14th International Congress on Parkinson's Disease
14th International Congress on Parkinson's Disease
What's the latest information about the pathophysiology and treatment of Parkinson's disease and related movement disorders? Find out in this easy-to-navigate collection of reports from the 14th International Congress on Parkinson's Disease, Helsinki, Finland, July 28-August 1, 2001, from the writers and editors at WE MOVE (http://www.wemove.org/), the organization dedicated to Worldwide Education and Awareness for Movement Disorders. Poster and Platform session numbers refer to those in the abstract book, published in Parkinsonism and Related Disorders. 2001;7(supplement).
Essential Tremor
Rajput AH, Hornykiewicz O, Deng Y, et al
Parkinsonism and Related Disorders. 2001; 7(suppl): Abstract P-MO-022
Noradrenaline is elevated in specific brain regions in essential tremor, according to this report. Brains from 3 patients with essential tremor (ET) and 3 matched controls were biochemically analyzed by a blinded investigator. Compared with controls, ET patients had elevated noradrenaline in the locus ceruleus (approximately 5-fold), the dentate nucleus (130-fold), and the cerebellar cortex (approximately 2-fold), with similar levels in the red nucleus. The investigators noted that these findings correlate with increased activity in brainstem and cerebellum as seen in PET studies, and the effectiveness of beta-adrenergic blockers in ET treatment.
Yamato H, Kannari K, Shen H, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-024
This study showed that aggravation of parkinsonism symptoms by selective serotonin reuptake inhibitors is likely due to reduction of extracellular dopamine. Rats with 6-OHDA lesions received intraperitoneal fluoxetine followed by levodopa. Compared with rats that did not receive fluoxetine, treated rats demonstrated a 59% reduction in extracellular striatal dopamine as determined by microdialysis (p<0.01), "suggesting that fluoxetine reduces concentrations of extracellular dopamine by activating 5-HT1A receptors on serotonergic neurons."
Multiple System Atrophy
Osaki Y, Wenning GK, Ben-Shlomo Y, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-035
These investigators found that clinical misdiagnosis of MSA remains common. Of 59 patients with a clinical diagnosis of MSA at the United Kingdom Parkinson's Disease Society Brain Research Center, 51 had pathologically confirmed MSA, 6 had PD, 1 had PSP, and 1 had vascular parkinsonism. Of 79 pathologically confirmed cases with MSA, 28 died with another clinical diagnosis, including 19 diagnosed with PD and the rest with a spectrum of disorders including cerebrovascular disease and Alzheimer's disease.
Nath U, McGee P, Zermansky AJ, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-213
Seven patients with parkinsonism-predominant MSA (MSA-P) received either placebo or up to 100 mg/day lamotrigine for 14 weeks followed by crossover to the other arm. Three patients withdrew while on placebo. No objective benefit was observed on a variety of motor and quality-of-life measures, though patients and clinicians alike noted subjective benefits of lamotrigine in all but 1 case. These researchers suggest that their findings support the need for larger studies of lamotrigine treatment of MSA.
Parkinson's Disease: Basic Science Studies of Pathogenesis
Kitami T, Kubo S, Sato K, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-014
These investigators performed biochemical assays with a variety of mutated parkins, which indicated that all possessed a reduced ability to ubiquitinate proteins. Additionally, parkin with mutations in the RING-finger domain lost the ability to bind its ubiquitinating partner, Ubch7, suggesting that "the functional loss of [ligase activity] in parkin is the underlying molecular cause of autosomal recessive juvenile parkinsonism."
Kubo S, Hattori N, Mizuno Y
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-015
In this study, immunocytochemistry of fractionated cultured cells indicated that parkin was localized to the trans-Golgi network and synaptic vesicles. Increasing ionic strength separated parkin from vesicles, implying an association by electrostatic attraction.
Mouatt-Prigent A, Muriel MP, Gu WJ, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-006
Immunocytochemistry of rat brain detected parkin in some but not all neurons and glial cell bodies and axons, localized to mitochondria, endoplasmic reticulum, large vesicles, and synaptic vesicles. The authors suggest that parkin may be involved in intracellular trafficking.
Transcranial Ultrasound in Parkinson's Disease
Sommer U, Gahn G, Becker G, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-037
Patients with Parkinson's disease have increased echogenicity of the substantia nigra that can be detected by noninvasive transcranial ultrasound, according to this report. Using this technique, ultrasonography was performed through the preauricular acoustic bone window.
Twelve patients with PD patients (ages 40-70), 3 with atypical parkinsonism (2 MSA, 1 PSP), and 12 controls, underwent ultrasound imaging of the substantia nigra. In controls, the mean hyper-echogenic area was 8.2 square mm (range 4.1-11.1), whereas in PD patients the mean area was 33.2 square mm (range 21.6-62.8), significant at p<0.001. Atypical parkinsonism patients had a mean area of 18.1 square mm (range 16.3-20.6), significantly different from both controls (p<0.001) and PD patients (p<0.05).
The researchers concluded, "These results confirm...that a hyperechogenic signal alteration in the SN is highly sensitive for idiopathic PD," and suggested that, in light of other results, ultrasound of the SN may provide a noninvasive technique for identifying persons at risk for developing PD.
Berg D, Becker G
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-027
This study found that ultrasound hyper-echogenicity of the substantia nigra correlates with reduced 18F-dopa uptake and increased SN iron deposition in non-PD subjects. A total of 20 healthy subjects below age 40 with SN hyper-echogenicity underwent PET imaging. Despite normal neuropsychological and motor performance, 18F-dopa uptake was reduced compared with controls who did not have SN hyper-echogenicity (p<0.05). In a separate experiment, post-mortem ultrasound and biochemical analysis of 20 patients who died without extrapyramidal disorders showed a correlation between hyper-echogenicity and increased iron content in the SN.
The investigators suggested that this technique provides a useful non-invasive tool for identifying reduced dopaminergic innervation in the substantia nigra.
Berg D, Jabs B, Merschdorf U, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-WE-463
Patients at risk for neuroleptic-induced parkinsonism have increased ultrasound echogenicity in the substantia nigra, according to this report.
Fifty-two psychiatric patients with severe neuroleptic-induced parkinsonism showed a significantly increased signal from the SN compared with 41 patients who had little or no parkinsonism symptoms (p<0.01). Eleven patients requiring neuroleptic treatment underwent transcranial ultrasonography before treatment. Evaluation of parkinsonian symptoms following treatment revealed more severe symptoms in those who had SN hyper-echogenicity (p<0.01).
Parkinson's Disease: Genetics
Autosomal Dominant Parkinson Disease Not Linked to Any Known Park Locus
Bertoli Avela AM, Giroud Benitez JL, Bonifati V, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-WE-416
Genetic analysis of a large Cuban family revealed 11 patients with Parkinson's disease among 213 family members. Inheritance appeared to be autosomal dominant with high penetrance. Affected members experienced typical adult-onset PD (mean age of onset 59.4 years), with unilateral onset, rest tremor, bradykinesia, rigidity, and good response to levodopa. Linkage and haplotype analysis has ruled out the alpha-synuclein gene, the parkin gene, the UCH-L1 gene, and PARK3.
