Safety and Efficacy of IPX203 in Parkinson's Disease: The RISE-PD Open-Label Extension Study.

BACKGROUND: IPX203 is a novel oral extended-release formulation of carbidopa/levodopa (CD/LD) developed to address the short half-life of immediate-release CD/LD. In the phase 3 RISE-PD trial, IPX203 significantly improved "Good On" time in patients with Parkinson's disease compared with immediate-release CD/LD. OBJECTIVES: To evaluate the safety and efficacy of IPX203 in an open-label extension of the pivotal phase 3 study. METHODS: This 9-month extension enrolled patients who completed the randomized, double-blind trial. Key efficacy endpoints included Movement Disorder Society-Unified Parkinson's Disease Rating Scale and Patient and Clinical Global Impression scores. Adverse events (AEs) were recorded. RESULTS: Improvements in efficacy were maintained and dosing frequency and total daily dose remained stable through the trial. A total of 52.7% of patients experienced ≥1 treatment-emergent AE, mostly mild or moderate and occurred within the first 90 days of treatment. CONCLUSIONS: In this phase 3 open-label extension, IPX203 exhibited a favorable safety and tolerability profile and sustained efficacy of comparable magnitude to the end of the double-blind study. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

IPX203 vs Immediate-Release Carbidopa-Levodopa for the Treatment of Motor Fluctuations in Parkinson Disease: The RISE-PD Randomized Clinical Trial.

Importance: Levodopa has a short half-life and a limited window of opportunity for absorption in the proximal small intestine. IPX203 is an oral, extended-release formulation of carbidopa-levodopa developed to address these limitations. Objective: To assess the efficacy and safety of IPX203 vs immediate-release carbidopa-levodopa in patients with Parkinson disease who are experiencing motor fluctuations. Design, Setting, and Participants: RISE-PD was a 20-week, randomized, double-blind, double-dummy, active-controlled, phase 3 clinical trial. The study was conducted between November 6, 2018, and June 15, 2021, at 105 academic and clinical centers in the US and Europe. Patients with Parkinson disease taking a total daily dose of 400 mg or more of levodopa and experiencing an average of 2.5 hours or more daily off-time were included in the study. A total of 770 patients were screened, 140 were excluded (those taking controlled-release carbidopa-levodopa apart from a single daily bedtime dose, Rytary (Amneal Pharmaceuticals), additional carbidopa or benserazide, or catechol O-methyl transferase inhibitors or who had a history of psychosis within the past 10 years), and 630 were enrolled in the trial. Interventions: Following open-label immediate-release carbidopa-levodopa dose adjustment (3 weeks) and conversion to IPX203 (4 weeks), patients were randomized in a 1:1 ratio to double-blind, double-dummy treatment with immediate-release carbidopa-levodopa or IPX203 for 13 weeks. Main Outcome and Measures: The primary end point was mean change in daily good on-time (ie, on-time without troublesome dyskinesia) from baseline to the end of the double-blind treatment period. Results: A total of 630 patients (mean [SD] age, 66.5 [8.95] years; 396 [62.9%] men) were enrolled, and 506 patients were randomly assigned to receive IPX203 (n = 256) or immediate-release carbidopa-levodopa (n = 250). The study met its primary end point, demonstrating statistically significant improvement in daily good on-time for IPX203 compared to immediate-release carbidopa-levodopa (least squares mean, 0.53 hours; 95% CI, 0.09-0.97; P = .02), with IPX203 dosed a mean 3 times per day vs 5 times per day for immediate-release carbidopa-levodopa. Good on-time per dose increased by 1.55 hours with IPX203 compared to immediate-release carbidopa-levodopa (95% CI, 1.37-1.73; P < .001). IPX203 was well tolerated. The most common adverse events in the double-blind phase (IPX203 vs immediate-release carbidopa-levodopa) were nausea (4.3% vs 0.8%) and anxiety (2.7% vs 0.0%). Conclusions and Relevance: In this study, IPX203 provided more hours of good on-time per day than immediate-release carbidopa-levodopa, even as IPX203 was dosed less frequently. Trial Registration: ClinicalTrials.gov Identifier: NCT03670953.

