Parkinson Disease: Lees AJ

Grosset DG, Lees AJ. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #15607986 links to  free full text

This publication has no abstract.

Lees AJ. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #12438454 links to  free full text

This publication has no abstract.

Lees AJ. · Reta Lila Weston Institute for Neurological Studies, Institute of Neurology, UCL and the National Hospital for Neurology and Neurosurgery, Queen Square, London. · Neurology. · Pubmed #19221309 No free full text.

Abstract: Although our concepts of what causes Parkinson disease (PD) are ever changing and the hunt for a reliable biomarker continues, the clinical picture remains as distinctive as when the malady was first described by James Parkinson and the neurologic Grand Masters of the nineteenth century. Hyposmia and visual hallucinations, however, can now be added as additional features of the clinical syndrome which may be helpful in distinguishing PD from atypical parkinsonism, as well as the growing list of causes of secondary parkinsonism. Selective vulnerability of catecholaminergic long axon projection neurons (part of the isodendritic core) in PD is an important, if recently somewhat neglected, fact and correlation of the severity of nigral loss with bradykinesia and rigidity is the only very reliable anatomo-clinical correlation. Although the Lewy body seems to be closely linked with our notion of PD as a clinicopathologic nosological entity, its role in the pathogenesis of the disorder is still obscure and hotly debated. Its presence in some of the long-surviving grafted neurons in fetal implants may provide important insights into its role in the disease process. Although Braak's hypothesis implicating the medulla oblongata as an obligate trigger for the subsequent spread of the pathologic process has generated much interest and encouraged more research, it seems unlikely as an explanation for the natural history of PD.

O'Sullivan SS, Evans AH, Lees AJ. · Reta Lila Weston Institute of Neurological Studies, Institute of Neurology, University College London, London, England. · CNS Drugs. · Pubmed #19173374 No free full text.

Abstract: Dopamine dysregulation syndrome (DDS) is a relatively recently described iatrogenic disturbance that may complicate long-term symptomatic therapy of Parkinson's disease. Patients with DDS develop an addictive pattern of dopamine replacement therapy (DRT) use, administering doses in excess of those required to control their motor symptoms. The prevalence of DDS in patients attending specialist Parkinson's disease centres is 3-4%. Amongst the behavioural disturbances associated with DDS are punding, which is a complex stereotyped behaviour, and impulse control disorders (ICDs), such as pathological gambling, hypersexuality, compulsive shopping and compulsive eating. We review the risk factors and potential mechanisms for the development of DDS, including personality traits, potential genetic influences and Parkinson's disease-related cognitive deficits. Impulsive personality traits are prominent in patients developing DDS, and have been previously associated with the development of substance dependence. Candidate genes affecting the dopamine 'D(2)-like' receptor family have been associated with impulsive personality traits in addition to drug and nondrug addictions. Impaired decision making is implicated in addictive behaviours, and decision-making abilities can be influenced by dopaminergic medications. In Parkinson's disease, disruption of the reciprocal loops between the striatum and structures in the prefrontal cortex following dopamine depletion may predispose to DDS. The role of DRT in DDS is discussed, with particular reference to models of addiction, suggesting that compulsive drug use is due to progressive neuroadaptations in dopamine projections to the accumbens-related circuitry. Evidence for neuroadaptations and sensitization occurring in DDS include enhanced levodopa-induced ventral striatal dopamine release. Levodopa is still considered the most potent trigger for DDS in Parkinson's disease, but subcutaneous apomorphine and oral dopamine agonists may also be responsible. In the management of DDS, further research is needed to identify at-risk groups, thereby facilitating more effective early intervention. Therefore, an increased awareness of the syndrome amongst treating physicians is vital. Medication reduction strategies are employed, particularly with regard to avoiding rapidly acting 'booster' DRT formulations. Psychosocial treatments, including cognitive-behavioural therapy, have been beneficial in treating substance use disorders and ICDs in non-Parkinson's disease patients, but there are currently no published trials of psychological interventions in DDS. Further studies are also required to identify factors that can predict those patients with DDS or ICDs who will derive benefit from surgical interventions such as deep brain stimulation.

Lees AJ. · Reta Lila Weston Institute of Neurological Studies, ION, UCL, London, UK. · CNS Neurosci Ther. · Pubmed #18482101 No free full text.

