The effects of withdrawal of dopaminergic medication in nursing home patients with advanced parkinsonism.

OBJECTIVE: To determine the effects of dopaminergic medication withdrawal in an elderly, demented and minimally ambulatory nursing home population with parkinsonism in New York City. METHODS: In our double-blind, randomized study, 11 patients (7 males, 4 females) were randomized into 2 groups: one group underwent levodopa medication withdrawal (experimental group) and the other group continued on their levodopa (control group). Patients were evaluated weekly over the course of a month with a neurologic examination and a series of assessment tools, including the motor UPDRS (Unified Parkinson's disease rating scale), Hoehn and Yahr staging scale, the Mini-Mental State Examination (MMSE) and the Nursing Assistant Behavioral Detection Form. SETTING: An academic nursing home in New York City. RESULTS: The patients had a mean age of 82.00 +/- 10.14 years, with a mean MMSE score of 9.50 +/- 6.60 out of 30.00 maximum. The control and experimental groups did not differ significantly with respect to age (P = .52), dementia severity (P = .35), nor severity of PD symptoms as measured by the UPDRS (P = .22) and Hoehn and Yahr staging (P = .65). Overall, no significant changes were observed between the control and experimental groups in cognitive, behavioral, and motor function across each time period. Of interest, 2 of the drug withdrawal patients showed modest improvements in cognitive function as measured by the MMSE. CONCLUSION: Our findings suggest that in patients with advanced parkinsonism and dementia, dopaminergic medication withdrawal may be a feasible way to reduce polypharmacy and potential medication-related side effects, with a minimal risk of worsening motor deterioration. Therefore, our findings may have potential implications for a medication intervention that could prevent potential deleterious side effects and improve health-related quality of life in this frail population.

Prevalence of movement disorders in an elderly nursing home population.

We studied the prevalence of movement disorders in a large nursing home population (397 patients, mean age 86 years) in New York City. Patients were first evaluated by specially trained research coordinators and final clinical diagnoses were confirmed by a movement disorder specialist. A movement disorder was identified in 21% of patients (83/397). The most frequent movement disorders were essential tremor (ET) (8.8%) and parkinsonism (7.1%). Only half of those admitted with a diagnosis of parkinsonism were confirmed in their diagnosis by the movement disorder specialists. Three percent of patients exhibited drug-induced tremor, 1.3% had dystonia, 0.5% had myoclonus and 0.3% had generalized dyskinesias. Overall, our findings underline the high frequency of movement disorders in a nursing home population. The discrepancy between our findings and the prevalence rates for parkinsonism reported on the initial transfer diagnosis emphasizes the difficulty of accurate diagnosis of movement disorders and in particular parkinsonism.

Subcutaneous apomorphine in patients with advanced Parkinson's disease: a dose-escalation study with randomized, double-blind, placebo-controlled crossover evaluation of a single dose.

OBJECTIVE: To further explore the efficacy and safety of subcutaneous apomorphine (APO) in treating off episodes in APO-naïve patients with advanced Parkinson's disease (PD). METHODS: 56 patients receiving optimized oral anti-PD medication were evaluated on separate days for response to single increasing doses of APO. Acute response to oral anti-PD medication and APO dose escalation (2-10 mg) was evaluated under unblinded conditions. At the 4 mg APO dose, placebo was randomly introduced under double-blind crossover conditions. RESULTS: Mean changes from pre-dose in Unified Parkinson's Disease Rating Scale motor scores indicated significant improvement following APO 4 mg versus placebo at 20 min (p=0.0002), 40 min (p<0.0001; maximum improvement) and 90 min (p=0.0229). Improvements showed significant dose-response at 20 min, 40 min (both p<0.0001) and 90 min (p=0.0049). Adverse events were more common with APO than placebo, and also showed significant dose-response (p<0.0001). Common adverse events associated with APO included yawning, dizziness, nausea, somnolence and dyskinesias, and were generally mild to moderate. There were no significant differences between APO and placebo in the incidence of hypotension associated with a postural change from a sitting to standing position. CONCLUSIONS: Subcutaneous APO provided rapid, effective relief of off episodes associated with advanced PD.