Real-World Experience with Carbidopa-Levodopa Extended-Release Capsules (Rytary®): Results of a Nationwide Dose Conversion Survey.

BACKGROUND: The introduction of carbidopa-levodopa extended-release (CD-LD ER) capsules (Rytary®) did not go as smoothly as expected, largely due to difficulty around dose conversion from available immediate-release (IR) levodopa (LD) formulations. The dose conversion table in the CD-LD ER prescribing information was similar to the table used in the pivotal clinical trial and is considered by many prescribing HCPs to be less than optimal. By the end of the dose conversion period in that trial, dosing in 76% of subjects was adjusted for symptom control; roughly 60% of patients required a higher dose and about half required more frequent administration than the recommended TID dosing. OBJECTIVE: The primary objective of our nationwide (US) survey was to determine the dose conversion strategy most commonly employed by CD-LD ER frequent prescribers. The survey also aimed to explore additional features regarding CD-LD ER use in clinical practice. METHODS: A survey consisting of 21 multiple-choice questions was developed and administered to experts in the use of CD-LD ER, based on prescription volume. RESULTS: Of the 394 HCPs who were invited to participate, 90 (23%) HCPs completed the survey. All respondents were aware of the dose conversion table; the largest group did not find the table to be helpful and did not use it to convert patients to CD-LD ER. The most common strategy in calculating the CD-LD ER dose was based on the total daily LD IR dose, with the majority of that group initiating dose conversion by doubling the total daily LD dose from CD-LD IR and administering CD-LD ER one less time per day. CONCLUSION: Overall, most survey respondents agreed that a good starting point for CD-LD ER conversion could be doubling the daily LD IR dose and administering it one time less frequently. Moreover, rapid patient follow-up after initial dose conversion to allow for further dose adjustments plays a critical role in achieving success. Gaining experience over time is important for satisfactory conversion.

Duration of benefit per Dose: Carbidopa-Levodopa immediate release vs. extended release capsules (Rytary®).

BACKGROUND: For patients with Parkinson's disease, clinicians commonly assess duration of benefit for individual doses of levodopa in order to consider medication changes. OBJECTIVE: To determine the mean duration of ON time per dose and mean duration of ON time without troublesome dyskinesia (WoTD) per dose of CD-LD IR vs. CD-LD ER in the ADVANCE-PD trial. METHODS: We performed a post hoc analysis of the ADVANCE-PD trial. Mean ON time per dose and ON time WoTD was calculated at baseline and end-of-study (EOS). Changes were compared between CD-LD IR and CD-LD ER (Rytary®) treatment groups using an ANCOVA model. RESULTS: Mean (SD) baseline ON time per dose of CD-LD IR (n = 393) was 2.20 h. Patients randomized to double-blind treatment with CD-LD IR (n = 192) experienced an increase in mean ON time per dose from baseline to EOS from 2.24 h to 2.38 h. In comparison, patients randomized to double-blind treatment with CD-LD ER (n = 201) experienced an increase in mean ON time per dose from baseline (on CD-LD IR) to EOS (on CD-LD ER) from 2.17 h to 3.55 h. Conversion and optimization with CD-LD ER increased ON time per dose by 1.21 h more than optimization of CD-LD IR (p < 0.0001). Similarly, CD-LD ER increased ON time WoTD per dose by 1.16 h more than CD-LD IR (p < 0.0001). CONCLUSION: In the ADVANCE-PD trial, CD-LD ER significantly increased ON time per dose compared to CD-LD IR (+1.21 h, p < 0.0001) and provided significantly more ON time per dose (3.55 h vs 2.38 h, p < 0.0001).

Carbidopa and Levodopa Extended Release Capsules in Patients with and without Troublesome and Non-Troublesome Dyskinesia.

