Federico Micheli

Preladenant in patients with Parkinson's disease and motor fluctuations: a phase 2, double-blind, randomised trial

BACKGROUND Preladenant is an adenosine 2A (A₂(A)) receptor antagonist. In animal models of Parkinsons disease, preladenant monotherapy improves motor function without causing dyskinesia and, as an adjunct to levodopa, it improves motor function without worsening dyskinesia. We aimed to assess the efficacy and safety of preladenant in patients with Parkinsons disease and motor fluctuations who were receiving levodopa and other antiparkinsonian drugs. METHODS In this phase 2, dose-finding trial, patients with Parkinsons disease who were receiving levodopa were enrolled and treated at 44 sites in 15 countries between December, 2006, and November, 2008. Assignment to treatment was done centrally with an interactive voice response system, according to a block randomisation schedule that was computer generated by the sponsor. Patients were assigned to receive 1, 2, 5, or 10 mg oral preladenant twice daily, or matching placebo for 12 weeks. Patients, study staff, investigators, and all sponsor personnel were masked to treatment assignment. The primary outcome was change in mean daily off time from baseline to week 12, as assessed by home diaries. Efficacy analysis included all patients who received at least one dose of study drug and had data for assessments after baseline. This trial is registered with ClinicalTrials.gov, number NCT00406029. FINDINGS 253 patients were randomised to receive preladenant (1 mg [n=49], 2 mg [n=49], 5 mg [n=49], 10 mg [n=57]) or placebo (n=49), of whom 234 on preladenant (1 mg [n=47], 2 mg [n=48], 5 mg [n=45], 10 mg [n=49]) and placebo (n=45) were eligible for the efficacy analysis. Mean daily off time from baseline to week 12 was reduced versus placebo in patients on 5 mg preladenant (difference -1·0 h, 95% CI -2·1 to 0·0; p=0·0486) and 10 mg preladenant (-1·2 h, -2·2 to -0·2; p=0·019). Changes in mean daily off time versus placebo were not significant for 1 mg preladenant (0·2 h, -0·9 to 1·2; p=0·753) or 2 mg preladenant (-0·7 h, -1·7 to 0·3; p=0·162). The most common adverse events in the combined preladenant group versus placebo were worsening of Parkinsons disease (22 [11%] vs 4 [9%]), somnolence (20 [10%] vs 3 [6%]), dyskinesia (18 [9%] vs 6 [13%]), nausea (17 [9%] vs 5 [11%]), constipation (15 [8%] vs 1 [2%]), and insomnia (15 [8%] vs 4 [9%]). INTERPRETATION 5 and 10 mg preladenant twice daily might be clinically useful to reduce off time in patients with Parkinsons disease and motor fluctuations. FUNDING Schering-Plough, a subsidiary of Merck.

Quantitative Study of Salivary Secretion in Parkinson's Disease

We examined basal and reflex salivary flow rate and composition in 46 patients with Parkinsons disease (PD), both in off and on conditions, compared to 13 age‐matched controls without underlying disease or treatment affecting autonomic function. Whole saliva was collected 12 hours after withdrawal of dopaminergic drugs and at the peak of levodopa‐induced motor improvement. Twenty‐three of the 46 PD patients had received domperidone a week before the study. Basal salivary flow rate was significantly lower in PD patients in the off state compared to controls (P < 0.005). Levodopa increased salivary flow rate (P < 0.05) both in the domperidone‐pretreated and untreated groups. Citric acid stimulated salivary flow rate in both the off and on states in PD patients. This effect was higher in the domperidone‐pretreated patients. Salivary concentration of sodium, chloride, and amylase was higher in PD patients than in controls and was not affected by levodopa or domperidone treatment. Levodopa stimulates both basal and reflex salivary flow rate in PD. The mechanism appears to be central, as the effect is not blocked by domperidone. Domperidone may have a peripheral effect that potentiates reflex salivary secretion. Salivary composition is abnormal in PD and is not affected by levodopa treatment.

Gastrointestinal manifestations in Parkinson’s disease: prevalence and occurrence before motor symptoms

To assess the prevalence of gastrointestinal symptoms (GIS) in Parkinson’s disease (PD) compared to control subjects and their timing of appearance in relationship to the onset of motor symptoms. There is a rostrocaudal gradient of alpha-synuclein (α-SYN) neuropathology in the enteric nervous system at early stages of PD with higher burden in the upper than the lower gut. However, only constipation has been recognized as a premotor gastrointestinal manifestation of PD. 129 PD patients and 120 controls underwent a structured questionnaire to assess the presence of GIS and, in PD patients, the time of their appearance respect to the onset of motor manifestations. GIS significantly more prevalent in PD patients were dry mouth, drooling, dysphagia, constipation and defecatory dysfunction. Constipation and defecatory dysfunction preceded motor manifestations. Whereas gastroparesis symptoms preceded motor manifestations, their prevalence was not significantly different from controls. Despite evidence of a higher α-SYN burden in the upper gut, only constipation and defecatory dysfunction were prominent premotor GIS of PD.

Flunarizine- and cinnarizine-induced extrapyramidal reactions.

