The role of apolipoprotein E polymorphisms in levodopa-induced dyskinesia.

OBJECTIVES: To determine the relationship between apolipoprotein E (APOE) polymorphisms to the time to appearance of levodopa-induced dyskinesia (LID) in patients with Parkinson's disease. METHODS: The APOE genotype of 155 consecutive patients treated with levodopa was determined and its effect on the time of onset of LID was examined using Cox regression model, controlling for gender, age of disease onset, time to initiation of levodopa treatment and history of smoking. RESULTS: Two patients were homozygous for the APOE ε2 allele, 7 had ε2/ε3, 1 had ε2/ε4, 130 had ε3/ε3, 12 had ε3/ε4 and 3 had ε4/ε4; LID appeared in 57.4% of the patients, appearing 4.1 ± 3.5 years after the initiation of levodopa treatment. The survival curve for LID was not affected by the APOE genotype (P = 0.34). CONCLUSION: APOE polymorphisms were found not to be associated with either the occurrence or the time to development of LID.

Age of Parkinson's disease onset as a predictor for the development of dyskinesia.

The risk of developing levodopa-associated dyskinesia is known to vary inversely with the age of Parkinson's disease onset. This study quantifies dyskinesia risks for different Parkinson's onset ages in a patient population treated at the Parkinson's Disease Research, Education, and Clinical Center at the San Francisco Veterans Affairs Medical Center. Medical records were reviewed to determine age of Parkinson's onset, medication history, and dyskinesia onset. Dyskinesia risks were determined by using Kaplan-Meier analysis. Cox proportional hazard models were used to compare age groups and to perform multivariate modeling. This study included 109 patients with Parkinson's, 105 of whom had onset of symptoms after 1989. At 5 years of levodopa treatment, the dyskinesia risk for patients with onset age 40-49 was 70%, decreasing to 42% for onset ages 50-59, 33% for onset ages 60-69, and 24% for onset ages 70-79. Pairwise comparisons between the 40-49 age group and the other age groups were statistically significant in time-to-event models. After 5 years of levodopa treatment, dyskinesia risks became uniformly high regardless of age of onset. These results suggest it is appropriate to use different baseline dyskinesia risks in clinical decision-making for patients on the basis of their ages of onset. However, the most significant difference occurs between ages 40-49 and ages 50-79, and if more than 5 years of levodopa therapy are anticipated, dyskinesia risk may have less utility when deciding upon Parkinson's therapy. Drug studies for Parkinson's disease should also take age of Parkinson's onset into account when analyzing dyskinesia outcomes.

Mortality and tardive dyskinesia: long-term study using the US National Death Index.

BACKGROUND: Whether the development of tardive dyskinesia leads to an increase in mortality is still unclear. AIMS: To explore the relationship between tardive dyskinesia and mortality over a 10-year period, using the National Death Index. METHOD: Death certificates were obtained from the National Death Index on 1621 people repeatedly assessed for tardive dyskinesia by trained raters. Variables with the potential for influencing survival time were also investigated. RESULTS: Tardive dyskinesia was significantly associated with an increase in mortality (P<0.001), but this association became non-significant when drug course and age were entered in the regression analysis. Those who had taken only conventional antipsychotics were twice as likely to die compared with those taking atypical agents (P<0.02). For those aged 53-65 years, conventional agents were associated with a sevenfold increase in mortality. CONCLUSIONS: Older individuals with tardive dyskinesia treated with conventional antipsychotics appear to have a shortened survival time.

Mortality rates among patients with schizophrenia and tardive dyskinesia.

Tardive dyskinesia (TD) is a severe and potentially irreversible movement, and previous studies have suggested increased mortality among patients with TD, but most of these studies are limited by small sample sizes and short periods of follow-up. This study examined the mortality rate of a cohort of 608 Asian patients with schizophrenia during a 6-year period and used survival analyses on time from case ascertainment to outcome (death). Data on the survival status were collected and compared between those with and without TD, and cross-tabulation was performed to show the correlation between survival and mortality rates among patients with and without TD.Seventy-two patients died, 39 (54.2%) of whom had TD previously. Of the 536 surviving cases, 239 (44.6%) have TD. The mortality rates between those with TD and those without TD were statistically significant (hazard ratio, 2.62; 95% confidence interval, 1.58-4.33; P = 0.0006).The mortality rate was dependent on age; nevertheless, the adverse effect of TD on survival rate, although reduced, remains after controlling for age (hazard ratio, 1.90; 95% confidence interval, 1.12-3.20; P = 0.017). Our finding showed a robust association with increased mortality rate and TD, but we failed to find any significant association with any specific cause of death and TD.