BACKGROUND: Carbidopa (CD) and levodopa (LD) extended release (CD-LD ER) capsules are designed to combine both immediate and extended release pharmacokinetics. In the phase 3, randomized, double-blind, ADVANCE-PD trial, patients randomized to CD-LD ER experienced a 1.17-hour greater reduction in OFF time compared to patients randomized to CD-LD IR (p < 0.0001). OBJECTIVE: To compare CD-LD IR optimization to CD-LD ER conversion based on patient dyskinesia status at baseline using data from the ADVANCE-PD trial. METHODS: This was a retrospective analysis of the ADVANCE-PD study. Patients were categorized by dyskinesia status at baseline into 1) those who had No Dyskinesia (ND), 2) those who had Non-Troublesome Dyskinesia Only (NTDO), and 3) those who had Troublesome Dyskinesia (TD). RESULTS: Comparative reductions in OFF time favoring CD-LD ER over CD-LD IR were similar for the ND (-1.08 h, p = 0.0071, n = 183) and NTDO (-1.12 h, p = 0.0104, n = 131) groups, and smaller for the TD group (-0.82 h, p = 0.2382, n = 79). Reductions in OFF time for both CD-LD ER conversion and CD-LD IR adjustment were largest within the ND group and smallest within the TD group (CD-LD ER: ND -2.86 h, NTDO -2.11 h, TD -1.36 h; CD-LD IR: ND -1.78 h, NTDO -0.99 h, TD -0.55 h). CONCLUSION: Responses to both CD-LD IR adjustment and CD-LD ER conversion depended on baseline dyskinesia status. Significant reductions in OFF time with CD-LD ER compared to CD-LD IR were observed in the ND and NTDO groups. In the TD group, comparing CD-LD ER conversion to CD-LD IR optimization, benefits were still observed, but there was less reduction in OFF time, less reduction in troublesome dyskinesia, and fewer patients self-rated themselves much or very much improved than in the ND and NTDO groups. These data suggest that in clinical practice, the best chances for success with conversion from CD-LD IR to CD-LD ER are in patients without TD.

Safety and Clinical Impact of MRI in Patients with Non-MRI-conditional Cardiac Devices.

PURPOSE: To explore the safety and clinical utility of MRI in participants with non-MRI-conditional cardiac implantable electronic devices, by establishing the Patient Registry of Magnetic Resonance Imaging in Non-Approved DEvices (PROMeNADe). MATERIALS AND METHODS: From September 2015 to June 2019, 532 participants (211 women) with a mean age of 69 years ± 14 (standard deviation) were enrolled prospectively in the PROMeNADe registry (ClinicalTrials.gov identifier: NCT03081364) and underwent a total of 608 MRI examinations (61 cardiac MRI examinations). All participants had device interrogations performed before and after each MRI. Pacemaker-dependent patients received asynchronous pacing. Patients with an implantable cardioverter defibrillator (ICD) had tachycardia therapies disabled during the MRI. An electrophysiology nurse monitored participants for any hemodynamic or rhythm abnormalities. Referring physicians were surveyed regarding the clinical utility of the MRI. Standard descriptive analyses included summary statistics with percentages and means. RESULTS: Cardiac devices included pacemakers (46%), ICDs (30%), cardiac resynchronization therapy (CRT) pacemakers (4%), and CRT defibrillators (17%), as well as abandoned leads (2%). Pacemaker-dependent patients comprised 27% of all MRI examinations. There were no patient- or device-related complications. Clinical utility surveys of MRI examinations were completed by 150 physicians. According to the survey responses, these MRI examinations changed the suspected diagnosis 25% of the time and changed suspected prognosis in 26% of participants, with planned medical or surgical treatment being changed 42% of the time. CONCLUSION: This registry demonstrates that MRI examinations, including thoracic MRI examinations, can be performed safely in patients who have non-MRI-conditional devices, in pacemaker-dependent patients with ICDs, and in patients with abandoned leads. These MRI examinations can have a substantial impact on patient care, justifying the extensive resources used to perform them.Supplemental material is available for this article.© RSNA, 2020See also the commentary by Peshock in this issue.

