Warren Olanow

Clinical diagnostic criteria for dementia associated with Parkinson's disease

Dementia has been increasingly more recognized to be a common feature in patients with Parkinsons disease (PD), especially in old age. Specific criteria for the clinical diagnosis of dementia associated with PD (PD‐D), however, have been lacking. A Task Force, organized by the Movement Disorder Study, was charged with the development of clinical diagnostic criteria for PD‐D. The Task Force members were assigned to sub‐committees and performed a systematic review of the literature, based on pre‐defined selection criteria, in order to identify the epidemiological, clinical, auxillary, and pathological features of PD‐D. Clinical diagnostic criteria were then developed based on these findings and group consensus. The incidence of dementia in PD is increased up to six times, point‐prevelance is close to 30%, older age and akinetic‐rigid form are associated with higher risk. PD‐D is characterized by impairment in attention, memory, executive and visuo‐spatial functions, behavioral symptoms such as affective changes, hallucinations, and apathy are frequent. There are no specific ancillary investigations for the diagnosis; the main pathological correlate is Lewy body‐type degeneration in cerebral cortex and limbic structures. Based on the characteristic features associated with this condition, clinical diagnostic criteria for probable and possible PD‐D are proposed.

The metric properties of a novel non-motor symptoms scale for Parkinson's disease: Results from an international pilot study

Non‐motor symptoms (NMS) in Parkinsons disease (PD) are common, significantly reduce quality of life and at present there is no validated clinical tool to assess the progress or potential response to treatment of NMS. A new 30‐item scale for the assessment of NMS in PD (NMSS) was developed. NMSS contains nine dimensions: cardiovascular, sleep/fatigue, mood/cognition, perceptual problems, attention/memory, gastrointestinal, urinary, sexual function, and miscellany. The metric attributes of this instrument were analyzed. Data from 242 patients mean age 67.2 ± 11 years, duration of disease 6.4 ± 6 years, and 57.3% male across all stages of PD were collected from the centers in Europe, USA, and Japan. The mean NMSS score was 56.5 ± 40.7, (range: 0–243) and only one declared no NMS. The scale provided 99.2% complete data for the analysis with the total score being free of floor and ceiling effect. Satisfactory scaling assumptions (multitrait scaling success rate >95% for all domains except miscellany) and internal consistency were reported for most of the domains (mean α, 0.61). Factor analysis supported the a prori nine domain structure (63% of the variance) while a small test–retest study showed satisfactory reproducibility (ICC > 0.80) for all domains except cardiovascular (ICC = 0.45). In terms of validity, the scale showed modest association with indicators of motor symptom severity and disease progression but a high correlation with other measures of NMS (NMSQuest) and health‐related quality of life measure (PDQ‐8) (both, rS = 0.70). In conclusion, NMSS can be used to assess the frequency and severity of NMS in PD patients across all stages in conjunction with the recently validated non‐motor questionnaire.

Placebo response in Parkinson's disease: Comparisons among 11 trials covering medical and surgical interventions

Placebo‐associated improvements have been previously documented in small series of Parkinsons disease (PD) patients. Using a strict definition of placebo‐associated improvement, we examined rates and timing of placebo responses to identify patient‐ and study‐based characteristics, predicting positive placebo response in several PD clinical trials. We collected individual patient data from the placebo groups of 11 medical and surgical treatment trials involving PD patients with differing PD severities and placebo‐assignment likelihoods. We defined a positive placebo response as ≥50% improvement in total Unified Parkinsons Disease Rating Scale motor (UPDRSm) score or a decrease by ≥2 points on at least two UPDRSm items compared to baseline. We calculated positive placebo response rates at early (3–7 weeks), mid (8–18 weeks), and late (23–35 weeks) stages of follow‐up. Odds ratios for patient‐ and study‐based characteristics were obtained from a model fitted using generalized estimating equations. There were 858 patients on placebo who met inclusion criteria for analysis. Three studies involved patients without need of symptomatic treatment, two involved patients without motor fluctuations needing symptomatic treatment, and six (three medical and three surgical) involved patients with motor fluctuations. The overall placebo response rate was 16% (range: 0–55%). Patients with higher baseline UPDRSm scores and studies that focused on PD with motor fluctuations, surgical interventions, or those with a higher probability of placebo assignment showed increased odds of positive placebo response. Placebo responses were temporally distributed similarly during early, mid, and late phases of follow‐up. Placebo‐related improvements occur in most PD clinical trials and are similarly distributed across all 6 months of follow‐up. Recognition of factors that impact placebo response rates should be incorporated into individual study designs for PD clinical trials.

