Intravenous lisuride corrects oscillations of motor performance in Parkinson's disease

Seventeen lisuride infusions were given to 12 patients with Parkinson's disease who showed daily oscillations in motor performance. The mean lisuride dose given in continuous intravenous infusion was 0.59 mg (range, 0.3 to 1.0 mg) during a mean period of 9.0 hours (range, 5 to 12 hours). A significant reduction in the number of hours "off" was obtained in all patients. Additional oral levodopa was necessary to maintain normal mobility throughout the infusions. Severe hypotension occurred in 2 patients which required termination of the infusions. Five patients experienced nausea, sweating, and malaise but this did not necessitate interruption of the infusions. Lisuride appears to be one of the best available dopamine agonists for continuous dopaminergic stimulation.     

Bromocriptine and lisuride in Parkinson disease

Lisuride was compared with bromocriptine in 25 parkinsonian patients in whom the response to levodopa had diminished; 19 had “wearing off,” “on-off” phenomena, or both. At the time bromocriptine was added to levodopa, the mean age of the patients was 62.7 years and mean disease duration was 8.9 years. Disability decreased by 34% in the on period and by 20% in the off period, and the number of hours the patients were on increased from 9.6 to 12.8. All these changes were significant (p ≤ 0.01 to 0.05). Bromocriptine, however, had to be discontinued in 11 patients because of adverse effects. In the remaining 14 patients, bromocriptine was eventually discontinued because of decreased efficacy. Mean dose of bromocriptine was 55 mg (range, 20 to 100 mg). At the time lisuride was added to levodopa the patients were older (65.4 years), had had the disease longer (11.4 years), and were more disabled. Nonetheless, disability decreased in the on period by 33% and in the off period by 17%, and the number of hours the patients were on increased from 3.9 to 8.9. All these changes were significant (p ≤ 0.01 to 0.05). The mean dose of lisuride was 2.8 mg (range, 0.6 to 5.0 mg). Lisuride was discontinued in 8 patients because of adverse effects. Both bromocriptine and lisuride are useful in managing patients with advanced Parkinson disease whose response to levodopa has diminished. While it is presently not possible to state which of the drugs is more effective, ultimately their usage will probably be determined by their relative cost.     

Nocturnal subcutaneous apomorphine infusion in Parkinson's disease and restless legs syndrome

OBJECTIVES: Nocturnal disabilities leading to fragmented sleep arising from parkinsonian off period related complications are common, under-reported and are difficult to treat. In this study, we evaluate the use of nocturnal continuous subcutaneous overnight apomorphine infusion in Parkinson's disease and restless legs syndrome. METHODS: Six parkinsonian patients and 2 patients with restless legs syndrome with nocturnal disabilities refractory to conventional oral therapy were assessed using a sleep diary while on standard treatment and during nocturnal apomorphine infusion. Three patients agreed to assessments during placebo infusion with normal saline. RESULTS: Apomorphine led to a dramatic reduction of nocturnal awakenings, nocturnal off periods, pain, dystonia and nocturia in parkinsonian patients. In patients with restless legs syndrome, apomorphine reduced nocturnal discomfort, reduced leg movements and improved pain and spasm scores significantly. Placebo infusion reproduced pain, nocturnal spasms and sleep disruption. CONCLUSION: This study suggests that overnight apomorphine infusion may be effective in overcoming refractory nocturnal disabilities in selected patients with Parkinson's disease and restless legs syndrome.     

Zydis selegiline reduces off time in Parkinson's disease patients with motor fluctuations: a 3-month, randomized, placebo-controlled study.

Zydis selegiline dissolves on contact with saliva and undergoes pregastric absorption. This minimizes first-pass metabolism and provides high plasma concentrations of selegiline. In this study, the efficacy and safety of Zydis selegiline was assessed in Parkinson's disease (PD) patients who were experiencing motor fluctuations with levodopa. Patients were randomly assigned to either drug or placebo in a 2:1 ratio in this double-blind, multicenter trial. Significant reductions in daily off time occurred at 4 to 6 weeks with the 1.25 mg dose (9.9%, P = 0.003) and 10 to 12 weeks with the 2.5 mg dose (13.2%, P < 0.001). The total number of off hours was reduced by 2.2 hours at Week 12 from baseline (compared with 0.6 hours in the placebo group). The average number of dyskinesia-free on hours for the Zydis selegiline patients increased by 1.8 hours at Week 12. There was no change in mean percentage of "Asleep" time throughout the study. No apparent differences were detected in the occurrence of drug-related adverse events between the Zydis selegiline group and placebo-treated groups. Adverse events were consistent with known effects of levodopa therapy. Zydis selegiline safely reduces daily off time when used as adjunctive therapy with levodopa in patients with PD.     

