Myths and realities of continuous dopaminergic stimulation

Motor fluctuations and dyskinesia in later stages of Parkinson's disease (PD) are caused by pharmacokinetic as well as pharmacodynamic factors, intermittent dopaminergic stimulation being one of the most important. In the healthy brain, dopamine neurons in the substantia nigra pars compacta fire tonically at a steady rate of about 4 cycles/second. In later stages of PD, steady firing is replaced by pulsatile stimulation which causes molecular and physiologic changes in the basal ganglia. Continuous dopaminergic stimulation has been shown to dramatically improve motor fluctuations and dyskinesia by modifications of oral treatment (dopamine agonists, smaller, more frequent levodopa doses, controlled-release formulation of levodopa, addition of agents that slow down the catabolism of dopamine, such as inhibitors of catechol-O-methyl transferase and monoamine oxidase), transdermal delivery (rotigotine), infusion therapies (intravenous levodopa, subcutaneous application of apomorphine and lisuride, duodenal infusion of levodopa) and deep brain stimulation of the subthalamic nucleus.     

Treatment of Parkinson's disease: Problems with a progressing disease

Summary Long-term follow-up of parkinsonian patients has shown that although levodopa treatment significantly improves the parkinsonian symptoms and the quality of life of parkinsonian patients for several years, various distressing difficulties arise during chronic levodopa treatment, such as the loss of benefit, dyskinesias, on-off phenomena, postural instability and dementia. Clinical, neuropsychological, mortality and post-mortem brain studies indicate that levodopa as a replacement therapy does not modify the progression of the underlying pathology and the natural course of the disease. It seems that levodopa has only a limited period of optimal usefulness in the treatment of Parkinson's disease. However, at present there is no better or more potent therapeutic agent available than levodopa and it is still the primary treatment of Parkinson's disease. It would be reasonable not to begin levodopa treatment in patients with mild symptoms but to withold levodopa until the severity of symptoms really makes its use necessary. Thus it is possible to get the maximal long functional benefit.Post-mortem brain studies have shown that in Parkinson's disease there is not only a progressive loss of dopaminergic substantia nigra neurons but there are also significant changes in the striatal dopamine receptors. In some patients a denervation supersensitivity seems to develop and in some others a loss of dopamine receptors in the striatum. However, in advanced parkinsonian patients with a deteriorating response to levodopa, there seem to be still enough dopamine receptors in the striatum for drugs stimulating the dopamine receptors directly to improve the parkinsonian disability. Indeed, recent evidence indicates that dopaminergic agonists, such as bromocriptine, seem to be a significant and valuable adjuvant therapy to levodopa in parkinsonian patients with a deteriorating response and/or the on-off phenomena. Although bromocriptine is not completely satisfactory, it is a significant opening to a new mode of treatment. In the future it will be very important to develop more potent and selective dopaminergic agonists affecting only those striatal receptors which are mainly responsible for the parkinsonian symptoms. Then a better therapeutic response is likely to occur and many central side effects can be avoided.Current difficulties in the management of Parkinson's disease greatly depend on the fact that we are dealing with a symptomatic therapy. It is hoped that future research will soon lead to a discovery of the primary cause and consequently to a causal therapy of Parkinson's disease.     

Effects of deep brain stimulation and levodopa on postural sway in Parkinson's disease