The Application of Failure Modes and Effects Analysis Methodology to Intrathecal Drug Delivery for Pain Management.

OBJECTIVE: This study aimed to utilize failure modes and effects analysis (FMEA) to transform clinical insights into a risk mitigation plan for intrathecal (IT) drug delivery in pain management. METHODS: The FMEA methodology, which has been used for quality improvement, was adapted to assess risks (i.e., failure modes) associated with IT therapy. Ten experienced pain physicians scored 37 failure modes in the following categories: patient selection for therapy initiation (efficacy and safety concerns), patient safety during IT therapy, and product selection for IT therapy. Participants assigned severity, probability, and detection scores for each failure mode, from which a risk priority number (RPN) was calculated. Failure modes with the highest RPNs (i.e., most problematic) were discussed, and strategies were proposed to mitigate risks. RESULTS: Strategic discussions focused on 17 failure modes with the most severe outcomes, the highest probabilities of occurrence, and the most challenging detection. The topic of the highest-ranked failure mode (RPN = 144) was manufactured monotherapy versus compounded combination products. Addressing failure modes associated with appropriate patient and product selection was predicted to be clinically important for the success of IT therapy. CONCLUSIONS: The methodology of FMEA offers a systematic approach to prioritizing risks in a complex environment such as IT therapy. Unmet needs and information gaps are highlighted through the process. Risk mitigation and strategic planning to prevent and manage critical failure modes can contribute to therapeutic success.

Clinical utility of DaTscan™ imaging in the evaluation of patients with parkinsonism: a US perspective.

INTRODUCTION: Single photon emission computed tomography (SPECT) with Ioflupane I123 injection (DaTscan™) was approved by the Food and Drug Administration in 2011 for striatal dopamine transporter visualization to assist in the evaluation of adult patients with suspected parkinsonian syndromes. While brain SPECT imaging using DaTscan is a covered service under Medicare policy, there is a lack of consensus on its role in routine clinical practice in the US. Areas covered: To address this issue, an expert group of US-based movement disorders neurologists convened to discuss the clinical utility of DaTscan in movement disorders practices within the US. The group identified and discussed routine clinical scenarios where imaging with DaTscan can provide useful information that may impact management and/or clarify clinical diagnoses. This paper summarizes a consensus reached by the expert group at this meeting. Expert commentary: The major utility of DaTscan imaging is the assistance it provides in distinguishing between nigrostriatal dopaminergic degeneration and non-nigrostriatal degeneration in patients displaying equivocal signs and symptoms of parkinsonism.

Smartphone-based tactile cueing improves motor performance in Parkinson's disease.

INTRODUCTION: Visual and auditory cueing improve functional performance in Parkinson's disease (PD) patients. However, audiovisual processing shares many cognitive resources used for attention-dependent tasks such as communication, spatial orientation, and balance. Conversely, tactile cues (TC) may be processed faster, with minimal attentional demand, and may be more efficient means for modulating motor-cognitive performance. In this study we aimed to investigate the efficacy and limitations of TC for modulating simple (heel tapping) and more complex (walking) motor tasks (1) over a range of cueing intervals, (2) with/without a secondary motor task (holding tray with cups of water). METHODS: Ten PD patients (71 ± 9 years) and 10 healthy controls (69 ± 7 years) participated in the study. TCs was delivered through a smart phone attached to subjects' dominant arm and were controlled by a custom-developed Android application. RESULTS: PD patients and healthy controls were able to use TC to modulate heel tapping (F(3.8,1866.1) = 1008.1, p < 0.001), and partially modulate walking (F(3.5,1448.7) = 187.5, p < 0.001) tasks. In the walking task, PD patients modulated performance over a narrower range of cueing intervals (R(2) = 0.56) than healthy controls (R(2) = 0.84; group difference F(3.5,1448.7) = 8.6, p < 0.001). TC diminished synchronization error associated with performance of secondary motor task during walking in PD patients and healthy controls (main effect of Task (F(1,494) = 0.4; p = 0.527), Task X Group interaction (F(1,494) = 0.5; p = 0.493)). CONCLUSION: This study expands modalities of TC usage for movement modulation and motor-cognitive integration in PD patients. The smartphone TC application was validated as a user-friendly movement modulation aid.