Apomorphine monotherapy in the treatment of refractory motor complications of Parkinson's disease: long-term follow-up study of 64 patients.

Continuous subcutaneous infusion of apomorphine is now increasingly recognized as an effective treatment for refractory off periods and peak-dose dyskinesias in Parkinson's disease. We have reviewed our experience with apomorphine infusions, after a strategy decision in 1995 based on emerging preclinical data, to treat all patients with steady-state plasma levels of apomorphine throughout the waking day, minimizing additional pulsatile stimulation either by oral dopaminergic medication or bolus parenteral injections of apomorphine. Sixty-four patients have been treated with apomorphine pumps and 45 of these successfully converted to monotherapy, managing to discontinue all other forms of dopaminergic stimulation during the daytime treatment period with apomorphine. Patients were followed up for a mean of 33.8 months (range, 4-108 months) and clinical data analyzed retrospectively. The mean maintenance dose of apomorphine was 98 mg per 24 hours (monotherapy group: 103 mg/24 hours; polytherapy group: 93 mg/24 hours), which did not significantly increase at final follow-up. There was a mean maximum dyskinesia reduction of 64% (S.D. = 20) in the monotherapy group, compared to 30% (S.D. = 33) in those continuing on polytherapy (P < 0.001), despite a maintained increase in on time (monotherapy group: 55%, P < 0.005; polytherapy group: 50%, P = 0.05). Fifteen patients failed to successfully convert to monotherapy but benefited nonetheless, and only 3 failed apomorphine infusional therapy altogether. Reasons for failure were mixed, including difficulty with compliance and adverse effects such as daytime somnolence, skin complications, and painful dystonias. There was a significantly higher success rate in patients able to manage the treatment either independently or with the help of their caregiver. These results confirm that subcutaneous apomorphine monotherapy can reset peak-dose dyskinesia threshold in levodopa-treated patients and further reduce off-period disability after all available forms of oral medication, including long-acting dopamine agonists, have been tried.     

Longitudinal study of the motor response to levodopa in Parkinson's disease.

In this prospective study of 34 patients with Parkinson's disease, measurements of the short duration levodopa motor response have been performed in defined off states at 3 yearly intervals over a mean period of 11.4 years from the point of commencement of levodopa treatment. Twenty-two patients were still available for study; 10 had died and 2 were lost to follow-up. The levodopa motor response amplitude increases over the first 5 years of treatment, and thereafter, on and off scores worsen in parallel with conservation of the response. Patients who developed motor fluctuations within the first 5 years of treatment had, on average, a stronger response to levodopa with significantly better on phase motor function (P = 0.003). Although the proportion of "midline" motor disability (affecting gait, balance, and cranial motor function) increases with time, these deficits do not actually become unresponsive to levodopa. Patients who developed dementia had a significantly more rapid decline in motor function. The latest graph of serial scores for the whole cohort shows an upward curving or exponential increase in motor disability after the first decade of treatment. Applying a notional untreated disability line to this graph--an estimate of the disability that would have accrued if drugs had never been given--we suggest that the long-duration response to levodopa eventually runs down with disease progression.     

Sublingual administration of apomorphine in the treatment of motor fluctuations in Parkinson disease]

Apomorphine, a mixed dopaminergic agonist was given sublingually to 12 patients with Parkinson's disease disabled by severe on-off fluctuations. The patient's mean age was 57 years and the duration of Parkinson's disease was 12 years. All patients were also given domperidone (60 mg/day). Apomorphine was administered as soon as the off periods appeared. On periods were observed in 11 patients, with a mean apomorphine dose of 40 mg for each administration (extremes values: 20-60 mg). One patient had no motor benefit after an apomorphine dose of 120 mg. The mean duration of daily off periods was reduced by 64 per cent in 11 patients, for a mean duration of 8 months (extremes values: 2-12 months). Four patients developed stomatitis or gingival edema and stopped treatment. This pilot study shows that sublingual apomorphine, during a mean period of 8 months, significantly decreases off periods in parkinsonian patients. Others studies are necessary to confirm these results.     