Hilker R, Pramstaller PP, Kis B, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-WE-426
Parkin heterozygotes have reduced 18F-dopa uptake, according to this study. PET analysis of patients heterozygous for parkin mutations revealed reduced 18F-dopa uptake compared with healthy controls (p<0.05), despite the absence of clinical symptoms. Uptake was greater than that in either homozygote parkin patients or sporadic PD patients (p<0.01). The investigators concluded, "These findings suggest the extent of striatal dopaminergic dysfunction, i.e., nigral cell death, depends on the proportion of mutant and intact alleles within the parkin gene locus."
Mandel S, Grunblatt E, Levites Y, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract I-WE-010
Levites Y, Mandel S, Maor G, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-119
Grunblatt E, Mandel S, Maor G, et al
J Neurochem. 2001;78:1-12
Two Congress presentations and a newly published paper from the same group explore the ability of gene microarrays to track gene expression changes in PD models. A constellation of 51 specific genes is reported to change in expression in both the MPTP model and the 6-OHDA model. Change in expression of many of these genes is counteracted by administration of apomorphine, both the S form used as a dopamine agonist and the nonsymptomatically active R form, and this counteractivity is correlated with neuroprotection in both models. Finally, the green tea polyphenol ECGC is shown to be a powerful neuroprotectant that affects many of these same genes. Together, these results suggest that common genetic pathways act in both models, and that interrupting these pathways can be neuroprotective.
Gene microarrays use custom DNA samples attached to a nylon membrane. Exposure to gene products purified from experimental cells or tissues leads to detectable signal changes from the microarray proportional to the level of gene expression in the experimental cells, which can be compared to standards to determine changes in expression levels.
In all 3 studies, Mandel, Youdim, and colleagues determined that 51 out of 1200 genes tested had significant up- or down-regulation of expression following exposure to MPTP or 6-OHDA in mouse models. Affected gene classes included stress response proteins, transcription factors, neurotrophic factors, apoptosis proteins, cell cycle regulators, and interleukins. Key examples of genes increasing their expression include interleukin-1B and NF-kappa-B, major inflammation regulators.
Administration of subcutaneous apomorphine of either form for 5 days prior to MPTP administration led to expression changes opposite those induced by MPTP alone for 8 genes, and attenuation of MPTP-induced changes in 8 others. For 26 genes, effects of apomorphine alone differed from effects of apomorphine with MPTP present. Time course of gene expression changes was also studied, indicating early activation by MPTP of interleukin-1B followed by reduced expression by 6 hours, and increasing activation of interleukin-10 from 24 hours to 5 days.
Administration of oral ECGC (2 mg/kg) for 10 days prior to MPTP or 6-OHDA administration provided dose-dependent protection against reduced striatal dopamine concentration and tyrosine hydroxylase activity. ECGC induced gene expression changes opposite those of MPTP alone for 22 genes.
In their presentations, Mandel and Youdim stressed the value of tracking gene changes, not only for elucidating pathogenic events in the PD models, but for testing the validity of the models themselves, through comparisons of changes in patient brains. These experiments are currently underway. In the published report, these investigators concluded that they "are confident that these findings could lead to development of novel and effective neuroprotective drugs," though Youdim noted that single agents are unlikely to be globally neuroprotective, given the wide variety of pathways in the pathological cascade indicated by these experiments.
Dyskinesias
Clarke C
Dyskinesias have a significant impact on quality of life and health care costs, according to data presented in a symposium by Dr. Carl Clarke. In this study, 321 patients spanning a range of disease severity were evaluated over 6 months for dyskinesias via UPDRS part 4a and the Goetz Scale. Other measures used included SF-36 for health parameters, MADRAS for depression, and patient diaries for health care visits and expenditures.
Increased dyskinesias were highly significantly correlated with decreased health on SF-36, with the major effect on mental health. Correlation, which was calculated after controlling for motor fluctuations and disease deterioration, was more significant for UPDRS score than for Goetz score. A similar correlation was found for dyskinesias versus MADRAS score, potentially indicating an important role for dyskinesias in aggravating reactive depression. Costs for the most severely dyskinetic patients were doubled compared to patients without dyskinesias, from approximately $3000/year to $6000/year.
Clarke suggested these results may provide an economic rationale for treatments that delay onset of dyskinesias.
Supported by Glaxo SmithKline.
Parkinson's Disease: Pharmacologic Treatment
Schwarz J, Arnold G, Gasser T, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract S-SA-002
Thirty-three patients (mean Hoehn and Yahr stage 2.5) on levodopa and dopamine agonist therapy received increasing doses of pergolide with simultaneous reduction of other agonists and levodopa. Baseline doses were 2.5 mg pergolide and 500 mg levodopa. At 24 weeks, doses reached 7.8 mg pergolide and 258 mg levodopa. Twenty-seven patients completed the trial; 2 patients dropped out for lack of efficacy, and 1 patient required hospitalization for psychosis. Motor symptoms on UPDRS part III improved from 26 at baseline to 22 at 24 weeks (p=0.01), with specific effect on tremor. Neither dyskinesias nor activities of daily living were significantly affected. Adverse events included anxiety, hallucinations, weakness, abdominal pain, and edema.
Dr. Schwarz noted that many patients have remained on high-dose pergolide for several years, although 2 developed ergotism requiring a reduction in dose.
Other E-MOVE reports on pergolide for PD are archived at
http://www.wemove.org/emove/article.asp?ID=223
http://www.wemove.org/emove/article.asp?ID=119
Acuna G, Foernzler F, Leong D, et al
Parkinsonism and Related Disorders. 2001; (suppl): Abstract P-MO-065
Susceptibility to liver damage from tolcapone is linked to specific alleles of a tolcapone-metabolizing enzyme, according to this report. Genotyping of 30 different alleles was performed in 409 patients on tolcapone, including 135 with asymptomatic elevated liver enzymes. Results showed that particular polymorphisms in UDP-glucuronosyltransferase (UGT), notably alleles 1A, 1A6 and 1A7, were strongly correlated with liver enzyme elevation, but only in males. "These results are consistent with the hypothesis that impaired elimination of tolcapone may contribute liver toxicity," the investigators concluded.
Supported by Hoffman-LaRoche
Hyson HC, Jog MS, Johnson A
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-194
Single drops of 1% atropine placed under the tongue can significantly reduce excess saliva and drooling in patients with PD, according to this report.
Seven PD patients with sialorrhea took 1 drop of 1% atropine ophthalmic solution sublingually twice daily for 1 week. Significant reductions were seen in both saliva production (p=0.046) and drooling (p=0.034). No changes in mean scores on Mini-Mental State Exam or PIMS questionnaire were noted during the study. One patient dropped out because of delirium, but this patient later resumed treatment. At present more than 30 patients are receiving the treatment, some of whom have been treated for over a year.