Absence of the apolipoprotein E epsilon4 allele is associated with working memory impairment in Parkinson's disease.

The apolipoprotein E (APOE) epsilon4 allele has been associated with an increased risk of Alzheimer's disease (AD) and weaker episodic memory among elderly. Although this APOE allele has been linked to earlier onset of Parkinson's disease (PD), an association with dementia in PD has been only inconsistently demonstrated. Given the heterogeneity of cognitive impairment patterns in PD, this study sought to determine whether an association exists between APOE genotype and specific cognitive deficits in PD. The neuropsychological test performance of 42 PD patients without an epsilon4 allele (PD-Non4) and of 20 with at least one epsilon4 allele (PD-epsilon4) was compared to that of 146 elderly control subjects (NC). The PD groups were comparable in overall severity of cognitive impairment and disease duration, but the PD-epsilon4 group was younger, had an earlier disease onset, and contained a higher proportion of persons with dementia. Both PD groups showed wide-ranging cognitive impairments relative to NC. Once age differences between groups were controlled for, the PD groups generally did not differ from each other in cognitive performance. However, only the PD-Non4 group demonstrated working memory/attention impairments (digit span, visual span, Trailmaking test) relative to the NC group. Results suggest that the APOE genotype may influence the cognitive phenotype of PD, and specifically that absence of the epsilon4 allele is associated with working memory impairment. Additionally, results are consistent with prior findings showing an association between the epsilon4 allele and earlier onset of PD and presence of dementia.

The diagnosis of manganese-induced parkinsonism.

Parkinsonism is a clinical syndrome consisting of tremor, bradykinesia, rigidity, gait, balance problems, in addition to various non-motor symptoms. There are many causes of parkinsonism such as neurodegenerative disease, drugs, vascular causes, structural lesions, infections, and toxicants. Parkinson's disease, or idiopathic parkinsonism, is the most common form of parkinsonism observed in the clinic. There is degeneration of the substantia nigra, pars compacta, which results in loss of striatal dopamine. Parkinson's disease is a slowly progressive condition in which there is a dramatic and sustained responsiveness to levodopa therapy. Manganese is an essential trace element that can be associated with neurotoxicity. Hypermanganism can occur in a variety of clinical settings. The clinical symptoms of manganese intoxication include non-specific complaints, neurobehavioral changes, parkinsonism, and dystonia. Although the globus pallidus is the main structure of damage, other basal ganglia areas can also be involved. MRI scans may show globus pallidus changes during (and for a short period after) exposure. Fluorodopa PET scans that assess the integrity of the substantia nigra dopaminergic system are abnormal in Parkinson's disease. However, these scans re-reported to be normal in a few cases studied with manganese-induced parkinsonism. The parkinsonism due to manganese may have some clinical features that occur less commonly in Parkinson's disease, such as kinetic tremor, dystonia, specific gait disturbances, and early mental, balance and speech changes. The clinical signs tend to be bilateral whereas Parkinson's disease begins on one side of the body. Patients with manganese-induced parkinsonism may be younger at the onset of the disease than with Parkinson's disease. Lastly, there appears to be a lack of response to levodopa therapy in manganese-induced parkinsonism. In summary it may be possible to differentiate manganese-induced parkinsonism from Parkinson's disease using clinical and imaging studies.

Clinical usefulness of the Parkinson's disease sleep scale.

OBJECTIVE: To test the usefulness of the Parkinson's disease sleep scale (PDSS) in identifying sleep disorders in the clinical practice setting. METHODS: Sixty-two PD patients were evaluated with the PDSS and the Epworth sleepiness scale (ESS). A cut-off of less than five for each PDSS item as an indicator of substantial sleep disturbance was chosen. If the ESS was equal to or greater than eight, patients were referred to a sleep disorder specialist and possible polysomnography. RESULTS: The mean total PDSS score was 104.7+/-21.5,which correlated with the mean Hoehn and Yahr score (1.9+/-0.9) as well as the mean ESS score (9.7+/-4.7). A significant correlation was also found between the ESS score and several items of the PDSS. CONCLUSIONS: The PDSS was useful in identifying sleep disturbances which were not previously diagnosed, such as sleep maintenance insomnia and excessive daytime sleepiness. Problems with the PDSS include ambiguities of some questions, lack of quantification and an inability to identify specific sleep disturbances such as sleep apnea.

