OBJECTIVE: To determine whether treatment with low dose aspirin and heparin leads to a higher rate of live births than that achieved with low dose aspirin alone in women with a history of recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies), lupus anticoagulant, and cardiolipin antibodies (or anticardiolipin antibodies). DESIGN: Randomised controlled trial. SETTING: Specialist clinic for recurrent miscarriages. SUBJECTS: 90 women (median age 33 (range 22-43)) with a history of recurrent miscarriage (median number 4 (range 3-15)) and persistently positive results for phospholipid antibodies. INTERVENTION: Either low dose aspirin (75 mg daily) or low dose aspirin and 5000 U of unfractionated heparin subcutaneously 12 hourly. All women started treatment with low dose aspirin when they had a positive urine pregnancy test. Women were randomly allocated an intervention when fetal heart activity was seen on ultrasonography. Treatment was stopped at the time of miscarriage or at 34 weeks' gestation. MAIN OUTCOME MEASURES: Rate of live births with the two treatments. RESULTS: There was no significant difference in the two groups in age or the number and gestation of previous miscarriages. The rate of live births with low dose aspirin and heparin was 71% (32/45 pregnancies) and 42% (19/45 pregnancies) with low dose aspirin alone (odds ratio 3.37 (95% confidence interval 1.40 to 8.10)). More than 90% of miscarriages occurred in the first trimester. There was no difference in outcome between the two treatments in pregnancies that advanced beyond 13 weeks' gestation. Twelve of the 51 successful pregnancies (24%) were delivered before 37 weeks' gestation. Women randomly allocated aspirin and heparin had a median decrease in lumbar spine bone density of 5.4% (range -8.6% to 1.7%). CONCLUSION: Treatment with aspirin and heparin leads to a significantly higher rate of live births in women with a history of recurrent miscarriage associated with phospholipid antibodies than that achieved with aspirin alone.

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Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies)

OBJECTIVE--To determine the outcome of administration of neuroleptics to patients with senile dementia of Lewy body type confirmed at necropsy. DESIGN--Retrospective analysis of clinical notes blind to neuropathological diagnosis. SETTING--Specialist psychogeriatric assessment units referring cases for necropsy to a teaching hospital neuropathology service. PATIENTS--41 elderly patients with diagnosis of either Alzheimer type dementia (n = 21) or Lewy body type dementia (n = 20) confirmed at necropsy. MAIN OUTCOME MEASURES--Clinical state including extrapyramidal features before and after neuroleptic treatment and survival analysis of patients showing severe neuroleptic sensitivity compared with the remainder in the group. RESULTS--16 (80%) patients with Lewy body type dementia received neuroleptics, 13 (81%) of whom reacted adversely; in seven (54%) the reactions were severe. Survival analysis showed an increased mortality in the year after presentation to psychiatric services compared with patients with mild or no neuroleptic sensitivity (hazard ratio 2.70 (95% confidence interval 2.50-8.99); (chi 2 = 2.68, p = 0.05). By contrast, only one (7%) of 14 patients with Alzheimer type dementia given neuroleptics showed severe neuroleptic sensitivity. CONCLUSIONS--Severe, and often fatal, neuroleptic sensitivity may occur in elderly patients with confusion, dementia, or behavioural disturbance. Its occurrence may indicate senile dementia of Lewy body type and this feature has been included in clinical diagnostic criteria for this type of dementia.

https://www.bmj.com/content/bmj/305/6855/673.full.pdf

Neuroleptic sensitivity in patients with senile dementia of Lewy body type.

