Malcolm Steiger

Rotigotine Effects on Early Morning Motor Function and Sleep in Parkinson's Disease: A Double-Blind, Randomized, pLacebo-Controlled Study (RECOVER)

In a multinational, double‐blind, placebo‐controlled trial (NCT00474058), 287 subjects with Parkinsons disease (PD) and unsatisfactory early‐morning motor symptom control were randomized 2:1 to receive rotigotine (2–16 mg/24 hr [n = 190]) or placebo (n = 97). Treatment was titrated to optimal dose over 1–8 weeks with subsequent dose maintenance for 4 weeks. Early‐morning motor function and nocturnal sleep disturbance were assessed as coprimary efficacy endpoints using the Unified Parkinsons Disease Rating Scale (UPDRS) Part III (Motor Examination) measured in the early morning prior to any medication intake and the modified Parkinsons Disease Sleep Scale (PDSS‐2) (mean change from baseline to end of maintenance [EOM], last observation carried forward). At EOM, mean UPDRS Part III score had decreased by −7.0 points with rotigotine (from a baseline of 29.6 [standard deviation (SD) 12.3] and by −3.9 points with placebo (baseline 32.0 [13.3]). Mean PDSS‐2 total score had decreased by −5.9 points with rotigotine (from a baseline of 19.3 [SD 9.3]) and by −1.9 points with placebo (baseline 20.5 [10.4]). This represented a significantly greater improvement with rotigotine compared with placebo on both the UPDRS Part III (treatment difference: −3.55 [95% confidence interval (CI) −5.37, −1.73]; P = 0.0002) and PDSS‐2 (treatment difference: −4.26 [95% CI −6.08, −2.45]; P < 0.0001). The most frequently reported adverse events were nausea (placebo, 9%; rotigotine, 21%), application site reactions (placebo, 4%; rotigotine, 15%), and dizziness (placebo, 6%; rotigotine 10%). Twenty‐four‐hour transdermal delivery of rotigotine to PD patients with early‐morning motor dysfunction resulted in significant benefits in control of both motor function and nocturnal sleep disturbances.

Levodopa-carbidopa intestinal gel in advanced Parkinson's disease: Final 12-month, open-label results

Motor complications in Parkinsons disease (PD) are associated with long‐term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. l‐dopa‐carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG‐J), which reduces l‐dopa‐plasma–level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54‐week, open‐label LCIG study. PD patients with severe motor fluctuations (>3 h/day “off” time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post‐LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary‐assessed off time, “on” time with/without troublesome dyskinesia, UPDRS, and health‐related quality‐of‐life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG‐J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty‐seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIGs safety profile consisted primarily of AEs associated with the device/procedure, l‐dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks.

A 10 year retrospective audit of long-term apomorphine use in Parkinson's disease.

ObjectivesApomorphine is a potent dopamine agonist useful in the treatment of Parkinson’s disease patients with disabling motor fluctuations and ‘off’ periods, not responding to oral medication. It can also be of benefit in reducing dyskinesia by providing more constant dopaminergic stimulation and permitting lower levodopa dosage. However, there is a paucity of information on long-term benefits of apomorphine, including no large-scale phase III trial. We have examined our experience of apomorphine over the last 10 years, to assess indications, pattern of use, efficacy, and side effect profile.MethodsAll patients requiring apomorphine were identified through the Parkinson’s disease Nurse Specialist’s records. An audit form was produced so that the same information was gathered from all case-notes.ResultsThere were 107 patients (61 males and 46 females). Mean age of disease onset was 50.9 years, SD±9.3 (range 29–78). The mean duration of disease at start of apomorphine treatment was 10 years (SD±4.8, range2–29). The most common indications for apomorphine were severe unpredictable ‘off’ periods (75.7 %), motor fluctuations (18.7 %) and dyskinesia (5.6 %). Most patients (63.6 %) used both intermittent subcutaneous injections and infusion via pump; 25.2% were on intermittent injection, and 11.2 % infusion alone. Mean dose per injection was 3.7mg. Mean infusion dose 69.8mg, running over a mean of 13.5 hours. The mean duration of intermittent apomorphine use was 48.2 months. The mean duration of infusion was 25.1 months. Complications included skin problems in 16 patients, 2 had symptomatic hypotension, 2 worsening confusion, 1 new confusion and 5 new hallucinations (after sometime on apomorphine). Sixteen patients have stopped using apomorphine completely. Thirteen have stopped the pump, but continue on intermittent injections.ConclusionSubcutaneous apomorphine is easy for patients to use, is well tolerated and has a low incidence of side effects, especially confusion.

Non-subtype-selective opioid receptor antagonism in treatment of levodopa-induced motor complications in Parkinson's disease

Opioid peptide transmission is enhanced in the striatum of animal models and Parkinsons disease (PD) patients with levodopa‐induced motor complications. Opioid receptor antagonists reduce levodopa‐induced dyskinesia in primate models of PD; however, clinical trials to date have been inconclusive. A double‐blind, placebo controlled, crossover design study in 14 patients with PD experiencing motor fluctuations was carried out, using the non‐subtype‐selective opioid receptor antagonist naloxone. Naloxone did not reduce levodopa‐induced dyskinesia. The duration of action of levodopa was increased significantly by 17.5%. Non‐subtype‐selective opioid receptor antagonism may prove useful in the treatment of levodopa‐related wearing‐off in PD but not in dyskinesia.