OBJECTIVE: To quantify postural sway in subjects with Parkinson's disease and elderly controls, and determine the effects of Parkinson's disease, deep brain stimulation, levodopa, and their interactions on postural control during quiet stance. METHODS: Centre of foot pressure (CoP) displacement under each foot was measured during three 60 s trials of quiet stance with eyes open in 11 controls and six patients with Parkinson's disease. Subjects with Parkinson's disease were tested in four treatment conditions: off both deep brain stimulation and levodopa (off condition); on deep brain stimulation; on levodopa; and on both deep brain stimulation and levodopa. The variables extracted from CoP included: root mean square distance (rms), mean velocity, 95% power frequency (f(95%)), area of the 95% confidence ellipse (ellipse area), direction of its major axis (mdir), and postural asymmetry between the feet. RESULTS: rms and area of postural sway were larger than normal in subjects with Parkinson's disease in the off condition, increased further with levodopa, and significantly decreased with deep brain stimulation. Mean velocity and f(95%) were also larger than normal but were restored to normal by all treatments, especially by deep brain stimulation. The combined effect of deep brain stimulation and levodopa resulted in a postural sway that was an average of the effect of each treatment individually. Levodopa increased sway more in the mediolateral than in the anterior-posterior direction. Subjects with Parkinson's disease had asymmetrical mean velocity and f(95%) between the feet, and this asymmetry increased with levodopa but decreased with deep brain stimulation. The f(95%) of the CoP correlated with tremor, posture, and gait subcomponents of the unified Parkinson's disease rating scale. CONCLUSIONS: Subjects with Parkinson's disease have abnormal postural sway in stance. Treatment with levodopa increases postural sway abnormalities, whereas treatment with deep brain stimulation improves postural sway. Quantitative evaluation of static posturography may be a useful adjunct to clinical measures in patients with Parkinson's disease.     

Dopamine agonists, receptor selectivity and dyskinesia induction in Parkinson's disease

Levodopa and the dopamine agonists are effective symptomatic treatments for Parkinson's disease, and all patients receive at least one of these agents during their illness. Long-term use of levodopa is commonly associated with motor complications such as dyskinesia, and both the dosing frequency and total daily dose of levodopa determine the rate of onset and severity. Dopamine agonists have gained popularity as first-line monotherapy in Parkinson's disease, as they effectively reverse motor deficits and reduce the risk of motor complications. Long-acting dopamine agonists providing continuous, rather than pulsatile, dopaminergic stimulation appear able to avoid dyskinesia induction. Current treatments act predominantly on D2 receptors, but drugs acting on both the D1 and D2 receptor families may produce an additive motor response, although this remains to be proven in patients with Parkinson's disease. Most currently used dopamine agonists are selective for D2-like receptors, with only pergolide and apomorphine potentially interacting with D1 receptor populations.     

Role of dopamine agonists in Parkinson's disease: an update

At present, dopamine agonists play an important role in antiparkinsonian therapy since they were proved effective in the management of both advanced- and early-stage Parkinson's disease. In the latter, they are often regarded as first-choice medication to delay the introduction of levodopa therapy. Despite sharing the capacity to directly stimulate dopamine receptors, dopamine agonists show different pharmacological properties as they act on different subsets of dopamine receptors. This, in theory, provides the advantage of obtaining a different antiparkinsonian activity or safety profile with each agent. However, there is very little evidence that any of the marketed dopamine agonists should be consistently preferred in the management of patients with Parkinson's disease. Pergolide and cabergoline are now considered a second-line choice after the proven association with valvular fibrosis. Transdermal administration (rotigotine) and subcutaneous infusion (apomorphine) of dopamine receptor agonists are now available alternatives to oral administration and provide continuous dopaminergic stimulation. Continuous subcutaneous apomorphine infusion during waking hours leads to a large reduction in daily 'off' time, dyskinesias and levodopa daily dose. Almost all currently used dopamine agonists are able to provide neuroprotective effects towards dopaminergic neurons during in vitro and in vivo experiments. This neuroprotection may be the result of different mechanisms including antioxidation, scavenging of free radicals, suppression of lipid peroxidation and inhibition of apoptosis. However, the disease-modifying effect of these agents in Parkinson's disease remains to be ascertained.     