Ten year outcome of tardive dyskinesia during continuous treatment with first generation antipsychotics.

OBJECTIVE: The aim of this study is to determine the course of tardive dyskinesia (TD) during continuous medication with first generation antipsychotics. SUBJECTS AND METHODS: Patients of a psychiatric nursing home were assessed for TD by means of the AIMS on two occasions ten years apart. RESULTS: Out of 10 patients who met criteria for TD at baseline the global judgement of severity of the AIMS improved in 5, worsened in 4 and remained unchanged in one patient. The mean sum score of the AIMS slightly increased from 5.5 to 6.3. No patient developed movements that incapacitated him in his daily activities. CONCLUSION: In concordance with the available literature these findings support the view that under continuous treatment with antipsychotics there is an equal chance for improvement as for deterioration. Progressive worsening to severe forms of TD was not observed.

Mortality rate of schizophrenic patients with tardive dyskinesia during 10 years: a controlled study.

We examined mortality rates (MR) during 10 years between schizophrenic inpatients with and without tardive dyskinesia (TD). The TD group had a significantly higher MR (41%), as compared with the control group (20%). However, we could not reveal critical factors to explain why the TD patients had the higher MR.

Movement disorder emergencies in childhood.

The literature on paediatric acute-onset movement disorders is scattered. In a prospective cohort of 52 children (21 male; age range 2mo-15y), the commonest were chorea, dystonia, tremor, myoclonus, and Parkinsonism in descending order of frequency. In this series of mainly previously well children with cryptogenic acute movement disorders, three groups were recognised: (1) Psychogenic disorders (n = 12), typically >10 years of age, more likely to be female and to have tremor and myoclonus (2) Inflammatory or autoimmune disorders (n = 22), including N-methyl-d-aspartate receptor encephalitis, opsoclonus-myoclonus, Sydenham chorea, systemic lupus erythematosus, acute necrotizing encephalopathy (which may be autosomal dominant), and other encephalitides and (3) Non-inflammatory disorders (n = 18), including drug-induced movement disorder, post-pump chorea, metabolic, e.g. glutaric aciduria, and vascular disease, e.g. moyamoya. Other important non-inflammatory movement disorders, typically seen in symptomatic children with underlying aetiologies such as trauma, severe cerebral palsy, epileptic encephalopathy, Down syndrome and Rett syndrome, include dystonic posturing secondary to gastro-oesophageal reflux (Sandifer syndrome) and Paroxysmal Autonomic Instability with Dystonia (PAID) or autonomic 'storming'. Status dystonicus may present in children with known extrapyramidal disorders, such as cerebral palsy or during changes in management e.g. introduction or withdrawal of neuroleptic drugs or failure of intrathecal baclofen infusion; the main risk in terms of mortality is renal failure from rhabdomyolysis. Although the evidence base is weak, as many of the inflammatory/autoimmune conditions are treatable with steroids, immunoglobulin, plasmapheresis, or cyclophosphamide, it is important to make an early diagnosis where possible. Outcome in survivors is variable. Using illustrative case histories, this review draws attention to the practical difficulties in diagnosis and management of this important group of patients.

Comparing acute toxicity of first- and second-generation antipsychotic drugs: a 10-year, retrospective cohort study.

OBJECTIVE: Second-generation antipsychotics (SGAs) are far more commonly used in the United States compared to first-generation antipsychotics (FGAs), but the relative safety of SGAs compared to FGAs following acute toxic ingestions has not been studied. METHOD: A retrospective cohort study was performed by chart review of the California Poison Control System electronic database of 1975 cases from the 10-year period 1997 to 2006 involving patients aged 18 to 65 years who ingested a single SGA or FGA. Cases were coded for overall severity of adverse outcome as defined by the American Association of Poison Control Centers criteria and for presence of specific symptoms and treatments. Odds ratios were calculated between SGAs and FGAs for various symptoms, treatments, and outcome severity. RESULTS: Odds of a major adverse outcome or death were significantly higher for SGAs than FGAs (OR = 1.71, 95% CI = 1.09 to 2.71). Patients taking SGAs had higher odds of respiratory depression (OR = 2.39, 95% CI = 1.09 to 5.26), coma (OR = 2.18, 95% CI = 1.30 to 3.65), and hypotension (OR = 1.80, 95% CI = 1.23 to 2.63) compared to those taking FGAs but lower odds of dystonia (OR = 0.12, 95% CI = 0.08 to 0.19) or rigidity (OR = 0.30, 95% CI = 0.10 to 0.90). CONCLUSION: SGAs appear no safer than FGAs in acute overdose. While neuromuscular symptoms appear less frequently with SGAs compared to FGAs, the relatively greater rates of central nervous system depression associated with SGA overdose may be more dangerous.

