The control of muscle tone, reflexes, and movement: Robert Wartenberg Lecture.
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OBJECTIVE: To examine whether either extrapyramidal signs or psychotic features are associated with more rapid progression of Alzheimer's disease. BACKGROUND: It has been unclear whether extrapyramidal signs and psychosis are predictors of faster course or are simply late signs. METHODS: Two hundred thirty-six patients with mild Alzheimer's disease were recruited in three cities and followed semiannually. RESULTS: Using Cox proportional hazards models that adjusted for age, sex, disease severity, and estimated duration of illness at study entry, the presence of extrapyramidal signs at entry was associated with higher relative risk (RR) of reaching moderate cognitive (RR = 2.35, 95% CI = 1.12 to 4.92) or functional (RR = 2.31, 95% CI = 1.37 to 3.90) severity, nursing home entry (RR = 2.51, 95% CI = 1.32 to 4.76), or death (RR = 3.04, 95% CI = 1.31 to 7.05). Psychosis predicted only the functional end point (RR = 1.85, 95% CI = 1.18 to 2.90). Using regression models, modified Mini-Mental State scores declined 1.30 points (95% CI = 0.16 to 2.44) per 6-month interval, more among patients with than those without extrapyramidal signs; patients with psychosis declined 1.15 (95% CI = 0.52 to 1.77) more mMMS points per interval. CONCLUSIONS: This study confirms extrapyramidal signs and psychosis as robust predictors of disease end points and rapid progression in Alzheimer's disease.
A 33-year-old woman admitted for meningoencephalitis had features of encephalitis lethargica develop on her third day of illness. She had ophthalmoplegia, akinetic mutism, and prominent extrapyramidal signs consisting of lip and hand tremors, cogwheel rigidity, and facial bradykinesia.
This study investigated the differential effects of graded spinal cord injury on the rat extrapyramidal motor evoked potential (exp-MEP) and pyramidal motor evoked potential (pyr-MEP) and the prognostic value of these effects in predicting postinjury motor performance in the rat model. In 20 rats subjected to graded spinal injury (10-100 g-cm), there was a differential injury threshold for ablation of exp-MEP and pyr-MEP. All peaks of the pyr-MEP were extinguished in the animals subjected to impact forces of 50 g-cm and above (n = 12). In contrast, the exp-MEP was completely abolished in only two animals at injuries of 80 g-cm or above. A residual exp-MEP response persisted in the remaining 18 animals. Motor performance was monitored in 16 additional animals for up to 1 week after spinal injury. The pyr-MEP was abolished in 100% of the rats subjected to a 50-g cm injury (n = 7), whereas the exp-MEP persisted up to the highest impact forces (80 g-cm). Hind leg paralysis was present in the five rats where the pyr-MEP was extinguished but with persistence of the exp-MEP. An 80% reduction in the amplitude of the pyr-MEP in four animals resulted in mild ataxia with motor improvement at the end of a week. An increase or a 70% loss in pyr-MEP peak amplitude resulted in no clinical motor deficits (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)
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Age is a major source of variation in drug response. Social, medical and physiological heterogeneity intertwines to complicate geriatric pharmacotherapy. Inappropriate and excessive use of medication may be the most significant treatable health problem in the elderly. Older people are especially sensitive to antipsychotics, which are disproportionately prescribed to them. Antipsychotic side effects and adverse reactions are intensified and protean in an older population, ranging from disabling to deadly. It is therefore essential that the use of antipsychotics be based on clear indications, guided by knowledge of both age-related and individual determinants of drug clearance and action. Prospective and frequent assessments for adverse effects are also essential.
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Psychotropic drugs are frequently employed to treat the wide range of neuropsychiatric syndromes that patients infected with the human immunodeficiency virus (HIV) may develop. In order to administer these agents properly, physicians should take certain factors into account: the central nervous systems of these patients are often impaired, the patients tend to suffer from medical illnesses, and they may be taking various other drugs. The possible interactions between substances taken by these patients may sometimes make it necessary to adjust the dosage of psychotropic agents administered. In addition, some of the antimicrobial, antifungal and antiviral agents used in the management of HIV infection may have adverse effects that include neuropsychiatric symptoms. The use of antipsychotic agents in these patients frequently results in the development of extrapyramidal symptoms. Tricyclic antidepressants are not well tolerated by patients with AIDS, due to the anticholinergic effects of these agents. The new antidepressants, which have fewer and milder adverse effects, are safer and have shown their efficacy in the treatment of the depressive episodes often seen in HIV-infected patients. Benzodiazepines must be prescribed with caution in patients with HIV infection and organic brain syndrome, since they can produce amnesia, confusion, lack of inhibition and paradoxical reactions. The indications for the use of psychostimulants in certain clinical situations, such as HIV-associated dementia and depression, is open to debate. Opiates are indicated in pain treatment, and in methadone maintenance programmes. Lithium and carbamazepine are advisable only in very restricted situations.