The effects of different sensory augmentation on weight-shifting balance exercises in Parkinson's disease and healthy elderly people: a proof-of-concept study.

BACKGROUND: Earlier versions of biofeedback systems for balance-related applications were intended primarily to provide "alarm" signals about body tilt rather than to guide rehabilitation exercise motion. Additionally, there have been few attempts to evaluate guidance modalities for balance rehabilitation exercises. The purpose of this proof-of-concept study is to evaluate the effects of guidance modalities during common dynamic weight-shifting exercises used in clinical settings. METHODS: A motion guidance system providing visual biofeedback, vibrotactile biofeedback, or both, was used during weight-shifting exercises. Eleven people with idiopathic Parkinson's disease (PD) and nine healthy elderly people participated. Each participant wore a six-degree-of-freedom inertial measurement unit (IMU) located near the sacrum and four linear vibrating actuators (Tactors) attached to the skin over the front, back, and right and left sides of the abdomen. The IMU measured angular displacements and velocities of body tilt in anterior-posterior (A/P) and medial-lateral (M/L) directions. Participants were instructed to follow a slow moving target by shifting their weight in either the A/P or M/L direction up to 90 % of their limits of stability (LOS). Real-time position error was provided to participants in one of three sensory modalities: visual, vibrotactile, or both. Participants performed 5 trials for each biofeedback modality and movement direction (A/P and M/L) for a total of 30 trials in a random order. To characterize performance, position error was defined as the average absolute difference between the target and participant movements in degrees. RESULTS: Simultaneous delivery of visual and vibrotactile biofeedback resulted in significantly lower position error compared to either visual or vibrotactile biofeedback alone regardless of the movement direction for both participant cohorts. The pairwise comparisons were not significantly different between visual and vibrotactile biofeedback. CONCLUSION: The study is the first attempt to assess the effects of guidance modalities on common balance rehabilitation exercises in people with PD and healthy elderly people. The results suggest that combined visual and vibrotactile biofeedback can improve volitional responses during postural tracking tasks. Index Terms - sensory augmentation, weight-shifting balance exercise, guidance modality, vibrotactile biofeedback, visual biofeedback, Parkinson's disease.

The relationship between the hypnotic induction profile and the stanford hypnotic susceptibility scale, form C: revisited.

Hilgard's comment raises some important issues, although many of these have little to do with the primary purpose of the study under discussion. This purpose was to objectively examine the relationship between three conceptually and operationally different procedures for measuring hypnotic responsivity. Hilgard's concern over the magnitude of the correlation between the HIP and SHSS:C is unfounded. A cross-validated correlation of .66 was found between the HIP and SHSS:C in a new sample of 44 student volunteers. This demonstrates that the HIP correlates about the same with SHSS:C as the Harvard Group Scale of Hypnotic Susceptibility. Hilgard's conception of the Eye-Roll (ER) hypothesis is clarified. Evidence which utilizes all cases in the correlational analysis is presented in support of the ER hypothesis. Happily, we all agree on a new methodology which will be definitive in testing the validity of the ER hypothesis.

The liver in pediatric gastrointestinal disease.

Hepatic involvement is often encountered in gastrointestinal (GI) diseases, in part because of the close anatomic and physiologic relations between the liver and GI tract. Drainage of the mesenteric blood supply to the portal vein permits absorbed and/or translocated nutrients, toxins, bacterial elements, cytokines, and immunocytes to gain hepatic access. Liver problems in digestive disorders may range from nonspecific hepatocellular enzyme elevations to significant pathologic processes that may progress to end-stage liver disease. Hepatobiliary manifestations of primary GI diseases in childhood and adolescence are not uncommon and include several well-described associations, such as sclerosing cholangitis with inflammatory bowel disease. Liver damage may also result from the effects of drugs used to treat GI diseases, for example, the hepatotoxicity of immunomodulatory therapies. This review highlights the important features of the hepatic and biliary abnormalities associated with 3 common pediatric GI conditions: inflammatory bowel disease, celiac disease, and cystic fibrosis.

