Comparative efficacy of two interventions to discontinue long-term benzodiazepine use: cluster randomised controlled trial in primary care.

BACKGROUND: Benzodiazepines are extensively used in primary care, but their long-term use is associated with adverse health outcomes and dependence. AIMS: To analyse the efficacy of two structured interventions in primary care to enable patients to discontinue long-term benzodiazepine use. METHOD: A multicentre three-arm cluster randomised controlled trial was conducted, with randomisation at general practitioner level (trial registration ISRCTN13024375). A total of 532 patients taking benzodiazepines for at least 6 months participated. After all patients were included, general practitioners were randomly allocated (1:1:1) to usual care, a structured intervention with follow-up visits (SIF) or a structured intervention with written instructions (SIW). The primary end-point was the last month self-declared benzodiazepine discontinuation confirmed by prescription claims at 12 months. RESULTS: At 12 months, 76 of 168 (45%) patients in the SIW group and 86 of 191 (45%) in the SIF group had discontinued benzodiazepine use compared with 26 of 173 (15%) in the control group. After adjusting by cluster, the relative risks for benzodiazepine discontinuation were 3.01 (95% CI 2.03-4.46, P<0.0001) in the SIW and 3.00 (95% CI 2.04-4.40, P<0.0001) in the SIF group. The most frequently reported withdrawal symptoms were insomnia, anxiety and irritability. CONCLUSIONS: Both interventions led to significant reductions in long-term benzodiazepine use in patients without severe comorbidity. A structured intervention with a written individualised stepped-dose reduction is less time-consuming and as effective in primary care as a more complex intervention involving follow-up visits.

Improvement of the neighborhood based Levenberg-Marquardt algorithm by local adaptation of the learning coefficient.

In this letter, an improvement of the recently developed neighborhood-based Levenberg-Marquardt (NBLM) algorithm is proposed and tested for neural network (NN) training. The algorithm is modified by allowing local adaptation of a different learning coefficient for each neighborhood. This simple add-in to the NBLM training method significantly increases the efficiency of the training episodes carried out with small neighborhood sizes, thus, allowing important savings in memory occupation and computational time while obtaining better performance than the original Levenberg-Marquardt (LM) and NBLM methods.

Neighborhood based Levenberg-Marquardt algorithm for neural network training.

Although the Levenberg-Marquardt (LM) algorithm has been extensively applied as a neural-network training method, it suffers from being very expensive, both in memory and number of operations required, when the network to be trained has a significant number of adaptive weights. In this paper, the behavior of a recently proposed variation of this algorithm is studied. This new method is based on the application of the concept of neural neighborhoods to the LM algorithm. It is shown that, by performing an LM step on a single neighborhood at each training iteration, not only significant savings in memory occupation and computing effort are obtained, but also, the overall performance of the LM method can be increased.

A combined pattern of movement disorders resulting from posterolateral thalamic lesions of a vascular nature: a syndrome with clinico-radiologic correlation.

We report a series of seven patients in whom a combined pattern of complex movement disorders restricted to one upper extremity emerged as a result of posterolateral thalamic lesions of vascular origin. This disorder was mainly characterized by choreiform and dystonic movements associated with variable, rhythmic, alternating movements of low frequency (myorhythmia). All cases showed, on computed tomography scan and/or magnetic resonance imaging, focal lesions involving the posterolateral quadrant of the thalamus. Review of similar cases reported with identical clinico-radiologic features allows us to conclude that it is possible to establish an accurate anatomoclinical correlation based on the clinical phenomenology, even before imaging studies are performed, in these cases. The opposite is not entirely possible, however, because lesions in the same quadrant of the thalamus are often associated with different patterns of abnormal movements or present without abnormal movements.

The evolution and origin of motor complications in Parkinson's disease.

Levodopa is the major symptomatic therapy for Parkinson's disease (PD), having revolutionized the treatment of PD and provided benefit to virtually all patients. However, after 5-10 years of treatment, levodopa therapy is complicated by the development of motor complications, which include dyskinesia and motor fluctuations. The initial long duration response to a dose of levodopa becomes progressively shorter, and periods in which the patient responds to the drug become complicated by involuntary dyskinetic movements. Thus, patients may cycle between "on" periods that are complicated by dyskinesia and "off" periods in which they are severely parkinsonian. As a consequence they may experience profound disability despite the fact that levodopa remains an effective anti-parkinson agent throughout the course of the disease. In this article we review the various motor complications associated with the treatment of PD and present current concepts on the origin of these problems.

Pilot study with clozapine in patients with HIV-associated psychosis and drug-induced parkinsonism.

Clozapine (CZP) is an atypical antipsychotic drug that does not appear to block striatal dopamine receptors. In six patients who met the criteria of HIV-associated psychosis and who had previously developed moderate parkinsonism as a result of the use of typical neuroleptic agents, CZP was added in an open, rising dose study. Subjects were evaluated at baseline after at least 7 days without neuroleptic drugs and then monthly for 3 months of the experimental treatment using three rating scales: Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), and motor examination of the Unified Parkinson's Disease Rating Scale (UPDRS). A significant reduction in psychopathology as represented in the BPRS total score (54.2 at baseline versus 23.9 at month 3) and CGI (2 and 8, respectively) was obtained with a mean CZP dose of 27.08 mg/day. Parkinsonism also improved by an average of 76.5% at the end of the study. One patient did not complete the study as a result of a progressive decrease in leukocyte count while on CZP. These preliminary results suggest that the pharmacologic properties of CZP may be of value in the management of HIV-psychotic patients.

