3,4-diaminopyridine base effectively treats the weakness of Lambert-Eaton myasthenia.

INTRODUCTION: 3,4-diaminopyridine has been used to treat Lambert-Eaton myasthenia (LEM) for 30 years despite the lack of conclusive evidence of efficacy. METHODS: We conducted a randomized double-blind placebo-controlled withdrawal study in patients with LEM who had been on stable regimens of 3,4-diaminopyridine base (3,4-DAP) for ≥ 3 months. The primary efficacy endpoint was >30% deterioration in triple timed up-and-go (3TUG) times during tapered drug withdrawal. The secondary endpoint was self-assessment of LEM-related weakness (W-SAS). RESULTS: Thirty-two participants were randomized to continuous 3,4-DAP or placebo groups. None of the 14 participants who received continuous 3,4-DAP had > 30% deterioration in 3TUG time versus 72% of the 18 who tapered to placebo (P < 0.0001). W-SAS similarly demonstrated an advantage for continuous treatment over placebo (P < 0.0001). Requirement for rescue and adverse events were more common in the placebo group. DISCUSSION: This trial provides significant evidence of efficacy of 3,4-DAP in the maintenance of strength in LEM. Muscle Nerve 57: 561-568, 2018.

Parkinson's disease-related fatigue: A case definition and recommendations for clinical research.

Fatigue is one of the most common and disabling symptoms in Parkinson's disease (PD). Since fatigue was first described as a common feature of PD 20 years ago, little progress has been made in understanding its causes or treatment. Importantly, PD patients attending the 2013 World Parkinson Congress voted fatigue as the leading symptom in need of further research. In response, the Parkinson Disease Foundation and ProjectSpark assembled an international team of experts to create recommendations for clinical research to advance this field. The working group identified several areas in which shared standards would improve research quality and foster progress including terminology, diagnostic criteria, and measurement. Terminology needs to (1) clearly distinguish fatigue from related phenomena (eg, sleepiness, apathy, depression); (2) differentiate subjective fatigue complaints from objective performance fatigability; and (3) specify domains affected by fatigue and causal factors. We propose diagnostic criteria for PD-related fatigue to guide participant selection for clinical trials and add rigor to mechanistic studies. Recommendations are made for measurement of subjective fatigue complaints, performance fatigability, and neurophysiologic changes. We also suggest areas in which future research is needed to address methodological issues and validate or optimize current practices. Many limitations in current PD-related fatigue research may be addressed by improving methodological standards, many of which are already being successfully applied in clinical fatigue research in other medical conditions (eg, cancer, multiple sclerosis). © 2016 International Parkinson and Movement Disorder Society.

Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with few therapeutic options. Mild obesity is associated with greater survival in patients with the disease, and calorie-dense diets increased survival in a mouse model. We aimed to assess the safety and tolerability of two hypercaloric diets in patients with amyotrophic lateral sclerosis receiving enteral nutrition. METHODS: In this double-blind, placebo-controlled, randomised phase 2 clinical trial, we enrolled adults with amyotrophic lateral sclerosis from participating centres in the USA. Eligible participants were aged 18 years or older with no history of diabetes or liver or cardiovascular disease, and who were already receiving percutaneous enteral nutrition. We randomly assigned participants (1:1:1) using a computer-generated list of random numbers to one of three dietary interventions: replacement calories using an isocaloric tube-fed diet (control), a high-carbohydrate hypercaloric tube-fed diet (HC/HC), or a high-fat hypercaloric tube-fed diet (HF/HC). Participants received the intervention diets for 4 months and were followed up for 5 months. The primary outcomes were safety and tolerability, analysed in all patients who began their study diet. This trial is registered with ClinicalTrials.gov, number NCT00983983. FINDINGS: Between Dec 14, 2009, and Nov 2, 2012, we enrolled 24 participants, of whom 20 started their study diet (six in the control group, eight in the HC/HC group, and six in the HF/HC group). One patient in the control group, one in the HC/HC group, and two in the HF/HC group withdrew consent before receiving the intervention. Participants who received the HC/HC diet had a smaller total number of adverse events than did those in the other groups (23 in the HC/HC group vs 42 in the control group vs 48 in the HF/HC group; overall, p=0.06; HC/HC vs control, p=0.06) and significantly fewer serious adverse events than did those on the control diet (none vs nine; p=0.0005). Fewer patients in the HC/HC group discontinued their study diet due to adverse events (none [0%] of eight in the HC/HC group vs three [50%] of six in the control group). During the 5 month follow-up, no deaths occurred in the nine patients assigned to the HC/HC diet compared with three deaths (43%) in the seven patients assigned to the control diet (log-rank p=0.03). Adverse events, tolerability, deaths, and disease progression did not differ significantly between the HF/HC group and the control group. INTERPRETATION: Our results provide preliminary evidence that hypercaloric enteral nutrition is safe and tolerable in patients with amyotrophic lateral sclerosis, and support the study of nutritional interventions in larger randomised controlled trials at earlier stages of the disease. FUNDING: Muscular Dystrophy Association, National Center for Research Resources, National Institutes of Health, and Harvard NeuroDiscovery Center.

