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    By F. Spike. The College of Saint Thomas More.

    It may manifest as discomfort buy provigil 200 mg mastercard, pulling at intravenous and bladder catheters purchase provigil 100 mg with visa, tracheal and nasogastric tubes, shouting, aggressive behavior, extreme restlessness, and confusion (Schnakers 2007). Pain is particularly common and often unrecognized because of General Neurological Treatment Strategies | 91 confusion and the difficulties with communication in the aphonic, aphasic or paralyzed patient. Clinical assessment may direct attention through finding of profuse sweating, sustained tachycardia and blood pressure fluctuations, and dilated pupils. Most patients will require sedation but there is a natural reluctance to sedate patients with an evolving CNS disorder (McMillian 2011). The first line of management is to reassure and calm the patient, ensuring a quiet environment and normal diurnal cycle. Next, there should be careful nursing and treatment of the underlying causes, including positioning, splinting, bed cages, catheterization, and physical treatments. In spite of reluctance to sedate patients with an evolving CNS disorder, sedative medications are mandatory and must be used, when indicated, to reduce pain, distress, and anxiety. Also they may be used to help patient toleration of tracheal tubes, IPPV, tracheal suction, and physiotherapy. Patients with neurologically-induced respiratory failure often require prolonged periods of mechanical ventilation in the NICU, and it is not desirable to keep such patients continuously sedated throughout their stay (Jacobi 2002). Furthermore, assessment of their condition and subsequent weaning is impossible when sedated. However, during periods of cardiorespiratory instability, raised ICP, and in cases of intubation, sedation may be essential. In the ICU environment, however, medications are often needed to calm patients. As many as 30 different medications are used, and the agents most frequently used are midazolam, olanzapine, propofol, lorazepam and opioid analgesics (Jacobi 2002). Bedside approach to the agitated patient Assess and manage immediate threat to life (airway, breathing, circulation and temperature). Assess pain by querying the patient about pain, and assess for noxious stimuli after measurement of pain score. Correct any identified causes, and if the patient is hemodynamically unstable, give fentanyl 25-100 µgm IV q5-15 minutes until 92 | Critical Care in Neurology desired effect is achieved, or hydromorphone 0. When patients have been on sedative and analgesic drug infusions for longer than 24 hours and begin to recover, daily interruptions of drug infusions for a time period sufficient to allow awakening is recommended (Blanchard 2002). Role of Rehabilitation Rehabilitation is a reiterative active, educational, problem- solving process, focused on the patient disability. The operational characteristics of rehabilitation services comprise a multidisciplinary group of people who work together towards common goals for each patient, involve and educate the patient and family in the process, have relevant expertise and experience (knowledge and skills) and can, between them, resolve most of the common problems faced by patients (Arnow 1993). The stages of rehabilitation involve general assessment to identify the nature and extent of the patient problems and the factors relevant to their solution, goal setting, then intervention, which may include treatments that affect the process of change and support (care), which maintain life and safety, and finally evaluation to check on the effects of the intervention. The aims of rehabilitation are to maximize the participation of the patient in his/her social setting, minimize the pain and distress experienced by the patient and family and/or carers (Collen 1990). The development of models for disability has fostered and clarified discussion about the nature of rehabilitation. Definition of rehabilitation refers to the operational characteristics of a rehabilitation service (structure), how rehabilitation service works (process) and the aims of rehabilitation services (outcome). Three specific core skills are particularly associated with rehabilitation: General Neurological Treatment Strategies | 93 1. An ability to set realistic but challenging goals in both the short and long term, a skill that depends upon an accurate evaluation of the likely prognosis and scope for effective intervention. An ability to participate in teamwork, working co-operatively with a group of other experts towards agreed common goals (Cunningham 2000). However, recent research, mostly related to stroke, does support various hypotheses. First, there is now evidence that even quite small levels of intervention can have powerful and specific effects. There is also some evidence of a dose response relationship between therapeutic input and outcome. Third, patients should be encouraged to seek review of medication at regular intervals, perhaps every 6 months, especially for drugs that have cognitive side effects and either slow or hinder the process of recovery.