Relationship between neuroleptic extrapyramidal syndromes and patients' all-cause mortality.

INTRODUCTION: It is important to understand factors contributing to a neuroleptic-related increased mortality risk. The objective of this study was to test whether the occurrence of neuroleptic-induced extrapyramidal syndromes (EPS) including tardive dyskinesia (TD) is associated with an increased patients' all-cause mortality. METHODS: In 1995, a sample of 200 patients on neuroleptics was assessed with regard to the presence of Parkinson syndrome, akathisia, and TD. By 2003-2004, i.e., during the following 8-9 year period, 63 patients had died. Patients who had died were compared with 120 patients known to be still alive with regard to several socio-demographic variables and the presence of EPS at the first examination. RESULTS: At the basic assessment, there were no significant differences between patients later still alive and deceased patients with regard to TD. The deceased patients were more frequently women, older, suffered more frequently from an organic disorder, had higher average scores for Parkinson syndrome and less frequently akathisia. Multivariate analysis confirmed age as the only factor contributing to the group difference. Repeating the meta-analysis by Ballesteros et al. (2000) after inclusion of our data, TD remains a weak but a significant predictor of death (OR=1.4). DISCUSSION: Neuroleptic-induced EPS of parkinsonism, akathisia, and TD did not contribute to the patients' all-cause mortality in this study. The association between TD and mortality merits further attention.

Thiopental exaggerates ischemic brain damage and neurological deficits after experimental stroke in spontaneously hypertensive rats.

Thiopental is an anesthetic used for controlling high intracranial pressure (ICP) caused by brain surgery, brain trauma, and severe stroke. However, it remains controversial whether Thiopental is detrimental or beneficial in ischemic stroke. In this study, we used an animal model of ischemic stroke in spontaneously hypertensive rats to determine whether or not Thiopental is neuroprotective in the setting of brain ischemia. We observed that Thiopental caused a prolonged duration of unconsciousness with a high rate of mortality, that Thiopental created exaggerated neurological deficits that were revealed through limb placement tests at 4 days and 4 weeks after brain ischemia, and that infarct volume was increased in Thiopental-anesthetized rats. These data suggest that Thiopental is detrimental in ischemic stroke. Thus, our findings raise a caution about the use of Thiopental in the setting of ischemic stroke.

Development of dyskinesias in a 5-year trial of ropinirole and L-dopa.

A 5-year trial of ropinirole and levodopa in early Parkinson's disease showed that ropinirole is associated with reduced incidence of dyskinesias. This post hoc analysis investigated whether the dyskinesia-sparing benefit of ropinirole is lost when levodopa is added to the regimen and evaluated other risk factors for developing dyskinesias. Patients receiving levodopa had a significantly higher risk of dyskinesias than those taking ropinirole monotherapy (hazard ratio [HR], 6.67; 95% confidence interval [CI], 3.23-14.29; P < 0.001). When patients randomized to ropinirole were treated with supplementary levodopa, the development of dyskinesias was not significantly different from that in those receiving levodopa from the start (HR, 0.80; 95% CI, 0.48-1.33; P = 0.39). However, the onset of dyskinesias was delayed by around 3 years compared with levodopa monotherapy. Adjusted analyses taking into account baseline and on-treatment factors that influenced use of supplementary levodopa or the development of dyskinesias produced similar results. In conclusion, the risk of developing dyskinesias during maintained initial ropinirole monotherapy is very low. Only once levodopa is added does the risk substantially change. Early use of ropinirole postpones the onset of dyskinesias, but these benefits decline when levodopa therapy is started, with no evidence of a subsequent rapid "catch-up" or a persisting preventive effect.

Morbidity and mortality in tardive dyskinesia: associations in chronic schizophrenia.

A population of 101 chronic schizophrenic inpatients were assessed for the presence or absence of tardive dyskinesia, and followed up 32 months later. At follow up, the mortality rates in 44 patients with and 57 patients without involuntary movements were 16% vs. 9% respectively; this difference widened when only the more prominent involuntary movements were considered. Of those surviving, patients with tardive dyskinesia were much more likely to contract an attack of respiratory tract infection, and to do so on multiple occasions, and tended to suffer from more cardiovascular disorders. They appeared more likely to show smoking-related pathology. Chronic schizophrenic patients with tardive dyskinesia constitute a more biologically disadvantaged group, suggesting a broader disease concept of the syndrome.