Effect of expectancy and personality on cortical excitability in Parkinson's disease.

Our previous studies in Parkinson's disease have shown that both levodopa and expectancy of receiving levodopa reduce cortical excitability. We designed this study to evaluate how degree of expectancy and other individual factors modulate placebo response in Parkinson's patients. Twenty-six Parkinson's patients were randomized to 1 of 3 groups: 0%, 50%, and 100% expectancy of receiving levodopa. All subjects received placebo regardless of expectancy group. Subjects completed the NEO-Five Factor Inventory, General Perceived Self-Efficacy Scale, and Perceived Stress Scale. Cortical excitability was measured by the amplitude of motor-evoked potential (MEP) evoked by transcranial magnetic stimulation. Objective physical fatigue of extensor carpi radialis before and after placebo levodopa was also measured. Responders were defined as subjects who responded to the placebo levodopa with a decrease in MEP. Degree of expectancy had a significant effect on MEP response (P < .05). Subjects in the 50% and 100% expectancy groups responded with a decrease in MEP, whereas those in the 0% expectancy group responded with an increase in MEP (P < .05). Responders tended to be more open to experience than nonresponders. There were no significant changes in objective physical fatigue between the expectancy groups or between responders and nonresponders. Expectancy is associated with changes in cortical excitability. Further studies are needed to examine the relationship between personality and placebo effect in Parkinson's patients. © 2013 Movement Disorder Society.

Treatment of severe hand impairment following stroke by combining assisted movement, muscle vibration, and biofeedback.

BACKGROUND AND PURPOSE: Few studies have addressed the rehabilitation of hand function in persons with severe impairment following stroke, and few therapeutic options are available for treatment. We investigated whether an intervention of robot-assisted movement and muscle vibration could reduce impairment and enable hand-opening to a greater extent when combined with torque biofeedback or electromyographic (EMG) biofeedback. METHODS: Forty-three participants with severe hand impairment due to chronic stroke (≥1 year poststroke) were randomized to 1 of 2 treatment groups receiving assisted movement and muscle vibration combined with either torque or EMG biofeedback. Each participant received 30 sessions (30 minutes duration per session) directed at the impaired hand over 10 to 12 weeks. Outcomes were assessed using the Upper Extremity Fugl-Meyer Assessment (UE-FMA), Stroke Impact Scale, and Box-and-Block Test scores. RESULTS: Twenty-eight of 43 participants had no baseline finger extension; the remainder had an average of 23 ± 26 mm extension in the most active finger. Assisted movement and muscle vibration were associated with a significant increase in all outcome measures across both treatment groups, and for the UE-FMA and Stroke Impact Scale within treatment groups, with no significant difference between groups. Based on the Box-and-Block Test scores, the assisted movement and muscle vibration intervention did not restore functional hand-opening to participants with baseline UE-FMA scores less than 17/66, regardless of the form of biofeedback. DISCUSSION AND CONCLUSIONS: Assisted movement and muscle vibration, combined with either EMG or torque biofeedback, appears to reduce upper limb impairment, improve volitional activation of the hand muscles, and restore a modicum of hand function in some persons with severe hand impairment due to chronic stroke.Video Abstract available (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A64) for more insights from the authors.