Djaldetti R, Giladi N, Knebel Y, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-178
This study found that levodopa ethyl ester tablets provide a more rapid rise in levodopa plasma level than standard levodopa tablets. A total of 29 patients were randomized to receive either standard levodopa/carbidopa or 1 of 3 formulations of levodopa ethyl ester: solution, dissolved tablets, or swallowed tablets. Compared with standard levodopa, all 3 formulations (which are dosed with carbidopa) had significantly faster T-max, with an average reduction of approximately 25 minutes. C-max was insignificantly elevated for the 2 liquid preparations, and elevated by approximately 15% for the tablets (p<0.05). Because of the faster availability, the area under the curve was greater for the tablets than for standard levodopa for the first 2 hours after dosing, but not at 4 hours.
"The pharmacokinetic profile of levodopa ethyl ester supports the potential clinical advantage of LDEE/CD tablets in reducing the delayed-on phenomenon in PD patients with motor fluctuations," according to these researchers.
Supported by Teva Pharmaceuticals
Viallet F, Gantcheva R, Glemet B, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-249
Twenty PD patients received levodopa with a minimal-protein breakfast and a normal-protein lunch, accompanied by frequent plasma levodopa monitoring. No significant difference was found between the 2 for either C-max or T-max. A slight increase in the area under the curve (AUC) was likely due to a higher lunch-time levodopa dose, according to the authors.
Hironishi M, Kondo T
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-192
Six patients switched from levodopa with decarboxylase inhibitor to levodopa alone. Four of the 6 achieved improved motor fluctuations, and 1 patient had improved psychosis. The authors suggest that the motor improvement is due to decreased fluctuations in levodopa plasma levels.
Rascol O, Brooks DJ, Clarke CE, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-226
The rate of dyskinesia development does not increase when levodopa is added to monotherapy with ropinirole, according to this report. This study addressed the question of whether the proven dyskinesia-delaying effect of early monotherapy with a dopamine agonist would be lost when addition of levodopa was required for symptom control in later PD.
Patients in this study were a subset of the 056 study of ropinirole as monotherapy (see http://www.wemove.org/ema/em_pd_01.html). Time to development of dyskinesias for patients randomized to initial levodopa treatment (n=89) was compared with time to dyskinesias for ropinirole patients following initiation of supplemental levodopa (n=179). No significant difference between the groups was found. A series of analyses was applied to determine whether results were affected by any of several confounding factors, including age, disease state, and total daily levodopa dose at dyskinesia onset. No effect was found for any of these factors.
The investigators concluded that these results indicate that "ropinirole delayed the development of dyskinesias by delaying the onset of levodopa therapy," and that the data argue against major effects on dyskinesia development in this population from either a positive protective effect of ropinirole, or simple disease duration.
Supported by Glaxo SmithKline
Kieburtz K, Parkinson Study Group
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-200
The MAO-B inhibitor rasagiline is effective for treatment of early PD, according to this study. A total of 404 early PD patients not requiring dopaminergic therapy were randomized to receive placebo or 1-2 mg/day rasagiline for 26 weeks. Compared with patients who received placebo, treated patients experienced improved UPDRS scores of 4.2 units for 1 mg (p<0.0001), and 2.74 units for 2 mg (p<0.0001). Quality of life scores on the PDQUALIF scale were also significantly improved for both doses. According to "Most of the improvement in quality of life was noted in the Self Image/Sexuality and Social Role/Function subscales," said the investigators. No significant increase in blood pressure was observed in either treatment group.
A previous report on rasagiline is archived at
http://www.wemove.org/emove/article.asp?ID=299
Polzer UF, Hundt H
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-222
In this study of 21 patients, mean ropinirole dose was increased from 8.2 mg/day to 29.7 mg/day, and mean levodopa dose reduced from 770 mg/day to 555 mg/day (p<0.001), over a period of 8 weeks or less. After 12 weeks, duration of daily dyskinesias was reduced from 30.4% of the day to 4.6%, while "off" periods were reduced from 42.6% to 14.6%. Four patients developed psychotic symptoms. One patient withdrew due to psychosis, and 6 others for reasons believed to be unconnected to treatment.
Supported by SmithKline Beecham
Pacchetti C, Mancini F, Zangaglia R, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-219
In this study of 36 PD patients, the mean dose of ropinirole was increased from 16 mg/day to 35 mg/day, and mean levodopa dose reduced from 752 mg/day to 588 mg/day (p=0.001). Dyskinesias during "on" periods were reduced 40%, and dystonia during "off" periods was reduced by 40%. No treatment-emergent side effects were reported.
Thus, in these 2 studies, high-dose ropinirole allowed reductions in levodopa doses and lessening of dyskinesias in advanced PD patients.
Appiah-Kubi L, Nisbet A, Forbes A, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-074
Cabergoline is well-tolerated among elderly PD patients, according to this study. Retrospective review of 299 patients on cabergoline indicated tolerability to long-term therapy (defined as at least 6 months of cabergoline use without side effects requiring discontinuation) occurred in 85% of patients under 65 years old, 80% of patients 65-74 years, and 83% of patients 75 years and older. Fifty-four patients discontinued the drug during the study, including 7 for lack of efficacy and 7 for hallucinations. The investigators noted that the slow titration of cabergoline over several months, probably contributed to the success of the treatment and minimization of side effects.
Parkinson's Disease: Surgery -PD) vs. Imitation Surgery in Patients With Parkinson's Disease (PD)
Watts RL, Freeman TB, Hauser RA, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-304
These investigators found that porcine cell implants are not more effective than placebo in reducing parkinsonism. Eighteen patients received either sham surgery and placebo immunosuppression or implantation of porcine dopaminergic cells into the caudate and putamen with cyclosporine and prednisone immunosuppression. At 18 months, the 2 groups had improved equally in UPDRS motor scores and time spent in off state (20-25%). One difference between groups was noted at 12 months--treated patients had a 12% reduction in time spent with dyskinesias, while control patients had a 7% increase (p=0.036). No evidence of porcine retroviruses was found in treated patients.
Minguez A, Lopez-Barneo J, Arjona V, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-285
Six patients received self-transplants of cells from the carotid body, a knot of nerve tissue at the fork of the carotid artery. Cells were implanted bilaterally in the caudate and putamen. Of the 5 patients with 6-month evaluations, change in off time as rated by a blinded investigator was -26%, -35%, -40%, -74%, and +14% (worsening). "The degree of improvement was directly related to the histological integrity of the implanted carotid body," researchers noted. After a mean follow-up of 16 months, no complications have been reported.
Schuurman PR, Bosch DA, Speelman JD
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-298
Thalamic stimulation is no more effective than thalamotomy for control of tremor in PD, but may provide more functional benefit, according to this study.