Myotatic reflexes and the on-off effect in patients with Parkinson's disease.

Reflex activity in the biceps and triceps muscles evoked by applied torque perturbations was studied in patients with Parkinson''s disease. The perturbations consisted of single pulses or of pseudo-random sequences of pulses of torque. The patients were treated with levodopa and some exhibited marked fluctuations in their clinical disabilities ("on-off" effect). The study was undertaken to see if reflex activity changed in parallel with the fluctuations of their clinical symptoms. It was found that the reflex activity in these patients could be classified into two types, a Type I response differing little from normal and a Type II response exhibiting marked high-frequency (8-14 Hz) oscillations in EMG activity. Both Type I and Type II responses were virtually the same in the "on" as in the "off" state.     

Sublingual apomorphine in Parkinson's disease: a clinical and pharmacokinetic study.

The clinical response and the pharmacokinetic parameters of 3 mg subcutaneous (SC) and 30 mg sublingual (SL) apomorphine were compared in nine patients with Parkinson's disease. The magnitude of the motor responses (evaluated by tapping and walking tests and the Webster scale) was similar for SC and SL apomorphine. However, the onset to action was delayed after SL when compared with SC apomorphine. No significant difference was found in bioavailability (area under the curve: AUC) or peak plasma concentration (Cmax) between SC and SL apomorphine, whereas time to peak plasma concentration (Tmax) was shorter after SC apomorphine. Eight other patients were treated for a mean time of 4 months with SL apomorphine with a significant reduction in daily "off" hours. However, four of these eight patients developed stomatitis after some weeks of treatment. These results indicated that (a) pharmacokinetics parallel the clinical response to SL apomorphine, (b) SL apomorphine can reduce severe off periods in parkinsonian patients when used chronically, and (c) its long-term use is limited by a severe side effect (stomatitis).     

Effects of subthalamic nucleus (STN) stimulation on motor cortex excitability

BACKGROUND: Deep brain stimulation of the internal global pallidus (GPi) and the subthalamic nucleus (STN) has become a treatment alternative in advanced PD. Although the effects of GPi stimulation have been examined recently, little is known about STN stimulation effects on motor cortex excitability. METHODS: The effects of STN stimulation were studied in eight patients with advanced PD using paired-pulse transcranial magnetic stimulation (TMS) in comparison with healthy control subjects. Motor evoked potentials following paired-pulse TMS (interstimulus interval 3 ms to test for corticocortical inhibition vs 13 ms for facilitation) have been recorded from the extensor carpi radialis and its functional antagonist, the flexor carpi radialis muscle. Silent period (SP) was also determined. Patients were examined under four conditions: medication "off"/stimulator "off" vs medication "on"/stimulator "off" vs medication "off"/stimulator "on" vs medication "on"/stimulator "on." RESULTS: Although the mean values for intracortical inhibition (ICI) were not significantly different, data variation was smaller and levels of significance higher with the STN stimulator switched "on," suggesting that ICI was more consistent. SP during stimulator "on"/medication "on" was longer than during stimulator "off"/medication "off." Motor performance as indicated by a finger-tapping test and Unified PD Rating Scale III was significantly better with dopaminergic medication and further improved with stimulator "on." CONCLUSIONS: Results suggest an effect of subthalamic nucleus stimulation on intracortical inhibitory mechanisms. This hypothesis could at least partially explain a more consistent depression of motor evoked potentials following inhibiting paired-pulse transcranial magnetic stimulation, a longer silent period (under stimulator "on"/medication "on"), and a reduction of akinesia and rigidity leading to a better motor performance in subthalamic nucleus-stimulated patients.     

Predicting beneficial response to a protein-redistribution diet in fluctuating Parkinson's disease.