Double-blind study of the activity and tolerability of cabergoline versus placebo in parkinsonians with motor fluctuations

The use of a dopamine agonist with a long duration of action has theoretical advantages in attempting to reduce the motor fluctuations in Parkinsons disease. We report the results of a double-blind controlled study of adding cabergoline, an ergot derivative with potent long-lasting high affinity for the D2 receptor, to levodopa therapy in 37 patients with severe fluctuations in response to treatment. Increasing dosages of cabergoline (19 patients) or placebo (18 patients) were added to each patients stable levodopa regime. The two patient groups were similar at baseline in terms of age, disease duration, duration of levodopa treatment, and average hours “off” per day. Following incremental dose titration, patients in the cabergoline group had a significant reduction in hours “off” per day from 5.0 (SD 2.1) to 3.0 (SD 2.5), but there was no change in this measure in the placebo group [4.0 (2.2) and 3.3 (2.3) respectively]. This was not at the expense of a significant increase in dyskinesia. However, there was no difference between the groups when comparing their average Hoehn and Yahr stage of disease, and Schwab and England activities of daily living index.

Use of the NeuroMate Stereotactic Robot in a Frameless Mode for Movement Disorder Surgery

Background/Aims: To evaluate the use of the NeuroMate stereotactic robot with a novel ultrasound registration system for movement disorder surgery (MDS). Methods: Using the robot in a frameless mode, 51 patients underwent MDS. Surgical planning was carried out using MRI data obtained more than 24 h before surgery. Results: 37 out of 50 targets in the subthalamic nucleus were satisfactorily identified with a single microelectrode trajectory and the final electrode positions were at a mean distance of 1.7 mm from the calculated target. There was a significant improvement in motor scores of the Unified Parkinson’s Disease Rating Scale III (off medication) at 6 (43%) and 18 months (51.7%) compared to pre-operative scores (p < 0.05). Conclusions: The frameless robot using only MRI data can be used for MDS. The temporal separation of imaging from the surgical procedure provides additional time for detailed image analysis and planning.

Risk of valvular heart disease associated with the use of dopamine agonists in Parkinson’s disease: a systematic review

A literature review was conducted to assess risk of cardiac valve regurgitation (CVR) associated with use of ergot-derived and non-ergot dopamine agonists (DAs) in patients with Parkinson’s disease (PD). Inclusion criteria: case-control/observational studies of >10 patients with PD treated with DAs, including a control group and assessment of incidence/risk of CVR. Of the 166 publications identified, 14 met all inclusion criteria and included 1,750 patients. In 11 of the studies, a significant increase in CVR frequency of any severity (at the aortic, mitral or tricuspid valve) in the ergot group vs. the non-ergot or control group was described. No study reported increased risk of CVR for non-ergot DAs, compared with controls. In the studies identified in the literature, the use of ergot-derived DAs (pergolide and cabergoline) in patients with PD was associated with increased risk of CVR. Increased risk of CVR was not associated with the use of non-ergot DAs.

Variability in position of the subthalamic nucleus targeted by magnetic resonance imaging and microelectrode recordings as compared to atlas co-ordinates.

Background: Traditional methods for localisation of target nuclei for deep brain stimulation (DBS) have used brain atlas co-ordinates for initial targeting. It is now possible to visualise the subthalamic nucleus (STN) on magnetic resonance imaging (MRI) and determine the individual variability of its position. Methods: The present study was performed in patients undergoing STN DBS for Parkinson’s disease. The STN was directly targeted from axially obtained MRI and verified with microelectrode recordings. Postoperatively, the most effective contact was identified for each patient, and its position was calculated. Results: Fifty electrodes were inserted in 25 patients. The target position varied considerably in relation to the mid-commissural point. The mean effective contact position lies just dorsal to the location of the STN in a standard brain atlas. Conclusion: The STN varies in position, and can be accurately targeted from MRI alone.

Deep brain stimulation of the subthalamic nucleus: effectiveness in advanced Parkinson’s disease patients previously reliant on apomorphine

Objectives: To assess the efficacy of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with advanced Parkinson’s disease previously reliant on apomorphine as their main antiparkinsonian medication. Methods: Seven patients with motor fluctuations despite optimal medical treatment given as predominantly apomorphine infusion (n=6), or intermittent apomorphine injections (n=1) underwent bilateral STN DBS using frameless stereotactic surgery. Standard assessments of parkinsonism and motor fluctuations, using Unified Parkinson’s Disease Rating Scale (UPDRS) were performed before and six months after surgery. Assessments were performed both on and off medication, and postoperative with the stimulators switched on and off. Results: Bilateral STN DBS improved motor scores (UPDRS III) by 61% when off medication (p<0.05). Clinical fluctuations (UPDRS IV items 36–39) were reduced by 46.2% (p<0.05). Total daily apomorphine dose was reduced by 68.9% (p<0.05) and apomorphine infusion via a pump was no longer required in four patients. There were no operative complications. Two patients required treatment for hallucinations postoperatively but there was no significant change in mini-mental state examination. Conclusions: In patients with advanced Parkinson’s disease, previously reliant on apomorphine, bilateral STN DBS is an effective treatment to reduce motor fluctuations and enable a reduction in apomorphine use.

Hyperekplexia and trismus due to brainstem encephalopathy

The brainstem is said to be the generator of pathological startle responses due to reticular reflex myoclonus or hyperekplexia. A patient with facial weakness, nystagmus, and pyramidal tract signs had generalised reflex spasms in response to auditory, visual and tactile stimuli which clinically and neurophysiologically resembled hyperekplexia. The case is unusual because as well as hyperekplexia, the patient’s initial presentation was with an equally rare manifestation of brainstem pathology—brainstem mediated trismus. The causes of brainstem trismus and exaggerated startle responses are discussed with respect to their underlying mechanisms.