablet (ODT)) for managing off episodes and for long-term safety. METHODS: This open-label extension evaluated long-term safety, efficacy, and tolerability of adjunctive selegiline ODT 2.5 mg in patients who completed either of two large phase 3 double-blind studies. The study was to end after 12 months but was amended to be open-ended. Investigators could increase levodopa doses and introduce controlled-release formulations of levodopa or dopamine agonists if warranted. Additionally, results of a small randomized trial of open-label selegiline ODT 1.25 mg in comparison to conventional selegiline was added only to the safety analysis. Efficacy variables included changes in daily off time and Patient's Global Impression of Improvement (PGI-I) and Clinical Global Impressions Severity of Disease (CGI-S) ratings. Safety assessments included adverse events and oropharyngeal findings. RESULTS: This study enrolled 254 patients: 248 from the large phase 3 studies (efficacy analysis) and an additional six from the prior open-label comparison (safety analysis) in order to evaluate a larger population for safety purposes. Mean reduction from baseline in daily off time was 9.4% (1.6 h) for patients previously given selegiline ODT, 6.0% (1.2 h) for those switched from placebo, and 8.1% (1.4 h) overall. PGI-I and CGI-S ratings indicated little or no change from baseline. Treatment-related adverse events occurred in 132 (52%) patients. No severe oral irritations were attributed to selegiline ODT or prompted discontinuation. CONCLUSIONS: Long-term selegiline ODT 2.5 mg/day was effective, safe, and well tolerated in patients with Parkinson's disease experiencing off episodes during levodopa therapy.

Subthalamic nucleus stimulation in Parkinson's disease patients intolerant to levodopa.

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.