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    Biphasic effect of ethanol on extra- cellular accumulation of glutamate in the hippocampus and the nucleus accumbens cheap provigil 100mg on line. Ascending and descending rates of dent modulation of CA1 local circuit inhibition order 200 mg provigil. J Neurosci change in blood alcohol concentrations and subjective intoxica- 1996;16:2034–2043. Strategies for understanding the pharmacological ef- 2. Acute alcohol intox- fects of ethanol with drug discrimination procedures. J StudAlcohol 1990;51: Biochem Behav 1999;64:261–267. Simple reaction time event- mice bred to be prone or resistant to ethanol withdrawal seizures. Genetic differences in psychomotor NMDA antagonists on operant behavior in ethanol withdrawal performance decrement after alcohol: a multivariate analysis. Brain regional specificity Chapter 100: Ethanol Abuse, Dependence, and Withdrawal 1437 and time-course of changes in the NMDA receptor-ionophore 48. Alcohol detoxification complex during ethanol withdrawal. Brain Res 1991;547: and withdrawal seizures: clinical support for a kindling hypothe- 129–134. Evidence of acoustic startle effects of the uncompetitive N-methyl-D-aspartate antagonist hyperreflexia in recently detoxified early onset male alcoholics: ( -)-5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d] cyclo- modulation by yohimbine and m-chlorophenylpiperazine hepten-5,10-imine (ADCI) with its structural analogs dizocil- (mCPP). Regional and subunit (SIGLY) site in recently detoxified alcoholics. Alcohol Clin Exp specific changes in NMDA receptor mRNA and immunoreac- Res 1999;22:94A. Anti-craving compounds for reactivity in rat hippocampus. J Neurochem 1994;62: ethanol: new pharmacological tools to study addictive processes. Relapse prevention by acam- bellar granule cells to ethanol results in increased NMDA recep- prosate. Results from a placebo-controlled study on alcohol de- tor function. Ethanol withdrawal is associated with 1996;53(12):1097]. Glutamate receptors in alcohol withdrawal- Denver, CO, 2000;3A. Dose-related ethanol- acetylhomotaurinate) decreases postsynaptic potentials in the like effects of the NMDA antagonist, ketamine, in recently de- rat neocortex: possible involvement of excitatory amino acid toxified alcoholics. Acam- dependent patients and controls [letter; comment]. Arch Gen prosate (calcium acetylhomotaurinate) enhances the N-methyl- Psychiatry 2000;57:291–292. D-aspartate component of excitatory neurotransmission in rat 37. Interactive effects hippocampal CA1 neurons in vitro. Alcohol Clin Exp Res 1996; of subanesthetic ketamine and haloperidol. Dextromethorphan challenge in alcohol alter GABA receptor-operated chloride channels. Interaction azepine antagonist of ethanol in the rat.

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    When brain imaging improves do the potential utilities of these imaging methods in ad- diagnostic homogeneity buy 200 mg provigil with mastercard, drug efficacy and safety studies are dressing timely neuropsychopharmacologic research issues purchase provigil 100mg overnight delivery. Brain imaging techniques are often categorized as either Another application of brain imaging is in the preclinical structural or functional, based on the primary form of infor- detection of AD. This classification method breaks down, brain imaging data point to a form of gradual age-related however, when considering newer applications of these cognitive decline that precedes AD (5). For example, magnetic resonance imaging ies, particularly when coupled with data on genetic riskof (MRI) equipment is used to provide functional brain re- AD, is an emerging strategy to identify candidates for phar- sponses with functional MRI (fMRI). Moreover, both posi- macologic interventions that delay cognitive decline pro- tron emission tomography (PET) and single photon emis- gression and disease onset. A related application is the use sion computed tomography (SPECT) have the potential of brain imaging data to predict and follow treatment re- to provide visualizations of the pathognomonic structural sponse in patients with the full dementia syndrome of AD. In this chapter, I tions through brain imaging has several clinical and research review both available and developing brain imaging tech- applications for AD and other dementias. Recognition of niques and emphasize neuroimaging techniques and mea- dementia is particularly difficult in its early stages, when sures for presymptomatic AD detection and monitoring family members and physicians often incorrectly attribute pharmacologic interventions. Systematic studies indicate that the frequency of unrecognized memory impairment, beyond that associated with normal aging, or STRUCTURAL NEUROIMAGING a dementia diagnosis can range from 50% to 90% of cases TECHNIQUES (3,4). A related application is the differential diagnosis of Computed Tomography Computed tomography (CT) measures the attenuation of Gary A. Small: Department of Psychiatry and Biobehavioral Sciences, an x-ray beam through body tissues. A ring of x-ray generators