Abstract: The relative efficacy has not been adequately established for the two catechol-O-methyltransferase (COMT) inhibitors that are currently available for adjunctive therapy in Parkinson's disease; tolcapone and entacapone. A recent Cochrane meta-analysis of 14 studies in 2566 patients, conducted to assess the efficacy and safety of tolcapone and entacapone, found both to be statistically superior to placebo in increasing ON time and decreasing OFF time. The meta-analysis also showed that the weighted mean difference from baseline to endpoint in tolcapone-treated patients was twice that in entacapone-treated patients for both placebo-corrected ON time and OFF time. Withdrawal rates were generally lower for tolcapone. Two additional studies have examined the switch between tolcapone and entacapone. In 40 Parkinson's disease patients with fluctuations who were switched from tolcapone to entacapone, improvements in ON time and reductions in OFF time were approximately twice the magnitude for tolcapone than for entacapone. In a second study examining the switch from entacapone to tolcapone, the results for several exploratory variables also suggested that tolcapone has greater efficacy than entacapone. These findings indicate that tolcapone should be considered in all patients with entacapone-refractory motor fluctuations.

Kempster PA, Hurwitz B, Lees AJ. · Neurosciences Department, Monash Medical Centre, Clayton, Victoria, Australia. · Neurology. · Pubmed #17664408 No free full text.

Abstract: James Parkinson's Essay on the Shaking Palsy, published in 1817, represents a landmark in the development of writing about neurologic disorders. Parkinson was an astute clinician-investigator, and his wide scientific interests and ideas on social advancement in many ways typified the spirit of the Age of Enlightenment. Our commentary on the text of his essay identifies important sources of its originality: the particular way in which Parkinson collected and categorized clinical material, his use of a field neurology method to identify affected individuals, and his skills as a narrative writer. Although the essay belongs to an older tradition of disease classification, it also anticipates the modern neurologist's reliance on accurate clinical description and natural history in establishing a diagnosis.

Scherfler C, Schwarz J, Antonini A, Grosset D, Valldeoriola F, Marek K, Oertel W, Tolosa E, Lees AJ, Poewe W. · Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. · Mov Disord. · Pubmed #17486648 No free full text.

Abstract: The diagnosis of idiopathic Parkinson's disease (PD) can be achieved with high degrees of accuracy in cases with full expression of classical clinical features. However, diagnostic uncertainty remains in early disease with subtle or ambiguous signs. Functional imaging has been suggested to increase the diagnostic yield in parkinsonian syndromes with uncertain clinical classification. Loss of striatal dopamine nerve terminal function, a hallmark of neurodegenerative parkinsonism, is strongly related to decreases of dopamine transporter (DAT) density, which can be measured by single photon emission computed tomography (SPECT). The use of DAT-SPECT facilitates the differential diagnosis in patients with isolated tremor symptoms not fulfilling PD or essential tremor criteria, drug-induced, psychogenic and vascular parkinsonism as well as dementia when associated with parkinsonism. This review addresses the value of DAT-SPECT in early differential diagnosis, and its potential as a screening tool for subjects at risk of developing PD as well as issues around the assessment of disease progression.

Evans AH, Lees AJ. · Reta Lila Weston Institute of Neurological Studies, University College London, The National Hospital for Neurology and Neurosurgery, London, UK. · Curr Opin Neurol. · Pubmed #15247533 No free full text.

Abstract: PURPOSE OF REVIEW: Dopamine replacement therapy in Parkinson's disease ameliorates motor symptoms. However, it has recently been recognized that a small sub-group of patients suffer motor and behavioural disturbances attributable to taking quantities of medication well beyond the dose required to treat their motor disabilities. This review examines the phenomenology of dopamine dysregulation syndrome in relation to the current understanding of basal ganglia function and its impact on long-term management. RECENT FINDINGS: Cortico-striato-thalamic circuits are implicated in the behavioural and motor disturbances associated with compulsive medication use in Parkinson's disease. Advances in understanding of the role of dopamine in psychostimulant addiction are important in helping to understand dopamine dysregulation. SUMMARY: Recognition of dopamine dysregulation syndrome and characterization of its phenomenology supports the notion that the medication used to treat Parkinson's disease can disrupt basal ganglia mediated motor and behavioural functioning. Refinement of clinical strategies to predict, identify and manage this syndrome will aid the future treatment of motor and non-motor complications of Parkinson's disease.