Deep brain stimulation and continuous dopaminergic stimulation in advanced Parkinson's disease

Patients receiving oral levodopa, the standard treatment for Parkinson's disease (PD), eventually develop motor fluctuations and dyskinesias. Treatment options for patients with these symptoms include high-frequency deep brain stimulation of the subthalamic nucleus (STN-DBS) or continuous dopaminergic stimulation (CDS). STN-DBS is the prevalent surgical therapy for PD and has shown efficacy, but behavioural disorders, including cognitive problems, depression and suicidality have been reported. CDS can be achieved with oral dopamine agonists with a long half-life, transdermal or subcutaneous delivery of dopamine agonists, or intestinal levodopa infusion. Of these, duodenal levodopa infusion appears to be the most promising option in terms of both efficacy and safety.     

Should levodopa be used anymore?

Levodopa is the most potent dopaminergic oral drug available in clinical practice. After chronic treatment, many patients with Parkinson's disease develop dyskinesia and motor fluctuations which are difficult to manage. It was hoped that introduction of dopaminergic agonists could diminish these side effects while keeping the same efficacy as levodopa. Prospective clinical data do not support this idea with the present drugs. Levodopa remains the most useful treatment and most clinicians believe that it is wise to associate early on levodopa with one of the dopamine agonists.     

A randomised controlled study of bromocriptine versus levodopa in previously untreated Parkinsonian patients: a 3 year follow-up.

The long term effects of a de novo treatment with levodopa versus bromocriptine were compared in respectively 13 and 15 previously untreated patients with Parkinson's disease in a prospective randomised trial. Thirteen patients were treated with levodopa alone (mean dose 444, SEM 63 mg daily) whereas 15 others received bromocriptine alone (mean dose 50, SEM 6 mg daily) during 37, SEM 4 and 32, SEM 4 months respectively. For a similar decrease in the Columbia rating scale, the nature of long term side effects was different in the two groups: three patients on levodopa developed peak-dose dyskinesias and one other dystonia. With bromocriptine, one patient developed a severe psychosis whereas 3 others suffered from primary lack of efficacy (1 case) or late decrease in efficacy (2 cases). These results demonstrate the potential of D2 dopamine agonists (like bromocriptine) in the de novo treatment of Parkinson's disease; however, their use is limited by their lack of efficacy and/or the occurrence of neuropsychiatric side effects.     

The timing of antiparkinsonian treatment reduction after subthalamic nucleus stimulation

The objective of this work was to precisely analyse the reduction of the antiparkinsonian treatment in 18 consecutive patients with Parkinson's disease (PD) operated on for bilateral subthalamic nucleus (STN) stimulation, first after 1 month of follow-up, then at 1 year postoperatively. Trihexyphenidyle, selegiline, entacapone, apomorphine and lisuride could be withdrawn shortly after starting STN electrical stimulation. The levodopa mean daily dose was reduced by 57% at 1 month after surgery and remained stable at 1 year. The mean ropinirole and bromocriptine daily dose decrements after surgery corresponded to 54 and 63%, respectively, at 1 month and to 77 and 40% at 1 year. At 12 months postoperatively, one third of the patients no longer received any antiparkinsonian drugs and the others were on monotherapy of either levodopa or dopamine agonists or received a combined treatment of a dopaminergic agonist and levodopa. In conclusion, STN stimulation allows a major reduction and simplification of antiparkinsonian treatment which can usually be achieved during the early postoperative period.     

Successful subthalamic stimulation, but levodopa-induced dystonia, in a genetic Parkinson’s disease