and detectors radiation exposure. Disadvantages include the possibility of obtains images of multiple brain slices as the patient is ad- artifact and the fact that the measures are relatively distant vanced through the scanner (6). Moreover, the precise physiologic meaning soft tissue, fluid, and gas with spatial resolution of less than of the measure is unclear. Intravenous contrast medium enhances such patho- areas can be reduced in AD and in vascular dementia. In logic features as bleeding, neoplasm, infection, and inflam- AD, the greatest reductions in coherence occur between mation. Limitations of CT include its inability to differen- intrahemispheric parietal and prefrontal cortical areas, tiate gray and white matter and to visualize the posterior whereas in vascular dementia, this reduction occurs between fossa clearly (6). Quantitative CT measures have demon- occipital and parietal areas (13). The rate of clinical decline in AD is also related to the rate of ventricular Single Photon Emission Computed volume change (8). Tomography SPECT involves administration of an inhaled or injected Magnetic Resonance Imaging tracer or unstable isotope. Tracer decay leads to single pho- ton emission, the scanner determines the site of the photon MRI measures the radiofrequency energy that hydrogen source, and a computer generates a three-dimensional image atoms of water molecules emit. In a static magnetic field, reflecting cerebral blood flow or receptor distribution (14). When irradiated at a tion, particularly for imaging deep structures. Moreover, specific frequency, some lower-energy nuclei absorb energy determining the source of single photon emitters is less pre- and align against the field. The MRI scanner detects energy cise compared with determining the two photons traveling emitted when the radiation is discontinued and the nuclei in opposite directions in PET scanning. Such energy level SPECT cannot demonstrate glucose metabolism. The rate that nuclei return to their low-energy state deter- mines the type of image produced: T1-weighted images dif- Positron Emission Tomography ferentiate gray and white matter, and T2 images delineate white matter hyperintensities (9). Because MRI does not PET tracers are positron-emitting nuclides. When a posi- involve ionizing radiation, patients can have multiple scans.

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    Aside tics associated with AN purchase 200 mg provigil with visa, such as introversion buy 200 mg provigil fast delivery, self-denial, from improved outcome, fluoxetine administration was as- limited spontaneity, and a stereotyped thinking style, may sociated with a significant reduction in obsessions and com- also persist after weight recovery. Studies in humans and pulsions and a trend toward a reduction in depression. Together, these data raise the possibility in some patients with AN. Women plicated in OCD (52) and only serotonin-specific medica- with AN, when malnourished and underweight, have re- tion has been found to be useful in treating OCD. In addition, low estrogen values during the malnour- patients with AN. Initial reports on cyproheptadine, a drug ished state may reduce serotonin activity by effects on gene that is thought to act on the serotonergic and histaminergic expression for serotonin receptors (64) or the serotonin system (53), indicated that it might have beneficial effects transporter (65). SSRIs are dependent on neuronal release on weight gain, mood, and attitude in some patients (54, of serotonin for their action. Cyproheptadine data from comparison trials with ami- compromised release of serotonin from presynaptic neu- triptyline and placebo found cyproheptadine to significantly ronal storage sites and reduced synaptic serotonin concen- improve weight gain in the restricting subtype of AN, trations, then a clinically meaningful response to an SSRI whereas amitriptyline was more effective in those patients might not occur (66). The possibility that fluoxetine is only with bulimic behavior (56). For example, CSF 5-HIAA levels are low might help patients with AN gain and/or maintain a healthy in underweight anorexics, normal in short-term weight-re- body weight. Recently, the Pittsburgh group reported a dou- stored anorexics, and elevated in long-term weight-restored ble-blind placebo-controlled trial of fluoxetine in 35 pa- anorexics (67). If CSF 5-HIAA levels accurately reflect CNS tients with restrictor-type AN (59). Subjects were started serotonin activity, then these data imply that a substantial on fluoxetine after they achieved weight restoration (approx- increase in serotonin activity occurs after weight gain. The use of serotonin-specific medications in the treat- Patients were randomly assigned to fluoxetine (N 16) ment of AN is promising but many questions remain. First, or placebo (N 19) after inpatient weight-restoration and only one double-blind placebo-controlled study has been then were followed as outpatients for 1 year. After 1 year completed in a relatively small number of restrictor-type of outpatient follow-up, 10 of 16 (63%) subjects