[Focal dystonia and tremor secondary to brain stem tuberculoma]. / Distonía focal y temblor secundarios a tuberculoma del tronco encefálico.

Brainstem tuberculoma is exceptionally observed. We report a 44 year-old immunocompetent man with proven diagnosis of miliary tuberculosis (TBC) who developed a complex neurological syndrome characterized by right ophtalmoplegia, left-sided hemiparesis and hemihypoesthesia and a gross ipsilateral postural and action tremor with hand dystonia. A ponto-mesencephalic mass was detected by CT and MRI studies of the brain. Clinical, bacteriological and neuroimaging studies allowed to suspect a ponto-mesencephalic tuberculoma. Long-term therapy with anti-TBC drugs and steroids was started, achieving clinical and imaging improvement which retrospectively confirmed the diagnosis. Although with less amplitude, tremor persisted but a complete disappearance of focal dystonia was observed. The pathogenesis of both abnormal movements is particularly discussed since hand dystonia has never been mentioned in the literature as a consequence of brainstem damage.

Cervical dystonia due to spinal cord ependymoma: involvement of cervical cord segments in the pathogenesis of dystonia.

We report a patient with a progressive motor disorder dominated by pyramidal signs in all four extremities and cervical dystonia in the form of torticollis, who had imaging features of cervical cord tumor on magnetic resonance imaging (MRI) scanning. Ependymoma was the final diagnosis by histology. Cervical dystonia presenting as a manifestation of an identified focal central nervous system (CNS) lesion is infrequent. We believe our patient to be the first adult example of cervical cord tumor giving rise to cervical dystonia. Adding this entity to the list of differential diagnosis of torticollis is considered, and its mechanisms are discussed.

Dystonia as the major manifestation of Leigh's syndrome.

We report eight patients who had a progressive illness dominated by generalised dystonia and who had clinical and imaging features suggestive of Leigh's syndrome (LS). Six of the eight cases were male. Early development was usually normal but three cases exhibited impaired mental and/or motor development, and three others had a history of an earlier unexplained encephalopathy or febrile illness. The onset of the dystonia occurred at a mean age of 3 years (range 2 months-7 years). All had abnormalities in the basal ganglia on brain imaging; symmetrical bilateral lucencies or calcification were seen in the basal ganglia on computed tomography scan in five cases, and high signal lesions were evident in these regions on T2-weighted magnetic resonance imaging sequences in seven cases. Other causes of such changes in the basal ganglia were excluded by appropriate investigations. Raised blood lactate levels were found in four of the eight patients. Muscle biopsies were done in seven patients but histology and histochemistry were normal. The common mitochondrial DNA mutations associated with LS in mitochondrial encephalopathies were not found in the six cases examined. LS presenting as a pure dystonic syndrome is uncommon, but should be considered in the differential diagnosis of symptomatic dystonia presenting in childhood.

Vascular chorea: case report with pathology.

We report a patient with long-standing systemic hypertension who developed progressive generalized chorea and dementia beginning at 70 years of age with no family history or other features to suggest Huntington's disease. At postmortem examination, congophilic angiopathy and atherosclerosis causing neostriatal neuronal loss and gliosis were found, in addition to plaques and neurofibrillary tangles in the cortex. This case is a rare demonstration of a vascular pathology causing late onset generalized chorea in association with dementia due to Alzheimer's-type cortical changes.

Motor response to apomorphine and levodopa in asymmetric Parkinson's disease.

The motor responses of 14 patients with Parkinson's disease (six previously untreated and eight chronically receiving levodopa) with pronounced asymmetry in the severity of motor signs between the left and right sides of the body were studied. The effects of a short (60 minutes) and a long (16-22 hours) intravenous levodopa infusion as well as of subcutaneous apomorphine (1-6 mg bolus) were assessed. Four different tapping tests were used to measure motor function. For all pharmacological tests, the more affected side showed a shorter response duration, increased latency, and greater response magnitude than the less affected side. These differences were more pronounced in those patients receiving chronic levodopa treatment. As apomorphine is not dependent on dopamine storage capacity, these findings suggest that postsynaptic mechanisms play an important part in the origin of motor fluctuations in Parkinson's disease.

Cabergoline in Parkinson's disease: long-term follow-up.