Sixty-eight patients with PD (n=45), essential tremor (n=13), or multiple sclerosis (n=10) were randomized to receive either thalamic stimulation or thalamotomy for tremor. Six-month follow-up indicated the 2 procedures were equally effective for control of tremor in PD and ET. Two-year follow-up indicated maintained benefit in PD patients, with some loss of benefit in ET patients receiving stimulation. MS patients received greater and more prolonged benefit from thalamotomy. Frenchay Activities Index scores were superior for stimulation in both PD and ET (approx. 4-6 point improvement, p=0.008), while MS patients had no functional benefit from either procedure. Adverse effects included dysarthria, balance difficulties, and cognitive deterioration, and occurred slightly more often in thalamotomy patients. One patient died following an intracerebral hemorrhage during electrode implantation.
The investigators suggest that patients should be fully educated about the risks and benefits of each procedure before choosing which procedure to undergo, but note that the labor-intensiveness of the stimulation procedure may argue against this option for tremor control.
Parkinson's Disease: Quality of Life Issues
Rojo A, Aguilar M, Garolera MT, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-WE-358
This study found that depression affects 57% of PD patients. Investigators evaluated 353 consecutive PD patients using the Yesavage Geriatric Depression Scale (GDS). Forty-three percent had no depression, 40% had mild-to-moderate depression, and 17% had severe depression. Depression was most strongly correlated with UPDRS ADL and motor scores, and female sex.
Depression in Parkinson's disease: The Relationships Between Depression and Motor Disability
Krystanek E, Ochudo S, Opala G, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-WE-344
A total of 54 non-demented PD patients were evaluated for depression using the Yesavage GDS. Mild-to-moderate depression was found in 39%, and severe depression in 17%. Depression was not correlated with motor impairment on the UPDRS.
Quality of Life in Parkinson's Disease (PD)Stages: Impact of Depression
Aguilar M, Ramos S, Rojo A, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-WE-320
Seventy-seven consecutive PD patients were assessed for depression with the Yesavage GDS, for PD severity with the Hoehn and Yahr scale, and for quality of life with the PDQ-39, a 100-point scale in which lower scores indicate better QoL. Non-depressed patients had a mean PDQ-39 score of 33.7, mild-to-moderately depressed patients had a mean score of 58.9, and moderate-to-severely depressed patients had a mean score of 76.0. Lower QoL was also correlated with disease severity. Based on their analysis of variance, "Depression has a higher influence than mobility and activities of daily living on quality of life," the researchers concluded.
Rektorova I, Rektor I, Bares M, et al
Parkinsonism and Related Disorders. 2001; 7(suppl): Abstract P-TU-229
Pramipexole improves depression independently of motor benefit, according to this study. Forty-one patients with mild-to-moderate depression and who were taking levodopa received either pramipexole or pergolide up to 4.5 mg/day for 6 weeks. Motor improvement was significant with both treatments, but was not different between the 2 treatments. Both groups had significant reductions in depression on the Zung self-rated scale. Pramipexole-treated patients, but not pergolide-treated patients, showed significant reductions in depression on the MADRS scale, rated by a blinded psychologist; these effects remained after accounting for motor improvements.
Takats A, Szombathelyi E, Farsang MI
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-242
Fifty-two patients on selegiline 10 mg/day received 450 mg/day of the MAO-A inhibitor moclobemide. Depression scores improved for 41 patients after 3 months of treatment. Eleven patients withdrew from the study because of sleep disturbance, increased blood pressure, or lack of response.
Royter V, Broonner G, Giladi N, et al
Parkinsonism and Related Disorders. 2001;7 (suppl): Abstract P-WE-359
Sexual desire and satisfaction decrease in PD patients, especially men, as disease stage advances, according to this report. Eighty-six patients (50 male, 36 female) answered detailed questionnaires about sexual function during the previous 5 years. Results for men indicated that during this time period, satisfaction decreased by 65% and desire by 85%, and erectile dysfunction increased significantly (p<0.0001), all of which correlated with disease stage. In women, satisfaction decreased by 33% and desire by 42%, which also correlated with disease stage, and there was a significant decline in ability to achieve orgasm (p<0.001) not related to disease stage.
Katsarou Z, Bostantjopoulou S, Kiosseoglou G, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-077
Caregivers of Parkinson's disease patients suffer significant stress, according to this report. Seventy-one primary caregivers, including 54 women and 17 men, were evaluated for stress using the Relative Stress Scale. Mean stress was 15 on a scale of 30, indicating moderate-to-high stress in this population. Higher stress was correlated with caring for patients with longer disease duration, deterioration of motor ability, and cognitive decline, as well as severe on-off fluctuations.
Homann CN, Suppan K, Wenzel K, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-WE-338
These investigators collected and analyzed 123 published cases of unintended sleep events in patients with PD. Events were classified as either slow onset with prodromal drowsiness, or sudden onset without prodrome, based on patient description and expert eyewitness accounts, including 2 cases of "sleep attack" witnessed by the first investigator in the study. These 2 cases occurred in the clinic one half hour following administration of a single dose of apomorphine. Patients experienced rapid and profound sleep onset, followed by unresponsiveness to pain or movement, and retrograde amnesia upon awakening.
In published cases, patients ranged from ages 34 to 87, with onset as early as 1 year after diagnosis. All dopaminergic medications were implicated. Of 17 events that occurred while patients were driving, 10 resulted in accidents. Dose reductions or drug elimination helped in most cases, but with resulting motor disability.
Brodsky MA, Godbold J, Olanow CW
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-WE-327
Of 77 consecutive PD patients (mean H&Y 2.25), 79% reported daytime sleepiness, and 52% had abnormal nighttime sleep. Twenty percent had an Epworth Sleepiness Scale score greater than 15, indicating high amounts of daytime sleepiness. Ten patients (13%) on a range of dopaminergic drugs had fallen asleep while driving.
Bliwise DL, Borchert LD, Cantor C, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-170
Twenty-two patients were evaluated by questionnaire and Multiple Sleep Latency Test. Based on history, patients were grouped as those with (n=16) or without (n=6) an unintended sleep episode. No differences were found between the 2 groups in dopaminergic medications taken, mean sleep latency, proportion of patients with pathological sleepiness (MSLT<5 minutes; 50% in each group), or proportion with stage II sleep during naps (71-73%), which indicates chronic sleep loss.
Pal S, Lomax C, Pezzella FR, et al
Parkinsonism and Related Disorders. 2001; (suppl): Abstract P-MO-161
A total of 102 patients completed the Parkinson's Disease Sleep Scale, a 15-question visual analog scale recently validated for assessment of sleep disability in PD. Scores were highly correlated with Epworth Sleepiness Scale scores. "This study in a consecutive group of PD patients provides the first formal evidence that nocturnal sleep disturbance is significantly associated with increases in daytime sleepiness scores and a predisposition to excessive daytime sleepiness," the researchers stated.