Paviour DC, Surtees RA, Lees AJ. · National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom. · Mov Disord. · Pubmed #14978667 No free full text.

Abstract: Juvenile parkinsonism (JP) describes patients in whom the clinical features of parkinsonism manifest before 21 years of age. Many reported cases that had a good response to levodopa have proved to have autosomal recessive juvenile parkinsonism (AR-JP) due to mutations in the parkin gene. With the exception of parkin mutations and dopa-responsive dystonia, most causes are associated with the presence of additional neurological signs, resulting from additional lesions outside of the basal ganglia. Lewy body pathology has only been reported in one case, suggesting that a juvenile form of idiopathic Parkinson's disease may be extremely rare.

Lawrence AD, Evans AH, Lees AJ. · MRC Cognition and Brain Sciences Unit, Cambridge, UK. · Lancet Neurol. · Pubmed #14505581 No free full text.

Abstract: Dopamine replacement therapy (DRT) is the most effective treatment for Parkinson's disease (PD); it provides substantial benefit for most patients, extends independence, and increases survival. A few patients with PD, however, take increasing quantities of medication far beyond those required to treat their motor disabilities. These patients demand rapid drug escalation and continue to request more DRT despite the emergence of increasingly severe drug-induced motor complications and harmful behavioural consequences. In this article we detail the features of compulsive DRT-seeking and intake in PD, in relation to theories of compulsive drug use.

Katzenschlager R, Lees AJ. · Reta Lila Weston Institute of Neurological Studies, Windeyer Building, 46 Cleveland Street, London W1T 4JF, United Kingdom. · J Neurol. · Pubmed #12375059 No free full text.

Abstract: The introduction of levodopa in the 1960s revolutionised the treatment of Parkinson's disease (PD), and it continues to be the most effective symptomatic therapy. The vast majority of PD patients who start treatment with L-dopa experience good to excellent functional benefit.In vitro studies with high doses of L-dopa and absent glia had shown that it may be neurotoxic, but other tissue culture studies show L-dopa to be neuroprotective. Most studies in animal models and clinico-pathological and mortality studies in humans failed to show evidence in favour of accelerated dopaminergic neuronal loss with long-term L-dopa therapy.L-dopa continues to be beneficial throughout the course of PD, although as the disease progresses, escape of some symptoms from adequate control may occur and refractory disabilities such as impaired balance, dysarthria, cognitive decline and hallucinations may emerge. Treatment of advanced PD may also be complicated by the emergence of motor fluctuations and dyskinesias. Studies in animal models and in humans show that these motor complications are not specific to a particular dopaminergic agent, but that they are related both to the extent of the striatal lesion and to the mode of application of dopaminergic agents: Pulsatile administration of L-dopa and of the dopamine agonist apomorphine causes more motor complications than continuous striatal dopaminergic receptor stimulation, and continuous administration can alleviate existing dyskinesias and fluctuations.Several controlled studies comparing levodopa and dopamine agonists as initial treatment have attempted to answer the question whether delaying L-dopa therapy can reduce the occurrence of motor complications. Three medium-term (3-5 years) and one 10-year study showed less dyskinesia in the first five years of treatment in patients who had started therapy with a dopamine agonist. However, these studies also consistently showed that levodopa provided better functional improvement in the first years of treatment. Ten-year follow-up data in patients randomised to L-dopa or bromocriptine also showed a slightly lower incidence of motor complications in the bromocriptine arm. However, this difference was not significant for the clinically relevant moderate and severe forms of dyskinesias and fluctuations, and was achieved at the expense of significantly worse disability scores during the first years of therapy. Furthermore, the relative impact of motor disability and dyskinesias on patients' quality of life remains to be established.Concordance is essential in the optimum treatment of PD and patients should be informed of the various therapeutic options available. Treatment should respect individual patients' needs and take into account their particular functional disabilities and specific handicaps. Low-dose L-dopa therapy (up to 400 mg/day), however, remains the most effective initial treatment of choice for the majority of patients.

O'Sullivan JD, Lees AJ. · Reta Lila Weston Institute of Neurological Studies, Royal Free and University College Medical School, University College London. · Hosp Med. · Pubmed #10707193 No free full text.