Current outcome in schizophrenia: women vs men.

This article reviews the 1980's literature on gender differences in schizophrenia outcome. Neuroleptic response, long-term course, and housing, appear to be superior in women. Mortality ratios are advantageous to schizophrenic men. After menopause, women may require higher neuroleptic doses than men and are more at risk for severe tardive dyskinesia. The antidopaminergic effects of estrogens appear to be responsible for some of the outcome differences.

Schizophrenia in the elderly: what nurses need to know.

People age 65 and older with schizophrenia comprise a small but growing number of the mentally ill that nurses, especially those who work in nursing homes, care for. Elderly schizophrenics are a heterogeneous group. They are subject to all of the chronic and acute illnesses common to elderly persons. In addition, their medical problems are frequently overlooked and are difficult to treat. As many as 50% of them have tardive dyskinesia, which has potentially fatal consequences, especially in the elderly.

Tardive dyskinesia associated with higher mortality in psychiatric patients: results of a meta-analysis of seven independent studies.

This article reports a meta-analysis of seven independent studies on the association of tardive dyskinesia with all-cause mortality in psychiatric patients. Most of the studies included provide either small sample sizes or follow-up periods too short to reach a substantive conclusion on their own. In the meta-analysis, the overall odds ratio (OR) was significant when calculated either by the fixed-effects model (OR = 1.4, 95% confidence interval [CI] = 1.2-1.7, p < 0.005) or the random-effects model (OR = 1.4, 95% CI = 1.1-1.8, p < 0.005). There was no overall heterogeneity (Q test = 8.1, df = 7,p = 0.32). The overall estimate changed within study designs (OR = 1.4,p = 0.002 in three prospective controlled studies; OR = 2.2, p = 0.02 in two prospective uncontrolled studies; and OR = 0.9, p = 0.80 in two retrospective controlled studies). It was modified upward when the two most influential studies (one prospective and one retrospective) were removed from the overview (OR = 2.2, 95% CI = 1.4-3.5,p = 0.001; Q test = 0.81, df = 4,p = 0.94). The conclusion of the meta-analysis was that tardive dyskinesia must be considered a weak risk factor in terms of mortality. It remains to be elucidated whether it is a risk factor on its own or just a surrogate for any unknown organic liability.

Early institution of bromocriptine in Parkinson's disease inhibits the emergence of levodopa-associated motor side effects. Long-term results of the PRADO study.

Long-term levodopa treatment in Parkinson's disease is typically associated with "motor side effects" consisting in dyskinesias and/or fluctuations in motility referred to as the on-off phenomena. The main objective of this prospective, randomized, multi-centre study was to determine to what extent the development of such complications could be prevented by partial substitution of levodopa monotherapy (L-DOPA/benserazide) by bromocriptine in patients with early symptoms of the disease. The basic trial population included 674 newly diagnosed Parkinsonian patients that were randomly allocated to monotherapy with levodopa or a combination therapy based upon a nearly 40% replacement of levodopa by bromocriptine. The two target regimens had to be consistently maintained for 42 months. Parkinsonian symptoms were assessed by means of the Webster rating scale, the Hoehn and Yahr scale, and the Zung Self-Rating Depression scale. Motor side effects and adverse events were recorded at each regular clinic visit. Neurological symptoms improved and stabilized in a similar manner during treatment with both regimens throughout the study period. Motor side effects were observed in more patients on levodopa alone than on combination therapy (28.8 vs 20%; p = 0.008). According to Kaplan-Meier estimates the cumulative probability of experiencing motor side effects was 0.43 on monotherapy, compared to 0.28 on combination therapy, which was equal to a one third reduction of risk (p = 0.025). In regard to motor side effects, the degree of substitution of levodopa proved relevant: patients with > 50% substitution by bromocriptine exhibited half the risk observed in those with < 30% (p = 0.045). The overall burden of motor side effects, as reflected by a sum score based upon the relevance, the severity and the extent of motor dysfunction, was also significantly less on combination therapy (p = 0.046). In conclusion, partial substitution of levodopa by bromocriptine (> 30%) as first-line treatment of Parkinson's disease proves active in the prophylaxis of levodopa associated motor side effects. Early combination therapy therefore extends the period of optimal disease control.