Screening cut-off scores for clinically significant fatigue in early Parkinson's disease.

Background: Fatigue is one of the most disabling non-motor symptoms in PD. Researchers have previously used cut-offs validated in non-PD conditions when using the Fatigue Severity Scale (FSS) or the Multidimensional Fatigue Inventory (MFI) scores to evaluate fatigue in PD. Objective: We used a set of criteria for diagnosing clinically significant fatigue in PD to identify the proper cut-offs of the FSS and MFI. Methods: One hundred thirty-one PD patients (59F; age 67.3 ± 7.6 y; H&Y 1.6 ± 0.7) were assessed for clinically significant fatigue, followed by the FSS, MFI, Center for Epidemiologic Studies Depression Scale (CES-D), and Montreal Cognitive Assessment (MOCA). Mean scores were compared between 17 patients who met diagnostic criteria (significant fatigue group, SFG) and 114 who did not (non-significant fatigue group, NSFG). Results: The SFG had significantly higher scores in the 9-item FSS (p <.0001), total MFI score (p <.0001), and every MFI dimension except reduced motivation (p =.1) than the NSFG. Using area under the curve (AUC) of receiver operating characteristic (ROC) analyses, we recommend the following cut-offs: 9-item FSS 37; total MFI 60; general fatigue 11; reduced activity 10; physical fatigue 9; mental fatigue 9; and reduced motivation 9. Conclusions: The recommended cut-offs for clinically significant fatigue in the FSS, MFI, and MFI dimensions will be valuable for diagnosing clinically significant fatigue and for future studies in investigating pathophysiology and potential treatments of fatigue in PD.

The Effect of Skeletal Muscle-Pump on Blood Pressure and Postural Control in Parkinson's Disease.

PURPOSE: Activation of the calf (gastrocnemius and soleus) and tibialis anterior muscles play an important role in blood pressure regulation (via muscle-pump mechanism) and postural control. Parkinson's disease is associated with calf (and tibialis anterior muscles weakness and stiffness, which contribute to postural instability and associated falls. In this work, we studied the role of the medial and lateral gastrocnemius, tibialis anterior, and soleus muscle contractions in maintaining blood pressure and postural stability in Parkinson's patients and healthy controls during standing. In addition, we investigated whether the activation of the calf and tibialis anterior muscles is baroreflex dependent or postural-mediated. METHODS: We recorded electrocardiogram, blood pressure, center of pressure as a measure of postural sway, and muscle activity from the medial and lateral gastrocnemius, tibialis anterior, and soleus muscles from twenty-six Parkinson's patients and eighteen sex and age-matched healthy controls during standing and with eyes open. The interaction and bidirectional causalities between the cardiovascular, musculoskeletal, and postural variables were studied using wavelet transform coherence and convergent cross-mapping techniques, respectively. RESULTS: Parkinson's patients experienced a higher postural sway and demonstrated mechanical muscle-pump dysfunction of all individual leg muscles, all of which contribute to postural instability. Moreover, our results showed that coupling between the cardiovascular, musculoskeletal, and postural variables is affected by Parkinson's disease while the contribution of the calf and tibialis anterior muscles is greater for blood pressure regulation than postural sway. CONCLUSION: The outcomes of this study could assist in the development of appropriate physical exercise programs that target lower limb muscles to improve the muscle-pump function and reduce postural instability in Parkinson's disease.

Effect of Parkinson's Disease on Cardio-postural Coupling During Orthostatic Challenge.