Unilateral stimulation of the subthalamic nucleus in Parkinson disease: a double-blind 12-month evaluation study.

OBJECT: Bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been established as an effective treatment for Parkinson disease (PD). Nevertheless, bilateral surgical procedures can be associated with frequent and severe complications. The aim in the present study was to assess the safety and efficacy of unilateral STN stimulation, and the need for a second procedure. METHODS: Twelve patients with PD underwent unilateral DBS of the STN and were followed up for 12 months. Patients were assessed at baseline and at each visit in a double-blind fashion by analyzing the Unified PD Rating Scale (UPDRS), ambulation speed, and home diaries. Levodopa-off/stimulation-on UPDRS motor scores were improved by 26 +/- 8% (p < 0.05, mean +/- standard deviation [SD]) compared with the baseline levodopa-off score; there was a 50% improvement in contralateral features, a 17% improvement ipsilaterally, and a 36% improvement in axial features. The mean ambulation speed increased by 83 +/- 44% (p < 0.01, mean +/- SD). The medication-on time with dyskinesias was significantly reduced (p < 0.01) and the daily levodopa dose was reduced by 19 +/- 6% (p < 0.05, mean +/- SD). There were no clinically significant side effects. CONCLUSIONS: Unilateral DBS of the STN is safe and well tolerated, and may provide sufficient benefit so that additional surgery is not required.

Neuroprotection in Parkinson's disease: an elusive goal.

Parkinson's disease is a chronic progressive condition that causes disability and reduction of quality of life. Symptomatic treatments are effective in the early disease; however, with time, most patients develop motor complications. Neuroprotective therapies are those that can slow disease progression; unfortunately, these agents are not available. Advances in the knowledge of the possible pathogenic events that can lead to nigral cell death have increased dramatically. These mechanisms include oxidative stress, mitochondrial dysfunction, inflammation, excitotoxicity, alterations in protein degradation, and ultimately apoptosis. Based on these laboratory scientific findings, a number of agents have been studied in clinical trials. However, how to assess disease evolution and establish reliable endpoints is still an unresolved issue. The monoamine oxidase inhibitors selegiline and rasagiline have been shown to be neuroprotective in vitro and in animal models, but so far this property was not demonstrated in clinical trials. Other agents have been studied and still others are undergoing clinical investigation. These include antiexcitotoxicity drugs like riluzole, the bioenergetic agent coenzyme Q10, trophic factors, and antiapoptotic drugs. Laboratory and clinical data suggest that dopamine agonists may have a neuroprotective action, but this has yet to be proven. However, as our basic and clinical knowledge on Parkinson's disease increases, it is likely that a neuroprotective drug will be found.

Effect of levodopa treatment for parkinsonism in welders: A double-blind study.

BACKGROUND: Manganese is known to cause a parkinsonian syndrome similar clinically to Parkinson disease (PD). L-Dopa responsiveness is a hallmark of PD; however, L-dopa's effect on manganese-induced parkinsonism is not well defined. OBJECTIVE: To access the efficacy and safety of L-dopa therapy in a double-blind, randomized, placebo-controlled trial. METHODS: Thirteen patients with manganese-induced parkinsonism were evaluated in a cross-over study with a modified Unified PD Rating Scale (UPDRS), timed walk test, tapping, and global clinical impression scores. Adverse reactions were assessed. RESULTS: There was no significant difference between placebo and L-dopa for any measure: motor UPDRS, 27.4 vs 28.8; walk time, 16.6 seconds vs 17.7 seconds; tapping right hand, 69.5 vs 64.7; and tapping left hand, 66.8 vs 64.4. There were no differences in the global impression scores. Adverse reactions occurred similarly in the two groups, including headaches, drowsiness, and diarrhea. CONCLUSIONS: L-Dopa therapy is not effective for the management of parkinsonism in welders. L-dopa unresponsiveness may be useful to distinguish manganese-induced parkinsonism from Parkinson disease.

Unmet medical needs in Parkinson's disease.