What's the latest information about the pathophysiology and treatment of Parkinson's disease and related movement disorders? Find out in this easy-to-navigate collection of reports from the 14th International Congress on Parkinson's Disease, Helsinki, Finland, July 28-August 1, 2001, from the writers and editors at WE MOVE (http://www.wemove.org/), the organization dedicated to Worldwide Education and Awareness for Movement Disorders. Poster and Platform session numbers refer to those in the abstract book, published in Parkinsonism and Related Disorders. 2001;7(supplement).
Essential Tremor
Rajput AH, Hornykiewicz O, Deng Y, et al
Parkinsonism and Related Disorders. 2001; 7(suppl): Abstract P-MO-022
Noradrenaline is elevated in specific brain regions in essential tremor, according to this report. Brains from 3 patients with essential tremor (ET) and 3 matched controls were biochemically analyzed by a blinded investigator. Compared with controls, ET patients had elevated noradrenaline in the locus ceruleus (approximately 5-fold), the dentate nucleus (130-fold), and the cerebellar cortex (approximately 2-fold), with similar levels in the red nucleus. The investigators noted that these findings correlate with increased activity in brainstem and cerebellum as seen in PET studies, and the effectiveness of beta-adrenergic blockers in ET treatment.
Yamato H, Kannari K, Shen H, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-024
This study showed that aggravation of parkinsonism symptoms by selective serotonin reuptake inhibitors is likely due to reduction of extracellular dopamine. Rats with 6-OHDA lesions received intraperitoneal fluoxetine followed by levodopa. Compared with rats that did not receive fluoxetine, treated rats demonstrated a 59% reduction in extracellular striatal dopamine as determined by microdialysis (p<0.01), "suggesting that fluoxetine reduces concentrations of extracellular dopamine by activating 5-HT1A receptors on serotonergic neurons."
Multiple System Atrophy
Osaki Y, Wenning GK, Ben-Shlomo Y, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-035
These investigators found that clinical misdiagnosis of MSA remains common. Of 59 patients with a clinical diagnosis of MSA at the United Kingdom Parkinson's Disease Society Brain Research Center, 51 had pathologically confirmed MSA, 6 had PD, 1 had PSP, and 1 had vascular parkinsonism. Of 79 pathologically confirmed cases with MSA, 28 died with another clinical diagnosis, including 19 diagnosed with PD and the rest with a spectrum of disorders including cerebrovascular disease and Alzheimer's disease.
Nath U, McGee P, Zermansky AJ, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-213
Seven patients with parkinsonism-predominant MSA (MSA-P) received either placebo or up to 100 mg/day lamotrigine for 14 weeks followed by crossover to the other arm. Three patients withdrew while on placebo. No objective benefit was observed on a variety of motor and quality-of-life measures, though patients and clinicians alike noted subjective benefits of lamotrigine in all but 1 case. These researchers suggest that their findings support the need for larger studies of lamotrigine treatment of MSA.
Parkinson's Disease: Basic Science Studies of Pathogenesis
Kitami T, Kubo S, Sato K, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-014
These investigators performed biochemical assays with a variety of mutated parkins, which indicated that all possessed a reduced ability to ubiquitinate proteins. Additionally, parkin with mutations in the RING-finger domain lost the ability to bind its ubiquitinating partner, Ubch7, suggesting that "the functional loss of [ligase activity] in parkin is the underlying molecular cause of autosomal recessive juvenile parkinsonism."
Kubo S, Hattori N, Mizuno Y
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-015
In this study, immunocytochemistry of fractionated cultured cells indicated that parkin was localized to the trans-Golgi network and synaptic vesicles. Increasing ionic strength separated parkin from vesicles, implying an association by electrostatic attraction.
Mouatt-Prigent A, Muriel MP, Gu WJ, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-006
Immunocytochemistry of rat brain detected parkin in some but not all neurons and glial cell bodies and axons, localized to mitochondria, endoplasmic reticulum, large vesicles, and synaptic vesicles. The authors suggest that parkin may be involved in intracellular trafficking.
Transcranial Ultrasound in Parkinson's Disease
Sommer U, Gahn G, Becker G, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-037
Patients with Parkinson's disease have increased echogenicity of the substantia nigra that can be detected by noninvasive transcranial ultrasound, according to this report. Using this technique, ultrasonography was performed through the preauricular acoustic bone window.
Twelve patients with PD patients (ages 40-70), 3 with atypical parkinsonism (2 MSA, 1 PSP), and 12 controls, underwent ultrasound imaging of the substantia nigra. In controls, the mean hyper-echogenic area was 8.2 square mm (range 4.1-11.1), whereas in PD patients the mean area was 33.2 square mm (range 21.6-62.8), significant at p<0.001. Atypical parkinsonism patients had a mean area of 18.1 square mm (range 16.3-20.6), significantly different from both controls (p<0.001) and PD patients (p<0.05).
The researchers concluded, "These results confirm...that a hyperechogenic signal alteration in the SN is highly sensitive for idiopathic PD," and suggested that, in light of other results, ultrasound of the SN may provide a noninvasive technique for identifying persons at risk for developing PD.
Berg D, Becker G
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-027
This study found that ultrasound hyper-echogenicity of the substantia nigra correlates with reduced 18F-dopa uptake and increased SN iron deposition in non-PD subjects. A total of 20 healthy subjects below age 40 with SN hyper-echogenicity underwent PET imaging. Despite normal neuropsychological and motor performance, 18F-dopa uptake was reduced compared with controls who did not have SN hyper-echogenicity (p<0.05). In a separate experiment, post-mortem ultrasound and biochemical analysis of 20 patients who died without extrapyramidal disorders showed a correlation between hyper-echogenicity and increased iron content in the SN.
The investigators suggested that this technique provides a useful non-invasive tool for identifying reduced dopaminergic innervation in the substantia nigra.
Berg D, Jabs B, Merschdorf U, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-WE-463
Patients at risk for neuroleptic-induced parkinsonism have increased ultrasound echogenicity in the substantia nigra, according to this report.
Fifty-two psychiatric patients with severe neuroleptic-induced parkinsonism showed a significantly increased signal from the SN compared with 41 patients who had little or no parkinsonism symptoms (p<0.01). Eleven patients requiring neuroleptic treatment underwent transcranial ultrasonography before treatment. Evaluation of parkinsonian symptoms following treatment revealed more severe symptoms in those who had SN hyper-echogenicity (p<0.01).
Parkinson's Disease: Genetics
Autosomal Dominant Parkinson Disease Not Linked to Any Known Park Locus
Bertoli Avela AM, Giroud Benitez JL, Bonifati V, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-WE-416
Genetic analysis of a large Cuban family revealed 11 patients with Parkinson's disease among 213 family members. Inheritance appeared to be autosomal dominant with high penetrance. Affected members experienced typical adult-onset PD (mean age of onset 59.4 years), with unilateral onset, rest tremor, bradykinesia, rigidity, and good response to levodopa. Linkage and haplotype analysis has ruled out the alpha-synuclein gene, the parkin gene, the UCH-L1 gene, and PARK3.