Cardiac baroreflex and leg muscles activation are two important mechanisms for blood pressure regulation, failure of which could result in syncope and falls. Parkinson's disease is known to be associated with cardiac baroreflex impairment and skeletal muscle dysfunction contributing to falls. However, the mechanical effect of leg muscles contractions on blood pressure (muscle-pump) and the baroreflex-like responses of leg muscles to blood pressure changes is yet to be comprehensively investigated. In this study, we examined the involvement of the cardiac baroreflex and this hypothesized reflex muscle-pump function (cardio-postural coupling) to maintain blood pressure in Parkinson's patients and healthy controls during an orthostatic challenge induced via a head-up tilt test. We also studied the mechanical effect of the heart and leg muscles contractions on blood pressure. We recorded electrocardiogram, blood pressure and electromyogram from 21 patients with Parkinson's disease and 18 age-matched healthy controls during supine, head-up tilt at 70°, and standing positions with eyes open. The interaction and bidirectional causalities between the cardiovascular and musculoskeletal signals were studied using wavelet transform coherence and convergent cross mapping techniques, respectively. Parkinson's patients displayed an impaired cardiac baroreflex and a reduced mechanical effect of the heart on blood pressure during supine, tilt and standing positions. However, the effectiveness of the cardiac baroreflex decreased in both Parkinson's patients and healthy controls during standing as compared to supine. In addition, Parkinson's patients demonstrated cardio-postural coupling impairment along with a mechanical muscle pump dysfunction which both could lead to dizziness and falls. Moreover, the cardiac baroreflex had a limited effect on blood pressure during standing while lower limb muscles continued to contract and maintain blood pressure via the muscle-pump mechanism. The study findings highlighted altered bidirectional coupling between heart rate and blood pressure, as well as between muscle activity and blood pressure in Parkinson's disease. The outcomes of this study could assist in the development of appropriate physical exercise programs to reduce falls in Parkinson's disease by monitoring the cardiac baroreflex and cardio-postural coupling effect on maintaining blood pressure.

Early Detection of Parkinson's Disease Using Center of Pressure Data and Machine Learning.

Parkinson's disease (PD) is a progressive neurodegenerative disorder resulting in abnormal body movements. Postural instability is one of the primary motor symptoms of PD and contributes to falls. Measurement of postural sway through center of pressure (COP) data might be an objective indicator of Parkinson's disease. The goal of this work is to use machine learning to evaluate if different features of postural sway can differentiate PD patients from healthy controls. Time domain, frequency domain, time-frequency, and structural features were extracted from COP data collected from 19 PD patients and 13 healthy controls (HC). The calculated parameters were input to various machine-learning models to classify PD and HC. Random Forest outperformed the rest of the classifiers in terms of accuracy, false negative rate, F1-score, and precision. Time domain features had the best performance in differentiating PD from HC compared to other feature groups.

Correlates of quality of life in ALS: Lessons from the minocycline study.

Improving quality of life (QoL) is a major goal in ALS palliative care. Previous studies performed on the general ALS population showed no relationship between QoL and disease progression. ALS subjects participating in clinical trials may differ from those in the general ALS population. We explored the relationship between QoL and disease progression in 412 subjects enrolled in a minocycline trial. We examined correlations between Single Item McGill Quality of Life Scale (MQoL-SIS) score and disease duration, ALS Functional Rating Scale Revised (ALSFRS-R) score, FVC, and survival rate. We also analyzed how NIV and PEG affect QoL. Within subjects, MQoL-SIS scores correlated with ALSFRS-R and FVC (p<0.001). MQoL-SIS declined over time (p<0.001) and correlated with the decline of ALSFRS-R (p<0.001). MQoL-SIS tended to improve after initiation of NIV (p=0.07). There was a significant reduction in the rate of MQoL-SIS decline (p<0.001) after initiation of PEG. Subjects with slower QoL decline survived seven months longer than those with faster QoL decline (p<0.01). Our study demonstrated that QoL does decline with advancing ALS in subjects who participated in a minocycline trial, that the slope of QoL predicts survival, and that both NIV and PEG have beneficial impacts on QoL.