Levodopa, introduced in the late 1960s, was the first highly effective drug for the symptomatic treatment of Parkinson's disease (PD) and remains the mainstay of pharmacologic treatment. However, long-term treatment has important limitations. The disease continues to progress despite treatment with levodopa, and a neuroprotective therapy is urgently required. In addition, motor complications associated with chronic levodopa therapy are an important source of disability. Treatment of these complications forms a major focus of modern PD management, and it is in this area that recent advances in our knowledge offer the best opportunity for therapeutic gain. In the search for improved therapies, suitable outcome measures to better assess overall disability in PD and disease progression are essential.

Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease.

We previously reported genetic linkage of loci controlling age-at-onset in Alzheimer disease (AD) and Parkinson's disease (PD) to a 15 cM region on chromosome 10q. Given the large number of genes in this initial starting region, we applied the process of 'genomic convergence' to prioritize and reduce the number of candidate genes for further analysis. As our second convergence factor we performed gene expression studies on hippocampus obtained from AD patients and controls. Analysis revealed that four of the genes [stearoyl-CoA desaturase; NADH-ubiquinone oxidoreductase 1 beta subcomplex 8; protease, serine 11; and glutathione S-transferase, omega-1 (GSTO1)] were significantly different in their expression between AD and controls and mapped to the 10q age-at-onset linkage region, the first convergence factor. Using 2814 samples from our AD dataset (1773 AD patients) and 1362 samples from our PD dataset (635 PD patients), allelic association studies for age-at-onset effects in AD and PD revealed no association for three of the candidates, but a significant association was found for GSTO1 (P=0.007) and a second transcribed member of the GST omega class, GSTO2 (P=0.005), located next to GSTO1. The functions of GSTO1 and GSTO2 are not well understood, but recent data suggest that GSTO1 maybe involved in the post-translational modification of the inflammatory cytokine interleukin-1beta. This is provocative given reports of the possible role of inflammation in these two neurodegenerative disorders.

Movement disorders.

Movement disorders are commonly encountered in clinical practice. The diagnosis of movement disorders relies on a focused history and neurologic examination. Diagnostic steps include (1) identification of the phenomenology of the movements (eg, tremor); (2) characterization of appropriate clinical syndromes; and (3) differential diagnosis of specific disease entities. Accurate diagnosis is essential because symptomatic treatment exists for most movement disorders.

Association study of Parkin gene polymorphisms with idiopathic Parkinson disease.

BACKGROUND: Previously, we detected linkage of idiopathic Parkinson disease (PD) to the region on chromosome 6 that contains the Parkin gene (D6S305; logarithm of odds score, 5.47) in families with at least one individual with age at onset younger than 40 years (families with early-onset disease). Further study demonstrated the presence of Parkin mutations in this data set. However, previous case-control studies have reported conflicting results regarding the role of more common Parkin polymorphisms as susceptibility alleles for idiopathic PD. OBJECTIVE: To investigate the association of 7 previously studied Parkin single-nucleotide polymorphisms (SNPs) throughout the promoter and most of the open reading frame with PD in a large cohort of patients with primarily late-onset PD. METHODS: One promoter, 3 intronic, and 3 exonic Parkin SNPs were genotyped in 1580 individuals belonging to 397 families, and their association with PD was evaluated using family-based association tests. RESULTS: No significant association (P>.05) between PD and any Parkin SNP allele or genotype was detected. Haplotype analysis and stratification by age at onset or family history also failed to produce significant results. CONCLUSIONS: These results suggest that these common variants of Parkin are not associated with PD in white patients, although Parkin mutations are known to cause early- and late-onset PD.

Benefits and risks of pharmacological treatments for essential tremor.