Recently, it is under scrutiny the possibility to anticipate the stereotactic implantation of the subthalamic nucleus (STN) even in relatively mild Parkinson’s disease (PD) patients with an unsatisfying response to drugs. In addition, it is debated whether levodopa (LD) and deep brain stimulation (DBS) are congruent or, instead, mutually exclusive. A 56-year-old LRRK2-positive PD patient, with 7 years of disease history, dominated by severe left resting tremor, was submitted to bilateral implantation of the subthalamic nucleus (STN). Before surgery, the combination of LD and dopamine agonists failed to handle tremor unless administered at doses, which induced undesirable adverse events. STN deep brain stimulation (DBS) abolished tremor but did not provide satisfying control of hypokinetic-rigid symptoms. The condition STIM-ON plus LD, albeit transiently beneficial, installed a painful dystonia developing slowly after 24–36 h. Only a chronic therapy combining rotigotine plus STN-DBS proved effective without side effects. This case report, based upon the surprising difference between the therapeutic response to the combination of LD and dopamine agonist (before surgery) and the combination of DBS and agonist after surgery, emphasizes how STIM and LD target different motor domains through mechanisms with differential plasticity and confirms the efficacy of STN-DBS in LRKK2 patients.     

Dopamine dysregulation syndrome after deep brain stimulation of the subthalamic nucleus in Parkinson's disease

Dopamine dysregulation syndrome is a complication of the dopaminergic treatment for Parkinson's disease, probably related to sensitization of the mesolimbic dopamine system. The relationship between dopamine dysregulation syndrome and deep brain stimulation of the subthalamic nucleus remains unclear. We report three patients with Parkinson's disease who developed de novo dopamine dysregulation syndrome after deep brain stimulation of the subthalamic nucleus. We hypothesized that the combined effect of dopaminergic replacement therapy and deep brain stimulation on the limbic territory of the subthalamic nucleus could have precipitated the dopamine dysregulation syndrome in these patients, by inducing hyperstimulation of the mesolimbic dopamine system. The outcome of postoperative dopamine dysregulation syndrome is poor despite deep brain stimulation adjustments, attempts to reduce the dose of dopaminergic drugs and the addition of quetiapine or antidepressants.     

Functional imaging of cognition in Parkinson's disease

PURPOSE OF REVIEW: Cognitive deficits that occur even early in the course of Parkinson's disease have received increasing attention in current imaging research. The exact physio-pathological processes mediating the deficits and the complex relationship of cognitive signs and antiparkinsonian treatment are not well understood. A clearer understanding of these mechanisms could potentially influence treatment choices, drug development and, ultimately, patient care. RECENT FINDINGS: Abnormal networks identified in studies of resting state metabolism in Parkinson's disease represent metabolic markers for remote effects of striato-nigral degeneration. These metabolic changes include subcortico-cortical networks, in particular cognitive cortico-striato-pallidal-thalamocortical loops. Recent brain studies focus on intervention-related brain changes. They illustrate different task-specific changes in brain activation with deep brain stimulation and with levodopa. Variable results of stimulation can be attributed to different effects on segregated cortico-striato-pallidal-thalamocortical loops during stimulation. By contrast, the heterogeneity observed in studies with levodopa possibly reflects the disease-stage and task-specific effects of levodopa. A decline in caudate dopamine modulated basal ganglia outflow appears to contribute to executive dysfunction and to brain activation changes in these loops at early Parkisnon's disease stages, while mesocortical degeneration mediated increases of inefficient dorsolateral prefrontal cortex activation may display a feature of more advanced disease stages only. SUMMARY: Despite evidence for the role of dopamine and cortico-striato-pallidal-thalamocortical loops in cognition, the specific contributions of mesocortical dopamine depletion and striatal dysfunction with downstream consequences on the loops remain to be separated. Additionally, more research is needed into the role of non-dopaminergic pathology in cognitive decline in Parkinson's disease.     

Motor fluctuations in Parkinson's disease

Parkinson's disease is characterized by progressive slowness in activities of daily living and is the most common cause of parkinsonism, whose symptoms include resting tremor, cogwheel rigidity, and bradykinesia. The introduction of levodopa and its positive effect on motor dysfunction in Parkinson's disease has allowed neurologists to focus on motor fluctuations. "End-of-dose wearing-off" and "morning akinesia" are terms to describe the transition between a patient's relatively normal motor performance when levodopa is effective and when it has transiently lost its effect on motor responses and parkinsonian symptoms reemerge. The choices available to alleviate these motor fluctuations range from altering the patient's levodopa/carbidopa dosing schedule to the addition of other agents to the regimen, including dopamine receptor agonists, catechol-O-methyltransferase inhibitors, monoamine oxidase inhibitors, and amantadine, as well as implementing dietary changes. Therapeutic decisions can be difficult because older agents have not been compared in head-to-head trials to determine which drugs are better than others and the order in which they should be tried or added to the levodopa regimen; however, all of the available treatments provide a good possibility of benefit to the patient. Deep brain stimulation surgery is an option for patients with medically intractable severe motor fluctuations.     