Placebo responses in Parkinson's disease.

Parkinson's disease (PD) patients exhibit strong placebo responses in clinical trials. Patient characteristics that affect placebo include patients' expectations of good outcomes, genetic variants, and personality. The presence of motor fluctuation and high baseline UPDRS motor scores predicted placebo response. However, gender, age, duration of PD, religion, or level of education do not correlate with placebo response. PD patients who are preconditioned with active treatment such as apomorphine have more robust placebo effects. Studies that focused on patients with motor fluctuations, surgical intervention, or higher probability of placebo assignment had higher rates of placebo response. Patients view participating in placebo-controlled trials positively. Placebo effect can be measured objectively using neuroimaging and neurophysiological techniques. PET studies show that placebo-induced improvement is associated with dopamine release in the dorsal striatum and that the expectation of receiving the reward, not the reward itself, increased dopamine release in the ventral striatum. Expectations of benefitting from repetitive transcranial magnetic stimulation also induced dopamine release. Expectations of receiving a dopaminergic drug induced changes in fMRI in a reward-learning task. Single cell recordings demonstrate that placebo response is associated with changes of single neuronal activities in the basal ganglia circuit. These studies demonstrate that placebo effects are genuine biological responses to the administration of placebo. In clinical trials, we can use several approaches to minimize placebo responses. In clinical practice, we can use approaches to harness the power of placebo and minimize nocebo effects to improve patients' outcome.

Physical and mental fatigue in Parkinson's disease: epidemiology, pathophysiology and treatment.

Fatigue is one of the most common non-motor complaints of Parkinson's disease (PD) patients and is associated with reduced activity and poorer quality of life. Fatigue can be experienced as a state of being tired or weary (subjective fatigue) or as a process of becoming tired or fatigued (fatigability). Subjective mental and physical fatigue are evaluated using self-report questionnaires such as the Multidimensional Fatigue Inventory. Physical fatigability is studied in a laboratory setting using physical exercise protocols and transcranial magnetic stimulation. Mental fatigability is evaluated by measuring attention over time using a reaction-time paradigm called the Attention Network Test (ANT). PD patients report more subjective physical and mental fatigue than controls on a variety of fatigue questionnaires. PD patients have increased physical fatigability in force generation and finger tapping. Levodopa and modafinil improve physical fatigability in PD subjects. Methylphenidate is useful for treating subjective physical fatigue. PD subjects have greater mental fatigability than control subjects and display abnormal performance in all three attention networks in the ANT. Therapies targeting the neurotransmitter systems involved in attention may be helpful for treating mental fatigability. Future fatigue research should focus on developing gold standards for fatigue measurement and developing treatments for fatigue and fatigability in PD.

Relationship between Ischemic Stroke and Pulse Rate Variability as a Surrogate of Heart Rate Variability.

Autonomic reflex ascertains cardiovascular homeostasis during standing. Impaired autonomic reflex could lead to dizziness and falls while standing; this is prevalent in stroke survivors. Pulse rate variability (PRV) has been utilized in the literature in lieu of heart rate variability (HRV) for ambulatory and portable monitoring of autonomic reflex predominantly in young, healthy individuals. Here, we compared the PRV with gold standard HRV for monitoring autonomic reflex in ischemic stroke survivors. Continuous blood pressure and electrocardiography were acquired from ischemic stroke survivors (64 ± 1 years) and age-matched controls (65 ± 2 years) during a 10-minute sit-to-stand test. Beat-by-beat heart period (represented by RR and peak-to-peak (PP) intervals), systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse arrival time (PAT), an indicator of arterial stiffness, were derived. Time and frequency domain HRV (from RR intervals) and PRV (from PP intervals) metrics were extracted. PAT was lower (248 ± 7 ms vs. 270 ± 8 ms, p < 0.05) suggesting higher arterial stiffness in stroke survivors compared to controls during standing. Further, compared to controls, the agreement between HRV and PRV was impaired in stroke survivors while standing. The study outcomes suggest that caution should be exercised when considering PRV as a surrogate of HRV for monitoring autonomic cardiovascular control while standing in stroke survivors.