Hilker R, Pramstaller PP, Kis B, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-WE-426
Parkin heterozygotes have reduced 18F-dopa uptake, according to this study. PET analysis of patients heterozygous for parkin mutations revealed reduced 18F-dopa uptake compared with healthy controls (p<0.05), despite the absence of clinical symptoms. Uptake was greater than that in either homozygote parkin patients or sporadic PD patients (p<0.01). The investigators concluded, "These findings suggest the extent of striatal dopaminergic dysfunction, i.e., nigral cell death, depends on the proportion of mutant and intact alleles within the parkin gene locus."
Mandel S, Grunblatt E, Levites Y, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract I-WE-010
Levites Y, Mandel S, Maor G, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-119
Grunblatt E, Mandel S, Maor G, et al
J Neurochem. 2001;78:1-12
Two Congress presentations and a newly published paper from the same group explore the ability of gene microarrays to track gene expression changes in PD models. A constellation of 51 specific genes is reported to change in expression in both the MPTP model and the 6-OHDA model. Change in expression of many of these genes is counteracted by administration of apomorphine, both the S form used as a dopamine agonist and the nonsymptomatically active R form, and this counteractivity is correlated with neuroprotection in both models. Finally, the green tea polyphenol ECGC is shown to be a powerful neuroprotectant that affects many of these same genes. Together, these results suggest that common genetic pathways act in both models, and that interrupting these pathways can be neuroprotective.
Gene microarrays use custom DNA samples attached to a nylon membrane. Exposure to gene products purified from experimental cells or tissues leads to detectable signal changes from the microarray proportional to the level of gene expression in the experimental cells, which can be compared to standards to determine changes in expression levels.
In all 3 studies, Mandel, Youdim, and colleagues determined that 51 out of 1200 genes tested had significant up- or down-regulation of expression following exposure to MPTP or 6-OHDA in mouse models. Affected gene classes included stress response proteins, transcription factors, neurotrophic factors, apoptosis proteins, cell cycle regulators, and interleukins. Key examples of genes increasing their expression include interleukin-1B and NF-kappa-B, major inflammation regulators.
Administration of subcutaneous apomorphine of either form for 5 days prior to MPTP administration led to expression changes opposite those induced by MPTP alone for 8 genes, and attenuation of MPTP-induced changes in 8 others. For 26 genes, effects of apomorphine alone differed from effects of apomorphine with MPTP present. Time course of gene expression changes was also studied, indicating early activation by MPTP of interleukin-1B followed by reduced expression by 6 hours, and increasing activation of interleukin-10 from 24 hours to 5 days.
Administration of oral ECGC (2 mg/kg) for 10 days prior to MPTP or 6-OHDA administration provided dose-dependent protection against reduced striatal dopamine concentration and tyrosine hydroxylase activity. ECGC induced gene expression changes opposite those of MPTP alone for 22 genes.
In their presentations, Mandel and Youdim stressed the value of tracking gene changes, not only for elucidating pathogenic events in the PD models, but for testing the validity of the models themselves, through comparisons of changes in patient brains. These experiments are currently underway. In the published report, these investigators concluded that they "are confident that these findings could lead to development of novel and effective neuroprotective drugs," though Youdim noted that single agents are unlikely to be globally neuroprotective, given the wide variety of pathways in the pathological cascade indicated by these experiments.
Dyskinesias
Clarke C
Dyskinesias have a significant impact on quality of life and health care costs, according to data presented in a symposium by Dr. Carl Clarke. In this study, 321 patients spanning a range of disease severity were evaluated over 6 months for dyskinesias via UPDRS part 4a and the Goetz Scale. Other measures used included SF-36 for health parameters, MADRAS for depression, and patient diaries for health care visits and expenditures.
Increased dyskinesias were highly significantly correlated with decreased health on SF-36, with the major effect on mental health. Correlation, which was calculated after controlling for motor fluctuations and disease deterioration, was more significant for UPDRS score than for Goetz score. A similar correlation was found for dyskinesias versus MADRAS score, potentially indicating an important role for dyskinesias in aggravating reactive depression. Costs for the most severely dyskinetic patients were doubled compared to patients without dyskinesias, from approximately $3000/year to $6000/year.
Clarke suggested these results may provide an economic rationale for treatments that delay onset of dyskinesias.
Supported by Glaxo SmithKline.
Parkinson's Disease: Pharmacologic Treatment
Schwarz J, Arnold G, Gasser T, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract S-SA-002
Thirty-three patients (mean Hoehn and Yahr stage 2.5) on levodopa and dopamine agonist therapy received increasing doses of pergolide with simultaneous reduction of other agonists and levodopa. Baseline doses were 2.5 mg pergolide and 500 mg levodopa. At 24 weeks, doses reached 7.8 mg pergolide and 258 mg levodopa. Twenty-seven patients completed the trial; 2 patients dropped out for lack of efficacy, and 1 patient required hospitalization for psychosis. Motor symptoms on UPDRS part III improved from 26 at baseline to 22 at 24 weeks (p=0.01), with specific effect on tremor. Neither dyskinesias nor activities of daily living were significantly affected. Adverse events included anxiety, hallucinations, weakness, abdominal pain, and edema.
Dr. Schwarz noted that many patients have remained on high-dose pergolide for several years, although 2 developed ergotism requiring a reduction in dose.
Other E-MOVE reports on pergolide for PD are archived at
http://www.wemove.org/emove/article.asp?ID=223
http://www.wemove.org/emove/article.asp?ID=119
Acuna G, Foernzler F, Leong D, et al
Parkinsonism and Related Disorders. 2001; (suppl): Abstract P-MO-065
Susceptibility to liver damage from tolcapone is linked to specific alleles of a tolcapone-metabolizing enzyme, according to this report. Genotyping of 30 different alleles was performed in 409 patients on tolcapone, including 135 with asymptomatic elevated liver enzymes. Results showed that particular polymorphisms in UDP-glucuronosyltransferase (UGT), notably alleles 1A, 1A6 and 1A7, were strongly correlated with liver enzyme elevation, but only in males. "These results are consistent with the hypothesis that impaired elimination of tolcapone may contribute liver toxicity," the investigators concluded.
Supported by Hoffman-LaRoche
Hyson HC, Jog MS, Johnson A
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-194
Single drops of 1% atropine placed under the tongue can significantly reduce excess saliva and drooling in patients with PD, according to this report.
Seven PD patients with sialorrhea took 1 drop of 1% atropine ophthalmic solution sublingually twice daily for 1 week. Significant reductions were seen in both saliva production (p=0.046) and drooling (p=0.034). No changes in mean scores on Mini-Mental State Exam or PIMS questionnaire were noted during the study. One patient dropped out because of delirium, but this patient later resumed treatment. At present more than 30 patients are receiving the treatment, some of whom have been treated for over a year.