To identify factors that might help in predicting the benefit to be gained from a protein-redistribution diet (PRD) we subjected 26 parkinsonian patients with motor fluctuations refractory to optimal timing and dosage of levodopa plus bromocriptine to a 2,000-2,500 Kcal., 65-80 g/d protein containing diet maintained for 8-12 weeks. Fifteen patients were eligible for evaluation, 10 of whom being benefited by the PRD (79 percent reduction in the mean "off" time in "on-off" charts). When the duration and pattern of the fluctuations were compared in the 10 diet-benefit patients with those in 5 diet-failure patients only dose-failures consistently occurring postprandially were resolved by the PRD. Wearing-off failures responded unpredictably while random "on-off" fluctuations were present only in the diet-failure group. Nocturnal akinesia and peak-dose dyskinesias often worsened. In no patient "on"-time quality was modified by the diet. In addition, the diet-failure group was characterized by a younger mean age at onset (p less than 0.05) and by longer duration in their fluctuations (p less than 0.001). Though requiring confirmation in a larger series, our results suggest that parkinsonian patients showing fluctuations over prolonged periods, particularly those having a pattern of random "on-off" oscillations in motor performance and dose-failures unrelated to meals are unlikely to benefit from a PRD.     

A comparison of the effects of controlled-release levodopa (Madopar CR) with conventional levodopa in late Parkinson''s disease.

In this multicentre study a controlled-release formulation of levodopa and the decarboxylase inhibitor benserazide (Madopar CR) was evaluated in patients with Parkinson's disease exhibiting dose-related fluctuations in motor performance in response to conventional levodopa preparations. The effect of Madopar CR, with or without conventional levodopa/benserazide, on the proportion of time spent "on", "off" or "intermediate" was compared with that of previous conventional levodopa/decarboxylase inhibitor therapy. Evaluation of the two periods of optimum therapy was based on both patient diary data and investigator opinion. Forty seven patients completed the study but full patient diaries were available for only 37. The mean optimum total daily dosage of conventional Madopar was 820 mg taken in a mean of 6.4 doses, compared with a mean optimum daily dosage of combined Madopar CR and conventional Madopar of 1088 mg, taken in a mean of 5.2 doses. Conventional Madopar was taken in addition to Madopar CR in all but eight patients. Madopar CR was felt to be advantageous in 83% and disadvantageous in 11% of patients completing the study. Considering the 37 patients for whom diary data were available, Madopar CR therapy resulted in an increase in the mean time spent "on" (p = 0.016) and a decrease in the mean time spent "off" (p = 0.029) compared with conventional Madopar alone. Individually 25 out of 37 had an increase in "on" time and 19 out of 37 experienced a decrease in "off" time. Thus Madopar CR was found to be beneficial in a significant proportion of patients experiencing fluctuations in response to conventional levodopa.     

Off-hours admission for acute stroke is not associated with worse outcome--a nationwide Israeli stroke project

Background and purpose: Several studies reported worse outcome for stroke patients arriving on weekends. We compared working hours to off‐work hours throughout the week as there is lack of experienced staff and special services during off‐hours. Methods: A nationwide stroke survey project on acute stroke was carried out in all acute care hospitals in Israel during 2004, 2007 and 2010 (2‐month each). ‘On‐hours’ were defined as regular Israel working hours and the rest, including holidays, were defined as ‘off‐hours’. The modified Rankin scale (mRS) at discharge was used for the main analysis on outcome. Results: A total of 4827 acute strokes patients were analyzed (2139 arrived on‐hours and 2688 during off‐hours). ‘Off‐hours’ patients were 1 year younger (mean 70 vs. 71 years in ‘on‐hours’) had lower rates of prior cardiac interventions, but had higher admission blood pressure levels and had more intracerebral hemorrhages (ICH) (11% vs. 8% in ‘on‐hours’ patients, P < 0.001). Death during hospitalization was recorded in 9% of ‘off‐hours’ vs. 6% of ‘on‐hours’ patient (P = 0.004). Controlling for age, blood pressure, stroke type, pre‐stroke mRS, admission NIHSS, and thrombolysis, the relative odds of poor outcome (i.e. mRS ≥ 2) amongst ‘off‐hours’ admissions compared to on‐hours was 1.09 (95% CI: 0.92–1.30). Odds ratio amongst ischaemic stroke patients was 1.08 (95% CI: 0.88–1.33). Conclusions: Off‐hours stroke admissions were associated with higher short‐term mortality rate, probably due to a higher rate of ICH. After controlling for the latter and other potential confounders, ‘off‐hours’ admissions were not different from ‘on‐hours’ with respect to poor outcome.     