Quantitative anal sphincter electromyography in primiparous women with anal incontinence.

OBJECTIVE: The purpose of this study was to determine whether evidence of denervation/reinnervation of the external anal sphincter is associated with anal incontinence symptoms immediately after delivery. STUDY DESIGN: After a first vaginal delivery, 42 women completed an anal incontinence questionnaire. They also underwent concentric needle electromyography of the external anal sphincter. For each subject, motor unit action potential and interference pattern parameters were determined. RESULTS: For the motor unit action potential, no difference was observed between patients with and without anal incontinence symptoms (t-test). For the interference pattern, the amplitude/turn was greater in subjects with fecal urgency (318 +/- 48 [SD] microV) and fecal incontinence (332 +/- 48 microV), compared with those without fecal urgency (282 +/- 38 microV) and fecal incontinence (286 +/- 41 microV; P = .02, t-test). CONCLUSION: In this group of postpartum women with mild anal incontinence symptoms, interference pattern analysis shows evidence of denervation and subsequent reinnervation.

Creatine monohydrate in ALS: effects on strength, fatigue, respiratory status and ALSFRS.

Our objective was to determine the effect of creatine monohydrate on disease progression in patients with amyotrophic lateral sclerosis (ALS). One hundred and seven patients with the diagnosis of probable or definite ALS, of less than five years duration from symptom onset, were randomized to either treatment with daily creatine monohydrate (5 g/d) or placebo. In this multicenter, double-blinded study we followed changes in disease progression: using quantitative measures of strength via maximal isometric voluntary contraction, forced vital capacity, ALSFRS, quality of life, fatigue and survival. Patients were followed for nine months. The results showed that creatine monohydrate did not significantly improve motor, respiratory or functional capacity in this patient population. The drug was well tolerated and the study groups well balanced, especially considering the absence of forced vital capacity criteria for entrance into the study. There was a trend toward improved survival in patients taking daily creatine monohydrate and this was identical to the trend seen in another recently published report of creatine in ALS patients 1. In conclusion, creatine monohydrate (5 g/d) did not have an obvious benefit on the multiple markers of disease progression measured over nine months. We measured fatigue during isometric contraction and found no significant improvement despite anecdotal patient reports prior to and during the study. The trend toward improved survival was also found in another recently completed blinded trial using creatine monohydrate. Further investigation on the possible survival benefit of creatine in this patient population is ongoing.

A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS.

Combining agents with different mechanisms of action may be necessary for meaningful results in treating ALS. The combinations of minocycline-creatine and celecoxib-creatine have additive effects in the murine model. New trial designs are needed to efficiently screen the growing number of potential neuroprotective agents. Our objective was to assess two drug combinations in ALS using a novel phase II trial design. We conducted a randomized, double-blind selection trial in sequential pools of 60 patients. Participants received minocycline (100 mg)-creatine (10 g) twice daily or celecoxib (400 mg)-creatine (10 g) twice daily for six months. The primary objective was treatment selection based on which combination best slowed deterioration in the ALS Functional Rating Scale-Revised (ALSFRS-R); the trial could be stopped after one pool if the difference between the two arms was adequately large. At trial conclusion, each arm was compared to a historical control group in a futility analysis. Safety measures were also examined. After the first patient pool, the mean six-month decline in ALSFRS-R was 5.27 (SD=5.54) in the celecoxib-creatine group and 6.47 (SD=9.14) in the minocycline-creatine group. The corresponding decline was 5.82 (SD=6.77) in the historical controls. The difference between the two sample means exceeded the stopping criterion. The null hypothesis of superiority was not rejected in the futility analysis. Skin rash occurred more frequently in the celecoxib-creatine group. In conclusion, the celecoxib-creatine combination was selected as preferable to the minocycline-creatine combination for further evaluation. This phase II design was efficient, leading to treatment selection after just 60 patients, and can be used in other phase II trials to assess different agents.