Cinnarizine and flunarizine are selective calcium blockers that have been used to treat and prevent vertigo. We studied 15 patients who had extrapyrqmidal syndromes after taking these drugs. Eleven patients had parkinsonism, one with persistent akathisia as well; one had an orofacial tremor; one, acute akathisia alone; and one an acute dystonic reaction. All but one improved when the drug therapy was discontinued. Seven patients were also depressed during treatment. Cinnarizine and flunarizine must therefore be added to the list of potentially risky drugs known to induce extrapyramidal reactions and depression.

Bruxism secondary to chronic antidopaminergic drug exposure

Eight cases of diurnal bruxism (DB) secondary to long-term antidopaminergic drug exposure are reported. Five exhibited a grinding pattern, one a clenching form, and two a mixed type. An odontological etiology was absent throughout. EMG recordings disclosed two distinct patterns of muscle activity, one with brief rhythmic, forceful contractions and the other featuring sustained prolonged contractions. Surface EMG and EEG monitoring during a 24-h period confirmed the absence of bruxism during sleep. Several drug trials failed to provide relief. Our findings support DB as a focal tardive dystonia syndrome.

Pallidal surgery for the treatment of primary generalized dystonia: Long-term follow-up

OBJECTIVE To describe the results and long-term follow-up after functional surgery of the internal segment of the globus pallidus (GPi) in 10 patients with primary generalized dystonia. PATIENTS AND METHODS Nine of the 10 patients were positive for the DYT1 gene mutation. Bilateral deep brain stimulation (DBS) of the GPi was performed in three cases, bilateral pallidotomy in two, and combined surgery (unilateral GPi lesion with contralateral stimulation) in the remaining five. All patients were evaluated with the Burke-Fahn-Marsden dystonia scale (BFMDS) before, immediately after surgery, at 3 weeks, 3 and 6 months and then yearly. Follow up time ranged from 15 to 105 months (mean: 66.1 months) with six patients having more than 6 years follow up. RESULTS All patients improved after surgery. All patients with unilateral or bilateral DBS experienced an immediate improvement before starting stimulation. The magnitude of this initial micro lesion effect did not predict the magnitude of the long-term benefit of DBS. The mean decrease in the in the BFMDS was 34%, 55%, and 65% in the movement scale; and 32%, 48%, and 49% in the disability scale for patients with bilateral pallidal DBS, combined unilateral DBS and contralateral pallidotomy, and bilateral pallidotomy, respectively. Worsening of dystonia after a plateau of sustained benefit was observed in three patients. Two patients required multiple pallidal surgeries. Adverse events included: permanent anarthria (1), misplacement of the electrode requiring further surgery (2), scalp infection (1), and hardware related problems (3). CONCLUSIONS This long-term follow up study confirms the beneficial effect of pallidal DBS or pallidotomy in primary generalized dystonia. In addition, our results extent previous observations by showing that, in these patients, (1) the microlesion effect of DBS is not predictive of long-term benefit; (2) combined DBS with contralateral pallidotomy appears to be more effective than bilateral pallidal DBS; and (3) dystonia can reappear after an initial good response during long term follow up.

Beneficial effects of botulinum toxin type A in trigeminal neuralgia

Botulinum toxin has been thoroughly studied as a potential tool in the treatment of several pain syndromes. Therefore, we assessed the clinical effects of botulinum toxin type A injections in 12 patients with otherwise unresponsive idiopathic trigeminal neuralgia. Patients were infiltrated with 20-50 units of botulinum toxin in trigger zones. Those who presented with mandibular involvement were also infiltrated in the masseter muscle. The patients were assessed on a weekly basis using the Visual Analogic Scale for pain. Ten of our patients reported a significant benefit from botulinum toxin injections, with reduction or even disappearance of pain, and remained pain free for as long as 60 days. Our findings suggest that botulinum toxin may represent a useful therapeutic tool in the management of patients with this entity.

Perampanel, an AMPA Antagonist, Found to Have No Benefit in Reducing ''Off'' Time in Parkinson's Disease

Perampanel is a selective, noncompetitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid receptor antagonist. Two multicenter randomized, double‐blind, placebo‐controlled, parallel‐group phase III studies assessed the efficacy and safety of adjunctive perampanel in patients with Parkinsons disease and motor fluctuations.

Beneficial effects of botulinum toxin type a for patients with painful tic convulsif.

Botulinum toxin is a well-known therapy for patients with diverse movement disorders. Its application has been extended to other disorders. Here, we document the case of a 70-year-old man with hemifacial spasm associated to trigeminal neuralgia secondary to an ectatic basilar artery. He was treated with botulinum toxin type A, 2.5 mouse units over five sites at the orbicularis oculi and one over the buccinator muscle. After botulinum toxin injections, relief was gained not only from twitching but also from pain. When the effects of the toxin vanished, spasms and pain recurred. Further infiltrations were given every 12 weeks following the same response pattern. This observation further validates the increasing role of botulinum toxin in pain management.

Familial hemifacial spasm

We present a family in which hemifacial spasm involving in all cases the left side of the face occurred in five persons in three generations. Blink reflexes recorded in two cases demonstrated an unexpected R1 component on the affected side during stimulation of the contralateral side.