Essential tremor can cause significant functional disability in some patients. The arms are the most common body part affected and cause the most functional disability. The treatment of essential tremor includes medications, surgical options and other forms of therapy. Presently there is no cure for essential tremor nor are there any medications that can slow the progression of tremor. Treatment for essential tremor is recommended if the tremor causes functional disability. If the tremor is disabling only during periods of stress and anxiety, propranolol and benzodiazepines can be used during those periods when the tremor causes functional disability. The currently available medications can improve tremor in approximately 50% of the patients. If the tremor is disabling, treatment should be initiated with either primidone or propranolol. If either primidone or propranolol do not provide adequate control of the tremor, then the medications can be used in combination. If patients experience adverse effects with propranolol, occasionally other beta-adrenoceptor antagonists (such as atenolol or metoprolol) can be used. If primidone and propranolol do not provide adequate control of tremor, occasionally the use of benzodiazepines (such as clonazepam) can provide benefit. Other medications that may be helpful include gabapentin or topiramate. If a patient has disabling head or voice tremor, botulinum toxin injections into the muscles may provide relief from the tremor. Botulinum toxin in the hand muscles for hand tremor can result in bothersome hand weakness and is not widely used. There are other medications that have been tried in essential tremor and have questionable efficacy. These drugs include carbonic anhydrase inhibitors (e.g. methazolamide), phenobarbital, calcium channel antagonists (e.g. nimodipine), isoniazid, clonidine, clozapine and mirtazapine. If the patient still has disabling tremor after medication trials, surgical options are usually considered. Surgical options include thalamotomy and deep brain stimulation of the thalamus. These surgical options provide adequate tremor control in approximately 90% of the patients. Surgical morbidity and mortality for these procedures is low. Deep brain stimulation and thalamotomy have been shown to have comparable efficacy but fewer complications have been reported with deep brain stimulation. In patients undergoing bilateral procedures deep brain stimulation of the thalamus is the procedure of choice to avoid adverse effects seen with bilateral ablative procedures. The use of medication and/or surgery can provide adequate tremor control in the majority of the patients.

Parkin mutations and susceptibility alleles in late-onset Parkinson's disease.

Parkin, an E2-dependent ubiquitin protein ligase, carries pathogenic mutations in patients with autosomal recessive juvenile parkinsonism, but its role in the late-onset form of Parkinson's disease (PD) is not firmly established. Previously, we detected linkage of idiopathic PD to the region on chromosome 6 containing the Parkin gene (D6S305, logarithm of odds score, 5.47) in families with at least one subject with age at onset (AAO) younger than 40 years. Mutation analysis of the Parkin gene in the 174 multiplex families from the genomic screen and 133 additional PD families identified mutations in 18% of early-onset and 2% of late-onset families (5% of total families screened). The AAO of patients with Parkin mutations ranged from 12 to 71 years. Excluding exon 7 mutations, the mean AAO of patients with Parkin mutations was 31.5 years. However, mutations in exon 7, the first RING finger (Cys253Trp, Arg256Cys, Arg275Trp, and Asp280Asn) were observed primarily in heterozygous PD patients with a much later AAO (mean AAO, 49.2 years) but were not found in controls in this study or several previous reports (920 chromosomes). These findings suggest that mutations in Parkin contribute to the common form of PD and that heterozygous mutations, especially those lying in exon 7, act as susceptibility alleles for late-onset form of Parkinson disease.

Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease.

Mitochondrial (mt) impairment, particularly within complex I of the electron transport system, has been implicated in the pathogenesis of Parkinson disease (PD). More than half of mitochondrially encoded polypeptides form part of the reduced nicotinamide adenine dinucleotide dehydrogenase (NADH) complex I enzyme. To test the hypothesis that mtDNA variation contributes to PD expression, we genotyped 10 single-nucleotide polymorphisms (SNPs) that define the European mtDNA haplogroups in 609 white patients with PD and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.34-0.91; P=.02) or K (OR 0.52; 95% CI 0.30-0.90; P=.02) demonstrated a significant decrease in risk of PD versus individuals carrying the most common haplogroup, H. Furthermore, a specific SNP that defines these two haplogroups, 10398G, is strongly associated with this protective effect (OR 0.53; 95% CI 0.39-0.73; P=.0001). SNP 10398G causes a nonconservative amino acid change from threonine to alanine within the NADH dehydrogenase 3 (ND3) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men (OR 0.43; 95% CI 0.27-0.71; P=.0009). In addition, SNP 9055A of ATP6 demonstrated a protective effect for women (OR 0.45; 95% CI 0.22-0.93; P=.03). Our results suggest that ND3 is an important factor in PD susceptibility among white individuals and could help explain the role of complex I in PD expression.