Abstract: Apomorphine is a dopamine agonist administered subcutaneously as intermittent injections or in a continuous infusion. It is useful in managing advanced Parkinson's disease, and provides an alternative to neurosurgical procedures. This review summarizes indications and practical guidelines for its use.

Katzenschlager R, Zijlmans J, Evans A, Watt H, Lees AJ. · Reta Lila Weston Institute of Neurological Studies, London, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #15548497 links to  free full text

Abstract: OBJECTIVE: To compare olfactory function in vascular parkinsonism and Parkinson's disease diagnosed according to published clinical diagnostic criteria. METHODS: The University of Pennsylvania smell identification test (UPSIT) was carried out in 14 patients with vascular parkinsonism, 18 with Parkinson's disease, and 27 normal controls matched for age, sex, and smoking status. RESULTS: UPSIT scores in vascular parkinsonism (mean 26.1, 95% confidence interval, 23.1 to 29.0) were significantly better than in Parkinson's disease (mean 17.1 (14.5 to 19.7)) (p<0.0001), and did not differ from the healthy controls (mean 27.6 (25.8 to 29.4)) (p = 0.32). CONCLUSIONS: Testing olfactory function may be helpful in differentiating vascular parkinsonism from Parkinson's disease.

Katzenschlager R, Evans A, Manson A, Patsalos PN, Ratnaraj N, Watt H, Timmermann L, Van der Giessen R, Lees AJ. · National Hospital for Neurology and Neurosurgery, London, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #15548480 links to  free full text

Abstract: BACKGROUND: The seed powder of the leguminous plant, Mucuna pruriens has long been used in traditional Ayurvedic Indian medicine for diseases including parkinsonism. We have assessed the clinical effects and levodopa (L-dopa) pharmacokinetics following two different doses of mucuna preparation and compared them with standard L-dopa/carbidopa (LD/CD). METHODS: Eight Parkinson's disease patients with a short duration L-dopa response and on period dyskinesias completed a randomised, controlled, double blind crossover trial. Patients were challenged with single doses of 200/50 mg LD/CD, and 15 and 30 g of mucuna preparation in randomised order at weekly intervals. L-dopa pharmacokinetics were determined, and Unified Parkinson's Disease Rating Scale and tapping speed were obtained at baseline and repeatedly during the 4 h following drug ingestion. Dyskinesias were assessed using modified AIMS and Goetz scales. RESULTS: Compared with standard LD/CD, the 30 g mucuna preparation led to a considerably faster onset of effect (34.6 v 68.5 min; p = 0.021), reflected in shorter latencies to peak L-dopa plasma concentrations. Mean on time was 21.9% (37 min) longer with 30 g mucuna than with LD/CD (p = 0.021); peak L-dopa plasma concentrations were 110% higher and the area under the plasma concentration v time curve (area under curve) was 165.3% larger (p = 0.012). No significant differences in dyskinesias or tolerability occurred. CONCLUSIONS: The rapid onset of action and longer on time without concomitant increase in dyskinesias on mucuna seed powder formulation suggest that this natural source of L-dopa might possess advantages over conventional L-dopa preparations in the long term management of PD. Assessment of long term efficacy and tolerability in a randomised, controlled study is warranted.

Katzenschlager R, Hughes A, Evans A, Manson AJ, Hoffman M, Swinn L, Watt H, Bhatia K, Quinn N, Lees AJ. · Reta Lila Weston Institute of Neurological Studies, University College London, United Kingdom. · Mov Disord. · Pubmed #15390035 No free full text.