LEVODOPA IN THE TREATMENT OF PARKINSON'S DISEASE : A CONSENSUS MEETING

Levodopa (in combination with a peripheral dopadecarboxylase inhibitor) substantially improves the quality of life of patients. However, physicians are not always comfortable prescribing it, and its administration is often delayed to retard the development of motor complications or is restricted to patients with relatively advanced disease, because there is a fear that the decreased response of parkinsonian symptoms may result from a self-limiting effect of the drug. Moreover, long-term treatment with levodopa is claimed by some to induce the degeneration of dopaminergic neurons, thereby accelerating disease progression. Whether long-term administration of levodopa in patients may result in the irreversible appearance of side effects or accelerate the neurodegenerative process is a crucial question, and it is therefore legitimate to ask whether one should delay the introduction or limit its use in patients. To address these questions, a meeting of experts was held in Paris (January 8–9, 1998) to see whether general agreement could be reached concerning the interpretation of studies of levodopa toxicity in tissue culture, in animal models of parkinsonism, and in patients. Most of the experts agreed that the administration of levodopa was not dangerous for patients. Nevertheless, there are still conflicting results and unanswered questions. This is why this consensus on levodopa treatment of patients with Parkinson’s disease (see below) is followed by additional comments made by some of the experts.

Onset of dyskinesia with adjunct ropinirole prolonged-release or additional levodopa in early Parkinson's disease.

Levodopa‐induced dyskinesia can result in significant functional disability and reduced quality of life in patients with Parkinsons disease (PD). The goal of this study was to determine if the addition of once‐daily ropinirole 24‐hour prolonged‐release (n = 104) in PD patients not optimally controlled with levodopa after up to 3 years of therapy with less than 600 mg/d delays the onset of dyskinesia compared with increasing doses of levodopa (n = 104). During the study, 3% of the ropinirole prolonged‐release group (mean dose 10 mg/d) and 17% of the levodopa group (mean additional dose 284 mg/d) developed dyskinesia (P < 0.001). There were no significant differences in change in Unified Parkinsons Disease Rating Scale activities of daily living or motor scores, suggesting comparable efficacy between the two treatments. Adverse events were comparable in the two groups with nausea, dizziness, insomnia, back pain, arthralgia, somnolence, fatigue, and pain most commonly reported. Ropinirole prolonged‐release delayed the onset of dyskinesia with comparable efficacy to increased doses of levodopa in early PD patients not optimally controlled with levodopa.

The administration of entacapone prevents L-dopa-induced dyskinesia when added to dopamine agonist therapy in MPTP-treated primates.

More continuous delivery of l-3,4-dihydroxyphenylalanine (l-dopa) achieved by combination with the catechol-O-methyl transfer (COMT) inhibitor entacapone reduces the onset of dyskinesia in MPTP-treated common marmosets compared with pulsatile l-dopa regimens. We now investigate whether l-dopa delivery also influences dyskinesia induction when added to dopamine agonist treatment. Drug-naive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-treated common marmosets were treated with ropinirole twice daily (BID) for 14 days which reversed motor disability and increased locomotor activity with minimal dyskinesia. Ropinirole treatment was continued but some animals also received l-dopa BID or four times daily (QID) with and without entacapone or vehicle for a further 16 days. Continuing ropinirole treatment alone maintained a similar reversal of motor deficits and low levels of dyskinesia for the first 14 days and the second 16 days. The addition of l-dopa BID or QID without entacapone produced only a minor further reversal of motor deficits, but significantly increased the intensity of dyskinesia. In contrast, the addition of l-dopa BID or QID with entacapone also produced some further improvement in motor function with the combination of entacapone and l-dopa BID significantly improving motor disability compared to l-dopa alone, but no further increase in dyskinesia intensity was observed compared with ropinirole alone treatment. The results show that combined treatment with l-dopa and entacapone has a marked effect on dyskinesia induction even when therapy has been introduced with a dopamine agonist.