Djaldetti R, Giladi N, Knebel Y, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-178
This study found that levodopa ethyl ester tablets provide a more rapid rise in levodopa plasma level than standard levodopa tablets. A total of 29 patients were randomized to receive either standard levodopa/carbidopa or 1 of 3 formulations of levodopa ethyl ester: solution, dissolved tablets, or swallowed tablets. Compared with standard levodopa, all 3 formulations (which are dosed with carbidopa) had significantly faster T-max, with an average reduction of approximately 25 minutes. C-max was insignificantly elevated for the 2 liquid preparations, and elevated by approximately 15% for the tablets (p<0.05). Because of the faster availability, the area under the curve was greater for the tablets than for standard levodopa for the first 2 hours after dosing, but not at 4 hours.
"The pharmacokinetic profile of levodopa ethyl ester supports the potential clinical advantage of LDEE/CD tablets in reducing the delayed-on phenomenon in PD patients with motor fluctuations," according to these researchers.
Supported by Teva Pharmaceuticals
Viallet F, Gantcheva R, Glemet B, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-249
Twenty PD patients received levodopa with a minimal-protein breakfast and a normal-protein lunch, accompanied by frequent plasma levodopa monitoring. No significant difference was found between the 2 for either C-max or T-max. A slight increase in the area under the curve (AUC) was likely due to a higher lunch-time levodopa dose, according to the authors.
Hironishi M, Kondo T
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-192
Six patients switched from levodopa with decarboxylase inhibitor to levodopa alone. Four of the 6 achieved improved motor fluctuations, and 1 patient had improved psychosis. The authors suggest that the motor improvement is due to decreased fluctuations in levodopa plasma levels.
Rascol O, Brooks DJ, Clarke CE, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-226
The rate of dyskinesia development does not increase when levodopa is added to monotherapy with ropinirole, according to this report. This study addressed the question of whether the proven dyskinesia-delaying effect of early monotherapy with a dopamine agonist would be lost when addition of levodopa was required for symptom control in later PD.
Patients in this study were a subset of the 056 study of ropinirole as monotherapy (see http://www.wemove.org/ema/em_pd_01.html). Time to development of dyskinesias for patients randomized to initial levodopa treatment (n=89) was compared with time to dyskinesias for ropinirole patients following initiation of supplemental levodopa (n=179). No significant difference between the groups was found. A series of analyses was applied to determine whether results were affected by any of several confounding factors, including age, disease state, and total daily levodopa dose at dyskinesia onset. No effect was found for any of these factors.
The investigators concluded that these results indicate that "ropinirole delayed the development of dyskinesias by delaying the onset of levodopa therapy," and that the data argue against major effects on dyskinesia development in this population from either a positive protective effect of ropinirole, or simple disease duration.
Supported by Glaxo SmithKline
Kieburtz K, Parkinson Study Group
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-200
The MAO-B inhibitor rasagiline is effective for treatment of early PD, according to this study. A total of 404 early PD patients not requiring dopaminergic therapy were randomized to receive placebo or 1-2 mg/day rasagiline for 26 weeks. Compared with patients who received placebo, treated patients experienced improved UPDRS scores of 4.2 units for 1 mg (p<0.0001), and 2.74 units for 2 mg (p<0.0001). Quality of life scores on the PDQUALIF scale were also significantly improved for both doses. According to "Most of the improvement in quality of life was noted in the Self Image/Sexuality and Social Role/Function subscales," said the investigators. No significant increase in blood pressure was observed in either treatment group.
A previous report on rasagiline is archived at
http://www.wemove.org/emove/article.asp?ID=299
Polzer UF, Hundt H
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-222
In this study of 21 patients, mean ropinirole dose was increased from 8.2 mg/day to 29.7 mg/day, and mean levodopa dose reduced from 770 mg/day to 555 mg/day (p<0.001), over a period of 8 weeks or less. After 12 weeks, duration of daily dyskinesias was reduced from 30.4% of the day to 4.6%, while "off" periods were reduced from 42.6% to 14.6%. Four patients developed psychotic symptoms. One patient withdrew due to psychosis, and 6 others for reasons believed to be unconnected to treatment.
Supported by SmithKline Beecham
Pacchetti C, Mancini F, Zangaglia R, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-219
In this study of 36 PD patients, the mean dose of ropinirole was increased from 16 mg/day to 35 mg/day, and mean levodopa dose reduced from 752 mg/day to 588 mg/day (p=0.001). Dyskinesias during "on" periods were reduced 40%, and dystonia during "off" periods was reduced by 40%. No treatment-emergent side effects were reported.
Thus, in these 2 studies, high-dose ropinirole allowed reductions in levodopa doses and lessening of dyskinesias in advanced PD patients.
Appiah-Kubi L, Nisbet A, Forbes A, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-074
Cabergoline is well-tolerated among elderly PD patients, according to this study. Retrospective review of 299 patients on cabergoline indicated tolerability to long-term therapy (defined as at least 6 months of cabergoline use without side effects requiring discontinuation) occurred in 85% of patients under 65 years old, 80% of patients 65-74 years, and 83% of patients 75 years and older. Fifty-four patients discontinued the drug during the study, including 7 for lack of efficacy and 7 for hallucinations. The investigators noted that the slow titration of cabergoline over several months, probably contributed to the success of the treatment and minimization of side effects.
Parkinson's Disease: Surgery -PD) vs. Imitation Surgery in Patients With Parkinson's Disease (PD)
Watts RL, Freeman TB, Hauser RA, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-304
These investigators found that porcine cell implants are not more effective than placebo in reducing parkinsonism. Eighteen patients received either sham surgery and placebo immunosuppression or implantation of porcine dopaminergic cells into the caudate and putamen with cyclosporine and prednisone immunosuppression. At 18 months, the 2 groups had improved equally in UPDRS motor scores and time spent in off state (20-25%). One difference between groups was noted at 12 months--treated patients had a 12% reduction in time spent with dyskinesias, while control patients had a 7% increase (p=0.036). No evidence of porcine retroviruses was found in treated patients.
Minguez A, Lopez-Barneo J, Arjona V, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-285
Six patients received self-transplants of cells from the carotid body, a knot of nerve tissue at the fork of the carotid artery. Cells were implanted bilaterally in the caudate and putamen. Of the 5 patients with 6-month evaluations, change in off time as rated by a blinded investigator was -26%, -35%, -40%, -74%, and +14% (worsening). "The degree of improvement was directly related to the histological integrity of the implanted carotid body," researchers noted. After a mean follow-up of 16 months, no complications have been reported.
Schuurman PR, Bosch DA, Speelman JD
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-298
Thalamic stimulation is no more effective than thalamotomy for control of tremor in PD, but may provide more functional benefit, according to this study.