Abstract: Continuous subcutaneous (SC) infusion of the dopamine agonist apomorphine was shown in retrospective studies to improve drug-induced dyskinesias in Parkinson's disease (PD). We prospectively assessed the antidyskinetic effect of continuous SC apomorphine therapy using subjective and objective measures, and sought to determine whether any observed dyskinesia reduction could be corroborated using single-dose dopaminergic challenges. Twelve PD patients with on-off fluctuations and disabling dyskinesias who were scheduled to start apomorphine pump treatment underwent acute levodopa and apomorphine challenges at baseline and 6 months later. Video recordings involving motor tasks were rated blindly by two independent raters using modified AIMS and Goetz dyskinesia scales. At 6 months, mean apomorphine dose was 75.2 mg per day and the mean L-dopa dose had been reduced by 55%. Daily off time in patients' diaries was reduced by 38% (2.4 hours). The L-dopa challenges showed a reduction of 44% in AIMS and 40% in Goetz scores (both P < 0.01). Apomorphine challenges showed a reduction of 39% in AIMS and 36% in Goetz scores (both P < 0.01). Patients' self-assessment scores reflected these significant changes. Dyskinesia improvement correlated with reduction in oral medication and with the final apomorphine dose (P < 0.05). This prospective study confirms marked dyskinesia reduction on continuous subcutaneous apomorphine therapy, paralleled by reduced dyskinesias during dopaminergic challenge tests. Our findings support the concept that replacement of short-acting oral antiparkinsonian medication with continuous dopamine receptor stimulation may reverse, at least partially, the sensitization process believed to mediate the development of drug-induced dyskinesias in PD.

Zijlmans JC, Debilly B, Rascol O, Lees AJ, Durif F. · National Hospital for Neurology and Neurosurgery, London, United Kingdom. · Mov Disord. · Pubmed #15372589 No free full text.

Abstract: We investigated whether administration of the catechol-O-methyl transferase (COMT) inhibitor entacapone, at doses of 200 mg and 400 mg, alters the pharmacokinetics of apomorphine in Parkinson's disease patients experiencing severe motor fluctuations. In addition, the pharmacodynamics and safety of entacapone and apomorphine coadministration in these patients were examined. The study followed a three-sequence, three-period, crossover design. Patients were randomly assigned to one of three sequences that included single oral doses of entacapone 200 mg, entacapone 400 mg, and placebo in a predefined order. On 3 separate test days, study treatment was administered before apomorphine. The study evaluations (pharmacokinetics, tapping test, and dyskinesia evaluation [Abnormal Involuntary Movements Scale - AIMS]) were performed on these days. Furthermore, Unified Parkinson Disease Rating Scale (UPDRS) scores were evaluated at baseline and study end. Pharmacokinetic parameters for apomorphine (C(max), AUC, t(max), t(1/2)) were unchanged by the administration of entacapone, and changes in both the tapping test and AIMS score were similar with all treatments (entacapone 200 mg, entacapone 400 mg, and placebo). There was no significant difference in mean total UPDRS scores between baseline and study end. The administration of entacapone did not change the pharmacokinetic or pharmacodynamic effects of apomorphine in these patients or prolong the clinical effect of apomorphine. Thus, apomorphine may be safely administered to patients receiving therapy with levodopa and entacapone, providing a useful addition to treatment for patients with advanced Parkinson's disease.

Katzenschlager R, Manson AJ, Evans A, Watt H, Lees AJ. · Reta Lila Weston Institute of Neurological Studies, University College London, National Hospital for Neurology and Neurosurgery, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #14742609 links to  free full text

Abstract: OBJECTIVE: Drug induced dyskinesias remain a challenging problem in the long term management of Parkinson's disease (PD). We have assessed the effect of quetiapine on dyskinesias in a double blind placebo controlled cross over study. METHODS: Nine patients with PD were enrolled and received 25 mg of quetiapine or placebo at night for two weeks in prerandomised order, with one week of wash out between treatment periods. Assessments were made using on-off diaries, self assessment of dyskinesias, and L-dopa challenges at baseline and after each treatment period. Videotapes were rated blindly by two raters using modified Abnormal Involuntary Movement Scale and Goetz scores. Patients subsequently went on open label quetiapine at 50 mg/day, for a mean duration of 30 days, and completed the same self assessment forms. RESULTS: During the double blind phase, no significant change in dyskinesias was found on either 25 mg of quetiapine or placebo. Duration of off states and Unified PD Rating Scale motor scores also remained unchanged. Moderate tiredness and daytime sleepiness occurred in two patients on quetiapine. One patient dropped out early for unrelated reasons. Eight patients completed the open label phase. On 50 mg/day of quetiapine, a slight reduction in dyskinesias occurred on some scales. Reduction in dyskinesia severity on visual analogue scales was by 50.1%. Off time was not significantly increased. This improvement was not strongly reflected in patients' overall impression of treatment effect. Drowsiness and daytime sleep episodes led to discontinuation in four patients, after completion of the study, and two additional patients stopped treatment after the study because of lack of effect. CONCLUSION: Our study failed to demonstrate an antidyskinetic effect of low dose (25 mg) quetiapine. The absence of an increase in parkinsonism combined with a possible antidyskinetic effect on higher doses warrants further investigation.