had a good patients. Thus, it will be important to replicate this work FIGURE 116. Survival of subjects with anorexia ner- vosa treated with fluoxetine or placebo. Chapter 116: Psychopharmacology of Eating Disorders 1679 in a larger group of patients. Second, more data are needed to determine if there are differential effects in the restricting of binge eating/purging subtypes of AN. Third, it needs to be determined whether certain features are especially re- sponsive to serotonin-specific medications: core anorexic symptoms, depression, anxiety, obsessionality, or eating be- havior. Guidelines for Clinical Treatment The first line of treatment for underweight patients with AN should be refeeding and weight restoration. As noted, although difficult, most patients will gain weight in a struc- tured eating disorders treatment program without the use of medication. Weight gain alone tends to reduce exaggerated obsessionality and dysphoric mood in many patients (68). Median percentage change in the number of binge-eating episodes among patients with bulimia nervosa re- There is limited evidence that fluoxetine and possibly other ceiving fluoxetine or placebo. It is important to emphasize that some physio- logic and cognitive alterations persist for months after achieving goal weight, including increased energy needs, menstrual disturbances, several neurotransmitter distur- of benefit from antidepressant treatment typically is quite bances, urges to engage in disordered eating patterns, and rapid (Fig. Thus, treatment should continue No trials have been published in which the efficacy of for at least 3 to 6 months after achieving goal weight, prefer- one antidepressant is compared directly to that of another. We strongly support use of the recent American oxetine, only fluvoxamine has been formally examined in Psychiatric Association (APA) guidelines for eating disor- BN. Fichter and colleagues reported a study of novel design ders (69), which describe comprehensive treatment of AN. Although fluvoxamine was associated with PHARMACOLOGIC TREATMENT OF BN a dropout rate of 38% over 19 weeks compared to 14% on placebo, the active drug was superior to placebo in reducing As summarized in Neuropsychopharmacology, the Fourth the re-emergence of bulimic behaviors and attitudes. In light Generation of Progress, a substantial body of work was pub- of these results, it is surprising that a large European trial lished during the 1980s and early 1990s demonstrating that has been reported to find no difference between the response antidepressants are more effective than placebo in the treat- to fluvoxamine and placebo in the initial treatment of out- ment of BN (70). In 1996, the FDA approved the use of patients with bulimia (Freeman, personal communication, fluoxetine (71,72) for this disorder, the only medication to 1999).

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    Such screening studies in a nonhomogeneous popula- rowly defining the phenotype understudy purchase 200mg provigil with amex. The premise in tion such as that of the United States buy 100mg provigil visa, wherein common the former case is that the number of genes contributing ancestors must be located in the very remote past, will re- to a particular disease phenotype within one or a few large quire use of the planned SNP map of around several families may be less than in many small families or the hundred thousand markers in order to detect regions of LD, population at large. This premise is also more likely to hold which, it has been hypothesized, may be as small as 3 kb if the number of disease loci in the population as a whole (10). Furthermore, a multiply affected family may indicate regions that are IBD among a sample of patients may also that the gene or genes involved are highly penetrant (pene- be carried out in extended pedigrees wherein the small num- trance refers to the likelihood that a person who has a disease ber of meioses separating affected individuals leads to a gene will manifest the disease phenotype) and may be easier greater length of IBD sharing around the disease gene. It can be difficult, however, instance, limiting the affected phenotype to include only to find recombinant individuals that will allow refinement the most extreme or distinct form of the illness under study of the candidate interval to a sufficiently small region to has also been critical to the success of mapping studies for facilitate positional cloning. We review the relative strengths complex traits, as such phenotypes are expected to reflect and weaknesses of pedigree- and population-based genetic a more homogeneous genetic etiology than more broadly studies below. Although such a and may be more robust when the true mode of inheritance gene may not contribute significantly to AD in the general is unknown. These methods were originally developed for population, it may still provide clues as to relevant biological samples of affected sibling pairs but have now been modified pathways that might suggest candidate genes for other map- for analysis of other types of relative pairs or