Effects of responsive electrical brain stimulation on intracranial electroencephalogram spikes.

OBJECTIVES: Responsive cortical electrical stimulation with implanted devices is under investigation for seizures. While designed to terminate seizures, might this stimulation also affect the underlying epileptic process of seizure generation? MATERIALS AND METHODS: Four patients undergoing intracranial electroencephalogram (EEG) for seizure localization had an external responsive neurostimulator (eRNS) connected to their seizure-onset zones. The eRNS detected interictal EEG spikes and stimulated at the focus. We quantified spikes at three locations: (1) near stimulation, (2) remote but in the same lobe as stimulation, and (3) in different lobe from stimulation. Ten-minute windows were analyzed at three times: (1) baseline, (2) after the first four hours of stimulation, and (3) poststimulation. One blinded investigator performed manual spike counts. Quantitative measures were total spikes, spike-free intervals (continuous ten-sec segments with no spikes), and spike clusters (one-sec intervals with three or more spikes). RESULTS: Some changes in spikes occurred in each patient, but no uniform pattern emerged. Two general observations were made: (1) spike counts within a given patient exhibited internally consistent changes with stimulation; (2) across patients, the nature of spike count changes varied, indicating patient-to-patient variability. For example, poststimulation, two patients had more and two patients had fewer total spikes. However, when spikes decreased near stimulation, they decreased at other sites, and when spikes increased near stimulation, they increased at other sites. CONCLUSIONS: Changes in spike occurrence, organization, and topography with stimulation suggest the eRNS affected spike generation and may affect the underlying interictal epileptic process. Case-to-case variability may be due to individual patient factors, and its significance is yet to be determined.

Strength and endurance adaptations to functional electrical stimulation leg cycle ergometry in spinal cord injury.

OBJECTIVES: To describe adaptations in power output, quadriceps muscle strength, and fatigability that occur during a 13-week regimen of Functional Electrical Stimulation Leg Cycle Ergometry (FES-LCE) in Spinal Cord Injury (SCI). To identify differences in outcomes between individuals with complete and incomplete motor impairment. DESIGN: Observational and longitudinal. SETTING: Rehabilitation and biomechanics research laboratory. PARTICIPANTS: Eleven (N = 11) individuals with SCI and no previous FES-LCE experience. INTERVENTION: 40 sessions of FES-LCE at a rate of three sessions per week. Continuous exercise was performed at a pedal cadence of 45 RPM against a constant resistance for up to 60 minutes. OUTCOME MEASURES: Mean power output was recorded for each session. Before and after the training regimen, each subject performed a fatigue test in which electrically stimulated knee extension torque and Fatigue Index were measured. RESULTS: Participants demonstrated significant increases in mean power output (9.0 to 20.3 W; p < 0.001), peak isometric knee extension torque (3.8 to 16.9 Nm; p = 0.006) and sustainable isometric knee extension torque (4.9 to 14.4 Nm; p = 0.001) after FES-LCE training (95% confidence intervals). Participants with incomplete motor impairment demonstrated a decrease in Fatigue Index (p = 0.021), and improved mean power output more than those with complete motor impairment (p = 0.037). CONCLUSIONS: Significant improvements in muscle conditioning and exercise performance are possible following the 13-week regimen of FES-LCE described in this article. Individuals with incomplete motor impairment experience greater improvements in mean power output than individuals with complete motor impairment.

Societal costs of intrathecal drug delivery systems--an administrative analysis based on patient claims.