Doder M, Rabiner EA, Turjanski N, Lees AJ, Brooks DJ, Anonymous00241. · Division of Neuroscience and MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, UK. · Neurology. · Pubmed #12601099 No free full text.

Abstract: BACKGROUND: The pathophysiologic mechanisms underlying parkinsonian tremor remain unclear. The response to dopaminergic treatment is variable and nondopaminergic mechanisms may play a role in tremor generation. Midbrain raphe 5-HT(1A) binding provides a functional measure of serotonergic system integrity. With PET, the aim of this study was to examine regional cerebral (11)C-WAY 100635 binding to 5-HT(1A) receptors in patients with PD and to correlate it with severity of tremor. METHODS: (11)C-WAY 100635 PET was performed on 23 patients with PD and eight age-matched healthy volunteers. Brain 5-HT(1A) receptor binding was computed using compartmental modeling with a cerebellar reference tissue input function. RESULTS: The authors found mean 27% reduction in the midbrain raphe 5-HT(1A) binding potential in patients with PD compared to healthy volunteers (p < 0.001). They also showed that Unified Parkinson's Disease Rating Scale composite tremor scores, but not rigidity or bradykinesia, correlate with 5-HT(1A) binding in the raphe (p < 0.01). CONCLUSIONS: These findings support previous indirect evidence that serotonergic neurotransmission is decreased in PD in vivo. The authors hypothesize that the reduction in raphe 5-HT(1A) binding represents receptor dysfunction or loss of cell bodies due to Lewy body degeneration in PD, or both. An association between 5-HT(1A) receptor availability in the raphe and severity of parkinsonian tremor was also found.

Pirtosek Z, Jahanshahi M, Barrett G, Lees AJ. · The National Hospital for Neurology and Neurosurgery and Institute of Neurology, London, UK. · Ann Neurol. · Pubmed #11706961 No free full text.

Abstract: Bradykinetic-rigid syndromes are often accompanied by cognitive impairment. Because prominent motor involvement in these disorders may interfere with neuropsychological testing, we used event-related potentials (ERPs) for the assessment of cognition and attention in 41 patients with various bradykinetic-rigid syndromes of less than 5 years duration: idiopathic Parkinson's disease corticobasal degeneration, Steele-Richardson-Olszewski syndrome (SRO), and multiple system atrophy. Patients were compared with matched normals. ERP abnormalities in the auditory "oddball" paradigm were found only in corticobasal degeneration and SRO. ERP abnormalities in selective attention tasks were present in all patient groups, changes in SRO being the most prevalent. Abnormalities in corticobasal degeneration were present under "less-attention-demanding" conditions and suggested involvement of posterior parts of the brain. Multiple system atrophy and idiopathic Parkinson's disease patient groups had minimal ERP abnormalities. However, reaction times in MSA were longer in all paradigms. The results of the study support the view that bradykinetic-rigid syndromes involve some attentional deficits, but also have distinct reaction time and ERP characteristics, which may be helpful in differential diagnosis.

Lees AJ, Katzenschlager R, Head J, Ben-Shlomo Y. · National Hospital for Neurology and Neurosurgery, London, UK. · Neurology. · Pubmed #11706112 No free full text.

Abstract: BACKGROUND: The long-term effectiveness of three different initial drug regimes in patients with early, mild PD was evaluated by the PD Research Group of the United Kingdom (PDRGUK). In 1995, the selegiline arm of the trial was terminated following an interim analysis. METHOD: This was an open, randomized trial. Between 1985 and 1990, 782 patients with de-novo PD were recruited and randomized to one of three treatment arms: levodopa plus dopa decarboxylase inhibitor; levodopa plus decarboxylase inhibitor and selegiline; or bromocriptine. The main endpoints were mortality, disability, and adverse events. Intention-to-treat analysis was used. RESULTS: There was no significant difference in mortality between the bromocriptine and the levodopa arms (hazard ratio 1.15 [95% CI 0.90, 1.47]). Patients initially randomized to bromocriptine had slightly worse disability scores throughout follow-up. This difference was significant during the first years. Patients in the bromocriptine arm returned to pretreatment disability levels one year earlier than those in the levodopa arm. Patients randomized to bromocriptine had a significantly lower incidence of dyskinesias than those randomized to levodopa (rate ratio 0.73 [95% CI 0.57, 0.93]). However, this difference was not significant when only moderate to severe dyskinesias were considered. Patients in the bromocriptine arm had slightly lower rates of dystonias and on-off fluctuations, but moderate and severe forms were equally frequent in both arms. CONCLUSION: Starting treatment with the dopamine agonist bromocriptine does not reduce mortality in PD. A slightly lower incidence of motor complications is achieved at the expense of significantly worse disability scores throughout the first years of therapy.