Objective: To investigate the contribution of neuroleptic drugs to cognitive decline in dementia. Design: Two year prospective, longitudinal study consisting of interviews every four months, with necropsy follow up. Setting: Community settings in Oxfordshire. Subjects: 71 subjects with dementia, initially living at home with informant. Main outcome measures: Cognitive function (score from expanded minimental state examination); behavioural problems (physical aggression, hallucinations, persecutory ideas, and disturbance of diurnal rhythm); and postmortem neuropathological assessment (cortical Lewy body pathology). Results: The mean (SE) decline in cognitive score in the 16 patients who took neuroleptics was twice that in the patients who did not (20.7 (2.9) v 9.3 (1.3), P=0.002). An increased rate of decline was also associated with aggression, disturbed diurnal rhythm, and persecutory ideas. However, only use of neuroleptics and severity of persecutory ideas were independently associated with more rapid cognitive decline when all other variables were adjusted for. The start of neuroleptic treatment coincided with more rapid cognitive decline: median rate of decline was 5 (interquartile range 8.5) points per year before treatment and 11 (12) points per year after treatment (P=0.02). Cortical Lewy body pathology did not account for association between neuroleptic use and more rapid decline. Conclusions: Neuroleptic drugs that are sometimes used to treat behavioural complications of dementia may worsen already poor cognitive function. Randomised controlled trials are needed to confirm a causal relation. Key messages Neuroleptic drugs are used to treat behavioural problems in patients with dementia, but they may cause more rapid decline in cognitive function In our longitudinal study of patients with dementia we found that the rate of cognitive decline in patients taking neuroleptics was twice that in those not taking neuroleptics Furthermore, the start of neuroleptic treatment was associated with an increase in the rate of cognitive decline Cortical Lewy body pathology at necropsy did not account for the association between neuroleptic use and more rapid decline Although our study does not prove a causal relation, we suggest that there should be regular review of the need for patients to continue taking neuroleptic drugs

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Do neuroleptic drugs hasten cognitive decline in dementia? Prospective study with necropsy follow up.

Pharmacotherapy of aggressive or agitated behaviors in the dementia patient has not been studied extensively, despite the prevalence of this problem. Neuroleptics have the most support for efficacy, with shorter acting benzodiazepines demonstrating benefit on occasion. However, studies done to date indicate that these drugs are effective only for a minority of patients and that side effects frequently make patients worse. Other medications, such as propranolol, carbamazepine, or lithium, may be helpful, but their efficacy in dementia patients has not been demonstrated in placebo-controlled studies. Until such studies are done, their use is most appropriate in special patient groups or in patients who have failed neuroleptic or benzodiazepine treatment. More studies are needed in elderly patients evaluating effectiveness of pharmacologic agents in specific types of dementia, particularly Alzheimer's disease. Most studies done to date have been of relatively short duration, usually two months or less. Because these medications often are given to dementia patients for prolonged periods, studies are needed to define the long-term clinical efficacy of these agents. In the clinical setting, these agents should be reduced periodically or discontinued to determine ongoing need. In addition, environmental, social, or behavioral methods of reducing agitated behaviors need to be explored as an adjunct to any medication trial.

Pharmacologic Treatment of Agitation Associated With Dementia

• Nine outpatients meeting research criteria for probable Alzheimer's disease who had psychosis or behavioral disturbance participated in a single-blind, placebo-controlled pilot study. Oral haloperidol in doses of 1 to 5 mg daily improved target symptoms, confirmed by doubleblind ratings of videotaped interviews. Patients could not be maintained on more than 4 mg of haloperidol daily due to the severity of extrapyramidal side effects. Modified Mini-Mental State scores worsened while taking haloperidol, with only partial recovery in the final 4-week placebo phase. Severe extrapyramidal side effects and decline in cognitive function may compromise the efficacy of commonly used doses of neuroleptic drugs in patients with Alzheimer's disease.

A pilot study of haloperidol treatment of psychosis and behavioral disturbance in Alzheimer's disease.

A survey was conducted of neuroleptic use amongst the residents of Local Authority homes for the elderly, and elderly patients in geriatric, psychogeriatric and general hospital wards in one of the London boroughs. Some 13% of the residents and patients surveyed were found to have received neuroleptics in the 24 h preceding the survey. Marked variation between homes and between wards and hospitals was observed, although for the sample overall associations were observed between disturbed behaviour and mood and the likelihood of receiving neuroleptics. Issues regarding the use of neuroleptics in the non-psychotic elderly are discussed.

K. Morgan

Papers

Patterns of neuroleptic use among the institutionalised elderly.