Following acceptance of clozapine as a superior antipsychotic agent with low risk of adverse extrapyramidal syndromes (EPS), such as dystonia, parkinsonism, akathisia or tardive dyskinesia, several novel antipsychotic drugs have been developed with properties modelled on those of clozapine. Though generally considered 'atypical' in their relatively low risk of inducing EPS, these agents vary considerably in their pharmacology and impact on neurological functioning. Although few comparative data are available, the atypical antipsychotics can be tentatively ranked by EPS risk (excluding akathisia and neuroleptic malignant syndrome) in the following order: clozapine < quetiapine < olanzapine = ziprasidone. At higher doses, risperidone is ranked with a higher EPS risk than olanzapine and ziprasidone, but its risk of EPS is lower with lower doses. In general, this ranking is inversely related to antidopaminergic (D2 receptor) potency. The high antiserotonergic (5-HT2A receptor) potency of risperidone, clozapine, ziprasidone and olanzapine, but not quetiapine, as well as the antimuscarinic activity of olanzapine and clozapine may also limit EPS. For the treatment of psychotic reactions to dopamine agonist therapy in Parkinson's disease, clozapine is both effective and relatively well tolerated; quetiapine may be tolerated, olanzapine is not well tolerated, risperidone is poorly tolerated, and amisulpride and ziprasidone have not been well evaluated. Clozapine, perhaps because of its anticholinergic activity, can reduce parkinsonian tremor. It is useful for ongoing psychosis with tardive dyskinesia, especially for dystonic features. No atypical antipsychotic is clearly effective for motor abnormalities in Huntington's disease or Tourette's syndrome, and the effect of these drugs on other neurological disorders have been well evaluated in only small numbers of patients. In summary, with the exception of clozapine, and perhaps quetiapine, atypical antipsychotics have brought only relative avoidance of EPS, strongly encouraging continued searches for novel antipsychotic agents.
CASE DESCRIPTION: 4 racehorses were examined because of markedly abnormal behavior following administration of fluphenazine decanoate. CLINICAL FINDINGS: Clinical signs included restlessness, agitation, profuse sweating, hypermetria, aimless circling, intense pawing and striking with the thoracic limbs, and rhythmic swinging of the head and neck alternating with episodes of severe stupor. Fluphenazine was detected in serum or plasma from all 4 horses. The dose of fluphenazine decanoate administered to 3 of the 4 horses was within the range (25 to 50 mg) routinely administered to adult humans. TREATMENT AND OUTCOME: In 2 horses, there was no response to IV administration of diphenhydramine hydrochloride, but the abnormal behavior in these 2 horses appeared to resolve following administration of benztropine mesylate, and both horses returned to racing. The other 2 horses responded to diphenhydramine administration. One returned to racing. The other was euthanized because of severe neurologic signs, respiratory failure, and acute renal failure. CLINICAL RELEVANCE: Findings indicate that adverse extrapyramidal effects may occur in horses given fluphenazine decanoate. These effects appear to be unpredictable and may be severe and life threatening. Use of fluphenazine decanoate as an anxiolytic in performance horses is not permitted in many racing and horse show jurisdictions, and analytic procedures are now available to detect the presence of fluphenazine in serum or plasma.
Characteristic patterns of laryngeal dysfunction due to central neurologic disease are documented by 16 mm ciné photography. Representative patients are used to describe typical patterns of abnormal laryngeal function which occur in upper motor neuron, extrapyramidal, cerebellar, nuclear and mixed foci of lesions. The pitfall of brief indirect laryngoscopy without visual documentation is emphasized as a factor in misdiagnosis of patients with laryngeal disease of central origin. The value of more careful evaluation of similar patients is emphasized in relation to better understanding of laryngeal function and improved patient care.
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Although it is known that extrapyramidal function is dependent upon a balance between cholinergic and dopaminergic effects, only anti-dopaminergic substances commonly induce extrapyramidal symptoms. This paper describes a patient who ingested chlorpyrifos and presented with choreo-athetosis and depressed cholinesterases. She responded to atropine therapy and made a complete recovery. Although not often described excessive cholinergic activity may also produce extrapyramidal symptoms.
This overview summarizes the major and minor side effects and drug interactions of fluoxetine. The adverse reactions include the "serotonin syndrome", cardiovascular complications, extrapyramidal side effects such as akathisia, dyskinesias, and parkinsonian-like syndromes and an apparently increased risk of suicidality. Fluoxetine-induced mania and hypomania, seizures and sexual disorders are evaluated along with minor symptoms of allergic reactions, stuttering, hematological changes, psoriasis, and inappropriate secretion of the antidiuretic hormone. The major fluoxetine-drug interactions involve the amino acids L-dopa and L-tryptophan, anorexiants, anticonvulsants, antidepressants, anxiolytics, calcium channel blockers, cyproheptadine, lithium salts, and drugs of abuse. The underlying mechanism and the paradoxical effects of fluoxetine are addressed.
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Neuropeptide Y (NPY), an apparent neuromodulating neuropeptide, has been linked to dopamine systems and dopamine-related psychotic disorders. Because of this association, we determined and compared the effects of psychotomimetic drugs on extrapyramidal and limbic NPY systems. We observed that phencyclidine, methamphetamine (METH), (+)methylenedioxymethamphetamine (MDMA), and cocaine, but not (-)MDMA, similarly reduced the striatal content of NPY-like immunoreactivity from 54% (phencyclidine) to 74% [(+) MDMA] of control. The effects of METH on NPY levels in the nucleus accumbens, caudate nucleus, globus pallidus, and substantia nigra were characterized in greater detail. We observed that METH decreased NPY levels in specific regions of the nucleus accumbens and the caudate, but had no effect on NPY in the globus pallidus or the substantia nigra. The dopamine D1 receptor antagonist SCH-23390 blocked these effects of METH, suggesting that NPY levels throughout the nucleus accumbens and the caudate are regulated through D1 pathways. The D2 receptor antagonist eticlopride did not appear to alter the METH effect, but this was difficult to determine because eticlopride decreased NPY levels by itself. A single dose of METH was sufficient to lower NPY levels, in some, but not all, regions examined. The effects on NPY levels after multiple METH administrations were substantially greater and persisted up to 48 h after treatment; this suggests that synthesis of this neuropeptide may be suppressed even after the drug is gone. These findings suggest that NPY systems may contribute to the D1 receptor-mediated effects of the psychostimulants.