Deep brain stimulation for Parkinson's disease: thinking about the long-term in the short-term.

Deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) or the globus pallidus pars interior (GPi) represents one of the major therapeutic breakthroughs in the treatment of Parkinson’s disease (PD). Despite the complexity of the procedure, the need to integrate a team of neurologists, neurosurgeons, neurophysiologists, and research nurses, and its high cost, DBS is now routinely used at PD centers around the world and it has benefited several thousands of patients. DBS of both the STN and the GPi has been shown to be effective for the treatment of levodopainduced motor complications and is superior to best medical management. These benefits have been confirmed in randomized, controlled, double-blind trials. For patients who suffer intolerable motor complications, the introduction of DBS has represented a ‘‘therapeutic miracle.’’ However, serious side effects may be associated with the procedure, the indwelling DBS system, and the stimulation itself. In addition to the risk of a devastating intracerebral hemorrhage (about 1%), hardware problems due to fracture, infection, or lead displacement can necessitate removal of the electrodes in as many as 2% of patients. Further, the clinical effects of DBS in PD patients are comparable to what can be achieved with continuous infusion of L-dopa and apomorphine. Indeed, no study has demonstrated that DBS provides anti-parkinsonian benefits that are superior to what can be achieved with L-dopa. On the other hand, DBS provides continuous 24-hour benefit, with maintenance of efficacy during the night, no evidence of tolerance, and a reduction in side effects associated with the use of high-dose dopaminergic medications. Medical therapy for PD is limited by disease progression and the development of features such as falling, freezing, and dementia. Accordingly, long-term follow-up studies of DBS procedures, to evaluate the quality and duration of benefits and the propensity to develop cumulative disability, are crucial to fully appreciate the risk or benefit of the procedure, and to appropriately counsel patients and their families. In this issue of the journal, Zibetti and colleagues report on 14 PD patients who were followed for 9 years after DBS-STN. This is the longest report on outcomes following STN-DBS in PD that has been provided to date. It expands on the results of similar studies of PD patients followed for 5 to 8 years after surgery. These reports share a common set of observations. They each indicate that the beneficial effects of DBS on the cardinal dopaminergic features of PD and on L-dopa–induced motor complications remain very well preserved. However, as observed in medically treated PD patients, freezing of gait, postural instability, falling, speech difficulties, and cognitive impairment emerge over time and become the major source of disability. Indeed, after 9 years of DBS treatment, and despite the sustained benefits on motor features and motor complications, the patients reported by Zibetti and colleagues showed a marked decline in their activities of daily living compared with what was observed at 1 and 5 years after DBS, which is consistent with deterioration due to disease progression. These studies have several methodological limitations, such as the relatively small number of patients, the lack of appropriate controls, the impossibility of controlling for confounding factors such as change in medication, and comorbidity. Nevertheless, the results seem clear.

Continuing efforts to obtain continuous delivery of levodopa.

