Hedonistic homeostatic dysregulation is a neuropsychological behavioural disorder associated with substance misuse and addiction. The disorder has been recognised as a consequence of dopamine replacement therapy (DRT) in 15 patients with Parkinson's disease. The syndrome typically develops in male patients with early onset Parkinson's disease, and can occur with orally and subcutaneously administered DRT. These patients take increasing quantities of their DRT, despite increasingly severe drug induced dyskinesias, and may develop a cyclical mood disorder with hypomania or manic psychosis. There is impairment of social and occupational functioning. Tolerance develops to mood elevating eVects of DRT and a negative aVective withdrawal state occurs if the drugs are withdrawn or doses decreased. The clinical features and guidelines for managing this syndrome are discussed. A set of diagnostic criteria for further investigating this condition is proposed. (J Neurol Neurosurg Psychiatry 2000;68:423-428) Keywords: Parkinson's disease; levodopa; apomorphine; addiction; drug misuse Parkinson's disease is defined clinically as an extrapyramidal motor disorder with signs of bradykinesia, rest tremor, rigidity, and postural instability. Pathologically, the disease is characterised by the presence of Lewy bodies and selective neuronal degeneration, particularly involving dopaminergic neurons in the substantia nigra pars compacta.1 The resulting dopamine depletion in nigrostriatal projections is thought to be responsible for the motor symptoms. Cell loss in dopaminergic neuronal populations giving rise to mesolimbic and mesocortical projections has been demonstrated in Parkinson's disease albeit it to lesser degrees than the nigrostriatal pathway.2 The deficiency of dopamine in these pathways may contribute to the bradyphrenia and mood disturbances which commonly accompany the motor manifestations of Parkinson's disease.Correcting the dopamine deficiency state in Parkinson's disease with levodopa or dopamine agonists attenuates the motor symptoms, and may also exert a beneficial eVect on the mood disorder and bradyphrenia. However, dopaminergic replacement therapy (DRT) in Parkinson's disease may also stimulate central dopaminergic pathways, which are intricately linked to the brain's reward system and are implicated in various states of addiction. 3 The stimulation of these pathways in some patients may initiate hedonistic homeostatic dysregulation, which ultimately leads to a behavioural disorder not too dissimilar from that associated with stimulant addiction. Although uncommon, this syndrome provides many challenges for the patient, their carers, and the treating physician. In this paper we describe the clinical features, propose a working definition, formulate a set of diagnostic criteria, and discuss management guidelines for this underrecognised phenomenon. Clinical syndrome CASE STUDYA 41 year old man presented with mild dystonic posturing of the left arm and hand, associated with mild rigidity and bradykines...

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.

Continuous subcutaneous infusion of apomorphine is now increasingly recognized as an effective treatment for refractory off periods and peak-dose dyskinesias in Parkinson's disease. We have reviewed our experience with apomorphine infusions, after a strategy decision in 1995 based on emerging preclinical data, to treat all patients with steady-state plasma levels of apomorphine throughout the waking day, minimizing additional pulsatile stimulation either by oral dopaminergic medication or bolus parenteral injections of apomorphine. Sixty-four patients have been treated with apomorphine pumps and 45 of these successfully converted to monotherapy, managing to discontinue all other forms of dopaminergic stimulation during the daytime treatment period with apomorphine. Patients were followed up for a mean of 33.8 months (range, 4-108 months) and clinical data analyzed retrospectively. The mean maintenance dose of apomorphine was 98 mg per 24 hours (monotherapy group: 103 mg/24 hours; polytherapy group: 93 mg/24 hours), which did not significantly increase at final follow-up. There was a mean maximum dyskinesia reduction of 64% (S.D. = 20) in the monotherapy group, compared to 30% (S.D. = 33) in those continuing on polytherapy (P < 0.001), despite a maintained increase in on time (monotherapy group: 55%, P < 0.005; polytherapy group: 50%, P = 0.05). Fifteen patients failed to successfully convert to monotherapy but benefited nonetheless, and only 3 failed apomorphine infusional therapy altogether. Reasons for failure were mixed, including difficulty with compliance and adverse effects such as daytime somnolence, skin complications, and painful dystonias. There was a significantly higher success rate in patients able to manage the treatment either independently or with the help of their caregiver. These results confirm that subcutaneous apomorphine monotherapy can reset peak-dose dyskinesia threshold in levodopa-treated patients and further reduce off-period disability after all available forms of oral medication, including long-acting dopamine agonists, have been tried.

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.

Levodopa-induced dyskinesias (LID) belong to the most common dose-limiting adverse effects of levodopa therapy. "Peak-dose" LID occur with the maximum effect of medication, 'diphasic dyskinesias' have a "beginning-and end-of-dose" pattern, and the, "off-period dyskinesia" occur during off-periods, most frequently in the early mornings and are typically dystonic in nature. The majority of patients will have developed dyskinesias after 10 years of treatment, and about 40-50% after 5 years. Occurrence of LID appears to be related to dose and duration of treatment with levodopa and severity and duration of disease. In addition, patients with younger age of onset have been reported to have an earlier onset and higher rate of LID. The important aetiological role of non-physiological pulsatile stimulation of dopaminergic receptors is increasingly recognized and more continuous dopaminergic stimulation with the longer acting dopamine agonists has been shown to reduce and delay the onset of dyskinesias. LID may not have a significant effect on quality of life in patients with early disease or in very advanced disease stages. when often other problems arise, but in other patients they may be severely disabling. Treatment strategies to overcome LID include adjustment of timing, type and amount of dopaminergic medication, treatment with amantadine and, in treatment resistant cases, stereotactic surgery involving deep brain stimulation or lesioning procedures. A number of other pharmacological options are also being explored. Several methods for the assessment of LID are available to attempt accurate assessment of efficacy, although all of these have limitations, and further evidence on their utility if needed.