Comparison of bromocriptine and levodopa as first line treatment of Parkinson's disease: results of a 3-year prospective randomized study

The long term effects of a first line treatment with levodopa or bromocriptine were compared in 36 previously untreated patients with Parkinson's disease in a prospective randomized trial: 18 patients were treated with levodopa alone (mean dose: 485 +/- 71 mg daily) whereas 18 others received bromocriptine alone (mean dose: 55 +/- 6 mg daily) during 36 +/- 3 and 31 +/- 3 months respectively. We observed a similar decrease in the Columbia rating scale but the nature of long term side effects was different in the two groups: patients on levodopa developed peak-dose dyskinesias (5 cases), wearing off akinesia (1 case) and on-off effects (1 case). Under bromocriptine treatment, 2 patients developed severe psychosis whereas one suffered from primary lack of drug effectiveness and 5 others from late decrease of drug effectiveness. These results suggest the potential value of relatively high doses of D2 dopamine agonists (such as bromocriptine) in the first line treatment of Parkinson's disease: however, their use can be limited by their decrease of effectiveness after several years and/or the occurrence of severe neuropsychiatric side-effects.     

Comparison of the clinical pharmacology of (-)NPA and levodopa in Parkinson''s disease.

Direct acting dopamine agonists are generally less effective than levodopa in relieving symptoms of Parkinson's disease. In an attempt to quantitate and explain this situation, the acute motor responses to intravenous injections of the dopamine agonist, (-)-N-n-propyl-norapomorphine hydrochloride (NPA), were compared with those of the dopamine precursor, levodopa. At optimum dose levels, the acute anti-Parkinsonian efficacy of NPA averaged only about 50% of maximum, while essentially total symptom suppression was obtained with levodopa in patients previously treated with the amine precursor. Dyskinesia severity, however, was similar with the two drugs. These differences in anti-Parkinsonian efficacy may reflect the fact that while NPA acts mainly on D-2 dopamine receptors, levodopa results in stimulation of both the D-1 and D-2 subsets of receptors at a more physiological ratio. Future efforts to develop dopamine agonists for the treatment of Parkinsonian symptoms may thus have to consider focusing on drugs having pharmacological profile more similar to that of dopamine.     

Deep brain stimulation for the treatment of Parkinson's disease.

Deep brain stimulation (DBS) is increasingly accepted as an adjunct therapy for Parkinson's disease (PD). It is considered a surgical treatment alternative for patients with intractable tremor or for those patients who are affected by long-term complications of levodopa therapy such as motor fluctuations and severe dyskinesias. Thalamic stimulation in the ventral intermediate nucleus (Vim) leads to a marked reduction of contralateral tremor but has no beneficial effect on other symptoms of Parkinson's disease. The subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) are targeted for the treatment of advanced Parkinson's disease. Several studies have proven the efficacy of STN-DBS and GPi-DBS in alleviating off motor symptoms and dyskinesias. Sub-thalamic nucleus deep brain stimulation is currently considered superior to GPi-DBS because the antiakinetic effect seems to be more pronounced, allows a more marked reduction of antiparkinsonian medication, and requires less stimulation energy. More recently, however, a number of reports on possible psychiatric and behavioral side effects of STN-DBS have been a matter of concern. Given the chronic nature of PD and the noncurative approach of DBS, both targets will need to be reevaluated on the basis of their long-term efficacy and their impact on quality of life. Despite the rapidly increasing numbers of DBS procedures, surprisingly few controlled clinical trials are available that address important clinical issues such as: When should DBS be applied during the course of disease? Which patients should be selected? Which target should be considered? Which guidelines should be followed during postoperative care? Here is summarized the available evidence on DBS as a therapeutic tool for the treatment of Parkinson's disease and the current state of debate on open issues.     