Manson AJ, Hanagasi H, Turner K, Patsalos PN, Carey P, Ratnaraj N, Lees AJ. · The Reta Lila Weston Institute for Neurological Studies, The Middlesex Hospital, The National Hospital for Neurology and Neurosurgery, Middlesex, UK. · Brain. · Pubmed #11157560 links to  free full text

Abstract: Six patients with Parkinson's disease and refractory motor fluctuations, with severe subcutaneous (s.c.) nodule formation as a result of long-term s.c. apomorphine infusions, were switched to intravenous (i.v.) therapy via a long-term in-dwelling venous catheter. Five patients were followed-up for a mean of 7 months (range 0.5-18 months). All patients had plasma apomorphine concentrations measured at baseline during s.c. infusions and three had follow-up measurements when stabilized on i.v. therapy, to test the hypothesis that motor fluctuations in these patients are largely due to impaired absorption of apomorphine. The mean i.v. rate of 9.0 mg/h (range 5-14 mg) and 24-h dose of 256.7 mg (range 90-456 mg) of apomorphine were not significantly reduced compared with the s.c. route (9.24 mg/h and 243.4 mg). However, additional oral anti-parkinsonian medication was reduced by a mean of 59%, and 'off' time was virtually eliminated (mean reduction from 5.4 to 0.5 h per day, P< 0.05). There was also a significant reduction in dyskinesias and markedly improved quality of life. Pharmacokinetic analysis demonstrated more reliable and smoother delivery of apomorphine via the i.v. route, although 'off' periods were not always explained by low plasma apomorphine concentrations. Complication rates were high and included three unforeseen hazardous intravascular thrombotic complications, secondary to apomorphine crystal accumulation, necessitating cardiothoracic surgery. We conclude that i.v. apomorphine therapy holds promise as a more effective way of controlling motor fluctuations than the s.c. route. However, further preclinical research is required before i.v. Britaject apomorphine can be recommended for routine clinical practice. Even when stable plasma apomorphine concentrations were achieved, motor fluctuations could not be totally eradicated, suggesting that postsynaptic receptor changes may also play a role in the refractory 'off' periods in these patients.

Manson AJ, Iakovidou E, Lees AJ. · The Reta Lila Weston Institute of Neurological Studies, University College London, Windeyer Institute of Medical Science, UK. · Mov Disord. · Pubmed #10752589 No free full text.

This publication has no abstract.

Manson AJ, Brown P, O'Sullivan JD, Asselman P, Buckwell D, Lees AJ. · National Hospital for Neurology and Neurosurgery, Queen Square, London, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #10644787 links to  free full text

Abstract: OBJECTIVES: New treatments are now becoming available for the management of levodopa induced dyskinesias in Parkinsons's disease. However, assessment of their efficacy is limited by the inadequacies of current methods of dyskinesia measurement. The objective was to develop and validate a portable device capable of objectively measuring dyskinesias during normal daily activities. METHODS: A portable device was developed based on a triaxial accelerometer, worn on the shoulder, and a data recorder that can record levodopa induced dyskinesias. A computer program plots raw acceleration and acceleration over 0.5 Hz frequency bands against time. The acceleration in the different bands can then be compared with the raw acceleration trace, enabling identification and exclusion of confounding activities such as tremor and walking, which have a characteristic appearance on the trace. The validity of this device was assessed on 12 patients and eight age matched controls by comparing accelerations in the 1-3 Hz frequency band with established clinical dyskinesia rating scales. While wearing the monitor, subjects were videorecorded sitting and during dyskinesia provocation tasks, including mental activation tasks, eating, drinking, writing, putting on a coat, and walking. The dyskinesias were graded with both modified abnormal involuntary movement (AIM) and Goetz scales. The clinical ratings were then compared with the mean acceleration scores. RESULTS: Acceleration in the 1-3 Hz frequency band correlated well against both scales, during all individual tasks. Acceleration produced by normal voluntary activity (with the exception of walking, which produced large accelerations, even in controls) was small compared with dyskinetic activity. With walking excluded, the mean acceleration over the rest of the recording time correlated strongly with both the modified AIM (Spearman's rank (r=0.972, p<0.001) and Goetz (r=0.951, p<0.001) scales. CONCLUSIONS: This method provides an accurate, objective means for dyskinesia assessment, and compares favourably with established methods currently used.