whole pedi- ping studies. Simply stated, nonparametric methods are designed Another way to refine an affected phenotype is to require to calculate the amount of IBD sharing of marker alleles the presence of an objective measure associated with the among affected relatives where the null hypothesis is that disorder such as elevated immunoglobulin E (IgE) levels transmission of alleles is independent of transmission of dis- in patients with asthma (17). For any pair of affected relatives, the probability that comparable biological markers for psychiatric disorders at the pair will share zero, one, or two alleles IBD can be least when these disorders are defined by current nosology. Linkage Hence, investigators are attempting to find endophenotypes is detected if the sharing of marker alleles among affected or subcomponents within psychiatric syndromes that may relatives is increased over the sharing expected given their be objectively measured and inherited in a more straightfor- relationship. What differ- multiple markers on the same chromosome, also known as entiates this strategy from other attempts to refine haplotypes, can definitively establish that a segment of DNA traditional psychiatric phenotypes is that family members has been inherited IBD and thus likely harbors a disease who have not received a psychiatric diagnosis may still be gene. For ex- terized to avoid misinterpretation of the allele sharing data. Abnormal ocular movements gene but be able to localize it only to a very broad genetic and failure to suppress evoked responses to auditory stimuli interval. The extent to which a genetic interval containing after a cue (the P50 response) are both thought to be trans- the disease locus can be narrowed to a small-enough interval mitted within families of schizophrenic probands whether for positional cloning purposes depends on the number of or not family members have a psychiatric diagnosis (21–25). Evidence for linkage to each phenotype implicated dif- though affected relative pairs are usually much easier to ferent loci (the 7-nicotinic acetylcholine receptor subunit collect than multiply affected pedigrees, very large numbers gene and a region in chromosome 22q11-12, respectively) are required to detect linkage, and the accuracy of gene and was stronger than evidence for linkage of the schizo- localization is usually much less than that provided by pedi- phrenia phenotype alone. Few endophenotypes have been characterized so far for Finally, when studying complex traits it is very likely that mood disorders; however, a possible endophenotype is that some individuals will be phenocopies, which means that of suicide (28). In this case, one may be significantly more monozygotic co-twins than dizygotic co- misled by apparent recombination events even in a single twins also attempted suicide, possibly arguing for a genetic individual, and may therefore incorrectly delineate the can- component to this behavior. Investigators are continuing to didate interval for a disease gene in a region. One such analysis of a population-based sample is frequently a pre- approach is the likelihood-based method of Terwilleger ferred strategy for high-resolution mapping of disease loci (36). A disadvantage of family-based LD methods is that it (31). One reason for this is that many meioses (and therefore can often be difficult to sample parents of affected individu- opportunities for recombination) have occurred since the als, especially for adult-onset disease. Risch and Merikangas also be problematic because a very large number of markers (32) also proposed that population mapping strategies must be used for LD genome screening studies, even in might be a more efficient means of initially localizing disease isolated populations, and statistical correction for multiple genes (given a sufficient sample size and an appropriately testing is necessary. Interpreting the significance of single- dense marker map), particularly for loci of relatively small point association tests in this setting becomes extremely dif- effect, as the sample sizes needed for affected relative pair ficult (37). Fortunately, the development of multipoint sta- strategies may be huge and thus not feasible. In case-control associa- the power to detect even weak LD signals coming from a tion studies, allele frequencies at a particular marker are subset of the sample. Such approaches are inherently more compared between a sample of patients and a sample of powerful than single-point tests of association and will be controls matched as closely as possible to cases in terms of essential for the evaluation of data generated from SNP ethnicity, age, gender, and other relevant socioeconomic maps. Unfortunately, perfect matching can never be One promising LD method, termed ancestral haplotype guaranteed, and unknown population stratification can reconstruction (AHR), assesses the likelihood that a sample occur if many of the cases or controls share an uninvesti- of patient haplotypes have descended from a common mu- gated variable.

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