Sixty-eight patients with PD (n=45), essential tremor (n=13), or multiple sclerosis (n=10) were randomized to receive either thalamic stimulation or thalamotomy for tremor. Six-month follow-up indicated the 2 procedures were equally effective for control of tremor in PD and ET. Two-year follow-up indicated maintained benefit in PD patients, with some loss of benefit in ET patients receiving stimulation. MS patients received greater and more prolonged benefit from thalamotomy. Frenchay Activities Index scores were superior for stimulation in both PD and ET (approx. 4-6 point improvement, p=0.008), while MS patients had no functional benefit from either procedure. Adverse effects included dysarthria, balance difficulties, and cognitive deterioration, and occurred slightly more often in thalamotomy patients. One patient died following an intracerebral hemorrhage during electrode implantation.
The investigators suggest that patients should be fully educated about the risks and benefits of each procedure before choosing which procedure to undergo, but note that the labor-intensiveness of the stimulation procedure may argue against this option for tremor control.
Parkinson's Disease: Quality of Life Issues
Rojo A, Aguilar M, Garolera MT, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-WE-358
This study found that depression affects 57% of PD patients. Investigators evaluated 353 consecutive PD patients using the Yesavage Geriatric Depression Scale (GDS). Forty-three percent had no depression, 40% had mild-to-moderate depression, and 17% had severe depression. Depression was most strongly correlated with UPDRS ADL and motor scores, and female sex.
Depression in Parkinson's disease: The Relationships Between Depression and Motor Disability
Krystanek E, Ochudo S, Opala G, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-WE-344
A total of 54 non-demented PD patients were evaluated for depression using the Yesavage GDS. Mild-to-moderate depression was found in 39%, and severe depression in 17%. Depression was not correlated with motor impairment on the UPDRS.
Quality of Life in Parkinson's Disease (PD)Stages: Impact of Depression
Aguilar M, Ramos S, Rojo A, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-WE-320
Seventy-seven consecutive PD patients were assessed for depression with the Yesavage GDS, for PD severity with the Hoehn and Yahr scale, and for quality of life with the PDQ-39, a 100-point scale in which lower scores indicate better QoL. Non-depressed patients had a mean PDQ-39 score of 33.7, mild-to-moderately depressed patients had a mean score of 58.9, and moderate-to-severely depressed patients had a mean score of 76.0. Lower QoL was also correlated with disease severity. Based on their analysis of variance, "Depression has a higher influence than mobility and activities of daily living on quality of life," the researchers concluded.
Rektorova I, Rektor I, Bares M, et al
Parkinsonism and Related Disorders. 2001; 7(suppl): Abstract P-TU-229
Pramipexole improves depression independently of motor benefit, according to this study. Forty-one patients with mild-to-moderate depression and who were taking levodopa received either pramipexole or pergolide up to 4.5 mg/day for 6 weeks. Motor improvement was significant with both treatments, but was not different between the 2 treatments. Both groups had significant reductions in depression on the Zung self-rated scale. Pramipexole-treated patients, but not pergolide-treated patients, showed significant reductions in depression on the MADRS scale, rated by a blinded psychologist; these effects remained after accounting for motor improvements.
Takats A, Szombathelyi E, Farsang MI
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-242
Fifty-two patients on selegiline 10 mg/day received 450 mg/day of the MAO-A inhibitor moclobemide. Depression scores improved for 41 patients after 3 months of treatment. Eleven patients withdrew from the study because of sleep disturbance, increased blood pressure, or lack of response.
Royter V, Broonner G, Giladi N, et al
Parkinsonism and Related Disorders. 2001;7 (suppl): Abstract P-WE-359
Sexual desire and satisfaction decrease in PD patients, especially men, as disease stage advances, according to this report. Eighty-six patients (50 male, 36 female) answered detailed questionnaires about sexual function during the previous 5 years. Results for men indicated that during this time period, satisfaction decreased by 65% and desire by 85%, and erectile dysfunction increased significantly (p<0.0001), all of which correlated with disease stage. In women, satisfaction decreased by 33% and desire by 42%, which also correlated with disease stage, and there was a significant decline in ability to achieve orgasm (p<0.001) not related to disease stage.
Katsarou Z, Bostantjopoulou S, Kiosseoglou G, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-MO-077
Caregivers of Parkinson's disease patients suffer significant stress, according to this report. Seventy-one primary caregivers, including 54 women and 17 men, were evaluated for stress using the Relative Stress Scale. Mean stress was 15 on a scale of 30, indicating moderate-to-high stress in this population. Higher stress was correlated with caring for patients with longer disease duration, deterioration of motor ability, and cognitive decline, as well as severe on-off fluctuations.
Homann CN, Suppan K, Wenzel K, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-WE-338
These investigators collected and analyzed 123 published cases of unintended sleep events in patients with PD. Events were classified as either slow onset with prodromal drowsiness, or sudden onset without prodrome, based on patient description and expert eyewitness accounts, including 2 cases of "sleep attack" witnessed by the first investigator in the study. These 2 cases occurred in the clinic one half hour following administration of a single dose of apomorphine. Patients experienced rapid and profound sleep onset, followed by unresponsiveness to pain or movement, and retrograde amnesia upon awakening.
In published cases, patients ranged from ages 34 to 87, with onset as early as 1 year after diagnosis. All dopaminergic medications were implicated. Of 17 events that occurred while patients were driving, 10 resulted in accidents. Dose reductions or drug elimination helped in most cases, but with resulting motor disability.
Brodsky MA, Godbold J, Olanow CW
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-WE-327
Of 77 consecutive PD patients (mean H&Y 2.25), 79% reported daytime sleepiness, and 52% had abnormal nighttime sleep. Twenty percent had an Epworth Sleepiness Scale score greater than 15, indicating high amounts of daytime sleepiness. Ten patients (13%) on a range of dopaminergic drugs had fallen asleep while driving.
Bliwise DL, Borchert LD, Cantor C, et al
Parkinsonism and Related Disorders. 2001;7(suppl): Abstract P-TU-170
Twenty-two patients were evaluated by questionnaire and Multiple Sleep Latency Test. Based on history, patients were grouped as those with (n=16) or without (n=6) an unintended sleep episode. No differences were found between the 2 groups in dopaminergic medications taken, mean sleep latency, proportion of patients with pathological sleepiness (MSLT<5 minutes; 50% in each group), or proportion with stage II sleep during naps (71-73%), which indicates chronic sleep loss.
Pal S, Lomax C, Pezzella FR, et al
Parkinsonism and Related Disorders. 2001; (suppl): Abstract P-MO-161
A total of 102 patients completed the Parkinson's Disease Sleep Scale, a 15-question visual analog scale recently validated for assessment of sleep disability in PD. Scores were highly correlated with Epworth Sleepiness Scale scores. "This study in a consecutive group of PD patients provides the first formal evidence that nocturnal sleep disturbance is significantly associated with increases in daytime sleepiness scores and a predisposition to excessive daytime sleepiness," the researchers stated.