Fatigue in amyotrophic lateral sclerosis.

Fatigue is a common and potentially debilitating symptom of amyotrophic lateral sclerosis (ALS). Questionnaire studies show that ALS subjects have increased subjective fatigue. Physiologic studies demonstrate that ALS subjects have increased physical fatigue, both central and peripheral in origin. No treatment has been proved effective through evidence-based medicine; however, modafinil (Provigil) may be a helpful pharmacologic treatment. Palliative care measures, such as noninvasive ventilation and high-frequency chest wall oscillation, may also reduce fatigue.

Centella asiatica triterpenes for diabetic neuropathy: a randomized, double-blind, placebo-controlled, pilot clinical study.

BACKGROUND: Diabetic neuropathy (DN), a common complication of diabetes mellitus, results from hyperglycemia, poor microcirculation and attendant nerve damage. Currently available treatments relieve symptoms, but do not modify the neurodegeneration underlying DN. Centella asiatica (CA) triterpenes improved microcirculation in earlier clinical studies, and showed neurotropic effects in preclinical models suggesting a potential disease modifying effect in DN. This 52-week, randomized, double-blind, placebo-controlled trial examined the effects of CAST, a standardized CA extract containing triterpenes, on neuropathy symptoms in Type II diabetic subjects. PATIENTS AND METHODS: The study enrolled patients with a history of Type II diabetes, with evidence of symptomatic symmetrical DN with total symptom score (TSS) ≥4, and stable HbA1c level <8. The primary outcome measure was TSS, which assessed intensity and frequency of parasthesia, numbness, pain and burning symptoms self-reported by patients. Secondary measures were nerve conduction, neurological impairment score, and quantitative sensory testing. RESULTS: Comparing CAST (n=21) and Placebo (n=22) groups, significant reductions from baseline for TSS (p<0.01) and paresthesia (p<0.01) were seen only in CAST treated groups. Numbness increased from baseline only in the Placebo group (p<0.05) and was significantly higher than for the CAST group (p<0.001). Burning sensation was reduced in both groups (p<0.01). Plasma triterpene levels in patients treated with CAST mirrored neurotropic concentrations in vitro. CONCLUSIONS: CAST is a potential oral treatment for diabetic neuropathy, as it is well tolerated and effective in reducing the severity of DN symptoms in patients with Type II diabetes.

Hand coordination as a quantitative measure of motor abnormality and therapeutic response in Parkinson's disease.

OBJECTIVE: The precision grip-and-lift task (PGLT) has been used to measure hand motor coordination in PD. We designed this study to investigate if the PGLT outcome variables correlate with the UPDRS motor scores and if all PGLT outcome variables are "responsive" to levodopa. METHODS: We used PGLT to assess hand motor coordination in 10 PD and 10 normal controls before and after levodopa. RESULTS: Factor analysis showed that the six PGLT parameters were reduced to two factors, a levodopa-responsive factor and a dopa-resistant factor that explained 74% of the total variance. The levodopa-responsive factor, which correlated significantly with "off" UPDRS motor scores, includes load preparation time, maximum vertical acceleration, maximum grip velocity and maximum grip force. The levodopa-resistant factor, which did not correlate with "off" UPDRS motor scores, included maximum negative load force and tremor during lift. Both dopa-responsive and dopa-resistant factors were altered in PD compared to controls before levodopa. Levodopa improved dopa-responsive, but not dopa-resistant factor in PD. CONCLUSIONS: PGLT can measure two aspects of fine motor performance, both affected by PD but differentially affected by levodopa. SIGNIFICANCE: PGLT can be useful in characterizing the response of motor abnormality in PD therapeutic trials.