Perampanel in patients with refractory and super‐refractory status epilepticus in a neurological intensive care unit: A single‐center audit of 30 patients

In refractory status epilepticus (SE), γ‐aminobutyric acidergic drugs become less effective and glutamate plays a major role in seizure perpetuation. Data on the efficacy of perampanel (PER) in treatment of refractory SE in humans are limited. Here, we present a single‐center case series of patients with refractory SE who received PER orally in an intensive care unit. We retrospectively analyzed treatment response, outcome, and adverse effects of all patients with refractory SE in our Neurological Intensive Care Unit who received add‐on PER between September 2012 and February 2018. Thirty patients with refractory SE (median = 72 years, range = 18‐91, 77% women) were included. In 14 patients (47%), a high‐dose approach was used, with a median initial dose of 24 mg (range = 16‐32). In five patients (17%), SE could be terminated after PER administration (median dose = 6 mg, range = 6‐20 mg, 2/5 patients in high‐dose group). Clinical response was observed after a median of 24 hours (range = 8‐48 hours), whereas electroencephalogram resolved after a median of 60 hours (range = 12‐72 hours). Time to treatment response tended to be shorter in patients receiving high‐dose PER (median clinical response = 16 hours vs 18 hours; electroencephalographic response = 24 hours vs 72 hours), but groups were too small for statistical analysis. Continuous cardiorespiratory monitoring showed no changes in cardiorespiratory function after “standard” and “high‐dose” treatment. Elevated liver enzymes without clinical symptoms were observed after a median of 6 days in seven of 30 patients (23%; 57% high dose vs 43% standard dose), of whom six also received treatment with phenytoin (PHT). Outcome was unfavorable (death, persistent vegetative state) in 13 patients (43%; 39% high dose vs 61% standard dose), and good recovery (no significant disability, moderate disability) was achieved in nine patients (56% high dose vs 44% standard dose). Oral PER in loading doses up to 32 mg were well tolerated but could terminate SE only in a few patients (5/30; 17%). Long duration of SE, route of administration, and severe underlying brain dysfunction might be responsible for the modest result. An intravenous formulation is highly desired to explore the full clinical utility in the treatment of refractory SE.     

Long-term outcome of young onset Parkinson's disease after subthalamic stimulation—A cross-sectional study

Objective

Age of onset is considered a poor prognostic factor for subthalamic deep brain stimulation (STN-DBS) outcome in the case of Parkinson's disease (PD). The goal of current study is to identify the long-term impact of STN-DBS for young onset PD (YOPD) patients.

Methods

17 YOPD patients with a mean disease onset at 32.3 years were prospectively followed up at 1, 2, 5 and 7 years after STN-DBS. Unified Parkinson's disease rating scale (UPDRS) was evaluated in 4 combinations of Med/DBS on/off.

Results

UPDRS part II–IV improved significantly 7 years after operation. While a slowly progressive worsening of levodopa response on part III, synergistic effect of medication and stimulation consistently improves motor disabilities. STN-DBS could remarkably reduce levodopa equivalent daily dose at 7 years. The morbidity rates were low. However, these patients seem to have more transient stimulation dyskinesia (47.1%) and dopamine dysregulation syndrome (11.8%) after surgery.

Conclusions

STN-DBS remains effective to improve motor disabilities over 7 years for YOPD and is a safe procedure concerning cognitive outcome and morbidity. However, stimulation dyskinesia and dopamine dysregulation syndrome deserve attention for the causal relationship between DBS surgery and behavioral outcomes.     