Wang HC, Lees AJ, Brown P. · Department of Neurology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan. · J Neurol Neurosurg Psychiatry. · Pubmed #10201414 links to  free full text

Abstract: OBJECTIVE: It has been suggested that the basal ganglia act to release cortical elements from idling (alpha) rhythms so that they may become coherent in the gamma range, thereby binding together those distributed activities necessary for the effective selection and execution of a motor act. This hypothesis was tested in 10 patients with idiopathic Parkinson's disease. METHODS: Surface EEG was recorded during self paced squeezing of the hand and elbow flexion performed separately, simultaneously, or sequentially. Recordings were made after overnight withdrawal of medication and, again, 1 hour after levodopa. The medication related improvement in EEG desynchronisation (in the 7.5-12.5 Hz band) over the 1 second before movement and during movement were separately correlated with the improvement in movement time for each electrode site. Correlation coefficients (r) > 0.632 were considered significant (p<0.05). RESULTS: Improvement in premovement desynchronisation correlated with reduction in bradykinesia over the contralateral sensorimotor cortex and supplementary motor area in flexion and squeeze, respectively. However, when both movements were combined either simultaneously or sequentially, this correlation shifted anteriorly, to areas overlying prefrontal cortex. Improvement in EEG desynchronisation during movement only correlated with reduction in bradykinesia in two tasks. Correlation was seen over the supplementary motor area during flexion, and central prefrontal and ipsilateral premotor areas during simultaneous flex and squeeze. CONCLUSIONS: The results are consistent with the idea that the basal ganglia liberate frontal cortex from idling rhythms, and that this effect is focused and specific in so far as it changes with the demands of the task. In particular, the effective selection and execution of more complex tasks is associated with changes over the prefrontal cortex.

Churchyard A, Mathias CJ, Lees AJ. · Institute of Neurology and University Department of Clinical Neurology, National Hospital for Neurology and Neurosurgery, London, UK. · Mov Disord. · Pubmed #10091617 No free full text.

Abstract: OBJECTIVES: The United Kingdom Parkinson's Disease Research Group (UKPDRG) trial found an increased mortality in patients with Parkinson's disease (PD) randomized to receive 10 mg selegiline per day and L-dopa compared with those taking L-dopa alone. Recently, we found that therapy with selegiline and L-dopa was associated with selective systolic orthostatic hypotension which was abolished by withdrawal of selegiline. This unwanted effect on postural blood pressure was not the result of underlying autonomic failure. The aims of this study were to confirm our previous findings in a separate cohort of patients and to determine the time course of the cardiovascular consequences of stopping selegiline in the expectation that this might shed light on the mechanisms by which the drug causes orthostatic hypotension. METHODS: The cardiovascular responses to standing and head-up tilt were studied repeatedly in PD patients receiving selegiline and as the drug was withdrawn. RESULTS: Head-up tilt caused systolic orthostatic hypotension which was marked in six of 20 PD patients on selegiline, one of whom lost consciousness with unrecordable blood pressures. A lesser degree of orthostatic hypotension occurred with standing. Orthostatic hypotension was ameliorated 4 days after withdrawal of selegiline and totally abolished 7 days after discontinuation of the drug. Stopping selegiline also significantly reduced the supine systolic and diastolic blood pressures consistent with a previously undescribed supine pressor action. CONCLUSION: This study confirms our previous finding that selegiline in combination with L-dopa is associated with selective orthostatic hypotension. The possibilities that these cardiovascular findings might be the result of non-selective inhibition of monoamine oxidase or of amphetamine and metamphetamine are discussed.