Dopamine agonists in the treatment of Parkinson's disease

Dopamine agonists are highly effective as adjunctive therapy to levodopa in advanced Parkinson's disease and have rapidly gained popularity as a monotherapy in the early stages of Parkinson's disease for patients less than 65-70 years old. In the latter case, dopamine agonists are about as effective as levodopa but patients demonstrate a lower tendency to develop motor complications. However, dopamine agonists lose efficacy over time and the number of patients remaining on agonist monotherapy decreases to less than 50% after 3 years of treatment. Thus, after a few years of treatment the majority of patients who started on dopamine agonists will be administered levodopa, in a combined dopaminergic therapy, in order to achieve a better control of motor symptoms.     

Rotigotine for the treatment of Parkinson's disease

Dopaminergic therapies, including levodopa and dopamine agonists, are the mainstays of therapy in Parkinson's disease. With the exception of the injectable short-acting dopamine agonist apomorphine, there is no other widely available non-oral dopaminergic therapy. Rotigotine is a lipid-soluble, non-ergot, D3, D2, D1 dopamine receptor agonist that has demonstrated efficacy as an alternative therapeutic option in both early and advanced Parkinson's disease. More importantly, it is uniquely formulated as a transdermal patch delivery system allowing for continuous, once-daily administration and better patient compliance. Preclinical and clinical trials have shown rotigotine to be a well-tolerated and effective treatment for early-stage Parkinson's disease. Rotigotine has also shown promise as adjunctive therapy with levodopa for the treatment of advanced Parkinson's disease.     

Treatment options for Parkinson's disease

PURPOSE OF REVIEW: Parkinson's disease is a common neurodegenerative disorder. Clinical trials designed to assess the safety and efficacy of novel neuroprotective as well as symptomatic medical and surgical strategies are being performed to increase and enhance treatment options. The purpose of this review is to summarize these therapeutic options, emphasizing reports published in the last year. RECENT FINDINGS: Experimental therapeutics in Parkinson's disease has focused on prevention of levodopa complications, treatment of dyskinesias associated with levodopa therapy, surgical intervention and neuroprotection. SUMMARY: There are at least four important implications of the recent therapeutic trials: (1) the incidence of levodopa-related dyskinesias decreases as a result of initial use of dopamine agonists; (2) surgery, primarily in the form of the bilateral, high-frequency stimulation of the subthalamic nucleus, is highly effective in patients who are responsive to levodopa but experience marked motor fluctuation or other complications; (3) while neuroprotection has not yet been demonstrated with any currently used therapeutic agent, improved understanding of mechanisms of cell death will undoubtedly result in the discovery of new drugs with potential disease-modifying effects; and (4) implantation of fetal mesencephalon tissue and other grafts may be effective in younger patients with Parkinson's disease, but is associated with significant complications and remains experimental.     

Using STN DBS and medication reduction as a strategy to treat pathological gambling in Parkinson's disease

We describe two patients with Parkinson's disease (PD) who developed clinical criteria of pathological gambling addiction in the setting of increased dopamine replacement therapy (levodopa and dopamine agonist medications). The second patient showed also signs of dopamine dysregulation syndrome, with an addiction to dopaminergic medication. Neither patients responded to the standard therapy for gambling behavior, but dramatically improved after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) and early postoperative withdrawal of dopaminergic therapy. The possible therapeutic role of subthalamic nucleus deep brain stimulation (STN-DBS) on such a disabling behavior needs to be investigated prospectively.