OBJECTIVES: To quantify the overall and disaggregated societal costs of intrathecal drug delivery systems (IDDSs) in the treatment of pain and spasticity in the United States. MATERIALS AND METHODS: A retrospective review of medical and pharmacy claims was performed on patients with IDDS. Patients were divided into three cohorts according to the conditions that their IDDSs were intended to treat pain, spasticity, or both. Patients also were stratified according to whether or not cost data were available for the implantation of their IDDSs. Total societal costs that were directly attributable to pain or spasticity were summarized, and medical/pharmaceutical encounters were enumerated. RESULTS: N = 38,951 patients (52.7% women, age 54.1 ± 14.1 years) with IDDSs were identified and included in this study. IDDS patients have an average of 34.0-52.7 (depending on cohort) medical encounters per year, of which an average of 6.3-10.1 is attributable to the condition their IDDS is intended to treat. The average societal cost of the attributable encounters is $12,233 to $20,049 per patient year (inflation-adjusted 2011 U.S. dollars); however, the distribution of these costs is extremely skewed in the positive direction. Inpatient treatment accounts for 65.9% of the societal costs incurred by IDDS patients. CONCLUSIONS: The societal costs for IDDS patients are high and extremely variable. A relatively small number of patients made an extreme number of medical encounters and represent a heavy societal cost burden. In order to reduce the growing societal cost of chronic pain and spasticity treatment, measures should be taken to reduce the resource utilization and costs of the most challenging patients.

Classification of rhythmic locomotor patterns in electromyographic signals using fuzzy sets.

BACKGROUND: Locomotor control is accomplished by a complex integration of neural mechanisms including a central pattern generator, spinal reflexes and supraspinal control centres. Patterns of muscle activation during walking exhibit an underlying structure in which groups of muscles seem to activate in united bursts. Presented here is a statistical approach for analyzing Surface Electromyography (SEMG) data with the goal of classifying rhythmic "burst" patterns that are consistent with a central pattern generator model of locomotor control. METHODS: A fuzzy model of rhythmic locomotor patterns was optimized and evaluated using SEMG data from a convenience sample of four able-bodied individuals. As well, two subjects with pathological gait participated: one with Parkinson's Disease, and one with incomplete spinal cord injury. Subjects walked overground and on a treadmill while SEMG was recorded from major muscles of the lower extremities. The model was fit to half of the recorded data using non-linear optimization and validated against the other half of the data. The coefficient of determination, R(2), was used to interpret the model's goodness of fit. RESULTS: Using four fuzzy burst patterns, the model was able to explain approximately 70-83% of the variance in muscle activation during treadmill gait and 74% during overground gait. When five burst functions were used, one function was found to be redundant. The model explained 81-83% of the variance in the Parkinsonian gait, and only 46-59% of the variance in spinal cord injured gait. CONCLUSIONS: The analytical approach proposed in this article is a novel way to interpret multichannel SEMG signals by reducing the data into basic rhythmic patterns. This can help us better understand the role of rhythmic patterns in locomotor control.

Prospective 12-month study of intrathecal baclofen therapy for poststroke spastic upper and lower extremity motor control and functional improvement.

OBJECTIVES: To assess the effects of intrathecal baclofen (ITB) therapy for the treatment of poststroke spastic hemiparesis on quality of life, functional independence, and upper, lower extremity (UE, LE) motor functions. MATERIALS AND METHODS: Prospective observational study of adult men and women with a minimum 6-month stroke-related spastic hemiparesis graded as ≥2 in UE and LE on Modified Ashworth Scale (MAS). Patients served as their own controls with measures compared pre-implant with 12 months post ITB including: MAS, manual muscle test (MMT), gait distance/velocity, Functional Independence Measures (FIM), stroke-specific quality of life scale (SSQL), and upper extremity manual activity log. RESULTS: After 12-month ITB therapy, 26 patients (poststroke=6.4±9 years) demonstrated 1) reduced MAS/increased MMT for most LE muscle groups (p≤0.0001); 2) reduced MAS/increased MMT most UE muscle groups (p≤0.01); 3) FIM scores improved (p≤0.05) except bed mobility and lower body dressing; 4) gait distance and velocity improved (p≤0.05); 5) SSQL domains of family roles, mobility, personality, self-care, social roles, thinking, UE function, and work/productivity improved (p≤0.05); 6) amount of use and quality of movement of the spastic UE in performing common activities of daily living increased (p<0.0001). CONCLUSIONS: Regardless of duration of spastic hemiparesis, a reduction in tone with ITB therapy facilitates motor strength improvement and is associated with clinically significant improvements in functional independence and quality of life.