Efficacy, safety, and tolerance of the non-ergoline dopamine agonist pramipexole in the treatment of advanced Parkinson's disease: a double blind, placebo controlled, randomised, multicentre study

OBJECTIVES: Pramipexole, a non-ergot dopamine D2/D3 receptor agonist, was investigated as an add on drug in advanced parkinsonian patients with motor fluctuations to assess efficacy, safety, and tolerance. METHODS: Seventy eight patients of either sex with advanced Parkinson's disease and treatment complications such as motor fluctuations were enrolled into a double blind, placebo controlled, randomised, multicentre study (phase II) and assigned to add on treatment with pramipexole (n=34) versus placebo (n=44) to a previously stabilised antiparkinsonian medication (7 week dose titration interval, 4 week maintenance period). The primary end point of efficacy was the change from baseline in the total score of the unified Parkinson's disease rating scale (UPDRS) in the on "period" (2 hours after intake of study medication). Safety and tolerability were assessed on the basis of adverse events, vital signs, laboratory measurements, and ECG recordings. RESULTS: There was a significant improvement of the pramipexole group in UPDRS total scores, subscores part II, III (activities of daily living and motor examination), and IV (complications of therapy). Mean UPDRS total score decreased by 37.3% under pramipexole compared with 12.2% under placebo (p<0.001). Patients under pramipexole reported an overall reduction in "off" periods of 12%--resulting in 1.7 more hours "on" time a day--compared with an increase in "off" periods of 2% under placebo. There were no unexpected safety results. The adverse event profile disclosed a high tolerability. The most important adverse events under pramipexole were fatigue, dyskinesia, and vivid dreams. CONCLUSION: Pramipexole administration is an efficacious and well tolerated add on therapy in patients with advanced Parkinson's disease with an improvement in activities of daily living, motor function, and treatment associated complications.     

Apomorphine in treatment of Parkinson's disease with fluctuations

Apomorphine is a non-specific dopamine agonist, most similar to it, with a strong action on D2, D3, D4 receptors and weaker action on D1 and D5 receptors. It has been known since 100 years, and in Parkinson's disease it was used first in 1970 by Schwab and Cotzias. Apomorphine is used in Parkinson's disease with high-grade fluctuations of symptoms which cannot be controlled by oral drugs, especially in off" periods resistant to levodopa. After subcutaneous administration it changes the "off" to "on" period within 5-10 minutes. Unfortunately, its effect is short-lasting and wears off after 40-90 minutes. Apomorphine is administered in repeated single subcutaneous injections or in continuous subcutaneous infusion, if more than 7-9 single injections are required daily. Before beginning of treatment the optimal dose of apomorphine should be determined. For counteracting its emetic action domperidon (Motilium) is given additionally 20 mg t.d.s. Apomorphine produces no tolerance and is not losing its effectiveness with continued treatment. The most frequent adverse effects during long-term treatment are local cutaneous reactions, increased intensity of dyskinesia during the "on" period, visual hallucinations whose illusory character is clear to the patient, psychoses, orthostatic hypotension. The authors treated 8 patients with marked fluctuations in Parkinson's disease treated with levodopa. In 7 cases the effects was good--6 of them received 2-3 mg s.c. 3-4 times in 24 hours for 7-12 days. One patient has been treated 9 months with good result. In one case the intensity of dyskinesia made impossible treatment continuation.     

Use and interpretation of on/off diaries in Parkinson's disease

OBJECTIVE: To explore the use and interpretation of self reported on/off diary data for assessment of daily motor fluctuations in Parkinson's disease. METHODS: 26 consecutive non-demented patients with fluctuating Parkinson's disease received standardised training on how to fill out the four category CAPSIT-PD on/off diary, followed by four hours of clinical observation and four weeks of daytime on/off diaries every 30 minutes at home. RESULTS: Overall patient-clinician agreement in diary entries was good (kappa = 0.62; weighted kappa = 0.84). Agreement for individual diary categories was good for "off" and "on with dyskinesias" (kappa = > or =0.72), but moderate for "partial off" and "on" (kappa = 0.49). The overall validity of patient kept diaries was supported by expected symptom severity variability across diary categories, as assessed in the clinic. One day's home diary data failed to predict outcomes from the full four weeks for all diary categories, and data from three days failed to yield good prediction (predefined as R(2) = > or =approximately 0.7) for the time spent in "off" and "partial off". Data from one week yielded good prediction (R(2) = > or =0.74) in all instances except "partial off", which could not be well predicted even when two weeks' home diary data were considered (R(2) = 0.52). CONCLUSIONS: The data provide support for the overall accuracy and validity of the four category CAPSIT-PD on/off diary, but suggest that a three category diary format may improve accuracy and validity. Interpretation of diary data beyond the assessed time frame should be made with caution unless diaries have been kept for sufficiently long periods.     