Motor complications such as wearing off and dyskinesia continue to represent problems for PD patients and to limit the full utility of levodopa. Studies over the past decade have demonstrated that under normal circumstances striatal dopamine levels are maintained at a relatively constant level. As levodopa has a relatively short plasma half-life of around 90 minutes, it is likely that intermittent doses of standard formulations of levodopa do not restore brain dopamine in a physiological manner. Further, intermittent doses of levodopa are associated with molecular and physiologic changes in basal ganglia nuclei that result in motor complications. Thus, it has been hypothesized that continuous delivery of levodopa might restore brain dopamine in a more physiologic manner and reduce the risk of the drug inducing motor complications. The importance of variable levodopa plasma levels in the management of patients with Parkinson’s disease (PD) suffering motor fluctuations and dyskinesias has been realized since the 1970’s. Initial attempts to stabilize plasma levodopa levels utilized continuous intravenous infusion. Trials of IV levodopa infusion in severe PD patients who suffered from catastrophic and seemingly random ‘‘off’’ episodes coupled with stormy dyskinetic ‘‘on’’ periods demonstrated marked benefits with substantial amelioration of both types of motor complications. The large volumes of fluid required for levodopa infusion and the impracticality of intravenous delivery led to trials of continuous subcutaneous infusion of the dopamine agonists lisuride and apomorphine which were also associated with significant reductions in both ‘‘off’’ time and ‘‘on’’ dyskinesias. Subsequently, continuous intraintestinal delivery of levodopa via a gastrostomy (Duodopa) was shown to provide stable plasma levodopa levels and substantially improve motor complications. Thus, experience with sustained delivery of dopaminergic drugs support the concept of Continuous Dopaminergic Stimulation for PD. However, while Duodopa provides further support to the value of continuous delivery and may be of great value for patients with advanced disease, this technique is not free of complications, some of which may be severe (intestinal paralysis, peritonitis, severe neuropathy). Based on experimental findings in animal models of PD and the theoretical considerations mentioned above, the pharmacologic treatment of PD over the last 15 years or so, has been dominated by the early use of long-acting DA agonist. However, most PD patients eventually required levodopa and this leads to the development of motor complications at a rate that is comparable to when levodopa is initiated as monotherapy. The question remains, whether continuous delivery of a dopaminergic agent can prevent the development of motor complications in early PD patients. Infusion therapies are not a practical consideration for early PD patients who can be satisfactorily controlled with oral levodopa, and thus an effort has been put forward to develop a long acting oral formulation of levodopa or other dopaminergic agents that might provide the benefits of levodopa without motor complications. Achievement of this goal has proven difficult. In the 1980’s Sinemet CR was evaluated based on its relatively long half-life but failed to show reduced motor complications in comparison to standard levodopa in double blind trials, possibly because it did not provide steady plasma levodopa levels. An alternate approach was the combination of levodopa with inhibitors of COMT, which blocks the peripheral metabolism of the drug and extends its elimination half-life. It was postulated that frequent administration of levodopa combined with a COMT inhibitor in early PD patients in whom central decarboxylation and pre-synaptic storing capacity are not completely impaired and compensatory mechanisms are still operative, might result in a more constant striatal dopamine levels and reduce the risk of motor complications. To test this hypothesis, the STRIDE PD study compared the risk of developing dyskinesia in patients initiated on levodopa combined with the COMT inhibitor entacapone administed four times per day at 3.5 hour intervals to patients randomized to receive levodopa alone. Patients receiving levodopa -----------------------------------------------------------Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article.

Dopamine agonists for Parkinson's disease

Sir—Yves Agid and colleagues (Aug 17, p 575) argue that levodopa is the most effective treatment for Parkinson’s disease and that the associated motor side-effects are related to the pulsatile delivery of this drug. They suggest that these complications can be prevented with long-acting dopaminergic medications or continuous infusion of levodopa. However, Agid and co-workers make no mention of the role of dopamine agonists as an alternative treatment strategy to levodopa in early disease. Many patients with Parkinson’s disease have motor complications, including dyskinesia, within 5–10 years of starting levodopa; these motor complications increase with the dose of levodopa. Dyskinesias are a particular problem in young-onset patients and are difficult to manage. Currently available controlled-release inhibitors of aromatic aminoacid decarboxylase are not proven to reduce levodopa-induced motor fluctuations in the long term. The alternative of continuous infusion is not a practical option for most patients with Parkinson’s disease. We do not know of any evidence that early use of inhibitors of aromatic aminoacid decarboxylase or catecholO-methyltransferase reduce motor complications. There is, however, evidence that dopamine agonists are associated with fewer motor sideeffects than standard levodopa therapy when treatment is started early in the disease. Preclinical studies suggest that dopamine agonists may reduce the loss of dopaminergic neurons, and slow the rate of disease progression. In double-blind trials with imaging endpoints, A Whone and colleagues and K Marek and co-workers noted that loss of dopamine-transporter function is significantly reduced with dopamine agonists compared with levodopa. We recommend that occurrence of motor complications can be kept to a minimum by use of a dopamine agonist in appropriate patients and by delaying introduction of levodopa in early disease to prevent neuronal priming to these effects. The objectives of management of Parkinson’s disease are changing—it is no longer appropriate just to provide short-term control of motor symptoms. The longer term objective to reduce all complications and ensure preservation of quality of life for as long as is possible is arguably of greater importance. The cognitive consequences of Parkinson’s disease remain a major concern for older patients, but we now have the opportunity to reduce the occurrence of motor complications associated with long-term levodopa therapy. The evidence is building in favour of offering dopamine agonists to all suitable patients from the onset of Parkinson’s disease.