Robot-assisted gait training for patients with hemiparesis due to stroke.

Robot-assisted devices are becoming a popular alternative to manual facilitation in stroke rehabilitation. These devices have the potential to reduce therapist burden and treatment costs; however, their effectiveness in terms of functional recovery remains in question. This pilot study compared the outcomes of a stroke rehabilitation program that incorporates robot-assisted gait training (RAGT) with a more traditional therapy program that does not. Twenty hemiparetic stroke patients were recruited at a rehabilitation hospital in Houston, Texas, and were randomly assigned to 2 groups. The control group (n = 10) received 24 1-hour sessions of conventional physical therapy, whereas the RAGT group (n = 10) received 24 1-hour sessions of conventional physical therapy combined with RAGT on a treadmill. Gait function was assessed before and after treatment by an 8-m walk test, a 3-minute walk test, and the Tinetti balance assessment. Both groups showed significant improvement in all 3 outcome measures following treatment (P < .05), but there was no difference between groups. It is concluded that RAGT may provide improvements in balance and gait comparable with conventional physical therapy. A larger multicenter trial is required to investigate the effectiveness of RAGT in hemiparetic stroke.

Interactive effects of insulin-like growth factor-1 and beta-estradiol on endothelial nitric oxide synthase activity in rat aortic endothelial cells.

Insulin-like growth factor-1 (IGF-1) and beta-estradiol (E2) have vasodilatory effects, in part, through stimulation of vascular nitric oxide (NO) production. However, their interactive effects on endothelial nitric oxide synthase (eNOS) and NO production have not been previously studied in endothelial cells (EC). Employing rat aortic EC (RAEC), the effects of acute (20 and 30 minutes) and prolonged (4 hours) stimulation with 100 nmol/L IGF-1 and 1 nmol/L E2 (alone or in combination) were assessed with respect to protein levels and enzymatic activities for phosphatidyl inositol 3-kinase (PI3K) and serine/threonine kinase Akt (Akt), enzymes involved in eNOS activation. Exposure to IGF-1 for 30 minutes or E2 for 20 minutes increased insulin receptor substrate-1 (IRS-1) association with the regulatory (p85) subunit of PI3K, enhanced tyrosine phosphorylation of p85, and increased PI3K activity. Combined treatment had a greater effect on p85 phosphorylation and PI3K activity then either agonist alone. Moreover, IGF-1 and E2 enhanced Akt Ser(473) phosphorylation, with the effect of IGF-1 being much greater. Acute expose to both E2 (20 minutes) and IGF-1 (30 minutes) were associated with an increase in eNOS activity. Prolonged exposure (4 hours) to either IGF-1 or E2 increased expression of the p85 subunit as well as eNOS activity. Pretreatment with PI3K antagonist wortmannin (WT) prevented this increase in eNOS activity. The results suggest that IGF-1 and E2 may interact through PI3K/Akt-related pathways to increase eNOS activity.

Intracranial balloon angioplasty of acute terminal internal carotid artery occlusions.

Acute embolic occlusion of the intracranial internal carotid bifurcation is associated with a poor prognosis. Recanalization rates of this lesion with intravenous or intraarterial thrombolysis are exceedingly low. We describe the use of balloon angioplasty after failed thrombolysis to achieve immediate recanalization of acute carotid T occlusions in two patients. At 1-month follow-up, both patients were alive with neurologic deficits. For acute carotid T occlusion, balloon angioplasty should be considered a first-line endovascular therapy.