We treated 36 patients with motor fluctuations and dyskinesias on chronic levodopa therapy with cabergoline (CBG) once a day for a mean period of 14.2 +/- 5.8 months. There was a significant increase in the "on" hours and a reduction in "off-period" dystonia. Ten patients continued to show a marked improvement after 28.3 months of treatment (mean dose, 11.3 +/- 4.5 mg). In 23 patients, increased dyskinesias (daily CBG dose, 11 +/- 4.3 mg) had complicated the positive effect after 17.2 +/- 4.8 months. Three patients (daily CBG dose, 14.3 mg) were therapeutic failures, and administration of CBG was stopped. Side effects leading to CBG discontinuation were visual hallucinations (n = 5), heart failure (n = 5), and nausea and vomiting (n = 1). Plasma CBG levels, measured in seven patients taking 3, 5, or 7 mg daily (po), showed fairly stable concentrations throughout the 24 hours. We concluded that CBG is an efficient dopamine agonist that can provide continuous dopaminergic stimulation when taken orally once a day.

Time interval between repeated injections conditions the duration of motor improvement to apomorphine in Parkinson's disease.

Behavioral hyposensitivity to repeated apomorphine administration occurs in fluctuating parkinsonian patients. To determine to what extent the interval between doses influences the response, we administered equal paired apomorphine injections to 10 fluctuating parkinsonian patients. Subjects received two apomorphine injections at 2-hour and at 4-hour intervals on different days after a 10- to 12-hour overnight period without levodopa. Following apomorphine doses at 2-hour intervals, the duration of response was reduced by 40% (61 versus 42 minutes, p less than 0.001) but was of equal duration when the doses were given at 4-hour intervals. These findings indicate that the interval between doses is a critical determinant of motor response. We postulate a time-dependent period of partial hyposensitivity to pulsatile DA stimulation.

[Motor fluctuations in Parkinson disease: risk factors]. / Fluctuaciones motoras en la enfermedad de Parkinson: factores de riesgo.

We studied the histories of 173 patients with Parkinson's disease (1985-1987) chronically treated with levodopa + dopa decarboxylase inhibitor. Ninety four patients had daily motor fluctuations and 79 showed stable motor response. The most significant differences between fluctuating and stable patients were given by age at disease onset and duration of levodopa therapy. Patient with disease onset before 60 had a greater risk (p less than 0.001) of developing fluctuations. Delaying the initiation of levodopa treatment was not associated with a smaller incidence of fluctuations.

Differences in the motor response to apomorphine between untreated and fluctuating patients with Parkinson's disease.

Behavioral hyposensitivity to repeated apomorphine administration has been observed in fluctuating parkinsonian patients. To investigate whether a similar phenomenon occurs in patients never treated with levodopa, we studied the response to apomorphine in 20 de novo patients with Parkinson's disease. Six patients showed no or minimal improvement after apomorphine injections (maximal dose 3.5 mg). Fourteen patients responded and were then given up to four repeated subcutaneous injections of apomorphine [minimal effective dose (MED)]. The responses of de novo patients were compared with responses in 10 patients with motor fluctuations previously studied by the same protocol. There was no significant difference in latency and duration of motor responses after repeated apomorphine injections in de novo patients. MED was similar in de novo and fluctuating patients, but duration of improvement induced by each apomorphine bolus was longer in the de novo group. These results indicate that response duration to apomorphine is longer in previously untreated patients and that behavioral tolerance associated with pulsatile dopaminergic stimulation by apomorphine occurs mainly in patients with more advanced disease under chronic levodopa therapy.

Neuroleptic malignant syndrome treated with subcutaneous lisuride infusion.

A schizophrenic patient developed a characteristic clinical picture of neuroleptic malignant syndrome (NMS) while admitted to the hospital during an exacerbation of his psychiatric symptoms. Oral treatment of the NMS with bromocriptine (7.5 mg/day) or levodopa/carbidopa (125/12.5 mg) provoked intense vomiting in spite of domperidone (60 mg/day), which led to their discontinuation. In view of the deterioration of the symptoms, treatment was begun with lisuride (1-2 mg/24 h) subcutaneously. An obvious improvement was shown in 24 h, but levodopa/carbidopa (125/12.5 mg t.d.s. orally) had to be added later to achieve complete resolution of the NMS. During the recovery phase, while being treated with subcutaneous lisuride infusion and levodopa (p.o.), the patient presented with confusion, agitation, and hallucination. Lisuride infusion was stopped and levodopa was continued until complete resolution of the NMS. This case indicates that parenteral administration of lisuride or other dopamine agents such as levodopa (i.v.) or apomorphine (s.c.) may be considered an effective and practical way of treating NMS, particularly when the patient's condition makes it difficult or impossible to use other dopaminergic drugs by the oral route.

Motor complications associated with chronic levodopa therapy in Parkinson's disease.

Fluctuations and dyskinesias are the 2 main motor complications associated with chronic levodopa therapy. Striatal denervation following degeneration of the substantia nigra dopaminergic projections is probably the major pathophysiologic mechanism underlying motor fluctuations. In addition, pathologic modification of striatal receptors, partially related to the nonphysiologic delivery of levodopa in a discontinuous pulsatile mode, may be responsible for the various types of dyskinesias and sudden "off" episodes. Drugs capable of providing a stable dopaminergic stimulation should be particularly useful for preventing the development of motor complications in patients not yet treated. At the other end of the clinical spectrum, patients with complex fluctuations are the least likely to improve with slow-release levodopa preparations.