5Effect of gastric electrical stimulation on cerebral blood flow in patients with gastroparesis

Introduction: Gastric electrical stimulation is a safe and efficient treatment option in medically refractory gastroparesis. Several controlled and open label trials have shown the effectiveness of gastric electrical stimulation in symptom palliation for patients with gastroparesis. Initial settings were established based on experiences in the animal model. We reviewed our experience using higher stimulator settings on symptom reduction after implantation of gastric electrical stimulators. Methods: 42 consecutive patients (38 females and 4 males, mean age 43 ± 1.8 years) with medically refractory gastroparesis were followed after implantation of gastric electrical stimulator between 1999 and 2005. The 42 patients included 29 patients with idiopathic gastroparesis and 13 patients with diabetic gastroparesis Baseline stimulation settings were 14 Hz, 5 mAmps, 330 micro‐sec pulse width, 0.1 sec on, and 5 sec off. At each follow‐up gastrointestinal symptom scores were assessed. If symptoms were unsatisfactory, stimulator settings were increased according to a standardized protocol. Dose response relationships were evaluated. Results: After a mean follow‐up of 19 ± 2.6 months, 83% of patients had higher settings (p < 0.001, Fisher's exact test). Solid gastric emptying time during this period decreased from 195 ± 45 to 106 ± 38 minutes (T1/2 value, p < 0.05, paired t‐test) along with an average weight change from 64 ± 5.3 to 62 ± 5.6 kg (p > 0.05, paired t‐test). There were 258 stimulator interrogations with a stepwise improvement in total symptom score (R² = 0.08, p < 0.001). Multivariate regression analysis showed that frequency of electric stimulation was independently associated with improvement of total symptom score (R² = 0.06, p < 0.02). A prolonged cycle on time correlated with worsening of nausea score (R² = 0.09, p < 0.02) and vomiting score (R² = 0.13, p < 0.001). A measurement of high impedance independently correlated with a low vomiting score (R² = 0.19, p < 0.0001). Though not statistically significant, most patients’ symptoms were optimized at mean current of 10 mAmps, frequency of 55 Hz, pulse width of 330 micro‐sec, cycle on time of 0.1 sec, and cycle off time of 1 sec. Conclusion: The majority of patients seem to benefit from higher than baseline settings. Optimal settings of the implanted device must be determined on an individual basis, but based upon experience in humans seem to be 10 mAmps, 55 Hz, 0.1 sec on, 0.4 to 1 sec off.     

Experience with selegiline and levodopa in advanced Parkinson's disease

We compared the results of treatment with selegiline (deprenyl, Eldepryl) in 17 patients with advanced Stage 4 Parkinson Disease (PD) who were on levodopa (as Sinemet) with 65 Stage 2 or 3 patients with early PD who were also on levodopa. The first group consisted of 17 patients with advanced Stage 4 PD without response fluctuations ("wearing off" or "on off" phenomena). Their mean age was 72.1 ± 7.5 years, their mean duration of PD was 7.4 ± 3.2 years. The second group consisted of 65 patients with Stage 2 or 3 PD who had recently been started on levodopa. Their mean age was 63 ± 12.1 years, their mean duration of PD was 7.4 ± 3.2 years. The mean dose of selegiline was 10.0 ± 1.8 mg per day (range 5–20 mg). The mean duration of treatment was 1.5 ± 0.8 years.
During the four years of observation 55.3 ± 8.0% of the Stage 2 or 3 patients improved while only 14.3 ± 13.5% of the Stage 4 patients improved. This difference was significant (p<0.05). During this time 22.0 ± 6.7% of the Stage 2 or 3 patients worsened and 60.7 ± of the Stage 4 patients worsened. This degree of worsening was significant (p<0.05). Adverse effects were minor and reversible.
Our observations suggest that selegiline is more effective (higher percent of patients improving, lower percent of patients worsening) when it is added earlier with patients on levodopa than when it is added later.